Clinical Review

Case Scenario

A 69-year-old man was transported to the ED via emergency medical services after a family member discovered him alone at home and confused. His wife stated that her husband had been sick with the flu and had been febrile for the previous several days. The patient’s blood pressure taken on the scene by the emergency medical technician was 80/40 mm Hg, and 1 L normal saline was infused during transport. Upon arrival to the ED, his vital signs were:  temperature, 103.3°F; heart rate,130 beats/minute; BP, 90/48 mm Hg; and respiratory rate, 24 breaths/minute. Oxygen saturation was 92% on nasal canula. An electrocardiogram showed sinus tachycardia with nonspecific changes.

Based on the patient’s symptoms, the emergency physician (EP) suspected sepsis and ordered the appropriate laboratory studies and radiographic images. During evaluation, the patient’s systolic BP decreased to 70 from 80 mm Hg, and the EP ordered another fluid bolus and considered assessing the patient’s volume status.

  

Introduction

There is a long-standing debate as to the most accurate method of determining the volume status of a critically ill patient, as well as the physiological ability to respond to fluid therapy. In the assessment of a critically ill patient receiving volume replacement, a wide variability of assessment options are available; however, the current literature has yet to determine which method is the best. This article reviews multiple approaches to estimating the intravascular volume status of critically ill patients and the use of modalities to determine a patient’s physiological response to fluid therapy.

  

Basic Physiology

Central venous pressure (CVP) is the pressure in the thoracic vena cava adjacent to the right atrium. The heart functions as a two-sided pump; the right side pumps volume at low pressure and the left side pumps against systemic arterial pressure. The major determinant of the filling pressure of the right ventricle (RV) at the end of diastole is CVP, which is affected by the initial stretching of the ventricles before contraction (preload).

  

Frank-Starling Mechanism

The Frank-Starling mechanism describes the relationship between cardiac performance and intravascular volume. Stroke volume increases in response to an increase in preload volume. The increased volume of blood stretches the ventricular wall, causing the cardiac muscle to contract more forcefully. The change in volume (∆V) of blood divided by the change in pressure (∆P) is termed compliance
(∆V/∆P).

The venous system is the major reservoir within the vascular system and is markedly more compliant than the arterial system. Thus, CVP will increase with a decrease in venous compliance and/or an increase in the venous volume. These relationships can be quite dynamic depending on the disease state.

  

History of CVP Monitoring

The resuscitation of hemodynamically unstable patients historically stressed the use of intravenous (IV) fluid boluses. However, measuring the efficacy of this approach has been difficult. This issue was first addressed in the 1960s and 1970s when clinicians began to use central venous catheters (CVCs) to measure CVP as a surrogate measure of right atrial volume, which had been interpreted as a measure of the amount of blood returning to the heart. However, CVP measurements were static measurements of a dynamic filtration, and derivation of cardiac output required a long and complex calculation. The Swan-Ganz pulmonary artery catheter was the first catheter that enabled continuous monitoring and allowed clinicians to obtain cardiac index calculations at the bedside.¹

The CVP is an approximation of the right atrial pressure and is an indicator of RV preload, which is a major determinant of RV filling pressure. Both RV preload and RV filling pressure correlate with intravascular volume. Lower CVP may occur with vasodilation or hypovolemia, which decreases the volume returning to the right atrium. This volume depletion creates a need for fluid replacement.

To illustrate this point, picture the body’s blood supply contained within a 6-L expandable tank. Vasodilation may expand the tank to a 9-L capacity, with a 3-L volume deficit. Similarly, blood loss from the 6-L tank may drain 3-L from the tank, leaving a 3-L deficit. Both mechanisms may cause a 3-L deficit, with the tank partially empty. Although it might make sense to replace the loss or “fill the tank in both scenarios,” fluid replacement may have risks. Overly aggressive fluid resuscitation may cause multiorgan dysfunction such as pulmonary edema, abdominal compartment syndrome, altered mental status, dilutional anemia, or dilutional coagulopathy. However, suboptimal fluid treatment may cause inadequate resuscitation that may be complicated by persistent hypotension, hypoperfusion, and end-organ damage and failure.

 

Up until the 1980s, it was believed that maintenance of normal hemodynamic parameters was the key to resuscitation of critically ill patients. Shoemaker et al^2,3  then published several papers about increasing patient survival by “supranormalizing” cardiac indices. They recommended increasing cardiac index, oxygen transport, and CVP to higher than normal. High-risk surgical patients had placement of a pulmonary artery catheter and were randomized into three groups: (1) normalization of CVP; (2) pulmonary artery catheter monitoring and normalization of CVP; or (3) a pulmonary artery catheter protocol based on increasing normal cardiac indices to supranormal values. The time to intervention was greater than 6 hours. The study demonstrated no mortality difference among the CVP and pulmonary artery control groups, but did demonstrate a significant mortality reduction in the pulmonary artery catheter protocol group where the hemodynamic markers were kept at values higher (supranormalization group) than normal.

Early Goal-Directed Therapy

The intervention time of 6 hours was questioned in a study by Rivers et al,⁴ who suggested this delay was too long. In this study, early goal-directed therapy (EGDT) was compared to standard therapy in the ED in severe sepsis and septic shock. A CVP catheter was used within the right atrium, and critically ill patients were randomized into the following two groups: (1) CVC with continuous central venous oxygen saturation (ScvO₂) measurements; and (2) the standard therapy group which was  treated at the clinician’s discretion according to standard ED care with the exception of placement of a CVC without ScvO₂ monitoring. Both groups had targeted goals of CVP, 8 to 12 mm Hg; mean arterial pressure, greater than 65 mm Hg; and urine output, greater than 0.5 mL/kg/h. Both groups received an equal volume of crystalloid fluids, which exceeded the commonly given amount of fluid to patients. The EDGT group received 4981± 2984 mL compared to the standard group which received 3499 ± 2438 mL. The EGDT-targeted supranormalization of ScvO₂ employs dobutamine to achieve a goal of ScvO₂ level greater than 70% and uses transfusion to achieve hematocrit level greater than 30%. The study showed 21% overall reduction in mortality in the EGDT group. Aggressive care and early recognition of disease seemed critical to patient survival. The study supported the measurement of CVP as a guide in fluid resuscitation in protocol-driven therapy during the initial 6 hours for patients who had severe sepsis and septic shock.⁴ The 2012 Surviving Sepsis Campaign guidelines for the treatment of severe sepsis and septic shock recommend maintaining CVP at 8 to 12 mm Hg for nonventilated patients and higher for ventilated patients.⁵

Since the publication of the EGDT study,⁴ the use of protocolized “bundle” therapy as a guide for resuscitation in severe sepsis and septic shock has been brought into question. The debate begs to answer which intervention within the bundle (CVP, transfusions, ScvO₂, serial lactate, blood transfusions) results in a mortality benefit.

Between 2014 and 2015, three trials were published with the goal of determining which bundle intervention of EGDT was important in decreasing mortality. These three randomized worldwide trials, the so-called “trilogy of EDGT,” were the Protocol-based Care for Early Septic Shock (PROCESS),⁶ Australasian Resuscitation in Sepsis Evaluation (ARISE),⁷ and Protocolised Management in Sepsis (ProMISe).⁸ The results of all three trials were consistent. From a population standpoint, if the comprehensive processes are in place for the early detection of sepsis, aggressive IV fluid administration, early antibiotic administration, and serial lactate measurement; the subsequent algorithm-driven EGDT (as defined by Rivers et al⁴), including continuous central venous oxygenation and CVP monitoring, did not lead to an improvement in outcomes. Patients in the usual care group received central-line and arterial-line placement at a much higher rate than expected.

One cannot jump to conclusion from the aforementioned three trials that EGDT trials are not an effective approach in hospitals that do not have an effective system for early identification (ie, 1-2 hours from triage), early IV fluids (ie, 2 L within the first 3 hours), early antibiotics (ie, within the first 1-2 hours from identification) and early lactate measurement.  Just because the results of the three trials cannot be reproduced in such a setting, does not mean that EGDT is not beneficial.

A number of potential reasons for differences in results from the original study by Rivers et al⁴ exist—eg, randomization occurred later, patients appeared to be less ill at baseline, all patients received antibiotics prior to randomization (Table 1). It is important to bear in mind that usual care, as defined in the “trilogy” may in fact not have been the “usual” care back in the mid-1990s when Rivers et al⁴ were conducting his EGDT. In addition, due to the influences of the original paper, the Surviving Sepsis Guidelines publications, improvement in EMS, critical care improvement, what Rivers et al⁴ termed usual care was really a modification of EDGT. One can, however, conclude from the trilogy is that placing a CVP or an ScvO₂ catheter just for the purpose of chasing a CVP is no longer recommended.

 

  

Central Venous Pressure Measurement

A CVC must be placed in a sterile fashion with the tip of the catheter at the junction between the right atrium and superior vena cava. After the catheter has been properly secured and placement has been confirmed, a pressure transducer is connected from the most distal port of the CVC to the monitor. The use of CVP in the treatment of critically ill patients has logistical, mechanical, and placement issues that can complicate the clinical picture. Additionally, placement of a CVC is an invasive procedure with a set of complications that can compromise an already complex patient picture.^9,10

The mechanical issues are numerous. The transducer is a water column that must be calibrated and set to zero at the level of the heart along the same plane of the right atrium (phlebostatic axis). The tip of the catheter inadvertently can be moved easily by health care workers, and a slight change in position may cause reading errors. The monitor must be recalibrated after the patient undergoes care by ancillary staff or is logrolled, moved, or repositioned in a way that affects the level of the heart. Some staff may not have adequate experience using the equipment. Misplacement of the catheter may cause erroneous and inaccurate measurements. The catheter tip must be in the right atrium, but using a catheter that is too long or short may have the catheter tip located in the superior vena cava, ventricle, or inferior vena cava (IVC). All these conditions will cause false reading of CVP.

  

Central Venous Pressure Interpretation

Normal CVP is 2 to 4 mm Hg, but interpretation of the value may vary. Low CVP typically indicates intravascular volume depletion and need for fluid replacement. However, caution is required with this approach. Depending on the cardiac compliance, some never have adequate volume with a low CVP and others with an elevated CVP may still augment cardiac output with additional fluid therapy (ie, a patient with hypertrophic Cardiomyopathy or advanced Pulmonary HTN).^11,12

CVP as a trend may be more useful when compared to a single reading. Patients may vary on an individual basis, thereby making CVP a poor static marker. It should be used in the context of the patient’s clinical condition as it indicates the relationship between circulating blood volume and the capacity of the heart at a given time. As a trend, it is more sensitive to guide continued resuscitation efforts.¹³

  

Dynamic Techniques to Monitor Cardiac Output and Determine Fluid Responsiveness

Central venous pressure can be affected by anatomical and physiological factors such as valvular heart disease, right heart failure, poor lung compliance, or arrhythmias. In 2008, Marik et al¹⁴ performed a systematic review of 24 studies reviewing the benefits of CVP in the management of fluid therapy. In 2013, Marik et al^14,15 repeated the meta-analysis of the literature which included 43 articles, and again concluded that there were no data to support the use of CVP to guide fluid therapy, and both papers conluded that CVP should not be used for fluid resuscitation. Static measures of fluid responsiveness such as CVP may not be the most appropriate measures, and may be less accurate physiologically than dynamic measures.

Dynamic measurements based on the Frank-Starling principle use the changes in the venous return (preload) and stroke volume as a marker of fluid responsiveness and may be more useful. There are several dynamic methods to assess fluid responsiveness. The first such method is the measurement of right atrial pressure. In a case series of 33 medical and surgical intensive care unit (ICU) patients who had pulmonary artery catheters, it was hypothesized that right atrial pressure predicted the response to fluid pressure as right atrial pressure should not decrease during spontaneous inspiration in patients who had a heart that was not volume responsive. Patients were classified as having a positive response test when right atrial pressure decreased ≥1 mm Hg during inspiration, or a negative response when right atrial pressure decreased <1 mm Hg. A positive response correlated with cardiac output increase of 250 mL/h.16

  

Evaluation of Pulse Pressure and Stroke Volume Variation

Pulse pressure variation (PPV), stroke volume variation (SVV), and variation of the amplitude of pulse oximeter plethysmographic waveform are highly predictive of fluid responsiveness in mechanically ventilated patients who have septic or hemorrhagic shock.^17,18 The PPV is derived from the analysis of the arterial waveform, and SVV is derived from pulse contour analysis. The PPV uses the physiologic changes that occur during positive pressure ventilation. The delivery of a mechanical breath increases pleural pressure on inspiration, causing the following: (1) a decrease in RV preload because of decreased venous return; and (2) increase in RV afterload because of increased transpulmonary pressure. These changes lead to decreased RV stroke volume, which is at a minimal level at the end of inspiration. The inspiration reduction in RV ejection leads to a decrease in LV filling after a phase lag of two to three heart beats because of long pulmonary transit time. Thus, the LV preload reduction may induce a decrease in LV stroke volume, which is at its minimum volume during the inspiratory period of mechanical ventilation.¹⁸ The variation between the RV and LV stroke volume are greatest when the ventricles operate on the steep part of the Frank-Starling curve (rather than the flat portion). The PPV is calculated as the difference between maximum and minimum pulse pressures divided by the average of their sum, and multiplied by 100%. A variation in PPV of greater than 13% is highly predictive of volume responsiveness.¹⁹ The use of PPV is feasible in the ED because the only requirements include arterial access, measurement of the minimum and maximum pulse pressures during 30 seconds, and performance of the calculation. The PPV has been validated in different patient populations. However, the use of PPV is limited to a conventional volume control mode of ventilation and restricted to tidal volumes (TVs) over 7 mL/kg, this method of measurement was validated in patients receiving tidal volumes of at least 8 cc/kg ideal body weight—which may be higher than seen in contemporary clinical practice with more restrictive TV, ventilation strategies in patients with acute respiratory distress syndrome.²⁰ Furthermore, patients must be ventilated passively, with heavy sedation or chemical paralysis to prevent spontaneous breathing. They must also have a normal heart rhythm. Most acute lung injury states are managed with lung protective strategy with TV of 4 to 6 mL/kg, PPV values obtained using lower TVs are less reliable and their use is not recommended.^20-22

 

The Pleth Variation Index (PVI) is similar to PPV but is an automated measure of the dynamic change in the perfusion index that occurs during a respiratory cycle. Perfusion index is the ratio of nonpulsatile to pulsatile blood flow through the peripheral bed, measured noninvasively with a pulse oximeter probe. The PVI can predict positive fluid response in mechanically ventilated patients. However, PVI has the same limitations as PPV, the patient must be in sinus rhythm, and PVI cannot be used in patients who are breathing spontaneously.²³

  

Ultrasonographic Assessment

Bedside ultrasonography is noninvasive, can be performed rapidly, and provides real-time clinically relevant data. There is much evidence that ultrasonography is effective in evaluating hemodynamic and volume status, and it may be used to assess fluid responsiveness during resuscitation.

Most importantly, ultrasonography can be repeated and used to guide resuscitation efforts and direct plan of care including decisions about administration of more fluids versus starting vasoactive agents. Bedside ultrasound can provide multiple data points to give a more complete view of a patient’s volume status. Right atrial pressure and CVP can be monitored during fluid resuscitation using the visualization of dynamic changes in the IVC diameter during inspiration and expiration. Afterload can also be assessed using left ventricular outflow tract stroke volume variation. Additionally, ultrasound can be used to estimate ejection fraction to ensure that the cardiac physiology can handle needed resuscitation.

As there is growing awareness of sepsis and fluid resuscitation, IVC measurements have grown in popularity as a noninvasive approach for such monitoring.²⁴ IVC collapsibility in spontaneously breathing patients and caval index in mechanically ventilated patients can be determined rapidly at the bedside. There are two views that most easily allow access to measure the IVC: subxyphoid and right upper quadrant. Using the phased array probe or a curvilinear probe, the IVC can be seen traversing through the liver with the hepatic vein joining the IVC just before the diaphragm and emptying into the right atrium.  Interrater reliability is often questioned when ultrasound is used. However, Fields et al²⁵ were able to show that there was a high degree of interrater reliability among EPs when measuring IVC collapsibility.

A systematic review by Zhang et al,²⁶ showed change in IVC measured with point-of-care ultrasonography can reliably predict fluid responsiveness, particularly in patients that are mechanically ventilated. A caval index of 0.72 corresponds to CVP less than 7 cm water; a caval index of 1.23 corresponds to CVP 8 to 12 cm water; and a caval index of 1.59 corresponds to CVP greater than 13 cm water. The distensibility index is similar and calculated based on the IVC diameter at end-expiration (IVCDmax) and end-inspiration (IVCDmin).²⁷ The ratio of (IVCDmax - IVCDmin)/IVCDmin is expressed as a percentage (dIVC%) in mechanically ventilated patients. A distensibility index less than 18% may indicate that the patient is not volume responsive (Tables 2 and 3; Figure 1).

  

Caval Index

A more widely utilized method for IVC evaluation is described by Nagdev et al.²⁹ The caval index is calculated as the relative decrease in inferior vena cava diameter during one respiratory cycle. A caval index greater than or equal to 50% is strongly associated with a low CVP with 91% sensitivity and 94% specificity.²⁹ It is important to remember, however, that IVC collapsibility is only useful at the extremes. Nevertheless, IVC measurement is limited by increased PEEP, increased TV, and increased intraabdominal pressure.

While IVC is the most commonly used vessel for sonographic volume status assessment, other vessels can also be used.  Kent et al³⁰ describe using the internal jugular vein as well as the femoral vein. Guarracino et al³¹ achieved similar results when using the internal jugular vein for distensibility index for assessing fluid responsiveness. When compared to the invasive  CVP measurements, new CVP quantification methods could be used as a reliable approach for monitoring hemodynamic status.

  

Stroke Volume Variation

Stroke volume can be assessed using pulse contour analysis as well as via ultrasonography.³² In the apical five (apical four plus left ventricular outflow tract), pulsed-wave Doppler can be used via a phased array probe. The Doppler gate is placed in the left ventricular outflow tract and stroke velocity is used to assess respiratory variability in the stroke volume. The percent change in velocity can be inferred as stroke volume variability (SVV). An SVV greater than 13% correlates with fluid responsiveness with an odd ratio of 18.4, sensitivity and specificity of 81% and 80%, respectively (Figure 2). The use of SVV is limited by atrial fibrillation, mitral valve abnormalities, and aortic valve abnormalities.³³

 

While not used regularly in the ED, respiratory changes in aortic blood velocity as measured by transesophageal echocardiography (TEE) may predict fluid responsiveness in mechanically ventilated patients.³⁴ Peak aortic blood flow velocity variation is measured by TEE. Similarly, ventilator-induced variation in descending aortic blood flow measured by esophageal Doppler monitoring may predict fluid responsiveness.³⁴ However peak aortic blood flow velocity measurements determined by TEE may have limited utility because TEE is an invasive procedure. Similarly, esophageal Doppler monitors can be used but are limited because of low predictive value and rare usage in the emergency setting.³⁵

  

Passive Leg Raise

In spontaneously breathing patients, passive leg raising (PLR) has been studied as a substitute for volume challenge due to the ease of performing PLR at the bedside and absence of adverse events such as volume overload. When performing PLR, the patient starts in a semirecumbent position and is repositioned supine with the legs raised to 45°. Blood transferred to the heart during PLR increases cardiac preload and tests preload responsiveness. The maximum hemodynamic response to PLR occurs within one minute of performing the maneuver.³⁶ The effects of PLR are assessed by the changes in cardiac output or stroke volume after PLR, which are extrapolated from aortic blood flow measured by esophageal Doppler, velocity time integral measured by transthoracic echocardiography, and femoral artery flow measured by arterial Doppler.³⁶ These modalities may provide additional data points in the evaluation of fluid responsiveness but is out of the scope of this review.

Data in mechanically ventilated patients with esophageal Doppler and arterial access demonstrated that an increase in aortic blood flow by 10% with PLR predicted a positive fluid response with sensitivity 97% and specificity 94%.³⁷ However, in the same study, the specificity in spontaneously breathing patients was markedly reduced (46%).^37,38

Another study used a more conventional noninvasive measurement with transthoracic echocardiography to determine whether PLR could predict fluid responsiveness in hemodynamically unstable patients. In this study, a PLR-induced increase in stroke volume greater than or equal to 12.5% predicted an increase in stroke volume by greater than or equal to 15% after fluid administration with specificity 100% and sensitivity 77%.³⁸ This study included patients on mechanical ventilation with active inspiration, patients without mechanical support, and patients with atrial fibrillation, enabling better generalization of results than previous studies.³⁹

  

Bioreactance Technology

Cardiac output measurement using bioreactance technology is an alternative noninvasive method to measure cardiac output using only four surface electrodes. This technology is based on an analysis of relative phase shifts of an oscillating current that occurs when the current traverses the thoracic cavity. The bioreactance device (NICOM, Cheetah Medical, Tel Aviv, Israel) is comprised of a high frequency (75 kHz) sine wave generator and four dual electrode stickers that are used to establish electrical contact with the body. The cardiac output measured by bioreactance correlates well with values measured by thermodilution and pulse contour analysis.⁴⁰ Performing PLR and determining its response using a bioreactance machine may be appropriate in the ED, in the ward, or at the initial presentation to the ICU because it is noninvasive and less labor intensive than other methods. In postoperative cardiac surgery patients, PLR-induced changes in cardiac output measured by bioreactance had sensitivity 88% and specificity 100%.⁴⁰ In hemodynamically unstable patients, the results were more encouraging with a sensitivity of 94% and a specificity of 100% in predicting fluid responsiveness (defined as greater than10% increase in stroke volume index).⁴¹ However, in a group of critically ill patients (83% septic, 10% hypovolemic, and 7% cardiogenic), bioreactance coupled with PLR was unable to measure cardiac index compared with transpulmonary thermodilution, and bioreactance failed to predict fluid responsiveness.⁴² More research on bioreactance technology is needed, and its noninvasive evaluation of critically ill patients who need cardiac output monitoring and fluid therapy.

  

Conclusion

There are many tools available to estimate the volume status and fluid responsiveness of the critically ill patient. One of these tools, CVP measurement, must be used cautiously as an assessment of fluid responsiveness. It is important to understand the limitations of this technology. While other more advanced tools, such as ultrasonography to measure the IVC at the bedside and assess IVC variation or TEE to assess LV diastolic size and contractility during fluid resuscitation, may provide a better diagnostic picture, these tools/devices are not always  available at most community hospitals.

The authors do not recommend placing a CVC simply to measure CVP; however, when a CVC or peripherally inserted central catheter is medically needed for treatment, the catheter can be used to trend CVP since the value of CVP is greatest as a trend to guide resuscitation. Other minimally invasive and noninvasive diagnostic tools currently are available, such as bedside ultrasound, and enable clinicians to assess volume responsiveness using dynamic procedures that challenge the Frank-Starling curve.⁴ These technologies have a useful place in resuscitation but each has its own limitations. With an understanding of the tools available, with their strengths and limitations, physicians can better individualize intravascular volume resuscitation.

 

  

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Dr Farcy is the chairman of the department of emergency medicine, medical director of intensivists at Mount Sinai Medical Center, Miami Beach, Florida; and clinical assistant professor, Florida International University Medical School, Miami, Florida. Dr Jain is an assistant professor, director of critical care ultrasound, department of emergency medicine at the SUNY Downstate Medical Center, Kings County Hospital Center, Brooklyn, New York. Dr Dalley is the emergency-medicine residency program director at Mount Sinai Medical Center, Miami Beach, Florida.
Dr Scalea holds the Francis X. Kelly professorship in trauma surgery, is the distinguished professor in trauma, and director, program in trauma at the University of Maryland School of Medicine, Baltimore; he is also the physician in chief, shock trauma center, and system chief for critical care services at the University of Maryland Medical System, Baltimore. 

Case Scenario

A 69-year-old man was transported to the ED via emergency medical services after a family member discovered him alone at home and confused. His wife stated that her husband had been sick with the flu and had been febrile for the previous several days. The patient’s blood pressure taken on the scene by the emergency medical technician was 80/40 mm Hg, and 1 L normal saline was infused during transport. Upon arrival to the ED, his vital signs were:  temperature, 103.3°F; heart rate,130 beats/minute; BP, 90/48 mm Hg; and respiratory rate, 24 breaths/minute. Oxygen saturation was 92% on nasal canula. An electrocardiogram showed sinus tachycardia with nonspecific changes.

Based on the patient’s symptoms, the emergency physician (EP) suspected sepsis and ordered the appropriate laboratory studies and radiographic images. During evaluation, the patient’s systolic BP decreased to 70 from 80 mm Hg, and the EP ordered another fluid bolus and considered assessing the patient’s volume status.

  

Introduction

There is a long-standing debate as to the most accurate method of determining the volume status of a critically ill patient, as well as the physiological ability to respond to fluid therapy. In the assessment of a critically ill patient receiving volume replacement, a wide variability of assessment options are available; however, the current literature has yet to determine which method is the best. This article reviews multiple approaches to estimating the intravascular volume status of critically ill patients and the use of modalities to determine a patient’s physiological response to fluid therapy.

  

Basic Physiology

Central venous pressure (CVP) is the pressure in the thoracic vena cava adjacent to the right atrium. The heart functions as a two-sided pump; the right side pumps volume at low pressure and the left side pumps against systemic arterial pressure. The major determinant of the filling pressure of the right ventricle (RV) at the end of diastole is CVP, which is affected by the initial stretching of the ventricles before contraction (preload).

  

Frank-Starling Mechanism

The Frank-Starling mechanism describes the relationship between cardiac performance and intravascular volume. Stroke volume increases in response to an increase in preload volume. The increased volume of blood stretches the ventricular wall, causing the cardiac muscle to contract more forcefully. The change in volume (∆V) of blood divided by the change in pressure (∆P) is termed compliance
(∆V/∆P).

The venous system is the major reservoir within the vascular system and is markedly more compliant than the arterial system. Thus, CVP will increase with a decrease in venous compliance and/or an increase in the venous volume. These relationships can be quite dynamic depending on the disease state.

  

History of CVP Monitoring

The resuscitation of hemodynamically unstable patients historically stressed the use of intravenous (IV) fluid boluses. However, measuring the efficacy of this approach has been difficult. This issue was first addressed in the 1960s and 1970s when clinicians began to use central venous catheters (CVCs) to measure CVP as a surrogate measure of right atrial volume, which had been interpreted as a measure of the amount of blood returning to the heart. However, CVP measurements were static measurements of a dynamic filtration, and derivation of cardiac output required a long and complex calculation. The Swan-Ganz pulmonary artery catheter was the first catheter that enabled continuous monitoring and allowed clinicians to obtain cardiac index calculations at the bedside.¹

The CVP is an approximation of the right atrial pressure and is an indicator of RV preload, which is a major determinant of RV filling pressure. Both RV preload and RV filling pressure correlate with intravascular volume. Lower CVP may occur with vasodilation or hypovolemia, which decreases the volume returning to the right atrium. This volume depletion creates a need for fluid replacement.

To illustrate this point, picture the body’s blood supply contained within a 6-L expandable tank. Vasodilation may expand the tank to a 9-L capacity, with a 3-L volume deficit. Similarly, blood loss from the 6-L tank may drain 3-L from the tank, leaving a 3-L deficit. Both mechanisms may cause a 3-L deficit, with the tank partially empty. Although it might make sense to replace the loss or “fill the tank in both scenarios,” fluid replacement may have risks. Overly aggressive fluid resuscitation may cause multiorgan dysfunction such as pulmonary edema, abdominal compartment syndrome, altered mental status, dilutional anemia, or dilutional coagulopathy. However, suboptimal fluid treatment may cause inadequate resuscitation that may be complicated by persistent hypotension, hypoperfusion, and end-organ damage and failure.

 

Up until the 1980s, it was believed that maintenance of normal hemodynamic parameters was the key to resuscitation of critically ill patients. Shoemaker et al^2,3  then published several papers about increasing patient survival by “supranormalizing” cardiac indices. They recommended increasing cardiac index, oxygen transport, and CVP to higher than normal. High-risk surgical patients had placement of a pulmonary artery catheter and were randomized into three groups: (1) normalization of CVP; (2) pulmonary artery catheter monitoring and normalization of CVP; or (3) a pulmonary artery catheter protocol based on increasing normal cardiac indices to supranormal values. The time to intervention was greater than 6 hours. The study demonstrated no mortality difference among the CVP and pulmonary artery control groups, but did demonstrate a significant mortality reduction in the pulmonary artery catheter protocol group where the hemodynamic markers were kept at values higher (supranormalization group) than normal.

Early Goal-Directed Therapy

The intervention time of 6 hours was questioned in a study by Rivers et al,⁴ who suggested this delay was too long. In this study, early goal-directed therapy (EGDT) was compared to standard therapy in the ED in severe sepsis and septic shock. A CVP catheter was used within the right atrium, and critically ill patients were randomized into the following two groups: (1) CVC with continuous central venous oxygen saturation (ScvO₂) measurements; and (2) the standard therapy group which was  treated at the clinician’s discretion according to standard ED care with the exception of placement of a CVC without ScvO₂ monitoring. Both groups had targeted goals of CVP, 8 to 12 mm Hg; mean arterial pressure, greater than 65 mm Hg; and urine output, greater than 0.5 mL/kg/h. Both groups received an equal volume of crystalloid fluids, which exceeded the commonly given amount of fluid to patients. The EDGT group received 4981± 2984 mL compared to the standard group which received 3499 ± 2438 mL. The EGDT-targeted supranormalization of ScvO₂ employs dobutamine to achieve a goal of ScvO₂ level greater than 70% and uses transfusion to achieve hematocrit level greater than 30%. The study showed 21% overall reduction in mortality in the EGDT group. Aggressive care and early recognition of disease seemed critical to patient survival. The study supported the measurement of CVP as a guide in fluid resuscitation in protocol-driven therapy during the initial 6 hours for patients who had severe sepsis and septic shock.⁴ The 2012 Surviving Sepsis Campaign guidelines for the treatment of severe sepsis and septic shock recommend maintaining CVP at 8 to 12 mm Hg for nonventilated patients and higher for ventilated patients.⁵

Since the publication of the EGDT study,⁴ the use of protocolized “bundle” therapy as a guide for resuscitation in severe sepsis and septic shock has been brought into question. The debate begs to answer which intervention within the bundle (CVP, transfusions, ScvO₂, serial lactate, blood transfusions) results in a mortality benefit.

Between 2014 and 2015, three trials were published with the goal of determining which bundle intervention of EGDT was important in decreasing mortality. These three randomized worldwide trials, the so-called “trilogy of EDGT,” were the Protocol-based Care for Early Septic Shock (PROCESS),⁶ Australasian Resuscitation in Sepsis Evaluation (ARISE),⁷ and Protocolised Management in Sepsis (ProMISe).⁸ The results of all three trials were consistent. From a population standpoint, if the comprehensive processes are in place for the early detection of sepsis, aggressive IV fluid administration, early antibiotic administration, and serial lactate measurement; the subsequent algorithm-driven EGDT (as defined by Rivers et al⁴), including continuous central venous oxygenation and CVP monitoring, did not lead to an improvement in outcomes. Patients in the usual care group received central-line and arterial-line placement at a much higher rate than expected.

One cannot jump to conclusion from the aforementioned three trials that EGDT trials are not an effective approach in hospitals that do not have an effective system for early identification (ie, 1-2 hours from triage), early IV fluids (ie, 2 L within the first 3 hours), early antibiotics (ie, within the first 1-2 hours from identification) and early lactate measurement.  Just because the results of the three trials cannot be reproduced in such a setting, does not mean that EGDT is not beneficial.

A number of potential reasons for differences in results from the original study by Rivers et al⁴ exist—eg, randomization occurred later, patients appeared to be less ill at baseline, all patients received antibiotics prior to randomization (Table 1). It is important to bear in mind that usual care, as defined in the “trilogy” may in fact not have been the “usual” care back in the mid-1990s when Rivers et al⁴ were conducting his EGDT. In addition, due to the influences of the original paper, the Surviving Sepsis Guidelines publications, improvement in EMS, critical care improvement, what Rivers et al⁴ termed usual care was really a modification of EDGT. One can, however, conclude from the trilogy is that placing a CVP or an ScvO₂ catheter just for the purpose of chasing a CVP is no longer recommended.

 

  

Central Venous Pressure Measurement

A CVC must be placed in a sterile fashion with the tip of the catheter at the junction between the right atrium and superior vena cava. After the catheter has been properly secured and placement has been confirmed, a pressure transducer is connected from the most distal port of the CVC to the monitor. The use of CVP in the treatment of critically ill patients has logistical, mechanical, and placement issues that can complicate the clinical picture. Additionally, placement of a CVC is an invasive procedure with a set of complications that can compromise an already complex patient picture.^9,10

The mechanical issues are numerous. The transducer is a water column that must be calibrated and set to zero at the level of the heart along the same plane of the right atrium (phlebostatic axis). The tip of the catheter inadvertently can be moved easily by health care workers, and a slight change in position may cause reading errors. The monitor must be recalibrated after the patient undergoes care by ancillary staff or is logrolled, moved, or repositioned in a way that affects the level of the heart. Some staff may not have adequate experience using the equipment. Misplacement of the catheter may cause erroneous and inaccurate measurements. The catheter tip must be in the right atrium, but using a catheter that is too long or short may have the catheter tip located in the superior vena cava, ventricle, or inferior vena cava (IVC). All these conditions will cause false reading of CVP.

  

Central Venous Pressure Interpretation

Normal CVP is 2 to 4 mm Hg, but interpretation of the value may vary. Low CVP typically indicates intravascular volume depletion and need for fluid replacement. However, caution is required with this approach. Depending on the cardiac compliance, some never have adequate volume with a low CVP and others with an elevated CVP may still augment cardiac output with additional fluid therapy (ie, a patient with hypertrophic Cardiomyopathy or advanced Pulmonary HTN).^11,12

CVP as a trend may be more useful when compared to a single reading. Patients may vary on an individual basis, thereby making CVP a poor static marker. It should be used in the context of the patient’s clinical condition as it indicates the relationship between circulating blood volume and the capacity of the heart at a given time. As a trend, it is more sensitive to guide continued resuscitation efforts.¹³

  

Dynamic Techniques to Monitor Cardiac Output and Determine Fluid Responsiveness

Central venous pressure can be affected by anatomical and physiological factors such as valvular heart disease, right heart failure, poor lung compliance, or arrhythmias. In 2008, Marik et al¹⁴ performed a systematic review of 24 studies reviewing the benefits of CVP in the management of fluid therapy. In 2013, Marik et al^14,15 repeated the meta-analysis of the literature which included 43 articles, and again concluded that there were no data to support the use of CVP to guide fluid therapy, and both papers conluded that CVP should not be used for fluid resuscitation. Static measures of fluid responsiveness such as CVP may not be the most appropriate measures, and may be less accurate physiologically than dynamic measures.

Dynamic measurements based on the Frank-Starling principle use the changes in the venous return (preload) and stroke volume as a marker of fluid responsiveness and may be more useful. There are several dynamic methods to assess fluid responsiveness. The first such method is the measurement of right atrial pressure. In a case series of 33 medical and surgical intensive care unit (ICU) patients who had pulmonary artery catheters, it was hypothesized that right atrial pressure predicted the response to fluid pressure as right atrial pressure should not decrease during spontaneous inspiration in patients who had a heart that was not volume responsive. Patients were classified as having a positive response test when right atrial pressure decreased ≥1 mm Hg during inspiration, or a negative response when right atrial pressure decreased <1 mm Hg. A positive response correlated with cardiac output increase of 250 mL/h.16

  

Evaluation of Pulse Pressure and Stroke Volume Variation

Pulse pressure variation (PPV), stroke volume variation (SVV), and variation of the amplitude of pulse oximeter plethysmographic waveform are highly predictive of fluid responsiveness in mechanically ventilated patients who have septic or hemorrhagic shock.^17,18 The PPV is derived from the analysis of the arterial waveform, and SVV is derived from pulse contour analysis. The PPV uses the physiologic changes that occur during positive pressure ventilation. The delivery of a mechanical breath increases pleural pressure on inspiration, causing the following: (1) a decrease in RV preload because of decreased venous return; and (2) increase in RV afterload because of increased transpulmonary pressure. These changes lead to decreased RV stroke volume, which is at a minimal level at the end of inspiration. The inspiration reduction in RV ejection leads to a decrease in LV filling after a phase lag of two to three heart beats because of long pulmonary transit time. Thus, the LV preload reduction may induce a decrease in LV stroke volume, which is at its minimum volume during the inspiratory period of mechanical ventilation.¹⁸ The variation between the RV and LV stroke volume are greatest when the ventricles operate on the steep part of the Frank-Starling curve (rather than the flat portion). The PPV is calculated as the difference between maximum and minimum pulse pressures divided by the average of their sum, and multiplied by 100%. A variation in PPV of greater than 13% is highly predictive of volume responsiveness.¹⁹ The use of PPV is feasible in the ED because the only requirements include arterial access, measurement of the minimum and maximum pulse pressures during 30 seconds, and performance of the calculation. The PPV has been validated in different patient populations. However, the use of PPV is limited to a conventional volume control mode of ventilation and restricted to tidal volumes (TVs) over 7 mL/kg, this method of measurement was validated in patients receiving tidal volumes of at least 8 cc/kg ideal body weight—which may be higher than seen in contemporary clinical practice with more restrictive TV, ventilation strategies in patients with acute respiratory distress syndrome.²⁰ Furthermore, patients must be ventilated passively, with heavy sedation or chemical paralysis to prevent spontaneous breathing. They must also have a normal heart rhythm. Most acute lung injury states are managed with lung protective strategy with TV of 4 to 6 mL/kg, PPV values obtained using lower TVs are less reliable and their use is not recommended.^20-22

 

The Pleth Variation Index (PVI) is similar to PPV but is an automated measure of the dynamic change in the perfusion index that occurs during a respiratory cycle. Perfusion index is the ratio of nonpulsatile to pulsatile blood flow through the peripheral bed, measured noninvasively with a pulse oximeter probe. The PVI can predict positive fluid response in mechanically ventilated patients. However, PVI has the same limitations as PPV, the patient must be in sinus rhythm, and PVI cannot be used in patients who are breathing spontaneously.²³

  

Ultrasonographic Assessment

Bedside ultrasonography is noninvasive, can be performed rapidly, and provides real-time clinically relevant data. There is much evidence that ultrasonography is effective in evaluating hemodynamic and volume status, and it may be used to assess fluid responsiveness during resuscitation.

Most importantly, ultrasonography can be repeated and used to guide resuscitation efforts and direct plan of care including decisions about administration of more fluids versus starting vasoactive agents. Bedside ultrasound can provide multiple data points to give a more complete view of a patient’s volume status. Right atrial pressure and CVP can be monitored during fluid resuscitation using the visualization of dynamic changes in the IVC diameter during inspiration and expiration. Afterload can also be assessed using left ventricular outflow tract stroke volume variation. Additionally, ultrasound can be used to estimate ejection fraction to ensure that the cardiac physiology can handle needed resuscitation.

As there is growing awareness of sepsis and fluid resuscitation, IVC measurements have grown in popularity as a noninvasive approach for such monitoring.²⁴ IVC collapsibility in spontaneously breathing patients and caval index in mechanically ventilated patients can be determined rapidly at the bedside. There are two views that most easily allow access to measure the IVC: subxyphoid and right upper quadrant. Using the phased array probe or a curvilinear probe, the IVC can be seen traversing through the liver with the hepatic vein joining the IVC just before the diaphragm and emptying into the right atrium.  Interrater reliability is often questioned when ultrasound is used. However, Fields et al²⁵ were able to show that there was a high degree of interrater reliability among EPs when measuring IVC collapsibility.

A systematic review by Zhang et al,²⁶ showed change in IVC measured with point-of-care ultrasonography can reliably predict fluid responsiveness, particularly in patients that are mechanically ventilated. A caval index of 0.72 corresponds to CVP less than 7 cm water; a caval index of 1.23 corresponds to CVP 8 to 12 cm water; and a caval index of 1.59 corresponds to CVP greater than 13 cm water. The distensibility index is similar and calculated based on the IVC diameter at end-expiration (IVCDmax) and end-inspiration (IVCDmin).²⁷ The ratio of (IVCDmax - IVCDmin)/IVCDmin is expressed as a percentage (dIVC%) in mechanically ventilated patients. A distensibility index less than 18% may indicate that the patient is not volume responsive (Tables 2 and 3; Figure 1).

  

Caval Index

A more widely utilized method for IVC evaluation is described by Nagdev et al.²⁹ The caval index is calculated as the relative decrease in inferior vena cava diameter during one respiratory cycle. A caval index greater than or equal to 50% is strongly associated with a low CVP with 91% sensitivity and 94% specificity.²⁹ It is important to remember, however, that IVC collapsibility is only useful at the extremes. Nevertheless, IVC measurement is limited by increased PEEP, increased TV, and increased intraabdominal pressure.

While IVC is the most commonly used vessel for sonographic volume status assessment, other vessels can also be used.  Kent et al³⁰ describe using the internal jugular vein as well as the femoral vein. Guarracino et al³¹ achieved similar results when using the internal jugular vein for distensibility index for assessing fluid responsiveness. When compared to the invasive  CVP measurements, new CVP quantification methods could be used as a reliable approach for monitoring hemodynamic status.

  

Stroke Volume Variation

Stroke volume can be assessed using pulse contour analysis as well as via ultrasonography.³² In the apical five (apical four plus left ventricular outflow tract), pulsed-wave Doppler can be used via a phased array probe. The Doppler gate is placed in the left ventricular outflow tract and stroke velocity is used to assess respiratory variability in the stroke volume. The percent change in velocity can be inferred as stroke volume variability (SVV). An SVV greater than 13% correlates with fluid responsiveness with an odd ratio of 18.4, sensitivity and specificity of 81% and 80%, respectively (Figure 2). The use of SVV is limited by atrial fibrillation, mitral valve abnormalities, and aortic valve abnormalities.³³

 

While not used regularly in the ED, respiratory changes in aortic blood velocity as measured by transesophageal echocardiography (TEE) may predict fluid responsiveness in mechanically ventilated patients.³⁴ Peak aortic blood flow velocity variation is measured by TEE. Similarly, ventilator-induced variation in descending aortic blood flow measured by esophageal Doppler monitoring may predict fluid responsiveness.³⁴ However peak aortic blood flow velocity measurements determined by TEE may have limited utility because TEE is an invasive procedure. Similarly, esophageal Doppler monitors can be used but are limited because of low predictive value and rare usage in the emergency setting.³⁵

  

Passive Leg Raise

In spontaneously breathing patients, passive leg raising (PLR) has been studied as a substitute for volume challenge due to the ease of performing PLR at the bedside and absence of adverse events such as volume overload. When performing PLR, the patient starts in a semirecumbent position and is repositioned supine with the legs raised to 45°. Blood transferred to the heart during PLR increases cardiac preload and tests preload responsiveness. The maximum hemodynamic response to PLR occurs within one minute of performing the maneuver.³⁶ The effects of PLR are assessed by the changes in cardiac output or stroke volume after PLR, which are extrapolated from aortic blood flow measured by esophageal Doppler, velocity time integral measured by transthoracic echocardiography, and femoral artery flow measured by arterial Doppler.³⁶ These modalities may provide additional data points in the evaluation of fluid responsiveness but is out of the scope of this review.

Data in mechanically ventilated patients with esophageal Doppler and arterial access demonstrated that an increase in aortic blood flow by 10% with PLR predicted a positive fluid response with sensitivity 97% and specificity 94%.³⁷ However, in the same study, the specificity in spontaneously breathing patients was markedly reduced (46%).^37,38

Another study used a more conventional noninvasive measurement with transthoracic echocardiography to determine whether PLR could predict fluid responsiveness in hemodynamically unstable patients. In this study, a PLR-induced increase in stroke volume greater than or equal to 12.5% predicted an increase in stroke volume by greater than or equal to 15% after fluid administration with specificity 100% and sensitivity 77%.³⁸ This study included patients on mechanical ventilation with active inspiration, patients without mechanical support, and patients with atrial fibrillation, enabling better generalization of results than previous studies.³⁹

  

Bioreactance Technology

Cardiac output measurement using bioreactance technology is an alternative noninvasive method to measure cardiac output using only four surface electrodes. This technology is based on an analysis of relative phase shifts of an oscillating current that occurs when the current traverses the thoracic cavity. The bioreactance device (NICOM, Cheetah Medical, Tel Aviv, Israel) is comprised of a high frequency (75 kHz) sine wave generator and four dual electrode stickers that are used to establish electrical contact with the body. The cardiac output measured by bioreactance correlates well with values measured by thermodilution and pulse contour analysis.⁴⁰ Performing PLR and determining its response using a bioreactance machine may be appropriate in the ED, in the ward, or at the initial presentation to the ICU because it is noninvasive and less labor intensive than other methods. In postoperative cardiac surgery patients, PLR-induced changes in cardiac output measured by bioreactance had sensitivity 88% and specificity 100%.⁴⁰ In hemodynamically unstable patients, the results were more encouraging with a sensitivity of 94% and a specificity of 100% in predicting fluid responsiveness (defined as greater than10% increase in stroke volume index).⁴¹ However, in a group of critically ill patients (83% septic, 10% hypovolemic, and 7% cardiogenic), bioreactance coupled with PLR was unable to measure cardiac index compared with transpulmonary thermodilution, and bioreactance failed to predict fluid responsiveness.⁴² More research on bioreactance technology is needed, and its noninvasive evaluation of critically ill patients who need cardiac output monitoring and fluid therapy.

  

Conclusion

There are many tools available to estimate the volume status and fluid responsiveness of the critically ill patient. One of these tools, CVP measurement, must be used cautiously as an assessment of fluid responsiveness. It is important to understand the limitations of this technology. While other more advanced tools, such as ultrasonography to measure the IVC at the bedside and assess IVC variation or TEE to assess LV diastolic size and contractility during fluid resuscitation, may provide a better diagnostic picture, these tools/devices are not always  available at most community hospitals.

The authors do not recommend placing a CVC simply to measure CVP; however, when a CVC or peripherally inserted central catheter is medically needed for treatment, the catheter can be used to trend CVP since the value of CVP is greatest as a trend to guide resuscitation. Other minimally invasive and noninvasive diagnostic tools currently are available, such as bedside ultrasound, and enable clinicians to assess volume responsiveness using dynamic procedures that challenge the Frank-Starling curve.⁴ These technologies have a useful place in resuscitation but each has its own limitations. With an understanding of the tools available, with their strengths and limitations, physicians can better individualize intravascular volume resuscitation.

 

  

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Dr Farcy is the chairman of the department of emergency medicine, medical director of intensivists at Mount Sinai Medical Center, Miami Beach, Florida; and clinical assistant professor, Florida International University Medical School, Miami, Florida. Dr Jain is an assistant professor, director of critical care ultrasound, department of emergency medicine at the SUNY Downstate Medical Center, Kings County Hospital Center, Brooklyn, New York. Dr Dalley is the emergency-medicine residency program director at Mount Sinai Medical Center, Miami Beach, Florida.
Dr Scalea holds the Francis X. Kelly professorship in trauma surgery, is the distinguished professor in trauma, and director, program in trauma at the University of Maryland School of Medicine, Baltimore; he is also the physician in chief, shock trauma center, and system chief for critical care services at the University of Maryland Medical System, Baltimore. 

Case Scenario

A 69-year-old man was transported to the ED via emergency medical services after a family member discovered him alone at home and confused. His wife stated that her husband had been sick with the flu and had been febrile for the previous several days. The patient’s blood pressure taken on the scene by the emergency medical technician was 80/40 mm Hg, and 1 L normal saline was infused during transport. Upon arrival to the ED, his vital signs were:  temperature, 103.3°F; heart rate,130 beats/minute; BP, 90/48 mm Hg; and respiratory rate, 24 breaths/minute. Oxygen saturation was 92% on nasal canula. An electrocardiogram showed sinus tachycardia with nonspecific changes.

Based on the patient’s symptoms, the emergency physician (EP) suspected sepsis and ordered the appropriate laboratory studies and radiographic images. During evaluation, the patient’s systolic BP decreased to 70 from 80 mm Hg, and the EP ordered another fluid bolus and considered assessing the patient’s volume status.

  

Introduction

There is a long-standing debate as to the most accurate method of determining the volume status of a critically ill patient, as well as the physiological ability to respond to fluid therapy. In the assessment of a critically ill patient receiving volume replacement, a wide variability of assessment options are available; however, the current literature has yet to determine which method is the best. This article reviews multiple approaches to estimating the intravascular volume status of critically ill patients and the use of modalities to determine a patient’s physiological response to fluid therapy.

  

Basic Physiology

Central venous pressure (CVP) is the pressure in the thoracic vena cava adjacent to the right atrium. The heart functions as a two-sided pump; the right side pumps volume at low pressure and the left side pumps against systemic arterial pressure. The major determinant of the filling pressure of the right ventricle (RV) at the end of diastole is CVP, which is affected by the initial stretching of the ventricles before contraction (preload).

  

Frank-Starling Mechanism

The Frank-Starling mechanism describes the relationship between cardiac performance and intravascular volume. Stroke volume increases in response to an increase in preload volume. The increased volume of blood stretches the ventricular wall, causing the cardiac muscle to contract more forcefully. The change in volume (∆V) of blood divided by the change in pressure (∆P) is termed compliance
(∆V/∆P).

The venous system is the major reservoir within the vascular system and is markedly more compliant than the arterial system. Thus, CVP will increase with a decrease in venous compliance and/or an increase in the venous volume. These relationships can be quite dynamic depending on the disease state.

  

History of CVP Monitoring

The resuscitation of hemodynamically unstable patients historically stressed the use of intravenous (IV) fluid boluses. However, measuring the efficacy of this approach has been difficult. This issue was first addressed in the 1960s and 1970s when clinicians began to use central venous catheters (CVCs) to measure CVP as a surrogate measure of right atrial volume, which had been interpreted as a measure of the amount of blood returning to the heart. However, CVP measurements were static measurements of a dynamic filtration, and derivation of cardiac output required a long and complex calculation. The Swan-Ganz pulmonary artery catheter was the first catheter that enabled continuous monitoring and allowed clinicians to obtain cardiac index calculations at the bedside.¹

The CVP is an approximation of the right atrial pressure and is an indicator of RV preload, which is a major determinant of RV filling pressure. Both RV preload and RV filling pressure correlate with intravascular volume. Lower CVP may occur with vasodilation or hypovolemia, which decreases the volume returning to the right atrium. This volume depletion creates a need for fluid replacement.

To illustrate this point, picture the body’s blood supply contained within a 6-L expandable tank. Vasodilation may expand the tank to a 9-L capacity, with a 3-L volume deficit. Similarly, blood loss from the 6-L tank may drain 3-L from the tank, leaving a 3-L deficit. Both mechanisms may cause a 3-L deficit, with the tank partially empty. Although it might make sense to replace the loss or “fill the tank in both scenarios,” fluid replacement may have risks. Overly aggressive fluid resuscitation may cause multiorgan dysfunction such as pulmonary edema, abdominal compartment syndrome, altered mental status, dilutional anemia, or dilutional coagulopathy. However, suboptimal fluid treatment may cause inadequate resuscitation that may be complicated by persistent hypotension, hypoperfusion, and end-organ damage and failure.

 

Up until the 1980s, it was believed that maintenance of normal hemodynamic parameters was the key to resuscitation of critically ill patients. Shoemaker et al^2,3  then published several papers about increasing patient survival by “supranormalizing” cardiac indices. They recommended increasing cardiac index, oxygen transport, and CVP to higher than normal. High-risk surgical patients had placement of a pulmonary artery catheter and were randomized into three groups: (1) normalization of CVP; (2) pulmonary artery catheter monitoring and normalization of CVP; or (3) a pulmonary artery catheter protocol based on increasing normal cardiac indices to supranormal values. The time to intervention was greater than 6 hours. The study demonstrated no mortality difference among the CVP and pulmonary artery control groups, but did demonstrate a significant mortality reduction in the pulmonary artery catheter protocol group where the hemodynamic markers were kept at values higher (supranormalization group) than normal.

Early Goal-Directed Therapy

The intervention time of 6 hours was questioned in a study by Rivers et al,⁴ who suggested this delay was too long. In this study, early goal-directed therapy (EGDT) was compared to standard therapy in the ED in severe sepsis and septic shock. A CVP catheter was used within the right atrium, and critically ill patients were randomized into the following two groups: (1) CVC with continuous central venous oxygen saturation (ScvO₂) measurements; and (2) the standard therapy group which was  treated at the clinician’s discretion according to standard ED care with the exception of placement of a CVC without ScvO₂ monitoring. Both groups had targeted goals of CVP, 8 to 12 mm Hg; mean arterial pressure, greater than 65 mm Hg; and urine output, greater than 0.5 mL/kg/h. Both groups received an equal volume of crystalloid fluids, which exceeded the commonly given amount of fluid to patients. The EDGT group received 4981± 2984 mL compared to the standard group which received 3499 ± 2438 mL. The EGDT-targeted supranormalization of ScvO₂ employs dobutamine to achieve a goal of ScvO₂ level greater than 70% and uses transfusion to achieve hematocrit level greater than 30%. The study showed 21% overall reduction in mortality in the EGDT group. Aggressive care and early recognition of disease seemed critical to patient survival. The study supported the measurement of CVP as a guide in fluid resuscitation in protocol-driven therapy during the initial 6 hours for patients who had severe sepsis and septic shock.⁴ The 2012 Surviving Sepsis Campaign guidelines for the treatment of severe sepsis and septic shock recommend maintaining CVP at 8 to 12 mm Hg for nonventilated patients and higher for ventilated patients.⁵

Since the publication of the EGDT study,⁴ the use of protocolized “bundle” therapy as a guide for resuscitation in severe sepsis and septic shock has been brought into question. The debate begs to answer which intervention within the bundle (CVP, transfusions, ScvO₂, serial lactate, blood transfusions) results in a mortality benefit.

Between 2014 and 2015, three trials were published with the goal of determining which bundle intervention of EGDT was important in decreasing mortality. These three randomized worldwide trials, the so-called “trilogy of EDGT,” were the Protocol-based Care for Early Septic Shock (PROCESS),⁶ Australasian Resuscitation in Sepsis Evaluation (ARISE),⁷ and Protocolised Management in Sepsis (ProMISe).⁸ The results of all three trials were consistent. From a population standpoint, if the comprehensive processes are in place for the early detection of sepsis, aggressive IV fluid administration, early antibiotic administration, and serial lactate measurement; the subsequent algorithm-driven EGDT (as defined by Rivers et al⁴), including continuous central venous oxygenation and CVP monitoring, did not lead to an improvement in outcomes. Patients in the usual care group received central-line and arterial-line placement at a much higher rate than expected.

One cannot jump to conclusion from the aforementioned three trials that EGDT trials are not an effective approach in hospitals that do not have an effective system for early identification (ie, 1-2 hours from triage), early IV fluids (ie, 2 L within the first 3 hours), early antibiotics (ie, within the first 1-2 hours from identification) and early lactate measurement.  Just because the results of the three trials cannot be reproduced in such a setting, does not mean that EGDT is not beneficial.

A number of potential reasons for differences in results from the original study by Rivers et al⁴ exist—eg, randomization occurred later, patients appeared to be less ill at baseline, all patients received antibiotics prior to randomization (Table 1). It is important to bear in mind that usual care, as defined in the “trilogy” may in fact not have been the “usual” care back in the mid-1990s when Rivers et al⁴ were conducting his EGDT. In addition, due to the influences of the original paper, the Surviving Sepsis Guidelines publications, improvement in EMS, critical care improvement, what Rivers et al⁴ termed usual care was really a modification of EDGT. One can, however, conclude from the trilogy is that placing a CVP or an ScvO₂ catheter just for the purpose of chasing a CVP is no longer recommended.

 

  

Central Venous Pressure Measurement

A CVC must be placed in a sterile fashion with the tip of the catheter at the junction between the right atrium and superior vena cava. After the catheter has been properly secured and placement has been confirmed, a pressure transducer is connected from the most distal port of the CVC to the monitor. The use of CVP in the treatment of critically ill patients has logistical, mechanical, and placement issues that can complicate the clinical picture. Additionally, placement of a CVC is an invasive procedure with a set of complications that can compromise an already complex patient picture.^9,10

The mechanical issues are numerous. The transducer is a water column that must be calibrated and set to zero at the level of the heart along the same plane of the right atrium (phlebostatic axis). The tip of the catheter inadvertently can be moved easily by health care workers, and a slight change in position may cause reading errors. The monitor must be recalibrated after the patient undergoes care by ancillary staff or is logrolled, moved, or repositioned in a way that affects the level of the heart. Some staff may not have adequate experience using the equipment. Misplacement of the catheter may cause erroneous and inaccurate measurements. The catheter tip must be in the right atrium, but using a catheter that is too long or short may have the catheter tip located in the superior vena cava, ventricle, or inferior vena cava (IVC). All these conditions will cause false reading of CVP.

  

Central Venous Pressure Interpretation

Normal CVP is 2 to 4 mm Hg, but interpretation of the value may vary. Low CVP typically indicates intravascular volume depletion and need for fluid replacement. However, caution is required with this approach. Depending on the cardiac compliance, some never have adequate volume with a low CVP and others with an elevated CVP may still augment cardiac output with additional fluid therapy (ie, a patient with hypertrophic Cardiomyopathy or advanced Pulmonary HTN).^11,12

CVP as a trend may be more useful when compared to a single reading. Patients may vary on an individual basis, thereby making CVP a poor static marker. It should be used in the context of the patient’s clinical condition as it indicates the relationship between circulating blood volume and the capacity of the heart at a given time. As a trend, it is more sensitive to guide continued resuscitation efforts.¹³

  

Dynamic Techniques to Monitor Cardiac Output and Determine Fluid Responsiveness

Central venous pressure can be affected by anatomical and physiological factors such as valvular heart disease, right heart failure, poor lung compliance, or arrhythmias. In 2008, Marik et al¹⁴ performed a systematic review of 24 studies reviewing the benefits of CVP in the management of fluid therapy. In 2013, Marik et al^14,15 repeated the meta-analysis of the literature which included 43 articles, and again concluded that there were no data to support the use of CVP to guide fluid therapy, and both papers conluded that CVP should not be used for fluid resuscitation. Static measures of fluid responsiveness such as CVP may not be the most appropriate measures, and may be less accurate physiologically than dynamic measures.

Dynamic measurements based on the Frank-Starling principle use the changes in the venous return (preload) and stroke volume as a marker of fluid responsiveness and may be more useful. There are several dynamic methods to assess fluid responsiveness. The first such method is the measurement of right atrial pressure. In a case series of 33 medical and surgical intensive care unit (ICU) patients who had pulmonary artery catheters, it was hypothesized that right atrial pressure predicted the response to fluid pressure as right atrial pressure should not decrease during spontaneous inspiration in patients who had a heart that was not volume responsive. Patients were classified as having a positive response test when right atrial pressure decreased ≥1 mm Hg during inspiration, or a negative response when right atrial pressure decreased <1 mm Hg. A positive response correlated with cardiac output increase of 250 mL/h.16

  

Evaluation of Pulse Pressure and Stroke Volume Variation

Pulse pressure variation (PPV), stroke volume variation (SVV), and variation of the amplitude of pulse oximeter plethysmographic waveform are highly predictive of fluid responsiveness in mechanically ventilated patients who have septic or hemorrhagic shock.^17,18 The PPV is derived from the analysis of the arterial waveform, and SVV is derived from pulse contour analysis. The PPV uses the physiologic changes that occur during positive pressure ventilation. The delivery of a mechanical breath increases pleural pressure on inspiration, causing the following: (1) a decrease in RV preload because of decreased venous return; and (2) increase in RV afterload because of increased transpulmonary pressure. These changes lead to decreased RV stroke volume, which is at a minimal level at the end of inspiration. The inspiration reduction in RV ejection leads to a decrease in LV filling after a phase lag of two to three heart beats because of long pulmonary transit time. Thus, the LV preload reduction may induce a decrease in LV stroke volume, which is at its minimum volume during the inspiratory period of mechanical ventilation.¹⁸ The variation between the RV and LV stroke volume are greatest when the ventricles operate on the steep part of the Frank-Starling curve (rather than the flat portion). The PPV is calculated as the difference between maximum and minimum pulse pressures divided by the average of their sum, and multiplied by 100%. A variation in PPV of greater than 13% is highly predictive of volume responsiveness.¹⁹ The use of PPV is feasible in the ED because the only requirements include arterial access, measurement of the minimum and maximum pulse pressures during 30 seconds, and performance of the calculation. The PPV has been validated in different patient populations. However, the use of PPV is limited to a conventional volume control mode of ventilation and restricted to tidal volumes (TVs) over 7 mL/kg, this method of measurement was validated in patients receiving tidal volumes of at least 8 cc/kg ideal body weight—which may be higher than seen in contemporary clinical practice with more restrictive TV, ventilation strategies in patients with acute respiratory distress syndrome.²⁰ Furthermore, patients must be ventilated passively, with heavy sedation or chemical paralysis to prevent spontaneous breathing. They must also have a normal heart rhythm. Most acute lung injury states are managed with lung protective strategy with TV of 4 to 6 mL/kg, PPV values obtained using lower TVs are less reliable and their use is not recommended.^20-22

 

The Pleth Variation Index (PVI) is similar to PPV but is an automated measure of the dynamic change in the perfusion index that occurs during a respiratory cycle. Perfusion index is the ratio of nonpulsatile to pulsatile blood flow through the peripheral bed, measured noninvasively with a pulse oximeter probe. The PVI can predict positive fluid response in mechanically ventilated patients. However, PVI has the same limitations as PPV, the patient must be in sinus rhythm, and PVI cannot be used in patients who are breathing spontaneously.²³

  

Ultrasonographic Assessment

Bedside ultrasonography is noninvasive, can be performed rapidly, and provides real-time clinically relevant data. There is much evidence that ultrasonography is effective in evaluating hemodynamic and volume status, and it may be used to assess fluid responsiveness during resuscitation.

Most importantly, ultrasonography can be repeated and used to guide resuscitation efforts and direct plan of care including decisions about administration of more fluids versus starting vasoactive agents. Bedside ultrasound can provide multiple data points to give a more complete view of a patient’s volume status. Right atrial pressure and CVP can be monitored during fluid resuscitation using the visualization of dynamic changes in the IVC diameter during inspiration and expiration. Afterload can also be assessed using left ventricular outflow tract stroke volume variation. Additionally, ultrasound can be used to estimate ejection fraction to ensure that the cardiac physiology can handle needed resuscitation.

As there is growing awareness of sepsis and fluid resuscitation, IVC measurements have grown in popularity as a noninvasive approach for such monitoring.²⁴ IVC collapsibility in spontaneously breathing patients and caval index in mechanically ventilated patients can be determined rapidly at the bedside. There are two views that most easily allow access to measure the IVC: subxyphoid and right upper quadrant. Using the phased array probe or a curvilinear probe, the IVC can be seen traversing through the liver with the hepatic vein joining the IVC just before the diaphragm and emptying into the right atrium.  Interrater reliability is often questioned when ultrasound is used. However, Fields et al²⁵ were able to show that there was a high degree of interrater reliability among EPs when measuring IVC collapsibility.

A systematic review by Zhang et al,²⁶ showed change in IVC measured with point-of-care ultrasonography can reliably predict fluid responsiveness, particularly in patients that are mechanically ventilated. A caval index of 0.72 corresponds to CVP less than 7 cm water; a caval index of 1.23 corresponds to CVP 8 to 12 cm water; and a caval index of 1.59 corresponds to CVP greater than 13 cm water. The distensibility index is similar and calculated based on the IVC diameter at end-expiration (IVCDmax) and end-inspiration (IVCDmin).²⁷ The ratio of (IVCDmax - IVCDmin)/IVCDmin is expressed as a percentage (dIVC%) in mechanically ventilated patients. A distensibility index less than 18% may indicate that the patient is not volume responsive (Tables 2 and 3; Figure 1).

  

Caval Index

A more widely utilized method for IVC evaluation is described by Nagdev et al.²⁹ The caval index is calculated as the relative decrease in inferior vena cava diameter during one respiratory cycle. A caval index greater than or equal to 50% is strongly associated with a low CVP with 91% sensitivity and 94% specificity.²⁹ It is important to remember, however, that IVC collapsibility is only useful at the extremes. Nevertheless, IVC measurement is limited by increased PEEP, increased TV, and increased intraabdominal pressure.

While IVC is the most commonly used vessel for sonographic volume status assessment, other vessels can also be used.  Kent et al³⁰ describe using the internal jugular vein as well as the femoral vein. Guarracino et al³¹ achieved similar results when using the internal jugular vein for distensibility index for assessing fluid responsiveness. When compared to the invasive  CVP measurements, new CVP quantification methods could be used as a reliable approach for monitoring hemodynamic status.

  

Stroke Volume Variation

Stroke volume can be assessed using pulse contour analysis as well as via ultrasonography.³² In the apical five (apical four plus left ventricular outflow tract), pulsed-wave Doppler can be used via a phased array probe. The Doppler gate is placed in the left ventricular outflow tract and stroke velocity is used to assess respiratory variability in the stroke volume. The percent change in velocity can be inferred as stroke volume variability (SVV). An SVV greater than 13% correlates with fluid responsiveness with an odd ratio of 18.4, sensitivity and specificity of 81% and 80%, respectively (Figure 2). The use of SVV is limited by atrial fibrillation, mitral valve abnormalities, and aortic valve abnormalities.³³

 

While not used regularly in the ED, respiratory changes in aortic blood velocity as measured by transesophageal echocardiography (TEE) may predict fluid responsiveness in mechanically ventilated patients.³⁴ Peak aortic blood flow velocity variation is measured by TEE. Similarly, ventilator-induced variation in descending aortic blood flow measured by esophageal Doppler monitoring may predict fluid responsiveness.³⁴ However peak aortic blood flow velocity measurements determined by TEE may have limited utility because TEE is an invasive procedure. Similarly, esophageal Doppler monitors can be used but are limited because of low predictive value and rare usage in the emergency setting.³⁵

  

Passive Leg Raise

In spontaneously breathing patients, passive leg raising (PLR) has been studied as a substitute for volume challenge due to the ease of performing PLR at the bedside and absence of adverse events such as volume overload. When performing PLR, the patient starts in a semirecumbent position and is repositioned supine with the legs raised to 45°. Blood transferred to the heart during PLR increases cardiac preload and tests preload responsiveness. The maximum hemodynamic response to PLR occurs within one minute of performing the maneuver.³⁶ The effects of PLR are assessed by the changes in cardiac output or stroke volume after PLR, which are extrapolated from aortic blood flow measured by esophageal Doppler, velocity time integral measured by transthoracic echocardiography, and femoral artery flow measured by arterial Doppler.³⁶ These modalities may provide additional data points in the evaluation of fluid responsiveness but is out of the scope of this review.

Data in mechanically ventilated patients with esophageal Doppler and arterial access demonstrated that an increase in aortic blood flow by 10% with PLR predicted a positive fluid response with sensitivity 97% and specificity 94%.³⁷ However, in the same study, the specificity in spontaneously breathing patients was markedly reduced (46%).^37,38

Another study used a more conventional noninvasive measurement with transthoracic echocardiography to determine whether PLR could predict fluid responsiveness in hemodynamically unstable patients. In this study, a PLR-induced increase in stroke volume greater than or equal to 12.5% predicted an increase in stroke volume by greater than or equal to 15% after fluid administration with specificity 100% and sensitivity 77%.³⁸ This study included patients on mechanical ventilation with active inspiration, patients without mechanical support, and patients with atrial fibrillation, enabling better generalization of results than previous studies.³⁹

  

Bioreactance Technology

Cardiac output measurement using bioreactance technology is an alternative noninvasive method to measure cardiac output using only four surface electrodes. This technology is based on an analysis of relative phase shifts of an oscillating current that occurs when the current traverses the thoracic cavity. The bioreactance device (NICOM, Cheetah Medical, Tel Aviv, Israel) is comprised of a high frequency (75 kHz) sine wave generator and four dual electrode stickers that are used to establish electrical contact with the body. The cardiac output measured by bioreactance correlates well with values measured by thermodilution and pulse contour analysis.⁴⁰ Performing PLR and determining its response using a bioreactance machine may be appropriate in the ED, in the ward, or at the initial presentation to the ICU because it is noninvasive and less labor intensive than other methods. In postoperative cardiac surgery patients, PLR-induced changes in cardiac output measured by bioreactance had sensitivity 88% and specificity 100%.⁴⁰ In hemodynamically unstable patients, the results were more encouraging with a sensitivity of 94% and a specificity of 100% in predicting fluid responsiveness (defined as greater than10% increase in stroke volume index).⁴¹ However, in a group of critically ill patients (83% septic, 10% hypovolemic, and 7% cardiogenic), bioreactance coupled with PLR was unable to measure cardiac index compared with transpulmonary thermodilution, and bioreactance failed to predict fluid responsiveness.⁴² More research on bioreactance technology is needed, and its noninvasive evaluation of critically ill patients who need cardiac output monitoring and fluid therapy.

  

Conclusion

There are many tools available to estimate the volume status and fluid responsiveness of the critically ill patient. One of these tools, CVP measurement, must be used cautiously as an assessment of fluid responsiveness. It is important to understand the limitations of this technology. While other more advanced tools, such as ultrasonography to measure the IVC at the bedside and assess IVC variation or TEE to assess LV diastolic size and contractility during fluid resuscitation, may provide a better diagnostic picture, these tools/devices are not always  available at most community hospitals.

The authors do not recommend placing a CVC simply to measure CVP; however, when a CVC or peripherally inserted central catheter is medically needed for treatment, the catheter can be used to trend CVP since the value of CVP is greatest as a trend to guide resuscitation. Other minimally invasive and noninvasive diagnostic tools currently are available, such as bedside ultrasound, and enable clinicians to assess volume responsiveness using dynamic procedures that challenge the Frank-Starling curve.⁴ These technologies have a useful place in resuscitation but each has its own limitations. With an understanding of the tools available, with their strengths and limitations, physicians can better individualize intravascular volume resuscitation.

 

  

---

Dr Farcy is the chairman of the department of emergency medicine, medical director of intensivists at Mount Sinai Medical Center, Miami Beach, Florida; and clinical assistant professor, Florida International University Medical School, Miami, Florida. Dr Jain is an assistant professor, director of critical care ultrasound, department of emergency medicine at the SUNY Downstate Medical Center, Kings County Hospital Center, Brooklyn, New York. Dr Dalley is the emergency-medicine residency program director at Mount Sinai Medical Center, Miami Beach, Florida.
Dr Scalea holds the Francis X. Kelly professorship in trauma surgery, is the distinguished professor in trauma, and director, program in trauma at the University of Maryland School of Medicine, Baltimore; he is also the physician in chief, shock trauma center, and system chief for critical care services at the University of Maryland Medical System, Baltimore. 

Case

The mother of a 3-year-old boy presented her son to the ED for evaluation after she noticed peeling of the skin in his perianal region. She stated that the peeling had started 1 day prior to presentation. Two days earlier, the mother had brought the same patient to the ED for evaluation of a fever, sore throat, and a slight rash over his face. The boy’s vital signs at the initial presentation were: temperature, 101.8°F; heart rate, 102 beats/minute; and respiratory rate, 28 breaths/minute. Oxygen saturation was 98% on room air.

During this first visit, the mother denied the child having had any fever, chills, headache, sore throat, facial rash, joint pain, or pain on defecation. He had no significant medical history and no known drug allergies. After examination, a throat culture was taken, and the patient was given acetaminophen and discharged home with a diagnosis of viral syndrome.

At the second presentation, physical examination revealed a well-developed child in no distress. The examination was negative except for a 4 x 2 cm area of desquamation present over the perianal region (Figure).

The area of desquamation was dry, mildly erythematous without discharge, and nontender. The patient’s vital signs at this presentation were stable, and he was afebrile. The remaining physical examination findings were normal. The throat culture taken during the first ED presentation was reported as negative. A perianal swab was sent for culture and sensitivity. This was later reported to be positive for group A β-hemolytic streptococci (GABHS), which is sensitive to penicillin. The patient was discharged home in the care of his mother with a prescription of penicillin.  A 10-day follow-up showed complete resolution of the skin rash.

  

Discussion

Perianal streptococcal dermatitis (PSD), which is caused by GABHS, is a frequently overlooked medical entity. Landolt et al¹ investigated the prevalence of PSD at the University Children’s Hospital Basel, Switzerland, from October 2000 to May 2001. In this study, 250 randomly selected patients were studied for signs of PSD by history, examination, and culture, the results of which showed that PSD was frequent in the study cohort. The study further underscored that, to appropriately treat affected patients, signs and symptoms of PSD should be searched for systematically.¹

The rash in this case was most likely the result of scarlet fever with an unusual presentation of PSD; the signs and symptoms of which include perianal erythema, itching, rectal pain, sometimes blood-streaked stools, rectal bleeding, irritation or pruritus, tissue loss and exudation, secondary constipation, and cellulitis. Perianal streptococcal dermatitis has also been described in the adult literature.² As with pediatric cases, PSD in adults is usually caused by GABHS.

Evaluation and Diagnosis

A rapid streptococcal test of suspicious areas can confirm the diagnosis. Fever, sore throat, and arthralgia are rare; however, culture from the perianal region grows GABHS. Titers are usually not elevated in laboratory evaluation. A routine skin culture is an alternative diagnostic aid.

Brilliant² described the bright red color of PSD as a sharply demarcated rash that is caused by GABHS. As previously stated, symptoms include perianal rash, itching, and rectal pain; blood-streaked stools may also be seen in one-third of patients. It primarily occurs in children between 6 months and 10 years of age and is often misdiagnosed and treated inappropriately.³

Prompt diagnosis of GABHS is important. If untreated, it can cause serious systemic infections, especially in elderly and in newborn patients. Treatment with antibiotics resolves the condition in the majority of patients.² In the acute stage, a white pseudomembrane may be present. As the rash becomes more chronic, the perianal eruption may consist of painful fissures, a dry mucoid discharge, or psoriasiform plaques. Perianal dermatitis can also be caused by Staphylococcus aureus or Candida. Confirmation of the diagnosis is accomplished by culturing a moderate-to-heavy growth of GABHS on 5% sheep-blood agar.

Treatment

A 10-day course of oral penicillin produces resolution of the dermatitis and other symptoms in most patients, but a relapse rate as high as 39% has been reported. Other treatment plans include amoxicillin, 40 mg/kg per day, divided into three doses, and/or topical applications of mupirocin 2% three times per day for 10 days. Penicillin, clindamycin phosphate, and erythromycin have also been used.

Although penicillin is generally recommended for treatment of GABHS infection, amoxicillin is often better tolerated in the pediatric population due to its superior palatability. Early antibiotic treatment causes a dramatic and rapid improvement of symptoms. However, according to Olson et al,⁴ PSD initially treated with amoxicillin or penicillin is consistently associated with a high risk of clinical recurrence. Whether treatment with a β-lactamase–resistant agent reduces this risk is uncertain.

 

  

Conclusion

This case represents an unusual presentation of scarlet fever manifesting as perianal dermatitis caused by GABHS. Although more common in the pediatric population, adult cases have been documented in the literature. As this case illustrates, early recognition and treatment with penicillin (or amoxicillin) produces rapid improvement and resolution of symptoms. 

  

---

Dr Nibhanipudi is a professor of clinical emergency medicine at New York Medical College - Metropolitan Hospital Center, New York.

Case

The mother of a 3-year-old boy presented her son to the ED for evaluation after she noticed peeling of the skin in his perianal region. She stated that the peeling had started 1 day prior to presentation. Two days earlier, the mother had brought the same patient to the ED for evaluation of a fever, sore throat, and a slight rash over his face. The boy’s vital signs at the initial presentation were: temperature, 101.8°F; heart rate, 102 beats/minute; and respiratory rate, 28 breaths/minute. Oxygen saturation was 98% on room air.

During this first visit, the mother denied the child having had any fever, chills, headache, sore throat, facial rash, joint pain, or pain on defecation. He had no significant medical history and no known drug allergies. After examination, a throat culture was taken, and the patient was given acetaminophen and discharged home with a diagnosis of viral syndrome.

At the second presentation, physical examination revealed a well-developed child in no distress. The examination was negative except for a 4 x 2 cm area of desquamation present over the perianal region (Figure).

The area of desquamation was dry, mildly erythematous without discharge, and nontender. The patient’s vital signs at this presentation were stable, and he was afebrile. The remaining physical examination findings were normal. The throat culture taken during the first ED presentation was reported as negative. A perianal swab was sent for culture and sensitivity. This was later reported to be positive for group A β-hemolytic streptococci (GABHS), which is sensitive to penicillin. The patient was discharged home in the care of his mother with a prescription of penicillin.  A 10-day follow-up showed complete resolution of the skin rash.

  

Discussion

Perianal streptococcal dermatitis (PSD), which is caused by GABHS, is a frequently overlooked medical entity. Landolt et al¹ investigated the prevalence of PSD at the University Children’s Hospital Basel, Switzerland, from October 2000 to May 2001. In this study, 250 randomly selected patients were studied for signs of PSD by history, examination, and culture, the results of which showed that PSD was frequent in the study cohort. The study further underscored that, to appropriately treat affected patients, signs and symptoms of PSD should be searched for systematically.¹

The rash in this case was most likely the result of scarlet fever with an unusual presentation of PSD; the signs and symptoms of which include perianal erythema, itching, rectal pain, sometimes blood-streaked stools, rectal bleeding, irritation or pruritus, tissue loss and exudation, secondary constipation, and cellulitis. Perianal streptococcal dermatitis has also been described in the adult literature.² As with pediatric cases, PSD in adults is usually caused by GABHS.

Evaluation and Diagnosis

A rapid streptococcal test of suspicious areas can confirm the diagnosis. Fever, sore throat, and arthralgia are rare; however, culture from the perianal region grows GABHS. Titers are usually not elevated in laboratory evaluation. A routine skin culture is an alternative diagnostic aid.

Brilliant² described the bright red color of PSD as a sharply demarcated rash that is caused by GABHS. As previously stated, symptoms include perianal rash, itching, and rectal pain; blood-streaked stools may also be seen in one-third of patients. It primarily occurs in children between 6 months and 10 years of age and is often misdiagnosed and treated inappropriately.³

Prompt diagnosis of GABHS is important. If untreated, it can cause serious systemic infections, especially in elderly and in newborn patients. Treatment with antibiotics resolves the condition in the majority of patients.² In the acute stage, a white pseudomembrane may be present. As the rash becomes more chronic, the perianal eruption may consist of painful fissures, a dry mucoid discharge, or psoriasiform plaques. Perianal dermatitis can also be caused by Staphylococcus aureus or Candida. Confirmation of the diagnosis is accomplished by culturing a moderate-to-heavy growth of GABHS on 5% sheep-blood agar.

Treatment

A 10-day course of oral penicillin produces resolution of the dermatitis and other symptoms in most patients, but a relapse rate as high as 39% has been reported. Other treatment plans include amoxicillin, 40 mg/kg per day, divided into three doses, and/or topical applications of mupirocin 2% three times per day for 10 days. Penicillin, clindamycin phosphate, and erythromycin have also been used.

Although penicillin is generally recommended for treatment of GABHS infection, amoxicillin is often better tolerated in the pediatric population due to its superior palatability. Early antibiotic treatment causes a dramatic and rapid improvement of symptoms. However, according to Olson et al,⁴ PSD initially treated with amoxicillin or penicillin is consistently associated with a high risk of clinical recurrence. Whether treatment with a β-lactamase–resistant agent reduces this risk is uncertain.

 

  

Conclusion

This case represents an unusual presentation of scarlet fever manifesting as perianal dermatitis caused by GABHS. Although more common in the pediatric population, adult cases have been documented in the literature. As this case illustrates, early recognition and treatment with penicillin (or amoxicillin) produces rapid improvement and resolution of symptoms. 

  

---

Dr Nibhanipudi is a professor of clinical emergency medicine at New York Medical College - Metropolitan Hospital Center, New York.

Case

The mother of a 3-year-old boy presented her son to the ED for evaluation after she noticed peeling of the skin in his perianal region. She stated that the peeling had started 1 day prior to presentation. Two days earlier, the mother had brought the same patient to the ED for evaluation of a fever, sore throat, and a slight rash over his face. The boy’s vital signs at the initial presentation were: temperature, 101.8°F; heart rate, 102 beats/minute; and respiratory rate, 28 breaths/minute. Oxygen saturation was 98% on room air.

During this first visit, the mother denied the child having had any fever, chills, headache, sore throat, facial rash, joint pain, or pain on defecation. He had no significant medical history and no known drug allergies. After examination, a throat culture was taken, and the patient was given acetaminophen and discharged home with a diagnosis of viral syndrome.

At the second presentation, physical examination revealed a well-developed child in no distress. The examination was negative except for a 4 x 2 cm area of desquamation present over the perianal region (Figure).

The area of desquamation was dry, mildly erythematous without discharge, and nontender. The patient’s vital signs at this presentation were stable, and he was afebrile. The remaining physical examination findings were normal. The throat culture taken during the first ED presentation was reported as negative. A perianal swab was sent for culture and sensitivity. This was later reported to be positive for group A β-hemolytic streptococci (GABHS), which is sensitive to penicillin. The patient was discharged home in the care of his mother with a prescription of penicillin.  A 10-day follow-up showed complete resolution of the skin rash.

  

Discussion

Perianal streptococcal dermatitis (PSD), which is caused by GABHS, is a frequently overlooked medical entity. Landolt et al¹ investigated the prevalence of PSD at the University Children’s Hospital Basel, Switzerland, from October 2000 to May 2001. In this study, 250 randomly selected patients were studied for signs of PSD by history, examination, and culture, the results of which showed that PSD was frequent in the study cohort. The study further underscored that, to appropriately treat affected patients, signs and symptoms of PSD should be searched for systematically.¹

The rash in this case was most likely the result of scarlet fever with an unusual presentation of PSD; the signs and symptoms of which include perianal erythema, itching, rectal pain, sometimes blood-streaked stools, rectal bleeding, irritation or pruritus, tissue loss and exudation, secondary constipation, and cellulitis. Perianal streptococcal dermatitis has also been described in the adult literature.² As with pediatric cases, PSD in adults is usually caused by GABHS.

Evaluation and Diagnosis

A rapid streptococcal test of suspicious areas can confirm the diagnosis. Fever, sore throat, and arthralgia are rare; however, culture from the perianal region grows GABHS. Titers are usually not elevated in laboratory evaluation. A routine skin culture is an alternative diagnostic aid.

Brilliant² described the bright red color of PSD as a sharply demarcated rash that is caused by GABHS. As previously stated, symptoms include perianal rash, itching, and rectal pain; blood-streaked stools may also be seen in one-third of patients. It primarily occurs in children between 6 months and 10 years of age and is often misdiagnosed and treated inappropriately.³

Prompt diagnosis of GABHS is important. If untreated, it can cause serious systemic infections, especially in elderly and in newborn patients. Treatment with antibiotics resolves the condition in the majority of patients.² In the acute stage, a white pseudomembrane may be present. As the rash becomes more chronic, the perianal eruption may consist of painful fissures, a dry mucoid discharge, or psoriasiform plaques. Perianal dermatitis can also be caused by Staphylococcus aureus or Candida. Confirmation of the diagnosis is accomplished by culturing a moderate-to-heavy growth of GABHS on 5% sheep-blood agar.

Treatment

A 10-day course of oral penicillin produces resolution of the dermatitis and other symptoms in most patients, but a relapse rate as high as 39% has been reported. Other treatment plans include amoxicillin, 40 mg/kg per day, divided into three doses, and/or topical applications of mupirocin 2% three times per day for 10 days. Penicillin, clindamycin phosphate, and erythromycin have also been used.

Although penicillin is generally recommended for treatment of GABHS infection, amoxicillin is often better tolerated in the pediatric population due to its superior palatability. Early antibiotic treatment causes a dramatic and rapid improvement of symptoms. However, according to Olson et al,⁴ PSD initially treated with amoxicillin or penicillin is consistently associated with a high risk of clinical recurrence. Whether treatment with a β-lactamase–resistant agent reduces this risk is uncertain.

 

  

Conclusion

This case represents an unusual presentation of scarlet fever manifesting as perianal dermatitis caused by GABHS. Although more common in the pediatric population, adult cases have been documented in the literature. As this case illustrates, early recognition and treatment with penicillin (or amoxicillin) produces rapid improvement and resolution of symptoms. 

  

---

Dr Nibhanipudi is a professor of clinical emergency medicine at New York Medical College - Metropolitan Hospital Center, New York.

Some areas of obstetric care are not as clearcut as others in this time of rapid medical evolution. In this Update, we discuss 3 of them:

• management of twin gestations
• management of chronic hypertension in pregnancy
• cell-free DNA screening for fetal aneuploidy.

To our benefit, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have weighed in on important aspects of these areas of obstetric care.

 

Management of chronic hypertension in pregnancy: Reserve therapy for severe hypertension

Cell-free DNA screening for fetal aneuploidy: Strengths and limitations

Some areas of obstetric care are not as clearcut as others in this time of rapid medical evolution. In this Update, we discuss 3 of them:

• management of twin gestations
• management of chronic hypertension in pregnancy
• cell-free DNA screening for fetal aneuploidy.

To our benefit, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have weighed in on important aspects of these areas of obstetric care.

 

Management of chronic hypertension in pregnancy: Reserve therapy for severe hypertension

Cell-free DNA screening for fetal aneuploidy: Strengths and limitations

Some areas of obstetric care are not as clearcut as others in this time of rapid medical evolution. In this Update, we discuss 3 of them:

• management of twin gestations
• management of chronic hypertension in pregnancy
• cell-free DNA screening for fetal aneuploidy.

To our benefit, both the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) have weighed in on important aspects of these areas of obstetric care.

 

Management of chronic hypertension in pregnancy: Reserve therapy for severe hypertension

Cell-free DNA screening for fetal aneuploidy: Strengths and limitations

CASE: Low-risk patient requests cell-free DNA screening
Ms. Smith is a 25-year-old woman (G1P0) presenting at 10 weeks’ gestation for her first prenatal visit. She requests cell-free DNA (cfDNA) screening to test for fetal aneuploidy. You explain that the current recommendations are for traditional screening, and inform her that her insurance may not cover the cost of cfDNA screening. She is anxious to learn the sex of her fetus as early as possible, and indicates that she would like to pursue cfDNA. After further discussion of the pros and cons, you order the test.

Prenatal screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus, regardless of maternal age or family history. There is a broad range of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester.

In addition, cfDNA screening for fetal aneuploidy has been clinically available since 2011 and has seen tremendous uptake, particularly in the high-risk population. Recent data indicate that cfDNA screening likewise has very high sensitivity and specificity for trisomy 21 in the low-risk population.^1,2

Many low-risk patients are asking providers about the pros and cons of cfDNA screening, and the appropriateness of this test as a primary screen, including in low-risk patients, is the focus of this article.

What is cfDNA?
cfDNA consists of small (<200 base pairs) fragments of DNA that are present in the maternal serum. After 10 weeks of gestation, about 10% of the total circulating cfDNA in the maternal serum is derived from the placenta and can therefore be used to test for fetal disorders (FIGURE).³

 

Although cfDNA screening has been reported to be possible for many different types of genetic conditions, such as RhD type and single-gene disorders such as achondroplasia,⁴ most clinical testing is done for fetal chromosomal disorders, including trisomies 13, 18, and 21 and the sex chromosomes. In addition, some laboratories provide testing for other trisomies (16 and 22), as well as some of the microdeletion syndromes (22q11.2, 1p36, Prader Willi syndrome, and others).⁵

Analysis of cfDNA to assess the risk for aneuploidy is done using a number of different approaches; these generally all include next-generation sequencing with advanced bioinformatics analyses.^3,6–9 Although the laboratories use somewhat different techniques, all of them share very high sensitivity and specificity for detection of trisomy 21 (TABLE 1).¹⁰

Sensitivities for trisomy 13 and sex chromosomal abnormalities are somewhat lower, but the specificity is greater than 99% for each condition, meaning that false-positive rates are very low.

The accuracy of cfDNA in identifying chromosomal aneuploidy depends on several factors, including the relative amount of fetal to maternal DNA, the chance that a chromosome abnormality is present (that is, the risk based on maternal age or results of other screening), and other factors such as the presence of twins or a nonviable second fetus, or the presence of placental mosaicism.

Because of these variables, both false-positive and false-negative results can occur, and the test is not diagnostic but rather is considered a screening test. A positive result does not mean that the fetus is definitely affected with aneuploidy.

What are the advantages of cfDNA screening for low-risk patients?
There are several benefits of cfDNA screening versus traditional screening or diagnostic testing, which are the other options available (TABLE 2). For Down syndrome, the detection rate is higher and the false-positive rate is lower than that seen with traditional aneuploidy screening using serum analytes and nuchal translucency ultrasonography.^1,2

 

The test can be done any time after 10 weeks’ gestation without the narrow gestational-age windows required or the need for accurate gestational age determination using traditional screening to accurately interpret results. cfDNA screening involves a single blood test that does not require integration with multiple serum markers or ultrasound findings. Finally, results are generally presented in a simple “Yes” or “No” format that is easy for providers and patients to understand.

 

CASE Continued
Your patient’s results are positive for trisomy 13. Her understanding is that the test is more than 99% accurate, and she interprets this to mean that the chance of trisomy 13 in her fetus is more than 99%. She is distraught and asks about pregnancy termination.

What are the limitations of cfDNA screening?
Similar to other noninvasive screening tests, cfDNA screening does not carry direct risk to the pregnancy. However, there are limitations to this testing. As a result, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recently have stated that traditional screening is the most appropriate option for most women.^11,12

One reason that cfDNA screening may not be the best choice for low-risk women is that Down syndrome is quite uncommon in this group, so cfDNA screening is a very precise test for a rare condition. Traditional multiple marker screening, on the other hand, is more effective at signaling risk for the broad range of adverse perinatal outcomes that can affect a pregnancy, including other structural birth defects, as well as such obstetric complications as preterm birth, preeclampsia, and fetal growth restriction.^13,14

Many women who undergo cfDNA screening are under the impression that they have had a definitive test for all birth defects when, in fact, the coverage of cfDNA for all possible birth defects in a low-risk woman is very limited; her residual risk for a birth defect is little changed by a normal cfDNA result.

The ease of obtaining a blood sample for cfDNA screening is an advantage of the test. However, because it is simple to perform, it often is done with inadequate pretest counseling or consideration. Just because the test is easily obtained does not negate the need for adequate discussion to assure that each woman understands what the test can and cannot measure, and the possible outcomes of testing.

Another perceived benefit of cfDNA screening is the simple presentation of results. While reports vary, they generally provide very dichotomized results. Aneuploidy risk is reported as “Positive” or “Negative,” or as “Detected” or “Not detected.”

Some laboratories report the chance of aneuploidy; this is almost always stated to be more than 99% in patients at increased risk, and less than 1 in 10,000 in patients at low risk.

All of these results suggest a near diagnostic certainty. However, this reporting is oversimplified and misleading, as it does not account for each patient’s prior or background risk. The chance that a positive result is a true positive is very different in a 20-year-old versus a 35-year-old woman, yet the reports do not reflect this difference in positive predictive value (PPV). See TABLE 1.

Accurate interpretation of risk for the individual patient, therefore, requires calculation by the provider; this can be done through an online calculator available through the Perinatal Quality Foundation (www.perina talquality.org).

CASE Continued
You explain to your patient that the chance her fetus has trisomy 13 is far lower than 99%, based in part on the very low prior risk given her age. You calculate the PPV using an online calculator, which estimates that there is only a 7% chance that this is a true positive result.

As mentioned earlier, there has been a tremendously rapid uptake of cfDNA screening. Given wider use by practitioners not as familiar with the complexities of genetic testing and statistical analysis, misunderstanding of the test characteristics carries risks if inappropriate recommendations or decisions are made or actions taken.

Most low-risk patients do not request or desire diagnostic testing. It is important during pretest counseling to explain that cfDNA cannot detect all significant chromosomal aneuploidies. Some serious abnormalities will be undetected; therefore, some women may prefer more comprehensive prenatal testing (TABLE 3).

 

ACOG recommends that diagnostic testing should be available to all pregnant women, regardless of age.¹⁵ In prenatal series, trisomies 13, 18, and 21 make up approximately two-thirds of all clinically significant aneuploidies.^16,17 Given that cfDNA detects only these aneuploidies, the other third will not be identified prenatally in patients who choose cfDNA. Traditional aneuploidy screening has been demonstrated to detect a broader range of these less common but clinically important chromosomal abnormalities.¹⁸

 

In one study of women found to be at increased risk based on traditional multiple marker screening, if cfDNA were chosen instead of diagnostic testing, 17% of the aneuploidies present in this group would not have been detected.¹⁸ Of all high-risk women in this study, 2%, or 1 in 50, had a chromosomal abnormality detectable by amniocentesis but not with cfDNA.

Successful tests require adequate placental DNA
Accurate interpretation of cfDNA screening also requires that an adequate quantity of placental DNA be present; this is often referred to as the “fetal fraction.” In some cases, the placental DNA volume is too low for accurate analysis, particularly in obese patients and women with specific chromosomal abnormalities.

Some laboratories measure this and do not report a result if the fetal fraction is below a specific cut-off, typically about 4%. Other laboratories do not measure or exclude cases with too little fetal DNA, raising concern that this could result in missing cases of aneuploidy. It has been noted that a placental DNA fraction of less than 8% is associated with less accurate test results, even if results are returned.⁸

Low fetal fraction also has been associated with maternal obesity, and in one study cfDNA failed to provide a result in 20% of women weighing more than 250 lb and 50% of women weighing more than 350 lb.¹⁹ Therefore, cfDNA is not the best option for obese women (TABLE 4).

 

While the free fraction is relatively constant from 10 to 22 weeks’ gestation, it is lower earlier than 10 weeks’ gestation and less likely to provide a result. For this reason, the test should not be attempted before 10 weeks’ gestation.

Recent evidence indicates that low fetal DNA fraction is associated with some chromosome abnormalities. Given this association, women with failed cfDNA results should be counseled and offered appropriate follow-up. As the association appears to be greater for trisomies 13 and 18, and triploidy, a careful ultrasound is likely to detect abnormalities in many such cases. However, it also is appropriate to offer the option of diagnostic testing, given the very high risk.

A repeat cfDNA test will be successful in some cases. Whether the patient chooses to attempt cfDNA again may depend in part on maternal body mass index (BMI), as well as gestational age—a patient at a more advanced gestation may not wish to delay obtaining definitive information given the high risk.

cfDNA screening has a low false-positive rate
One of the greatest benefits of cfDNA screening is a lower false-positive rate than is reported with traditional screening. However, when “no results” cases are also considered, the percentage of patients who require follow-up after cfDNA is close to that of traditional screening.

The chance of test failure is reported to be 0.9% to 8.1%,^7,9,10 and varies in part by whether the laboratory measures fetal fraction and requires a minimum concentration.

A recent meta-analysis estimated the overall test failure rate at 3%.¹⁰ When comparing cfDNA to traditional screening, if “no results” cases are included with the “screen positive” group, the benefits of cfDNA over traditional screening are much less clear, particularly in a low-risk population.

ACOG: Offer traditional multiple-marker screening first
While multiple marker and cfDNA screening have differing performance characteristics, there are no data to support doing both tests concurrently. In fact, in a recent survey of nearly 200 women presented with different testing scenarios, women found it preferable and more reassuring to have a positive traditional screen followed by normal cfDNA results, rather that discrepant results of the 2 tests done concurrently.²⁰

For many reasons, the approach recommended by ACOG and SMFM is to offer traditional multiple-marker screening first, and cfDNA screening or diagnostic testing as a follow-up for patients that screen positive. In that scenario, the benefits and limitations of diagnostic testing versus follow-up with cfDNA screening should be explained carefully.

 

In all patients who have a positive cfDNA result, diagnostic testing for confirmation should be offered and strongly recommended prior to pregnancy termination if that is considered. Even if a structural abnormality is present and a true positive result is highly likely, karyotyping is important to determine if there may be an inherited translocation putting subsequent pregnancies at higher risk.

Components of pretest counseling
A woman of any age can have a fetus with trisomy or another chromosomal abnormality, and some women prefer diagnostic testing or no testing regardless of age. It is therefore appropriate to offer diagnostic testing, screening, or the option of no testing to all women.

Recent studies have demonstrated that providing well-informed access to all prenatal tests results in more informed choices and no increase in uptake of invasive testing.²² However, the offer of prenatal testing requires discussion of the pros and cons of all test options, including the detection rates of all significant abnormalities, the screen positive rates, and recommended follow-up if an abnormal result is obtained. See TABLE 4.

Cost-effectiveness
Although the detection rate of cfDNA for trisomy 21 is higher than that of traditional screening, the detection rate of traditional screening is also quite high at lower cost. For low-risk women, therefore, traditional screening provides a less expensive alternative to cfDNA. Because aneuploidy is rare in low-risk patients, the residual chance of aneuploidy after a normal traditional screen is very low, and the cost per additional case of Down syndrome detected by cfDNA is very high.

In one study, this was estimated at $3.6 million.²³ These authors suggested that, at present, cfDNA is optimally used as a secondary screen for high-risk women. Other cost analyses also have demonstrated that the most cost-effective strategy is a model in which cfDNA is used as a follow-up test in patients found to be screen positive by traditional screening.^15,24 A recent cost utility analysis compared outcomes of 6 approaches to prenatal screening, including sequential screening, cfDNA screening, nuchal translucency only, and diagnostic testing with microarray (alone, in combination, or in sequence).

The clinical outcomes included fetal abnormalities detected, taking into account all chromosomal abnormalities, as well as failed cfDNA tests. For younger women (<40 yr), traditional sequential screening provided the highest detection of all abnormalities and was the optimal testing strategy, while cfDNA was preferable for women aged 40 or older, given the higher prevalence of trisomy 21.²⁰

Incidental findings
Given that the cfDNA in maternal serum is a mixture of maternal and placental DNA, a number of biologic phenomena can cause a false-positive cfDNA result. In many cases, these false-positives reveal unanticipated or unexpected maternal conditions and information that the woman may have preferred not to know. A few cases of maternal malignancies with chromosomal abnormalities within the tumor have been reported in patients with false-positive cfDNA results.²⁶

These case reports have raised the question about the need for further evaluation for maternal malignancy in women with false-positive results. Maternal genetic disorders also can cause false-positive results, and may lead to unanticipated detection of adult-onset conditions. In some cases, positive results for sex chromosomal aneuploidy can occur in pregnant women who themselves have a sex chromosomal abnormality, often in mosaic form and previously undiagnosed.²⁷

Again, this has led to discussion of the possible health benefit of karyotyping women who have a false-positive cfDNA result to rule out a mosaic chromosomal abnormality in the mother.

At this time, the clinical utility of such investigations is unknown and there are no recommendations regarding appropriate follow-up for such cases.

CASE Resolved
Given the results of her cfDNA screening, your patient opts to undergo diagnostic testing. In that testing, trisomy 13 is ruled out and she goes on to have a healthy daughter.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE: Low-risk patient requests cell-free DNA screening
Ms. Smith is a 25-year-old woman (G1P0) presenting at 10 weeks’ gestation for her first prenatal visit. She requests cell-free DNA (cfDNA) screening to test for fetal aneuploidy. You explain that the current recommendations are for traditional screening, and inform her that her insurance may not cover the cost of cfDNA screening. She is anxious to learn the sex of her fetus as early as possible, and indicates that she would like to pursue cfDNA. After further discussion of the pros and cons, you order the test.

Prenatal screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus, regardless of maternal age or family history. There is a broad range of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester.

In addition, cfDNA screening for fetal aneuploidy has been clinically available since 2011 and has seen tremendous uptake, particularly in the high-risk population. Recent data indicate that cfDNA screening likewise has very high sensitivity and specificity for trisomy 21 in the low-risk population.^1,2

Many low-risk patients are asking providers about the pros and cons of cfDNA screening, and the appropriateness of this test as a primary screen, including in low-risk patients, is the focus of this article.

What is cfDNA?
cfDNA consists of small (<200 base pairs) fragments of DNA that are present in the maternal serum. After 10 weeks of gestation, about 10% of the total circulating cfDNA in the maternal serum is derived from the placenta and can therefore be used to test for fetal disorders (FIGURE).³

 

Although cfDNA screening has been reported to be possible for many different types of genetic conditions, such as RhD type and single-gene disorders such as achondroplasia,⁴ most clinical testing is done for fetal chromosomal disorders, including trisomies 13, 18, and 21 and the sex chromosomes. In addition, some laboratories provide testing for other trisomies (16 and 22), as well as some of the microdeletion syndromes (22q11.2, 1p36, Prader Willi syndrome, and others).⁵

Analysis of cfDNA to assess the risk for aneuploidy is done using a number of different approaches; these generally all include next-generation sequencing with advanced bioinformatics analyses.^3,6–9 Although the laboratories use somewhat different techniques, all of them share very high sensitivity and specificity for detection of trisomy 21 (TABLE 1).¹⁰

Sensitivities for trisomy 13 and sex chromosomal abnormalities are somewhat lower, but the specificity is greater than 99% for each condition, meaning that false-positive rates are very low.

The accuracy of cfDNA in identifying chromosomal aneuploidy depends on several factors, including the relative amount of fetal to maternal DNA, the chance that a chromosome abnormality is present (that is, the risk based on maternal age or results of other screening), and other factors such as the presence of twins or a nonviable second fetus, or the presence of placental mosaicism.

Because of these variables, both false-positive and false-negative results can occur, and the test is not diagnostic but rather is considered a screening test. A positive result does not mean that the fetus is definitely affected with aneuploidy.

What are the advantages of cfDNA screening for low-risk patients?
There are several benefits of cfDNA screening versus traditional screening or diagnostic testing, which are the other options available (TABLE 2). For Down syndrome, the detection rate is higher and the false-positive rate is lower than that seen with traditional aneuploidy screening using serum analytes and nuchal translucency ultrasonography.^1,2

 

The test can be done any time after 10 weeks’ gestation without the narrow gestational-age windows required or the need for accurate gestational age determination using traditional screening to accurately interpret results. cfDNA screening involves a single blood test that does not require integration with multiple serum markers or ultrasound findings. Finally, results are generally presented in a simple “Yes” or “No” format that is easy for providers and patients to understand.

 

CASE Continued
Your patient’s results are positive for trisomy 13. Her understanding is that the test is more than 99% accurate, and she interprets this to mean that the chance of trisomy 13 in her fetus is more than 99%. She is distraught and asks about pregnancy termination.

What are the limitations of cfDNA screening?
Similar to other noninvasive screening tests, cfDNA screening does not carry direct risk to the pregnancy. However, there are limitations to this testing. As a result, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recently have stated that traditional screening is the most appropriate option for most women.^11,12

One reason that cfDNA screening may not be the best choice for low-risk women is that Down syndrome is quite uncommon in this group, so cfDNA screening is a very precise test for a rare condition. Traditional multiple marker screening, on the other hand, is more effective at signaling risk for the broad range of adverse perinatal outcomes that can affect a pregnancy, including other structural birth defects, as well as such obstetric complications as preterm birth, preeclampsia, and fetal growth restriction.^13,14

Many women who undergo cfDNA screening are under the impression that they have had a definitive test for all birth defects when, in fact, the coverage of cfDNA for all possible birth defects in a low-risk woman is very limited; her residual risk for a birth defect is little changed by a normal cfDNA result.

The ease of obtaining a blood sample for cfDNA screening is an advantage of the test. However, because it is simple to perform, it often is done with inadequate pretest counseling or consideration. Just because the test is easily obtained does not negate the need for adequate discussion to assure that each woman understands what the test can and cannot measure, and the possible outcomes of testing.

Another perceived benefit of cfDNA screening is the simple presentation of results. While reports vary, they generally provide very dichotomized results. Aneuploidy risk is reported as “Positive” or “Negative,” or as “Detected” or “Not detected.”

Some laboratories report the chance of aneuploidy; this is almost always stated to be more than 99% in patients at increased risk, and less than 1 in 10,000 in patients at low risk.

All of these results suggest a near diagnostic certainty. However, this reporting is oversimplified and misleading, as it does not account for each patient’s prior or background risk. The chance that a positive result is a true positive is very different in a 20-year-old versus a 35-year-old woman, yet the reports do not reflect this difference in positive predictive value (PPV). See TABLE 1.

Accurate interpretation of risk for the individual patient, therefore, requires calculation by the provider; this can be done through an online calculator available through the Perinatal Quality Foundation (www.perina talquality.org).

CASE Continued
You explain to your patient that the chance her fetus has trisomy 13 is far lower than 99%, based in part on the very low prior risk given her age. You calculate the PPV using an online calculator, which estimates that there is only a 7% chance that this is a true positive result.

As mentioned earlier, there has been a tremendously rapid uptake of cfDNA screening. Given wider use by practitioners not as familiar with the complexities of genetic testing and statistical analysis, misunderstanding of the test characteristics carries risks if inappropriate recommendations or decisions are made or actions taken.

Most low-risk patients do not request or desire diagnostic testing. It is important during pretest counseling to explain that cfDNA cannot detect all significant chromosomal aneuploidies. Some serious abnormalities will be undetected; therefore, some women may prefer more comprehensive prenatal testing (TABLE 3).

 

ACOG recommends that diagnostic testing should be available to all pregnant women, regardless of age.¹⁵ In prenatal series, trisomies 13, 18, and 21 make up approximately two-thirds of all clinically significant aneuploidies.^16,17 Given that cfDNA detects only these aneuploidies, the other third will not be identified prenatally in patients who choose cfDNA. Traditional aneuploidy screening has been demonstrated to detect a broader range of these less common but clinically important chromosomal abnormalities.¹⁸

 

In one study of women found to be at increased risk based on traditional multiple marker screening, if cfDNA were chosen instead of diagnostic testing, 17% of the aneuploidies present in this group would not have been detected.¹⁸ Of all high-risk women in this study, 2%, or 1 in 50, had a chromosomal abnormality detectable by amniocentesis but not with cfDNA.

Successful tests require adequate placental DNA
Accurate interpretation of cfDNA screening also requires that an adequate quantity of placental DNA be present; this is often referred to as the “fetal fraction.” In some cases, the placental DNA volume is too low for accurate analysis, particularly in obese patients and women with specific chromosomal abnormalities.

Some laboratories measure this and do not report a result if the fetal fraction is below a specific cut-off, typically about 4%. Other laboratories do not measure or exclude cases with too little fetal DNA, raising concern that this could result in missing cases of aneuploidy. It has been noted that a placental DNA fraction of less than 8% is associated with less accurate test results, even if results are returned.⁸

Low fetal fraction also has been associated with maternal obesity, and in one study cfDNA failed to provide a result in 20% of women weighing more than 250 lb and 50% of women weighing more than 350 lb.¹⁹ Therefore, cfDNA is not the best option for obese women (TABLE 4).

 

While the free fraction is relatively constant from 10 to 22 weeks’ gestation, it is lower earlier than 10 weeks’ gestation and less likely to provide a result. For this reason, the test should not be attempted before 10 weeks’ gestation.

Recent evidence indicates that low fetal DNA fraction is associated with some chromosome abnormalities. Given this association, women with failed cfDNA results should be counseled and offered appropriate follow-up. As the association appears to be greater for trisomies 13 and 18, and triploidy, a careful ultrasound is likely to detect abnormalities in many such cases. However, it also is appropriate to offer the option of diagnostic testing, given the very high risk.

A repeat cfDNA test will be successful in some cases. Whether the patient chooses to attempt cfDNA again may depend in part on maternal body mass index (BMI), as well as gestational age—a patient at a more advanced gestation may not wish to delay obtaining definitive information given the high risk.

cfDNA screening has a low false-positive rate
One of the greatest benefits of cfDNA screening is a lower false-positive rate than is reported with traditional screening. However, when “no results” cases are also considered, the percentage of patients who require follow-up after cfDNA is close to that of traditional screening.

The chance of test failure is reported to be 0.9% to 8.1%,^7,9,10 and varies in part by whether the laboratory measures fetal fraction and requires a minimum concentration.

A recent meta-analysis estimated the overall test failure rate at 3%.¹⁰ When comparing cfDNA to traditional screening, if “no results” cases are included with the “screen positive” group, the benefits of cfDNA over traditional screening are much less clear, particularly in a low-risk population.

ACOG: Offer traditional multiple-marker screening first
While multiple marker and cfDNA screening have differing performance characteristics, there are no data to support doing both tests concurrently. In fact, in a recent survey of nearly 200 women presented with different testing scenarios, women found it preferable and more reassuring to have a positive traditional screen followed by normal cfDNA results, rather that discrepant results of the 2 tests done concurrently.²⁰

For many reasons, the approach recommended by ACOG and SMFM is to offer traditional multiple-marker screening first, and cfDNA screening or diagnostic testing as a follow-up for patients that screen positive. In that scenario, the benefits and limitations of diagnostic testing versus follow-up with cfDNA screening should be explained carefully.

 

In all patients who have a positive cfDNA result, diagnostic testing for confirmation should be offered and strongly recommended prior to pregnancy termination if that is considered. Even if a structural abnormality is present and a true positive result is highly likely, karyotyping is important to determine if there may be an inherited translocation putting subsequent pregnancies at higher risk.

Components of pretest counseling
A woman of any age can have a fetus with trisomy or another chromosomal abnormality, and some women prefer diagnostic testing or no testing regardless of age. It is therefore appropriate to offer diagnostic testing, screening, or the option of no testing to all women.

Recent studies have demonstrated that providing well-informed access to all prenatal tests results in more informed choices and no increase in uptake of invasive testing.²² However, the offer of prenatal testing requires discussion of the pros and cons of all test options, including the detection rates of all significant abnormalities, the screen positive rates, and recommended follow-up if an abnormal result is obtained. See TABLE 4.

Cost-effectiveness
Although the detection rate of cfDNA for trisomy 21 is higher than that of traditional screening, the detection rate of traditional screening is also quite high at lower cost. For low-risk women, therefore, traditional screening provides a less expensive alternative to cfDNA. Because aneuploidy is rare in low-risk patients, the residual chance of aneuploidy after a normal traditional screen is very low, and the cost per additional case of Down syndrome detected by cfDNA is very high.

In one study, this was estimated at $3.6 million.²³ These authors suggested that, at present, cfDNA is optimally used as a secondary screen for high-risk women. Other cost analyses also have demonstrated that the most cost-effective strategy is a model in which cfDNA is used as a follow-up test in patients found to be screen positive by traditional screening.^15,24 A recent cost utility analysis compared outcomes of 6 approaches to prenatal screening, including sequential screening, cfDNA screening, nuchal translucency only, and diagnostic testing with microarray (alone, in combination, or in sequence).

The clinical outcomes included fetal abnormalities detected, taking into account all chromosomal abnormalities, as well as failed cfDNA tests. For younger women (<40 yr), traditional sequential screening provided the highest detection of all abnormalities and was the optimal testing strategy, while cfDNA was preferable for women aged 40 or older, given the higher prevalence of trisomy 21.²⁰

Incidental findings
Given that the cfDNA in maternal serum is a mixture of maternal and placental DNA, a number of biologic phenomena can cause a false-positive cfDNA result. In many cases, these false-positives reveal unanticipated or unexpected maternal conditions and information that the woman may have preferred not to know. A few cases of maternal malignancies with chromosomal abnormalities within the tumor have been reported in patients with false-positive cfDNA results.²⁶

These case reports have raised the question about the need for further evaluation for maternal malignancy in women with false-positive results. Maternal genetic disorders also can cause false-positive results, and may lead to unanticipated detection of adult-onset conditions. In some cases, positive results for sex chromosomal aneuploidy can occur in pregnant women who themselves have a sex chromosomal abnormality, often in mosaic form and previously undiagnosed.²⁷

Again, this has led to discussion of the possible health benefit of karyotyping women who have a false-positive cfDNA result to rule out a mosaic chromosomal abnormality in the mother.

At this time, the clinical utility of such investigations is unknown and there are no recommendations regarding appropriate follow-up for such cases.

CASE Resolved
Given the results of her cfDNA screening, your patient opts to undergo diagnostic testing. In that testing, trisomy 13 is ruled out and she goes on to have a healthy daughter.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

CASE: Low-risk patient requests cell-free DNA screening
Ms. Smith is a 25-year-old woman (G1P0) presenting at 10 weeks’ gestation for her first prenatal visit. She requests cell-free DNA (cfDNA) screening to test for fetal aneuploidy. You explain that the current recommendations are for traditional screening, and inform her that her insurance may not cover the cost of cfDNA screening. She is anxious to learn the sex of her fetus as early as possible, and indicates that she would like to pursue cfDNA. After further discussion of the pros and cons, you order the test.

Prenatal screening is currently recommended in pregnancy for a number of genetic disorders, chromosomal aneuploidy, and structural birth defects in the fetus, regardless of maternal age or family history. There is a broad range of sonographic and maternal serum-based options available for carrying out aneuploidy risk assessment in the first and/or second trimester.

In addition, cfDNA screening for fetal aneuploidy has been clinically available since 2011 and has seen tremendous uptake, particularly in the high-risk population. Recent data indicate that cfDNA screening likewise has very high sensitivity and specificity for trisomy 21 in the low-risk population.^1,2

Many low-risk patients are asking providers about the pros and cons of cfDNA screening, and the appropriateness of this test as a primary screen, including in low-risk patients, is the focus of this article.

What is cfDNA?
cfDNA consists of small (<200 base pairs) fragments of DNA that are present in the maternal serum. After 10 weeks of gestation, about 10% of the total circulating cfDNA in the maternal serum is derived from the placenta and can therefore be used to test for fetal disorders (FIGURE).³

 

Although cfDNA screening has been reported to be possible for many different types of genetic conditions, such as RhD type and single-gene disorders such as achondroplasia,⁴ most clinical testing is done for fetal chromosomal disorders, including trisomies 13, 18, and 21 and the sex chromosomes. In addition, some laboratories provide testing for other trisomies (16 and 22), as well as some of the microdeletion syndromes (22q11.2, 1p36, Prader Willi syndrome, and others).⁵

Analysis of cfDNA to assess the risk for aneuploidy is done using a number of different approaches; these generally all include next-generation sequencing with advanced bioinformatics analyses.^3,6–9 Although the laboratories use somewhat different techniques, all of them share very high sensitivity and specificity for detection of trisomy 21 (TABLE 1).¹⁰

Sensitivities for trisomy 13 and sex chromosomal abnormalities are somewhat lower, but the specificity is greater than 99% for each condition, meaning that false-positive rates are very low.

The accuracy of cfDNA in identifying chromosomal aneuploidy depends on several factors, including the relative amount of fetal to maternal DNA, the chance that a chromosome abnormality is present (that is, the risk based on maternal age or results of other screening), and other factors such as the presence of twins or a nonviable second fetus, or the presence of placental mosaicism.

Because of these variables, both false-positive and false-negative results can occur, and the test is not diagnostic but rather is considered a screening test. A positive result does not mean that the fetus is definitely affected with aneuploidy.

What are the advantages of cfDNA screening for low-risk patients?
There are several benefits of cfDNA screening versus traditional screening or diagnostic testing, which are the other options available (TABLE 2). For Down syndrome, the detection rate is higher and the false-positive rate is lower than that seen with traditional aneuploidy screening using serum analytes and nuchal translucency ultrasonography.^1,2

 

The test can be done any time after 10 weeks’ gestation without the narrow gestational-age windows required or the need for accurate gestational age determination using traditional screening to accurately interpret results. cfDNA screening involves a single blood test that does not require integration with multiple serum markers or ultrasound findings. Finally, results are generally presented in a simple “Yes” or “No” format that is easy for providers and patients to understand.

 

CASE Continued
Your patient’s results are positive for trisomy 13. Her understanding is that the test is more than 99% accurate, and she interprets this to mean that the chance of trisomy 13 in her fetus is more than 99%. She is distraught and asks about pregnancy termination.

What are the limitations of cfDNA screening?
Similar to other noninvasive screening tests, cfDNA screening does not carry direct risk to the pregnancy. However, there are limitations to this testing. As a result, the American College of Obstetricians and Gynecologists (ACOG) and the Society for Maternal-Fetal Medicine (SMFM) recently have stated that traditional screening is the most appropriate option for most women.^11,12

One reason that cfDNA screening may not be the best choice for low-risk women is that Down syndrome is quite uncommon in this group, so cfDNA screening is a very precise test for a rare condition. Traditional multiple marker screening, on the other hand, is more effective at signaling risk for the broad range of adverse perinatal outcomes that can affect a pregnancy, including other structural birth defects, as well as such obstetric complications as preterm birth, preeclampsia, and fetal growth restriction.^13,14

Many women who undergo cfDNA screening are under the impression that they have had a definitive test for all birth defects when, in fact, the coverage of cfDNA for all possible birth defects in a low-risk woman is very limited; her residual risk for a birth defect is little changed by a normal cfDNA result.

The ease of obtaining a blood sample for cfDNA screening is an advantage of the test. However, because it is simple to perform, it often is done with inadequate pretest counseling or consideration. Just because the test is easily obtained does not negate the need for adequate discussion to assure that each woman understands what the test can and cannot measure, and the possible outcomes of testing.

Another perceived benefit of cfDNA screening is the simple presentation of results. While reports vary, they generally provide very dichotomized results. Aneuploidy risk is reported as “Positive” or “Negative,” or as “Detected” or “Not detected.”

Some laboratories report the chance of aneuploidy; this is almost always stated to be more than 99% in patients at increased risk, and less than 1 in 10,000 in patients at low risk.

All of these results suggest a near diagnostic certainty. However, this reporting is oversimplified and misleading, as it does not account for each patient’s prior or background risk. The chance that a positive result is a true positive is very different in a 20-year-old versus a 35-year-old woman, yet the reports do not reflect this difference in positive predictive value (PPV). See TABLE 1.

Accurate interpretation of risk for the individual patient, therefore, requires calculation by the provider; this can be done through an online calculator available through the Perinatal Quality Foundation (www.perina talquality.org).

CASE Continued
You explain to your patient that the chance her fetus has trisomy 13 is far lower than 99%, based in part on the very low prior risk given her age. You calculate the PPV using an online calculator, which estimates that there is only a 7% chance that this is a true positive result.

As mentioned earlier, there has been a tremendously rapid uptake of cfDNA screening. Given wider use by practitioners not as familiar with the complexities of genetic testing and statistical analysis, misunderstanding of the test characteristics carries risks if inappropriate recommendations or decisions are made or actions taken.

Most low-risk patients do not request or desire diagnostic testing. It is important during pretest counseling to explain that cfDNA cannot detect all significant chromosomal aneuploidies. Some serious abnormalities will be undetected; therefore, some women may prefer more comprehensive prenatal testing (TABLE 3).

 

ACOG recommends that diagnostic testing should be available to all pregnant women, regardless of age.¹⁵ In prenatal series, trisomies 13, 18, and 21 make up approximately two-thirds of all clinically significant aneuploidies.^16,17 Given that cfDNA detects only these aneuploidies, the other third will not be identified prenatally in patients who choose cfDNA. Traditional aneuploidy screening has been demonstrated to detect a broader range of these less common but clinically important chromosomal abnormalities.¹⁸

 

In one study of women found to be at increased risk based on traditional multiple marker screening, if cfDNA were chosen instead of diagnostic testing, 17% of the aneuploidies present in this group would not have been detected.¹⁸ Of all high-risk women in this study, 2%, or 1 in 50, had a chromosomal abnormality detectable by amniocentesis but not with cfDNA.

Successful tests require adequate placental DNA
Accurate interpretation of cfDNA screening also requires that an adequate quantity of placental DNA be present; this is often referred to as the “fetal fraction.” In some cases, the placental DNA volume is too low for accurate analysis, particularly in obese patients and women with specific chromosomal abnormalities.

Some laboratories measure this and do not report a result if the fetal fraction is below a specific cut-off, typically about 4%. Other laboratories do not measure or exclude cases with too little fetal DNA, raising concern that this could result in missing cases of aneuploidy. It has been noted that a placental DNA fraction of less than 8% is associated with less accurate test results, even if results are returned.⁸

Low fetal fraction also has been associated with maternal obesity, and in one study cfDNA failed to provide a result in 20% of women weighing more than 250 lb and 50% of women weighing more than 350 lb.¹⁹ Therefore, cfDNA is not the best option for obese women (TABLE 4).

 

While the free fraction is relatively constant from 10 to 22 weeks’ gestation, it is lower earlier than 10 weeks’ gestation and less likely to provide a result. For this reason, the test should not be attempted before 10 weeks’ gestation.

Recent evidence indicates that low fetal DNA fraction is associated with some chromosome abnormalities. Given this association, women with failed cfDNA results should be counseled and offered appropriate follow-up. As the association appears to be greater for trisomies 13 and 18, and triploidy, a careful ultrasound is likely to detect abnormalities in many such cases. However, it also is appropriate to offer the option of diagnostic testing, given the very high risk.

A repeat cfDNA test will be successful in some cases. Whether the patient chooses to attempt cfDNA again may depend in part on maternal body mass index (BMI), as well as gestational age—a patient at a more advanced gestation may not wish to delay obtaining definitive information given the high risk.

cfDNA screening has a low false-positive rate
One of the greatest benefits of cfDNA screening is a lower false-positive rate than is reported with traditional screening. However, when “no results” cases are also considered, the percentage of patients who require follow-up after cfDNA is close to that of traditional screening.

The chance of test failure is reported to be 0.9% to 8.1%,^7,9,10 and varies in part by whether the laboratory measures fetal fraction and requires a minimum concentration.

A recent meta-analysis estimated the overall test failure rate at 3%.¹⁰ When comparing cfDNA to traditional screening, if “no results” cases are included with the “screen positive” group, the benefits of cfDNA over traditional screening are much less clear, particularly in a low-risk population.

ACOG: Offer traditional multiple-marker screening first
While multiple marker and cfDNA screening have differing performance characteristics, there are no data to support doing both tests concurrently. In fact, in a recent survey of nearly 200 women presented with different testing scenarios, women found it preferable and more reassuring to have a positive traditional screen followed by normal cfDNA results, rather that discrepant results of the 2 tests done concurrently.²⁰

For many reasons, the approach recommended by ACOG and SMFM is to offer traditional multiple-marker screening first, and cfDNA screening or diagnostic testing as a follow-up for patients that screen positive. In that scenario, the benefits and limitations of diagnostic testing versus follow-up with cfDNA screening should be explained carefully.

 

In all patients who have a positive cfDNA result, diagnostic testing for confirmation should be offered and strongly recommended prior to pregnancy termination if that is considered. Even if a structural abnormality is present and a true positive result is highly likely, karyotyping is important to determine if there may be an inherited translocation putting subsequent pregnancies at higher risk.

Components of pretest counseling
A woman of any age can have a fetus with trisomy or another chromosomal abnormality, and some women prefer diagnostic testing or no testing regardless of age. It is therefore appropriate to offer diagnostic testing, screening, or the option of no testing to all women.

Recent studies have demonstrated that providing well-informed access to all prenatal tests results in more informed choices and no increase in uptake of invasive testing.²² However, the offer of prenatal testing requires discussion of the pros and cons of all test options, including the detection rates of all significant abnormalities, the screen positive rates, and recommended follow-up if an abnormal result is obtained. See TABLE 4.

Cost-effectiveness
Although the detection rate of cfDNA for trisomy 21 is higher than that of traditional screening, the detection rate of traditional screening is also quite high at lower cost. For low-risk women, therefore, traditional screening provides a less expensive alternative to cfDNA. Because aneuploidy is rare in low-risk patients, the residual chance of aneuploidy after a normal traditional screen is very low, and the cost per additional case of Down syndrome detected by cfDNA is very high.

In one study, this was estimated at $3.6 million.²³ These authors suggested that, at present, cfDNA is optimally used as a secondary screen for high-risk women. Other cost analyses also have demonstrated that the most cost-effective strategy is a model in which cfDNA is used as a follow-up test in patients found to be screen positive by traditional screening.^15,24 A recent cost utility analysis compared outcomes of 6 approaches to prenatal screening, including sequential screening, cfDNA screening, nuchal translucency only, and diagnostic testing with microarray (alone, in combination, or in sequence).

The clinical outcomes included fetal abnormalities detected, taking into account all chromosomal abnormalities, as well as failed cfDNA tests. For younger women (<40 yr), traditional sequential screening provided the highest detection of all abnormalities and was the optimal testing strategy, while cfDNA was preferable for women aged 40 or older, given the higher prevalence of trisomy 21.²⁰

Incidental findings
Given that the cfDNA in maternal serum is a mixture of maternal and placental DNA, a number of biologic phenomena can cause a false-positive cfDNA result. In many cases, these false-positives reveal unanticipated or unexpected maternal conditions and information that the woman may have preferred not to know. A few cases of maternal malignancies with chromosomal abnormalities within the tumor have been reported in patients with false-positive cfDNA results.²⁶

These case reports have raised the question about the need for further evaluation for maternal malignancy in women with false-positive results. Maternal genetic disorders also can cause false-positive results, and may lead to unanticipated detection of adult-onset conditions. In some cases, positive results for sex chromosomal aneuploidy can occur in pregnant women who themselves have a sex chromosomal abnormality, often in mosaic form and previously undiagnosed.²⁷

Again, this has led to discussion of the possible health benefit of karyotyping women who have a false-positive cfDNA result to rule out a mosaic chromosomal abnormality in the mother.

At this time, the clinical utility of such investigations is unknown and there are no recommendations regarding appropriate follow-up for such cases.

CASE Resolved
Given the results of her cfDNA screening, your patient opts to undergo diagnostic testing. In that testing, trisomy 13 is ruled out and she goes on to have a healthy daughter.

Share your thoughts on this article! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

 

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

 

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

 

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

 

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

Despite advances in human immunodeficiency virus (HIV) screening and treatment over the last 30 years, HIV remains a public health concern. In the United States, after an initial decline, total HIV incidence has failed to significantly decrease in the last 25 years. More than 1.2 million people are living with HIV in the United States, and 12.8% of them (156,300) are unaware they are affected.¹ Of those diagnosed with HIV, only 30% are receiving treatment and are virally suppressed.² Due to structural inequalities and psychosocial factors, African American and Latino patients remain disproportionately affected.³ The incidence of HIV infection among men who have sex with men has increased, and the incidence of HIV infection among people who inject drugs has plateaued after years of progressive decline.⁴

HIV prevention strategies are highly effective, but in general are underutilized. This article reviews 3 prevention strategies that can be administered by family physicians: HIV screening, pre-exposure prophylaxis (PrEP), and harm reduction.

Who and how to screen for HIV

Early identification of HIV infection generally leads to reduced transmission because diagnosis is associated with decreases in risky behavior.^5,6 In addition, antiretroviral therapy (ART) is more effective when initiated early, before the development of advanced immunosuppression.^7-9

The “window period” of acute HIV infection (AHI) is the time from when the virus is transmitted to when markers of infection can be detected. Because this window period is associated with high viral transmission rates, family physicians must be familiar with symptoms of AHI (TABLE 1)^10,11 and associated risk factors (eg, recent condomless sex or sharing of drug injection equipment with someone who is HIV-positive or of unknown HIV status).

Screening for HIV solely based on the presence of risk factors or clinical symptoms is not enough, however. The United States Preventive Services Task Force (USPSTF) recommends screening all pregnant women and individuals ages 15 to 65 for HIV.¹² Screening based solely on risk factors or clinical symptoms frequently leads to missed diagnoses and identification of HIV infection at more advanced stages.^13,14 Both the USPSTF and the Centers for Disease Control and Prevention (CDC) recommend universal opt-out screening (patients are informed that HIV screening will be performed and that they may decline testing) because such screening identifies HIV earlier and is associated with higher testing rates than opt-in screening, which requires explicit written consent and extensive pre-test counseling.

Which test to use. HIV screening with a fourth-generation antigen/antibody combination immunoassay—which detects both HIV p24 antigen and HIV antibodies—provides greater diagnostic accuracy than older tests.¹⁵ These newer tests detect HIV approximately 15 days after initial infection, reducing the window period of AHI.^15,16 If you suspect a patient has AHI, consider early repeat HIV testing with a fourth-generation assay, or initial co-testing with a fourth-generation assay and a nucleic acid amplification test for HIV RNA, which makes it possible to detect infection approximately 5 days earlier than fourth-generation assays.¹⁵

Offer pre-exposure prophylaxis to high-risk patients

PrEP is the use of ART prior to HIV exposure to prevent transmission of the virus. It should be used with conventional risk reduction strategies, such as providing condoms, counseling patients about reducing risky behaviors, supporting medication adherence, and screening for and treating other sexually transmitted infections.

Both the USPSTF and the CDC recommend universal opt-out HIV screening because such screening is associated with higher testing rates than opt-in screening.

The US Food and Drug Administration (FDA) has approved only one medication, Truvada (tenofovir disoproxil fumarate/emtricitabine; TDF/FTC), for use as PrEP. Oral tenofovir-based regimens can effectively prevent HIV transmission,^17-20 and strong adherence is associated with a risk reduction of 90% to 100%.^17-23 The protective effect of oral PrEP is particularly strong in high-risk populations (eg, men who have sex with men, people who inject drugs), where the number needed to treat to prevent one HIV infection ranges from 12 to 100, depending on the patients’ risk profile.^24-26 The CDC and Department of Health and Human Services have issued guidelines for using PrEP in high-risk patients.²⁷ 

Barriers to implementing PrEP. Despite being highly effective, PrEP is not routinely prescribed to high-risk patients; modeling suggests that current use of PrEP is insufficient to significantly impact the incidence of HIV.²⁸ Demand for PrEP is high among target groups,^21,29,30 but patients have expressed concerns about adverse effects³¹ and stigma related to ART, HIV, and being at risk for HIV.^32,33 Young age, lack of social support, low perception of risk, and failure to show up for appointments are also barriers to PrEP use.^28,30,34

 

Some physicians have expressed concern that prescribing PrEP may promote high-risk sexual behavior.³⁵ However, because PrEP is most beneficial in individuals who already engage in high-risk sexual behavior, strategic delivery of PrEP remains an effective risk-reducing strategy.^{17,18,21,26,36,37} Even in instances where PrEP has been associated with higher-risk sexual behavior and higher rates of sexually transmitted infections, it still prevents as much as 100% of new HIV infections.³⁸

Fear of drug resistance also contributes to slow implementation of PrEP. Drug resistance has been observed in clinical trials of PrEP, but it has been exceedingly rare and predominantly limited to patients who had unrecognized AHI when they started PrEP.³⁹ Furthermore, the few cases of drug resistance attributable to PrEP pale in comparison to the large number of estimated HIV infections averted—infections that would require lifelong ART with its own associated risks of drug resistance. By decreasing HIV transmission, PrEP is expected to decrease total drug resistance.⁴⁰

Cost is another obstacle. Truvada costs approximately $1,540 per month.⁴¹ However, analysis has demonstrated that PrEP is cost-effective when targeted to high-risk patients.⁴² Most insurance plans cover PrEP, but often require high deductibles and copays; fortunately, this financial burden for patients can be mitigated or eliminated by co-pay assistance programs. The manufacturer of Truvada offers assistance programs for both insured and uninsured patients who are candidates for PrEP; details are available at http://www.truvada.com/truvada-patient-assistance.

Stigma has historically burdened individuals who seek to protect their sexual health, including HIV-negative individuals who are candidates for PrEP. Stigma surrounding HIV may decrease ART-based HIV prevention in men who have sex with men,⁴³ while increasing high-risk behaviors⁴⁴ and all-cause mortality.⁴⁵

The resources listed in TABLE 2 can help physicians overcome some of the barriers to implementing PrEP.

How to deliver PrEP

Whether HIV specialists or primary care clinicians are best suited to provide PrEP is a subject of debate. HIV specialists are most familiar with ART and routine monitoring of adherence; however, they have less access to HIV-negative patients, who are the target group for PrEP.³⁵ Family physicians tend to work in closer proximity and maintain longitudinal relationships with PrEP target groups, but in general have less experience with ART and evaluating AHI. Some may argue that competing demands may make it impractical to take a detailed sexual history during a primary care visit.⁴⁶ In truth, both HIV specialists and family physicians can be appropriately equipped to provide PrEP.

TABLE 3 outlines the steps necessary to provide a patient with PrEP.⁴⁷ Assessing risk is the initial step; PrEP is beneficial for patients who have one or more risk factors for HIV infection. To be eligible for TDF/FTC, a patient must be HIV-negative, and should be tested for hepatitis B virus (HBV) infection and kidney disease. Because TDF/FTC treats HBV infection, candidates for PrEP who test positive for HBV should be evaluated for treatment of HBV before initiating PrEP. Candidates for PrEP who test negative for HBV infection and immunity should be vaccinated.

Candidates for PrEP should also be screened and monitored for kidney disease. TDF can cause increased serum creatinine due to tubular toxicity. A patient who has an estimated creatinine clearance <60 mL/min should not receive TDF/FTC for PrEP. If a patient’s estimated creatinine clearance falls below 60 mL/min or serum creatinine increases by 0.3 mg/dL above baseline after PrEP is started, TDF/FTC should be discontinued, and the patient should be evaluated for the underlying cause of the kidney disease.²⁷

Before starting PrEP, candidates should be screened for HIV infection and symptoms of AHI. Strongly consider testing for sexually transmitted infections that may increase the risk of HIV transmission, such as syphilis, gonorrhea, or chlamydia.

Strong adherence to pre-exposure prophylaxis for HIV is associated with a risk reduction of 90% to 100%.

Candidates who are eligible for PrEP must be counseled on medication adverse effects, adherence strategies, and symptoms of sexually transmitted infections. To initiate PrEP, candidates may be given a one-month supply of TDF/FTC; adherence, adverse effects, and other risk-reduction strategies are assessed at an office visit 3 to 4 weeks later. Subsequent prescriptions are then dispensed as a 3-month supply, with office visits to monitor PrEP scheduled for at least once every 3 months. During these monitoring visits, evaluate the patient’s HIV status, pregnancy status, adherence, adverse effects, risk-reduction behaviors, and indications for continued PrEP. Every 6 months, renal function and sexually transmitted infection status should be reassessed. 

Reducing risk of harm among patients who inject drugs

Nonsexual transmission of HIV is a route of high infectivity.⁴⁸ It includes transfusion of infected blood, sharing of equipment during injection drug use, and percutaneous needle sticks. Sharing of equipment during injection drug use is estimated to account for 8% of new infections in the United States.⁴

 

Harm reduction is a collection of strategies meant to reduce complications of illicit drug use, including HIV transmission. These strategies include needle and syringe programs that provide injection drug users with sterile equipment, and opioid substitution therapy.

Needle and syringe programs decrease HIV transmission⁴⁹ and risky behaviors related to injection drug use,⁵⁰ but federal funding of such programs is prohibited. Opioid substitution therapy reduces the incidence of HIV,^50,51 injection drug use, sharing of drug preparation and injection equipment, and drug-related behaviors associated with a high risk of HIV transmission.^50,52 However, in the United States, the quality of these programs varies; a study of opioid substitution therapy delivery found that 22.8% of programs provided doses that were too low to be effective.⁵³

In clinical trials of pre-exposure prophylaxis, drug resistance has been rare and mostly limited to those who had unrecognized acute HIV infection.

FDA-approved medications for opioid substitution therapy include sublingual buprenorphine, sublingual buprenorphine/naloxone tablets or strips (Suboxone), and oral methadone. Buprenorphine-based regimens can be provided by appropriately trained primary care clinicians; methadone requires a referral to a narcotic treatment program. TABLE 4 provides training and support resources for physicians who want to integrate opioid substitution therapy into their clinical practice.

CORRESPONDENCE
Richard Moore II, MD, 250 Smith Church Road, Roanoke Rapids, NC 27870; [email protected].

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

 

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

 

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

 

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

 

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

 

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

 

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

 

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

 

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

 

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

 

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

 

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

 

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

 

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

 

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

TALKING OUT CHILDHOOD OBESITY
Resnicow K, McMaster F, Bocian A, et al. Motivational interviewing and dietary counseling for obesity in primary care: an RCT. Pediatrics. 2015;135(4):649-657.

Counseling parents of overweight children using motivational interviewing from both health care providers and registered dietitians can significantly improve BMI, according to a study of 42 practices in the Pediatric Research in Office Settings Network of the American Academy of Pediatrics.

Researchers randomly assigned parents of overweight children, ages 2 through 8, to one of three groups: (1) usual care, (2) four provider-delivered motivational interviewing sessions over two years, or (3) four provider-delivered motivational interviewing sessions plus six sessions with a registered dietitian over two years. At study end, BMI percentile and change in BMI for the different groups were as follows:

COMMENTARY
The results of this study are exciting. Motivational interviewing is a technique in which the practitioner asks questions of a patient and allows the patient to discover his/her own conclusions about the topic. By so doing, the patient is more engaged in the discussion and is less resistant to input. This technique, with excellent evidence of effectiveness in the area of drug and alcohol abuse, has been shown to facilitate effective behavioral change in many areas and is recommended by the American Heart Association for behavioral change in adults.1,2 This is an exciting paper demonstrating evidence-based efficacy in addressing childhood obesity—a critical health issue—and is worth trying in the office. 

1. Rubak S, Sandbaek A, Lauritzen T, Christensen B. Motivational interviewing: a systematic review and meta-analysis. Br J Gen Pract. 2005;55(513):305-312.
2. Spring B, Ockene JK, Gidding SS, et al; American Heart Association Behavior Change Committee of the Council on Epidemiology and Prevention, Council on Lifestyle and Cardiometabolic Health, Council for High Blood Pressure Research, and Council on Cardiovascular and Stroke Nursing. Better population health through behavior change in adults: a call to action. Circulation. 2013;128(19):2169-2176. doi: 10.1161/01.cir.0000435173.25936.e1. 

Continue for long-acting reversible contraception among teens >>

 

LONG-ACTING REVERSIBLE CONTRACEPTION AMONG TEENS
Romero L, Pazol K, Warner L, et al. Vital signs: trends in use of long-acting reversible contraception among teens aged 15-19 years seeking contraceptive services – United States, 2005-2013. MMWR Morb Mortal Wkly Rep. 2015;64(13):363-369.

Efforts to improve teen access to long-acting reversible contraception (LARC) have increased use of these methods, according to a CDC review of services provided at Title X National Family Planning Program centers. The report found
• LARC rates among teen patients increased from 0.4% in 2005 to 7.2% in 2013.
• In 2013, 2.8% of those seeking contraception used IUDs and 4.3% used implants.
• Among Title X patients, 7.6% of 18- and 19-year-olds used LARC, compared with 6.5% of 15- to 17-year-olds.
• Rates of LARC were lowest in Mississippi (0.7%) and highest in Colorado (25.8%).

COMMENTARY
LARCs, which include IUD and implantable hormonal contraceptive devices, require no effort for adherence on the part of the user; once in place, they are effective without further action. Current CDC guidelines on contraceptive use clearly recommend LARC for teenagers based on the efficacy and safety.¹ LARCs are favored for teenagers because poor compliance has yielded suboptimal effectiveness of oral contraceptives and condoms in teenagers, who often forget to take their birth control pills or don’t use condoms when they should. Many clinicians have been slow to recommend LARCs in teenagers based on safety concerns related to adverse experience with IUDs 20 to 30 years ago. According to CDC guidelines, IUDs and implantable contraceptive devices now have robust safety data, and this article shows that they are being increasingly made available to teenagers who need them.

1. Division of Reproductive Health, National Center for Chronic Disease Prevention and Health Promotion, CDC. US Selected Practice Recommendations for Contraceptive Use, 2013: adapted from the World Health Organization selected practice recommendations for contraceptive use, 2nd edition. MMWR Recomm Rep. 2013;62(RR-05):1-60.

Continue to testing for celiac in pediatric rheumatology patients >>

 

TESTING FOR CELIAC IN PEDIATRIC RHEUMATOLOGY PATIENTS
Sherman Y, Karanicolas R, DiMarco B, et al. Unrecognized celiac disease in children presenting for rheumatology evaluation. Pediatrics. 2015; [Epub ahead of print].

Children presenting for rheumatology evaluation should be screened for celiac disease, according to a review of 2,125 pediatric patients who were screened for celiac as part of the standard initial serologic evaluation.

Researchers identified 36 new cases of celiac disease (2.0% prevalence rate). The most common presenting complaints among these patients were myalgia, arthralgia, and rash. Less frequent complaints included gastrointestinal complaints of abdominal pain, nausea, and diarrhea.

After initiating a gluten-free diet, all of the patients with celiac disease reported improvement or complete resolution of musculoskeletal symptoms.

COMMENTARY
Celiac disease has a prevalence of 0.5% to 1% in the US and can present with a range of symptoms that include diarrhea, abdominal discomfort, and weight loss. In addition to these typical symptoms, celiac disease can cause a wide range of systemic symptoms, including osteopenia, abnormal liver function tests, anemia, neurologic symptoms, and general malaise and fatigue.¹ This study suggests that celiac testing be considered in children presenting with rheumatologic symptoms, including myalgia, arthralgia, and rash.

1. Presutti RJ, Cangemi JR, Cassidy HD, et al. Celiac disease. Am Fam Physician. 2007;76(12):1795-1802, 1809-1810.

Continue for educating parents about antibiotic use >>

 

EDUCATING PARENTS ABOUT ANTIBIOTIC USE
Vaz LE, Kleinman KP, Lakoma MD, et al. Prevalence of parental misconceptions about antibiotic use. Pediatrics. 2015;136:221-231.

Misperceptions about antibiotic use persist and continue to be more prevalent among parents of Medicaid-insured children, according to a study of 1,500 Massachusetts parents.

Investigators examined antibiotic-related knowledge and attitudes among both Medicaid-insured and private-insured parents and found
• Fewer Medicaid parents answered questions correctly, except for one regarding bronchitis.
• Medicaid patients were more likely to request unnecessary antibiotics.
• More parents in 2013 understood that green nasal discharge did not require antibiotics than in 2000.
• Medicaid-insured parents were younger, less likely to be white, and had less education than those commercially insured.

COMMENTARY
Decreasing the unnecessary use of antibiotics for viral infections is an important component of decreasing the development of antibiotic-resistant organisms. An important driver of clinician use of antibiotics is patients’ expectations for antibiotics. This study shows that much work remains to be done in changing patient expectations, which is not surprising to any practicing clinician. This study also suggests that the expectation for antibiotics is greater among those individuals with Medicaid insurance, which suggests that an opportunity exists for Medicaid insurance plans to do targeted patient education on this issue—which should improve patient outcomes, decrease cost from use of unneeded antibiotics, and decrease the development of antibiotic-resistant organisms.

Continue for newborn pulmonary hypertension and maternal antidepressant use >>

 

NEWBORN PULMONARY HYPERTENSION AND MATERNAL ANTIDEPRESSANT USE
Huybrechts KF, Bateman BT, Palmsten K, et al. Antidepressant use late in pregnancy and risk of persistent pulmonary hypertension of the newborn. JAMA. 2015;313(21):2142-2151.

Taking antidepressants during late pregnancy may increase the risk for persistent pulmonary hypertension of the newborn (PPHN), according to a nested cohort study of more than 3.7 million pregnant women in the 2000-2010 Medicaid Analytic eXtract.

Investigators compared offspring of mothers who used selective serotonin reuptake inhibitors (SSRIs) or non-SSRI monotherapy in the last 90 days of pregnancy to those who did not and found 3.4% of women filled at least one prescription for antidepressants late in pregnancy, primarily SSRIs.

Rates and odds ratios (ORs) of PPHN stratified by use and type of antidepressant were as follows:

The study authors note the absolute risk is small, and the increased risk is more modest than previous studies found.

COMMENTARY
Depression affects more than 12% of pregnancies and has important consequences, including increased risk for suicide, preterm birth, poor fetal growth, and impaired fetal and infant development.¹ PPHN is a serious condition that can require intubation and can be fatal in 10% to 20% of cases. This study adds to the conflicting data suggesting that SSRI use in pregnancy can lead to an increase in this rare condition. The decision to use an antidepressant during pregnancy is a difficult one, because depression has serious consequences but so, potentially, does treatment. The treatment of depression during pregnancy requires thoughtful, informed discussion between patient and provider. 

1. Stewart DE. Clinical practice. Depression during pregnancy. N Engl J Med. 2011;365(17):1605-1611. doi:10.1056/NEJMcp1102730.

Continue for new infant vaccine treats 6 diseases >>

 

NEW INFANT VACCINE TREATS 6 DISEASES
Marshall GS, Adams GL, Leonardi ML, et al. Immunogenicity, safety, and tolerability of a hexavalent vaccine in infants. Pediatrics. 2015:136(2):323-332.

The safety and immunogenicity of DTaP5-IPV-Hib-HepB fully liquid investigational hexavalent vaccine are comparable with the analogous licensed component vaccines and provide a new combination vaccine option aligned with the recommended US infant immunization schedule, according to a phase III study of 1,465 participants. Overall, 981 healthy infants were vaccinated in group 1 with the hexavalent vaccine and 484 in group 2 with the analogous licensed component vaccines.

The study found
• Immune responses in group 1 to all antigens contained in the vaccine one month after dose 3 were essentially noninferior to those in group 2.
• Adverse event rates after any dose were similar in both groups.

COMMENTARY
Vaccine administration has led to many diseases, including Haemophilus influenzae type b, polio, and measles, becoming quite rare. As we have recently seen with the resurgence of measles, continued vigilance and high immunization rates are important in ensuring that these diseases remain rare. The development of a hexavalent vaccine is another step in making immunization easier for clinicians to administer and for patients to accept.

Continue for treating infants with bronchiolitis >>

 

TREATING INFANTS WITH BRONCHIOLITIS
Silver AH, Esteban-Cruciani N, Azzarone G, et al. 3% hypertonic saline versus normal saline in inpatient bronchiolitis: a randomized controlled trial. Pediatrics. 2015;136:1036-1043.

Infants hospitalized with bronchiolitis saw no difference in length of stay or seven-day readmission rates when treated with nebulized 3% hypertonic saline (HS) compared with nebulized normal saline (NS), according to a randomized, controlled study of 227 infants who were younger than 12 months when admitted. Patients received either 4 mL nebulized 3% HS (113 infants) or 4 mL 0.9% NS (114 infants) every four hours from enrollment until hospital discharge. Researchers found
• Median length of stay of HS and NS groups was 2.1 days vs 2.1 days, respectively.
• Seven-day readmission rates for HS and NS groups were 4.3% vs 3.1%, respectively.
• Clinical worsening events were similar between groups.

COMMENTARY
Bronchiolitis, the most common lower respiratory tract infection in infants, is usually due to a viral infection, most often respiratory syncytial virus, and can cause disease that ranges in severity from mild to life-threatening. Infants with bronchiolitis typically present with rhinitis, tachypnea, wheezing, and cough, and occasionally crackles and use of accessory muscles. While many medications are used, supportive care and monitoring are the mainstays of therapy. Maintaining pulse above 90% is important, using supplemental oxygen when needed to achieve this. Alpha-adrenergic and beta-adrenergic bronchodilators are often used; though the evidence suggests that they are not usually helpful, they can be tried and continued if they appear to help. Systemic steroids are often used, but they too lack evidence of efficacy.¹ This study shows that hypertonic saline can now join the list of interventions used with evidence of a lack of efficacy.

1. Diagnosis and management of bronchiolitis. Subcommittee on diagnosis and management of bronchiolitis. Pediatrics. 2006;118(4):1774-1793. doi:10.1542/peds.2006-2223.

Continue for azithromycin and preschool children >>

 

AZITHROMYCIN AND PRESCHOOL CHILDREN: CAN ANTIBIOTICS LESSEN ONSET OF SEVERE LRTIs?
Bacharier LB, Guilbert TW, Mauger DT, et al. Early administration of azithromycin and prevention of severe lower respiratory tract illnesses in preschool children with a history of such illnesses: a randomized clinical trial. JAMA. 2015;314(19):2034-2044.

The use of azithromycin early during an apparent respiratory tract illness (RTI) reduced the likelihood of severe lower RTI (LRTI) among young children with a history of recurrent severe LRTI, compared with placebo, according to a study of 607 children ages 12 to 71 months. Participants were randomized in a 1:1 ratio to receive either azithromycin (12 mg/kg/d for 5 d) or matching placebo at the start of an RTI. Researchers found
• A total of 937 treated RTIs were experienced by 443 children, including 92 severe LRTIs (azithromycin group, 35; placebo group, 57).
• Azithromycin significantly reduced the risk for progression to severe LRTI relative to placebo (HR, 0.64).
• Induction of azithromycin-resistant organisms and adverse events were infrequent.

COMMENTARY
Recurrent episodes of severe wheezing with RTI are an important and common occurrence, affecting up to 15% to 20% of children prior to age 6.¹ LRTI was defined in this study as RTI that required the use of additional rescue medication. The current approach to RTI is to try to minimize the use of antibiotics unless an infection is clearly bacterial in origin, and to treat severe LRTI when it occurs. The results of this trial suggest that in children at high risk for severe LRTI, identified by their episodes of recurrent wheezing, early treatment of RTI with azithromycin may decrease the development of severe LRTI by more than 35%—an important result. It is important to recognize that this study does not suggest treating all RTIs with antibiotics, but rather that the use of a macrolide antibiotic may be considered, perhaps, in the select group of children similar to those studied, with a history of recurrent wheezing with previous RTIs.

1. Ly NP, Gold DR, Weiss ST, Celedón JC. Recurrent wheeze in early childhood and asthma among children at risk for atopy. Pediatrics. 2006;117(6):e1132-e1138.

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

 

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

 

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

 

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

 

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

While editing this month’s Renal Consult, I noted the mention of “paired kidney exchange” with particular interest. In 2005, I heard about a relatively new concept: matching two or more incompatible kidney donor-recipient pairs to create compatible matches. After conducting some research and interviewing experts, I wrote an article on paired kidney exchange for our sister publication, Clinician News. In the subsequent decade, the concept of paired exchange has expanded to the point that as many as 70 people have participated in a 35-kidney exchange. —AMH

Last year, almost 27,000 Americans received an organ transplant—a new national record, according to the US Department of Health and Human Services. Donations from living persons reached nearly 7,000, an increase of 2.3% from 2003. But despite these positive numbers, nearly 88,000 people are on the waiting list for an organ, and about 6,200 died last year before one became available.

But in some areas of the country, an innovative program is gaining momentum: paired kidney exchange, which puts together two or more incompatible donor-recipient pairs to create compatible matches. And while it will not close the gap between patients in need and those who receive, experts believe it could help thousands of people each year.

The real struggle is finding more willing donors. But Francis Delmonico, MD, Medical Director, New England Organ Bank, Newton, Massachusetts, says paired exchange is “an adjunct. When it can be of help, it’s helped a number of people already. And as with any of this, it’s a lot of work but it’s a tactic that we ought to try and apply anytime we can.”

“There are about 10,000 people who could be put into a program like this,” says Michael A. Rees, MD, PhD, Associate Professor, Department of Urology, Medical College of Ohio, Toledo. “Once you put them into the program, we would hope that 2,000 to 3,000 per year could be matched up and we could do that many extra kidney transplants a year. And that would certainly help to close the gap.”

Continue for how it works >>

 

HOW IT WORKS
Paired kidney exchange got its start in the US at Johns Hopkins Comprehensive Transplant Center, Baltimore, in 2001. The concept is simple: Recipient A needs a kidney and has a family member or friend, Donor A, who is willing to give. However, testing reveals that Donor A and Recipient A are incompatible. Meanwhile, Recipient B and Donor B find themselves with the same problem. But, it turns out, Donor B could give to Recipient A and Donor A could give to Recipient B. The patients and their donors are approached with the idea of an exchange, and if they agree, two people receive needed organs.

Twenty-two patients have received kidneys through the Johns Hopkins program, according to Robert A. Montgomery, MD, PhD, Director, Incompatible Kidney Transplant Programs (InKTP). Surgeons at Johns Hopkins have also expanded the exchange to three donor-recipient pairs; “triple swap” operations were performed at the hospital in 2003 and 2004.

“Everyone, when they come for an incompatible transplant, is offered the option of a paired exchange, because … if there’s any way to get a compatible kidney, that’s what you try for first,” says Janet Hiller, RN, MSN, Clinical Nurse Specialist, InKTP. “We’ve only had probably two out of a hundred [patients] who have thought, ‘No, I’d rather just get the kidney from my spouse or loved one.’”

“Patients are surprisingly open to this option, and almost all of them … request it when they are initially seen by me,” Montgomery told Clinician News via e-mail. “Some [recipients] have expressed apprehension about not knowing the donor and not being sure they have taken good care of their kidney. The donors have rarely expressed any concerns; they just want their loved one to receive a kidney…. It has universally been a positive experience.”

Ohio’s Rees first heard about paired exchange at a conference in 2001. He returned to his institution and consulted with the living donor coordinator to see if any pairs could be formed from people who had been willing to donate but unable due to blood type or other incompatibility problems. After identifying two pairs (out of 10 possibilities) for whom an exchange might work, Rees brought the patients and donors in for testing. But alas, the match wasn’t quite right.

“It became clear to me that if I really wanted to make this work, I needed a lot more than 10 pairs [to start with],” Rees says. “The numbers—if you try to match up people—go up logarithmically the more pairs that you have. So the chances you have of creating pairs go up exponentially.”

With this realization in mind, Rees set out to find someone willing to write a computer program that could identify potential matches from a larger bank of people pooled from several facilities. After some false starts—no computer programmer would work on the project for academic glory, the only reward Rees could offer—he convinced his father, Alan, to help. The senior Rees’ prototype was the basis for the current system, which links 10 transplant centers in Ohio.

Working with a larger pool of colleagues required numerous teleconference calls to iron out details for the statewide program. Among the questions were, “Are we going to make the donor travel, or are we going to cut the kidney out at home and ship the kidney in a box of ice to the place where it’s going to be transplanted?” he recalls. “And we decided that the donor has to travel.”

The first kidney exchange in the state of Ohio was performed in early November 2004. The third was scheduled for mid-April.

Creating one system to be shared by medical institutions that would normally be competitors took some work. “Trying to get us all to play in the same sandbox was very difficult,” Rees acknowledges. “But we did that; we stuck it out. And we all agreed to come up with something that we all think is a great idea and should help our patients.”

Delmonico, who is also a Professor of Surgery at Harvard Medical School and Visiting Surgeon in the Transplant Unit at Massachusetts General Hospital, Boston, has also seen the gratifying cooperation between medical professionals. “Institutions are competitive in terms of medical care—that’s no mystery,” he says. “But in this instance, the physicians have been simply magnificent in trying to help patients. Innovative programs can be developed and sustained through the kind of collaboration that is going on here.”

The New England paired exchange program, dating back to 2002, is a collaboration involving a dozen hospitals. It started with a paper-and-pen effort (blood type–incompatible patients would be brought to the attention of Delmonico, who would then contact each transplant center, seeking others) but now has its own computer system.

New England also has another variation on the exchange program that is unique to the region, according to Delmonico. “Let’s say I wanted to give to you but I can’t. I’ll give to somebody on the list, and as a result of that donation, you would get a priority for the next available deceased donor kidney in New England,” he explains. “We’ve done that about 20 times now.”

Continue for going national >>

 

GOING NATIONAL
So where does paired exchange go from here? Johns Hopkins’ Montgomery organized a consensus meeting in March to discuss the possibility of creating a national network; Hiller, Rees, and Delmonico attended.

“I think our goal should be to one day have a national program,” Rees says. “But shipping somebody from Toledo down to Cincinnati is a lot easier to sell to a patient than shipping somebody from Toledo to Los Angeles. And the logistics of trying to do that when you have a whole different set of insurance companies … would be a lot more complicated. So, I think the way to begin is to do it on a more regional basis and prove that the concept works, that people can be satisfied with it, and then begin to expand it.”

Delmonico also thinks a national program is essential. “We need to enlarge the possibility of paired donation and exchange,” he says. “It will not happen successfully in a regional system. There aren’t enough patients that can be identified.” Questions to be answered before such a program could exist, Delmonico notes, include where the system will be based and who will administer it.

“There was a lot of agreement—though not total consensus—on the fact that UNOS, the United Network for Organ Sharing, would be the most likely place to ‘house’ and to manage the data,” Hiller reports. “They have all those systems in place already [and] are capable of managing this large database.”

Delmonico, as Vice President of UNOS, points out, “We have no authority to do that yet. Whether or not the country wants us to do that also remains to be determined.” But the UNOS Board of Directors is open to the idea; last year, they endorsed the concept of establishing a national paired exchange program with the understanding that details would have to be worked out over time, according to a UNOS spokesperson.

Another obstacle to widespread paired donation may be perceptions of it in the eyes of the government and critics: Could it be construed as a violation of the 1984 National Organ Transplant Act, which says that an organ should not be transplanted for a “value consideration”? Legal experts have assured Delmonico that paired exchanges can be interpreted as a gift.

“The government is also, properly, not wanting to see this as a slope toward buying and selling organs,” Delmonico says. “And I am adamantly opposed to that. In the instances that we’ve done paired exchange here, that’s not in the mix. That’s not our motivation, nor has it been the motivation of these donors. We wouldn’t do it if we felt that was the case.”

Montgomery says it will take several years to get a national system set up. But the bottom line for transplant surgeons is that a national paired kidney exchange program would do a world of good, two people at a time. “This is clearly what is best for our patients,” Montgomery says.

“The bigger we can get, if we can spread it nationally, the more people it will help,” Rees says. “And so we have to think of a way to do this so that we’re all satisfied that it’s moving forward in a way that will make everyone happy.”

Reprinted from Clinician News. 2005;9(5):cover, 3, 15.

CASE Lauren C, age 35, presents with fatigue, which she says started at least eight months ago and has progressively worsened. The patient, a clerical worker, says she manages to do an adequate job but goes home feeling utterly exhausted each night.

Lauren says she sleeps well, getting more than eight hours of sleep per night on weekends but less than seven hours per night during the week. But no matter how long she sleeps, she never awakens feeling refreshed. Lauren reports that she doesn’t smoke, has no more than four alcoholic drinks per month, and adheres to an “average” diet. She is too tired to exercise.

Lauren is single, with no children. Although she says she has a strong network of family and friends, she increasingly finds she has no energy for socializing. If Lauren were your patient, what would you do?

Fatigue is a common presenting symptom in primary care, accounting for about 5% of adult visits.¹ Defined as a generalized lack of energy, fatigue that persists despite adequate rest or is severe enough to disrupt an individual’s ability to participate in key social and/or occupational activities warrants a thorough investigation.

Because fatigue is a nonspecific symptom that may be linked to a number of medical and psychiatric illnesses or to medications used to treat them, determining the cause can be difficult. In about half of all cases, no specific etiology is found.²This review, which includes the elements of a work-up and management strategies for patients presenting with ongoing fatigue, will help you arrive at the appropriate diagnosis and provide optimal treatment.

CHRONIC FATIGUE: DEFINING THE TERMS
A definition of chronic fatigue syndrome (CFS) was initially published in 1988.³In subsequent years, the term myalgic encephalomyelitis (ME) became popular. Although the terms are sometimes used interchangeably, ME often refers to patients whose condition is thought to have an infectious cause and for whom postexertional malaise is a hallmark symptom.⁴

CDC criteria. While several sets of diagnostic criteria for CFS have been developed, the most widely used is that of the CDC, published in 1994 (see Table 1).^5,6A diagnosis of CFS is made on the basis of exclusion, subjective clinical interpretation, and patient self-report.

When the first two criteria—fatigue not due to ongoing exertion or other medical conditions that has lasted ≥ 6 months and is severe enough to interfere with daily activities—but fewer than four of the CDC’s eight concurrent symptoms (eg, headache, unrefreshing sleep, and postexertion malaise lasting > 24 h) are present, idiopathic fatigue, rather than CFS, is diagnosed.⁶

International Consensus Criteria (ICC). In 2011, the ICC for ME were proposed in an effort to provide more specific diagnostic criteria (see Table 2).⁷The ICC emphasize fatigability, or what the authors identify as “post-exertional neuroimmune exhaustion.”

The ICC have not yet been broadly researched. But an Australian study of patients with chronic fatigue found that those who met the ICC definition were sicker and more homogeneous, with significantly lower scores for physical and social functioning and bodily pain, compared with those who fulfilled the CDC criteria alone.⁸

Continue for common threads of chronic fatigue & neuropsychiatric conditions >>

 

CHRONIC FATIGUE & NEUROPSYCHIATRIC CONDITIONS: COMMON THREADS
Recent research has made it clear that depression, somatization, and CFS share some biological underpinnings. These include biomarkers for inflammation, cell-mediated immune activation—which may be related to the symptoms of fatigue—autonomic dysfunction, and hyperalgesia.⁹Evidence suggests that up to two-thirds of patients with CFS also meet the criteria for a psychiatric disorder.¹⁰The most common psychiatric conditions are major depressive disorder (MDD), affecting an estimated 22% to 32% of those with CFS; anxiety disorder, affecting about 20%; and somatization disorder, affecting about 10%—at least double the incidence of the general population.¹⁰

Others point out, however, that up to half of those with CFS do not have a psychiatric disorder.¹¹A diagnosis of somatization disorder, in particular, depends largely on a subjective interpretation of whether the presenting symptoms have a physical cause.¹⁰

CFS and MDD comorbidity. The most widely studied association between CFS and psychiatric disorders involves MDD. Observational studies have found patients with CFS have a lifetime prevalence of MDD of 65%,^12,13which is higher than that of patients with other chronic diseases. Overlapping symptoms include fatigue, sleep disturbance, poor concentration, and memory problems. However, those with CFS have fewer symptoms related to anhedonia, poor self-esteem, guilt, and suicidal ideation compared with individuals with MDD.^12,13

There are several possible explanations for CFS and MDD comorbidity, which are not necessarily mutually exclusive.¹⁰One theory is that CFS is an atypical form of depression; another holds that the disability associated with CFS leads to depression, as is the case with many other chronic illnesses; and a third points to overlapping pathophysiology.¹⁰

An emerging body of evidence suggests that CFS and MDD have some common oxidative and nitrosative biochemical pathways. Activated by infection, psychologic stress, and immune disorders, they are believed to have damaging free radical and nitric oxide effects at the cellular level.¹⁴The cellular effects can result in fatigue, muscle pain, and flulike malaise.

Cortisol response differs
CFS and MDD might be distinguishable by another pathway—the hypothalamic-pituitary-adrenal (HPA) axis. MDD is classically associated with activation and raised cortisol levels, while CFS is consistently associated with impaired HPA axis functioning and reduced cortisol levels.¹⁰The majority of patients with CFS report symptoms of cognitive decline, with the acquisition of new verbal learning and information-processing speed particularly likely to be impaired.¹⁵

A meta-analysis of 50 studies of patients with CFS showed deficits in attention, memory, and reaction time, but not in fine motor speed, vocabulary, or reasoning.¹⁶Autonomic dysfunction has also been observed, including disordered sympathetic activity. The most frequently observed abnormalities on autonomic testing are postural hypotension, tachycardia syndrome, neurally mediated hypotension, and heart rate variability during tilt table testing.¹⁶

THE LINK BETWEEN INFECTION AND CFS
Several infectious agents have been associated with ME/CFS, including the Epstein-Barr virus (EBV), herpes simplex virus 6, parvovirus, Q fever, and Lyme disease.^8,17,18 Most agents that have been linked to ME/CFS are associated with persistent infection and thus incitement of the immune system.

Numerous observational studies^17,18have documented postinfectious fatigue syndromes after acute viral and bacterial infections and symptoms suggestive of infection, such as fever, myalgias, and respiratory and gastrointestinal distress. In one prospective Australian study,¹⁹investigators identified 253 cases of acute EBV, Ross River virus, and Q fever. Of those 253 patients, 12% went on to develop CFS, with a higher likelihood among those with more severe acute symptoms. No correlation with preexisting psychiatric disorders was found.

Muscle mitochondria studies have demonstrated what appear to be acquired abnormalities in those with CFS.^20,21Signs of increased oxidative stress have been found in both blood and muscle samples from patients with CFS, and longitudinal studies suggest that oxidative stress is greatest during periods of clinical exacerbation.²²Increased lactate levels suggest increased anaerobic metabolism in the central nervous system consistent with mitochondrial dysfunction. Several studies have demonstrated that exercise can precipitate oxidative stress in patients with CFS, in contrast with healthy controls and controls with other chronic illnesses, suggesting a physiologic basis for their postexertional symptoms.¹⁷

Autoinflammatory syndrome induced by adjuvants, a rare syndrome associated with vaccine administration, has been linked to postvaccination adverse events, exposure to silicone implants, Gulf War syndrome (related to multiple vaccinations), and macrophagic myofasciitis. All involve exposure to immune adjuvants and have similar clinical manifestations. The corresponding exposures appear to trigger an autoimmune response in susceptible individuals. The hepatitis B vaccine is most often associated with CFS, with symptoms occurring within 90 days of administration.²³

Continue for the clinical work-up >>

 

THE CLINICAL WORK-UP: PUTTING KNOWLEDGE INTO PRACTICE
Familiarity with potential causes of and connections with ME/CFS will help you ensure that patients who say they’re always tired receive a thorough work-up. Start with a medical history, inquiring directly about medical and psychiatric disorders that may contribute to fatigue (see Table 3).^5,24,25 Include a medication history as well, to help determine whether the fatigue is drug-related (see Table 4).^5,25 

What to ask. Determine the onset, course, duration, daily pattern, and impact of fatigue on the patient’s daily life. Inquire, too, about related symptoms of daytime sleepiness, dyspnea on exertion, generalized weakness, and depressed mood. The prominence of any of these rather than fatigue, per se, point to a diagnosis of a chronic illness other than ME/CFS.

Keep in mind, too, that patients with an organ-based medical illness tend to associate their fatigue with activities that they are unable to complete, such as shopping or light housework. In contrast, those with fatigue that is not organ-based typically say that they’re tired all the time. Their fatigue is not necessarily related to exertion, nor does it improve with rest.²⁶

To address this distinction, take a sleep history, assessing both the quality and quantity of the patient’s sleep to determine how it affects symptoms.²⁷ Consider using a questionnaire designed to help distinguish between sleepiness—and a primary sleep disorder—and fatigue,²⁸ such as the Fatigue Severity Scale of Sleep Disorders (www.healthywomen.org/sites/default/files/FatigueSeverityScale.pdf).

What to rule out. In addition to a medical history, the physical examination should be oriented toward ruling out secondary causes of fatigue. In addition to a system-by-system approach to the differential diagnosis, carefully observe the patient’s general appearance, with attention to his or her level of alertness, grooming, and psychomotor agitation or retardation as possible signs of a psychiatric disorder. To rule out neurologic causes, evaluate muscle bulk, tone, and strength; deep tendon reflexes; and sensory and cranial nerves, as well.²⁹

Lab tests to consider. In most cases of ME/CFS, basic studies—complete blood count with differential, erythrocyte sedimentation rate, blood chemistry, and thyroid-stimulating hormone (TSH) levels—are sufficient. When no medical or psychiatric cause has been found, additional tests may be ordered on a case-by-case basis, although laboratory analysis affects the management of fatigue in less than 5% of such patients.³⁰ Tests to consider include:
• Creatine kinase (for patients who report pain or muscle weakness)
• Pregnancy test (for women of childbearing age)
• Ferritin testing (for young women who might benefit from iron supplementation for levels < 50 ng/mL even if anemia is not present)³¹
• Hepatitis C screening (recommended by the US Preventive Services Task Force for those born between 1945 and 1965)³²
• HIV screening and the purified protein derivative test for tuberculosis (based on patient ­history).

Forego routine testing for other infections
Routine testing for infectious diseases and conditions associated with fatigue, such as EBV or Lyme disease, immune deficiency (eg, immunoglobulins), inflammatory disease (eg, antinuclear antibodies, rheumatoid factor), celiac disease, vitamin D deficiency, vitamin B₁₂ deficiency, or heavy metal toxicity, is unlikely to be helpful.²⁹ Additional testing simply to reassure a worried patient usually does not accomplish that objective.³³

Additional studies, referrals to consider. If you suspect that a patient has a sleep disorder, a referral to a sleep clinic to rule out idiopathic sleep disorders, obstructive sleep apnea, or movement disorders that interfere with sleep may be in order. Spirometry and echocardiography may be helpful for some patients. If you suspect peripheral muscle fatigue, a referral for neuromuscular testing is indicated.

Lauren’s medical history reveals that she also has irritable bowel syndrome, which she manages with diet and OTC medication, as needed for constipation or diarrhea. She denies having any other chronic conditions. Her only other symptoms, she reports, are mild upper back pain after spending long hours at the computer and arthralgias in her left knee and both hands. She admits to being “somewhat depressed” in the last few months but denies the presence of anhedonia.

The patient’s physical examination is normal, and her depression screen does not meet the criteria for MDD. Her metabolic chemistry panel, complete blood count, TSH, and sedimentation rate are all normal, as well.

Continue for symptom management and coping strategies >>

 

SYMPTOM MANAGEMENT AND COPING STRATEGIES
When no specific cause of chronic fatigue is found, the focus shifts from diagnosis to symptom management and coping strategies. This requires engagement with the patient. It is important to acknowledge the existence of his or her symptoms and to reassure the patient that further investigation may be warranted later, should new symptoms emerge. Advise the patient, too, that periods of remission and relapse are likely.

Strategies designed to motivate patient self-management, as well as the formulation of patient-centered treatment plans, have been shown to reduce symptom scores.³⁴ Participation in a support group, as well as frequent follow-up visits with a primary care provider, a behavioral therapist, or both, may help to provide needed psychologic support.

Evidence of the effectiveness of specific therapies for ME/CFS is limited; however, the best-studied approaches are cognitive behavioral therapy (CBT) and graded exercise therapy.³⁵ Exercise should be low intensity, such as walking or cycling for 30 minutes three times a week, with a gradual increase in duration and frequency over a period of weeks to months. Patients with cancer-related fatigue may benefit from yoga, group therapy, and stress management.³⁶

Associated mood and pain symptoms should be treated, as well. Bupropion, which is somewhat stimulating, may be considered as an initial treatment for patients with depression and clinically significant fatigue.

Other potentially beneficial approaches include a healthy diet, avoidance of more than nominal amounts of alcohol, relative avoidance of caffeine (no more than one cup of a caffeinated beverage in the morning), and stress reduction techniques.

Attention to good sleep hygiene may be especially beneficial, including a regular bedtime routine and sleep schedule, and elimination of bedroom light and noise. Pharmacologic treatments for insomnia should be used with caution, if at all.

Lauren receives a referral for CBT and is scheduled for a return visit in four weeks. At the advice of both her primary care provider and the behavioral therapist, she gradually makes several lifestyle changes. She begins going to bed earlier on weeknights to ensure that she sleeps for at least seven hours. She improves her diet, with increasing emphasis on vegetables, fruits, and whole grains. She also starts a walking program, increasing gradually to a total of three hours per week. After four months, she adds a weekly trip to a gym, where she practices resistance training for about 40 minutes.

Lauren also increases her social activities on weekends and recently accepted an invitation to join a book club. Six months from her initial visit, she notes that although she is still more easily fatigued than most people, she has made significant improvement

REFERENCES
1. Nijrolder I, van der Windt DA, van der Horst HE. Prognosis of fatigue and functioning in primary care: a 1-year follow-up study. Ann Fam Med. 2008;6:519-527.
2. Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry. 2008;10:120-128.
3. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-389.
4. Morris G, Maes M. Case definitions and diagnostic criteria for myalgic encephalomyelitis and chronic fatigue syndrome: from clinical consensus to evidence-based case definitions. Neuro Endocrinol Lett. 2013;34:185-199.
5. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.
6. CDC. Chronic fatigue syndrome. www.cdc.gov/cfs/diagnosis/index.html. Accessed December 17, 2015.
7. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327-338.
8. Johnston SC, Brenu EW, Hardcastle S, et al. A comparison of health status in patients meeting alternative definitions for chronic fatigue syndrome/myalgic encephalomyelitis. Health Qual Life Outcomes. 2014;12:64.
9. Anderson VR, Jason LA, Hlavaty LE, et al. A review and meta-synthesis of qualitative studies on myalgic encephalomyelitis/chronic fatigue syndrome. Patient Educ Couns. 2012;86:147-155.
10. Christley Y, Duffy T, Everall IP, et al. The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma. Curr Psychiatry Rep. 2013;15:353.
11. Henningsen P, Zimmermann T, Sattel HH. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528-533.
12. Nater UM, Jones JF, Lin JM, et al. Personality features and personality disorders in chronic fatigue syndrome: a population-based study. Psychother Psychosom. 2010;79:312-318.
13. Taylor RR, Jason LA, Jahn SC. Chronic fatigue and sociodemographic characteristics as predictors of psychiatric disorders in a community-based sample. Psychosom Med. 2003;65:896-901.
14. Leonard B, Maes M. Mechanistic explanations of how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36:764-785.
15. DeLuca J, Christodoulou C, Diamond BJ, et al. Working memory deficits in chronic fatigue syndrome: differentiating between speed and accuracy of information processing. J Int Neuropsychol Soc. 2004;10:101-109.
16. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010;40:1253-1267.
17. Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011;31:325-337.
18. Naess H, Sundal E, Myhr KM, et al. Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo. 2010;24:185-188.
19. Hickie I, Davenport T, Wakefield D, et al; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575.
20. Plioplys AV, Plioplys S. Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome.Neuropsychobiology. 1995;32: 175-181.
21. Vernon SD, Whistler T, Cameron B, et al. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006;6:15.
22. Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010;25:319-323.
23. Rosenblum H, Shoenfeld Y, Amital H. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect Dis Clin North Am. 2011;25:851-863.
24. Vincent A, Brimmer DJ, Whipple MO, et al. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota as estimated using the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87:1145-1152.
25. Goroll AH, Mulley AG. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 7th ed. Morrisville, PA: Wolters Kluwer; 2014.
26. Brown RF, Schutte NS. Direct and indirect relationships between emotional intelligence and subjective fatigue in university students. J Psychosom Res. 2006;60:585-593.
27. Pigeon WR, Sateia MJ, Ferguson RJ. Distinguishing between excessive daytime sleepiness and fatigue: toward improved detection and treatment. J Psychosom Res. 2003;54:61-69.
28. Bailes S, Libman E, Baltzan M, et al. Brief and distinct empirical sleepiness and fatigue scales. J Psychosom Res. 2006;60:605-613.
29. National Collaborating Centre for Primary Care (UK). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London, UK: Royal College of General Practitioners; 2007.
30. Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990;299:313-318.
31. Vaucher P, Druisw PL, Waldvogel S, et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.CMAJ. 2012;184:1247-1254.
32. US Preventive Services Task Force. Hepatitis C: Screening. US Preventive Services Task Force Web site. www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. Accessed December 17, 2015.
33. Rolfe A, Burton C. Reassurance after diagnostic testing with a low pretest probability of serious disease: a systematic review and meta-analysis. JAMA Intern Med. 2013;173:407-416.
34. Smith RC, Lyles JS, Gardiner JC, et al. Primary care clinicians treat patients with medically unexplained symptoms: a randomized controlled trial. J Gen Intern Med. 2006;21:671-677.
35. White PD, Goldsmith KA, Johnson AL, et al; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue (PACE): a randomised trial. Lancet. 2011;377:823-836.
36.  van Weert E, Hoekstra-Weebers J, Otter R, et al. Cancer-related fatigue: predictors and effects of rehabilitation. Oncologist. 2006;11:184-196.

CASE Lauren C, age 35, presents with fatigue, which she says started at least eight months ago and has progressively worsened. The patient, a clerical worker, says she manages to do an adequate job but goes home feeling utterly exhausted each night.

Lauren says she sleeps well, getting more than eight hours of sleep per night on weekends but less than seven hours per night during the week. But no matter how long she sleeps, she never awakens feeling refreshed. Lauren reports that she doesn’t smoke, has no more than four alcoholic drinks per month, and adheres to an “average” diet. She is too tired to exercise.

Lauren is single, with no children. Although she says she has a strong network of family and friends, she increasingly finds she has no energy for socializing. If Lauren were your patient, what would you do?

Fatigue is a common presenting symptom in primary care, accounting for about 5% of adult visits.¹ Defined as a generalized lack of energy, fatigue that persists despite adequate rest or is severe enough to disrupt an individual’s ability to participate in key social and/or occupational activities warrants a thorough investigation.

Because fatigue is a nonspecific symptom that may be linked to a number of medical and psychiatric illnesses or to medications used to treat them, determining the cause can be difficult. In about half of all cases, no specific etiology is found.²This review, which includes the elements of a work-up and management strategies for patients presenting with ongoing fatigue, will help you arrive at the appropriate diagnosis and provide optimal treatment.

CHRONIC FATIGUE: DEFINING THE TERMS
A definition of chronic fatigue syndrome (CFS) was initially published in 1988.³In subsequent years, the term myalgic encephalomyelitis (ME) became popular. Although the terms are sometimes used interchangeably, ME often refers to patients whose condition is thought to have an infectious cause and for whom postexertional malaise is a hallmark symptom.⁴

CDC criteria. While several sets of diagnostic criteria for CFS have been developed, the most widely used is that of the CDC, published in 1994 (see Table 1).^5,6A diagnosis of CFS is made on the basis of exclusion, subjective clinical interpretation, and patient self-report.

When the first two criteria—fatigue not due to ongoing exertion or other medical conditions that has lasted ≥ 6 months and is severe enough to interfere with daily activities—but fewer than four of the CDC’s eight concurrent symptoms (eg, headache, unrefreshing sleep, and postexertion malaise lasting > 24 h) are present, idiopathic fatigue, rather than CFS, is diagnosed.⁶

International Consensus Criteria (ICC). In 2011, the ICC for ME were proposed in an effort to provide more specific diagnostic criteria (see Table 2).⁷The ICC emphasize fatigability, or what the authors identify as “post-exertional neuroimmune exhaustion.”

The ICC have not yet been broadly researched. But an Australian study of patients with chronic fatigue found that those who met the ICC definition were sicker and more homogeneous, with significantly lower scores for physical and social functioning and bodily pain, compared with those who fulfilled the CDC criteria alone.⁸

Continue for common threads of chronic fatigue & neuropsychiatric conditions >>

 

CHRONIC FATIGUE & NEUROPSYCHIATRIC CONDITIONS: COMMON THREADS
Recent research has made it clear that depression, somatization, and CFS share some biological underpinnings. These include biomarkers for inflammation, cell-mediated immune activation—which may be related to the symptoms of fatigue—autonomic dysfunction, and hyperalgesia.⁹Evidence suggests that up to two-thirds of patients with CFS also meet the criteria for a psychiatric disorder.¹⁰The most common psychiatric conditions are major depressive disorder (MDD), affecting an estimated 22% to 32% of those with CFS; anxiety disorder, affecting about 20%; and somatization disorder, affecting about 10%—at least double the incidence of the general population.¹⁰

Others point out, however, that up to half of those with CFS do not have a psychiatric disorder.¹¹A diagnosis of somatization disorder, in particular, depends largely on a subjective interpretation of whether the presenting symptoms have a physical cause.¹⁰

CFS and MDD comorbidity. The most widely studied association between CFS and psychiatric disorders involves MDD. Observational studies have found patients with CFS have a lifetime prevalence of MDD of 65%,^12,13which is higher than that of patients with other chronic diseases. Overlapping symptoms include fatigue, sleep disturbance, poor concentration, and memory problems. However, those with CFS have fewer symptoms related to anhedonia, poor self-esteem, guilt, and suicidal ideation compared with individuals with MDD.^12,13

There are several possible explanations for CFS and MDD comorbidity, which are not necessarily mutually exclusive.¹⁰One theory is that CFS is an atypical form of depression; another holds that the disability associated with CFS leads to depression, as is the case with many other chronic illnesses; and a third points to overlapping pathophysiology.¹⁰

An emerging body of evidence suggests that CFS and MDD have some common oxidative and nitrosative biochemical pathways. Activated by infection, psychologic stress, and immune disorders, they are believed to have damaging free radical and nitric oxide effects at the cellular level.¹⁴The cellular effects can result in fatigue, muscle pain, and flulike malaise.

Cortisol response differs
CFS and MDD might be distinguishable by another pathway—the hypothalamic-pituitary-adrenal (HPA) axis. MDD is classically associated with activation and raised cortisol levels, while CFS is consistently associated with impaired HPA axis functioning and reduced cortisol levels.¹⁰The majority of patients with CFS report symptoms of cognitive decline, with the acquisition of new verbal learning and information-processing speed particularly likely to be impaired.¹⁵

A meta-analysis of 50 studies of patients with CFS showed deficits in attention, memory, and reaction time, but not in fine motor speed, vocabulary, or reasoning.¹⁶Autonomic dysfunction has also been observed, including disordered sympathetic activity. The most frequently observed abnormalities on autonomic testing are postural hypotension, tachycardia syndrome, neurally mediated hypotension, and heart rate variability during tilt table testing.¹⁶

THE LINK BETWEEN INFECTION AND CFS
Several infectious agents have been associated with ME/CFS, including the Epstein-Barr virus (EBV), herpes simplex virus 6, parvovirus, Q fever, and Lyme disease.^8,17,18 Most agents that have been linked to ME/CFS are associated with persistent infection and thus incitement of the immune system.

Numerous observational studies^17,18have documented postinfectious fatigue syndromes after acute viral and bacterial infections and symptoms suggestive of infection, such as fever, myalgias, and respiratory and gastrointestinal distress. In one prospective Australian study,¹⁹investigators identified 253 cases of acute EBV, Ross River virus, and Q fever. Of those 253 patients, 12% went on to develop CFS, with a higher likelihood among those with more severe acute symptoms. No correlation with preexisting psychiatric disorders was found.

Muscle mitochondria studies have demonstrated what appear to be acquired abnormalities in those with CFS.^20,21Signs of increased oxidative stress have been found in both blood and muscle samples from patients with CFS, and longitudinal studies suggest that oxidative stress is greatest during periods of clinical exacerbation.²²Increased lactate levels suggest increased anaerobic metabolism in the central nervous system consistent with mitochondrial dysfunction. Several studies have demonstrated that exercise can precipitate oxidative stress in patients with CFS, in contrast with healthy controls and controls with other chronic illnesses, suggesting a physiologic basis for their postexertional symptoms.¹⁷

Autoinflammatory syndrome induced by adjuvants, a rare syndrome associated with vaccine administration, has been linked to postvaccination adverse events, exposure to silicone implants, Gulf War syndrome (related to multiple vaccinations), and macrophagic myofasciitis. All involve exposure to immune adjuvants and have similar clinical manifestations. The corresponding exposures appear to trigger an autoimmune response in susceptible individuals. The hepatitis B vaccine is most often associated with CFS, with symptoms occurring within 90 days of administration.²³

Continue for the clinical work-up >>

 

THE CLINICAL WORK-UP: PUTTING KNOWLEDGE INTO PRACTICE
Familiarity with potential causes of and connections with ME/CFS will help you ensure that patients who say they’re always tired receive a thorough work-up. Start with a medical history, inquiring directly about medical and psychiatric disorders that may contribute to fatigue (see Table 3).^5,24,25 Include a medication history as well, to help determine whether the fatigue is drug-related (see Table 4).^5,25 

What to ask. Determine the onset, course, duration, daily pattern, and impact of fatigue on the patient’s daily life. Inquire, too, about related symptoms of daytime sleepiness, dyspnea on exertion, generalized weakness, and depressed mood. The prominence of any of these rather than fatigue, per se, point to a diagnosis of a chronic illness other than ME/CFS.

Keep in mind, too, that patients with an organ-based medical illness tend to associate their fatigue with activities that they are unable to complete, such as shopping or light housework. In contrast, those with fatigue that is not organ-based typically say that they’re tired all the time. Their fatigue is not necessarily related to exertion, nor does it improve with rest.²⁶

To address this distinction, take a sleep history, assessing both the quality and quantity of the patient’s sleep to determine how it affects symptoms.²⁷ Consider using a questionnaire designed to help distinguish between sleepiness—and a primary sleep disorder—and fatigue,²⁸ such as the Fatigue Severity Scale of Sleep Disorders (www.healthywomen.org/sites/default/files/FatigueSeverityScale.pdf).

What to rule out. In addition to a medical history, the physical examination should be oriented toward ruling out secondary causes of fatigue. In addition to a system-by-system approach to the differential diagnosis, carefully observe the patient’s general appearance, with attention to his or her level of alertness, grooming, and psychomotor agitation or retardation as possible signs of a psychiatric disorder. To rule out neurologic causes, evaluate muscle bulk, tone, and strength; deep tendon reflexes; and sensory and cranial nerves, as well.²⁹

Lab tests to consider. In most cases of ME/CFS, basic studies—complete blood count with differential, erythrocyte sedimentation rate, blood chemistry, and thyroid-stimulating hormone (TSH) levels—are sufficient. When no medical or psychiatric cause has been found, additional tests may be ordered on a case-by-case basis, although laboratory analysis affects the management of fatigue in less than 5% of such patients.³⁰ Tests to consider include:
• Creatine kinase (for patients who report pain or muscle weakness)
• Pregnancy test (for women of childbearing age)
• Ferritin testing (for young women who might benefit from iron supplementation for levels < 50 ng/mL even if anemia is not present)³¹
• Hepatitis C screening (recommended by the US Preventive Services Task Force for those born between 1945 and 1965)³²
• HIV screening and the purified protein derivative test for tuberculosis (based on patient ­history).

Forego routine testing for other infections
Routine testing for infectious diseases and conditions associated with fatigue, such as EBV or Lyme disease, immune deficiency (eg, immunoglobulins), inflammatory disease (eg, antinuclear antibodies, rheumatoid factor), celiac disease, vitamin D deficiency, vitamin B₁₂ deficiency, or heavy metal toxicity, is unlikely to be helpful.²⁹ Additional testing simply to reassure a worried patient usually does not accomplish that objective.³³

Additional studies, referrals to consider. If you suspect that a patient has a sleep disorder, a referral to a sleep clinic to rule out idiopathic sleep disorders, obstructive sleep apnea, or movement disorders that interfere with sleep may be in order. Spirometry and echocardiography may be helpful for some patients. If you suspect peripheral muscle fatigue, a referral for neuromuscular testing is indicated.

Lauren’s medical history reveals that she also has irritable bowel syndrome, which she manages with diet and OTC medication, as needed for constipation or diarrhea. She denies having any other chronic conditions. Her only other symptoms, she reports, are mild upper back pain after spending long hours at the computer and arthralgias in her left knee and both hands. She admits to being “somewhat depressed” in the last few months but denies the presence of anhedonia.

The patient’s physical examination is normal, and her depression screen does not meet the criteria for MDD. Her metabolic chemistry panel, complete blood count, TSH, and sedimentation rate are all normal, as well.

Continue for symptom management and coping strategies >>

 

SYMPTOM MANAGEMENT AND COPING STRATEGIES
When no specific cause of chronic fatigue is found, the focus shifts from diagnosis to symptom management and coping strategies. This requires engagement with the patient. It is important to acknowledge the existence of his or her symptoms and to reassure the patient that further investigation may be warranted later, should new symptoms emerge. Advise the patient, too, that periods of remission and relapse are likely.

Strategies designed to motivate patient self-management, as well as the formulation of patient-centered treatment plans, have been shown to reduce symptom scores.³⁴ Participation in a support group, as well as frequent follow-up visits with a primary care provider, a behavioral therapist, or both, may help to provide needed psychologic support.

Evidence of the effectiveness of specific therapies for ME/CFS is limited; however, the best-studied approaches are cognitive behavioral therapy (CBT) and graded exercise therapy.³⁵ Exercise should be low intensity, such as walking or cycling for 30 minutes three times a week, with a gradual increase in duration and frequency over a period of weeks to months. Patients with cancer-related fatigue may benefit from yoga, group therapy, and stress management.³⁶

Associated mood and pain symptoms should be treated, as well. Bupropion, which is somewhat stimulating, may be considered as an initial treatment for patients with depression and clinically significant fatigue.

Other potentially beneficial approaches include a healthy diet, avoidance of more than nominal amounts of alcohol, relative avoidance of caffeine (no more than one cup of a caffeinated beverage in the morning), and stress reduction techniques.

Attention to good sleep hygiene may be especially beneficial, including a regular bedtime routine and sleep schedule, and elimination of bedroom light and noise. Pharmacologic treatments for insomnia should be used with caution, if at all.

Lauren receives a referral for CBT and is scheduled for a return visit in four weeks. At the advice of both her primary care provider and the behavioral therapist, she gradually makes several lifestyle changes. She begins going to bed earlier on weeknights to ensure that she sleeps for at least seven hours. She improves her diet, with increasing emphasis on vegetables, fruits, and whole grains. She also starts a walking program, increasing gradually to a total of three hours per week. After four months, she adds a weekly trip to a gym, where she practices resistance training for about 40 minutes.

Lauren also increases her social activities on weekends and recently accepted an invitation to join a book club. Six months from her initial visit, she notes that although she is still more easily fatigued than most people, she has made significant improvement

REFERENCES
1. Nijrolder I, van der Windt DA, van der Horst HE. Prognosis of fatigue and functioning in primary care: a 1-year follow-up study. Ann Fam Med. 2008;6:519-527.
2. Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry. 2008;10:120-128.
3. Holmes GP, Kaplan JE, Gantz NM, et al. Chronic fatigue syndrome: a working case definition. Ann Intern Med. 1988;108:387-389.
4. Morris G, Maes M. Case definitions and diagnostic criteria for myalgic encephalomyelitis and chronic fatigue syndrome: from clinical consensus to evidence-based case definitions. Neuro Endocrinol Lett. 2013;34:185-199.
5. Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med. 1994;121:953-959.
6. CDC. Chronic fatigue syndrome. www.cdc.gov/cfs/diagnosis/index.html. Accessed December 17, 2015.
7. Carruthers BM, van de Sande MI, De Meirleir KL, et al. Myalgic encephalomyelitis: International Consensus Criteria. J Intern Med. 2011;270:327-338.
8. Johnston SC, Brenu EW, Hardcastle S, et al. A comparison of health status in patients meeting alternative definitions for chronic fatigue syndrome/myalgic encephalomyelitis. Health Qual Life Outcomes. 2014;12:64.
9. Anderson VR, Jason LA, Hlavaty LE, et al. A review and meta-synthesis of qualitative studies on myalgic encephalomyelitis/chronic fatigue syndrome. Patient Educ Couns. 2012;86:147-155.
10. Christley Y, Duffy T, Everall IP, et al. The neuropsychiatric and neuropsychological features of chronic fatigue syndrome: revisiting the enigma. Curr Psychiatry Rep. 2013;15:353.
11. Henningsen P, Zimmermann T, Sattel HH. Medically unexplained physical symptoms, anxiety, and depression: a meta-analytic review. Psychosom Med. 2003;65:528-533.
12. Nater UM, Jones JF, Lin JM, et al. Personality features and personality disorders in chronic fatigue syndrome: a population-based study. Psychother Psychosom. 2010;79:312-318.
13. Taylor RR, Jason LA, Jahn SC. Chronic fatigue and sociodemographic characteristics as predictors of psychiatric disorders in a community-based sample. Psychosom Med. 2003;65:896-901.
14. Leonard B, Maes M. Mechanistic explanations of how cell-mediated immune activation, inflammation and oxidative and nitrosative stress pathways and their sequels and concomitants play a role in the pathophysiology of unipolar depression. Neurosci Biobehav Rev. 2012;36:764-785.
15. DeLuca J, Christodoulou C, Diamond BJ, et al. Working memory deficits in chronic fatigue syndrome: differentiating between speed and accuracy of information processing. J Int Neuropsychol Soc. 2004;10:101-109.
16. Cockshell SJ, Mathias JL. Cognitive functioning in chronic fatigue syndrome: a meta-analysis. Psychol Med. 2010;40:1253-1267.
17. Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011;31:325-337.
18. Naess H, Sundal E, Myhr KM, et al. Postinfectious and chronic fatigue syndromes: clinical experience from a tertiary-referral centre in Norway. In Vivo. 2010;24:185-188.
19. Hickie I, Davenport T, Wakefield D, et al; Dubbo Infection Outcomes Study Group. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006;333:575.
20. Plioplys AV, Plioplys S. Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome.Neuropsychobiology. 1995;32: 175-181.
21. Vernon SD, Whistler T, Cameron B, et al. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006;6:15.
22. Miwa K, Fujita M. Fluctuation of serum vitamin E (alpha-tocopherol) concentrations during exacerbation and remission phases in patients with chronic fatigue syndrome. Heart Vessels. 2010;25:319-323.
23. Rosenblum H, Shoenfeld Y, Amital H. The common immunogenic etiology of chronic fatigue syndrome: from infections to vaccines via adjuvants to the ASIA syndrome. Infect Dis Clin North Am. 2011;25:851-863.
24. Vincent A, Brimmer DJ, Whipple MO, et al. Prevalence, incidence, and classification of chronic fatigue syndrome in Olmsted County, Minnesota as estimated using the Rochester Epidemiology Project. Mayo Clin Proc. 2012;87:1145-1152.
25. Goroll AH, Mulley AG. Primary Care Medicine: Office Evaluation and Management of the Adult Patient. 7th ed. Morrisville, PA: Wolters Kluwer; 2014.
26. Brown RF, Schutte NS. Direct and indirect relationships between emotional intelligence and subjective fatigue in university students. J Psychosom Res. 2006;60:585-593.
27. Pigeon WR, Sateia MJ, Ferguson RJ. Distinguishing between excessive daytime sleepiness and fatigue: toward improved detection and treatment. J Psychosom Res. 2003;54:61-69.
28. Bailes S, Libman E, Baltzan M, et al. Brief and distinct empirical sleepiness and fatigue scales. J Psychosom Res. 2006;60:605-613.
29. National Collaborating Centre for Primary Care (UK). Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy): Diagnosis and Management of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (or Encephalopathy) in Adults and Children. London, UK: Royal College of General Practitioners; 2007.
30. Lane TJ, Matthews DA, Manu P. The low yield of physical examinations and laboratory investigations of patients with chronic fatigue. Am J Med Sci. 1990;299:313-318.
31. Vaucher P, Druisw PL, Waldvogel S, et al. Effect of iron supplementation on fatigue in nonanemic menstruating women with low ferritin: a randomized controlled trial.CMAJ. 2012;184:1247-1254.
32. US Preventive Services Task Force. Hepatitis C: Screening. US Preventive Services Task Force Web site. www.uspreventiveservicestaskforce.org/uspstf/uspshepc.htm. Accessed December 17, 2015.
33. Rolfe A, Burton C. Reassurance after diagnostic testing with a low pretest probability of serious disease: a systematic review and meta-analysis. JAMA Intern Med. 2013;173:407-416.
34. Smith RC, Lyles JS, Gardiner JC, et al. Primary care clinicians treat patients with medically unexplained symptoms: a randomized controlled trial. J Gen Intern Med. 2006;21:671-677.
35. White PD, Goldsmith KA, Johnson AL, et al; PACE trial management group. Comparison of adaptive pacing therapy, cognitive behaviour therapy, graded exercise therapy, and specialist medical care for chronic fatigue (PACE): a randomised trial. Lancet. 2011;377:823-836.
36.  van Weert E, Hoekstra-Weebers J, Otter R, et al. Cancer-related fatigue: predictors and effects of rehabilitation. Oncologist. 2006;11:184-196.

CASE Lauren C, age 35, presents with fatigue, which she says started at least eight months ago and has progressively worsened. The patient, a clerical worker, says she manages to do an adequate job but goes home feeling utterly exhausted each night.

Lauren says she sleeps well, getting more than eight hours of sleep per night on weekends but less than seven hours per night during the week. But no matter how long she sleeps, she never awakens feeling refreshed. Lauren reports that she doesn’t smoke, has no more than four alcoholic drinks per month, and adheres to an “average” diet. She is too tired to exercise.

Lauren is single, with no children. Although she says she has a strong network of family and friends, she increasingly finds she has no energy for socializing. If Lauren were your patient, what would you do?

Fatigue is a common presenting symptom in primary care, accounting for about 5% of adult visits.¹ Defined as a generalized lack of energy, fatigue that persists despite adequate rest or is severe enough to disrupt an individual’s ability to participate in key social and/or occupational activities warrants a thorough investigation.

Because fatigue is a nonspecific symptom that may be linked to a number of medical and psychiatric illnesses or to medications used to treat them, determining the cause can be difficult. In about half of all cases, no specific etiology is found.²This review, which includes the elements of a work-up and management strategies for patients presenting with ongoing fatigue, will help you arrive at the appropriate diagnosis and provide optimal treatment.

CHRONIC FATIGUE: DEFINING THE TERMS
A definition of chronic fatigue syndrome (CFS) was initially published in 1988.³In subsequent years, the term myalgic encephalomyelitis (ME) became popular. Although the terms are sometimes used interchangeably, ME often refers to patients whose condition is thought to have an infectious cause and for whom postexertional malaise is a hallmark symptom.⁴

CDC criteria. While several sets of diagnostic criteria for CFS have been developed, the most widely used is that of the CDC, published in 1994 (see Table 1).^5,6A diagnosis of CFS is made on the basis of exclusion, subjective clinical interpretation, and patient self-report.

When the first two criteria—fatigue not due to ongoing exertion or other medical conditions that has lasted ≥ 6 months and is severe enough to interfere with daily activities—but fewer than four of the CDC’s eight concurrent symptoms (eg, headache, unrefreshing sleep, and postexertion malaise lasting > 24 h) are present, idiopathic fatigue, rather than CFS, is diagnosed.⁶

International Consensus Criteria (ICC). In 2011, the ICC for ME were proposed in an effort to provide more specific diagnostic criteria (see Table 2).⁷The ICC emphasize fatigability, or what the authors identify as “post-exertional neuroimmune exhaustion.”

The ICC have not yet been broadly researched. But an Australian study of patients with chronic fatigue found that those who met the ICC definition were sicker and more homogeneous, with significantly lower scores for physical and social functioning and bodily pain, compared with those who fulfilled the CDC criteria alone.⁸

Continue for common threads of chronic fatigue & neuropsychiatric conditions >>

 

CHRONIC FATIGUE & NEUROPSYCHIATRIC CONDITIONS: COMMON THREADS
Recent research has made it clear that depression, somatization, and CFS share some biological underpinnings. These include biomarkers for inflammation, cell-mediated immune activation—which may be related to the symptoms of fatigue—autonomic dysfunction, and hyperalgesia.⁹Evidence suggests that up to two-thirds of patients with CFS also meet the criteria for a psychiatric disorder.¹⁰The most common psychiatric conditions are major depressive disorder (MDD), affecting an estimated 22% to 32% of those with CFS; anxiety disorder, affecting about 20%; and somatization disorder, affecting about 10%—at least double the incidence of the general population.¹⁰

Others point out, however, that up to half of those with CFS do not have a psychiatric disorder.¹¹A diagnosis of somatization disorder, in particular, depends largely on a subjective interpretation of whether the presenting symptoms have a physical cause.¹⁰

CFS and MDD comorbidity. The most widely studied association between CFS and psychiatric disorders involves MDD. Observational studies have found patients with CFS have a lifetime prevalence of MDD of 65%,^12,13which is higher than that of patients with other chronic diseases. Overlapping symptoms include fatigue, sleep disturbance, poor concentration, and memory problems. However, those with CFS have fewer symptoms related to anhedonia, poor self-esteem, guilt, and suicidal ideation compared with individuals with MDD.^12,13

There are several possible explanations for CFS and MDD comorbidity, which are not necessarily mutually exclusive.¹⁰One theory is that CFS is an atypical form of depression; another holds that the disability associated with CFS leads to depression, as is the case with many other chronic illnesses; and a third points to overlapping pathophysiology.¹⁰

An emerging body of evidence suggests that CFS and MDD have some common oxidative and nitrosative biochemical pathways. Activated by infection, psychologic stress, and immune disorders, they are believed to have damaging free radical and nitric oxide effects at the cellular level.¹⁴The cellular effects can result in fatigue, muscle pain, and flulike malaise.

Cortisol response differs
CFS and MDD might be distinguishable by another pathway—the hypothalamic-pituitary-adrenal (HPA) axis. MDD is classically associated with activation and raised cortisol levels, while CFS is consistently associated with impaired HPA axis functioning and reduced cortisol levels.¹⁰The majority of patients with CFS report symptoms of cognitive decline, with the acquisition of new verbal learning and information-processing speed particularly likely to be impaired.¹⁵

A meta-analysis of 50 studies of patients with CFS showed deficits in attention, memory, and reaction time, but not in fine motor speed, vocabulary, or reasoning.¹⁶Autonomic dysfunction has also been observed, including disordered sympathetic activity. The most frequently observed abnormalities on autonomic testing are postural hypotension, tachycardia syndrome, neurally mediated hypotension, and heart rate variability during tilt table testing.¹⁶

THE LINK BETWEEN INFECTION AND CFS
Several infectious agents have been associated with ME/CFS, including the Epstein-Barr virus (EBV), herpes simplex virus 6, parvovirus, Q fever, and Lyme disease.^8,17,18 Most agents that have been linked to ME/CFS are associated with persistent infection and thus incitement of the immune system.

Numerous observational studies^17,18have documented postinfectious fatigue syndromes after acute viral and bacterial infections and symptoms suggestive of infection, such as fever, myalgias, and respiratory and gastrointestinal distress. In one prospective Australian study,¹⁹investigators identified 253 cases of acute EBV, Ross River virus, and Q fever. Of those 253 patients, 12% went on to develop CFS, with a higher likelihood among those with more severe acute symptoms. No correlation with preexisting psychiatric disorders was found.

Muscle mitochondria studies have demonstrated what appear to be acquired abnormalities in those with CFS.^20,21Signs of increased oxidative stress have been found in both blood and muscle samples from patients with CFS, and longitudinal studies suggest that oxidative stress is greatest during periods of clinical exacerbation.²²Increased lactate levels suggest increased anaerobic metabolism in the central nervous system consistent with mitochondrial dysfunction. Several studies have demonstrated that exercise can precipitate oxidative stress in patients with CFS, in contrast with healthy controls and controls with other chronic illnesses, suggesting a physiologic basis for their postexertional symptoms.¹⁷

Autoinflammatory syndrome induced by adjuvants, a rare syndrome associated with vaccine administration, has been linked to postvaccination adverse events, exposure to silicone implants, Gulf War syndrome (related to multiple vaccinations), and macrophagic myofasciitis. All involve exposure to immune adjuvants and have similar clinical manifestations. The corresponding exposures appear to trigger an autoimmune response in susceptible individuals. The hepatitis B vaccine is most often associated with CFS, with symptoms occurring within 90 days of administration.²³

Continue for the clinical work-up >>

 

THE CLINICAL WORK-UP: PUTTING KNOWLEDGE INTO PRACTICE
Familiarity with potential causes of and connections with ME/CFS will help you ensure that patients who say they’re always tired receive a thorough work-up. Start with a medical history, inquiring directly about medical and psychiatric disorders that may contribute to fatigue (see Table 3).^5,24,25 Include a medication history as well, to help determine whether the fatigue is drug-related (see Table 4).^5,25 

What to ask. Determine the onset, course, duration, daily pattern, and impact of fatigue on the patient’s daily life. Inquire, too, about related symptoms of daytime sleepiness, dyspnea on exertion, generalized weakness, and depressed mood. The prominence of any of these rather than fatigue, per se, point to a diagnosis of a chronic illness other than ME/CFS.

Keep in mind, too, that patients with an organ-based medical illness tend to associate their fatigue with activities that they are unable to complete, such as shopping or light housework. In contrast, those with fatigue that is not organ-based typically say that they’re tired all the time. Their fatigue is not necessarily related to exertion, nor does it improve with rest.²⁶

To address this distinction, take a sleep history, assessing both the quality and quantity of the patient’s sleep to determine how it affects symptoms.²⁷ Consider using a questionnaire designed to help distinguish between sleepiness—and a primary sleep disorder—and fatigue,²⁸ such as the Fatigue Severity Scale of Sleep Disorders (www.healthywomen.org/sites/default/files/FatigueSeverityScale.pdf).

What to rule out. In addition to a medical history, the physical examination should be oriented toward ruling out secondary causes of fatigue. In addition to a system-by-system approach to the differential diagnosis, carefully observe the patient’s general appearance, with attention to his or her level of alertness, grooming, and psychomotor agitation or retardation as possible signs of a psychiatric disorder. To rule out neurologic causes, evaluate muscle bulk, tone, and strength; deep tendon reflexes; and sensory and cranial nerves, as well.²⁹

Lab tests to consider. In most cases of ME/CFS, basic studies—complete blood count with differential, erythrocyte sedimentation rate, blood chemistry, and thyroid-stimulating hormone (TSH) levels—are sufficient. When no medical or psychiatric cause has been found, additional tests may be ordered on a case-by-case basis, although laboratory analysis affects the management of fatigue in less than 5% of such patients.³⁰ Tests to consider include:
• Creatine kinase (for patients who report pain or muscle weakness)
• Pregnancy test (for women of childbearing age)
• Ferritin testing (for young women who might benefit from iron supplementation for levels < 50 ng/mL even if anemia is not present)³¹
• Hepatitis C screening (recommended by the US Preventive Services Task Force for those born between 1945 and 1965)³²
• HIV screening and the purified protein derivative test for tuberculosis (based on patient ­history).

Forego routine testing for other infections
Routine testing for infectious diseases and conditions associated with fatigue, such as EBV or Lyme disease, immune deficiency (eg, immunoglobulins), inflammatory disease (eg, antinuclear antibodies, rheumatoid factor), celiac disease, vitamin D deficiency, vitamin B₁₂ deficiency, or heavy metal toxicity, is unlikely to be helpful.²⁹ Additional testing simply to reassure a worried patient usually does not accomplish that objective.³³

Additional studies, referrals to consider. If you suspect that a patient has a sleep disorder, a referral to a sleep clinic to rule out idiopathic sleep disorders, obstructive sleep apnea, or movement disorders that interfere with sleep may be in order. Spirometry and echocardiography may be helpful for some patients. If you suspect peripheral muscle fatigue, a referral for neuromuscular testing is indicated.

Lauren’s medical history reveals that she also has irritable bowel syndrome, which she manages with diet and OTC medication, as needed for constipation or diarrhea. She denies having any other chronic conditions. Her only other symptoms, she reports, are mild upper back pain after spending long hours at the computer and arthralgias in her left knee and both hands. She admits to being “somewhat depressed” in the last few months but denies the presence of anhedonia.

The patient’s physical examination is normal, and her depression screen does not meet the criteria for MDD. Her metabolic chemistry panel, complete blood count, TSH, and sedimentation rate are all normal, as well.

Continue for symptom management and coping strategies >>

 

SYMPTOM MANAGEMENT AND COPING STRATEGIES
When no specific cause of chronic fatigue is found, the focus shifts from diagnosis to symptom management and coping strategies. This requires engagement with the patient. It is important to acknowledge the existence of his or her symptoms and to reassure the patient that further investigation may be warranted later, should new symptoms emerge. Advise the patient, too, that periods of remission and relapse are likely.

Strategies designed to motivate patient self-management, as well as the formulation of patient-centered treatment plans, have been shown to reduce symptom scores.³⁴ Participation in a support group, as well as frequent follow-up visits with a primary care provider, a behavioral therapist, or both, may help to provide needed psychologic support.

Evidence of the effectiveness of specific therapies for ME/CFS is limited; however, the best-studied approaches are cognitive behavioral therapy (CBT) and graded exercise therapy.³⁵ Exercise should be low intensity, such as walking or cycling for 30 minutes three times a week, with a gradual increase in duration and frequency over a period of weeks to months. Patients with cancer-related fatigue may benefit from yoga, group therapy, and stress management.³⁶

Associated mood and pain symptoms should be treated, as well. Bupropion, which is somewhat stimulating, may be considered as an initial treatment for patients with depression and clinically significant fatigue.

Other potentially beneficial approaches include a healthy diet, avoidance of more than nominal amounts of alcohol, relative avoidance of caffeine (no more than one cup of a caffeinated beverage in the morning), and stress reduction techniques.

Attention to good sleep hygiene may be especially beneficial, including a regular bedtime routine and sleep schedule, and elimination of bedroom light and noise. Pharmacologic treatments for insomnia should be used with caution, if at all.

Lauren receives a referral for CBT and is scheduled for a return visit in four weeks. At the advice of both her primary care provider and the behavioral therapist, she gradually makes several lifestyle changes. She begins going to bed earlier on weeknights to ensure that she sleeps for at least seven hours. She improves her diet, with increasing emphasis on vegetables, fruits, and whole grains. She also starts a walking program, increasing gradually to a total of three hours per week. After four months, she adds a weekly trip to a gym, where she practices resistance training for about 40 minutes.

Lauren also increases her social activities on weekends and recently accepted an invitation to join a book club. Six months from her initial visit, she notes that although she is still more easily fatigued than most people, she has made significant improvement

REFERENCES
1. Nijrolder I, van der Windt DA, van der Horst HE. Prognosis of fatigue and functioning in primary care: a 1-year follow-up study. Ann Fam Med. 2008;6:519-527.
2. Griffith JP, Zarrouf FA. A systematic review of chronic fatigue syndrome: don’t assume it’s depression. Prim Care Companion J Clin Psychiatry. 2008;10:120-128.
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