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A 44-year-old woman sought care at the emergency department (ED) because she was having difficulty breathing and felt faint. She had been fine until that morning. Three days earlier the patient, who had a history of high blood pressure and elevated cholesterol levels, had driven from Connecticut to New York and back, spending a total of 4 hours in her car. The patient indicated that she’d been taking oral contraceptives (OCPs) for several years, but she did not smoke. There was no history of hemoptysis, recent surgery, or trauma. Neither blood clots nor cancer were part of her or her family’s history.

In the ED, the patient did not have any signs or symptoms of a deep venous thrombosis (DVT). She was obese, with a body mass index of 40.3 kg/m²; other vitals were: blood pressure (BP), 134/88 mm Hg; heart rate (HR), 64 beats per minute (bpm); respiratory rate (RR), 12; and O₂ saturation, 99% with ambulation.

The ED physician strongly suspected a pulmonary embolism (PE), but the patient’s score on a clinical probability algorithm (using the Wells criteria) was a 3, indicating only “moderate probability“ of a PE (TABLE 1). (She scored a 3 because an “alternative diagnosis [was] less likely than PE.”) In addition, her D-dimer level was 160 ng/mL using the Triage D-Dimer Test by Biosite, Inc (normal <400 ng/mL), which ruled out a PE. (Many ED physicians at our institution are more cautious when using this D-dimer assay and use a lower cutoff value.)

Given these results, the ED physician did not order imaging studies because the expense and radiation exposure outweighed the probability of the patient having a PE. A subsequent coronary work-up was also negative. The patient was discharged to home and advised to follow up with her primary care physician a few days later.

Two days later we saw the patient at our office. Not only had her dyspnea gotten worse while the presyncope remained, but she now had left-sided pleuritic chest pain. She also reported mild pain in her right calf. On examination, the patient’s BP was 126/86 mm Hg, HR was 82 bpm, RR was 12, and O₂ saturation was 96% with ambulation. Her Wells score was now 6, still a moderate probability for PE. (She received another 3 points for the new DVT symptoms—“clinically suspected DVT.”)

Although the patient did not also have signs of a DVT, her additional symptoms along with the original symptoms’ persistence and the existence of other risk factors (OCP use and obesity) led us to reconsider a PE diagnosis. These suspicions prompted us to send the patient back to the ED, where a Doppler ultrasound of the right lower extremity was negative, but the D-dimer was positive at 565 ng/mL.

A pulmonary computed tomography angiogram (CTA) showed 2 small pulmonary emboli within the distal left upper lobe pulmonary arteries.

The patient was treated with heparin and warfarin and discharged without complications.

TABLE 1
Calculating and interpreting the Wells score^4,5,7,9,10

Discussion

The incidence of PE in the United States varies significantly: Individuals younger than 40 have a risk of 1 in 10,000 compared with 1 in 100 for those older than 80.¹ Mortality associated with undiagnosed PE varies widely, from 9.2% to 51%.² This percentage is significant given that half of all PEs go undiagnosed.³ In addition, when left untreated, PE will recur in 30% to 50% of patients, with a fatality rate of 10% to 45%.¹ Further, up to 4% of patients with acute PE develop chronic PE and subsequent pulmonary hypertension.^4,5 Given the consequences of failing to diagnose a PE, clinicians must consider this condition in patients who present with unexplained hypotension, dyspnea, or chest pain.⁶

Not an easy diagnosis
This case report demonstrates the inherent difficulty in diagnosing a PE. Still, certain clinical symptoms/signs can aid in the decision-making process. Fever, crackles, and wheezes decrease the probability of PE, whereas syncope, hemodynamic shock, leg edema, and hemoptysis increase its likelihood.⁷ Despite the many commonly reported risk factors for PE, only malignancy, recent surgery, or a history of DVT/PE significantly increase the risk of developing a clot.⁸

The Wells criteria. This scoring system groups patients according to the probability of having a PE: low (score: <2), moderate (score: 2-6), and high (score: >6).⁶ An alternative classification scheme divides patients into 2 groups: likely to have a PE (score: >4) or unlikely to have a PE (score: ≤4).⁸

This case report illustrates a key problem with the Wells criteria—the somewhat subjective nature of the scoring. Some physicians find it questionable to award 3 points for “alternative diagnosis less likely than PE,” for example.⁴ Similarly, with respect to immobilization, some clinicians might have awarded our patient 1.5 points for her recent car trip to New York. We did not think that riding in a car for 2 uninterrupted hours for each leg of the trip was significant enough. However, awarding this patient 1.5 points could have made an important difference in her clinical management if the alternative classification scheme was used. Instead of having a score of 3, the patient would have had a score of 4.5, placing her in the “likely to have a PE” group and prompting us to perform a CTA sooner (FIGURE).

FIGURE
Diagnostic algorithm for pulmonary embolism^6,7,10

Inappropriate work-ups are common
Some physicians ignore algorithms when working up a PE and simply order a CTA. In fact, a large multicenter trial showed that 43% of patients suspected of having a PE were inappropriately managed diagnostically.⁹ Similarly, a meta-analysis of 4 studies including 1660 patients found that only 58% of those with a positive D-dimer had the requisite CTA, as did 7% of patients with a negative D-dimer.²

Physicians should not be concerned about ruling out a PE in the setting of a negative D-dimer, as a meta-analysis found that this diagnostic approach has a negative predictive value (NPV) of 99.7%.² It is important to note that the NPV is significantly affected by the sensitivity of the D-dimer assay used. If the D-dimer assay is highly sensitive, a negative result in combination with a low, moderate, or unlikely probability Wells score rules out the diagnosis of PE. If the assay is moderately sensitive, however, only a low or unlikely probability Wells score rules out PE.¹⁰

The inappropriate work-up of this group of patients is significant and extends beyond the ultimate goal of preventing morbidity and mortality. The unnecessary use of pulmonary CTA is extremely expensive, exposes patients to unnecessary radiation, and results in contrast nephrotoxicity in about 4% of patients.⁹ Although pulmonary CTA is the standard diagnostic test for PE, other imaging modalities are more appropriate in some cases (TABLE 2).

TABLE 2
Alternative imaging modalities for diagnosing PE^1,4,7,11

The bottom line
This case report illustrates the importance of using sound clinical judgment when diagnosing a PE. Although our patient initially had a moderate probability Wells score and a negative D-dimer, her symptoms persisted. Her history of OCP use, persistent dyspnea, and new symptoms of a DVT prompted us to reinitiate the diagnostic algorithm and eventually diagnose a PE.

It is always essential to treat the patient and not simply react to laboratory values. To avoid unnecessary testing, however, adhering to the algorithm is equally important.

CORRESPONDENCE
Michael S. Kelleher, MD, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030; [email protected]

A 44-year-old woman sought care at the emergency department (ED) because she was having difficulty breathing and felt faint. She had been fine until that morning. Three days earlier the patient, who had a history of high blood pressure and elevated cholesterol levels, had driven from Connecticut to New York and back, spending a total of 4 hours in her car. The patient indicated that she’d been taking oral contraceptives (OCPs) for several years, but she did not smoke. There was no history of hemoptysis, recent surgery, or trauma. Neither blood clots nor cancer were part of her or her family’s history.

In the ED, the patient did not have any signs or symptoms of a deep venous thrombosis (DVT). She was obese, with a body mass index of 40.3 kg/m²; other vitals were: blood pressure (BP), 134/88 mm Hg; heart rate (HR), 64 beats per minute (bpm); respiratory rate (RR), 12; and O₂ saturation, 99% with ambulation.

The ED physician strongly suspected a pulmonary embolism (PE), but the patient’s score on a clinical probability algorithm (using the Wells criteria) was a 3, indicating only “moderate probability“ of a PE (TABLE 1). (She scored a 3 because an “alternative diagnosis [was] less likely than PE.”) In addition, her D-dimer level was 160 ng/mL using the Triage D-Dimer Test by Biosite, Inc (normal <400 ng/mL), which ruled out a PE. (Many ED physicians at our institution are more cautious when using this D-dimer assay and use a lower cutoff value.)

Given these results, the ED physician did not order imaging studies because the expense and radiation exposure outweighed the probability of the patient having a PE. A subsequent coronary work-up was also negative. The patient was discharged to home and advised to follow up with her primary care physician a few days later.

Two days later we saw the patient at our office. Not only had her dyspnea gotten worse while the presyncope remained, but she now had left-sided pleuritic chest pain. She also reported mild pain in her right calf. On examination, the patient’s BP was 126/86 mm Hg, HR was 82 bpm, RR was 12, and O₂ saturation was 96% with ambulation. Her Wells score was now 6, still a moderate probability for PE. (She received another 3 points for the new DVT symptoms—“clinically suspected DVT.”)

Although the patient did not also have signs of a DVT, her additional symptoms along with the original symptoms’ persistence and the existence of other risk factors (OCP use and obesity) led us to reconsider a PE diagnosis. These suspicions prompted us to send the patient back to the ED, where a Doppler ultrasound of the right lower extremity was negative, but the D-dimer was positive at 565 ng/mL.

A pulmonary computed tomography angiogram (CTA) showed 2 small pulmonary emboli within the distal left upper lobe pulmonary arteries.

The patient was treated with heparin and warfarin and discharged without complications.

TABLE 1
Calculating and interpreting the Wells score^4,5,7,9,10

Discussion

The incidence of PE in the United States varies significantly: Individuals younger than 40 have a risk of 1 in 10,000 compared with 1 in 100 for those older than 80.¹ Mortality associated with undiagnosed PE varies widely, from 9.2% to 51%.² This percentage is significant given that half of all PEs go undiagnosed.³ In addition, when left untreated, PE will recur in 30% to 50% of patients, with a fatality rate of 10% to 45%.¹ Further, up to 4% of patients with acute PE develop chronic PE and subsequent pulmonary hypertension.^4,5 Given the consequences of failing to diagnose a PE, clinicians must consider this condition in patients who present with unexplained hypotension, dyspnea, or chest pain.⁶

Not an easy diagnosis
This case report demonstrates the inherent difficulty in diagnosing a PE. Still, certain clinical symptoms/signs can aid in the decision-making process. Fever, crackles, and wheezes decrease the probability of PE, whereas syncope, hemodynamic shock, leg edema, and hemoptysis increase its likelihood.⁷ Despite the many commonly reported risk factors for PE, only malignancy, recent surgery, or a history of DVT/PE significantly increase the risk of developing a clot.⁸

The Wells criteria. This scoring system groups patients according to the probability of having a PE: low (score: <2), moderate (score: 2-6), and high (score: >6).⁶ An alternative classification scheme divides patients into 2 groups: likely to have a PE (score: >4) or unlikely to have a PE (score: ≤4).⁸

This case report illustrates a key problem with the Wells criteria—the somewhat subjective nature of the scoring. Some physicians find it questionable to award 3 points for “alternative diagnosis less likely than PE,” for example.⁴ Similarly, with respect to immobilization, some clinicians might have awarded our patient 1.5 points for her recent car trip to New York. We did not think that riding in a car for 2 uninterrupted hours for each leg of the trip was significant enough. However, awarding this patient 1.5 points could have made an important difference in her clinical management if the alternative classification scheme was used. Instead of having a score of 3, the patient would have had a score of 4.5, placing her in the “likely to have a PE” group and prompting us to perform a CTA sooner (FIGURE).

FIGURE
Diagnostic algorithm for pulmonary embolism^6,7,10

Inappropriate work-ups are common
Some physicians ignore algorithms when working up a PE and simply order a CTA. In fact, a large multicenter trial showed that 43% of patients suspected of having a PE were inappropriately managed diagnostically.⁹ Similarly, a meta-analysis of 4 studies including 1660 patients found that only 58% of those with a positive D-dimer had the requisite CTA, as did 7% of patients with a negative D-dimer.²

Physicians should not be concerned about ruling out a PE in the setting of a negative D-dimer, as a meta-analysis found that this diagnostic approach has a negative predictive value (NPV) of 99.7%.² It is important to note that the NPV is significantly affected by the sensitivity of the D-dimer assay used. If the D-dimer assay is highly sensitive, a negative result in combination with a low, moderate, or unlikely probability Wells score rules out the diagnosis of PE. If the assay is moderately sensitive, however, only a low or unlikely probability Wells score rules out PE.¹⁰

The inappropriate work-up of this group of patients is significant and extends beyond the ultimate goal of preventing morbidity and mortality. The unnecessary use of pulmonary CTA is extremely expensive, exposes patients to unnecessary radiation, and results in contrast nephrotoxicity in about 4% of patients.⁹ Although pulmonary CTA is the standard diagnostic test for PE, other imaging modalities are more appropriate in some cases (TABLE 2).

TABLE 2
Alternative imaging modalities for diagnosing PE^1,4,7,11

The bottom line
This case report illustrates the importance of using sound clinical judgment when diagnosing a PE. Although our patient initially had a moderate probability Wells score and a negative D-dimer, her symptoms persisted. Her history of OCP use, persistent dyspnea, and new symptoms of a DVT prompted us to reinitiate the diagnostic algorithm and eventually diagnose a PE.

It is always essential to treat the patient and not simply react to laboratory values. To avoid unnecessary testing, however, adhering to the algorithm is equally important.

CORRESPONDENCE
Michael S. Kelleher, MD, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030; [email protected]

A 44-year-old woman sought care at the emergency department (ED) because she was having difficulty breathing and felt faint. She had been fine until that morning. Three days earlier the patient, who had a history of high blood pressure and elevated cholesterol levels, had driven from Connecticut to New York and back, spending a total of 4 hours in her car. The patient indicated that she’d been taking oral contraceptives (OCPs) for several years, but she did not smoke. There was no history of hemoptysis, recent surgery, or trauma. Neither blood clots nor cancer were part of her or her family’s history.

In the ED, the patient did not have any signs or symptoms of a deep venous thrombosis (DVT). She was obese, with a body mass index of 40.3 kg/m²; other vitals were: blood pressure (BP), 134/88 mm Hg; heart rate (HR), 64 beats per minute (bpm); respiratory rate (RR), 12; and O₂ saturation, 99% with ambulation.

The ED physician strongly suspected a pulmonary embolism (PE), but the patient’s score on a clinical probability algorithm (using the Wells criteria) was a 3, indicating only “moderate probability“ of a PE (TABLE 1). (She scored a 3 because an “alternative diagnosis [was] less likely than PE.”) In addition, her D-dimer level was 160 ng/mL using the Triage D-Dimer Test by Biosite, Inc (normal <400 ng/mL), which ruled out a PE. (Many ED physicians at our institution are more cautious when using this D-dimer assay and use a lower cutoff value.)

Given these results, the ED physician did not order imaging studies because the expense and radiation exposure outweighed the probability of the patient having a PE. A subsequent coronary work-up was also negative. The patient was discharged to home and advised to follow up with her primary care physician a few days later.

Two days later we saw the patient at our office. Not only had her dyspnea gotten worse while the presyncope remained, but she now had left-sided pleuritic chest pain. She also reported mild pain in her right calf. On examination, the patient’s BP was 126/86 mm Hg, HR was 82 bpm, RR was 12, and O₂ saturation was 96% with ambulation. Her Wells score was now 6, still a moderate probability for PE. (She received another 3 points for the new DVT symptoms—“clinically suspected DVT.”)

Although the patient did not also have signs of a DVT, her additional symptoms along with the original symptoms’ persistence and the existence of other risk factors (OCP use and obesity) led us to reconsider a PE diagnosis. These suspicions prompted us to send the patient back to the ED, where a Doppler ultrasound of the right lower extremity was negative, but the D-dimer was positive at 565 ng/mL.

A pulmonary computed tomography angiogram (CTA) showed 2 small pulmonary emboli within the distal left upper lobe pulmonary arteries.

The patient was treated with heparin and warfarin and discharged without complications.

TABLE 1
Calculating and interpreting the Wells score^4,5,7,9,10

Discussion

The incidence of PE in the United States varies significantly: Individuals younger than 40 have a risk of 1 in 10,000 compared with 1 in 100 for those older than 80.¹ Mortality associated with undiagnosed PE varies widely, from 9.2% to 51%.² This percentage is significant given that half of all PEs go undiagnosed.³ In addition, when left untreated, PE will recur in 30% to 50% of patients, with a fatality rate of 10% to 45%.¹ Further, up to 4% of patients with acute PE develop chronic PE and subsequent pulmonary hypertension.^4,5 Given the consequences of failing to diagnose a PE, clinicians must consider this condition in patients who present with unexplained hypotension, dyspnea, or chest pain.⁶

Not an easy diagnosis
This case report demonstrates the inherent difficulty in diagnosing a PE. Still, certain clinical symptoms/signs can aid in the decision-making process. Fever, crackles, and wheezes decrease the probability of PE, whereas syncope, hemodynamic shock, leg edema, and hemoptysis increase its likelihood.⁷ Despite the many commonly reported risk factors for PE, only malignancy, recent surgery, or a history of DVT/PE significantly increase the risk of developing a clot.⁸

The Wells criteria. This scoring system groups patients according to the probability of having a PE: low (score: <2), moderate (score: 2-6), and high (score: >6).⁶ An alternative classification scheme divides patients into 2 groups: likely to have a PE (score: >4) or unlikely to have a PE (score: ≤4).⁸

This case report illustrates a key problem with the Wells criteria—the somewhat subjective nature of the scoring. Some physicians find it questionable to award 3 points for “alternative diagnosis less likely than PE,” for example.⁴ Similarly, with respect to immobilization, some clinicians might have awarded our patient 1.5 points for her recent car trip to New York. We did not think that riding in a car for 2 uninterrupted hours for each leg of the trip was significant enough. However, awarding this patient 1.5 points could have made an important difference in her clinical management if the alternative classification scheme was used. Instead of having a score of 3, the patient would have had a score of 4.5, placing her in the “likely to have a PE” group and prompting us to perform a CTA sooner (FIGURE).

FIGURE
Diagnostic algorithm for pulmonary embolism^6,7,10

Inappropriate work-ups are common
Some physicians ignore algorithms when working up a PE and simply order a CTA. In fact, a large multicenter trial showed that 43% of patients suspected of having a PE were inappropriately managed diagnostically.⁹ Similarly, a meta-analysis of 4 studies including 1660 patients found that only 58% of those with a positive D-dimer had the requisite CTA, as did 7% of patients with a negative D-dimer.²

Physicians should not be concerned about ruling out a PE in the setting of a negative D-dimer, as a meta-analysis found that this diagnostic approach has a negative predictive value (NPV) of 99.7%.² It is important to note that the NPV is significantly affected by the sensitivity of the D-dimer assay used. If the D-dimer assay is highly sensitive, a negative result in combination with a low, moderate, or unlikely probability Wells score rules out the diagnosis of PE. If the assay is moderately sensitive, however, only a low or unlikely probability Wells score rules out PE.¹⁰

The inappropriate work-up of this group of patients is significant and extends beyond the ultimate goal of preventing morbidity and mortality. The unnecessary use of pulmonary CTA is extremely expensive, exposes patients to unnecessary radiation, and results in contrast nephrotoxicity in about 4% of patients.⁹ Although pulmonary CTA is the standard diagnostic test for PE, other imaging modalities are more appropriate in some cases (TABLE 2).

TABLE 2
Alternative imaging modalities for diagnosing PE^1,4,7,11

The bottom line
This case report illustrates the importance of using sound clinical judgment when diagnosing a PE. Although our patient initially had a moderate probability Wells score and a negative D-dimer, her symptoms persisted. Her history of OCP use, persistent dyspnea, and new symptoms of a DVT prompted us to reinitiate the diagnostic algorithm and eventually diagnose a PE.

It is always essential to treat the patient and not simply react to laboratory values. To avoid unnecessary testing, however, adhering to the algorithm is equally important.

CORRESPONDENCE
Michael S. Kelleher, MD, University of Connecticut School of Medicine, 263 Farmington Avenue, Farmington, CT 06030; [email protected]

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

Responsibility for delayed Dx cuts both ways

A 44-YEAR-OLD WOMAN went to a university medical clinic complaining of weight gain and fatigue. The clinic was staffed by residents supervised by clinical faculty. The resident who examined the woman found a 1.5-cm mobile mass in one of her breasts. After consultation with the supervising physician, a mammogram with ultrasound was ordered. The supervising physician didn’t see the patient, but signed off on the treatment plan.

The mammogram was performed 2 days later and the mass was evaluated as probably benign. The patient was advised to follow up in 6 months. A month later, a second resident consulted with the patient and told her that she could have a biopsy or follow her condition on her own. The patient decided against a biopsy.

Eight months later, the clinic sent a reminder to the patient to return for follow-up, which she did. At that time, the skin on her breast had the texture of orange rind and the mass had grown. Metastatic breast cancer was diagnosed. Aggressive treatment was recommended, but the patient opted for herbal and other homeopathic remedies.

The initial trial of the case ended in a defense verdict, which was appealed after the patient died. A second trial led to a verdict finding the supervising physician 99% at fault and the patient 1% at fault. The jury award was set aside by the trial court.

PLAINTIFF’S CLAIM Failure to diagnose breast cancer promptly constituted negligence. A needle biopsy was needed.

THE DEFENSE The follow-up plan was reasonable; the patient didn’t return for evaluation when her condition changed.

VERDICT $2.4 million verdict in the second trial, set aside by a Tennessee judge.

COMMENT Failure to appropriately diagnose breast cancer is a leading cause of medical malpractice. A persistent breast mass, no matter the mammographic findings, needs to be followed aggressively and appropriate evaluation and referral pursued.

Missed pulmonary embolism proves fatal

TWO FAINTING EPISODES caused a 41-year-old man to be transported to the emergency department (ED), where he was found to have decreased blood oxygenation, increased respiratory rate, and heart strain. The patient had hypertension and had recently taken 2 4-hour airplane trips.

An ED physician examined the man initially and admitted him to the hospital. About 12 hours after admission, an attending family physician saw the patient, but didn’t order any immediate testing. The patient subsequently died from a pulmonary embolism.

PLAINTIFFS’ CLAIM Prompt testing was needed to rule out pulmonary embolism.

THE DEFENSE Fainting isn’t a common sign of pulmonary embolism. A 4-hour plane ride usually isn’t sufficient to cause deep vein thrombosis.

VERDICT $975,000 New Jersey settlement.

COMMENT Although pulmonary embolism certainly has more classic presentations than this one, the combination of the patient’s history and clinical findings were of sufficient concern to warrant prompt evaluation.

Warfarin + a twisted back = bad outcome

A FALL DOWN A FLIGHT OF STAIRS in her home caused an 85-year-old woman to twist her back when she grabbed for the bannister (she caught herself before landing). She was taken to an emergency department, where the staff noted that she was taking warfarin; she was diagnosed with acute low back pain and strain. The patient continued to receive anticoagulation therapy.

Because the patient also had decreased sensation in her lower legs, a magnetic resonance imaging (MRI) scan of the lumbosacral spine was ordered. The wet read of the MRI reported degenerative joint disease at L4-5 and mild-to-moderate spinal stenosis at L1-2, L2-3, L3-4, and L4-5, with no other abnormalities. The radiologist who issued the formal report described similar findings.

The next morning, the patient complained of numbness in her legs. She couldn’t move either leg and needed help to turn in bed. By noon, she had minimal motor control of her legs and couldn’t stand.

The attending physician was notified, but didn’t assess the woman. When a nurse called the doctor to let her know that the physical therapist had concerns about the patient, the doctor said that she’d address the concerns the following morning.

A neurologist ultimately assessed the patient and reported that she had neurologic deficits in her legs that interfered with her ability to walk. The patient continues to have significantly impaired function in her legs.

PLAINTIFF’S CLAIM The radiologists failed to identify abnormal signal intensity on the MRI, which should have raised concerns about bleeding and prompted an immediate assessment. The patient’s warfarin therapy wasn’t managed properly.

THE DEFENSE Subdural bleeding in the spine is rare. The fall caused the neurologic impairment, which was unlikely to improve regardless of the timing of diagnosis or treatment. The proper orders were given based on the reported MRI results. Discontinuing warfarin posed a risk in light of the patient’s history of mini-strokes.

VERDICT $1.5 million Massachusetts settlement.

COMMENT Although we could debate the cause of this patient’s disability, anyone on warfarin is at risk for occult bleeding and requires careful assessment after a fall or injury.

Colon cancer blamed on failure to screen

AFTER HER PHYSICIAN LEFT HIS PRACTICE, a woman started seeing another doctor in the practice almost exclusively. The second doctor never discussed or recommended colon cancer screening. Seven years later, at 66 years of age, the patient was diagnosed with stage IIB adenocarcinoma of the colon. She underwent surgery to remove part of the large intestine and required 6 months of chemotherapy.

PLAINTIFF’S CLAIM The doctor was negligent for failing to recommend colon cancer screening. The patient wouldn’t have developed cancer if she’d undergone screening.

THE DEFENSE A screening recommendation wasn’t required because the patient visited the doctor’s office only for acute-care issues.

VERDICT $357,130 Illinois verdict.

COMMENT Even patients who are casual users of our practices should receive clearly documented screening recommendations or requests to have a complete physical.

Quinolone leads to tendon damage in patient with known allergy

SINUSITIS PROMPTED A 35-YEAR-OLD WOMAN to visit an otolaryngologist. The physician prescribed moxifloxacin, despite the woman’s well-documented history of allergy to quinolone antibiotics.

After 2 doses of the drug, the patient developed a reaction marked by tendon damage in the hips. She suffered ongoing limited mobility, which affected her work and interfered with her ability to pursue her hobbies.

PLAINTIFF’S CLAIM The doctor was negligent in prescribing moxifloxacin.

THE DEFENSE Although moxifloxacin belongs to the quinolone antibiotic class, it has differences that make prescribing it a matter of judgment.

VERDICT $203,614 Kentucky verdict.

COMMENT Although we don’t know the exact nature of the patient’s “allergy” to quinolone antibiotics—we all know of cases in which allergy is defined as a bit of diarrhea or stomach upset. I have to wonder whether the decision-making process that led to using moxifloxacin (instead of another antibiotic) was documented clearly.

Back pain, then sudden death

BACK AND CHEST PAIN prompted a 42-year-old man to see a doctor. The family physician took the man’s blood pressure, which was 184/130, but performed no other testing. He prescribed pain medication and sent the patient home. The man died 3 days later of an aortic dissection.

PLAINTIFF’S CLAIM The physician was negligent because he did not try to lower the patient’s blood pressure or order a radiograph before sending him home.

THE DEFENSE There was no reason to suspect aortic dissection; the rupture was sudden and catastrophic.

VERDICT Alabama defense verdict.

COMMENT Although the defense prevailed, this case reminds us to always consider less common causes of low back pain.

Increase in morphine dose has fatal results

BREATHING DIFFICULTIES associated with chronic obstructive pulmonary disease led to the hospitalization of a 79-year-old woman. While there, she suffered respiratory arrest and a code was called. The pulmonologist on duty and the attending physician responded. After the patient was bagged, she started breathing on her own.

The attending physician subsequently discussed the patient’s treatment plan and prognosis with her daughter, who agreed to a do-not-resuscitate order. He ordered 2 mg morphine as needed for comfort.

Minutes later, the pulmonologist overrode the order and ordered 20 mg morphine by IV push. After it was given, the patient lost consciousness while talking to her daughter and granddaughter. She died about 3 hours later without regaining consciousness.

PLAINTIFF’S CLAIM The patient was improving until the night before her arrest, when she failed to get her scheduled breathing treatment. The pulmonologist was negligent in ordering 20 mg morphine, and the hospital nurses were negligent in administering it.

THE DEFENSE No negligence occurred. The patient would have died sooner than 3 hours after the morphine dose if morphine was, indeed, the cause of death.

VERDICT $3 million Georgia verdict.

COMMENT Do not resuscitate does not mean negligible risk of malpractice. Orders for 20 mg (!) of morphine will always be difficult to defend—even in a terminally ill patient.

Breast cancer diagnosis falls through the cracks

AFTER NOTICING A LUMP IN HER LEFT BREAST, a woman in her 40s underwent a screening mammogram rather than a diagnostic mammogram at a local facility. The mammogram showed no abnormalities, but an ultrasound examination the following year was abnormal. The report was faxed to her physician, who reportedly didn’t receive it. No follow-up occurred.

A year later, the patient made a follow-up appointment on her own and underwent diagnostic mammography and surgical biopsy, which revealed advanced breast cancer. A vacuum-assisted core biopsy and clip localization the following month revealed infiltrating ductal carcinoma. Neoadjuvant chemotherapy resulted in complications and hospitalization. The patient subsequently underwent additional chemotherapy and radiation treatments.

PLAINTIFF’S CLAIM The defendant health care facility didn’t properly evaluate the patient for breast cancer.

THE DEFENSE The defendant denied liability and asserted that its personnel acted within the standard of care.

VERDICT $575,000 South Carolina settlement.

COMMENT Follow-up and tracking of results remain key in preventing malpractice.

Back pain, then sudden death

BACK AND CHEST PAIN prompted a 42-year-old man to see a doctor. The family physician took the man’s blood pressure, which was 184/130, but performed no other testing. He prescribed pain medication and sent the patient home. The man died 3 days later of an aortic dissection.

PLAINTIFF’S CLAIM The physician was negligent because he did not try to lower the patient’s blood pressure or order a radiograph before sending him home.

THE DEFENSE There was no reason to suspect aortic dissection; the rupture was sudden and catastrophic.

VERDICT Alabama defense verdict.

COMMENT Although the defense prevailed, this case reminds us to always consider less common causes of low back pain.

Increase in morphine dose has fatal results

BREATHING DIFFICULTIES associated with chronic obstructive pulmonary disease led to the hospitalization of a 79-year-old woman. While there, she suffered respiratory arrest and a code was called. The pulmonologist on duty and the attending physician responded. After the patient was bagged, she started breathing on her own.

The attending physician subsequently discussed the patient’s treatment plan and prognosis with her daughter, who agreed to a do-not-resuscitate order. He ordered 2 mg morphine as needed for comfort.

Minutes later, the pulmonologist overrode the order and ordered 20 mg morphine by IV push. After it was given, the patient lost consciousness while talking to her daughter and granddaughter. She died about 3 hours later without regaining consciousness.

PLAINTIFF’S CLAIM The patient was improving until the night before her arrest, when she failed to get her scheduled breathing treatment. The pulmonologist was negligent in ordering 20 mg morphine, and the hospital nurses were negligent in administering it.

THE DEFENSE No negligence occurred. The patient would have died sooner than 3 hours after the morphine dose if morphine was, indeed, the cause of death.

VERDICT $3 million Georgia verdict.

COMMENT Do not resuscitate does not mean negligible risk of malpractice. Orders for 20 mg (!) of morphine will always be difficult to defend—even in a terminally ill patient.

Breast cancer diagnosis falls through the cracks

AFTER NOTICING A LUMP IN HER LEFT BREAST, a woman in her 40s underwent a screening mammogram rather than a diagnostic mammogram at a local facility. The mammogram showed no abnormalities, but an ultrasound examination the following year was abnormal. The report was faxed to her physician, who reportedly didn’t receive it. No follow-up occurred.

A year later, the patient made a follow-up appointment on her own and underwent diagnostic mammography and surgical biopsy, which revealed advanced breast cancer. A vacuum-assisted core biopsy and clip localization the following month revealed infiltrating ductal carcinoma. Neoadjuvant chemotherapy resulted in complications and hospitalization. The patient subsequently underwent additional chemotherapy and radiation treatments.

PLAINTIFF’S CLAIM The defendant health care facility didn’t properly evaluate the patient for breast cancer.

THE DEFENSE The defendant denied liability and asserted that its personnel acted within the standard of care.

VERDICT $575,000 South Carolina settlement.

COMMENT Follow-up and tracking of results remain key in preventing malpractice.

Back pain, then sudden death

BACK AND CHEST PAIN prompted a 42-year-old man to see a doctor. The family physician took the man’s blood pressure, which was 184/130, but performed no other testing. He prescribed pain medication and sent the patient home. The man died 3 days later of an aortic dissection.

PLAINTIFF’S CLAIM The physician was negligent because he did not try to lower the patient’s blood pressure or order a radiograph before sending him home.

THE DEFENSE There was no reason to suspect aortic dissection; the rupture was sudden and catastrophic.

VERDICT Alabama defense verdict.

COMMENT Although the defense prevailed, this case reminds us to always consider less common causes of low back pain.

Increase in morphine dose has fatal results

BREATHING DIFFICULTIES associated with chronic obstructive pulmonary disease led to the hospitalization of a 79-year-old woman. While there, she suffered respiratory arrest and a code was called. The pulmonologist on duty and the attending physician responded. After the patient was bagged, she started breathing on her own.

The attending physician subsequently discussed the patient’s treatment plan and prognosis with her daughter, who agreed to a do-not-resuscitate order. He ordered 2 mg morphine as needed for comfort.

Minutes later, the pulmonologist overrode the order and ordered 20 mg morphine by IV push. After it was given, the patient lost consciousness while talking to her daughter and granddaughter. She died about 3 hours later without regaining consciousness.

PLAINTIFF’S CLAIM The patient was improving until the night before her arrest, when she failed to get her scheduled breathing treatment. The pulmonologist was negligent in ordering 20 mg morphine, and the hospital nurses were negligent in administering it.

THE DEFENSE No negligence occurred. The patient would have died sooner than 3 hours after the morphine dose if morphine was, indeed, the cause of death.

VERDICT $3 million Georgia verdict.

COMMENT Do not resuscitate does not mean negligible risk of malpractice. Orders for 20 mg (!) of morphine will always be difficult to defend—even in a terminally ill patient.

Breast cancer diagnosis falls through the cracks

AFTER NOTICING A LUMP IN HER LEFT BREAST, a woman in her 40s underwent a screening mammogram rather than a diagnostic mammogram at a local facility. The mammogram showed no abnormalities, but an ultrasound examination the following year was abnormal. The report was faxed to her physician, who reportedly didn’t receive it. No follow-up occurred.

A year later, the patient made a follow-up appointment on her own and underwent diagnostic mammography and surgical biopsy, which revealed advanced breast cancer. A vacuum-assisted core biopsy and clip localization the following month revealed infiltrating ductal carcinoma. Neoadjuvant chemotherapy resulted in complications and hospitalization. The patient subsequently underwent additional chemotherapy and radiation treatments.

PLAINTIFF’S CLAIM The defendant health care facility didn’t properly evaluate the patient for breast cancer.

THE DEFENSE The defendant denied liability and asserted that its personnel acted within the standard of care.

VERDICT $575,000 South Carolina settlement.

COMMENT Follow-up and tracking of results remain key in preventing malpractice.

Evidence summary

A systematic review of 3 RCTs with a total of 649 participants evaluated office spirometry as a motivational tool to improve quit rates by comparing spirometry plus cessation advice with cessation advice alone. All participants were men and women 19 to 75 years of age recruited from outpatient clinics.¹

In 1 trial, the intervention group received repeated counseling at 4 visits and underwent spirometry; the control group had 1 counseling session and was given a brochure. In the other 2 trials, the intervention group had both carbon monoxide measurements and spirometry, and all participants received more extensive counseling, including cessation skills training.

At 9 to 12 months’ follow-up, quit rates ranged from 6% to 24% in the intervention groups vs 5% to 14% in the control groups (not significantly different).¹

A subsequent study randomized 221 smokers to receive either spirometry plus brief cessation advice or advice alone. Researchers recruited patients 15 to 80 years of age who were willing to quit smoking from 16 general practice clinics in Belgium. Fifty-one percent of patients in both groups used nicotine replacement therapy (a larger percentage than is typical in studies done in the United States). At 6, 12, and 24 months, 5%, 2%, and 5% more smokers, respectively, from the spirometry group quit smoking compared with the control group, but this difference was not significant.²

Reporting spirometry results in terms of lung age may spur quitting
One RCT found significantly improved quit rates when patients who smoked were given their office spirometry results in terms of “lung age” (the age of an average healthy person with similar spirometry results) rather than as forced expiratory volume in 1 second (FEV1). Investigators performed office spirometry and gave smoking cessation advice to 561 smokers older than 35 years who were recruited from 5 general practices. They randomized patients to receive their spirometry results as either lung age or FEV1 and recorded quit rates at 12 months (smoking cessation was verified by measuring blood levels of carbon monoxide).

Patients whose spirometry results were reported as lung age were significantly more likely to quit than smokers whose results were given as FEV1 (13.6% vs 6.4%; P=.005; number needed to treat [NNT]=14 smokers counseled using lung age to cause 1 more patient to quit). Smokers with normal lung ages were no more likely to quit than smokers with abnormal results.³

Abnormal results also may be a motivator
However, 3 prospective cohort studies demonstrated that patients with abnormal spirometry results were more likely to quit than patients with normal spirometry. In the first study, 4494 patients with at least 10 pack-years of smoking from 10 outpatient chest clinics in Poland underwent spirometry and were counseled to quit smoking; 1177 had abnormal spirometry results.

One year later, 16.3% of smokers with abnormal results had quit smoking, compared with 12% in the group with normal spirometry (P=.0003; NNT=23).⁴

The second study, also at outpatient chest clinics in Poland, evaluated spirometry plus cessation advice among 558 smokers, 297 of whom had abnormal spirometry results. At 1 year, 10.6% of patients with abnormal results had quit, compared with 8.4% of patients with normal lung function. A subgroup of 109 patients with moderate to severe airflow limitation showed significantly higher quit rates when compared with patients with mildly abnormal spirometry (16.5% vs 6.4%; P<.0001; NNT=10).⁵

In the third study, 6 primary care sites in Sweden provided spirometry and brief cessation advice to 445 smokers, 119 of whom were found to have abnormal lung function. At 3-year follow-up, 29% of patients with abnormal lung function had quit smoking, compared with 14% of patients with normal lung function (P=.001; NNT=7). Forty-five smokers with mildly abnormal lung function were recruited from this study to participate in another study, which may have biased the results toward higher quit rates among smokers with worse spirometry results.⁶

Recommendations

The US Preventive Services Task Force recommends against using spirometry to screen for chronic obstructive pulmonary disease, but advocates screening all adults for tobacco use and encouraging cessation.⁷

The authors of a Cochrane review found insufficient evidence to recommend using biomedical risk assessment (carbon monoxide blood levels, spirometry, genetic testing for alpha-1 antitrypsin deficiency) as a smoking cessation aid.⁸

Evidence summary

A systematic review of 3 RCTs with a total of 649 participants evaluated office spirometry as a motivational tool to improve quit rates by comparing spirometry plus cessation advice with cessation advice alone. All participants were men and women 19 to 75 years of age recruited from outpatient clinics.¹

In 1 trial, the intervention group received repeated counseling at 4 visits and underwent spirometry; the control group had 1 counseling session and was given a brochure. In the other 2 trials, the intervention group had both carbon monoxide measurements and spirometry, and all participants received more extensive counseling, including cessation skills training.

At 9 to 12 months’ follow-up, quit rates ranged from 6% to 24% in the intervention groups vs 5% to 14% in the control groups (not significantly different).¹

A subsequent study randomized 221 smokers to receive either spirometry plus brief cessation advice or advice alone. Researchers recruited patients 15 to 80 years of age who were willing to quit smoking from 16 general practice clinics in Belgium. Fifty-one percent of patients in both groups used nicotine replacement therapy (a larger percentage than is typical in studies done in the United States). At 6, 12, and 24 months, 5%, 2%, and 5% more smokers, respectively, from the spirometry group quit smoking compared with the control group, but this difference was not significant.²

Reporting spirometry results in terms of lung age may spur quitting
One RCT found significantly improved quit rates when patients who smoked were given their office spirometry results in terms of “lung age” (the age of an average healthy person with similar spirometry results) rather than as forced expiratory volume in 1 second (FEV1). Investigators performed office spirometry and gave smoking cessation advice to 561 smokers older than 35 years who were recruited from 5 general practices. They randomized patients to receive their spirometry results as either lung age or FEV1 and recorded quit rates at 12 months (smoking cessation was verified by measuring blood levels of carbon monoxide).

Patients whose spirometry results were reported as lung age were significantly more likely to quit than smokers whose results were given as FEV1 (13.6% vs 6.4%; P=.005; number needed to treat [NNT]=14 smokers counseled using lung age to cause 1 more patient to quit). Smokers with normal lung ages were no more likely to quit than smokers with abnormal results.³

Abnormal results also may be a motivator
However, 3 prospective cohort studies demonstrated that patients with abnormal spirometry results were more likely to quit than patients with normal spirometry. In the first study, 4494 patients with at least 10 pack-years of smoking from 10 outpatient chest clinics in Poland underwent spirometry and were counseled to quit smoking; 1177 had abnormal spirometry results.

One year later, 16.3% of smokers with abnormal results had quit smoking, compared with 12% in the group with normal spirometry (P=.0003; NNT=23).⁴

The second study, also at outpatient chest clinics in Poland, evaluated spirometry plus cessation advice among 558 smokers, 297 of whom had abnormal spirometry results. At 1 year, 10.6% of patients with abnormal results had quit, compared with 8.4% of patients with normal lung function. A subgroup of 109 patients with moderate to severe airflow limitation showed significantly higher quit rates when compared with patients with mildly abnormal spirometry (16.5% vs 6.4%; P<.0001; NNT=10).⁵

In the third study, 6 primary care sites in Sweden provided spirometry and brief cessation advice to 445 smokers, 119 of whom were found to have abnormal lung function. At 3-year follow-up, 29% of patients with abnormal lung function had quit smoking, compared with 14% of patients with normal lung function (P=.001; NNT=7). Forty-five smokers with mildly abnormal lung function were recruited from this study to participate in another study, which may have biased the results toward higher quit rates among smokers with worse spirometry results.⁶

Recommendations

The US Preventive Services Task Force recommends against using spirometry to screen for chronic obstructive pulmonary disease, but advocates screening all adults for tobacco use and encouraging cessation.⁷

The authors of a Cochrane review found insufficient evidence to recommend using biomedical risk assessment (carbon monoxide blood levels, spirometry, genetic testing for alpha-1 antitrypsin deficiency) as a smoking cessation aid.⁸

Evidence summary

A systematic review of 3 RCTs with a total of 649 participants evaluated office spirometry as a motivational tool to improve quit rates by comparing spirometry plus cessation advice with cessation advice alone. All participants were men and women 19 to 75 years of age recruited from outpatient clinics.¹

In 1 trial, the intervention group received repeated counseling at 4 visits and underwent spirometry; the control group had 1 counseling session and was given a brochure. In the other 2 trials, the intervention group had both carbon monoxide measurements and spirometry, and all participants received more extensive counseling, including cessation skills training.

At 9 to 12 months’ follow-up, quit rates ranged from 6% to 24% in the intervention groups vs 5% to 14% in the control groups (not significantly different).¹

A subsequent study randomized 221 smokers to receive either spirometry plus brief cessation advice or advice alone. Researchers recruited patients 15 to 80 years of age who were willing to quit smoking from 16 general practice clinics in Belgium. Fifty-one percent of patients in both groups used nicotine replacement therapy (a larger percentage than is typical in studies done in the United States). At 6, 12, and 24 months, 5%, 2%, and 5% more smokers, respectively, from the spirometry group quit smoking compared with the control group, but this difference was not significant.²

Reporting spirometry results in terms of lung age may spur quitting
One RCT found significantly improved quit rates when patients who smoked were given their office spirometry results in terms of “lung age” (the age of an average healthy person with similar spirometry results) rather than as forced expiratory volume in 1 second (FEV1). Investigators performed office spirometry and gave smoking cessation advice to 561 smokers older than 35 years who were recruited from 5 general practices. They randomized patients to receive their spirometry results as either lung age or FEV1 and recorded quit rates at 12 months (smoking cessation was verified by measuring blood levels of carbon monoxide).

Patients whose spirometry results were reported as lung age were significantly more likely to quit than smokers whose results were given as FEV1 (13.6% vs 6.4%; P=.005; number needed to treat [NNT]=14 smokers counseled using lung age to cause 1 more patient to quit). Smokers with normal lung ages were no more likely to quit than smokers with abnormal results.³

Abnormal results also may be a motivator
However, 3 prospective cohort studies demonstrated that patients with abnormal spirometry results were more likely to quit than patients with normal spirometry. In the first study, 4494 patients with at least 10 pack-years of smoking from 10 outpatient chest clinics in Poland underwent spirometry and were counseled to quit smoking; 1177 had abnormal spirometry results.

One year later, 16.3% of smokers with abnormal results had quit smoking, compared with 12% in the group with normal spirometry (P=.0003; NNT=23).⁴

The second study, also at outpatient chest clinics in Poland, evaluated spirometry plus cessation advice among 558 smokers, 297 of whom had abnormal spirometry results. At 1 year, 10.6% of patients with abnormal results had quit, compared with 8.4% of patients with normal lung function. A subgroup of 109 patients with moderate to severe airflow limitation showed significantly higher quit rates when compared with patients with mildly abnormal spirometry (16.5% vs 6.4%; P<.0001; NNT=10).⁵

In the third study, 6 primary care sites in Sweden provided spirometry and brief cessation advice to 445 smokers, 119 of whom were found to have abnormal lung function. At 3-year follow-up, 29% of patients with abnormal lung function had quit smoking, compared with 14% of patients with normal lung function (P=.001; NNT=7). Forty-five smokers with mildly abnormal lung function were recruited from this study to participate in another study, which may have biased the results toward higher quit rates among smokers with worse spirometry results.⁶

Recommendations

The US Preventive Services Task Force recommends against using spirometry to screen for chronic obstructive pulmonary disease, but advocates screening all adults for tobacco use and encouraging cessation.⁷

The authors of a Cochrane review found insufficient evidence to recommend using biomedical risk assessment (carbon monoxide blood levels, spirometry, genetic testing for alpha-1 antitrypsin deficiency) as a smoking cessation aid.⁸

CASE 1: Lauren W*

Two years ago, Lauren W, a 57-year-old Caucasian woman, sought care at our medical center after learning that her pregnant daughter tested positive during a prenatal cystic fibrosis mutation genetic screen. Lauren had clinical symptoms of malodorous and greasy bowel movements, dyspepsia, early satiety, and a history of recurrent bronchitis since childhood.

According to her history, she did not suffer from failure to thrive as a child. She’d had 5 episodes of adult-onset acute pancreatitis and had 2 surgeries for sinusitis.

On physical exam, we heard no crackles during lung auscultation. Lauren also had mild digital clubbing.

Testing: We ordered a chest x-ray, which revealed left upper lobe atelectasis, but there was no bronchiectasis.

Pulmonary function tests indicated mild obstructive lung disease with forced vital capacity (FVC) 2.39 L or 84% predicted; forced expiratory volume in 1 second (FEV₁) 1.59 L or 68% predicted; and an FEV₁/FVC of 0.66.

A sweat chloride test was positive on both arms: 77 and 83 mmol/L. Genetic testing revealed compound heterozygosity for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations Δ F508 and R117H with a 5T allele. To test for pancreatic insufficiency, we performed a 72-hour fecal fat testing while she was on a low-fat diet; it revealed 5.5 g of fat per 24-hour period, suggesting fat malabsorption. Based on positive quantitative sweat test ≥60 mmol/L and the presence of 2 cystic fibrosis–causing mutations, we made the diagnosis of cystic fibrosis.

Treatment: We put Lauren on albuterol and recombinant human DNase respiratory treatments, pancreatic enzymes, and multivitamins with extra lipid-soluble vitamins and calcium supplements. We also continued her low-fat diet of 1500 to 1800 calories per day due to a diagnosis of coronary artery disease.

*Patients’ names have been changed to protect their privacy.

CASE 2: Zack P*

Zack P, a 6-year-old Caucasian boy, was admitted to the hospital with what we suspected was acute gastroenteritis. Serum testing revealed elevated pancreatic enzymes. He had recently sustained an injury to the mid-abdomen during a soccer game and also had a history of chronic sinusitis. One month after his release from the hospital, his symptoms resolved, but his pancreatic enzymes remained elevated (amylase 130 U/L, lipase 177 U/L).

Testing: He underwent 2 sweat chloride tests, which were borderline elevated at 49 mmol/L on the right arm and 40 mmol/L on the left arm; repeat testing was 49 mmol/L on the left arm, 43 mmol/L on the right arm. Genetic testing revealed heterozygosity for CFTR gene mutation Δ F508 with the presence of 7T and 9T allele variants. Over an 8-month period, Zack remained asymptomatic, but his pancreatic enzymes were persistently elevated.

Zack’s physical exam showed that his weight had dropped from the 75th to the 50th percentile. A magnetic resonance cholangiopancreatography indicated homogeneous parenchyma and normal enhancement throughout his pancreas. Similarly, we could not find evidence of acute pancreatitis or biliary or pancreatic duct dilation, and a 72-hour fecal fat study was normal. Given Zack’s borderline sweat chloride, compound heterozygosity of cystic fibrosis mutations, and his phenotype of recurrent pancreatitis, he was given a diagnosis of atypical cystic fibrosis.

Treatment: Based on our diagnostic workup, pancreatic enzyme therapy was not warranted.

*Patients’ names have been changed to protect their privacy.

These 2 cases illustrate how clinically diverse cystic fibrosis can be. The cystic fibrosis phenotype can range from a patient with 2 disease-causing cystic fibrosis mutations with significant sweat gland dysfunction and childhood onset of mild cystic fibrosis symptomatology with normal growth—Lauren—to a patient who is CFTR heterozygous with pancreatitis and a borderline sweat chloride concentration—Zack. Both cases emphasize the need to think “outside the box” and not expect all patients with cystic fibrosis to come in with typical signs and symptoms.

What does the “nonclassic” cystic fibrosis patient look like?

Patients with cystic fibrosis are usually diagnosed during childhood with pulmonary disease, pancreatic insufficiency, malabsorption, malnutrition, elevated sweat chloride, and male infertility. But more recently, patients have been diagnosed in adulthood because either they lacked significant clinical symptoms in childhood or they came in with atypical signs or symptoms (pancreatic sufficiency and sweat chloride <60 mmol/L).

In the past, cystic fibrosis patients rarely lived past their second decade, but those with atypical cystic fibrosis tend to have milder disease, including less severe respiratory signs and symptoms. The good news is that often translates into a long lifespan.¹ As recently as 2005, the Cystic Fibrosis Foundation had listed a median survival age of 37.² Advances in respiratory, gastrointestinal, and nutritional therapies have significantly contributed to the increased survival of these patients. Unfortunately, such milder cases can easily go undetected.

Sweat chloride testing remains a gold standard for the diagnosis of cystic fibrosis. As previously mentioned, classic cystic fibrosis patients are typically diagnosed during childhood and have a sweat chloride concentration ≥60 mmol/L and more severe multiorgan involvement (sinopulmonary and gastrointestinal disease with failure to thrive).

There are 5 classes of CFTR mutations that result in compromised CFTR function: The presence of 2 severe CFTR mutations (classes I-III) completely abolishes CFTR function. It is diagnosed in childhood and usually results in the classic clinical features of pancreatic insufficiency and failure to thrive. However, patients who are compound heterozygous for the milder CFTR mutations (classes IV and V) experience partial CFTR function, which in turn results in atypical features such as pancreatic sufficiency and normal or borderline sweat chloride concentrations. That makes the diagnosis more elusive during early childhood.^1,3

The severity of sweat gland and exocrine pancreatic dysfunction produced by a cystic fibrosis mutation depends on the class of CFTR gene mutation and the level of CFTR gene and protein expression.^4,5 In certain genetic backgrounds, the 5T allele associated with a high number of TG (thymine/guanine) repeats found in compound heterozygosity with a disease-causing CFTR mutation acts as a “mild CFTR mutation,” resulting in the nonclassic cystic fibrosis phenotype.³ Individuals with atypical cystic fibrosis diagnosed later in life may have single organ involvement, such as mild lung disease, nasal polyposis, recurrent pancreatitis, biliary cirrhosis, portal hypertension, or obstructive azoospermia.¹

Lauren had several classic cystic fibrosis features, including recurrent lung disease, pancreatic insufficiency, and sweat gland dysfunction, but it’s likely that her relatively mild pulmonary presentation, normal body mass index, and lack of failure to thrive led to a delay in her diagnosis.

Some patients with atypical cystic fibrosis seek care for idiopathic chronic pancreatitis (ICP), and researchers have found a link between ICP and CFTR gene mutations. For instance, recent studies of ICP patients compared with geographically and ethnically matched controls revealed a higher frequency of abnormal CFTR alleles in the ICP population.^6,7 Milder CFTR mutations resulting in partial CFTR function have also been associated with ICP.^7,8

Zack was heterozygous for Δ F508, a common CFTR mutation in the Caucasian population. Cohn et al found a higher frequency of this mutation in ICP patients from Europe (mostly English, Italian, and Czech).⁹ Poly T allele variants such as 5T, 7T, and 9T have not been associated with a higher frequency of ICP.^6,7

Early detection may translate into better treatment

Although patients diagnosed with cystic fibrosis as adults are less likely to present with classic clinical features, they may develop bronchiectasis and advanced lung disease.^10,11 Those who are identified early on—including those who are asymptomatic and have normal lung function—may benefit from respiratory therapy to prevent or delay lung disease.¹² Several studies have shown that patients with mild cystic fibrosis disease and stable spirometry results have evidence of bronchiectasis on their x-rays and advanced lung disease that appears on high-resolution CT.^13,14

Judge et al have suggested that mucus plugging occurs early in cystic fibrosis lung disease and at a milder stage of lung function impairment, and that bronchiectasis may be an end result of such abnormalities.¹⁴ Nonclassic cystic fibrosis patients often have episodes of “bronchitis,” and once the practitioner becomes concerned, the radiographic image may already show evidence of bronchiectasis. Once again, this emphasizes the importance of early detection and prompt treatment.¹⁵

CASE 1: Lauren

Unfortunately, Lauren was unable to benefit from early use of respiratory therapies like tobramycin, hypertonic saline, and recombinant human DNase. She began these treatments after developing advanced lung disease. Studies have shown that tobramycin, long-term inhaled hypertonic saline, and recombinant human DNase can reduce the number of pulmonary exacerbations and increase both FVC and FEV₁ values in previously stable cystic fibrosis patients.^16-18

Similarly, because Lauren’s pancreatitis was due to pancreatic insufficiency, early recognition of pancreatic insufficiency and enzyme therapy may have greatly reduced the number and severity of her pancreatic episodes.¹⁹

Unfortunately, over the last few years, Lauren’s lung function has declined and she has been hospitalized for cystic fibrosis exacerbations and sinusitis; she has had 3 additional episodes of acute pancreatitis. Although her FEV₁ is lower than on initial evaluation, she is clinically stable.

CASE 2: Zack

Clinically, Zack is stable and his recent amylase and lipase are elevated at 92 U/L and 71 U/L, respectively. He has had no acute exacerbations.

Patients like Lauren and Zack serve to remind us of the need to recognize and closely monitor patients with nonclassic cystic fibrosis. These patients may come to the office with “asthma-like” symptoms, bronchitis, polyps, pancreatitis, cholelithiasis, constipation, abdominal bloating/flatus, and infertility. Because their symptoms may not be severe enough to be referred to a subspecialist, family physicians play a critical role in recognizing these overlooked cases early on.

CORRESPONDENCE Anupama Chawla, MD, Director, Division of Pediatric Gastroenterology and Nutrition, Stony Brook University Hospital, Stony Brook, NY 11794; [email protected]

CASE 1: Lauren W*

Two years ago, Lauren W, a 57-year-old Caucasian woman, sought care at our medical center after learning that her pregnant daughter tested positive during a prenatal cystic fibrosis mutation genetic screen. Lauren had clinical symptoms of malodorous and greasy bowel movements, dyspepsia, early satiety, and a history of recurrent bronchitis since childhood.

According to her history, she did not suffer from failure to thrive as a child. She’d had 5 episodes of adult-onset acute pancreatitis and had 2 surgeries for sinusitis.

On physical exam, we heard no crackles during lung auscultation. Lauren also had mild digital clubbing.

Testing: We ordered a chest x-ray, which revealed left upper lobe atelectasis, but there was no bronchiectasis.

Pulmonary function tests indicated mild obstructive lung disease with forced vital capacity (FVC) 2.39 L or 84% predicted; forced expiratory volume in 1 second (FEV₁) 1.59 L or 68% predicted; and an FEV₁/FVC of 0.66.

A sweat chloride test was positive on both arms: 77 and 83 mmol/L. Genetic testing revealed compound heterozygosity for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations Δ F508 and R117H with a 5T allele. To test for pancreatic insufficiency, we performed a 72-hour fecal fat testing while she was on a low-fat diet; it revealed 5.5 g of fat per 24-hour period, suggesting fat malabsorption. Based on positive quantitative sweat test ≥60 mmol/L and the presence of 2 cystic fibrosis–causing mutations, we made the diagnosis of cystic fibrosis.

Treatment: We put Lauren on albuterol and recombinant human DNase respiratory treatments, pancreatic enzymes, and multivitamins with extra lipid-soluble vitamins and calcium supplements. We also continued her low-fat diet of 1500 to 1800 calories per day due to a diagnosis of coronary artery disease.

*Patients’ names have been changed to protect their privacy.

CASE 2: Zack P*

Zack P, a 6-year-old Caucasian boy, was admitted to the hospital with what we suspected was acute gastroenteritis. Serum testing revealed elevated pancreatic enzymes. He had recently sustained an injury to the mid-abdomen during a soccer game and also had a history of chronic sinusitis. One month after his release from the hospital, his symptoms resolved, but his pancreatic enzymes remained elevated (amylase 130 U/L, lipase 177 U/L).

Testing: He underwent 2 sweat chloride tests, which were borderline elevated at 49 mmol/L on the right arm and 40 mmol/L on the left arm; repeat testing was 49 mmol/L on the left arm, 43 mmol/L on the right arm. Genetic testing revealed heterozygosity for CFTR gene mutation Δ F508 with the presence of 7T and 9T allele variants. Over an 8-month period, Zack remained asymptomatic, but his pancreatic enzymes were persistently elevated.

Zack’s physical exam showed that his weight had dropped from the 75th to the 50th percentile. A magnetic resonance cholangiopancreatography indicated homogeneous parenchyma and normal enhancement throughout his pancreas. Similarly, we could not find evidence of acute pancreatitis or biliary or pancreatic duct dilation, and a 72-hour fecal fat study was normal. Given Zack’s borderline sweat chloride, compound heterozygosity of cystic fibrosis mutations, and his phenotype of recurrent pancreatitis, he was given a diagnosis of atypical cystic fibrosis.

Treatment: Based on our diagnostic workup, pancreatic enzyme therapy was not warranted.

*Patients’ names have been changed to protect their privacy.

These 2 cases illustrate how clinically diverse cystic fibrosis can be. The cystic fibrosis phenotype can range from a patient with 2 disease-causing cystic fibrosis mutations with significant sweat gland dysfunction and childhood onset of mild cystic fibrosis symptomatology with normal growth—Lauren—to a patient who is CFTR heterozygous with pancreatitis and a borderline sweat chloride concentration—Zack. Both cases emphasize the need to think “outside the box” and not expect all patients with cystic fibrosis to come in with typical signs and symptoms.

What does the “nonclassic” cystic fibrosis patient look like?

Patients with cystic fibrosis are usually diagnosed during childhood with pulmonary disease, pancreatic insufficiency, malabsorption, malnutrition, elevated sweat chloride, and male infertility. But more recently, patients have been diagnosed in adulthood because either they lacked significant clinical symptoms in childhood or they came in with atypical signs or symptoms (pancreatic sufficiency and sweat chloride <60 mmol/L).

In the past, cystic fibrosis patients rarely lived past their second decade, but those with atypical cystic fibrosis tend to have milder disease, including less severe respiratory signs and symptoms. The good news is that often translates into a long lifespan.¹ As recently as 2005, the Cystic Fibrosis Foundation had listed a median survival age of 37.² Advances in respiratory, gastrointestinal, and nutritional therapies have significantly contributed to the increased survival of these patients. Unfortunately, such milder cases can easily go undetected.

Sweat chloride testing remains a gold standard for the diagnosis of cystic fibrosis. As previously mentioned, classic cystic fibrosis patients are typically diagnosed during childhood and have a sweat chloride concentration ≥60 mmol/L and more severe multiorgan involvement (sinopulmonary and gastrointestinal disease with failure to thrive).

There are 5 classes of CFTR mutations that result in compromised CFTR function: The presence of 2 severe CFTR mutations (classes I-III) completely abolishes CFTR function. It is diagnosed in childhood and usually results in the classic clinical features of pancreatic insufficiency and failure to thrive. However, patients who are compound heterozygous for the milder CFTR mutations (classes IV and V) experience partial CFTR function, which in turn results in atypical features such as pancreatic sufficiency and normal or borderline sweat chloride concentrations. That makes the diagnosis more elusive during early childhood.^1,3

The severity of sweat gland and exocrine pancreatic dysfunction produced by a cystic fibrosis mutation depends on the class of CFTR gene mutation and the level of CFTR gene and protein expression.^4,5 In certain genetic backgrounds, the 5T allele associated with a high number of TG (thymine/guanine) repeats found in compound heterozygosity with a disease-causing CFTR mutation acts as a “mild CFTR mutation,” resulting in the nonclassic cystic fibrosis phenotype.³ Individuals with atypical cystic fibrosis diagnosed later in life may have single organ involvement, such as mild lung disease, nasal polyposis, recurrent pancreatitis, biliary cirrhosis, portal hypertension, or obstructive azoospermia.¹

Lauren had several classic cystic fibrosis features, including recurrent lung disease, pancreatic insufficiency, and sweat gland dysfunction, but it’s likely that her relatively mild pulmonary presentation, normal body mass index, and lack of failure to thrive led to a delay in her diagnosis.

Some patients with atypical cystic fibrosis seek care for idiopathic chronic pancreatitis (ICP), and researchers have found a link between ICP and CFTR gene mutations. For instance, recent studies of ICP patients compared with geographically and ethnically matched controls revealed a higher frequency of abnormal CFTR alleles in the ICP population.^6,7 Milder CFTR mutations resulting in partial CFTR function have also been associated with ICP.^7,8

Zack was heterozygous for Δ F508, a common CFTR mutation in the Caucasian population. Cohn et al found a higher frequency of this mutation in ICP patients from Europe (mostly English, Italian, and Czech).⁹ Poly T allele variants such as 5T, 7T, and 9T have not been associated with a higher frequency of ICP.^6,7

Early detection may translate into better treatment

Although patients diagnosed with cystic fibrosis as adults are less likely to present with classic clinical features, they may develop bronchiectasis and advanced lung disease.^10,11 Those who are identified early on—including those who are asymptomatic and have normal lung function—may benefit from respiratory therapy to prevent or delay lung disease.¹² Several studies have shown that patients with mild cystic fibrosis disease and stable spirometry results have evidence of bronchiectasis on their x-rays and advanced lung disease that appears on high-resolution CT.^13,14

Judge et al have suggested that mucus plugging occurs early in cystic fibrosis lung disease and at a milder stage of lung function impairment, and that bronchiectasis may be an end result of such abnormalities.¹⁴ Nonclassic cystic fibrosis patients often have episodes of “bronchitis,” and once the practitioner becomes concerned, the radiographic image may already show evidence of bronchiectasis. Once again, this emphasizes the importance of early detection and prompt treatment.¹⁵

CASE 1: Lauren

Unfortunately, Lauren was unable to benefit from early use of respiratory therapies like tobramycin, hypertonic saline, and recombinant human DNase. She began these treatments after developing advanced lung disease. Studies have shown that tobramycin, long-term inhaled hypertonic saline, and recombinant human DNase can reduce the number of pulmonary exacerbations and increase both FVC and FEV₁ values in previously stable cystic fibrosis patients.^16-18

Similarly, because Lauren’s pancreatitis was due to pancreatic insufficiency, early recognition of pancreatic insufficiency and enzyme therapy may have greatly reduced the number and severity of her pancreatic episodes.¹⁹

Unfortunately, over the last few years, Lauren’s lung function has declined and she has been hospitalized for cystic fibrosis exacerbations and sinusitis; she has had 3 additional episodes of acute pancreatitis. Although her FEV₁ is lower than on initial evaluation, she is clinically stable.

CASE 2: Zack

Clinically, Zack is stable and his recent amylase and lipase are elevated at 92 U/L and 71 U/L, respectively. He has had no acute exacerbations.

Patients like Lauren and Zack serve to remind us of the need to recognize and closely monitor patients with nonclassic cystic fibrosis. These patients may come to the office with “asthma-like” symptoms, bronchitis, polyps, pancreatitis, cholelithiasis, constipation, abdominal bloating/flatus, and infertility. Because their symptoms may not be severe enough to be referred to a subspecialist, family physicians play a critical role in recognizing these overlooked cases early on.

CORRESPONDENCE Anupama Chawla, MD, Director, Division of Pediatric Gastroenterology and Nutrition, Stony Brook University Hospital, Stony Brook, NY 11794; [email protected]

CASE 1: Lauren W*

Two years ago, Lauren W, a 57-year-old Caucasian woman, sought care at our medical center after learning that her pregnant daughter tested positive during a prenatal cystic fibrosis mutation genetic screen. Lauren had clinical symptoms of malodorous and greasy bowel movements, dyspepsia, early satiety, and a history of recurrent bronchitis since childhood.

According to her history, she did not suffer from failure to thrive as a child. She’d had 5 episodes of adult-onset acute pancreatitis and had 2 surgeries for sinusitis.

On physical exam, we heard no crackles during lung auscultation. Lauren also had mild digital clubbing.

Testing: We ordered a chest x-ray, which revealed left upper lobe atelectasis, but there was no bronchiectasis.

Pulmonary function tests indicated mild obstructive lung disease with forced vital capacity (FVC) 2.39 L or 84% predicted; forced expiratory volume in 1 second (FEV₁) 1.59 L or 68% predicted; and an FEV₁/FVC of 0.66.

A sweat chloride test was positive on both arms: 77 and 83 mmol/L. Genetic testing revealed compound heterozygosity for cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations Δ F508 and R117H with a 5T allele. To test for pancreatic insufficiency, we performed a 72-hour fecal fat testing while she was on a low-fat diet; it revealed 5.5 g of fat per 24-hour period, suggesting fat malabsorption. Based on positive quantitative sweat test ≥60 mmol/L and the presence of 2 cystic fibrosis–causing mutations, we made the diagnosis of cystic fibrosis.

Treatment: We put Lauren on albuterol and recombinant human DNase respiratory treatments, pancreatic enzymes, and multivitamins with extra lipid-soluble vitamins and calcium supplements. We also continued her low-fat diet of 1500 to 1800 calories per day due to a diagnosis of coronary artery disease.

*Patients’ names have been changed to protect their privacy.

CASE 2: Zack P*

Zack P, a 6-year-old Caucasian boy, was admitted to the hospital with what we suspected was acute gastroenteritis. Serum testing revealed elevated pancreatic enzymes. He had recently sustained an injury to the mid-abdomen during a soccer game and also had a history of chronic sinusitis. One month after his release from the hospital, his symptoms resolved, but his pancreatic enzymes remained elevated (amylase 130 U/L, lipase 177 U/L).

Testing: He underwent 2 sweat chloride tests, which were borderline elevated at 49 mmol/L on the right arm and 40 mmol/L on the left arm; repeat testing was 49 mmol/L on the left arm, 43 mmol/L on the right arm. Genetic testing revealed heterozygosity for CFTR gene mutation Δ F508 with the presence of 7T and 9T allele variants. Over an 8-month period, Zack remained asymptomatic, but his pancreatic enzymes were persistently elevated.

Zack’s physical exam showed that his weight had dropped from the 75th to the 50th percentile. A magnetic resonance cholangiopancreatography indicated homogeneous parenchyma and normal enhancement throughout his pancreas. Similarly, we could not find evidence of acute pancreatitis or biliary or pancreatic duct dilation, and a 72-hour fecal fat study was normal. Given Zack’s borderline sweat chloride, compound heterozygosity of cystic fibrosis mutations, and his phenotype of recurrent pancreatitis, he was given a diagnosis of atypical cystic fibrosis.

Treatment: Based on our diagnostic workup, pancreatic enzyme therapy was not warranted.

*Patients’ names have been changed to protect their privacy.

These 2 cases illustrate how clinically diverse cystic fibrosis can be. The cystic fibrosis phenotype can range from a patient with 2 disease-causing cystic fibrosis mutations with significant sweat gland dysfunction and childhood onset of mild cystic fibrosis symptomatology with normal growth—Lauren—to a patient who is CFTR heterozygous with pancreatitis and a borderline sweat chloride concentration—Zack. Both cases emphasize the need to think “outside the box” and not expect all patients with cystic fibrosis to come in with typical signs and symptoms.

What does the “nonclassic” cystic fibrosis patient look like?

Patients with cystic fibrosis are usually diagnosed during childhood with pulmonary disease, pancreatic insufficiency, malabsorption, malnutrition, elevated sweat chloride, and male infertility. But more recently, patients have been diagnosed in adulthood because either they lacked significant clinical symptoms in childhood or they came in with atypical signs or symptoms (pancreatic sufficiency and sweat chloride <60 mmol/L).

In the past, cystic fibrosis patients rarely lived past their second decade, but those with atypical cystic fibrosis tend to have milder disease, including less severe respiratory signs and symptoms. The good news is that often translates into a long lifespan.¹ As recently as 2005, the Cystic Fibrosis Foundation had listed a median survival age of 37.² Advances in respiratory, gastrointestinal, and nutritional therapies have significantly contributed to the increased survival of these patients. Unfortunately, such milder cases can easily go undetected.

Sweat chloride testing remains a gold standard for the diagnosis of cystic fibrosis. As previously mentioned, classic cystic fibrosis patients are typically diagnosed during childhood and have a sweat chloride concentration ≥60 mmol/L and more severe multiorgan involvement (sinopulmonary and gastrointestinal disease with failure to thrive).

There are 5 classes of CFTR mutations that result in compromised CFTR function: The presence of 2 severe CFTR mutations (classes I-III) completely abolishes CFTR function. It is diagnosed in childhood and usually results in the classic clinical features of pancreatic insufficiency and failure to thrive. However, patients who are compound heterozygous for the milder CFTR mutations (classes IV and V) experience partial CFTR function, which in turn results in atypical features such as pancreatic sufficiency and normal or borderline sweat chloride concentrations. That makes the diagnosis more elusive during early childhood.^1,3

The severity of sweat gland and exocrine pancreatic dysfunction produced by a cystic fibrosis mutation depends on the class of CFTR gene mutation and the level of CFTR gene and protein expression.^4,5 In certain genetic backgrounds, the 5T allele associated with a high number of TG (thymine/guanine) repeats found in compound heterozygosity with a disease-causing CFTR mutation acts as a “mild CFTR mutation,” resulting in the nonclassic cystic fibrosis phenotype.³ Individuals with atypical cystic fibrosis diagnosed later in life may have single organ involvement, such as mild lung disease, nasal polyposis, recurrent pancreatitis, biliary cirrhosis, portal hypertension, or obstructive azoospermia.¹

Lauren had several classic cystic fibrosis features, including recurrent lung disease, pancreatic insufficiency, and sweat gland dysfunction, but it’s likely that her relatively mild pulmonary presentation, normal body mass index, and lack of failure to thrive led to a delay in her diagnosis.

Some patients with atypical cystic fibrosis seek care for idiopathic chronic pancreatitis (ICP), and researchers have found a link between ICP and CFTR gene mutations. For instance, recent studies of ICP patients compared with geographically and ethnically matched controls revealed a higher frequency of abnormal CFTR alleles in the ICP population.^6,7 Milder CFTR mutations resulting in partial CFTR function have also been associated with ICP.^7,8

Zack was heterozygous for Δ F508, a common CFTR mutation in the Caucasian population. Cohn et al found a higher frequency of this mutation in ICP patients from Europe (mostly English, Italian, and Czech).⁹ Poly T allele variants such as 5T, 7T, and 9T have not been associated with a higher frequency of ICP.^6,7

Early detection may translate into better treatment

Although patients diagnosed with cystic fibrosis as adults are less likely to present with classic clinical features, they may develop bronchiectasis and advanced lung disease.^10,11 Those who are identified early on—including those who are asymptomatic and have normal lung function—may benefit from respiratory therapy to prevent or delay lung disease.¹² Several studies have shown that patients with mild cystic fibrosis disease and stable spirometry results have evidence of bronchiectasis on their x-rays and advanced lung disease that appears on high-resolution CT.^13,14

Judge et al have suggested that mucus plugging occurs early in cystic fibrosis lung disease and at a milder stage of lung function impairment, and that bronchiectasis may be an end result of such abnormalities.¹⁴ Nonclassic cystic fibrosis patients often have episodes of “bronchitis,” and once the practitioner becomes concerned, the radiographic image may already show evidence of bronchiectasis. Once again, this emphasizes the importance of early detection and prompt treatment.¹⁵

CASE 1: Lauren

Unfortunately, Lauren was unable to benefit from early use of respiratory therapies like tobramycin, hypertonic saline, and recombinant human DNase. She began these treatments after developing advanced lung disease. Studies have shown that tobramycin, long-term inhaled hypertonic saline, and recombinant human DNase can reduce the number of pulmonary exacerbations and increase both FVC and FEV₁ values in previously stable cystic fibrosis patients.^16-18

Similarly, because Lauren’s pancreatitis was due to pancreatic insufficiency, early recognition of pancreatic insufficiency and enzyme therapy may have greatly reduced the number and severity of her pancreatic episodes.¹⁹

Unfortunately, over the last few years, Lauren’s lung function has declined and she has been hospitalized for cystic fibrosis exacerbations and sinusitis; she has had 3 additional episodes of acute pancreatitis. Although her FEV₁ is lower than on initial evaluation, she is clinically stable.

CASE 2: Zack

Clinically, Zack is stable and his recent amylase and lipase are elevated at 92 U/L and 71 U/L, respectively. He has had no acute exacerbations.

Patients like Lauren and Zack serve to remind us of the need to recognize and closely monitor patients with nonclassic cystic fibrosis. These patients may come to the office with “asthma-like” symptoms, bronchitis, polyps, pancreatitis, cholelithiasis, constipation, abdominal bloating/flatus, and infertility. Because their symptoms may not be severe enough to be referred to a subspecialist, family physicians play a critical role in recognizing these overlooked cases early on.

CORRESPONDENCE Anupama Chawla, MD, Director, Division of Pediatric Gastroenterology and Nutrition, Stony Brook University Hospital, Stony Brook, NY 11794; [email protected]

CASE An 84-year-old man was admitted to our family medicine inpatient service with increasing weakness, fatigue, nausea, jaundice, and anorexia after undergoing thoracentesis for recurrent large right-sided pleural effusion twice within the past 6 weeks. The patient had no fever, chills, night sweats, chest pain, or chronic cough.

His past medical history included coronary artery disease and hyperlipidemia, and he had undergone coronary artery bypass grafting 6 years prior to this admission.

Initial vital signs included a blood pressure of 116/68 mm hg and a pulse rate of 78 beats per minute. physical examination revealed a thin but otherwise active and functional man, with the presence of scleral icterus and a 2/6 systolic murmur that was loudest at the left upper sternal border, with no pericardial knocks or rubs. There was no jugular venous distension. The patient had decreased breath sounds at the right base, but no appreciable rales, rhonchi, or wheezes, and an enlarged liver with an irregular edge approximately 7 cm below the costal margin. he had bilateral trace pitting edema of the lower extremities and an erythematous chronic venous stasis ulcer on his left lower leg that was being treated with sulfamethoxazole and trimethoprim and rifampin.

Laboratory findings included a sodium level of 130 mEq/L; creatinine, 1.6 mg/dL; total bilirubin, 4.2 mg/dL; and an international normalized ratio (INR) of 1.6, with an otherwise normal liver profile. pleural fluid was transudative by light’s criteria, with negative pleural fluid cultures.

A chest x-ray showed right-sided airspace disease, with an associated small effusion (FIGURE 1), and an electrocardiogram (EKG) revealed a right axis deviation with flipped T waves in V3-V6 (FIGURE 2). A computed tomography (CT) scan of the chest performed 2 months prior to admission revealed a small right pleural effusion, moderate emphysema, and pleural plaques. A transthoracic echocardiogram performed a week earlier was significant for a normal ejection fraction without pericardial thickening, and mild dilation of the left and right atria and the right ventricle.

Our patient had recurrent transudative pleural effusions with no history of congestive heart failure, a normal thyroid-stimulating hormone, no signs of nephrotic syndrome, no risk factors for lung cancer, and a presentation that was not consistent with an acute pulmonary embolus. he had jaundice, but no risk factors for cirrhosis. A comprehensive hepatology consult suggested that the jaundice was associated with recent rifampin use, along with hepatic congestion likely due to cardiac etiology.

The patient also had a documented history of constrictive pericarditis. Although a cardiac CT scan 15 months prior to his hospital admission showed normal pericardial thickness, constrictive pericarditis remained high on our differential.

To further evaluate the patient’s cardiac function, a cardiologist performed a right-sided cardiac catheterization. in constrictive pericarditis, equalization of end-diastolic pressures occurs due to limitation of the total volume of the ventricles by a rigid pericardium. in our patient, these pressures did not equalize. his right and left ventricular pressure tracings did, however, have the classic square root sign often seen in constrictive pericarditis (FIGURE 3). This “dip and plateau” is the result of rapid filling of the ventricles during early diastole, with the inflexible pericardium causing an abrupt halt in ventricular filling.¹

We considered restrictive cardiomyopathy in the differential, too, but the signs and symptoms weren’t a perfect fit there, either. equalization of left and right ventricular end-diastolic pressures in cardiac catheterization is usually not seen in restrictive cardiomyopathy, but neither is the square-root sign evident on ventricular pressure monitors.¹

FIGURE 1
X-ray shows right-sided airspace disease

FIGURE 2
Right axis deviation with flipped T waves

FIGURE 3
Classic square root sign

WHAT IS THE MOST LIKELY EXPLANATION FOR HIS CONDITION?

Constrictive pericarditis

On the advice of a cardiologist who specializes in advanced cardiac imaging, our patient underwent tissue Doppler velocity echocardiography—a diagnostic test that provides evidence of a diseased myocardium (as in restrictive cardiomyopathy), as well as changes in diastolic blood flow that differentiate constrictive pericarditis from restrictive cardiomyopathy. Our patient’s tissue Doppler velocity echocardiogram revealed a normal myocardium with an abrupt cessation of early left ventricular filling, consistent with constrictive pericarditis. Along with his clinical presentation and history, this test was conclusive enough to diagnose constrictive pericarditis.

Making the diagnosis in more “typical” cases
Symptoms of constrictive pericarditis include fluid overload (eg, recurrent pleural effusions^2-4) hepatic dysfunction, and peripheral edema. Studies show that 44% to 54% of patients with constrictive pericarditis present with pleural effusions;⁵ chest pain and dyspnea are other common symptoms.⁶ Past medical history is also important, considering the 3 most common risks for constrictive pericarditis: cardiac surgery, pericarditis, and irradiation of the mediastinum (TABLE).⁷

Typical physical exam findings in patients with constrictive pericarditis include an elevated jugular venous pressure, third spacing of fluids, a pericardial knock, and Kussmaul’s sign. Our patient had third spacing of fluids, including mild peripheral edema and the recurrent effusions as noted, as well as signs of hepatic dysfunction that were initially attributed to his rifampin use. While these symptoms raise the suspicion of constrictive pericarditis, none is specific to that condition alone.

Studies that help in the diagnosis of constrictive pericarditis include chest x-ray, cardiac CT, echocardiography, cardiac magnetic resonance imaging (MRI), and cardiac catheterization. EKG has no specific findings, but cardiac arrhythmias (eg, atrial fibrillation) are common.⁸ Pericardial thickening on cardiac CT scan is a definitive but not universal finding; in a Mayo Clinic study, such thickening was not evident in 26 of 143 patients with confirmed constrictive pericarditis.⁸ Cardiac MRI has been shown to have 88% sensitivity and 100% specificity,⁹ but will miss up to 18% of patients with constrictive pericarditis.⁸

Differentiating between restriction and constriction. It can be difficult to distinguish between constrictive pericarditis and restrictive cardiomyopathy. Although these conditions can present in a similar manner, they require different modes of treatment. Laboratory testing, cardiac catheterization, and tissue Doppler velocity echocardiography (which we relied on) can help to distinguish between them.

TABLE
Causes of constrictive pericarditis⁷

Pericardiectomy is the treatment of choice

Pericardiectomy, the optimal treatment for most patients with constrictive pericarditis, carries a 30-day perioperative mortality of approximately 6%.^5,7 Patients with minimal symptoms can be monitored for up to 2 months, but only 17% of cases are self-limited.⁶ Patients with end-stage disease or those who have radiation-induced constrictive pericarditis experience poor surgical outcomes, and may be better served by medical management.⁷

In light of our patient’s excellent baseline functional status, clinical presentation, and Doppler test results, a cardiothoracic surgeon performed a pericardiectomy. His symptoms improved postoperatively, and he has had no further pleural effusions. The patient’s fatigue, anorexia, weight loss, and dyspnea fully resolved, as well.

CORRESPONDENCE Jeffrey S. Morgeson, MD; 2123 Auburn Avenue, 340 MOB, Cincinnati, OH 45219; [email protected]

CASE An 84-year-old man was admitted to our family medicine inpatient service with increasing weakness, fatigue, nausea, jaundice, and anorexia after undergoing thoracentesis for recurrent large right-sided pleural effusion twice within the past 6 weeks. The patient had no fever, chills, night sweats, chest pain, or chronic cough.

His past medical history included coronary artery disease and hyperlipidemia, and he had undergone coronary artery bypass grafting 6 years prior to this admission.

Initial vital signs included a blood pressure of 116/68 mm hg and a pulse rate of 78 beats per minute. physical examination revealed a thin but otherwise active and functional man, with the presence of scleral icterus and a 2/6 systolic murmur that was loudest at the left upper sternal border, with no pericardial knocks or rubs. There was no jugular venous distension. The patient had decreased breath sounds at the right base, but no appreciable rales, rhonchi, or wheezes, and an enlarged liver with an irregular edge approximately 7 cm below the costal margin. he had bilateral trace pitting edema of the lower extremities and an erythematous chronic venous stasis ulcer on his left lower leg that was being treated with sulfamethoxazole and trimethoprim and rifampin.

Laboratory findings included a sodium level of 130 mEq/L; creatinine, 1.6 mg/dL; total bilirubin, 4.2 mg/dL; and an international normalized ratio (INR) of 1.6, with an otherwise normal liver profile. pleural fluid was transudative by light’s criteria, with negative pleural fluid cultures.

A chest x-ray showed right-sided airspace disease, with an associated small effusion (FIGURE 1), and an electrocardiogram (EKG) revealed a right axis deviation with flipped T waves in V3-V6 (FIGURE 2). A computed tomography (CT) scan of the chest performed 2 months prior to admission revealed a small right pleural effusion, moderate emphysema, and pleural plaques. A transthoracic echocardiogram performed a week earlier was significant for a normal ejection fraction without pericardial thickening, and mild dilation of the left and right atria and the right ventricle.

Our patient had recurrent transudative pleural effusions with no history of congestive heart failure, a normal thyroid-stimulating hormone, no signs of nephrotic syndrome, no risk factors for lung cancer, and a presentation that was not consistent with an acute pulmonary embolus. he had jaundice, but no risk factors for cirrhosis. A comprehensive hepatology consult suggested that the jaundice was associated with recent rifampin use, along with hepatic congestion likely due to cardiac etiology.

The patient also had a documented history of constrictive pericarditis. Although a cardiac CT scan 15 months prior to his hospital admission showed normal pericardial thickness, constrictive pericarditis remained high on our differential.

To further evaluate the patient’s cardiac function, a cardiologist performed a right-sided cardiac catheterization. in constrictive pericarditis, equalization of end-diastolic pressures occurs due to limitation of the total volume of the ventricles by a rigid pericardium. in our patient, these pressures did not equalize. his right and left ventricular pressure tracings did, however, have the classic square root sign often seen in constrictive pericarditis (FIGURE 3). This “dip and plateau” is the result of rapid filling of the ventricles during early diastole, with the inflexible pericardium causing an abrupt halt in ventricular filling.¹

We considered restrictive cardiomyopathy in the differential, too, but the signs and symptoms weren’t a perfect fit there, either. equalization of left and right ventricular end-diastolic pressures in cardiac catheterization is usually not seen in restrictive cardiomyopathy, but neither is the square-root sign evident on ventricular pressure monitors.¹

FIGURE 1
X-ray shows right-sided airspace disease

FIGURE 2
Right axis deviation with flipped T waves

FIGURE 3
Classic square root sign

WHAT IS THE MOST LIKELY EXPLANATION FOR HIS CONDITION?

Constrictive pericarditis

On the advice of a cardiologist who specializes in advanced cardiac imaging, our patient underwent tissue Doppler velocity echocardiography—a diagnostic test that provides evidence of a diseased myocardium (as in restrictive cardiomyopathy), as well as changes in diastolic blood flow that differentiate constrictive pericarditis from restrictive cardiomyopathy. Our patient’s tissue Doppler velocity echocardiogram revealed a normal myocardium with an abrupt cessation of early left ventricular filling, consistent with constrictive pericarditis. Along with his clinical presentation and history, this test was conclusive enough to diagnose constrictive pericarditis.

Making the diagnosis in more “typical” cases
Symptoms of constrictive pericarditis include fluid overload (eg, recurrent pleural effusions^2-4) hepatic dysfunction, and peripheral edema. Studies show that 44% to 54% of patients with constrictive pericarditis present with pleural effusions;⁵ chest pain and dyspnea are other common symptoms.⁶ Past medical history is also important, considering the 3 most common risks for constrictive pericarditis: cardiac surgery, pericarditis, and irradiation of the mediastinum (TABLE).⁷

Typical physical exam findings in patients with constrictive pericarditis include an elevated jugular venous pressure, third spacing of fluids, a pericardial knock, and Kussmaul’s sign. Our patient had third spacing of fluids, including mild peripheral edema and the recurrent effusions as noted, as well as signs of hepatic dysfunction that were initially attributed to his rifampin use. While these symptoms raise the suspicion of constrictive pericarditis, none is specific to that condition alone.

Studies that help in the diagnosis of constrictive pericarditis include chest x-ray, cardiac CT, echocardiography, cardiac magnetic resonance imaging (MRI), and cardiac catheterization. EKG has no specific findings, but cardiac arrhythmias (eg, atrial fibrillation) are common.⁸ Pericardial thickening on cardiac CT scan is a definitive but not universal finding; in a Mayo Clinic study, such thickening was not evident in 26 of 143 patients with confirmed constrictive pericarditis.⁸ Cardiac MRI has been shown to have 88% sensitivity and 100% specificity,⁹ but will miss up to 18% of patients with constrictive pericarditis.⁸

Differentiating between restriction and constriction. It can be difficult to distinguish between constrictive pericarditis and restrictive cardiomyopathy. Although these conditions can present in a similar manner, they require different modes of treatment. Laboratory testing, cardiac catheterization, and tissue Doppler velocity echocardiography (which we relied on) can help to distinguish between them.

TABLE
Causes of constrictive pericarditis⁷

Pericardiectomy is the treatment of choice

Pericardiectomy, the optimal treatment for most patients with constrictive pericarditis, carries a 30-day perioperative mortality of approximately 6%.^5,7 Patients with minimal symptoms can be monitored for up to 2 months, but only 17% of cases are self-limited.⁶ Patients with end-stage disease or those who have radiation-induced constrictive pericarditis experience poor surgical outcomes, and may be better served by medical management.⁷

In light of our patient’s excellent baseline functional status, clinical presentation, and Doppler test results, a cardiothoracic surgeon performed a pericardiectomy. His symptoms improved postoperatively, and he has had no further pleural effusions. The patient’s fatigue, anorexia, weight loss, and dyspnea fully resolved, as well.

CORRESPONDENCE Jeffrey S. Morgeson, MD; 2123 Auburn Avenue, 340 MOB, Cincinnati, OH 45219; [email protected]

CASE An 84-year-old man was admitted to our family medicine inpatient service with increasing weakness, fatigue, nausea, jaundice, and anorexia after undergoing thoracentesis for recurrent large right-sided pleural effusion twice within the past 6 weeks. The patient had no fever, chills, night sweats, chest pain, or chronic cough.

His past medical history included coronary artery disease and hyperlipidemia, and he had undergone coronary artery bypass grafting 6 years prior to this admission.

Initial vital signs included a blood pressure of 116/68 mm hg and a pulse rate of 78 beats per minute. physical examination revealed a thin but otherwise active and functional man, with the presence of scleral icterus and a 2/6 systolic murmur that was loudest at the left upper sternal border, with no pericardial knocks or rubs. There was no jugular venous distension. The patient had decreased breath sounds at the right base, but no appreciable rales, rhonchi, or wheezes, and an enlarged liver with an irregular edge approximately 7 cm below the costal margin. he had bilateral trace pitting edema of the lower extremities and an erythematous chronic venous stasis ulcer on his left lower leg that was being treated with sulfamethoxazole and trimethoprim and rifampin.

Laboratory findings included a sodium level of 130 mEq/L; creatinine, 1.6 mg/dL; total bilirubin, 4.2 mg/dL; and an international normalized ratio (INR) of 1.6, with an otherwise normal liver profile. pleural fluid was transudative by light’s criteria, with negative pleural fluid cultures.

A chest x-ray showed right-sided airspace disease, with an associated small effusion (FIGURE 1), and an electrocardiogram (EKG) revealed a right axis deviation with flipped T waves in V3-V6 (FIGURE 2). A computed tomography (CT) scan of the chest performed 2 months prior to admission revealed a small right pleural effusion, moderate emphysema, and pleural plaques. A transthoracic echocardiogram performed a week earlier was significant for a normal ejection fraction without pericardial thickening, and mild dilation of the left and right atria and the right ventricle.

Our patient had recurrent transudative pleural effusions with no history of congestive heart failure, a normal thyroid-stimulating hormone, no signs of nephrotic syndrome, no risk factors for lung cancer, and a presentation that was not consistent with an acute pulmonary embolus. he had jaundice, but no risk factors for cirrhosis. A comprehensive hepatology consult suggested that the jaundice was associated with recent rifampin use, along with hepatic congestion likely due to cardiac etiology.

The patient also had a documented history of constrictive pericarditis. Although a cardiac CT scan 15 months prior to his hospital admission showed normal pericardial thickness, constrictive pericarditis remained high on our differential.

To further evaluate the patient’s cardiac function, a cardiologist performed a right-sided cardiac catheterization. in constrictive pericarditis, equalization of end-diastolic pressures occurs due to limitation of the total volume of the ventricles by a rigid pericardium. in our patient, these pressures did not equalize. his right and left ventricular pressure tracings did, however, have the classic square root sign often seen in constrictive pericarditis (FIGURE 3). This “dip and plateau” is the result of rapid filling of the ventricles during early diastole, with the inflexible pericardium causing an abrupt halt in ventricular filling.¹

We considered restrictive cardiomyopathy in the differential, too, but the signs and symptoms weren’t a perfect fit there, either. equalization of left and right ventricular end-diastolic pressures in cardiac catheterization is usually not seen in restrictive cardiomyopathy, but neither is the square-root sign evident on ventricular pressure monitors.¹

FIGURE 1
X-ray shows right-sided airspace disease

FIGURE 2
Right axis deviation with flipped T waves

FIGURE 3
Classic square root sign

WHAT IS THE MOST LIKELY EXPLANATION FOR HIS CONDITION?

Constrictive pericarditis

On the advice of a cardiologist who specializes in advanced cardiac imaging, our patient underwent tissue Doppler velocity echocardiography—a diagnostic test that provides evidence of a diseased myocardium (as in restrictive cardiomyopathy), as well as changes in diastolic blood flow that differentiate constrictive pericarditis from restrictive cardiomyopathy. Our patient’s tissue Doppler velocity echocardiogram revealed a normal myocardium with an abrupt cessation of early left ventricular filling, consistent with constrictive pericarditis. Along with his clinical presentation and history, this test was conclusive enough to diagnose constrictive pericarditis.

Making the diagnosis in more “typical” cases
Symptoms of constrictive pericarditis include fluid overload (eg, recurrent pleural effusions^2-4) hepatic dysfunction, and peripheral edema. Studies show that 44% to 54% of patients with constrictive pericarditis present with pleural effusions;⁵ chest pain and dyspnea are other common symptoms.⁶ Past medical history is also important, considering the 3 most common risks for constrictive pericarditis: cardiac surgery, pericarditis, and irradiation of the mediastinum (TABLE).⁷

Typical physical exam findings in patients with constrictive pericarditis include an elevated jugular venous pressure, third spacing of fluids, a pericardial knock, and Kussmaul’s sign. Our patient had third spacing of fluids, including mild peripheral edema and the recurrent effusions as noted, as well as signs of hepatic dysfunction that were initially attributed to his rifampin use. While these symptoms raise the suspicion of constrictive pericarditis, none is specific to that condition alone.

Studies that help in the diagnosis of constrictive pericarditis include chest x-ray, cardiac CT, echocardiography, cardiac magnetic resonance imaging (MRI), and cardiac catheterization. EKG has no specific findings, but cardiac arrhythmias (eg, atrial fibrillation) are common.⁸ Pericardial thickening on cardiac CT scan is a definitive but not universal finding; in a Mayo Clinic study, such thickening was not evident in 26 of 143 patients with confirmed constrictive pericarditis.⁸ Cardiac MRI has been shown to have 88% sensitivity and 100% specificity,⁹ but will miss up to 18% of patients with constrictive pericarditis.⁸

Differentiating between restriction and constriction. It can be difficult to distinguish between constrictive pericarditis and restrictive cardiomyopathy. Although these conditions can present in a similar manner, they require different modes of treatment. Laboratory testing, cardiac catheterization, and tissue Doppler velocity echocardiography (which we relied on) can help to distinguish between them.

TABLE
Causes of constrictive pericarditis⁷

Pericardiectomy is the treatment of choice

Pericardiectomy, the optimal treatment for most patients with constrictive pericarditis, carries a 30-day perioperative mortality of approximately 6%.^5,7 Patients with minimal symptoms can be monitored for up to 2 months, but only 17% of cases are self-limited.⁶ Patients with end-stage disease or those who have radiation-induced constrictive pericarditis experience poor surgical outcomes, and may be better served by medical management.⁷

In light of our patient’s excellent baseline functional status, clinical presentation, and Doppler test results, a cardiothoracic surgeon performed a pericardiectomy. His symptoms improved postoperatively, and he has had no further pleural effusions. The patient’s fatigue, anorexia, weight loss, and dyspnea fully resolved, as well.

CORRESPONDENCE Jeffrey S. Morgeson, MD; 2123 Auburn Avenue, 340 MOB, Cincinnati, OH 45219; [email protected]