Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Chronic obstructive pulmonary disease (COPD) has seen several changes in its assessment and treatment in recent years, reflecting advances in our understanding of this common and serious disease.

This review updates busy practitioners on the major advances, including new assessment tools and new therapies.

COMMON AND INCREASING

COPD is the third leading cause of death in the United States, behind heart disease and cancer,¹ and of the top five (the others being stroke and accidents), it is the only one that increased in incidence between 2007 and 2010.² The 11th leading cause of disability-adjusted life years worldwide in 2002, COPD is projected to become the seventh by the year 2030.³

CHARACTERIZED BY OBSTRUCTION

COPD is characterized by persistent and progressive airflow obstruction associated with chronic airway inflammation in response to noxious particles and gases. Disease of the small airways (inflammation, mucus plugging, and fibrosis) and parenchymal destruction (emphysema) limit the flow of air.

COPD is diagnosed by spirometry—specifically, a ratio of forced expiratory volume in 1 second to forced vital capacity (FEV₁/FVC) of less than 0.7 after a bronchodilator is given. The severity of airflow limitation is revealed by the FEV₁ as a percent of the predicted value.

Cigarette smoking is the major cause of COPD, but the prevalence of COPD is 6.6% in people who have never smoked, and one-fourth of COPD patients in the United States have never smoked.⁴

GOLDEN GOALS: FEWER SYMPTOMS, LOWER RISK

The Global Initiative for Chronic Obstructive Lung Disease (GOLD) periodically issues evidence-based statements on how to prevent and treat COPD.

In its 2013 update,⁵ GOLD suggested two goals: improving symptoms and reducing the risk of death, exacerbations, progression of disease, and treatment-related adverse effects. The latter goal—reducing risk—is relatively new.

Exacerbations are acute inflammatory events superimposed on chronic inflammation. The inflammation is often brought on by infection⁶ and increases the risk of death⁷ and the risk of a faster decline in lung function.⁸

Exacerbations may characterize a phenotype of COPD. The Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) analyzed the frequency of COPD exacerbations and associated factors in 2,138 patients with COPD over a period of 3 years.⁹ Although patients with more severe obstruction tended to have more exacerbations, some patients appeared susceptible to exacerbations irrespective of the severity of obstruction. The best predictor of exacerbations was a history of exacerbations.

HOW DO I ASSESS A PATIENT WITH COPD ON PRESENTATION?

Markers of airflow obstruction such as the FEV₁ do not correlate strongly with exertional capacity and health status in patients with COPD.^10,11

The BODE index (body mass index, obstruction, dyspnea score, and exercise oximetry) takes into account the multidimensional nature of COPD. It performs better than the FEV₁ in predicting the risk of death.¹² The propensity for exacerbations and comorbidities further modulates outcome.

Assessing symptoms

The modified British Medical Research Council (mMRC) dyspnea scale, based on work by Fletcher in 1952,¹³ has five grades, numbered 0 through 4:

• Grade 0—Breathless with strenuous exercise only
• Grade 1—Breathless when hurrying on level ground or walking up a slight hill
• Grade 2—Walks slower than people of the same age on level ground because of shortness of breath or has to stop when walking at own pace on level ground
• Grade 3—Stops for breath after walking about 100 yards or after a few minutes on level ground
• Grade 4—Too breathless to leave the house or breathless when dressing or undressing.

Grade 2 or higher separates symptomatic from asymptomatic COPD.

The COPD Assessment Test (CAT) (www.catestonline.org) is a proprietary questionnaire. Patients use a 6-point scale (numbered 0 though 5) to rate eight symptoms (cough, mucus production, chest tightness, shortness of breath on exertion, limitations in home activities, lack of confidence leaving the home, poor sleep, and lack of energy). A total score of 10 or higher is abnormal.

Four GOLD groups

The new GOLD guidelines (Table 1)⁵ define four groups of patients according to their severity of airflow obstruction, symptoms, and exacerbation history:

• Group A—fewer symptoms, low risk: Fewer symptoms (“less symptoms,” as worded in the guidelines) means a CAT score less than 10 or an mMRC grade less than 2; “low risk” means no more than one exacerbation per year and an FEV₁ of at least 50%
• Group B—more symptoms, low risk: “More symptoms” means a CAT score of 10 or more or an mMRC grade of 2 or more
• Group C—fewer symptoms, high risk: “High risk” means two or more exacerbations per year or an FEV₁ less than 50%
• Group D—more symptoms, high risk.

Thus, a patient with an FEV₁ of 60% (moderate airflow limitation) who has had one exacerbation during the past year and a CAT score of 8 would be in group A. In contrast, a patient who has an FEV₁ of 40% (severe airflow limitation), no history of exacerbations, and a CAT score of 20 would be in group D.

Updated GOLD guidelines suggest utilizing a stepwise approach to treatment, akin to asthma management guidelines, based on patient grouping.⁵

How accurate is the new GOLD system?

Although practical and suited for use in primary care, the new GOLD system is arbitrary and has not been thoroughly studied, and may therefore need refinement.

Lange et al¹⁴ compared the new GOLD system with the previous one in 6,628 patients with COPD. As anticipated, the new system was better at predicting exacerbations, as it incorporates a history of exacerbations in stratification. The presence of symptoms (as determined by an mMRC grade ≥ 2) was a marker of mortality risk that distinguished group A from group B, and group C from group D. Surprisingly, the rate of death was higher in group B (more symptoms, low risk) than in group C (fewer symptoms, high risk).

Notably, most patients in group C qualified for this group because of the severity of airflow obstruction, not because of a history of exacerbations. Therefore, patients whose symptoms are out of proportion to the severity of obstruction may be at higher risk of death, possibly because of comorbidities such as cardiovascular disease.¹⁵ Patients who qualified for groups C and D by having both a history of frequent exacerbations (≥ 2 per year) and symptoms rather than either one alone had a higher risk of death in 3 years.

Similarly, the symptom-assessment tool that is used—ie, the mMRC grade or the CAT score—also makes a difference.

The Health-Related Quality of Life in COPD in Europe Study¹⁶ retrospectively analyzed data from 1,817 patients to determine whether the cutoff points for symptoms as assessed by mMRC grade and CAT score were equivalent. Although the mMRC grade correlated well with overall health status, the cutoff mMRC grade of 2 or higher did not correspond to a CAT score of 10 or higher, classifying patients with health status impairment as asymptomatic (mean weighted kappa 0.626). The two tools agreed much better when the cutoff was set at an mMRC grade of 1 or higher (mean weighted kappa 0.792).¹⁶

Although assessment schemes continue to evolve as data accumulate, we believe the new system is a welcome initiative that reflects the changing notions of COPD.

Comorbidities matter

Another shift is the recognition that certain comorbidities increase the risk of death. In 1,664 patients with COPD who were followed for 51 months, 12 distinct comorbidities were associated with a higher risk of death after multivariate analysis.¹⁷

The COTE index (COPD-Specific Comorbidity Test) is based on these findings. It awards points as follows:

• 6 points for cancer of the lung, esophagus, pancreas, or breast, or for anxiety
• 2 points for all other cancers, liver cirrhosis, atrial fibrillation or flutter, diabetes with neuropathy, or pulmonary fibrosis
• 1 point for congestive heart failure, gastric or duodenal ulcer, or coronary artery disease.

A COTE index score of 4 or higher was associated with a risk of death 2.2 times higher in each quartile of the BODE index.

We strongly recommend being aware of comorbidities in COPD patients, particularly when symptoms are out of proportion to the severity of obstruction.

SHOULD I USE ANTIBIOTICS TO TREAT ALL COPD EXACERBATIONS?

Infections are thought to cause more than 80% of acute exacerbations of COPD.

Anthonisen et al,¹⁸ in a landmark trial, found broad-spectrum antibiotics to be most helpful if the patient had at least two of the three cardinal symptoms of COPD exacerbation (ie, shortness of breath, increase in sputum volume, and sputum purulence). Antibiotics decreased the rate of treatment failure and led to a more rapid clinical resolution of exacerbation. However, they did not help patients who had milder exacerbations.

Antibiotics may nevertheless have a role in ambulatory patients with mild to moderate COPD who present with exacerbations characterized by one or more cardinal symptoms.

Llor et al,¹⁹ in a multicenter randomized double-blind placebo-controlled trial in Spain, concluded that amoxicillin clavulanate (Augmentin) led to higher clinical cure rates and longer time to the next exacerbation in these patients. Most of the benefit was in patients with more symptoms, consistent with the results of the study by Anthonisen et al.¹⁸

There is also strong evidence to support the use of antibiotics in addition to systemic corticosteroids in hospitalized patients with acute exacerbations of COPD. A 7-day course of doxycycline (Vibramycin) added to a standard regimen of corticosteroids was associated with higher rates of clinical and microbiological cure on day 10 of the exacerbation.²⁰ In a large retrospective cohort study in 84,621 hospitalized patients with COPD exacerbations, fewer of those who received antibiotics needed mechanical ventilation, died, or were readmitted.²¹ Although sicker patients received antibiotics more frequently, their mortality rate was lower than in those who did not receive antibiotics, who were presumably less sick.

A meta-analysis confirmed the salutary effect of antibiotics in inpatients and particularly those admitted to the intensive care unit.²² Mortality rates and hospital length of stay were not affected in patients who were not in intensive care.

Biomarkers such as procalcitonin might help reduce the unnecessary use of antibiotics. Stolz et al²³ conducted a randomized controlled trial in which they based the decision to give antibiotics on a threshold procalcitonin level of at least 1 μg/L in hospitalized patients with COPD exacerbation. The rate of antibiotic use was reduced by more than 40% in the procalcitonin group without any difference in clinical outcomes, 6-month exacerbation rate, or rehospitalization compared with controls. Nonstandardized procalcitonin assays are a possible barrier to the widespread adoption of this threshold.

Comment. In general, we recommend antibiotics for hospitalized patients with COPD exacerbation and look forward to confirmatory data that support the use of biomarkers. For outpatients, we find the Anthonisen criteria useful for decision-making at the point of care.

ARE THERE ANY NEW INTERVENTIONS TO PREVENT COPD EXACERBATIONS?

Macrolides

Macrolides have a proven role in managing chronic suppurative respiratory diseases such as cystic fibrosis²⁴ and diffuse panbronchiolitis.²⁵ Since they are beneficial at lower doses than those used to treat infection, the mechanism may be anti-inflammatory rather than antimicrobial.

Albert et al²⁶ assigned 1,142 patients who had had a COPD exacerbation within a year before enrollment or who were on home oxygen therapy to receive azithromycin (Zithromax) 250 mg daily or placebo.²⁵ The azithromycin group had fewer acute exacerbations (hazard ratio 0.73, 95% CI 0.63–0.84, P < .001), and more patients in the azithromycin group achieved clinically significant improvements in quality of life, ie, a reduction in the St. George’s Respiratory Questionnaire (SGRQ) score of at least 4 points (43% vs 36%, P = .03). Adverse events that were more common in the azithromycin group were hearing loss (25% vs 20%) and macrolide-resistant strains in nasopharyngeal secretions (81% vs 41%). In subgroup analysis, the benefit in terms of reducing exacerbations was greater in patients over age 65, patients on home oxygen, and patients with moderate or severe obstruction compared with those with very severe obstruction.

Comment. Macrolides are a valuable addition to the agents available for preventing COPD exacerbation (Table 2), but their role is still uncertain. Potential topics of research are whether these drugs have a role in patients already on preventive regimens, whether they would have a greater effect in distinct patient populations (eg, patients who have two or more exacerbations per year), and whether their broader use would lead to a change in the resident flora in the community.

Clinicians should exercise caution in the use of azithromycin in light of recent concern about associated cardiac morbidity and death. All patients should undergo electrocardiography to assess the QTc interval before starting treatment, as in the trial by Albert et al.²⁶

Phosphodiesterase inhibitors

Roflumilast (Daliresp) is an oral phosphodiesterase 4 inhibitor approved for treating exacerbations and symptoms of chronic bronchitis in patients with severe COPD (Table 3). Phosphodiesterase 4, one of the 11 isoforms of the enzyme, is found in immune and inflammatory cells and promotes inflammatory responses. Roflumilast has anti-inflammatory properties but no acute bronchodilatory effect.²⁷ Several phase 3 trials found the compound to have beneficial effects.

Calverley et al²⁸ performed two placebo-controlled double-blind trials in outpatients with the clinical diagnosis of COPD who had chronic cough; increased sputum production; at least one recorded exacerbation requiring corticosteroids or hospitalization, or both; and an FEV₁ of 50% or less. Patients were randomized to receive roflumilast 500 μg once a day (n = 1,537) or placebo (n = 1,554) for 1 year. The rate of moderate to severe exacerbations was 1.17 per year with roflumilast vs 1.37 with placebo (P < .0003). Adverse events were significantly more common with roflumilast and were related to the known side effects of the drug, namely, diarrhea, weight loss, decreased appetite, and nausea.

Fabbri et al²⁹ performed two other placebo-controlled double-blind multicenter trials, studying the combinations of roflumilast with salmeterol (Serevent) and roflumilast with tiotropium (Spiriva) compared with placebo in 1,676 patients with COPD who had post-bronchodilator FEV₁ values of 40% to 70% of predicted. The mean prebronchodilator FEV₁ improved by 49 mL (P < .0001) in the salmeterol-plus-roflumilast trial and by 80 mL (P < .0001) in the tiotropium-plus-roflumilast trial compared with placebo. Fewer patients on roflumilast had exacerbations of any severity in both trials (risk ratio 0.82, P = .0419 and risk ratio 0.75, P = .0169, respectively).

No trial has yet addressed whether roflumilast is better than the combination of a long-acting muscarinic antagonist and a beta agonist, or whether roflumilast can be substituted for inhaled corticosteroids in a new triple-therapy combination. Clinicians should also be aware of psychiatric side effects of roflumilast, which include depression and, possibly, suicide.

ARE THERE ANY NEW BRONCHODILATORS FOR PATIENTS WITH COPD?

Long-acting muscarinic antagonists

Reversible airflow obstruction and mucus secretion are determined by the vagal cholinergic tone in patients with COPD.³⁰ Antagonism of cholinergic (muscarinic) receptors results in bronchodilation and reduction in mucus production. Consequently, inhaled anticholinergic agents are the first-line therapy for COPD (Table 4).

Tiotropium bromide is a long-acting antimuscarinic approved in 2002 by the US Food and Drug Administration (FDA). The UPLIFT trial (Understanding Potential Long-Term Impacts on Function With Tiotropium)³¹ enrolled 5,993 patients with a mean FEV₁ of 48% of predicted. Over a 4-year follow-up, significant improvements in mean FEV₁ values (ranging from 87 mL to 103 mL before bronchodilation and 47 mL to 65 mL after bronchodilation, P < .001) in the tiotropium group were observed compared with placebo. The rate of the primary end point—the rate of decline in mean FEV₁—was not different between tiotropium and placebo. However, there were important salutary effects in multiple clinical end points in the tiotropium group. Health-related quality of life as measured by the SGRQ improved in a clinically significant manner (> 4 points) in favor of tiotropium in a higher proportion of patients (45% vs 36%, P < .001). Tiotropium reduced the number of exacerbations per patient year (0.73 ± 0.02 vs 0.85 ± 0.02, RR = 0.86 (95% CI 0.81–0.91), P < .001) and the risk of respiratory failure (RR = 0.67, 95% CI 0.51–0.89). There were no significant differences in the risk of myocardial infarction, stroke, or pneumonia.

Aclidinium bromide (Tudorza Pressair) is a long-acting antimuscarinic recently approved by the FDA. Compared with tiotropium, it has a slightly faster onset of action and a considerably shorter half-life (29 hours vs 64 hours).^32,33 Its dosage is 400 μg twice daily by inhalation. It provides sustained bronchodilation over 24 hours and may have a favorable side-effect profile, because it undergoes rapid hydrolysis in human plasma.³⁴

ACCORD COPD I³⁵ and ATTAIN,³⁶ two phase 3 trials in patients with moderate-to severe COPD, found that twice-daily aclidinium was associated with statistically and clinically significant (> 100 mL) improvements in trough and peak FEV₁ compared with placebo. Health status (assessed by SGRQ) and dyspnea (assessed by transitional dyspnea index) also improved significantly. However, improvements beyond minimum clinically significant thresholds were achieved only with 400 μg twice-daily dosing.

To date, no study has evaluated the impact of aclidinium on COPD exacerbation as a primary end point. Fewer moderate to severe exacerbations were reported in an earlier 52-week study of once-daily aclidinium (ACCLAIM COPD II) but not in ACCLAIM COPD I.³⁷

Aclidinium may offer an advantage over tiotropium in patients who have nocturnal symptoms. Twice-daily aclidinium 400 μg was associated with superior FEV₁ area-under-the-curve values compared with placebo and tiotropium, the difference mostly owing to improved nocturnal profile.³⁸

Long-acting beta-2 agonists

Stimulation of airway beta-2 receptors relaxes smooth muscles and consequently dilates bronchioles via a cyclic adenosine monophosphate-dependent pathway.³⁹

Short-acting beta-2 agonists such as albuterol and terbutaline have long been used as rescue medications for obstructive lung disease. Long-acting beta-2 agonists provide sustained bronchodilation and are therefore more efficacious as maintenance medications. Salmeterol, formoterol (Foradil), and arformoterol (Brovana) are long-acting beta-2 agonists in clinical use that are taken twice daily.

Clinical studies indicate that use of long-acting beta-2 agonists leads to significant improvements in FEV₁,^40–42 dynamic hyperinflation, exercise tolerance,^43,44 and dyspnea.^45,46 These drugs have also been associated with significant improvements in health-related quality of life and in the frequency of exacerbations.^47–49

In patients with asthma, long-acting beta agonists may increase the risk of death.⁵⁰ In contrast, in patients with COPD, they appear to offer a survival advantage when used in combination with inhaled corticosteroids,⁵¹ and some argue that this benefit is entirely from the long-acting beta agonist (a 17% reduction in mortality) rather than the inhaled corticosteroid (0% reduction in mortality).⁵²

Indacaterol (Arcapta), approved in July 2011, is the first once-daily beta agonist or “ultra-long-acting” beta agonist (Table 5). Possibly because it has a high affinity for the lipid raft domain of the cell membrane where beta-2 receptors are coupled to second messengers,⁵³ the drug has a 24-hour duration of action.

In patients with COPD, inhaled indacaterol 150 μg once daily improved airflow obstruction and health status as measured by SGRQ compared with salmeterol 50 μg twice daily and placebo.⁵⁴ At the higher dose of 300 μg daily, the 52-week INVOLVE trial⁵⁵ demonstrated early and more sustained improvement in FEV₁ compared with placebo and formoterol. In this study, a lower exacerbation rate than with placebo was also noted. The drug has also shown equivalent bronchodilator efficacy at 150 μg and 300 μg daily dosing compared with tiotropium.⁵⁶

The benefits of a longer-acting bronchodilator such as indacaterol are likely mediated by smoothing out airway bronchomotor tone over 24 hours without the dips seen with shorter-acting agents and by improvement of the FEV₁ trough before the subsequent dose is due, aptly named “pharmacologic stenting.”⁵⁷ Once-daily dosing should also foster better adherence. The safety profile appears excellent with no increase in cardiovascular or cerebrovascular events compared with placebo.⁵⁸

The FDA approved the 75-μg daily dose instead of the higher doses used in the studies mentioned above. This decision was based on the observation that there appeared to be a flattened dose-response in patients with more severe COPD, with no further improvement in trough FEV₁ at higher doses.⁵⁹

DOES VITAMIN D SUPPLEMENTATION HAVE A ROLE IN COPD MANAGEMENT?

Vitamin D is vital for calcium and phosphate metabolism and bone health. Low vitamin D levels are associated with diminished leg strength and falls in the elderly.⁶⁰ Osteoporosis, preventable with vitamin D and calcium supplementation, is linked to thoracic vertebral fracture and consequent reduced lung function.^61,62

Patients with COPD are at higher risk of vitamin D deficiency, and more so if they also are obese, have advanced airflow obstruction, are depressed, or smoke.⁶² Therefore, there are sound reasons to look for vitamin D deficiency in patients with COPD and to treat it if the 25-hydroxyvitamin D level is less than 10 ng/ mL (Table 6).

Vitamin D may also have antimicrobial and immunomodulatory effects.⁶³ Since COPD exacerbations are frequently caused by infection, it was hypothesized that vitamin D supplementation might reduce the rate of exacerbations.

In a study in 182 patients with moderate to very severe COPD and a history of recent exacerbations, high-dose vitamin D supplementation (100,000 IU) was given every 4 weeks for 1 year.⁶⁴ There were no differences in the time to first exacerbation, in the rate of exacerbation, hospitalization, or death, or in quality of life between the placebo and intervention groups. However, subgroup analysis indicated that, in those with severe vitamin D deficiency at baseline, the exacerbation rate was reduced by more than 40%.

Comment. We recommend screening for vitamin D deficiency in patients with COPD. Supplementation is appropriate in those with low levels, but data indicate no role in those with normal levels.

WHAT ARE THE NONPHARMACOLOGIC APPROACHES TO COPD TREATMENT?

Noninvasive positive-pressure ventilation

Nocturnal noninvasive positive-pressure ventilation may be beneficial in patients with severe COPD, daytime hypercapnia, and nocturnal hypoventilation, particularly if higher inspiratory pressures are selected (Table 7).^65,66

For instance, a randomized controlled trial of noninvasive positive-pressure ventilation plus long-term oxygen therapy compared with long-term oxygen therapy alone in hypercapnic COPD demonstrated a survival benefit in favor of ventilation (hazard ratio 0.6).⁶⁷

In another randomized trial,⁶⁸ settings that aimed to maximally reduce Paco₂ (mean inspiratory positive airway pressure 29 cm H₂O with a backup rate of 17.5/min) were compared with low-intensity positive airway pressure (mean inspiratory positive airway pressure 14 cm H₂O, backup rate 8/min). The high inspiratory pressures increased the daily use of ventilation by 3.6 hours per day and improved exercise-related dyspnea, daytime Paco₂, FEV₁, vital capacity, and health-related quality of life⁶⁶ without disrupting sleep quality.⁶⁸

Caveats are that acclimation to the high pressures was achieved in the hospital, and the high pressures were associated with a significant increase in air leaks.⁶⁶

Comments. Whether high-pressure noninvasive positive-pressure ventilation can be routinely implemented and adopted in the outpatient setting, and whether it is associated with a survival advantage remains to be determined. The advantages of noninvasive positive-pressure ventilation in the setting of hypercapnic COPD appear to augment those of pulmonary rehabilitation, with improved quality of life, gas exchange, and exercise tolerance, and a slower decline of lung function.⁶⁹

Pulmonary rehabilitation

Pulmonary rehabilitation is a multidisciplinary approach to managing COPD (Table 8).

Patients participate in three to five supervised sessions per week, each lasting 3 to 4 hours, for 6 to 12 weeks. Less-frequent sessions may not be effective. For instance, in a randomized trial, exercising twice a week was not enough.⁷⁰ Additionally, a program lasting longer than 12 weeks produced more sustained benefits than shorter programs.⁷¹

A key component is an exercise protocol centered on the lower extremities (walking, cycling, treadmill), with progressive exercise intensity to a target of about 60% to 80% of the maximal exercise tolerance,⁷² though more modest targets of about 50% can also be beneficial.⁷³

Exercise should be tailored to the desired outcome. For instance, training of the upper arms may help with activities of daily living. In one study, unsupported (against gravity) arm training improved upper-extremity function more than supported arm training (by ergometer).⁷⁴ Ventilatory muscle training is less common, as most randomized trials have not shown conclusive evidence of benefit. Current guidelines do not recommend routine inspiratory muscle training.⁷¹

Even though indices of pulmonary function do not improve after an exercise program, randomized trials have shown that pulmonary rehabilitation improves exercise capacity, dyspnea, and health-related quality of life; improves cost-effectiveness of health care utilization; and provides psychosocial benefits that often exceed those of other therapies. Although there is no significant evidence of whether pulmonary rehabilitation improves survival in patients with COPD,⁷¹ an observational study documented improvements in BODE scores as well as a reduction in respiratory mortality rates in patients undergoing pulmonary rehabilitation.⁷⁵

A limitation of pulmonary rehabilitation is that endurance and psychological and cognitive function decline significantly if exercise is not maintained. However, the role of a maintenance program is uncertain, with long-term benefits considered modest.⁷¹

Lung-volume reduction surgery

Lung-volume reduction consists of surgical wedge resections of emphysematous areas of the lung (Table 9).

The National Emphysema Treatment Trial⁷⁶ randomized 1,218 patients to undergo either lung-volume reduction surgery or maximal medical therapy. Surgery improved survival, quality of life, and dyspnea in patients with upper-lobe emphysema and a low exercise capacity (corresponding to < 40 watts for men or < 25 watts for women in the maximal power achieved on cycle ergometry). While conferring no survival benefit in patients with upper-lobe-predominant emphysema and high exercise capacity, this surgery is likely to improve exercise capacity and quality of life in this subset of patients.

Importantly, the procedure is associated with a lower survival rate in patients with an FEV₁ lower than 20%, homogeneous emphysema, a diffusing capacity of the lung for carbon monoxide lower than 20%, non-upper-lobe emphysema, or high baseline exercise capacity.

The proposed mechanisms of improvement of lung function include placing the diaphragm in a position with better mechanical advantage, reducing overall lung volume, better size-matching between the lungs and chest cavity, and restoring elastic recoil.^76,77

Ongoing trials aim to replicate the success of lung-volume reduction using nonsurgical bronchoscopic techniques with one-way valves, coils, biologic sealants, thermal ablation, and airway stents.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

Worker prepares capsules

to be used in a clinical trial

Credit: Esther Dyson

Many in the research community have lauded the European Medicines Agency’s (EMA’s) plans to make clinical trial data available to the public.

But the agency has also drawn criticism for the way it plans to go about increasing transparency.

The EMA has said it plans to make trial data available online in a “read-only” mode. So readers will not be able to save or transfer the data, making scientific analysis difficult, if not impossible.

The EMA also plans to allow drug manufacturers to omit some trial data from its public posts.

In response to this news, the European Ombudsman, Emily O’Reilly, wrote a letter to the EMA expressing concern about their seemingly significant change in policy.

“We were pleased when EMA announced, in 2012, a new pro-active transparency policy, giving the broadest possible public access to clinical trial data,” O’Reilly said.

“I am now concerned about what appears to be a significant change in EMA’s policy, which could undermine the fundamental right of public access to documents established by EU law. European citizens, doctors, and researchers need maximum information about the medicines they take, prescribe, and analyze.”

Beate Wieseler, PhD, and her colleagues from the German Institute for Quality and Efficiency in Health Care, echoed this sentiment in a “rapid response” published in the British Medical Journal.

The authors said the proposed read-only mode of accessing data makes scientific analyses, such as risk-benefit assessments of drugs, impossible.

For these assessments, an enormous amount of data must be viewed, annotated and saved, pooled from different studies, analyzed statistically, and shared among researchers. But the read-only mode would not allow for that.

Dr Wieseler and other critics also take issue with EMA’s decision to allow drug manufacturers to omit some trial data from its public posts.

The EMA has said that, within the context of market approval, drug manufacturers will be able to submit 2 versions of a clinical study report to the EMA: a complete one, by means of which the agency will decide on approval, and an incomplete one for the public.

The EMA previously decided that individual patient data, which could allow patients to be identified, would be deleted from the study reports. Now, this step has been extended to cover study results.

For example, the EMA believes deleting information is acceptable in cases of results on exploratory outcomes that are not supportive for the approval decision. However, Dr Weiseler and her colleagues noted that such study results often contain analyses of patient-relevant outcomes such as health-related quality of life.

“We are talking about studies in people who participated in a clinical study because they hoped that, with the information gained, better treatments would be developed,” Dr Wieseler said. “This information can only be used to improve patient care if it is publicly available to all.”

About the policy change

In June 2013, the EMA released for public consultation a draft policy on “publication and access to clinical trial data.” In that draft, the agency proposed publishing data submitted in support of marketing-authorization applications (only for centrally approved medicines from 2014 onward).

The idea was that interested parties would no longer need to invoke the European Freedom of Information Regulation (Regulation [EC] N°1049/2001), when exercising their right to access documents held by the EMA.

However, according to documents the EMA shared during a stakeholder consultation earlier this month, the EMA now plans to allow systematic censorship by pharmaceutical companies and impose both strict confidentiality requirements and restrictions on the use of data.

For more information on the policy, see the EMA website.

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

ANSWER

The image shows a comminuted and depressed fracture of the lateral tibial plateau. It is depressed approximately 6 to 7 mm. The patient was admitted, and orthopedic consultation was obtained. The patient subsequently underwent an open reduction and internal fixation of the fracture.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

A 26-year-old man presented to the emergency department (ED) with a chief complaint of abdominal pain. After triage was complete, he was transported to an examination room, where the clinician obtained the history of presenting illness. The onset of pain was approximately 90 minutes prior to arrival at the ED and woke the patient from a “sound sleep.”  He stated that the pain initially started as a “3 out of 10” but had progressed to a “12 out of 10,” and he described it as being in the right lower quadrant of his abdomen, with radiation to his right testicle. However, he was unsure where the pain started or if it was worse in either location. Nausea was the primary associated symptom, but he denied vomiting, diarrhea, fever, dysuria, or hematuria. Last, the patient denied history of trauma.   

Medical history was noncontributory: He denied previous gastrointestinal diseases, and there was no history of renal stones, urinary tract infection, or any other genitourinary disease. He had no surgical history. The patient smoked less than a pack of cigarettes per day but denied alcohol or drug use.

Physical examination revealed a young man in moderate discomfort. Despite describing his pain as a “12 out of 10,” he had a blood pressure of 121/72 mm Hg; pulse, 59 beats/min; respiratory rate, 20 breaths/min; and temperature, 96.8°F. HEENT and cardiovascular, respiratory, musculoskeletal, and neurologic exam results were all within normal limits. Abdominal examination revealed a mildly tender right lower quadrant with deep palpation, but no rebound or guarding. Murphy sign was negative.

Because of the complaint of pain radiating to the testicles, a genitourinary examination was performed. The penis appeared unremarkable, with no lesions or discharge. There was no inguinal lymphadenopathy. The scrotum appeared appropriate in size and was also grossly unremarkable. The left testicle was nontender. However, palpation of the right testicle elicited moderate to severe pain. There was no visible swelling, and there were no palpable hernias or other masses. Cremasteric reflex was assessed bilaterally and deemed to be absent on the right side.

A workup was initiated that included a complete blood count, comprehensive metabolic panel, and urinalysis; the results of these tests were unremarkable. A differential diagnosis was formed, with emphasis on appendicitis and testicular torsion. Because of the specific nature and location of the pain, both ultrasound and CT of the abdomen/pelvis were considered. It was decided to order the ultrasound, with a plan to perform CT only if ultrasound was unremarkable. The patient was medicated for his pain and the ultrasound commenced. Halfway through the imaging, the clinician and attending physician were summoned to the examination room to review the image seen in Figure 1.

On the next page: Discussion and diagnosis >>

DISCUSSION

Testicular torsion may occur if the testicle twists or rotates on the spermatic cord. The twisting causes arterial ischemia and venous outflow obstruction, cutting off the testicle’s blood supply.^1,2 Torsion may be extravaginal or intravaginal, depending on the extent of involvement of the surrounding structures.²

Extravaginal torsion is most commonly seen in neonates and occurs because the entire testicle may freely rotate prior to fixation to the scrotal wall via the tunica vaginalis.²Intravaginal torsion is more common in adolescents and often occurs as a result of a condition known as bell clapper deformity. This congenital abnormality enables the testicle to rotate within the tunica vaginalis and rest transversely in the scrotum instead of in a more vertical orientation.^2,3 Torsion occurs if the testicle rotates 90° to 180°, with complete torsion occurring at 360° (torsion may extend to as much as 720°).² Torsion may also occur as a result of trauma.¹

Peak incidence of testicular torsion occurs at ages 13 to 14, but it can occur at any age; torsion affects approximately 1 in 4,000 males younger than 25.^2-5 Ninety-five percent of all torsions are intravaginal.² Torsion is the most common pathology for males who undergo surgical exploration for scrotal pain.³

The main goal in the diagnosis and treatment of torsion is testicular salvage. Torsion is considered a urologic emergency, making early diagnosis and treatment critical to prevent testicular loss. In fact, a review of the relevant literature reveals that the rate of testicular salvage is much higher if the diagnosis is made within 6 to 12 hours.^1,2,5 Potential sequelae from delayed treatment include testicular infarction, loss of testicle, infertility problems, infections, cosmetic deformity, and increased risk for testicular malignancy.²

Because many men hesitate to seek medical attention for symptoms of testicular pain and swelling, the primary care clinician should openly discuss testicular disorders, especially with preadolescent males, during testicular examinations.⁶

Diagnosis

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. The cremasteric reflex should be assessed because it can help differentiate among the causes of testicular pain.⁷ It is performed by gently stroking the upper inner thigh and observing for contraction of the ipsilateral testicle. One study found that, in cases of torsion, the absence of a cremasteric reflex had a sensitivity of 96% and a specificity of 88%.⁷ See the Table for the differential diagnosis for acute testicular pain.

While it is often possible to make the diagnosis of testicular torsion clinically, ultrasound with color Doppler is the diagnostic test of choice in cases for which the cause of acute scrotal pain is unclear.⁸ Ultrasound provides anatomic detail of the scrotum and its contents, and perfusion is assessed by adding the color Doppler images.⁸ It is important to note that, while the absence of blood flow is considered diagnostic for testicular torsion, the presence of flow does not necessarily exclude it.⁴

On the next page: Treatment >>

Treatment

Surgical exploration with intraoperative detorsion and orchiopexy (fixation of the testicle to the scrotal wall) is the mainstay of treatment for testicular torsion.¹ Orchiopexy is often performed bilaterally in order to prevent future torsion of the unaffected testicle. In about 40% of males with the bell clapper deformity, the condition is present on both sides.² Orchiectomy, the complete removal of the testicle, is necessary when the degree of torsion and subsequent ischemia have caused irreversible damage to the testicle.⁶ In one study in which 2,248 cases of torsion were reviewed, approximately 34% of males required orchiectomy.⁶

If surgery may be delayed, the clinician may attempt manual detorsion at the bedside. Despite the “open book” method described in many texts—which instructs the practitioner to rotate the testicle laterally—a review of the literature reveals that torsion takes place medially only 70% of the time.^1,5 The clinician should always consider this when any attempts at manual detorsion are made and correlate his or her technique with physical examination and the patient’s response.⁵

Relief of pain and return of the testicle to its natural longitudinal lie are considered indicators of successful detorsion.¹ Color Doppler ultrasound should be used to confirm the return of circulation. However, in one case review of pediatric patients who underwent surgical exploration after manual detorsion, some degree of residual torsion remained in 32%.⁵ Because of this risk, surgery is still indicated even in cases of successful bedside detorsion.⁵

On the next page: Case continuation >> 

CASE CONTINUATION

The decision to perform bedside ultrasound was made because the diagnosis of testicular torsion is a surgical emergency, and the window of time to prevent complications can be extremely narrow. If the ultrasound had been normal, then a CT scan may have provided additional data on which to base the diagnosis.

The patient was given adequate parenteral pain medication. After color Doppler ultrasound confirmed the torsion, the testicle was laterally rotated approximately 360°. The patient reported alleviation of his symptoms. Color Doppler was again performed to confirm the return of hyperemic blood flow to the affected testicle (Figure 2). The urologist arrived shortly thereafter and the patient was taken to the operating room, where he underwent scrotal exploration and bilateral orchiopexy.

On the next page: Conclusion >>

CONCLUSION

A testicular examination should be performed on any male presenting with a chief complaint of lower abdominal pain, back/flank pain, or any pain that radiates to the groin. Testicular torsion is most commonly seen in infants and adolescents but can occur at any age. The condition is a surgical emergency and the goal is testicular salvage, which is most likely to occur before 12 hours have elapsed since the onset of symptoms. An important component of the physical examination is attempting to elicit the cremasteric reflex, which is likely to be absent in the presence of torsion.

The primary care provider’s goal is to rapidly diagnose testicular torsion, then refer the patient immediately to a urologist or ED. The skilled clinician may attempt manual detorsion, based on his/her expertise and comfort level; however, this procedure should never delay prompt surgical intervention.

REFERENCES

1. Eyre RC. Evaluation of the acute scrotum in adults. www.uptodate.com/contents/evaluation-of-the-acute-scrotum-in-adults. Accessed May 16, 2014.

2. Ogunyemi OI, Weiker M, Abel EJ. Testicular torsion. http://emedicine.medscape.com/article/2036003-overview. Accessed May 16, 2014.

3. Khan F, Muoka O, Watson GM. Bell clapper testis, torsion, and detorsion: a case report. Case Rep Urol. 2011;2011:631970.

4. Molokwu CN, Somani BK, Goodman CM. Outcomes of scrotal exploration for acute scrotal pain suspicious of testicular torsion: a consecutive case series of 173 patients. BJU Int. 2011;107(6):990-993.

5. Sessions AE, Rabinowitz R, Hulbert WC, et al. Testicular torsion: direction, degree, duration and disinformation. J Urol. 2003;169(2):663-665.

6. Mansbach JM, Forbes P, Peters C. Testicular torsion and risk factors for orchiectomy. Arch Pediatr Adolesc Med. 2005;159:1167-1171.

7. Schmitz D, Safranek S. How useful is a physical exam in diagnosing testicular torsion? J Fam Pract. 2009;58(8):433-434.

8. D’Andrea A, Coppolino F, Cesarano E, et al. US in the assessment of acute scrotum. Crit Ultrasound J. 2013;5(suppl 1):S8. www.criticalultrasound journal.com/content/5/S1/S8/. Accessed May 16, 2014.

During a routine physical examination, a 65-year-old man wants to find out if he has “Low T.” He complains of fatigue, decreased libido, and erectile dysfunction (ED) for the past five years. He has a history of type 2 diabetes, hypertension, hyperlipidemia, obstructive sleep apnea, and chronic low back pain. His current medications include metformin, glipizide, lisinopril, atorvastatin, and hydrocodone for back pain. Given these clinical features, the next step will be to find out if he has hypogonadism (androgen ­deficiency).

The Endocrine Society defines hypogonadism as a clinical syndrome in which the testes produce insufficient testosterone as a consequence of an interruption of the hypothalamic-­pituitary-testicular axis. Although prevalence is high in older men, the Endocrine Society does not recommend screening the general population for hypogonadism.¹ Rather, screening should be limited to patients with clinical conditions associated with high prevalence of hypogonadism. Of note, approximately 30% of adults with type 2 diabetes have a subnormal testosterone concentration.²

Q: What is pertinent in the history?

The first step in evaluation of hypogonadism is a detailed history. Signs and symptoms such as decreased libido, hot flashes, decreased shaving frequency, breast enlargement/tenderness, and decreased testicular size are highly suggestive of hypogonadism. Other, less specific signs and symptoms include dysthymia, poor concentration, sleep disturbances, fatigue, reduction in muscle strength, and diminished work performance.

If these signs and symptoms are present, the likelihood of hypogonadism is high and further evaluation is needed.^1,3 Note any history of alcoholism, liver problems, and testicular trauma or surgery.

A detailed medication history is also important. Some medications, such as opiates, can affect the release of gonadotropins. Among men taking long-term opiates for chronic noncancer pain, the prevalence of hypogonadism is 75%.⁴ Other drugs, such as spironolactone, can block the androgen effect and lead to hypogonadism.¹

Recent reports have suggested an association between testosterone replacement therapy and increased cardiovascular events, making a detailed cardiovascular history essential.^5,6 One study found that men ages 75 and older with limited mobility and other comorbidities who used testosterone gel had an increased risk for cardiovascular events.⁷ Therefore, clinicians need to be cognizant of this risk when considering testosterone therapy for their patients.

On the next page: Physical exam, lab tests, and treatments >>

Q: What does the physical exam reveal?

In hypogonadotropic hy­ po­gonadism, physical examination does not usually provide much information, as compared to congenital hypogonadal syndromes (eg, Klinefelter and ­Kallmann syndromes). However, small testicular volume and/or gynecomastia would indicate hypogonadism.

Q: What lab tests should be ordered?

Serum total and free testosterone should be measured, preferably by liquid gas chromatography. The sample should be drawn before 10 am to limit the effects of diurnal variation. If the total testosterone is less than
300 ng/dL, a second morning sample should be drawn and tested. Serum prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), complete blood count, prostate-specific antigen (PSA), comprehensive metabolic panel, and ferritin should also be measured.

There is generally little benefit to testosterone therapy when total testosterone is greater than 350 ng/dL.⁸ The level of testosterone at which hypogonadal symptoms manifest and testosterone replacement provides improvement is yet to be determined. Buvat et al suggest that men with total testosterone levels less than 230 ng/dL usually benefit from therapy.⁸ If the total testosterone level is less than 150 ng/dL in the setting of secondary hypogonadism (low to low-normal LH/FSH) or if prolactin is elevated, MRI of the sella is recommended to rule out pituitary adenoma.¹

Q: Once the diagnosis is confirmed, what treatment should you recommend?

The goal of therapy for confirmed hypogonadism is to normalize the testosterone level. Testosterone replacement therapy may help to improve libido, fatigue, muscle strength, and bone density. However, in the elderly (particularly those older than 70), these therapeutic benefits have not been proven. Therefore, before initiating therapy, the clinician should discuss in detail the risks versus the benefits of testosterone replacement for a particular patient.

Simple lifestyle modifications, such as weight loss and exercise, have been shown to increase total and free testosterone levels.^3,8 For patients with obstructive sleep apnea (OSA), a known risk factor for hypogonadism, compliance with CPAP therapy has been associated with modest improvement in testosterone level. If it is appropriate for the patient to discontinue use of certain medications, such as opiates, he or she may experience an improvement in testosterone level as a result.

If the patient’s testosterone levels remain low after these changes have been implemented, consider testosterone therapy. Testosterone products currently available in the United States include transdermal preparations (gel, patch), intramuscular injection, and subcutaneous pellets.

On the next page: Contraindications, adverse effects, and follow-up >>

Q: What are the contraindications to testosterone therapy?

Testosterone therapy is contraindicated in patients with metastatic prostate cancer and breast cancer. An unevaluated prostate nodule, indurated prostate, PSA greater than 4 ng/mL, elevated hematocrit (>50%), severe lower urinary tract symptoms, poorly controlled congestive heart failure, and untreated severe OSA are associated with moderate to high risk for adverse outcomes; the Endocrine Society has recommended against using testosterone in affected patients.¹

Q: What are the adverse effects of testosterone replacement therapy?

Testosterone replacement may worsen symptoms of benign prostatic hyperplasia (ie, urinary urgency, hesitancy, and frequency). Also, testosterone replacement can lead to marked elevation of hemoglobin and hematocrit levels.

Increased cardiovascular events have been associated with androgen replacement, especially in men with prior coronary artery disease. A positive cardiovascular history necessitates discussion with the patient regarding the risks versus the benefits of testosterone replacement therapy.⁵ In a recent study of obese, hypogonadal men with severe OSA, testosterone therapy was associated with transient worsening of sleep apnea.⁹

Q: What does monitoring/ follow-up entail?

In patients with long-standing hypogonadism, a lower starting dose of testosterone is recommended, which can be gradually increased. After starting testosterone therapy, patients should be monitored in the first three to six months for total ­testosterone, PSA, and hematocrit and for improvement of symptoms (ie, fatigue, ED, decreased libido) or worsening of benign prostatic hyperplasia signs/symptoms.

For men ages 40 and older, if the baseline PSA is greater than 0.6 ng/mL, a digital rectal exam (DRE) is recommended prior to initiation of therapy and should be followed in accordance with prostate cancer screening guidelines.¹

Patients placed on testosterone cypionate/enanthate IM in­jections should have their testosterone checked at a midpoint between their injections, with the target testosterone level between 400 and 700 ng/dL.¹ For those using gel or transdermal preparations, a morning total testosterone level should be measured.

Urology consultation is recommended if the PSA concentration rises by 1.4 ng/dL within 12 months, if the American Urological Association/International Prostate Symptom Score is greater than 19, or if there is an abnormal DRE.^1,8 Treatment with testosterone should be postponed or withheld if the patient’s hematocrit is greater than 54% but may be resumed when it has decreased to normal levels.¹ 

On the next page: References >>

REFERENCES

1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.

2. Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9): 2643-2651.

3. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95(4):1810-1818.

4. Fraser LA, Morrison D, Morley-Forster P, et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117(1):38-43.

5. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17): 1829-1836.

6. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One. 2014;9(1): e85805.

7. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone admin­istration. N Engl J Med. 2010;363(2):109-122.

8. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med. 2013;10(1): 245-284.

9. Hoyos CM, Killick R, Yee BJ, et al. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2012;77(4):
599-607.

During a routine physical examination, a 65-year-old man wants to find out if he has “Low T.” He complains of fatigue, decreased libido, and erectile dysfunction (ED) for the past five years. He has a history of type 2 diabetes, hypertension, hyperlipidemia, obstructive sleep apnea, and chronic low back pain. His current medications include metformin, glipizide, lisinopril, atorvastatin, and hydrocodone for back pain. Given these clinical features, the next step will be to find out if he has hypogonadism (androgen ­deficiency).

The Endocrine Society defines hypogonadism as a clinical syndrome in which the testes produce insufficient testosterone as a consequence of an interruption of the hypothalamic-­pituitary-testicular axis. Although prevalence is high in older men, the Endocrine Society does not recommend screening the general population for hypogonadism.¹ Rather, screening should be limited to patients with clinical conditions associated with high prevalence of hypogonadism. Of note, approximately 30% of adults with type 2 diabetes have a subnormal testosterone concentration.²

Q: What is pertinent in the history?

The first step in evaluation of hypogonadism is a detailed history. Signs and symptoms such as decreased libido, hot flashes, decreased shaving frequency, breast enlargement/tenderness, and decreased testicular size are highly suggestive of hypogonadism. Other, less specific signs and symptoms include dysthymia, poor concentration, sleep disturbances, fatigue, reduction in muscle strength, and diminished work performance.

If these signs and symptoms are present, the likelihood of hypogonadism is high and further evaluation is needed.^1,3 Note any history of alcoholism, liver problems, and testicular trauma or surgery.

A detailed medication history is also important. Some medications, such as opiates, can affect the release of gonadotropins. Among men taking long-term opiates for chronic noncancer pain, the prevalence of hypogonadism is 75%.⁴ Other drugs, such as spironolactone, can block the androgen effect and lead to hypogonadism.¹

Recent reports have suggested an association between testosterone replacement therapy and increased cardiovascular events, making a detailed cardiovascular history essential.^5,6 One study found that men ages 75 and older with limited mobility and other comorbidities who used testosterone gel had an increased risk for cardiovascular events.⁷ Therefore, clinicians need to be cognizant of this risk when considering testosterone therapy for their patients.

On the next page: Physical exam, lab tests, and treatments >>

Q: What does the physical exam reveal?

In hypogonadotropic hy­ po­gonadism, physical examination does not usually provide much information, as compared to congenital hypogonadal syndromes (eg, Klinefelter and ­Kallmann syndromes). However, small testicular volume and/or gynecomastia would indicate hypogonadism.

Q: What lab tests should be ordered?

Serum total and free testosterone should be measured, preferably by liquid gas chromatography. The sample should be drawn before 10 am to limit the effects of diurnal variation. If the total testosterone is less than
300 ng/dL, a second morning sample should be drawn and tested. Serum prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), complete blood count, prostate-specific antigen (PSA), comprehensive metabolic panel, and ferritin should also be measured.

There is generally little benefit to testosterone therapy when total testosterone is greater than 350 ng/dL.⁸ The level of testosterone at which hypogonadal symptoms manifest and testosterone replacement provides improvement is yet to be determined. Buvat et al suggest that men with total testosterone levels less than 230 ng/dL usually benefit from therapy.⁸ If the total testosterone level is less than 150 ng/dL in the setting of secondary hypogonadism (low to low-normal LH/FSH) or if prolactin is elevated, MRI of the sella is recommended to rule out pituitary adenoma.¹

Q: Once the diagnosis is confirmed, what treatment should you recommend?

The goal of therapy for confirmed hypogonadism is to normalize the testosterone level. Testosterone replacement therapy may help to improve libido, fatigue, muscle strength, and bone density. However, in the elderly (particularly those older than 70), these therapeutic benefits have not been proven. Therefore, before initiating therapy, the clinician should discuss in detail the risks versus the benefits of testosterone replacement for a particular patient.

Simple lifestyle modifications, such as weight loss and exercise, have been shown to increase total and free testosterone levels.^3,8 For patients with obstructive sleep apnea (OSA), a known risk factor for hypogonadism, compliance with CPAP therapy has been associated with modest improvement in testosterone level. If it is appropriate for the patient to discontinue use of certain medications, such as opiates, he or she may experience an improvement in testosterone level as a result.

If the patient’s testosterone levels remain low after these changes have been implemented, consider testosterone therapy. Testosterone products currently available in the United States include transdermal preparations (gel, patch), intramuscular injection, and subcutaneous pellets.

On the next page: Contraindications, adverse effects, and follow-up >>

Q: What are the contraindications to testosterone therapy?

Testosterone therapy is contraindicated in patients with metastatic prostate cancer and breast cancer. An unevaluated prostate nodule, indurated prostate, PSA greater than 4 ng/mL, elevated hematocrit (>50%), severe lower urinary tract symptoms, poorly controlled congestive heart failure, and untreated severe OSA are associated with moderate to high risk for adverse outcomes; the Endocrine Society has recommended against using testosterone in affected patients.¹

Q: What are the adverse effects of testosterone replacement therapy?

Testosterone replacement may worsen symptoms of benign prostatic hyperplasia (ie, urinary urgency, hesitancy, and frequency). Also, testosterone replacement can lead to marked elevation of hemoglobin and hematocrit levels.

Increased cardiovascular events have been associated with androgen replacement, especially in men with prior coronary artery disease. A positive cardiovascular history necessitates discussion with the patient regarding the risks versus the benefits of testosterone replacement therapy.⁵ In a recent study of obese, hypogonadal men with severe OSA, testosterone therapy was associated with transient worsening of sleep apnea.⁹

Q: What does monitoring/ follow-up entail?

In patients with long-standing hypogonadism, a lower starting dose of testosterone is recommended, which can be gradually increased. After starting testosterone therapy, patients should be monitored in the first three to six months for total ­testosterone, PSA, and hematocrit and for improvement of symptoms (ie, fatigue, ED, decreased libido) or worsening of benign prostatic hyperplasia signs/symptoms.

For men ages 40 and older, if the baseline PSA is greater than 0.6 ng/mL, a digital rectal exam (DRE) is recommended prior to initiation of therapy and should be followed in accordance with prostate cancer screening guidelines.¹

Patients placed on testosterone cypionate/enanthate IM in­jections should have their testosterone checked at a midpoint between their injections, with the target testosterone level between 400 and 700 ng/dL.¹ For those using gel or transdermal preparations, a morning total testosterone level should be measured.

Urology consultation is recommended if the PSA concentration rises by 1.4 ng/dL within 12 months, if the American Urological Association/International Prostate Symptom Score is greater than 19, or if there is an abnormal DRE.^1,8 Treatment with testosterone should be postponed or withheld if the patient’s hematocrit is greater than 54% but may be resumed when it has decreased to normal levels.¹ 

On the next page: References >>

REFERENCES

1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.

2. Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9): 2643-2651.

3. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95(4):1810-1818.

4. Fraser LA, Morrison D, Morley-Forster P, et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117(1):38-43.

5. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17): 1829-1836.

6. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One. 2014;9(1): e85805.

7. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone admin­istration. N Engl J Med. 2010;363(2):109-122.

8. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med. 2013;10(1): 245-284.

9. Hoyos CM, Killick R, Yee BJ, et al. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2012;77(4):
599-607.

During a routine physical examination, a 65-year-old man wants to find out if he has “Low T.” He complains of fatigue, decreased libido, and erectile dysfunction (ED) for the past five years. He has a history of type 2 diabetes, hypertension, hyperlipidemia, obstructive sleep apnea, and chronic low back pain. His current medications include metformin, glipizide, lisinopril, atorvastatin, and hydrocodone for back pain. Given these clinical features, the next step will be to find out if he has hypogonadism (androgen ­deficiency).

The Endocrine Society defines hypogonadism as a clinical syndrome in which the testes produce insufficient testosterone as a consequence of an interruption of the hypothalamic-­pituitary-testicular axis. Although prevalence is high in older men, the Endocrine Society does not recommend screening the general population for hypogonadism.¹ Rather, screening should be limited to patients with clinical conditions associated with high prevalence of hypogonadism. Of note, approximately 30% of adults with type 2 diabetes have a subnormal testosterone concentration.²

Q: What is pertinent in the history?

The first step in evaluation of hypogonadism is a detailed history. Signs and symptoms such as decreased libido, hot flashes, decreased shaving frequency, breast enlargement/tenderness, and decreased testicular size are highly suggestive of hypogonadism. Other, less specific signs and symptoms include dysthymia, poor concentration, sleep disturbances, fatigue, reduction in muscle strength, and diminished work performance.

If these signs and symptoms are present, the likelihood of hypogonadism is high and further evaluation is needed.^1,3 Note any history of alcoholism, liver problems, and testicular trauma or surgery.

A detailed medication history is also important. Some medications, such as opiates, can affect the release of gonadotropins. Among men taking long-term opiates for chronic noncancer pain, the prevalence of hypogonadism is 75%.⁴ Other drugs, such as spironolactone, can block the androgen effect and lead to hypogonadism.¹

Recent reports have suggested an association between testosterone replacement therapy and increased cardiovascular events, making a detailed cardiovascular history essential.^5,6 One study found that men ages 75 and older with limited mobility and other comorbidities who used testosterone gel had an increased risk for cardiovascular events.⁷ Therefore, clinicians need to be cognizant of this risk when considering testosterone therapy for their patients.

On the next page: Physical exam, lab tests, and treatments >>

Q: What does the physical exam reveal?

In hypogonadotropic hy­ po­gonadism, physical examination does not usually provide much information, as compared to congenital hypogonadal syndromes (eg, Klinefelter and ­Kallmann syndromes). However, small testicular volume and/or gynecomastia would indicate hypogonadism.

Q: What lab tests should be ordered?

Serum total and free testosterone should be measured, preferably by liquid gas chromatography. The sample should be drawn before 10 am to limit the effects of diurnal variation. If the total testosterone is less than
300 ng/dL, a second morning sample should be drawn and tested. Serum prolactin, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), complete blood count, prostate-specific antigen (PSA), comprehensive metabolic panel, and ferritin should also be measured.

There is generally little benefit to testosterone therapy when total testosterone is greater than 350 ng/dL.⁸ The level of testosterone at which hypogonadal symptoms manifest and testosterone replacement provides improvement is yet to be determined. Buvat et al suggest that men with total testosterone levels less than 230 ng/dL usually benefit from therapy.⁸ If the total testosterone level is less than 150 ng/dL in the setting of secondary hypogonadism (low to low-normal LH/FSH) or if prolactin is elevated, MRI of the sella is recommended to rule out pituitary adenoma.¹

Q: Once the diagnosis is confirmed, what treatment should you recommend?

The goal of therapy for confirmed hypogonadism is to normalize the testosterone level. Testosterone replacement therapy may help to improve libido, fatigue, muscle strength, and bone density. However, in the elderly (particularly those older than 70), these therapeutic benefits have not been proven. Therefore, before initiating therapy, the clinician should discuss in detail the risks versus the benefits of testosterone replacement for a particular patient.

Simple lifestyle modifications, such as weight loss and exercise, have been shown to increase total and free testosterone levels.^3,8 For patients with obstructive sleep apnea (OSA), a known risk factor for hypogonadism, compliance with CPAP therapy has been associated with modest improvement in testosterone level. If it is appropriate for the patient to discontinue use of certain medications, such as opiates, he or she may experience an improvement in testosterone level as a result.

If the patient’s testosterone levels remain low after these changes have been implemented, consider testosterone therapy. Testosterone products currently available in the United States include transdermal preparations (gel, patch), intramuscular injection, and subcutaneous pellets.

On the next page: Contraindications, adverse effects, and follow-up >>

Q: What are the contraindications to testosterone therapy?

Testosterone therapy is contraindicated in patients with metastatic prostate cancer and breast cancer. An unevaluated prostate nodule, indurated prostate, PSA greater than 4 ng/mL, elevated hematocrit (>50%), severe lower urinary tract symptoms, poorly controlled congestive heart failure, and untreated severe OSA are associated with moderate to high risk for adverse outcomes; the Endocrine Society has recommended against using testosterone in affected patients.¹

Q: What are the adverse effects of testosterone replacement therapy?

Testosterone replacement may worsen symptoms of benign prostatic hyperplasia (ie, urinary urgency, hesitancy, and frequency). Also, testosterone replacement can lead to marked elevation of hemoglobin and hematocrit levels.

Increased cardiovascular events have been associated with androgen replacement, especially in men with prior coronary artery disease. A positive cardiovascular history necessitates discussion with the patient regarding the risks versus the benefits of testosterone replacement therapy.⁵ In a recent study of obese, hypogonadal men with severe OSA, testosterone therapy was associated with transient worsening of sleep apnea.⁹

Q: What does monitoring/ follow-up entail?

In patients with long-standing hypogonadism, a lower starting dose of testosterone is recommended, which can be gradually increased. After starting testosterone therapy, patients should be monitored in the first three to six months for total ­testosterone, PSA, and hematocrit and for improvement of symptoms (ie, fatigue, ED, decreased libido) or worsening of benign prostatic hyperplasia signs/symptoms.

For men ages 40 and older, if the baseline PSA is greater than 0.6 ng/mL, a digital rectal exam (DRE) is recommended prior to initiation of therapy and should be followed in accordance with prostate cancer screening guidelines.¹

Patients placed on testosterone cypionate/enanthate IM in­jections should have their testosterone checked at a midpoint between their injections, with the target testosterone level between 400 and 700 ng/dL.¹ For those using gel or transdermal preparations, a morning total testosterone level should be measured.

Urology consultation is recommended if the PSA concentration rises by 1.4 ng/dL within 12 months, if the American Urological Association/International Prostate Symptom Score is greater than 19, or if there is an abnormal DRE.^1,8 Treatment with testosterone should be postponed or withheld if the patient’s hematocrit is greater than 54% but may be resumed when it has decreased to normal levels.¹ 

On the next page: References >>

REFERENCES

1. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2010;95(6):2536-2559.

2. Dandona P, Dhindsa S. Update: hypogonadotropic hypogonadism in type 2 diabetes and obesity. J Clin Endocrinol Metab. 2011;96(9): 2643-2651.

3. Tajar A, Forti G, O’Neill TW, et al. Characteristics of secondary, primary, and compensated hypogonadism in aging men: evidence from the European Male Ageing Study. J Clin Endocrinol Metab. 2010;95(4):1810-1818.

4. Fraser LA, Morrison D, Morley-Forster P, et al. Oral opioids for chronic non-cancer pain: higher prevalence of hypogonadism in men than in women. Exp Clin Endocrinol Diabetes. 2009;117(1):38-43.

5. Vigen R, O’Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013;310(17): 1829-1836.

6. Finkle WD, Greenland S, Ridgeway GK, et al. Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. PloS One. 2014;9(1): e85805.

7. Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone admin­istration. N Engl J Med. 2010;363(2):109-122.

8. Buvat J, Maggi M, Guay A, Torres LO. Testosterone deficiency in men: systematic review and standard operating procedures for diagnosis and treatment. J Sex Med. 2013;10(1): 245-284.

9. Hoyos CM, Killick R, Yee BJ, et al. Effects of testosterone therapy on sleep and breathing in obese men with severe obstructive sleep apnoea: a randomized placebo-controlled trial. Clin Endocrinol (Oxf). 2012;77(4):
599-607.

ANSWER

There are three significant findings on this ECG. First, the rhythm shows complete heart block. The ventricular rate is 56 beats/min, and the QRS complex is narrow, resulting in a junctional rhythm. The atrial rate is 98 beats/min (consistent with a sinus rhythm), and there is no relationship of the P waves to the QRS complexes.

The second finding is a rightward axis deviation. Note that the QRS complexes are negative in lead I and positive in lead aVF. To meet criteria for a right-axis deviation, the QRS complex must also be positive in lead aVR. In this case, the QRS complex appears to be isoelectric in aVR, so we call the axis rightward.

The presence of rightward axis deviation is a result of the third finding, an anterior MI. This is due to the LAD artery occlusion discovered at catheterization. It is evident on the ECG by the absence of significant R waves in leads V₁ through V₄.

Given the need for a β-blocker with titration of dose, the patient underwent implantation of a permanent pacemaker system.

ANSWER

There are three significant findings on this ECG. First, the rhythm shows complete heart block. The ventricular rate is 56 beats/min, and the QRS complex is narrow, resulting in a junctional rhythm. The atrial rate is 98 beats/min (consistent with a sinus rhythm), and there is no relationship of the P waves to the QRS complexes.

The second finding is a rightward axis deviation. Note that the QRS complexes are negative in lead I and positive in lead aVF. To meet criteria for a right-axis deviation, the QRS complex must also be positive in lead aVR. In this case, the QRS complex appears to be isoelectric in aVR, so we call the axis rightward.

The presence of rightward axis deviation is a result of the third finding, an anterior MI. This is due to the LAD artery occlusion discovered at catheterization. It is evident on the ECG by the absence of significant R waves in leads V₁ through V₄.

Given the need for a β-blocker with titration of dose, the patient underwent implantation of a permanent pacemaker system.

ANSWER

There are three significant findings on this ECG. First, the rhythm shows complete heart block. The ventricular rate is 56 beats/min, and the QRS complex is narrow, resulting in a junctional rhythm. The atrial rate is 98 beats/min (consistent with a sinus rhythm), and there is no relationship of the P waves to the QRS complexes.

The second finding is a rightward axis deviation. Note that the QRS complexes are negative in lead I and positive in lead aVF. To meet criteria for a right-axis deviation, the QRS complex must also be positive in lead aVR. In this case, the QRS complex appears to be isoelectric in aVR, so we call the axis rightward.

The presence of rightward axis deviation is a result of the third finding, an anterior MI. This is due to the LAD artery occlusion discovered at catheterization. It is evident on the ECG by the absence of significant R waves in leads V₁ through V₄.

Given the need for a β-blocker with titration of dose, the patient underwent implantation of a permanent pacemaker system.

ANSWER

The correct answer is eruptive xanthomata (choice “b”) caused by an accumulation of lipid-filled macrophages as a result of pathologic levels of serum triglyceride—a situation discussed more fully below.

Neurofibromatosis type I (choice “a”), also known as von Recklinghausen disease, can present with multiple intradermal nodules. However, it usually appears in the second or third decade of life, with lesions that are fixed and soft. Biopsy would have confirmed this diagnosis.

Diabetic dermopathy (choice “c”) manifests with atrophic patches on anterior tibial skin. The patches occasionally become superficially eroded but do not resemble this patient’s lesions at all.

Juvenile xanthogranuloma (choice “d”) usually presents on children as a solitary yellowish brown papule. It can resemble eruptive xanthomata histologically but not clinically.

DISCUSSION

Eruptive xanthomata (EX) are relatively common, manifesting rapidly as papules and nodules, most frequently in the setting of hypertriglyceridemia. The latter can be familial and may be worsened by poorly controlled diabetes. Persons with Fredrickson types I, IV, and V hyperlipidemia are especially prone to EX.

As might be expected, patients with EX are at risk for several associated morbidities, including acute pancreatitis (especially in childhood cases) and atherosclerotic vessel disease. EX have also been associated with hypothyroid states and nephrotic syndromes.

Elevations in cholesterol, with normal triglyceride levels, can be associated with several types of xanthoma, including plane xanthomas and xanthelasma. The latter, often benign, can manifest in a normolipemic patient as well (necessitating a problem-directed history, physical, and lipid check).

Biopsy is often required to confirm the diagnosis of EX. As in this case, it typically shows monotonous collections of lipid-laden macrophages. Frozen sections of EX can be successfully stained for lipids, but routine processing of specimens effectively removes any lipids, replacing them with paraffin.

TREATMENT

Treatment entails controlling lipids with medication (fenofibrate), diet, and exercise and getting diabetes under control, as indicated. It is also essential to assess for atherosclerotic vessel disease and rule out pancreatitis.

Within a month of institution of treatment, this patient’s lesions had all but disappeared. His serum amylase and lipase were within normal limits, and testing for atherosclerotic vessel disease was pending.

Click here for more DermaDiagnosis cases, including 
• The Value of Certainty in Diagnosis
• A Purplish Rash on the Instep
• Hair Loss at a Very Young Age.

ANSWER

The correct answer is eruptive xanthomata (choice “b”) caused by an accumulation of lipid-filled macrophages as a result of pathologic levels of serum triglyceride—a situation discussed more fully below.

Neurofibromatosis type I (choice “a”), also known as von Recklinghausen disease, can present with multiple intradermal nodules. However, it usually appears in the second or third decade of life, with lesions that are fixed and soft. Biopsy would have confirmed this diagnosis.

Diabetic dermopathy (choice “c”) manifests with atrophic patches on anterior tibial skin. The patches occasionally become superficially eroded but do not resemble this patient’s lesions at all.

Juvenile xanthogranuloma (choice “d”) usually presents on children as a solitary yellowish brown papule. It can resemble eruptive xanthomata histologically but not clinically.

DISCUSSION

Eruptive xanthomata (EX) are relatively common, manifesting rapidly as papules and nodules, most frequently in the setting of hypertriglyceridemia. The latter can be familial and may be worsened by poorly controlled diabetes. Persons with Fredrickson types I, IV, and V hyperlipidemia are especially prone to EX.

As might be expected, patients with EX are at risk for several associated morbidities, including acute pancreatitis (especially in childhood cases) and atherosclerotic vessel disease. EX have also been associated with hypothyroid states and nephrotic syndromes.

Elevations in cholesterol, with normal triglyceride levels, can be associated with several types of xanthoma, including plane xanthomas and xanthelasma. The latter, often benign, can manifest in a normolipemic patient as well (necessitating a problem-directed history, physical, and lipid check).

Biopsy is often required to confirm the diagnosis of EX. As in this case, it typically shows monotonous collections of lipid-laden macrophages. Frozen sections of EX can be successfully stained for lipids, but routine processing of specimens effectively removes any lipids, replacing them with paraffin.

TREATMENT

Treatment entails controlling lipids with medication (fenofibrate), diet, and exercise and getting diabetes under control, as indicated. It is also essential to assess for atherosclerotic vessel disease and rule out pancreatitis.

Within a month of institution of treatment, this patient’s lesions had all but disappeared. His serum amylase and lipase were within normal limits, and testing for atherosclerotic vessel disease was pending.

Click here for more DermaDiagnosis cases, including 
• The Value of Certainty in Diagnosis
• A Purplish Rash on the Instep
• Hair Loss at a Very Young Age.

ANSWER

The correct answer is eruptive xanthomata (choice “b”) caused by an accumulation of lipid-filled macrophages as a result of pathologic levels of serum triglyceride—a situation discussed more fully below.

Neurofibromatosis type I (choice “a”), also known as von Recklinghausen disease, can present with multiple intradermal nodules. However, it usually appears in the second or third decade of life, with lesions that are fixed and soft. Biopsy would have confirmed this diagnosis.

Diabetic dermopathy (choice “c”) manifests with atrophic patches on anterior tibial skin. The patches occasionally become superficially eroded but do not resemble this patient’s lesions at all.

Juvenile xanthogranuloma (choice “d”) usually presents on children as a solitary yellowish brown papule. It can resemble eruptive xanthomata histologically but not clinically.

DISCUSSION

Eruptive xanthomata (EX) are relatively common, manifesting rapidly as papules and nodules, most frequently in the setting of hypertriglyceridemia. The latter can be familial and may be worsened by poorly controlled diabetes. Persons with Fredrickson types I, IV, and V hyperlipidemia are especially prone to EX.

As might be expected, patients with EX are at risk for several associated morbidities, including acute pancreatitis (especially in childhood cases) and atherosclerotic vessel disease. EX have also been associated with hypothyroid states and nephrotic syndromes.

Elevations in cholesterol, with normal triglyceride levels, can be associated with several types of xanthoma, including plane xanthomas and xanthelasma. The latter, often benign, can manifest in a normolipemic patient as well (necessitating a problem-directed history, physical, and lipid check).

Biopsy is often required to confirm the diagnosis of EX. As in this case, it typically shows monotonous collections of lipid-laden macrophages. Frozen sections of EX can be successfully stained for lipids, but routine processing of specimens effectively removes any lipids, replacing them with paraffin.

TREATMENT

Treatment entails controlling lipids with medication (fenofibrate), diet, and exercise and getting diabetes under control, as indicated. It is also essential to assess for atherosclerotic vessel disease and rule out pancreatitis.

Within a month of institution of treatment, this patient’s lesions had all but disappeared. His serum amylase and lipase were within normal limits, and testing for atherosclerotic vessel disease was pending.

Click here for more DermaDiagnosis cases, including 
• The Value of Certainty in Diagnosis
• A Purplish Rash on the Instep
• Hair Loss at a Very Young Age.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Researchers in the lab

Credit: Rhoda Baer

Researchers say they have identified a source of drug resistance in chronic lymphocytic leukemia (CLL).

In a letter to The New England Journal of Medicine, the team described how a mutation in Bruton’s tyrosine kinase (BTK) triggers resistance to ibrutinib, a drug that treats CLL by inhibiting BTK.

The researchers discovered this point mutation in a CLL patient enrolled in a clinical trial. The patient initially responded well to ibrutinib but stopped responding after almost 20 months.

“In a way, we are repeating, at a faster pace, the story of Gleevec [imatinib],” said study author Y. Lynn Wang, MD, PhD, of the University of Chicago in Illinois.

“That story began with development of an effective drug with few side effects, but, in many patients, the leukemia eventually found a way around it after long-term use. So researchers developed second-line drugs to overcome resistance.”

The ibrutinib study began in 2010 at Weill Cornell Medical College in New York, one of several sites for a phase 1 trial of ibrutinib. The researchers recruited 16 patients with CLL whose disease had progressed or relapsed despite multiple treatments.

Dr Wang arranged to track the progress of each patient’s leukemic cells before and during treatment and to correlate any cellular or molecular changes with each patient’s disease activity.

One of the 16 patients in the trial seemed to be unusual. This 61-year-old woman was diagnosed in 2000 at age 49. She had unsuccessfully received several different treatments before entering the study.

Within 18 months of starting ibrutinib, she showed significant improvement. At about 20 months, however, she started to decline, developing a respiratory infection that did not improve with treatment. By 21 months, it was clear she was having a relapse. The clinical team increased her dose, with no discernable effect.

Dr Wang’s team quickly began analyzing her blood samples, looking for changes that occurred between the period when she was responding well to ibrutinib and after she began to relapse.

Because complete gene sequencing would be time consuming, Dr Wang asked a graduate student working on the project, Menu Setty from Memorial Sloan-Kettering in New York, to first focus on 3 proteins that were likely candidates. One of the candidates was BTK.

And sure enough, Setty discovered a tiny but consistent change in BTK in about 90% of post-relapse cells. It was a thymidine-to-adenine mutation at nucleotide 1634 of the BTK complementary DNA, leading to a substitution of serine for cysteine at residue 481 (C481S).

When the researchers later analyzed the entire set of the patient’s genes, they found no other genetic changes that correlated with the patient’s clinical course. BTK made perfect sense as the cause for drug resistance, the researchers noted, as it’s the primary target of ibrutinib binding, and it plays a central role in rapid cell proliferation.

Dr Wang and her colleagues used structural and biochemical measures to confirm that the C481S mutation made CLL cells resistant to ibrutinib. The studies indicated that ibrutinib was 500 times less likely to bind to mutant BTK.

In an attempt to save the patient, the researchers tested alternative kinase inhibitors against the patient’s leukemic cells in the lab.

They found some kinase inhibitors remained effective against ibrutinib-resistant cells. (These studies are described in a separate manuscript that has been submitted for publication.) Unfortunately, despite this effort, the patient passed away a few weeks later, due to sepsis.

The researchers noted that the C481S mutation is one of several mechanisms that underlie resistance to ibrutinib, but this research highlights the mutation’s role in disease development and drug resistance.

Understanding the molecular and cellular mechanisms of resistance is the first step toward monitoring, early detection, and development of novel strategies to overcome drug resistance.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.

Thrombus

Credit: Andre E.X. Brown

The US Food and Drug Administration has cleared for marketing a device that facilitates the treatment of pulmonary embolism (PE).

The EkoSonic Endovascular System is intended for controlled and selective infusion of physician-specified fluids, including thrombolytics, into the peripheral vasculature.

The device is designed to gently accelerate the penetration of thrombolytic agents into thrombi, thereby providing high levels of lysis.

The EkoSonic Endovascular System is the only minimally invasive endovascular therapy that is FDA-cleared for the treatment of PE. The device is manufactured by EKOS Corporation.

“The EKOS clinical data established that patients stricken with a life-threatening pulmonary embolism can be successfully and safely treated with the EkoSonic system,” said Samuel Z. Goldhaber, MD, of Brigham and Woman’s Hospital in Boston, Massachusetts.

The system produced favorable results in the ULTIMA and SEATTLE II trials.

Results of the ULTIMA trial were published in Circulation. The trial showed that, for PE patients at intermediate risk of adverse events, EKOS treatment was clinically superior to anticoagulation with heparin alone in reversing right ventricular dilation at 24 hours, without an increase in bleeding complications.

The results of SEATTLE II, the prospective, single-arm, multicenter trial of 150 patients, were released at the American College of Cardiology’s 63rd Annual Scientific Session & Expo.

SEATTLE II showed that ultrasound-facilitated catheter-directed low-dose fibrinolysis for acute PE minimizes the risk of intracranial hemorrhage, improves right ventricle function, and decreases pulmonary hypertension.