The Journal of Family Practice

Gastroesophageal reflux disease (GERD) is fertile soil for medical and psychiatric comorbid conditions, with sleep disorders leading the way, according to Maurice M. Ohayon, MD, who presented the findings of a longitudinal, population-based study on GERD and its "fellow travelers" at the annual meeting of the Associated Professional Sleep Societies. Insomnia, obstructive sleep apnea, and restless legs syndrome were among the most prevalent comorbidities of GERD. However, one sleep disorder symptom was reported to be a problem in up to 46% of those with the digestive disease. To learn more, see Family Practice News at: http://www.familypracticenews.com/specialty-focus/pulmonary-sleep-medicine/single-article-page/gerd-and-sleep-disorders-often-go-hand-in-glove/1dc81a99b64d296e03b86aa28893fbc7.html.

Gastroesophageal reflux disease (GERD) is fertile soil for medical and psychiatric comorbid conditions, with sleep disorders leading the way, according to Maurice M. Ohayon, MD, who presented the findings of a longitudinal, population-based study on GERD and its "fellow travelers" at the annual meeting of the Associated Professional Sleep Societies. Insomnia, obstructive sleep apnea, and restless legs syndrome were among the most prevalent comorbidities of GERD. However, one sleep disorder symptom was reported to be a problem in up to 46% of those with the digestive disease. To learn more, see Family Practice News at: http://www.familypracticenews.com/specialty-focus/pulmonary-sleep-medicine/single-article-page/gerd-and-sleep-disorders-often-go-hand-in-glove/1dc81a99b64d296e03b86aa28893fbc7.html.

Gastroesophageal reflux disease (GERD) is fertile soil for medical and psychiatric comorbid conditions, with sleep disorders leading the way, according to Maurice M. Ohayon, MD, who presented the findings of a longitudinal, population-based study on GERD and its "fellow travelers" at the annual meeting of the Associated Professional Sleep Societies. Insomnia, obstructive sleep apnea, and restless legs syndrome were among the most prevalent comorbidities of GERD. However, one sleep disorder symptom was reported to be a problem in up to 46% of those with the digestive disease. To learn more, see Family Practice News at: http://www.familypracticenews.com/specialty-focus/pulmonary-sleep-medicine/single-article-page/gerd-and-sleep-disorders-often-go-hand-in-glove/1dc81a99b64d296e03b86aa28893fbc7.html.

Patients with hepatitis C virus (HCV) infections may have the best long-term outcomes if they achieve sustained viral response (SVR) before they develop clinically significant portal hypertension, according to a study reported on in the July issue of Gastroenterology. On the other hand, patients in stage 2 cirrhosis were more likely than stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” said Dr. Vito Di Marco and his associates from the University of Palermo, Italy. More on the study, and its limitations, is available at Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/early-sustained-viral-response-linked-to-better-outcomes-among-hcv-patients/5089546903e73ad3c6947ff3bd3f8dbc.html.

Patients with hepatitis C virus (HCV) infections may have the best long-term outcomes if they achieve sustained viral response (SVR) before they develop clinically significant portal hypertension, according to a study reported on in the July issue of Gastroenterology. On the other hand, patients in stage 2 cirrhosis were more likely than stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” said Dr. Vito Di Marco and his associates from the University of Palermo, Italy. More on the study, and its limitations, is available at Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/early-sustained-viral-response-linked-to-better-outcomes-among-hcv-patients/5089546903e73ad3c6947ff3bd3f8dbc.html.

Patients with hepatitis C virus (HCV) infections may have the best long-term outcomes if they achieve sustained viral response (SVR) before they develop clinically significant portal hypertension, according to a study reported on in the July issue of Gastroenterology. On the other hand, patients in stage 2 cirrhosis were more likely than stage 1 patients to develop liver decompensation and to die of hepatocellular carcinoma, regardless of SVR. “The available evidence, including our own, suggests that it is opportune to treat HCV as early as possible, in order to reduce progression to stages of cirrhosis in which a viral cure may be less likely lead to ultimate achievement of a major benefit,” said Dr. Vito Di Marco and his associates from the University of Palermo, Italy. More on the study, and its limitations, is available at Family Practice News: http://www.familypracticenews.com/specialty-focus/infectious-diseases/single-article-page/early-sustained-viral-response-linked-to-better-outcomes-among-hcv-patients/5089546903e73ad3c6947ff3bd3f8dbc.html.

Many commonly used prescription drugs, over-the-counter agents, and several complimentary or alternative medications can either trigger heart failure or exacerbate the disease in patients with existing heart failure, according to a scientific statement written by a committee of the American Heart Association that was released on July 11. The comprehensive statement lists 88 distinct prescription drugs or drug classes. Read more about the statement at Cardiology News, available here: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/statement-warns-of-drugs-causing-or-exacerbating-heart-failure/e62f58d7bf5e124f84a09242a258bfb5.html.

Many commonly used prescription drugs, over-the-counter agents, and several complimentary or alternative medications can either trigger heart failure or exacerbate the disease in patients with existing heart failure, according to a scientific statement written by a committee of the American Heart Association that was released on July 11. The comprehensive statement lists 88 distinct prescription drugs or drug classes. Read more about the statement at Cardiology News, available here: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/statement-warns-of-drugs-causing-or-exacerbating-heart-failure/e62f58d7bf5e124f84a09242a258bfb5.html.

Many commonly used prescription drugs, over-the-counter agents, and several complimentary or alternative medications can either trigger heart failure or exacerbate the disease in patients with existing heart failure, according to a scientific statement written by a committee of the American Heart Association that was released on July 11. The comprehensive statement lists 88 distinct prescription drugs or drug classes. Read more about the statement at Cardiology News, available here: http://www.ecardiologynews.com/specialty-focus/heart-failure/single-article-page/statement-warns-of-drugs-causing-or-exacerbating-heart-failure/e62f58d7bf5e124f84a09242a258bfb5.html.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Because delayed diagnosis is thought to be associated with adverse outcomes, physicians are encouraged to follow available guidelines and test for the disease in all symptomatic adults with fixed airflow obstruction. This article from the Cleveland Clinic Journal of Medicine describes how to detect this genetic condition and the promising new therapies that are being investigated to treat it. The article is available at: http://www.ccjm.org/current-issue/issue-single-view/alpha-1-antitrypsin-deficiency-an-underrecognized-treatable-cause-of-copd/405de7ef6d4fcd6663e0af929c45b845.html.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Because delayed diagnosis is thought to be associated with adverse outcomes, physicians are encouraged to follow available guidelines and test for the disease in all symptomatic adults with fixed airflow obstruction. This article from the Cleveland Clinic Journal of Medicine describes how to detect this genetic condition and the promising new therapies that are being investigated to treat it. The article is available at: http://www.ccjm.org/current-issue/issue-single-view/alpha-1-antitrypsin-deficiency-an-underrecognized-treatable-cause-of-copd/405de7ef6d4fcd6663e0af929c45b845.html.

Alpha-1 antitrypsin deficiency is a common but underrecognized genetic condition that increases the risk of chronic obstructive pulmonary disease (COPD) and liver disease. Because delayed diagnosis is thought to be associated with adverse outcomes, physicians are encouraged to follow available guidelines and test for the disease in all symptomatic adults with fixed airflow obstruction. This article from the Cleveland Clinic Journal of Medicine describes how to detect this genetic condition and the promising new therapies that are being investigated to treat it. The article is available at: http://www.ccjm.org/current-issue/issue-single-view/alpha-1-antitrypsin-deficiency-an-underrecognized-treatable-cause-of-copd/405de7ef6d4fcd6663e0af929c45b845.html.

Historically, the standard of care was for primary care providers to monitor warfarin therapy, but recently, there has been a shift to monitoring patients in anticoagulation clinics. This article from Federal Practitioner provides an overview of the studies done to evaluate the safety and efficacy of face-to-face vs telephone anticoagulation clinics. Find out which method was more effective—if any—at: http://www.fedprac.com/the-publication/issue-single-view/efficacy-and-safety-outcomes-for-patients-taking-warfarin-who-were-switched-from-face-to-face-to-telephone-anticoagulation-clinic/b1833e94751e2fa5c22da1ae82d20f47/ocregister.html.

Historically, the standard of care was for primary care providers to monitor warfarin therapy, but recently, there has been a shift to monitoring patients in anticoagulation clinics. This article from Federal Practitioner provides an overview of the studies done to evaluate the safety and efficacy of face-to-face vs telephone anticoagulation clinics. Find out which method was more effective—if any—at: http://www.fedprac.com/the-publication/issue-single-view/efficacy-and-safety-outcomes-for-patients-taking-warfarin-who-were-switched-from-face-to-face-to-telephone-anticoagulation-clinic/b1833e94751e2fa5c22da1ae82d20f47/ocregister.html.

Historically, the standard of care was for primary care providers to monitor warfarin therapy, but recently, there has been a shift to monitoring patients in anticoagulation clinics. This article from Federal Practitioner provides an overview of the studies done to evaluate the safety and efficacy of face-to-face vs telephone anticoagulation clinics. Find out which method was more effective—if any—at: http://www.fedprac.com/the-publication/issue-single-view/efficacy-and-safety-outcomes-for-patients-taking-warfarin-who-were-switched-from-face-to-face-to-telephone-anticoagulation-clinic/b1833e94751e2fa5c22da1ae82d20f47/ocregister.html.

CASE › Joan C is a 68-year-old woman who presents to the office complaining of an enlarging left chest wall mass that appeared within the past month. She was treated for small-cell lung cancer 11 years ago. She has a 45 pack-year smoking history (she quit when she received the diagnosis) and has heart failure, which is controlled. Your examination reveals a large (5 cm) firm mass on her left chest wall. There is no erythema or tenderness. She has no other complaints. You recommend surgical biopsy and refer her to surgery.

Ms. C returns to your office several days later complaining of new and worsening shortness of breath with exertion that began the previous day. The presentation is similar to prior asthma exacerbation episodes. She denies any cough, fever, chest pain, symptoms at rest, or hemoptysis. On exam she appears comfortable and not in any acute distress. You refill her albuterol.

The next day you learn that she is being admitted to the hospital with respiratory distress. An x-ray of her chest shows a concerning mass in her right upper lung.

Dyspnea is an uncomfortable awareness of breathing that occurs when complex neurochemical pathways used to maintain oxygenation and ventilation are disrupted. (See "The variable, and subjective, process of dyspnea"^1-5). Sometimes described as air hunger, increased work of breathing, chest tightness, or chest constriction, the symptom is usually disproportionate to the patient’s level of exertion.

Most of the time dyspnea is due to either a primary lung or cardiovascular problem such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary embolism (PE), pneumonia, congestive heart failure (CHF), or myocardial infarction. However, many other illnesses can also produce this symptom (TABLE 1). This article will review the uncommon etiologies of dyspnea that should be considered when the usual suspects have been eliminated.

Cardiovascular culprits

Dyspnea is a common symptom with cardiovascular diseases because cardiac output relates directly to tissue oxygenation. Any pathology that decreases the ability of the heart and blood vessels to transport oxygen will likely trigger discord between the central, peripheral, and neurochemical respiratory centers. Two uncommon cardiovascular etiologies of dyspnea are pericarditis and myocarditis.

Pericarditis

Pericarditis is generally a self-limited condition that responds promptly to initial treatment, although it can cause significant morbidity and mortality. One study showed that acute pericarditis accounted for 5% of patients presenting to the emergency department with non-ischemic chest pain.⁶ Another study found that the in-hospital mortality rate for acute pericarditis was 1.1%.⁷

Pericarditis causes dyspnea by restricting the heart’s ability to relax, thus decreasing preload and cardiac output. This occurs with large effusions (>20 mm in width on echocardiography) and can lead to cardiac tamponade—a medical emergency that should be suspected in patients with muffled heart sounds, hypotension, and increased jugular venous distention (Beck’s triad).

Pericarditis etiologies include:

• infectious causes (viral and bacterial entities, myocarditis),
• rheumatologic causes (gout, systemic lupus erythematosus, tumor necrosis factor receptor-associated periodic syndrome [TRAPS], familial Mediterranean fever),
• post-cardiac injury syndromes (either of the acute [2-4 days post injury] or late [Dressler syndrome] variety),
• metabolic disorders (hypothyroid disease, dialysis-related conditions), and
• malignancy.

More than 80% of pericarditis cases in developed countries are idiopathic and are assumed to have a viral source.⁸

Diagnosis. Acute pericarditis is diagnosed when 2 or more of the following symptoms are present:

• pleuritic chest pain radiating to the trapezius that is relieved by leaning forward
• pericardial friction rub
• electrocardiographic changes showing ST segment elevation in all leads but aVR and V1 and diffuse PR interval depression
• pericardial effusion on echocardiography.

Treatment. Treat non-severe and non-life threatening pericarditis with nonsteroidal anti-inflammatory drugs (NSAIDs). Avoid steroids because research has shown that they increase the risk for developing recurrent pericarditis.⁸ Hospitalize patients with large pericardial effusions and consider them for pericardiocentesis. Treat cardiac tamponade with urgent pericardiocentesis and hospitalization.

Myocarditis

Suspect pulmonary arterial hypertension in younger patients with exertional dyspnea, fatigue, chest pains, or palpitations who don't have other heart or lung disease signs or symptoms.

Myocarditis can have a variety of etiologies (TABLE 2^9,10). Myocarditis causes dyspnea either by causing pericardial effusion or heart failure.

Diagnosis. Myocarditis can be difficult to diagnose. Suspect it in any patient with cardiogenic shock, acute or subacute left ventricular dysfunction, or myocardial damage from a non-coronary artery disease source. Echocardiography and cardiac serum biomarkers can help diagnose myocarditis, but the diagnostic gold standard remains myocardial biopsy.

Treatment. Treatment is focused on 2 goals: treating the specific etiology suspected and stabilizing any hemodynamic instability. Patients with mild cases can be treated and monitored in the outpatient setting.

Immunosuppressive therapy with immunoglobulin or steroids is not routinely recommended, but a trial may be considered in children, patients with severe hemodynamic compromise, or patients with giant cell arteritis, another autoimmune condition, sarcoidosis, or eosinophilic or non-viral myocarditis.

Because of the risk of sudden death from ventricular arrhythmias, any patient with cardiac symptoms such as chest pain, dyspnea, or palpitations should be admitted for cardiopulmonary monitoring. Patients with heart failure secondary to myocarditis should be treated according to the American Heart Association treatment guidelines for heart failure (available at: http://circ.ahajournals.org/content/128/16/e240.extract). Some patients may benefit from surgical interventions such as percutaneous cardiopulmonary support, extracorporeal membrane oxygenation, mechanical circulatory support, and left ventricular assistive devices. Ventricular arrhythmias may require implantable defibrillators or pacemakers.¹⁰

Pulmonary causes

Shortness of breath is common with most pulmonary diseases, although it may not be an initial symptom and may have an insidious onset. It occurs once oxygenation of blood becomes inadequate, resulting in peripheral nervous system activation and neurochemical dissociation. Most patients with a pulmonary infection, asthma exacerbation, or COPD will have dyspnea. Once infection, asthma, and COPD have been ruled out, other pathologic processes that interrupt oxygenation should be considered. Unlike COPD and infections, patients with lung cancer may not have dyspnea until the end stages of their disease.¹¹ The following entities should be considered in patients with dyspnea when more common causes have been eliminated.

Restrictive lung diseases

Restrictive lung disease occurs when functional lung volume is decreased, either by an intrinsic or extrinsic source. As a result, these lung diseases cover a wide variety of pathologies and disease processes including interstitial lung diseases (which we’ll discuss here), environmental exposures, neuromuscular diseases, and other forms of chest wall dysfunction.

Interstitial lung disease occurs in the presence of lung parenchymal scarring or thickening, which can have many causes including pulmonary fibrosis, connective tissue diseases (eg, sarcoidosis or rheumatoid arthritis), and inflammatory processes (eg, hypersensitivity pneumonitis and coal worker's pneumoconiosis). Dyspnea results because parenchymal thickening decreases oxygen diffusion between the alveolar and capillary endothelium. Additionally, the lung’s ability to exchange air is restricted by parenchymal stiffness and decreased total lung and functional lung capacity. Treatment is disease specific.

Idiopathic pulmonary fibrosis is the most common interstitial pneumonia with a prevalence of 13 to 20 per 100,000 people.¹² It commonly affects men between the ages of 50 and 75 years. Risk factors include cigarette smoking, dust exposure (to metals, woods, vegetables), and exposure to livestock or other animals.¹² Suspect it when you have a middle-aged farmer or mill worker who complains of shortness of breath.

The 6-minute walk test is the best way to estimate prognosis and disease severity in patients with pulmonary arterial hypertension.

Treatment recommendations have changed recently and now consist of using only nintedanib (a tyrosine-kinase inhibitor), antacid medication, and pirfenidone. Anticoagulation (with warfarin), steroids, other immunologic agents including azathioprine, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors are not recommended.¹³

Pulmonary arterial hypertension and cor pulmonale

Pulmonary arterial hypertension (PAH) is defined as a mean resting precapillary pulmonary artery pressure >25 mm Hg or >30 mm Hg with activity. It can be idiopathic or caused by a variety of agents, diseases, and conditions (TABLE 3¹⁴). PAH is rare (15 in one million adults) and underdiagnosed, and more often occurs in 20- to 30-year-old black women.¹⁴

Suspect PAH in younger, otherwise healthy patients who complain of exertional dyspnea, fatigue, chest pain, or palpitations who do not have any other heart or lung disease signs or symptoms. A diagnosis of PAH is often delayed because patients are worked up for other etiologies such as CHF, coronary artery disease, PE, and COPD.

Diagnosis. When PAH is suspected, the initial work-up should include:

• an echocardiogram with a possible bubble study,
• arterial blood gas measurements,
• complete blood count,
• complete metabolic panel,
• human immunodeficiency virus (HIV) testing,
• thyroid-stimulating hormone levels,
• chest x-ray (which is abnormal in 90% of patients and shows right ventricular enlargement, a prominent central pulmonary artery, or peripheral hypovascularity),¹⁴
• electrocardiogram (to rule out other acute cardiac etiologies, but not to diagnosis PAH because of poor sensitivity and specificity),
• liver ultrasound, and
• pulmonary function tests.

If clinically suggested, tests for anticentromere antibody, antinuclear antibodies, anti-Scl-70 antibodies, and ribonucleoprotein antibodies should be ordered, as well as sickle cell screening, cardiac magnetic resonance imaging, and chest computed tomography. A right heart catheterization is required to confirm PAH and determine disease severity.

Vasoreactivity testing helps guide treatment because it identifies which patients will benefit from calcium channel blockers. The 6-minute walk test is the best way to estimate prognosis and disease severity. It is a simple test you can perform in the office by measuring how far your patient can walk in 6 minutes. Miyamoto et al showed the test to be predictive of survival in idiopathic PAH.¹⁵ A lung biopsy is never indicated or needed for diagnosis, disease severity classification, or prognosis.

Treatment. Collaboration between primary and subspecialty physicians is usually recommended because PAH treatment requires advanced testing such as right heart catheterization or vasoreactivity testing. Research has shown anticoagulation with warfarin prolongs survival and improves quality of life.¹⁶ Oxygen may improve symptomatic control and should be started for anyone with saturation less than 90%.

Newer medications that target various pathways resulting in vasodilation include prostacyclin analogues (epoprostenol, iloprost, treprostinil), endothelin receptor antagonists (ambrisentan, bosentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil).¹⁴

Hematologic diseases

Hematologic diseases, including sickle cell disease, gammopathies, and malignancies, can cause dyspnea primarily by decreasing the body’s ability to transport oxygen. This usually is due to anemia, but it also can be caused by increased viscosity or sickling. Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud’s-like symptoms.

Sickle cell disease

Sickle cell disease is a heterogeneous genetic disease with varied physical manifestations. The sickling phenomenon occurs in patients who inherit the homozygous hemoglobin S trait or heterozygous hemoglobin S and C (hemoglobin SC) disease. Sickle cell patients develop dyspnea due to comorbid anemia, infectious processes, or cardiopulmonary disease.

Cardiac disease is common and an often unrecognized comorbidity. It is the leading cause of mortality in adults with sickle cell disease, resulting in 26% of deaths (usually from pulseless electrical activity, pulmonary emboli, multiorgan failure, or stroke).¹⁷ Nonfatal cardiac complications may also develop, including chronic heart disease from prolonged increased cardiac output (leading to ventricular hypertrophy), heart failure, or arrhythmias; non-atherosclerotic MI;¹⁸ and hemosiderosis-induced cardiomyopathy from repeat blood transfusions.

Pulmonary-related complications may be chronic or acute and may include restrictive lung disease, chronic hypoxemia, pulmonary hypertension, and interstitial fibrosis. Acute chest syndrome and cor pulmonale cause sudden pulmonary disease. Acute chest syndrome is often caused by pneumonia, in situ thrombosis infarction of the lung, or embolic infarction from fat or bone marrow. It is a medical emergency that should be considered in any patient with pulmonary symptoms, fever, chest pain, or cough and an infiltrate on chest x-ray.

Treatment for acute chest syndrome consists of oxygen, aggressive analgesia, antibiotics (if infection is suspected), and transfusions. Research has shown that steroids provide improvement, but result in more hospital readmissions.¹⁹

Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud's-like symptoms.

Multiple myeloma and other hematologic malignancies

Multiple myeloma and Waldenstrom macroglobulinemia (discussed here), as well as leukemia, and other hematologic malignancies, can cause dyspnea or dyspnea on exertion through anemia, increasing blood viscosity, or direct lung involvement.

Multiple myeloma, a plasma cell neoplasm, is associated with anemia in 73% of patients at time of diagnosis.²⁰ This is because of bone marrow destruction. Anemia prevalence increases in patients treated with chemotherapy because of the agent's adverse effects. The decision to treat with irradiated, leukoreduced red cell transfusion is based on anemia severity, the presence of symptoms, and whether the patient is currently undergoing chemotherapy.

Waldenstrom macroglobulinemia is an IgM-specific monoclonal gammopathy associated with a lymphoplasmacytic lymphoma in the bone marrow. Dyspnea results from hyperviscosity syndrome, hemolytic or other anemias, and/or direct lung involvement including pleural effusion, pulmonary infiltrates, or a mass.

Hyperviscosity syndrome usually results in neurologic symptoms such as vision changes, headaches, vertigo, dizziness, dementia, or other changes in consciousness. Heart failure, which is often associated with comorbid anemia, can develop in severe cases.

Patients are generally asymptomatic if serum viscosity is <3 centipoises (cP). Symptoms increase in frequency and severity with increasing serum viscosity so that about two-thirds (67%) of patients have symptoms when viscosity is >4 cP and 75% have symptoms when viscosity is >5 cP.²¹

Neuromuscular diseases

Dyspnea occurs when respiratory muscles are weakened by neuromuscular diseases such as myasthenia gravis (discussed here), multiple sclerosis, or muscular dystrophy. Such diseases can cause respiratory insufficiency, increased rates of infection, or complete respiratory failure. Respiratory involvement is usually a manifestation of advanced disease. Suspect neuromuscular causes of dyspnea when you are seeing a patient admitted to the nursing home for long-term care because of profound weakness affecting their ability to do activities of daily living.

Myasthenia gravis

Myasthenia gravis, an autoimmune-mediated destruction of the postsynaptic acetylcholine receptors of the neuromuscular junction, is the most common disorder of neuromuscular transmission. It often affects the ocular (>50%; ptosis, diplopia), bulbar (15%; dysarthria, dysphagia, fatigable chewing), limb (<5%; usually proximal weakness), and respiratory muscles. Weakness typically fluctuates and worsens with muscle fatigue. Myasthenic crisis, an acute respiratory failure that occurs in 15% to 20% of patients, is often precipitated by an event such as surgery, an infection, or a medication change.²²

Suspect neuromuscular causes of dyspnea when a patient is admitted to a nursing home because of profound weakness affecting his or her ability to perform activities of daily living.

Diagnosis. Myasthenia gravis is diagnosed by a clinical history and exam suggestive of the disease. Suspect it if signs and symptoms include weakness worse with fatigue especially of the ocular muscles (ptosis or diplopia), dysphagia, dysphonia, chewing difficulty, or limb weakness. Consider laboratory testing with an anti-acetylcholine receptor (AChR) antibody assay, an assay for muscle-specific kinase (MuSK) antibody, or an anti-striated muscle (anti-SM) antibody assay if the history and exam are suggestive of the disorder.

The most reliable test is the anti-AChR antibody assay, which is positive in 50% to 90% of patients with the disease.²² Less reliable is the anti-MuSK antibody assay, which can be positive in 40% to 60% of patients who are AChR-seronegative.²³ An anti-striated muscle antibody assay is only helpful in patients with thymoma or onset of disease after age 40 years.²⁴

Consider electrophysiologic tests, including repetitive nerve stimulation studies and single-fiber electromyography, if the above laboratory tests are inconclusive.²⁵

Treatment depends on symptom severity and frequency. It can range from observation for mild occasional symptoms to chronic steroids and immunosuppressant medications in severe cases.

CASE › You see Ms. C in the intensive care unit the next day. She is intubated and has been responding poorly to the diuresis and breathing treatments used overnight. Her biopsy pathology results return and show recurrence of her small-cell lung cancer. She begins chemotherapy immediately and is extubated a few days later. She is discharged from the hospital a week later. Her shortness of breath is mild at this time, although she does require 2 liters of continuous oxygen.

CORRESPONDENCE
Christopher Taggart, MD, St. Mary’s Medical Center, Department of Family Medicine, 2698 Patterson Rd, Grand Junction, CO 81506; [email protected].

CASE › Joan C is a 68-year-old woman who presents to the office complaining of an enlarging left chest wall mass that appeared within the past month. She was treated for small-cell lung cancer 11 years ago. She has a 45 pack-year smoking history (she quit when she received the diagnosis) and has heart failure, which is controlled. Your examination reveals a large (5 cm) firm mass on her left chest wall. There is no erythema or tenderness. She has no other complaints. You recommend surgical biopsy and refer her to surgery.

Ms. C returns to your office several days later complaining of new and worsening shortness of breath with exertion that began the previous day. The presentation is similar to prior asthma exacerbation episodes. She denies any cough, fever, chest pain, symptoms at rest, or hemoptysis. On exam she appears comfortable and not in any acute distress. You refill her albuterol.

The next day you learn that she is being admitted to the hospital with respiratory distress. An x-ray of her chest shows a concerning mass in her right upper lung.

Dyspnea is an uncomfortable awareness of breathing that occurs when complex neurochemical pathways used to maintain oxygenation and ventilation are disrupted. (See "The variable, and subjective, process of dyspnea"^1-5). Sometimes described as air hunger, increased work of breathing, chest tightness, or chest constriction, the symptom is usually disproportionate to the patient’s level of exertion.

Most of the time dyspnea is due to either a primary lung or cardiovascular problem such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary embolism (PE), pneumonia, congestive heart failure (CHF), or myocardial infarction. However, many other illnesses can also produce this symptom (TABLE 1). This article will review the uncommon etiologies of dyspnea that should be considered when the usual suspects have been eliminated.

Cardiovascular culprits

Dyspnea is a common symptom with cardiovascular diseases because cardiac output relates directly to tissue oxygenation. Any pathology that decreases the ability of the heart and blood vessels to transport oxygen will likely trigger discord between the central, peripheral, and neurochemical respiratory centers. Two uncommon cardiovascular etiologies of dyspnea are pericarditis and myocarditis.

Pericarditis

Pericarditis is generally a self-limited condition that responds promptly to initial treatment, although it can cause significant morbidity and mortality. One study showed that acute pericarditis accounted for 5% of patients presenting to the emergency department with non-ischemic chest pain.⁶ Another study found that the in-hospital mortality rate for acute pericarditis was 1.1%.⁷

Pericarditis causes dyspnea by restricting the heart’s ability to relax, thus decreasing preload and cardiac output. This occurs with large effusions (>20 mm in width on echocardiography) and can lead to cardiac tamponade—a medical emergency that should be suspected in patients with muffled heart sounds, hypotension, and increased jugular venous distention (Beck’s triad).

Pericarditis etiologies include:

• infectious causes (viral and bacterial entities, myocarditis),
• rheumatologic causes (gout, systemic lupus erythematosus, tumor necrosis factor receptor-associated periodic syndrome [TRAPS], familial Mediterranean fever),
• post-cardiac injury syndromes (either of the acute [2-4 days post injury] or late [Dressler syndrome] variety),
• metabolic disorders (hypothyroid disease, dialysis-related conditions), and
• malignancy.

More than 80% of pericarditis cases in developed countries are idiopathic and are assumed to have a viral source.⁸

Diagnosis. Acute pericarditis is diagnosed when 2 or more of the following symptoms are present:

• pleuritic chest pain radiating to the trapezius that is relieved by leaning forward
• pericardial friction rub
• electrocardiographic changes showing ST segment elevation in all leads but aVR and V1 and diffuse PR interval depression
• pericardial effusion on echocardiography.

Treatment. Treat non-severe and non-life threatening pericarditis with nonsteroidal anti-inflammatory drugs (NSAIDs). Avoid steroids because research has shown that they increase the risk for developing recurrent pericarditis.⁸ Hospitalize patients with large pericardial effusions and consider them for pericardiocentesis. Treat cardiac tamponade with urgent pericardiocentesis and hospitalization.

Myocarditis

Suspect pulmonary arterial hypertension in younger patients with exertional dyspnea, fatigue, chest pains, or palpitations who don't have other heart or lung disease signs or symptoms.

Myocarditis can have a variety of etiologies (TABLE 2^9,10). Myocarditis causes dyspnea either by causing pericardial effusion or heart failure.

Diagnosis. Myocarditis can be difficult to diagnose. Suspect it in any patient with cardiogenic shock, acute or subacute left ventricular dysfunction, or myocardial damage from a non-coronary artery disease source. Echocardiography and cardiac serum biomarkers can help diagnose myocarditis, but the diagnostic gold standard remains myocardial biopsy.

Treatment. Treatment is focused on 2 goals: treating the specific etiology suspected and stabilizing any hemodynamic instability. Patients with mild cases can be treated and monitored in the outpatient setting.

Immunosuppressive therapy with immunoglobulin or steroids is not routinely recommended, but a trial may be considered in children, patients with severe hemodynamic compromise, or patients with giant cell arteritis, another autoimmune condition, sarcoidosis, or eosinophilic or non-viral myocarditis.

Because of the risk of sudden death from ventricular arrhythmias, any patient with cardiac symptoms such as chest pain, dyspnea, or palpitations should be admitted for cardiopulmonary monitoring. Patients with heart failure secondary to myocarditis should be treated according to the American Heart Association treatment guidelines for heart failure (available at: http://circ.ahajournals.org/content/128/16/e240.extract). Some patients may benefit from surgical interventions such as percutaneous cardiopulmonary support, extracorporeal membrane oxygenation, mechanical circulatory support, and left ventricular assistive devices. Ventricular arrhythmias may require implantable defibrillators or pacemakers.¹⁰

Pulmonary causes

Shortness of breath is common with most pulmonary diseases, although it may not be an initial symptom and may have an insidious onset. It occurs once oxygenation of blood becomes inadequate, resulting in peripheral nervous system activation and neurochemical dissociation. Most patients with a pulmonary infection, asthma exacerbation, or COPD will have dyspnea. Once infection, asthma, and COPD have been ruled out, other pathologic processes that interrupt oxygenation should be considered. Unlike COPD and infections, patients with lung cancer may not have dyspnea until the end stages of their disease.¹¹ The following entities should be considered in patients with dyspnea when more common causes have been eliminated.

Restrictive lung diseases

Restrictive lung disease occurs when functional lung volume is decreased, either by an intrinsic or extrinsic source. As a result, these lung diseases cover a wide variety of pathologies and disease processes including interstitial lung diseases (which we’ll discuss here), environmental exposures, neuromuscular diseases, and other forms of chest wall dysfunction.

Interstitial lung disease occurs in the presence of lung parenchymal scarring or thickening, which can have many causes including pulmonary fibrosis, connective tissue diseases (eg, sarcoidosis or rheumatoid arthritis), and inflammatory processes (eg, hypersensitivity pneumonitis and coal worker's pneumoconiosis). Dyspnea results because parenchymal thickening decreases oxygen diffusion between the alveolar and capillary endothelium. Additionally, the lung’s ability to exchange air is restricted by parenchymal stiffness and decreased total lung and functional lung capacity. Treatment is disease specific.

Idiopathic pulmonary fibrosis is the most common interstitial pneumonia with a prevalence of 13 to 20 per 100,000 people.¹² It commonly affects men between the ages of 50 and 75 years. Risk factors include cigarette smoking, dust exposure (to metals, woods, vegetables), and exposure to livestock or other animals.¹² Suspect it when you have a middle-aged farmer or mill worker who complains of shortness of breath.

The 6-minute walk test is the best way to estimate prognosis and disease severity in patients with pulmonary arterial hypertension.

Treatment recommendations have changed recently and now consist of using only nintedanib (a tyrosine-kinase inhibitor), antacid medication, and pirfenidone. Anticoagulation (with warfarin), steroids, other immunologic agents including azathioprine, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors are not recommended.¹³

Pulmonary arterial hypertension and cor pulmonale

Pulmonary arterial hypertension (PAH) is defined as a mean resting precapillary pulmonary artery pressure >25 mm Hg or >30 mm Hg with activity. It can be idiopathic or caused by a variety of agents, diseases, and conditions (TABLE 3¹⁴). PAH is rare (15 in one million adults) and underdiagnosed, and more often occurs in 20- to 30-year-old black women.¹⁴

Suspect PAH in younger, otherwise healthy patients who complain of exertional dyspnea, fatigue, chest pain, or palpitations who do not have any other heart or lung disease signs or symptoms. A diagnosis of PAH is often delayed because patients are worked up for other etiologies such as CHF, coronary artery disease, PE, and COPD.

Diagnosis. When PAH is suspected, the initial work-up should include:

• an echocardiogram with a possible bubble study,
• arterial blood gas measurements,
• complete blood count,
• complete metabolic panel,
• human immunodeficiency virus (HIV) testing,
• thyroid-stimulating hormone levels,
• chest x-ray (which is abnormal in 90% of patients and shows right ventricular enlargement, a prominent central pulmonary artery, or peripheral hypovascularity),¹⁴
• electrocardiogram (to rule out other acute cardiac etiologies, but not to diagnosis PAH because of poor sensitivity and specificity),
• liver ultrasound, and
• pulmonary function tests.

If clinically suggested, tests for anticentromere antibody, antinuclear antibodies, anti-Scl-70 antibodies, and ribonucleoprotein antibodies should be ordered, as well as sickle cell screening, cardiac magnetic resonance imaging, and chest computed tomography. A right heart catheterization is required to confirm PAH and determine disease severity.

Vasoreactivity testing helps guide treatment because it identifies which patients will benefit from calcium channel blockers. The 6-minute walk test is the best way to estimate prognosis and disease severity. It is a simple test you can perform in the office by measuring how far your patient can walk in 6 minutes. Miyamoto et al showed the test to be predictive of survival in idiopathic PAH.¹⁵ A lung biopsy is never indicated or needed for diagnosis, disease severity classification, or prognosis.

Treatment. Collaboration between primary and subspecialty physicians is usually recommended because PAH treatment requires advanced testing such as right heart catheterization or vasoreactivity testing. Research has shown anticoagulation with warfarin prolongs survival and improves quality of life.¹⁶ Oxygen may improve symptomatic control and should be started for anyone with saturation less than 90%.

Newer medications that target various pathways resulting in vasodilation include prostacyclin analogues (epoprostenol, iloprost, treprostinil), endothelin receptor antagonists (ambrisentan, bosentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil).¹⁴

Hematologic diseases

Hematologic diseases, including sickle cell disease, gammopathies, and malignancies, can cause dyspnea primarily by decreasing the body’s ability to transport oxygen. This usually is due to anemia, but it also can be caused by increased viscosity or sickling. Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud’s-like symptoms.

Sickle cell disease

Sickle cell disease is a heterogeneous genetic disease with varied physical manifestations. The sickling phenomenon occurs in patients who inherit the homozygous hemoglobin S trait or heterozygous hemoglobin S and C (hemoglobin SC) disease. Sickle cell patients develop dyspnea due to comorbid anemia, infectious processes, or cardiopulmonary disease.

Cardiac disease is common and an often unrecognized comorbidity. It is the leading cause of mortality in adults with sickle cell disease, resulting in 26% of deaths (usually from pulseless electrical activity, pulmonary emboli, multiorgan failure, or stroke).¹⁷ Nonfatal cardiac complications may also develop, including chronic heart disease from prolonged increased cardiac output (leading to ventricular hypertrophy), heart failure, or arrhythmias; non-atherosclerotic MI;¹⁸ and hemosiderosis-induced cardiomyopathy from repeat blood transfusions.

Pulmonary-related complications may be chronic or acute and may include restrictive lung disease, chronic hypoxemia, pulmonary hypertension, and interstitial fibrosis. Acute chest syndrome and cor pulmonale cause sudden pulmonary disease. Acute chest syndrome is often caused by pneumonia, in situ thrombosis infarction of the lung, or embolic infarction from fat or bone marrow. It is a medical emergency that should be considered in any patient with pulmonary symptoms, fever, chest pain, or cough and an infiltrate on chest x-ray.

Treatment for acute chest syndrome consists of oxygen, aggressive analgesia, antibiotics (if infection is suspected), and transfusions. Research has shown that steroids provide improvement, but result in more hospital readmissions.¹⁹

Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud's-like symptoms.

Multiple myeloma and other hematologic malignancies

Multiple myeloma and Waldenstrom macroglobulinemia (discussed here), as well as leukemia, and other hematologic malignancies, can cause dyspnea or dyspnea on exertion through anemia, increasing blood viscosity, or direct lung involvement.

Multiple myeloma, a plasma cell neoplasm, is associated with anemia in 73% of patients at time of diagnosis.²⁰ This is because of bone marrow destruction. Anemia prevalence increases in patients treated with chemotherapy because of the agent's adverse effects. The decision to treat with irradiated, leukoreduced red cell transfusion is based on anemia severity, the presence of symptoms, and whether the patient is currently undergoing chemotherapy.

Waldenstrom macroglobulinemia is an IgM-specific monoclonal gammopathy associated with a lymphoplasmacytic lymphoma in the bone marrow. Dyspnea results from hyperviscosity syndrome, hemolytic or other anemias, and/or direct lung involvement including pleural effusion, pulmonary infiltrates, or a mass.

Hyperviscosity syndrome usually results in neurologic symptoms such as vision changes, headaches, vertigo, dizziness, dementia, or other changes in consciousness. Heart failure, which is often associated with comorbid anemia, can develop in severe cases.

Patients are generally asymptomatic if serum viscosity is <3 centipoises (cP). Symptoms increase in frequency and severity with increasing serum viscosity so that about two-thirds (67%) of patients have symptoms when viscosity is >4 cP and 75% have symptoms when viscosity is >5 cP.²¹

Neuromuscular diseases

Dyspnea occurs when respiratory muscles are weakened by neuromuscular diseases such as myasthenia gravis (discussed here), multiple sclerosis, or muscular dystrophy. Such diseases can cause respiratory insufficiency, increased rates of infection, or complete respiratory failure. Respiratory involvement is usually a manifestation of advanced disease. Suspect neuromuscular causes of dyspnea when you are seeing a patient admitted to the nursing home for long-term care because of profound weakness affecting their ability to do activities of daily living.

Myasthenia gravis

Myasthenia gravis, an autoimmune-mediated destruction of the postsynaptic acetylcholine receptors of the neuromuscular junction, is the most common disorder of neuromuscular transmission. It often affects the ocular (>50%; ptosis, diplopia), bulbar (15%; dysarthria, dysphagia, fatigable chewing), limb (<5%; usually proximal weakness), and respiratory muscles. Weakness typically fluctuates and worsens with muscle fatigue. Myasthenic crisis, an acute respiratory failure that occurs in 15% to 20% of patients, is often precipitated by an event such as surgery, an infection, or a medication change.²²

Suspect neuromuscular causes of dyspnea when a patient is admitted to a nursing home because of profound weakness affecting his or her ability to perform activities of daily living.

Diagnosis. Myasthenia gravis is diagnosed by a clinical history and exam suggestive of the disease. Suspect it if signs and symptoms include weakness worse with fatigue especially of the ocular muscles (ptosis or diplopia), dysphagia, dysphonia, chewing difficulty, or limb weakness. Consider laboratory testing with an anti-acetylcholine receptor (AChR) antibody assay, an assay for muscle-specific kinase (MuSK) antibody, or an anti-striated muscle (anti-SM) antibody assay if the history and exam are suggestive of the disorder.

The most reliable test is the anti-AChR antibody assay, which is positive in 50% to 90% of patients with the disease.²² Less reliable is the anti-MuSK antibody assay, which can be positive in 40% to 60% of patients who are AChR-seronegative.²³ An anti-striated muscle antibody assay is only helpful in patients with thymoma or onset of disease after age 40 years.²⁴

Consider electrophysiologic tests, including repetitive nerve stimulation studies and single-fiber electromyography, if the above laboratory tests are inconclusive.²⁵

Treatment depends on symptom severity and frequency. It can range from observation for mild occasional symptoms to chronic steroids and immunosuppressant medications in severe cases.

CASE › You see Ms. C in the intensive care unit the next day. She is intubated and has been responding poorly to the diuresis and breathing treatments used overnight. Her biopsy pathology results return and show recurrence of her small-cell lung cancer. She begins chemotherapy immediately and is extubated a few days later. She is discharged from the hospital a week later. Her shortness of breath is mild at this time, although she does require 2 liters of continuous oxygen.

CORRESPONDENCE
Christopher Taggart, MD, St. Mary’s Medical Center, Department of Family Medicine, 2698 Patterson Rd, Grand Junction, CO 81506; [email protected].

CASE › Joan C is a 68-year-old woman who presents to the office complaining of an enlarging left chest wall mass that appeared within the past month. She was treated for small-cell lung cancer 11 years ago. She has a 45 pack-year smoking history (she quit when she received the diagnosis) and has heart failure, which is controlled. Your examination reveals a large (5 cm) firm mass on her left chest wall. There is no erythema or tenderness. She has no other complaints. You recommend surgical biopsy and refer her to surgery.

Ms. C returns to your office several days later complaining of new and worsening shortness of breath with exertion that began the previous day. The presentation is similar to prior asthma exacerbation episodes. She denies any cough, fever, chest pain, symptoms at rest, or hemoptysis. On exam she appears comfortable and not in any acute distress. You refill her albuterol.

The next day you learn that she is being admitted to the hospital with respiratory distress. An x-ray of her chest shows a concerning mass in her right upper lung.

Dyspnea is an uncomfortable awareness of breathing that occurs when complex neurochemical pathways used to maintain oxygenation and ventilation are disrupted. (See "The variable, and subjective, process of dyspnea"^1-5). Sometimes described as air hunger, increased work of breathing, chest tightness, or chest constriction, the symptom is usually disproportionate to the patient’s level of exertion.

Most of the time dyspnea is due to either a primary lung or cardiovascular problem such as chronic obstructive pulmonary disease (COPD), asthma, pulmonary embolism (PE), pneumonia, congestive heart failure (CHF), or myocardial infarction. However, many other illnesses can also produce this symptom (TABLE 1). This article will review the uncommon etiologies of dyspnea that should be considered when the usual suspects have been eliminated.

Cardiovascular culprits

Dyspnea is a common symptom with cardiovascular diseases because cardiac output relates directly to tissue oxygenation. Any pathology that decreases the ability of the heart and blood vessels to transport oxygen will likely trigger discord between the central, peripheral, and neurochemical respiratory centers. Two uncommon cardiovascular etiologies of dyspnea are pericarditis and myocarditis.

Pericarditis

Pericarditis is generally a self-limited condition that responds promptly to initial treatment, although it can cause significant morbidity and mortality. One study showed that acute pericarditis accounted for 5% of patients presenting to the emergency department with non-ischemic chest pain.⁶ Another study found that the in-hospital mortality rate for acute pericarditis was 1.1%.⁷

Pericarditis causes dyspnea by restricting the heart’s ability to relax, thus decreasing preload and cardiac output. This occurs with large effusions (>20 mm in width on echocardiography) and can lead to cardiac tamponade—a medical emergency that should be suspected in patients with muffled heart sounds, hypotension, and increased jugular venous distention (Beck’s triad).

Pericarditis etiologies include:

• infectious causes (viral and bacterial entities, myocarditis),
• rheumatologic causes (gout, systemic lupus erythematosus, tumor necrosis factor receptor-associated periodic syndrome [TRAPS], familial Mediterranean fever),
• post-cardiac injury syndromes (either of the acute [2-4 days post injury] or late [Dressler syndrome] variety),
• metabolic disorders (hypothyroid disease, dialysis-related conditions), and
• malignancy.

More than 80% of pericarditis cases in developed countries are idiopathic and are assumed to have a viral source.⁸

Diagnosis. Acute pericarditis is diagnosed when 2 or more of the following symptoms are present:

• pleuritic chest pain radiating to the trapezius that is relieved by leaning forward
• pericardial friction rub
• electrocardiographic changes showing ST segment elevation in all leads but aVR and V1 and diffuse PR interval depression
• pericardial effusion on echocardiography.

Treatment. Treat non-severe and non-life threatening pericarditis with nonsteroidal anti-inflammatory drugs (NSAIDs). Avoid steroids because research has shown that they increase the risk for developing recurrent pericarditis.⁸ Hospitalize patients with large pericardial effusions and consider them for pericardiocentesis. Treat cardiac tamponade with urgent pericardiocentesis and hospitalization.

Myocarditis

Suspect pulmonary arterial hypertension in younger patients with exertional dyspnea, fatigue, chest pains, or palpitations who don't have other heart or lung disease signs or symptoms.

Myocarditis can have a variety of etiologies (TABLE 2^9,10). Myocarditis causes dyspnea either by causing pericardial effusion or heart failure.

Diagnosis. Myocarditis can be difficult to diagnose. Suspect it in any patient with cardiogenic shock, acute or subacute left ventricular dysfunction, or myocardial damage from a non-coronary artery disease source. Echocardiography and cardiac serum biomarkers can help diagnose myocarditis, but the diagnostic gold standard remains myocardial biopsy.

Treatment. Treatment is focused on 2 goals: treating the specific etiology suspected and stabilizing any hemodynamic instability. Patients with mild cases can be treated and monitored in the outpatient setting.

Immunosuppressive therapy with immunoglobulin or steroids is not routinely recommended, but a trial may be considered in children, patients with severe hemodynamic compromise, or patients with giant cell arteritis, another autoimmune condition, sarcoidosis, or eosinophilic or non-viral myocarditis.

Because of the risk of sudden death from ventricular arrhythmias, any patient with cardiac symptoms such as chest pain, dyspnea, or palpitations should be admitted for cardiopulmonary monitoring. Patients with heart failure secondary to myocarditis should be treated according to the American Heart Association treatment guidelines for heart failure (available at: http://circ.ahajournals.org/content/128/16/e240.extract). Some patients may benefit from surgical interventions such as percutaneous cardiopulmonary support, extracorporeal membrane oxygenation, mechanical circulatory support, and left ventricular assistive devices. Ventricular arrhythmias may require implantable defibrillators or pacemakers.¹⁰

Pulmonary causes

Shortness of breath is common with most pulmonary diseases, although it may not be an initial symptom and may have an insidious onset. It occurs once oxygenation of blood becomes inadequate, resulting in peripheral nervous system activation and neurochemical dissociation. Most patients with a pulmonary infection, asthma exacerbation, or COPD will have dyspnea. Once infection, asthma, and COPD have been ruled out, other pathologic processes that interrupt oxygenation should be considered. Unlike COPD and infections, patients with lung cancer may not have dyspnea until the end stages of their disease.¹¹ The following entities should be considered in patients with dyspnea when more common causes have been eliminated.

Restrictive lung diseases

Restrictive lung disease occurs when functional lung volume is decreased, either by an intrinsic or extrinsic source. As a result, these lung diseases cover a wide variety of pathologies and disease processes including interstitial lung diseases (which we’ll discuss here), environmental exposures, neuromuscular diseases, and other forms of chest wall dysfunction.

Interstitial lung disease occurs in the presence of lung parenchymal scarring or thickening, which can have many causes including pulmonary fibrosis, connective tissue diseases (eg, sarcoidosis or rheumatoid arthritis), and inflammatory processes (eg, hypersensitivity pneumonitis and coal worker's pneumoconiosis). Dyspnea results because parenchymal thickening decreases oxygen diffusion between the alveolar and capillary endothelium. Additionally, the lung’s ability to exchange air is restricted by parenchymal stiffness and decreased total lung and functional lung capacity. Treatment is disease specific.

Idiopathic pulmonary fibrosis is the most common interstitial pneumonia with a prevalence of 13 to 20 per 100,000 people.¹² It commonly affects men between the ages of 50 and 75 years. Risk factors include cigarette smoking, dust exposure (to metals, woods, vegetables), and exposure to livestock or other animals.¹² Suspect it when you have a middle-aged farmer or mill worker who complains of shortness of breath.

The 6-minute walk test is the best way to estimate prognosis and disease severity in patients with pulmonary arterial hypertension.

Treatment recommendations have changed recently and now consist of using only nintedanib (a tyrosine-kinase inhibitor), antacid medication, and pirfenidone. Anticoagulation (with warfarin), steroids, other immunologic agents including azathioprine, endothelin receptor antagonists, and phosphodiesterase-5 inhibitors are not recommended.¹³

Pulmonary arterial hypertension and cor pulmonale

Pulmonary arterial hypertension (PAH) is defined as a mean resting precapillary pulmonary artery pressure >25 mm Hg or >30 mm Hg with activity. It can be idiopathic or caused by a variety of agents, diseases, and conditions (TABLE 3¹⁴). PAH is rare (15 in one million adults) and underdiagnosed, and more often occurs in 20- to 30-year-old black women.¹⁴

Suspect PAH in younger, otherwise healthy patients who complain of exertional dyspnea, fatigue, chest pain, or palpitations who do not have any other heart or lung disease signs or symptoms. A diagnosis of PAH is often delayed because patients are worked up for other etiologies such as CHF, coronary artery disease, PE, and COPD.

Diagnosis. When PAH is suspected, the initial work-up should include:

• an echocardiogram with a possible bubble study,
• arterial blood gas measurements,
• complete blood count,
• complete metabolic panel,
• human immunodeficiency virus (HIV) testing,
• thyroid-stimulating hormone levels,
• chest x-ray (which is abnormal in 90% of patients and shows right ventricular enlargement, a prominent central pulmonary artery, or peripheral hypovascularity),¹⁴
• electrocardiogram (to rule out other acute cardiac etiologies, but not to diagnosis PAH because of poor sensitivity and specificity),
• liver ultrasound, and
• pulmonary function tests.

If clinically suggested, tests for anticentromere antibody, antinuclear antibodies, anti-Scl-70 antibodies, and ribonucleoprotein antibodies should be ordered, as well as sickle cell screening, cardiac magnetic resonance imaging, and chest computed tomography. A right heart catheterization is required to confirm PAH and determine disease severity.

Vasoreactivity testing helps guide treatment because it identifies which patients will benefit from calcium channel blockers. The 6-minute walk test is the best way to estimate prognosis and disease severity. It is a simple test you can perform in the office by measuring how far your patient can walk in 6 minutes. Miyamoto et al showed the test to be predictive of survival in idiopathic PAH.¹⁵ A lung biopsy is never indicated or needed for diagnosis, disease severity classification, or prognosis.

Treatment. Collaboration between primary and subspecialty physicians is usually recommended because PAH treatment requires advanced testing such as right heart catheterization or vasoreactivity testing. Research has shown anticoagulation with warfarin prolongs survival and improves quality of life.¹⁶ Oxygen may improve symptomatic control and should be started for anyone with saturation less than 90%.

Newer medications that target various pathways resulting in vasodilation include prostacyclin analogues (epoprostenol, iloprost, treprostinil), endothelin receptor antagonists (ambrisentan, bosentan), and phosphodiesterase type 5 inhibitors (sildenafil, tadalafil).¹⁴

Hematologic diseases

Hematologic diseases, including sickle cell disease, gammopathies, and malignancies, can cause dyspnea primarily by decreasing the body’s ability to transport oxygen. This usually is due to anemia, but it also can be caused by increased viscosity or sickling. Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud’s-like symptoms.

Sickle cell disease

Sickle cell disease is a heterogeneous genetic disease with varied physical manifestations. The sickling phenomenon occurs in patients who inherit the homozygous hemoglobin S trait or heterozygous hemoglobin S and C (hemoglobin SC) disease. Sickle cell patients develop dyspnea due to comorbid anemia, infectious processes, or cardiopulmonary disease.

Cardiac disease is common and an often unrecognized comorbidity. It is the leading cause of mortality in adults with sickle cell disease, resulting in 26% of deaths (usually from pulseless electrical activity, pulmonary emboli, multiorgan failure, or stroke).¹⁷ Nonfatal cardiac complications may also develop, including chronic heart disease from prolonged increased cardiac output (leading to ventricular hypertrophy), heart failure, or arrhythmias; non-atherosclerotic MI;¹⁸ and hemosiderosis-induced cardiomyopathy from repeat blood transfusions.

Pulmonary-related complications may be chronic or acute and may include restrictive lung disease, chronic hypoxemia, pulmonary hypertension, and interstitial fibrosis. Acute chest syndrome and cor pulmonale cause sudden pulmonary disease. Acute chest syndrome is often caused by pneumonia, in situ thrombosis infarction of the lung, or embolic infarction from fat or bone marrow. It is a medical emergency that should be considered in any patient with pulmonary symptoms, fever, chest pain, or cough and an infiltrate on chest x-ray.

Treatment for acute chest syndrome consists of oxygen, aggressive analgesia, antibiotics (if infection is suspected), and transfusions. Research has shown that steroids provide improvement, but result in more hospital readmissions.¹⁹

Suspect a hematologic cause of dyspnea when a patient repeatedly returns to your office complaining of progressive dyspnea on exertion and possible Raynaud's-like symptoms.

Multiple myeloma and other hematologic malignancies

Multiple myeloma and Waldenstrom macroglobulinemia (discussed here), as well as leukemia, and other hematologic malignancies, can cause dyspnea or dyspnea on exertion through anemia, increasing blood viscosity, or direct lung involvement.

Multiple myeloma, a plasma cell neoplasm, is associated with anemia in 73% of patients at time of diagnosis.²⁰ This is because of bone marrow destruction. Anemia prevalence increases in patients treated with chemotherapy because of the agent's adverse effects. The decision to treat with irradiated, leukoreduced red cell transfusion is based on anemia severity, the presence of symptoms, and whether the patient is currently undergoing chemotherapy.

Waldenstrom macroglobulinemia is an IgM-specific monoclonal gammopathy associated with a lymphoplasmacytic lymphoma in the bone marrow. Dyspnea results from hyperviscosity syndrome, hemolytic or other anemias, and/or direct lung involvement including pleural effusion, pulmonary infiltrates, or a mass.

Hyperviscosity syndrome usually results in neurologic symptoms such as vision changes, headaches, vertigo, dizziness, dementia, or other changes in consciousness. Heart failure, which is often associated with comorbid anemia, can develop in severe cases.

Patients are generally asymptomatic if serum viscosity is <3 centipoises (cP). Symptoms increase in frequency and severity with increasing serum viscosity so that about two-thirds (67%) of patients have symptoms when viscosity is >4 cP and 75% have symptoms when viscosity is >5 cP.²¹

Neuromuscular diseases

Dyspnea occurs when respiratory muscles are weakened by neuromuscular diseases such as myasthenia gravis (discussed here), multiple sclerosis, or muscular dystrophy. Such diseases can cause respiratory insufficiency, increased rates of infection, or complete respiratory failure. Respiratory involvement is usually a manifestation of advanced disease. Suspect neuromuscular causes of dyspnea when you are seeing a patient admitted to the nursing home for long-term care because of profound weakness affecting their ability to do activities of daily living.

Myasthenia gravis

Myasthenia gravis, an autoimmune-mediated destruction of the postsynaptic acetylcholine receptors of the neuromuscular junction, is the most common disorder of neuromuscular transmission. It often affects the ocular (>50%; ptosis, diplopia), bulbar (15%; dysarthria, dysphagia, fatigable chewing), limb (<5%; usually proximal weakness), and respiratory muscles. Weakness typically fluctuates and worsens with muscle fatigue. Myasthenic crisis, an acute respiratory failure that occurs in 15% to 20% of patients, is often precipitated by an event such as surgery, an infection, or a medication change.²²

Suspect neuromuscular causes of dyspnea when a patient is admitted to a nursing home because of profound weakness affecting his or her ability to perform activities of daily living.

Diagnosis. Myasthenia gravis is diagnosed by a clinical history and exam suggestive of the disease. Suspect it if signs and symptoms include weakness worse with fatigue especially of the ocular muscles (ptosis or diplopia), dysphagia, dysphonia, chewing difficulty, or limb weakness. Consider laboratory testing with an anti-acetylcholine receptor (AChR) antibody assay, an assay for muscle-specific kinase (MuSK) antibody, or an anti-striated muscle (anti-SM) antibody assay if the history and exam are suggestive of the disorder.

The most reliable test is the anti-AChR antibody assay, which is positive in 50% to 90% of patients with the disease.²² Less reliable is the anti-MuSK antibody assay, which can be positive in 40% to 60% of patients who are AChR-seronegative.²³ An anti-striated muscle antibody assay is only helpful in patients with thymoma or onset of disease after age 40 years.²⁴

Consider electrophysiologic tests, including repetitive nerve stimulation studies and single-fiber electromyography, if the above laboratory tests are inconclusive.²⁵

Treatment depends on symptom severity and frequency. It can range from observation for mild occasional symptoms to chronic steroids and immunosuppressant medications in severe cases.

CASE › You see Ms. C in the intensive care unit the next day. She is intubated and has been responding poorly to the diuresis and breathing treatments used overnight. Her biopsy pathology results return and show recurrence of her small-cell lung cancer. She begins chemotherapy immediately and is extubated a few days later. She is discharged from the hospital a week later. Her shortness of breath is mild at this time, although she does require 2 liters of continuous oxygen.

CORRESPONDENCE
Christopher Taggart, MD, St. Mary’s Medical Center, Department of Family Medicine, 2698 Patterson Rd, Grand Junction, CO 81506; [email protected].

A 60-year-old woman visited our clinic complaining of an area on the right side of her middle back that was itchy, and had been bothering her for the past 10 years. She said her symptoms began without a trigger, and that a darkened area had appeared in the location of the itch. She had already been prescribed topical corticosteroids and antifungals and had tried over-the counter aids, but nothing relieved the itch. The patient had a history of cervical radiculopathy and was morbidly obese at the time of the visit.

On examination, the pruritic area consisted of a hyperpigmented, non-infiltrated 7-cm patch that was lateral to the vertebral column and within the dermatomes T4 to T6 (FIGURE). The patient also had hyperesthesia to light touch in this region and scratch abrasions.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Notalgia paresthetica

The location of the pruritic area and the patient’s clinical presentation led us to diagnose notalgia paresthetica. NP is a common dermatologic complaint characterized by unilateral pruritus that is medial or inferior to the scapula with dermatomal distribution.

The etiology of NP remains unknown, although it is thought to be a neuropathic itch caused by afferent nerve entrapment. The dorsal rami of the thoracic spinal nerves T2 to T6 are considered to be responsible for these symptoms. NP is not only a skin disease, but a cutaneous sign of an underlying spinal condition, including degenerative cervical spine disease.^1-3

NP is a clinical diagnosis. There is typically a history of localized pruritus on the unilateral infrascapula area and there are few or no visible signs of disease. Patients frequently report a spider-bite sensation, prickly feelings, and/or an indescribable itch sensation. In addition, they may experience dysesthesia with diffuse mild burning, some surface numbness, and “under the skin” discomfort.

On physical examination, the patient may have a unilateral and ill-defined tan, pink, or hyperpigmented nonindurated patch on the infrascapular back that is a result of long-time scratching. Secondary skin changes such as lichenification, excoriations, eczema, xerosis, and infection often occur. Mild sensory alterations to light touch, vibration, and pin pricks may round out the clinical picture.^1-3 Atypical forms of NP include localized pruritus on the upper back, neck, scalp, or shoulder.

Pruritus without other skin lesions can help pinpoint the Dx

The differential diagnosis for NP includes atopic dermatitis, contact dermatitis, drug eruptions, herpes zoster, idiopathic pruritus and systemic disease (such as renal, cholestatic, or hematologic pruritus, or pruritus associated with malignancy), tinea corporis, tinea versicolor, and xerosis.

Clues in the history. The chronic evolution of pruritus without other skin lesions, like vesicles or squamous areas, and the location of a hyperpigmented patch near the scapula region in a midlife patient, should prompt you to consider NP. A biopsy may show signs of post-inflammatory infiltrate of the papillary dermis with dermal melanophages.^4,5

Notalgia paresthetica is not only a skin disease, but a cutaneous sign of an underlying spinal condition.

Although imaging tests are not required for a diagnosis of NP, basic cervical and possibly thoracic radiographs or magnetic resonance imaging (MRI) may be helpful in patients with symptoms of spine pain, tenderness, spasms, decreased range of motion, or any history of spinal trauma or injury. The images may reveal spinal disorders, including osteoarthritic lesions such as kyphosis, kyphoscoliosis, and vertebral hyperostosis.⁴

The exact cause of NP is unclear, but the evidence suggests that it results from damage to the cutaneous branches of the posterior divisions of the spinal nerves. This can occur by either impingement from degenerative changes in the spine or by spasms in the paraspinal musculature.²

The itch is neuropathic; antihistamines, steroids won’t help

It is difficult to treat NP without treating the underlying disease, which is usually spinal damage.⁴ Little has been published on the treatment of NP, and most of the literature on the subject involves case reports. Because the pruritus in NP is neuropathic, antihistamines and topical steroids are ineffective.⁴

The most commonly used treatment for NP among dermatologists is capsaicin as a 0.025% cream or 8% patch. One study with 20 patients reported improvement of pruritus in 70% of patients at 2 weeks, with some relapsing in about a month.⁶

Another treatment that has been used is cutaneous botulinum toxin type A injections, but its use is controversial. This strategy was proposed by Weinfeld⁷ after successful treatment of 2 patients. However, other studies have had variable outcomes with no resolution of pruritus.⁸

Other treatments include gabapentin,⁹ transcutaneous electrical nerve stimulation,¹⁰ and narrow-band ultraviolet-B.¹¹ It is appropriate to consider surgical decompression or neurolysis of the nerve when other forms of treatment fail.¹²

Our patient was treated with topical capsaicin cream 0.25 mg/g, which lessened the intensity of her itching. After 2 months, the patient reported improvement of her symptoms.

CORRESPONDENCE
Joana Sequeira, MD, Estrada da Mata nº56, Leiria, Portugal; [email protected].

A 60-year-old woman visited our clinic complaining of an area on the right side of her middle back that was itchy, and had been bothering her for the past 10 years. She said her symptoms began without a trigger, and that a darkened area had appeared in the location of the itch. She had already been prescribed topical corticosteroids and antifungals and had tried over-the counter aids, but nothing relieved the itch. The patient had a history of cervical radiculopathy and was morbidly obese at the time of the visit.

On examination, the pruritic area consisted of a hyperpigmented, non-infiltrated 7-cm patch that was lateral to the vertebral column and within the dermatomes T4 to T6 (FIGURE). The patient also had hyperesthesia to light touch in this region and scratch abrasions.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Notalgia paresthetica

The location of the pruritic area and the patient’s clinical presentation led us to diagnose notalgia paresthetica. NP is a common dermatologic complaint characterized by unilateral pruritus that is medial or inferior to the scapula with dermatomal distribution.

The etiology of NP remains unknown, although it is thought to be a neuropathic itch caused by afferent nerve entrapment. The dorsal rami of the thoracic spinal nerves T2 to T6 are considered to be responsible for these symptoms. NP is not only a skin disease, but a cutaneous sign of an underlying spinal condition, including degenerative cervical spine disease.^1-3

NP is a clinical diagnosis. There is typically a history of localized pruritus on the unilateral infrascapula area and there are few or no visible signs of disease. Patients frequently report a spider-bite sensation, prickly feelings, and/or an indescribable itch sensation. In addition, they may experience dysesthesia with diffuse mild burning, some surface numbness, and “under the skin” discomfort.

On physical examination, the patient may have a unilateral and ill-defined tan, pink, or hyperpigmented nonindurated patch on the infrascapular back that is a result of long-time scratching. Secondary skin changes such as lichenification, excoriations, eczema, xerosis, and infection often occur. Mild sensory alterations to light touch, vibration, and pin pricks may round out the clinical picture.^1-3 Atypical forms of NP include localized pruritus on the upper back, neck, scalp, or shoulder.

Pruritus without other skin lesions can help pinpoint the Dx

The differential diagnosis for NP includes atopic dermatitis, contact dermatitis, drug eruptions, herpes zoster, idiopathic pruritus and systemic disease (such as renal, cholestatic, or hematologic pruritus, or pruritus associated with malignancy), tinea corporis, tinea versicolor, and xerosis.

Clues in the history. The chronic evolution of pruritus without other skin lesions, like vesicles or squamous areas, and the location of a hyperpigmented patch near the scapula region in a midlife patient, should prompt you to consider NP. A biopsy may show signs of post-inflammatory infiltrate of the papillary dermis with dermal melanophages.^4,5

Notalgia paresthetica is not only a skin disease, but a cutaneous sign of an underlying spinal condition.

Although imaging tests are not required for a diagnosis of NP, basic cervical and possibly thoracic radiographs or magnetic resonance imaging (MRI) may be helpful in patients with symptoms of spine pain, tenderness, spasms, decreased range of motion, or any history of spinal trauma or injury. The images may reveal spinal disorders, including osteoarthritic lesions such as kyphosis, kyphoscoliosis, and vertebral hyperostosis.⁴

The exact cause of NP is unclear, but the evidence suggests that it results from damage to the cutaneous branches of the posterior divisions of the spinal nerves. This can occur by either impingement from degenerative changes in the spine or by spasms in the paraspinal musculature.²

The itch is neuropathic; antihistamines, steroids won’t help

It is difficult to treat NP without treating the underlying disease, which is usually spinal damage.⁴ Little has been published on the treatment of NP, and most of the literature on the subject involves case reports. Because the pruritus in NP is neuropathic, antihistamines and topical steroids are ineffective.⁴

The most commonly used treatment for NP among dermatologists is capsaicin as a 0.025% cream or 8% patch. One study with 20 patients reported improvement of pruritus in 70% of patients at 2 weeks, with some relapsing in about a month.⁶

Another treatment that has been used is cutaneous botulinum toxin type A injections, but its use is controversial. This strategy was proposed by Weinfeld⁷ after successful treatment of 2 patients. However, other studies have had variable outcomes with no resolution of pruritus.⁸

Other treatments include gabapentin,⁹ transcutaneous electrical nerve stimulation,¹⁰ and narrow-band ultraviolet-B.¹¹ It is appropriate to consider surgical decompression or neurolysis of the nerve when other forms of treatment fail.¹²

Our patient was treated with topical capsaicin cream 0.25 mg/g, which lessened the intensity of her itching. After 2 months, the patient reported improvement of her symptoms.

CORRESPONDENCE
Joana Sequeira, MD, Estrada da Mata nº56, Leiria, Portugal; [email protected].

A 60-year-old woman visited our clinic complaining of an area on the right side of her middle back that was itchy, and had been bothering her for the past 10 years. She said her symptoms began without a trigger, and that a darkened area had appeared in the location of the itch. She had already been prescribed topical corticosteroids and antifungals and had tried over-the counter aids, but nothing relieved the itch. The patient had a history of cervical radiculopathy and was morbidly obese at the time of the visit.

On examination, the pruritic area consisted of a hyperpigmented, non-infiltrated 7-cm patch that was lateral to the vertebral column and within the dermatomes T4 to T6 (FIGURE). The patient also had hyperesthesia to light touch in this region and scratch abrasions.

WHAT IS YOUR DIAGNOSIS?
HOW WOULD YOU TREAT THIS PATIENT?

Diagnosis: Notalgia paresthetica

The location of the pruritic area and the patient’s clinical presentation led us to diagnose notalgia paresthetica. NP is a common dermatologic complaint characterized by unilateral pruritus that is medial or inferior to the scapula with dermatomal distribution.

The etiology of NP remains unknown, although it is thought to be a neuropathic itch caused by afferent nerve entrapment. The dorsal rami of the thoracic spinal nerves T2 to T6 are considered to be responsible for these symptoms. NP is not only a skin disease, but a cutaneous sign of an underlying spinal condition, including degenerative cervical spine disease.^1-3

NP is a clinical diagnosis. There is typically a history of localized pruritus on the unilateral infrascapula area and there are few or no visible signs of disease. Patients frequently report a spider-bite sensation, prickly feelings, and/or an indescribable itch sensation. In addition, they may experience dysesthesia with diffuse mild burning, some surface numbness, and “under the skin” discomfort.

On physical examination, the patient may have a unilateral and ill-defined tan, pink, or hyperpigmented nonindurated patch on the infrascapular back that is a result of long-time scratching. Secondary skin changes such as lichenification, excoriations, eczema, xerosis, and infection often occur. Mild sensory alterations to light touch, vibration, and pin pricks may round out the clinical picture.^1-3 Atypical forms of NP include localized pruritus on the upper back, neck, scalp, or shoulder.

Pruritus without other skin lesions can help pinpoint the Dx

The differential diagnosis for NP includes atopic dermatitis, contact dermatitis, drug eruptions, herpes zoster, idiopathic pruritus and systemic disease (such as renal, cholestatic, or hematologic pruritus, or pruritus associated with malignancy), tinea corporis, tinea versicolor, and xerosis.

Clues in the history. The chronic evolution of pruritus without other skin lesions, like vesicles or squamous areas, and the location of a hyperpigmented patch near the scapula region in a midlife patient, should prompt you to consider NP. A biopsy may show signs of post-inflammatory infiltrate of the papillary dermis with dermal melanophages.^4,5

Notalgia paresthetica is not only a skin disease, but a cutaneous sign of an underlying spinal condition.

Although imaging tests are not required for a diagnosis of NP, basic cervical and possibly thoracic radiographs or magnetic resonance imaging (MRI) may be helpful in patients with symptoms of spine pain, tenderness, spasms, decreased range of motion, or any history of spinal trauma or injury. The images may reveal spinal disorders, including osteoarthritic lesions such as kyphosis, kyphoscoliosis, and vertebral hyperostosis.⁴

The exact cause of NP is unclear, but the evidence suggests that it results from damage to the cutaneous branches of the posterior divisions of the spinal nerves. This can occur by either impingement from degenerative changes in the spine or by spasms in the paraspinal musculature.²

The itch is neuropathic; antihistamines, steroids won’t help

It is difficult to treat NP without treating the underlying disease, which is usually spinal damage.⁴ Little has been published on the treatment of NP, and most of the literature on the subject involves case reports. Because the pruritus in NP is neuropathic, antihistamines and topical steroids are ineffective.⁴

The most commonly used treatment for NP among dermatologists is capsaicin as a 0.025% cream or 8% patch. One study with 20 patients reported improvement of pruritus in 70% of patients at 2 weeks, with some relapsing in about a month.⁶

Another treatment that has been used is cutaneous botulinum toxin type A injections, but its use is controversial. This strategy was proposed by Weinfeld⁷ after successful treatment of 2 patients. However, other studies have had variable outcomes with no resolution of pruritus.⁸

Other treatments include gabapentin,⁹ transcutaneous electrical nerve stimulation,¹⁰ and narrow-band ultraviolet-B.¹¹ It is appropriate to consider surgical decompression or neurolysis of the nerve when other forms of treatment fail.¹²

Our patient was treated with topical capsaicin cream 0.25 mg/g, which lessened the intensity of her itching. After 2 months, the patient reported improvement of her symptoms.

CORRESPONDENCE
Joana Sequeira, MD, Estrada da Mata nº56, Leiria, Portugal; [email protected].

If the cervical cytology report you receive for a woman in her mid-20s is negative, how soon would you plan to repeat testing? Recommendations from the United States Preventive Services Task Force (USPSTF) and other leading organizations advise a combination of cytology and human papillomavirus (HPV) testing at specified intervals depending on a patient’s age. However, a study published in 2015 analyzed data from a statewide registry on provider behavior and found a wide array of screening intervals in practice and infrequent use of HPV testing.¹ Clearly, adherence to published guidelines has been inconsistent.

Now, recommendations by several specialty groups are evolving based on newer evidence regarding HPV testing. These alternative guidelines recommend primary high-risk HPV testing for all women. This change is the topic of much national debate and is being researched for the USPSTF’s 2018 update on cervical cancer screening.

In this article, I review the USPSTF’s present recommendations and look ahead to how “best practices” for cervical cancer screening may be changing.

Current cervical cancer screening guidelines

Many subspecialty organizations and government agencies publish cervical cancer screening guidelines. The USPSTF guidelines, reviewed here, are evidence based, frequently updated, and widely used by primary care providers (TABLE).^2,3 These guidelines recommend initiating cytology testing at age 21 and, if results are normal, repeating every 3 years. Reflex HPV testing is recommended if cytology results reveal atypical squamous cells of undetermined significance (ASCUS). For women ages 30 to 65, the preferred option is to undergo a combination of cytology and HPV testing every 5 years.² Women older than 65 may discontinue screening.² HPV immunization status does not affect USPSTF recommendations. Nationwide rates of HPV vaccination among females ages 13 to 17 vary among states, from ≤49% to ≥70%.⁴

The USPSTF urges cytology testing starting at age 21 and repeating it every 3 years, with reflex HPV testing if results reveal atypical squamous cells of undetermined significance.

What the guidelines do, and do not, cover. The USPSTF screening intervals apply as long as testing results are normal.² These guidelines apply to all women regardless of the age at which they began sexual activity. These guidelines do not apply to women who have had abnormal cytology or HPV results and have not undergone adequate follow-up to ensure their lesion has cleared.⁵ These guidelines also do not apply to women who are immunosuppressed, who were exposed to diethylstilbestrol (DES) in utero, who have had a hysterectomy for non-oncologic reasons, or who have had cervical cancer.⁵ A woman may stop routine screening after age 65 if she has had adequate follow-up including either 3 negative cytology samples or 2 negative co-tests (cytology and HPV test) in the last 10 years.⁶ A woman may also discontinue screening if she has had a total hysterectomy and has no history of cervical dysplasia.⁷

Evidence behind the guidelines. The USPSTF guidelines were updated to their current state in 2012 reflecting a growing body of evidence that, for women 30 years and older, detection of cervical intraepithelial neoplasia (CIN) 3+ lesions improves with HPV co-testing. The supporting studies also found that the risk of a high-grade lesion appearing 5 years following co-testing was equivalent to the risk seen with cytology samples alone taken at 3-year intervals.⁸ The sensitivity of a single cytology test is only about 50%.⁹ A patient’s risk of cervical cancer 18 months after 3 negative cytology tests is about 1.5/100,000.¹⁰ The risk at 36 months following 3 negative cytology results is about 4.5/100,000. Annual screening would require almost 100,000 women to be screened to detect 3 additional cases of cervical cancer.¹⁰

Additional benefits of the updated USPSTF guidelines. The updated strategy decreases the number of visits for patients and the number of colposcopies, minimizing harm and patient anxiety. The current management algorithms also recommend more conservative management of women in their early 20s who have reported abnormal cytology, as the likelihood of their lesion clearing within 12 to 24 months is high.⁵ The recommendation does not call for high-risk HPV testing of women ages 21 to 29 because the infection is highly prevalent in this age group and is also likely to clear before any significant pathology arises. This avoids unnecessary and potentially harmful treatment of younger women.¹¹

What about the alternative screening guideline?

In early 2015, the American Society for Colposcopy and Cervical Pathology (ASCCP) and the Society of Gynecologic Oncology (SGO) co-sponsored an expert panel representing several specialty societies. The panel released interim guidelines for cervical cancer screening reflecting a growing body of evidence that favors HPV testing as the primary modality.¹² Additionally, in January 2016, these guidelines received an evidence-level B rating from the American Congress of Obstetricians and Gynecologists.¹³ Primary HPV screening is also the topic of research and discussion for USPSTF’s pending 2018 update of cervical cancer screening strategies.¹⁴

The alternative algorithm from the ASCCP and SGO recommends cervical cancer screening with HPV testing alone starting at the age of 25 and, if results are negative, repeating at 3-year intervals.¹² If a patient tests positive for any of the 14 identified high-risk HPV types, reflex cytology is indicated with a referral for colposcopy if an abnormality is identified.¹² If the cytology result is normal, follow-up with another HPV test in 12 months is recommended.¹²

Over the last 12 years, multiple international studies have demonstrated the efficacy of high-risk HPV testing in primary screening for cervical cancer.¹⁵ The most recent study conducted in the United States from 2008 to 2011—Addressing THE Need for Advanced HPV Diagnostics (ATHENA)—enrolled 42,000 women older than 25 years to compare the screening modalities of cytology alone, cytology and HPV testing combined, and HPV testing alone.¹⁶ The purpose of the study was to determine the safety of the cobas HPV test as a co-test and as a primary screening modality in women older than 25 years. (Many HPV tests are commercially available, but only the cobas HPV test is FDA-approved for primary screening.¹²)

The USPSTF strategy decreases the number of visits for patients and the number of colposcopies.

ATHENA researchers concluded that HPV testing was more sensitive than cytology, but less specific.¹⁶ The researchers also concluded that adding cytology to the HPV test increased the sensitivity by less than 5% and that HPV was better at detecting CIN 2+ lesions than cytology alone.^12,16 Another recently published study conducted at a tertiary care hospital with a smaller sample (1000 patients) corroborated the ATHENA results.¹⁷

For patients in their late 20s, this alternative strategy may increase the number of subsequent colposcopies. However, during the clinical trials just described, the absolute number of colposcopies needed to detect high-grade disease was the same as seen with the current guidelines. This finding indicates that, with the current algorithm, clinically significant pathology due to high-risk HPV may be missed in the 25-to-29 age group.⁸

Looking ahead. The alternative screening strategy is already being adopted in Australia, the Netherlands, and the United Kingdom.¹⁵ For providers in the United States considering this alternative strategy, the recommendation is to initiate cervical cancer screening with cytology alone at age 21, manage results appropriately, and then transition the patient to primary HPV testing with the FDA-approved test at age 25.¹² This recommendation may be modified in the future. However the guidelines might change, patients will benefit only if the guidelines are implemented consistently in practice.

CORRESPONDENCE
Sabrina Hofmeister, DO, 1121 E. North Ave, Milwaukee, WI 53212; [email protected].

If the cervical cytology report you receive for a woman in her mid-20s is negative, how soon would you plan to repeat testing? Recommendations from the United States Preventive Services Task Force (USPSTF) and other leading organizations advise a combination of cytology and human papillomavirus (HPV) testing at specified intervals depending on a patient’s age. However, a study published in 2015 analyzed data from a statewide registry on provider behavior and found a wide array of screening intervals in practice and infrequent use of HPV testing.¹ Clearly, adherence to published guidelines has been inconsistent.

Now, recommendations by several specialty groups are evolving based on newer evidence regarding HPV testing. These alternative guidelines recommend primary high-risk HPV testing for all women. This change is the topic of much national debate and is being researched for the USPSTF’s 2018 update on cervical cancer screening.

In this article, I review the USPSTF’s present recommendations and look ahead to how “best practices” for cervical cancer screening may be changing.

Current cervical cancer screening guidelines

Many subspecialty organizations and government agencies publish cervical cancer screening guidelines. The USPSTF guidelines, reviewed here, are evidence based, frequently updated, and widely used by primary care providers (TABLE).^2,3 These guidelines recommend initiating cytology testing at age 21 and, if results are normal, repeating every 3 years. Reflex HPV testing is recommended if cytology results reveal atypical squamous cells of undetermined significance (ASCUS). For women ages 30 to 65, the preferred option is to undergo a combination of cytology and HPV testing every 5 years.² Women older than 65 may discontinue screening.² HPV immunization status does not affect USPSTF recommendations. Nationwide rates of HPV vaccination among females ages 13 to 17 vary among states, from ≤49% to ≥70%.⁴

The USPSTF urges cytology testing starting at age 21 and repeating it every 3 years, with reflex HPV testing if results reveal atypical squamous cells of undetermined significance.

What the guidelines do, and do not, cover. The USPSTF screening intervals apply as long as testing results are normal.² These guidelines apply to all women regardless of the age at which they began sexual activity. These guidelines do not apply to women who have had abnormal cytology or HPV results and have not undergone adequate follow-up to ensure their lesion has cleared.⁵ These guidelines also do not apply to women who are immunosuppressed, who were exposed to diethylstilbestrol (DES) in utero, who have had a hysterectomy for non-oncologic reasons, or who have had cervical cancer.⁵ A woman may stop routine screening after age 65 if she has had adequate follow-up including either 3 negative cytology samples or 2 negative co-tests (cytology and HPV test) in the last 10 years.⁶ A woman may also discontinue screening if she has had a total hysterectomy and has no history of cervical dysplasia.⁷

Evidence behind the guidelines. The USPSTF guidelines were updated to their current state in 2012 reflecting a growing body of evidence that, for women 30 years and older, detection of cervical intraepithelial neoplasia (CIN) 3+ lesions improves with HPV co-testing. The supporting studies also found that the risk of a high-grade lesion appearing 5 years following co-testing was equivalent to the risk seen with cytology samples alone taken at 3-year intervals.⁸ The sensitivity of a single cytology test is only about 50%.⁹ A patient’s risk of cervical cancer 18 months after 3 negative cytology tests is about 1.5/100,000.¹⁰ The risk at 36 months following 3 negative cytology results is about 4.5/100,000. Annual screening would require almost 100,000 women to be screened to detect 3 additional cases of cervical cancer.¹⁰

Additional benefits of the updated USPSTF guidelines. The updated strategy decreases the number of visits for patients and the number of colposcopies, minimizing harm and patient anxiety. The current management algorithms also recommend more conservative management of women in their early 20s who have reported abnormal cytology, as the likelihood of their lesion clearing within 12 to 24 months is high.⁵ The recommendation does not call for high-risk HPV testing of women ages 21 to 29 because the infection is highly prevalent in this age group and is also likely to clear before any significant pathology arises. This avoids unnecessary and potentially harmful treatment of younger women.¹¹

What about the alternative screening guideline?

In early 2015, the American Society for Colposcopy and Cervical Pathology (ASCCP) and the Society of Gynecologic Oncology (SGO) co-sponsored an expert panel representing several specialty societies. The panel released interim guidelines for cervical cancer screening reflecting a growing body of evidence that favors HPV testing as the primary modality.¹² Additionally, in January 2016, these guidelines received an evidence-level B rating from the American Congress of Obstetricians and Gynecologists.¹³ Primary HPV screening is also the topic of research and discussion for USPSTF’s pending 2018 update of cervical cancer screening strategies.¹⁴

The alternative algorithm from the ASCCP and SGO recommends cervical cancer screening with HPV testing alone starting at the age of 25 and, if results are negative, repeating at 3-year intervals.¹² If a patient tests positive for any of the 14 identified high-risk HPV types, reflex cytology is indicated with a referral for colposcopy if an abnormality is identified.¹² If the cytology result is normal, follow-up with another HPV test in 12 months is recommended.¹²

Over the last 12 years, multiple international studies have demonstrated the efficacy of high-risk HPV testing in primary screening for cervical cancer.¹⁵ The most recent study conducted in the United States from 2008 to 2011—Addressing THE Need for Advanced HPV Diagnostics (ATHENA)—enrolled 42,000 women older than 25 years to compare the screening modalities of cytology alone, cytology and HPV testing combined, and HPV testing alone.¹⁶ The purpose of the study was to determine the safety of the cobas HPV test as a co-test and as a primary screening modality in women older than 25 years. (Many HPV tests are commercially available, but only the cobas HPV test is FDA-approved for primary screening.¹²)

The USPSTF strategy decreases the number of visits for patients and the number of colposcopies.

ATHENA researchers concluded that HPV testing was more sensitive than cytology, but less specific.¹⁶ The researchers also concluded that adding cytology to the HPV test increased the sensitivity by less than 5% and that HPV was better at detecting CIN 2+ lesions than cytology alone.^12,16 Another recently published study conducted at a tertiary care hospital with a smaller sample (1000 patients) corroborated the ATHENA results.¹⁷

For patients in their late 20s, this alternative strategy may increase the number of subsequent colposcopies. However, during the clinical trials just described, the absolute number of colposcopies needed to detect high-grade disease was the same as seen with the current guidelines. This finding indicates that, with the current algorithm, clinically significant pathology due to high-risk HPV may be missed in the 25-to-29 age group.⁸

Looking ahead. The alternative screening strategy is already being adopted in Australia, the Netherlands, and the United Kingdom.¹⁵ For providers in the United States considering this alternative strategy, the recommendation is to initiate cervical cancer screening with cytology alone at age 21, manage results appropriately, and then transition the patient to primary HPV testing with the FDA-approved test at age 25.¹² This recommendation may be modified in the future. However the guidelines might change, patients will benefit only if the guidelines are implemented consistently in practice.

CORRESPONDENCE
Sabrina Hofmeister, DO, 1121 E. North Ave, Milwaukee, WI 53212; [email protected].

If the cervical cytology report you receive for a woman in her mid-20s is negative, how soon would you plan to repeat testing? Recommendations from the United States Preventive Services Task Force (USPSTF) and other leading organizations advise a combination of cytology and human papillomavirus (HPV) testing at specified intervals depending on a patient’s age. However, a study published in 2015 analyzed data from a statewide registry on provider behavior and found a wide array of screening intervals in practice and infrequent use of HPV testing.¹ Clearly, adherence to published guidelines has been inconsistent.

Now, recommendations by several specialty groups are evolving based on newer evidence regarding HPV testing. These alternative guidelines recommend primary high-risk HPV testing for all women. This change is the topic of much national debate and is being researched for the USPSTF’s 2018 update on cervical cancer screening.

In this article, I review the USPSTF’s present recommendations and look ahead to how “best practices” for cervical cancer screening may be changing.

Current cervical cancer screening guidelines

Many subspecialty organizations and government agencies publish cervical cancer screening guidelines. The USPSTF guidelines, reviewed here, are evidence based, frequently updated, and widely used by primary care providers (TABLE).^2,3 These guidelines recommend initiating cytology testing at age 21 and, if results are normal, repeating every 3 years. Reflex HPV testing is recommended if cytology results reveal atypical squamous cells of undetermined significance (ASCUS). For women ages 30 to 65, the preferred option is to undergo a combination of cytology and HPV testing every 5 years.² Women older than 65 may discontinue screening.² HPV immunization status does not affect USPSTF recommendations. Nationwide rates of HPV vaccination among females ages 13 to 17 vary among states, from ≤49% to ≥70%.⁴

The USPSTF urges cytology testing starting at age 21 and repeating it every 3 years, with reflex HPV testing if results reveal atypical squamous cells of undetermined significance.

What the guidelines do, and do not, cover. The USPSTF screening intervals apply as long as testing results are normal.² These guidelines apply to all women regardless of the age at which they began sexual activity. These guidelines do not apply to women who have had abnormal cytology or HPV results and have not undergone adequate follow-up to ensure their lesion has cleared.⁵ These guidelines also do not apply to women who are immunosuppressed, who were exposed to diethylstilbestrol (DES) in utero, who have had a hysterectomy for non-oncologic reasons, or who have had cervical cancer.⁵ A woman may stop routine screening after age 65 if she has had adequate follow-up including either 3 negative cytology samples or 2 negative co-tests (cytology and HPV test) in the last 10 years.⁶ A woman may also discontinue screening if she has had a total hysterectomy and has no history of cervical dysplasia.⁷

Evidence behind the guidelines. The USPSTF guidelines were updated to their current state in 2012 reflecting a growing body of evidence that, for women 30 years and older, detection of cervical intraepithelial neoplasia (CIN) 3+ lesions improves with HPV co-testing. The supporting studies also found that the risk of a high-grade lesion appearing 5 years following co-testing was equivalent to the risk seen with cytology samples alone taken at 3-year intervals.⁸ The sensitivity of a single cytology test is only about 50%.⁹ A patient’s risk of cervical cancer 18 months after 3 negative cytology tests is about 1.5/100,000.¹⁰ The risk at 36 months following 3 negative cytology results is about 4.5/100,000. Annual screening would require almost 100,000 women to be screened to detect 3 additional cases of cervical cancer.¹⁰

Additional benefits of the updated USPSTF guidelines. The updated strategy decreases the number of visits for patients and the number of colposcopies, minimizing harm and patient anxiety. The current management algorithms also recommend more conservative management of women in their early 20s who have reported abnormal cytology, as the likelihood of their lesion clearing within 12 to 24 months is high.⁵ The recommendation does not call for high-risk HPV testing of women ages 21 to 29 because the infection is highly prevalent in this age group and is also likely to clear before any significant pathology arises. This avoids unnecessary and potentially harmful treatment of younger women.¹¹

What about the alternative screening guideline?

In early 2015, the American Society for Colposcopy and Cervical Pathology (ASCCP) and the Society of Gynecologic Oncology (SGO) co-sponsored an expert panel representing several specialty societies. The panel released interim guidelines for cervical cancer screening reflecting a growing body of evidence that favors HPV testing as the primary modality.¹² Additionally, in January 2016, these guidelines received an evidence-level B rating from the American Congress of Obstetricians and Gynecologists.¹³ Primary HPV screening is also the topic of research and discussion for USPSTF’s pending 2018 update of cervical cancer screening strategies.¹⁴

The alternative algorithm from the ASCCP and SGO recommends cervical cancer screening with HPV testing alone starting at the age of 25 and, if results are negative, repeating at 3-year intervals.¹² If a patient tests positive for any of the 14 identified high-risk HPV types, reflex cytology is indicated with a referral for colposcopy if an abnormality is identified.¹² If the cytology result is normal, follow-up with another HPV test in 12 months is recommended.¹²

Over the last 12 years, multiple international studies have demonstrated the efficacy of high-risk HPV testing in primary screening for cervical cancer.¹⁵ The most recent study conducted in the United States from 2008 to 2011—Addressing THE Need for Advanced HPV Diagnostics (ATHENA)—enrolled 42,000 women older than 25 years to compare the screening modalities of cytology alone, cytology and HPV testing combined, and HPV testing alone.¹⁶ The purpose of the study was to determine the safety of the cobas HPV test as a co-test and as a primary screening modality in women older than 25 years. (Many HPV tests are commercially available, but only the cobas HPV test is FDA-approved for primary screening.¹²)

The USPSTF strategy decreases the number of visits for patients and the number of colposcopies.

ATHENA researchers concluded that HPV testing was more sensitive than cytology, but less specific.¹⁶ The researchers also concluded that adding cytology to the HPV test increased the sensitivity by less than 5% and that HPV was better at detecting CIN 2+ lesions than cytology alone.^12,16 Another recently published study conducted at a tertiary care hospital with a smaller sample (1000 patients) corroborated the ATHENA results.¹⁷

For patients in their late 20s, this alternative strategy may increase the number of subsequent colposcopies. However, during the clinical trials just described, the absolute number of colposcopies needed to detect high-grade disease was the same as seen with the current guidelines. This finding indicates that, with the current algorithm, clinically significant pathology due to high-risk HPV may be missed in the 25-to-29 age group.⁸

Looking ahead. The alternative screening strategy is already being adopted in Australia, the Netherlands, and the United Kingdom.¹⁵ For providers in the United States considering this alternative strategy, the recommendation is to initiate cervical cancer screening with cytology alone at age 21, manage results appropriately, and then transition the patient to primary HPV testing with the FDA-approved test at age 25.¹² This recommendation may be modified in the future. However the guidelines might change, patients will benefit only if the guidelines are implemented consistently in practice.

CORRESPONDENCE
Sabrina Hofmeister, DO, 1121 E. North Ave, Milwaukee, WI 53212; [email protected].

THE CASE

An 85-year-old woman sought care at our outpatient clinic for a 9-month history of severe pruritus and crusted lesions on her face, extremities, and trunk. She had been diagnosed with hepatitis C virus (HCV) infection one year ago and was not taking any medication. The patient, who had been living with her family, had visited various clinics for her complaints and was diagnosed as having contact dermatitis and senile pruritus. She was prescribed topical mometasone furoate and moisturizers.

After 6 months of using this therapy, widespread grey-white plaques and minimal excoriation appeared on her face, scalp, and trunk. This was diagnosed as psoriasis, and the patient was prescribed topical corticosteroids, which she used for 9 months until she came to our clinic. She said the lesions regressed minimally with the topical corticosteroids, but did not fully clear.

Dermatologic examination revealed widespread erythema and grey-white, cohesive, thick, pruritic plaques on her scalp, face, trunk, and bilateral extremities (FIGURE 1). A punch biopsy specimen was taken from the border of a plaque on her trunk.

THE DIAGNOSIS

A complete blood cell count and wide biochemistry panel, including tumor markers and viral serology for human immunodeficiency virus (HIV), were normal. The patient had lymphadenopathy in her posterior cervical, bilateral preauricular, and bilateral inguinal regions.

Histopathologic examination revealed hyperkeratosis, acanthosis, and spongiotic edema in the epidermis, and vesiculation and mites in the stratum corneum. The dermal changes consisted of perivascular and diffuse cell infiltrates that were mainly mononuclear cells and eosinophilic granulocytes.

Based on the dermatologic examination and the histopathologic findings, we diagnosed the patient with crusted (Norwegian) scabies.

DISCUSSION

Crusted (Norwegian) scabies is a rare, highly contagious form of scabies that is characterized by the presence of millions of Sarcoptes scabiei var hominis mites in the epidermis.¹ This variant of scabies can affect individuals of any age, gender, or race.² It was first described by Boeck and Danielssen in 1848 in Norway and was named Norwegian scabies by von Hebra in 1862.³ In 2010, more than 200 cases of crusted scabies were reported in the literature.⁴

Crusted scabies is usually seen in immunocompromised patients, such as the elderly, those who’ve had solid organ transplantation, and those with HIV, malignancy, or malnutrition. Crusted scabies may also occur in patients with decreased sensory function (such as those with leprosy) or decreased ability to scratch, intellectual disabilities, and in those who use biologic agents or systemic/topical corticosteroids.^4-8

Crusted scabies is associated with increased morbidity and mortality, especially in children and the elderly, because of complications such as secondary bacterial infections and sepsis.^1,3 Widespread inflammation may also cause erythroderma, which can lead to metabolic disorders.

Distinguish it from other pruritic papulosquamous diseases

The differential diagnosis for crusted scabies includes psoriasis, eczema, cutaneous lymphoma, Darier disease, and adverse drug reactions.⁹ Crusted scabies can be differentiated from these other diagnoses by its clinical presentation and histopathological examination.

Crusted scabies is characterized by hyperkeratosis and wart-like crusts that are due to extreme proliferation of mites in the stratum corneum of the epidermis.² Lesions are usually localized on acral sites (especially the hands), although the entire body, including the face and the scalp, can be involved.¹ Psoriasiform or bullous pemphigoid-like eruptions have also been reported in the literature.^5,9

Our patient presented with widespread erythema and psoriasiform grey-white crusts on her scalp, face, chest, periareolar region, and extremities. In addition, she did not have an immunosuppressant disease or medication history.

However, the fact that our patient was using topical corticosteroids for so long explained the extent of her condition. Topical corticosteroids have been linked to scabies incognito.¹⁰ Topical or systemic corticosteroid use for long periods of time may alter the skin immune system by suppressing cellular immunity, thereby reducing the inflammatory response. This may lead to progression of the regular variant of scabies to crusted scabies, as our patient had.

Topical treatments, oral ivermectin proven to be effective

Topical keratolytics, permethrin 5%, lindane 1%, crotamiton 10%, sulfur ointment (5%-10%), malathion 0.5%, benzyl benzoate (10%-25%), oral ivermectin (2 doses of 200 mcg/kg/dose), and systemic antihistamines are appropriate therapies.³ While oral ivermectin is effective, it is not available in Turkey.

Because of our patient’s hepatic disorder, we opted for a topical, rather than a systemic, treatment and recommended repeated applications of topical permethrin. Repeated treatment with topical permethrin is often sufficient in patients who are unable to take systemic therapy. In fact, Binic et al⁴ reported a case in which an elderly patient with crusted scabies (who had previously been treated with systemic and topical corticosteroids) responded well to repeated topical treatment with lindane 1%, 25% benzyl benzoate, and 10% precipitated sulfur.

Our patient. We prescribed topical 5% permethrin lotion for our patient to apply to her entire body 4 times a week and advised her to wash her clothing and bed linens at 140° F. She was scheduled for biweekly check-ups. We also advised the patient’s family to use the same topical therapy 2 times per week because crusted scabies is highly contagious. One month later, our patient’s lesions had resolved (FIGURE 2).

THE TAKEAWAY

Early diagnosis and treatment of crusted scabies is important, both for the treatment of the patient and to stop the spread of the disease. Although rare, crusted scabies should be included in the differential diagnosis of long-term pruritic papulosquamous diseases, and the possibility of an atypical presentation in all patients should be considered—whether their immunity is compromised or not. Scabies should also be considered in patients with a positive family history of the disease and in those with chronic pruritus that is unresponsive to topical therapies.