Pulmonary Health Hub

The Food and Drug Administration has amended the boxed warning on labels for fluoroquinolone antibiotics, taken either orally or by injection, to reflect recent findings of the drugs’ alarming potential adverse events.

“These medicines are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” the FDA stated in its Safety Announcement.

As a result, health care providers should reserve systemic fluoroquinolones for patients who have no other treatment options for any of the following conditions: acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTIs). The FDA also said that, for some serious bacterial infections, the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.

Patients taking fluoroquinolones must also be vigilant and let their provider know immediately if they begin suffering from any new pain in their joints, tendons, or muscles. Additionally, if patients begin feeling any numbness in their arms and legs, a prickling or “pins and needles” sensation, or confusion and hallucinations, they should contact their health care provider right away so that they may be switched onto a nonfluoroquinolone antibacterial drug for the remainder of their treatment regimen.

Avelox; Cipro, both standard and extended release; Factive; Levaquin; and ofloxacin are the fluoroquinolones currently approved by the FDA for systemic use. Their active ingredients are moxifloxacin, ciprofloxacin, gemifloxacin, levofloxacin, and ofloxacin, respectively.

Additional side effects for patients taking fluoroquinolones could include tendinitis, tendon rupture, and joint swelling. Central nervous system afflictions could include depression and thoughts of suicide. Fluoroquinolones could also bring about skin rashes, sunburn, arrhythmia, diarrhea, as well as aggravate myasthenia gravis in patients who suffer from it. Warnings regarding these conditions are already included on the drugs’ existing boxed warning.

“In addition to updating information in the Boxed Warning, we are also including information about these safety issues in the Warnings and Precautions section of the label,” the FDA stated. “The Indications and Usage section contains new limitation-of-use statements to reserve fluoroquinolones for patients who do not have other available treatment options for ABS, ABECB, and uncomplicated UTIs.”

The FDA also added that it will continue to monitor and assess safety issues associated with fluoroquinolones and will issue any further updates if necessary.

[email protected]

The Food and Drug Administration has amended the boxed warning on labels for fluoroquinolone antibiotics, taken either orally or by injection, to reflect recent findings of the drugs’ alarming potential adverse events.

“These medicines are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” the FDA stated in its Safety Announcement.

As a result, health care providers should reserve systemic fluoroquinolones for patients who have no other treatment options for any of the following conditions: acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTIs). The FDA also said that, for some serious bacterial infections, the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.

Patients taking fluoroquinolones must also be vigilant and let their provider know immediately if they begin suffering from any new pain in their joints, tendons, or muscles. Additionally, if patients begin feeling any numbness in their arms and legs, a prickling or “pins and needles” sensation, or confusion and hallucinations, they should contact their health care provider right away so that they may be switched onto a nonfluoroquinolone antibacterial drug for the remainder of their treatment regimen.

Avelox; Cipro, both standard and extended release; Factive; Levaquin; and ofloxacin are the fluoroquinolones currently approved by the FDA for systemic use. Their active ingredients are moxifloxacin, ciprofloxacin, gemifloxacin, levofloxacin, and ofloxacin, respectively.

Additional side effects for patients taking fluoroquinolones could include tendinitis, tendon rupture, and joint swelling. Central nervous system afflictions could include depression and thoughts of suicide. Fluoroquinolones could also bring about skin rashes, sunburn, arrhythmia, diarrhea, as well as aggravate myasthenia gravis in patients who suffer from it. Warnings regarding these conditions are already included on the drugs’ existing boxed warning.

“In addition to updating information in the Boxed Warning, we are also including information about these safety issues in the Warnings and Precautions section of the label,” the FDA stated. “The Indications and Usage section contains new limitation-of-use statements to reserve fluoroquinolones for patients who do not have other available treatment options for ABS, ABECB, and uncomplicated UTIs.”

The FDA also added that it will continue to monitor and assess safety issues associated with fluoroquinolones and will issue any further updates if necessary.

[email protected]

The Food and Drug Administration has amended the boxed warning on labels for fluoroquinolone antibiotics, taken either orally or by injection, to reflect recent findings of the drugs’ alarming potential adverse events.

“These medicines are associated with disabling and potentially permanent side effects of the tendons, muscles, joints, nerves, and central nervous system that can occur together in the same patient,” the FDA stated in its Safety Announcement.

As a result, health care providers should reserve systemic fluoroquinolones for patients who have no other treatment options for any of the following conditions: acute bacterial sinusitis (ABS), acute bacterial exacerbation of chronic bronchitis (ABECB), and uncomplicated urinary tract infections (UTIs). The FDA also said that, for some serious bacterial infections, the benefits of fluoroquinolones outweigh the risks, and it is appropriate for them to remain available as a therapeutic option.

Patients taking fluoroquinolones must also be vigilant and let their provider know immediately if they begin suffering from any new pain in their joints, tendons, or muscles. Additionally, if patients begin feeling any numbness in their arms and legs, a prickling or “pins and needles” sensation, or confusion and hallucinations, they should contact their health care provider right away so that they may be switched onto a nonfluoroquinolone antibacterial drug for the remainder of their treatment regimen.

Avelox; Cipro, both standard and extended release; Factive; Levaquin; and ofloxacin are the fluoroquinolones currently approved by the FDA for systemic use. Their active ingredients are moxifloxacin, ciprofloxacin, gemifloxacin, levofloxacin, and ofloxacin, respectively.

Additional side effects for patients taking fluoroquinolones could include tendinitis, tendon rupture, and joint swelling. Central nervous system afflictions could include depression and thoughts of suicide. Fluoroquinolones could also bring about skin rashes, sunburn, arrhythmia, diarrhea, as well as aggravate myasthenia gravis in patients who suffer from it. Warnings regarding these conditions are already included on the drugs’ existing boxed warning.

“In addition to updating information in the Boxed Warning, we are also including information about these safety issues in the Warnings and Precautions section of the label,” the FDA stated. “The Indications and Usage section contains new limitation-of-use statements to reserve fluoroquinolones for patients who do not have other available treatment options for ABS, ABECB, and uncomplicated UTIs.”

The FDA also added that it will continue to monitor and assess safety issues associated with fluoroquinolones and will issue any further updates if necessary.

[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].

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].

Acinetobacter baumanii was the most common cause of ventilator-associated pneumonia in ICU patients, and the risk of A. baumannii infection was significantly higher when airways were colonized with Candida species, based on data from 618 adults.

A. baumannii is a frequent cause of ventilator-associated pneumonia (VAP) in ICU patients, but its potential interactions with Candida species have not been well studied, wrote Dr. Xiaojiang Tan of Southern Medical University, Guangzhou, China, and colleagues (Med Mycol. 2016 Aug 1;54[6]:557-66. doi: 10.1093/mmy/myw009). The researchers reviewed data from 264 ICU patients on mechanical ventilation who had Candida species airway colonization and 354 who did not.

Overall, Candida was an independent risk factor for A. baumannii VAP; patients with Candida were significantly more likely than those without Candida to develop A. baumannii (23% vs. 15%). Other independent risk factors for A. baumannii VAP included the use of a central venous catheter and the use of mechanical ventilation for at least 7 days. Among patients on mechanical ventilation for at least 48 hours, Candida airway colonization occurred in 43%, and A. baumannii VAP occurred in 18%.

GrahamColm/Wikimedia Commons

Candida albicans showed an especially strong association with A. baumannii VAP; it was identified in 38% of cases, compared with 21% caused by non-albicans species.

No significant differences in hospital stay or in-hospital mortality were noted between Candida-colonized and noncolonized patients, and antifungal treatment had no apparent impact on the development of A. baumannii VAP, but antifungals were associated with higher in-hospital mortality (53% vs. 39%, P = .037).

The results were limited by the retrospective nature of the study and the use of data from a single center; thus, the relationship between Candida and A. baumannii VAP may not be generalizable, the researchers noted. However, “the strong independent association between the two suggests that Candida spp. growth from the lower respiratory tract in intubated patients could be an important indicator of the risk for VAP, and even that C. albicans airway colonization may play a role in subsequent development of A. baumannii VAP,” they wrote.

The researchers reported having no relevant financial conflicts.

Acinetobacter baumanii was the most common cause of ventilator-associated pneumonia in ICU patients, and the risk of A. baumannii infection was significantly higher when airways were colonized with Candida species, based on data from 618 adults.

A. baumannii is a frequent cause of ventilator-associated pneumonia (VAP) in ICU patients, but its potential interactions with Candida species have not been well studied, wrote Dr. Xiaojiang Tan of Southern Medical University, Guangzhou, China, and colleagues (Med Mycol. 2016 Aug 1;54[6]:557-66. doi: 10.1093/mmy/myw009). The researchers reviewed data from 264 ICU patients on mechanical ventilation who had Candida species airway colonization and 354 who did not.

Overall, Candida was an independent risk factor for A. baumannii VAP; patients with Candida were significantly more likely than those without Candida to develop A. baumannii (23% vs. 15%). Other independent risk factors for A. baumannii VAP included the use of a central venous catheter and the use of mechanical ventilation for at least 7 days. Among patients on mechanical ventilation for at least 48 hours, Candida airway colonization occurred in 43%, and A. baumannii VAP occurred in 18%.

GrahamColm/Wikimedia Commons

Candida albicans showed an especially strong association with A. baumannii VAP; it was identified in 38% of cases, compared with 21% caused by non-albicans species.

No significant differences in hospital stay or in-hospital mortality were noted between Candida-colonized and noncolonized patients, and antifungal treatment had no apparent impact on the development of A. baumannii VAP, but antifungals were associated with higher in-hospital mortality (53% vs. 39%, P = .037).

The results were limited by the retrospective nature of the study and the use of data from a single center; thus, the relationship between Candida and A. baumannii VAP may not be generalizable, the researchers noted. However, “the strong independent association between the two suggests that Candida spp. growth from the lower respiratory tract in intubated patients could be an important indicator of the risk for VAP, and even that C. albicans airway colonization may play a role in subsequent development of A. baumannii VAP,” they wrote.

The researchers reported having no relevant financial conflicts.

Acinetobacter baumanii was the most common cause of ventilator-associated pneumonia in ICU patients, and the risk of A. baumannii infection was significantly higher when airways were colonized with Candida species, based on data from 618 adults.

A. baumannii is a frequent cause of ventilator-associated pneumonia (VAP) in ICU patients, but its potential interactions with Candida species have not been well studied, wrote Dr. Xiaojiang Tan of Southern Medical University, Guangzhou, China, and colleagues (Med Mycol. 2016 Aug 1;54[6]:557-66. doi: 10.1093/mmy/myw009). The researchers reviewed data from 264 ICU patients on mechanical ventilation who had Candida species airway colonization and 354 who did not.

Overall, Candida was an independent risk factor for A. baumannii VAP; patients with Candida were significantly more likely than those without Candida to develop A. baumannii (23% vs. 15%). Other independent risk factors for A. baumannii VAP included the use of a central venous catheter and the use of mechanical ventilation for at least 7 days. Among patients on mechanical ventilation for at least 48 hours, Candida airway colonization occurred in 43%, and A. baumannii VAP occurred in 18%.

GrahamColm/Wikimedia Commons

Candida albicans showed an especially strong association with A. baumannii VAP; it was identified in 38% of cases, compared with 21% caused by non-albicans species.

No significant differences in hospital stay or in-hospital mortality were noted between Candida-colonized and noncolonized patients, and antifungal treatment had no apparent impact on the development of A. baumannii VAP, but antifungals were associated with higher in-hospital mortality (53% vs. 39%, P = .037).

The results were limited by the retrospective nature of the study and the use of data from a single center; thus, the relationship between Candida and A. baumannii VAP may not be generalizable, the researchers noted. However, “the strong independent association between the two suggests that Candida spp. growth from the lower respiratory tract in intubated patients could be an important indicator of the risk for VAP, and even that C. albicans airway colonization may play a role in subsequent development of A. baumannii VAP,” they wrote.

The researchers reported having no relevant financial conflicts.

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

Medicaid status did not significantly affect costs for children who were hospitalized because of asthma, according to Jeffrey H. Silber, MD, and his associates.

In a study of 17,739 matched pairs of children with and without Medicaid who were hospitalized because of asthma, the median cost for Medicaid patients was $4,263; for non-Medicaid patients, it was $4,160. The median difference in cost between Medicaid and non-Medicaid patients was $84, and the mean difference in cost was $49.

Both Medicaid and non-Medicaid patients had similar lengths of stay, with a median of 1 day for both groups. Intensive care unit use was similar, with 10.1% of Medicaid patients visiting the ICU, compared with 10.6% of non-Medicaid patients.

“Our study should serve to provide potential benchmarks for use and reimbursement standards, with implications for care and payment even when children are hospitalized outside the [Pediatric Hospital Information System],” the investigators wrote.

Find the full study in Pediatrics (doi: 10.1542/peds.2016-0371).

[email protected]

Evidence summary

A 2014 systematic review included 8 RCTs in adults (3954 patients) and one RCT in children (669 patients) with influenza and compared time to alleviation of symptoms with oseltamivir and placebo.¹ Symptoms were defined as local (nasal discharge, dry cough, sore throat) and systemic (fever, myalgia, headache, fatigue). Methodology for diagnosis varied by trial.

Oral oseltamivir (75, 150, or 300 mg for 5 to 10 days) reduced time to first alleviation of symptoms by 17 hours (95% confidence interval [CI], 8.4-25 hours) compared with placebo for adults and 29 hours (95% CI, 12-47 hours) for the otherwise healthy children.

The systematic review also included 2 RCTs involving 660 children with chronic asthma who received treatment with oseltamivir. Researchers found no reduction in time to symptom alleviation with the oseltamivir.

Treatment with oseltamivir increased the risk of nausea (number needed to harm [NNH]=28) and vomiting (NNH=22) in adults and the risk of vomiting (NNH=19) in children. Sources of bias included industry sponsorship of all trials, differing placebo components, inadequate recruitment, and use of other medication.

Shorter fever duration?

A 2012 meta-analysis of 6 observational studies (5842 patients) compared the effect of oral oseltamivir with no treatment on duration of signs and symptoms (definition not given) in patients with influenza (method of diagnosis not stated).² Oseltamivir reduced fever duration by 33 hours (95% CI, 21-45 hours) compared with no treatment.

The authors describe the evidence as being of very low quality because of study heterogeneity, lack of control for confounding variables, selection bias, and study sources (many unpublished industry studies).

There’s benefit even with late Tx

A 2014 double-blind RCT, not included in the previously described reviews, of 130 adults and 1070 children with a positive rapid influenza test examined the effect of oseltamivir and placebo on symptom duration.³ Research assistants visited participants at home each day until patients were asymptomatic for 7 consecutive days.

Treatment with oseltamivir reduced symptom duration by a median of one day compared with no treatment (hazard ratio=0.87; 95% CI, 0.79-0.95). This benefit was observed regardless of whether treatment was initiated fewer or more than 48 hours after symptom onset. One notable limitation was failure to control for paracetamol (acetaminophen) usage, a possible confounder for duration of symptoms, such as fever.

Evidence summary

A 2014 systematic review included 8 RCTs in adults (3954 patients) and one RCT in children (669 patients) with influenza and compared time to alleviation of symptoms with oseltamivir and placebo.¹ Symptoms were defined as local (nasal discharge, dry cough, sore throat) and systemic (fever, myalgia, headache, fatigue). Methodology for diagnosis varied by trial.

Oral oseltamivir (75, 150, or 300 mg for 5 to 10 days) reduced time to first alleviation of symptoms by 17 hours (95% confidence interval [CI], 8.4-25 hours) compared with placebo for adults and 29 hours (95% CI, 12-47 hours) for the otherwise healthy children.

The systematic review also included 2 RCTs involving 660 children with chronic asthma who received treatment with oseltamivir. Researchers found no reduction in time to symptom alleviation with the oseltamivir.

Treatment with oseltamivir increased the risk of nausea (number needed to harm [NNH]=28) and vomiting (NNH=22) in adults and the risk of vomiting (NNH=19) in children. Sources of bias included industry sponsorship of all trials, differing placebo components, inadequate recruitment, and use of other medication.

Shorter fever duration?

A 2012 meta-analysis of 6 observational studies (5842 patients) compared the effect of oral oseltamivir with no treatment on duration of signs and symptoms (definition not given) in patients with influenza (method of diagnosis not stated).² Oseltamivir reduced fever duration by 33 hours (95% CI, 21-45 hours) compared with no treatment.

The authors describe the evidence as being of very low quality because of study heterogeneity, lack of control for confounding variables, selection bias, and study sources (many unpublished industry studies).

There’s benefit even with late Tx

A 2014 double-blind RCT, not included in the previously described reviews, of 130 adults and 1070 children with a positive rapid influenza test examined the effect of oseltamivir and placebo on symptom duration.³ Research assistants visited participants at home each day until patients were asymptomatic for 7 consecutive days.

Treatment with oseltamivir reduced symptom duration by a median of one day compared with no treatment (hazard ratio=0.87; 95% CI, 0.79-0.95). This benefit was observed regardless of whether treatment was initiated fewer or more than 48 hours after symptom onset. One notable limitation was failure to control for paracetamol (acetaminophen) usage, a possible confounder for duration of symptoms, such as fever.

Evidence summary

A 2014 systematic review included 8 RCTs in adults (3954 patients) and one RCT in children (669 patients) with influenza and compared time to alleviation of symptoms with oseltamivir and placebo.¹ Symptoms were defined as local (nasal discharge, dry cough, sore throat) and systemic (fever, myalgia, headache, fatigue). Methodology for diagnosis varied by trial.

Oral oseltamivir (75, 150, or 300 mg for 5 to 10 days) reduced time to first alleviation of symptoms by 17 hours (95% confidence interval [CI], 8.4-25 hours) compared with placebo for adults and 29 hours (95% CI, 12-47 hours) for the otherwise healthy children.

The systematic review also included 2 RCTs involving 660 children with chronic asthma who received treatment with oseltamivir. Researchers found no reduction in time to symptom alleviation with the oseltamivir.

Treatment with oseltamivir increased the risk of nausea (number needed to harm [NNH]=28) and vomiting (NNH=22) in adults and the risk of vomiting (NNH=19) in children. Sources of bias included industry sponsorship of all trials, differing placebo components, inadequate recruitment, and use of other medication.

Shorter fever duration?

A 2012 meta-analysis of 6 observational studies (5842 patients) compared the effect of oral oseltamivir with no treatment on duration of signs and symptoms (definition not given) in patients with influenza (method of diagnosis not stated).² Oseltamivir reduced fever duration by 33 hours (95% CI, 21-45 hours) compared with no treatment.

The authors describe the evidence as being of very low quality because of study heterogeneity, lack of control for confounding variables, selection bias, and study sources (many unpublished industry studies).

There’s benefit even with late Tx

A 2014 double-blind RCT, not included in the previously described reviews, of 130 adults and 1070 children with a positive rapid influenza test examined the effect of oseltamivir and placebo on symptom duration.³ Research assistants visited participants at home each day until patients were asymptomatic for 7 consecutive days.

Treatment with oseltamivir reduced symptom duration by a median of one day compared with no treatment (hazard ratio=0.87; 95% CI, 0.79-0.95). This benefit was observed regardless of whether treatment was initiated fewer or more than 48 hours after symptom onset. One notable limitation was failure to control for paracetamol (acetaminophen) usage, a possible confounder for duration of symptoms, such as fever.

Although we reserve the term “PURL” for our popular feature, Priority Updates from the Research Literature, I’m proud to comment on the collection of articles in this issue of JFP, each of which contains important “pearls” of information for family physicians and other primary care clinicians.

Managing sport-related concussion. Revelations about serious head injuries in the National Football League have catalyzed important research regarding the management of sports-related head injuries, and the evidence for diagnosis and treatment is evolving. The article in this issue by Dr. Sprouse and colleagues provides some of the latest information regarding brain changes after concussion straight from the American Academy of Neurology’s 2016 Sports Concussion Conference held in Chicago in July, as well as valuable return-to-play recommendations.

Family medicine ultrasound. Because of advances in technology and reductions in the cost of portable machines, ultrasound use is rapidly moving into family medicine offices. Drs. Steinmetz and Oleskevich provide a no-nonsense review of the current uses of ultrasound in family medicine, leading me to wonder whether ultrasound might become the stethoscope of the future.

This month’s review of the current uses of ultrasound in family medicine made me wonder whether ultrasound might become the stethoscope of the future.

Shortness of breath. Although the diagnosis of shortness of breath is straightforward in many cases, misdiagnosis is not uncommon. Recently, I cared for a new patient who was diagnosed with asthma 15 years ago. Because of fine rales on exam, I suspected the patient’s diagnosis was incorrect. Indeed, he had pulmonary fibrosis, not asthma, and he is doing fine now without his asthma inhalers. Dr. Taggart outlines a thoughtful approach to the evaluation of shortness of breath, one that alerts you to when to suspect something beyond the usual culprits.

Cervical cancer screening. The days of yearly Pap smears for all women are over. Combined screening with cytology and human papillomavirus testing is now recommended at 5-year intervals for women 30 to 65 years of age who are at low risk for cervical cancer. In addition, Dr. Hofmeister reviews recent randomized trials that suggest HPV screening alone may be sufficient for low-risk women.

On-demand HIV prophylaxis. Our PURL for the month discusses an effective prevention strategy—other than condoms—that can be used as needed by people at high risk for human immunodeficiency virus.

We hope you enjoy this PURL—and the other “pearls”—this month. As diagnosis and treatments evolve, JFP will continue to bring you the information you need to provide the best possible care for your patients.

Although we reserve the term “PURL” for our popular feature, Priority Updates from the Research Literature, I’m proud to comment on the collection of articles in this issue of JFP, each of which contains important “pearls” of information for family physicians and other primary care clinicians.

Managing sport-related concussion. Revelations about serious head injuries in the National Football League have catalyzed important research regarding the management of sports-related head injuries, and the evidence for diagnosis and treatment is evolving. The article in this issue by Dr. Sprouse and colleagues provides some of the latest information regarding brain changes after concussion straight from the American Academy of Neurology’s 2016 Sports Concussion Conference held in Chicago in July, as well as valuable return-to-play recommendations.

Family medicine ultrasound. Because of advances in technology and reductions in the cost of portable machines, ultrasound use is rapidly moving into family medicine offices. Drs. Steinmetz and Oleskevich provide a no-nonsense review of the current uses of ultrasound in family medicine, leading me to wonder whether ultrasound might become the stethoscope of the future.

This month’s review of the current uses of ultrasound in family medicine made me wonder whether ultrasound might become the stethoscope of the future.

Shortness of breath. Although the diagnosis of shortness of breath is straightforward in many cases, misdiagnosis is not uncommon. Recently, I cared for a new patient who was diagnosed with asthma 15 years ago. Because of fine rales on exam, I suspected the patient’s diagnosis was incorrect. Indeed, he had pulmonary fibrosis, not asthma, and he is doing fine now without his asthma inhalers. Dr. Taggart outlines a thoughtful approach to the evaluation of shortness of breath, one that alerts you to when to suspect something beyond the usual culprits.

Cervical cancer screening. The days of yearly Pap smears for all women are over. Combined screening with cytology and human papillomavirus testing is now recommended at 5-year intervals for women 30 to 65 years of age who are at low risk for cervical cancer. In addition, Dr. Hofmeister reviews recent randomized trials that suggest HPV screening alone may be sufficient for low-risk women.

On-demand HIV prophylaxis. Our PURL for the month discusses an effective prevention strategy—other than condoms—that can be used as needed by people at high risk for human immunodeficiency virus.

We hope you enjoy this PURL—and the other “pearls”—this month. As diagnosis and treatments evolve, JFP will continue to bring you the information you need to provide the best possible care for your patients.

Although we reserve the term “PURL” for our popular feature, Priority Updates from the Research Literature, I’m proud to comment on the collection of articles in this issue of JFP, each of which contains important “pearls” of information for family physicians and other primary care clinicians.

Managing sport-related concussion. Revelations about serious head injuries in the National Football League have catalyzed important research regarding the management of sports-related head injuries, and the evidence for diagnosis and treatment is evolving. The article in this issue by Dr. Sprouse and colleagues provides some of the latest information regarding brain changes after concussion straight from the American Academy of Neurology’s 2016 Sports Concussion Conference held in Chicago in July, as well as valuable return-to-play recommendations.

Family medicine ultrasound. Because of advances in technology and reductions in the cost of portable machines, ultrasound use is rapidly moving into family medicine offices. Drs. Steinmetz and Oleskevich provide a no-nonsense review of the current uses of ultrasound in family medicine, leading me to wonder whether ultrasound might become the stethoscope of the future.

This month’s review of the current uses of ultrasound in family medicine made me wonder whether ultrasound might become the stethoscope of the future.

Shortness of breath. Although the diagnosis of shortness of breath is straightforward in many cases, misdiagnosis is not uncommon. Recently, I cared for a new patient who was diagnosed with asthma 15 years ago. Because of fine rales on exam, I suspected the patient’s diagnosis was incorrect. Indeed, he had pulmonary fibrosis, not asthma, and he is doing fine now without his asthma inhalers. Dr. Taggart outlines a thoughtful approach to the evaluation of shortness of breath, one that alerts you to when to suspect something beyond the usual culprits.

Cervical cancer screening. The days of yearly Pap smears for all women are over. Combined screening with cytology and human papillomavirus testing is now recommended at 5-year intervals for women 30 to 65 years of age who are at low risk for cervical cancer. In addition, Dr. Hofmeister reviews recent randomized trials that suggest HPV screening alone may be sufficient for low-risk women.

On-demand HIV prophylaxis. Our PURL for the month discusses an effective prevention strategy—other than condoms—that can be used as needed by people at high risk for human immunodeficiency virus.

We hope you enjoy this PURL—and the other “pearls”—this month. As diagnosis and treatments evolve, JFP will continue to bring you the information you need to provide the best possible care for your patients.

The accuracy of idiopathic pulmonary fibrosis (IPF) diagnoses is improving with the use of multidisciplinary team meetings and updated guidelines, based on the findings of a study that compared diagnostic agreement of individual clinicians and teams evaluating patients with interstitial lung disease.

Pulmonologists who participate in multidisciplinary team meetings said the findings validate the team approach.

“The [study’s] data confirm what we see in clinical practice ... it takes a multidisciplinary – and perhaps often multiple pulmonologists – to review these cases,” Marilyn K. Glassberg, MD,professor of medicine and surgery and director of the interstitial lung disease program at the University of Miami Health System, said in an interview.“This study demonstrates the importance of multiple perspectives when evaluating a patient and coming to a diagnosis at a time when reliable biomarkers are not available.”

The study, published in The Lancet Respiratory Medicine (2016;4[7]:557-65), is the first evaluation of multidisciplinary team agreement on diagnosis of interstitial lung disease since updated guidelines were published, according to Simon L. F. Walsh, MD, of Kings College Hospital NHS Foundation Trust, London, and his colleagues.

In 2015, the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALTA) adopted joint guidelines for the treatment of IPF. In 2013, the ATS and ERS updated guidelines for the classification and terminology for idiopathic interstitial pneumonias.

“Our study shows ... in [IPF], MDTMs (multidisciplinary team meetings) have a higher level of agreement on diagnoses, assign diagnoses with higher confidence more frequently, and provide diagnoses that have non-significant greater prognostic separation than do clinicians or radiologists in most cases,” the researchers wrote.

Before MDTMs were initiated, the clinicians, radiologists, and pathologists who would be participating in them independently reviewed each patient’s case without consulting other specialists and provided up to five diagnoses with diagnostic likelihoods for each patient.

For the study, 70 patients were evaluated and the level of diagnostic agreement was assessed at seven international centers for the diagnosis of interstitial lung disease (diffuse parenchymal lung disease). Following independent reviews of the 70 cases, the clinician, radiologist, and pathologist from each center met as a multidisciplinary team to review the same cases together and give up to five diagnoses with diagnostic likelihoods.

All clinical information supplied in the first stage of the study, including pulmonary function test results, high-resolution CT at presentation, and digitalized surgical lung biopsy slides, were available to the multidisciplinary team. The patients’ outcomes were used to validate the diagnoses. The survival period for each patient was calculated based on the date of referral to the host institution to the minimum date of death, date patient was last known to be alive, or June 1, 2015 – the end of the study period.

The inter-MDTM agreement was better than interobserver agreement for all diagnoses (unweighted kappa value (K) = 0.50), and inter-MDTM agreement was highest for IPF (K = 0.60) and connective tissue disease-related interstitial lung disease (K = 0.64).

“We have shown an acceptable level [based on a K of greater than 0.40 being deemed clinically acceptable] of diagnostic agreement exists between multidisciplinary teams in the setting of diffuse parenchymal lung disease. Additionally, we showed that this agreement was validated by the nonsignificant increases toward greater prognostic separation of an IPF diagnosis made by multidisciplinary teams than by individual clinicians or radiologists,” the researchers wrote.

The weighted kappa (KW) values for estimation of diagnostic likelihood for diagnoses of IPF were 0.72 (0.67-0.76) for clinicians, 0.60 (0.46-0.66) for radiologists, 0.58 (0.45-0.66) for pathologists and 0.71 (0.64-0.77) for MDTMs.

For connective tissue disease–related interstitial lung diseases, the KW for estimation of diagnostic likelihood for diagnoses for MDTMs were 0.73 (0.68-0.78), compared with 0.76 (0.70-0.78) for clinicians, 0.17 (0.08-0.31) for radiologists, and 0.21 (0.06-0.36) for pathologists.

Krishna Thavarajah, MD,, who sees patients with interstitial lung disease within the Henry Ford Health System in Detroit, has been participating in MDTMs for nearly 6 years.

“The accuracies of diagnoses for patients with IPF are much better than even 10 years ago,” she said in an interview. “I think this is because of the improvement in consistency in diagnostic criteria based on the updated guidelines in IPF. Among the MDTMs that participated in the study, the agreement about diagnoses was highest for IPF. The interobserver agreement for clinicians was also pretty high for IPF.”

In her work within an academic center, Dr. Glassberg sees patients in an IPF clinic and in a separate autoimmune disorders clinic. For each clinic, there is a multidisciplinary team. In the IPF clinic, there are three pulmonologists and a radiologist, and when there is a biopsy, there are two pathologists. Dr. Glassberg’s IPF team also includes four pulmonary radiologists.

During her MDTMs, Dr. Thavarajah, a radiologist, and a pathologist will examine a patient’s chest imaging and pathology slides. They sit together until they become confident of their diagnosis in the absence of a biopsy.

There are times when the team tells a patient the probable diagnosis and acknowledges the small chance of an alternative diagnosis. “It was comforting to me that, in the Lancet study, there was a good level of agreement in diagnosis of IPF among multidisciplinary teams, whether the patients had undergone a biopsy or not,” said Dr. Thavarajah. “The mortality of patients given a diagnosis of IPF was worse than those given a diagnosis of non-IPF to validate the IPF diagnosis.”

Establishing and implementing MDTMs is challenging, though, said Dr. Glassberg.

“[We] need to address how multidisciplinary teams could work for doctors who are in smaller cities or who are not in academic centers. We need to utilize existing channels to create new avenues for these colleagues to present their cases – particularly challenging ones or patients who need to be referred – to be evaluated by an interdisciplinary team. The Internet may offer these opportunities for networking and decision making, said Dr. Glassberg.

The study was funded by the National Institute of Health Research, Imperial College London. Several of the study’s authors declared receiving personal fees, grants, or research support from a variety of sources, but had no financial disclosures relevant to this study.

[email protected]

The accuracy of idiopathic pulmonary fibrosis (IPF) diagnoses is improving with the use of multidisciplinary team meetings and updated guidelines, based on the findings of a study that compared diagnostic agreement of individual clinicians and teams evaluating patients with interstitial lung disease.

Pulmonologists who participate in multidisciplinary team meetings said the findings validate the team approach.

“The [study’s] data confirm what we see in clinical practice ... it takes a multidisciplinary – and perhaps often multiple pulmonologists – to review these cases,” Marilyn K. Glassberg, MD,professor of medicine and surgery and director of the interstitial lung disease program at the University of Miami Health System, said in an interview.“This study demonstrates the importance of multiple perspectives when evaluating a patient and coming to a diagnosis at a time when reliable biomarkers are not available.”

The study, published in The Lancet Respiratory Medicine (2016;4[7]:557-65), is the first evaluation of multidisciplinary team agreement on diagnosis of interstitial lung disease since updated guidelines were published, according to Simon L. F. Walsh, MD, of Kings College Hospital NHS Foundation Trust, London, and his colleagues.

In 2015, the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALTA) adopted joint guidelines for the treatment of IPF. In 2013, the ATS and ERS updated guidelines for the classification and terminology for idiopathic interstitial pneumonias.

“Our study shows ... in [IPF], MDTMs (multidisciplinary team meetings) have a higher level of agreement on diagnoses, assign diagnoses with higher confidence more frequently, and provide diagnoses that have non-significant greater prognostic separation than do clinicians or radiologists in most cases,” the researchers wrote.

Before MDTMs were initiated, the clinicians, radiologists, and pathologists who would be participating in them independently reviewed each patient’s case without consulting other specialists and provided up to five diagnoses with diagnostic likelihoods for each patient.

For the study, 70 patients were evaluated and the level of diagnostic agreement was assessed at seven international centers for the diagnosis of interstitial lung disease (diffuse parenchymal lung disease). Following independent reviews of the 70 cases, the clinician, radiologist, and pathologist from each center met as a multidisciplinary team to review the same cases together and give up to five diagnoses with diagnostic likelihoods.

All clinical information supplied in the first stage of the study, including pulmonary function test results, high-resolution CT at presentation, and digitalized surgical lung biopsy slides, were available to the multidisciplinary team. The patients’ outcomes were used to validate the diagnoses. The survival period for each patient was calculated based on the date of referral to the host institution to the minimum date of death, date patient was last known to be alive, or June 1, 2015 – the end of the study period.

The inter-MDTM agreement was better than interobserver agreement for all diagnoses (unweighted kappa value (K) = 0.50), and inter-MDTM agreement was highest for IPF (K = 0.60) and connective tissue disease-related interstitial lung disease (K = 0.64).

“We have shown an acceptable level [based on a K of greater than 0.40 being deemed clinically acceptable] of diagnostic agreement exists between multidisciplinary teams in the setting of diffuse parenchymal lung disease. Additionally, we showed that this agreement was validated by the nonsignificant increases toward greater prognostic separation of an IPF diagnosis made by multidisciplinary teams than by individual clinicians or radiologists,” the researchers wrote.

The weighted kappa (KW) values for estimation of diagnostic likelihood for diagnoses of IPF were 0.72 (0.67-0.76) for clinicians, 0.60 (0.46-0.66) for radiologists, 0.58 (0.45-0.66) for pathologists and 0.71 (0.64-0.77) for MDTMs.

For connective tissue disease–related interstitial lung diseases, the KW for estimation of diagnostic likelihood for diagnoses for MDTMs were 0.73 (0.68-0.78), compared with 0.76 (0.70-0.78) for clinicians, 0.17 (0.08-0.31) for radiologists, and 0.21 (0.06-0.36) for pathologists.

Krishna Thavarajah, MD,, who sees patients with interstitial lung disease within the Henry Ford Health System in Detroit, has been participating in MDTMs for nearly 6 years.

“The accuracies of diagnoses for patients with IPF are much better than even 10 years ago,” she said in an interview. “I think this is because of the improvement in consistency in diagnostic criteria based on the updated guidelines in IPF. Among the MDTMs that participated in the study, the agreement about diagnoses was highest for IPF. The interobserver agreement for clinicians was also pretty high for IPF.”

In her work within an academic center, Dr. Glassberg sees patients in an IPF clinic and in a separate autoimmune disorders clinic. For each clinic, there is a multidisciplinary team. In the IPF clinic, there are three pulmonologists and a radiologist, and when there is a biopsy, there are two pathologists. Dr. Glassberg’s IPF team also includes four pulmonary radiologists.

During her MDTMs, Dr. Thavarajah, a radiologist, and a pathologist will examine a patient’s chest imaging and pathology slides. They sit together until they become confident of their diagnosis in the absence of a biopsy.

There are times when the team tells a patient the probable diagnosis and acknowledges the small chance of an alternative diagnosis. “It was comforting to me that, in the Lancet study, there was a good level of agreement in diagnosis of IPF among multidisciplinary teams, whether the patients had undergone a biopsy or not,” said Dr. Thavarajah. “The mortality of patients given a diagnosis of IPF was worse than those given a diagnosis of non-IPF to validate the IPF diagnosis.”

Establishing and implementing MDTMs is challenging, though, said Dr. Glassberg.

“[We] need to address how multidisciplinary teams could work for doctors who are in smaller cities or who are not in academic centers. We need to utilize existing channels to create new avenues for these colleagues to present their cases – particularly challenging ones or patients who need to be referred – to be evaluated by an interdisciplinary team. The Internet may offer these opportunities for networking and decision making, said Dr. Glassberg.

The study was funded by the National Institute of Health Research, Imperial College London. Several of the study’s authors declared receiving personal fees, grants, or research support from a variety of sources, but had no financial disclosures relevant to this study.

[email protected]

The accuracy of idiopathic pulmonary fibrosis (IPF) diagnoses is improving with the use of multidisciplinary team meetings and updated guidelines, based on the findings of a study that compared diagnostic agreement of individual clinicians and teams evaluating patients with interstitial lung disease.

Pulmonologists who participate in multidisciplinary team meetings said the findings validate the team approach.

“The [study’s] data confirm what we see in clinical practice ... it takes a multidisciplinary – and perhaps often multiple pulmonologists – to review these cases,” Marilyn K. Glassberg, MD,professor of medicine and surgery and director of the interstitial lung disease program at the University of Miami Health System, said in an interview.“This study demonstrates the importance of multiple perspectives when evaluating a patient and coming to a diagnosis at a time when reliable biomarkers are not available.”

The study, published in The Lancet Respiratory Medicine (2016;4[7]:557-65), is the first evaluation of multidisciplinary team agreement on diagnosis of interstitial lung disease since updated guidelines were published, according to Simon L. F. Walsh, MD, of Kings College Hospital NHS Foundation Trust, London, and his colleagues.

In 2015, the American Thoracic Society (ATS), European Respiratory Society (ERS), Japanese Respiratory Society (JRS), and Latin American Thoracic Association (ALTA) adopted joint guidelines for the treatment of IPF. In 2013, the ATS and ERS updated guidelines for the classification and terminology for idiopathic interstitial pneumonias.

“Our study shows ... in [IPF], MDTMs (multidisciplinary team meetings) have a higher level of agreement on diagnoses, assign diagnoses with higher confidence more frequently, and provide diagnoses that have non-significant greater prognostic separation than do clinicians or radiologists in most cases,” the researchers wrote.

Before MDTMs were initiated, the clinicians, radiologists, and pathologists who would be participating in them independently reviewed each patient’s case without consulting other specialists and provided up to five diagnoses with diagnostic likelihoods for each patient.

For the study, 70 patients were evaluated and the level of diagnostic agreement was assessed at seven international centers for the diagnosis of interstitial lung disease (diffuse parenchymal lung disease). Following independent reviews of the 70 cases, the clinician, radiologist, and pathologist from each center met as a multidisciplinary team to review the same cases together and give up to five diagnoses with diagnostic likelihoods.

All clinical information supplied in the first stage of the study, including pulmonary function test results, high-resolution CT at presentation, and digitalized surgical lung biopsy slides, were available to the multidisciplinary team. The patients’ outcomes were used to validate the diagnoses. The survival period for each patient was calculated based on the date of referral to the host institution to the minimum date of death, date patient was last known to be alive, or June 1, 2015 – the end of the study period.

The inter-MDTM agreement was better than interobserver agreement for all diagnoses (unweighted kappa value (K) = 0.50), and inter-MDTM agreement was highest for IPF (K = 0.60) and connective tissue disease-related interstitial lung disease (K = 0.64).

“We have shown an acceptable level [based on a K of greater than 0.40 being deemed clinically acceptable] of diagnostic agreement exists between multidisciplinary teams in the setting of diffuse parenchymal lung disease. Additionally, we showed that this agreement was validated by the nonsignificant increases toward greater prognostic separation of an IPF diagnosis made by multidisciplinary teams than by individual clinicians or radiologists,” the researchers wrote.

The weighted kappa (KW) values for estimation of diagnostic likelihood for diagnoses of IPF were 0.72 (0.67-0.76) for clinicians, 0.60 (0.46-0.66) for radiologists, 0.58 (0.45-0.66) for pathologists and 0.71 (0.64-0.77) for MDTMs.

For connective tissue disease–related interstitial lung diseases, the KW for estimation of diagnostic likelihood for diagnoses for MDTMs were 0.73 (0.68-0.78), compared with 0.76 (0.70-0.78) for clinicians, 0.17 (0.08-0.31) for radiologists, and 0.21 (0.06-0.36) for pathologists.

Krishna Thavarajah, MD,, who sees patients with interstitial lung disease within the Henry Ford Health System in Detroit, has been participating in MDTMs for nearly 6 years.

“The accuracies of diagnoses for patients with IPF are much better than even 10 years ago,” she said in an interview. “I think this is because of the improvement in consistency in diagnostic criteria based on the updated guidelines in IPF. Among the MDTMs that participated in the study, the agreement about diagnoses was highest for IPF. The interobserver agreement for clinicians was also pretty high for IPF.”

In her work within an academic center, Dr. Glassberg sees patients in an IPF clinic and in a separate autoimmune disorders clinic. For each clinic, there is a multidisciplinary team. In the IPF clinic, there are three pulmonologists and a radiologist, and when there is a biopsy, there are two pathologists. Dr. Glassberg’s IPF team also includes four pulmonary radiologists.

During her MDTMs, Dr. Thavarajah, a radiologist, and a pathologist will examine a patient’s chest imaging and pathology slides. They sit together until they become confident of their diagnosis in the absence of a biopsy.

There are times when the team tells a patient the probable diagnosis and acknowledges the small chance of an alternative diagnosis. “It was comforting to me that, in the Lancet study, there was a good level of agreement in diagnosis of IPF among multidisciplinary teams, whether the patients had undergone a biopsy or not,” said Dr. Thavarajah. “The mortality of patients given a diagnosis of IPF was worse than those given a diagnosis of non-IPF to validate the IPF diagnosis.”

Establishing and implementing MDTMs is challenging, though, said Dr. Glassberg.

“[We] need to address how multidisciplinary teams could work for doctors who are in smaller cities or who are not in academic centers. We need to utilize existing channels to create new avenues for these colleagues to present their cases – particularly challenging ones or patients who need to be referred – to be evaluated by an interdisciplinary team. The Internet may offer these opportunities for networking and decision making, said Dr. Glassberg.

The study was funded by the National Institute of Health Research, Imperial College London. Several of the study’s authors declared receiving personal fees, grants, or research support from a variety of sources, but had no financial disclosures relevant to this study.

[email protected]

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

SCOTTSDALE, ARIZ. – Children with severe atopic dermatitis were significantly more likely to log at least 5 hours of screen time a day, and were significantly less likely to exercise than were nonatopic controls, said the lead investigator of a large national study.

“Atopic dermatitis overall was not associated with sedentary behavior. It was severe disease only,” said Mark Strom of the department of dermatology, Northwestern University, Chicago, during an oral presentation at the annual meeting of the Society for Investigative Dermatology. Patients tended to be even more sedentary if they suffered from disturbed sleep in addition to severe eczema, he added.

Heat and sweat worsen the intense itch of atopic dermatitis. Hypothesizing that this would deter affected children from physical activity, Mr. Strom and his associates analyzed data for 131,783 respondents aged 18 and under from the National Survey of Children’s Health. The survey assesses physical activity by asking how many days a week the respondent sweated and breathed hard for at least 20 minutes. Screen time is measured by asking about daily hours spent watching television and playing video games, and sleep quality is assessed by asking how many nights a week the child slept the normal amount for his or her age.

Simply having atopic dermatitis was linked with only a slight increase in the chance of having a sedentary lifestyle after controlling for demographic factors, insurance status, geographic location, and educational level, according to Mr. Strom. Specifically, eczema was significantly associated with a 12% lower odds of having exercised on at least 3 days of the previous week (odds ratio, 0.88). However, severe atopic dermatitis significantly reduced the odds that a child exercised at least one day a week by 61% (OR, 0.39). Furthermore, severe atopic dermatitis was associated with more than double the odds of having at least 5 hours of daily screen time (OR, 2.62). And having either moderate or severe eczema was tied to a significant decrease in the odds of having participated in sports in the past year, Mr. Strom said.

“Atopic dermatitis and sleep disturbance each contribute to sedentary behavior,” he reported. Nonatopic children who did not sleep enough on most nights had nearly double the odds of heavy television and video game use, compared with children who slept more, a significant difference. When poor sleepers also had atopic dermatitis, their odds of heavy screen use more than tripled. Poor sleepers were also significantly less likely to join sports teams, even when they did not have eczema, Mr. Strom said.

“Children with more severe atopic dermatitis may have more profound exacerbations of activity-related symptoms, which would lead to these findings,” he concluded. Future studies should explore whether better symptom control can help improve sedentary behaviors, he added.

The study was sponsored by the Maternal and Child Health Bureau of the U.S. Department of Health and Human Services. Mr. Strom had no disclosures.

Elevated Aspergillus RNA blood levels after 4-6 weeks of antifungal treatment predict poor response at week 12 in patients with proven or probable invasive aspergillosis, according to results of a small observational study of 41 evaluable patients.

The investigators are working to address the need for reliable biomarkers of early invasive aspergillosis (IA) treatment response. Standard clinical and radiological criteria are somewhat subjective, and serial biopsies and bronchoalveolar lavage are often impractical, reported Yanan Zhao, PhD, of the New Jersey Medical School–Rutgers Biomedical and Health Sciences, Newark, and her associates.

Study participants’ blood was checked for serum galactomannan (GM), 1, 3-beta-D-glucan (BG), and Aspergillus RNA within 24 hours of starting antifungal therapy, then twice per week during the first 2 weeks, then once during weeks 4, 6, and 12, the investigators reported (Med Mycol. 2016 Jun 22. pii: myw043).

Ribosomal Aspergillus RNA – like GM and BG, a marker of fungal load – was measured by nucleic acid sequence-based amplification (NASBA), a robust isothermal amplification technique more sensitive than polymerase chain reaction due largely “to increased starting target numbers (RNA versus DNA) and more robust amplification.” Although NASBA has been used before to diagnose IA, using it to monitor treatment “is still in its infancy,” the authors noted.

Eleven of 14 patients who did not respond to treatment at 12 weeks (79%) had Aspergillus RNA in their blood after 4 weeks of treatment, and 12 (86%) were positive at 6 weeks.

Among patients who did respond at 12 weeks, 11 of 27 (41%) had RNA in their blood at 4 weeks, and 14 (52%) at 6 weeks. The findings were statistically significant.

There was no correlation between Aspergillus RNA and serum GM levels in terms of outcomes, but the kinetics of circulating Aspergillus RNA correlated with BG in some patients, with an excellent match in three.

Serum GM responds fairly soon if treatment is working. Aspergillus RNA, however, responds more slowly, like BG. “This may explain ... the correlation between Aspergillus RNA and BG ... Therefore, the combination of Aspergillus RNA and BG might be useful to assess therapeutic response, particularly in GM negative cases,” the investigators said.

This work was funded by Merck. Four investigators are current or former employees.

[email protected]

Elevated Aspergillus RNA blood levels after 4-6 weeks of antifungal treatment predict poor response at week 12 in patients with proven or probable invasive aspergillosis, according to results of a small observational study of 41 evaluable patients.

The investigators are working to address the need for reliable biomarkers of early invasive aspergillosis (IA) treatment response. Standard clinical and radiological criteria are somewhat subjective, and serial biopsies and bronchoalveolar lavage are often impractical, reported Yanan Zhao, PhD, of the New Jersey Medical School–Rutgers Biomedical and Health Sciences, Newark, and her associates.

Study participants’ blood was checked for serum galactomannan (GM), 1, 3-beta-D-glucan (BG), and Aspergillus RNA within 24 hours of starting antifungal therapy, then twice per week during the first 2 weeks, then once during weeks 4, 6, and 12, the investigators reported (Med Mycol. 2016 Jun 22. pii: myw043).

Ribosomal Aspergillus RNA – like GM and BG, a marker of fungal load – was measured by nucleic acid sequence-based amplification (NASBA), a robust isothermal amplification technique more sensitive than polymerase chain reaction due largely “to increased starting target numbers (RNA versus DNA) and more robust amplification.” Although NASBA has been used before to diagnose IA, using it to monitor treatment “is still in its infancy,” the authors noted.

Eleven of 14 patients who did not respond to treatment at 12 weeks (79%) had Aspergillus RNA in their blood after 4 weeks of treatment, and 12 (86%) were positive at 6 weeks.

Among patients who did respond at 12 weeks, 11 of 27 (41%) had RNA in their blood at 4 weeks, and 14 (52%) at 6 weeks. The findings were statistically significant.

There was no correlation between Aspergillus RNA and serum GM levels in terms of outcomes, but the kinetics of circulating Aspergillus RNA correlated with BG in some patients, with an excellent match in three.

Serum GM responds fairly soon if treatment is working. Aspergillus RNA, however, responds more slowly, like BG. “This may explain ... the correlation between Aspergillus RNA and BG ... Therefore, the combination of Aspergillus RNA and BG might be useful to assess therapeutic response, particularly in GM negative cases,” the investigators said.

This work was funded by Merck. Four investigators are current or former employees.

[email protected]

Elevated Aspergillus RNA blood levels after 4-6 weeks of antifungal treatment predict poor response at week 12 in patients with proven or probable invasive aspergillosis, according to results of a small observational study of 41 evaluable patients.

The investigators are working to address the need for reliable biomarkers of early invasive aspergillosis (IA) treatment response. Standard clinical and radiological criteria are somewhat subjective, and serial biopsies and bronchoalveolar lavage are often impractical, reported Yanan Zhao, PhD, of the New Jersey Medical School–Rutgers Biomedical and Health Sciences, Newark, and her associates.

Study participants’ blood was checked for serum galactomannan (GM), 1, 3-beta-D-glucan (BG), and Aspergillus RNA within 24 hours of starting antifungal therapy, then twice per week during the first 2 weeks, then once during weeks 4, 6, and 12, the investigators reported (Med Mycol. 2016 Jun 22. pii: myw043).

Ribosomal Aspergillus RNA – like GM and BG, a marker of fungal load – was measured by nucleic acid sequence-based amplification (NASBA), a robust isothermal amplification technique more sensitive than polymerase chain reaction due largely “to increased starting target numbers (RNA versus DNA) and more robust amplification.” Although NASBA has been used before to diagnose IA, using it to monitor treatment “is still in its infancy,” the authors noted.

Eleven of 14 patients who did not respond to treatment at 12 weeks (79%) had Aspergillus RNA in their blood after 4 weeks of treatment, and 12 (86%) were positive at 6 weeks.

Among patients who did respond at 12 weeks, 11 of 27 (41%) had RNA in their blood at 4 weeks, and 14 (52%) at 6 weeks. The findings were statistically significant.

There was no correlation between Aspergillus RNA and serum GM levels in terms of outcomes, but the kinetics of circulating Aspergillus RNA correlated with BG in some patients, with an excellent match in three.

Serum GM responds fairly soon if treatment is working. Aspergillus RNA, however, responds more slowly, like BG. “This may explain ... the correlation between Aspergillus RNA and BG ... Therefore, the combination of Aspergillus RNA and BG might be useful to assess therapeutic response, particularly in GM negative cases,” the investigators said.

This work was funded by Merck. Four investigators are current or former employees.

[email protected]

DENVER – Transdermal or sublingual flumazenil is well worth considering for treatment of carefully selected patients with hypersomnolence refractory to conventional wake-promoting medications, Lynn Marie Trotti, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Her retrospective chart review of 153 consecutive patients treated with flumazenil (Romazicon) showed that 63% derived symptomatic benefit, and 39% of patients remained on the drug at the end of the review period, which averaged 6.8 months, reported Dr. Trotti, a neurologist and sleep scientist at Emory University in Atlanta.

©Monkey Business Images Ltd/Thinkstock

Make no mistake: This is off-label therapy. Flumazenil’s approved indication is as intravenous therapy for benzodiazepine sedation. Given orally, the drug is almost entirely eliminated on first-pass metabolism, so she and her coinvestigators had flumazenil compounded at a pharmacy in two formulations: a 6-mg sublingual lozenge and a transcutaneous lotion in a dispenser providing 3 mg of flumazenil per click of the device.

This novel therapy is supported by a plausible mechanistic rationale. Dr. Trotti and colleagues have previously shown that most patients with central hypersomnolence have abnormal potentiation of GABA-A receptors in their cerebrospinal fluid (CSF).

“Functionally speaking, it’s as though they’re producing an endogenous benzodiazepinelike substance,” she explained.

The investigators showed further that the macrolide antibiotic clarithromycin, a negative allosteric modulator of GABA-A receptors, reduced sleepiness in patients with central hypersomnolence syndromes in a randomized, double-blind, crossover trial (Ann Neurol. 2015 Sep;78[3]:454-65).

“It’s not great to use an antibiotic to treat people who don’t have a bacterial infection, so it would be really lovely if we had a GABA antagonist or negative allosteric modulator of GABA-A receptors that was not clarithromycin. And that’s where flumazenil comes into the picture,” according to Dr. Trotti.

As a requirement for receiving flumazenil at the Emory sleep disorders center, patients had to have been refractory to all conventional therapies. Indeed, they had been refractory to an average of 4.6 medications for excessive sleepiness. Also, their hypersomnolence had to have a serious impact on their daily life, for example a job at risk because of inability to drive to and from work safely. Initially, it was further required as a condition for treatment that patients had to show abnormal CSF potentiation of GABA-A receptors; however, the investigators quit requiring a CSF sample after roughly the first 100 candidates proved positive.

Dosing of the sublingual flumazenil lozenges began at one 6-mg lozenge four times daily, titrating up by adding an extra lozenge every 4-5 days until reaching a maximum of 12 per day. The lotion is rubbed on the inside of the forearm at a dose of 3 mg on each arm up to four times per day.

Among the 40 treatment responders who completed the Epworth Sleepiness Scale at baseline and after an average of 6.8 months on flumazenil, the average score improved from 15 to 10.3.

Fifty-seven patients obtained no benefit from flumazenil, 10 stopped the drug because of side effects, 3 quit because they preferred clarithromycin, 8 stopped owing to the cost, and the rest dropped the drug for an assortment of reasons, including planned pregnancy.

The most common treatment-emergent adverse events included dizziness in 13% of subjects, anxiety in 7%, and other mood disturbances in 6%.

Two serious adverse events occurred. One patient with a history of atrial fibrillation experienced a transient ischemic attack. And a patient with systemic lupus erythematous developed asymptomatic CNS lupus vasculopathy. It’s not possible to say whether these events were treatment related because the experience with chronic flumazenil therapy is so limited. After all, the drug is given for its approved indication for no longer than a few days, Dr. Trotti observed.

“This is all clinical data. Obviously I’m not suggesting that everybody should start prescribing flumazenil. That being said, we really need better treatment options,” she said.

The long-term treatment continuation rate with modafinil for hypersomnolence is about 50%, anywhere from 29% to 66% for amphetamines, 38% for clarithromycin, and 37% for pitolisant.

“If you look globally at how likely people with idiopathic hypersomnolence or narcolepsy are to get a satisfactory response to conventional therapies, probably 15%-20% do not get satisfactorily treated with what we currently have available. Prospective controlled studies of flumazenil for treatment of hypersomnolence are certainly needed, but in the absence of those data there’s at least a rationale for people who are severely affected and have nowhere else to turn to consider flumazenil,” Dr. Trotti concluded.

She reported having no financial conflicts regarding her study, supported by the National Institutes of Health.

[email protected]

DENVER – Transdermal or sublingual flumazenil is well worth considering for treatment of carefully selected patients with hypersomnolence refractory to conventional wake-promoting medications, Lynn Marie Trotti, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Her retrospective chart review of 153 consecutive patients treated with flumazenil (Romazicon) showed that 63% derived symptomatic benefit, and 39% of patients remained on the drug at the end of the review period, which averaged 6.8 months, reported Dr. Trotti, a neurologist and sleep scientist at Emory University in Atlanta.

©Monkey Business Images Ltd/Thinkstock

Make no mistake: This is off-label therapy. Flumazenil’s approved indication is as intravenous therapy for benzodiazepine sedation. Given orally, the drug is almost entirely eliminated on first-pass metabolism, so she and her coinvestigators had flumazenil compounded at a pharmacy in two formulations: a 6-mg sublingual lozenge and a transcutaneous lotion in a dispenser providing 3 mg of flumazenil per click of the device.

This novel therapy is supported by a plausible mechanistic rationale. Dr. Trotti and colleagues have previously shown that most patients with central hypersomnolence have abnormal potentiation of GABA-A receptors in their cerebrospinal fluid (CSF).

“Functionally speaking, it’s as though they’re producing an endogenous benzodiazepinelike substance,” she explained.

The investigators showed further that the macrolide antibiotic clarithromycin, a negative allosteric modulator of GABA-A receptors, reduced sleepiness in patients with central hypersomnolence syndromes in a randomized, double-blind, crossover trial (Ann Neurol. 2015 Sep;78[3]:454-65).

“It’s not great to use an antibiotic to treat people who don’t have a bacterial infection, so it would be really lovely if we had a GABA antagonist or negative allosteric modulator of GABA-A receptors that was not clarithromycin. And that’s where flumazenil comes into the picture,” according to Dr. Trotti.

As a requirement for receiving flumazenil at the Emory sleep disorders center, patients had to have been refractory to all conventional therapies. Indeed, they had been refractory to an average of 4.6 medications for excessive sleepiness. Also, their hypersomnolence had to have a serious impact on their daily life, for example a job at risk because of inability to drive to and from work safely. Initially, it was further required as a condition for treatment that patients had to show abnormal CSF potentiation of GABA-A receptors; however, the investigators quit requiring a CSF sample after roughly the first 100 candidates proved positive.

Dosing of the sublingual flumazenil lozenges began at one 6-mg lozenge four times daily, titrating up by adding an extra lozenge every 4-5 days until reaching a maximum of 12 per day. The lotion is rubbed on the inside of the forearm at a dose of 3 mg on each arm up to four times per day.

Among the 40 treatment responders who completed the Epworth Sleepiness Scale at baseline and after an average of 6.8 months on flumazenil, the average score improved from 15 to 10.3.

Fifty-seven patients obtained no benefit from flumazenil, 10 stopped the drug because of side effects, 3 quit because they preferred clarithromycin, 8 stopped owing to the cost, and the rest dropped the drug for an assortment of reasons, including planned pregnancy.

The most common treatment-emergent adverse events included dizziness in 13% of subjects, anxiety in 7%, and other mood disturbances in 6%.

Two serious adverse events occurred. One patient with a history of atrial fibrillation experienced a transient ischemic attack. And a patient with systemic lupus erythematous developed asymptomatic CNS lupus vasculopathy. It’s not possible to say whether these events were treatment related because the experience with chronic flumazenil therapy is so limited. After all, the drug is given for its approved indication for no longer than a few days, Dr. Trotti observed.

“This is all clinical data. Obviously I’m not suggesting that everybody should start prescribing flumazenil. That being said, we really need better treatment options,” she said.

The long-term treatment continuation rate with modafinil for hypersomnolence is about 50%, anywhere from 29% to 66% for amphetamines, 38% for clarithromycin, and 37% for pitolisant.

“If you look globally at how likely people with idiopathic hypersomnolence or narcolepsy are to get a satisfactory response to conventional therapies, probably 15%-20% do not get satisfactorily treated with what we currently have available. Prospective controlled studies of flumazenil for treatment of hypersomnolence are certainly needed, but in the absence of those data there’s at least a rationale for people who are severely affected and have nowhere else to turn to consider flumazenil,” Dr. Trotti concluded.

She reported having no financial conflicts regarding her study, supported by the National Institutes of Health.

[email protected]

DENVER – Transdermal or sublingual flumazenil is well worth considering for treatment of carefully selected patients with hypersomnolence refractory to conventional wake-promoting medications, Lynn Marie Trotti, MD, said at the annual meeting of the Associated Professional Sleep Societies.

Her retrospective chart review of 153 consecutive patients treated with flumazenil (Romazicon) showed that 63% derived symptomatic benefit, and 39% of patients remained on the drug at the end of the review period, which averaged 6.8 months, reported Dr. Trotti, a neurologist and sleep scientist at Emory University in Atlanta.

©Monkey Business Images Ltd/Thinkstock

Make no mistake: This is off-label therapy. Flumazenil’s approved indication is as intravenous therapy for benzodiazepine sedation. Given orally, the drug is almost entirely eliminated on first-pass metabolism, so she and her coinvestigators had flumazenil compounded at a pharmacy in two formulations: a 6-mg sublingual lozenge and a transcutaneous lotion in a dispenser providing 3 mg of flumazenil per click of the device.

This novel therapy is supported by a plausible mechanistic rationale. Dr. Trotti and colleagues have previously shown that most patients with central hypersomnolence have abnormal potentiation of GABA-A receptors in their cerebrospinal fluid (CSF).

“Functionally speaking, it’s as though they’re producing an endogenous benzodiazepinelike substance,” she explained.

The investigators showed further that the macrolide antibiotic clarithromycin, a negative allosteric modulator of GABA-A receptors, reduced sleepiness in patients with central hypersomnolence syndromes in a randomized, double-blind, crossover trial (Ann Neurol. 2015 Sep;78[3]:454-65).

“It’s not great to use an antibiotic to treat people who don’t have a bacterial infection, so it would be really lovely if we had a GABA antagonist or negative allosteric modulator of GABA-A receptors that was not clarithromycin. And that’s where flumazenil comes into the picture,” according to Dr. Trotti.

As a requirement for receiving flumazenil at the Emory sleep disorders center, patients had to have been refractory to all conventional therapies. Indeed, they had been refractory to an average of 4.6 medications for excessive sleepiness. Also, their hypersomnolence had to have a serious impact on their daily life, for example a job at risk because of inability to drive to and from work safely. Initially, it was further required as a condition for treatment that patients had to show abnormal CSF potentiation of GABA-A receptors; however, the investigators quit requiring a CSF sample after roughly the first 100 candidates proved positive.

Dosing of the sublingual flumazenil lozenges began at one 6-mg lozenge four times daily, titrating up by adding an extra lozenge every 4-5 days until reaching a maximum of 12 per day. The lotion is rubbed on the inside of the forearm at a dose of 3 mg on each arm up to four times per day.

Among the 40 treatment responders who completed the Epworth Sleepiness Scale at baseline and after an average of 6.8 months on flumazenil, the average score improved from 15 to 10.3.

Fifty-seven patients obtained no benefit from flumazenil, 10 stopped the drug because of side effects, 3 quit because they preferred clarithromycin, 8 stopped owing to the cost, and the rest dropped the drug for an assortment of reasons, including planned pregnancy.

The most common treatment-emergent adverse events included dizziness in 13% of subjects, anxiety in 7%, and other mood disturbances in 6%.

Two serious adverse events occurred. One patient with a history of atrial fibrillation experienced a transient ischemic attack. And a patient with systemic lupus erythematous developed asymptomatic CNS lupus vasculopathy. It’s not possible to say whether these events were treatment related because the experience with chronic flumazenil therapy is so limited. After all, the drug is given for its approved indication for no longer than a few days, Dr. Trotti observed.

“This is all clinical data. Obviously I’m not suggesting that everybody should start prescribing flumazenil. That being said, we really need better treatment options,” she said.

The long-term treatment continuation rate with modafinil for hypersomnolence is about 50%, anywhere from 29% to 66% for amphetamines, 38% for clarithromycin, and 37% for pitolisant.

“If you look globally at how likely people with idiopathic hypersomnolence or narcolepsy are to get a satisfactory response to conventional therapies, probably 15%-20% do not get satisfactorily treated with what we currently have available. Prospective controlled studies of flumazenil for treatment of hypersomnolence are certainly needed, but in the absence of those data there’s at least a rationale for people who are severely affected and have nowhere else to turn to consider flumazenil,” Dr. Trotti concluded.

She reported having no financial conflicts regarding her study, supported by the National Institutes of Health.

[email protected]