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One You May Have Missed: Resident Rounds
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A 13-year-old boy was referred to our center for evaluation of pulmonary nontuberculous mycobacterial infection superimposed on chronic lung disease.
He was very well until approximately age 11 when he developed progressive dry cough, shortness of breath and fatigue. Over time his condition progressed to include hypoxemia. Fever was largely absent. He lives in an urban area, and had not experienced toxic or farm exposures. His family history is negative for chronic lung disease and immune deficiency. On physical examination, he was thin and in no acute distress but had baseline tachypnea and mild retractions. He had diffuse fine crackles on lung auscultation.
Eventually the symptoms and lack of response to bronchodilators and antibiotics led to a chest computed tomography scan that showed a “crazy paving” pattern (Figure 1). Lung biopsy revealed a diffuse alveolar process characterized by periodic acid-Schiff–positive material forming globular structures (Figure 2). These findings, as well as further laboratory evaluation, led to the diagnosis of:
- Cystic fibrosis
- Hypersensitivity pneumonitis
- Pulmonary alveolar proteinosis
- Alpha-1-antitrypsin deficiency
Answer
This patient has (C) pulmonary alveolar proteinosis, a disease often associated with positive antigranulocyte-macrophage colony stimulating factor antibodies, as it was in this case (titers >1:12,800). His chest computed tomography scan and pathology findings were classic for this disease, as were super-infections with nontuberculous mycobacteria.
PAP is characterized by the accumulation of a lipoproteinaceous material in the alveoli. There are three main types: primary PAP caused by GM-CSF autoantibodies; a congenital form caused by defective surfactant B production; and a secondary form that may be associated with a variety of infections, malignancies or other conditions.
This patient had PAP associated with autoantibodies to GM-CSF. This type of PAP is more typically seen in individuals in their fourth or fifth decades. The clinical presentation is typically insidious and nonspecific with progressive dyspnea and nonproductive cough.
Fever is typically absent unless super-infection of the lung occurs, and then the cough may become productive. The diagnosis is usually made by imaging studies, with the chest CT characteristically showing a “crazy paving” pattern with ground glass consolidations and interlobular septal thickening. Pulmonary function tests usually show restriction with decreased diffusing capacity. Fluid obtained on bronchoscopy has large amounts of lipoproteinaceous material, and pathology shows terminal bronchioles and alveoli filled with periodic acid-Schiff–positive material. Despite the presence of GM-CSF autoantibodies, these individuals may respond to GM-CSF therapy (subcutaneous or inhaled) along with whole-lung lavage. Whole lung lavage removes some of the alveolar lipoproteinaceous material, and also may remove autoantibodies or other immunomodulators.
This patient was initially treated with whole lung lavage plus subcutaneous GM-CSF; however, the PAP progressed, requiring frequent lavage. He was changed to inhaled GM-CSF several months before seeing us, which appeared to ameliorate his course. Also, a three-drug antimycobacterial regimen has likely improved his pulmonary function.
Cystic fibrosis should always be considered in individuals with progressive lung disease; testing was negative in this patient. Typically, the symptoms would have started at a younger age, the cough would have been more productive and the CT scan would have shown bronchiectasis. Nontuberculous mycobacteria are seen in cystic fibrosis, as they were in this patient. Several forms of hypersensitivity pneumonitis depend on specific exposures: farmer’s lung, pigeon-breeder’s lung, hot tub lung. The presentation may be chronic, as it was for our patient, with progressive dyspnea and hypoxemia, but it is more often acute with fevers occurring soon after the exposure. Imaging suggests and biopsy confirms fibrotic changes in the chronic form of this disease, and it lacks the lipoproteinaceous material within the alveoli found in PAP. Alpha-1-antitrypsin deficiency can present with progressive shortness of breath, but the symptoms result from progressive emphysematous changes, and thus the imaging, bronchoscopic and pathologic changes would look much different than in this patient. In addition, with alpha-1-antitrypsin deficiency, there may be associated liver disease.
For more information:
- Alexandra Freeman, MD, and Kenneth Olivier, MD, both work for the NIH. Olivier is a staff clinician at the Laboratory of Clinical Infectious Diseases at NIAID, NIH.
- Ioachimescu OC, Kavuru MS. Pulmonary alveolar proteinosis. Chronic Respiratory Diseases. 2006;3:149-159.
- Uchida K, Beck DC, Yamamoto T, et al. GM-CSF autoantibodies and neutrophil dysfunction in pulmonary alveolar proteinosis. N Engl J Med. 2007;356:567-579.