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A 73-year-old woman presented to our institution for evaluation of progressive shortness of breath that had gradually worsened during the previous year. Initially, her symptoms were mild and noticeable only with moderate exertion. By presentation, however, she reported severe dyspnea with only minimal exertion. Walking 3 to 6 meters resulted in such severe dyspnea that she had to discontinue activity. She also reported a harsh cough with occasional clear sputum production. A provisional diagnosis of asthma had been suggested before her presentation. This diagnosis was not supported by objective testing nor had bronchodilators been beneficial.

During the preceding year, she had unintentionally lost 13.6 kg. She had no history of chest pain, orthopnea, or paroxysmal nocturnal dyspnea. She had a remote smoking history of 3 pack-years approximately 50 years previously.

Her history included hypertension, gastroesophageal reflux disease, hyperlipidemia, and hypothyroidism. Medications on presentation included diltiazem, clopidogrel, losartan, levothyroxine, furosemide, sertraline, and omeprazole. There was no family history of lung disease. The patient had worked as a landscape designer.

Physical examination revealed a thin woman who appeared moderately dyspneic at rest. Her blood pressure was 110/60 mm Hg and her heart rate was 76 beats/min, both within normal physiologic ranges. Her respiratory rate was 24 breaths/min, with an oxygen saturation of 82% by pulse oximetry while breathing room air. Cardiac auscultation revealed a regular rate and rhythm without murmurs or rubs and no elevation of jugular venous pressures. Lung auscultation revealed dry bibasilar inspiratory crackles, as well as fine expiratory squeaks. Exhalation was not prolonged. On examination of extremities, digital clubbing but no cyanosis or peripheral edema was noted. Complete blood cell count revealed a hemoglobin of 15.4 g/dL (reference ranges provided parenthetically) (12.0-15.5 g/dL) and a white blood cell count of 8.7 x 109 (3.5-10.5 x 109), with 4.9% eosinophils (0.8%-7.2%). Electrocardiography showed normal sinus rhythm. Arterial blood gas revealed a normal pH and Paco2 but significant hypoxemia with a Pa02 of 42 mm Hg while breathing room air. The alveolar-arterial gradient was considerably elevated at 64 torr. Pulmonary function tests (PFTs) revealed decreased vital capacity, forced vital capacity (FVC), and forced expiratory volume in the first second of expiration (FEV1) with a normal FEV1/FVC ratio, suggesting a restrictive process. The patient was unable to complete maneuvers to determine total lung capacity. Diffusing capacity of lung for carbon monoxide (Dlco) was severely reduced at 27% of predicted value. Chest radiography showed bilateral mixed alveolar-interstitial infiltrates with basilar predominance. The cardiac silhouette and pulmonary vasculature were unremarkable.

1. Which one of the following is the most likely diagnosis in this patient?

   1. Chronic heart failure (CHF)

   2. Constrictive bronchiolitis

   3. Chronic obstructive pulmonary disease

   4. Interstitial lung disease (ILD)

   5. Acute eosinophilic pneumonia (AEP)

   Chronic heart failure can present with worsening dyspnea and hypoxemia, and restrictive changes on PFTs are consistent with CHF. However, historical and examination findings supportive of a diagnosis of CHF, including orthopnea, paroxysmal nocturnal dyspnea, jugular venous distention, extra heart sounds, and peripheral edema, were all notably absent. Digital clubbing is uncommon in patients with CHF. Alveolar and interstitial infiltrates may be seen on radiographs in patients with CHF, but cardiomegaly and pleural effusions are commonly present. Both constrictive bronchiolitis and chronic obstructive pulmonary disease often present with progressive dyspnea and low Dlco, as found in this patient, but both typically cause obstructive, not restrictive, changes on PFTs, making these 2 diagnoses unlikely. Interstitial lung disease encompasses a number of diseases that present as worsening dyspnea and dry cough. Physical examination reveals dry bilateral crackles on chest auscultation and clubbing of the fingers secondary to chronic hypoxia. Chest imaging classically shows bilateral interstitial infiltrates. Interstitial lung disease presents as a restrictive pattern on PFTs, and arterial blood gas values usually reveal profound hypoxia and increased alveolar-arterial gradient. Our patient's history of progressive dyspnea, dry crackles, and digital clubbing on examination, as well as restrictive changes on PFTs, diminished Dlco, and chest infiltrates, made ILD the most likely diagnosis. Acute eosinophilic pneumonia may cause restrictive changes on PFTs and radiographic changes similar to those seen in this patient. However, AEP presents as an acute febrile illness with associated dyspnea and cough of less than 3-weeks duration.

   Because ILD has many causes, we thought further testing was necessary in this patient to confirm and better characterize the disease.

2. Which one of the following is the most appropriate next test?

   1. High-resolution computed tomography (HRCT) of the chest

   2. Transthoracic echocardiography

   3. Ventilation/perfusion scanning

   4. Repeated PFTs with methacholine challenge

   5. Serum rheumatoid factor (RF)

   High-resolution computed tomography of the chest is helpful in characterizing diffuse ILD and suggesting a specific diagnosis. Characteristic findings on HRCT in the setting of a supportive history can establish the diagnosis of idiopathic pulmonary fibrosis due to usual interstitial pneumonitis with a specificity approaching that of open lung biopsy.1,2 Additionally, HRCT is helpful in guiding lung biopsy by localizing the most profoundly affected areas. Transthoracic echocardiography is helpful in assessing systolic or diastolic ventricular dysfunction and valvular heart disease leading to dyspnea. The patient's symptoms and presentation, however, were not very suggestive of cardiac dysfunction as the cause of dyspnea. Transthoracic echocardiography is also helpful in assessing for secondary pulmonary hypertension due to chronic hypoxemia, but it will not help characterize the patient's ILD. Ventilation/perfusion scanning is most useful in establishing the diagnosis of acute or chronic venous thromboembolic disease but is not indicated in the evaluation of suspected ILD. Methacholine challenge is used to establish the presence of nonspecific bronchial hyperreactivity. Methacholine challenge testing is commonly used to establish if a patient's symptoms are due to asthma. Our patient's findings on lung examination, PFT, and radiography do not suggest asthma, making this test unlikely to be of benefit. Serum RF is a marker for rheumatoid arthritis (RA). Rheumatoid arthritis is associated with ILD, and lung disease due to RA may precede the development of arthritis. However, RF is not specific for RA, and an elevated RF level does not confirm that the pulmonary disease is due to RA.

   Extensive bilateral ground glass opacities and increased interstitial markings at the lung bases were visible on HRCT. Further conversations with the patient revealed that she had an affinity for birds. During the past 40 years, she had a variety of birds, including cockatiels, parrots, and pigeons in and around her home. During the preceding 3 years, her exposure had become even more intense after several birds were moved into the living room from other parts of her home and the outside. This additional history in conjunction with the clinical findings suggested a diagnosis of hypersensitivity pneumonitis (HP). Also known as allergic extrinsic alveolitis, HP is an immunologically mediated inflammatory lung disease. Although it can occur after exposure to a variety of organic antigens, avian exposure is the most commonly recognized antigen leading to disease.

3. Which one of the following diagnostic tests would be most helpful in establishing the diagnosis of HP?

   1. Serum IgG subclasses

   2. Bronchoalveolar lavage (BAL) with lung biopsy

   3. Urinalysis

   4. Antineutrophilic cytoplasmic antibody

   5. Serum IgE levels

   Levels of precipitating antibodies to the inciting antigen are commonly elevated in the serum of patients with HP. Antibodies are usually of the IgG subclass but may also be of the IgA or IgM subclass. The presence of precipitating antibodies is not specific for disease because antibodies can be present in exposed persons without disease.3 Because of the limitation in the panel of antibodies tested and lack of standardization, the absence of precipitating antibodies does not exclude the diagnosis. Hypersensitivity pneumonitis is characterized by a markedly increased BAL cellularity with a striking lymphocytosis.4 Also typical of HP is a ratio of CD4+ to CD8+ lymphocytes of less than 1%.5 Tissue confirmation is unnecessary when clinical evidence convincingly supports the diagnosis. The pathologic hallmark of HP is the presence of small, poorly formed granulomas that may be associated with multinucleated giant cells and that are located near respiratory or terminal bronchioles. Well-formed granulomas are not commonly seen. A patchy mononuclear cell infiltration of the alveolar walls may also be observed. Biopsy can generally differentiate HP from other diffuse lung diseases; however, differentiation from nonspecific interstitial pneumonitis, even on biopsy, may be challenging. Unlike vasculitic diseases that can affect the lung and kidney, the manifestations of HP are limited to the lung, and therefore urinalysis is unlikely to show any abnormalities. Hypersensitivity pneumonitis is not a vasculitis, and thus elevations in levels of antineutrophilic cytoplasmic antibody would not be expected. As an immune complex— and cell-mediated immunologic disease, not an atopic disease, HP is unlikely to be associated with elevations in IgE.

   Bronchoscopy was performed in our patient. Airway inspection was unremarkable. Bronchial washings were negative for malignancy. Pathology review of the transbronchial biopsy specimens revealed mild alveolar septal thickening and scattered giant cells but no evidence of malignancy. Bacterial, fungal, and acid-fast bacilli cultures of the bronchial washing and biopsy samples yielded negative results.

4. Which one of the following treatments would be most appropriate for this patient?

   1. Initiate systemic corticosteroids (60 mg/d of prednisone orally)

   2. Eliminate exposure to the antigen (ie, remove the birds from the household)

   3. Prescribe 7- day course of broad-spectrum antibiotics

   4. Initiate inhaled β-agonist therapy

   5. Initiate azathioprine

   The role of systemic corticosteroids in the treatment of HP is incompletely understood. For most patients with acute HP, avoidance of the antigen results in marked clinical improvement. For those with severe manifestations of acute HP, antigen avoidance in conjunction with prednisone (40-60 mg/d for 1 to 2 weeks and then tapered for 4 to 6 weeks) is recommended.6 Systemic corticosteroids are also recommended for patients with severe or progressive chronic HP, but therapeutic efficacy is variable.7 Once the diagnosis of HP is suspected, complete and immediate avoidance of the offending antigen is mandatory. Continued exposure leads to persistent symptoms and progressive lung damage.8 Antigen avoidance is critical to prevent the worsening of disease, and therefore every effort must be made to identify the offending antigen. Because HP is an immune reaction to offending antigens, not an infective process, antibiotics are not indicated. β-Agonists are helpful in the treatment of reversible airway obstruction. Evidence is lacking to show a therapeutic efficacy in HP, which is largely a restrictive lung disease. Azathioprine or other immunosuppressive therapy is not indicated as an initial therapy for HP.

   The patient was encouraged to remove all birds from her residence and have it professionally cleaned. We did not initiate corticosteroids because of concerns about adverse effects and because we wished to see if the symptoms improved with removal of the offending antigen. Follow-up with the patient several months later revealed that her shortness of breath had almost completely resolved after the removal of the birds. Follow-up HRCT continued to show ILD without fibrosis.

   At her follow-up visit, the patient asked about her long-term prognosis.

5. Which one of the following best describes the patient's long-term prognosis?

   1. She will have complete resolution of symptoms and no residual abnormalities on PFTs

   2. Her risk of developing non—small cell lung cancer is greatly increased

   3. She will need to undergo lung transplant

   4. Repeated antigen exposure is not contraindicated because she has now developed immunity to the antigen

   5. Although the outcome is difficult to predict with certainty, some persistent symptoms and residual PFT abnormalities may occur

   Patients with subacute and chronic disease generally have some symptomatic and PFT improvement but rarely have complete normalization even after exposure to the inciting antigen has been completely abated.9 There is no evidence that HP increases the likelihood of developing non—small cell lung cancer. Lung transplant is reserved for patients with advanced fibrotic disease that results in severe functional impairment and does not improve with antigen avoidance. As with most immune-mediated diseases, repeated antigen exposure often results in relapse of symptoms. Our patient responded to treatment (avoidance of the antigen) and has had some recovery from her disease subjectively, but one would expect long-term symptoms from the persistent ILD.

   Continued follow-up with the patient showed that her dyspnea at rest was much improved. She still occasionally required home oxygen, especially with exertion. Despite subjective clinical improvement, she had persistent PFT abnormalities at the time of follow-up. Her Dlco remained low at 27% of predicted value, but her FVC and FEV1 values were mildly improved.

Hypersensitivity pneumonitis is an immunologically mediated lung disease caused by hypersensitivity to a variety of inhaled organic antigens. Cell-mediated immunity and immune complex formation play key roles in the pathophysiology of disease. Although more than 200 antigens have been identified as causing HP,10 avian proteins found in bird excrement and feathers as well as Saccharopolyspora rectivirgula found in moldy hay are common inciting antigens. Hypersensitivity pneumonitis can present as acute, subacute, or chronic disease. Although prospective categorization is difficult, acute disease typically results in shortness of breath, dry cough, fevers, and malaise 4 to 6 hours after antigen exposure. Patients with acute HP typically look acutely ill. These patients tend to improve quickly after removal from the antigen source. Subacute disease occurs in patients with recurrent, low-level exposures to the antigen. Shortness of breath, fatigue, and low-grade temperature elevation are common symptoms. Symptoms tend to resolve on removal from the antigen but recur on reexposure. Persistent or frequent exposure to the antigen may lead to chronic HP, which may lead to irreversible pulmonary fibrosis.

Diagnosing HP can often be quite challenging. Although various diagnostic algorithms have been proposed, they are limited by a lack of validation. Establishing the diagnosis of HP requires the compilation of historical, radiologic, and pathologic findings. Hypersensitivity pneumonitis develops after exposure to an aerosolized antigenic stimulus in a susceptible host. The aerosolized particle must be small enough (≤3 μm) to reach the alveolus. Therefore, an extensive environmental history is mandatory in patients in whom the disease is suspected. Although many antigens have been implicated, exposure to avian proteins is a particularly strong stimulus. Hypersensitivity pneumonitis can present as an acute illness or as a subacute or chronic disease. Subacute or chronic disease develops in susceptible persons who have sustained or repeated exposure to the inciting antigen. Chronic HP often can be difficult to differentiate from other forms of ILD. The diagnosis of HP is made on clinical findings in the setting of supportive historical and pathologic evidence. In acute HP, chest radiographs often show reticulonodular infiltrates in the lower lung zones. Ground glass opacities with clearly discernible micronodules are visible on HRCT. Patients with subacute or chronic disease may show micronodules, linear fibrosis, and mosaic attenuation on HRCT. In advanced chronic HP, HRCT findings, such as honeycombing and traction bronchiectasis, make chronic HP indistinguishable from end-stage lung disease due to other entities. Precipitating antibodies (usually IgG) to specific antigens can be helpful in establishing the diagnosis of HP. However, antibody development is often seen in exposed persons without disease. Some patients who are exposed to an antigen or even mount an antibody response do not develop disease, suggesting that host susceptibility influences disease development. Hypersensitivity pneumonitis occurs almost exclusively in nonsmokers, perhaps because the immunosuppressive effects of tobacco smoking depress the immune mechanisms necessary for clinical manifestations of disease.11 An increase in BAL cellularity with marked lymphocytosis is supportive of the diagnosis of HP. Although BAL lymphocytosis is not specific for the diagnosis of HP, its absence makes the diagnosis distinctly unlikely.12

The most important learning point of this case is the necessity of a comprehensive medical history. Only by taking a complete pulmonary history, including home and occupational exposures, is one able to gather the vital data necessary to a proper diagnosis. Although leading questions are usually discouraged in medical history gathering, in suspected cases of HP their directive nature may trigger the patient to recall relevant history that had been forgotten or overlooked.13 By completing the history-taking process and following up by intensively questioning the patient, we were able to identify the causative agent and to make the proper diagnosis of HP. This discovery led to appropriate therapeutic guidance, stabilization and improvement in lung function, and avoidance of further invasive testing.

Correct answers: 1. d, 2. a, 3. b, 4. b, 5. e

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