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A 12-Year-Old Girl With Dyspnea and a Normal Chest Radiographic Finding* FREE TO VIEW

Kristin B. Highland, MD; Patrick A. Flume, MD, FCCP
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*From the Division of Pulmonary and Critical Care Medicine, Medical University of South Carolina, Charleston, SC.

Correspondence to: Patrick A. Flume, MD, FCCP, Associate Professor, Division of Pulmonary and Critical Care Medicine, 96 Jonathan Lucas St, Suite 812-CSB, PO Box 250623, Charleston, SC 29425; e-mail: flumepa@MUSC.edu

Chest. 2001;120(4):1372-1376. doi:10.1378/chest.120.4.1372
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A 12-year-old white girl was referred for the evaluation of a several-year history of progressive dyspnea on exertion. She denied shortness of breath at rest but was unable to run or complete one flight of stairs, and she described herself as “huffing and puffing” after walking the length of the hallway at school. She denied having wheezing, significant cough or sputum production, active sinus symptoms, chest pain, lower-extremity edema, paroxysmal nocturnal dyspnea, and orthopnea. She denied specific exacerbating causes of her dyspnea. She had been prescribed inhaled medications for possible exercise-induced airways disease without any improvement. Workup data from her referring physician included an unremarkable chest radiograph (CXR) finding.

Her medical history was significant for seasonal allergic rhinitis with recurrent sinusitis, bronchitis, and depression with suicidal ideation. Current medications included valproic acid, bupropion, and lithium carbonate. She had no known drug allergies. She was a never-smoker and denied alcohol or recreational drug use. She lived with her mother and stepfather and had missed numerous days of seventh grade. Her family history was noncontributory. Findings of a detailed review of systems were positive only for occasional arthralgia, typically her large joints, including her hip.

On presentation, the patient appeared to be in no distress. Her temperature was 36.8°C, heart rate was 73 beats/min, BP was 110/80 mm Hg, respiratory rate was 16 breaths/min, and oxygen saturation was 96% while breathing room air. Head, eye, ear, nose, and throat examination findings were normal, and the neck was without elevation of jugular venous pulse. The chest examination revealed faint end inspiratory crackles diffusely. There were no wheezes. Cardiovascular examination revealed a regular rhythm without murmurs, gallops, or rubs, and there was a normally split S2 sound. Findings of the abdominal examination were normal, and the extremities were without clubbing, cyanosis, or edema.

Results of pulmonary function studies revealed a FVC of 1.00 L (39% predicted), FEV1 of 0.94 L (42% predicted), total lung capacity of 1.63 L (48% predicted), functional residual capacity of 0.95 L (52% of predicted), and residual volume of 0.70 L (79% of predicted). Diffusion capacity of the lung for carbon monoxide corrected for hemoglobin was 22% of predicted, and diffusion capacity of the lung for carbon monoxide corrected for alveolar volume was 56% predicted.

A CBC count and findings of comprehensive metabolic panel, thyroid function tests, sedimentation rate, antinuclear antibody, and rheumatoid factor were all normal. Arterial blood gas analysis on room air revealed a pH of 7.42, Pco2 of 36 mm Hg, and Po2 of 101 mm Hg.

Echocardiography findings were normal, with the exception of mild tricuspid regurgitation and elevated peak right ventricular systolic pressure of 55 mm Hg. High-resolution CT (HRCT) findings of the chest were normal (Fig 1 ).

Answer: Hypersensitivity pneumonitis.

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a diffuse interstitial granulomatous lung disease that results from a complex immunologic reaction to an inhaled organic antigen. One of the more common examples is bird- fancier’s disease. The clinical, radiographic, and pathologic presentation may be categorized as acute, subacute, or chronic. This is based on the characteristic of biological dust inhaled, the intensity and frequency of the exposure, the severity of the immune inflammatory response, sequelae of the inflammatory response, and various host factors.

Clinical features of HP are nonspecific: it is a syndrome of respiratory symptoms with or without systemic features. Acute HP is the most common form and presents 4 to 6 h after exposure as a flu-like syndrome with cough, dyspnea, fever, chills, myalgia, and malaise, which typically resolves after 18 h. Subacute HP occurs after exposure to a lesser amount of antigen over a longer period of time. Symptoms are more insidious and include progressive dyspnea, cough with sputum production, anorexia, and weight loss. Chronic HP is characterized by irreversible pulmonary damage and carries a long-term mortality rate of approximately 10%. It is often without systemic features, consisting primarily of progressive dyspnea on exertion and cough.

Physical examination in acute and subacute HP usually reveals an ill-appearing, dyspneic patient with inspiratory crackles; wheezing is rare. Laboratory examination findings often show a leukocytosis with a shift toward more immature forms. Eosinophilia is not a usual finding. The arterial blood gas analysis frequently shows hypoxemia, and 50% of patients may have a positive rheumatoid factor. There is an abnormal lymphocytosis in BAL with predominantly CD8-type lymphocytes. Detection of serum precipitins to the suspected antigen allows for a diagnosis in the proper clinical setting.

The pulmonary physiology of HP is complex, because there is a potential for varying degrees of involvement of the airways and interstitium. Typically, there is restrictive impairment with a diffusion defect and hypoxemia. However, in some patients, there is an initial obstructive phase occurring within minutes of exposure, while in other patients significant obstruction develops.

In acute HP, the CXR may show miliary nodules and reticulations in most lung fields, most severe in the lower lung zones and frequently sparing the apices. There may be patchy alveolar infiltrates and, rarely, hilar adenopathy. The CXR in patients with subacute HP usually shows nodular infiltrates or early fibrosis that is more severe in the mid-lung zones; in chronic HP, diffuse fibrosis is more severe in the upper lung zones. However, the CXR findings in patients with HP may vary considerably or be nonspecific, and there have been a number of conflicting reports on the radiographic features and distribution of abnormalities. The CXR is not diagnostic or predictive of the clinical stage of HP, nor does it correlate with clinical or functional impairment. An abnormal CXR finding is not required for the diagnosis and the radiograph may be normal in up to 87% of patients. HP is the most common diffuse lung disease in patients with normal radiographic findings. The CXR finding may be normal in patients with HP because small lesions scattered in a large volume of normal lung may be below the threshold of roentgenographic visibility. Alternatively, mild but diffuse interstitial thickening or desquamation into alveolar spaces may cause a generalized increase in absorption of roentgen rays that is not easily appreciated visually.

CT is superior to CXR in the assessment of the extent, type, and distribution of abnormalities seen in patients with HP. However, the usefulness of CT in the diagnosis of HP is yet to be determined. In one study investigating the accuracy of CT in correctly establishing the diagnosis in diffuse lung diseases, the one condition diagnosed inconsistently was HP. A variety of HRCT features characteristic for HP that varied with stage of disease has been reported. In acute HP, there is nonspecific airspace opacification. In patients with subacute HP, there are small rounded opacities and patchy soft airspace opacification that does not obscure underlying interstitial markings. Chronic HP is characterized by a mixed pattern of patchy airspace opacification and linear fibrosis that is nonspecific and difficult to differentiate from other conditions. A centrilobular distribution for small, poorly defined nodules is highly suggestive of HP. Other common CT features include ground-glass opacification, increased density of the lung, decreased attenuation, and mosaicism. Regardless, the predominant abnormality is usually within the mid-lung zones.

It is not known how prevalent normal findings on HRCT scans are in patients with HP who have pulmonary symptoms. In a series of 22 patients with HP, 3 patients had normal CT findings, which suggests that false-negative examination results may be a problem with CT, just as is seen with the CXR. In a series of 118 patients with chronic diffuse infiltrative lung disease, CT was not useful for the detection of HP because CT findings did not correlate with pathologic specimens or with the clinical stage of disease. In a series of 31 patients referred for possible HP, 11 of whom had biopsy-proven disease, HRCT had a sensitivity of only 45%.

Histologically, HP is characterized by perivascular accumulations of lymphocytes and plasma cells, noncaseating granulomas, and bronchiolitis with and without bronchiolitis obliterans. The acute stage of HP is characterized by the filling of the airspaces and small airways by neutrophils and lymphocytes. In subacute HP, there is an interstitial lymphocytic infiltrate, poorly defined granulomas, and cellular bronchiolitis. Chronic HP is characterized by lymphocytic interstitial pneumonitis, granulomas, fibrosis with a peribronchiolar distribution, bronchiolitis obliterans, and honeycombing. There have only been a limited number of CT-pathologic correlated studies, and there are conflicting reports regarding whether HRCT correlates with pathologic specimens or with the clinical stage of disease. Micronodules probably represent cellular bronchiolitis/bronchiolitis obliterans, active alveolitis filling alveoli, and granulomas. Increased lung density or a ground-glass appearance may reflect diffuse interstitial infiltrates of chronic inflammatory cells and granulomas, and patchy airspace consolidation may indicate foci of obstructive pneumonia with foamy histiocytes in airspaces. Bronchial obstruction may explain areas of hyperlucency that conform to a lobular distribution.

The mainstay of therapy is avoidance of the inciting antigen. This may require environmental cleanup, as the antigen can persist in the environment. Systemic corticosteroids remain the only proven effective drug therapy and may be required when environmental controls or avoidance cannot be accomplished. It is imperative to make an early diagnosis and to reduce ongoing exposure to inciting antigen, since the acute and subacute stages are reversible, but chronic HP is characterized by permanent pulmonary parenchymal changes.

An exposure history was obtained from the patient and it coincided with her symptoms. She had an extensive list of animals residing at her property, including a cougar, a feral dog, two lynx, wolves, multiple snakes including a rattlesnake, a python, a cobra, a bearded dragon, a tree frog, a dwarf crocodile, a caiman, hamsters, ostriches, prairie dogs, and tarantulas. Additionally, four lovebirds resided in her bedroom for the past several years and she was responsible for cleaning their cage.

The patient underwent an open-lung biopsy that proved HP. All birds were removed from the home, and treatment with prednisone, 60 mg/d, was initiated with return of her lung function to near normal. A repeat echocardiogram also revealed resolution of her pulmonary hypertension. After 3 months, the patient continued to do well; steroid therapy was weaned completely during the ensuing 3 months.

  1. A detailed exposure history is an essential component in the evaluation of the patient with chronic dyspnea.

  2. The CXR finding may be normal in up to 87% of patients, and HRCT has a sensitivity of only 45% in patients with HP; therefore, a normal HRCT finding does not exclude the diagnosis.

  3. There is a poor correlation between radiographic features of HP and its histologic findings or physiologic impairments.

  4. Treatment is complete removal of the offending antigen and a course of corticosteroids for severe symptoms and/or incomplete avoidance.

  5. Acute and subacute stages are reversible, while chronic HP is characterized by permanent changes.

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