Bird Droppings and a Chronic Cough

A 46-year-old man presents to the emergency department (ED) with a 4-day history of dry cough, fever, chills, night sweats, a 13-lb (5.9-kg) weight loss, (over a 2-week period), shortness of breath, and easy fatigability. Two weeks before presentation, he went with a friend to clean an abandoned house in Kentucky. The house was very dusty and had a lot of bird droppings. His friend developed a fever with cough and could not continue working after 4 days. Our patient, however, continued to work until the job was done (a total of 7 days). He has not had any hemoptysis, chest pain, or any other symptoms, except as noted above. He has mild asthma, uses an albuterol inhaler once every 3-4 months, has smoked half of a pack of cigarettes per day for the last 30 years, does not drink alcohol, and does not use any illicit drugs. He has no significant family history and is not allergic to any medications.

On physical examination, his oral temperature is 98.9°F (37.2°C). His pulse is regular, with a rate of 98 bpm, and his blood pressure is 137/91 mm Hg. He is mildly tachypneic, with a respiratory rate of 22 breaths/min. The patient is thin but not emaciated, and he has poor dentition; his head and neck examination is otherwise normal, with no palpable lymph nodes. He has normal S1 and S2 heart sounds. Chest auscultation reveals fine rales in the mid and lower zones of both lungs. His abdomen is soft and nontender, with normal bowel sounds. He does not have any lower limb edema, and he has normal peripheral pulses.

A basic metabolic panel is obtained, with a sodium of 135 mEq/L (135 mmol/L), potassium of 3.9 mEq/L (3.9 mmol/L), blood urea nitrogen (BUN) of 17 mg/dL (6.07 mmol/L), creatinine of 0.9 mg/dL (79.56 µmol/L), chloride of 100 mEq/L (100 mmol/L), and a bicarbonate of 25 mEq/L (25 mmol/L). His complete blood cell (CBC) count reveals a hemoglobin of 11.6 g/dL (116 g/L; normal range, 13.5-16.5 g/dL); a white blood cell (WBC) count of 4.3 × 103/µL (4.3 × 109/L; normal range, 4.5-11 × 103/µL), with a normal differential; and a platelet count of 142 × 103/µL (142 × 109/L; normal range, 150-400 × 103/µL). His liver function tests are remarkable for an albumin level of 2.4 g/dL (24 g/L; normal range, 3.5-5.5 g/dL) and an elevated lactate dehydrogenase (LDH) of 241 units/L (241 U/L). The values for aspartate transaminase (AST), alanine transaminase (ALT), and γ-glutamyltransferase (GGT) are within normal limits. The total bilirubin and alkaline phosphatase (ALP) are within normal limits, at 1.2 mg/dL (20.5 µmol/L) and 42 unit/L (42 U/L), respectively. Arterial blood gas (ABG) on room air shows a pH of 7.42, a partial pressure of carbon dioxide (pCO2) of 43.4 mm Hg, and a partial pressure of oxygen (pO2) of 62.6 mm Hg. His human immunodeficiency virus (HIV) test is nonreactive.

A chest xray shows diffuse miliary infiltrates in both lung fields.

CASE DISCUSSION:

The urine antigen test for Histoplasma capsulatum (enzyme immunoassay [EIA]) was 11.4 U, interpreted as highly positive (the normal range is below 4.0 U). The diagnosis in this patient was suspected from his clinical presentation of fever, cough, and shortness of breath within 2 weeks of heavy exposure to H capsulatum in an endemic area. The chest radiograph shows miliary shadows; the urine antigen for H capsulatum confirmed the diagnosis.

Histoplasmosis is caused by H capsulatum, which is a dimorphic fungus that was first described by Darling in 1906.[1] It is found worldwide; within the United States, infection is most common in the states located within the Ohio and Mississippi River Valley regions. Up to 50 million people in the United States have been infected by H capsulatum, and up to 500,000 new infections occur each year.[2] H capsulatum proliferates best in soil that is contaminated with bird or bat droppings. Heavy exposure usually occurs with activities that disturb a large accumulation of droppings in an enclosed area, such as in a cave or an attic.

The lungs provide the portal of entry for H capsulatum in the vast majority of cases. Conidia or mycelial fragments are inhaled and, if these fragments evade nonspecific lung defenses, cause a localized or patchy bronchopneumonia. The clinical spectrum of acute histoplasmosis varies according to the extent of the exposure, the presence of underlying lung disease, the patient's general immune status, and specific immunity to H capsulatum.

With low-inoculum exposure, fewer than 5% of exposed individuals develop symptomatic disease.[3] The initial presentation usually involves a pulmonary infection weeks to months following exposure to H capsulatum. The symptoms include cough, fever, chills, headache, myalgia, anorexia, and pleuritic chest pain, suggesting an influenzalike illness; however, coryza and sore throat are not typical of histoplasmosis, and their presence should suggest an alternative diagnosis.[4] The physical examination may reveal fever, rales, or findings suggestive of pulmonary consolidation. Chest radiographs may show focal infiltrates and/or mediastinal or hilar lymphadenopathy; however, the chest radiograph may be normal. Cavitary lesions are rare, except in patients with underlying obstructive lung disease.

Patients who inhale a large inoculum (as in our patient) may develop acute diffuse pulmonary infection.[5] The clinical presentation is more acute, occurring within 1-2 weeks of exposure. Chest radiographs may reveal diffuse reticulonodular or miliary infiltrates, and the clinical picture can progress to respiratory failure or progressive extrapulmonary dissemination.

Patients with underlying lung disease may develop chronic pulmonary histoplasmosis with productive cough, dyspnea, chest pain, fatigue, fever, and sweats. Chest radiographs or chest computed tomography (CT) scans may show fibrotic apical infiltrates, with cavitations resembling those observed in patients with tuberculosis.

A less common long-term complication of histoplasmosis includes broncholithiasis, in which calcified lymph nodes and pulmonary granulomas erode into adjacent structures several years after exposure to H capsulatum. Patients present with chronic cough, wheezing, hemoptysis, fever, chills, and purulent sputum, and some individuals may expectorate small stones, gravel, or gritty material.[6] Massive hemoptysis may result if the bronchial arteries are involved.[7]

Other complications include:

* Mediastinal granulomas, which are enlarging, encapsulated, caseous mediastinal lymph nodes that can compress compliant structures such as the esophagus, pulmonary vessels, and, occasionally, the airways. This, in turn, can cause chest pain, cough, hemoptysis, and dyspnea. Involvement of the trachea can cause respiratory distress, and prolonged obstruction can cause bronchiectasis or bronchial stenosis. Involvement of the esophagus may result in dysphagia, odynophagia, or chest pain, and, rarely, in the development of a bronchoesophageal or tracheoesophageal fistula.
* Fibrosing mediastinitis is an excessive fibrotic response to a previous episode of histoplasmosis. In most cases, the acute episode of histoplasmosis is not identified.[8] Common symptoms of fibrosing mediastinitis are cough, dyspnea, hemoptysis, pleurisy, and dysphagia. It may result in entrapment, distortion, and invasion of structures adjacent to mediastinal lymph nodes, including the heart, great vessels, airways, and esophagus.
* Extrapulmonary manifestations of histoplasmosis may include pericarditis, arthritis (usually polyarticular), erythema nodosum, and erythema multiforme.

The differential diagnosis of pulmonary histoplasmosis includes sarcoidosis, tuberculosis, and malignancy.

Diagnostic testing for histoplasmosis is performed as follows:

1. Histopathology: Morphologic findings in biopsy specimens include granulomas (in most cases), lymphohistiocytic aggregates, and diffuse mononuclear cell infiltrates. Histopathologic examination of lung or mediastinal lymph node tissue using special stains that highlight fungi permits rapid diagnosis of histoplasmosis, but this method has a lower sensitivity than that of culture or antigen detection.[8] Yeast-phase organisms of H capsulatum are ovoid in shape, measure 3-5 µm in diameter, and demonstrate narrow-based budding.
2. Fungal cultures: Cultures are most useful in patients with chronic pulmonary histoplasmosis. Submission of multiple sputum or bronchoalveolar lavage samples for culture produces a positive yield in 60-85% of cases[9]; however, the sensitivity of respiratory cultures is much lower in cases of localized disease (15%) or diffuse acute disease (40%).[10] The organism may not grow in culture for 2-4 weeks.
3. Antigen detection: Detection of antigens using the histoplasma antigen detection EIA in the urine, blood, or bronchoalveolar lavage fluid of infected patients provides rapid diagnostic information. Using the antigen EIA, the H capsulatum glycoprotein antigen can be detected in 75% of patients with diffuse acute pulmonary histoplasmosis.[10] Based upon results in patients with disseminated histoplasmosis, the sensitivity is higher in immunosuppressed patients than in those who are not immunosuppressed.[11] The sensitivity of antigen detection is higher in urine than serum. Cross-reactions can be seen in patients with blastomycosis, coccidioidomycosis, penicilliosis (caused by Penicillium marneffei), paracoccidioidomycosis, and African histoplasmosis,[12] but not in patients infected with Aspergillus, Candida, or Cryptococcus.[10]
4. Serology: Serologic testing is useful in the diagnosis of histoplasmosis in patients with consistent clinical presentations and epidemiologic risk. Less than 1% of residents in endemic areas are seropositive by the immunodiffusion test, and less than 5% have positive complement fixation assays; therefore, background seropositivity is not a major limitation to serologic testing.[13]
1. Acute disease: Serologic tests are positive in about 90% of symptomatic patients with acute pulmonary histoplasmosis[10]; however, 4-8 weeks are required for antibodies to develop following acute infection, which would explain why the initial testing may be negative, but it then has a positive result when repeated 1 month later.
2. Chronic disease: Nearly 100% of patients with chronic pulmonary histoplasmosis have a positive serologic test; however, the sensitivity of serology in the diagnosis of other chronic forms of histoplasmosis (eg, granulomatous or fibrosing mediastinitis, broncholithiasis, and pulmonary nodules) is uncertain.

In this case, the patient was admitted and treated with oral itraconazole 200 mg 3 times daily for 3 days, followed by a 12-week course of 200 mg daily. He made a good clinical recovery while in the hospital.

Case excerpted from eMedicine 11/08
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