Coccidioidomycosis with diffuse miliary pneumonia

Abstract

Coccidioidomycosis is a well-known infection in the southwestern United States, and its occurrence is becoming more frequent in endemic areas. This disease can have a significant economic and medical impact; therefore, accurate diagnosis is crucial. In conjunction with patient symptoms, residence in or travel to an endemic area is essential for diagnosis. Diagnosis is usually made with serology, culture, or biopsy and confirmed with DNA probe technology. Pulmonary disease is the most common presentation and is seen in almost 95% of all cases. One-half to two-thirds of all Coccidioides infections are asymptomatic or subclinical. Most pulmonary infections are self-limited and do not require treatment except in special populations. When treatment is warranted, itraconazole and fluconazole are frequently used. Diffuse miliary pneumonia is uncommon and is especially rare in immunocompetent patients. Herein we describe a rare presentation of miliary coccidioidomycosis in a nonimmunocompromised patient.

Coccidioidomycosis is a well-known infection in the southwestern US (1, 2) that has become more frequent in endemic areas, with an increase from 5.3 new cases per 100,000 persons in 1998 to 42.6 new cases per 100,000 in 2011 (3). The increase is likely influenced by population migration, an increased number of immunosuppressed patients, and increased awareness of the disease (1, 2, 4). Pulmonary disease is the most common presentation of coccidioidomycosis. Most cases are asymptomatic or resolve spontaneously, but some patients with diverse risk factors may develop severe disease. Diffuse miliary pneumonia is uncommon, and it is usually found in immunocompromised patients, in whom it has a poor prognosis (1, 4, 5, 6).

CASE DESCRIPTION

A previously healthy 49-year-old black man was sent from a prison unit to the emergency center. He presented with 2 weeks of new-onset progressive dyspnea associated with dry cough and intermittent fevers and chills. His blood pressure was 124/75 mm Hg; temperature, 97.5°F; heart rate, 105 beats/minute; and respiration, 28 breaths/minute with an oxygen saturation of 86% on room air. His body mass index was 20.4 kg/m². He was in moderate respiratory distress and had bilateral fine crackles. His leukocyte count was 12.4 K/μL with neutrophil predominance and eosinophilia of 1.4 K/μL. Chest radiography and computed tomography of the chest are shown in Figure 1. The patient was given ceftriaxone and azithromycin but his fever and hypoxemia persisted, and fluconazole was started on the third day of hospitalization.

Figure 1.

(a) A chest x-ray shows bilateral miliary infiltrates. (b) Chest computed tomography scan without contrast shows bilateral miliary infiltrates and bilateral pleural effusions (arrows).

Additional laboratory tests were obtained to evaluate for atypical pneumonia (Table 1). A transbronchial biopsy showed loose granulomas with moderate chronic and mild acute inflammation and occasional spherules with interstitial fibrosis. Bronchial washing cultures were positive for Coccidioides immitis per DNA probe. He was discharged on oral fluconazole 400 mg daily and supplemental oxygen. Approximately 1 month later, he no longer required oxygen supplementation (with an oxygen saturation of 94% on room air), and it was recommended he complete 1 year of antifungal therapy.

Table 1.

Atypical pneumonia evaluation

Test performed	Patient's value	Reference range
Procalcitonin (ng/mL)	0.13	0.51–1.99
HIV ELISA	Negative	Negative
Influenza (A and B) PCR	Negative	Negative
Sputum culture	Negative	Negative
Coccidioides complement fixation antibody	1:512	<1:2
Urine Legionella antigen	Not detected	Not detected
Mycoplasma pneumoniae culture	Negative	Negative
(1,3) B-D Glucan (pg/mL)	146	<60
Quantiferon-TB	Negative	Negative
Urine Histoplasma galactomannan antigen (ng/mL)	<0.5	<0.5

ELISA indicates enzyme-linked immunosorbent assay; PCR, polymerase chain reaction.

DISCUSSION

Coccidioides sp., a dimorphic fungus present in the soil as a mold, is found only in the Western hemisphere and is endemic in the southwestern US, northern Mexico, and South America. Arthroconidia disperse into the air and can be inhaled by animals or humans. Within the human body, they transform into spherical structures called spherules that eventually grow and break open, releasing hundreds to thousands of endospores, which perpetuate the cycle. Endospores may spread via hematogenous and/or lymphatic drainage (1, 4). Two species have been described: C. immitis (which seems to be limited to the San Joaquin Valley) and C. posadasii (2, 4).

One-half to two-thirds of these infections are asymptomatic or subclinical (4, 5). Individuals older than 60 years and patients with congestive heart failure, chronic lung disease, cancer, AIDS, or other immunocompromised states are prone to symptomatic disease (5). Immunosuppressed patients, pregnant women in the third trimester, persons of Filipino or African American ancestry, diabetics, the elderly, and smokers are at increased risk for severe or disseminated disease (4, 6). This disease has five main clinical presentations: acute pneumonia, chronic progressive fibrocavitary pneumonia, pulmonary nodules and cavities, extrapulmonary nonmeningeal disease, and meningitis (1). Pulmonary disease is seen in almost 95% of cases (4, 6).

Acute pneumonia is an acute respiratory infection that usually occurs 1 to 3 weeks after exposure (1, 5) and can be associated with generalized symptoms and/or cutaneous manifestations (1, 4). The chest x-rays of patients with acute pneumonia are similar to those for other etiologies of community-acquired pneumonia (1, 4). Coccidioidomycosis can account for 17% to 29% of cases of community-acquired pneumonia in endemic areas (3). Residents and recent travelers to endemic areas with compatible symptoms should be evaluated for coccidioidomycosis (5).

Diffuse miliary pneumonia is uncommon and presents as bilateral reticulonodular or miliary infiltrates on imaging studies. It can be associated with large inoculums, fungemia, or lymphatic spread. The presence of diffuse miliary pneumonia suggests underlying immunodeficiency, and those patients are usually critically ill, with the vast majority developing acute respiratory distress syndrome (ARDS) (1, 4, 5). ARDS has a mortality of nearly 100% in immunosuppressed patients (4, 6). Miliary disease in immunocompetent patients is very rare. The largest series of immunocompetent patients with diffuse miliary pneumonia reported 8 patients, 2 of whom were pregnant; 5 (62.5%) developed ARDS, and 3 (37.5%) died (7).

Diagnosis is usually made with serology, culture, or biopsy (4). All cultures should be confirmed with DNA probe technology (6). The finding of spherules in any body fluid or tissue is always indicative of infection. Serologic testing is based on finding antibodies to a coccidioidal-related antigen. Diagnosis is also based on immunologic evidence of disease in the form of detection of IgM or IgG by immunodiffusion, enzyme immunoassay, latex agglutination, tube precipitin, or complement fixation (8, 9). Skin testing (coccidioidin) cannot differentiate between recent or past infection (10).

Most pulmonary infections are self-limited and do not require treatment. Treatment should be considered for patients at high risk for severe disease (1, 4–6). Itraconazole and fluconazole are the most commonly used drugs (1, 5). Galgiani et al compared fluconazole to itraconazole in a randomized controlled trial and found that itraconazole had better outcomes (11). Fluconazole has excellent bioavailability and tissue penetration and few drug interactions, making it the agent of choice (4). Treatment is usually given for 3 to 6 months for acute pneumonia (1, 4, 5). Diffuse miliary pneumonia may require several weeks of amphotericin B, followed by maintenance therapy with an azole for a year or indefinitely (4, 6).