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(Chest. 2000;117:404-409.)
© 2000 American College of Chest Physicians

Miliary Coccidioidomycosis in the Immunocompetent*

Edward L. Arsura, MD{dagger} and William B. Kilgore, BA{ddagger}

* From the Kern Medical Center, Department of Internal Medicine, Bakersfield, CA (affiliate of the University of California, Los Angeles). {dagger} Current affiliation: Veterans Affairs Medical Center, Salem, VA. {ddagger} Current affiliation: University of California, San Diego, CA.

Correspondence to: Edward L. Arsura, MD, Medical Service (111), Veterans Affairs Medical Center, 1970 Roanoke Blvd, Salem, VA 24153


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Miliary coccidioidomycosis indicates hematogenous or lymphatic spread of Coccidioides immitis and is characterized by the development of multiple small granulomas throughout the lungs and other organs. Previous reports have suggested that this disorder occurs almost exclusively in immunocompromised patients, with most patients succumbing to progressive respiratory failure. In this article, we describe the largest series of immunocompetent patients with miliary coccidioidomycosis, define clinical characteristics, and outline important aspects of diagnosis and treatment.

Materials and methods: We identified eight patients (five men and three women; age range, 23 to 65 years) with miliary coccidioidomycosis diagnosed at Kern Medical Center (located in an endemic area) from 1990 to 1997. Four of the patients were white, two were African American, and two were Hispanic. A miliary pattern was defined as the presence of discrete 2- to 10-mm lesions diffusely distributed throughout both lung fields, as shown on chest radiograph. Microscopic examination and culture of C immitis from sputum, tissue, or body fluid confirmed diagnosis. Patients with HIV were excluded.

Results: These patients constituted approximately 1% of those admitted to our institution for coccidioidomycosis from 1990 to 1997. Four patients had symptoms for <= 1 week before admission (acute), and four had symptoms for between 5 and 12 weeks (chronic). Four patients demonstrated a miliary pattern on initial chest radiograph, and two of these patients received an initial diagnosis of miliary coccidioidomycosis. Five patients required mechanical ventilation. Arterial blood gas measurements revealed a mean PO2 of 54.2 ± 8.6 mm Hg and a mean PCO2 of 32.5 ± 3.2 mm Hg. Five patients developed ARDS. Five patients had extrapulmonary involvement, with the meninges (n = 4) and skin (n = 4) being the most common sites. All patients were treated with fluconazole and/or amphotericin B. Three patients died; all had chronic involvement and received mechanical ventilation.

Conclusion: We present eight immunocompetent patients with a lower mortality rate and better outcome than previously reported. In our series, miliary coccidioidomycosis manifested as either an acute respiratory illness or an advanced stage of a chronic illness occurring in the context of widespread dissemination. All who died had chronic involvement. Prompt recognition of miliary coccidioidomycosis is crucial, but may be hindered by the large differential diagnosis. Important diagnostic factors include a history of travel through endemic areas, ethnicity, immunologic status, involvement of multiple organ sites, and pronounced hypoxemia not accounted for by the degree of pulmonary involvement seen on chest radiograph.

Key Words: ARDS • Coccidioides immitis • coccidioidomycosis • dissemination • immunocompetent • miliary


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The finding of a miliary pattern on chest radiograph is an uncommon, yet ominous, complication of infection with the pathogenic fungus Coccidioides immitis. This pattern indicates hematogenous or lymphatic spread of C immitis and is characterized by the development of multiple coccidioidal granulomas throughout the lungs and other organs.

Sixty percent of C immitis infections are asymptomatic or indistinguishable from an upper respiratory infection.1 Extrapulmonary dissemination is common, appearing in 4 to 5% of clinically apparent cases.2 3 4 Miliary dissemination is a sign of serious disease, with most patients succumbing to progressive respiratory failure.5 6 The frequency of a miliary pattern is unknown in coccidioidomycosis patients, with only a few cases presented in the literature. This disorder has traditionally been described in immunocompromised patients.5 7 8 9 10 11 12 13 14 15 In this article, we describe the largest series of immunocompetent patients with miliary coccidioidomycosis in an effort to better define this clinical entity and to bring attention to this underappreciated complication. Important aspects of diagnosis and treatment are presented.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
We retrospectively identified eight patients with miliary coccidioidomycosis presenting to Kern Medical Center, a 270-bed county facility in Bakersfield, CA, an endemic area. All known patients from November 1990 to August 1997 were collected, excluding four patients with HIV infections. Patients were obtained from a hospital research database of all known coccidioidomycosis patients. Patients admitted with a diagnosis of coccidioidomycosis were obtained through a hospital database of diagnosis codes. None of our patients were immunocompromised by illness, and none were taking medications adversely affecting their immune status. Total lymphocyte counts were evaluated. HIV testing was done with an enzyme-linked immunosorbent assay.

The diagnosis of coccidioidomycosis was made in the presence of a compatible illness including symptoms of cough, fever, pleurisy, sputum production, and radiographic abnormalities. Detection of any IgM antibodies (by immunodiffusion) or the presence of a complement fixation (CF) titer of >= 1:4 confirmed the diagnosis. The Kern County Public Health Department performed serology. C immitis was isolated from sputum, tissues, or body fluids in all patients. Microscopic confirmation was made using Gomori methenamine silver stain modified for C immitis. The organism was cultured on Sabouraud’s dextrose agar, potato dextrose agar, mycobiotic agar, and Sabouraud’s dextrose and brain heart infusion with chloramphenicol and cycloheximide incubated at 30°C for 4 weeks. C immitis in culture exhibits coarse, septated, branched hyphae that produce thick-walled, barrel-shaped arthroconidia. Arthroconidia are 2 to 4 x 3 to 6 µm in size and alternate with empty cells. A miliary pattern was defined as the presence of discrete 2- to 10-mm lesions diffusely distributed throughout both lung fields on radiograph. ARDS was diagnosed in the presence of pronounced hypoxemia (arterial oxygen saturation of < 90% with an fraction of inspired oxygen of >= 0.5) accompanied by diffuse bilateral infiltrates. Six patients had hemodynamic monitoring performed that revealed parameters consistent with noncardiogenic pulmonary edema. In two patients, the pulmonary insult reversed itself with therapy directed at coccidioidomycosis and not at cardiogenic pulmonary edema. All means are presented ±SD.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Demographics and underlying illnesses of the eight patients are shown in Table 1 . There were five men and four whites. Age ranged from 23 to 65 years. Two patients were pregnant, and three abused drugs. All patients were HIV negative.


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  		Table 1. Demographics and Underlying Illnesses of Eight Patients With Miliary Coccidioidomycosis*

 
These patients constituted approximately 1% of patients (8 of 739) admitted to Kern Medical Center for coccidioidomycosis from 1990 to 1997. Table 2 displays clinical characteristics. In two patients, miliary coccidioidomycosis was originally diagnosed, although four demonstrated a miliary pattern on initial chest radiograph. A chest radiograph with a miliary pattern is shown in Figure 1 . The duration of symptoms before admission ranged from < 1 week to 12 weeks. The mean hospital stay was 43 ± 45 days. Mean arterial PO2 (on room air) was 54.2 ± 8.6 mm Hg (range, 45 to 73 mm Hg), and the mean PCO2 was 32.5 ± 3.2 mm Hg (range, 27 to 37 mm Hg). Five patients required mechanical ventilation, and five had dissemination to sites outside the lung.


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  		Table 2. Clinical Characteristics of Eight Patients With Miliary Coccidioidomycosis*

 


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  		Figure 1. Miliary pattern on chest radiograph from patient 2.

 
Table 3 displays laboratory findings. All coccidioidal skin test results were negative. Four patients had peak CF titers of 1:1024. Peak WBC counts ranged from 11.5 to 69.5 x 109/L, and peak eosinophil counts ranged from 1.2 to 51%. Total lymphocyte counts averaged 2.0 x 109/L (range, 1.2 to 7.7 x 109/L). All tuberculin skin test results were negative.


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  		Table 3. Laboratory Findings of Eight Patients With Miliary Coccidioidomycosis*

 
All patients received fluconazole and/or amphotericin B. Three patients died. One patient survived his original presentation with miliary disease, but died 3 years later of progressive bone, soft tissue, and intra-abdominal involvement culminating in septic shock.


   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
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References
 
In the majority of symptomatic cases, coccidioidomycosis is a self-limited pulmonary infection.1 16 Typical, chest radiographic findings are consistent with segmental or lobar pneumonia; mediastinal and hilar lymphadenopathy also occur.17 Less frequently, coccidioidomycosis disseminates to extrapulmonary sites and may present with a miliary pattern on chest radiograph. Miliary coccidioidomycosis is characterized by the development of numerous small, "millet seed" granulomas throughout the lungs and other organs. This pattern indicates hematogenous or lymphatic spread and has been associated with a high mortality rate.5 6

We describe eight immunocompetent patients with miliary coccidioidomycosis seen over a 7-year period at one institution. These patients comprised 1% of those hospitalized for coccidioidomycosis. Miliary coccidioidomycosis has been portrayed as a form of dissemination most commonly appearing in the severely immunocompromised or immunosuppressed. Reports have described miliary coccidioidomycosis during prolonged corticosteroid therapy,7 8 10 11 12 renal failure,5 after renal transplant,5 and in pregnant women.5 9 The association with immunocompromise appears to be more pronounced in miliary coccidioidomycosis than in other forms of coccidioidal dissemination. Larsen et al6 described 37 patients with respiratory failure and miliary coccidioidomycosis from the literature. Sixty-eight percent were receiving immunosuppressive therapy, and all had coexisting conditions with malignancy (27%), renal failure (24%), collagen vascular disease (22%), and myeloid metaplasia (8%) being the most common.

Characteristics of the study institution may account for the lack of severe immunocompromise in our patients. Kern Medical Center is a public hospital in a growing area and tends to serve young and working-class patients. It is not an organ transplant center, and it is in an area with a low incidence of HIV infection. From 1985 to 1997, 35 cases of concomitant HIV and coccidioidomycosis occurred in Kern County, including four cases of miliary involvement not presented here.

We noted two distinct clinical courses of miliary coccidioidomycosis in the immunocompetent: an acute respiratory illness, and a later stage of chronic coccidioidomycosis in the context of widespread organ involvement. Three white patients presented with an acute illness and primarily respiratory symptoms; they had no overt sites of extrapulmonary involvement and all recovered with therapy. The chronic form was seen in patients who were ethnically predisposed to serious coccidioidal disease. These individuals had multiple sites of involvement and significant morbidity. Extensive involvement in this context leads to eventual overwhelming of the host’s ability to contain the organism and to hematogenous spread. All four patients with a long duration of illness had skin involvement and three had meningitis. The explanation for these different presentations is unknown. As in many infectious diseases, the clinical course depends on the infectivity and virulence of the organism as well as host factors. In addition to the host response, some patients came from disadvantaged environments with limited access to health care and social circumstances prohibiting medical treatment until weeks after the development of symptoms. These two clinical courses should be differentiated from the course in the severely immunocompromised (not presented here). In the immunocompromised, miliary coccidioidomycosis is generally a fulminant illness, heralded by the acute appearance of severe pulmonary disease eventuating in progressive respiratory failure with elevated mortality.

Five patients’ disease progressed to respiratory failure secondary to ARDS. Although this is an ominous finding, three survived, with one of the survivors dying 3 years later from widespread dissemination and septic shock. Of the four white patients, three eventually recovered from their illness, and the one patient who did not recover presented to the hospital after 3 weeks of severe symptoms. The duration of symptoms before the development of a miliary pattern in the patients who recovered tended to be short, and there were no other sites of involvement.

Early recognition of miliary spread and prompt treatment are crucial in avoiding mortality.5 7 18 19 Recognition may be hindered by mistaken diagnoses due to the extensive differential diagnosis of a miliary pattern. Although none of our patients were believed to have tuberculosis (perhaps due to the high clinical suspicion of coccidioidomycosis in Kern County), many examples of this diagnostic error have been reported.5 7 8 14 19 20 This diagnostic difficulty makes it extremely important to perform coccidioidal serology and to elicit a history of travel through endemic areas in the presence of an unconfirmed diagnosis.

Factors pertinent to early recognition are the clinical history and immunologic status of the host, travel through endemic areas, ethnicity, and the involvement of multiple organ sites, particularly the skin and meninges. A high index of suspicion is important, as skin test results are negative and serology is commonly unrevealing early in the course of the illness. Frequent concomitant involvement of extrapulmonary sites make it wise to perform a lumbar puncture, bone scan, and to examine the patient carefully for skin involvement. Pronounced hypoxemia was characteristic of patients in this and other studies5 14 and is another possible clue to miliary spread. Hypoxemia not accounted for by the degree of involvement seen on chest radiograph may be suggestive of forthcoming miliary disease.

The relatively low mortality rate observed in our series contrasts with the literature. Heightened awareness and increased diagnostic accuracy may account for our lower mortality rate. However, this could also be due to the immunocompetency of our patients. It is noteworthy that, with treatment, three of our cases converted to chronic involvement, with other sites of dissemination becoming the focus of disease activity.

Shortcomings of our study include the small number of patients retrospectively gathered from one institution and our inexact definition of immunocompetent. Although total lymphocyte counts were within normal limits, there was no definitive proof of immunocompetency. Two pregnant patients, two IV drug abusers (both HIV negative), and a patient with hepatic encephalopathy (from coccidioidal involvement of the liver without preexisting liver disease) were included in our study. The small sample size selected from 739 coccidioidomycosis patients reflects the rarity of miliary coccidioidomycosis.

Miliary dissemination is a manifestation of coccidioidomycosis with different implications, depending on host characteristics and the time before development of miliary disease. Miliary coccidioidomycosis does not necessarily have the mortality portrayed in the literature, especially with early recognition. In the ethnically or otherwise predisposed, a miliary pattern may signify the beginning of chronic coccidioidal disease, with other sites of involvement becoming the target of treatment.


   Footnotes
 
Abbreviation: CF = complement fixation

Received for publication October 30, 1998. Accepted for publication September 13, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Smith, CE, Beard, RR, Whiting, EG, et al (1946) Varieties of coccidioidal infection in relation to the epidemiology and control of the diseases. Am J Public Health 36,1394-1402
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  5. Rowland, VS, Westfall, RE, Hinchliffe, WA, et al (1977) Acute respiratory failure in miliary coccidioidomycosis. Ajello, L eds. Coccidioidomycosis: current clinical and diagnostic status ,139-155 Symposia Specialists Miami, FL.
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