Final Diagnosis
Disseminated Coccidioides Posadasii
Discussion
Molecular testing by the reference laboratory yielded the identification of Coccidioides posadasii. The cytology findings do raise concerns for a second mold, namely Blastomyces dermatitidis due to the morphology present. It would be difficult to detect a second filamentous mold isolate on fungal cultures as the agar surface would be overgrown by the Coccidioides posadasii isolate. Overlapping Coccidioides endospores from a ruptured spherule can appear like budding yeast. Further, Blastomyces Antigen testing of the BAL fluid was negative.
Coccidioides posadasii as a Pathogen
Coccidioidomycosis is caused by two genetically distinct but clinically indistinguishable dimorphic fungi: Coccidioides immitis and Coccidioides posadasii. C. posadasii is widely distributed throughout the southwestern United States, including Arizona, as well as northern Mexico and parts of Central and South America, while C. immitis is primarily confined to California and select western states. The patient's travel history to Arizona placed them at risk for acquiring C. posadasii, which is the predominant species in that region. Both species exist as mycelial forms in soil and convert to spherules in tissue, with infection typically occurring through inhalation of arthroconidia1,2.
In patients with HIV, the risk of severe coccidioidomycosis increases substantially when CD4 counts fall below 250 cells/mm³ and when HIV viremia is not suppressed. Clinical presentations range from focal pneumonia in those with higher CD4 counts to diffuse pulmonary disease and extrathoracic dissemination in severely immunocompromised individuals. Diffuse pneumonia presents with fever, dyspnea, and reticulonodular infiltrates that can mimic Pneumocystis jirovecii pneumonia, while disseminated disease may involve meningitis, osteoarticular infection, and other extrathoracic sites3–5.
Morphologic Overlap and Diagnostic Challenges
A significant challenge in diagnosing fungal infections in immunocompromised patients is the morphologic overlap between different fungal species on histopathology. While Coccidioides species produce distinctive large spherules (40-90 μm) with doubly refractile walls containing endospores that stain strongly with hematoxylin and eosin, Gomori methenamine silver (GMS), and periodic acid-Schiff (PAS) stains, other endemic fungi can present with overlapping features that complicate diagnosis6.
Histopathological examination alone may not reliably distinguish between different fungal genera and species. For instance, Cryptococcus neoformans/gattii and Histoplasma capsulatum can present atypical features that lead to diagnostic errors, with one study finding that expert pathologist review modified initial diagnoses in 25.9% of cases7,8. Similarly, morphological features of filamentous fungi, including septation, filament size, and branching angles, show considerable overlap among genera, making definitive identification by microscopy alone unreliable. The presence of pseudohyphae from Candida species can be confused with true filamentous fungi, further complicating interpretation6,7.
Endemic dimorphic fungi do possess more specific morphological characteristics that can aid identification: Histoplasma appears as small intracellular budding yeasts (2-4 μm), Blastomyces dermatitidis as thick-walled broad-based budding yeasts, and Paracoccidioides brasiliensis with a characteristic pilot-wheel configuration. However, cross-reactivity in serologic testing between endemic mycoses, such as positive Histoplasma antigen results in patients with coccidioidomycosis, adds another layer of diagnostic complexity4,9.
Laboratory Detection and Culture Considerations
The diagnosis of coccidioidomycosis relies on a combination of serology, culture, histopathology, and increasingly molecular methods. Unlike other endemic fungi, Coccidioides species grow relatively rapidly at 37°C on routine bacterial media, particularly blood agar, with growth observable in as few as 3 to 7 days. This rapid growth presents a significant biosafety hazard because arthroconidia can become airborne if culture plates are disturbed, necessitating biosafety level 3 or 2+ containment for identification1,10.
Laboratory personnel should be alerted when coccidioidomycosis is suspected, and culture plate lids must be secured with tape to prevent accidental exposure. Despite these precautions, culture sensitivity is limited, and blood cultures are positive in fewer than 15% of cases overall, primarily in those with diffuse pulmonary disease, while cerebrospinal fluid cultures are positive in fewer than 50% of children with meningitis and only 7% to 33% of adults4,11.
Serologic and Antigen-Based Diagnostics
Serologic testing provides the laboratory basis for diagnosis in most cases, though antibody development may take several weeks in immunocompetent hosts and longer in immunocompromised patients. Screening with enzyme immunoassay (EIA) for IgM and IgG antibodies offers rapid turnaround and high sensitivity, though false-positive results can occur, particularly for IgM. Positive EIA results should be confirmed with immunodiffusion (ID) and complement fixation (CF) testing1,4,12.
However, serology may be falsely negative in immunocompromised hosts who cannot mount robust antibody responses. In such cases, Coccidioides antigen detection in urine, serum, or cerebrospinal fluid can be valuable, with particularly high sensitivity and specificity for diagnosing coccidioidal meningitis. Real-time PCR assays are commercially available and can be performed on unfixed clinical specimens and formalin-fixed tissue, though these have not been FDA-approved or extensively tested in HIV-infected populations1,3,4,12.
The timing of diagnostic testing is critical in immunocompromised patients. Repeat serologic testing every 1 to 2 weeks should be considered if the patient remains ill and the diagnosis has not been established, as negative serology cannot definitively rule out disease. For patients with suspected invasive fungal disease, all samples should be cultured for fungi using specific media, and specimens from invasive procedures should undergo microscopic examination with appropriate stains1,13,14.
Treatment Considerations in HIV-Infected Patients
The Infectious Diseases Society of America recommends antifungal therapy for all HIV-infected patients with clinical evidence of coccidioidomycosis and CD4 counts below 250 cells/mm³, with treatment continued as long as immunosuppression persists. Azole antifungals (fluconazole, itraconazole, voriconazole, posaconazole, isavuconazole) are first-line agents for most presentations, though amphotericin B formulations may be necessary for severe disease or central nervous system involvement5,15.
Antiretroviral therapy (ART) is a critical therapeutic element in managing HIV-associated coccidioidomycosis, as immune reconstitution directly impacts disease severity and outcomes. The incidence and severity of coccidioidomycosis have declined dramatically since the introduction of potent ART. However, clinicians must be aware of complex and potentially bidirectional drug interactions between azole antifungals and certain antiretroviral agents, particularly as itraconazole, voriconazole, and posaconazole are potent inhibitors of hepatic cytochrome P450 3A43,15.
For patients living in endemic areas, yearly serologic screening and chest radiography are recommended, even in the absence of symptoms, as elevated Coccidioides antibody titers can indicate risk of subsequent symptomatic disease when CD4 counts decline. Antifungal prophylaxis is generally not recommended15.
References
1. Kirkland TN, Stevens DA, Hung CY, et al. Coccidioides Species: A Review of Basic Research: 2022. Journal of Fungi [Internet] 2022 [cited 2025 Dec 14];8(8):859. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC9409882/
2. Hector RF, Rutherford GW, Tsang CA, et al. The Public Health Impact of Coccidioidomycosis in Arizona and California. International Journal of Environmental Research and Public Health 2011, Vol 8, Pages 1150-1173 [Internet] 2011 [cited 2025 Dec 14];8(4):1150–73. Available from: https://www.mdpi.com/1660-4601/8/4/1150
3. Blair JE, Ampel NM, Hoover SE. Coccidioidomycosis in selected immunosuppressed hosts. Med Mycol [Internet] 2019 [cited 2025 Dec 14];57(Supplement_1):S56–63. Available from: https://pubmed.ncbi.nlm.nih.gov/29669037/
4. - Panel on Guidelines for the Prevention N, of Opportunistic Infections in Adults T, with HIV A. Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV How to Cite the Adult and Adolescent Opportunistic Infection Guidelines: Panel on Guidelines for the Prevention and Treatment of Opportunistic Infe…. [cited 2025 Dec 14];Available from: https://clinicalinfo.hiv.gov/
5. Ampel NM. Coccidioidomycosis in persons infected with HIV-1. Ann N Y Acad Sci [Internet] 2007 [cited 2025 Dec 14];1111:336–42. Available from: https://pubmed.ncbi.nlm.nih.gov/17363429/
6. Sangoi AR, Rogers WM, Longacre TA, Montoya JG, Baron EJ, Banaei N. Challenges and Pitfalls of Morphologic Identification of Fungal Infections in Histologic and Cytologic Specimens: A Ten-Year Retrospective Review at a Single Institution. Am J Clin Pathol [Internet] 2009 [cited 2025 Dec 14];131(3):364–75. Available from: https://dx.doi.org/10.1309/AJCP99OOOZSNISCZ
7. Sunagawa K, Nakamura S, Sato Y, et al. Morphological and genetic identification of fungal genus/species in formalin-fixed, paraffin-embedded specimens obtained from patients with histologically proven fungal infection. Mycoses [Internet] 2021 [cited 2025 Dec 14];64(8):851–9. Available from: https://pubmed.ncbi.nlm.nih.gov/34028893/
8. Trecourt A, Rabodonirina M, Donzel M, et al. Cryptococcus neoformans/gattii and Histoplasma capsulatum var. capsulatum infections on tissue sections: Diagnostic pitfalls and relevance of an integrated histomolecular diagnosis. Med Mycol [Internet] 2024 [cited 2025 Dec 14];63(1). Available from: https://pubmed.ncbi.nlm.nih.gov/39732625/
9. Schwartz S, Kontoyiannis DP, Harrison T, Ruhnke M. Advances in the diagnosis and treatment of fungal infections of the CNS. Lancet Neurol [Internet] 2018 [cited 2025 Dec 14];17(4):362–72. Available from: https://pubmed.ncbi.nlm.nih.gov/29477506/
10. Thompson GR, Le T, Chindamporn A, et al. Global guideline for the diagnosis and management of the endemic mycoses: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology. Lancet Infect Dis [Internet] 2021 [cited 2025 Dec 14];21(12):e364–74. Available from: https://pubmed.ncbi.nlm.nih.gov/34364529/
11. Panel on Opportunistic Infections in Children with N, to HIV E. Guidelines for the Prevention and Treatment of Opportunistic Infections in Children With and Exposed to HIV How to Cite the Pediatric Opportunistic Infection Guidelines. [cited 2025 Dec 14];Available from: https://clinicalinfo.hiv.gov/
12. Hage CA, Carmona EM, Epelbaum O, et al. Microbiological Laboratory Testing in the Diagnosis of Fungal Infections in Pulmonary and Critical Care Practice. An Official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med [Internet] 2019 [cited 2025 Dec 14];200(5):535. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC6727169/
13. Lehrnbecher T, Becker K, Groll AH. Current Algorithms in Fungal Diagnosis in the Immunocompromised Host. Methods Mol Biol [Internet] 2017 [cited 2025 Dec 14];1508:67–84. Available from: https://pubmed.ncbi.nlm.nih.gov/27837498/
14. Schelenz S, Barnes RA, Barton RC, et al. British Society for Medical Mycology best practice recommendations for the diagnosis of serious fungal diseases. Lancet Infect Dis [Internet] 2015 [cited 2025 Dec 14];15(4):461–74. Available from: https://pubmed.ncbi.nlm.nih.gov/25771341/
15. Galgiani JN, Ampel NM, Blair JE, et al. 2016 Infectious Diseases Society of America (IDSA) Clinical Practice Guideline for the Treatment of Coccidioidomycosis. Clinical Infectious Diseases [Internet] 2016 [cited 2025 Dec 14];63(6):e112–46. Available from: https://dx.doi.org/10.1093/cid/ciw360