INTRODUCTION
Histoplasmosis, the most prevalent endemic fungal infection in North America, presents a broad spectrum of clinical manifestations, ranging from pulmonary to disseminated forms, and acute to chronic courses. The causative agent, Histoplasma capsulatum, is a thermally dimorphic fungus, existing as a mold in the environment and transforming into a yeast form within the human body at body temperature. While the definitive diagnosis of histoplasmosis has traditionally relied on the identification of the yeast form in tissue samples and the isolation of the mold in cultures from clinical specimens, the advent of antigen detection assays has significantly advanced diagnostic capabilities. Introduced in 1986, Histoplasma antigen testing offers a rapid, non-invasive, and highly sensitive method for diagnosis, also serving as a valuable tool for monitoring treatment response. Serologic tests for histoplasmosis remain a widely used diagnostic approach, particularly beneficial in chronic disease presentations where antigen detection may be less sensitive. Furthermore, molecular diagnostic methods are emerging with the potential to transform histoplasmosis diagnosis, although they are not yet widely available for routine clinical application.
The European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) have established standardized criteria for diagnosing invasive fungal infections, including those caused by dimorphic fungi (1). According to these criteria, a proven diagnosis necessitates confirmation through histopathology or culture, whereas a probable diagnosis is established based on a compatible clinical presentation, predisposing factors, and mycological evidence, such as the detection of antigen in urine. The Council of State and Territorial Epidemiologists (CSTE) has also developed a consensus case definition for histoplasmosis to standardize reporting across different states and enhance epidemiologic surveillance. These definitions emphasize the multifaceted nature of histoplasmosis diagnosis, often requiring robust laboratory evidence. This review provides a comprehensive overview of current laboratory diagnostics for identifying H. capsulatum, highlighting the complexities of testing and the context-dependent utility of each method for accurate Histoplasmosis Diagnosis Test interpretation.
CULTURE AND MICROSCOPY
Culture remains the cornerstone for the definitive diagnosis of histoplasmosis, considered the gold standard for identifying H. capsulatum. In a clinical microbiology laboratory, H. capsulatum can be detected in cultures after inoculation of clinical specimens onto appropriate media and incubation to allow for fungal growth. Direct microscopy, using specific stains on body fluids and tissue specimens, also aids in rapid presumptive identification. Unlike Candida and Cryptococcus, H. capsulatum yeast cells stain poorly with Gram stain and are rarely identified using this method. Calcofluor white, a fluorescent stain binding to chitin in fungal cell walls, proves valuable for identifying H. capsulatum in specimens submitted for microbiological analysis.
When incubated at 25 to 30°C on suitable media, the mycelial phase of H. capsulatum typically grows within 2 to 3 weeks, but may require up to 8 weeks. Once a colony develops, a lactophenol cotton blue preparation (tease mount) is performed to assess mold morphology. Initially, septated hyphae are observed, followed by smooth (or less frequently, spiny) microconidia (2 to 5 μm in size), and finally, characteristic tuberculate macroconidia (7 to 15 μm in size). If plates are initially incubated at 37°C, yeast-like colonies emerge, and microscopy reveals small, round, narrow-budding yeast cells. Conversion from the mycelial to yeast phase by incubating the mold form at 37°C, while historically used to confirm dimorphism, is now considered impractical for routine diagnosis due to its low success rate. The presence of tuberculate macroconidia is highly suggestive of H. capsulatum, but morphologically similar fungi, such as Sepedonium species, necessitate further confirmation. Commercially available molecular probes offer rapid identification of H. capsulatum isolates (see Molecular Methods), replacing older, more cumbersome methods like exoantigen testing. Due to its infectious nature, H. capsulatum must be handled under biosafety level 3 conditions.
The sensitivity of culture for detecting H. capsulatum is influenced by the clinical presentation (pulmonary vs. disseminated), the patient’s immune status, and the fungal burden (Table 1). Disseminated histoplasmosis exhibits higher culture positivity rates (74%) compared to acute pulmonary histoplasmosis (42%) (3). In HIV/AIDS patients, respiratory cultures can be positive in up to 90% of cases, while blood cultures may be positive in up to 50% (4). Lysis centrifugation blood culture tubes, although less commonly used now, have demonstrated superior sensitivity for H. capsulatum recovery from blood compared to conventional and Bactec MYCO/F Lytic blood cultures (5–7).
TABLE 1.
Summary of diagnostic test for histoplasmosisa
HISTOPATHOLOGY
Histopathologic demonstration of yeast cells consistent with H. capsulatum in tissue provides strong diagnostic support for histoplasmosis, although it does not definitively confirm active infection. H. capsulatum var. capsulatum yeast cells are typically ovoid, measuring 2 to 4 μm, with thin, nonrefractile cell walls and characteristic narrow-based budding. These yeast cells are predominantly found within macrophages and histiocytes, often clustered, but can also be present extracellularly. H. capsulatum var. duboisii, the causative agent of African histoplasmosis, is larger (6 to 12 μm) and easily distinguished from the more common variety. Differential diagnoses to consider when identifying H. capsulatum histopathologically include Cryptococcus spp., Blastomyces dermatitidis, Candida glabrata, Pneumocystis jirovecii, Coccidioides spp., Talaromyces (formerly Penicillium) marneffei, Leishmania spp., Toxoplasma gondii, and Trypanosoma cruzi.
Specific histochemical stains aid in differentiating these pathogens. Gomori methenamine silver (GMS) and periodic acid-Schiff (PAS) stains are particularly useful for visualizing H. capsulatum in tissue sections by staining the yeast cell wall. Hematoxylin and eosin (H&E) staining is often less sensitive for H. capsulatum detection, except when the organism burden is high. Mucicarmine stain helps distinguish Cryptococcus by staining its capsule, creating characteristic halos, although unencapsulated Cryptococcus strains can be differentiated using Fontana-Masson stain to detect cryptococcal melanin. Blastomyces dermatitidis yeast cells are generally larger than H. capsulatum, and their broad-based budding and thicker walls are distinguishing features for smaller forms. Candida glabrata, due to its small size and lack of pseudohyphae, can closely resemble H. capsulatum. Distinguishing features include cellular location (intracellular for H. capsulatum, extracellular for C. glabrata), size and shape uniformity, and histopathologic response (granulomatous vs. suppurative) (8). Pneumocystis jirovecii cysts, like H. capsulatum, stain with PAS and GMS but are larger, lack budding, are predominantly extracellular, and do not stain with mucicarmine. Coccidioides spp. endospores can mimic H. capsulatum in size and shape, necessitating a search for spherules. T. marneffei exhibits a unique transverse septum and does not bud. Leishmania spp., Toxoplasma gondii, and Trypanosoma cruzi are protozoa that do not stain with GMS or PAS but are often visible with H&E. Wright-Giemsa stain on peripheral blood smears can identify intracellular yeast clusters, especially in disseminated disease.
The presence of H. capsulatum yeast in certain tissues or sterile body fluids (e.g., skin lesions) in a compatible clinical context (e.g., acute pneumonia) is highly suggestive of active infection. However, nonviable organisms can persist in mediastinal or lung granulomas for years post-infection. Pathology in these cases often shows incomplete granulomas or fibrosis rather than well-formed pyogranulomatous reactions. Negative cultures, absence of symptoms, and antigenemia assessment are crucial to differentiate between resolved, old, and active infection.
CYTOPATHOLOGY
Cytopathologic examination of tissue aspirates and fluids offers presumptive evidence of histoplasmosis by analyzing individual cells rather than intact tissue architecture. Similar to histopathology, GMS or PAS staining of cytological preparations typically reveals narrow-based budding yeast cells predominantly within macrophages. The sensitivity of cytopathology varies with clinical manifestation (Table 1). Bronchoalveolar lavage (BAL) fluid cytopathology, a relatively non-invasive procedure, has approximately 50% sensitivity for acute pulmonary histoplasmosis. Combining BAL fluid cytopathology with Histoplasma antigen testing significantly increases sensitivity to 97% (9). Fine-needle aspiration is another safe and effective diagnostic method for obtaining cytodiagnosis of histoplasmosis from various sites, including lymph nodes and adrenal glands (10).
ANTIGEN DETECTION
Antigen detection has emerged as a leading modality for histoplasmosis diagnosis test due to its non-invasive nature, broad clinical accessibility, and favorable performance characteristics. Although definitive histoplasmosis diagnosis requires culture or histopathologic confirmation, a probable diagnosis can be established based on host factors (immunocompromise), a compatible clinical presentation, and mycological evidence such as positive antigen testing (1).
The first Histoplasma antigen assay, a sandwich radioimmunoassay, was developed in 1986 and subsequently reformulated into an enzyme immunoassay (EIA) in 1989. A second-generation EIA in 2004 enabled semi-quantitative results, and the third-generation MiraVista H. capsulatum Galactomannan EIA, offering improved specificity and quantitative results, was introduced in 2007. Unlike the MiraVista assay, which requires centralized laboratory processing, the IMMY ALPHA Histoplasma EIA, an in vitro diagnostic EIA approved by the FDA in 2007 for urine specimens, is designed for local facility use. However, studies have shown the IMMY ALPHA assay to have lower sensitivity and specificity compared to the MiraVista assay (11). A later analyte-specific reagent (ASR) H. capsulatum antigen EIA (IMMY) has demonstrated improved performance (12) and high concordance with the MiraVista EIA (13). Nevertheless, direct comparisons between IMMY ASR EIA and MiraVista EIAs have indicated higher sensitivity and generally higher numerical values with the MiraVista EIAs (12, 13).
A large multicenter study evaluating the MiraVista EIA Histoplasma antigen test revealed the highest sensitivity in disseminated histoplasmosis, followed by chronic and acute pulmonary histoplasmosis (91.8%, 87.5%, and 83%, respectively), and the lowest sensitivity in subacute histoplasmosis (30%) (14) (Table 1). The assay’s sensitivity is particularly high in HIV/AIDS patients with disseminated disease, with antigenuria detectable in 95% of cases (15). Mediastinal histoplasmosis manifestations, including mediastinal granuloma and fibrosing mediastinitis, typically do not result in positive antigen tests.
Urine antigen detection generally exhibits slightly higher sensitivity than serum antigen detection across all histoplasmosis manifestations. Combining urine and serum testing enhances antigen detection rates (16). Antigen testing has also been applied to BAL fluid and cerebrospinal fluid (CSF). In pulmonary histoplasmosis, BAL fluid Histoplasma antigen testing can complement urine and serum tests. An earlier study in HIV/AIDS patients reported BAL fluid antigen sensitivity of 70%, compared to 93% in urine and 88.5% in serum (17). However, a more recent study demonstrated superior sensitivity of BAL fluid antigen testing (93%) compared to both urine (79%) and serum (65%), identifying cases missed by urine and serum methods (9). In Histoplasma meningitis, antigen detection in CSF has a reported sensitivity ranging from 40% to 65% (18, 19). More recent data suggest CSF antigen sensitivity may reach up to 85% when samples are drawn within 14 days of antifungal treatment initiation in proven CNS histoplasmosis cases (unpublished data). It is important to note that antigen testing on non-FDA-approved specimens often relies on less robust data, may be affected by interfering substances, and requires validation studies to establish performance characteristics.
Beyond diagnosis, the quantitative nature of the third-generation Histoplasma antigen EIA enables sequential monitoring of antigen clearance. Serum antigen levels have been shown to decrease with effective treatment and increase with treatment failure, serving as a valuable marker for treatment response. Data on antigenemia and antigenuria monitoring are most robust in HIV/AIDS patients, where antigen levels in urine and serum below 2 ng/mL typically correlate with successful therapy (20).
A significant limitation of Histoplasma antigen testing is cross-reactivity with antigens from other fungi, including Blastomyces dermatitidis, Paracoccidioides brasiliensis, T. marneffei, and less frequently, Coccidioides immitis and Coccidioides posadasii (see Table 2). False-positive reactions have also been observed in 15% of transplant recipients receiving anti-thymocyte globulin for rejection prophylaxis (21). While low-positive results are more likely to be false positives, they can still be clinically significant. A study of 25 patients with low-positive results and no prior histoplasmosis history revealed that 13 had active histoplasmosis confirmed by other methods (histopathology, culture, serology, or PCR), and 5 had other endemic fungal infections (blastomycosis or coccidioidomycosis) (22).
TABLE 2.
Cross-reactivity of Histoplasma antigen with other fungi
aData based on single patient.
SEROLOGY
Antibody detection typically becomes positive 4 to 8 weeks after infection onset, rendering serology less useful for diagnosing early acute histoplasmosis. Serologic testing is most valuable for subacute and chronic histoplasmosis forms (including mediastinal histoplasmosis), where circulating antibodies are present and antigen detection sensitivity may be suboptimal (Table 1). Similar to other serologic tests, a positive H. capsulatum antibody test indicates prior exposure to the fungus. However, in specific contexts, serologic findings can provide evidence of acute infection (Table 3). The three primary serologic assays for histoplasmosis are immunodiffusion (ID), complement fixation (CF), and enzyme immunoassay (EIA).
The CF test detects serum antibodies based on complement fixation to complexes of patient antibodies with yeast-phase and mycelium-phase (histoplasmin) antigens. Acute infection is defined by a ≥4-fold rise in antibody titers between acute and convalescent-phase sera. A titer of 1:8 is considered positive, indicating past H. capsulatum exposure. A titer of ≥1:32 or a 4-fold titer increase is strongly suggestive of active infection (23). Antibody titers usually decline with disease resolution, but the decrease is slow and often incomplete, limiting its utility for assessing treatment response. The ID test detects precipitating serum antibodies to H and M H. capsulatum antigens in agar gel. The M band is detected in most acute histoplasmosis patients (80%) but can persist long-term, making a single positive M band unable to differentiate active from latent or resolved disease. H precipitins are less frequent (20%) but, when present, confirm acute infection. CF is generally more sensitive than ID (90% vs. 80%, respectively) (23). Cross-reactivity with other fungal infections or conditions (especially granulomatous diseases like tuberculosis and sarcoidosis) can occur with both assays, but is more common with CF (24). EIA methods, while more sensitive than CF and ID, may exhibit lower specificity (25). Serology remains useful even in highly endemic areas, where surprisingly, less than 5% of individuals have positive serology by CF or ID (23). CSF antibody detection by CF or ID is diagnostic for Histoplasma meningitis and more sensitive than CSF cultures (26). The CSTE has defined serologic criteria confirming acute infection, with a single criterion being sufficient for diagnosis (Table 3). Immunosuppressed patients, especially those with impaired humoral immunity, may not mount an antibody response. Studies suggest that most patients on tumor necrosis factor inhibitors have positive serology, while only 25 to 30% of solid organ transplant recipients develop an antibody response (27, 28). Combining antibody and antigen testing can significantly improve diagnostic sensitivity in acute pulmonary histoplasmosis (29).
TABLE 3.
Serologic evidence of acute infection per CSTE criteriaa
aFulfillment of a single criterion is sufficient for a diagnosis of acute histoplasmosis.
bCF, complement fixation; ID, immunodiffusion.
cCSF, cerebrospinal fluid.
MOLECULAR METHODS
Molecular methods offer high analytical specificity and faster turnaround times compared to traditional histoplasmosis diagnosis test methods. However, currently, no FDA-approved molecular assays are available for direct clinical specimen testing for H. capsulatum. Various laboratory-developed PCR assays targeting different molecular targets have been developed (Table 4). Compared to culture and criterion-based or clinical diagnosis of histoplasmosis, molecular assay sensitivity in studies ranges from 67 to 100% (30–35) and 33 to 87% (36, 37, respectively. Fluorescence in situ hybridization (FISH) techniques detecting H. capsulatum rRNA in blood cultures may eliminate the need for colony growth, enabling faster definitive diagnosis (35). Although culture is considered the gold standard, molecular methods may exhibit higher sensitivity. A study comparing real-time PCR to culture showed that 10 of 11 culture-negative, PCR-positive samples were confirmed as histoplasmosis based on positive cultures from other sites or histopathology (33). Fewer studies compare molecular methods to antigen and antibody detection. A PCR-enzyme immunoassay method showed only 18.5% sensitivity compared to high-level antigenuria (>20 U) (34), while a nested PCR detected 86% of cases with elevated H. capsulatum-specific antibodies (1:320 to 1:2,560) (38). The heterogeneity of molecular assays, targets, small patient numbers, varied specimen types, and comparator diagnostic methods limit the generalizability of these findings. Nonetheless, molecular methods hold significant potential to revolutionize histoplasmosis diagnosis, and improved assays are expected to play a larger role in the future.
TABLE 4.
Laboratory-developed molecular methods for detection of H. capsulatum in clinical specimens
aLAMP, Loop-mediated isothermal amplification; EIA, enzyme immunoassay; FISH, fluorescence in situ hybridization.
bNAALADase, N-acetyl-l-aspartyl-l-glutamate peptidase. “[220]” refers to a 220-bp fragment that was amplified using primers 1281 to 1283.
cPDH, progressive disseminated histoplasmosis; EORTC, European Organization for Research and Treatment of Cancer. *, all patients except 1 were HIV positive. N NR, number not reported.
dBAL, bronchoalveolar lavage; CSF, cerebrospinal fluid; FFPE, formalin-fixed paraffin-embedded tissue.
eNR, not reported; ND, not done.
Currently, the primary molecular histoplasmosis diagnosis test in clinical practice involves applying rapid DNA probes to fungal isolates from cultures. The AccuProbe test utilizes a chemiluminescent-labeled single-stranded DNA probe complementary to fungal rRNA sequences. Luminometer-measured fluorescence from labeled DNA:RNA hybrids determines positivity based on predefined cutoff values (39). Certain commercial laboratories offer tissue-based PCR testing and sequencing, including broad-range PCR of fungal 28S ribosome and internal transcribed spacer (ITS) sequences, as well as Histoplasma-specific PCR assays. However, the performance and clinical validation of these assays require further clarification.
SUMMARY AND CONCLUSIONS
Culture isolation of H. capsulatum and histopathologic yeast identification remain the gold standards for histoplasmosis diagnosis. Antigen testing provides a highly sensitive, easily interpretable, and clinically accessible alternative. Molecular methods are promising for future diagnostics, though current assays lack FDA approval for routine clinical use. Optimal histoplasmosis diagnosis test selection depends on the disease stage, infection site, clinical specimen type, and patient’s immune status. Clinical microbiology laboratories are crucial resources for clinicians in selecting and interpreting appropriate diagnostic tests for histoplasmosis.
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