This systematic synthesis of 508 unique published cases shows that reported histoplasmosis in India is geographically widespread and clinically heterogeneous, with extrapulmonary and disseminated disease prominently represented. These findings should be interpreted as patterns within the published literature rather than estimates of national epidemiology, incidence, endemicity, or geographic burden. The reported distribution has historically been linked to the Ganga–Yamuna river basin, where environmental conditions may favour the growth of Histoplasma capsulatum [12, 13]. Reports from West Bengal and Delhi likely reflect a combination of ecological factors, referral patterns, and historical mycological expertise [9, 13,14,15]. However, referral pathways, diagnostic infrastructure, clinician awareness, and publication practices likely influence the apparent geographic clustering. The increase in reported cases after 2015 may similarly reflect improved recognition, diagnostic access, reporting, journal indexing, and online availability rather than a true rise in incidence. In the absence of prospective surveillance or population-based data, this review cannot determine whether the true national burden has increased.

The predominance of extrapulmonary and disseminated disease should be interpreted in light of disease biology, diagnostic ascertainment, and publication bias. After inhalation of Histoplasma microconidia, many exposed individuals remain asymptomatic or develop self-limited pulmonary disease [1]. Symptomatic pulmonary disease may resemble influenza-like illness, community-acquired pneumonia, tuberculosis, or sarcoidosis and may resolve without diagnosis; therefore, pulmonary, subacute, nodular, and less severe forms are likely underdiagnosed and under-reported in India [1, 4]. In contrast, disseminated histoplasmosis often produces conspicuous and biopsy-accessible extrapulmonary manifestations. Cutaneous and mucosal lesions may provide an early diagnostic clue [16]. Adrenal involvement, often presenting as bilateral adrenal enlargement with or without adrenal insufficiency, is well recognised in Indian case series [17]. Its frequent reporting may reflect both biological susceptibility and diagnostic ascertainment, as Histoplasma disseminates within macrophages to reticuloendothelial organs and the adrenal glands are highly vascular [18, 19]. Lymph node, liver, spleen, and bone marrow involvement may also prompt biopsy or aspiration [20, 21]. Consequently, the published Indian literature likely over-represents severe, unusual, disseminated, and biopsy-confirmed disease, and the organ-wise frequencies should not be interpreted as the true anatomical distribution of histoplasmosis in India [22].

The exploratory comparisons should be interpreted cautiously. The included reports span several decades and differ in diagnostic methods, completeness of reporting, referral context, treatment availability, and publication era. The immunosuppression category was also heterogeneous, including HIV infection, diabetes mellitus, transplantation, malignancy, and immunosuppressive drug exposure. Host defence against Histoplasma capsulatum depends largely on cell-mediated immunity, particularly CD4⁺ T-cell-mediated macrophage activation and granuloma formation [1, 3, 23]. Impairment of these pathways, as occurs in advanced HIV infection or immunosuppressive therapy, may facilitate intracellular proliferation and dissemination [24]. In this context, the higher frequency of lymph node involvement among immunosuppressed patients and the higher frequency of laryngeal involvement among apparently immunocompetent patients may reflect differences in host immunity, site-specific recognition, or reporting patterns rather than distinct disease entities. These findings should therefore be viewed as hypothesis-generating observations rather than adjusted clinical associations [25].

A major finding of this review is the dependence on tissue-based diagnosis. The combined microscopy/histopathology/cytology category accounted for most diagnoses, while culture, antigen detection, and molecular testing were used far less often. Histopathology and cytology remain pragmatic diagnostic tools in many low- and middle-income settings because they are relatively accessible and can rapidly demonstrate characteristic yeasts. However, fungal culture remains the traditional reference standard [1, 26]. Antigen detection can support rapid, non-invasive diagnosis, particularly in disseminated disease, but its reported use was limited [4, 27]. This diagnostic pattern likely shaped the published literature by favouring biopsy-confirmed disseminated disease while under-representing pulmonary, self-limited, or diagnostically challenging cases.

Treatment data were also incomplete; therefore, treatment findings should be interpreted as descriptions of reported practice rather than evidence of comparative effectiveness. Most patients with available treatment data received amphotericin B, itraconazole, or both, consistent with broad treatment principles for histoplasmosis [1, 3, 28, 29]. Liposomal amphotericin B is generally preferred in severe disseminated disease because of better tolerability, but cost and access remain important constraints; amphotericin B deoxycholate, therefore, remains relevant in resource-limited settings when renal toxicity can be monitored [30]. Shortened high-dose liposomal amphotericin B induction regimens are promising but were not represented among the Indian cases included in this review and require further evaluation in the Indian context [31]. Mortality remained substantial, with deaths more frequently reported among patients with pleural, gastrointestinal, hepatic, splenic, lymph node, and bone marrow involvement. Adrenal involvement was less frequent among patients who died than among survivors. These findings should be interpreted as unadjusted descriptive patterns within reported cases rather than adjusted prognostic associations [4, 32].

This review has several limitations inherent to its reliance on published case reports and case series. First, it characterises patterns among reported cases rather than the true epidemiology of histoplasmosis in India. It cannot estimate incidence, prevalence, endemicity, national burden, or geographic risk. Publication bias is likely, with severe, unusual, disseminated, fatal, or biopsy-confirmed cases preferentially reported. Mild, self-limited, pulmonary, or otherwise nonspecific presentations are probably under-recognised. Referral pathways, clinician awareness, specialist centres, diagnostic infrastructure, and publication practices also influence the apparent geographic distribution. Although we used a comprehensive search strategy across three databases and screened reference lists, some older or inadequately indexed reports may have been missed. Anatomical site involvement was defined using prespecified criteria, but compatible clinico-radiological involvement of additional organs was accepted in patients with confirmed histoplasmosis when direct tissue confirmation was unavailable. Some degree of organ misclassification cannot be excluded.

Several reports also lacked complete diagnostic, treatment, follow-up, or outcome data. This limited assessment of treatment effectiveness, temporal changes in management, and robust prognostic analyses. The exploratory comparisons between immunosuppressed and immunocompetent patients and between survivors and non-survivors were unadjusted. They may have been influenced by residual confounding, diagnostic delay, treatment access, completeness of reporting, and era of diagnosis. Nevertheless, by synthesising individual patient-level data from 508 unique reported cases across more than six decades, this review provides the most comprehensive description to date of how histoplasmosis has been recognised, diagnosed, treated, and reported in India.

In summary, this systematic review of 508 unique published cases demonstrates that reported histoplasmosis in India is geographically widespread and clinically heterogeneous. Extrapulmonary and disseminated disease are prominently represented in the published literature. Diagnosis has relied mainly on tissue-based microscopy, histopathology, and cytology, whereas culture, antigen detection, and molecular methods have been used far less often. Pulmonary, self-limited, and less dramatic presentations are likely under-recognised and under-reported. Although this review cannot define the true epidemiology or burden of histoplasmosis in India, it maps the reported clinical, diagnostic, treatment, and outcome patterns across the country. Improved awareness, better access to modern diagnostics, and prospective multicentre studies are needed to define the full clinical spectrum and epidemiology of histoplasmosis in India.