Clinical spectrum of pediatric histoplasmosis in Mexico: description of seven cases and literature review

Introduction

Histoplasmosis is an endemic systemic mycosis caused by the dimorphic fungi Histoplasma capsulatum. Recent taxonomic changes recognize five phylogenetic distinct species of H. capsulatum: H.capsulatum sensu stricto, H. mississippiense, H. suramericacum, H. ohiense and an african lineage of Histoplasma (1). In 2024, Sepulveda et al. discovered that these species not only differ in their genetic lineage but also in their phenotypic characteristics like morphology, size of colonies, growth and production of proteases (1). Although histoplasmosis has worldwide distribution (excluding Antarctica), it exhibits high endemicity in most regions of America (2). In North America, histoplasmosis is mainly found in the Ohio, Mississippi, and St. Lawrence River valleys. Meanwhile in Latin America and the Caribbean, epidemiological models developed by Adenis et al. estimate a global prevalence of exposure of 32.2% with the use of skin reactivity tests with variations ranging from 0.1% in Chile to 57.2% in Guatemala (3). The higher rates of exposure (>30%) are located in the Guianas region, Venezuela, Argentina and Central America; however, Mexico, Brazil and Colombia, house the higher burden of disease in the region, with more than 1500 cases each year (3).

Epidemiologic information of histoplasmosis in Mexico is scarce, and the previously reported estimated annual rate of 0.29/100,000 is highly underestimated because it is based on information from outbreaks between 1988 – 1994 (4). In Mexico, histoplasmosis is not a reportable disease, therefore there are no surveillance programs; there is low clinical suspicion, even in endemic regions, and access to diagnostic tests is limited. However, histoplasmosis is widely distributed throughout Mexico, with the highest prevalence in the central and southeastern regions (5). Even more limited is the information regarding pediatric cases in Mexico. At least three case series have been previously reported: 25 cases by Mohs et al. in 1975, 38 cases by Jimenez et al. in 1980 highlighting a high mortality of 61%, and 8 autopsy cases by García et al., 1993 (6–8).

Histoplasmosis exhibits a wide spectrum of clinical manifestations, ranging from an asymptomatic to disseminated disease; asymptomatic infection is the most common clinical presentation occurring in almost 90% of all cases (9, 10). Histoplasmosis infection is classified in: acute and subacute pulmonary histoplasmosis, cavitary pulmonary histoplasmosis, pulmonary nodules, mediastinal histoplasmosis and disseminated disease (9). Acute infection usually presents 1 to 3 weeks after exposure with the microorganism, mimicking the symptoms of a community acquired pneumonia like fever, cough, dyspnea and chest pain while a subacute infection will present as a milder form of acute disease with clinical improvement after 30 days in most patients. Non respiratory manifestations may occur in a select group of patients principally with arthritis, pericarditis and erythema nodosum or multiforme (9, 10). Chronic cavitary form presents in 2-8% of all the patients with histoplasmosis, it is often progressive and symptoms might take years to develop; this form of infection resembles the clinical course of pulmonary tuberculosis (9, 10). Pulmonary nodules are usually asymptomatic and often difficult to distinguish from malignancy or tuberculosis (9, 10). Mediastinal histoplasmosis usually presents after an acute infection and is self-limiting but in some cases this can develop into a granulomatous mediastinitis that might give symptoms associated with obstruction or impingement or fibrosing mediastinitis being hemoptysis the most common presentation (9, 10). Disseminated histoplasmosis is most commonly seen in immunocompromised patients specially those with an impaired cell-mediated immunity either caused by a primary disease like human immunodeficiency virus (HIV) or by immunotherapy such as TNF-alpha-targeted antibodies. Disseminated histoplasmosis is defined as a clinical course that does not improve after 3 weeks of observation; these patients present fever, weight loss, fatigue, night sweats that might progress to adrenal insufficiency, hemophagocytic syndrome or shock (9, 10).

Humid soils enriched with nitrogen and phosphates from bat and bird droppings are the ecological niche of Histoplasma spp (2, 11). Infection is acquired via inhalation of aerosolized microconidia following mechanical disruption of these microfoci (2). In immunocompetent hosts, cellular immune response contains the primary infection resulting in asymptomatic or self-limited respiratory disease. However clinical severity and progression depend on the exposure of inoculum size, integrity of the respiratory tract, host’s cellular immunity and extremes of age (11). Unlike adults, pediatric patients present distinct anatomical, immunological and socioeconomic vulnerabilities. Immaturity of the immune system in infants and young children facilitates the development of progressive disseminated histoplasmosis with central nervous system (CNS) involvement and high mortality (2, 12). Additionally, pediatric histoplasmosis represents a diagnostic challenge because of non-specific clinical features, frequently mimicking tuberculosis which leads to misdiagnosis and treatment delays that increase mortality (12). Therefore, the aim of this article is to describe the clinical, radiological and laboratory characteristics of a case series of children with histoplasmosis, to optimize early recognition and timely clinical management.

Materials and methods

We conducted a retrospective descriptive study including all proven cases of histoplasmosis diagnosed and managed over a 5-year period, between January 2020 and December 2025, at the Instituto Nacional de Pediatría in Mexico City, a tertiary referral pediatric center serving patients from across Mexico, particularly from the central and southern regions of the country. Only cases of proven histoplasmosis were included, according to the criteria established by the European Organization for Research and Treatment of Cancer/Mycoses Study Group Education and Research Consortium (EORTC/MSGERC): identification of H.capsulatum by culture or the visualization of intracellular yeasts in histopathological examination (32).

The collected variables included age, sex, demographic characteristics, underlying immunological status, comorbidities, clinical manifestations, laboratory findings, imaging studies, diagnostic methods, antifungal treatment, and clinical outcomes. Data were extracted from medical records using a standardized collection form. Data management and analysis were performed using descriptive statistics.

Case descriptions

Case 1

15-year-old male from Veracruz (Table 1) with a 2-month history of a progressive mass in the left inguinal region (4x6 cm), associated with nocturnal fever, a 5 kg weight loss, and dyspnea. An abdominal-pelvic CT scan revealed retroperitoneal lymph nodes compressing adjacent structures. A presumptive diagnosis of classical Hodgkin lymphoma was established via lymph node biopsy and immunohistochemistry in the referring center. A review of the histopathological study also identified granulomatous inflammation with areas of necrosis, multinucleated giant cells, and PAS- and Grocott-positive yeast structures. The presence of bats around the household was confirmed. Management for Gray Zone Lymphoma with rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was started, preceded by 2 weeks of liposomal amphotericin B (L-AmB) due to the concurrent diagnosis of disseminated histoplasmosis confirmed by histopathology and a chest CT scan that showed mediastinal lymphadenopathy. He continued treatment with itraconazole for 1 year while completing oncological therapy. A new PET-CT for lymphoma surveillance showed pulmonary nodules 10 months after discontinuing itraconazole, without other symptoms; lymphoma relapse was ruled out. Itraconazole therapy was restarted at 400mg/day for 6 months with complete resolution, leading to treatment completion. The patient currently remains under clinical and radiological surveillance, with no signs of disease.

Table 1. Clinical and demographic characteristics of patients with histoplasmosis (n=7).

Ver, Veracruz; Gro, Guerrero; Edo, State of México; Oax, Oaxaca; HIV, Human Immunodeficiency Virus; LH, Langerhans Histiocytosis; ALL, Acute Lymphoblastic Leukemia; DH, Disseminated Histoplasmosis; CPH, Chronic Pulmonary Histoplasmosis; APH, Acute Pulmonary Histoplasmosis ; BMB, Bone Marrow Biopsy; L-AmB, Liposomal Amphotericin B.

*Computed tomography findings.

**Magnetic Resonance Imaging findings.

Case 2

15-year-old male from Guerrero with a 7-month history of weight loss (>8 kg), nocturnal diaphoresis, asthenia/adynamia, and abdominal pain, later associated with dysphagia and an episode of herpes zoster. HIV infection was confirmed with positive ELISA and NAAT (Nucleic Acid Amplification Test) tests and antiretroviral therapy was started with bictegravir/emtricitabine/tenofovir. Weeks later he developed fever and progressive abdominal distension, as well as oral and esophageal candidiasis. Due to the persistent constitutional symptoms and chest and abdominal-pelvic CT findings showing retroperitoneal lymph node conglomerates and a diffuse pulmonary micronodular pattern, he was referred to our center for evaluation suspecting of disseminated tuberculosis versus lymphoproliferative disease. Upon admission the patient was classified as stage 3 (AIDS) with a CD4 count of 31 cells/µL. Diagnostic workup ruled-out Mycobacterium tuberculosis infection and Pneumocystis jirovecii pneumonia with negative cultures and bronchoalveolar lavage (BAL) PCR. Due to persistent dysphagia and a history of Candida esophagitis, gastrointestinal tract biopsies were performed reporting chronic duodenitis with abundant intracellular yeasts compatible with Histoplasma spp. Subsequently mesenteric lymph node biopsies identified abundant intracellular yeasts compatible with Histoplasma spp., thereby establishing the diagnosis of disseminated histoplasmosis. Treatment was initiated with L-AmB, followed by itraconazole as consolidation therapy. He completed 21 months of antifungal treatment; however, due to the persistence of significant cellular immunosuppression associated with HIV infection (CD4 count of 178 cells/µL), secondary prophylaxis with itraconazole was restarted 1 month later. The patient currently remains without clinical signs of infectious activity and continues follow-up with the infectious diseases department.

Case 3

12-year-old female from the State of Mexico with diagnosis of acute lymphoblastic leukemia (ALL) receiving maintenance chemotherapy with methotrexate and mercaptopurine. Her condition involved prolonged fever (>1 month) with an extensive diagnostic workup, including blood and bone marrow cultures, yielding no microbiological isolation. Initially, discordant findings existed in the histopathological interpretation of bone marrow biopsies; however, a biopsy performed 2 months after the onset of fever reported moderate bone marrow hypoplasia (cellularity of 50%) also showing intracellular yeast within macrophages in the Wright stain, compatible with Histoplasma spp., establishing the diagnosis of disseminated histoplasmosis. At that moment, the patient was asymptomatic, and chest imaging showed no abnormalities. Due to a history of anaphylaxis to amphotericin B, management was initiated with itraconazole (10mg/kg/day). At 6 months of treatment, a new bone marrow biopsy showed no yeasts, and there was no growth of Histoplasma spp. in culture. She remains under itraconazole treatment for 8 months, with hematology and infectious diseases follow up without clinical signs of active histoplasmosis.

Case 4

15-year-old female from Chilpancingo, Guerrero with history of Langerhans cell histiocytosis at 6-month surveillance, when a PET-CT found a 15.6mm pulmonary nodule. This was evident 4 months later with increased dimensions (17.5 x 18.4 mm), regular borders, and hypermetabolism. An excisional biopsy was performed, and histopathology reported a nodular granulomatous lesion with central caseous necrosis, surrounded by inflammatory cells, with PAS and Grocott positive clustered budding yeast structures. Upon re-interrogation she confirmed the presence of intermittently productive cough and night sweats. A relevant epidemiological history included cave exposure approximately one year before symptom onset. Chronic pulmonary histoplasmosis was diagnosed and treatment with itraconazole (dose 10 mg/kg/day) for 12 weeks was indicated, resulting in a favorable clinical response.

Case 5

8-year-old male from Veracruz with history of left renal transplant from deceased donor 3 years prior due to stage V chronic renal disease secondary to posterior urethral valves. He was receiving immunosuppressive treatment with prednisone (1 mg/kg/dose), mycophenolic acid and tacrolimus. He consulted because of a 5-day history of fever up to 39.4 °C, accompanied by generalized abdominal pain and non-mucoid, non-bloody diarrhea. At admission he had anemia, leukopenia with lymphopenia and thrombocytopenia. A lower respiratory tract infection with Coronavirus 229E was diagnosed with multiplex viral PCR, subsequently respiratory failure and septic shock developed so antibiotics were empirically escalated to meropenem and linezolid, however the patient remained febrile with elevated C-reactive protein (CRP) and procalcitonin of 42.7 mg/dL and 50 ng/mL, respectively. Hepatomegaly of 6 cm was detected, with ferritin levels of 4,670 ng/mL. Secondary hemophagocytic lymphohistiocytosis (sHLH) was suspected; therefore, a bone marrow aspirate was performed, which reported cystic-like structures in the cytoplasm of neutrophils and macrophages, highly suggestive of Histoplasma yeasts (Figures 1A, B). Furthermore, H.capsulatum grew from tracheal aspirate culture. With this, disseminated histoplasmosis was diagnosed, and management with L-AmB was initiated. Chest and abdomen CT revealed nodular lesions in the right lower lobe (Figure 2B), partially calcified mediastinal and right hilar lymph nodes, as well as calcified granulomas in the spleen. Currently, maintenance treatment with itraconazole (10 mg/kg/day) is being administered with an adequate clinical response and preservation of the renal graft.

Case 6

12-year-old previously healthy male from the state of Mexico complaining of 2-week history of lower limb paresthesia, beginning with shooting pain in the right thigh; 2 days later, the same symptoms began in the left limb with gait alteration and weakness. Physical examination highlighted altered sensation at L4–L5, hyperreflexia of the lower extremities, and positive Romberg test. An MRI was performed, reporting an hypointense lesion on T2-weighted sequences extending from T6 to T9 (Figure 2C), located in the right posterior epidural space, causing a mass effect and effacement of the posterior subarachnoid space. Resection of the T8 lesion was performed and histopathologic evaluation revealed chronic caseous and non-caseous granulomatous inflammation with Langhans-type giant cells, bone marrow biopsy showed spherical, encapsulated-appearing, PAS- and Grocott-positive intracytoplasmic yeasts. At re-interrogation of the patient, he confirmed close contact with bats and their presence inside his house. Disseminated histoplasmosis diagnosis was stablished with management with L-AmB for 14 days, followed by itraconazole (10 mg/kg/day), resulting in clinical recovery.

Case 7

24-month-old male from Oaxaca, with glucose-6-phosphate dehydrogenase (G6PD) deficiency diagnosis, was referred to our center because of 1-month history of fever up to 39.5 °C, accompanied by productive cough, progressive respiratory distress, and three episodes of non-bloody, non-mucoid diarrhea. Physical examination revealed hepatomegaly and splenomegaly. A chest X-ray showed a ground-glass pattern with diffuse bilateral nodular opacities, and chest CT demonstrated a diffuse bilateral alveolar pattern with bilateral perihilar consolidations (Figure 2D). A diagnostic workup for tuberculosis was negative; BAL galactomannan antigen was positive at 1.92, and direct microscopy of the BAL revealed multiple intracellular yeasts. A pleural and lung biopsy confirmed the presence of Grocott-positive intracellular yeasts. L-AmB was initiated (5 mg/kg/day) and 10 days later the patient developed ventilatory and hemodynamic deterioration with respiratory acidosis, followed by cardiorespiratory arrest and death at day 17 of treatment.

Results

Seven pediatric patients were diagnosed with histoplasmosis between 2020 and 2025 at our center. The median age was 12 years (range: 1–15 years), with male predominance (71.4%, 5/7). Four patients had a history of immunosuppression or an underlying disease at the time of diagnosis (HIV/AIDS, ALL, Langerhans cell histiocytosis, and renal transplant) (Table 1).

Significant epidemiologic risk factors were identified in 5 of 7 cases, including exposure to caves, contact with bats or poultry, or residence in endemic regions of southeastern Mexico (Veracruz, Guerrero, and Oaxaca). The median time from the onset of symptoms or imaging findings to diagnostic confirmation was 4 weeks (range: 3–35 weeks). A greater delay was observed in patients with extrapulmonary presentation or those with high suspicion of other differential diagnoses such as disseminated tuberculosis, hematological malignancy relapse, or lymphoproliferative disease.

Persistent fever (defined as fever lasting > 7 days) was the most frequent clinical feature (6/7, 85.7%). Other clinical findings included weight loss (4/7, 57.1%), cough (4/7, 57.1%), lymphadenopathy (3/7, 42.8%), dyspnea (3/7, 42.8%), abdominal pain (3/7, 42.8%), hepatosplenomegaly (2/7, 28.5%), and neurological involvement (1/7, 14.2%). Clinical presentations included acute pulmonary (14.2%), chronic pulmonary (14.2%), and disseminated histoplasmosis (71.4%). Three patients (42.8%) presented with extrapulmonary involvement, including mesenteric lymph node, bone marrow, and epidural involvement. One patient debuted with a spinal cord syndrome secondary to an epidural lesion, and another developed secondary HLH due to disseminated histoplasmosis.

Diagnosis was mostly achieved through histopathology using PAS and/or Grocott stains (6/7, 85.7%). Samples included lymph node, lung, bone marrow, gastrointestinal, and epidural tissue biopsies. In one case (14.2%), microbiological isolation of H.capsulatum was obtained from a tracheal aspirate culture. Imaging studies included PET-CT for evaluating lymph node activity and high-resolution computed tomography (HRCT) to characterize pulmonary and extrapulmonary involvement. Five patients (71.4%) received initial treatment with L-AMB followed by itraconazole as maintenance/consolidation therapy. In one case (14.2%), itraconazole was used as initial treatment due to a history of anaphylaxis to L-AmB.

The clinical course was favorable in most cases following the start of antifungal therapy. Two patients were admitted to the pediatric intensive care unit for the management of the disease, one of these patients, an infant with acute pulmonary histoplasmosis, died from respiratory and hemodynamic deterioration despite L-AmB treatment. The overall mortality was 14.2%. One patient required a second course of treatment with itraconazole due to suspected histoplasmosis reactivation, and two immunocompromised patients remained on itraconazole secondary prophylaxis, one with HIV/AIDS and the other under immunosuppressive therapy for renal transplantation.

Discussion

Pediatric histoplasmosis has a wide range of clinical presentations. Acute pulmonary (APH) and progressive disseminated disease (DH) are the most frequent clinical forms in children according to published literature. In our study, 71.4% of cases were classified as DH, 14.2% as CPH and one case as APH in an infant with a fatal outcome. The systematic review published by MacInnes et al. in 2021 that included 83 pediatric cases, found that DH was the most frequent clinical presentation in 79% followed by pulmonary histoplasmosis (PH) in 15.3% (13). However, a large pediatric cohort (73 patients) from an endemic region (Ohio, United States) reported that PH was the main clinical presentation in 71% of patients with DH in 29%, although it is worth noting that most of this cohort were non immunocompromised or previously healthy patients (14). A more recent pediatric cohort with 122 patients from an endemic area in Kansas, Missouri also had pulmonary and thoracic histoplasmosis as the most frequent clinical presentation 58.2% followed by DH in 21.3%. In this study patients with immunosuppressive therapy (chemotherapy and biologics) and complex chronic medical conditions presented more frequently with DH compared to PH; 76.9% and 33% versus 4.2% and 12.7%, respectively, with statistical significance (P<0.001) (15). The discrepancy between our case series and other larger cohorts regarding the most frequent clinical presentation of histoplasmosis, may be explained by the limited sample size of our study, as well as by the characteristics of our hospital, which serves as a referral center for patients with significant underlying diseases and more severe clinical presentations. Additionally, APH can be self-limited resolving within two weeks, potentially resulting in underrepresentation in hospital-based case series.

Age and gender findings from our study match with most published series; the Ohio cohort with 73 pediatric cases reported a median age of 13 years, with male predominance (56%) (14). This was also evident in the Colombian series of 45 pediatric patients with male predominance and most cases located in the age groups of school age (6–10 years) and older children (>10 years), with 29% and 27% respectively (15). This male predominance can be explained by the association with work and recreational activities in endemic regions mainly performed by young males, nevertheless this is not seen in immunocompromised patients, as seen in the Ohio cohort (14). However another theory that might explain the male sex predominance, not only in histoplasmosis but in other invasive fungal diseases, is hormone homeostasis such as the testosterone immunosuppression effects that cause a reduced production in IL-12 as well a Th1 cell diminished response, different from females who mount a stronger cellular response derived from estrogen effect that amplifies the production of proinflammatory cytokines like IFN-G (gamma-interferon) and TNF (tumor necrosis factor). These cytokines possess nuclear hormone response elements (HREs) which interact with estrogen and androgen hormones (14). This is was described in a systematical review that found a male predominance in most of fungi infections but more importantly in endemic fungi like Coccidioides spp., Histoplasma spp. and Blastomyces spp., with 61 to 66.8% of male cases (16).

Most of the patients in our review had an underlying disease or were immunosuppressed. Some risk factors associated with the development of histoplasmosis, and more importantly with DH, are cell-mediated immune deficiencies, hematological malignancies, chemotherapy, prolonged steroid therapy, solid organ transplant and the use immune modulator therapies like tumor necrosis factor (TNF) antagonists (17). Around 73% of the 83 cases reported in the systematic review by MacInnes et al., had an underlying immunocompromising condition such as an Inborn error of immunity (IEI) in 14.3%, followed by HIV/AIDS in 12.9% and solid organ transplant, specifically renal, in 11%. Notably, most of these immunocompromised patients developed DH (13). In patients with HIV, particularly those with low CD4 cell counts, DH continues to be considered one of the leading opportunistic fungal infections in Latin America (3). Pediatric hematological malignancies are probably the commonest predisposing factor for histoplasmosis infection in non-HIV pediatric patients. Nevertheless, histoplasmosis is recognized as the most frequent invasive fungal infection (IFI) in children under treatment with TNF alfa inhibitors (18, 33).

It has been well established that patients with solid organ transplant have a higher risk to develop disseminated or more severe presentations of histoplasmosis due to T- cell immune defects. One of the cases presented in our study was an 8-year male with a history of kidney transplantation that developed a severe disease with secondary hemophagocytic lymphohistiocytosis (sHLH). IFI in kidney recipients account for approximately 5–10% of all infectious complications, with an overall incidence ranging from 5% to 20%. Among these, histoplasmosis has been reported with an incidence of less than 3%, even in endemic areas, although it confers a high mortality ranging from 10 to 62% (18). In a 10-year adult series of solid organ transplant recipients from an endemic region in the United States, the incidence rate of histoplasmosis was low: 1 case per 1000 transplant-person-years (95% confidence interval, 0.6-1.7). All cases were disseminated, and no deaths were reported (19). In a series of six pediatric kidney transplant recipients with histoplasmosis, infection occurred at a median of 14.8 months (IQR 2.2–38.3) after transplantation, with 33% presenting during the first post-transplant year. All patients survived, although one experienced a relapse following a second transplantation. While several patients developed cytopenias, there were no reports of sHLH (20).

Regarding the development of sHLH, a recent literature review that evaluated the association between HLH and IFIs in more than 1,000 patients, the majority of whom were adults, IFI were identified as the underlying trigger in approximately 9% (range, 2–24%) of cases. Histoplasmosis was the fungal infection most frequently associated with HLH, accounting for 50–84% of reported cases. Specifically in pediatric patients, different published reports state that talaromycosis (infection caused by Talaromyces marneffei) and histoplasmosis were most common IFI associated with sHLH in children (21–23). Reports of pediatric kidney transplant recipients who developed HLH secondary to histoplasmosis are exceedingly rare. Only three individual pediatric cases have been reported, involving patients aged 22, 18, and 13 years, respectively (24–26). Therefore, the present series includes one of the few documented cases of histoplasmosis-associated HLH in pediatric kidney transplant recipients.

Relevant epidemiological exposures were identified in five of the seven cases, including close contact with bats, poultry, visits to caves, and residence in regions classified as endemic in Mexico (Oaxaca, Veracruz and Guerrero). This is consistent with the findings of Adenis et al. who identified exposure to caves, birds, and bats among the most frequently reported epidemiological risk factors for histoplasmosis in Latin America (3). Similar findings were reported in the Colombian pediatric cohort, where approximately one-third of patients had a history of environmental exposure (12). Our findings highlight the importance of obtaining a detailed epidemiological history in children with suspected histoplasmosis. However, the absence of recognized epidemiological exposures should not exclude the diagnosis. Schwartz et al. reported that although more than three-quarters of reported outbreaks are related to exposure to bats or birds and their droppings, only one-quarter of patients with sporadic histoplasmosis recall these classic epidemiological risk factors (27) This likely reflects that environmental exposure in endemic regions is more common than patients recognize, as inhalation of aerosolized microconidia from contaminated soil may occur during everyday activities without a single memorable exposure. Furthermore, progression from infection to clinically significant disease is determined not only by the magnitude of the fungal inoculum but also by the integrity of host cell-mediated immunity. While immunocompetent individuals usually contain infection after these low-level exposures, immunocompromised hosts are more likely to develop disseminated histoplasmosis following an unrecognized environmental exposure. Therefore, the absence of clear epidemiological history should not rule out diagnostic suspicion of histoplasmosis in patients with compatible clinical manifestations (2, 17, 27).

A relevant finding was the delay in diagnosis, with a median time of four weeks and, in some cases, up to 35 weeks. This was also investigated in the study from Kansas City; they found a median time from symptom onset to diagnosis of 27 days (range of 12–28 days) for DH and 26 days (range 16–70 days) for PH, which differs from our findings (15). The longest delays occurred in patients with extrapulmonary or DH and in those who were initially evaluated for alternative diagnoses, like pulmonary or miliary tuberculosis. There is an overlap in clinical (prolonged fever, weight loss, lymphadenopathy, and pulmonary involvement) and radiological manifestations, particularly in regions where both diseases are highly endemic contributing to delays in diagnosis and treatment (3, 28). A comparative study of tuberculosis and histoplasmosis in HIV/AIDS adult patients from French Guyana demonstrated that the presence of abdominal symptoms, hepatomegaly and splenomegaly, higher fever and lymphadenopathy of >2cm were more frequent in patients with histoplasmosis compared to tuberculosis. In contrast the presence of cough/chest pain and pleuro/pulmonary symptoms was more present in individuals diagnosed with tuberculosis (29).

When evaluating the clinical presentation of these patients, persistent fever and weight loss were the predominant symptoms, consistent with the findings in the Kansas cohort where 88.5% of cases with DH presented with fever and 76% with fatigue (15). This spectrum of symptoms results from the T-cell-mediated inflammatory response triggered by inhaled conidia, which are initially phagocytosed by macrophages as the first line of host defense, leading to a marked inflammatory response (1). A logistic regression analysis from the Kansas cohort showed that fever, abdominal pain and the use of immunosuppressive therapy were highly associated with DH (15). In our review of cases, only one patient had neurological symptoms with a paravertebral lesion that manifested with progressive lower limbs paresis and gait limitation, however, the Colombian cohort reported CNS involvement in almost 30% of patients, highlighting a higher frequency of neurologic symptoms in school-age children compared to adults with histoplasmosis (12).

Histopathological examination was the most frequently used diagnostic method in our study, accounting for 85% of cases, similar to findings from a 10-year retrospective study conducted at a referral hospital in Costa Rica, where diagnosis was established by biopsy in 55% of patients (30). The predominance of histopathology may reflect the heterogeneous clinical manifestations of histoplasmosis, which can mimic malignancies, granulomatous diseases, or tuberculosis. Nevertheless, other diagnostic modalities with superior sensitivity are available, including polymerase chain reaction (PCR), serum and urinary antigen detection, and serological antibody testing, with reported sensitivities of 98%, 95%, and 71%, respectively (34). In highly suggestive clinical scenarios, these methods may reduce the need for invasive procedures such as biopsies and tissue cultures (30).

The mortality rate observed in our study was 14%, comparable to that reported by MacInnes et al. and Al-Tahhan et al., both of whom described mortality rates of 11%, however, mortality varies according to the patients’ underlying conditions (13, 15). A systematic review reported mortality rates as high as 53% among patients with HIV/AIDS, whereas solid organ transplant recipients had a mortality rate of 11%. Likewise, the clinical presentation significantly influences prognosis, with central nervous system histoplasmosis being associated with mortality rates approaching 44% (31).

This study is one of the few reports involving the Mexican pediatric population and provides recent and valuable epidemiological and clinical information on an underdiagnosed disease in an endemic region. Nevertheless, an important limitation is the small number of cases. This study also highlights a case of histoplasmosis-associated secondary HLH in a renal transplant recipient, a rare complication that has been only infrequently reported in the literature. We believe that there is a subestimation of the real number of cases of pediatric histoplasmosis, not only in our center but in other referral pediatric institutions that receive patients from endemic Mexican regions. There is restricted availability of diagnostic tools, including urinary or serum antigen detection, molecular assays, and serological testing, which could facilitate diagnosis without the need for invasive procedures such as biopsies and cultures. Limited access to these tests likely contributes to delays in diagnosis and underestimation of the true prevalence of this mycosis.

Conclusion

Pediatric histoplasmosis remains an underrecognized and frequently underdiagnosed disease due to its heterogeneous clinical presentation, particularly among immunocompromised patients. Our findings highlight the importance of obtaining a thorough epidemiologic history of exposure to environments known to serve as Histoplasma spp. reservoirs and maintaining a high index of suspicion in patients presenting with persistent fever, weight loss, hepatosplenomegaly, or nonspecific pulmonary lesions, especially in those with underlying immunosuppression. Early initiation of antifungal therapy is associated with favorable outcomes in most patients. Nevertheless, the observed mortality and the occurrence of severe complications, including HLH and CNS involvement, underscore the potentially invasive and life-threatening nature of this mycosis in the pediatric population.

We believe that this case series provides valuable clinical and epidemiological insights into pediatric histoplasmosis in Mexico, particularly in the setting of a national referral center. Furthermore, it emphasizes the need to improve early recognition of the disease, expand access to diagnostic tools, and include histoplasmosis among the leading differential diagnoses of prolonged febrile syndrome in endemic regions.

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Footnotes

Edited by: María Guadalupe Frías De León, Hospital Regional de Alta Especialidad de Ixtapaluca, Mexico

Reviewed by: María Del Rocío Alicia Reyes-Montes, National Autonomous University of Mexico, Mexico

Esperanza Duarte-Escalante, National Autonomous University of Mexico, Mexico