Histoplasmosis in Africa: Current perspectives, knowledge gaps, and research priorities.

BACKGROUND: Histoplasmosis is a chronic granulomatous disease caused by the thermally dimorphic fungus Histoplasma capsulatum. The 2 variants Histoplasma capsulatum var. capsulatum (Hcc) and Histoplasma capsulatum var. duboisii (Hcd) causes infection in humans and commonly termed classical or American histoplasmosis and African histoplasmosis, respectively. Histoplasma capsulatum var. farciminosum (Hcf) affects equines. In recent times, there have been heightened sensitization on fungal infections such as histoplasmosis in Africa, aimed at improving awareness among relevant stakeholders, particularly healthcare workers. This effort is expected to be paralleled with increased detection of both classical and African histoplasmosis, which has remained underdiagnosed over the years. In this narrative review, we describe the current perspectives of histoplasmosis in Africa, identify knowledge gaps, and suggest research priorities. METHODS: A PubMed, Google Scholar, and Africa Journal Online (AJOL) literature search was conducted for studies on histoplasmosis in Africa between 2000 and 2020. Histoplasmosis essays in medical mycology textbooks were also consulted. This narrative review was prepared from the data gathered. FINDINGS: In the past 2 decades, histoplasmosis in general has seen a relative increase in case detection in some Africa countries, probably attributable to the gradually increasing medical mycology advocacy efforts in Africa. Histoplasmosis cases are dominated by African histoplasmosis mostly in Western and Central Africa, while classical histoplasmosis is more common in Southern and Northern Africa. Although both classical and African histoplasmosis are common in Africa, the latter is more restricted to Africa, and cases outside the continent usually have a travel history to the continent. Despite the clinical and laboratory difference between African histoplasmosis and classical histoplasmosis, it is not straightforward to distinguish them. The typical manifestation of African histoplasmosis is the appearance of lesions affecting the skin, bones, and lymph nodes and unusually linked to human immunodeficiency virus (HIV)/AIDS. By contrast, classical histoplasmosis mostly affects the lungs and is often associated with immunosuppression, mainly HIV/AIDS. The present perspectives of histoplasmosis in Africa highlight unclear details on the true burden, strain diversity, infection route and genetic basis of African histoplasmosis, availability of specie-specific diagnostic tools, and compliance with recommended antifungal therapy. These knowledge gaps represent research questions that require scientific exploration. CONCLUSIONS: Despite a subtle increase in identifying histoplasmosis cases in Africa, it remains underdiagnosed and neglected in some parts of the continent. Increasing awareness and training among healthcare workers, bridging diagnostic and therapeutic gaps, and encouraging more research in Africa are crucial to improve the current perspectives of histoplasmosis in Africa.

Histoplasmosis pulmonar cavitada en un paciente pediátrico: reporte de caso / Acute cavitated pulmonary histoplasmosis in a pediatric patient: a case report

La histoplasmosis es una micosis producida por el Histoplasma capsulatum. Esta condición es endémica en Estados Unidos, Suramérica, América central y África. Suele presentarse en todas las edades, pero en niños; en especial en aquellos inmunodeprimidos, se han descrito presentaciones graves o atípicas. Se presenta el caso de un paciente de 16 años con antecedentes de trasplante renal, que inicia con síntomas respiratorios inespecíficos, tos y alzas térmicas intermitentes. La radiografía de tórax mostró una imagen de condensación cavitada en el lóbulo superior izquierdo, por lo que se realiza una fibrobroncoscopia, lavado broncoalveolar y cultivos para patógenos habituales, micobacterias y hongos, lográndose aislar al Histoplasma capsulatum. EL objetivo de este trabajo es el de resaltar la consideración de histoplasmosis como diagnóstico diferencial de lesiones cavitadas en parénquima pulmonar en pacientes inmunodeprimidos con la presentación de un caso clínico.

Histoplasmosis is a mycosis caused by Histoplasma capsulatum. This condition is endemic in the United States, South America, Central America, and Africa. It usually occurs in all ages, but in children, especially those immunosuppressed, serious or atypical presentations have been described. We present the case of a 16-year-old patient with a history of kidney transplantation that began with nonspecific respiratory symptoms, cough, and intermittent fever peaks. Imaging findings suggestive of cavitation were found, which by means of a fiberoptic bronchoscopy and bronchoalveolar lavage study isolated Histoplasma capsulatum by means of a deep mycosis culture. The main interest of the case presented is the consideration of histoplasmosis in the presence of cavitated lesions in the lung parenchyma in immunosuppressed patients.

Isolated gastrointestinal histoplasmosis: A rare diagnosis of pediatric chronic abdominal pain.

Gastrointestinal (GI) histoplasmosis usually occurs as a part of disseminated histoplasmosis in immunocompromised or elderly subjects. Isolated histoplasmosis involving the GI tract in an immunocompetent host is very rare. It is also not considered as an etiology for chronic abdominal pain in children. Here we present an 8-year-old boy with abdominal pain and weight loss who underwent treatment for tuberculosis but on reinvestigation was diagnosed as GI histoplasmosis. He responded well to treatment and achieved good catch up growth.

Mucocutaneous nasal histoplasmosis in an immunocompetent dog.

BACKGROUND: Histoplasma (H.) capsulatum is a dimorphic fungus, and infection is typically via inhalation of microconidia. After conversion to the yeast phase within the lung, the organism is subsequently disseminated to other tissues by macrophages. Nasal histoplasmosis appears to be a rare condition in dogs. CASE PRESENTATION: We report the clinical case of a 4.5-year-old male neutered Cocker spaniel/Poodle mix, 7.7 kg, body condition score 6/9, that presented with a 3-month history of sneezing and left-sided mucoid nasal discharge. The history also included a mild swelling (transient) of the right carpus with a lameness (grade II-III/IV), coinciding with the onset of sneezing and nasal discharge. The dog lived primarily indoors in the Texas Gulf Coast area. On physical examination, the dog was febrile, and the left nostril was swollen, ulcerative, deformed, and hypopigmented. Mandibular lymph nodes were firm and mildly enlarged bilaterally. Mild lymphopenia, thrombocytopenia, and hyperglobulinemia were noted. Thoracic radiographs were unremarkable. Computed tomography and rhinoscopy revealed swelling of the rostral portion of the left and right nasal passages. Cytology and histology of biopsies of the affected nasal tissue showed pyogranulomatous inflammation and yeast organisms consistent with H. capsulatum. Weak antigenuria was detected on the MVista H. capsulatum antigen test. Treatment with oral itraconazole led to a resolution of the nasal signs and normalization of the appearance of the nostril over 13 weeks, and neither antigenuria nor antigenemia was detected on several recheck examinations. The dog remained in good general and physical condition and showed no signs of disease recurrence more than 6 years after the last examination. CONCLUSION: We report a rare case of nasal mucocutaneous histoplasmosis in an immunocompetent dog, with an excellent clinical response to oral itraconazole. This case documents that histoplasmosis in dogs can affect primarily the nasal cavity, which responds rapidly to triazole antifungal therapy and has a good prognosis. A similar case has only been reported in human medicine in a young adult.

Histoplasmosis in the Republic of Congo dominated by African histoplasmosis, Histoplasma capsulatum var. duboisii.

The Republic of Congo (RoC) is one of the African countries with the most histoplasmosis cases reported. This review summarizes the current status regarding epidemiology, diagnostic tools, and treatment of histoplasmosis in the RoC. A computerized search was performed from online databases Medline, PubMed, HINARI, and Google Scholar to collect literature on histoplasmosis in the RoC. We found 57 cases of histoplasmosis diagnosed between 1954 and 2019, corresponding to an incidence rate of 1-3 cases each year without significant impact of the AIDS epidemic in the country. Of the 57 cases, 54 (94.7%) were cases of Histoplasma capsulatum var. duboisii (Hcd) infection, African histoplasmosis. Three cases (5.3%) of Histoplasma capsulatum var. capsulatum infection were recorded, but all were acquired outside in the RoC. The patients' ages ranged between 13 months to 60 years. An equal number of cases were observed in adults in the third or fourth decades (n = 14; 24.6%) and in children aged ≤15 years. Skin lesions (46.3%), lymph nodes (37%), and bone lesions (26%) were the most frequent clinical presentations. Most diagnoses were based on histopathology and distinctive large yeast forms seen in tissue. Amphotericin B (AmB) was first line therapy in 65% of the cases and itraconazole (25%) for maintenance therapy. The occurrence of African histoplasmosis in apparently normal children raises the possibility that African histoplasmosis is linked to environmental fungal exposure.

Histoplasmosis.

Histoplasmosis is one of the commonest endemic mycoses in the Americas yet is often underdiagnosed and neglected as a public health priority. This review outlines the evolving understanding of its epidemiology and the clinical syndromes of histoplasmosis, in addition to up-to-date diagnostic and treatment guidelines. A focus on histoplasmosis in advanced HIV is included. The challenges pertinent to histoplasmosis management in Latin America, with recommendations made through international expert consensus are discussed.

Cutaneous Histoplasmosis in HIV Seronegative Patients: A Clinicopathological Analysis.

BACKGROUND: Diagnosis of extrapulmonary histoplasmosis in HIV seronegative and immunocompetent patients is often challenging, so a high index of suspicion is required. Cutaneous manifestation of infection shows a wide spectrum of lesions including erythematous plaques; maculopapules; crusted, verrucous, or desquamative papules and nodules; abscesses; and mucocutaneous ulcers among others. Due to the variations in its clinical presentation, histopathology plays a very important role in the detection of spores and the confirmation of diagnosis. OBJECTIVES: The aim of our study was to analyze clinicopathological characteristics of cutaneous manifestations of biopsy-proven histoplasmosis in HIV seronegative individuals. We also examined the utility of Fite stain for the diagnosis of Histoplasma capsulatum on tissue biopsy sections. METHODS: This was a retrospective, observational study on 7 patients who were HIV seronegative and clinically manifested with isolated cutaneous lesions or disseminated disease. Skin biopsy from the lesions was performed on all 7 patients. In addition to H&E staining and special stains for detecting fungus, Fite staining was performed on all of the cases to study its utility in detecting H. capsulatum spores. RESULTS: The skin lesions were widely disseminated in all patients and the most common cutaneous lesions were papules, present in all 7 patients. On review of the H&E-stained slides, the most common pattern was histiocytic lobular panniculitis-like infiltrate observed in 4 cases. Fite stain highlighted the yeast as magenta-colored spores on a blue background in all cases, except for 1 with a granulomatous pattern. CONCLUSION: A primary cutaneous manifestation of H. capsulatum infection in non-HIV-infected individuals is extremely rare. Fite stain could aid in differentiating the spores of H. capsulatum from those of other fungi, Cryptococcus and Candida in particular.

Peptidogalactomannan from Histoplasma capsulatum yeast cell wall: role of the chemical structure in recognition and activation by peritoneal macrophages.

Histoplasma capsulatum is the causative agent of histoplasmosis, a systemic disease responsible for most reported causes of morbidity and mortality among immunosuppressed individuals. Peptidogalactomannan (pGM) was purified from the yeast cell wall of H. capsulatum isolated from bats, and its structure and involvement in modulating the host immune response were evaluated. Gas chromatography, methylation analysis, and two-dimensional nuclear magnetic resonance (2D-NMR) were used for the structural characterization of pGM. Methylation and 2D-NMR data revealed that pGM comprises a main chain containing α-D-Manp (1 → 6) residues substituted at O-2 by α-D-Manp (1 → 2)-linked side chains, non-reducing end units of α-D-Galf, or ß-D-Galp linked (1→ 6) to α-D-Manp side chains. The involvement of H. capsulatum pGM in antigenic reactivity and in interactions with macrophages was demonstrated by ELISA and phagocytosis assay, respectively. The importance of the carbohydrate and protein moieties of pGM in sera reactivity was evaluated. Periodate oxidation abolished much pGM antigenic reactivity, suggesting that the sugar moiety is the most immunogenic part of pGM. Reactivity slightly decreased in pGM treated with proteinase K, suggesting that the peptide moiety plays a minor role in pGM antigenicity. In vitro experiments suggested that pGM is involved in the phagocytosis of H. capsulatum yeast and induction of IL-10 and IFN-γ secretion by peritoneal macrophages from C57BL/6 mice. These findings demonstrated the role of pGM in the H. capsulatum-host interaction.

Molecular detection of Histoplasma capsulatum in bats of the Amazon biome in Pará state, Brazil.

Histoplasma capsulatum, the fungus causing histoplasmosis, has a strong impact on public health. Histoplasmosis is one of the most prevalent systemic mycoses in the Americas and occurs in several mammalian species. Bats are important in the epidemiological cycle of histoplasmosis because they disseminate the fungus throughout the environment. The aim of the present study was to investigate natural H. capsulatum infection in bats located in forested areas, which have undergone anthropogenic perturbations, as well as in the urban areas of the state of Pará. Twenty-two species of bats were captured in 18 municipalities of Pará; the samples obtained from these animals were subjected to nested PCR for amplification of H. capsulatum DNA. The HCI/HCII and HCIII/HCIV primers were used, and the final 210-pb fragment was amplified. Of the 100 bats analysed, two were confirmed to be positive for H. capsulatum. Samples amplified by nested PCR were sequenced and found to share identity and have 100% match with H. capsulatum DNA. H. capsulatum was detected in the area of study: the state of Pará has a wide diversity of bat species, and the region under investigation is situated in the north of the state, which suffers the most severe environmental and climatic changes. Therefore, it is essential to elucidate the distribution of H. capsulatum hosts in this region to facilitate the implementation of effective disease surveillance.

Epidemiology of epizootic lymphangitis of carthorses in northern Ethiopia using conventional diagnostic methods and nested polymerase chain reaction.

BACKGROUND: Epizootic lymphangitis (EL), caused by Histoplasma capsulatum variety farciminosum (HCF) is a contagious, chronic disease of equines, characterized by development of nodular lesions in the lymph nodes, lymphatic vessels and skin. It is one of the most important diseases of equines in Ethiopia, causing significant economic loss, particularly in the livelihood of carthorse owners. To date there is neither effective diagnostic nor control measure implemented in the country. Furthermore, there is a shortage of data on the epidemiology of the disease in different regions of this country. The aim of this study was to investigate epidemiology of EL in northern Ethiopia, using the conventional methods as well as nested polymerase chain reaction (PCR). RESULTS: The presence of HCF genetic material was confirmed in 44% (84/191) of the carthorses. Subclinical infection was observed in 18.2% (22/121) of the apparently healthy carthorses. Considering the nested PCR as a gold standard, sensitivity and specificity of clinical examination were 74% and 92.5%, respectively, while the area under the ROC curve (AUR) was 0.83 (95% confidence interval, 0.77, 0.896). Moreover, a moderate (k = 0.675) agreement observed between the nested PCR and clinical examination. CONCLUSIONS: This study demonstrated widespread occurrence of EL in northern Ethiopia, and the advantage of the nested PCR in detecting infection of HCF, even before the clinical symptoms became apparent.

Continuous ambulatory peritoneal dialysis-associated Histoplasma capsulatum peritonitis: a case report and literature review.

BACKGROUND: Fungal peritonitis (FP) is a rare complication of peritoneal dialysis. We herein describe the second case in Asia of Histoplasma capsulatum peritonitis associated with continuous ambulatory peritoneal dialysis (CAPD). CASE PRESENTATION: An 85-year-old woman with end-stage renal disease (ESRD) who had been on CAPD for 3 years and who had a history of 3 prior episodes of peritonitis presented with intermittent abdominal pain for 2 weeks and high-grade fever for 3 days. Elevated white blood cell (WBC) count and rare small oval budding yeasts were found in her peritoneal dialysis (PD) fluid. From this fluid, a white mold colony was observed macroscopically after 7 days of incubation, and numerous large, round with rough-walled tuberculate macroconidia along with small smooth-walled microconidia were observed microscopically upon tease slide preparation, which is consistent with H. capsulatum. The peritoneal dialysis (PD) catheter was then removed, and it also grew H. capsulatum after 20 days of incubation. The patient was switched from CAPD to hemodialysis. The patient was successfully treated with intravenous amphotericin B deoxycholate (AmBD) for 2 weeks, followed by oral itraconazole for 6 months with satisfactory result. The patient remains on hemodialysis and continues to be clinically stable. CONCLUSION: H. capsulatum peritonitis is an extremely rare condition that is associated with high morbidity and mortality. Demonstration of small yeasts upon staining of PD fluid, and isolation of slow growing mold in the culture of clinical specimen should provide important clues for diagnosis of H. capsulatum peritonitis. Prompt removal of the PD catheter and empirical treatment with amphotericin B or itraconazole is recommended until the culture results are known.

Metagenomic next-generation sequencing identified Histoplasma capsulatum in the lung and epiglottis of a Chinese patient: A case report.

Histoplasmosis is an endemic disease mainly occurring in North America and is rare in China. Confirmation of histoplasmosis should be based on a compatible clinical scenario and a positive culture or histopathology. However, there are still many cases that are misdiagnosed or missed, especially in individuals from non-endemic areas. In recent years, metagenomic next-generation sequencing (mNGS) has led to the accurate and timely diagnosis of some rare and complicated infectious diseases. We describe the case of a 27-year-old Chinese man who had chronic progressive pulmonary lesions without any symptoms for more than 1year, until the lesions reached the epiglottis and led to progressive pharyngeal pain. There were no positive results from bronchoalveolar lavage fluid (BALF) and epiglottis tissue cultures, or from epiglottis and lung pathological examinations, but mNGS was able to identify Histoplasma capsulatum in the epiglottis tissues and BALF as the cause of the lesions. The patient was treated successfully with itraconazole.

COVID-19 associated with AIDS-related disseminated histoplasmosis: a case report.

Limited information is available concerning the coexistence of COVID-19 and opportunistic infections in people living with HIV. The possible association of COVID-19 with AIDS-related respiratory diseases should be considered, particularly in patients with advance immunosuppression. We report the case of a male patient with AIDS-related disseminated histoplasmosis associated with COVID-19.

Desperate times, desperate measures: successful use of chemotherapy in treatment of haemophagocytic lymphohistiocytosis (HLH) due to disseminated histoplasmosis.

We describe a case of haemophagocytic lymphohistiocytosis (HLH) secondary to disseminated histoplasmosis, which was treated with chemotherapy in addition to standard antifungal therapy. While HLH in the setting of infections is very well described, its treatment in this setting is controversial, with some physicians treating only the underlying infection, whereas others using immune suppression in addition to antimicrobials. To the best of our knowledge, this is the first report documenting the successful treatment of an adult patient with HLH due to disseminated histoplasmosis using etoposide chemotherapy after initial antifungal therapy failed to show improvement.

Mediastinal histoplasmosis with cardiac involvement in a cat.

Histoplasmosis is the second most common fungal infection reported among domestic felines in the United States. Dissemination of the organism after inoculation is common and affected organ systems include the respiratory tract, gastrointestinal tract, reticuloendothelial organs, skeletal system, integument, and ocular system. However, histoplasmosis presenting as a discrete granulomatous mass identified on echocardiogram has never been reported in the veterinary literature. Here, we describe the first case of feline histoplasmosis presenting as a granuloma with cardiac involvement. The patient, a 6-year-old male neutered domestic longhair feline, was referred for tachypnea and dyspnea. A mass in the cranial mediastinum abutting the heart was diagnosed via two-dimensional echocardiography. Cytology of fine needle aspirates from the mass revealed round yeast structures consistent with Histoplasma spp. The patient was treated with oral fluconazole therapy, and subsequent rechecks have shown marked improvement in clinical parameters, lesion size, and antigen concentrations.

Urine antigen-negative disseminated histoplasmosis mimicking post-transplant lymphoproliferative disorder.

A 50-year-old woman with a history of kidney transplant presented with 2 days of abdominal pain after 6 months of recurrent streptococcal pharyngitis, fevers, weight loss and a new rash on her chest and back. Her examination was notable for a unilateral tonsillar exudate and 2-3 mm pink papules with a fine scale over her chest and back. CT of the abdomen and chest demonstrated several large lymph nodes, and laboratory investigation revealed new cytopenias and elevated transaminases. Urine antigen testing for Histoplasma capsulatum was negative, but a fungal complement fixation panel was reactive for Histoplasma antibodies. Skin biopsy revealed intracellular organisms consistent with H. capsulatum She underwent treatment with liposomal amphotericin B but due to nephrotoxicity, drug interactions and worsening transaminitis, therapy was changed to itraconazole. The diagnosis and management of disseminated histoplasmosis presents multiple challenges, which are of particular importance in patients with a history of renal transplantation.