Epidemiology and Knowledge Gap of Histoplasmosis in Africa

Abstract

A dimorphic fungus called Histoplasma capsulatum is the cause of the granulomatous disease known as histoplasmosis. Histoplasma capsulatum var. capsulatum (Hcc) and Histoplasma capsulatum var. duboisii (Hcd), 2 variants of this fungus can infect humans and cause, classical or American histoplasmosis and African histoplasmosis, respectively. To improve the knowledge of health professionals, awareness of most fungal diseases, such as histoplasmosis, has been increased in Africa. In this review, we provide an overview of the current status of histoplasmosis in Africa, identify information gaps, and suggest targets for further study. The histoplasmosis literature in medical mycology textbooks and published articles from Google Scholar on histoplasmosis in Africa and the rest of the world were searched and reviewed. There was no restriction on the year of publications Conclusions were drawn from this review. Whereas the Western world has advanced technologies to diagnose histoplasmosis, this is not the case in Africa. Pulmonary histoplasmosis is therefore usually misdiagnosed as pulmonary tuberculosis because it has a similar clinical presentation. Due to a lack of knowledge and diagnostic tools, most national health systems in Africa are unable to correctly diagnose histoplasmosis, leading to misdiagnosis of the disease despite the fact that the continent has a sizable population of HIV/AIDS patients who are susceptible to contracting the illness. Under-recognition and under-diagnosis remain key issues caused by the lack of competent workers and diagnostic facilities. Therefore, this issue must be addressed by coordinated efforts. Also, it is crucial for doctors practicing outside of endemic areas to understand this illness’ symptoms and treatment options. This is especially significant in light of African migration patterns.

1. Introduction

One of the endemic mycoses is histoplasmosis. A fungal disease is caused by dimorphic fungi, that typically grow as yeasts at body temperature but exist in the environment as mycelial forms in the soil. Other endemic mycoses are blastomycosis, coccidioidomycosis, paracoccidioidomycosis, sporotrichosis, and penicilliosis, and they are all restricted to particular geographical areas and epidemiological contexts [1]. Histoplasmosis often spreads through airborne conidia inhalation, similar to other endemic mycoses, yet in some instances, the fungus is inoculated through the skin. Clinically, histoplasmosis presentation largely dependent on the host’s immune status. For immunocompetent persons, primary infection may be symptomatic and may resolve on its own. However, initial infection typically escalates to widespread disease in patients with weakened host defense, such as transplant recipients taking immunosuppressive medication and HIV patients. Histoplasma capsulatum has the ability to develop into a mold in soil or culture at temperatures below 30°C, and a yeast-like fungus in living tissue at 37°C is due to its dimorphism characteristic. There are three varieties of Histoplasma capsulatum depending on the clinical disease: Histoplasma capsulatum var. capsulatum (Hcc), the cause of Classical histoplasmosis, also known as the American histoplasmosis; Histoplasma capsulatum var. duboisii (Hcd) also known as the African type of histoplamosis that causes African histoplasmosis and Histoplasma capsulatum var. farciminosum causes lymphangitis among equines. Soil rich in chicken, starling, and bat droppings has been used to create fungal environmental isolations.

This chapter investigates the epidemiology of the histoplasmosis pandemic in Africa as well as the knowledge gap among healthcare professionals.

2. Epidemiology

Histoplasmosis is a disease that affects people all over the world, but it is especially prevalent in North and Central America and South America along the valleys of the Ohio and Mississippi Rivers. It has been identified in Madagascar, West Africa, South Africa, Eastern and Central Africa, and Africa. Additionally, isolated cases from the Mediterranean Basin and Southeast Asia have been documented [2, 3, 4, 5]. Uganda, Nigeria, the Democratic Republic of the Congo, and Senegal are the countries where African histoplasmosis disease has been most frequently documented, as Hcd only occurs on the continent of Africa. African histoplasmosis accounted for 61% of the 470 histoplasmosis cases that were documented in Africa from 1952 to 2017 [3]. Central and western Africa accounted for 87% of all cases of histoplasmosis in Africa. Eastern and Southern Africa have recorded fewer occurrences than other continents. The bulk of histoplasmosis cases found in southern Africa are caused by Hcc, whereas Hcd is more common in the west, central Africa, and 4Madagascar [6]. The majority (n = 119) of the 150 cases that were reported from Southern Africa were brought on by H. capsulatum var. capsulatum (Hcc), and neither Hcd nor Hcc had any case reports from Northern Africa [6]. It’s important to remember that, unlike Hcd, which is only found in Africa, Hcc is more prevalent in North and South America, even if it can also be found in Europe, Asia, and other parts of the world.

The predominance of Hcd in Africa has been confirmed by the 400 cases of African histoplasmosis alone that have been reported from 32 African nations in 2020, either as case reports or as case series [7]. In the Democratic Republic of the Congo and Togo, studies conducted during the previous six and fifteen years, respectively, identified 17 and 36 cases [8, 9].

Surveys of Histoplasma skin sensitivity remain crucial for identifying endemic regions or preclinical histoplasmosis. However, a survey conducted in Nigeria, revealed a 4% Histoplasma skin-positive rate [10]. Histoplasmosis is an unknown public health concern in Africa that is mistakenly diagnosed for tuberculosis, as evidenced by the detection of H. capsulatum in 13% of HIV-infected individuals in Cameroonian research [11]. It’s vital to avoid undervaluing the diagnosis of disseminated histoplasmosis (HD) in HIV-infected people due to the endemicity of tuberculosis, the main HIV-defining disease in Africa.

According to various case studies, 2:1 more men than women contract histoplasmosis [8]. Cases have been documented among people between 13 months and 70 years, but all age groups may be affected [12]. Histoplasmosis, particularly classical histoplasmosis, frequently co-occurs with TB and HIV and is expected to be a major health burden in sub-Saharan Africa. However, there appears to be little correlation between HIV and African histoplasmosis [13]. Epizootic histoplasmosis can affect nonhuman primates, including dogs, cats, horses, baboons, and dogs. In Ethiopia, an African nation, equine histoplasmosis has been extensively reported [14]. A recent case of histoplasmosis associated with Hcd in a baboon in America has been related to the import of baboons from Senegal [15]. Still, there is lack of evidence for either human-to-human or animal-to-animal transmission.

3. Knowledge gap

The prevalence of histoplasmosis in Africa is unclear. Consequently, the disease’s burden is underestimated. The largest rate of HIV infection, which increases the risk of histoplasmosis, is found in Africa [16]. Whereas the Western world has advanced technologies to diagnose histoplasmosis, it’s not the same case in Africa. Thus, there is a general knowledge gap among health workers in Africa to diagnose histoplasmosis. Pulmonary histoplasmosis could be mostly misdiagnosed as pulmonary tuberculosis since it presents with similar clinical presentations. On the same note, histoplasmosis skin test surveys done in Africa indicated a 0–35% positive rate which proves there is an existing unknown burden of histoplasmosis [3]. As a result of clinical signs that are similar to TB, histoplasmosis is frequently mistaken as TB. Because histoplasmosis and tuberculosis (TB) present clinically similarly, some misdiagnoses may occur due to a lack of diagnostic resources. Both pulmonary TB and chronic pulmonary histoplasmosis have similar signs and symptoms, such as malaise, fever, lethargy, cough, and sputum production. However, sputum production, weight loss, and night sweats are less common in histoplasmosis patients than in TB. Chronic pulmonary histoplasmosis frequently progresses to pulmonary insufficiency at some point. Histoplasmosis rarely kills if untreated in immune-competent people, unlike TB in an advanced stage [1].

Studies comparing TB with histoplasmosis in the presence of HIV infection found that while the two diseases have many traits, with the majority of publications concentrating on disseminated Hcc infection, however, there are also important and substantial differences between the two diseases [11]. Disseminated histoplasmosis is common in the HIV/AIDS context, typically with lung involvement, but other clinical signs are more apparent, most prominently diarrhea and other gastrointestinal symptoms, skin lesions, and pancytopenia that vary by region. In 8–15% of cases, there has been evidence of co-infection with histoplasmosis. Reticulonodular lesions, many pulmonary nodules, hilar and mediastinal adenopathy, and advancing fibrosis are further characteristics.

Patients that are misdiagnosed with tuberculosis instead of histoplasmosis due to clinical similarities [17, 18] frequently receive presumptive anti-tuberculosis therapy, even when tuberculosis has not been diagnosed. The patients eventually pass away from what is most likely disseminated histoplasmosis (DH), and postmortem tissue samples may ultimately reveal the fungus infection [19]. Despite not being on the World Health Organization’s official list, Hcd histoplasmosis is regarded as a neglected tropical illness. Since the first report in 1952, about only 400 Hcd cases have been documented; nevertheless, due to the small number of case series, the epidemiologic and clinical traits as well as the best therapeutic therapy are still unknown [7]. As previously mentioned, there are few options for laboratory diagnosis in low-income countries, and 55% of cases may only be determined through direct inspection or histological study of clinical specimen(s). As a result, several diagnoses are in doubt [7].

According to studies, the frequency of Hcd infection is likely underestimated since cases are frequently ignored, particularly in developing countries with limited incomes. As a result of the disease’s very pleiomorphic clinical presentation, it ought to be considered quite often. The prevalence of HIV coinfection (20% of patients) significantly alters this clinical picture. Most diagnoses are made through direct examination, which calls for specialized laboratory supplies and microscopist abilities that aren’t usually available in Africa.

There is an urgent need for more precise and user-friendly diagnostic tools to confirm diagnoses and distinguish between Hcd and Hcc disorders, both of which are prevalent on the African continent. When seen under a direct microscope, Histoplasma var. duboisii typically stands out from Hcc due to the abundance of big yeasts it displays.

4. Diagnosis

Histoplasmosis differential diagnosis usually begins with clinical presentation in a patient; however, these clinical signs and symptoms are not always specific because they are similar to those of other diseases like pulmonary tuberculosis, mistaking it for classical histoplasmosis. Unlike classical histoplasmosis which normally affects the lungs and at dissemination, affects the central nervous system (brain and the spinal cord); Osteoarticular, ganglionic, and very infrequently pulmonary sites are affected by African histoplasmosis [8, 20]. Rare incidences of urogenital skin injury often involve secondary skin invasions in people with widespread cases [21, 22]. African histoplasmosis also presents clinically as a “localized skin, bone, lymph node infections or as disseminated with multiple cutaneous lesions present all over the body, subcutaneous abscesses, enlarged lymph nodes, liver and spleen, and visceral organ enlargement [20, 23, 24]. Cutaneous manifestations are clearly isolated, and sometimes present with nodules, papules, or ulcers [20, 25]. Most frequent symptoms of Hcd include lesions mainly on the limbs, trunk, and face; osteoarticular infections in the spine, thorax, and bones of the upper and lower limbs; superficial and deep-seated lymphadenopathies. Rarely does Hcd cause infection in the Lungs, Adrenal glands, and nasal or buccal cavity, gastrointestinal tract (gastric or duodenal lesions), peritoneal cavity [7]. In general, Hcd manifestation is different from classical histoplasmosis, usually affecting bones and the skin and infrequently the lungs [4], and it has been observed in HIV infections less frequently than Hcc [26, 27, 28, 29]. Microscopy and culture are the only readily available diagnostic tools in Africa; serological, immunological, radiological, and molecular methods are still lacking, and are therefore unable to be used to diagnose histoplasmosis (for example, by detecting the H. capsulatum circulating antigen in bodily fluids using an enzyme immunoassay methods) [30].

Histoplasmosis is diagnosed with microscopic histopathologic investigations of bone marrow aspirate or biopsy material, bronchoalveolar lavage fluid or lung biopsy material, sputum, urine, white blood cells in peripheral blood, and skin lesions [31, 32, 33, 34, 35]. Microscopically, Hcd is identified as an ovoid budding yeast with thick cell walls, bigger (6–12 m in diameter), and intracellular fat droplets [36]. On the histology of a tissue specimen, Hcc however, shows up as 2–4um narrow-based budding yeast [36]. Other yeasts can be distinguished from Histoplasma yeasts by their dominant cellular location (intracellular for H. capsulatum and extracellular for C. glabrata), size and form variation (uniform versus heterogeneous), and histopathologic response (granulomatous versus suppurative). It is possible to distinguish between these infections by using particular histochemical stains, such as periodic acid-Schiff, Gomori methenamine silver, hematoxylin and eosin, and Giemsa [36]. A conclusive diagnosis of invasive infection is made by histopathologic analysis of the bone marrow [37]. These microscopic examinations are important in alerting the laboratory about a suspectible pathogen [38]. However, due to the H. capsulatum yeasts similar structure to other yeasts such as Candida glabrata, Penicillium marneffei, Pneumocystis (carinii) jeroveci, Toxoplasma gondii, Leishmania donovani and Cryptococcus neoformans many diagnostic techniques lack sensitivity and specificity which can lead to misidiagnosis [39, 40, 41].

Having access to a level 3 biosafety facility is necessary for culture since it poses a risk to laboratory staff and is not commonly found in African healthcare settings [17]. The culture, isolation, and confirmation of H. capsulatum from clinical and biological materials on selective media, such as Sabouraud agar, and incubation at 25°C for 6 to 12 weeks still serve as the basis for the final diagnosis. When incubated at 35–37°C, H. capsulatum molds are microscopically made up of hyaline septated hyphae with micro and tuberculate. Although the rate of conversion is modest and makes the procedure unusable as a diagnostic tool, it has been used to demonstrate that H. capsulatum is dimorphic. After conversion, smooth white to brown yeast colonies are seen and on microscopic examination, small round narrow budding yeasts are observed [38]. Gram-stained H. capsulatum exhibits poor staining compared to yeast cells from Candida and Cryptococcus, which are primarily extracellular macroconidia. Through culturing on enriched media like blood agar or Brain-Heart Infusion Agar (BHI) containing cysteine, H. caspulatum can be converted from to yeast phase. The majority of patients with an asymptomatic or moderate form of histoplasmosis have negative cultures since culture diagnosis is 100% specific but its sensitivity relies on the number of fungi present [41]. The most recent BACTEC type [42] is more successful than both lysis centrifugation and traditional biphasic blood systems [43, 44]. However, lysis centrifugation has more sensitivity than conventional and Bactec MYCO/F Lytic blood cultures for the recovery of H. capsulatum [45].

There are currently no molecular assays for H. capsulatum accepted by the FDA that are directly applicable to clinical specimens; however, laboratory-developed PCR assays using a range of target genes have been developed and show more sensitivity than cultures, such as between 59 and 100% [46] and 33 and 87% [47, 48, 49]. There is no recorded molecular method that has been used to detect histoplasmosis in Africa. The general lack of expertise in Africa to skillfully diagnose histoplasmosis makes it difficult to accurately diagnose histoplasmosis. Academic tertiary institutions provide theoretical knowledge but cannot provide practical high-end standard methods for diagnosing histoplasmosis. In situations where there is a minimal fungal burden, such as in asymptomatic or chronic pulmonary histoplasmosis, serology tests for anti-Histoplasma antibodies are incredibly helpful [1, 17]. Immunocompromised HIV-infected patients have lower sensitivity to antibody detection by immuno-diffusion or complement fixation than immunocompetent patients [50, 51]. Anti-H and anti-M antibody detection is the main focus of serologic diagnosis. Histoplasmin (HMIN) can be used to identify such antibodies. The antigenic extract of H. capsulatum mycelial culture is identified as HMIN. Centrifugation at 1050× g for 10 min is used to remove the cells, and the supernatant is then filtered through a 0.45 m membrane, concentrated and dialyzed using phosphate-buffered saline (PBS) [52, 53, 54, 55, 56, 57]. The M antigen is a catalase [58, 59] while the H antigen is a β-glucosidase [55]. Antibodies against the M and H antigens can be especially helpful in diagnosis due to their increased specificity to H. capsulatum [60, 61, 62]. Precipitating antibodies (H and M precipitin lines or bands) are qualitatively measured by the immunodiffusion (ID) test [63, 64]. Due to a noted rise in false-negative results, these approaches should not be utilized in patients with the disseminated type of histoplasmosis. As Histoplasma-like antigens are present in patients with other prevalent pathogens such TB, lymphoma, sarcoidosis, and other fungal diseases [65], serologic cross-reactions may happen. Western blot test strips have shown high sensitivity and specificity rates [66]. However, Miravista Histoplasma antibody enzyme immunoassay (EIA) has proved to be more sensitive than other antibody assays, detecting both immunoglobulin G (IgG) and IgM antibodies, and complements antigen detection [67]. Thus becoming the best method to diagnose acute pulmonary histoplasmosis by combining antigen and EIA antibody tests. The invention of Histoplasma antigen testing has greatly aided in the diagnosis of disseminated histoplasmosis. A variety of EIA techniques have been used to find Hcc circulating antigens. Patients with immunosuppressed are more sensitive to disseminated histoplasmosis antigen testing in blood or urine, and individuals with a more severe illness have greater titers [68, 69]. The extent of the disease is proportional to the antigen level [70]. However, one of the gold standards for identifying histoplasmosis in immunocompromised patients remains Histoplasma antigen testing. The Histoplasma antigen does not interact with C. neoformans [71, 72]. Serology was only identified as being used to make a diagnosis in five African countries (Tanzania, Benin, South Africa, Egypt, and Uganda), and in three of those instances, the samples were processed in Western countries. Histology and culture were used to diagnose most reported cases from Africa [3].

5. Treatment

The preferred medications for treating histoplasmosis are intravenous amphotericin B and itraconazole. However, these medications are extremely expensive and scarcely available in Africa. Therefore, the antifungal medications used to treat Hcd and Hcc infection, primarily intravenous amphotericin B and itraconazole, must be made available at a lower cost [3]. Histoplasmosis laboratory diagnosis typically takes a long turnaround time, which raises the risk of the disease progressing.

Whether or not a patient exhibits notable symptoms, doctors have two alternatives for starting treatment for those with a high probability of having histoplasmosis: intravenous (IV) amphotericin B or oral itraconazole [30]. Even though it is frequently fungicidal and has proven beneficial in terms of survival, amphotericin B is nephrotoxic [73]. Liposomal amphotericin is superior to traditional amphotericin B for treating disseminated histoplasmosis, especially in AIDS patients with compromised immune systems [73]. For the majority of isolates of H. capsulatum, itraconazole is similarly fungicidal; however, oral capsules are not always well absorbed in advanced AIDS patients, and it is linked to numerous medication interactions, including rifampicin for situations when TB is present. Itraconazole is a good alternative for subacute disseminated infection, but amphotericin B is preferred for the initial treatment of AIDS-related disseminated histoplasmosis [30]. Amphotericin B is unlicensed and unavailable in several African nations, which is concerning yet when available, the price could be exorbitant [74]. Amphotericin B liposomal is extremely expensive and unavailable throughout most of Africa. Despite being accessible in the most of African nations, itraconazole is excessively expensive [74].

6. Conclusion

Most of Africa’s health national health systems are incapacitated to diagnose histoplasmosis due to a lack of expertise and diagnostic technologies, thus causing miss diagnosis of the same disease. However, the continent also includes a sizable population of HIV/AIDS patients at risk of contracting the illness. Due to a shortage of trained persons and facilities to perform this diagnosis, it is inevitable to misdiagnose histoplasmosis. Coordinated efforts must be undertaken to address this. In addition, medical professionals practicing outside of endemic areas need to understand this disease and how to treat it. Considering the migration patterns of African migrants, this is of great importance [75].

Acknowledgments

I acknowledge EDCTP, European Union, MUST and MeMoF project for the support and funding provided for this work.