Current Medical Mycology

2021, 7(1): 63-70

Epidemiology of fungal diseases in Africa: A review of diagnostic drivers

Felix Bongomin1*, Samuel Adetona Fayemiwo2, 3

1 Department of Medical Microbiology and Immunology, Faculty of Medicine, Gulu University, Gulu, Uganda 2 Department of Medical Microbiology and Parasitology, College of Medicine, University of Ibadan, University Hospital Ibadan, Ibadan, Nigeria 3 Division of , Immunity and Respiratory Medicine, Faculty of Biological Sciences, University of Manchester, Manchester, UK

Article Info A B S T R A C T

Article type: Background and Purpose: There has been a significant increase in the burden of fungal Review article diseases in the last few decades which has imposed a global threat to the health of humans, animals, and plants. Epidemiology of fungal diseases is not completely understood in Africa. Most of these diseases are under-reported or not reported at all mainly due to the challenges related to the availability of and access to fungal Article History: diagnostics and the lack of human resources in clinical and diagnostic mycology across Received: 08 September 2020 the continent. Therefore, it is imperative to highlight the epidemiology of the endemic Revised: 22 November 2020 and epidemic of emerging and re-emerging fungal diseases as well as their diagnostic Accepted: 18 January 2021 challenges in Africa based on the available data. Moreover, it is important to underline the existing gaps in this regard as well. Materials and Methods: For the purposes of the study, Medline and Google Scholar were searched to retrieve articles on these prominent fungal diseases, as well as their * Corresponding author: etiologies and available diagnostics. Felix Bongomin Results: It was found that and other AIDS-associated mycoses have been Department of Medical Microbiology reported in Africa, including , , and paracocci- and Immunology, Faculty of Medicine, dioidomycosis. Other reported were fungal neglected tropical diseases, Gulu University, Gulu, Uganda. especially , , mycetoma, and as well Email: [email protected] as emerging fungal diseases, such as Emergomyces africanus, , and Blastomyces emzantsi. In Africa, the major drivers of fungal diseases include human infection, , and poverty. Conclusion: Serious fungal diseases are common in Africa; however, the true burden remains unknown.

Keywords: , , , Emergomycosis, Fungal disease, Mycetoma

 How to cite this paper Bongomin F, Adetona Fayemiwo S. Epidemiology of fungal diseases in Africa: A review of diagnostic drivers. Curr Med Mycol. 2021; 7(1): 63-70. DOI: 10.18502/cmm.7.1.6246

Introduction n the last few decades, there has been a cancer, asthma, and diabetes mellitus. It is noteworthy significant increase in the burden of fungal that > 25 million (~70%) out of the estimated 37.9 I diseases which continues to pose a global threat million people living with HIV (PLHIV) worldwide to the health of humans, plants, and animals are in Africa [4]. [1]. More than a billion fungal diseases with variable Despite the popularity of antiretroviral therapy severity occur every year worldwide [2]. These fungal (ART), cryptococcosis, , histoplasmosis, infections include dermatophytosis, vulvovaginal and other opportunistic fungal infections continue to candidiasis, allergic diseases, subcutaneous infections, threaten the lives of PLHIV, particularly those who and life-threatening invasive systemic diseases [2]. present with advanced HIV disease or failed their ART Over 300 fungal species cause human diseases, mainly [4, 5]. Moreover, the fungal neglected tropical diseases in the immunocompromised individuals and those with (FNTD), notably mycetoma, chromoblastomycosis, a competent immune system, especially people who sporotrichosis, and dermatophytosis occur in areas with have underlying chronic respiratory diseases and co- poverty. morbidities or live in poverty [3]. The spectrum of fungal diseases has posed a heavy Main drivers of fungal diseases in Africa include burden on Africa which differs in one way or the other the human immunodeficiency (HIV) and tuberculosis from the global statistics. However, the epidemiology (TB) syndemic, poverty, and the growing number of of fungal diseases in Africa is not understood individuals with non-communicable diseases, notably completely. This is mainly due to the challenges

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A review of fungal disease drivers in Africa Bongomin F and Adetona Fayemiwo S. related to the availability of and access to fungal Intradermal histoplasmin skin test (HST) is required diagnostics and the lack of human resources in clinical for the determination of prior subclinical infections. In and diagnostic mycology across the continent. Africa, the prevalence rate of positive HST is within the Definitive diagnosis of fungal disease requires range of 0-35% [7]. Almost 40% of cases of confirmation of the causative pathogen through culture histoplasmosis in Africa occur in PLHIV with very high and microscopy, histopathology, immunodiagnostics, case fatality rates [8]. Diagnosis of acute disseminated biomarkers, molecular assays, and advanced molecular histoplasmosis requires urinary antigen detection, alone or in combination. In many parts of tests, histological examination, and cultures of the Africa, this is practically hampering accurate appropriate specimens, such as marrow and tissues evaluation of the incidence of fungal infections. from organs [9]. As practicing mycologists in Africa, we are faced There has been no report of with several endemic, epidemic, emerging, and or its causative agents, Paracoccidioides braziliensis/ re-emerging fungal diseases requiring correct lutzii, in Africa [6]. Several cases of blastomycosis, identification and appropriate treatment. This article two cases of talaromycoses, and five cases of aimed to highlight the key fungal diseases, their coccidiodomycosis have been documented across methods of diagnosis, and the challenges in Africa. Africa, in West Africa, and in Uganda, respectively [6, 10]. These endemic mycoses were diagnosed by culture Materials and Methods and histopathological examinations [6, 10]. Literature review The related literature was found in Medline Fungal neglected tropical diseases (through PubMed) and Google Scholar. In total, four The FNTDs consist of a diverse group of search strategies were used to retrieve the articles: 1) implantation mycoses which usually present much later each of the fungal diseases was searched, such as after the initial infection. These diseases include “cryptococcosis”, “emergomyces”, “chronic sporotrichosis, mycetoma (Madura foot), chromoblasto- pulmonary aspergillosis”, and “Madura foot” plus (chromomycosis), lacaziosis (), and “Africa”, 2) etiologic fungal genus or species were entomophthoromycosis (subcutaneous ). searched, namely “”, “Emergomyces The causative organisms primarily affect the cutaneous africanus”, and “” plus and subcutaneous tissues; however, in most cases, they “Africa”, 3) “Africa” was also replaced with each of also involve adjacent structures, such as the lymphatic, the individual 54 countries of Africa, and 4) the words cartilage, fascia, joints, and [11]. used in the first three strategies were combined with Mycetoma may be caused by a the word “diagnostics”. Alternative names or (), a filamentous bacterium (actinomy- syndromes of each of the disease entities were used as cetoma), or both. It is a chronic, progressive, and well, such as cryptococcosis, cryptococcal meningitis, destructive inflammatory disease usually of the or asymptomatic cryptococcaemia. subcutaneous tissues, mostly caused by a fungus called The related literature in English was reviewed and Madurella mycetomatis. It is not a modifiable disease; there was no restriction on the year of publication. therefore, the global burden of the disease is poorly References of the retrieved studies were scrutinized to defined [12, 13]. find additional articles that might not have been Mycetoma has been found in many African included in the results of these search strategies. The countries within the “mycetoma belt”, like Sudan, University Ethics Committee code was not applicable Senegal, Nigeria, Mauritania, Kenya, Cameroon, in this article. Somalia, Tunisia, Niger, and Ethiopia [14,15]. Diagnosis is usually made by both histological and Results and Discussion cultural methods. It is estimated that over 10,000 cases Endemic mycoses of mycetoma annually occur in Africa with the Primary “endemic” mycoses majority of documented cases being taken care of at Fungal mycoses cause disease in susceptible the Mycetoma Research Centre in Khartoum, Sudan individuals irrespective of their immune status and are [14, 15]. endemic which means they are found in specific Chromoblastomycosis (CBM) is a fungal disease geographical locations. These infections include caused by melanised fungi, most especially Fonsecaea histoplasmosis, blastomycosis, coccidioidomycosis, pedrosoi, and Cladophialophora carrionii [16]. The and paracoccidioidomycosis [6]. Incidence of both CBM lesions are usually polymorphic and should be overt and subclinical human histoplasmosis caused by distinguished from those associated with other benign H. capsulatum and have been or malignant clinical syndromes [16]. The true burden reported in Africa. Clinical manifestations of this of this disease in Africa may be underestimated due to disease are broad and can vary from asymptomatic the paucity of epidemiological studies in the continent. disease or chronic cavitary pulmonary disease to It is noteworthy that Madagascar has the most cases of life-threatening acute progressive disseminated CBM in Africa [16]. histoplasmosis in patients with advanced HIV Diagnosis of CBM requires laboratory confirmation infection. by direct mycological examination and/or histopa-

64 Curr Med Mycol, 2021, 7(1): 63-70 Bongomin F and Adetona Fayemiwo S. A review of fungal disease drivers in Africa

thology. To confirm the diagnosis of this disease, the Sabouraud dextrose agar plates containing muriform cells in clinical specimens must be visualized chloramphenicol with and without cycloheximide [28]. [11]. Serological and intradermal tests have not been One of the newest methods is trichoscopy which is a standardized for CBM and are not used in the routine useful and rapid method for the diagnosis of tinea laboratory. However, an Enzyme-linked immunosorbent capitis. The new diagnostic methods that vary from assay diagnostic technique could be used which usually dermoscopy to molecular laboratory tests have been shows the existence of asymptomatic infection [17]. developed despite the fact that some of these facilities Sporotrichosis, caused by the have not been incorporated into the routine practice in complex is a chronic granulomatous mycosis acquired many African health centers [29, 30]. by traumatic inoculation among gardeners and farmers following pricks or scratches by thorns or other small Epidemic mycoses injuries [18,19]. It must be noted that occasionally, The HIV pandemic predominantly drives epidemic traumatic exposure could be absent. Many cases of fungal diseases in Africa [5, 31]. occupational and leisure activities, like fishing, Cryptococcosis, (PCP), hunting, horticulturing, gardening, and farming, could oropharyngeal, and oesophageal candidiasis, and to facilitate exposure to the organism [20]. It is also some extent, disseminated histoplasmosis and considered an important zoonosis, especially in Brazil, emergomycosis are the main fungal diseases that occur where Sporothrix braziliensis is transmitted through cat among HIV-infected individuals in Africa. scratches [18]. This disease has been reported regularly in South Africa since the first case was described in the Cryptococcosis early 20th century [18,19]. Cryptococcosis, caused mainly by the of the Sporotrichosis was reported in Gauteng province species and Cryptococcus that included Pretoria, Botswana, Mpumalanga, and gattii, is among the commonest causes of meningitis North West provinces, especially among gold mine among HIV-infected individuals in Africa [32]. workers [18, 19]. Several cases were reported in Egypt, Cryptococcal meningitis accounts for up to 15% of Congo, Tanzania, Zimbabwe, Sudan, and Nigeria. Due AIDS-related deaths worldwide. In sub-Saharan to the few medical mycology laboratories in the Africa, 162,500 (73% of global cases) and 135,900 continent, the accurate distribution of the disease in (75% of global cases) individuals catch cryptococcal Africa has not been clearly mapped [18,19]. There are meningitis with an annual high mortality rate [33]. In still challenges in the establishment of a diagnostics addition, 4.0-15.0% of patients with HIV have molecular microbiology laboratory in developing asymptomatic cryptococcaemia which may progress countries, especially in Africa [21]. into overt meningitis [33]. Entomophthoromycosis is another group of Cryptococcal antigen (CrAg) test is the mainstay of subcutaneous zygomycosis caused primarily by diagnosis for both asymptomatic cryptococcaemia and and overt cryptococcal meningitis. This test is cheap, [22]. Cases of infections have highly sensitive, and specific with a turnaround time of been reported in equatorial Africa [23]. It is usually ~15 min allowing rapid and accurate point of care diagnosed by microscopy and isolation of C. coronatus diagnosis. Blood culture and cerebrospinal fluid (CSF) in culture. The isolates can be demonstrated by cultures may be obtained in patients with relapses or in the macroscopic and microscopic morphologic research settings. The CrAg screening is routine in characteristics suggestive of C. coronatus and agents of many countries in Africa [5]. entomophthoromycosis [22]. Any delay in diagnosis leads to increased mortality which could be worse in Pneumocystis pneumonia sub-Saharan Africa [22]. The PCP caused by the opportunistic fungi is also endemic among children in remains an important cause of Africa; however, it is not officially recognized as an hospitalization and deaths among hospitalized PLHIV. FNTD [24]. Tinea capitis is the most common From 1995 to 2015, PCP was diagnosed in about 15.0– infection of the scalp, skin, and caused by 4.0% of PLHIV, mainly in-patients, 22.4% of whom . Its clinical manifestations vary from were in sub-Saharan Africa. About 18.8% of these mild scaling with little alopecia to large inflammatory patients died, and PCP accounted for 6.5% of them and pustular plaques with extensive alopecia [25]. [34]. Over the years, the widespread use of ART and Tinea capitis is still a common infection with early diagnosis of HIV has led to a marked reduction in prevalence rates exceeding 40% in some communities the incidence of PCP among PLHIV. However, the in Africa [26]. infection is not well documented in most African In a recent systematic review, we found the pooled countries due to a lack of diagnostic facilities [35, 36]. prevalence of tinea capitis to be about 23% with an Treatment of PCP with high doses of cotrimoxazole estimated 138 million children being affected by this is found to be effective; nevertheless, it has condition in Africa [27]. The infection is diagnosed in considerable toxicity. Concurrent administration of the laboratory by microscopic examination of the scalp has been found to reduce PCP mortality hair and skin samples and their cultivation on in AIDS patients and accelerate the incidence of other

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A review of fungal disease drivers in Africa Bongomin F and Adetona Fayemiwo S. opportunistic infections. histoplasmosis has declined significantly in the past Any delay in the initiation of appropriate few years due to ART [52, 53]. Disseminated antimicrobial treatment for PCP could lead to poor histoplasmosis and miliary tuberculosis are clinically clinical outcomes [37]. Meanwhile, microscopy has very similar; therefore, it is difficult to differentiate been the mainstay for the diagnosis of PCP since P. between the two [54]. Moreover, histoplasmosis– jirovecii does not grow in culture in the laboratory. tuberculosis co-infections are relatively common [55]. Detection of beta-D-glucan in blood could be useful Epidemiology of histoplasmosis is not understood due to its sensitivity, while not specific [38]. completely in Africa largely due to the lack of Alternative methods of PCP diagnosis, which are faster diagnostic tests and also the lack of awareness and and more accurate, include Real-time polymerase chain under-recognition of the disease among clinicians [10, reaction and immunofluorescence microscopy. 56]. However, an increasing number of cases of Sensitivity of PCR is about 15-20% better than histoplasmosis are being reported among African classical staining (Giemsa, Diff-Quick, Gomori patients with advanced HIV disease [57]. From 1952 to methenamine-silver or Toluidine O blue) [39]. Few of 2017, 470 cases of histoplasmosis were reported the samples with excellent diagnostic yield include mainly in the West African (n=179, 38.1%) region and induced and expectorated sputum, bronchoalveolar in those infected with HIV (n=178, 38%) [8]. lavage, and nasopharyngeal aspirates [40,41]. In young In the immunocompromised person, Histoplasma children, only nasopharyngeal aspirates are able to polysaccharide antigen detection tests allow rapid provide a realistic sample for the PCR diagnosis [42]. diagnosis of disseminated histoplasmosis in urine, serum, bronchoalveolar lavage, and CSF samples before positive cultures can be identified [58]. The Oral candidiasis is the commonest opportunistic antigen concentration is greatest in urine and can be fungal infection among immunocompromised used to monitor the response to therapy and individuals that is observed in 7.6-75.0% of patients identify recurrent patients [59]. In AIDS patients with with HIV infection [43]. It must be noted that it has a disseminated disease, Histoplasma antigen has been higher prevalence among those with advanced detected in 95-100% and 80% of urine and serum HIV disease. Oral candidiasis is the commonest samples, respectively [53–61]. manifestation of HIV infection in Nigeria and other parts of Africa [44]. Moreover, oral candidiasis and Emerging and re-emerging mycoses oesophageal candidiasis often co-exist in patients with Emerging fungal diseases are increasing due to the advanced HIV disease. wider use of immunosuppressive , Oesophageal candidiasis is an AIDS-defining HIV pandemic, and the rapid rise of the number illness seen in about 12% of patients with HIV/AIDS of immunocompromised patients with increased in sub-Saharan Africa [45]. Symptoms of susceptibility to uncommon fungal pathogens [62, 63]. oropharyngeal candidiasis include a burning sensation in the mouth, oral pain, dry mouth, throat pain, and Candidaemia and Candida auris impaired taste. [44]. Epidemiology of oral candidiasis is a life-threatening clinical is still unclear and there is a need for the accurate condition that endangers critically ill patients and has a identification of the species which could be limited to high fatality rate, ranging from 29% to 76% [64]. Africa. is known to be the most Recently, the incidence rate of invasive candidiasis common cause; however, non-albicans Candida caused by the non-albicans Candida species has species are increasingly being recognized as the cause undergone an increase [65]. Candidaemia and the of more than 30% of oral candidiasis cases [43]. rising incidence of resistance to antifungal medications It has been shown that C. dubliniensis is primarily pose an increasing threat to both the immunoco- associated with oral carriage and oropharyngeal mpromised and immunocompetent individuals, infections in HIV-infected patients [46]. The C. including cancer patients. The C. albicans is the albicans complex needs the application of accurate and species responsible for > 50% of invasive candidiasis reliable tests demanding DNA analysis, such as DNA globally. Diagnostic challenges could also arise from amplification by PCR [46]. the effect of C. albicans hyphae and biofilm development. Disseminated histoplasmosis in HIV/AIDS Candida bloodstream infections can cause Patients with advanced HIV disease in areas significant mortality especially among the patients in endemic for histoplasmosis usually present with acute the intensive care unit. The C. albicans remains the disseminated histoplasmosis (ADH) [47, 48]. The most frequently isolated Candida species in the clinical ADH is one of the major AIDS-defining infections and setting; however, there is an increase in the incidence a major killer of HIV-infected patients in South and rate of non-albicans Candida species infections in Central America where it accounts for ~5,000-10,000 some countries, including sub-Saharan Africa [66]. out of the estimated 24,000 annual deaths from AIDS The C. auris is an emerging species and a [49–51]. multidrug-resistant fungal pathogen that is associated In the USA, the incidence of AIDS-associated with severe clinical disease. The C. auris infections

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have also been reported in Africa, especially Kenya diagnoses. It should be noted that they should be and South Africa as early as 2009 [67, 68]. Diagnosis present for at least three months [76]. of C. auris infections is usually confirmed by Elevation of the Aspergillus antibody observed in the conventional blood culture and antifungal over 90% of patients is the cornerstone for CPA susceptibility testing. However, despite its rapid global diagnosis [76]. Culture of respiratory samples is spread and the threat imposed by this species of insensitive and laborious. In addition, chest-imaging Candida, it is still difficult to predict the actual burden findings are not pathognomonic and may resemble TB of the infection [69]. In Africa, most pathology or cancers. Based on the results of two laboratories cannot fully identify the species level of all epidemiological studies performed in Africa, CPA Candida isolates and the isolates were mostly reported affects 5-10% of patients in their last month of TB as Candida species [70]. treatment to two years after successful TB treatment [78,79]. Serological diagnosis of CPA is currently not Blastomyces emzantsi possible in most parts of Africa due to the non- Blastomyces dermatitidis, B. percursus, and B. availability of the required kits. emzantsi are the causative agents of blastomycosis [71]. Extrapulmonary (skin or bone) disease, probably Fungal asthma resulting from haematogenous spread from a primary Number of patients with Asthma is growing in lung infection, is the commonest presentation among Africa, and based on the findings of a few studies, the patients who were infected with these organisms. fungal sensitization or allergic bronchopulmonary aspergillosis (ABPA) has been observed among this Emergomycosis population group. Severe asthma with fungal Emergomyces is a with human sensitization is diagnosed among patients with pathogenic potential and consists of five known species bronchial asthma, positive type-1 skin prick test that have been reported globally. These species include to Aspergillus allergens and/or raised Aspergillus Es. pasteurianus, Es. africanus, Es. canadensis, Es. fumigatus-specific IgE, negative (usually) A. fumigatus Orientalis, and Es. europaeus. Es. pasteurianus and specific IgG, total IgE < 1000 IU/mL (usually less than Es. africanus are commonly isolated from Africa 500 IU/mL), normal or central bronchiectasis in less (Lesotho, Uganda, and South Africa) [72,73]. The than three lobes, no centrilobular nodules/mucoid earliest known isolate among these Emergomyces impaction/hyperdense mucus, and eosinophil count species was discovered in 1992. It remains unclear if generally < 500 cells/microliter [80]. these fungi have truly emerged or whether they are just Meanwhile, in the diagnosis of ABPA, the recognized due to the increase in the number of following criteria have to be met: 1) a predisposing susceptible hosts, improved microbiology capacity, underlying condition of either asthma or cystic fibrosis; and/or the widespread adoption of molecular 2) an elevated total IgE level greater than 1000 IU/mL identification techniques in clinical and research and either a positive Aspergillus skin prick test or laboratories [74,75]. detectable A. fumigatus–specific IgE; and 3) at least Majority of patients with these infections were two of the following three criteria of serum immunocompromised [75,76]. Moreover, most patients precipitating or Aspergillus–specific IgG antibodies, with Es. Africanus infection usually have cutaneous characteristic radiographic findings, and elevated total lesions and pulmonary diseases [75,76]. Emergomycosis eosinophil count [81]. can be diagnosed through a biopsy of affected tissue In a systemic review of studies published in Africa, for histopathology and fungal culture. When the fungal the prevalence of fungal sensitization was relatively cultures are negative (or omitted), the PCR of the high (3–52%) in the asthmatic population with an affected fresh tissue using internal transcribed spacer average of 28% and a pooled estimate of 23.3%, amplification and sequencing may establish the correct mostly due to Aspergillus species. About 1.6–21.2% of diagnosis [74,75]. patients with fungal sensitization had ABPA [82], the majority of whom had been diagnosed using a skin Chronic pulmonary aspergillosis prick test. Serological detection of Aspergillus-specific Chronic pulmonary aspergillosis (CPA) is a slowly IgG and IgE is scarce in Africa. progressive and debilitating parenchymal lung disease occurring in patients with underlying lung diseases and Other fungal diseases subtle immunodeficiency [76]. Previously treated TB is Candida vulvovaginitis or vulvovaginal candidiasis the most common risk factor for CPA reported in 15- (VVC) is a typical infection in females which occurs 93% of cases [77]. Diagnosis of CPA requires a primarily in women of reproductive age and could combination of clinical characteristics which include one affect as many as one out of every two women [83]. or more cavities (with or without a fungal ball present) Most women in their childbearing age develop VVC at or nodules on thoracic imaging. Other diagnostics least once in their lifetime [84]. The VVC is include direct evidence of Aspergillus infection (in recognized with of inflammation microscopy or culture from biopsy) or immunological in the presence of a positive culture for Candida response to Aspergillus spp. and exclusion of alternative species and the absence of other infective agents [85].

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A review of fungal disease drivers in Africa Bongomin F and Adetona Fayemiwo S.

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