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SYSTEMATIC REVIEW AND META-ANALYSIS ARTICLE
Year : 2023 | Volume
: 30
| Issue : 1 | Page : 12-17
Current epidemiology of histoplasmosis in Nigeria: A systematic review and meta-analysis
Bassey Ewa Ekeng1, Adeyinka Afolake Davies2, Iriagbonse Iyabo Osaigbovo3, Ubleni Ettah Emanghe4, Ubong Aniefiok Udoh5, Mary Adanma Alex-Wele6, Oluwaseun Chinaza Adereti7, Rita Okeoghene Oladele8
1 Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital, Calabar; Medical Mycology Society of Nigeria, Lagos, Nigeria
2 Medical Mycology Society of Nigeria, Lagos; Department of Medical Microbiology and Parasitology, Olabisi Onabanjo University Teaching Hospital, Sagamu, Nigeria
3 Medical Mycology Society of Nigeria, Lagos; Department of Medical Microbiology, School of Medicine, College of Medical Sciences, University of Benin, Benin City, Nigeria
4 Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital; Department of Medical Microbiology and Parasitology, Faculty of Basic Clinical Sciences, College of Medical Sciences, University of Calabar, Calabar, Nigeria
5 Department of Medical Microbiology and Parasitology, University of Calabar Teaching Hospital, Calabar; Medical Mycology Society of Nigeria, Lagos; Department of Medical Microbiology and Parasitology, Faculty of Basic Clinical Sciences, College of Medical Sciences, University of Calabar, Calabar, Nigeria
6 Medical Mycology Society of Nigeria, Lagos; Department of Medical Microbiology and Parasitology, University of Port-Harcourt Teaching Hospital, Port-Harcourt, Nigeria
7 Department of Medical Microbiology and Parasitology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
8 Medical Mycology Society of Nigeria; Department of Medical Microbiology and Parasitology, Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Lagos, Nigeria
Correspondence Address:
Bassey Ewa Ekeng
University of Calabar Teaching Hospital, Calabar
Nigeria
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/npmj.npmj_311_22
Introduction: Histoplasmosis commonly occurs in the advanced HIV disease population and also in immunocompetent individuals. Previous reviews and recent studies highlight several cases of histoplasmosis reported in Nigeria. We aimed to describe the current epidemiology of histoplasmosis in Nigeria and the need for active surveillance in the at-risk populations. Methods: Literature searches for all publications on histoplasmosis in Nigeria were performed using online databases including Google scholar, PubMed and African Journal online. The following search terms: 'histoplasmosis' and 'Nigeria', AND/OR 'Histoplasma and Nigeria' were used. No limitations on the date or other search criteria were applied, to avoid the exclusion of articles on histoplasmosis in Nigeria. All publications on histoplasmosis outside Nigeria were excluded. Results: Our review identified a total of 231 cases of histoplasmosis reported from Nigeria: 128 were from individual case reports and case series while 103 were cases from two observational studies. Of the 231 cases, 97 (42.0%) were from South West Nigeria, 66 (28.6%) were from South-South Nigeria, 24 (10.4%) were from North West, 22 (9.5%) from North Central Nigeria, 17 (7.4%) from South East Nigeria and 5 (2.2%) from the North East. Based on Nigeria's current population size of 216,953,585 the burden of histoplasmosis per 100,000 inhabitants was estimated to be 0.1%. The sheer number of cases detected in recent observational studies compared with individual case reports and series reported over a longer duration of 6 decades suggests gross under-reporting of histoplasmosis in Nigeria. Conclusion: Histoplasmosis is not an uncommon clinical entity in Nigeria. Histoplasmosis case finding should be improved by training and retraining healthcare professionals and providing much-needed diagnostic capacity and infrastructure across health facilities in Nigeria.
Keywords: Diagnosis, epidemiology, histoplasmosis, research
Histoplasmosis is a serious fungal disease occurring worldwide, endemic in the Americas, South East Asia and most of Africa.[1],[2],[3] Histoplasmosis in humans is associated with Histoplasma capsulatum var capsulatum (Hcc) and Histoplasma capsulatum var duboisii (Hcd) infection also known as classical or American histoplasmosis and African histoplasmosis, respectively.[1],[2],[3] Clinical presentation may be asymptomatic, acute pulmonary or chronic pulmonary disease, or disseminated.[4],[5],[6] The disseminated form is the most fatal and is commonly associated with people living with HIV/AIDS.[4],[5],[6] As of 2021, 1.9 million Nigerians including adults and children were estimated to be living with HIV (UNAIDS 2021).[7] Besides HIV/AIDS, environmental and occupational exposure, malnutrition and chronic illnesses including tuberculosis (TB) and malignancies and their therapies, and increased use of immunosuppressants are other predisposing factors to histoplasmosis in Nigeria.[4],[6],[8],[9] A retrospective review conducted in 2018 identified 124 cases of histoplasmosis reported from Nigeria, making Nigeria the country with the highest number of cases in Africa.[4] Despite this, the epidemiology of the disease in the country is ill-defined. In addition, the geographical distribution of histoplasmosis cases in Nigeria is not well described. Two recent observational studies documented several histoplasmosis cases but were limited to just five sites across Nigeria.[2],[3] Our review aims at updating the epidemiology of histoplasmosis in Nigeria while driving awareness for active case finding, the need for prompt diagnosis and treatment and prioritising research into this disease.
MethodsThe PRISMA Extension Statement for Reporting of Systematic Reviews Incorporating Network Meta-analyses of Health Care Interventions checklist was used for this review.[10] Literature searches for all publications on histoplasmosis in Nigeria were performed using online databases including Google scholar, PubMed and African Journal online (BEE). The following search terms: 'histoplasmosis' and 'Nigeria' AND/OR 'Histoplasma and Nigeria' were used. No limitations on the date or other search criteria were applied, to avoid the exclusion of articles on histoplasmosis in Nigeria. Some of the case reports were not full texts and only their abstracts were used to derive data for this review. References in all relevant papers were further reviewed for additional publications of case reports regarding the topic that may not have been captured in the searched databases. All publications on histoplasmosis outside Nigeria were excluded. To prevent selection bias, a second author (AAD) independently repeated the entire search and selection process. Any inconsistencies were discussed until a consensus was reached as to what studies should be included. Data extracted from each case included: age, gender, disease type (single organ vs. disseminated disease), sites of infection, clinical features, diagnostic test results, treatment and patient outcome. Case reports with defined HIV status were documented as such, while case reports with undefined HIV status were indicated as 'not stated'.
ResultsEpidemiology
We identified a total of 40 publications, amounting to a total of 231 cases of histoplasmosis reported from Nigeria. Of the 231, 128 were individual case reports and case series while 103 were cases from observational studies; 97 (42.0%) were from South West Nigeria, 66 (28.6%) from South-South Nigeria, 24 (10.4%) from North West, 22 (9.5%) from North Central Nigeria, 17 (7.4%) from South East Nigeria and 5 (2.2%) from the North East [Supplementary Table 1] and [Figure 1]. The number of cases reported per state is as follows; Oyo (n = 88), Cross River (n = 55), Enugu (n = 16), Kaduna (n = 16), Benue (n = 14), Rivers (n = 10), Sokoto (n = 7), Borno (n = 5), Lagos (n = 5), Niger (n = 4), Osun (n = 4), Jos (n = 3), Abia (n = 1), Edo (n = 1), Kano (n = 1) and Kwara (n = 1). The federal capital territory and 16 states had no data on histoplasmosis. [Figure 2] shows the number of cases reported per region grouped as individual and/or observational studies. The incidence of histoplasmosis in Nigeria per 100,000 inhabitants based on the total population of 216,953,585 as of August 2022 was estimated to be 0.1%. Of the 128 reported cases, gender was specified in only 47 cases, and these were predominantly male (n = 33, 70.2%). Patients' ages were found in only 47 reports, 20 (42.6%) were children while the remaining 27 (57.4%) were adults. The age range was 20 months–66 years and a median of 23.5. Fifty-eight cases were reported before the advent of HIV/AIDS (1981). HIV status was positive in 4 cases, negative in 17 cases, and not stated in the remainder. Risk factors for histoplasmosis were present in ten cases: farming (n = 4), trauma (n = 3), malnutrition (n = 1), immunodeficiency (CD4 count < 300 cells/mm3, HIV negative, n = 1) and proximity to caves (n = 1). 111 cases were resident in urban areas, and the setting was unclear in 17. On the contrary, from the observational studies, the predominant was females (n = 53, 51.5%). The number of HIV-positive cases was 82 (79.6%). Significant risk factors identified in these studies were occupation (P < 0.001) and smoking (P = 0.037) [Supplementary Table 1] and [Supplementary Table 2].
Figure 1: Geographical distribution of reported histoplasmosis cases in Nigeria
Figure 2: Number of individual cases compared with observational studies across Nigeria's geopolitical zones
Disease characteristics
Amongst the 128 individual cases, the anatomic site of the disease was mentioned in 125 cases. [Figure 3] summarises the affected sites and their respective proportions. We excluded the cases from observational studies from this analysis as these studies focused on targeted populations: the advanced HIV disease (AHD) population and presumptive pulmonary TB patients, respectively [Supplementary Table 1]. Clinical presentation was predominantly extrapulmonary (n = 117, 91.4%) involving the skin, mucosa, subcutaneous tissues, bone, lymph nodes, liver, spleen, gastrointestinal tract and sinuses, 11 (8.6%) were disseminated forms with only a single case (0.8%) of pulmonary histoplasmosis. 3 cases (2.3%) were reportedly caused by Hcc, 109 (85.2%) were caused by Hcd and specie identification was not attempted in 16 cases. Histoplasmosis was initially misdiagnosed as several clinical entities including TB, cancers, osteomyelitis, neurofibromatosis and cystic lesions [Supplementary Table 1]. With regards to the observational studies, all participants had clinical symptoms suggestive of TB or histoplasmosis as stipulated in the inclusion criteria of both studies.[2],[3]
Diagnosis
Of 128 individual cases, diagnostic modality was specified in 121: histopathology (n = 115, 89.8%), culture (n = 6, 4.7%), microscopy (n = 1, 0.8%), urinary Histoplasma antigen assay (n = 2, 1.6%), serum antibody (n = 1, 0.8%) and PCR (n = 1, 0.8%). Diagnostic modalities used in the observational studies were urinary Histoplasma antigen testing and sputum PCR [Supplementary Table 1] and [Supplementary Table 2].
Treatment and outcomes
Antifungal treatment was identified in only 21 case reports, and in one case, there was no treatment given. The patient had only surgery and was reported to have recovered spontaneously without antifungal therapy. Amphotericin B (n = 14) was predominantly used for therapy: in combination with azoles in three cases, rifampin in two cases and surgery in one. Azole monotherapy was used in 6 cases and combination with surgery in one case. Cotrimoxazole was also used for treatment as monotherapy in two cases and combination with surgery in one case. The outcome was revealed in 29 cases and unstated in the remainder. Twenty-three had favourable outcomes, 3 were lost to follow-up and 3 were fatal [Supplementary Table 1]. The observational studies were cross-sectional studies so outcomes were not determined.
DiscussionHistoplasmosis has been reported sporadically in Nigeria since 1968, but only a few studies have been conducted. This review highlights the epidemiology of histoplasmosis in Nigeria based on case reports, case series and a couple of recent observational studies. The national incidence of 0.1%/100,000 population should, therefore, be interpreted with caution as it is likely to be an underestimate. Contrary to findings from a previous review (1952–2017) on histoplasmosis in Africa by Oladele et al. which documented the highest number of histoplasmosis cases from Nigeria, the incidence of histoplasmosis in Nigeria was similar to that from South Africa (0.1/100,000) but lower than that of Cameroon (16/100,000), Ghana (2.5/100,000), Mozambique (0.6/100,000) and Tanzania (0.3/100,000).[49],[50],[51],[52],[53],[54] The reasons for these variations may be attributed to varied methodologies engaged in the estimation of incidence as well as the target population.[49],[50],[51],[52],[53],[54] Whereas our calculations for histoplasmosis incidence in Nigeria were based on her total population, the rates for Cameroon, Ghana and South Africa were predicated on people living with HIV/AIDS while the rate for Mozambique targeted people with respiratory disease and HIV/AIDS.[49],[50],[51],[53] In addition, the incidence rates of histoplasmosis for Cameroon, Tanzania and Mozambique were extrapolations from prevalence rates from previous studies. Moreover, we cannot ascertain whether these cases were confirmed or not.
Several interrelated factors contribute to the poor understanding of the epidemiology of histoplasmosis in Nigeria. To begin with, histoplasmosis is a fungal disease and awareness of fungal diseases is poor amongst health workers.[55] Research in human mycology and by extension histoplasmosis is also very limited in Nigeria.[56] No large-scale epidemiological studies on histoplasmosis have been conducted until very recently: a cross-sectional multicentre study which focused on ascertaining the burden of histoplasmosis amongst the AHD population in Nigeria and another cross-sectional study from Calabar, South-South Nigeria focused on the prevalence of histoplasmosis amongst presumptive TB patients.[2],[3] These studies revealed a high prevalence of histoplasmosis amongst studied populations: one documented a prevalence of 7.7% while the other reported a 12.7% prevalence.[2],[3] The number (n = 103) of histoplasmosis cases identified from these studies constitutes 44.6% (103/231) of the total number of cases highlighted in this review. This suggests that histoplasmosis is grossly under-reported. Before the conduct of these observational studies, HIV/AIDS appeared not to be an important risk factor for histoplasmosis in Nigeria, possibly because a significant proportion (45.3%, 58/128) of cases was reported before the advent of HIV/AIDS. However, the findings from Oladele et al.'s study amongst persons with AHD proved otherwise.[2] Similarly, only a few cases of Hcc were documented before Ekeng et al.'s study among persons with suspected TB but the results of that study proved that classical histoplasmosis caused by Hcc is a strong differential of pulmonary TB.[3]
The fact that the clinical and radiological features of histoplasmosis mimic TB lead to delayed and/or misdiagnosis of histoplasmosis and this constitutes an important factor undermining reports of the disease from Nigeria. This position is supported by some of the cases in this review.[5],[25],[40] In the recent study from Calabar, the prevalence of histoplasmosis amongst confirmed TB patients (7.4% [7/94]) was significantly lower than in unconfirmed patients (16.8% [20/119]) P = 0.04), who were presumed to have TB when they had histoplasmosis.[3] Co-occurrence of histoplasmosis and TB has also been reported, so a TB diagnosis does not conclusively rule out histoplasmosis.[2],[3] The challenge of misdiagnosing histoplasmosis as other clinical entities, particularly TB is further driven by the fact that Nigeria is endemic for TB and currently ranks as the 6th highest TB-burdened country globally, hence the tendency for an attending clinician to consider TB as an initial diagnosis or a differential is much higher compared to histoplasmosis, whereas the diagnosis in the index case could be histoplasmosis or co-occurrence of both entities.[5],[25],[39],[40],[47]
A final but equally important factor which hampers histoplasmosis case-finding is the general lack of diagnostics for fungal infections in Nigeria. A gap analysis survey from 22 tertiary hospitals spread across the six geopolitical zones of Nigeria showed amongst other deficits, a lack of the Histoplasma enzyme immunoassay for detecting Histoplasma antigen in urine.[57] This assay has become the diagnostic method of choice for the detection of histoplasmosis in people living with HIV and is listed by the World Health Organization as an essential diagnostic test.[2],[58] Our review showed that most case reports of histoplasmosis were diagnosed using histopathology which is useful mostly for cutaneous and subcutaneous lesions.[2],[4],[6],[59] Culture was rarely done probably due to little expertise and the lack of biocontainment facilities.[4],[59] Of note, the two observational studies utilised modern diagnostic techniques such as enzyme immunoassay and polymerase chain reaction which are not routinely available in most health facilities.[57]
Limitations of the study
The results of this review are limited by the search strategy employed. As this review relied on internet search, cases documented in grey literature and journal articles not available online would have been missed. Missing data from the cases reviewed such as age and sex also limit our synthesis of the epidemiology of the disease.
ConclusionHistoplasmosis is not an uncommon disease entity in Nigeria. It occurs as an opportunistic infection in the AHD population and has a high prevalence amongst patients presumed to have TB, the majority of whom are HIV-negative. Lack of awareness coupled with little research in the field of mycology, misdiagnosis of histoplasmosis as TB and lack of diagnostics have obscured the true burden of the disease. Improving awareness, providing diagnostics and instituting surveillance will aid in better case detection and understanding of the epidemiology of histoplasmosis in Nigeria.
Recommendations
More studies are needed to ascertain the true burden of histoplasmosis in Nigeria. Instituting active surveillance for histoplasmosis in the at-risk populations-those with AHD and those presumed to have TB-across all states of the federation would improve case-finding tremendously and lead to a better understanding of the disease's epidemiology. For surveillance activities to be effective, knowledge and awareness gaps must be addressed by training and re-training of the health workforce. Diagnostic assays must also be made readily available. Integrating the use of these assays into existing programmes on HIV/AIDS and TB would go a long way in ensuring that at-risk populations are promptly and effectively screened for histoplasmosis.
Authors' contributions
BEE Conceptualisation, data curation, literature review and writing-original draft and main manuscript, review and editing. AAD Data curation, resources and writing. IIO Resources, writing, review and editing UEE, UAU, MAA, OCA, ROO resources, review and editing. All authors have agreed to the final version of this manuscript.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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