Magnitude of Cryptococcosis among HIV patients in sub-Saharan Africa countries: a systematic review and meta-analysis

Background Cryptococcus is encapsulated opportunistic yeast that causes life threatening meningoencephalitis of patients with human immunodeficiency virus (HIV). The magnitude of Cryptococcosis among HIV patients varies from 1–10% in Western countries as opposed to almost a one third of HIV-infected individuals in sub-Saharan Africa where it is associated with high mortality. Methodology By using key terms “Cryptococcosis among HIV patients in sub-saharan Africa countries”, articles that published in different journals from 2010–2017 searched on Pub-Med and Google scholar database. Those freely accessible and included the prevalence of Cryptococcosis in the result section, their PDF file was downloaded and the result extracted manually and presented in table. Articles that did not report the prevalence of Cryptococcosis, with a study design otherthan cross sectional, or a sample size less than 100, and those duplicated in the same study area and period by the same authors were excluded. The article selection followed the PRISMA guidelines and meta- analysis was performed using OpenMeta(analyst). Results The overall pooled magnitude of Cryptococcosis among HIV patients in sub saharan African countries was 8.3% (95%CI 6.1–10.5%). The highest prevalence was from Uganda (19%) and the least was from Ethiopia at 1.6%. There was 87.2 % of substantial heterogeneity among the studies with p-value<0.001. The symmetry ofthe forest plot showed that there was little publication bias. The most commonly used method for diagnosis of Cryptococcosis was lateral flow assay and latex agglutination test and culture was the least method employed. Conclusion The overall pooled magnitude of Cryptococcosisis high among HIV patients in sub-Saharan African countries. The studies showed substantial heterogeneity, and little publication bias. Most of the studies relied on LFA & LA that showed the scarcity of facilities for fungal culture. Therefore, paying attention to screening HIV patients; those with signs and symptoms of meningitis may help to reduce the loss of HIV patients.


Introduction
Cryptococcus is an encapsulated opportunistic yeast that causes life threatening meningoencephalitis of patients with the Human Immunodeficiency Virus (HIV) 1 . It is dangerous and leads to death in nearly all patients who are not treated.Nevetheless, , the treatment is efficacious 2 . This basidiomycete fungus was first isolated in 1894 by Sanfelice in fruit juices and subsequently recovered from the tibial lesion of a patient by Busse and Buschke 3 . Cryptococcosis is caused by two species in the genus Cryptococcus, Cryptococcus neoformans (CN) and C. gattii. CN (serotypes A, D, and AD) is found worldwide and causes Cryptococco-African Health Sciences Vol 20 Issue 1, March, 2020 114 sis most frequently in HIV patients. C. gattii (serotypes B and C) is geographically restricted and is infrequently diagnosed in HIV patients except in some areas of Africa 4 .
The magnitude of Cryptococcus meningitis among HIV patients varies from 1-10% in Western countries as opposed to almost a third of HIV-infected individuals in sub-Saharian Africa and SouthEast Asia where it is associated with high mortality 5 . Since the introduction of highly active antiretroviral therapy (HAART), the national HIV surveillance programs implemented in Western countries have reported a sharp decrease in the incidence of HIV cases and the estimated number of deaths among HIV patients.While the number of persons living with HIV has increased, the incidence of opportunistic infections like CM has decreased 5 . Meningoencephalitis is the most common clinical manifestation of CN infection, and it is usually incurable, despite antifungal therapy 6 . In the pre-ART era, lifelong fluconazole was recommended after a presentation with CM, but it now appears that late relapse is unlikely during successful ART. International guidelines state that immune restoration by ART permits discontinuation of maintenance therapy. However, evidence to support cessation of secondary prophylaxis is weaker when induction/consolidation therapy is not fungicidal (e.g., fluconazole monotherapy), and isolated CM relapses have been described in patients on ART with CD4 counts up to 495 cells/μL [6][7][8] . Despite antifungal treatment, acute mortality in low income countries remains between 24% and 43% and Cryptococcus meningitis (CM) accounts for 10-20% of all HIV-related deaths in sub-Saharan Africa 9 .
Although effective treatment for HIV disease has decreased the incidence of CM significantly in high income countries, it remains a common cause of morbidity and mortality especially among patients living in sub-Saharan Africa and South East Asia 3 . The causative organism, Cryptococcus, is a facultative intracellular pathogen that has developed numerous strategies allowing it to survive and replicate inside macrophages 10,11 . In the context of impaired adaptive immune responses, the ability of Cryptococcus to evade macrophage killing leads to dissemination, disease and ultimately death 12 . The primary immune defect leading to development of CN is impairment of CD4+ T-cell responses, usually secondary to HIV infection 13 .
As far as we know, there is no systematic review and meta-analysis about cryptococcosis among HIV patients in sub-Saharan African countries, Therefore, this study can be used as a basis for policy makers, clinicians and researchers.

Eligibility
Articles that reported the magnitude of Cryptococcus among HIV patients; those with a cross sectional study design, published in the English language,with sample size of more than 100 and published after 2010 were included.

Data analysis
A Systematic review was performed according to the PRISMA protocol. A data extraction tool was used for abstraction of data from each article selected for review and presented in a table. The data analysis was performed using OpenMeta (analyst) software and presented in forest plot. Random effect model was used to calculate the pooled prevalence and heterogeneity of the study were identified by using I2 at 95% CI and p-value <0.05.

Data quality
The quality of data was checked by each of individual authors for the similarity of study design, sample size greater than 100 and the inclusions/exclusions criteria was strictly followed.

Results
Based on our inclusions criteriafive articles from Ethiopia 14,19,20,  All the studies wereconducted using a cross sectional design. The largest sample size was from Ethiopia is 375 participants 14

Outcome of interest
According to our meta-analysis presented on the forest plot on figure below the pooled magnitude of Cryptococcosis in sub-Saharan African countries was 8.3 % (95%CI 6.1-10.5%, P<0.001).The random effect model showed that there is substantial heterogeneity among the studies which is I2 = 87.17% with p value <0.001.

Discussion
Cryptococcusis a cosmopolitan fungus that causes human disease mainly in patients infected with HIV that is mainly presented as Cryptococcosis worldwide 30 . However, the condition is more serious in low income countries, especially in sub-Saharan African countries where HIVAIDS is more prevalent and resources for diagnosis CM are scarce. 31 According to our study the overall pooled prevalence of Cryptococcosis was 8.3 % (95% CI, 6.1-10.5%, P<0.001) which is higher than a study conducted in USA (2.8 %) 32 .
It is also comparable with a report on global burden of CM that is 6.0% in HIV patients with CD4 count lower than 100 cells/µl 33 and one meta-analysis study in the world population with HIV that is 6.5% 34 . Even if there is lack of meta-analysis data for each continent, the prevalence of Cryptococcosisis high in sub-Saharan African countries when compared to the rest of the world. Even though the prevalence is comparable with the external world Cryptococcosis is a neglected disease in sub-Saharan African countries that need immediate attention especially for thosewith low CD4 counts.
Since the study population is from different countries the random effect model was used to determine the effect size. The random effect model showed that there is higher heterogeneity among the studies which is mostly considered.If I2> 75%, this indicates higher heterogeneity. In our case I2 = 87.17%, p-value <0.001 that showedsubstantial heterogeneity and it is also statistically significant. The symmetry of forest plot funnel showed that some studies caused insignificant publication bias since the study is conducted with the same study design and study populations even though there is a difference between study area and period.
Cryptococcus is a fungus that lives in the environment throughout the world. People can become infected with Cryptococcus after breathing in the microscopic fungus, although most people who are exposed to the fungus never get sick from it. Cryptococcus infections are extremely rare in people who are otherwise healthy; most cases occur in people who have weakened immune systems, particularly those who have advanced HIV/AIDS 35 . In sub-Saharan Africa countries since there is lack of facilities for diagnosis of Cryptococcus which is based on Indian ink if available, it may leadfalse positive or negative results since there is lack of culture facility, relying on availability of LFA &LA tests for confirmation. As we tried to present in Table 1 from our systematic review most of the studies rely on LFA and LA test in which only one study used fungal culture that supported our idea.

Conclusion
The overall pooled magnitude of Cryptococcosis is high among HIV patients in sub-Saharan African countries.
The studies showed substantial heterogeneity with little bias. Most of the studies relied on LFA & LA that showed the scarcity of facility for fungal culture. Even though our meta-analysis showed results comparable to the rest of the world, attention to screening the HIV patientsespecially thosewith signs and symptoms of meningitis may help to reduce the loss of HIV patients. LFA & LA is helpful for the diagnosis Cryptococcus as point of care test.

Authors' contribution
TA: Conceived the idea, searched the articles, extracted the data performed systematic review and Meta-analysis and prepared the manuscript. SA, TA, and DD: Participated on article selection, advised and editing of the manuscript. All authors have read the final manuscript.

Ethical approval
Ethical clearance was not required and was not necessary for this study.

Conflicts of interest
We authors declare that they have no conflicts of interest