Cryptococcal antigenemia and its predictors among HIV infected patients in resource limited settings: a systematic review

According to the 2019 United Nations Programme on AIDS (UNAIDS) report, around 37.9 million people globally were living with HIV in 2018. In the same year, about 1.7 million people were newly infected and 700, 000 people died from AIDS-related illnesses globally [1]. Cryptococcosis is one of the most important opportunistic infections among people living with advanced AIDS having defective cellular immune component and is a major contributor to AIDS-related mortality worldwide [2]. In spite of the increasing availability of antiretroviral treatment (ART), cryptococcal disease continues to be a leading cause of death among HIV infected patients in the developing world [3‐5]. Considerable number of HIV-infected population still presents late to care with advanced AIDS [6, 7].

The burden of the disease is greatest in middle and low-income countries where there is a high prevalence HIV infection [8‐13]. Patients taking immunosuppressive drugs and some immunocompetent hosts are also at risk [14]. Although the infection begins in the lungs, certainly the most common presentation of cryptococcal disease is cryptococcal meningitis (C M) which accounts for 15–20% of all AIDS-related deaths globally, three quarter of which are in sub-Saharan Africa. Coupled with loose adherence to ART and retention in HIV care, an estimated 223, 100 cases of CM resulted in 181, 100 deaths among people living with HIV in 2014 [2, 4, 7, 13, 15]. Screening patients for subclinical cryptococcal infection at the time of entry into ART programs using point-of-care tools like, cryptococcal antigen (CrAg) immunoassays is highly effective in identifying patients at risk of developing CM, allowing these patients to then be targeted with pre-emptive antifungal therapy to prevent the development of severe disease and mortality [16].

Cryptococcal infection is primarily caused by Cryptococcus neoformans and C. gattii species [8, 9]. C. neoformans is encapsulated yeast that can be found in pigeon droppings which causes mild to severe infections like meningitis or disseminated disease in individuals with impaired immunity [10]. The yeast demonstrates several well-characterized virulence factors that contribute to the success of infection. To mention the common one; tolerance to mammalian body temperature at 37 °C, owning a polysaccharide capsule that protects the yeast from phagocytosis, and a thick cell wall with the deposition of phenolic melanin, which has been proposed to protect the yeast from oxidation [11, 12].

While the gold standard for diagnosis of cryptococcal disease is culture from bodily fluids, CrAg test is used to presumptively diagnose the disease with sensitivity and specificity close to 100%. There are several methods to detect cryptococcal antigen in CSF or plasma/serum: latex agglutination (LA), enzyme immunoassay (EIA), and lateral flow assay (LFA) [6]. Recent advances in point-of-care testing, like CrAg test, has made screening and diagnosis of CM rapid, practical, and affordable and have been improving long-term survival. Targeted screening and pre-emptive treatment programs for CrAg are a cost effective method for reducing early mortality [17].

Some of the independent predictors of positive serum cryptococcal antigenemia includes; CD4(+) T cell counts of ≤100 cells/mm, low body mass index, presenting with neck pain, signs of meningeal irritation, and a recent diagnosis of HIV infection [18‐21]. Routine screening of such category of patients may detect cryptococcosis, and hence provide an opportunity for early intervention.

Despite the high burden of cryptococcal meningitis related morbidity and mortality in resource limited settings, reviewed data on prevalence of cryptococcal antigenemia and its predictors is missing [22, 23]. Hence, data is required on this field to inform policy makers for input to tailor intervention measures. Therefore, this systematic review was conducted to describe the the level of cryptococcal antigenemia and its predictors in resource limited settings.

Cryptococcal meningitis, a deadly opportunistic fungal infection, is a leading cause of death among people with advanced HIV in resource limited settings [15, 49, 50]. However, it is one of the neglected topics by public health authorities while most deaths from the diseases are avoidable [23, 50‐53]. There is quite few data regarding the prevalence of cryptococcosis in resource limited settings for public health measures. Therefore, in this systematic review data of some 8338 HIV positive individuals is described to uncover the prevalence of cryptococcal antigenemia and its possible predictors. The median age of the patients in the included studies range 30–40 years which implies that HIV infection continue affecting the productive segment of the population.

In this review the reported median CD4 count of the HIV patients was between 20 and 123cell/μl. Except a study [39], the rest reported mean CD4 count of the participants below 100 cells (range 23–97 cells/μl). On top of this twelve studies [18, 29, 30, 32, 34, 36, 42, 43, 45‐48] reported that all the participants were ART naïve. Consequently, low CD4 count coupled with not starting ART would expose HIV infected patients for higher risk of different opportunistic infections including, cryptococcosis.

Our review result showed the overall prevalence of cryptococcal antigenemia between 1.7 and 33%; the pooled prevalence was at 8% (95%CI: 6–10%). A review by Firacative et al. (2018) on the status of cryptococcosis in Latin America reported prevalence of 10–21% [22] in the context of HIV patients with CM. Although the papers included in the present review recruited patients with different clinical ground, including their different CM status, our finding is still in line with the above report. Similarly, based on Rajasingham et al. (2017) review report on the Global burden of HIV-associated cryptococcal meningitis, the estimated global cryptococcal antigenaemia was at 6% (95%CI 5.8–6.2%) among people with a CD4 cell count of less than 100 cells per μL in 2014. This finding is in line with our pooled estimate at (8%). In addition, according to this report, the Sub-Saharan Africa accounted for 73% of the estimated cryptococcal meningitis cases in 2014. Moreover, the report also highlighted that there might be an ongoing burden of HIV-associated cryptococcal disease, primarily in sub-Saharan Africa [54]. Ford and his colleague (2018) on their review article reported the global pooled prevalence of cryptococcal antigenemia at 6.5% among HIV patients with CD4 count ≤100 cells/μL which is still comparable with our report [55].

Another review by Park et al. (2009) aimed at estimating the current global burden of cryptococcal meningitis among persons living with HIV showed an incidence ranged from 0.04 to 12% per year. Sub-Saharan Africa had the highest yearly burden estimate (median incidence at 3.2%). In contrast, the median incidence was lowest in Western and Central Europe and Oceania (</=0.1% each) [5]. This implies that the overall prevalence of the disease would be much higher, may be close to or greater than our pooled report at (8%), in poor settings. In contrast, the prevalence of cryptococcosis in the developed world has decreased as there is quite low burden of HIV and is also being diagnosed earlier, but is still significant, and the problem in resource-limited settings is exceedingly high [56] in which over half of patients die within 10 weeks of diagnosis compared to as few as 10% of patients from developed nations [57].

The pooled prevalence of cryptococcal antigenemia in Ethiopia was at 7% (95%CI: 3–11%) among HIV infected patients at different clinical context. Comparable reports have been released in Ethiopia and overseas; Bite et al. (2016) had reported (8.5%) positive cryptococcal antigenemia proportion in Addis Ababa, Ethiopia [58]. Thomsen et al. (2018) reported that, of HIV patients included in a study in Guinea-Bissau, (10%) had a positive cryptococcal antigen test [59]. On top of this, in our review the pooled prevalence of cryptococcal antigenemia was 11% (Uganda), 4% (Tanzania) and 7% (South Africa). As the HIV patients had different CD4 count, ART status and other background variables, i.e. due to clinical variability, minor variation in the prevalence of cryptococcal antigenemia is likely to happen in different settings. Further, as most of the participants had CD4 count less than 100 cells/μl, relatively higher proportion of Cryptococcal antigenemia is more likely to be reported among these immunosuppressed HIV patients in these settings [42]. In contrast to our result, a relatively lower prevalence (2.9%) of Cryptococcal antigenemia among HIV/AIDS patients was reported in United States in 2012 [21]. Difference in ART adherence and HIV care might contribute for the lower prevalence of the case in the US than most African countries.

With regard to the possible predictors of cryptococcal antigenemia, body mass index< 18.5 kg/m2, CD4 count < 100 cells, presented with headache and male gender were reported by two or more articles as an important predictors of cryptococcal antigenemia that could potentially be utilized for public health measures. These all might directly or indirectly contributed for reduced immune status of individuals that could put them at risk for different opportunistic infections, including cryptococcosis. Specifically, lower CD4 count has strong correlation with sever immune depletion, hence risk of opportunistic infections. Liechty et al. (2007) reported that among HIV-infected individuals with CD4 cell count < 100 cells/μl, cryptococcal antigenemia was associated with a higher risk of death than CrAg negative participants [30]. Other studies in different settings also reported that lower CD4 count (usually < 100 cells/mm), low body mass index, having neck pain and signs of meningeal irritation were an important predictors of cryptococcal antigenemia [18‐21, 55]. Thomsen et al. (2018) reported that self-reported headache and fever were also predictors of a positive CrAg test [59].

In our review almost half of the papers reported 10–80.6% proportion of headache and 17.9 and 100% proportion of clinical stage IV HIV disease among HIV patients. Few of other papers reported these variables as an important predictor of cryptococcal antigenemia [44, 45, 47, 48]. Therefore, stakeholders and policy makers should consider target screening and management of HIV patients coming-up with such kind of associated factors to decrease the morbidity and mortality associated with cryptococcal infection in resource limited settings.

The pooled prevalence of cryptococcal antigenemia among HIV infected patients at different CD4 count and ART status was at 8%. Body mass index< 18.5 kg/m², CD4 count < 100 cells, presenting with headache and male gender were reported by two or more articles as an important predictors of cryptococcal antigenemia. Therefore, it will be good to consider routine screening for CrAg among HIV infected patients specifically those presenting with these predictors. Policy makers should consider the implementation of targeted screening and treatment interventions for asymptomatic cryptococcal antigenemia patients in resource limited settings. Meningitis associated with cryptococcosis might be a reflection of HIV treatment programme failure; therefore timely HIV testing and rapid linkage to care will have paramount importance for patients. Finally, further work is needed to better define the scope of the problem and track the epidemiology of this infection, in order to prioritize prevention, diagnosis, and treatment strategies.