Varicella zoster virus-associated morbidity and mortality in Africa – a systematic review

Varicella zoster virus (VZV), a member of the herpesviridiae family, is responsible for two distinct disease entities: varicella (chicken pox) and herpes zoster (shingles). VZV is a ubiquitous virus and both diseases of varicella and herpes zoster occur commonly throughout the world [1, 2]. Primary infection with VZV results in varicella, a usually benign disease of childhood characterized by fever and a pruritic vesicular rash. Complications, such as bacterial skin infections, pneumonia and encephalitis, can however, occur and may result in significant morbidity and mortality, particularly if the primary infection occurs in adults or those who are immunosuppressed [1].

Following the primary infection, VZV remains dormant in the host. With decreased immunity, as seen in elderly persons or with human immunodeficiency virus (HIV)-associated immunosuppression, VZV reactivates causing herpes zoster, a painful vesicular rash with a dermatomal distribution. A common complication of herpes zoster is post-herpetic neuralgia, which can result in significant morbidity. Eye involvement, including uveitis with the risk of blindness, can also occur. Occasionally herpes zoster may present without a rash (zoster sine herpete) and VZV neurological complications can sometimes occur in the absence of a rash [3]. The epidemiology of these atypical presentations of VZV is, however, still not clear. In Africa, risk factors for VZV include the rapidly growing elderly population [4] and a high HIV prevalence [5].

Molecular epidemiological analysis of VZV shows some evidence of geographical segregation, which may partly be explained by climatic conditions [6]. The VZV genotype M1, belonging to clade 5, has been associated with African origin [7]. Understanding the VZV genotypes distribution is an important factor to consider when implementing vaccination programs against the diseases in any geographical setting.

Safe and effective vaccines against both varicella and herpes zoster exist [2]. The varicella vaccine has also been shown to be safe and immunogenic in immunosuppressed children, including those with HIV (provided the child is not severely immunosuppressed and the CD4+ T-cell count is >15%) [8, 9]. The World Health Organisation (WHO) recommends routine childhood vaccination against varicella in certain settings: where varicella is ‘an important public health and socioeconomic problem’; vaccination is affordable; and high vaccination coverage can be sustained [9]. Settings that meet these WHO recommendations are mainly in high income countries, where routine varicella vaccination is now widespread [8]. This is in contrast to Africa, where other public health priorities, suboptimal healthcare infrastructure, inability to reach high vaccination coverage rates and lack of epidemiological data all contribute to the vaccine against VZV being rarely used.

The vaccine (live attenuated VZV) used against herpes zoster is similar to that for varicella, but the herpes zoster vaccine has 14-fold more plaque-forming units of the attenuated virus per dose [2, 10]. As of 2014, the WHO had not issued recommendations on the routine vaccination against herpes zoster, due to limited evidence [2].

In Africa, there are several other vaccine preventable diseases (VPD’s) associated with a greater public health burden [11, 12], compared to VZV-associated diseases. Immunization priorities and strategies are largely driven by the public health burden and the severity of VPD’s. Routine vaccination against VZV is therefore, not considered a priority in Africa. Although VZV-associated morbidity and mortality rates are generally low in most settings, both varicella and herpes zoster can cause considerable strain on healthcare systems and society, in the absence of preventative measures [1].

For Africa to design effective strategies that can mitigate the VZV-associated disease burden, it is crucial to understand the epidemiology of both varicella and herpes zoster on the continent. Most of the available and published VZV epidemiology data come from settings such as Europe and North America [8]. This epidemiological data on VZV in developed countries cannot be extrapolated to Africa because of several differences between the two settings, including climate, the HIV epidemic and malnutrition [13, 14]. In addition, suboptimal access to healthcare services may exacerbate the VZV-associated disease burden in Africa. Data from Brazil shows that varicella in the pre-vaccine period was associated with significant morbidity and mortality [15]. Similar findings are, therefore, expected from some countries in the African continent, such as South Africa.

Prior to this review, there has been no synthesised literature on VZV epidemiology in Africa. Our review aimed to address this gap in knowledge by describing the epidemiology of VZV in Africa, taking into account both varicella and herpes zoster. Because HIV/AIDS is prevalent in Africa, we were also interested in assessing the impact of the HIV/AIDS epidemic on the epidemiology of varicella and herpes zoster.

The complete raw data-set is available as a supplementary file (Additional file 1: Table S1).

Limited VZV epidemiology data in Africa

Our first aim was to establish which countries in Africa have reported published data on the VZV epidemiology between 1974 and 2015. There were 20 published studies conducted in 13 different African countries (24% of all countries on the continent) included in the final analysis (Fig. 2).

Burden of VZV-associated disease in Africa is high but variable

We evaluated the reported incidence, prevalence, hospitalization and mortality data from the included studies (Table 2 and Figs. 3 and 4 ). Across the included studies, variable case definitions for VZV disease were used, and these can be broadly categorised into two types: serological and clinical. Only two (10%) studies combined both serological and clinical criteria for the VZV case definition. According to our results, the available data from the 13 (65%) studies on the burden of VZV disease in Africa is mostly from adult populations.

Author (year of publication)	Study population	Case definition	Incidence (per 100,000)	Hospitalization & Mortality
Varicella incidence
Poulsen, A., et al. (2002)	children & adults	clinical & serology	441 per 100,000	NS; 0%
Poulsen, A., et al. (2005)	children & adults	clinical & serology	3420 per 100,000	NS; 0.13%
Zoster incidence
Rubaihayo, J., et al. (2015)	adults	clinical	751 per 100,000	NS; NS

Incidence

Of the 20 included studies, only 3 (15%) reported incidence of VZV. Two of the three incidence studies reported varicella in Guinea Bissau, and these studies were published by the same authors and used a combination of serology and clinical tests to diagnose VZV (Table 2 and Figs. 3 and 4 ). Using population registers to estimate the denominator, ncidences of 441 per 100,000 and 3420 per 100,000 were reported by Poulsen et al., 2002 and 2005 respectively [22, 23]. As the denominator was estimated by the authors, the accuracy of the incidences reported is not clear. The median age for the varicella cases reported by the incidence studies were 3 [22] and 4.4 years [23]. Co-morbidity reported by the two incidence studies were pneumonia at 1.8% and 10% [22, 23] respectively. Other complications reported by Poulsen et al., 2002 were bacterial skin infections (43.6%), cough (23.6%), conjunctivitis (4%) and diarrhoea (1.8%). Poulsen et al., 2005 reported a case-fatality rate of 0.13%. Poulsen et al., 2002 did not report mortality.

The study by Rubaihayo et al., 2015 diagnosed herpes zoster clinically and reported an annual incidence of 751 per 100,000 in Ugandan HIV positive patients [26]. Median age of participants in this study was 32 years (range 26–39) and median CD4 at antiretroviral treatment (ART) initiation was 128 cells/mm³.

Prevalence

There were eight (40%) studies that reported prevalence of VZV-associated disease quantified by viral detection using PCR. Although expensive and requiring greater technical expertise and resources, PCR tests, whether quantitative or qualitative, show superior sensitivity and specificity compared to antibody detection tests [27]. Of the eight studies that used PCR, three were quantitative [28–30], two qualitative [31, 32], and the remaining three did not specify if the PCR used was quantitative or qualitative [33–35]. Four of the eight studies were performed on CSF (in patients that presented with signs of central nervous system [CNS] infections), whereas two studies were performed on ocular fluids (mostly from patients with uveitis). The eight studies found a VZV prevalence that ranged from 0% to 90% (Fig. 3). This big variation could be explained by the fact that these studies had recruited highly selected patient populations (i.e. patients presenting to healthcare facilities with a possible CNS infection or uveitis). It is unlikely that the VZV prevalence reported from these patients can, therefore, be extrapolated to the general population.

Seroprevalence

Evaluation of antibodies to VZV (IgG, IgM or both) was reported in ten studies (Fig. 4). IgG provides an indication of previous infection or vaccination, and therefore immunity, while IgM suggests recent or acute infection [36]. Nine of the ten studies measured IgG, and of these, two also tested IgM. The nine studies used the enzyme linked immunoassay for the antibody measurements, while the tenth study used the complement fixation method without specifying the type of antibody measured. A combination of commercially available kits and inhouse immunoassays were used and there was high variability in how the ten studies tested for anti-VZV antibodies (IgG or IgM). In addition, cut-offs for anti-VZV antibodies positivity were not provided except by Schoub et al., 1985 who indicated that a 0.15 regression value of the EIA was the cut-off positivity value [37]. The assay variability and lack of defined positivity cut-offs partly contributed to our inability to perform a meta-analysis on the seroprevalence in this review. Seroprevalences ranged from 21.9% (in hospitalized children with co-morbidities in Kenya [38]) to 100% (elderly patients in rural Uganda [39]). In general, and as expected in settings without routine vaccination, children showed lower proportions of seropositivity to VZV than adults (Fig. 4).

We successfully conducted a systematic review on the epidemiology of VZV in Africa. A high but variable burden of VZV-associated disease was found. In this review, we observed high VZV seroprevalence (IgG) in adults. This review identified limited VZV seroprevalence data in children which was insufficient to compare with data from adults. One study by Adamani et al. showed relatively low rates of detectable antibodies in children [38]. In contrast, high rates of detectable VZV antibodies in adults were reported [24, 25, 28, 37, 39, 41, 42, 44, 45]. Because vaccination against VZV is not routine in Africa, we presume the high seroprevalence rates in adults indicates previous natural exposure or infection.

Although this review identified limited data on VZV in children, increasing age, even in adults was found to be associated with increased VZV seropositivity. A South African study reported that only a moderately high proportion of young adults had detectable VZV antibodies, compared to all individuals at 60 years of age in the same setting [37]. The VZV seropositive status was also found to be independently associated with age in HIV positive patients [41]. Taken together the VZV seropositivity results reported in this review suggests that primary VZV infection occurs at a later age in Africa, compared to other regions [1]. Interestingly later acquisition of varicella is thought to be possibly protective against developing shingles, as immunity developed during the initial infection could last longer [46].

Climatic conditions are known to influence the transmission of VZV [8]. Africa has widely varying climates, including large areas of tropical and sub-tropical climates that may result in a lower transmission of VZV and therefore primary infection at older ages, as has been seen in studies from India and South East Asia [14, 47]. Our results corroborate those of Lee et al., who reported VZV seroconversion in Asian tropical countries peaking in adolescence and adulthood [14]. In contrast, seroconversion with VZV appears to peak during childhood in temperate countries [48].

Exposure to VZV is cumulative over time and seroconversion, therefore, is expected to increase with age. Seropositivity depends on what antibody level cut offs were used, and were unfortunately not reported for most studies in this review. Understanding the age of primary VZV infection in a given setting is crucial in the design of an optimal vaccination strategy. The only two studies that looked at varicella incidence (both from Guinea-Bissau) reported high incidence rates in both children and adults [22, 23]. The incidence rates reported in Guinea-Bissau seem higher than those observed in some temperate climates for a similar age group, [49, 50]. However, the Guinea-Bissau incidence rates are comparable to pooled incidence rates reported in Latin America [51].

Climatic conditions vary greatly between and within African countries, and, therefore, the data from Guinea-Bissau cannot be extrapolated to the whole continent. In addition, high levels of household overcrowding might negate the effect of a tropical climate on VZV transmission [8]. There were, however, eight studies that tested for VZV using PCR, as well as two that utilised IgM, which gave some indication of recent or current infection. Of the eight studies that utilised PCR, all excluding the Compston et al., 2009 study, were all in patients suffering from neurological or ocular diseases, and, therefore, cannot be extrapolated to the general population.

Important risk factors in the development of herpes zoster include advanced age and altered cell mediated immunity, as seen in malignancy, immunosuppressive treatment and HIV infection [36]. HIV positive individuals are thought to have a 12–17-fold greater risk of developing zoster [13]. In Sub-Saharan Africa where the burden of HIV is high, zoster has a high positive predictive value for underlying HIV infection [13]. A study conducted in Rwanda after the 1994 genocide found that amongst HIV positive patients, post-traumatic stress disorder was significantly associated with zoster (the study used patient self-reports to diagnose zoster and was, therefore, not included in this review) [52]. In a study amongst HIV positive patients in Zambia with CNS infections, VZV was the fourth most common viral infection and VZV case fatality rates were high [32]. In comparison, a study looking at viral meningitis in Malawi, where more than half of the patients were HIV positive, detected no VZV co-infection [34]. This was unexpected as VZV is a common identifiable cause of viral meningitis in industrialised countries [34]. A study by Compston et al. found that HIV was associated with VZV seropositivity [28]. The authors hypothesized that in individuals, who were previously exposed to VZV but remained seronegative, HIV-driven immune dysfunction leads to relatively small increases in VZV replication and reactivation. This in turn results in boosting of VZV antibodies and higher VZV seroprevalences in HIV [28].

The widespread and increasing availability of antiretroviral treatment (ART) in Africa [5] will likely have a positive impact on VZV epidemiology. Restored immune function on ART is thought to be protective against herpes zoster [53]. This is observed in Rubaihayo et al., study where the VZV incidence dramatically decreased from the pre-ART era, compared to the ART era [26]. These findings are consistent with data from HIV positive patients in the USA [54]. The development of zoster while on ART has been suggested to be a marker of non-adherence to ART [55]. Taken together, these results suggest that HIV treatment programs should be strengthened when establishing vaccination programs against VZV in African countries. It must also be noted that as ART is allowing HIV positive people to live longer, the HIV population in Africa is aging [56]. The implications of an ageing HIV positive population on the epidemiology of zoster are not clear.

Optimal vaccination programmes against VZV are effective in mitigating the disease burden [8]. There are currently no routine vaccination programs against VZV in any African county unlike many developed countries, that have adopted a universal vaccination policy against varicella [8]. In 2006, some developed countries reported a case fatality rate for varicella of 2–4 per 100,000 [50, 57]. Slightly higher case fatality rates of 11 per 100,000 were reported in Latin America where vaccination programs have been introduced in some countries [51]. However, as shown in our review, case fatality rates of up to 130 per 100,000 were reported in Guinea-Bissau [23]. The VZV associated mortality is known to be about 30 times higher in adulthood than childhood [1]. We were not able to find any reported rates of hospitalization from our included studies. Rates of complications, including the development of post-herpetic neuralgia, were also not reported.

Our review is limited by a paucity of data on VZV in Africa. Between 1974 and 2015, only 20 studies from 13 countries met the inclusion criteria for our review. The countries that contributed to the review may not be representative of the continent as a whole [58]. As our review included only published studies, and did not consider grey literature, there is potential for bias in our findings. In addition, the quality of the included studies is also poor, as the review mostly consisted of cross-sectional studies that depended on serology for their case definition. The serological tests were mainly enzyme linked assays detecting IgG, lacked information on positivity cut-offs and the assays do not discriminate current infection from previous infection, previous exposure or vaccination. Furthermore, many of the studies were conducted in a health facility on patients already hospitalized with complications of possible VZV. While this does give us some indication of the burden that VZV imposes on the health system, the prevalences and mortality rates obtained from these studies cannot be extrapolated to the general population.

Effective vaccines for both varicella and herpes zoster exist. We observed low and high levels of VZV seropositvity in children and adults respectively. The observations are worrisome, particularly in the context of a high HIV burden and an ageing population in Africa, as it suggests some primary exposure to VZV may be happening in adulthood. Primary VZV infection is more severe in adults than children. The resultant increased risk of morbidity and mortality from VZV could be mitigated by vaccines. Where universal varicella vaccination may not be feasible, such as in most African countries, vaccination of high risk individuals, such as healthcare workers, immunocompromised patients and their household contacts has been suggested [8]. But improved surveillance of VZV-associated diseases and cost-effectiveness data on the continent is first needed before vaccination can be considered. Future research must focus on generating quality primary data and feasibility of interventions on VZV in Africa.