Prevalence Pattern of Chikungunya Virus Infection in Nigeria: A Four Decade Systematic Review and Meta-analysis

ABSTRACT

Chikungunya (CHIK) is a re-emerging and myo-arthritogenic arboviral infection that has affected significant global population. However, CHIK is a neglected disease in Nigeria. This study aimed to estimate the pooled prevalence pattern of CHIK virus infection in Nigeria. A systematic review of eligible articles was conducted from “PubMed”, “Scopus”, “Google Scholar” and “Web of Science”, between January 1980 to February 2020. Peer-reviewed articles describing CHIKV infection in cross-sectional studies were systematically reviewed. Random-effect model was used to pool the prevalence of CHIKV infection and associated sociodemographic data reported from eligible studies. In total, there were 10 published articles on CHIKV infection. Of these, 7 were cross-sectional studies, which comprised of 1347 pooled participants. The pooled anti-CHIKV IgM and IgG seroprevalence were 26.7% (95% CI: 23.2 – 30.4) and 29.3% (95% CI: 26.2 -32.6), respectively.  Of the pooled studies, there were 3.8% (95% CI: 2.0-6.4) CHIKV RNA positive cases and 46.1% prevalence of CHIKV neutralizing antibodies. Of the 6 geopolitical zones in Nigeria, Northeast had the highest serological evidence of CHIKV infection. There was a significance association between the prevalence of anti-CHIKV and geopolitical zones of Nigeria (χ²= 70.04; p˂0.0001). Sex (p ˂0.0001; OR= 1.87 [1.47 – 2.38]) and level of education (p ˂0.0001; OR= 2.74 [1.89 – 3.95]) were significant risk factors for pooled anti-CHIKV IgM seropositivity. However, no significant association was found with other sociodemographic variables (p ˃0.05). Although there was paucity of data on CHIKV research in Nigeria, this meta-analysis revealed a high prevalence of CHIKV infection in the country.

Introduction

Chikungunya is a neglected tropical disease caused by Chikungunya virus (CHIKV). CHIKV has been classified as a reemerging mosquito-borne alphavirus by the World Health Organization [1]. Chikungunya virus is a member of Togaviridae and causes severe acute febrile illness, which is often followed by a wide spectrum of rheumatologic and musculoskeletal disorders [1,2]. CHIKV infection is notoriously arthritogenic and endemic in certain parts of West Africa where human serosurveys have identified anti-CHIKV antibodies in 35–50% of the population [2].

CHIKV is a positive-sense single-stranded RNA virus with a genome of about 11.8 kb and two open reading frames encoding the nonstructural (nsP1, nsP2, nsP3, and nsP4) and structural polyproteins (C, E3, E2, 6K, and E1) [3]. Based on sequence analysis of the E1 gene of CHIKV, 4 genotypes (lineages) of CHIKV have been identified corresponding to their respective geographical origins; the East-Central-South-African (ECSA), West African (WA), and the Asian (A). Lately, a fourth genotype, called the Indian Ocean (IO) lineage, a variant of the ECSA, was discovered [3]. The severity of CHIKV infection depends on viral genotype implicated and host immune response to the infection. A worldwide meta-analysis reported the highest prevalence and virulence of IO genotype compared to others [3]. In the same study, out of the 6532 pooled CHIK patients, 48% and 21% reported no recovery after infection, at 3 and 12 months, respectively [3].

Day biting Aedes mosquitoes account for CHIKV transmission to humans through the urban cycle as well as for the maintenance of the virus during inter-epidemic periods, through viral cycling between vectors and wild animals in sylvatic cycle [4]. CHIKV is horizontally transmitted to vectors during a blood meal on a viremic host [4]. Following an infected mosquito bite, CHIKV is introduced into the bloodstream through the skin, causing high viremia. Through the blood and lymphatics, it reaches its target tissues, i.e. fibroblasts and myofibers [5]. Unlike dengue virus, CHIKV causes symptoms in a high majority (72% to 95%) of infected people [5,6].

CHIKV infection has two successive phases. After an incubation period of 2 to 4 days (range: 1 to 14 days) [5–7], the initial phase of acute illness begins and this is typically characterized by an abrupt onset of febrile illness (>39°C in 92% of patients), which lasts for about 2 weeks. Chikungunya acute fever is frequently accompanied (2nd phase) by musculoskeletal symptoms (87% of patients), presenting as intense muscle pains in the arms, calves, and thighs, as well as arthralgia in the ankles, elbows, knees, and wrists, within 2 to 12 days of infection [5,7]. This is due to CHIKV’s ability to infect both the skeletal muscle progenitor cells and fibroblasts in the connective tissues of muscles and joints, which are richly supplied by nociceptive nerves [7].

Previous reports have indicated that CHIKV infection produces acute arthritis in humans by large area of necrosis and collagenosis or fibrosis [8,9]. The ability of CHIKV to infect musculoskeletal progenitor cells and to induce skeletal myocytes necrosis could explain the myopathies associated with CHIKV replication and implicate the muscle as a site of viral persistence. Hence, CHIKV infections and its associated long-term musculoskeletal complications can lead to loss of human productivity in the affected working population [10].

In consideration of the recent upsurge in self-reported cases of musculoskeletal illnesses after history of acute high fever especially among young adults and elderly population; the potential of CHIK virus (CHIKV) to be misdiagnosed for other tropical infections; and indeed, congenital transmission, it is therefore essential to investigate chikungunya virus infection in Nigeria. It is hoped that this study will encourage the formulation of effective disease and vector control strategies, determination of accurate CHIKV prevalence and other associated epidemiological data in Nigeria.

Methodology

The methodology adopted for this study includes the consideration of cross-sectional studies. In the case of duplicate reports, the most comprehensive/complete and up-to-date version was included. We reviewed studies conducted outside periods of presumptive CHIKV outbreaks. Case studies in which CHIKV infections were reported among Nigerians in other countries (cross-border and international transmission) were excluded. Thus, our population of interest was people living in Nigeria. The primary focus of our study was the pooled prevalence of CHIKV infection in Nigeria. The search for CHIKV infection had to be conducted systematically in Nigeria from hospital-based studies that reported CHIKV detection by RT-PCR technique, ELISA, or plaque reduction neutralization test (PRNT) on human samples. In order to be eligible or qualify for the present systematic review and meta-analysis, either one or more of CHIKV RNA, anti-CHIKV IgM, anti-CHIKV IgG, or CHIKV-neutralizing antibodies detection must have been reported in these studies. Studies with no or inadequate extractable primary data, and/or explicit descriptive methodology were excluded from this meta-analysis.

Search strategy

Using direct database search and MeSH, the following terms and their variants were used for CHIKV infection, viz: ‘CHIKV’, ‘chikungunya virus’, ‘pyrexia of unknown origin’, ‘febrile illness’, ‘prevalence’, ‘outbreak’, ‘anti-CHIKV’, and ‘Nigeria’. Individual names of Nigerian states and cities were also used as additional search terms for more abstracts on the subject. Titles and abstracts of all eligible peer-reviewed articles were thoroughly scrutinized and full texts of articles were accessed. The search strategy conducted between 1 January 1980 to 29 February 2020 from all databases and search outputs, and numbers of included and excluded articles is shown in Figure 1.

Figure 1.

Flowchart of literature search results from database.

Authors independently extracted data including first author’s name, study design, date of publication, research setting, sampling technique, criteria for inclusion of study participants, timing of data analysis, states and cities of participants enrollment, clinical presentation of study participants (e.g. febrile or not), number of participants tested for CHIKV, number of participants with detected CHIKV, test protocol utilized, and ratio of male participants to female. Random-effect model was used to pool the prevalence of CHIKV infections and associated sociodemographic data reported from eligible studies. Crude prevalence of CHIKV infection was first calculated based on crude numerators and denominators provided by all eligible studies. Heterogeneity of pooled prevalence was calculated using Cochrane’s Q Chi-squared test which was quantified by H and I² values. Substantial heterogeneity was inferred if I² values ˃70%. Medcalc software Version 2019.19.0.7 (Ostend, Belgium) was used for all statistical analysis. P values less than 0.05 at 95% confidence interval (CI) were considered statistically significant.

Results

We identified 6588 records; after the elimination of duplicates, 30 remained. After screening titles and abstracts, we retained and assessed 27 full-text articles for eligibility. Finally, 7 full texts were included because they were the only available cross-sectional studies (Figure 1). After further screening, 2 studies identified CHIKV infection using anti-CHIKV IgM ELISA; 1 study using anti-CHIKV IgM rapid diagnostic test (RDT); 4 using anti-CHIKV IgG ELISA; and 2 using CHIKV RNA RT-PCR and 1 using PRNT (Table 1). Three of CHIKV studies (42.9%) were from the South-western part of Nigeria (Table 1). North-eastern Nigeria had the highest pooled prevalence of anti-CHIKV IgG, 46.9% followed by South-west, 43.4% then North-central, 21.0%. However, no record was reported from South-east, North-west, and South-south zones (Figure 2). There was a significant association between the prevalence of anti-CHIKV by geopolitical zones of Nigeria (χ² = 70.04, p ˂ 0.0001).

Table 1.

Characteristics of studies included for meta-analysis of CHIKV infection in Nigeria.

Characteristics	N = 7 studies [1347 participants]
Year of publication search (range)	1980–2020
Period of inclusion of participants	2013–2020
Age range (years)	1–80
Sex
Male (%)	532 (42.2)
Female (%)	726 (57.8)
Study area (No. of studies [No. Participants])
Urban	6 [1277]
Rural	1 [70]
Both	0 [0]
Geo-political zone (No. of studies [No. Participants])
North east	1 [310]
North west	0 [0]
North Central	3 [508]
South west	3 [529]
South East	0 [0]
South South	0 [0]
Laboratory methods [No. Participants])
Anti-CHIKV IgM	3 [607]
Anti-CHIKV IgG	4 [812]
Viral RNA	2 [341]
PRNT	1 [310]
Clinical presentation
Acute febrile illness	6 [1258]
Apparently healthy	1 [89]

Keys:

IgM: Immunoglobulin M.

IgG: Immunoglobulin G.

PRNT: Plaque Reduction Neutralization Test.

RNA: Ribonucleic Acid.

Figure 2.

Prevalence of Pooled anti-CHIKV IgG based on geopolitical zones in Nigeria.

Df = 5, χ² = 70.04, p ˂0.0001.

Out of the six geopolitical regions, CHIKV infection has not been reported in North-western, South-southern, and South-eastern Nigeria. In total, there were 10 published articles on CHKV. Of this, 2 were outbreak reports, 1 retrospective report, and the remaining 7 were cross-sectional studies, which comprised 1347 pooled participants (Table 2). The pooled anti-CHIKV IgM and IgG seroprevalence were 26.7% (95% CI: 23.2–30.4) and 29.3% (95% CI: 26.2−32.6), respectively. Of the pooled studies, there were 13 (3.8%) CHIKV RNA positive cases and 46.1% broadly neutralizing antibodies to CHIKV reported from febrile persons (Table 3). Sex (p ˂ 0.0001; OR = 1.87 [1.47–2.38]) and level of education (p ˂ 0.0001; OR = 2.74 [1.89–3.95]) was a significant risk factor for pooled anti-CHIKV IgM seropositivity. However, no significant association was found with other sociodemographic variables (p ˃ 0.05) (Table 4).

Table 2.

Characteristics of studies that reported chikungunya virus infection in Nigeria.

Year	Study type	Sample Size	CHIKV Positive cases	Laboratory protocol for CHIKV detection	Reference
1974	Outbreak report	217	30	Complement-fixation test	Moore et al. [6]
1975	Retrospective report	251	121	Hemagglutination inhibition (HI) test	Tomori et al. [7]
1991	Outbreak report	477	66	Hemagglutination inhibition (HI) test	Adesina and Odelola [8]
2013	Cross-sectional	310	143	Plaque reduction neutralization test	Baba et al. [9]
2016	Cross-sectional	60	13	Rapid Diagnostic test kit	Ayorinde et al. [10]
2017	Cross-sectional	176	10	ELISA and RT-PCR	Kolawole et al. [25]
2017	Cross-sectional	255	66	ELISA	Olajiga et al. [26]
2017	Cross-sectional	165	3	RT-PCR	Adesina et al. [27]
2019	Cross-sectional	89	22	ELISA	Udeze et al. [28]
2020	Cross-sectional	243	100	ELISA	Omotola et al. [29]

Table 3.

Pooled prevalence of chikungunya virus infection in Nigeria.

CHIKV biomarkers	Number of studies	Number of participants	Prevalence (95% CI)	H	I2
IgM seroprevalence	3	607	26.7 (23.2 – 30.4)	0.46	0.49
IgG seroprevalence	3	812	29.3 (26.2 -32.6)	54.6	˂0.0001
Viral RNA prevalence	2	341	3.8 (2.0-6.4)	3.8	0.06
Neutralizing antibody prevalence	1	310	46.1 (40.5-51.9)	NA	NA

*Significant heterogeneity determined by Cochrane’s Chi-Squared test.

Key:

NA: Not available.

Table 4.

Pooled sociodemographic risk factors of active chikungunya virus infection in Nigeria.

Variables	No. of pooled participants [no. of studies]	No. with pooled anti-CHIKV IgM cases (%)	OR (95% CI)	p value
Age
≤20	223 [5]	74 (33.2)
21–50	835 [5]	244 (29.2)	1.29 (0.86 to 1.95)	0.252
51	130 [5]	30 (23.1)	1.14 (0.89 to 2.12)	0.149
Sex
Male	518 [5]	214 (41.3)
Female	691 [5]	189 (27.4)	1.87(1.47–2.38)	˂0.0001*
Residence
Urban	1198 [5]	162 (13.5)
Rural	60 [1]	13 (81.3)	0.57 (0.301–1.074)	0.082
Level of Education
No formal	64 [3]	27 (42.2)
Primary	97 [3]	36 (37.1)	1.24 (0.65–2.36)	0.519
High School	295 [3]	66 (22.4)	2.23 (1.47–3.39)	0.002*
Tertiary	373 [3]	47 (12.6)	2.74 (1.89–3.95)	˂0.0001*
Marital status
Single	297 [2]	94 (31.6)
Married	377 [2]	96 (25.4)	1.36 (0.97–1.89)	0.077

*Significance determined by Multivariate Logistic Regression.

Discussion

This systematic review and meta-analysis of 7 cross-sectional studies involving 1347 individuals. The figures 26.7% CHKV IgM (indicating those who had active infection) and 3.8% CHIKV RNA detection (signifying the presence of CHIKV) reported in the previous studies constitute an epidemiological and public significance in view of associated severe morbidity and significant mortality.

Compared to other reports, the prevalence of anti-CHIKV IgM in this systematic review was higher than those reported from an African systematic review which reported pooled prevalence of anti-CHIKV IgM and anti-CHIKV IgG of 9.7% and 16.4%, respectively, from a 2000–2017 systematic review [11]. However, it was within the range of a similar meta-analysis study conducted in Middle East and North African cities (i.e. 0–43%) from 1970 to 2015 [12].

The pooled anti-CHIKV IgG of 29.3% from our study is significantly lower than the 36.1% reported from pregnant women living in Cotonou [13] and higher than 2.7% reported among Senegalese Nomadic Pastoralists [14]. This indicates a high heterogeneity of immune response against CHIKV among these West African studies. However, CHIKV seroprevalence studies in endemic countries are often limited by the inadequate specificity of classical serological methods due to cross-reactions with co-circulating and closely related alphaviruses [15].

In other African countries, the prevalence of CHIKV was reported in Sudan as high as 73.1% CHIKV RNA detection [16]. Anti-CHIKV IgG of 14% and anti-CHIKV IgM of 1.5% were reported in Tanzania [17]. However, the prevalence of CHIKV infection from other locations such as Asia was as high as 68% at Kerala, India [18]. These variations in prevalence may be due to differences in clinical presentation of subjects, ecological and climatic factors that favor enzootic circulation of CHIKV, difference in laboratory techniques used to detect CHIKV, heterogeneity in endemicity of CHIKV, and timing of the studies. Hence, these findings should be interpreted with caution because certain geographical zones and areas (especially southern-eastern and Northwestern Nigeria) have no documented data on CHIKV activities. Therefore, future studies could significantly modify the current findings from this meta-analysis.

After risk factors analyses for CHIKV prevalence, there was no association between CHIKV positivity and available socio-demographic variables of participants in the pooled studies. However, we found an association of CHIKV prevalence with the sex and level of education of the pooled participants. Risk factors for pooled anti-CHIKV IgM were significantly higher in females than males. The higher female preponderance of pooled anti-CHIKV IgM seropositivity in this study conforms with that of Rueda et al. [19] which reported 54.5% versus 53.0% female to male CHIKV infection. This could be because CHIKV vector activities peak during daytime, whereas, in Nigeria, females are more likely to remain indoor carrying out activities during the day when the mosquitoes are most active [19–21]. This could explain the relatively higher prevalence of CHIKV infection in females.

Even though the distribution of Aedes mosquitoes (CHIKV vectors) is ubiquitous in sub-Saharan Africa, its overall population density tends to be higher in areas in proximity to the thick rain forest [19]. This may explain why the majority of available studies were from South-western and neighboring cities (such as Ilorin). Furthermore, temperature, humidity, and enzootic interaction that are different within geopolitical zones may also influence the density of CHIKV vectors and infections. Most of the studied population (about 70%) had no evidence of CHIKV (antibodies and RNA negatives). This points toward the fact that majority of the communities are susceptible to future CHIKV.

Majority of the population with evidence of CHIKV infection were observed to be those with no formal or only primary education. In addition, relatively higher seroprevalence of CHIKV infection was found among teenagers and children (≤20 years). This suggests that older persons had been actively involved in outdoor activities which could have left them less susceptible to bite by mosquitoes carrying CHIKV [21]. Two African studies also reported higher CHIKV seroprevalence rates in individuals belonging to the lower age group [20,21]. This is similar to the findings from Beninese and Tanzanian studies indicating that CHIKV mainly circulates in children during endemic periods [14,22].

Persons lower or no formal education had the highest pooled anti-CHIKV IgM seropositivity and least in those with tertiary education. It has been reported that people with low or no formal education are more likely to exposed to mosquito bites, due to their little knowledge on the implication of mosquito-borne viruses. Similar observation was reported in the study of Whiteman et al. [23], which reported high proportions of residents with low education should be the target of arbovirus prevention programs because of their vulnerability to vector bite [23].

There is no published data describing the circulation of CHIKV infection among mosquitoes in Nigeria. This may have better explained the distribution of CHIKV infection in humans across the geographical zones. In West Africa, human CHIKV infection is known to occur via direct exposure to the enzootic cycle of non-human primates-to-mosquitoes-to-human and the urban cycle which comprised human-to-mosquito-to-human transmission [24].

In Nigeria, there is evidence of the sylvan mechanism of CHIKV, where 2.3% of 220 animals investigated for CHIKV antibodies were Hemagglutination Inhibition (HI) positive [8]. This might have amplified periodic enzootic transmission of CHIKV within that region [23]. However, there is a need for active arboviruses surveillance to identify places with enzootic CHIKV circulation and those with potential urban transmission in Nigeria.

Findings from this study are not without limitations. First, there is significant heterogeneity in the estimation of the prevalence of anti-CHIKV IgG across the eligible studies. Moreover, we were unable to assess factors such as climatic conditions and vectorial CHIKV carriage that might influence this outcome, as they were not reported on articles included in this systematic review. Second, all studies that used ELISA to test anti-CHIKV IgM and anti-CHIKV IgG did not use PRNT to confirm positive cases. The use of PRNT is the serology gold standard for the diagnosis of most arboviruses including CHIKV. Finally, our systematic review is limited due to paucity of data on CHIKV data in Nigeria. This highlights the need for more and better research on this subject matter. Despite these possible limitations, to the best of our knowledge, this is the first systematic review and meta-analysis on prevalence of CHIKV infection in Nigeria.

Conclusion

This meta-analysis revealed a high prevalence of CHIKV infection. Therefore, there is a need for active CHIKV surveillance and re-training of health-care professionals on CHIK diagnosis to enhance accurate detection and prompt medical intervention. There is also the need for adoption of integrated vector control measures accompanied by extensive media enlightenment campaign to limit the spread of CHIKV infection and associated morbidity and mortality among the populace.

Disclosure statement

No potential conflict of interest was reported by the authors.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.