Prevalence and relative risk of Rotavirus Gastroenteritis in children under five years in Nigeria: a systematic review and meta-analysis

ABSTRACT

Rotavirus is responsible for most cases of gastroenteritis and mortality in children below 5 years of age, especially in developing countries, including Nigeria. Nonetheless, there is limited data on the nationwide estimate for the prevalence of rotavirus. This systematic review and meta-analysis sought to determine the pooled prevalence of rotavirus infections and its relative risk among children below 5 years of age in Nigeria. Eligible published studies between 1982 and 2021 were accessed from ‘PubMed’, ‘Science Direct’, ‘Google Scholar’ and ‘African Journal Online’, ‘Web of Science’, ‘Springer’, ‘Wiley’ were systematically reviewed. The pooled prevalence, relative risk and regional subgroup analyses were calculated using the random effects model at 95% confidence interval (CI). A total of 62 selected studies, including 15 studies case-control studies, were processed in this review from a pooled population of 18,849 children. The nationwide pooled prevalence of rotavirus among children below 5 years of age in Nigeria was 23% (CI 95%; 19–27). Regional subgroup analysis showed that the Southern region had a prevalence of 27% (CI 95%; 21–32) while the Northern region had a 20% (CI 95%; 16–25%) prevalence, although the difference was not significant (P = 0.527). Rotavirus was implicated in most cases of acute gastroenteritis with a relative risk of 5.7 (95% CI: 2.9–11.2). The high prevalence and relative risk of rotavirus infections among children in Nigeria shows that rotavirus is an important cause of acute gastroenteritis in Nigeria. Thus, there is a need for further surveillance, especially at community levels together with the introduction of rotavirus vaccines into the national immunization program.

1. Background

Diarrheal disease is the second-leading cause of death in children under 5-years old globally. An estimated 1.7 billion cases and mortality of 525,000 in infants have been attributed to diarrhea annually [1]. According to the Global Enteric Multicentre Study (GEMS), a follow-up, age-grouped and case-control study conducted in seven Asian and sub-Saharan African countries, identified rotavirus, among all the agents responsible for diarrhea, to be strongly associated with cases of moderate-to-severe diarrhea in children under 5-years old [2–3].

Rotavirus is a member of the Reoviridae family with a size of 70–75 nm and is classified into 10 serogroups (A-J) based on the outer protein (VP6). Among these serogroups, rotavirus group A is responsible for most gastroenteritis cases in human populations 11Rotavirus is transmitted via the fecal-oral route, through both fomites and close person-to-person contact. They are shed in enormous quantities in the stools of infected persons and few virions (<100 virions) are sufficient to cause disease in a susceptible host. Symptoms such as diarrhea, malaise, vomiting and fever are associated with rotavirus infection and can result in dehydration in some cases [4,5]. The incubation period of gastroenteritis caused by rotavirus is one to 3 days and symptoms normally resolve in 3 to 7 days [6].

The majority of rotavirus-associated gastroenteritis occurs in Sub-Saharan Africa due to poor hygiene, malnutrition and lack of access to potable water. It has been estimated that about 215,000 infants die each year due to rotavirus-associated gastroenteritis and almost half of these deaths occur in four countries: Nigeria, Pakistan, India and Democratic Republic of Congo. Nigeria alone accounts for 14% (30,800) estimated rotavirus associated deaths in 2013 [7]. A more recent study estimated that rotavirus is responsible for about 47,898 deaths in children under 5-years old in Nigeria [8].

Rotavirus vaccines have been introduced in more than 107 countries globally, and their use has led to substantial reductions in morbidity and mortality [9]. However, Nigeria is yet to introduce the rotavirus vaccine into its national immunization program, despite the huge burden of rotavirus infection among children in Nigeria. For the most efficient health care and the distribution of rotavirus vaccine, information on the prevalence of rotavirus infections in different parts of the country is crucial. Therefore, this systematic review and meta-analysis seek to provide the prevalence and relative risk of rotavirus infection in children ≤5 years of age in Nigeria. Our aim was to determine:

1. The pooled prevalence of rotavirus infection among children below 5 years of age with gastroenteritis in Nigeria.

2. The relative risk of rotavirus infection in case-control studies conducted among children below 5 years of age in Nigeria.

2. Materials and methods

The review was developed after searching Cochran and PROSPERO databases for the availability of identical reviews to avoid repetition of any previously performed study. Presently, this is the first attempt at providing a pooled prevalence from several studies conducted on rotavirus-associated gastroenteritis in Nigeria. The protocol used for this review was designed and registered on PROSPERO with registration number CRD42021261373.

2.1. Data search

We identified primary studies on the prevalence of rotavirus infection in children below 5 years of age conducted in Nigeria using PubMed, Google Scholar and AJOL (African Journals Online), Web of Science, Springer, and Wiley databases. Grey literatures, such as conference papers, were also included to avoid publication biases. Publications were identified using keywords such as: ‘rotavirus Nigeria’, ‘viral diarrh* in Nigeria’, ‘prevalence’, ‘infants’, ‘children’, ‘acute viral gastroenteritis Nigeria’. Boolean operators such as (AND, NOT, OR) were also used. All the identified citations were downloaded into Zotero bibliographic management software for further processing. Last search for studies was conducted 17/12/2021. Further details on search methods are detailed in the Supplementary Material.

2.2. Eligibility criteria for the studies

Studies were included in the review when the following conditions were fulfilled:

1. The population of study were children under 5-years old with acute gastroenteritis/diarrhea.

2. The numerators, i.e. the cases, were defined.

3. The denominators, i.e. the total number of population/participants sampled, were defined.

4. In this review, an arbitrary sample size of ≥50 to avoid publication bias.

5. The study was conducted within Nigeria in any setting, such as hospital, clinics or community in Nigeria.

6. If the papers described co-infection studies and the prevalence of rotavirus in children under 5 years was clearly stated.

7. If children above 5 years of age were included in the studies but prevalence of those below 5-years old was separately calculated.

Studies that did not meet the eligibility criteria mentioned above were excluded.

2.3. Study selection and critical appraisal

Studies were selected from the first primary research on rotavirus-associated gastroenteritis among the population of interest in Nigeria for the past 39 years (from January 1982 to December 2021). Studies obtained were those that estimated the prevalence of rotavirus in the population using viral antigen detection methods, such as electron microscopy (EM), enzyme immunoassay (EIA), latex agglutination and lateral flow immunoassays (immunochromatography), nucleic acid detection on polyacrylamide gel or by polyacrylamide gel electrophoresis (PAGE), and nucleic acid amplification using reverse transcription PCR (RT-PCR) as stipulated in the guidelines for rotavirus detection and characterization [10].

1. Publications were assessed based on the Joanna Briggs Institute (JBI) critical appraisal tool for prevalence studies, and each of the conditions were awarded 10 points for yes and zero for no. There was no moderate point. Two independent reviewers (D.D. and P.C) also reviewed the studies based on the criteria and discrepancies in selection were resolved by a third reviewer (V.C).

2.4. Subgroup meta-analyses

Subgroup analysis was done based on the calculated sample size. Other subgroup analyses were performed based on the region of the country where the study was conducted. Subgroup meta-analyses were performed using the sample size obtained from the pooled prevalence of all the included studies in this review, using the Cochran’s sample size calculation formula:

$$n=\frac{z^{2}p\left(1-p\right)}{d^2}$$

Where n = sample size

Z = Z statistics for a level of confidence (1.96)

P = expected prevalence or proportion and (23% random effect pooled prevalence)

d = precision (margin of error, if its 5%, then d = 0.05)

$$n=\frac{{1.96}^2\left(1-23\right)}{{0.05}^2}$$

n = 273.

2.5. Data extraction

Information, such as author(s), region, patients’ age, detection method(s), year of study, settings (hospital/clinic or community) and prevalence (sample size and cases) were collected from the selected studies. When the study was sampled across different regions of the country, it was excluded in the regional grouping.

2.6. Statistical analysis

The data were analyzed using MetaXL (v5.2) and MedCalc statistical software (v20). The random effects model was used to determine the pooled prevalence due to heterogeneity in these primary studies such as sample size. The prevalence was calculated using the freeman-double arcsine transformation. The test for heterogeneity was done using Cochran’s Q-test and I² test and was considered significant if the p value for Q test was ≤ 0.05. When the I² test is greater than 75%, the studies were considered highly heterogeneous [12]. Tests for publication bias were evaluated using doi plots where Luis Frya-Kanamori (LFK) index is considered asymmetry if it has a value greater than ± 2, which indicates publication bias [11,12]. Egger’s and Begg’s tests were also used to assess for publication bias in the study, with p-value <0.05 suggesting the presence of publication bias while p-value >0.05 indicates the absence of publication bias in the studies [13,14]

3. Results

A total of 966 studies were accessed from Google Scholar, PubMed, African Journals Online (AJOL), Web of Science, Springer and Wiley online databases. Of these, 423 duplicate research articles were removed and another 469 articles were expunged after screening for study titles and abstracts because they are irrelevant to this review. Seventy-one full-text articles were eventually retrieved while three were inaccessible, i.e. both abstract and full-text articles could not be found. Finally, during the data extraction, nine articles were excluded for the following reasons: four articles did not meet the age criteria, one used sample size <50, one did not specify the age group of study and three were pure molecular studies lacking information on prevalence. Thus, 62 articles were accessed based on the specified criteria, as listed in Supplementary Table 1. All the 62 articles were also used for meta-analyses and studies that accessed both case control and prevalence were used for both analyses. The studies were reported using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) protocol [15] (Figure 1).

Table 1.

Studies included in the systematic review and meta-analysis.

S/N	Author/year	Region	Study design	Setting	Detection method	Cases	Sample size	Proportion%	JBI assessment
1	31	North	Prevalence	HF	EIA	45	314	14.331	70
2	32	North	Prevalence	HF	EIA	7	98	7.143	50
3	33	North	Prevalence	HF	EIA	30	100	30.00	50
4	34	North	Prevalence	HF	EIA/RT-PCR	99	378	26.19	60
5	35	North	Prevalence	HF	PAGE	145	467	31.049	70
6	36	North	Prevalence	HF	EIA/PAGE/RT-PCR	51	200	25.5	60
7	37	North	Prevalence	HF	EIA	96	188	51.064	50
8	38	North	Prevalence	HF	EIA/ RT-PCR	25	93	26.882	50
9	39	North	Prevalence/Case control	community	EIA	156	869	17.952	80
10	40	North	Prevalence/Case control	HF	EIA	12	134	8.955	60
11	41	North	Prevalence/Case control	HF	EIA	84	340	24.706	70
12	20	North	Prevalence	HF	RT-PCR	67	770	8.701	80
13	42	North	Prevalence	HF	EIA	21	200	10.5	60
14	21	South	Prevalence	HF	RT-PCR	16	71	22.535	50
15	22	South	Prevalence	HF	RT-PCR	29	175	16.571	50
16	24	N/A	Prevalence	HF	EIA/RT-PCR	36	108	33.333	50
17	23	N/A	Prevalence	HF	EIA/RT-PCR	84	287	29.268	60
18	43	South	Prevalence	HF	PAGE	17	66	25.758	50
19	44	South	Prevalence	HF	EIA	75	302	24.834	60
20	45	South	Prevalence	HF	EIA	37	164	22.561	50
21	46	North	Prevalence	HF	EIA	36	144	25	50
22	47	North	Prevalence/Case control	HF	EIA	27	198	13.636	50
23	25	South	prevalence	HF	RT-PCR	29	157	18.471	70
24	3	South	Prevalence/Case control	HF	EIA	18	84	21.429	50
25	48	North	Prevalence	HF	EIA	30	160	18.75	50
26	49	North	Prevalence	HF	EIA	51	415	12.289	70
27	50,35,36	North	Prevalence	HF	EIA	146	442	33.032	70
28	51–52	North	Prevalence	HF	EIA	108	392	27.551	80
29	53	North	Prevalence	HF	EIA	54	303	17.822	70
230	54	South	Prevalence/Case control	HF	ICT	63	223	28.251	60
31	26	South	Prevalence	HF	EIA/RT-PCR	90	470	19.149	70
32	27	South	Prevalence	community	RT-PCR	19	55	34.545	70
33	55	South	Prevalence	HF	EIA/ RT-PCR	49	103	47.573	60
34	28	South	Prevalence	HF	RT-PCR	41	103	39.806	70
35	56	North	Prevalence	HF	EIA	87	152	57.237	50
36	57	North	Prevalence	HF	EIA	22	160	13.75	50
37	58	North	Prevalence	HF	EIA	8	150	5.33	50
38	59	North	Prevalence	HF	EIA	9	150	6	50
39	60	North	Prevalence	HF	EIA/RT-PCR	27	600	4.5	70
40	61	North	Prevalence	HF	EIA	192	401	47.88	70
41	62	North	Prevalence/Case control	HF	EIA	17	322	5.28	70
42	63–64	North	Prevalence	HF	EIA	20	182	10.989	50
43	65	South	Prevalence/Case control	HF	ICT	25	200	12.5	50
44	66	North	Prevalence/Case control	HF	EIA	167	299	55.853	60
45	67	South	Prevalence/Case control	HF	EIA	48	215	22.326	50
46	68	South	Prevalence/Case control	HF	EIA	46	146	31.507	50
47	69	South	Prevalence	HF	ICT	31	125	24.8	50
48	70	South	Prevalence/Case control	HF	EIA	57	376	15.16	70
49	71	South	Prevalence	HF	EIA	64	186	34.409	50
50	72	South	Prevalence	HF	EIA	32	173	18.497	50
51	73	North	Prevalence/Case control	HF	EIA	20	300	6.667	60
52	74	South	Prevalence	HF	EIA	16	116	13.793	50
53	75	North	Prevalence/Case control	HF	EIA	104	666	15.616	80
54	76	North	Prevalence/Case control	HF	EIA	61	375	16.267	70
55	77	South	Prevalence	HF	EIA	21	150	14	50
56	78	North	Prevalence	HF	EIA	116	672	17.262	80
57	79	South	Prevalence	HF	EIA	344	615	55.935	80
58	80	South	Prevalence	HF	EIA	1242	2694	46.102	80
59	81	South	Prevalence	HF	EIA	89	290	30.69	60
60	82	North	Prevalence	HF	EIA	36	144	25	50
61	83	South	Prevalence	HF	EIA/RT-PCR	49	132	37.121	50
62	84	North	Prevalence	HF	EIA/RT-PCR	104	285	36.491	60

Figure 1.

PRISMA flow chart for study assessments of rotavirus in Nigeria.

3.1. Rotavirus detection methods used in selected studies

Among the included studies, the commonly used detection methods include EIA, PAGE, ICT and RT-PCR which were used in 52/62, 2/62, 3/62 and 17/62 (7 studies used RT-PCR for prevalence while 10 studies performed secondary characterization using RT-PCR) of the studies, respectively. Case control study design was used in 15/62 of the studies while all the 62 studies also accessed the prevalence of infection within the target population. The number of studies carried out in the northern Nigeria (34/62) were greater than those in the southern part (26/62), while only 2/62 studies were carried out in both regions. The majority of the studies were conducted in a healthcare facility (60/62), while 2/62 was carried out in the community.

3.2. Prevalence of rotavirus associated gastroenteritis among under-five children in Nigeria

The 62 selected studies sampled a total of 18,849 diarrheal stool samples, out of which 4,947 samples were positive for rotavirus. In addition, the prevalence of rotavirus in Nigeria among the studies ranges from 5.3% to 57.2%. The pooled prevalence of rotavirus associated with gastroenteritis among children below 5 years of age in Nigeria, based on the random effects model, was 23% (95% CI, 19.3–26.9%), as shown in Figure 2.

Figure 2.

Forest plot of the pooled prevalence of rotavirus using the random effects model.

Heterogeneity among the studies was determined using the Cochran’s Q test and I² statistics. Cochran’s Q test was 2307.8 and was statistically significant (P < 0.001) while I² showed 97.3% heterogeneity between the studies. In order to test for publication bias, doi plot with LFK index was used (Figure 3). The LFK index was −0.01 showing no asymmetry (publication bias). Egger’s and Begg’s test showed the absence of a statistically significant publication bias (p = 0.06) and (p = 0.20)

Figure 3.

Doi plot of the rotavirus studies to evaluate publication bias.

3.3. Subgroup analysis

Based on the calculated sample size of 273, subgroup analysis of studies that used sample sizes ≥273 showed a prevalence of 23% (95% CI 17.4–29.7%). Regional subgrouping showed that studies conducted in the southern part of the country had a prevalence of 27% (95% CI 21–32%) than studies carried out in the northern part of the country with prevalence of 20% (95% CI 16–25%) as shown in Figures 4 and 5. However, this difference was not statistically significant (P = 0.5269). Subgroup analysis based on the viral detection methods showed that studies where RT-PCR was used for primary detection had prevalence of 21% (95% CI 14–30%) while studies that used EIA for detection had prevalence of 23% and this difference was statistically insignificant (P = 0.9065). Additional subgroup analysis based on study settings was performed, which showed prevalence of 23% (95% CI 19–27%) for studies performed in healthcare facility (HF) while studies carried out in the community had prevalence of 24% (95% CI 9–42%). Similarly, this difference was not statistically significant (P = 0.9739).

Figure 4.

Forest plot of the prevalence of studies conducted in the Southern Nigeria.

Figure 5.

Forest plot of prevalence studies conducted in the Northern Nigeria.

The relative risk of rotavirus infection among case-control studies was 5.7 (95% CI 2.9–11.2) with few studies showing little or no samples positive for rotavirus in their control (Figure 6, Supplementary Table 2). This implies that diarrhea among children under 5 years of age in Nigeria is strongly associated with rotavirus.

Figure 6.

Forest plot of the relative risk of rotavirus gastroenteritis in Nigeria.

Table 2.

Case-control studies for relative risk of rotavirus among 0–5 children in Nigeria.

Study /year	Cases	Controls	Relative risk	CI 95%	Weights	z	P
40	156/869	14/194	2.488	1.473 - 4.202	12.51
40	12/134	0/20	3.889	0.239 - 63.259	4.03
41	84/340	3/32	2.635	0.883 - 7.863	9.95
47	27/198	1/20	2.727	0.391 - 19.021	6.32
3	18/84	0/28	12.624	0.785 - 202.923	4.06
54	63/223	0/59	34.018	2.136 - 541.862	4.08
62	17/322	0/78	8.560	0.520 - 140.828	4.01
65	25/200	0/200	51.000	3.126 - 832.048	4.03
66	167/299	0/240	269.117	16.850-4298.216	4.07
67	48/215	9/100	2.481	1.268 - 4.854	11.92
68	46/146	0/33	21.510	1.359 - 340.418	4.09
70	57/376	0/80	24.708	1.543 - 395.698	4.06
73	20/300	0/52	7.219	0.443 - 117.563	4.03
76	61/375	4/122	4.961	1.842 - 13.363	10.44
75	104/666	13/170	2.042	1.176 - 3.544	12.41
Total (random effects].	905/4747	44/1428	5.737	2.941 to 11.193	100.00	5.123	<0.001

4. Discussion

The burden of rotavirus is high among children below 5 years of age living in resource poor countries in Sub-Saharan Africa due to poor hygiene, limited access to healthcare and malnutrition [2]. This study is the first attempt at providing an estimate for rotavirus-associated gastroenteritis among children below 5 years of age in Nigeria. Our findings suggest that rotavirus is responsible for a substantial proportion of cases (19–27%) of acute gastroenteritis among children less than 5-years old in Nigeria. This is consistent with systematic reviews and meta-analysis conducted in Ethiopia and LAC (Latin America and Caribbean countries) with a mean prevalence of 23% and 24.3%, respectively [16, 17, 18]. However, a higher rotavirus prevalence (35–39.9%) was noted amongst Iranian children [19]. This might be attributed to study differences such as geographical location, sample sizes and viral detection methods. The majority of these studies used EIA method and only a few studies used RT-PCR for primary detection of the viruses, which is more sensitive than EIA [20–28]. These factors may contribute to the significant heterogeneity within the studies.

The pooled prevalence of 23% determined in this study was shown to be robust by testing for sensitivity through exclusion of studies with sample sizes below 273. This sensitivity analysis had a prevalence of 23%, which is the same with

the pooled prevalence. Regional subgroup analysis revealed that, even though greater numbers of studies were conducted in the north, its prevalence (16–25%) in the region is lower than that of the southern region of Nigeria, which had a slightly higher prevalence (21–32%). Factors, such as age differences, climatic conditions and immune status of children can be responsible for these differences across the regions. Furthermore, there is a possibility that the health seeking practices of the people living in the various regions might have influenced the prevalence of the studies since most of the studies were conducted in health care facilities [29]. On the other hand, there is a possibility of overestimation of the prevalence since only the most severe cases of gastroenteritis visit the hospital.

Based on the weight of evidence from the case-control studies with a relative risk of 5.7 (95% CI 2.9–11.2), there are indications that most diarrhea cases among children under 5-years old are attributable to rotavirus since there are few asymptomatic cases of rotavirus infection among the samples. This is similar to the results of a pre-vaccination study carried out in Mozambique, where rotavirus was detected in cases of moderate-to-severe diarrhea with an odds ratio of 6.4 [30].

5. Conclusions and recommendations

The weight of evidence presented in this systematic review and meta-analysis showed that rotavirus is responsible for a considerable proportion of acute gastroenteritis among children in Nigeria. This reinforces the need for the implementation of rotavirus vaccine in the national immunization program to reduce this huge burden in children. Furthermore, these findings reveal the need for more prospective and case-control research to access the rotavirus disease burden. Most studies reviewed here were carried out in healthcare and clinical settings, however very limited information is available on viral diseases in community settings. More importantly, future studies should adopt more sensitive acute gastroenteritis diagnostic techniques for accurate and valid estimation of viral burden among the study population.

Funding Statement

This work was supported by the Bangor University [HEFCW grant (W19/36HE)]; University Of Nigeria Nsukka [TETFUND/DESS/UNI/NSUKKA/2018/RP/VOL.I].

Disclosure statement

No potential conflict of interest was reported by the author(s).

Supplementary material

Supplemental data for this article can be accessed here