Skip to main content
Download PDF

Hepatitis E outbreak in the health district of Bocaranga-Koui, Central African Republic, 2018–2019

BMC Infectious Diseases volume 24, Article number: 215 (2024) Cite this article

Abstract

Background

Hepatitis E virus (HEV) is a major public health disease causing large outbreaks and sporadic cases of acute hepatitis. We investigated an outbreak of HEV infection that occurred in September 2018 in the health district (HD) of Bocaranga-Koui, located in the northwestern part of Central African Republic (CAR).

Methods

Blood samples were collected from 352 patients aged 0–85 years suspected to be infected with yellow fever (YF), according to the World Health Organization YF case definition. The notification forms from recorded cases were used. Water consumed in the HD were also collected. Human samples found negative for anti-YF IgM were then tested by ELISA for anti-HEV IgM and IgG antibodies. Positive anti-HEV (IgM and/or IgG) samples and collected water were then subjected to molecular biology tests using a real time RT-PCR assay, followed by a nested RT-PCR assay for sequencing and phylogenetic analysis.

Results

Of the 352 icterus patients included, anti-HEV IgM was found in 142 people (40.3%) and anti-HEV IgG in 175 (49.7%). Although HEV infection was detected in all age groups, there was a significant difference between the 0–10 age groups and others age groups (P = 0.001). Elevated levels of serum aminotransferase were observed in anti-HEV IgM-positive subjects. Phylogenetic analysis showed HEV genotype 1e in infected patients as well as in the contaminated water.

Conclusion

This epidemic showed that CAR remains an HEV-endemic area. The genotype 1e strain was responsible for the HEV outbreak in Bocaranga-Koui HD. It is necessary to implement basic conditions of hygiene and sanitation to prevent further outbreaks of a HEV epidemics, to facilitate access to clean drinking water for the population, to launch intensive health education for basic hygiene measures, to sett up targeted hygiene promotion activities and, finally, to ensure that formal health care is available.

Peer Review reports

Introduction

Hepatitis E virus (HEV) is a major public health disease causing large outbreaks and sporadic cases of acute hepatitis. It is estimated that one-third of the world’s population is living in an HEV endemic area [1, 2]. HEV is the most common cause of acute viral hepatitis, in both resource-poor and wealthy countries [3]. HEV is a spherical, non-enveloped, single-stranded RNA virus belonging to the Hepeviridae family and the genus Paslahepevirus [4]. Although more than 8 HEV genotypes have been proposed to exist [5], four major HEV genotypes with 24 subtypes have been well described in humans [6, 7]: i) genotypes 1 and 2, which exclusively infect humans through fecal–oral transmission, circulate predominantly in regions with low sanitary level such as Africa, Asia, Latin America and Middle Eastern countries; ii) genotypes 3 and 4 are of zoonotic origin, predominate in developed countries [8, 9] and are globally distributed. Usually the HEV infection is self-limiting, but occasionally causes serious disease, such as fulminant hepatitis leading to neurological sequelae, spontaneous abortions, and sometimes death [10, 11]. Several outbreaks of HEV have occurred in low-income countries, often resulting in fulminant hepatitis with a case/fatality rate between 1 and 2% in the population of young adults, and this rate can increase to 20% among pregnant women during their last trimester of pregnancy [12, 13]. HEV is therefore potentially devastating in areas with degraded security situations, where access to essential sanitation is limited.

In September 2018, an outbreak of jaundice was notified in the health district (HD) of Bocaranga-Koui, in the northwestern part of Central African Republic (CAR) (Fig. 1), through the yellow fever (YF) national surveillance system (YFNSS). In this study, we report HEV infection through differential diagnosis of YF and molecular characterization of the HEV strains identified during this outbreak.

Fig. 1
figure 1

Map showing districts reporting suspect cases, northwestern Central African Republic, 2018–2019

Full size image

Materials and methods

Studied population and data collection

Blood was collected from all individuals living in Bocaranga-Koui HD who presented with jaundice and a fever, according to the WHO YF-case definition [14]. The notification forms and blood samples were transported to the Institut Pasteur de Bangui (IPB). In addition, the clinical features observed in patients were reported by consulting physicians, and samples of water from several locations consumed by the population of these two districts were collected in sterile containers, packed with ice packs, and transported via the reverse cold chain to IPB for testing.

Water samples preparation

Collected water samples were first processed using the 2-phase separation method with Dextran T40 and PEG 6000 and then a double treatment with 20% chloroform, according to the WHO- developed protocol for poliovirus testing for concentrating water [15]. Briefly, 500 ml of the collected water was centrifuged at 1500 g at + 4 °C for 20 min. The supernatant was collected, and the pellet was kept at + 4 °C. The supernatant (pH 7.0—7.4) was mixed with polyethylene glycol (PEG 6000), Dextran T40 and NaCl 5N. This mixture was homogenized for at least one hour and then poured into a separating funnel and kept at + 4 °C overnight. The low and intermediate phases were collected in a sterile tube. The starting pellet, together with 20% chloroform and 1 g of sterile glass ball, were added to the collected phases. The mixture was vigorously shaken and then centrifuged at 1500 g for 20 min at + 4 °C. Approximately 5 ml of supernatant was collected and used for viral RNA extraction. Extracted RNA were submitted for molecular biology tests using a real time RT-PCR assay, followed by a nested RT-PCR assay for sequencing and phylogenetic analysis.

Biological and biochemistry testing

Serum samples collected during the epidemic in the Bocaranga-Koui HD through the YF surveillance that were found negative for anti-YF IgM were retrospectively tested by HEV IgM and IgG ELISA Dia.Pro kit reference EVM.CE (Diagnostic Bioprobes srl, Milan, Italy) [16, 17] and by real-time RT-PCR, as previously described [18]. A HEV case was confirmed if the sample was positive for IgM antibodies and/or for real time RT-PCR (Fig. 2). Samples which were found positive for YF were discarded from our study (Fig. 2).

Fig. 2
figure 2

Flow chart of HEV detection in blood samples

Full size image

For the RT-PCR testing, viral RNA was extracted from 140 µl serum samples positive for HEV IgM ELISA and concentrated water samples, using QIAamp Viral RNA Mini Kit (QIAGEN, Courtaboeuf, France), and then retrotranscribed into cDNA using the High-Capacity cDNA Reverse Transcription Kit (Applied Biosystems, Foster City, CA, USA) according to the manufacturer's instructions. Real-time RT-PCR was carried out in 96-well plates using the TaqMan® Universal RT-PCR Master Mix Reagent (Applied Biosystems, Foster City, CA, USA), the reaction mixture contained the following ingredients: 12,5 μl of 2X PCR Master mix, 5 μl of the resulting cDNA, 1 µM for each primers and probe, and sterile water to make up the final volume of 25 µl, according to the manufacturers' recommendation. The primers and probe (10 μM) employed were: Taq HEV-F (5´-GCCCGGTCAGCCGTCTGG-3´); Taq HEV-R (5´-CTGAGAATCAACCCGGTCAC-3´); TaqHEV-S (5´-FAM- CGGTTCCGGCGGTGGTTTCT-TAMRA-3´) [18]. Real-time RT-PCR amplification was performed using an ABI PRISM® 7500 real-time PCR instrument (Applied Biosystems, Foster City, CA, USA) under the following conditions: 50 °C for 2 min and 95 °C for 10 min, followed by 45 cycles at 95 °C for 15 s and 60 °C for 1 min. A sample was considered positive if the cycle threshold (CT) was < 37 amplification cycles.

For all suspected cases, serum samples were analyzed for alanine aminotransferase (ALAT) and aspartate aminotransferase (ASAT) using ABX Pentra 400 (RAB1251FR).

Phylogenetic analysis

A nested RT-PCR amplifying a 348-bp portion of the open reading frame 2 region was performed as previously described [19] on RNA samples that tested positive with the real-time RT-PCR using the thermocycler Gene Amp PCR System 97,000 (Applied Biosystems). Briefly, 2 mM of each primers 3156N (5’-AATTAGCYCAGTAYCGRGTTG-3’) and 3157N (5-CCCTTRTCYTGCTGMGCATTCTC-3’) and Titan One Tube RT-PCR kit (Roche, diagnosis, Germany) were used. Cycling for the first reaction were as follows: 50 °C for 30 min, 94 °C for 2 min followed by 40 cycles of 94 °C for 30 s, 42 °C for 1 min, 68 °C for 1 min, and a final extension at 68 °C for 7 min. The second reaction was performed with 01 mM of each primers 3158N (5’GTWATGCTYATWCATGGCT-3’) and 3159N (5’- AGCCGAAATCAATTCTGTC-3’) and Taq DNA polymerase Kit (Roche, Diagnosis, Germany) were used. Cycling for the second reaction were as follows: 94 °C for 3 min, 40 cycles at 94 °C for 45 s, 42 °C for 45 s, and 72 °C for 45 s, and a final elongation step at 72 °C for 5 min. Amplified PCR products of the second reaction were separated by 3% (w/v) agarose gel electrophoresis. The amplicons were purified using QIAquick PCR Purification Kit (QIAGEN, Hilden, Germany) and then sent to GATC Biotech (Konstanz, Germany) for direct sequencing. Phylogenetic analysis of the partial ORF2 gene of HEV was conducted with MEGA7 software (www.megasoftware.net) and aligned by CLUSTAL Muscle algorithm. A Phylogenetic tree was constructed using the neighbour-joining method and the Kimura-2 model with 1000 bootstrap replicates using MEGA 7 [20]. HEV reference strains of genotypes/subtypes were included [21]. The sequences obtained in this study were deposited in GenBank with accession numbers MN901844 to MN901869 and MW258967 to MW258978.

Statistical analysis

Data analysis was performed using STATA version 14 (Stata Corp LP, College Station, TX, United States). Odds ratios (OR) and their respective 95% confidence intervals (CI) were calculated for each association. Pearson chi-squared or, when necessary, Fisher exact tests were used to compare distribution for categorical variables for the different groups. Statistical significance was assumed at P < 0.05 in the univariate analysis.

Results

Blood samples were collected from 352 people living in the Bocaranga-Koui HD, including 172 women (48.3%) and 180 men (51.7%), with a sex ratio of 1.07, aged between 0 and 85 years (mean, 22.6 years, SD ± 17.4).

The serology results reported in Table 1 shows that, by ELISA analysis, 142 people (40.3%) had HEV-positive IgM antibodies, indicating that a high proportion of the population had an ongoing HEV infection, with more infected women (43.3%) than men (38.9%). A similar observation was made in the case of HEV IgG antibodies, with 53.0% of women infected and 50.6% of men. The difference observed between genders was not statistically significant in either case (P = 0.39). However, the distribution of HEV serology (IgM and IgG) showed a statistically significant difference according to age group, with the 21–30-year-old age group and those over 40 years of age being significantly more positive for HEV IgM antibodies than the 0–20 year-old and 31–40 year-old groups (P = 0.001).

Table 1 Demographic Characteristics and serum aminotransferase levels for HEV infection in 352 people with acute jaundice
Full size table

Among those who were IgM anti-HEV antibody positive, three patients (a 30-year-old pregnant woman, a 35-year-old man and a 12 month-old child) died during this epidemic.

More than 50% of patients who were anti-HEV IgM antibody positive had higher than average ALT (59.8%) and AST (71.8%) values during this epidemic (Table 1). Dual amplification by real-time RT-PCR and nested RT-PCR resulted in 73 (51.4%) of the 142 sera being amplified as IgM anti-HEV positive (Fig. 2).

The clinical characteristics and source of drinking water of patients who were anti-HEV IgM positive during this epidemic are described in Table 2.

Table 2 Clinical features and additional parameters of study population
Full size table

The clinical symptoms most frequently observed in these patients were jaundice (71.8%), followed by fever (62.6%), and other signs such as general fatigue (11.9%), abdominal pain (7.7%), dark-colored urine (7.7%), and loss of appetite (6.3%). Regarding the origin of water drunk by anti-HEV IgM antibody-positive patients, well water was the most frequently consumed (68.3%), followed by other water sources (10.5%), and the combination of well water and hand-pump water (8.4%). It should be noted that at least 7% of people who consumed only public fountain water were also found to be IgM antibody positive, and only 4% of these patients consumed only pump water. Determination of the persistence of infection in the population was measured from September 2018, considering the variation in positive anti-HEV antibodies IgM (Fig. 3). The highest prevalence was recorded in November, three months after the onset of the epidemic. From December 2018, prevalence fell back to a lower level and remained constant until May 2019.

Fig. 3
figure 3

Distribution of anti-HEV IgM per month (From September 2018 to July 2019)

Full size image

HEV genotyping

In total, 39 out of the 73 samples that were positive by RT-PCR and one water sample from one of the wells out of the 52 water samples used by the patients were amplified and sequenced. Phylogenetic analysis of the sequences (Fig. 4) showed that the HEV strains isolated from the different samples belonged to genotype 1e and were close to strains already isolated in 2008 and 2009 during previous epidemics in CAR [22].

Fig. 4
figure 4

Phylogenetic analysis of sequences obtained in the study in comparison to reference sequences from GenbanK. Strains isolated from the Bocaranga and Koui patients samples during the 2018 epidemic are indicated by a red circle and from the water well sample by a blue triangle  . HEV genotype 1e sequences obtained in the present study were deposited in the NCBI GenBank database on the accession numbers MN901844 to MN901869 and MW258967 to MW258978. Bootstrap values are indicated when > 70% as a percentage obtained from 1000 re-samplings of the data

Full size image

Discussion

During the hepatitis E epidemic in the HD of Bocaranga-Koui, over 40% of sampled people were recently infected (IgM) with HEV, and 49% had already been in contact with this virus. This prevalence in patients with acute jaundice shows that hepatitis E is endemic in the CAR causing major epidemics [22,23,24].

This high prevalence is not surprising, because the Bocaranga-Koui HD is in an area of social instability, with persistent military-political conflicts that have long-term effects. In addition, the region has a very high crime rate, forcing most of the population to live in the bush or in host communities where hygiene conditions are precarious. Among those infected, more women than men carried HEV antibodies, although we found that this difference was not statistically significant. This observation has been reported in previous studies [25], in which more women than men were infected during these epidemics. In our study, this high prevalence of HEV infection among women can be explained by the fact that most household activities are carried out by women in this rebel-held health district. In addition, to avoid capture by rebels, many men have left this area for security reasons. In any case, this observation confirms that HEV infection is not inherently linked to gender, but rather because of it is waterborne and thus linked to certain professional and/or household activities [25]. The proportion of HEV cases during this epidemic varied with age, but was not significantly different. Two age groups, namely those aged 21 to 30 years old and those over 40 years old were more infected than those under 21 years old and between 30 and 40 years old. This finding may result from the fact that people 21–30 and over 40 are more active in daily activities of caring for their families and may therefore be in more frequent contact with this virus, especially during epidemics. This situation may be aggravated by insecurity in densely populated sites, where hygiene conditions are far from optimal, as previously reported [26]. Data from the UN Office for the Coordination of Humanitarian Affairs (OCHA) estimates that 146,251 people lived in this health district in 2018, and that over 25,000 are "internally displaced persons, IDPs" living in conditions of humanitarian distress. In addition, to this population are voluntary returnees from Cameroon and Chad who had taken refuge in these countries during the 2013 military-political crisis in CAR. These displaced people live under extremely precarious conditions, characterized by a lack of sanitation and hygiene services, which may account for the spread of infections from one region to another and can lead to epidemics if the population’s collective immunity is low [27].

The main risk factor for HEV contamination in this district would be drinking water. Indeed, the main sources of water consumed and used by households in this health district were untreated well water, stored rainwater, water from river springs, or the rivers themselves. The proximity of latrines to these main water sources meant that the likelihood of contamination from these sources is high, given overcrowding in the area. Indeed, the exposure to diseases among populations living in displaced persons' camps where hygiene and sanitation services are lacking has been well described in the literature [28].

Two main symptoms were reported during this epidemic, namely jaundice (71.8%) and fever (62.6%). These symptoms were similar to those reported in other HEV epidemics [9], confirming that jaundice and fever are the main symptoms of this infection in HEV-endemic areas. It is therefore important to undertake a differential diagnosis between yellow fever and HEV infection whenever these symptoms are present, so that the infection can be managed properly at an early stage.

Transaminase levels were two to five times higher than normal in HEV-infected individuals, confirming the presence of hepatic cytolysis that usually accompanies HEV infection [29].

This epidemic resulted in three deaths during the time frame of the study, giving a case-fatality rate of 0.8%. Among these deaths was a woman in her last trimester of amenorrhea who died following a spontaneous abortion, probably due to HEV infection as previously reported [30]. This is not surprising, as pregnant women constitute a high-risk group, with a mortality rate in the third trimester of pregnancy of around 20% [12]. It is likely that there were other cases of death linked to this epidemic that were not identified in this study.

The epidemic curve, based on the presence of detected HEV antibodies, enabled us to assess the intensity and duration of the epidemic. Many more people had been infected with HEV in the first three months of the epidemic, between September to December 2018, coinciding with the rainy season as reported in previous studies [22].

Molecular analysis of HEV strains, obtained from infected patients, revealed that genotype 1e was the source of contamination during this epidemic. These results from our phylogenetic analysis are consistent with previous findings regarding the subtypes circulating in the CAR [22, 31] and neighboring countries [32, 33], and with waterborne transmission usually associated with HEV genotypes 1 and 2. Our genotypes 1e strains formed a cluster which were close to those found in the country during the 2008–2009 outbreak and in neighboring countries [22, 32, 34]. Our results show that HEV evolves very little and has circulated endemically in this area for almost 15 years. This demonstrates the capacity of HEV to persist for many years in the environment and because transmission is essentially fecal–oral, to cause an epidemic under certain conditions, notably low levels of hygiene, political and social insecurity and the contamination of the water supply.

We investigated the origin of the infection by analyzing water from HD wells. The results of the molecular analysis revealed only one positive water sample from one of the wells. The most likely wells water contaminated with human, or animal feces could be a major source of the epidemic, especially because wells are the main sources of drinking water. Although we found HEV in water samples from just one well, it is likely that HEV transmission during this epidemic may have resulted from well water consumption and then amplified by direct human-to-human transmission, as previously demonstrated [35]. Fecal contamination of tap water as the source of the hepatitis E epidemic has been reported in various studies in regions where HEV is endemic [22, 24, 32, 36]. The cessation of the epidemic after the distribution of non-food item (NFI) kits, the treatment of water points in the district, and awareness-raising on good hygiene and sanitation practices all support the hypothesis that fecal contamination of water was the source of this epidemic.

This epidemic showed that CAR remains an HEV-endemic area. In such regions, the eruption of an epidemic takes just a small perturbation in hygiene and sanitation conditions to trigger an HEV epidemic. The differential diagnosis of HEV/yellow fever in all cases of conjunctival icterus accompanied by fever must be carried out as a matter of urgency, to detect early cases of HEV infection, and thus to curb the onset of a hepatitis E epidemic at an early stage. However, for full operative results, it is also necessary to implement the minimum conditions of hygiene and sanitation to prevent the outbreak of a hepatitis E epidemic, to facilitate full access to clean drinking water, carry out educational campaigns on basic hygiene measures, sett up targeted hygiene promotion activities and, finally, to ensure that formal health care is available to all. All of these measures require a peaceful social and political environment.

Availability of data and materials

All data generated or analyzed during this study are included in this published article. The sequences obtained in this study were deposited in GenBank with accession numbers MN901844 to MN901869 and MW258967 to MW258978.

Abbreviations

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

CAR:

Central African Republic

HD:

Health district

HEV:

Hepatitis E virus

IgG:

Immunoglobulin G

IgM:

Immunoglobulin M

IPB:

Institut Pasteur de Bangui

NFI:

Non Food Items

OCHA:

UN Office for the Coordination of Humanitarian Affairs

OR:

Odds ratios

RT-PCR:

Reverse transcriptase-polymerase chain reaction

WHO:

World Health Organization

YF:

Yellow fever

YFNSS:

Yellow fever national surveillance system

References

  1. Mirazo S, Ramos N, Mainardi V, Gerona S, Arbiza J. Transmission, diagnosis, and management of hepatitis E: an update. Hepat Med. 2014;3(6):45–59.

    Google Scholar 

  2. Kim JH, Nelson KE, Panzner U, Kasture Y, Labrique AB, Wierzba TF. Erratum to: a systematic review of the epidemiology of hepatitis E virus in Africa. BMC Infect Dis. 2017;17(1):187.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Pallerla SR, Harms D, Johne R, Todt D, Steinmann E, Schemmerer M, et al. Hepatitis E virus infection: circulation, molecular epidemiology, and impact on global health. Pathogens. 2020;9(10):856.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Purdy MA, Drexler JF, Meng XJ, Norder H, Okamoto H, Van der Poel WHM et al. ICTV Virus taxonomy profile: Hepeviridae 2022. J Gen Virol. 2022;103(9). https://doi.org/10.1099/jgv.0.001778.

  5. Sridhar S, Teng JLL, Chiu TH, Lau SKP, Woo PCY. Hepatitis E virus genotypes and evolution: emergence of camel hepatitis E variants. Int J Mol Sci. 2017;18(4):869.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Khuroo MS, Khuroo MS. Hepatitis E: an emerging global disease - from discovery towards control and cure. J Viral Hepat. 2016;23(2):68–79.

    Article  CAS  PubMed  Google Scholar 

  7. Sridhar S, Lau SKP, Woo PCY. Hepatitis E: a disease of reemerging importance. J Formos Med Assoc. 2015;114(8):681–90.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Smith DB, Simmonds P, Jameel S, Emerson SU, Harrison TJ, Meng XJ, et al. Consensus proposals for classification of the family Hepeviridae. J Gen Virol. 2014;95(Pt 10):2223–32.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wedemeyer H, Pischke S, Manns MP. Pathogenesis and Treatment of hepatitis E virus Infection. Gastroenterology. 2012;142(6):1388-1397.e1.

    Article  CAS  PubMed  Google Scholar 

  10. Péron JM, Bureau C, Poirson H, Mansuy JM, Alric L, Selves J, et al. Fulminant liver failure from acute autochthonous hepatitis E in France: description of seven patients with acute hepatitis E and encephalopathy. J Viral Hepat. 2007;14(5):298–303.

    Article  PubMed  Google Scholar 

  11. Kumar S, Subhadra S, Singh B, Panda BK. Hepatitis E virus: the current scenario. Int J Infect Dis. 2013;17(4):e228–33.

    Article  PubMed  Google Scholar 

  12. Kumar A, Beniwal M, Kar P, Sharma JB, Murthy NS. Hepatitis E in pregnancy. Int J Gynecol Obstet. 2004;85(3):240–4.

    Article  CAS  Google Scholar 

  13. Tsega E, Krawczynski K, Hansson BG, Nordenfelt E. Hepatitis E virus infection in pregnancy in Ethiopia. Ethiop Med J. 1993;31(3):173–81.

    CAS  PubMed  Google Scholar 

  14. World Health Organization. WHO-recommended standards for surveillance of selected vaccine preventable diseases. World Health Organization; 1999. Report No.: WHO/EPI/GEN/98.01 Rev.2. Available from: https://apps.who.int/iris/handle/10665/64165. Cited 2023 Aug 30.

  15. World Health Organization. Guidelines for environmental surveillance of poliovirus circulation. World Health Organization; 2003. Report No.: WHO/V&B/03.03. Available from: https://apps.who.int/iris/handle/10665/67854. Cited 2023 Aug 30.

  16. Pas SD, Streefkerk RHRA, Pronk M, de Man RA, Beersma MF, Osterhaus ADME, et al. Diagnostic performance of selected commercial HEV IgM and IgG ELISAs for immunocompromised and immunocompetent patients. J Clin Virol. 2013;58(4):629–34.

    Article  CAS  PubMed  Google Scholar 

  17. Norder H, Karlsson M, Mellgren Å, Konar J, Sandberg E, Lasson A, et al. Diagnostic performance of five assays for anti-hepatitis E virus IgG and IgM in a large cohort study. J Clin Microbiol. 2016;54(3):549–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Enouf V, Dos Reis G, Guthmann JP, Guerin PJ, Caron M, Marechal V, et al. Validation of single real-time TaqMan® PCR assay for the detection and quantitation of four major genotypes of hepatitis E virus in clinical specimens. J Med Virol. 2006;78(8):1076–82.

    Article  CAS  PubMed  Google Scholar 

  19. Huang FF, Haqshenas G, Guenette DK, Halbur PG, Schommer SK, Pierson FW, et al. Detection by reverse transcription-PCR and genetic characterization of field isolates of swine hepatitis E virus from pigs in different geographic regions of the United States. J Clin Microbiol. 2002;40(4):1326–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kumar S, Stecher G, Tamura K. MEGA7: molecular evolutionary genetics analysis version 7.0 for bigger datasets. Mol Biol Evol. 2016;33(7):1870–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Smith DB, Simmonds P, Izopet J, Oliveira-Filho EF, Ulrich RG, Johne R, et al. Proposed reference sequences for hepatitis E virus subtypes. J Gen Virol. 2016;97(Pt 3):537–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Tricou V, Bouscaillou J, Laghoe-Nguembe GL, Béré A, Konamna X, Sélékon B, et al. Hepatitis E virus outbreak associated with rainfall in the Central African Republic in 2008–2009. BMC Infect Dis. 2020;20(1):260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Goumba AI, Konamna X, Komas NP. Clinical and epidemiological aspects of a hepatitis E outbreak in Bangui, Central African Republic. BMC Infect Dis. 2011;14(11):93.

    Article  Google Scholar 

  24. Escribà JM, Nakoune E, Recio C, Massamba PM, Matsika-Claquin MD, Goumba C, et al. Hepatitis E, Central African Republic. Emerg Infect Dis. 2008;14(4):681–3.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lagare A, Ibrahim A, Ousmane S, Issaka B, Zaneidou M, Kadadé G, et al. Outbreak of hepatitis E virus infection in displaced persons camps in Diffa Region, Niger, 2017. Am J Trop Med Hyg. 2018;99(4):1055–7.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Chandra V, Taneja S, Kalia M, Jameel S. Molecular biology and pathogenesis of hepatitis E virus. J Biosci. 2008;33(4):451–64.

    Article  CAS  PubMed  Google Scholar 

  27. Elduma AH, Zein MMA, Karlsson M, Elkhidir IME, Norder H. A single lineage of hepatitis E virus causes both outbreaks and sporadic hepatitis in Sudan. Viruses. 2016;8(10):273.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Desai AN, Mohareb AM, Elkarsany MM, Desalegn H, Madoff LC, Lassmann B. Viral hepatitis E outbreaks in refugees and internally displaced populations, sub-Saharan Africa, 2010–2020. Emerg Infect Dis. 2022;28(5):1074–6.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Conte DD, de Luna LKS, Passarini A, Alves VRG, Caldeira DB, Cruz JS, et al. Hepatitis E virus infection among patients with altered levels of alanine aminotransferase. Braz J Infect Dis. 2021;25(6):101655.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Goumba CM, Yandoko-Nakouné ER, Komas NP. A fatal case of acute hepatitis E among pregnant women, Central African Republic. BMC Res Notes. 2010;15(3):103.

    Article  Google Scholar 

  31. Bouscaillou J, Komas N, Tricou V, Nakouné E, Sélékon B, Fontanet A, Kazanji M. Imported hepatitis e virus, central african republic, 2011. Emerg Infect Dis. 2013;19(2):335–7. https://doi.org/10.3201/eid1902.120670.

    Article  PubMed  Google Scholar 

  32. Modiyinji AF, Rivero-Juarez A, Lopez-Lopez P, Atsama MA, Monamele CG, Nola M, et al. First molecular characterization of the hepatitis E virus in humans in Cameroon: confirmation of the HEV outbreak in Touboro, North-Cameroon. J Med Virol. 2021;93(6):4018–22.

    Article  CAS  PubMed  Google Scholar 

  33. Spina A, Lenglet A, Beversluis D, de Jong M, Vernier L, Spencer C, Andayi F, Kamau C, Vollmer S, Hogema B, Irwin A, Ngueremi Yary R, Mahamat Ali A, Moussa A, Alfani P, Sang S. A large outbreak of Hepatitis E virus genotype 1 infection in an urban setting in Chad likely linked to household level transmission factors, 2016–2017. PLoS One. 2017;12(11):e0188240. https://doi.org/10.1371/journal.pone.0188240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Akanbi OA, Harms D, Wang B, Opaleye OO, Adesina O, Osundare FA, Ogunniyi A, Naidoo D, Devaux I, Wondimagegnehu A, Peter C, Ifeanyi O, Ogundiran O, Ugochukwu U, Mba N, Omilabu SA, Ihekweazu C, Bock CT. Complete genome sequence of a hepatitis E virus genotype 1e strain from an outbreak in Nigeria, 2017. Microbiol Resour Announc. 2019;8(1):e01378-e1418. https://doi.org/10.1128/MRA.01378-18.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Guthmann JP, Klovstad H, Boccia D, Hamid N, Pinoges L, Nizou JY, et al. A large outbreak of hepatitis E among a displaced population in Darfur, Sudan, 2004: the role of water treatment methods. Clin Infect Dis. 2006;42(12):1685–91.

    Article  PubMed  Google Scholar 

  36. Ashbolt NJ. Microbial contamination of drinking water and disease outcomes in developing regions. Toxicology. 2004;198(1):229–38.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Authors acknowledge the Ministry of public Health & population, CAR, in supporting the investigation, the World Health Organization [WHO] and the « Médecins Sans Frontières » team in CAR for providing logistic support for transporting samples to the viral hepatitis laboratory at Institut Pasteur de Bangui, Dr Brice Yambiyo for his help in statistical analysis, Dr Gilles Ngaya and the health agents of medical laboratory of the Institut Pasteur de Bangui for their help in biochemical tests. We also thank the rural communities of Bocaranga-Koui for their cooperation and are grateful to the health agents at the health district of Bocaranga and Koui for their help in blood and water sample collection. We are also grateful to Dr Marc Benhamou, Nicole Meyers and Tamara Giles-Vernick for their critical reading of the manuscript and checking the English.

Funding

WHO grant number 2021/1098759–0.

Author information

Authors and Affiliations

  1. Viral Hepatitis Laboratory, Institut Pasteur de Bangui, PO Box 923, Bangui, Central African Republic

    Marina Prisca de Marguerite Nombot-Yazenguet, Philippe Armand Zemingui-Bembete & Narcisse Patrice Joseph Komas

  2. Enteric Viruses and Measles Laboratory, Institut Pasteur de Bangui, PO Box 923, Bangui, Central African Republic

    Joël Wilfried Doté & Ionela Gouandjika-Vasilache

  3. Laboratoire National de Biologie Clinique Et de Santé Publique, PO Box 1426, Bangui, Central African Republic

    Giscard Wilfried Koyaweda

  4. Arboviruses, Hemorragic Fever Viruses and Zoonosis Virus Laboratory, Institut Pasteur de Bangui, PO Box 923, Bangui, Central African Republic

    Benjamin Selekon & Emmanuel Nakoune

  5. Department of Medicine, Infectious and Tropical Diseases Unit, Hôpital de L’Amitié Sino-Centrafricaine, Bangui, Central African Republic

    Ulrich Vickos

  6. Epidemiological Service, Institut Pasteur de Bangui, PO Box 923, Bangui, Central African Republic

    Alexandre Manirakiza

Authors
  1. Marina Prisca de Marguerite Nombot-Yazenguet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joël Wilfried Doté
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giscard Wilfried Koyaweda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Philippe Armand Zemingui-Bembete
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benjamin Selekon
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ulrich Vickos
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Alexandre Manirakiza
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Emmanuel Nakoune
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Ionela Gouandjika-Vasilache
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Narcisse Patrice Joseph Komas
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceptualization: NPJK, MPMNY, UV and EN. Data curation: MPMNY, BS, EN and NPJK. Formal analysis: MPMNY, GWK, BS, UV, AM, and NPJK. Funding acquisition: NPJK and EN. Investigation: MPMNY, PAZ, BS and NPJK. Methodology: NPJK and MPMNY. Supervision: NPJK. Writing ± original draft: MPMNY, JWD, GWK, UV, IGV and NPJK. Writing ± review & editing: All authors reviewed the manuscript.

Corresponding author

Correspondence to Narcisse Patrice Joseph Komas.

Ethics declarations

Ethics approval and consent to participate

The research was approved by the Ethics and Scientific Committee of the Faculty of Health Sciences, University of Bangui, Central African Republic (decision number N°38/UB/FACSS/IPB/CES.023) and conducted within the guidelines of the Declaration of Helsinki. Because samples were taken as part of the national surveillance of yellow fever, and that the differential diagnosis of yellow fever is hepatitis E virus infection, the informed consent of the participants was not required.

Written informed consent was waived by the « Comité Éthique et Scientifique/Faculté des Sciences, Université de Bangui/Institut Pasteur de Bangui (CES). Hence the CES gave authorization to publish the results from yellow fever national surveillance data used in the differential diagnosis of HEV infection without requiring informed consent. As the state of hepatitis E outbreak had been declared by the Ministry of Health and Population of the Central African Republic in this health district during this time, any person presenting conjunctival jaundice accompanied by a fever had to be systematically sampled for a HEV serological test, and symptomatic treatment was initiated if the serology (anti-HEV-IgM antibodies) of the HEV infection was positive.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Marguerite Nombot-Yazenguet, M.P., Doté, J.W., Koyaweda, G.W. et al. Hepatitis E outbreak in the health district of Bocaranga-Koui, Central African Republic, 2018–2019. BMC Infect Dis 24, 215 (2024). https://doi.org/10.1186/s12879-024-09116-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12879-024-09116-3

Keywords

BMC Infectious Diseases

ISSN: 1471-2334

Contact us