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Epidemiological trends of Lassa fever in Nigeria from 2015-2021: A review

Introduction: Lassa fever is a viral haemorrhagic fever with non-specific symptoms that has shown an upward trend in Nigeria and other West African countries, which is depicted by high incidence and case fatality in recent years. There are different reports on the yearly case burden of Lassa fever from the Federal Ministry of Health in Nigeria, through the regulatory body – Nigeria Centre for Disease Control (NCDC). Being the epicentre of the disease, Lassa fever has been exported from Nigeria to both neighbouring and distant countries.Methods: The aim of this review was to carry out a retrospective analysis from January 2015 to 26 September 2021 of the weekly and yearly outbreak of Lassa fever in Nigeria based on selected publications. The focus was on timely diagnosis, treatment option, public health interventions and progress of clinical trials for vaccine candidates, and to identify proactive measures that can be sustained to curb periodic outbreaks. The review was done using percentages, cross-tabulation and graphical charts. Results: The predominant age group infected was 21 to 40 years with a male to female ratio of 1:0.8. A total of 3311 laboratory-confirmed Lassa fever cases out of 20,588 suspected cases were identified from 29 states. Edo, Ondo, Taraba, Ebonyi, Bauchi, Plateau and Nasarawa had yearly Lassa fever incidence over the time frame considered. Contact tracing was done on over 33,804 individuals with about 90% completing follow-up. Case fatality rate within the period ranged from 9.3% to 29.2%. There is a sharp decline in the epidemiological trend of Lassa fever in the yearly seasonal peaks from weeks 1 to 13 with about 75% reduction in incidence between 2020 and 2021. Conclusion: The effective management of Lassa fever needs the implementation of preventive methods, prompt laboratory diagnosis, timely treatment, provision of personal protective equipment, cross-border surveillance, contact tracing, community awareness and vector control in order to minimise spread.


Introduction
Lassa fever (LF) has been identified as a yearly outbreak in West Africa with Nigeria having the highest yearly incidence. Seasonal peaks of this viral haemorrhagic fever occur during the dry season from November to April, and it is common in Sierra Leone, Ghana, Mali, Nigeria, Benin, Togo, Guinea and Liberia. 1 Delay in LF diagnosis often occurs because of non-specific symptoms such as fever and the assumption that the febrile illness is caused by other factors, especially malaria that is endemic in sub-Saharan Africa. 2 Identifying the onset of the disease is often difficult due to the generalised symptoms and clinical presentation such as fever, vomiting, fatigue, abdominal pain, sore throat, chest pain and myalgia. It may progress to serious complications such as encephalitis, respiratory difficulty, haemorrhage, neurological problems and hearing loss. 1,3 LF is a viral haemorrhagic fever of zoonotic origin from the urine and faeces of multimammate rat Mastomys natalensis. Person-to-person transmission occurs by contacting aerosol or fluid secretions such as sputum, sneezing, blood, seminal fluid and stool. [1][2][3] It was first discovered in 1969 when a nurse became ill at Lassa town of Borno, Nigeria. The first nosocomial spread was observed among the health workers where the nurse was admitted before becoming endemic in different parts of Nigeria and West Africa. The Lassa virus is an enveloped, single-stranded, bisegmented negative-strand RNA virus belonging to the family Arenaviridae. 2,4-6 LF cases are categorised based on suspected, confirmed and probable case. Suspected cases involve individuals who have symptoms and a history of contact with a probable or confirmed LF case within a 21-day period. There are public health concerns about its incidence, virulence and potential as a bioterrorism agent. [7][8][9][10][11] LF has an incubation period of 1 to 3 weeks, and this long incubation period means infected person resident on endemic regions can travel both locally and internationally thereby causing an epidemic. 4 The interconnection between West African countries and the ease of human movement escalates the risk of international spread of disease. Disease surveillance systems and comprehensive outbreak response is needed as a public health procedure in cross-border migration. 12 According to a probabilistic model on exported cases by Tuite et al., 7 a low probability of case exportation was quantified using the 2018 LF outbreak; however, countries with close proximity to Nigeria needed to be on the alert for LF importation and ensure prompt epidemic response. 7 Previous cases of LF outbreaks in Nigeria were exported to neighbouring countries and even more distant countries especially via international air travels.
The aim of this study is to carry out a retrospective analysis of the national outbreak of LF in Nigeria from January 2015 to 26 September 2021 with a focus on the weekly and yearly available report, importance of prompt and accurate diagnosis, treatment option, public health interventions and progress of clinical trials for vaccine candidates, and to identify proactive measures that can be sustained to curb periodic outbreaks.

Method
The systematic literature review was conducted using the search term 'Lassa fever and Nigeria' in online databases, including PubMed, Google Scholar Africa Journal Online, WHO Library Database, Research Gate, Nigeria Centre for Disease Control (NCDC) website and the Federal Ministry of Health of Nigeria. The NCDC is the public health institute for the nation, and it was carved out from different divisions in the Federal Ministry of Health to handle preparedness in public health emergencies with the detection and response to infectious disease outbreaks. Characteristics of data are period of inclusion, demographics, contact tracing, yearly trend of confirmed cases and the effect of national proactive measures in LF outbreaks. The raw data obtained were collated using Excel spreadsheets and analysed using basic statistics such as percentages, cross-tabulation and graphical chart.

Quantitative analysis and state distribution of LF in Nigeria
The age group and gender infected by LF over the years vary. Considering the recent outbreak in 2021, the predominant age group affected were 21 to 30 years with a male to female ratio of 1:0.8 in the confirmed cases ( Table 1). The details of those who had come in contact with infected persons during the yearly outbreak was obtained and intense followup done to identify those that were symptomatic and the laboratory-confirmed cases ( Table 2). Report on the yearly LF outbreak from the Federal Ministry of Health in Nigeria and NCDC indicates different percentage of mortality ( Table 3). The significantly high mortality rate from LF outbreaks is often associated with the poor sanitary conditions and daily environmental lifestyle common in high-risk areas. 9 Prior to 2018, the yearly confirmed cases ranged from 25 to 143. The first largest outbreak having 633 confirmed cases of LF occurred in 2018 (Table  3), followed by a persistent increase of confirmed cases of LF in subsequent years (NCDC, 2021). The high case count of laboratory-confirmed LF may be due to the availability of Lassa virus diagnostic centres within the states and heightened surveillance sensitivity. 6 It is encouraging to note that there is a steady decline in the fatality rate from 2018 to 2020.
The 53-week epidemiological trend shows an active LF outbreak from weeks 1 to 13 of 2016 to 2021, which tapers down in the remaining weeks of the year. In the first 24 weeks of 2021, the trend of LF confirmed cases is lower compared with what was observed within the same time frame in 2020 (Figures 1 and 2). According to NCDC LF situation report from 2015 to 26 September 2021, the epicentre having the highest number of confirmed cases of LF is Edo, Ondo, Ebonyi and Taraba. 16 The coordinated sensitisation and response activities across different states have helped in curbing the seasonal peaks previously experienced.

Community lifestyle
In different countries of West Africa, bacterial and viral infection seems to be re-occurring with fluctuating preparedness in handling such outbreaks. Community lifestyle that made LF endemic in some locations includes consumption of rats, forceful ingestion of bathing water from dead corpses as part of an age-long tradition and overnight drying of agricultural products thereby exposing it to contamination from rat urine and faeces. 4,9,18 Preventive and surveillance measures include public enlightenment on mode of transmission, effect of personal and environmental hygiene, the need for timely medical intervention and contact tracing of people exposed to the infected person. Our aim was to review the epidemiological trend of LF in Nigeria, the national level of preparedness and the effect that proactive activities will have in curbing the recurrent outbreaks.

Public health interventions for LF in Nigeria
The World Health Organization (WHO) posited that the capacity of Nigeria to fully implement disease surveillance to handle LF and initiate appropriate public health measures has contributed to the repeated LF outbreaks at the state and national level. 3 Negligence on the part of the Nigerian government to health care contributed significantly in the high mortality rate observed yearly. 8 In recent years, the provision and use of  Laboratory diagnosis of LF Laboratory diagnosis of LF is often confirmed with a reverse-transcriptase polymerase chain reaction (RT-PCR), antibody enzyme-linked immunosorbent assay, virus isolation using cell culture and antigen detection tests. 5 The increase in laboratory detection and reporting of confirmed cases is attributed to the setting up of LF laboratories in endemic areas, initiating a workable sample transport system and strengthening laboratory capacity. 23 Correct diagnosis became possible based on clinical manifestations, confirmatory laboratory tests and the epidemiological findings. 1 Other laboratory investigations such as full blood count, urinalysis, liver function test, urine and blood culture, and microscopy for malaria parasites are also carried out to aid in diagnosis and treatment. Any suspected case with laboratory confirmation involving positive IgM antibody, molecular detection and virus isolation were referred to as confirmed case. The probable

Treatment
Ribavirin, a broad spectrum guanosine analogue, is the recommended treatment for LF and for post-exposure prophylaxis using both oral and intravenous administration. Initiating early treatment is vital to improve the rate of survival. Oral ribavirin is indicated in the dose of 500 to 600 mg every 6 h for 7 to 10 days while intravenous dosing begins with a loading dose of 2.4 g, followed by 1 g every 6 h for 10 days based on average weight adults. 1,4,24,25 According to Ilori et al., 6    by receiving a two-dose regimen injection on days 0 and 28 while being evaluated for immunogenicity and safety within an African population. 27,28 The DNA plasmid induces target antigen production, which triggers T cell and antibody-mediated cellular immunity. A major factor limiting the LF vaccine development has been associated with the high cost of bio-containment required. 13 Detailed understanding of the pathogenesis, course of the disease, signs and symptoms, and possible complications is needed in the development of the LF vaccine and other antiviral compounds. 2

Conclusion
From this overview, it is vital to note that LF is highly endemic in Nigeria with public health implications that require prompt action. Strategic preventive methods and awareness need to be put in place routinely to curb the spread. Setting up LF diagnostic laboratories in other locations can improve diagnosis and increase the number of confirmed cases in locations with seemingly low incidence, while ensuring timely treatment of LF. Provision of PPE for health care workers in endemic areas and other essential resources is necessary to strengthen the porous health care system in West African countries. Ribavirin, the choice drug for LF treatment, should be made readily available in public health centres and clinics within the endemic areas.

Author contributions
J.-U.A.G. was involved in study conceptualisation and draft manuscript preparation. J.-U.A.G., I.J.E. and N.U. were involved in data collection, analysis and interpretation, and have contributed to resources. All the authors read and gave their consent for the submission of this manuscript.