Outcome of Epidemiological Investigation of COVID-19 Outbreak in a South West State of Nigeria, March to August 2020

Background: On 3 rd April 2020, an outbreak of Coronavirus disease-2019 (COVID-19) was confirmed in Ondo State, Southwest Nigeria. Field investigations were conducted by the State Ministry of Health (MoH) to identify and confirm additional cases. This paper provides the outcome of the epidemiological investigation of the outbreak to further guide outbreak response activities. Methods: Field epidemiology methods coordinated by the State Public Health Emergency Operations Center (PHEOC) were used in the outbreak investigation. Suspected cases were reported through the routine Inte-grated Disease Surveillance and Response (IDSR) network in the State. Also, active case search/finding to communities and health facilities using the operational case definitions was conducted. Furthermore, the state COVID-19 emergency call center was established with toll-free phone number provided to members of the public to call-in to report suspected persons with symptoms consistent with the COVID-19 operational case definition (signal). All cases reported were investigated with nasopharyngeal sample collected and confirmatory testing for COVID-19 done by real-time polymerase chain reaction (RT-PCR) in a national reference laboratory. Information of each case investigated was documented using the COVID-19 case investigation form and COVID-19 line-list which captured socio-demographic characteristics, history of exposure to COVID-19, presenting symptoms, travel history and sample collection details. Data were extracted from the case investigation form and line list and analyzed using SPSS version 20, with a p-value set at < 0.05. Results: A total of 4353 suspected cases were reported and investigated, of which 1316 cases were confirmed between March 19, 2020 and August 9, 2020. The mean age of the confirmed cases was 37.8 ± 14.8 years. The highest proportion of COVID-19 cases and deaths occurred in the age group 20 - 39 years (50.6%) and ≥60 years (13.5%), respectively. More males (52.4%) were affected than females (45.8%). There were 404 (30.7%) healthcare workers infection. About a quarter (325; 24.7%) of the cases was symptomatic and presented with key symptoms such as cough (98/325; 30.2%) and fever (74/325; 22.8%) during the investigation. A case fatality rate (CFR) of 2.2% was recorded in 7 of the 17 Local Government Areas (LGAs) where confirmed cases were reported in the State. Most of the confirmed cases, 1169 (88.8%) reside in urban LGAs of the State. The epidemic curve shows a propagated pattern of transmission with the outbreak reaching its peak on July 2, 2020. Significantly, higher proportion of death was recorded in the age group ≥ 60 years (14; 13.5%) and among males (26; 3.6%) (p < 0.001). Conclu-sions: Our investigation found high transmission of COVID-19 infection among urban residents (LGAs) and health care workers with high mortality among males in older age group in the State. Hence, we recommend intensified risk communication and use of community structures to ensure compliance with public health COVID-19 preventive protocols including enforcing infection prevention and control compliance, particularly among high-risk groups.


Introduction
Coronavirus disease-2019 (COVID- 19) is an infectious disease caused by a newly discovered coronavirus called Severe Acute Respiratory Coronavirus 2 (SARS-CoV2) [1]. The SARS-CoV2 belongs to a family of viruses that cause illness with various symptoms such as pneumonia, fever, breathing difficulty and lung infections [2]. The virus is one of the main pathogens of respiratory infection alongside others such as SARSCoV and Middle East Respiratory Syndrome Coronavirus (MERSCoV) that caused severe respiratory syndrome in humans [3]. The term 2019 novel coronavirus was first used to refer to the virus that affected the lower respiratory tract of patients with pneumonia in a local Huanan South China Seafood market in Wuhan City, China on 29 December 2019 [4] [5]. Afterwards, the World Health Organization (WHO) announced the official name of the 2019 novel coronavirus to be coronavirus disease (COVID-19) [1].
The SARS-CoV2 has been understood to be zoonotic, however, no specific animal association has been identified [6]. Human to human transmission has been proven through small droplets expelled from the nose or mouth when a person with COVID-19 coughs, sneezes, or speaks [7]. The virus has been found to adhere to surfaces which act as fomites for the transmission of the disease [8]. The SARS-CoV2 presents in different ways which range from severe illness and mortality to mild symptoms and asymptomatic [9]. Early patterns of COVID-19 transmission have shown a trend similar to SARS and MERS coronaviruses however, unlike other coronaviruses, asymptomatic cases can still transmit the infection, which raises public health concerns [10] [11].
The COVID-19 outbreak is increasing and spreading rapidly globally, with over 20 million cases and 800,000 thousand deaths reported in 216 countries as on 28 th August 2020 [12]. Since the report of the index case in Nigeria in February 2020 by the Nigeria Center for Disease Control (NCDC), daily records of confirmed cases have been reported in all states in the country, including Ondo State. As on 28 th August 2020, a total of 53, 477 cases and 1011 deaths have been reported in Nigeria, while Ondo State ranked 11 th among the states with high confirmed cases in the country [13].
This paper presents the outcome of the epidemiological investigation of COVID-19 outbreak in Ondo State, Nigeria from March to August 2020 to further guide the outbreak response activities.

Outbreak Settings
Ondo State is in the South-West Zone of Nigeria with her capital at Akure. The State is situated between longitudes 40,151E and 60,001E of the Greenwich median and latitudes 50,451N and 70,451N, which are to the North of the equator in the Southwestern geopolitical zones of the country. The surface area of the State is approximately 15,317 square kilometers and is bounded by Edo and Delta States on the east, Ogun and Osun States on the west, Ekiti and Kogi States on the north and Bight of Benin and the Atlantic Ocean on the South. The State consists of 18 Local Government Areas (LGAs) and 3 senatorial districts namely Ondo Central, North and South districts; and has a projected population of 5,205,141 in 2020 with an annual growth rate of 3% based on the 2006 population census [14]. The basic occupation by a vast majority of the population is farming, while other economic activities include small scale businesses, trading and civil service [15].

Field Investigation
The investigation was conducted as part of outbreak control and response measures hence permission to conduct the study was obtained from the State Ministry of Health (SMoH).
Investigation commenced following an alert from clinicians at a government-owned Hospital, Akure on 30 March 2020 of a suspected case of COVID-19, a 34-year-old male with recent travel history to India. He arrived at Ondo State on 21st March 2020 and presented at the hospital with cough, sore throat and running nose with the onset of symptoms on 23 rd March 2020. The State public health emergency Rapid Response Team (RRT) comprising of Commissioner for Health, State Epidemiologist, State and LGA surveillance officers, and health development partners in the state visited the hospital to investigate and imple-ment public health response. Nasopharygeal and oropharyngeal samples were collected and tested for COVID-19 and returned positive from the national reference laboratory on the 3 rd of April 2020.
The State Public Health Emergency Operation Center (PHEOC) was activated to coordinate the outbreak response. Furthermore, the state COVID-19 emergency call center was established with toll-free phone number provided to members of the public to call-in to report suspected persons with symptoms consistent with the COVID-19 operational case definition (signal) for investigation.
Using the COVID-19 operational case definitions developed by the Nigeria Center for Disease Control, active case search visits/case finding was conducted to communities and health facilities across the 18 local government areas (LGAs) by State RRT to identify additional suspected cases. All public health signals received through the State COVID-19 emergency call center were investigated with nasopharyngeal and oropharyngeal samples collected and transported under reverse cold chain temperatures (2˚C to 8˚C) to designated national reference laboratory for confirmatory testing for COVID-19 by real-time polymerase chain reaction (RT-PCR).
Furthermore, nasopharyngeal and oropharyngeal samples of close contacts of confirmed COVID-19 cases enrolled for 14-days contact follow-up exercise was collected and tested before they exit the follow-up exercise. Data of all cases investigated were documented using the national COVID-19 case investigation form and State COVID-19 line-list. The information documented were name, age/date of birth, gender, address/settlement and LGA of residence, occupation, clinical symptoms/presentations, date of onset of symptoms, travel history, sample collection details, phone contact and epidemiological exposures. Each case investigated was given an Epidemiological number as a unique identifier.

Operational Definitions
During the onset of the outbreak, three categories of case definitions for COVID-19 were used to guide the outbreak investigations according to the NCDC guidelines [16].
Suspect case: 1) This is a patient with acute respiratory illness (fever and at least one sign/ symptom of respiratory disease (e.g., cough, shortness of breath) and a history of travel to or residence in a country/area or territory reporting local transmission of COVID-19 disease during the 14 days prior to symptom onset; 2) or a patient/health care worker with any acute respiratory illness and has been in contact with a confirmed COVID-19 case in the last 14 days prior to the onset of symptoms; 3) or a patient with a severe acute respiratory infection (fever and at least one sign/symptom of respiratory disease (e.g., cough, shortness of breath) and requiring hospitalization and with no other aetiology that fully explains the clinical presentation; 4) or a case for whom testing for COVID-19 is inconclusive.
Confirmed case: A person with laboratory confirmation of COVID-19 infection, irrespective of clinical signs and symptoms.
Probable case: Any suspected case for whom testing for COVID-19 is indeter-Open Journal of Epidemiology minate test result or for whom testing was positive on a pan-coronavirus assay.

Data Analysis
The State COVID-19 line-list and case investigation forms of all COVID-19 cases from 19 th March to 9 th August 2020 were retrieved from the state disease surveillance unit, information on key variables were extracted and exported into SPSS version 20 and analyzed. Descriptive statistics such as frequency table, mean (standard deviation) and charts were used to describe key variables including LGA, age, sex, occupation and education and clinical conditions of cases. The week of report of cases and outcomes was used to generate the epidemic curve. The Chi-square test was used to compare categorical variables including the socio-demographic characteristics, clinical condition and outcome of cases. Two-sided P-values < 0.05 were considered statistically significant.

Socio-Demographic Characteristics of Cases
A total of 4353 suspected cases were reported and tested for COVID-19 of which 1316 COVID-19 cases were confirmed, with a case fatality rate of 2.2% recorded in 7 of the 17 LGAs which reported at least a confirmed case ( Figure 1, Table 1). Most of the confirmed cases (1169; 88.8%), reside in urban areas (LGAs) as shown in Table 1 and Table 2.    Table 2.

Admission and Clinical Conditions of Confirmed Cases
From    Association between socio-demographic characteristics, clinical conditions and outcomes of cases Table 4 below shows the association between the treatment outcomes with characteristics and clinical conditions of cases. A significant proportion of death occurred among cases within the age group 60 years and above (14; 13.5%) compared to other age groups (p < 0.001). Death occurred among males (26; 3.6%) compared to the females (3; 0.5%) (p < 0.001). Furthermore, symptomatic cases had higher proportion (27; 8.3%) of deaths compare to asymptomatic cases (2; 0.2%) (P < 0.001). Among the symptomatic cases, a high proportion of death was found among those with difficulty in breathing (3; 20%), fever (11; 14.9%), new loss of taste (1; 11.1%), cough (9; 9.2%) and sore throat (2; 8.3%) (P < 0.001)

Discussion
The finding in this investigation that a high proportion of the confirmed COVID-19 cases were males and between the age group of 20 to 59 years is consistent with previous studies in Oyo State, Nigeria [3] and Wuhan, China [17]. The high proportion of COVID-19 infection among the male age group could be attributed to the fact that this is an economically active age group, suggesting a potential role of socio-economic or work-related activities rather than immunological capacity. In the Nigeria system, men are more likely to engage in economic activities outside of the household and potentially become more exposed to SARS-CoV-2 infection than women [18]. Also, Bwire [19], De La Vega et al., [20] and Isere et al., [11] in their studies reported poor compliance and attitude towards COVID-19 preventive measures and protocol such as frequent hand washing, wearing of face mask, and stay at home orders among men compare to women. Similarly, our investigation shows a high proportion of infection among healthcare workers which is consistent with a previous investigation by Usman et.al., [3]. This might be attributed to poor compliance to COVID-19 IPC protocol by health care workers due to key issues such as knowledge gaps and access to PPEs in the health care settings. This is of serious public health importance as it could potentially enhance disease transmission [21] and further weaken a health system that already struggles with insufficient human resources for health [18]. Also, the high proportion of infection among healthcare workers could also be attributed to poor level of preparedness for the COVID-19 outbreak in the health care settings, and this is also in consonance with the report of Elhadi et al., [22].
The epidemic curve of the outbreak suggests a propagated pattern of transmission of the disease. This is consistent with previous COVID-19 outbreak reports and studies in other regions of Nigeria NCDC [23], Usman et al., [3], Elimian et.al., [18] and in China by Chen et al., [24]. The pattern of the outbreak is suggestive of person-to-person transmission which further explains the findings in this investigation that most of the cases (88.8%) occurred in urban settings where crowded conditions, clustered settlement pattern of the houses and large-scale human interactions due to daily commercial activities could have facilitated the spread of the outbreak [25] [26].
The most common COVID-19 symptoms reported in our investigation were fever and cough. Grant et al., [27] and Tahvildari et al., [28] have reported similar findings from previous studies. Furthermore, the lower proportions of fever and cough reported in this study compared to other studies could be attributed to the fact that our investigation is a population-based study where symptoms were self-reported alongside testing, unlike previous studies where testing was limited to patients on admission at the hospital in the early phase of the outbreak [27] [28]. More importantly, fever which is one of the common symptoms reported in this investigation is often common in endemic febrile illnesses (malaria and Lassa fever) in Ondo State [18]. Hence, co-infection with these diseases could be responsible for the high report of fever as a symptom in this investigation compared to other symptoms.
The low case fatality rate (CFR) found in this study is consistent with that previous reports in the Nigeria [23] and other Africa countries such as South Africa and Senegal [12]. This could be associated with the mild to asymptomatic clinical presentation of most cases in this study who are more likely to recover from the infection [11] [29]. Also, our investigation shows a significantly high mortality rate among cases in the older age group who were mostly male compared to females. This sex-biased mortality could be attributed to sex differences in immune response as females are known to mount more robust innate, cell-mediated, and humoral immune response than males [30]. Sex chromosome constitution could also play an important role in disease outcome. Females have two copies of X chromosomes while males have one [31] [32] [33]. The X chromosome contains a high density of immune-related genes. Males and females show a distinct difference in immune system responses with females eliciting stronger immune responses to pathogens [31] [32] [33].
This difference in immune system responses may be a major contributing factor to viral load, disease severity, and mortality [30]. Also, differences in sex hormone milieus could be a determinant of viral infections as estrogen has immunoenhancing effects while testosterone has immunosuppressive effects [30].
The sex-specific severity of COVID-19 infection, however, indicates that further research on understanding the sex differences is needed [30].
Some key limitations of this investigation include misclassification bias as most cases were asymptomatic and their clinical presentations were not consistent with the surveillance operational case definition. However, a consistent review of the operational case definition using daily data generated from the field investigation assisted in minimizing misclassification bias. In addition, the data presented in this investigation is a preliminary finding of the outbreak investigation which might change with time as the outbreak is still ongoing. Finally, the epi-curve was generated using the week of report as opposed to the typical use of the date of onset of symptoms. This was because of the asymptomatic clinical status of most of the confirmed cases during the investigation. In addition, social desirability bias is suspected as community perception about the COVID-19 disease might have stigmatized respondents. However, probing questions were asked to ensure correct responses where possible.

Conclusion
The outcome of this investigation indicates that high transmission among urban residence and health care workers are key public health concerns in the response to the COVID-19 outbreak in Ondo State, Nigeria. Furthermore, high case mortality among the older age groups requires public health intervention. Thus, we recommend intensified risk communication, enhanced surveillance activities, and use of community structures such as community and religious leaders, market and commercial vehicles associations, Ward Development Committee (WDC) and Village Development Committee (VDC) to ensure compliance with public health COVID-19 preventive measures particularly in the urban areas and among those facing a high risk of death. Furthermore, there is a need to prioritize public health interventions including training and vaccination among the vulnerable groups including health care workers who serve as front liners during case investigation, testing and case management.