PREVALENCE, PATTERN AND OUTCOME OF PEDIATRIC LASSA FEVER DISEASE (LFD) IN A TERTIARY HOSPITAL, SOUTHEAST NIGERIA

The prevalence and case fatality rates of Pediatric Lassa fever disease (LFD) are not well documented. This study was aimed at determining the prevalence, pattern and outcome of Pediatric LFD. It was a prospective observational study. A total of 183 subjects that met the criteria for LFD suspects were recruited consecutively and subjected to Lassa virus PCR test. Structured questionnaire was used to collect information. Of the 183 children recruited, 24 tested positive to Lassa virus PCR, giving a positivity rate of 13.1%. Mean duration of illness at presentation was 8.54 ± 3.83 days. Fever, abdominal pain and vomiting were the three highest presenting complaints. Seven out of 24 children died giving a case fatality rate (CFR) of 29.2%. Subjects with bleeding, poor urine output, convulsions and unconsciousness were more likely to die of LFD. Positivity and CFR of LFD are high. Improved case finding and prompt treatment is

non-specific symptoms. Lassa fever disease can masquerade as malaria, typhoid and pharyngotonsillitis (10,11). McCarthy (12) observed four stages of disease. Starting with fever (>39 0 C), general weakness, malaise in the first three days of illness then finally with coma and death after 14 days of illness. Akhuemokhan et al (8) reported vomiting and bleeding as symptoms that were significantly associated with an increased prevalence of LFD. Common symptoms of LFD as observed by Ajayi et al (10) in their study were fever (100%), sore throat (70%), abdominal pain (85%), and vomiting (50%), headache (35%), body pain and weakness (25%). Akpede et al (13) in their five case series of Lassa fever in children noted that the clinical features were myriad but fever was a constant feature while vomiting, gastritis and tonsillitis were common. Similarly Webb et al (9) reported that 60% of the children with LFD presented with fever, vomiting and cough. Features of shock, seizures, deafness and disorientation are seen in terminal illness and usually complications of the disease.
There is paucity of data on pediatric Lassa fever disease in endemic states and none from Ebonyi state. This study is therefore aimed at determining the epidemiology, clinical course and outcome of pediatric Lassa fever in Ebonyi state; it hopes to guide in better surveillance and management of children with Lassa fever

STUDY AREA
Ebonyi State is located in the rain forest zone; the climate is tropical. The annual rainfall varies from 2,000mm in the Southern areas to 1,150mm in the north (14). The temperature throughout the year ranges between 21 0 C to 30 0 C. It has two seasons, dry and wet. The dry season lasts from November to March while the rainy season lasts from April to October (14). It has a total population of 2,173,501 people, majority of which are Ibos (15).

Study design
The study is a hospital based observational study carried out in the children emergency room and the virology center of the Alex-Ekwueme Federal University Teaching Hospital Abakaliki (AE-FUTHA), Ebonyi State, from January 2019 to January 2020.

SAMPLE SELECTION
All children aged 0-17 years admitted to newborn and Children emergency room with symptoms of unremitting fever for more than 2 days despite administration of anti-malarial and/or antibiotics ± sore throat, bleeding from orifices and body pain were tagged as LFD suspects according to guideline by National Center for Disease Control (16). These LFD suspects were recruited consecutively to the study after obtaining informed consent from caregivers for the period of study. Blood samples from these patients were subjected to Lassa virus reverse transcriptase Polymerase chain reaction (RT-PCR) tests. The PCR was used to detect viral antigens in the child. Those infected with LFD as identified with positive PCR test were transferred to virology unit and followed up until discharge or death. Structured questionnaire was used to collect information on bio-data, socio-demographics, symptoms and signs at presentation, management given while on admission in virology center and outcome of the case.

Approval for the study was sought and obtained from the Health Research and Ethical
Committee of Alex-Ekwueme Federal University Teaching Hospital Abakaliki (AE-FUTHA).

DATA ANALYSIS
The data obtained was entered into a spread sheet using the Microsoft excel 2007 and the analysis was done using the Statistical Package for Social Sciences version 19.0. Quantitative variables were summarized using means and standard deviations. Frequency tables were constructed as appropriate. The significance of associations between variables was tested using Chi-square test for comparison of proportion. Epi Info version 7.0 was used for multivariate analysis of data. The level of statistical significance was achieved if p < 0.05.

RESULTS
Of the 183 LFD suspects recruited during the study period, 24 tested positive to Lassa PCR, giving a prevalence rate of 13.1%. Mean duration of illness at presentation was 8.54 ± 3.83 days, range of 2 to 14 days. Table 1 shows that 41.6% of the Lassa fever infected children were within 6-12 years age bracket. Majority were females with a male to female ratio of 1:1.7 and children from lower social class were mostly affected.
All the infected children had a history of fever, while half of them reported history of contact with probable or confirmed Lassa fever patients. Abdominal pain and vomiting were second to fever in frequency of presentation with 41.7%. A quarter of the children presented with convulsions, cough and dyspnoea, bleeding and poor urine output as shown in Table 2 The pie chart in Figure 1 represents the outcome of Lassa fever disease; a total of 7 children died during the study period, giving a case fatality rate of 29.2%. Three out of these deaths received their results post-mortem as such did not receive intravenous ribavirin medication. For the remaining 4 deaths, 3 occurred within 7 days on admission while the last occurred on the 8 th day on admission. Five (71.4%) out of the 7 deaths were females, 3 (42.8%) were less than 6 years of age, 2 (28.6%) deaths within the 6-12 years age bracket and 2 (28.6%) of the deaths were teenagers. There were no significant relationships between age and gender with outcome of Lassa fever disease in children (p= 0.387 and 0.562 respectively) Majority (87.5%) of the children that had Lassa fever disease received intravenous ribavirin medication. A total of 12.5% of the children that tested positive to Lassa virus PCR and were unable to receive ribavirin medication died as depicted on the pie chart in Figure 2 All the children that had abdominal pain, sore throat and headache were discharged. A total of 66.7% of the children who had convulsions died compared to 83.3% that did not have convulsions and were discharged home. Two-thirds of the children that had diarrhea and 70.0% that presented with vomiting were discharged home. There were significant relationships between symptoms such as abdominal pain and convulsions with or without coma and outcome of the Lassa fever disease (p= 0.008 and 0.02 respectively) as shown in the Table 3A Half of children that had cough in the course of illness and two-thirds of those with facial puffiness were discharged home. Majority (83.3%) of children that bled and had poor urine output in the course of the Lassa fever illness died while 91.7% of children with a positive history of contact with a Lassa fever confirmed or probable case were discharged home. All the children  Table 3B We did a multivariate analysis of variables and outcome. We found that children who presented with convulsion and coma were 10 times more likely to die from Lassa fever disease compared to other symptoms. Bleeding and poor urine output as symptoms had very high odds for death among Lassa fever infected subjects. Of the 21 children who received ribavirin, 3 (60.0%) died within the first week of commencement of ribavirin while one death occurred after a week on ribavirin having developed complication of deafness. Subjects that completed ribavirin for more than 7 days were more likely to be discharged as shown in Table 4 Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted: 16 May 2020 doi:10.20944/preprints202005.0269.v1

DISCUSSION
Lassa fever disease positivity rate of 13.1% observed in children that met the case definition of Lassa fever suspect is rather high when compared to previously reported data by Ajayi et al (10) where only two paediatric cases were isolated. This may be explained by the study being a prospective study and focused on children unlike the study by Ajayi et al (10). Also increased availability of testing kit for Lassa fever disease and increasing awareness of disease symptoms by health care providers may be possible explanations to finding. More females than males were affected with LFD similar to that reported by Webb et al (9). It is possible that because females are more domesticated than males, there are more likely to have contact with the feces and urine of rodents or food and foodstuffs contaminated by urine and feces of rodents when engaging in house chores. Majority of the children infected by the Lassa virus were within the aged 6-12 age bracket. This is also similar to that reported by Webb et al (9).
Presenting symptoms were varied in index study similar to the experience of previous authors (9, 10, 13) However like most studies; a history of fever was a predominant finding in this study.
This study noted abdominal pain and vomiting as common features after fever and studies by Ajayi et al (10) and Akpede et al (13) also reported sore throat, abdominal pain and vomiting as common presenting features following fever. Similarly Webb et al (9) reported that 60% of the children with LFD presented with fever, vomiting and cough. In all the above mentioned studies vomiting was a predominant finding followed by abdominal pain. This suggests that abdominal pain with vomiting in febrile children with unremitting fever spikes despite antimalaria and or antibiotic use should heighten the suspicion of the pediatrician working in Lassa fever endemic regions. Akhuemokhan et al (8) reported vomiting and bleeding as symptoms that were significantly associated with an increased prevalence of LFD. The abdominal pain found in index study were either localized or generalized in character, mimicking typhoid enteritis in most cases, appendicitis (two had surgery for appendicitis and was discovered to be LFD postoperatively) and hepatitis. The masquerading of LFD with non-specific symptoms may explain the average duration of illness of 8.54 ± 3.83 days before presentation at the facility.
Dongo et al (17) (19). This was corroborated by previous authors that noted that patients on ribavirin were less likely to die compared to those who had no ribavirin (6, 10) The case fatality rate (CFR) observed in this study was 29.2%. This may largely be attributed to delayed presentation as the mean duration of illness before presentation to the health facility was 8.54 ± 3.83 days. This is comparable to 15-50% CFR reported in endemic countries (3,4).
Prognosis for Lassa fever is generally good considering that 80% of infected persons have subclinical infection requiring no admission, however majority of mortalities occur among admitted patients with late presentation contributing largely to demise (14). Akhuemokhan et al (8) reported a case fatality rate of 23.1% in children with LFD while Ajayi et al (10) reported 30% case fatality among LFD subjects. Of the five cases reported by Akpede et al (13), mortality occurred in 40% of them while 60% fully recovered and were discharged.
More females compared to males died from complications of Lassa fever disease. This may be attributed to more females having the disease compared to males. Mortality was also observed more in children less than 6 years of age, although no significant relationships were found between age/sex and outcome of the disease. This is similar to finding by Yinka-Ogunleye et al (20)