The national and provincial burden of medically attended influenza‐associated influenza‐like illness and severe acute respiratory illness in the Democratic Republic of Congo, 2013‐2015

Background Estimates of influenza‐associated outpatient consultations and hospitalizations are severely limited in low‐ and middle‐income countries, especially in Africa. Methods We conducted active prospective surveillance for influenza‐like illness (ILI) and severe acute respiratory illness (SARI) at 5 healthcare facilities situated in Kinshasa Province during 2013‐2015. We tested upper respiratory tract samples for influenza viruses using a reverse transcription‐polymerase chain reaction assay. We estimated age‐specific numbers and rates of influenza‐associated ILI outpatient consultations and SARI hospitalizations for Kinshasa Province using a combination of administrative and influenza surveillance data. These estimates were extrapolated to each of the remaining 10 provinces accounting for provincial differences in prevalence of risk factors for pneumonia and healthcare‐seeking behavior. Rates were reported per 100 000 population. Results During 2013‐2015, the mean annual national number of influenza‐associated ILI outpatient consultations was 1 003 212 (95% Confidence Incidence [CI]: 719 335‐1 338 050 ‐ Rate: 1205.3; 95% CI: 864.2‐1607.5); 199 839 (95% CI: 153 563‐254 759 ‐ Rate: 1464.0; 95% CI: 1125.0‐1866.3) among children aged <5 years and 803 374 (95% CI: 567 772‐1 083 291 ‐ Rate: 1154.5; 95% CI: 813.1‐1556.8) among individuals aged ≥5 years. The mean annual national number of influenza‐associated SARI hospitalizations was 40 361 (95% CI: 24 014‐60 514 ‐ Rate: 48.5; 95% CI: 28.9‐72.7); 25 452 (95% CI: 19 146‐32 944 ‐ Rate: 186.5; 95% CI: 140.3‐241.3) among children aged <5 years and 14 909 (95% CI: 4868‐27 570 ‐ Rate: 21.4; 95% CI: 28.9‐72.7) among individuals aged ≥5 years. Conclusions The burden of influenza‐associated ILI outpatient consultations and SARI hospitalizations was substantial and was highest among hospitalized children aged <5 years.


| INTRODUC TI ON
Influenza virus infections cause substantial morbidity and mortality globally, in particular among young children and older adults. [1][2][3] In addition, global studies highlighted a higher burden of influenzaassociated mortality in Africa compared with other Regions. 1 An elevated burden of influenza-associated hospitalization among African children has also been reported. 2,3 However, the majority of influenza disease burden estimates available for global studies are from industrialized countries.
The World Health Organization (WHO) highlighted that there is a need for influenza disease burden estimates especially from low-and middle-income countries. 4 Such estimates would enable governments to make informed and evidence-based decisions when allocating scarce resources and planning intervention strategies to limit the impact and spread of the disease. In addition, national estimates would assist to refine the global understanding of the burden of influenza-associated illness and inform global public health priorities.
In recent years, influenza sentinel surveillance has been established in several African countries 5 and influenza virus infection has been found to be associated with mild and severe illness including death. 5,6 Nonetheless, national estimates of influenzaassociated hospitalization [7][8][9][10][11][12] and outpatient consultations 7,10,13 across age groups remain limited in Africa. In the Democratic Republic of Congo (DRC), there are currently no recommendations for influenza immunization or treatment.
In this study, we aimed to estimate the national and provincial number and rates of medically attended influenza-associated influenza-like illness (ILI) outpatient consultation, and severe acute respiratory illness (SARI) hospitalization among persons of different age groups, DRC from January 2013 through December 2015.

| Data source 1: Number of respiratory hospitalizations and outpatient consultations in Kinshasa Province
We obtained the number of respiratory outpatient consultations and

| Data source 2: Retrospective record review of respiratory admissions and outpatient consultations in selected healthcare facilities
To assess the completeness of the administrative data reported to the MoH-DRC (data source 1), we implemented an anonymized retrospective record review (using healthcare facilities consultation or admission books) of any respiratory outpatient consultation or admission in 5% of randomly selected healthcare facilities situated in Kinshasa Province from January 2013 through December 2015. We implemented a presurvey to compile a list of the most common respiratory outpatient consultations or admission diagnoses recorded by the attending clinicians in consultation or admission books.
Respiratory outpatient consultations were considered any upper respiratory tract infections such as rhinitis, pharyngitis, or laryngitis; whereas respiratory admissions were considered any lower respiratory tract infections such as bronchitis, bronchiolitis, or pneumonia.

| Data source 3: Influenza virus surveillance among patients with ILI or SARI
We conducted active, prospective surveillance among outpatients with ILI at 2 clinics (Boyambi and RVA) and at the outpatient de- A case of ILI was defined as an outpatient of any age presenting with a recorded temperature ≥38°C and cough or sore throat of duration of ≤7 days. A case of SARI was defined as a hospitalized person who had illness onset within 7 days of admission and who met age-specific clinical inclusion criteria. A SARI case in children aged 2 days to <5 years included any hospitalized patient with cough or difficulty breathing and at least one of the following danger signs: unable to drink or breastfeed, lethargic, vomits everything, convulsion, chest in drawing, or stridor in a calm child.
A SARI case in persons aged ≥5 years included any hospitalized patient with fever (≥38°C), cough, and shortness of breath or difficulty breathing.
The procedures of this surveillance program have been previously described. 14 Briefly, trained surveillance staff (doctors, nurses, or laboratory technicians) completed case report forms that included demographic, clinical, and epidemiological information for all enrolled ILI and SARI cases. All respiratory admission or outpatient consultations and those meeting the ILI and SARI case definition were also recorded. In addition, respiratory specimens (nasopharyngeal and oropharyngeal swabs) were collected from all enrolled patients, placed in the same vial containing universal transport medium, stored at 4-8°C, and transported to the national influenza laboratory (the Institut National de Recherche Biomédicale, Kinshasa, DRC) within 72 hours of collection for testing. Specimens were tested for influenza A and B viruses using a real-time reverse transcription-polymerase chain reaction assay. 14 Influenza Apositive samples were further subtyped. 15 Verbal informed consent was obtained from all patients prior to data and specimen collection.
For children aged <15 years, verbal consent was obtained from a parent or legal guardian.

| Data source 4: Prevalence of risk factors for pneumonia and healthcare-seeking behavior for acute respiratory infection
We obtained the provincial-level prevalence of known risk factors for pneumonia and the provincial data on healthcare-seeking be-

| Estimation of the national number and rate of SARI and influenza-associated SARI hospitalizations
To estimate the national number and rates of SARI and influenzaassociated SARI hospitalization, we used a four-step approach.
In Step 1, we estimated the SARI hospitalization rate in Kinshasa Province (considered to be the base province in our estimation approach). In Step 2, we estimated the SARI hospitalization rates for the other provinces from the base province using a previously described methodology. 8,11,12,18,19 In Step 3, we estimated the influenza-associated SARI hospitalization rate using available virological surveillance data for influenza. In Step 4, we obtained the number of SARI and influenza-associated SARI hospitalizations using the estimated rates and the population at risk in each province.
The description of the estimation approach for each step is provided below and in Figure 1. All estimates were obtained overall and within the following age categories: <1, 1-4, 5-24, 25-44, 45-64, ≥65, <5, and ≥5 years of age. Rates were reported per 100 000 population. We reported mean annual estimates over the study period.

| Step 1: Estimation of the SARI hospitalization rate in Kinshasa Province
To estimate the SARI hospitalization rate in Kinshasa Province, we followed WHO guidelines for estimating the disease burden associated with seasonal influenza. 4

| Step 2: Estimation of SARI hospitalization rates in other provinces
Estimates of SARI hospitalization rates for the other 10 provinces in DRC were derived by adjusting the Kinshasa Province rate (base provinceobtained in Sep 1) for the provincial-level prevalence of known risk factors for pneumonia obtained from the DHS (data source 4) as previously described (Step 2.a). 8,11,12,18,19 Risk factors included HIV infection, exposure to indoor air pollution, and crowding for all ages, and, in addition, for children aged <5 years malnutrition, low birthweight and nonexclusive breastfeeding. 8,11,12,18,19 The relative risk of SARI associated with each risk factor was determined from the published literature. 8,11,12,[18][19][20][21][22] In addition, we adjusted the provincial rates by the proportion of ARI cases seeking care in the given province to the proportion of ARI cases seeking care in the base province using data from the DHS (data source 4) as previously described (Step 2.b). 8,11,12,18,19 We used the healthcareseeking behavior among ARI cases as a proxy for SARI cases. An adjustment factor >1 resulted in a greater SARI hospitalization rate in the given province relative to the base province and vice versa. The equations used for the provincial adjustments and the estimated adjustment factors (Table S1) are provided in the Supplementary Material.

| Step 3: Estimation of influenza-associated SARI hospitalization rates in all provinces
We estimated the provincial rates of influenza-associated SARI hospitalization by multiplying the estimated provincial SARI hospitalization rates (obtained in Step 1 and 2) by the influenza virus detection rate obtained from influenza sentinel surveillance implemented among inpatients with SARI (data source 3). 8,11,12,18,19 F I G U R E 2 Method used to estimate the numbers and rates of influenza-like illness (ILI) and influenza-associated ILI outpatient consultations in the Democratic Republic of Congo, 2013-2015. Data inputs steps are in light gray boxes, and data outputs are in dark gray boxes

| Step 4: Estimation of the number of SARI and influenza-associated SARI hospitalizations in all provinces
We estimated the provincial number of SARI and influenzaassociated SARI hospitalizations by multiplying the provincial SARI (obtained in Steps 1 and 2) and influenza-associated SARI (obtained in Step 3) hospitalization rates by the population at risk in each province over the study period. 8,11,12,18,19

| Estimation of the national number and rate of ILI and influenza-associated ILI outpatient consultations
To estimate the national number and rates of ILI and influenzaassociated ILI outpatient consultation, we used the same approach as for SARI with the exception that for the provincial adjustment, we used only the healthcare-seeking behavior for ARI in the given province to the base province and we used the influenza virus detection rate obtained from influenza sentinel surveillance implemented among outpatients with ILI (data source 3) (Figure 2).

| Calculation of confidence intervals
We obtained the 95% confidence intervals (CI) using bootstrap resampling over 1000 replications for all parameters included in the calculations. 8,11,12,18,19 This included (a) the age-, year-, and healthcare facility-specific proportion of underreporting (data source 1 and 2), (b) the age-, year-, and healthcare facility-specific proportion of ILI/SARI cases over total respiratory consultations/admissions (data source 3), (c) the provincial prevalence of the risk factors for pneumonia (data source 4), (d) the provincial proportion of ARI cases seeking care (data source 4), and (e) the age-and year-specific influenza virus percentage positive among ILI/SARI cases tested (data source 3). The lower and upper limits of the 95% CI were the 2.5th and 97.5th percentiles of the estimated values obtained from the 1000 resampled datasets, respectively. 8,11,12,18,19 The statistical analysis was implemented using Stata 14.2 (StataCorp, College Station, Texas, USA).

| Ethical approval
The influenza sentinel surveillance (data source 3) and the collection of aggregated data on any respiratory consultations/admissions (data source 2) were deemed nonresearch by the MoH-DRC and the US Centers for Disease Control and Prevention. The number of respiratory consultations/admissions in Kinshasa Province reported to the MoH-DRC (data source 1), the DHS (data source 4) and the census data (data source 5) were publicly available.

| National number and rate of ILI and influenzaassociated ILI outpatient consultations
The estimated mean annual number of ILI outpatient consultations An inverted U-shaped trend of the magnitude of the ILI and influenza-associated ILI outpatient consultation rates was observed across age groups (Table 1 and Figure 4 panel A). No substantial differences (with overlapping CIs) of the ILI and influenza-associated ILI outpatient consultations rates were observed across provinces ( Table 1).
The provincial number and rates of ILI and influenza-associated ILI outpatient consultations by age group are provided in Table S2.
TA B L E 1 Estimated mean annual numbers and rates of influenza-like illness and influenza-associated influenza-like illness outpatient consultations,  A U-shaped trend of the magnitude of the SARI and influenzaassociated SARI hospitalization rates was observed across age groups ( Table 2 and Figure 4 panel B). No substantial differences (with overlapping CIs) of the SARI and influenza-associated SARI hospitalizations rates were observed across provinces ( Table 2). The provincial number and rates of SARI and influenza-associated SARI hospitalizations by age group are provided in Table S3.

| D ISCUSS I ON
We reported national and provincial estimates of medically attended influenza-associated ILI and SARI in DRC over a 3-year period. Influenza virus infections were associated with mild (ILI) and severe (SARI) respiratory illness across age groups. However, the In our study, the estimated rate of influenza-associated SARI hospitalization among individuals aged ≥5 years (21 per 100 000 population) was almost 9 times lower than that estimated among children aged <5 years. Lower rates (per 100 000 population) of influenza-associated SARI hospitalization among individuals aged ≥5 compared to <5 years were observed also in other studies conducted in Africa: 7 in Kenya, 8 12 in Madagascar, 12 11 in Rwanda,9 31 in South Africa, 10 and 13 in Zambia. 11 In our study, we did not observe substantial differences (with overlapping CIs) in the provincial rates of medically attended influenza-associated ILI or SARI. For SARI, this was observed also in studies conducted in Madagascar, 12 Rwanda, 9 South Africa, 19 and TA B L E 2 Estimated mean annual numbers and rates of severe acute respiratory illness and influenza-associated severe acute respiratory illness hospitalizations, Zambia. 11 This may suggest that geographical variations within countries may not significantly affect influenza disease burden estimates.
Our study has limitations that warrant discussion. First, whereas we estimated national numbers and rates of medically attended influenza-associated ILI or SARI using a previously described methodology, 8,11,12,18,19  been reported in other studies conducted in Africa 8,13,18,19 ; hence, our estimates should be considered minimum estimates. Cultural differences and differential access to healthcare across different countries can also play a role in differential healthcare-seeking behavior that in return may be responsible for differences in outpatient consultation and hospitalization rates.
In conclusion, we estimated a large number of influenzaassociated ILI outpatient consultations and SARI hospitalizations in DRC. The hospitalization rates were highest in children aged <5 years and individuals aged ≥65 years. These estimates provide the foundation for future cost-effectiveness studies to potentially guide influenza immunization policies. Should an influenza vaccination program be introduced in DRC, young children and the elderly may benefit most from annual influenza immunization. No influenza vaccine is licensed for children aged <6 months, but this group may be protected through the vaccination of their mothers during pregnancy. 29,30 Nonetheless, given the limited financial resources in our setting, estimation of the disease burden associated with other pathogens should also be considered to inform prioritization of interventions.

ACK N OWLED G EM ENTS
We thank all members involved in ILI and SARI surveillance and the DRC Ministry of Health for data collection and sharing.

CO N FLI C T O F I NTE R E S T
All authors declare that they have no commercial or other associations that may pose a conflict of interest.

D I SCL A I M ER
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention, USA, or the DRC Ministry of Health.

E TH I C S
The influenza sentinel surveillance and the collection of aggregated data on any medical, respiratory, and SARI hospitalizations were