Estimating the burden of influenza‐associated hospitalization and deaths in Oman (2012‐2015)

Background Influenza is a serious vaccine‐preventable disease with high incidence, hospitalization, and mortality in high‐risk groups. The epidemiology, seasonality, and risk factors for influenza are well defined in most of the temperate countries, but estimating influenza burden in the World Health Organization (WHO) Region for the Eastern Mediterranean is scarce. In Oman, despite the advancements in influenza surveillance, the clinical burden and seasonality of influenza remain not fully understood. Objectives To estimate the incidence of influenza‐associated hospitalizations and in‐hospital death in Oman. Patients and methods Influenza‐associated hospitalizations and in‐hospital deaths were estimated using hospital discharge records based on ICD‐10 codes (J09‐J18), results of virological analysis and population census for the period between 2012 and 2015. Results During 2012 and 2015, we identified a total of 19 405 influenza‐associated hospitalization and 847 deaths. Influenza positivity percentage ranged from 6.4% in 2013 to 20.6% in 2015. Influenza‐associated hospitalization incidence rate was 7.3 (95% CI: 6.4‐8.1) per 100 000 in 2013 and 27.5 (95% CI: 25.9‐29.1) per 100 000 in 2015 with an overall rate of 20.6 (95% CI: 19.9‐21.3) per 100 000. The highest incidence of influenza‐associated death was among those aged ≥65 years and ranged between 39.5 (95% CI: 27.3‐51.8) per 100 000 in 2014 and 11.3 (95% CI: 7.5‐15.1) in 2015. Conclusions Influenza causes a substantial number of hospitalizations and deaths in Oman. Hospitalization rates were highest among children, and adults ≥65 years showed the highest death rate. The potential value of using seasonal influenza vaccine in these groups should be considered.


| INTRODUCTION
Influenza is believed to be an important cause of morbidity and mortality worldwide. It is a vaccine-preventable disease that annually affects 5%-10% of the population globally. 1 It causes approximately 1 million influenza-associated hospitalizations among children younger than 5 years and 500 000 deaths among all age groups. 2,3 The wide spectrum of clinical presentation and outcomes of influenza 4 and the low care seeking level with ill-defined symptoms that are often treated empirically without respiratory sampling make it difficult to estimate the true burden of influenza. 5 However, it is very important to document the clinical burden of influenza in order to reveal the pattern of severe illness, and to guide public health policies and justify the costly investment in the seasonal influenza vaccination, 6 and to assess influenza vaccine impact 7 which remains the key preventive intervention for influenza-related hospitalizations and deaths.
Influenza-associated hospitalization has been studied in many countries around the world, 8,9 but such estimate remains scarce, especially in the World Health Organization (WHO) Region for the Eastern Mediterranean.
The investment in epidemiology and laboratory capacity during recent years to face many emerging and re-emerging diseases from respiratory origin, for example, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome corona virus (MERS-CoV), and novel influenza pathogens such as H5N1 and influenza pandemics, substantially improved surveillance and data quality about acute respiratory infections. 10 Oman is a country situated in Southwest Asia, between Yemen, United Arab Emirates (UAE), and the Kingdom of Saudi Arabia. The country has an area of 309 500 square kilometers and is composed of varying topographic features: valleys and desert account for 82 percent of the land mass; mountain ranges, 15 percent; and the coastal plain, 3 percent. The weather is a hot dry interior, humid coastal strip, and a mountainous southern region with seasonal (May-September) monsoon rainfall. 11 Oman is divided into eleven governorates/ provinces with total 60 wilayats. The Sultanate of Oman has a total population of 4 588 683 with about 45.9% expatriates. 12 Oman is considered a high-income country according to the World Bank list of economies. 13 In Oman, a computerized online system named "Nabdh Al Shifa" is established and has direct access to patient records and generating data from the 11 regional hospitals. The reports are generated through software (COGNOS) in response to input of International Classifications of Disease (ICD-10 code). The ICD-10 codes/J course is related to respiratory diseases and ICD-10 codes (J09-J18) are corresponding to patients hospitalized with pneumonia or influenza which are the WHO proxies for severe acute respiratory infections (SARI). 14 The objective of this study was to estimate the incidence of influenza-associated hospitalizations and in-hospital death in Oman.

| PATIENTS AND METHODS
Hospital discharge and in-hospital death based on ICD-10 codes (J09-J18), results of virological analysis, and population census data were retrieved for the period between January 1, 2012 and December 31, 2015 to estimate influenza-associated hospitalizations and in-hospital deaths using a mathematical formula used in previous study with the same purpose. 5

| Calculating the number of SARI and inhospital death
Although, SARI surveillance was developed in Oman since 2008 in four sentinel sites using WHO case definition of SARI. This study was based on ICD-10 codes (J09-J18) which are the WHO proxies 14 for SARI to estimate the national burden of influenza.
Hospital discharge records based on ICD-10 codes (ICD-10 codes J09-J18) and in-hospital death data generated from directorate general of information technology in the ministry of health were examined.

| Calculating influenza positivity
Results of virological testing using real-time reverse transcription polymerase chain reaction (RT-PCR) for the respiratory tested samples collected from SARI patients were retrieved from the National Influenza Center (NIC) influenza surveillance line list. The age-stratified influenza positivity proportion was calculated for each month of the studied period by dividing the number of influenza positive samples by the total tested sample in the same month.
We excluded from the analysis 2.5%-5% of cases due to duplication, rejected samples, results pending, missing age group or samples requested for non-influenza.

| Calculating the population at risk based upon population census
The population at risk was considered as the total population as it is assumed that each individual was susceptible for developing SARI that requires admission in a public hospital. The number of population was provided from the National Center for Statistics and Information (NCSI) and stratified by year and age group.

| Estimating the burden
The incidence of influenza-associated hospitalization and death was estimated as the sum of products of the number of the age-stratified monthly hospital discharge and in-hospital death based on ICD-10 codes (J09-J18) by the monthly influenza positivity of respiratory samples withdrawn from the corresponding age group. This estimated monthly age-stratified number of influenza-associated hospitalizations and deaths was divided by the number of midyear population in that age group (population at risk). We calculated 95% confidence intervals (95% CI) assuming a Poisson distribution.

| Ethical issues
All data sources used in this study were anonymous records, and personal identifiers were deleted. And as analyzed data are part of the ARI surveillance, according to ethical regulations, it was exempt of IRB review.

| RESULTS
The age structure of the population remained almost the same throughout the study period, that is, those aged <1 year represented 1.7% while the ≥65 years were <4% of the total population (Table 1) During the study period (2012)(2013)(2014)(2015) in Oman, a total of 19 405 SARI cases that correspond to (ICD-10 J09-J18) were identified and 847 related deaths. Children aged 1-<5 years comprised 30% of the total hospitalizations while the greatest proportion of in-hospital deaths occurred among those aged ≥65 years (65.8%). (Table 1).

| DISCUSSION
This is the first study in Oman to estimate the clinical burden (incidence rate of morbidity and mortality per 100 000 population) of influenza on the national level.
During the study period, which lasts for 4 years, neither influenza immunization strategy nor age distribution changed.
The results show that influenza caused a substantial morbidity and mortality in Oman, and during the study period, it is estimated that it lead to 3253 influenza-associated hospitalizations and 142 deaths. Our results are more consistent with those reported from Iran where the overall incidence of influenza-associated SARI in three provinces was estimated at 29.0 per 100 000 population. 17 Findings regarding the age distribution of estimated incidence of morbidity and mortality in this study were consistent with other studies reported all over the world. For example, our results showed that very young children (<1 year) were most commonly hospitalized as a result of influenza. A meta-analysis study 2 estimated the global burden of influenza in young children reported that highest incidence of influenza episodes, influenza-associated acute lower respiratory infections, and influenza-associated severe aLRI occurred in the first year of life.  Another study estimated the incidence of influenza-associated hospitalizations using the same tool as in our study in 5 countries of Central America showed the highest distribution of influenza-associated hospitalization in children aged <5 years. 5 Death rates calculated in this study were lower than those estimated for deaths from pneumonia associated with influenza in This study has some limitations. First, SARI-ICD data in this study were obtained from the Health information and statistics department generating data from all Ministry of Health (MoH) institutions, but SARI data for non-MoH institutions are not included in our study estimate (represents about 1%).
The second limitation is that the age grouping in this study is not matched with that recommended by WHO and used in many studies as it was based on the groups available by Health information and statistics department. Thus, one of the significant age groups (0-<2 years) was distributed between 2 groups <1 year and 1-<5 years. This limits the capacity of the study to describe the epidemiological picture of SARI and seasonal influenza in this important age group and hinders the comparison of our results with other studies.
Also, the specific selection of patients only under ICD-10 codes (J09-J18) as SARI "than selecting the whole J codes (respiratory diseases)" may lead to underestimation of the burden because not all influenza cases are recorded under ICD-10 codes (J09-J18) and sometimes recorded as codes related to other respiratory diseases or exacerbation of comorbidities. Finally, the burden of influenzaassociated mortality may be underestimated as it reflects only the in-hospital deaths associated with influenza adding to that the common poor documentation of death causes in developing countries.

| CONCLUSIONS AND RECOMMENDATIONS
Despite limitations, this study is the first one providing a preliminary estimation for the clinical burden of influenza in Oman on the national level throughout the period of 4 years. Our findings suggest that the potential value of introducing seasonal influenza vaccines for children and the elderly is substantial. Further stratification of the first age group (<1 year) to 0-<6 and ≥6 months is recommended to give a practical view for vaccination strategy in this age group. Additional work is needed for better estimates of the influenza burden in risk groups other than age-based groups, for example, pregnant and associated comorbidity in order to support informed decision-making regarding the selection of high priority groups for targeting seasonal influenza vaccination.