Epidemiology and outcome of influenza‐associated infections among hospitalized patients with acute respiratory infections, Egypt national surveillance system, 2016‐2019

Abstract Introduction Egypt has established different types of surveillance systems to monitor influenza activities, early detect outbreaks, and tailor efficient prevention and control strategies. This is the first study to describe epidemiology and outcome of influenza‐associated infections among hospitalized patients using the National Electronic Disease Surveillance System (NEDSS) data, 2016‐2019. Methods Data reported from 284 hospitals all over Egypt were extracted from the NEDSS. Data of hospitalized patients with Acute Respiratory Infections (ARI), 2016‐2019, were included in the analysis. Laboratory testing for influenza by RT‐PCR according to US CDC testing protocol was used to confirm influenza type and subtype. Results Overall 46 417 patients hospitalized with ARI were identified, their mean age was 30.9 ± 26 and 52.9% were males. Among 41 512 (89.4%) laboratory‐tested patients, 7167 (17.3%) were positive for one or more types of influenza viruses. Influenza viruses circulated in all ages and throughout the year, with higher rates in winter, late childhood, and middle ages. Mortality from influenza was significantly higher than other causes of ARIs (5.0% vs 3.8%, P < .001), and it was associated with older ages, December‐May, delay in hospital admission, residence in urban and frontier governorates and infection with A/H1N1 virus. The distribution of influenza subtype by time shows alternate pattern between A/H1N1 and H3N2, each subtype peaks every other year with a high peak of A/H1N1 in 2016. Conclusions The national Egyptian surveillance succeeded to describe the epidemiology of hospitalized patients with ARIs and influenza in Egypt over time. Surveillance with strain‐specific laboratory testing and annual assessment of associated severity might be useful to guide influenza prevention and control strategies including vaccination and case management.


| INTRODUC TI ON
Influenza-associated infections are a major contributor to morbidity and mortality worldwide. The World Health Organization (WHO) has indicated that about 3-5 million cases and 290 000-650 000 deaths occur annually from seasonal influenza epidemics. 1 Influenza remains a global public health priority because of the threat of a new global pandemic.
Data on influenza epidemiology and burden are available from developed countries, yet little is known about the disease in lowincome and tropical countries. In response to this gap, WHO led an initiative to establish virological surveillance systems as part of national pandemic preparedness efforts. 2 Although those systems have produced substantial data on the epidemiology and impact of influenza, yet lack of quality data on disease severity and outcomes, and high-risk groups remains a problem. 3 In In response to the 2009 A/H1N1 pandemic influenza, a memorandum was issued by MoHP requiring all governmental hospitals to report any patient with Acute Respiratory Infection (ARI) attending outpatient clinic or admitted to governmental hospital through NEDSS within 48 hours. In addition, all other types of hospitals including teaching, health insurance, university, and private hospitals were invited to voluntarily report aggregate data on ARI on a weekly basis to MoHP. This report presents the results of the national laboratory-based surveillance for hospitalized patients with ARI in 284 hospitals all over Egypt, 2016-2019. The study aims at describing the epidemiology and exploring severity and mortality of influenza-associated infections among hospitalized ARI patients to identify target groups for influenza prevention and control strategies.

| Study subjects, patients' enrollment, and data collection
Subjects are all patients hospitalized with history or measured fever of ≥38°C and cough within the last 10 days prior to disease onset and all those who are clinically or radiologically diagnosed having pneumonia, 2016-2019. The WHO case definition for Severe Acute Respiratory Infections (SARI) and/ or physician clinical judgment was used for patient enrollment. Enrolled patients were interviewed using the surveillance standard form.
All patients are requested to provide oropharyngeal and nasopharyngeal swabs for influenza testing by RT-PCR to identify the influenza type and subtype using the CDC protocol. 4 Specimens are placed in Viral Transport Media (VTM) and kept in an icebox, before being transferred within 24 hours to the nearest regional laboratory or Central Public Health Laboratory (CPHL) in Cairo for testing. Patients are interviewed by the hospital surveillance officer using a standardized questionnaire that includes patient demographic data, signs and symptoms and ARI risk factors. Data are entered using the online NEDSS application.

| Data extraction, validation, and analysis
National data for patients hospitalized with ARI were extracted from the NEDSS database from 2016-2019. All patients hospitalized with ARIs during this period were included in the study, while patients attended outpatient clinic were excluded. Data were completed and validated by surveillance officers at each reporting site using facility records. Descriptive data analysis was performed for available data including demographics, influenza type and subtype, history of comorbidities, and patient outcome using SPSS ver. 25. Influenza-associated infection (FAI) rate was calculated as the proportion of specimens positive for influenza out of the total specimens tested. Seasonality was described by calculating rate of influenza positivity by month, with the highest positivity rate considered as peak.
Difference between influenza-positive and influenza-negative hospitalized patients was examined using bivariate analysis. Influenza mortality risk factors were evaluated by comparing patients with influenza-associated infections who died at hospital to those discharged alive. Risk factors included (age, gender, days from symptom onset to hospitalization, chronic conditions, year, season, region, and influenza subtype). Pearson's chi-square was used to evaluate the difference between categorical variables and t test for continuous variables, with statistical significance set at P value <.05. Linear regression was performed to examine the relation between influenza A/H1N1 and influenza mortality by region and year's season.

| Comparison between influenza types/subtypes
The distribution of influenza subtype by time shows alternate pattern between A/H1N1 and H3N2, each subtype peaks every other year with a high peak of A/H1N1 in 2016. There was an unusual peak of Flu-B in 2017 which caused next influenza season to start late in November (Figure 2).

| Influenza mortality
The case fatality rate was highest in old age-groups 50-64 and ≥65 years (7.8 and 11.3%, respectively), while it was lowest in late Mortality was associated with diagnosis of pneumonia (Table 3) Most of the patients (77.3%) with confirmed influenza who died during hospitalization had history of one or more chronic disease including 23.1% diabetics, 9.6% had chronic obstructive pulmonary disease, 5.8% cardiovascular disease, 4.6% chronic hepatic disease, and 6.5% others (renal, neurologic, malignancy, or autoimmune disease).
A positive correlation was found between percent of A/H1N1 subtype and CFR from influenza among hospitalized patients by Egyptian regions and season of the year (R 2 =0.75 and 0.90, respectively). The variation of CFR from influenza among hospitalized patients by Egyptian regions and season of the year is linked to percent of A/H1N1 infections in those groups. (Figures 3 and 4). The high mortality rate among FAIs identified in this study among older age-groups is also reported by many studies which indicated that risk of fatality from influenza increases with age. [16][17][18] Similar to previous studies that reported high mortality due to influenza among hospitalized patients and higher CFRs for A/H1N1, 8 this study reported high influenza mortality rate and indicated that >¾ of all deaths from influenza was due to A/H1N1. This highlights the value of laboratory influenza testing by type and subtype especially for severe cases and the continuous revision of influenza management guidelines based on surveillance results.

| D ISCUSS I ON
The high CFR and the positive correlation between percent of A/H1N1 and fatal outcome by region and season reported in this study was in line with many other studies that reported high pathogenicity and mortality rates from A/H1N1. 19,20 The cause of death from A/H1N1 is usually the higher possibility of severe This study proved that pneumonia as a complication was significantly higher in patients who died from influenza than those who discharged alive a finding reported from other studies. 6,19 This could be related to the high possibility of lung affection in A/H1N1 and should be considered in diagnosis and treatment of hospitalized patients with acute respiratory infection. Influenza severity and mortality are aggravated in winter, old age and with underlying medical conditions. Surveillance with strain-specific laboratory testing can be useful, and annual assessment of associated severity might be important to guide influenza prevention and control strategies including vaccination and treatment. Elderly and persons with comorbidities should be specifically targeted for vaccination and early antiviral treatment to reduce the risk of influenza-related complications. Further studies are needed to accurately describe the burden of epidemic-prone acute ARI and influenza in Egypt to help developing evidence-based disease prevention and control strategies.

CO N FLI C T O F I NTE R E S T S
None declared.

E TH I C A L A PPROVA L
This study used the national acute respiratory surveillance data which is a public health activity organized by the Ministry of Health and Population in Egypt and has standing authorization from the National Ethical Committee. All personal identifiers were excluded.

PE E R R E V I E W
The peer review history for this article is available at https://publo ns.com/publo n/10.1111/irv.12867.

DATA AVA I L A B I L I T Y S TAT E M E N T
The data that support the findings of this study are available from Egypt Ministry of Health and Population but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are however available from the Ministry of Health and Population upon reasonable request.