Influenza virus infections cause substantial morbidity and mortality globally, in particular among individuals aged <5 and ≥65 years and persons with underlying medical conditions, including HIV infection.1, 2, 3, 4, 5, 6

The World Health Organization (WHO) highlighted that there is a need for influenza disease burden estimates especially from low‐ and middle‐income countries.7 Such estimates would enable governments to make informed 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 contribute to the global understanding of the burden of influenza‐associated severe illness and inform global public health priorities.

Whereas estimates of influenza‐associated mortality have been generated mainly from ecological studies,1, 5, 6, 8, 9, 10 the majority of estimates of influenza‐associated hospitalization and outpatient consultation have been obtained from laboratory‐confirmed influenza surveillance conducted at selected sentinel sites.2, 3, 4, 11 In recent years, such surveillance systems have relied on the use of polymerase chain reaction (PCR) assays for the detection of influenza viruses and the use of standard case definitions for the identification and inclusion of patients in the surveillance programs.

Although the wide use of PCR assays has increased diagnostic and surveillance capacity, establishing a clinical association between pathogen detection and illness remains challenging. A study conducted in South Africa suggested that the attributable fraction (AF) of influenza virus detection to mild and severe respiratory illness (referred to as INF‐AF hereafter) varies by age group and HIV serostatus.12 However, the effect of the INF‐AF on influenza disease burden estimates has not been fully investigated.

In addition, the WHO recommends the implementation of influenza sentinel surveillance using standard case definitions among outpatients with influenza‐like illness (ILI) and inpatients with severe acute respiratory illness (SARI).13 The WHO recommended case definitions were updated in 2012 to include, among other changes, patients with symptoms duration of ≤10 days (compared to ≤7 days as previously recommended) with the aim to increase sensitivity of influenza virus detection.13 Nonetheless, the effect of symptom duration on influenza disease burden estimates among individuals of different age groups and HIV serostatus is not fully understood.

A better understanding of the effects of the INF‐AF and the duration of symptoms as a surveillance inclusion criterion on influenza disease burden estimates could provide insights on the vaccine‐preventable fraction of illness and contextualize the use of recommended surveillance case definitions for the estimation of disease burden.

We aimed to assess the effects of the INF‐AF and the duration of symptoms on influenza disease burden estimates among HIV‐infected and HIV‐uninfected patients of different age groups presenting with ILI, SARI, and severe chronic respiratory illness (SCRI) in South Africa from January 2013 through December 2015.

We described the effects of the INF‐AF and duration of symptoms on influenza disease burden estimates among HIV‐infected and HIV‐uninfected patients of different age groups with mild or severe respiratory illness. A minimal difference was observed between unadjusted and AF‐adjusted rates or RR associated with HIV infection across syndromes, age groups, and HIV serostatus. Whereas shifting the symptom duration cutoff for inclusion in SARI surveillance from ≤7 to ≤10 days resulted in an overall 27% increase in estimated influenza‐associated hospitalization rates, 34% of patients with influenza‐associated severe respiratory illness of any duration had symptom duration >10 days. The latter would have been missed by applying the symptom duration cutoff of ≤10 days suggested by WHO. The proportion of cases that could have been missed by applying the ≤10 symptom duration cutoff was higher (44%) among individuals aged ≥5 years and lower among children aged <5 years (8%). A similar pattern was observed among HIV‐infected and HIV‐uninfected individuals. Persons aged <5 years and ≥65 years and HIV‐infected individuals experienced elevated rates of influenza‐associated respiratory illness hospitalization.

The minimal difference between unadjusted and AF‐adjusted rates observed in this study is likely a reflection of the high INF‐AF used for adjustment in this study (ILI: 92.6%; SARI‐10: 87.4%; SCRI‐10: 86.2%).12

HIV‐infected patients were at increased risk of influenza‐associated mild or severe illness compared to HIV‐uninfected patients. HIV infection has been reported to be associated with increased risk of influenza‐associated SARI hospitalization in other studies.4, 23, 24 The RR of HIV infection to illness among influenza‐positive patients with ILI or SCRI has not been described to our knowledge.

The magnitude of the INF‐AF used for adjustment in this study was highest among HIV‐uninfected persons aged <1 and ≥65 years and lowest among persons aged 25‐44 years for all syndromes, but not among HIV‐infected patients whereby the magnitude of the INF‐AF was similar across age groups for all syndromes.12 We observed the highest percent increase in the AF‐adjusted compared to unadjusted RR due to HIV infection among individuals aged 25‐44 years. This is due to the highest difference of the magnitude of the INF‐AF between HIV‐infected and HIV‐uninfected individuals in this age group.12 However, the percent increase in the AF‐adjusted compared to unadjusted RR due to HIV infection was minimal across age groups and syndromes.

In our study, only 8% of children aged <5 years presented with symptom duration >10 days compared to 44% among individuals aged ≥5 years. This may be due to differential healthcare‐seeking behavior across different age groups whereby young children are brought for medical attention at the earlier stages of illness compared to older individuals. Nonetheless, it should be noted that the SARI case definition used in this study among children aged <5 years is broader than those recommended by WHO. Among influenza‐positive children aged <5 years hospitalized with any severe respiratory illness, 68.1% met the WHO SARI case definition; 57.5% among infants aged <1 year and 79.6% among children aged 1‐4 years, respectively. This suggests that by applying the current WHO SARI case definition a high percentage of influenza‐associated severe respiratory illness would have been missed also among young children. In young children, the use of fever and cough as inclusion criteria for SARI surveillance as recommended by WHO may play more of an important role in the sensitivity of the case definition compared to symptom duration; however, this was not explicitly explored in this analysis.

In our study, individuals aged 5‐24 years experienced the highest rates of influenza‐associated ILI. This was similar to a study conducted in the United States whereby individuals aged 2‐17 years experienced the highest rates of influenza‐associated medically attended ILI,25 suggesting the importance of this age group in the transmission of influenza viruses.26 We observed a U‐shaped trend of the magnitude of the influenza‐associated SARI and SCRI hospitalization rates across age groups. Young children and older individuals are known to be at increased risk of influenza‐associated severe illness.4, 23 In our study, the highest rates of influenza‐associated SARI hospitalization were among children aged <1 year, whereas the highest rates of influenza‐associated SCRI hospitalization were among individuals aged ≥65 years. This suggests that using the recommended WHO SARI case definition may underestimate the burden of influenza‐associated severe illness particularly in older individuals in our setting.

Our study has limitations that warrant discussion. First, we did not enroll ILI cases with symptoms duration >10 days hindering our ability to estimate the burden of influenza‐associated medically attended ILI in this group of patients. Second, whereas we enrolled patients with respiratory illness of any duration, patients not meeting the clinical inclusion criteria may have been missed, especially in adults. In addition, we evaluated only the effects of duration of symptoms on disease burden estimates, whereas effects based on other clinical inclusion criteria (such as the presence of fever or cough) were not investigated. Third, whereas PRC is considered a sensitive diagnostic test, the sensitivity of the assay may be lower in individuals presenting at healthcare facilities several days post‐infection. This may underestimate the burden of influenza‐associated illness in this group of patients. Last, ecological studies have suggested that influenza viruses are also responsible for hospitalizations and deaths among patients presenting with circulatory illnesses or even syndromes other than respiratory and circulatory.5, 6, 8, 9, 27 In addition, individuals that may have developed influenza‐associated severe illness, but did not seek care would have been missed in our study. Hence, our estimates should be considered minimum estimates focusing only on influenza‐associated medically attended respiratory illness.

In conclusion, the AF‐adjusted rates and RR due to HIV infection reported in this study reflect a more accurate description of the burden of influenza‐associated mild and severe respiratory illness among HIV‐infected and HIV‐uninfected South African patients. Nonetheless, the marginal differences between unadjusted and AF‐adjusted rates and RR due to HIV infection are unlikely to affect policies or prioritization of interventions. On the contrary, the use of the duration of symptoms included in the WHO SARI case definition may importantly underestimate influenza‐associated severe disease burden in both children and adults in our settings. The use of such surveillance case definition for disease burden estimation should be evaluated in different settings, especially in low‐ and middle‐income countries where cultural differences and limited access to care may affect the time of presentation at healthcare facilities among patients seeking medical attention.

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 National Institute for Communicable Diseases, South Africa.

All authors declare that they have no commercial or other associations that may pose a conflict of interest.

This work was supported by the National Institute for Communicable Diseases, of the National Health Laboratory Service and the US Centers for Disease Control and Prevention (co‐operative agreement number: 5U51IP000155).

The SCRI and SARI protocols were approved by the University of the Witwatersrand Human Research Ethics Committee (HREC) and the University of KwaZulu‐Natal Human Biomedical Research Ethics Committee (BREC) protocol numbers M081042 and BF157/08, respectively. The ILI and controls protocol were approved by BREC protocol number (BREC BF 080/12). This surveillance was deemed non‐research by the US Centers for Disease Control and Prevention (non‐research determination number: 2012‐6197).

All authors had full access to the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Tempia S and Cohen C. involved in study concept and design. Tempia S, Walaza S, Moyes J, Cohen AL, von Mollendorf C, Treurnicht F, Venter M, Pretorius M, Hellferscee O, Nguweneza A, Wolter N, von Gottberg A, Dawood H, Variava E, and Cohen C. involved in acquisition, analysis or interpretation of data. Tempia S. involved in drafting of the manuscript. Tempia S, Walaza S, Moyes J, Cohen AL, von Mollendorf C, McMorrow ML, Mhlanga S, Teurnicht FK, Venter M, Pretorius M, Hellferscee O, Nguweneza A, McAnerney JM, Wolter N, von Gottberg A, Dawood H, Variava E, Madhi SA and Cohen C involved in critical revision of the manuscript for important intellectual content.