DISCUSSION
We estimated the AF of nine respiratory viruses among patients with ILI and SRI as well as the mean annual number and rates of these syndromes and that associated with respiratory viruses after adjusting for the estimated AF in South Africa during 2013-2015. The burden of ILI and SRI was substantial with approximately half of the population experiencing one episode of ILI (rate: 51,383 per 100,000 population) and approximately 4% of the population experiencing one episode of SRI (rate: 4,196 per 100,000 population) annually. Twenty six percent of ILI and 46% of SRI episodes were medically attended, indicating a heavy burden of these syndromes on the healthcare system.
Estimates of the burden of ILI in Africa are scarce. Our estimated rates of medically attended ILI (13,381 per 100,000 population) are similar to those reported in a study conducted in the Democratic Republic of Congo (DRC) (11,890 per 100,000 population) [11Babakazo P, Lubula L, Disasuani W, et al. 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. Influenza Other Respir Viruses. 2018 ;12(6):695-705. doi: 10.1111/irv.12601.]. Our estimated rates of medically attended SRI (1,945 per 100,000 population) are higher than those estimated in other countries for severe acute respiratory illness (SARI): DRC (795 per 100,000 population) [19], Kenya (350 per 100,000 population) [22Dawa JA, Chaves SS, Nyawanda B, et al. National burden of hospitalized and non-hospitalized influenza-associated severe acute respiratory illness in Kenya, 2012-2014. Influenza Other Respir Viruses. 2018 ;12(1):30-37. doi: 10.1111/irv.12488.], Rwanda (571 per 100,000 population) [33Nyamusore J, Rukelibuga J, Mutagoma M, et al. The national burden of influenza-associated severe acute respiratory illness hospitalization in Rwanda, 2012-2014. Influenza Other Respir Viruses.2018 ;12(1):38-45. doi: 10.1111/irv.12494.], Uganda (267-647 per 100,000 population) [44Emukule GO, Namagambo B, Owor N, et al. Influenza-associated pneumonia hospitalizations in Uganda, 2013-2016. PLoS One.2019 ;14(7):e0219012. doi: 10.1371/journal.pone.0219012.] and Zambia (843 per 100,000 population) [55Theo A, Tempia S, Cohen AL, et al. The national burden of influenza-associated severe acute respiratory illness hospitalization in Zambia, 2011-2014. Influenza Other Respir Viruses. 2018 ;12(1):46-53. doi: 10.1111/irv.12492.]. It should be noted that the SARI case definition used in these studies included patients with a symptom duration of 7 (mostly) or 10 days, whereas our SRI case definition included patients with symptoms of any duration, which would include more patients. In a study conducted in South Africa, the rates of influenza-associated SRI (67 per 100,000 population) were 2.6 times higher than those of influenza associated SARI with symptoms duration of 7 days [66Tempia S, Walaza S, Moyes J, et al. The effects of the attributable fraction and the duration of symptoms on burden estimates of influenza-associated respiratory illnesses in a high HIV prevalence setting, South Africa, 2013-2015. Influenza Other Respir Viruses. 2018 ;12(3):360-373. doi: 10.1111/irv.12529.]. Besides the difference in case definitions, difference in rates in different settings can also be attributed to differences in access to healthcare, healthcare seeking behavior and the prevalence of risk factors for pneumonia in the general population such as HIV and other underlying medical conditions.
In our study, among patients with ILI, the most commonly detected virus was rhinovirus, followed by influenza and adenovirus. These viruses were detected at high frequencies also in other studies conducted in Africa among outpatients with respiratory illness [77Uchi Nyiro J, Munywoki P, Kamau E, et al. Surveillance of respiratory viruses in the outpatient setting in rural coastal Kenya: baseline epidemiological observations. Wellcome Open Res. 2018 ;3:89. doi: 10.12688/wellcomeopenres.14662.1.,88Kadjo HA, Ekaza E, Coulibaly D, et al. Sentinel surveillance for influenza and other respiratory viruses in Côte d’Ivoire, 2003-2010. Influenza Other Respir Viruses.2013 ;7(3):296-303. doi: 10.1111/j.1750-2659.2012.00389.x.,99Dia N, Diene Sarr F, Thiam D, et al. Influenza-like illnesses in Senegal: not only focus on influenza viruses. PLoS One. 2014 ;9(3):e93227. doi: 10.1371/journal.pone.0093227.,1010Razanajatovo NH, Richard V, Hoffmann J, PLoS One. Viral etiology of influenza-like illnesses in Antananarivo, Madagascar, July 2008 to June 2009.2011 ;6(3):e17579. doi: 10.1371/journal.pone.0017579.,1111Njouom R, Yekwa EL, Cappy P, et al. Viral etiology of influenza-like illnesses in Cameroon, January-December 2009. J Infect Dis. 2012 ;206 Suppl 1(Suppl 1):S29-35. doi: 10.1093/infdis/jis573.]. Rhinovirus, RSV and adenovirus were the most commonly detected viruses among patients with SRI in our study, and, although variability was observed in different settings, these viruses were frequently detected among hospitalized patients with SARI/ARI in other studies from African countries [1212Feikin DR, Njenga KM, Bigogo, et al. Viral and bacterial causes of severe acute respiratory illness among children aged less than 5 years in a high malaria prevalence area of western Kenya, 2007-2010. Pediatr Infect Dis J.2013 ;32(1):e14-9. doi: 10.1097/INF.0b013e31826fd39b.  ,1313Kenmoe S, Tchendjou P, Vernet MA, et al. Viral etiology of severe acute respiratory infections in hospitalized children in Cameroon, 2011-2013. Influenza Other Respir Viruses. 2016 ;10(5):386-93. doi: 10.1111/irv.12391.,1414Razanajatovo NH, Guillebaud J, Harimanana A, et al. Epidemiology of severe acute respiratory infections from hospital-based surveillance in Madagascar, November 2010 to July 2013. PLoS One. 2018 ;13(11):e0205124. doi: 10.1371/journal.pone.0205124.  ,1515Lagare A, Maïnassara HB, Issaka B, et al. Viral and bacterial etiology of severe acute respiratory illness among children < 5 years of age without influenza in Niger. BMC Infect Dis. 2015 ;15:515. doi: 10.1186/s12879-015-1251-y.].
Among patient with ILI the AF of influenza, RSV, HMPV and PIV types 1-3 were generally high (range: 68.7%-91.9%); whereas those of adenovirus and enterovirus were generally low (range: 16.4%-46.9%). A similar pattern was observed among patients with SRI and this has been reported in other studies [16,17,1616Pretorius MA, Tempia S, Walaza S, et al. J Clin Virol. The role of influenza, RSV and other common respiratory viruses in severe acute respiratory infections and influenza-like illness in a population with a high HIV sero-prevalence, South Africa 2012-2015. J Clin Virol.2016 ;75:21-6. doi: 10.1016/j.jcv.2015.12.004.].
Rhinovirus was the most detected virus among patients with ILI and SRI but its attributable fraction was moderate (<55% for both syndromes among individuals of any age). The AF of rhinovirus found in this study was similar to those reported in other studies (range: 39.8%-59.2%) [16,34]. Despite its moderate AF, the AF-adjusted prevalence of rhinovirus remained the highest (compared with those of other viruses) among patients of any age with ILI or SRI, due to the high level of detection. This was reported also in another study conducted in South Africa [34]. Rhinovirus has been well described as one of the most common causes of common cold [1717Peltola V, Waris M, Osterback R, et al. Clinical effects of rhinovirus infections. J Clin Virol. 2008 ;43(4):411-4. doi: 10.1016/j.jcv.2008.08.014.]; however, its role as causal agent of more severe respiratory illness is less well described. In our study, only RSV had an AF-adjusted prevalence higher than that of rhinovirus among children aged <5 years with SRI. In the PERCH study, RSV had the highest AF and associated etiological fraction among HIV-uninfected children aged <5 years with severe pneumonia [2]. In the same study rhinovirus had varying detection frequency and etiological fraction in the different participating countries [2]. Nonetheless, in the pooled analysis rhinovirus had a moderate, but significant AF and the second highest etiological fraction (after RSV) among the investigated viruses; which is similar to the findings of our study. Studies on the etiological fraction of rhinovirus among patients aged >5 years with SRI are scarce. In our study, the AF-adjusted prevalence of rhinovirus among patients aged >5 years with SRI was the highest and it was similar to that observed in other South African studies [16,34]. Studies in this group of patients in other settings are warranted.
Among patients with ILI, the rates associated with the different viruses evaluated in this study was highest among children aged <1 and 1-4 years, with the exception of influenza and adenovirus, where the highest rates were among individuals aged 5-24 years and PIV type 2 where the highest rates were among individuals aged ≥65 years. Young children have been described to be particularly susceptible to viral respiratory infections [1818Cohen C, Walaza S, Moyes J, et al. Epidemiology of viral-associated acute lower respiratory tract infection among children <5 years of age in a high HIV prevalence setting, South Africa, 2009-2012. Pediatr Infect Dis J.2015 ;34(1):66-72. doi: 10.1097/INF.0000000000000478.] and a prominent role of school-aged children and young adults in the transmission of influenza virus has been described in other studies [1919Cohen C, Kleynhans J, Moyes J, et al. Asymptomatic transmission and high community burden of seasonal influenza in an urban and a rural community in South Africa, 2017-18 (PHIRST): a population cohort study. Lancet Glob Health.2021 ;9(6):e863-e874. doi: 10.1016/S2214-109X(21)00141-8.]. Among patients with SRI the rates associated with the different viruses evaluated in this study was also the highest among young children, with the exception of PIV type 2 where the highest rates were among individuals aged ≥65 years. When compared with other viruses, RSV had the highest rates among children aged <5 years; whereas influenza had the highest rates among individuals aged ≥65 years. A heavy burden of these 2 pathogens in these age groups has been described in other studies [18,2020Moyes J, Cohen C, Pretorius M, et al. Epidemiology of respiratory syncytial virus-associated acute lower respiratory tract infection hospitalizations among HIV-infected and HIV-uninfected South African children, 2010-2011. J Infect Dis. 2013 ;208 Suppl 3:S217-26. doi: 10.1093/infdis/jit479.].
This study has limitations that warrant discussion. First, the WHO ILI case definition used in this study does not capture the entire clinical spectrum of mild respiratory illness. This has been well described for influenza where only 30%-50% of patients with mild influenza illness present with fever and cough [37,2121Furuya-Kanamori L, Cox M, Milinovich GJ, et al. Heterogeneous and Dynamic Prevalence of Asymptomatic Influenza Virus Infections. Emerg Infect Dis. 2016 ;22(6):1052-6. doi: 10.3201/eid2206.151080.,2222Ip DKM, Lau LLH, Leung NHL, et al. Viral Shedding and Transmission Potential of Asymptomatic and Paucisymptomatic Influenza Virus Infections in the Community. Clin Infect Dis. 2017 ;64(6):736-742. doi: 10.1093/cid/ciw841.]. This proportion is poorly understood for other respiratory viruses, but an underestimate of the burden of mild illness associated with the different respiratory viruses is likely to occur when restricting the identification of cases among patients with ILI. The SRI case definition used in this study is broader than the SARI case definition recommended by WHO for influenza surveillance, but some severe respiratory cases may also have been missed using our SRI case definition. Hence, our estimates should be considered minimum estimates of the total burden of these respiratory viruses. Second we did not test for the full spectrum of respiratory viruses nor for bacteria and we collected only upper respiratory tract specimens. This hindered our ability to account for the full spectrum of respiratory pathogens and the results from multiple specimens (as implemented in other studies such as PERCH) in our analysis. Lastly, studies such as ours aim to provide a more “accurate” estimate of the disease burden associated with different pathogens by estimating the fraction of pathogens detection that is not associated with illness using controls. When the etiological fraction of different pathogens to a syndrome is estimated one pathogen is then “assigned as the cause” of the observed illness. Nonetheless, there is a potential inherent “bias” in such approach, in that the observed illness may be the result of the interaction of multiple pathogens [2]. Such limitation should be acknowledged when interpreting the results of studies like ours and the estimated burden associated to a specific pathogen should not be considered completely mutually exclusive from those of others. Despite this limitation, these studies have value to contextualize the detection of different pathogens as causal of an observed illness and to provide an indication of the relative contribution of different pathogens to a syndrome, whether interaction of different pathogens occurs or not.
In conclusion, there was a substantial burden of ILI and SRI in South Africa before the COVID-19 pandemic. Our study suggests that, among the investigated viruses, influenza and rhinovirus had a prominent disease burden among patients with ILI. The results of our study support the results of other studies that identified RSV as the most prominent cause of severe respiratory illness in children [2]; whereas influenza has a substantial role in severe respiratory illness in the elderly. The high burden of disease caused by these pathogens lends support to initiatives to accelerate the development of specific preventive interventions such as vaccination and expanded use of vaccination where vaccines exist. Ongoing surveillance is needed in the context of the COVID-19 pandemic as mitigation measures have impacted the circulation of respiratory viruses in South Africa and in other countries globally [2323Tempia S, Walaza S, Bhiman JN, at al. Decline of influenza and respiratory syncytial virus detection in facility-based surveillance during the COVID-19 pandemic, South Africa, January to October 2020. Euro Surveill. 2021 ;26(29):2001600. doi: 10.2807/1560-7917.ES.2021.26.29.2001600.,2424Olsen SJ, Azziz-Baumgartner E, Budd AP, et al. Decreased influenza activity during the COVID-19 pandemic-United States, Australia, Chile, and South Africa, 2020. Am J Transplant. 2020 ;20(12):3681-3685. doi: 10.1111/ajt.16381.