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.