Viral etiologies of lower respiratory tract infections in children < 5 years of age in Addis Ababa, Ethiopia: a prospective case–control study

Lower respiratory tract infections (LRTIs) are a major cause of morbidity and mortality in children worldwide. In 2019, LRTIs contributed 13.9% of the 5.30 million deaths among children younger than 5 years, and were the primary cause of mortality among children aged 1–59 months [1]. Low socio-demographic index regions, like Sub-Saharan Africa, had the heaviest burden of LRTIs, which contributed to 50% of these deaths [2, 3].

After the introduction of the pneumococcal conjugate vaccine (PCV) and Haemophilus influenzae type b (Hib) vaccine, mortality due to bacterial LRTIs has decreased globally, and hence virus-associated LRTIs are likely to comprise an increasing proportion [4]; however, laboratory diagnosis of viral LRTIs remains challenging despite advances in diagnostic laboratory technology [5, 6]. Furthermore, distinguishing colonization from infection is an important factor in making the correct diagnosis of LRTIs [7]. To solve this diagnostic challenge, several studies use a case–control study design and compare the infection status of people with LRTIs (cases) to people without LRTIs (controls) [6, 8‐13]. A number of studies have detected respiratory syncytial virus, influenza, and human metapneumovirus more commonly in cases than in controls [8, 10‐13]. The case–control study design approach can help to solve the diagnostic issue at a population level, but it has been used only rarely in etiological studies [5].

Virus load in the nasopharyngeal could also help in distinguishing colonization from infection and could further predict disease severity. Several studies reported that LRTIs cases have a higher nasopharyngeal viral density (lower CT value) than asymptomatic children or children with moderate respiratory illnesses [14‐21]. For instance, a multicenter study conducted in nine developing countries reported a higher mean viral load for adenovirus, Human bocavirus, Human metapneumovirus, parainfluenza virus 1, parainfluenza virus 3, rhinovirus, and respiratory syncytial virus in nasopharyngeal/oropharyngeal swabs from children with pneumonia than without pneumonia [16]. Similarly, a study conducted among children < 5 years old with severe respiratory illness in Kenya reported a lower mean CT value for RSV among cases (27.2) than asymptomatic controls (35.8, p = 0.008) [19].

A better understanding of the contribution of specific respiratory viruses to childhood LRTIs is needed to guide clinical management and preventive measures. Despite the heaviest burden of LRTIs in Sub-Saharan Africa, to date, we have found no published studies reporting comprehensive viral etiologies of LRTIs among children. Therefore, we conducted this prospective case–control study in Ethiopia to estimate the contribution of respiratory viruses to LRTIs among hospitalized children younger than 5 years.

We found that the likelihood of detecting one or more respiratory viruses from the NP/OP of children with LRTIs compared to the control group was higher (83.8% vs. 50.3%). Previously conducted similar studies by Kelly et al., Stephen R. C. et al., Breiman et al., Hammitt et al., and Juliet O et al., also revealed a higher rate of virus detection among cases than controls, with (74.8% vs. 33.8%), (93.1% vs. 79.8%), (72.9% vs. 53.0%), (16.2%vs. 7.4%) and (86.9% vs. 75.4%), respectively [19, 22‐26]. Additionally, our results revealed that Influenza A virus, PIV 1, and RSV were associated with LRTIs. Several potential pathogens were identified in children with LRTIs, adding to the evidence that childhood LRTIs and severe disease might often not be due to a single organism [27, 28].

The highest OR were observed for RSV A (OR: 14.6, 95% CI 4.1–52.3) and RSV B (OR: 8.1, 95% CI 2.3–29.1); the corresponding PAF were 17.3% and 10.3%, respectively. The PAF is frequently interpreted as the proportion of disease risk (in our case 17.3% LRTIs cases were attributable to RSV A), that could be eliminated from the population if exposure (RSV A) were eliminated. The PAF has a practical value for those interested in public health prevention policy, particularly when dealing with an exposure that is modifiable through appropriate prevention and treatment strategies [29]. The dominance of RSV was also reported in a number of case–control studies in sub-Saharan Africa among < 5 years of children, in which RSV was most strongly associated with LRTI [8, 19, 22‐27, 30‐35].

In children, recognition of severe outcomes following influenza virus infection has been comparatively recent [36]. In this study, Influenza A viruses were found predominantly in children with LRTIs compared with controls (OR: 5.8, 95% CI 1.5–22.9). Various studies in sub-Saharan Africa also reported a significant association between Influenza A virus and LRTI [22, 24, 32, 34], while some studies found no significant association [23, 24, 26, 31, 35]. A meta-analysis by Nair et al. [37] estimated that between 28,000 and 111,500 deaths in children aged less than 5 years are attributable to influenza-related causes, the vast majority of which occur in developing countries. Effective vaccines for IFV are available, and the World Health Organization (WHO) strongly recommends pregnant women be vaccinated to protect both the mothers and the infants [38]. Although Ethiopia established influenza sentinel surveillance in 2008 with the aim of knowing the burden and circulating influenza strains in the country, the vaccination program has not yet been introduced [39]. This finding should encourage the acceleration of targeted interventions against Influenza infections in the country.

We also found a significant association of Parainfluenza 1 with LRTIs. A number of studies reported a significant association between Parainfluenza 1 virus and LRTI cases when compared with asymptomatic children or children with mild respiratory infections [22, 25, 33, 34], while others found no difference [8, 23, 24, 31, 35]. We found no association between Parainfluenza 2, 3 and 4 and LRTIs, this finding is consistent with the results of similar case–control studies in sub-Saharan Africa [22, 25, 31‐34]. Prevention and treatment strategies targeting RSV, Influenza A virus, and PIV1 may have a beneficiary effect on combating LRTI in children.

We also tested all the NP/OP swab samples for SARS-CoV-2 and found only two positive results from the control group. Large epidemiological studies also reported that children comprise only 1–2% of all SARS-CoV-2 cases [40‐42]. Early after the new SARS-CoV-2 was first described in the Hubei province of China, it became clear that most children infected with SARS-CoV-2 were asymptomatic or had mild symptoms [43, 44]. Whether children are also less likely to get infected by SARS-CoV-2 is an ongoing debate. However, more recent studies reported that children are less often infected by SARS-CoV-2 after contact with a SARS-CoV-2-positive individual [44].

Pathogen density in the nasopharynx could provide additional information and may further aid in distinguishing asymptomatic from symptomatic infections [45]. We found that the mean CT values were lower in all of the viruses detected in the cases with the exception of coronaviruses and human rhinoviruses. Generally, children with LRTI had a higher total viral load and harbored more viruses than asymptomatic children or children with mild respiratory infections. A number of studies from sub-Saharan Africa reported higher nasopharyngeal viral density in LRTIs cases compared with non-LRTI controls [14‐19]. For some viruses, increased nasopharyngeal viral load has been associated with the clinical severity of LRTIs in children [45].

These findings underscore the importance of developing prevention strategies for RSV and Influenza A virus in Ethiopia and support the importance of developing an effective vaccine against these viruses. RSV vaccines designed for children are in the pipeline and immediate launch of RSV vaccination soon after approval shall be recommended for children in Ethiopia. The introduction of Influenza A vaccination shall also be recommended. Regarding SARS-CoV-2, only 2 children were positive out of 420 children; therefore, further research should be done before launching a vaccination campaign for < 5 years children against Covid-19 in resource-limited countries like Ethiopia. Further work should be done to inform a reliable CT value cut-off for specific viruses to diagnose LRTIs cases in clinical settings.