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Review Article

Review on Clinical and Molecular Epidemiology of Human Rhinovirus–Associated Lower Respiratory Tract Infections in African and Southeast Asian Children

Baillie, Vicky L. PhD*,†; Olwagen, Courtney P. PhD*,†; Madhi, Shabir A. MBBCh, FCPaeds, PhD*,†

Author Information

From the *Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, University of the Witwatersrand, Johannesburg, South Africa

†Department of Science and Technology/National Research Foundation, Pretoria, South Africa.

Accepted for publication September 20, 2017.

V.L.B. and C.P.O. are PhD students at the University of Witwatersrand, and S.A.M. is supervising the project.

The authors have no funding or conflicts of interest to disclose.

V.L.B. wrote the protocol while S.A.M. and C.P.O. critically appraised, edited and provided guidance during the development of the protocol. All authors approved the final version of the protocol and took responsibility for its content.

Address for correspondence: Shabir A. Madhi, MBBCh, FCPaeds, PhD, Medical Research Council, Respiratory and Meningeal Pathogens Research Unit, Chris Hani Baragwanath Hospital, Chris Hani Road, New Nurses Residence, 11th Floor West Wing, 2013 Bertsham, Johannesburg, South Africa. E-mail: [email protected].

The Pediatric Infectious Disease Journal: July 2018 - Volume 37 - Issue 7 - p e185-e194
doi: 10.1097/INF.0000000000001897
  • Free

Abstract

Pneumonia is the leading cause of childhood morbidity and mortality globally, including approximately 120 million cases annually, 95% of which occur in low-income countries.1 In 2013, approximately 6.6 million children <5 years of age died with 3.257 million deaths due to infectious causes with pneumonia causing the majority of these deaths (0.935 million deaths).2 Approximately 60% of all deaths of children <5 years occurred in sub-Saharan Africa.2 Interventions to reduce severe pneumonia illness and deaths remain challenging, in part due to gaps in knowledge on the etiology and pathogenesis of pneumonia.2–5

Human rhinovirus (HRV) was first identified in 1956 in patients presenting with mild upper respiratory tract infection (URTI),6 and has since been reported to be the most widespread cause of the common cold. Presently more than 100 HRV serotypes have been classified into 3 species, including HRV-A (74 serotypes), HRV-B (25 serotypes) and most recently HRV-C.7 Studies from Africa, Asia, Europe, America and Australia8–11 suggest that HRV-C may cause severe illness, associated with acute asthma exacerbation12 and is more prevalent in lower respiratory tract infections (LRTI), especially in individuals with influenza-like illnesses.13 Furthermore, HRV-C might differ to other HRV species in relation to seasonal circulation patterns.14

The use of molecular techniques, including reverse transcriptase polymerase chain reaction, has led to more widespread investigation of HRV among children presenting with pneumonia, otitis media, sinusitis and bronchiolitis.15–18 HRV has also been implicated as cause of severe respiratory disease and death, as evident by an outbreak at a Vietnamese orphanage, in which 7 of 12 hospitalized children, who tested positive for HRV infection and 90% with HRV being the only pathogen detected, having demised.19

Attributing causality of illness to HRV is, however, complicated by its high prevalence of detection in asymptomatic individual,20 and that virus shedding can continue for up to 14–30 days.21,22 Regardless, HRV and enteroviruses (both from the Picornaviridae family of viruses) are increasingly attributed as an important cause of respiratory illness in children in high-income countries. There is, however, limited number of studies from low-middle income countries in children <5 years of age where respiratory morbidity and mortality is greatest, and its role in the pathogenesis and etiology of LRTI remains to be fully characterized.23

We undertook a systematic review and meta-analysis of studies reporting on HRV infections in children from low-middle–income countries in Africa and Southeast Asia, with a focus on the prevalence and molecular epidemiology of HRV-associated LRTI.

MATERIALS AND METHODS

The systematic review was undertaken per the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guidelines24 and included all publications up until November 30, 2015 using the search terms: “Human Rhinovirus” or “Rhinoviruses” and “Africa” and “Southeast Asia” or “South-east Asia” or “South east Asia.” We searched PubMed, Scopus, Cochrane, MEDLINE, Global Health library and the World Health organization regional databases. Google Scholar was used to search for “Human rhinovirus” and each African and Southeast Asian country individually. Furthermore, we screened the references in the reviewed manuscripts for any additional relevant manuscripts. Two authors (V.L.B. and C.P.O.) independently carried out searches and determined the articles for inclusion into the study with a third author (S.A.M.) adjudicating on any disagreement between them. All articles published in English, French or Portuguese were included. Because of the limited sensitivity of culture techniques for HRV,16,25 only studies which employed molecular diagnostic techniques were included. After deleting duplicate articles, the titles, abstracts and full texts of the articles were systematically reviewed to identify which of the articles fulfilled all our inclusion and exclusion criteria.

Inclusion and Exclusion Criteria

Studies reporting on observational surveillance reports, cross-sectional, retrospective, cohort, and prospective data for prevalence rates of HRV were included. Review articles were excluded from this review; however, we did assess references in these to identify any additional citations that were relevant to this review. We included all appropriate studies regardless of sex of study participant or case definition used for the study. Only studies which reported on HRV in children were included. Citations which detailed studies done outside of Africa and Southeast Asia were excluded. In cases where multiple reports were identified from the same authors with overlapping study periods, only the most recent or most comprehensive article was included in the review.

Data Abstraction and Assessment

Articles which met the above criteria were assessed and the following information extracted if available: study region and population, study design, period of recruitment, recruitment of cases and controls, case definitions, age range of cases and controls and HRV prevalence in cases and controls, molecular epidemiology of HRV in cases and controls, the prevalence and coinfections with other respiratory viruses.

Meta-analysis

A meta-analysis, using exact conditional logistical regression, was undertaken to compare the prevalence of HRV detection in the case–control studies to determine the pooled OR and confidence intervals (CIs) for identification of HRV among cases versus controls. Furthermore, meta-analysis was conducted on the case studies which reported HRV prevalence by age categories (1–12 months, 1–5 years and 5–10 years) to determine the OR for HRV infection by age-group strata. All data analyses were conducted using STATA version 13.0 (College Station, TX) and SAS version 9.2 (Cary, NC). Two-tailed P values <0.05 were considered to be statistically significant.

RESULTS

Our search identified 712 citations from the reviewed databases, of which 635 were removed through elimination of duplicate articles (n = 120), screening of the article titles (n = 341) or abstracts (n = 174) (Fig. 1). This left 77 articles for full-text review, of which 55 did not pass the study inclusion criteria; the main reasons being that the studies included adults and did not separately report on children (n = 19) and duplication of study participants being included in more than 1 publication (n = 11). An additional 8 manuscripts were identified through reviewing the references in the included manuscripts and through Google Scholar search for country-wide reporting on HRV prevalence.19,26–32 Consequently, 31 articles were included in this systematic review (Fig. 1).

F1
FIGURE 1.:
Article selection.

We identified 23 manuscripts reporting on HRV prevalence from 13 (24%) of 54 African countries, including 6 from South Africa,33–38 4 from Kenya,39–42 2 each from Madagascar27,43 and Mozambique26,44 and 1 each from Angola,45 Botswana,46 Burkina Faso,47 Burundi,17 Morocco,48 Niger,49 Nigeria,50 Senegal51 and Zambia.52 From Southeast Asia, we identified 8 manuscripts reporting on HRV prevalence from 6 (55%) of the 11 Southeast Asian, including 2 each from Vietnam19,30 and Thailand31,53 and 1 each from Cambodia,29 Malaysia,32 The Philippines54 and Singapore.55

Studies Reporting on HRV Prevalence Among Cases and Controls

Seven identified studies enrolled both cases with severe respiratory disease and asymptomatic controls or controls with mild respiratory disease, to determine the attributable role of HRV in the etiology of LRTI29,38–40,42,46,53 (Table 1). Of these 7 studies included in the meta-analysis, there were higher odds for HRV to be prevalent in LRTI cases than controls in only the South African study [odds ratio (OR): 2.42; 95% CI: 1.11–5.84]; however, the lower bound of 95% CI of these estimates approximated 1.0 (Fig. 2).38

T1
TABLE 1.:
Human Rhinovirus Prevalence Reported in Case–Control Studies
F2
FIGURE 2.:
Studies reporting on the proportion of HRV-associated cases and controls. Using exact conditional logistic regression, odds ratios were used to compare the proportions of children with HRV-associated severe disease (cases) versus children with asymptomatic HRV infections (controls).

This study from South African study38 enrolled children with acute LRTI (ALRTI) presenting at the emergency room but not requiring hospitalization, children hospitalized and patients requiring intensive care unit treatment. The controls (n = 48) were enrolled from an immunization center. HRV was detected as a monoinfection in 50% of the ALRTI cases not requiring hospitalization, and 88% of the hospitalized cases. A significantly greater proportion of the children with HRV monoinfections had to be hospitalized and required intensive care unit treatment compared with children hospitalized with HRV coinfections (P < 0.001). They also investigated for Respiratory syncytial virus (RSV), influenza virus, Parainfluenza virus (PIV) type 1–3, human coronavirus (HCoV), Adenovirus (AdV), Human metapneumovirus (HMPV) and human bocavirus (HBoV) among the cases and found that HRV was the most prevalent virus detected (33%) followed by RSV (30.1%) and HBoV (6.1%).38

The Cambodian study29 was the only other study which analyzed the detection of HRV in cases and controls. They found that HRV (20%) was detected in similar prevalence to RSV (19%) among cases. They also investigated for influenza (A and B), PIV type 1–4, AdV, HMPV, HBoV, HCoV and enterovirus. HRV was the second most commonly detected monoinfection (n = 169/204, 83%) following RSV (n = 167/192, 87%); and HRV was most commonly detected together with RSV (n = 10/35, 29%) and the HBoV (n = 8/35, 23%). They found that infections with RSV and HRV could not be distinguished clinically for either infants or children 1–4 years of age. They also enrolled 50 controls but did not elaborate on the inclusion criteria for these controls or how they were enrolled. HRV was detected in 12% (n = 6/50) of the controls and RSV was detected in 8% (n = 4/50).29 The number of controls was too small for any additional analysis.

The remaining 5 studies found no difference in HRV prevalence between cases (47.5%–18%) and the controls (19%–50%)39,40,42,46,53 and hence did not undertake any further analysis specific to HRV. The only studies which matched community controls to cases were from Botswana, with matching including for age, HIV status and period of enrolment46 and Kenya42 which age frequency matched the cases and controls, as well as matched for month of the year of enrolment. The controls for the remainder of the studies were either a convenience sample of children presenting for routine immunization or in vaccine trials. This could have biased their generalizability to the population. Furthermore, the number of cases enrolled greatly outnumbered the number of control participants, possibly further compromising statistical comparisons.

Overall, there was no difference observed in the meta-analysis on prevalence of HRV identification between cases of ARI (23.9%; which varied in their severity and clinical presentation between studies) and controls (23.7%; P = 0.197; which varied in their representativity to the general population; Fig. 2). Also, this meta-analysis needs to be interpreted with caution, since in addition to differences in case definitions and control selection between the studies, the studies also varied in the age groups included (Table 1).

Studies Only Reporting on the Prevalence of HRV Among Cases

The remaining 17 studies were primarily surveillance studies conducted in children presenting with respiratory infections and mainly focused on other more established respiratory pathogens such as RSV and influenza virus27,41,43,44,48,49,51 (Table 2). HRV prevalence in these studies was reported as part of the general surveillance, and no further analyses of the prevalence or clinical presentation of HRV were undertaken in these studies. Furthermore, the studies varied in age groups of children enrolled, case definition with some focusing only on URTI,37,41 others only on LRTI,26,33,34,43,48,49,52 others reported on both URTI and LRTI separately,19,27 while others did not differentiate between URTI and LRTI cases.36,44,45,47,50,51

T2
TABLE 2.:
The Prevalence of HRV in Pediatric Surveillance Studies of Respiratory Disease

Of the surveillance studies which focused on LRTI in children, 7 were hospital based26,34,43,48,49,52,56 and 2 enrolled hospitalized children with either LRTI or URTI and reported the results separately19,27 (Table 2). In these studies, the prevalence of HRV ranged from 17% to 53% among LRTI cases, with the Madagascar study reporting the lowest prevalence (17%). In the latter study, HRV was the third most common detected virus, following RSV (44%) and influenza-A virus (24%).43 HRV was detected as a monoinfection in 14% cases, and more commonly detected as coinfection with RSV (24%) and influenza-A virus (18%). The study from Morocco reported the highest HRV prevalence (53%), followed by RSV (18%) and adenovirus (17%).48 No further analysis was conducted on HRV in this study, as was the case in the majority of the other observational studies, with many authors suggesting that the pathogenic role of HRV during disease remained uncertain due to the high prevalence reported in asymptomatic individuals.19,27,33,49,52

Similarly, in the studies which did not distinguish between LRTI or URTI, the prevalence of HRV ranged from 10% to 42%. The study conducted in Senegal in children <5 years age with fever and any other sign of respiratory infection had the lowest prevalence of HRV (10%).51 The inclusion of fever as a prerequisite for screening might explain why influenza virus was the most prevalent virus detected in this study (31%), followed by RSV (16%). Nevertheless, HRV was predominantly identified as a monoinfection (88%), with only a single case of HRV–RSV mixed infection observed.

The other studies were conducted in children presenting with URTI, the first included children with acute otitis media, among whom HRV was identified on nasopharyngeal swabs in 38% of cases,37 and as the most prevalent virus identified irrespective of HIV status (33% in HIV-infected children and 39% in HIV-uninfected children). In the study from Kenya41 among older children (5–10 years) presenting with malaria-like symptoms, HRV was detected in 26% of cases, including among 37% of the cases who tested positive for malaria.

The differences in age groups and clinical definitions could account for the variability in HRV detection (16%–53%) between the studies (Table 2). Of the 17 surveillance studies, 10 provided the prevalence of HRV among LRTI cases by age groups. The majority of the studies stratified for infants and age 1–5 years (9/10). Furthermore, 3 studies included prevalence in children <5 years. Nevertheless, the meta-analysis on prevalence of HRV did not differ by age groups, including 39% (range: 32%–46%) among the 1- to 12-month age group (Fig. 3A) and 36% in the 1- to 5-year group (range: 31%–41%) (Fig. 3B) and 5- to 10-year age group (range 22%–52%) (Fig. 3C).

F3
FIGURE 3.:
The prevalence of HRV in children under the age of 10 years. Using exact conditional logistic regression, odds ratios were used to compare the proportions of children with HRV-associated disease in infants (A); among children 1–5 years of age (B) and among children 5–10 years of age (C).

Studies Reporting on HRV Epidemiology

Of the 31 manuscripts included in the review, 9 also reported on the molecular epidemiology of HRV within the population,17,30–32,35,39,46,54,55 of which only 2 (Kenya and Botswana) also enrolled controls39,46 (Table 3).

T3
TABLE 3.:
Human Rhinovirus Prevalence and Molecular Epidemiology by Region (Africa and Southeast Asia) and Country

In the Kenyan study,39 hospitalized children <12 years of age with any severity of LRTI were enrolled, as well as children with or without an URTI as a control group that were recruited when arriving at the hospital for routine immunization. HRV was detected in 22% of the cases (HRV-A, HRV-B and HRV-C constituting 47%, 5% and 48%, respectively) and 24% of the controls (HRV-A, HRV-B and HRV-C constituting 41%, 15% and 44%, respectively; P = 0.38). None of the HRV species were associated with more severe disease; and the prevalence of HRV detection and species distribution was similar between cases compared with controls with URTI. Nevertheless, the authors cautioned that due to the study design, including imbalance between case and control enrolment, they were unable to make definitive conclusion on HRV epidemiology and disease severity. Also, 25% of the samples failing to amplify during sequencing, which was significantly higher among controls (44%, n = 27/61) than cases (22%, n = 82/280; P < 0.001). Furthermore, due to limited availability of clinical data, they were unable to analyze for any association between the HRV types and disease severity; and the presence of other respiratory virus coinfection was not evaluated.39

Similarly in Botswana,46 no difference was found in prevalence of HRV between cases 1–23 months of age hospitalized for pneumonia (31%) and controls (30%; P > 0.99) who were matched for age and date of enrolment. Seventy-five percent of cases had at least 1 respiratory virus detected, including RSV, which in contrast to HRV, was detected in 35% of the cases and only 2% of the controls (P < 0.001). Among the HRV cases, coinfections with other viruses occurred among 8% of cases, of which 64% was with RSV. Among the HRV episodes for which serotyping was performed, the distribution of species among 34 cases (HRV-A = 44%, HRV-B = 15% and HRV-C = 41%) was similar to those of 31 controls (HRV-A = 51%, HRV-B = 10% and HRV-C = 39%; P = 0.99).46

The remaining 7 studies which analyzed the clinical and molecular epidemiology of HRV did not enroll controls. Two of the studies sequenced <100 HRV-positive samples and only provided a descriptive analysis of the molecular characterization of HRV without associating it with disease outcome.35,55 The South African35 study focused on wheezing in children <5 years and found that HRV was the most common virus detected (58%), with HRV-C being the most common species (HRV-A = 37%, HRV-B = 11% and HRV-C = 52%) among the 71 positive samples which were serotyped. Smuts et al35 also investigated for RSV, influenza virus, adenovirus, PIVs, HMPV, HCoV and human bocavirus; and reported coinfection in 16% (n = 20/128) of the HRV-associated cases, most common being HMPV (6.3%), followed by HBoV (4.7%) and HCoV (0.8%). From Singaporean Tan et al,55 also identified HRV as the most common respiratory virus (13%; n = 64/500) in children hospitalized with ARI, including 48% of 64 LRTI episodes, 25% of 64 URTI cases and 27% among 64 cases with undefined symptoms. The molecular epidemiology showed a dominance of HRV-A (HRV-A = 73%, HRV-B = 14% and HRV-C = 3%). Coinfections with other viruses were detected in 8% of the HRV-associated cases, most commonly HBoV (7/10), followed by RSV (n = 2/10). Sixty-percent of these coinfections were in children hospitalized with LRTI. In the remaining 5 studies which examined the clinical and molecular epidemiology of HRV, there were suggestive associations between HRV infection and disease severity. In the Burundian study17 which enrolled children 1 month to 14 years of age hospitalized with LRTI, HRV was identified among 40% of cases, with a dominance of HRV-A (HRV-A = 55%, HRV-B = 12% and HRV = 32%). In this study, HRV-A was the most frequent HRV species in children diagnosed with pneumonia and bronchiolitis, whereas, HRV-C infections were most common in children presenting with wheezing. In the Malaysian study,32 165 children <5 years of age hospitalized with ALRTIs were enrolled, among whom the prevalence of HRV was 33%. Although these cases were also investigated for RSV, HMPV, influenza-A and influenza-B, PIVs, HCoVs, HBoV and adenovirus, the majority (67%) of HRV cases were monoinfections, while RSV (n = 11/18; 61%) was the most common coinfecting virus with among HRV cases. Children with HRV infections were less likely to be febrile (67%) compared with RSV (92%; P < 0.003) and influenza (100%; P = 0.044)-associated LRTI cases. The molecular distribution of the HRV monoinfections were 61% HRV-A and 39% HRV-C, with HRV-C being more commonly associated with wheezing, vomiting, rhonchi, higher neutrophil counts and generally more severe disease compared with HRV-A infections. Furthermore, HRV-A was detected more frequently in younger age groups (6–11 months) and HRV-C in older children (12–23 months).32

In the Thai study,31 of children hospitalized with ALRTI, 30% were positive for HRV, with HRV-C being most common (58%), then HRV-A (33%) and HRV-B (9%). HRV was a monoinfection in 62% of the cases. Among those with coinfections, again RSV (36%) was the most common, followed by influenza and adenovirus (18% each). Other viruses investigated for included PIVs, HBoV, adenovirus, HMPV and polyomaviruses (WU/KI). The authors, however, concluded that the sample size was inadequate for statistical analysis between disease outcomes of HRV compared with other respiratory viruses or by HRV species and disease severity.

The Vietnamese30 study enrolled children hospitalized with ARI, with HRV identified in 30% of cases, including 72% monoinfections. Of the 91 mixed HRV coinfections, RSV accounted for 53% of coinfections, with other viruses that were investigated for including influenza-A and influenza-B, HMPV, PIVs, HCoVs, adenovirus and HBoV. Furthermore, similar to the South African35 and Malaysian study,32 children with HRV monoinfections were less likely to present with febrile disease compared with the other virus monoinfections (P < 0.001). HRV monoinfections were also more likely associated with hypoxia (12.4%) compared with RSV (3.8%; P = 0.002) and PIVs monoinfections (0%; P = 0.02); and presented more often with wheezing (63.2%) compared with influenza monoinfections (42.3%; P = 0.038). On comparison of mono and mixed HRV infections, generally there were no differences in clinical features, except that HRV coinfections were more likely to be associated with chest retractions (70.3% vs. 57.3%; P = 0.032). Of the 18% of the HRV serotyped, HRV-A was the most dominant 76%) followed by HRV-C (24%).30

Finally, in The Philippino study,54 HRV was identified in 33% of children hospitalized with severe pneumonia. The molecular epidemiology of these cases also indicated HRV-A as being the most dominant (56%), followed by HRV-C (35%), then HRV-B (10%); and 10% were identified as enteroviruses. In this study, viremia for HRV was identified among 12% (n = 30/243) of the HRV cases, with cases with HRV-C being 15.04-fold more likely to be viremic (31%) compared with HRV-A (3%; P < 0.01) and HRV-B (0%; P < 0.01). Furthermore, cases with HRV-viremia had lower oxygen saturation for both HRV-A and HRV-C compared with those without viremia. Also, HRV-A cases with viremia were significantly more likely to have wheezing (100%) compared with HRV-A cases without viremia (45%; P < 0.05), with a similar trend observed for HRV-C (69% vs. 48%; P = 0.1). Case fatality ratio, however, did not differ by the presence (3%) or absence (9.5%; P = 0.37) of viremia. This study concluded that HRV-C is more likely to be associated with viremia,54 which could explain that the association of increased disease severity reported in several studies with HRV-C compared with the other HRV species.8–11 This study did not investigate any other respiratory virus infections.54

DISCUSSION

Our systematic review on HRV in low- to middle-income countries in Africa and Southeast Asian confirms the scarcity and limitations of the available clinical and molecular epidemiology data. This further emphasizes the uncertainty on the role of HRV in the pathogenesis of childhood respiratory disease, even though in HRV was once of the most if not the most prevalent virus detected in the majority of studies. In the studies which reported on more than just the prevalence of HRV in the study population, it was evident that HRV was most commonly detected as the only respiratory virus among both cases and controls. None of the studies, however, analyzed for coinfections with bacteria even though HRV infections have been shown to enhance both subsequent infections with Streptococcus pneumoniae and Staphylococcus aureus through the upregulation of bacterial adhesion to the respiratory epithelial cells and through the modulation of the host immune responses.57,58 This is most likely because bacterial coinfection relationships are difficult to fully elucidate as the currently available diagnostic tools for diagnosing bacterial pneumonia are insensitive, with blood culture sensitivity ranging between 15% and 30%, while obtaining samples from the site of infection is challenging with direct aspiration of the lungs rarely performed.42,59

The need for a large sample size was highlighted by the 2 studies which investigated the HRV molecular epidemiology in both case and controls,39,46 but failed to analyze the epidemiology in terms of clinical outcomes, disease severity or even basic comparison between case and control populations due to the limited statistical power of the study. In the studies which did not enroll controls,17,30–32,35,54,55 the analysis of the different HRV species in terms of clinical outcomes and disease outcome showed that the HRV species could in fact have different clinical presentations; however, without the controls, it is uncertain what the contribution of different HRV types is in the pathogenesis of LRTI. Nevertheless, the studies provide some indication that HRV might be an important respiratory pathogen, especially in developing countries where HRV is found to be the most prevalent virus detected in RTI cases irrespective of age group and clinical syndromes.

Future Study

A large-scale surveillance project is needed which looks at both severe RTI and a health cohort to fully elucidate the attributable pathogenic role of the different HRV species in children in the developing world. This project will need to take an in-depth clinical and socioeconomically background from both the sick and health cohort to fully study the clinical manifestation and risk factors for HRV infection, as well as to try and understand the implications of HIV status on HRV infection. A multicountry study conducted for several years would be preferable as it would increase the generalizability of the studies’ findings thus increasing the studies power to direct future treatment plans for all low- to middle-income high-risk countries. One such study is the Pneumonia Etiology for Child Health Project which is a case–control study aimed at fully characterizing the etiology of World Health organization–defined severe and very severe pneumonia in children age 28 days to 59 months in 9 sites across 7 countries in Africa and Southeast Asia making it the biggest study looking at the etiology of childhood pneumonia since the Board of Science and Technology for International Development studies which were conducted in the late 1980s.60 Pneumonia Etiology for Child Health Project detected for a large number of bacterial and respiratory viruses including HRV in both cases and controls (>8500 participants), as well as collected in-depth information on clinical and socioeconomical demographics of all the cases and controls.61,62 Once this study’s results are published, it might help to shed light on the attributable role of HRV during severe respiratory disease episodes. In addition to this, a longitudinal cohort study is also needed to fully study the role of HRV infection during early childhood and its long-term effects on wheezing disease and predisposing children to asthma.

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Keywords:

human rhinovirus; low-middle income countries; children; acute respiratory infections

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