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Original Studies

Defining Age-specific Relationships of Respiratory Syncytial Virus and Rhinovirus Species in Hospitalized Children With Acute Wheeze

Oo, Stephen W.C. MBBS*,†; Khoo, Siew-Kim BSc*,‡; Cox, Des W. MD*; Chidlow, Glenys PhD§; Franks, Kimberley*,‡; Prastanti, Franciska*,‡; Bochkov, Yury A. PhD; Borland, Meredith L. MBBS*,∥,**; Zhang, Guicheng*,††; Gern, James E. MD; Smith, David W. MBBS§,‡‡; Bizzintino, Joelene A. PhD*,‡; Laing, Ingrid A. PhD*,‡; Le Souëf, Peter N. MD*,†

Author Information
The Pediatric Infectious Disease Journal: October 2021 - Volume 40 - Issue 10 - p 873-879
doi: 10.1097/INF.0000000000003194

Abstract

Acute wheezing is one of the most common causes of hospital presentation for children in developed countries and, with recent improvements in viral detection methodologies, 80–90% of childhood wheezing episodes have been shown to be attributable to viral respiratory infections.1–6 Age has an influence on virus susceptibility, for example, respiratory syncytial virus (RSV) has been recognized as a major cause of wheezing in infancy, but rhinovirus (RV) is now also viewed as being important in this age group.7 In early and later childhood, RV is now recognized as the most common cause of wheezing and asthma exacerbations.1,2,8–12 The discovery of a third species of RV, species C (RV-C) in addition to the previously known species A (RV-A) and B (RV-B), has prompted a re-evaluation of how much RV-C impacts wheezing in children.13,14 Given that age also impacts wheezing diagnosis (bronchiolitis, viral wheezing and asthma) and treatment including salbutamol and steroids, an understanding of the role of RV-C, is important to further developing targeted treatment options.

The relative importance of the 3 RV species in acute wheezing has been unclear. RV-C has been identified as the most common virus in children hospitalized for wheezing in many studies.3,4,8,9,15 In studies of asthmatic children that included acute cases not severe enough to present to hospital, RV-A has been reported to be more common.16–18 The few adult asthma cohorts that type RV have reported a greater prevalence of RV-A and also lower rates of viral detection,12,19,20 suggesting that the relative importance of RV species could change with age.

The aim of the current study was to define the age-specificity of respiratory viruses causing moderate to severe wheezing exacerbations in childhood. We hypothesized that RV-C would be the dominant virus detected after infancy and throughout childhood with acute wheezing severe enough to present to the hospital. This investigation was made possible by analyzing a large, prospectively-collected cohort of children recruited on presentation to a busy children’s tertiary hospital emergency department (ED).

METHODS

Study Population

Cases were children 0–16 years recruited as part of the Mechanisms of Acute Viral Respiratory Infection in Children study on presentation to Princess Margaret Hospital (PMH) for Children, Perth, Western Australia between January 2004 and January 2014. Cases recruited had an acute wheezing illness with no other comorbid conditions besides asthma eczema, or atopy. Diagnosis was based on an ED physician-assigned primary diagnosis for every child seen.

Controls were children 0–16 years of age with no pre-existing chronic disease including chronic respiratory illness, recruited from 4 sources: siblings and relatives of cases, PMH patients presenting with minor injury/fractured limbs (and not a primary respiratory presentation) or volunteers from the local community and day care facilities. Controls were permitted to have symptoms of acute respiratory infection including nasal and acute cough symptoms but no wheeze.

Cases and controls were recruited through all seasons, and a questionnaire (see questionnaire, Supplemental Digital Content 1; https://links.lww.com/INF/E396) was administered to both to determine symptoms of the illness including coryzal symptoms.

This study was approved by the hospital’s ethics committee and parents/guardians of all children provided written informed consent before participation.

Viral Detection

A nasal blow or wash was collected at recruitment from both cases and controls and immediately stored at −80°C before processing. Nasal specimens were typed for RV species using methods previously described3,21,22 with improved primers.23 Briefly, a semi-nested RT-PCR with primers that amplify the 260-bp variable region of the 5′ untranslated region of the RV genome was completed. RV-positive samples were sequenced and assigned an RV strain and hence species following comparison with sequences of the 101 classic serotypes and the 53 newly assigned genotypes using ClustalX software (University College Dublin, Dublin, Ireland).21 Representative samples of each genotype have previously been sequenced at the 420-bp viral protein (VP)4-VP2 coding region to confirm the species assignment.24,25

A second aliquot from each nasal specimen was tested for RSV, influenza A and B, parainfluenza 1-4, RSV and human metapneumovirus by the hospital virology laboratory using routine diagnostic methods including PCR,26 direct or indirect fluorescent antibody testing, or immunofluorescence after cell culture as previously described.27 Where possible, samples were also tested for coronavirus, and bocavirus.

Oxygen Saturation, Admission Rate and Length of Stay

Pulse oximeter oxygen saturation (SpO2) was measured on hospital presentation without the child receiving supplemental oxygen, and clinical diagnosis was assessed by the treating pediatric emergency physician independent of study personnel, and without knowledge of respiratory infection test results. Admission rates and length of stay were determined from hospital databases that record presentation, admission and discharge dates and times.

Statistical Analysis

Chi-square and Fisher exact tests were used to compare virus detection rates between groups. Student’s t-tests and chi-square tests were used to compare means and ratios in demographic data. Unadjusted odds ratios were used to compare viral detections between cases and controls. For further analysis comparing viral subgroups, those with multiple infections were excluded. To conform to a normal distribution, age was transformed by square root, length of stay was log transformed and SpO2 was transformed using log(101-SpO2). For SpO2, Mann-Whitney U tests were used to compare median values in untransformed data and geometric means were compared with Student’s T tests using transformed SpO2 data. Length of stay, SpO2 and age were compared by Pearson correlation coefficients using transformed data. Analyses were performed using IBM SPSS Statistics for Windows, Version 22.0, and GraphPad Prism for Windows, version 6.07. Statistical significance was defined as a P value <0.05.

RESULTS

In total, 460 cases and 229 controls were recruited between 2004 and 2014. Sufficient nasal specimens were obtained from 390/460 (84.8%) cases, and 190/229 (83.0%, P = 0.539) controls to complete testing for RV and other common respiratory viruses. The mean age of cases (4.21 years, SD 3.36) was less than controls (5.18 years, SD 3.96, P = 0.004) and there was a higher proportion of males amongst cases (61.0%) compared with controls (48.7%, P = 0.006). Coryzal symptoms were more common in cases (88.9%) compared with controls (34.1%, P < 0.001).

Overall Viral Respiratory Infections

At least one respiratory virus was identified in 87.7% of cases, and 51.0% of controls (P < 0.001). For virus-positive children, a high proportion of cases had coryzal symptoms (89.7 %) compared with controls (48.8%, P < 0.001). Noncoryzal cases also exhibited high viral detection rates (81.4%) compared with asymptomatic controls (36.0%, P < 0.001). Two or more viruses were detected in 13.6% of cases and 10.5% of controls (a listing of those cases and controls with multiple viruses is provided in Supplemental Digital Content 2 [Table]; https://links.lww.com/INF/E397). In individuals with multiple viruses, each was included in the following analyses as a separate detection (Fig. 1). Due to reduced testing of samples for coronavirus (cases = 40.3%, controls = 100%) and bocavirus (cases = 28.2%, controls = 91.6%), the proportion positive was corrected to the number of samples tested rather than the full cohort and corrected proportions are presented (Fig. 1).

FIGURE 1.
FIGURE 1.:
Relative proportions of infection in cases compared with controls. Inner circle represents cases, and outer circle represents controls. Relative proportions of respiratory infections based on detection positivity in all samples tested. In individuals with multiple viruses, each was included in the following analyses as a separate detection. Due to reduced testing of samples for coronavirus (cases = 40.3%, controls = 100%) and bocavirus (cases = 28.2%, controls = 91.6%), the proportion positive was corrected to the number of samples tested rather than the full cohort and corrected proportions are presented. *Significant difference, P < 0.05, between cases and controls.

RV was the most common virus in both cases (72.1%) and controls (33.7%, P < 0.001). The second most common virus detected in cases was RSV (15.1%), which was significantly higher than in controls (4.7%, P < 0.001).

Adenovirus was the only other virus to show significant differences between cases (2.1%) and controls (6.3%, P = 0.008). The seasonal variation in detection of viruses for cases and controls show greater predisposition for the winter months for both RV and RSV but more so for RSV (see Figure, Supplemental Digital Content 3; https://links.lww.com/INF/E398).

RV Species

RV species identification was successful in 377/390 (96.7%) of cases and 198 (100%) controls. Dual RV-A and RV-C infection was found in one case and 2 controls. There were 10 cases where RV species was unidentifiable. In cases, prevalence of RV-C (46.6%) was higher than RV-A (23.4%, P < 0.001) or RV-B (1.5%, P < 0.001). Compared with cases, controls had lower detection of RV-C (12.1%, P < 0.001), and similar detection of RV-A (18.2%, P = 0.229) and RV-B (3.7%, P = 0.133).

Age Distribution of Viruses

Age-specific distribution of viruses in cases is presented (Fig. 2). For the first 6 months of life, RSV was the dominant virus associated with wheezing as it was at least 4 times more commonly detected than any other virus (P < 0.001). For children 6 months to 2 years of age, RSV, RV-A and RV-C were all commonly associated with wheezing. In children of age 2–6 years, RV-C was the dominant virus associated with wheezing as it was detected in 50–60% of cases, which was 2–3 times more often than RV-A, the next most prevalent virus, with RSV isolation increasingly rare with increasing age. From 4 to 7 years of age, RSV was absent and RV-B was rare at all ages. After 10 years, RV-A and RV-C were the 3 most common viruses detected.

FIGURE 2.
FIGURE 2.:
Wheezing cases: infection detected as a proportion of each age group. Virus detected of the predominant respiratory viruses as a percentage of samples tested versus age in wheezing cases. Almost all cases were admitted to hospital (96.4%). Age groups were 6 months up to 2 years, yearly to 12 years, then combined for 12–16 years due to small numbers. Where more than one virus was detected in a patient, both were presented. P value represents proportion comparisons between RV-C and RV-A which are the 2 most common viruses found. RSV indicates respiratory syncytial virus; RV, rhinovirus.

Control data are presented (Fig. 3). Controls exhibited no dominant virus at any age, although numbers of controls were limited <1 year of age (n = 13). Comparing between cases and controls (Table 1): RV-C odds ratio (OR) was 6.33 times (95% confidence interval (CI): 3.94–10.10) higher in cases; not significantly different in RV-A (OR 1.29, 95% CI: 0.84–1.97); and RSV was slightly higher in cases 2.4 (95% CI: 1.14–5.05). In individual age groups, it was noted that RSV was markedly higher in cases <2 years OR 13.83 (95% CI: 1.82–105.05); whereas RV-C substantially higher in cases 2–6 years of age OR 15.81 (95% CI: 7.04–38.46) and those 6–12 years (OR 4.10, 95% CI: 1.64–10.27). RV-A was only significantly higher in cases in the >12 years group (OR 16.00, 95% CI: 1.27–200.92).

TABLE 1. - Comparison of Odds Ratios Between Cases and Controls for Detecting a Specific Virus by Age Group
Age Group RV-C RV-A RSV
Odds Ratio 95% CI Odds Ratio 95% CI Odds Ratio 95% CI
all ages 6.33 3.94–10.1 1.29 0.84–1.97 2.40 1.14–5.05
<2 years 1.67 0.72–3.86 0.82 0.38–1.77 13.83 1.82–105.05
2–5 years 15.81 7.24–34.53 1.26 0.66–2.42 1.00 0.33–3.08
6–12 years 4.10 1.64–10.28 1.83 0.68–4.96 0.44 0.06–3.22
13–16 years N/A N/A 16.00 1.27–200.92 N/A N/A
Significant differences are highlighted in bold where 95% confidence intervals (CIs) do not pass through 1.

FIGURE 3.
FIGURE 3.:
Controls: infection detected as a proportion of each age group. Data are presented as per cases (Fig. 2). RSV indicates respiratory syncytial virus; RV, rhinovirus.

Clinical Diagnosis

The treating clinician assigned 3 clinical diagnoses for primary wheezing presentations: bronchiolitis, wheezing illnesses/viral wheeze and asthma exacerbation (Table 2). In general, the diagnoses were strongly related to age regardless of virus. No significant differences were found between any viral group for the proportion of diagnoses in each age group. The highest proportion of diagnoses in each age bracket were: bronchiolitis for the first year of life, wheezing illness/viral-induced wheeze in 1–3 year-olds, both viral wheeze/wheezing illness and asthma in 3–6 year-olds, and asthma from 6 years.

TABLE 2. - Emergency Physician Assigned Clinical Diagnosis According to Virus and Age
Age (years) Viral Category Bronchiolitis (n) Viral Wheeze/Wheezing Illness (n) Asthma (n)
0–1 RSV 25 1 0
RV-A 10 0 0
RV-C 7 1 0
No virus 4 0 0
>1–3 RSV 1 16 3
RV-A 0 17 4
RV-C 1 42 11
No virus 1 8 2
>3–6 RSV 0 2 0
RV-A 0 7 18
RV-C 0 15 53
No virus 0 2 9
>6 RSV 0 0 4
RV-A 0 4 21
RV-C 0 6 33
No virus 0 1 19
The 4 most common virus detections and number of cases per given diagnosis in each age group are presented. Age group where the diagnosis is most common is emphasized in bold.
RSV indicates respiratory syncytial virus; RV, rhinovirus.

Acute Wheezing Presentation SpO2, Admissions and Length of Stay

Both mean and median SpO2 (Fig. 4) in cases when compared between respiratory viruses showed similar results. RV-C was associated with the lowest geometric mean SpO2 (94.2%) and was significantly lower when compared with all other cases (95.5%, P < 0.001), RSV (96.2%, P = 0.006), RV-B (98.2%, P = 0.006), and all other viruses (non-RSV and non-RV) (96.3%, P = 0.04); but SpO2 with RV-C was similar to both SpO2 with RV-A (95.0%, P = 0.07) and SpO2 in those with no virus detected (94.3%, P = 0.818). Presentation SpO2 was lower in older children (r = 0.199, P < 0.001).

FIGURE 4.
FIGURE 4.:
Acute wheezing presentation median oxygen saturation (SpO2) for each virus category. Individual SpO2 for cases immediately before oxygen administration is plotted. Viral groups represent patients with only single virus detections. Other viruses (non-RV and RSV) were grouped together for comparison. Whiskers represent interquartile ranges with the central line showing median. Mann-Whitney U test P values compare median SpO2 between RV-C with other virus categories as displayed. RSV indicates respiratory syncytial virus; RV, rhinovirus.

The majority of cases were admitted (96.4%). Admission rates were not different between RV-A, RV-B, RV-C and RSV (95.8%, 100%, 97.8% and 100%, respectively). The length of stay was similar regardless of virus (see Figure, Supplemental Digital Content 4; https://links.lww.com/INF/E399). RSV showed a trend to shorter length of stay with increasing age (r = −0.36, P = 0.005), this was not found for any other viral group (RV-C r = 0.098, P = 0.194; RV-A r = −0.05, P = 0.645; no virus r = 0.203, P = 0.166). A weak trend was found between lower presentation SpO2 and longer lengths of stay (r = 0.134, P = 0.012).

DISCUSSION

We have defined the age-specific distribution of respiratory viruses detected in a large prospective study of children with acute moderate to severe wheezing. The results are striking in their clarity. For the first 6 months of life, RSV was the dominant cause of wheezing. From 6 months to 2 years, RSV, RV-A and RV-C were equally associated with wheezing, and rates for RV-C and RV-A were not significantly different to controls. From 2 to 10 years, RV-C was the significantly dominant cause of wheezing. After 10 years, RV-A and RV-C were the 2 most common viruses detected.

After the first 18 months of life, RSV rapidly declines in prevalence to reach zero cases by 5 years of age. RV-C prevalence increases in an almost linear fashion between 6 months and 5 years of age, then gradually decline until children are 10 years old. In contrast, RV-A shows no clear pattern and RV-B remains rare throughout. Numbers of subjects were high in the first 5 years of life with a sharp and consistent drop in numbers thereafter. This means that RSV and RV-C cause the greatest burden of disease as they are the predominant viruses in children less than 5 years of age when acute severe wheezing is most common. It may also help explain why the variation in prevalence with each year of age is lower in the first 5 years than after 5 years of age.

Our findings are highly consistent with previous published data on RSV and RV species, but more importantly, they make a major contribution to clarifying data from other centers. In particular, they help resolve apparent discrepancies in the literature on the predominance of RV-C in acute wheezing. In cases severe enough to result in presentation to hospital, populations where mean age falls between 2 and 10 years report higher rates of RV-C3,4,8,9,15 compared with other respiratory viruses, whereas those in older age groups and adults show a relatively higher prevalence of RV-A.10,12,16,17,19,28 In studies that include either community and nonhospitalized asthmatic children or children or adults who do not have acute wheezing, higher rates of RV-A compared with RV-C in controls have been found.29,30 In other words, our findings and those of others are consistent with RV-C being the most common virus detected in children of age 2–10 years with moderate or severe acute wheezing, but not in milder cases or in older subjects.

Although RSV age distributions have been previously described,31 this is the first study that relates RSV to RV species across a range of age groups from 0 to 16 years, accounting for acute wheezing severe enough for children to present to the hospital across a spectrum of childhood ages. Our results show that RSV ceases to be important in these cases after 4 or 5 years of age.

RV-C was associated with lower presentation SpO2. This is consistent with our previous findings linking RV-C with higher asthma severity scores in older wheezing children.3 to have sufficient power to find clinical differences, substantial numbers of patients were required and this study is one of the largest investigating differences between RSV and RV species specifically in the context of acute moderate to severe wheezing. We found cases with RSV had higher presentation SpO2; however, this may simply be a reflection of the age association with SpO2. Cases with RV-A and cases where no viruses were detected had comparable presentation SpO2 to RV-C suggesting that they both produce a wheezing illness of similar severity to RV-C, but as shown, largely affect an older population. The cause of wheezing in those without virus detected is unclear, and while nonviral factors may contribute, failed viral detection is possible and this becomes more likely in older ages due to reductions in nasal viral load.32

Although these results are from a single center, this study was conducted over a decade across all seasons and includes all age groups and is likely to be independent of annual viral variations. To avoid the potential limitations of diagnosis, we included all cases with acute wheezing rather than a specific diagnosis. We found that regardless of viral etiology, the diagnosis seems largely determined by age: bronchiolitis for 1–2 years of life, thereafter wheezing illness/viral-induced wheeze, and asthma was more commonly diagnosed after 5 years of age. This highlights a need for more objective determinants for diagnosis as our findings suggest that clinical manifestations are not virus specific but may be linked to age-related changes in host response to virus.

The relatively higher detection rate of viruses in the study’s controls compared with other studies20 may be due to using children from sources that would give higher exposures to respiratory infections (siblings/relatives of cases, daycare children and other hospitalized children). Given that nonwheezing sibling/relative controls had high exposure but low rates of RV-C further demonstrates that RV-C is a wheeze-related pathogen in children. The high rate of asymptomatic viral detection in controls is similar to that found in other community studies.25,33 A male bias in cases reflects epidemiologic findings where wheezing is more common in boys of this age range.34 Cases were younger than controls but data for individual ages were examined and presented. Also, as expected, there were fewer older than younger cases.35 To allow for this, older age group years were combined to facilitate comparisons.

The reasons why children are prone to more severe wheezing with RV-C and why this susceptibility peaks in preschool years are unclear. The mechanisms for RV-C infection are still under investigation, but progress in this area has been hampered by difficulties culturing RV-C, and a possible cellular receptor for RV-C has only recently been identified.36 Our understanding of adaptive RV-C immunity remains limited, but specific immune responses to RV-C appear to be impaired in asthmatics and nonasthmatics. Iwasaki et al37 demonstrated that RV-C-specific IgG1 antibodies are universally low in adults and children compared with RV-A, and RV-B, and the majority of the total antibody response to RV-C is cross-reactive with RV-A. Testing of antibodies in our cohort showed low-species specific RV-C titers in both asthmatic and nonasthmatic children even when the virus was found.38 However, total (specific and cross-reactive) antibody response to RV-A, RV-B and RV-C was increased in the asthmatic group. The susceptibility to wheezing with RV-C in young children suggests that a protective adaptive immune response to RV-C may take longer to develop and that innate immunity may play a larger, more important role in this age group. This supports other studies showing defects in innate antiviral immunity in asthma and wheezing particularly in childhood.20 Another possibility is that by age 10 most children will have been infected with, and acquired immunity to, the majority of the approximately 50 RV-C strains. Importantly, our study establishes that when investigating wheezing, asthma and immune responses to RV, age, disease severity and RV species must be considered.

In conclusion, this study used data from a large prospective study to establish the age-specific distribution of respiratory viruses in children with acute moderate to severe wheezing. RSV was the dominant virus associated with wheezing in the first 6 months of life and RV-C was by far the most important between 2 and 6 years of age establishing as the “pre-school wheezing virus.” These data have important implications in interpreting previous data on RV species and in directing future research both in clinical environments and in the laboratory.

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Keywords:

pediatric asthma; wheeze; rhinovirus; RSV; age

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