Enhanced Neutralizing Antibody Responses to Rhinovirus C and Age-Dependent Patterns of Infection

Abstract

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ²) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

Keywords: CDHR3; epidemiology; genetics; rhinovirus; wheezing.

Figure 1.

Relationship of age to frequency of rhinovirus (RV) C and RV-A detection during illnesses in the COAST (Childhood Origins of Asthma) birth cohort. RV types and species (A, B, and C) were determined in nasal samples by partial sequencing. Detection rates (%) of RV-A and RV-C at different ages are shown as bar plots. Odds ratios (ORs) refer to the odds of RV-C relative to RV-A at older ages compared with younger ages. Groups were compared using Fisher’s exact test. P values of <0.05 were considered to indicate statistical significance. Illnesses: OR = 0.31; 95% confidence interval (CI), 0.21–0.45); P < 0.0001. Scheduled visits: OR = 0.31; 95% CI, 0.14–0.64; P = 0.0006. N represents the number of samples analyzed for each age category.

Figure 2.

Neutralizing antibody (nAb) responses to selected rhinovirus (RV) A and RV-C types in the COAST (Childhood Origins of Asthma) study children. Heatmaps show the presence of nAbs to indicated RV-A (blue) and RV-C (red) types in plasma (ages 2, 10, and 16 yr; each row represents serial sampling from the same subjects) from COAST study participants (n = 20). Odds ratios (ORs) refer to odds of finding nAbs to RV-C relative to RV-A at different ages. Age 2: OR = 3.9; 95% confidence interval (CI), 1.6–9.5; age 10: OR = 4.0; 95% CI, 2.0–7.7; and age 16: OR = 7.1; 95% CI, 3.8–13.3. The differences in nAb responses to RV-A versus RV-C were highly significant at all ages tested. (P < 0.0001, generalized estimating equation logistic regression). A7 = RV-A7; A16 = RV-A16; A36 = RV-A36; C2 = RV-C2; C15 = RV-C15; C41 = RV-C41.

Figure 3.

Frequency of detection for each rhinovirus type and ratio of detection proportions for sick versus well visits in the pooled dataset. The species is color coded, and individual types are numbered within each species. The size of the numbers is proportional to the negative logarithm of the P value, and numbers in boxes are significant at the 5% level (unadjusted for multiple comparisons). Error bars (vertical lines) represent 95% confidence intervals for the ratio of detection proportions. Horizontal lines point at error bars for numbers that were scattered from them in congested areas to avoid overlapping.

Figure 4.

Ratio of rhinovirus (RV) C to RV-A in illness samples from the pooled dataset with respect to age. Individual points represent the RV-C to RV-A detection ratio for each year of age. The line and shaded area represent the logistic regression model fitted to the sample-level data and the associated 95% confidence intervals, respectively.

Figure 5.

Age distribution of 14 study cohorts (see Table E1 in the online supplement) included in pooled sample analysis. Symbols represent samples included in this analysis by cohort and the age of sample acquisition. Age windows were used in the multivariable analyses, and start points and endpoints were assigned based on ages at which a study or studies started contributing samples or stopped contributing samples to the overall pool.

Figure 6.

Analysis of covariates related to the rhinovirus (RV) C to RV-A ratio. Odds ratios (logistic regression) were calculated to compare the RV-C/RV-A ratio to the CDHR3 asthma risk allele (A) (rs6967330_G→A, 1 or 2 risk alleles compared with 0) and to illness type (B and C) (B, lower respiratory illness [LRI] vs. upper respiratory illness [URI]; C, wheezing LRI vs. URI). Odds ratios for each age interval were calculated together with an overall odds ratio including all ages. Whisker bars represent 95% confidence intervals.