Human Rhinovirus Species and Season of Infection
Determine Illness Severity
Wai-Ming Lee1, Robert F. Lemanske, Jr.1,2, Michael D. Evans3, Fue Vang1, Tressa Pappas1,
Ronald Gangnon3, Daniel J. Jackson1, and James E. Gern1,2
1Department of Pediatrics,2Department of Medicine, and3Department of Biostatistics and Medical Informatics, University of Wisconsin School of
Medicine and Public Health, Madison, Wisconsin
Rationale: Human rhinoviruses (HRVs) consist of approximately
160 types that cause a wide range of clinical outcomes, including
asymptomatic infections, common colds, and severe lower respi-
Objectives: To identify factors that influence the severity of HRV
Methods: HRV species and types were determined in 1,445 nasal la-
in a birth cohort who had at least one HRV infection. Questionnaires
were used during each illness to identify moderate to severe illnesses
Measurements and Main Results: Altogether, 670 HRV infections were
identified, and 519 of them were solitary infections (only one HRV
type). These 519 viruses belonged to 93 different types of three
species: 49 A, 9 B, and 35 C types. HRV-A (odds ratio, 8.2) and
HRV-B. In addition, HRV infections were 5- to 10-fold more likely to
cause MSI in the winter months (P , 0.0001) compared with sum-
significant differences in host susceptibility to MSI (P ¼ 0.004) were
considered, strain-specific rates of HRV MSI ranged from less than
1% to more than 20%.
Conclusions: Factors related to HRV species and type, season, and
host susceptibility determine the risk of more severe HRV illness in
infancy. These findings suggest that anti-HRV strategies should fo-
cus on HRV-A and -C species and identify the need for additional
studies to determine mechanisms for seasonal increases of HRV se-
verity, independent of viral prevalence, in cold weather months.
Keywords: rhinovirus; severe illness; species; type; seasonality
Human rhinoviruses (HRVs) are the most prevalent human re-
spiratory viruses. Annually, they infect billions of people and are
responsible for at least one-half of all acute upper respiratory
illnesses (common colds), the most common illness of humans (1–
3). In addition to common colds, infections with HRV result in
a wide range of other clinical outcomes ranging from asymptomatic
infection to severe lower respiratory illnesses, such as bronchi-
olitis, pneumonia, and exacerbations of asthma (1, 4–7). It is
likely that host, viral, and environmental factors contribute to
the severity of illness caused by HRV infection. Indeed, more
severe HRV infections are associated with phenotypic charac-
teristics such as extremes in age; chronic respiratory diseases
such as asthma; reduced interferon responses in the blood and
airway; and, in early life, male sex and reduced lung function (4,
8). Little is known about viral and environmental determinants
of illness severity.
HRVs are a large group of genetically diverse RNA viruses
and are classified phylogenetically into three species (A, B, and
C). The 100 classical serotypes are found within species A and B,
and approximately 50 newly identified types are HRV-Cs (5,
9–15). This tremendous genetic diversity represents a major ob-
stacle toward developing both antivirals and vaccines for HRV,
and identification of HRV species or types with greater viru-
lence could help to focus these efforts.
The role of environmental and lifestyle determinants of HRV
illness severity is also of great interest. Factors associated with
more severe HRV respiratory symptoms include smoking, atten-
dance at day care, and, in individuals with respiratory allergies,
exposure to relevant allergens (4). There is some evidence that
vitamin D status may also affect the frequency and severity of
common colds (16), although data on HRV infections per se are
lacking. The time-honored axiom that being chilled increases
the susceptibility to or severity of colds is not supported by
experimental data (17).
To test the hypothesis that HRV species and types differen-
tially contribute to illness severity, we analyzed 1,445 samples
collected from 209 infants during scheduled and sick visits in
(Received in original form February 26, 2012; accepted in final form August 17, 2012)
Funded by National Institutes of Health (National Heart, Lung, and Blood Insti-
tute) grant P01 HL070831 and (National Center for Advancing Translational
Sciences) grant UL1TR000427.
Author Contributions: W.-M.L. directed and performed the virologic analyses and
wrote the manuscript; R.F.L. is the principal investigator of the birth cohort study
and contributed to study design and interpretation; M.D.E. and R.G. performed
the statistical analysis; F.V. and T.P. performed the viral diagnostics; D.J.J. con-
tributed to study design and interpretation; J.E.G. directed all aspects of the
project. All authors contributed to editing the manuscript.
Correspondence and requests for reprints should be addressed to Wai-Ming Lee,
Ph.D., Biological Mimetics Inc., 124 Byte Drive, Frederick, MD 21702. E-mail:
This article has an online supplement, which is accessible from this issue’s table of
contents at www.atsjournals.org
Am J Respir Crit Care Med
Copyright ª 2012 by the American Thoracic Society
Originally Published in Press as DOI: 10.1164/rccm.201202-0330OC on August 23, 2012
Internet address: www.atsjournals.org
Vol 186, Iss. 9, pp 886–891, Nov 1, 2012
AT A GLANCE COMMENTARY
Scientific Knowledge on the Subject
Why human rhinovirus (HRV) infections cause mild illness
in some children and more severe illness in others is not
What This Study Adds to the Field
We present definitive data to show HRV-A and HRV-C
cause more severe respiratory illnesses in infants. Given
the genetic diversity of HRVs, this provides an important
advantage in the design of therapies that can now be more
narrowly focused on HRV-A and HRV-C viruses. In ad-
dition, we report that season of infection has a major effect
on HRV virulence. Although peak prevalence occurs in the
spring and fall, virulence is greatest in the winter. These
advances in understanding the pathogenesis and risk factors
for more severe disease of HRV infections should lead to
new strategies for prevention and treatment.
the first year of life. These infants were enrolled in the COAST
(Childhood Origins of ASThma) cohort study (18) and are at
increased risk for developing allergies and asthma based on
parental histories. Sensitive and specific molecular assays (14,
19) were used to identify the HRV infections that were caused
by only one HRV type (solitary infection), and then HRV spe-
cies and type were compared with illness severity. In addition,
we tested whether the month of the year in which the illness
occurred could additionally influence illness severity. Prelimi-
nary findings from this study were previously published in ab-
stract form (20).
Study Subjects and Study Design
The Human Subjects Committee of the School of Medicine and Public
Health, University of Wisconsin-Madison approved this study. Written
informed consent was obtained from the parents. Of the 289 subjects
enrolled in the COAST Study at birth, 285 were followed prospectively
for 12 months. Eligibility criteria included having one or both parents
with allergic sensitization (one or more positive aeroallergen skin tests)
and/or asthma, and birth at 37 weeks’ gestation or more (18, 21–24).
Enrollment occurred during the prenatal period and commenced only
after obtaining informed consent from the parents. All specimens were
collected between November 1998 and May 2001.
Families were asked to contact the study center each time the infant
study personnel to perform a nasal wash at home or in the clinic. In ad-
dition, a nasal wash was performed at each of five scheduled visits (2, 4,
6, 9, and 12 mo) whether the infant was sick or well. Nasal washes were
tested for solitary HRV infection as described below. Altogether, 209
infants (72.3%) had at least one solitary HRV infection during the first
year of life and are included in this analysis.
Definitions of Illnesses
Symptom score was assigned to each visit according to a predefined re-
spiratory symptom scorecard (21). Illness was considered mild if the
score was 1 to 4 and moderate to severe (MSI) if a clinical symptom score
was 5 or greater. Viral detection in the absence of symptoms (score ¼ 0)
was considered asymptomatic infection.
HRV Molecular Detection and Typing
All nasal mucus samples were screened by respiratory multicode assay
(19) for infection of 20 different common respiratory viruses: HRVs,
enteroviruses, adenoviruses (B, C, and E), influenza (A, B), parain-
fluenza (1–3, 4a, 4b), coronaviruses (SARS, OC43, 229E, and NL63),
RSV (A, B), metapneumovirus, and bocavirus. Typing of HRV-
positive samples was performed as described (14) or by direct sequenc-
ing of polymerase chain reaction fragments of 59 noncoding region. An
isolate is assigned as a classical serotype (prefixed with R) or a new
type (W) by phylogenetic tree analysis. Briefly, if the new sequence
clusters with the sequence of one of the 101 classical serotypes, it was
assigned as that serotype, and if the new sequence has 9% pairwise
nucleotide divergence from the nearest serotype or type, it was desig-
nated as a new type (see online supplement for additional data). To
confirm the species assignment of the new types, representative samples
of each type were sequenced at the VP4-VP2 coding region (420-nt)
(25). All new sequences described in this report are deposited in the
GenBank (accession numbers JX041186-JX041253).
inducedMSIsdetectedatscheduledvisits as a functionofmonthand age.
To account for differential sampling of asymptomatic/mild infections and
MSIs, observed asymptomatic/mild infections were weighted by the in-
verse probability ofdetection ofMSI at scheduled visits (8.5) for analysis.
Becausea total of214 HRV MSIsweredetectedand25ofthemoccurred
at scheduled visits, the probability of detecting MSI at scheduled visits is
calculated to be 11.7%. Assuming that the detection probability of
asymptomatic/mild infections is similar to that of MSI at scheduled visits,
each asymptomatic/mild infection observed at a scheduled visit is repre-
sentative of a total of 8.5 (¼ 100/11.7) asymptomatic/mild infections
throughout the year. Mixed effects logistic regression models were con-
structed in terms of month and HRV group (A/B/C) as fixed effects,
subject and type as random effects, and the log-transformed probability
of detection as an offset term. Best linear unbiased estimators of the type
effects, subject effects, and their corresponding standard errors were
used to construct 95% empirical Bayes credible intervals for the type
(virulence) and subject (susceptibility) effects.
Infections and Illnesses
Overall, 209 infants had 1,445 nasal wash specimens in their first
year of life (Table 1). Of these specimens, 958 were from sched-
uled study visits and 487 were obtained during unscheduled sick
visits. Of the scheduled visits, 707 involved healthy infants (well
visit, symptom score ¼ 0), 223 involved mild respiratory ill-
nesses (symptom score 1–4), and 28 involved MSIs. All of the
unscheduled samples (n ¼ 487) were obtained during MSI. Vi-
rus was identified in 962 of the 1,445 samples (66.6%), and the
frequency of viral detection increased with illness severity (Fig-
ure 1; no illness, 44.6% [315 of 707]; mild illness, 78.5% [175 of
223]; MSI, 91.7% [472 of 515]). All common respiratory viruses
were detected (HRV, RSV A and B; coronaviruses NL63 and
OC43; parainfluenza 1, 2, 3, 4a, and 4b; human metapneumovi-
rus; influenza A and B; adenoviruses B, C, and E; enterovirus;
and bocavirus), and HRV was most common (696 [72.3%] of
virus-positive samples). More than one nasal mucus specimen
was collected during some illnesses: 223 specimens obtained
during mild illnesses were linked to 205 discrete illnesses, and
515 specimens were linked to 488 MSIs (Table 1).
HRV was detected in 696 of 1,445 samples (48.2%), and typ-
ing was successful in 98.7% of these samples. After accounting
for repeat samples during the same infection (n ¼ 26), coinfec-
tion with viruses other than HRV (n ¼ 123), coinfections with
two different HRV types (n ¼ 21), and negative typing results
(n ¼ 7), there were 519 infections with single HRV types.
Seasonality of HRV Infection and Illness
After statistically weightingto account formissed asymptomatic/
mild infections not seen at scheduled visits, there were 12.2
HRV infections per infant-year (95% confidence interval [CI]
Figure 1. Prevalence of human rhinovirus (HRV) infection according to
severity of illness. A total of 1,445 samples of nasal mucus collected
from 209 infants in their first year of life between March 1999 and
May 2001 were tested for common respiratory viruses. Viruses in the
non-HRV category included respiratory syncytial virus A and B, corona-
viruses NL63 and OC43, parainfluenza viruses 1 to 4, human meta-
pneumovirus, influenza A and B, adenovirus B and C, enteroviruses,
Lee, Lemanske, Evans, et al.: Rhinovirus Species and Season Determine Illness Severity887
8.7–18.9), with 49% asymptomatic, 46% mild illnesses, and 5%
MSI. HRV infections occurred year-round and were greatest in
the spring and fall (Figure 2A). Rates of HRV infection were
approximately threefold higher during peak prevalence months
in March, September, and October (4.6, 4.3, 4.3 infections per
100 child-days, respectively), compared with January and July
(1.3, 2.0 infections per 100 child-days).
We tested whether the month of infection influenced the
probability that an HRV infection would produce MSI among
the 519 infections caused by a single virus. The severity of
HRV illnesses had a clear seasonal pattern (P , 0.0001), and
infections were most likely to cause MSI during December to
February (12–23%) and least likely to cause MSI during April
to August (2–3%, Figure 2B).
Virulence of HRV Species and Types
A viruses, 37 HRV-B, and 225 HRV-C. Both HRV-A (odds ratio
[OR], 8.2; 95% confidence interval [CI], 2.7–25) and HRV-C
(OR, 7.6; 95% CI, 2.6–23) were significantly more likely than
HRV-B to induce MSI (Figure 3).
The 519 solitary HRV isolates belonged to 93 types: 49 HRV-
A, 9 HRV-B, and 35 HRV-C types. Eighteen types were found
only once. The remaining 75 types were identified two or more
times, and 19 types were detected ten or more times (R19, R28,
R52, R56, R78, R88, R89, W01, W05, W06, W11, W12, W23,
W24, W26, W28, W29, W32, and W38; see online supplement
for details in type assignment). The 93 types segregated into two
groups according to their probability of inducing MSI (“viru-
lence”). The nine HRV-B types clustered together in the low-
virulence group, and HRV-B-R52 had the lowest virulence
(0.5%; 95% CI, 0.3–0.8%). The 84 HRV-C and HRV-A types
were more virulent; in this cluster, the probability of MSI ranged
from 3.1% (HRV-C-W36; 95% CI, 2.1–4.4%) to 11.7% (HRV-C-
W12; 95% CI, 8.7–15.5%).
Of the 214 HRV-induced MSIs, 41 (19%) were associated
with wheezing. Although the number of wheezing illnesses was
too low to be modeled, there were numerically fewer wheezing
illnesses caused by HRV-B (n ¼ 0) compared with either HRV-
A (n ¼ 27) or HRV-C (n ¼ 14). There were 186 acute care visits
for HRV illnesses, including 111 HRV-A, 4 HRV-B, and 71
HRV-C. Only two HRV illnesses required hospitalization, and
both of these were due to HRV-A infections.
(P ¼ 0.004). When significant differences in host susceptibility
to MSI (P ¼ 0.004) were considered, strain-specific rates of
HRV MSI ranged from less than 1% to more than 20% (Figure
4). The mean risk of MSI per infection was approximately 2%
for children in the least susceptible tertile, 5% for average chil-
dren, and about 10% for more susceptible children. Given
the estimated frequency of 12.2 infections per child per year,
the corresponding risks of at least one HRV MSI per year were
22%, 47%, and 72%, respectively. The effect of virus type on
MSI risk was most pronounced for more susceptible infants;
however, HRV-B types were unlikely to cause MSI regardless
of individual susceptibility (Figure 4).
The advent of sensitive molecular techniques for viral diagnosis
has led to an increased appreciation of the strikingly broad range
of clinical illness caused by HRVs. Epidemiologic studies rou-
tinely report high rates of HRV detection in children with com-
mon colds, wheezing illnesses, and pneumonia, and even in the
absence of symptoms. In this study of infants participating in
a birth cohort study who were prospectively monitored for evi-
dence of infection and illness, the results provide definitive
evidence that HRV species and type impact the severity of re-
spiratory illness. HRV species A and C were each about seven
the nine individual HRV-B types clustered together into a low-
virulence group and were unlikely to cause MSI even in more
susceptible children. Collectively, these findings strongly suggest
that antiviral strategies aimed at reducing HRV-related morbid-
ity in high-risk infants should focus on HRV-A and HRV-C spe-
cies viruses. Another novel finding was that the peak prevalence
and severity of HRV infections did not correspond; HRV infec-
tions were most frequent in the spring and fall but were more
likely to cause severe illnesses in winter (December to Febru-
ary). Identifying factors related to season and host that promote
TABLE 1. NASAL MUCUS SPECIMENS AND TOTAL ILLNESSES
Specimens According to Visit Type
Illness CategoryScheduledUnscheduled Total Total Illnesses*
MSI ¼ moderate to severe illness.
*Some illnesses (n ¼ 45) had more than one associated nasal mucus specimen.
Figure 2. Epidemiology of hu-
man rhinovirus (HRV) infec-
infections were identified in
670 of 1,445 samples, and in-
fection rates (per 100 child-
days) were plotted according
to the month of sampling
(A). The seasonality of res-
piratory syncytial virus infec-
tions in the study is included
for contrast. To examine the
relationship between season
and severity of illness, the
percent of solitary HRV infec-
tions (n ¼ 519) that caused
moderate to severe illness (MSI) was estimated using mixed effects logistic regression models (B). Month of infection was strongly associated
with the risk of MSI (P , 0.0001). Error bars represent 95% confidence intervals.
888AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINEVOL 186 2012
more severe HRV illnesses is an important goal, especially in the
absence of specific therapies.
The recent discovery of the HRV-C species (12–15) prompted
renewed interest in studying the etiology and epidemiology of
HRV infections. Since then, multiple studies have compared the
virulence of HRV-C relative to the classical HRV-A and -B
species (13, 26–36). In several of these studies, HRV-C viruses
appear to be overrepresented compared with HRV-A and -B
in infants and children with lower respiratory infections and in
exacerbations of childhood asthma. These studies focused on
analysis of samples from ill (usually hospitalized) children and
were limited by the lack or paucity of concurrent sampling of
asymptomatic or mild illnesses. In this study, we prospectively
obtained samples from infants with clinically significant respira-
tory symptoms and also from those with mild or no symptoms.
Our model indicates that approximately one-half of the HRV
infections were asymptomatic (Figure 2A), which underscores
the importance of including routine sampling in determining pat-
terns of HRV infection and illness. In addition, both HRV-A
and HRV-C viruses were more virulent than HRV-B viruses
in infants. This finding is in agreement with a recent case-
control study of hospitalized children (37).
The finding that HRV-B types seldom cause more severe ill-
ness has implications for antiviral drug development. For exam-
ple, the A and B species designations roughly correspond to
patterns of sensitivity of HRV to capsid-binding drugs, such
as pleconaril or WIN compounds (38). These data suggest that,
at least for infants, capsid-binding agents could be designed
to target HRV-A and HRV-C, which is phylogenetically closer
to HRV-A than to HRV-B (11, 39). The same principles could
also apply to other antiviral agents and to efforts to develop
a vaccine for HRV. Once considered extremely unlikely due
to the large number of serotypes, there have been reports of
antibody responses to shared HRV epitopes with some neutral-
izing capability (40).
Multiple studies have shown that HRV illnesses have a pre-
dominant peak in the fall and a smaller but still distinct peak
in the spring and are present at low rates (20–30% of the fall
peak) throughout the rest of the year (2, 3, 41). The times of peak
prevalence were similar in our study of infants, but in contrast to
other studies the infection rate remained relatively high (63–85%
of the fall peak) in 7 of the remaining 9 months and substantial
(30 and 45%) even in the 2 lowest months. The higher-than-
expected prevalence rate outside of fall and spring could be
due to the inclusion of asymptomatic HRV infections in our
analysis, in contrast to sampling only symptomatic infections in
most other studies. However, a similar pattern of seasonality was
obtained when we limited the analysis to symptomatic infections
only (Figure 2A). Another potential explanation for the higher
off-season HRV prevalence is that infants are more susceptible
to HRV infection than older children and adults, which implies
that young children could serve as an important reservoir for
HRV during periods when prevalence is low in other age groups.
Despite the relatively low prevalence of HRV infections dur-
ing the winter, infections at this time of year were more likely to
cause MSIs. This finding raises interesting questions about un-
derlying mechanisms for the observed seasonality of illness
severity. The summer nadir and winter peak suggest the possi-
bility that vitamin D reduces the severity of HRV illness, and
there are epidemiologic studies that support this theory (16).
Alternatively, the prevalence of many other respiratory patho-
gens peaks in the winter, and it is possible that recent infection
with other respiratory viruses or interactions with colonizing
bacteria enhance the severity of subsequent HRV illness. Ad-
ditional studies are warranted to investigate these and other
Figure 3. Differential virulence of human rhinovirus (HRV)
species and types. The species and types of the 519 soli-
tary HRV infections were determined by partial genome
sequencing. The probability of inducing moderate to se-
vere illness (MSI) by each species (A) and type (B) was
estimated using mixed effects logistic regression models.
Error bars represent 95% confidence intervals.
Figure 4. Risk of human rhinovirus (HRV) moderate to severe illness
(MSI) depends on both susceptibility and virus type. Using mixed
effects logistic regression models, we estimated the virulence (propen-
sity to cause MSI) of the 93 different HRV types (x axis, ordered low to
high), and the susceptibility to MSI for 219 study participants (y axis,
ordered low to high). The graph illustrates the risk of MSI for all combi-
nations of subject susceptibility and HRV type. The species of each type
is indicated on the upper color bar (A ¼ black; B ¼ green; C ¼ red).
Lee, Lemanske, Evans, et al.: Rhinovirus Species and Season Determine Illness Severity 889
This study has a number of strengths and some limitations to
consider in interpreting these data. Up to 20 HRV types circu-
late simultaneously in a community (2, 42), and the spectrum of
types changes from season to season (3, 42, 43). To define the
virulence of individual types, it is therefore advantageous to
analyze a large number of samples collected over relatively
few seasons. In this study, 1,445 samples were collected in
2.3 years, yielding 519 solitary HRV infections. State of the
art viral diagnostics were used; typing of the HRVs detected in
this study was successful in a very high percentage (98.7%) of
samples, which provided an unbiased data set to test for rela-
tionships between species, type, and illness outcomes. The
study included young infants with little previous exposure to
other HRVs, which minimized the effects of adaptive immu-
nity to prior infections. It should be considered that clinical
responses to HRV infections could be age dependent, and
whether these findings hold true for other age groups remains
to be determined. Finally, our findings do not distinguish whether
species-specific differences in illness severity are related to dis-
tinct patterns of viral replication or inflammatory responses.
In conclusion, the development of antiviral drugs for the
treatment of HRV infections is an important and unmet medical
need that is especially important for high-risk patients, including
challenge to these efforts, and our findings suggest that narrow-
ing the focus of anti-HRV medications or vaccines to target A
and C species viruses is a viable strategy. Finally, understanding
the individual and seasonal factors that contribute to more se-
vere illnesses could lead to the development of new therapeutic
approaches to reduce the overall burden of respiratory illness in
Author disclosures are available with the text of this article at www.atsjournals.org.
Acknowledgments: The authors thank the clinical coordinators for their efforts in
patient recruitment, retention, and the procurement of all of the biologic speci-
mens used in these analyses. They also thank the Wisconsin State Lab of Hygiene
for support, the many health care professionals within the surrounding commu-
nities for their cooperation, and the COAST families for their enthusiastic partic-
ipation. They also thank Mr. Robert Gordon (Department of Pediatrics, University
of Wisconsin-Madison) for graphic illustrations.
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