RSV and Asthma: The Chicken or the Egg?
Tina V Hartert, MD, MPH1,*
1
Department of Medicine, Division of Allergy, Pulmonary and Critical Care Medicine, Vanderbilt
University School of Medicine, Center for Asthma & Environmental Sciences Research, 6107
MCE, Nashville, TN 37232-8300
*Corresponding author
Tina V. Hartert, M.D., M.P.H.
Division of Allergy, Pulmonary and Critical Care Medicine
Center for Asthma & Environmental Sciences Research, 6107 MCE
Vanderbilt University School of Medicine
Nashville, TN 37232-8300
Phone: 615-322-3412
Fax: 615-936-1269
E-mail: tina.hartert@vanderbilt.edu
Keywords: Respiratory syncytial virus, lower respiratory tract infection, bronchiolitis, asthma,
recurrent wheezing
Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract
infections (LRTIs), during infancy, and almost all children have been infected at least once by
age 2 years. By age 2, almost all children have been infected with RSV and most have been
infected twice. The initial RSV infection is usually the most severe, causing LRTI, such as
bronchiolitis, in 20-30% of infants. However, for reasons that are not fully understood, the
immune response to RSV is incomplete and reinfection with RSV occurs throughout the life.
There are well established links between RSV illness and asthma. First, it is well established
that among infants who require hospitalization for RSV bronchiolitis, as many as 20-40% in
various studies develop asthma by age 13 years. Second, viral infections are the most frequent
and important cause of asthma exacerbations in children, implicated in up to 85% of disease
exacerbations.
While these data convincingly demonstrate that infants who develop viral-associated
bronchiolitis have a high risk of developing asthma, and animal studies demonstrate biologically
plausible mechanisms through which RSV may contribute to asthma, these studies can not
answer the question of whether RSV contributed to asthma inception or was merely the first
manifestation of reactive airway disease in a genetically predisposed child. The aims of this
overview are to review the evidence of the relationship between RSV infection and subsequent
asthma.
Studies of the influence of RSV infection on the risk and severity of childhood asthma
The occurrence of recurrent wheezing after RSV LRTI has been recognized for decades.
We and others have demonstrated that children hospitalized for RSV bronchiolitis during
infancy are more likely to have subsequent episodes of wheezing and asthma during the first
decade of life compared with children without a history of a bronchiolitis hospitalization during
infancy [1-7]. Whether this risk persists throughout adolescence and into adult life is less clear,
as longitudinal studies suffer from significant patient drop-out. Those studies which follow
children longitudinally past 10 years suggest that RSV may no longer be significantly associated
with asthma risk. The association of increased asthma risk among infants with RSV LRTI during
infancy is consistent in most studies, and most pronounced during the first 6 years of life.
Two ongoing longitudinal studies of infants with RSV bronchiolitis suggest that RSV
infection does increase the risk of wheezing and later childhood asthma [1,2]. Sigurs and
colleagues reported an increased prevalence of asthma or recurrent wheezing and allergic
sensitization in children with RSV bronchiolitis at multiples timepoints, including at age 18,
where 39% of the children who had suffered from RSV bronchiolitis in infancy were
documented to have asthma or recurrent wheezing compared to only 9% in the control group.
Somewhat different results were obtained in the Tucson Children’s Respiratory Study which
prospectively enrolled 1246 infants born between 1980 to 1984 [1]. In this study, LRTI with
confirmed RSV infection was associated with increased risks of infrequent and frequent
wheezing at age 6, but the risk was reduced as children became older, and was not statistically
significant by age 13 years. Taken together, these studies demonstrate that severe RSV
bronchiolitis is associated with a 30 to 40% increased risk of subsequent asthma, at least within
the first decade of life. The difference in asthma risk after the first decade of life between the
two studies might be simply due to the differences in the populations studied, as well as the
severity of infant RSV infection between the two groups. Recently, follow up of the children at
age 22 years in the Tucson Children’s Respiratory Study has been reported. Asthma at age 22
years has been found to be associated with recurrent wheezing at age 6 years [7]. Although the
relationship between RSV infection in early childhood and later asthma development was not
significant at age 13 years in this cohort of children, a revisit of the association of asthma at age
22 years with RSV infection during early childhood will provide insights into the importance of
this early life event.
The causal relationship of RSV infection on the development of wheezing and asthma
Is the increased association of asthma following infant RSV infection an epiphenomenon
due to enhanced airway inflammation and injury among those genetically predisposed to
develop asthma, or does RSV alter the host defense, lung and/or immunity and truly cause
asthma? A few recent studies have been aimed to address this question. We identified a dosedependent relationship between increasing infant bronchiolitis severity and both increased
asthma risk and increased asthma severity among a population-based cohort of children
covered under a US state-based health insurance plan, the TABS (Tennessee Asthma &
Bronchiolitis Study) cohort.[4,8] This has been replicated using data from a managed care
organization by Escobar and colleagues.[6]
In the TABS study, we specifically evaluated the causal role of winter viral respiratory
epidemics in the development of asthma among nearly 100,000 infants in a retrospective birth
cohort [8]. We did this by investigating the relationship between infant age at the first winter
viral peak following birth and subsequent asthma risk during the fifth to sixth year of life.
Infants who were 4 months old at the peak of winter viral season were more likely to develop
both clinical bronchiolitis and childhood asthma. Despite the winter viral peak shifting by nearly
two months over the six winter viral seasons studied, the risk of asthma shifted in any given
year with the shift in the peak of the winter viral peak such that infants born approximately 4
months prior to the first winter viral peak they encountered following birth were at the highest
risk of developing childhood asthma. This strongly suggests a causal role of early RSV infection
on asthma development.
Three additional studies provide evidence, however, to dispute RSV causality. In a
population based study among Denmark twins [9]. Thomsen and colleagues fitted genetic
variance components and direction of causation models to over 8,000 twin pairs [9]. A model in
which RSV hospitalization causes asthma was rejected, whereas one in which asthma causes
RSV hospitalization was not. In another attempt to detect the causality between RSV and
asthma, Stensballe and colleagues reported that the effect of RSV hospitalization on asthma
was only short term (2 months after RSV hospitalization) and no longer significant 1 year later
[10]. Lastly, a study of 37 monozygotic twin pairs discordant for severe RSV bronchiolitis in
infancy indicated no differential effect of severity of RSV infection on the development of
asthma [11]. All three twin studies utilized RSV bronchiolitis information from patient registries.
Twins who were discordant for RSV hospitalization were highly likely to be concordant for RSV
infection given the known high infectivity. Therefore, any conclusion about causality suffers
from the misclassification of twins not hospitalized with RSV infection to an uninfected group.
In addition, asthma was defined at an early age in two of the three twin studies. Children were
considered as having asthma as early as infancy or by age 3 years, which may well reflect
children with “transient early wheezing” but not asthma.
The impact of prevention or treatment of RSV on asthma risk
Ultimately to address the question of whether RSV infection during infancy causes
asthma, showing that prevention or delay in infant infection prevents asthma will be necessary.
There is very limited data, in the form of two small studies, which suggest that RSV
immunoprophylaxis may lower the likelihood for the development of asthma. The first is a
small investigation of 13 children identified retrospectively as having received RSV
immunoprophylaxis, showing that receipt of RSV immunoprophylaxis during infancy may have
long-term effects on respiratory and immunologic parameters relevant to the development of
asthma [12]. The second study is an industry-sponsored investigation of open-label
compassionate-use RSV immunoprophylaxis among a European cohort of preterm infants
showing decreased wheezing outcomes among infants receiving immunoprophylaxis. There are
substantial limitations to the design and selection of subjects, including use of RSV
immunoprophylaxis on a compassionate use basis with no delineated indications nor standard
recommendations for use in each child [13]. In addition, the age of the children in this
investigation at follow-up was only 19-43 months. Lastly, an open-label study assessing the
impact of treating (not preventing) active RSV bronchiolitis with the anti-viral agent ribavirin
showed a reduction of the risk of asthma and allergic sensitization at age 6 years among
children 2 years and less who did and did not receive ribavirin for RSV bronchiolitis [14]. This
study also has limitations, in that those who did and did not receive ribavirin differed
significantly in age of RSV bronchiolitis, prematurity and disease severity.
Summary
To summarize the evidence in support of a role of RSV in asthma causation there is: (1)
Ecological evidence of increasing rates of infant bronchiolitis in the last ten years mirroring the
5-year offset increases in asthma at age 5 years among these same children; (2) Dose-response
relationship with a positive severity-dependent association with both asthma risk and asthma
morbidity; (3) Known common host immune factors for both diseases, with persons with
asthma known to be at increased risk for viral infections and invasive bacterial infections; (4)
Genetic evidence with genes predisposing to asthma also linked to susceptibility and severity of
RSV infection; and lastly (5) Causal evidence with demonstration for the first time that timing of
birth in relationship to when RSV circulates independently predicts asthma development, with
birth timing conferring a nearly 30% increase in risk of early childhood asthma. Ultimately,
however, showing that prevention or delay in infant infection prevents asthma will definitively
answer the question of whether RSV causes asthma, and potentially provide an important
primary asthma prevention strategy.
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