Discussion
In our large prospective study investigating the burden of multiple
respiratory viruses in hospitalized Jordanian children under two years,
more than half of the subjects presented with wheezing, and the vast
majority of subjects had virus detected. The most frequently detected
viruses in wheezing subjects in order of highest frequency were RSV,
HRV, AdV and HMPV.
Other studies have demonstrated a similar relative proportion of RSV and
HRV detected in subjects hospitalized with wheezing illness; in a
Japanese study of children under three years hospitalized with lower
respiratory tract infections, among wheezing subjects, 33% had RSV,
14% HRV, and 2% HMPV20. In a 4-year study
of infants <12 months hospitalized with bronchiolitis in
Greece, 79% had RSV, 17% HRV, 2% HMPV, 10% influenza, 3%
coronaviruses, and 1% PIV21. In contrast with
our cohort, a Finnish cohort of children 3 months-16 years (median age 2
years) admitted with acute wheezing, they detected a lower frequency of
subjects with RSV (14%), but more subjects had HRV (27%) and 9% had
HMPV. The older cohort may explain more HRV detected compared with RSV,
as studies have shown that HRV-associated LRTI becomes more common as
children age 21. This
study also excluded children with severe wheezing and ICU treatment, but
noted that RSV-positive children tend to have more severe manifestations
of LRTIs than those with HRV21.
We also found that RSV and HMPV were detected in a significantly higher
percentage of subjects with wheezing than in those without wheezing, and
this persisted after adjusting for multiple variables. Supporting our
findings, RSV has been reported to be the leading cause of LRTIs
requiring hospitalization in young infants3,5,22,23.
HMPV has also been identified as an important pathogen in upper and
lower respiratory tract infections8. Studies of children
with acute LRTIs reported HMPV frequency similar to our cohort, ranging
from 2-13%3,5,10,20,21,24,
including hospitalized children in the Middle East17. Given that HMPV
resembles RSV infection cytopathologically, clinically and
epidemiologically, it is not surprising that it was found to be an
important contributor to wheezing illness in our study.
While HRV was identified in a significant proportion of young,
hospitalized patients in our study, we did not observe a significant
difference in HRV among those with wheezing versus those without
wheezing. Possible reasons for this observation include the fact that
the median age of our wheezing subjects was five months, a minority had
atopic mothers, relatively few of the children themselves were atopic,
and all patients presented with severe symptoms requiring
hospitalization. The prevalence of HRV in patients with wheezing and/or
bronchiolitis increases with age and is more common in children with
recurrent wheezing2,7,21.
A Finnish study 7 of
hospitalized children found that those with HRV infection were older
than those with RSV infection; this is supported by our finding that RSV
was detected more frequently in younger subjects with wheezing than
older subjects. Studies have also shown that HRV-associated wheezing is
observed more frequently in atopic children7,25and that maternal atopic asthma is a risk factor for HRV-associated
wheezing 7. An
outpatient study of patients with an atopic parent found that HRV was
the most frequently detected infection in LRTIs (40.7%) and contributed
to three times the number of LRTI and wheezing LRTIs than RSV3. Our young cohort with
less predominant personal and parental atopic history may explain the
predominant effect of RSV (and not HRV) on wheezing.
In our cohort, personal history of RAD or family history of asthma were
associated with higher OR of wheezing, but maternal atopy and asthma
were not associated with wheezing. According to the Tucson Children’s
Respiratory Study, there are four patterns of wheezing in early
childhood: never wheeze, transient early wheeze, late-onset wheeze and
persistent wheeze 26.
Although the current study was not a longitudinal study that would allow
us to accurately determine the ultimate wheezing phenotype of our
subjects, since most children who wheeze before two years of age do not
develop recurrent wheeze or asthma later in childhood2,27,
it is likely that a significant proportion of children in our cohort
were of the transient early wheeze phenotype. Such children do not tend
to have history of maternal asthma or personal history of atopy2,26.
Alternatively, a potential impact of maternal asthma on development of
childhood wheeze may not have been detected due to the low frequency of
maternal asthma in our cohort. A follow-up study of these children could
provide insight regarding whether or not they developed asthma.
This study has both strengths and limitations. Given the large cohort,
we were able to compare differences among multiple viruses and the
association of wheezing. However, since this was not a longitudinal
study and there was no follow-up of subjects to determine if they
developed recurrent wheezing or asthma beyond the age of five, we are
unable to directly ascertain the link between virus-induced wheezing and
recurrent wheeze or asthma. While epidemiological studies are often
limited by difficulty in accurately diagnosing wheezing in young
children, particularly through clinical assessment by parents28, in our study
wheezing was diagnosed by both clinical assessment and physical exam by
a physician, making the diagnosis more reliable. This study investigated
wheezing illness specifically in hospitalized children, which provides
useful information for patients with potentially more severe disease.
This is a year-round surveillance study conducted over a period of three
years, and therefore allows us to capture viruses during several
seasons. It also is one of the few studies in Jordan/Middle East that
used highly a sensitive molecular diagnostic technique for detection of
viruses in such a large cohort of hospitalized patients29.
In summary, this investigation demonstrates that wheezing in children
under two years is associated with RSV and HMPV. Although HRV is a known
important risk factor for wheezing, particularly in older children with
atopic parental or personal history, an association between HRV and
wheezing was not seen in our cohort. This study provides useful data on
the burden of respiratory viruses with clinical and demographic factors
for wheezing illness. These data can be used to design future
longitudinal studies to evaluate the association between early childhood
viral acute respiratory infections and recurrent wheezing later in
childhood, and to determine which virus interventions, such as
vaccination or antiviral therapy that would be most effective at
preventing development of wheezing illness.