4. Discussion:
Our study shows a significant impact of bronchiolitis in our setting
during the 2022-2023
season. We observed a remarkable number of children requiring critical
care and MV,
compared to the last five seasons, and a significant rise in the
severity of bronchiolitis as
expressed by increased urgent codes at ED presentation, increased need,
and median duration of respiratory support, and increased median length
of stay.
We also confirmed a progressive increase in seasonal admissions for
bronchiolitis, mostly sustained by RSV which is shown to be persistently
more prevalent after the SARS-CoV-2
pandemic.
Conversely, we observed a decrease in SARS-CoV-2 cases, confirming what
is known from the literature about the limited role of SARS-CoV-2 as an
etiological agent of bronchiolitis [14].
The non-pharmaceutical interventions imposed by the pandemic initially
determined a
dramatic reduction in incidence rates of all infections, including
bronchiolitis [15-17], followed by a significant resurgence
associated with epidemiological changes, including out-of-season
outbreaks [6,10,18].
In our setting, as we have previously described, we had an out-of-season
resurgence in summer 2021, mainly driven by RSV, followed by an intense
and early 2021-2022 bronchiolitis season. In the last season, an
unprecedented peak of admissions, with an even earlier start was
observed. However, the seasonality pattern seems to be realigning to the
pre-pandemic seasons, and the 2023-2024 season may confirm this
observation.
Interestingly, as in the out-of-season period (May-August) 2021, we had
a significant number of children with out-seasonal bronchiolitis
requiring hospitalization in 2023. However, all 2023 cases were
sustained by different viruses other than RSV and had a mild disease
course.
The so-called “immunity debt”, is one of the possible explanations for
these epidemiological events observed worldwide [19]. It refers to
the lack of immune stimulation due to the reduced circulation of viral
and bacterial agents during the pandemic which may have increased the
pool of immunologically vulnerable individuals, specifically children.
The ”immunity debt” may be responsible for the increased impact of the
disease at the time of the RSV resurgence with the relaxing of the
non-pharmaceutical interventions.
In support of this theory, a decline in neutralizing RSV antibody titers
was found in infants and women of childbearing age in the Vancouver
metropolitan area, over one year (May – June 2020 and February – June
2021) [20].
Usually, infants achieve partial and transient immunity each year by
transplacental transfer. The decreased spread of RSV as a result of
anti-COVID-19 measures may have reduced the natural protection of the
population (including parents) against RSV thus powering the
intra-familial transmission. As a matter of fact, in our series, we had
a high number of infants aged 3 months or less affected by severe
disease.
More than three years after the beginning of the pandemic, the worsening
epidemiological trends seem to persist and the observation of such an
increase in disease severity must be carefully considered as a
substantial warning sign in our setting and demands adequate
interventions.
Currently, the only available strategy against RSV is the use of
palivizumab, a monoclonal
antibody that guarantees passive immunity in high-risk categories. The
use of palivizumab
is limited by high costs and the need for monthly administration
throughout the whole RSV season.
Recently, Nirsevimab a highly potent, long-acting, human recombinant
monoclonal antibody has been approved for use by the European Medicines
Agency [21].
The possibility of administering only one dose at the beginning of the
RSV season opens the opportunity for universal prophylaxis for all
newborns, not only for at-risk categories.
Indeed, in our series, most of the patients who required intubation and
MV were previously healthy infants with no comorbidities and no
indication for RSV prophylaxis. This confirms the efficacy of our
prophylaxis strategies in at-risk infants, which were modified according
to the epidemiological observations of the previous seasons. Moreover,
it highlights the urgent need for therapeutic/preventive interventions
to protect all newborns and infants without risk factors.
The potential reasons for the observed increase in the severity of
bronchiolitis are unclear. Pre-SARS-CoV-2 pandemic studies already
showed a rising trend in ICU admissions in
Europe over the last two decades [22], likely due to the increased
utilization of non-invasive respiratory support modalities, while the
number of patients requiring MV remained stable.
In our hospital, we observed a significant rise in the use of HFNC but,
at the same time, we were overwhelmed by the high number of children
requiring MV, determining substantial distress on hospital resources and
threatening critical care accessibility for other conditions. In
”normal” RSV seasons the number of mechanically ventilated bronchiolitis
in our center is unremarkable. For three months during this season,
one-fourth of the ICU beds were occupied by patients with severe
bronchiolitis.
Nevertheless, the establishment of a new stand-alone pediatric IMCU in
our Institute in December 2020 may have helped in relieving pressure on
the ICU and saving hospital costs and resources, allowing the management
outside the ICU of a significant number of cases not strictly requiring
critical care.
Other authors have tried to explain the increase in severity, suggesting
also that factors related to the COVID-19 pandemic may have favored the
emergence of more transmissible or virulent RSV strains [23], or
that SARS-CoV-2 infections may have induced immune dysregulation in
children, increasing their susceptibility to other respiratory viruses,
such as RSV [24]. However, current data does not appear to support
these hypotheses.
A recent study carried out in Rome, Italy [25], found that the
intense RSV peak in 2021–2022 was driven by RSV-A phylogenetically
related to pre-pandemic strains and therefore was attributable to the
immune debt created by pandemic restrictions. Interestingly, as in our
study, they observed an increase in disease severity in 2022-2023 with
most of the cases sustained by a genetically divergent strain of RSV-B.
This genetic divergence may have increased the RSV-B-specific immune
debt, being a possible contributor to bronchiolitis severity in
2022–2023. Unfortunately, we did not perform genetic characterization
of viral strains and cannot confirm these observations.
Limitations include the retrospective design and the single center
setting of the study. Moreover, our findings may be influenced by local
factors. In our series, 59% of patients who required MV were referred
to our center from local pediatric EDs. This could suggest that
intubation may have been a precautionary measure for the transport thus
overestimating the severity. However, our hospital has always been the
referral center for the Liguria region and the clinical management of
bronchiolitis refers to well-defined clinical and therapeutic pathways
with no changes in the last decade. Moreover, the ICU Critical Care and
ECMO Transfer Team of our hospital oversees all transfers, and
intubation was never reported as a precautionary measure in this cohort.
Similarly, although the organization of our hospital was modified at the
end of 2020 with the establishment of a new standing-alone IMCU, the
management of bronchiolitis in our institution has not changed in terms
of clinical and therapeutic decisions.