Discussion
This study reported that children between 1-60 months with viral
coinfection increased the risk of admission to the ICU for
HFNCO/BiPAP/IMV assistance. While RSV and HRV (except for between 25-60
months) coinfections were associated with severe disease in all ages,
PIV3 (7-24 months) and HBoV (7-12 months) coinfections led to severe
LRTI in early childhood. Besides, our study showed that influenza A
coinfection was independently a risk factor for severe LRTI in children
between 7-12 months and 25-60 months.
In our study, children with viral coinfection constituted 28.3% of the
study population, and HBoV was the most common virus after RSV and HRV.
Previous studies conducted in Barcelona and Rome20,21,
where the Mediterranean climate is dominant, like Izmir, had similar
results to that presented here. On the contrary, other studies reported
from Canada and Japan7,22, where the continental and
subtropical climate is dominant, found that viral coinfection was 17.2%
and 15.8% of the patients, with the third common virus as influenza A
and HMPV, respectively. These results emphasize that the seasonal
distribution and frequency of viruses may vary in different countries
according to their geographical and meteorological characteristics.
Furthermore, the annual circulation of infections and the composition of
the study population and method used in virus detection may also affect
the viral coinfection rate. For example, the studies conducted in
infants or hospitalized patients may determine a higher viral
coinfection rate than those held in adults or population-based studies
because of the more frequent detection of multiple-viruses in these
patients21. The authors should interpret the viral
coinfection rate carefully among different studies. Children with viral
coinfection were 3.4 times more at risk of admission to the ICU than
those with a single virus infection, concordant with the previous
studies6,23. Several possible explanations for these
results are that the direct interactions among viral genes or gene
products and host immune system, the indirect interactions of host
environmental changes, and the immunological interactions may determine
the course of LRTI in children with viral
co-infection24,25. The first virus may boost viral
superinfection by consuming host defense, similar to bacterial
infection26. Moreover, the coinfection of two distinct
virus types may have affected the natural course of LRTI in children.
Although HRV generally causes a common cold in
children27, it reduces cell proliferation and
bronchial epithelial cells’ self-repair capacity28.
Thus, any secondary virus infection may increase the risk of severe
illness. Besides, HRVs are a large group of genetically diverse RNA
viruses, and HRV sub-types, particularly HRV-A and -C, have been shown
to cause severe LRTI in children29. Unfortunately, we
could not determine HRV sub-types in the respiratory specimens because
of our virus detection method. These sub-types might have infected some
severe cases. This issue stands as an interesting subject for further
research. Richard et al.6 found that infants with RSV
coinfection were at 2.7 times higher risk of admission to the ICU, while
Semple et al.23 determined a 10-fold higher risk of
IMV in children under two years of age who had RSV and HMPV coinfection.
Additionally, our results suggested that RSV coinfection remains an
essential agent for severe LRTI not only in children younger than 24
months but also in those beyond 24 months. Since there is no existing
vaccine for RSV, the consideration of passive immunoprophylaxis during
RSV season may protect children with an underlying medical condition
from severe RSV co-infections17.
Coinfection with other viruses is very common during influenza
infection30. In recent
meta-analyses31,32, COVID-19 coinfection was
identified more commonly with influenza A and RSV. Although it was
suggested that children with COVID-19 had a better prognosis than
adults, influenza A coinfection with COVID-19 may inhibit the host’s
immune system, increase antibacterial therapy intolerance, and be
harmful disease’s prognosis31. Besides, secondary
bacterial infections may exist at a rate of 40% in influenza A
infections33. Therefore, we note that any secondary
bacterial infection, which was not detected, might increase influenza
A’s severity. However, a comprehensive and extensive sample size study
should be needed. Although there is no licensed influenza vaccine for
children under six months, alternative strategies, including maternal
vaccination during pregnancy and household vaccination, might reduce
severe influenza infections. Increasing influenza and bacterial
vaccination, with environmental precautions such as frequent hand
washing, decontamination of hands, and cleaning concrete surfaces with
water and disinfectants, are essential to prevent transmission of the
respiratory viruses and reduce the severe disease burden. The efficacy
of neuraminidase inhibitors in healthy children is limited and does not
recommend general treatment34. Nevertheless, early
initiation of neuraminidase inhibitors is associated with shorter
symptoms, decreased complications, and
hospitalization34.
Human bocavirus was first identified in children’s respiratory tract in
2005; 75% of the HBoV infections are associated with multiple viral
infections16. HBoV infection usually results in a
mild, self-limiting respiratory tract infection and might even be
asymptomatic4. However, several case reports reported
that HBoV coinfection with other viruses could cause complications such
as pneumothorax, pneumomediastinum, and severe respiratory failure
requiring ICU/IMV35. Slow elimination of the viral
antigens by the immature immune system might explain the coinfection
with HBoV and the severity of the illness in infants. Considering the
National Respiratory and Enteric Viruses Surveillance System study
conducted from 1990 to 200436, PIV3 (52%) was the
most frequently determined serotype. In the US, the estimated LRTI and
hospitalization related to PIV3 were reported at 1.1million and 29.000,
respectively37. Parainfluenza virus 3 leads to LRTI
more common than other serotypes in neonates and infants and is
clinically indistinguishable from RSV infection. Additionally, PIV and
RSV belong to the Paramyxoviridae family, enveloped RNA, similar
epidemiologic, and clinical outcomes22. Thus, children
aged younger than 24 months with PIV3 coinfection may need equal medical
attention to those with RSV coinfection regarding disease severity.
Our regression analysis determined that young age, prematurity,
malnutrition, exposure to tobacco smoke, and atopy history were
independent risk factors for severe LRTI, aligned with earlier
studies6,15. Young age and prematurity cause more
severe respiratory stress because of the limited aerobic respiratory
capacity associated with the relatively smaller airway size, the immune
system’s naivety, and less strength and respiratory muscle
endurance24. Malnutrition may result in secondary
immunosuppression, atrophy of the respiratory muscles, and inadequate
muscle contraction because of the electrolyte
disturbance15. Taking measures to prevent
malnutrition, such as providing information and supporting the mother
about breastfeeding, using prophylactic vitamin D and iron supplements,
and a regular follow-up of the anthropometric measurements, may protect
children from severe disease.
An unanswered question has been whether the presence of a pre-existing
abnormality of the immune response in some infants leads to severe
illness. A recently published study has demonstrated that both viral
infection and allergic sensitization are strongly correlated with asthma
development after six years old in children14.
Furthermore, severe disease is found to be related to allergic
sensitization before symptomatic HRV infection. Our results showing that
allergic sensitivity increases the disease’s severity is one of our
relevant findings, which are rarely supported by the literature but can
shed light on studies investigating this relationship. Tobacco smoking
continues to be a fundamental health problem worldwide, and a recently
published meta-analysis has confirmed the effect of exposure to tobacco
smoke on developing LRTI in children38. Increasing
comprehensive bans on tobacco advertising, promotion, sponsorship, and
tobacco taxes might reduce tobacco consumption. Additionally, ample
pictorial or graphic health warnings, with hard-hitting messages, might
convince smokers to protect the health of non-smokers by not smoking
inside the home38.
In children with CLD, the increased inflammatory markers, impaired
airway anatomy, and mucociliary clearance could support the progression
to severe LRTI, whereas altered pulmonary mechanics, cyanosis, pulmonary
hypertension, and ventilation-perfusion mismatch in children with CHD
could increase the severity of the disease. Children with NMD expose
severe illness because of impaired or inadequate mucociliary activity
and immobility. These findings are essential when considering the
increased survival of children with a chronic underlying condition. The
presence of neutrophilia, lymphopenia, and high CRP values were
independent risks for severe disease. Previous studies have shown that
many neutrophils detected during influenza A and RSV infections are
associated with a more severe condition, and lymphopenia increases virus
replication39,40. The prognosis can be predicted to be
more severe in children with neutrophilia, lymphopenia, and high CRP
values. However, larger-population studies are required to monitor
children with LRTI according to hematologic values.
Our study’s limitations include those related to retrospective studies,
including bias regarding patient selection and accuracy related to the
medical record. To minimize bias, we developed a standardized data form
to guide data collection, only included patients with the medical
records’ information, and the same experienced clinician performed data
collection. Second, patients who visit the hospital later may present
with more severe signs and symptoms than those who visit the hospital
immediately after illness onset. However, we could not compare this
potential effect on disease severity because of the study’s
retrospective design. Third, including only children presented to the
tertiary hospital might have resulted in the study population’s
heterogeneity. Finally, a reliable test for bacterial co-detection was
not available at the time of the study, which could cause that we might
have underestimated the impact of bacteria on severe LRTI.
In conclusion, children between
1-60 months hospitalized with LRTI and detected viral coinfection were
at about 3.5 times higher risk for HFNCO/BiPAP/IMV assistance.
Respiratory syncytial virus and HRV (except for between 25-60 months)
coinfections caused severe LRTI in all age groups, whereas PIV3 (4-24
months) and HBoV (7-12 months) coinfections were associated with severe
LRTI in early childhood. Additionally, influenza A coinfection led to
severe LRTI in children between 7-12 months and 25-60 months.