Old foes following news ways?—Pandemic-related changes in the epidemiology of viral respiratory tract infections

Respiratory tract infections (RTIs) are among the most common childhood illnesses resulting in a high number of physician contacts and hospitalizations. RTIs contribute decisively to morbidity and mortality in the early years of life [1]. Infections with respiratory syncytial virus (RSV) and Rhinovirus type A and C are associated with chronic lung disease, like asthma, later in life [2‐4]. RTIs are characterized by an epidemic occurrence at virus-specific seasonal times [5, 6]. Climatic factors such as temperature and humidity affect respiratory virus stability and transmission rates, and appear to affect the host’s intrinsic, innate, and adaptive immune responses to RTIs. This may explain why most viral infections were observed in the fall and winter seasons [7, 8]. However, human behavioral patterns are a crucial factor in the spread of viruses influencing contact rates between infected individuals and susceptible hosts. With the onset of the COVID-19 pandemic, contact rates were significantly reduced to contain the spread of SARS-CoV-2. In addition, NPI such as the use of masks and hand hygiene significantly reduced the transmission of viruses. This led not only to containment of the pandemic but also to a significant decrease in other viral infections, such as Influenza A/B and RSV [9, 10]. After easing of pandemic-related measures, a rising and persistent wave of non-COVID-19 RTIs in children was observed in various countries since June 2021 [11‐14].

After initially assuming that respiratory viruses would only occur outside of their typical season, it quickly became apparent that the number of infected children was also increasing [12]. The actual impact on epidemiological changes that occurred by the end of 2022, the consequences and potential causes of these changes are not well-understood [15].

At the beginning of the pandemic, infections with SARS-CoV-2 played only a minor role in children. From autumn 2021, with the beginning of the circulation of the omicron variant, younger patients got increasingly infected [16]. Initially, only mild acute infections occurred, with admissions to children’s hospitals increasing from September 2021. Agathis et al. described that patients with co-detection of other respiratory viruses other than RSV and Rhino/Enterovirus (RV), showed a more severe course of disease [17].

Although several European countries reported an increase in RTIs in 2022, there is hardly any data as to whether the frequency and clinical impact of coinfections differed compared to the pre-pandemic period. It remains unclear whether this development will only remain a short-term phenomenon. It is equally unclear whether children with severe courses of acute infection will have to fear long-term consequences. We know that infections with RV or RSV, even if they take a mild course, significantly increase the risk of respiratory complications and chronic respiratory illness [4].

In this study, we aimed to illustrate the spectra of circulating viruses, patterns of coinfections and age and seasonality of RTIs in children from 2019 to 2022. We set out to provide a better understanding of pandemic-related changes in the epidemiology and the interaction of viral respiratory diseases—whose impact has since increased drastically on the population and healthcare system.

At the Hauner Children’s Hospital (Munich), a large tertiary care university hospital, the number of detected viral infections in patients between January 2019 and November 2022 was investigated. We analyzed 4702 (2019 with n = 550, 2020 with n = 735, 2021 with n = 1243, and 2022 with n = 2243) positive viral results from routine clinical specimens of both outpatients and inpatients (n = 4131). We included all patients presenting as outpatients or inpatients in the defined study period that had a positive test result at the in-house microbiology laboratory for at least one of the following viruses: Influenza A/B, RSV, Parainfluenza virus, human Metapneumovirus, Adenovirus, seasonal Coronaviruses (OC43, NL63, E229, HKU1) SARS-CoV-2, and Rhino/Enterovirus. Testing was performed at the discretion of the attending physician when an acute respiratory illness was diagnosed requiring either inpatient admission or outpatient drug treatment. Particular criteria were: reduction in oxygen saturation below 92%, wheezing, fever, poor general condition or young age of the patient. During the COVID-19 pandemic, multiplex-PCR testing (including RSV, Influenza A/B, and SARS-CoV-2) was performed on patients regardless of specific respiratory symptoms in case of hospital admission. Samples were taken by nasal or pharyngeal. All samples were tested by immunofluorescence assay (Quidel Sofia 1) [18] or using of a Mulitplex PCR system; (BioMerieux Biofire, Askim, SWEDEN [19]; Extraction by Nimbus and subsequent analysis by BioRad CFX, Seegene PCR-Kit) [20].

In this study, we observed a dramatic increase in pediatric RTIs with an incrementing spectrum of viruses and an astonishing rise in RV infections leading to a high rate of hospital admissions in 2022. Hospitalizations due to upper and lower respiratory tract infections were observed more frequently in the post-lockdown than in the pre-lockdown period. There were significant changes in the age of affected children and a notable variation in the association between virus infections with sex in 2021–2022 compared to the pre-pandemic year 2019. More female and older children were particularly affected. The annual numbers of coinfections changed markedly, especially in younger children infected with RV.

Epidemics involving viral RTIs have always vary in regional intensity and duration—This is thought to be due to the genetic diversity of circulating viruses and their respective virulence. Climatic changes also seem to impact on virus spread [7, 22, 23]. Numerous studies have shown that NPIs reduce the circulation of SARS-CoV-2 and other respiratory pathogens [24]. While certain non-respiratory infections, such as Rotavirus, occurred less frequently in times of hard lockdowns, a rebound of Rota- and other viruses were already evident when NPIs were still in place. Consistent with our data, Engels et al. reported that Adeno- and Rhino/Enteroviruses detections increased as early as the second and third COVID-19 waves [25]. Interestingly, these are non-enveloped viruses, rendering them less sensitive to disinfection agents. Most other respiratory viruses are transmitted by aerosols. However, Rota-, Adeno- and Rhino/Enterovirus are also following a contact-transmission route and may therefore, be less preventable by the use of facemasks. This corroborates the observation in our study, that RV was highly present despite NPIs. Our results are supported by Buchholz et al.: The authors describe high numbers of RSV infection at the beginning of the year 2020, a sharp decline and low numbers during the lockdown periods and rising numbers in the end of 2021 and 2022. The observation that RV/EV was hardly affected by the hygiene measures and continued to lead to respiratory tract infections from 2020–2021 was also demonstrated. Consistent with our data, an overall increase in infections in 2022 was observed in their multicenter study, on observation that is complemented by our data covering an additional period until November 2022 [26].

We noted that the virus-specific seasonality observed in pre-pandemic years changed in the post-lockdown period. This, however, was not observed for all viruses but was predominantly prevalent for infections with RV, Adenovirus and Metapneumovirus. Host-specific properties of these viruses may also contribute to this finding. While RV is consistently detected in children, RSV is predominantly found in young children during epidemic phases [27]. Outside of epidemics, RSV was mainly detected in adults at risk (usually with COPD—chronic obstructive pulmonary disease) or children with immune deficiency [28, 29]. While RV was able to spread unhindered among children, the occurrence of RSV was long prevented by mandatory masking for adults, which reduced transmission events. This supports our observation that RSV only occurred more frequently after the lifting of the mask regulation in September 2022. Infections with RV, Parainfluenza, Metapneumovirus, and Adenovirus occurred despite the NPIs and were also detected more frequently than before the pandemic. The presence or absence of certain pathogens could have played a role.

In previous studies, virus-virus interactions could be disentangled, which caused a promoting or inhibiting effect on the pathogenicity of viruses [30, 31]. Greer et al. demonstrated that RV detection was associated with a reduced probability of detecting human Adenoviruses, Coronaviruses, Bocavirus, Metapneumovirus, respiratory syncytial virus, Parainfluenza virus and Influenza A virus [32]. A negative interaction was also observed between RV and SARS-CoV-2 by Dee et al., leading to the hypothesis that RV infections could reduce the number COVID-19 cases [33]. The presence of RV could therefore, reduce susceptibility for other RTIs. However, it remains unclear whether the absence of certain viruses influenced susceptibility and pathogenicity of the host towards RV. Contrary to this assumption, the data from our study shows an increase in co-detections, particularly in conjunction with RV. The significance of the increasing virus co-detections cannot be clarified with certainty at present. In chronically ill patients, who make up a large proportion of the inpatients in this study, RV in particular can represent a colonization rather than a trigger for the underlying complaints. Nevertheless, the significant increase in hospital admissions in 2022 in our data indicates a serious clinical impact of multiple detections of respiratory viruses in children.

In addition to the exposure to viral pathobionts, bacteria probably play an equally important role. Initial studies suggest that the reduced exposure to pathogens could have led to a change in the lung microbiome [34]. The development and stability of the microbiome of the respiratory tract are decisive factors in susceptibility to viral infections, which also determine the risk of developing chronic lung diseases such as asthma [35].

Frequent occurrence coinfections, particularly seen in young patients, were complemented by a change in the mean age of the affected children. In 2022, RSV infections were significantly more common in older children. This might be attributed to a lack of exposure to the virus in early childhood and to a lack in transfer of protective antibodies from unexposed mothers. Thus, an increase in the number of cases could be due to an accumulation of various infections in larger group of children including a wider age range who have missed out exposure to pathogens.

Finally, our data indicates that a combination of many confounding factors has caused the increase in detection rates and coinfections and changes in the seasonal pattern of viral RTIs. A limitation of this monocentric study is that it only draws a regional picture and does not allow deductive statements about the impact on the clinical course of the virus detections. This issue needs to be addressed in a follow-up study. Since test strategies have changed during the pandemic, a bias in the detection of viruses cannot be ruled out. However, while short-term consequences for the morbidity of children are already obvious, the impact on resulting chronic lung disease is unclear and remains the focus of further studies.

COVID-19 pandemic-related interventions caused a profound change in the epidemiology of viral RTIs in children, with an increasing spectrum of circulating viruses and an astonishing peak in RV infections leading to a high rate of hospital admissions in 2022. Compared to pre-pandemic years, infections occurred more frequently in female and older children. The annual number of coinfections changed markedly – especially in younger children, predominantly in conjunction with RV. The underlying factors associated with the increase in cases, the peak in coinfections, and changes in the seasonal pattern of viral RTIs are not completely understood and remain the focus of further studies.