Globally, seasonal epidemics of respiratory syncytial virus (RSV) is one of the leading causes of hospitalization and mortality among children, particularly those under the age of 5 (1). The severe manifestations of RSV disease include pneumonia and bronchiolitis, with the latter typically being self-limiting (2). This is supported by the Pediatric Etiology Research for Child Health (PERCH), which identified RSV as the most common pathogen isolated from hospitalized children with severe pneumonia in Africa and Asia, accounting for 31% of all cases (3). In 2015, an estimated 33 million episodes of lower respiratory tract infections (LRTIs) were attributed to RSV infections in children under the age of 5, resulting in 3.2 million hospitalizations and 120, 000 deaths worldwide (4). Despite the known morbidity and mortality associated with RSV, there is currently no approved vaccine to prevent RSV infections (1). Thus, preventive measures aimed at reducing the spread of RSV remain the most promising intervention in controlling these seasonal epidemics.

Respiratory diseases reached a catastrophic milestone with the emergence of severe acute respiratory syndrome coronavirus (COVID-19) in December 2019 in Wuhan, China, impacting millions of adults and children (5). Within 1 year after its emergence, global reported deaths due to this pandemic had reached 5.94 million by 31st December 2021. Interestingly, this figure was hypothesized to be underestimated by a factor of 3.07 based on excess mortality rates, which is the net difference between the actual number of deaths during the pandemic and the expected number based on past trends in all-cause mortality (6). In Malaysia, COVID-19 was first detected in January 2020 and surged in March 2020, prompting the government to implement Movement Control Order (MCO) to restrict mass movements and gatherings in combating the pandemic.

Importantly, COVID-19 shares a similar air-borne transmission mechanism with RSV (1). Therefore, the preventive recommendations implemented during the MCO to mitigate COVID-19 transmission may have also helped to preventing local transmission of RSV. Notably, the United States reported historically low weekly percentages of positive RSV rates early in the pandemic (<1.0% per week compared to approximately 12–16% during the pre-COVID era) while an Australian study also observed decreased RSV activity due to COVID-19 restrictions (7, 8). Regionally in Asia, China also experienced two sharp declines in RSV infections during the two national outbreaks of the COVID-19 pandemic (9). In our previous epidemiological study, we observed a sharp decline in RSV cases in 2020, possibly due to reduced exposure to RSV as a result of the nationwide lockdown. (10).

The COVID-19 pandemic has presented a unique opportunity for the widespread implementation of public health interventions on a global scale for a limited period of time (1). However, there is a lack of evidence regarding the effectiveness of these public health measures in local and regional contexts, contributing to the decreased transmission of RSV during the pandemic. As a result, the widened epidemiology gap has intrigued researchers worldwide to comprehend the possible shift in RSV seasonality in assessing the timing and effectiveness of prophylactic and therapeutic interventions. To address this knowledge gap, it is crucial to establish large-scale surveillance that can improve our understanding of RSV epidemiology, particularly in the context of COVID-19. Therefore, our study represents a pioneering effort aimed at advancing the comprehension of disease epidemiology within the framework of the COVID-19 pandemic, particularly regarding RSV. We aim to potentially identify a larger scale or a shifted paradigm of RSV infections compared to previous years in Malaysia.

Severe RSV infections have indirectly posed a substantial economic burden on healthcare systems, governments. and society (17). Many studies have shown that the disease burden extends beyond affected children, impacting caregivers, leading to a loss of work productivity and increased hospitalization costs (17). Butel et al. estimated an average total cost per patient of around EUR 2000 (equivalent to USD 2163) for the first episode of acute bronchiolitis, mainly attributed to hospitalization costs (18). Prior to COVID-19, RSV accounted for 5.4% of all detected positive respiratory pathogens in the United States between December 2019 and March 2020. However, during the implementation of public health measures to combat COVID-19, the RSV positivity rate dropped dramatically to 0.03% from December 2020 to March 2021 (19). Besides, studies in Spain and Germany reported that preventive measures implemented against COVID-19 resulted in fewer hospitalizations for RSV bronchiolitis during the autumn-winter season of 2020 to 2021 (20, 21). In Asia, Japanese investigators reported a significant reduction in RSV infections among children aged between 0 to 11 months, which had highest prevalence before the pandemic. South Korean researchers reported an 81 and 91% reduction in RSV-positive cases during 2020 (22, 23). Therefore, these findings align with a growing body of evidence suggesting that stringent public health measures can effectively reduce the spread of epidemic respiratory viruses (24).

In our latest epidemiological study, we identified two peaks of RSV seasonality occurring in distinct monsoon periods, specifically during July to August and October to December, coinciding with previous local and regional studies. (10, 25–27). Surprisingly, in this study, we observed an unusual increase of RSV cases throughout the first half of 2021. This is deemed as a global phenomenon as many countries reported a change in the seasonal variation of RSV during the COVID-19 pandemic (28). Typically, RSV infections peak during colder temperatures and reduced humidity, conditions favorable for the stability and transmission of the virus (10). However, in Shanghai, China, Ran Jia et al. documented an unusual increase in the RSV detection rate during the summer of 2021 (28). Interestingly, in Japan, there was a shift in RSV cases occurring in the spring of 2021, with a higher magnitude compared to the pre-COVID-19 period (29). Similarly, in Taiwan, Lee et al. observed a delay in the RSV season, with cases occurring during the winter of 2020–2021 instead of the usual peaks in spring and fall (30).

Several factors have been identified as responsible for the seasonality change in RSV and its unusual resurgence. Firstly, the relaxation of public health measures has revealed a strong association with increased RSV activity (31). The return of children to schools and the lifting of social gathering restrictions indirectly contribute to the transmission of RSV among children. Moreover, many studies have emphasized the role of adults as reservoirs for RSV, which was previously underestimated (31). During the COVID-19 period, public health measures were strictly implemented on older children and adults for better compliance than younger children (32). Consequently, while adults benefited from the easing of restrictions earlier in 2021, RSV cases increased significantly among younger children who remained restricted due to closed childcare facilities. This raises speculation that adults play a major role in household chains of RSV transmission.

Secondly, the substantial decrease in protective immunity, termed as immunity debt, resulted from extended periods of low exposure to pathogens (33). The children’s immune systems have now weakened due to reduced exposure to pathogens, a consequence of the public health response to the pandemic (34, 35). This immunity debt poses a particular concern for RSV in younger children, especially with the waning of maternal antibodies and a lack of seasonal exposure, rendering them susceptible to future and potentially more severe infections (35). In addition to public health measures, the phenomenon of viral interference may also help to explain the sudden disappearance of RSV in the context of COVID-19 (36). Briefly, it has long been hypothesized that respiratory viral infections can prevent superinfection of other respiratory pathogens through to the activation of innate immunity, mainly via interferon response. This is widely evidenced by the delay of Influenza Virus (H1N1) in 2009 during the first pandemic by Rhinovirus in September–October 2009 period (37). Accordingly, we agree with the hypothesis proposed by Raffaella et al. that the sharp decline in RSV circulation may have been partly contributed by the ongoing spread of the highly contagious and abundant COVID-19 Omicron variant surge in late 2021, particularly affecting unvaccinated children (36).

Although the implementation of public health measures has disrupted the transmission of RSV and COVID-19, it is unlikely that these measures can entirely eliminate the infections (31). One classic example to emulate is the Ebola Virus disease (EVD), where the African health authorities, despite being highly prepared to manage the endemic after several regional outbreaks over the last decade, still maintain extreme vigilance to avoid cross-border exportation of EVD and further international lockdowns triggered by COVID-19 (38). Moreover, it is crucial to highlight the importance of protecting immunocompromised children who are at a higher risk of RSV and other infections, while also being cautious of the ongoing prevalence and high contagiousness of COVID-19 within our communities (34, 39–42). To date, Palivizumab, a recombinant humanized monoclonal antibody targeting RSV F-protein, is the only passive immunization that could reduce the rate and severity of RSV infections when administered intramuscularly to children as pre-exposure prophylaxis (31). Over the years, Palivizumab has been clinically recommended for high-risk children under 2 years of age, including preterm infants and infants with congenital heart disease and chronic lung disease. Considering the shift in RSV seasonality following the emergence of COVID-19, the American Academy of Pediatrics (AAP) recommended more than five consecutive doses of Palivizumab for the best efficacy (43). Hence, it is imperative for clinicians to determine the optimal timing of RSV immunization, in light of the changed seasonality, as a promising pharmaceutical strategy for preventing RSV infections.

We have identified several limitations in our study. Firstly, due to the retrospective nature of the study spanning a period of 6 years, we were unable to ensure consistent nasal swab testing for all children with symptoms of ARTI. This may have resulted in underestimating the true burden of RSV infection, particularly during the COVID-19 pandemic period. Secondly, our reported data on COVID-19 cases were based on daily national statistics instead of state-focused data, which may limit the accuracy of assessing the relationship between COVID-19 and RSV cases in the exact locality. Nevertheless, it is worth noting that our study area, which covered Kuala Lumpur and Selangor, remained one of the highest contributors to daily COVID-19 cases throughout the three-year study period (44). Regretfully, we did not exclusively demonstrate pediatric COVID-19 infection as Malaysia was lagging in COVID-19 detection rate compared to other developed countries, thus the main catchment area was to aim at adults, rather than pediatric population. In addition, our study focused solely on RSV infection, and we were unable to comprehensively assess the epidemiological characteristics of other common respiratory viruses before and during the pandemic. This includes the detection of any co-infections by our DFA kit, which could have influenced the clinical outcomes of the patients. Although our diagnostic RSV test used has commendable sensitivity (95.5%) and specificity (98.3%), false negatives and false positives of the results may affect the actual prevalence from what we reported. During the pandemic, COVID-19 was detected using real-time polymerase chain reaction (PCR), which have higher sensitivities than DFA detection of RSV, thus explained the large ratio between COVID-19 and RSV positive cases. The impact of these inaccuracies can vary depending on the context in which the test is used, the prevalence of RSV in the population, and the potential consequences of misdiagnosis.

The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.

This study received ethical approval and support from the Secretariat of Research and Innovation Universiti Kebangsaan Malaysia (UKM) (Project code: JEP-2021-780).

Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

AA: Conceptualization, Funding acquisition, Project administration, Supervision and Writing- review & editing; CM: Data curation, Formal analysis, Investigation, Methodology, Writing-original draft; AW: Conceptualization, Supervision, Writing- review & editing. All authors contributed to the manuscript revision, read, and approved the submitted version.