Clinical and epidemiological characteristics of 96 pediatric human metapneumovirus infections in Henan, China after COVID-19 pandemic: a retrospective analysis

Human metapneumovirus (HMPV), a member of paramyxovirus family, was first identified in 2001 [1]. It has since been commonly implicated in acute respiratory tract infections (ARTI) affecting both pediatric and adult populations worldwide. Despite efforts, a live-attenuated recombinant HMPV vaccine has demonstrated inadequate immunogenicity in children aged 6–59 months [2], and to date, no licensed vaccines or specific drugs are available for HMPV infections. Primary infections typically occur before the age of 5 years, with HMPV prevalence among this age group ranging from 1.1% to 86% globally [3]. In 2018, HMPV-associated hospital admissions among children under 5 years old globally amounted to 643,000, with 16,100 (hospital and community) HMPV-associated ARTI deaths [4]. These figures underscore the substantial socio-economic impact and disease burden associated with HMPV infection.

Over the past 3 years, the unprecedented implementation of non-pharmaceutical interventions during the COVID-19 pandemic has significantly impacted the epidemiology of various pediatric infectious diseases [5‐7]. The return of respiratory virus circulation to pre-pandemic levels is anticipated as COVID-19 mitigation measures gradually ease [8]. The concept of “immunity debt” has been proposed to characterize the paucity of protective immunity resulting from prolonged decreased exposure to various pathogens [9]. In Western Australia, the incidence of HMPV infection surged threefold in 2021 compared to the period of 2017 ~ 2019. Moreover, the proportion of respiratory-coded admissions undergoing HMPV testing doubled in 2021 [10, 11]. Similarly, in the United States, the number of HMPV infections suddenly spiked to record levels in the spring of 2023 (https://​www.​cdc.​gov/​surveillance/​nrevss/​hmpv/​region.​html). In China, several studies conducted before the COVID-19 pandemic have examined the prevalence and genotypic diversity of HPMV, as well as the epidemiological and clinical characteristics of hospitalized patients with HPMV infection [12‐16]. A study conducted in the Netherlands demonstrated that the clinical impact of HMPV infection remained consistent between the non-COVID-19 period and the examined COVID-19 period, with no significant changes observed in terms of incidence and/or disease severity [17]. Nevertheless, the epidemiological and clinical characteristics of HMPV infections have shown disparities following the COVID-19 pandemic. Consequently, there is an urgent need for clinical investigations, particularly focusing on children hospitalized with HMPV infection, to provide a reference for clinical diagnosis and management. In this study, we present a detailed analysis of the clinical and epidemiological features of 96 pediatric patients in central China from April 29 to June 5, 2023. Our findings contribute to a comprehensive understanding of the characteristics of HMPV infections in the post-COVID-19 pandemic era.

All subjects were stratified into different subsets based on the duration from illness onset to hospitalization, including subsets of 2–3, 4–5, 6–7, and ≥ 8 days. The altered indicators (P ≤ 0.2) were analyzed within these subgroups. As shown in Fig. 5, there was no statistically significant difference in PLT, percentage of BASO, uric acid, AST, CK-MB, ESR and C3 between the two groups. Obviously, most indicators exhibited significant changes after 4–5 days of illness onset. Compared to mild patients, severe cases exhibited significantly increased WBC count, NEUT count, MONO count, percentage of NEUT, and LDH, ALT, GGT in the peripheral blood at 4–5 days after illness onset. Conversely, LYMPH count, EOS count, percentage of LYMPH, percentage of LYMPH, and creatinine, IgG, and C4 in the serum were significantly reduced during the same period. The changes in percentage of LYMPH and NEUT remained consistent after 4–5 days after illness onset. Figure 5 showed specific changes in other indicators.

The etiological significance of HMPV in ARTI has been the focus of increasing attention worldwide [3]. HMPV infection among hospitalized children with ARTIs experienced a significant decrease during COVID-19 pandemic [14]. However, with the relaxation of COVID-19 mitigation measures, HMPV transmission has surpassed pre-epidemic levels [10]. The immunity debt [9] and the alterations in prevalent genetic subtypes [14] following the COVID-19 pandemic have raised our concerns. Hence, this study aimed to evaluate the epidemiological and clinical characteristics of HMPV infections in hospitalized children in Henan, China from April 29 to June 5, 2023.

In this study, we observed that the majority (87.5%) of infected children were under 5 years, with more than half (65.63%) being under 3 years old. Previous study has indicated that the hospital admission rate for HMPV-associated ARTI is notably higher among infants compared to older children, with approximately 58% of hospital admissions in children under 5 years occurring within the first year of life [4, 21]. The elevated burden on infants may be attributed to the immaturity of their immune systems and the decline of maternal antibodies during the first months of life [22].

Upon admission, we observed that patients presenting with concurrent cough and wheezing, as well as those with simultaneous fever, cough, and wheezing, tended to be more severely ill. Generally, HMPV-associated respiratory diseases manifest along a spectrum from mild fever and cough to severe bronchiolitis and pneumonia [13, 15]. A study involving hospitalized children in Beijing similarly reported that the majority of patients presented with cough and fever [14]. Wheezing is a common manifestation in children with HMPV infection, often progressing to life-threatening bronchiolitis and pneumonia [23]. A study has indicated that 13.0% ~ 60.7% of children infected with HMPV experience recurrent wheezing or receive a diagnosis of asthma [24]. However, distinguishing HMPV-associated pneumonia from infection caused by other pathogens based solely on clinical features remains challenging [25‐27]. Several respiratory pathogens, including HMPV, exhibit similar incidence rates and clinical characteristics, thereby posing a diagnostic challenge for attending physicians.

A previous study revealed that HMPV was the third most common virus associated with coinfection [28]. Viral cocirculation can lead to competition among viruses, whereby the stronger virus may survive and/or mutate, potentially resulting in higher mortality and morbidity rates [29]. In our study, we identified 43 patients who were coinfected with another virus, with coinfections of HMPV with EBV (15.6%) or HRV type A (12.5%) being common. EBV infects over 95% of the global population and is often asymptomatic, typically occurring at a young age [30]. Unlike EBV, HRV type A is responsible for more than 50% of upper respiratory tract infections globally and it is the most common virus associated with wheezing in children aged between one and two years [31]. Previous studies have identified influenza, HRSV, adenoviral, and human bocavirus as the most common respiratory viruses involved in coinfections [14, 15, 23, 32]. Our results findings diverged from previously published data, which could be attributed to the seasonality of different viruses [33], variations in sample types, and differences in sample sizes among studies. In our study, the rate of HRSV coinfections was significantly higher in the severe group compared to the mild group. Previous research has indicated that dual infections with HMPV and RSV are associated with severe bronchiolitis and an increased risk of Intensive Care Unit admission for mechanical ventilation [34]. Additionally, coinfections with bacterial pathogens often lead to a more severe course and increased mortality. While HMPV-associated pneumonia is generally less severe than bacterial pneumonia, it can be as severe as or even more severe than infections caused by other common pathogens [27]. In our study, Hin and SNP were the two most common bacterial coinfections, accounting for 52.1% and 41.7%, respectively. Therefore, further data are necessary to elucidate the cumulative clinical effects on disease severity resulting from coinfecting with other respiratory pathogens.

Significant alterations in several indicators among severe patients were notably observed at 4–5 days after the onset of illness, marking a critical time point for disease progression, and necessitating timely decisions regarding treatment interventions. Therefore, we should pay more attention to the diagnosis and intervention in the early stage of the disease. In our study, we observed a lower level of IL-12p70 in severe patients. However, previous research suggested that HMPV failed to induce production of IL-12p70 in BALF in a mouse model [35]. In terms of immune cells, we observed a more pronounced decline in the lymphocyte percentage among severe patients, while the percentage of B lymphocyte was significantly elevated. In other words, the function of the specific cellular immunity was decreased, while the function of humoral immune was increased. Nevertheless, the decreased concentrations of Immunoglobulin G and Immunoglobulin A in the severe group contradicted these results. In fact, interpreting these results is often challenging due to the complexities of the disease and the involvement of mixed infections. In clinical practice, patients with single HMPV infections are rare, emphasizing the necessity for further research on patients with mixed infections.

This study also had several limitations. Firstly, our focus was primarily on the epidemiological and clinical features of HMPV positive cases. Thus, other common respiratory pathogens were not excluded. Subsequently, our results more reflect the cumulative clinical effects of coinfection. Secondly, children with more severe symptoms are more likely to receive hospital care, which may affect our understanding of the clinical features of HMPV-positive patients. Despite these shortcomings, our results offer a valuable insight into the epidemiological and clinical characteristics of hospitalized patients with HMPV infection in Henan, China.

Our study elucidated important epidemiological and clinical characteristics of HMPV infection in Henan, China. These findings hold potential significance for informing policy development aimed at the prevention and control of HMPV infection. Additionally, our results may provide important insights for guiding HMPV research efforts in the post- COVID-19 pandemic era.