Immunity Debt Associated With Increased Immunological Reactions of M. pneumoniae Pneumonia in Children After the COVID‐19 Pandemic

Mycoplasma pneumoniae (M. pneumoniae) is a major cause of respiratory tract infections that can range in severity from mild to life threatening, accounting for up to 40% of community-acquired pneumonia (CAP) in children [1]. M. pneumoniae can be transmitted by respiratory droplets via coughing or sneezing. The emergence of the COVID-19 pandemic prompted the implementation of non-pharmaceutical interventions (NPIs), including wearing masks, frequent hand washing, and social distancing policies. These measures may also prevent the spread of other pathogens in children, resulting in a reduced incidence of community-acquired infections during the pandemic period [2]. The lack of immune stimulation due to the reduced circulation of microbial agents and the related reduced vaccine uptake could induce an "immunity debt," which would have negative consequences when the pandemic is under control [3]. This could lead to a rebound of many infectious diseases after relaxation of NPIs. There is evidence that the immunity debt after COVID-19 pandemic contributed to increased respiratory syncytial virus (RSV) infections [4]. Due to the lack of seasonal exposure, immunity decreases and susceptibility to future, and potentially more severe RSV infections would increase [4]. We also noted that China had an outbreak of M. pneumoniae infections in children in almost the whole year of 2023, that was different from previous prevalent features predominantly in summer or early fall [1]. However, the underlying mechanisms remain unclear. We speculated that the immunity debt could be associated with increased M. pneumoniae infections. Therefore, we conducted a retrospective study to assess clinical characteristics of M. pneumoniae pneumonia (MPP) in children before and after the COVID-19 pandemic, and to further explore the difference of inflammatory indicators between them. A primary cohort of hospitalized patients with MPP was performed before (from 2015 to 2017, pre-pandemic) and after the COVID-19 pandemic (from March to December 2023, post-pandemic). The diagnosis of MPP was based on either fourfold changes in antibody titers between paired acute and convalescent sera, positive IgM antibody, or positive M. pneumoniae DNA in throat swabs or bronchoalveolar lavages, combined with chest imaging [5]. The clinical data was analyzed, including age, gender, whole cell counts, C reactive protein, serum cytokine levels, and lymphocyte subtype percentages. Oral or intravenous methylprednisolone at a dosage of 1–2 mg/kg/d was administered in most of children with MPP according to Chinese guidelines [6]. Our previous studies demonstrated that children with MMP had different serum levels of cytokines in different age and pneumonia classification groups [5]. Therefore, propensity score analysis (PSA) was used to account for the baseline differences in pre-pandemic and post-pandemic MPP patients based on age, gender and length of stay (Figure 1). This study was approved by the Ethic Review Board of the Children's Hospital, Zhejiang University School of Medicine (2024-IRB-0118) based on Declaration of Helsinki. There was no significant difference in age, gender, length of stay, days of fever, and frequency of corticosteroid use between pre-pandemic and post-pandemic MPP patients (Table 1). Additionally, there were no significant differences in the proportions of myocardial damage, liver function damage, skin rash, and pleural effusions between the pre-pandemic and post-pandemic groups. However, the post-pandemic MPP children had a longer days of corticosteroid use (3.26 vs. 2.47, p = 0.002) compared with the pre-pandemic MPP patients. Notably, the post-pandemic patients with MPP showed increased platelet counts (320.74 vs. 298.39, p = 0.007), elevated circulating CD3+ lymphocyte percentages (69.06 vs. 63.73, p < 0.001), higher serum interferon-γ levels (IFN-γ, 24.16 vs. 16.36, p = 0.002), and lower C reactive protein levels (14.50 vs. 32.54, p < 0.001) relative to those pre-pandemic patients (Table 1). There was no statistical significance in other serum cytokine levels between them. In the current outbreak in China, MPP is characterized by younger age, increased hypoxemia, local lung damage, worsening systemic inflammation, and increased co-infection [7]. There have been more and more studies demonstrating that macrolide-resistant M. pneumoniae (MRMP) have emerged widely in Asian countries and are increasing rapidly, which representing approximately 80% of MPP cases in China [7, 8]. However, under similar hospitalization stay, MPP patients from the current outbreak need longer days of corticosteroid use compared with pre-pandemic MPP patients. Moreover, the post-pandemic MPP had higher serum IFN-γ levels and lower C reactive protein levels. Given the fact that increased serum IFN-γ levels indicate a stronger immune response [9], we speculate that longer fever in MPP could be mainly caused by immune response rather than inflammatory reactions directly caused by M. pneumoniae infections. Corticosteroid therapy may be more effective compared to the previous understanding that most of M. pneumoniae was resistant to macrolides and thus required switching antibiotics. This stronger immune response could be associated with less infection exposures during the COVID-19 pandemic. Lower pathogen exposure in children would expand immunity debt and reduce protective immunity, probably affecting the development of training immunity [2]. Our study also suggested the importance of vaccination programs in children against the immune debt associated with the pandemic. Nevertheless, whether strong immune responses of post-pandemic MPP children were associated with immunity debt and training immunity still need further investigation. Taken together, post-pandemic MPP children have strong immune reaction and need longer corticosteroid use compared with pre-pandemic MPP patients. Immunity debt and subsequent changes of immune status could play a major role. The post-pandemic MPP children have strong immune reaction and need longer corticosteroid use. Immunity debt and subsequent changes of immune status could be associated with increased immunological reactions of MPP children after the pandemic. Meiping Lu: conceptualization, writing–review and editing, funding acquisition, writing–original draft. Yana Wang: methodology, software, writing–review and editing, investigation, resources. William D. Hardie: writing–review and editing. Yini Wang: methodology, Formal analysis, resources, writing–review and editing. Yun Zhou: writing–review and editing, resources, formal analysis, software, data curation, validation. Xuefeng Xu: conceptualization, investigation, supervision, writing–original draft, writing–review and editing, methodology, formal analysis, project administration, visualization. This work was supported by grants from Key R&D Program of Zhejiang (2023C03032). The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The need for patients' written consent was deemed unnecessary by the hospital ethic review boards as we did not contact the patients to conduct this retrospective study. The authors declare no conflicts of interest. The data that support the findings of this study are available from the corresponding author upon reasonable request. The original data can be obtained from the corresponding author upon reasonable request.