Epidemic features and clinical analysis of pediatric Mycoplasma pneumoniae respiratory infection before, during, and after COVID-19 pandemic: a 7-year study in southern China

Introduction

Mycoplasma pneumoniae (M. pneumoniae) is a significant etiological agent of community-acquired pneumonia among children and young adolescents as the major disease-related burden (1). Infections persist throughout the year across diverse climatic regions globally, with epidemic outbreaks occurring at intervals of several years (2,3). Previously obtained data have indicated a temporal interval of 1 to 3 years between epidemics of M. pneumoniae in Europe and Israel (3). The periodic emergence of epidemics can be attributed to multiple factors, such as the decline of herd immunity and the introduction of novel subtypes into the population (4). The most recent epidemic emerged in late 2019 to early 2020, concurrently affecting multiple countries, including China (5).

In March 2020, the implementation of non-pharmaceutical interventions (NPIs) targeting coronavirus disease 2019 (COVID-19) led to a sudden cessation of these epidemics and a significant global reduction in the detection of M. pneumoniae (6). In comparison to the pre-pandemic incidence rate of M. pneumoniae, which was 8.61% during the period from 2017 to 2020, a substantial decrease to 1.69% was observed in the first year following the implementation of NPIs from 2020 to 2021 (6), similar to the incidence observed for other respiratory pathogens (7). An additional unprecedented and significant decline in the incidence of M. pneumoniae was observed in the second year (0.70%, 2021–2022) (8), when the resurgence of other respiratory pathogens served as an indicator of community transmission (8,9). Given the heavy burden of pediatric M. pneumoniae respiratory infection in the recent period, we reported on a single center retrospective study from January 1, 2018 to September 30, 2024, to investigate the epidemic patterns of M. pneumoniae respiratory infection before and after the COVID-19 pandemic and analyze the clinical characteristics of pediatric patients in southern China. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-914/rc).

Methods

Participants

The study enrolled pediatric patients who sought medical care in outpatient clinics, emergency departments, and inpatient wards of Meizhou Maternal and Children’s Health Hospital from January 1, 2018 to September 30, 2024, retrospectively. The inclusion criteria were: (I) age between 28 days and 18 years old; (II) patients were clinically diagnosed with respiratory tract infections accompanied by upper respiratory symptoms (such as cough, nasal congestion, sneezing) and lower respiratory tract symptoms (dyspnea, rales, wheezing, or chest X-ray findings); (III) positive pathogen detection for M. pneumoniae, including a single serum M. pneumoniae-IgM titer of ≥1:160 and/or polymerase chain reaction (PCR) method detecting M. pneumoniae-DNA in children’s throat swabs and/or sputum, bronchoalveolar lavage fluid. Exclusion criteria: (I) patients with compromised immune systems resulting from solid or hematological malignancies, immunosuppressive therapies, or genetic disorders; (II) individuals presenting with chronic pulmonary, cardiac, metabolic, or neurological conditions, whether congenital in origin (such as cystic fibrosis, Tetralogy of Fallot, or hypoxic ischemic encephalopathy) or acquired (for example, hyperreactive airway disease); (III) missing clinical record data. A death occurring within 30 days following a positive test for M. pneumoniae was classified as an M. pneumoniae-related death.

Refractory Mycoplasma pneumoniae pneumonia (RMPP) was defined as follows: (I) prolonged fever for 7 days or more or (II) increasing cough and infiltrates seen by chest radiography despite the administration of appropriate antibiotics (10). Severity was classified at the end of the enrolment. Severe Mycoplasma pneumoniae pneumonia (SMPP) were defined as follows (11): (I) major criteria include the requirement for invasive mechanical ventilation; fluid-refractory shock; an acute necessity for noninvasive positive pressure ventilation; and hypoxemia necessitating a fraction of inspired oxygen (FiO₂) exceeding the concentration or flow achievable in a general care setting; (II) minor criteria encompass a respiratory rate surpassing the World Health Organization (WHO) age-specific classification; episodes of apnea; increased work of breathing, as evidenced by signs such as retractions, dyspnea, nasal flaring, and grunting; a partial pressure of arterial oxygen (PaO₂)/FiO₂ ratio below 250; the presence of multilobar infiltrates; a Pediatric Early Warning Score greater than 6; altered mental status; hypotension; the presence of pleural effusion; and existing comorbid conditions (e.g., hemoglobin SS disease, immunosuppression, and immunodeficiency); and unexplained metabolic acidosis. The diagnosis of SMPP was confirmed if a patient met ≥1 major criterion or ≥3 minor criteria. All diagnoses of RMPP and SMPP were determined via a standardized retrospective chart review and dual-adjudication process by two independent senior pediatricians (≥10 years of experience in pediatric respiratory infections) who were blinded to the study’s hypotheses and stage grouping.

For pediatric patients with RMPP, the effectiveness of macrolide antibiotics was defined as the achievement of a favorable clinical response to standard-dose macrolide monotherapy (azithromycin/clarithromycin/erythromycin) within 7 days of initiation (no need for antibiotic escalation or adjuvant anti-inflammatory therapy). Macrolide-resistant Mycoplasma pneumoniae (MRMP) was defined in accordance with genotypic criteria (12). Genotypic resistance was defined by the presence of acquired point mutations in the V domain of the 23S rRNA gene of M. pneumoniae (the core resistance mechanism accounting for >95% of clinical MRMP strains), with A2063G and A2064G as the most prevalent global mutations associated with high-level macrolide resistance (13). Clinically, MRMP was identified as M. pneumoniae strains meeting genotypic resistance criteria, which was further correlated with clinical non-response to macrolide monotherapy in pediatric patients with MPP.

This study protocol was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and approved by the Ethics Committee of Meizhou Maternal and Children’s Health Hospital (No. mzsfybjy2024015). Informed consent was obtained from the patients’ parents or legal guardians.

M. pneumoniae nucleic acids were determined by the SLAN-96P quantitative real-time polymerase chain reaction (qRT-PCR) instrument (Shanghai Hongshi) using the M. pneumoniae DNA fluorescence diagnostic kit (Guangzhou Daan Gene Co., Ltd.).

Procedures

Electronic medical health records were obtained for patients admitted to our hospital for durations exceeding 24 hours, utilizing the unique social security number assigned to everyone. Clinical information pertaining to the infectious episode-including clinical manifestations and sequelae-as well as the parent-reported date of disease onset and patient sex, were extracted from the electronic medical records and systematically recorded in a database.

According to the announcements of the National Health Commission, the study included eight seasons encompassing two pre-COVID-19 seasons (2018–2019, and 2019–2020), three COVID-19 seasons (2020–2021, 2021–2022 and 2022–2023), and one post-COVID-19 season (2023–2024). The demographic characteristics and the distribution of upper and lower respiratory tract infections among the three seasons of M. pneumoniae infected children were analyzed, as well as the differences in clinical characteristics of children with lower respiratory tract infections.

Statistical analysis

IBM SPSS 26.0 software was used for statistical analysis. Continuous numerical variables were tested for normality using the Kolmogorov-Smirnov (K-S) test. Data that conformed to a normal distribution were expressed as the mean ± standard deviation (SD) and were compared between groups using independent samples t-tests. Data that did not conform to a normal distribution were expressed as the median [interquartile range (IQR)] and were compared between groups using the Mann-Whitney U test. Qualitative data were expressed as percentages (%), and group comparisons were made using the Chi-squared test. Multivariable logistic regression models were used to assess the individual impact of each variable. A P value below 0.05 was regarded as indicating a statistically significant difference.

Results

This study collected a total of 76,859 cases of M. pneumoniae testing from 2018 to September 2024, with 19,884 positive cases, among which 19,884 tested positive, resulting in a positive rate of 25.9%. Among the positive cases, 9,891 were boys and 9,993 were girls (gender ratio, 1:1.01). The results showed that before the COVID-19 pandemic, there were 27,539 cases, with an average of 13,769 cases per year and a positivity rate of 19.1%, peaking from July to November each year. During the COVID-19 pandemic, there were a total of 26,578 cases, with an average of 8,859 cases per year and a positive rate of 19.2%. After the COVID-19 pandemic, a total of 9,521 cases were found, with a positive rate of 41%. There was a significant increase in cases starting from June 2023, with a sharp rise in infections from October to December, continuing until June 2024. The positivity rate of M. pneumoniae infection testing after the COVID-19 pandemic was significantly higher than the other two seasons (P<0.05).

The results showed that M. pneumoniae infections experienced a significant outbreak in 2019 of pre-COVID-19 season, with a peak in the summer and autumn seasons. During the COVID-19 pandemic, M. pneumoniae infections occurred sporadically. In post-COVID-19 season, M. pneumoniae infections showed an explosive outbreak starting from June 2023, with a sharp increase in the number of infections from October to December, which continued until June 2024 (Figure 1).

Figure 1 Epidemic of Mycoplasma pneumoniae respiratory infections in pediatric patients from 2018 to September 2024. Mycoplasma pneumoniae, M. pneumoniae.

In terms of demographics, the median age of children diagnosed with M. pneumoniae infection after COVID-19 pandemic was recorded at 46 months (IQR, 24–71 months), which represented a statistically significant increase compared to the median ages observed in the two preceding seasons (P<0.05). The infection rate of M. pneumoniae among children aged 1–2 years was found to be 32.9%, a decrease from the pre-epidemic rate of 40.2% and the epidemic rate of 40.1% (P<0.05). Conversely, for children over the age of 6, the infection rate was 19.5%, which was an increase from the pre-epidemic rate of 13.2% and the epidemic rate of 8.8% (P<0.05).

Post-COVID-19 pandemic, the incidence of lower respiratory tract infections attributable to M. pneumoniae in children reached 2,856 cases, constituting 30% of the total. The hospitalized patients included 660 pre-COVID-19, 128 during COVID-19, and 2,573 post-COVID-19 (total n=3,361). Age distribution in the hospitalized patients shifted post-COVID-19: the proportion of children >6 years increased from 16.9% (pre-COVID-19) and 10.5% (COVID-19) to 21.9% (post-COVID-19, P<0.01), while children aged 1–5 years (the predominant group pre-/during COVID-19) decreased in proportion (P<0.05) (Table 1).

This study included 3,361 hospitalized pediatric patients, of which 2,573 cases were identified after the COVID-19 pandemic. The main clinical symptoms were fever and cough, with no statistically significant differences noted across the three seasons analyzed. Notably, the M. pneumoniae DNA load in children following the COVID-19 pandemic was recorded at 62.1×10³ copies/mL [IQR, (3.7–3,540)×10³ copies/mL], which was significantly higher than the levels observed in the preceding two seasons (P<0.05). Additionally, the incidence of bilateral consolidation attributable to M. pneumoniae infection post-pandemic was 13.5%, and the occurrence of complications involving pleural effusion was 3.7%, both of which were significantly elevated compared to the earlier seasons (P<0.05). Furthermore, the incidence of coinfections rose significantly to 67% after the pandemic, with the incidence of coinfections with viral pathogens also surpassing that of the previous two seasons (P<0.05). The incidence of RMPP was 47% after COVID-19 pandemic, which was higher than the rates recorded in the earlier seasons (P<0.05). However, no statistically significant differences were found in the incidence of SMPP, length of hospital stay, or mortality rates across the three seasons (P>0.05). Refer to Table 2 for further details.

In Table 3, the study revealed that among hospitalized pediatric patients diagnosed with RMPP, the percentage of children over the age of six after COVID-19 pandemic was 57.7%, which was significantly elevated compared to the proportions observed in the preceding two seasons (P<0.05). The incidence of dyspnea among children with RMPP after the pandemic was recorded at 74.5%, which also surpassed the rates noted in the earlier seasons (P<0.05). Conversely, the occurrence of lobar pneumonia and/or atelectasis was found to be lower than in the previous two cohorts (P<0.001). In terms of complications, rash emerged as the predominant complication among RMPP patients, with rates of 7%, 4%, and 11.7% across the three seasons, although these differences did not reach statistical significance (P>0.05). Consequently, the proportion of children necessitating oxygen therapy increased to 70%, which was significantly higher than those recorded prior to and during the pandemic (P<0.05). The study also indicated that the prevalence of MRMP among RMPP cases was 80.4% before the pandemic, 75% during the pandemic, and 85.3% after the pandemic, with no statistically significant differences among these groups (P>0.05). Notably, the effectiveness of macrolide antibiotics in treating RMPP in children after the pandemic was determined to be 67.5%, in stark contrast to the 100% efficacy observed before and during the pandemic, highlighting a significant decline in the effectiveness of macrolides after the pandemic (P<0.001). Furthermore, there were no significant differences across the three seasons concerning pediatric intensive care unit (PICU) admissions, sequelae, length of hospital stay, or mortality rates (P>0.05).

A total of 3,361 pediatric patients were included in the analysis of RMPP (24 cases in the pandemic period vs. 1,301 cases in the non-pandemic period). Multivariate analysis of risk factors in hospitalized patients with RMPP, the COVID-19 period was independently associated with a significantly reduced risk of RMPP compared with the non-pandemic period [odds ratio (OR) =0.3162, 95% confidence interval (CI): 0.1771–0.5643, P<0.001]. The other independent risk factors for RMPP were higher M. pneumoniae DNA load (OR =1.0000, 95% CI: 1.0000–1.0000, P=0.0003) and elevated C-reactive protein (CRP) level (OR =1.0101, 95% CI: 1.0064–1.0138, P<0.001) (Table 4).

Discussion

In response to the COVID-19 pandemic, numerous NPIs were implemented globally to mitigate viral transmission within communities. These measures included the use of face masks, promotion of hand hygiene, enforcement of social distancing, imposition of travel restrictions, and closure of educational institutions. Subsequently, a marked decline in both asymptomatic and symptomatic COVID-19 cases was observed. However, the extent of this reduction varied across countries, influenced by the specific nature and duration of the interventions employed (14). Therefore, the COVID-19 pandemic has been accompanied by significant variations in the global incidence of infectious diseases. As a result, the lack of immunity to respiratory viruses other than SARS-CoV-2 led to the unusual “off-season”, “see-saw”, and “upsurge” patterns of various infectious diseases in children (15). Moreover, apart from the persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), outbreaks of M. pneumoniae infection led to twindemics or tripledemics during the following years (4). In the current study, we conducted a 7-year analysis of the pediatric M. pneumoniae respiratory infection in southern China before and post pandemic. Specifically, we focus on the epidemic patterns of childhood M. pneumoniae respiratory infection and clinical characterizations of M. pneumoniae in the recent prevalence in s/outhern China, to provide valuable strategy for infectious disease control.

It was shown in previous studies that the COVID-19 pandemic policy and the associated NPIs have had a significant impact on the incidence of respiratory infections (5,16,17). Before the pandemic, there was a small peak of M. pneumoniae infection in late 2019 in our study as previous reports. But a sudden decrease of M. pneumoniae respiratory tract infections in hospitals from early 2020 was observed due to the leading implementation of NPIs in China. There was reported that an increase in case numbers was noted in some countries from January to September 2023 (4,18). Here, we present an analysis of the subsequent developments over the following year, up to September 2024, after the implementation of NPIs in southern China. In this study, it was shown that a rapid surge in infections started in June 2023, marked by a significant rise in cases from October to December 2023, and this trend persisted until June 2024. Compared with 2019 M. pneumoniae epidemic season, it’s a terrific, longer lasting in 2023–2024. It is now widely recognized that the rise in M. pneumoniae respiratory infections in 2023–2024 was probably due to a lack of population immunity in children, either because they had not been previously exposed to M. pneumoniae or because their immunity had decreased after 3 years of limited exposure during the COVID-19 pandemic (19). However, this postponed resurgence is notable due to its occurrence well after the cessation of NPIs (20). The extended generation time of approximately six hours, the prolonged incubation period ranging from 1 to 3 weeks, and the comparatively low transmission rate may contribute to an increased duration necessary for the re-establishment of M. pneumoniae infection within a population (4). Therefore, a year-long outbreak of M. pneumoniae infection after NPIs in southern China deserved our attention.

It was reported that this outbreak has shown a younger age trend in children under 3 years in China (21). But in our study, M. pneumoniae respiratory infection has increasingly been seen in children aged 6 years and above, which was consistent with a nationwide cohort study in Denmark (19). M. pneumoniae infection can involve both the upper and lower respiratory tracts, leading to clinical symptoms such as fever, sore throat, paroxysmal dry cough, and headache (22). Mycoplasma pneumoniae pneumonia (MPP) has long been the focus of pediatricians. The pandemic of M. pneumoniae respiratory infection after COVID-19 caused lower respiratory tract infections in more children than before, and more than 30% of children were admitted in hospital because of MPP. A higher proportion of pediatric patients diagnosed with RMPP after COVID-19 pandemic, which may reflect a trend of the increasing proportion of MRMP in China (21,23,24). The marked increase in RMPP incidence in the post-COVID-19 period alongside a stable SMPP rate is a striking observation driven primarily by the synergistic effects of population immunity debt and rising MRMP prevalence in southern China, two well-recognized drivers of RMPP in post-pandemic pediatric populations (21); yet this discrepancy is further shaped by a constellation of clinical and systemic changes in pediatric respiratory infection management in the post-COVID-19 era, with findings aligning closely with contemporary global pediatric MPP research including the recent Italian pediatric center study by Bianchi et al. (25). In our research, despite the increase in the proportion of M. pneumoniae lower respiratory tract infections and RMPP in children, there was no significant increase in severe cases in this outbreak.

Previous research has indicated that clinicians are able to estimate the severity of a pediatric patient’s condition by assessing the copy number of M. pneumoniae DNA, thereby enabling them to adjust medication dosages to attain the optimal therapeutic outcome (26). Furthermore, local M. pneumoniae DNA load can objectively reflect the balance between the pathogen and host immune clearance capacity (27). In our study, M. pneumoniae DNA load after COVID-19 pandemic was significantly higher than the other two seasons. It was found that the CRP levels in children in the high-load group were significantly higher than those of children in the low-load group (28). We also examined this characteristic from a different perspective and provided an explanation for the increasing of RMPP cases at post-COVID-19 pandemic.

Imaging findings of MPP vary and have been studied extensively, especially homogeneous lobar consolidation and parapneumonic effusion (29,30). After the COVID-19 pandemic, the incidences of bilateral lobar consolidation and parapneumonic effusion were significantly higher than before. MRMP emerged and has spread globally might lead to imaging changes (24,31). Moreover, despite thorough investigation, we found viral coinfections in approximately 38% of pediatric patients with M. pneumoniae lower respiratory tract infections after COVID-19 pandemic, more than before and during COVID-19. Many viral respiratory pathogens had earlier resurgence after COVID-19 pandemic, including respiratory syncytial virus (RSV) and influenza (32), therefore, viral confections increased obviously in this study. This delayed re-emergence is unusual and likely unprecedented for M. pneumoniae, these clinical characteristics should be strongly considered.

According to initial study findings, China has gone through a concurrent outbreak of pediatric respiratory diseases, particularly the MRMP outbreak after the pandemic (33). Some researchers have suggested that continuing the use of macrolide remains effective in most cases of MRMP patients (34). In this study, we also affirmed the therapeutic effect of macrolide on MRMP patients before and during the pandemic. However, after the COVID-19 pandemic, the effectiveness of macrolides such as azithromycin has significantly diminished. This decline is a matter of concern for clinicians, highlighting the urgent necessity to address MRMP in pediatric populations.

Nevertheless, this study had several limitations. Primarily, the research was conducted using patient data obtained from a single medical center, although this was a 7-year study, our conclusions and the applicability of the nomogram warrant rigorous validation through future multicenter studies. Additionally, this study employed a retrospective design and excluded participants with incomplete data, which may introduce selection bias. Due to the objective limitations of the hospital’s electronic medical record system during the 7-year study period, the initial clinical setting (outpatient/emergency department) of the included patients could not be accurately distinguished and stratified. Finally, the study’s case definition for M. pneumoniae infection included a single serum M. pneumoniae-IgM titer ≥1:160, which has inherent serological limitations that may be amplified in the post-COVID-19 period. While we mitigated this limitation by combining M. pneumoniae-IgM testing with M. pneumoniae-DNA PCR for case definition, the sole reliance on a single M. pneumoniae-IgM titer remains a constraint for definitive acute M. pneumoniae infection diagnosis.

Conclusions

In summary, we observe a local M. pneumoniae upsurge in southern China. The outbreak of M. pneumoniae respiratory infections after COVID-19 had higher incidence and longer duration than before COVID-19. During this M. pneumoniae season, the proportion of school-age children increased, and lower respiratory tract infections occurred in more children, especially MPP. The incidence of RMPP also increased but SMPP did not vary significantly over the season. Clinical characteristics should be considered in patients with respiratory symptoms, including imaging findings and coinfections. To gain a more comprehensive understanding of the recent rise in incidence, it is essential to examine data pertaining to factors such as disease severity, the circulating strains, and the extent of macrolide resistance.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-914/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-914/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-914/prf

Funding: This research was supported by Meizhou Municipal Science and Technology Bureau, China (grant Nos. 2023C0301111; 2024C0301031).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-914/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study protocol was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and approved by the Ethics Committee of Meizhou Maternal and Children’s Health Hospital (No. mzsfybjy2024015). Informed consent was obtained from the patients’ parents or legal guardians.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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