An exceptionally large wave of M. pneumoniae infections among children in Tianjin post COVID-19 pandemic

Introduction

Mycoplasma pneumoniae (M. pneumoniae) is a prevalent pathogen commonly associated with upper or lower respiratory tract infections (RTIs) in children. The prevalence of M. pneumoniae infection in China is the second highest among bacterial acute respiratory infections, following only Streptococcus pneumoniae (S. pneumoniae). It accounts for 18.6% of total bacterial infections in the entire population. Moreover, it emerges as the predominant type of bacterial infection among school-age children, accounting for 56.7% (1). Epidemic of M. pneumoniae infection occurs every 3 to 7 years (2) and it is responsible for approximately 30% to 40% of community-acquired pneumonia (CAP) in children (3,4). In addition, its epidemiologic characteristics may vary across different age groups, genders and quarters (5,6). Different geographic areas also exhibit distinct pathogen spectrums and epidemiological features. The last epidemic of M. pneumoniae occurred from 2015 to 2016 (4,7). The incidence of M. pneumoniae infections in China exhibited an upward trend in 2019. However, a cliff decline was observed in 2020 (6,8). Data from a collaborative global network indicated a continued scarcity of M. pneumoniae until 2022, prompting the question of its whereabouts (9). Therefore, this study retrospectively analyzed the prevalence of M. pneumoniae among pediatric outpatients from 2019–2023 to explore the characteristics of children with M. pneumoniae in Tianjin (China), and reported an exceptionally large wave of MP infections post the coronavirus disease-2019 (COVID-19) pandemic in 2023. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-24-228/rc).

Methods

Study population and samples

A total of 78,886 pediatric patients with respiratory infection, who visited the outpatient/emergency department of General Hospital of Tianjin Medical University, Tianjin, China between January 1st, 2019 and December 31st, 2023, were included in this study. Diagnoses were determined according to the World Health Organization’s criteria. Of the 78,886 patients, 42,467 children were male and 36,419 were female. Patients’ ages ranged from 1 month to 14 years old. These patients were divided into four groups with 3-year intervals. Peripheral blood was collected from each child for routine blood test. This study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and received approval from the Ethics Committee of Tianjin Medical University General Hospital (No. IRB2024-WZ-010). It is a retrospective analysis, in which all patient information was reported in an anonymous manner. In accordance with the guidelines set by the Ethics Committee at the Tianjin Medical University General Hospital, individual participant content was waived due to the retrospective nature of the study.

Detection

The M. pneumoniae specific immunoglobulin M (IgM) in blood samples collected from 78,886 patients was tested using the rapid immunochromatographic assay kit (manufactured by Zhuhai Lizhu Reagent Co., Ltd., Zhuhai, China) according to the manufacturer’s instructions. The blood samples were added to the antigen-coated test strips. A positive result was determined if both a test line and a quality control line appeared within 5–10 minutes after the test. This testing approach showed no significant disparity compared to the passive particle agglutination method when the antibody titer was equal to or greater than 1:160, and repeated tests within three months only recorded once (6).

Statistical analysis

The data analysis was performed using the statistical software SPSS 26.0 (IBM Corp., Chicago, IL, USA). The occurrence of M. pneumoniae positive cases was examined across different years, months, quarters, as well as among patients with varying genders, ages, and diagnosis groups. Chi-squared test was employed to compare the variables. A significance level of P<0.05 was considered statistically significant.

Results

Annual cases from 2019 to 2023

Of the 78,886 blood samples, 11,268 were positive for M. pneumoniae specific-IgM antibody. The average positive rate in the 5 years was 14.3%. The number of M. pneumoniae positive cases in 2019 was recorded as 3,635, which subsequently dropped to 518 in 2020, followed by 532 in 2021 and 713 in the year of 2022 (during the COVID-19 pandemic). However, it is noteworthy that the number of M. pneumoniae positive cases in 2023 surged to an unprecedented high at 5,870, surpassing the figures observed in previous years and even exceeding the cumulative count of the past 4 years. The corresponding positive rates in each year were 15.7%, 11.6%, 6.6%, 16.4% and 15.1%, respectively.

Epidemiological characteristics of M. pneumoniae over months

Monthly, M. pneumoniae dropped dramatically to extremely low levels in February 2020, and kept low levels during the COVID-19 pandemic. Since September 2023, there had been a significant surge in the incidence of M. pneumoniae, reaching its peak at 1,717 cases in November 2023, followed by a subsequent decline observed in December 2023 (Figure 1).

Figure 1 Monthly positive cases and rates (%) of M. pneumoniae IgM antibody from 2019 to 2023. M. pneumoniae, Mycoplasma pneumoniae; IgM, immunoglobulin M.

Epidemiological characteristics of M. pneumoniae in different quarters

The number of M. pneumoniae positive cases showed a successive increase in the four quarters of 2023. The positive cases in the first and second quarters of 2023 was lower compared to that in 2019, while it was higher in the third quarter of 2023 compared to the same period in 2019 (828 vs. 748). Moreover, there was a significant surge in M. pneumoniae positive cases during the fourth quarter of 2023 compare to that in 2019 (4,610 vs. 1,209) (Figure 2).

Figure 2 Quarterly positive cases of M. pneumoniae IgM antibody from 2019 to 2023. M. pneumoniae, Mycoplasma pneumoniae; IgM, immunoglobulin M.

Epidemiological characteristics of M. pneumoniae in cases of different age groups

The 11,268 positive cases were aged 7.50±4.18 years (range, 0–14 years). These cases were divided into four groups with 3-year intervals. M. pneumoniae infection was predominantly observed in children aged 4–6 and 7–9 years both before and during the COVID-19 pandemic. However, there was a significant increase in the proportion of children aged 10–14 years after the pandemic (χ²=393.897, P<0.001). The positive rate of M. pneumoniae in children aged 0–3 years was the lowest both before and after the COVID-19 epidemic (Figure 3).

Figure 3 The M. pneumoniae IgM antibody positive cases of different age groups from 2019 to 2023. M. pneumoniae, Mycoplasma pneumoniae; IgM, immunoglobulin M.

Epidemiological characteristics of M. pneumoniae in cases of different genders

Among the 11,268 positive cases, 5,600 (49.70%) cases were boys, and 5,668 (50.30%) were girls, with a gender ratio of 1:1. The positive rate (%) of M. pneumoniae specific-IgM antibody in blood samples in boys was 13.19% (5,600/42,467), which was lower than that in girls (15.56%, 5,668/36,419), with significant difference (χ²=90.444, P<0.001). In 2019 and 2023, the annual positive rates in girls were both higher than those in boys, with significant difference (P<0.001). However, there was no significant difference in cases of different genders during the COVID-19 pandemic from 2020 to 2022 (Table 1).

The constituent ratios of cases of M. pneumoniae infection

The constituent ratio of M. pneumoniae infection cases in 2023 exhibited a significant disparity compared to previous years (χ²=1,395.770, P<0.001). The highest proportion of M. pneumoniae antibody-positive cases was pneumonia, accounting for 37.9% in 2023. Furthermore, the proportion of pneumonia was significantly higher than that observed in previous years (χ²=263.864, P<0.001). Conversely, the incidence of tracheitis and bronchitis decreased in 2023, while there was a notable rise in the occurrence of upper RTIs (Figure 4).

Figure 4 The constituent ratios of M. pneumoniae IgM antibody positive cases. URI, upper respiratory infection; M. pneumoniae, Mycoplasma pneumoniae; IgM, immunoglobulin M.

Discussion

M. pneumoniae is a common atypical pathogen that can cause RTI (10). However, the global prevalence of M. pneumoniae has been significantly impacted by the non-pharmaceutical interventions (NPIs) implemented during the COVID-19 pandemic outbreak in late 2019. Global data showed an ongoing scarcity of M. pneumoniae until 2022, while other pathogens resurged as an indicator of community transmission (9,11). In our study, an M. pneumoniae outbreak was found in Tianjin starting from September 2023, with a peak annual incidence of positive cases (5,870), surpassing the cumulative count of the preceding 4 years. M. pneumoniae is usually sporadic, with regional outbreaks every 3 to 7 years, and each outbreak lasts for 1 to 2 years (7,12). The last outbreak of M. pneumoniae occurred from 2015 to 2016 (4). The prevalence of M. pneumoniae infections in China showed an increasing pattern throughout 2019 (6). However, similar to previous findings (6,7), there was a significant decline in M. pneumoniae infections at the beginning of 2020, and since then the prevalence of M. pneumoniae remained consistently low. China implemented NPIs in January 2020, followed by numerous countries in March. These measures had been temporally associated with a global and unprecedented suppression of viral and bacterial respiratory infections (13-15). However, as COVID-19 restrictions gradually relaxed in 2021 and 2022, there was a rebound in the transmission of enveloped respiratory viruses such as influenza A virus and respiratory syncytial virus (16). Moreover, non-enveloped viruses like rhinovirus and enterovirus progressively increased after only a few months, reaching pre-pandemic or even higher levels, despite the persistence of NPIs (17,18). Additionally, Streptococcus pneumoniae invasive diseases resurged in 2021 (19), while the scarlet fever and invasive Group A Streptococcus infections resurged in 2022 (20). However, M. pneumoniae remained scarce until summer 2023, which probably attributes to its slow generation time (6 h) and spread rate (incubation period of 1–3 weeks). In our study, M. pneumoniae positive cases in 2023 reached 5,870, surpassing the cumulative count of the preceding 4 years. The most recent two epidemics of M. pneumoniae occurred from 2015 to 2016 (4) and 2019 respectively. The outbreak may have been influenced by the cyclical nature of M. pneumoniae epidemics, which occur every 3–7 years. Furthermore, it should be noted that the present wave of M. pneumoniae infections exhibited a significantly higher incidence compared to previous epidemics. The implementation of NPIs may have led to limited exposure to M. pneumoniae, resulting in a notable deficit in children’s immunity and an increased risk of infection development. Moreover, pathogens such as parainfluenza, adenovirus and influenza B can act as independent risk factors for children M. pneumoniae infection (21). These pathogens may also facilitate the infection of M. pneumoniae in 2023. Additionally, the recent increased focus on M. pneumoniae in the wider media has facilitated voluntary testing for M. pneumoniae.

In 2019, the positive numbers of M. pneumoniae were higher in both the second and fourth quarters, consistent with the study of Cheng et al. in the same period in Beijing (6). However, in 2023, the incidence of M. pneumoniae positive cases exhibited a significant surge during the fourth quarter, which can be attributed to the resurgence of M. pneumoniae post COVID-19 pandemic beginning in the third quarter of 2023. Based on the previous pattern of M. pneumoniae epidemic, it is anticipated that its prevalence will remain elevated until at least 2024 or beyond. Therefore, vigilance towards M. pneumoniae should be maintained, especially in the second and fourth quarters of 2024.

M. pneumoniae infection was predominantly observed in children aged 4–6 and 7–9 years both before and during the COVID-19 pandemic. However, there was a significant increase in the proportion of children aged 10–14 years post the pandemic. A single genotype of M. pneumoniae is unlikely to be the main cause of the epidemic, as previous research has indicated that both endemic and epidemic spreads of M. pneumoniae can involve multiple genotypes (22,23). Therefore, it is possible that the observed age distribution pattern during the two periods could be attributed to interactions between the pathogen and the immune status of the human population. Since the immune system of older children is more fully developed and they are more likely to have been exposed to M. pneumoniae in the past, they are protective against M. pneumoniae attack in 2019. However, after 3 years absence of M. pneumoniae during the COVID-19 pandemic, children of all age groups, including those aged 10–14 years, had limited opportunities to acquire immunity against M. pneumoniae, leading to a phenomenon known as ‘immunity debt’. Consequently, M. pneumoniae positive children aged 10–14 years increased significantly in 2023. Younger individuals had less contact with external environments and thus fewer chances to be exposed to M. pneumoniae. This explains why the positive rate of M. pneumoniae in children aged 0–3 years was the lowest both before and post the COVID-19 epidemic.

In our study, a significant gender-based disparity was observed both before and post COVID pandemic, with girls exhibiting higher susceptibility to M. pneumoniae compared to boys, consistent with previous findings (6,7,23). However, no significant difference in cases between genders was found during the COVID-19 pandemic, which may be attributed to the limited sample size. The underlying factors contributing to gender disparities before and post COVID pandemic remain unclear. Cheng et al. hypothesize that this phenomenon may be explained by disparities in outdoor activity duration between girls and boys (6).

As reported, M. pneumoniae infection is usually a form of relatively mild disease and usually self-limiting, but that hit children hard in China last winter (24). In our study, pneumonia accounted the highest proportion of M. pneumoniae antibody-positive cases in 2023, reaching 37.9%, followed by upper respiratory infection (URI), bronchitis and tracheitis. Moreover, the proportion of pneumonia in 2023 was significantly higher than that in previous years. This perhaps is due to increased population susceptibility to respiratory infections following 3 years of COVID measures, known as immunity debt. The M. pneumonia infection progressed rapidly, and soon progressed from upper RTI to pneumonia in 2023, resulting in a relatively low incidence of bronchitis and tracheitis. Patients with M. pneumonia may be at risk of developing severe pneumonia in epidemic times (5). However, only 62 cases of severe pneumonia were found and all occurred in 2023 in our study, which can be attributed to the fact that only outpatients were included in this study.

There are several limitations in this study. First, we assessed the positivity rate by detecting the M. pneumoniae specific IgM antibody and did not conduct any nucleic acid testing. As the accuracy of IgM antibody test results can be affected by the timing and duration of antibody production, combining nucleic acid testing with antibody detection provides a more dependable approach for diagnosing (25). Secondly, an extended follow-up period is needed to gain a more comprehensive understanding of the epidemiology of M. pneumoniae subsequent to the COVID-19 pandemic.

Conclusions

In conclusion, this study demonstrated that an M. pneumoniae outbreak started in September 2023 in Tianjin following a prolonged lowering number of cases due to the COVID-19 pandemic. By comparing the different characteristics of M. pneumoniae in 2023 to those of other years, we found that the proportion of M. pneumoniae positive children in the older age group increased in 2023. Additionally, there was a notable increase in the proportion of pneumonia cases among those tested positive for M. pneumoniae in 2023, indicating the gravity of this outbreak and emphasizing the imperative to enhance identification and control measures for rare severe cases. It is advisable to implement appropriate non-pharmacological preventive measures such as utilization of masks and regular hand sanitization for children in 2024, particularly during the fourth quarters.

Acknowledgments

Funding: None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-24-228/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-228/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-228/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-228/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 was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study has received approval from the Ethics Committee of Tianjin Medical University General Hospital (No. IRB2024-WZ-010). It is a retrospective analysis, in which all patient information was reported in an anonymous manner. In accordance with the guidelines set by the Ethics Committee at the Tianjin Medical University General Hospital, individual participant content was waived due to the retrospective nature of the study.

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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