Understanding the unconventional reemergence of M. pneumoniae epidemics during the COVID-19 pandemic

Introduction

Mycoplasma pneumoniae (M. pneumoniae) frequently leads to respiratory tract infections, placing community-acquired pneumonia as the primary burden associated with the disease in children and adults (1). While the majority of pediatric cases of M. pneumoniae infections are relatively mild, it is essential to note that some cases can lead to more severe outcomes, such as pleural effusion, bronchiolitis obliterans, bronchiectasis, and atelectasis. Previous studies suggested that there is typically an interval of 2–4 years between epidemics of M. pneumoniae in Europe and Asia (2-4). The latest epidemic of M. pneumoniae before coronavirus disease 2019 (COVID-19) pandemic occurred in late 2019, affecting multiple nations concurrently, with a predominant impact observed in Europe and Asia (5).

Since 2020, the implementation of non-pharmaceutical interventions (NPIs) to combat COVID-19 has led to a sudden cessation of these epidemics and a notable decrease in the global detection of M. pneumoniae (5), as well as other respiratory pathogens (6). After the relaxation of major NPIs in many areas, several virus infections emerged and continued to persist, while M. pneumoniae did not resurge until 2023. Although the outbreak of M. pneumoniae occurred later compared to other viral infections, it follows the usual cycle of 2 to 4 years. However, unlike previous patterns, it is unconventional that there has been a significant increase in the number of cases in multiple regions in 2023, far surpassing the levels observed before the COVID-19 pandemic (7-9) (Figure 1).

Figure 1 Modelling of M. pneumoniae and common respiratory viruses in children before and after the COVID-19 pandemic. The model is based on relevant research data (7,9). During the pandemic, the implementation of NPIs led to a sharp decline in infections. As NPIs were relaxed, the number of infections with common respiratory viruses first increased, until an unconventional outbreak of Mycoplasma pneumoniae infections occurred in 2023. COVID-19, coronavirus disease 2019; M. pneumoniae, Mycoplasma pneumoniae; NPIs, non-pharmaceutical interventions.

Documenting and comprehending the atypical alterations in M. pneumoniae circulation during the COVID-19 pandemic can contribute valuable insights to shape forthcoming public health responses. The purpose of this article is to review the existing evidence and explore various theories that underpin the atypical shifts in the epidemiology of M. pneumoniae during the COVID-19 pandemic.

Decline of M. pneumoniae immunity at the population level

At the end of 2019, there was an outbreak of M. pneumoniae infection, leading to the population acquiring temporary herd immunity to M. pneumoniae. Given the typical three-year interval between M. pneumoniae epidemics, this temporary herd immunity likely helped suppress the resurgence of the infection for an extended period. The absence of continuous immune stimulation by M. pneumoniae or other respiratory pathogens for extended periods may have expanded the population of immunologically vulnerable individuals, particularly among children. The Pediatric Infectious Disease Group has introduced the concept of an “immunity debt” to explain this phenomenon (10). Waning humoral immunity, characterized by lower antibody titers, could increase the susceptibility to infection, thereby contributing to a higher incidence of respiratory infections (11). The decline in the detection of M. pneumoniae-specific immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies may further confirm this point (12).

Our recent study summarized the dynamic changes in M. pneumoniae IgG antibodies in children aged 1–14 years before and after the epidemic, and for the first time, provided evidence of M. pneumoniae immunity gap following an extended period with low exposure to the microbe (7). In the late stage of the pandemic, the decline in IgG levels was more pronounced in children over 9 years old. Another study confirmed a significant reduction in IgA and IgM levels in the pediatric population during this period (13). Further research is needed to investigate antibody levels against M. pneumoniae in adults.

Prior to the introduction of NPIs, children had regular opportunities to be exposed to and develop immunity against M. pneumoniae, following the normal infection cycle. However, during the period when NPIs were implemented in China from 2020 to 2022, susceptible children were not exposed to M. pneumoniae infections. As a result, the efficacy of M. pneumoniae immunoglobulin G (MP-IgG) antibodies decreased more than expected, resulting in an immune gap. Additionally, infants born during this period had limited exposure to antigens, resulting in a relatively weaker immune response. Therefore, by 2023, the cumulative effect of a new susceptible cohort and the gradual decline in immunity over time widened the immune gap, potentially contributing to a significant increase in the number of affected children.

Circulation of different genetic types and emergence of new macrolide-resistant M. pneumoniae (MRMP) variants

The genome of M. pneumoniae is highly conserved, and the total number of genes is close to saturation, indicating a relatively restricted pan-genome.

In Switzerland, P1-1 and P1-2 alternate in dominance (14). The United States experienced a shift from P1-1 to P1-2 (15). In East Asia, P1-1 was the initially dominant strain, aligning with reports from Japan, where P1-2 was predominant from 2017 (16).

Recent studies have noted a trend in certain regions of China shifting from P1-1 to P1-2 (17). Particularly post-pandemic, there has been a significant increase in the proportion of P1-2 among school-aged children in China, although this change has not been observed in children, adults, and the elderly (16). This is consistent with a study conducted in Suzhou, where the transition from EC1 in P1-1 to EC2 in P1-2 was observed, showing complete resistance to macrolide antibiotics (18). This suggests a shift in the predominant M. pneumoniae patterns, leading to changes in the distribution of macrolide-resistant strains.

Besides, new research in Vietnam has revealed the emergence of a novel C2353T variant, which showed resistance to macrolide antibiotics (19). The known MRMP mutation A2063G is the most prevalent mutation compared with other infrequent mutations (e.g., A2063T/C, A2067G, A2064G, A1290G, and C2617A) (20). Mutations at site 2063 are strongly linked to elevated macrolide resistance levels (21). The circulation of different MRMP variants or emergence of new MRMP variants may contribute to the recent M. pneumoniae infections outbreak among children (18).

As patients with macrolide-resistant infections experience longer duration of fever, prolonged hospital stays, and greater treatment challenges compared to those with macrolide-sensitive infections (21). The transition in genotypes and the emergence of novel variants have increased the number of patients with MRMP infections, leading to a rise in hospitalizations due to M. pneumoniae infections.

Immune dysregulations following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection

SARS-CoV-2 infection elicits a robust immune response that plays a crucial role in clearing the initial infection. This response involves the generation of neutralizing antibodies and the activation of CD4 and CD8 T cells. Neutralizing antibodies can prevent infection and clear pathogens, playing a key role in providing long-term immunity (22). Similar to most acute respiratory virus infections, SARS-CoV-2 infection triggers a neutralizing antibody response (22). However, with the recent emergence of the SARS-CoV-2 Omicron variant, there has been a decrease in the production of neutralizing antibodies. These variants carry numerous protein mutations that can evade broad-spectrum neutralizing antibodies, leading to a compromised immune function, which underscores the increasing immunological importance of T-cell responses targeting conserved epitopes in cellular immunity (23). Compared to other respiratory viruses, the host’s immune response to SARS-CoV-2 fails to initiate a robust type I and type III interferon response, while inducing high levels of chemokines and pro-inflammatory cytokines (24). Additionally, despite the effectiveness of interferons in blocking SARS-CoV-2 replication, the virus employs mechanisms to inhibit the induction of endogenous interferons and interferon receptor signaling (25). This reduction in early interferon response can result in an imbalanced host immune response and an inability to clear the virus (24). Consequently, the lack of this interferon response allows for sustained viral replication, leading not only to severe SARS-CoV-2 infection but also to large-scale respiratory viral infection events observed in populations after the lifting of NPIs. Immunological dysregulation may lead to a larger population and more severe M. pneumoniae infections. Currently, there is no literature specifically addressing this, but there are reports regarding the impact of immunological dysregulation on viral activity (6). Similarly, a weakened humoral immune response may increase the likelihood of infection, leading to more infections, increased replication of M. pneumoniae, and a higher chance of mutations, thereby resulting in the emergence of new variants that can impact the activity of M. pneumoniae infections.

Other potential factors

Changes in the colonization of upper respiratory tract (URT) bacteria in children

The URT colonization includes bacteria, viruses, and M. pneumoniae, which interact in a symbiotic or antagonistic manner (26). Changes in URT colonization can affect the infection process through various pathways, for instance, by upregulating adhesion receptors, thereby increasing the binding of certain pathogens to epithelial cells and amplifying the inflammatory response (26). Infection by M. pneumoniae initially requires adhesion to the host bronchial epithelium, inducing an inflammatory response in infected cells (27), a process that may also be influenced by URT colonization. A study from South Africa reported changes in URT colonization in children before and after COVID-19 (28), with such changes potentially affecting the current infections of M. pneumoniae.

Potential interaction between respiratory viruses and M. pneumoniae

In our country, where NPIs were lifted in 2022, the resurgence of both common respiratory viruses and M. pneumoniae occurred in 2023. In 2023, children began experiencing multiple viral infections, including influenza, adenovirus, and respiratory syncytial virus, starting in March (29). The rise in viral infections may have contributed to immunological dysregulation, increasing children’s susceptibility to M. pneumoniae, which re-emerged following the viral outbreaks. Besides, the co-infection of viruses and M. pneumoniae is a common occurrence (30). When compared to a singular M. pneumoniae infection, children admitted to the hospital with M. pneumoniae along with simultaneous viral infections, particularly adenovirus and influenza, display more severe clinical symptoms and necessitate an extended treatment duration (31). The simultaneous resurgence of multiple viruses, along with M. pneumoniae, has further contributed to an increase in hospitalizations.

The impact of environmental factors on M. pneumoniae infection

Meteorological factors and environmental pollutants strengthen the susceptibility to respiratory pathogens, including M. pneumoniae, especially in the transmission of M. pneumoniae infections. A previous study has shown particulate matter 2.5 (PM_2.5), nitrogen dioxide (NO₂), and sulfur dioxide (SO₂) concentrations have influence on M. pneumoniae infections in children (32). Compared to the period of NPIs, exposure to environmental air pollutants post-pandemic may impact the transmission of respiratory pathogens, promoting inflammatory states and leading to immune system dysregulation (33).

Conclusions

This study documents and analyzes the atypical epidemiological changes of M. pneumoniae during the COVID-19 pandemic. A sudden decrease in M. pneumoniae cases and a significant global reduction in detection rates due to NPIs implemented for COVID-19. However, as these interventions were gradually relaxed, a delayed resurgence of M. pneumoniae was observed, with large-scale outbreaks occurring in China in October and November 2023. The resurgence of M. pneumoniae infections in children may be associated with various factors as mentioned earlier (Figure 2).

Figure 2 Factors associated with the resurgence of M. pneumoniae infections. Decline of M. pneumoniae immunity, circulation of different genetic types and emergence of new macrolide-resistant M. pneumoniae variants, immune dysregulation following SARS-CoV-2 infection and other factors. COVID-19, coronavirus disease 2019; M. pneumoniae, Mycoplasma pneumoniae; MP-IgG, Mycoplasma pneumoniae immunoglobulin G; MRMP, macrolide-resistant Mycoplasma pneumoniae; NO₂, nitrogen dioxide; NPIs, non-pharmaceutical interventions; PM2.5, particulate matter 2.5; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; SO₂, sulfur dioxide.

In the future, for comprehensive management of M. pneumoniae, especially considering the long-term impact of the COVID-19 pandemic, continuous monitoring of immunity levels is crucial. Simultaneously, in-depth research on the relationship between genetic changes in M. pneumoniae and antibiotic resistance is essential. M. pneumoniae lacks a comprehensive reporting system across all age groups, unlike infectious diseases such as pertussis, with limited research worldwide in adults and the elderly, particularly regarding serological and genetic levels. We call for greater international attention and more discussion on M. pneumoniae on a global scale. Cross-regional collaboration will enhance our comprehension of the scope of M. pneumoniae outbreaks, facilitate sharing experiences, and enable a collective response. By maintaining vigilance and promoting global cooperation, we can improve strategies for prevention and treatment, ultimately better safeguarding public health.

Acknowledgments

None.

Footnote

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-24-482/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-24-482/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.

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/.

References

1. Waites KB, Xiao L, Liu Y, et al. Mycoplasma pneumoniae from the Respiratory Tract and Beyond. Clin Microbiol Rev 2017;30:747-809. [Crossref] [PubMed]
2. Beeton ML, Zhang XS, Uldum SA, et al. Mycoplasma pneumoniae infections, 11 countries in Europe and Israel, 2011 to 2016. Euro Surveill 2020;25:1900112. [Crossref] [PubMed]
3. Gao LW, Yin J, Hu YH, et al. The epidemiology of paediatric Mycoplasma pneumoniae pneumonia in North China: 2006 to 2016. Epidemiol Infect 2019;147:e192. [Crossref] [PubMed]
4. Kogoj R, Mrvic T, Praprotnik M, et al. Prevalence, genotyping and macrolide resistance of Mycoplasma pneumoniae among isolates of patients with respiratory tract infections, Central Slovenia, 2006 to 2014. Euro Surveill 2015;
5. Meyer Sauteur PM, Beeton ML, Uldum SA, et al. Mycoplasma pneumoniae detections before and during the COVID-19 pandemic: results of a global survey, 2017 to 2021. Euro Surveill 2022;27:2100746. [Crossref] [PubMed]
6. Chow EJ, Uyeki TM, Chu HY. The effects of the COVID-19 pandemic on community respiratory virus activity. Nat Rev Microbiol 2023;21:195-210. [Crossref] [PubMed]
7. Liu B, Xu L, Ma Y, et al. Evidence of immunity gap: Decline in antibodies against M. pneumoniae during the COVID-19 pandemic. J Infect 2024;89:106209. [Crossref] [PubMed]
8. Xu Y, Yang C, Sun P, et al. Epidemic features and megagenomic analysis of childhood Mycoplasma pneumoniae post COVID-19 pandemic: a 6-year study in southern China. Emerg Microbes Infect 2024;13:2353298. [Crossref] [PubMed]
9. Xu X, Meng L, Li J, et al. Analysis of the potentially pathogenic bacteria of lower respiratory tract infections in children per-, during and post-COVID-19: a retrospective study. Eur J Clin Microbiol Infect Dis 2025;44:167-80. [Crossref] [PubMed]
10. Cohen R, Ashman M, Taha MK, et al. Pediatric Infectious Disease Group (GPIP) position paper on the immune debt of the COVID-19 pandemic in childhood, how can we fill the immunity gap? Infect Dis Now 2021;51:418-23. [Crossref] [PubMed]
11. Jiang W, Xu L, Wang Y, et al. Exploring immunity debt: Dynamic alterations in RSV antibody levels in children under 5 years during the COVID-19 pandemic. J Infect 2024;88:53-6. [Crossref] [PubMed]
12. Meyer Sauteur PM, Beeton ML. European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycoplasma and Chlamydia Infections (ESGMAC), and the ESGMAC Mycoplasma pneumoniae Surveillance (MAPS) study group. Mycoplasma pneumoniae: delayed re-emergence after COVID-19 pandemic restrictions. Lancet Microbe 2024;5:e100-1. [Crossref] [PubMed]
13. Tang L, Zheng K, Ma L, et al. Epidemiologic trends and changes in humoral immunity and lymphocyte subsets levels among hospitalized children with Mycoplasma pneumoniae infection during 2019-2023. Eur J Clin Microbiol Infect Dis 2024;43:1837-45. [Crossref] [PubMed]
14. Meyer Sauteur PM, Pánisová E, Seiler M, et al. Mycoplasma pneumoniae Genotypes and Clinical Outcome in Children. J Clin Microbiol 2021;59:e0074821. [Crossref] [PubMed]
15. Xiao L, Ratliff AE, Crabb DM, et al. Molecular Characterization of Mycoplasma pneumoniae Isolates in the United States from 2012 to 2018. J Clin Microbiol 2020;58:e00710-20. [Crossref] [PubMed]
16. You H, Yang B, Liu H, et al. Unravelling distinct patterns of metagenomic surveillance and respiratory microbiota between two P1 genotypes of Mycoplasma pneumoniae. Emerg Microbes Infect 2025;14:2449087. [Crossref] [PubMed]
17. Guo Z, Liu L, Gong J, et al. Molecular features and antimicrobial susceptibility of Mycoplasma pneumoniae isolates from paediatric inpatients in Weihai, China: Characteristics of M. pneumoniae In Weihai. J Glob Antimicrob Resist 2022;28:180-4. [Crossref] [PubMed]
18. Li H, Li S, Yang H, et al. Resurgence of Mycoplasma pneumonia by macrolide-resistant epidemic clones in China. Lancet Microbe 2024;5:e515. [Crossref] [PubMed]
19. Nguyen DD, Ho NT, Dover LG, et al. Novel Variant and Known Mutation in 23S rRNA Gene of Mycoplasma pneumoniae, Northern Vietnam, 2023. Emerg Infect Dis 2024;30:1034-6. [Crossref] [PubMed]
20. Wang N, Xu X, Xiao L, et al. Novel mechanisms of macrolide resistance revealed by in vitro selection and genome analysis in Mycoplasma pneumoniae. Front Cell Infect Microbiol 2023;13:1186017. [Crossref] [PubMed]
21. Chen YC, Hsu WY, Chang TH. Macrolide-Resistant Mycoplasma pneumoniae Infections in Pediatric Community-Acquired Pneumonia. Emerg Infect Dis 2020;26:1382-91. [Crossref] [PubMed]
22. Gruell H, Vanshylla K, Weber T, et al. Antibody-mediated neutralization of SARS-CoV-2. Immunity 2022;55:925-44. [Crossref] [PubMed]
23. Koutsakos M, Reynaldi A, Lee WS, et al. SARS-CoV-2 breakthrough infection induces rapid memory and de novo T cell responses. Immunity 2023;56:879-892.e4. [Crossref] [PubMed]
24. Blanco-Melo D, Nilsson-Payant BE, Liu WC, et al. Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19. Cell 2020;181:1036-1045.e9. [Crossref] [PubMed]
25. Xia H, Cao Z, Xie X, et al. Evasion of Type I Interferon by SARS-CoV-2. Cell Rep 2020;33:108234. [Crossref] [PubMed]
26. Man WH, de Steenhuijsen Piters WA, Bogaert D. The microbiota of the respiratory tract: gatekeeper to respiratory health. Nat Rev Microbiol 2017;15:259-70. [Crossref] [PubMed]
27. Jiang Z, Li S, Zhu C, et al. Mycoplasma pneumoniae Infections: Pathogenesis and Vaccine Development. Pathogens 2021;10:119. [Crossref] [PubMed]
28. Olwagen CP, Downs SL, Izu A, et al. Bacterial nasopharyngeal colonisation in children in South Africa before and during the COVID-19 pandemic: an observational study. Lancet Microbe 2024;5:e34-42. [Crossref] [PubMed]
29. Zhao P, Zhang Y, Wang J, et al. Epidemiology of respiratory pathogens in patients with acute respiratory infections during the COVID-19 pandemic and after easing of COVID-19 restrictions. Microbiol Spectr 2024;12:e0116124. [Crossref] [PubMed]
30. Huang H, Wu B, Lin W. Characterising respiratory infections among hospitalised children during the COVID-19 pandemic in southeastern China: a cross-sectional study of pathogens and clinical association. BMJ Open 2024;14:e076824. [Crossref] [PubMed]
31. Shin S, Koo S, Yang YJ, et al. Characteristics of the Mycoplasma pneumoniae Epidemic from 2019 to 2020 in Korea: Macrolide Resistance and Co-Infection Trends. Antibiotics (Basel) 2023;12:1623. [Crossref] [PubMed]
32. Zhang D, Li Y, Chen Q, et al. The relationship between air quality and respiratory pathogens among children in Suzhou City. Ital J Pediatr 2019;45:123. [Crossref] [PubMed]
33. Shim SR, Kim HJ, Hong M, et al. Effects of meteorological factors and air pollutants on the incidence of COVID-19 in South Korea. Environ Res 2022;212:113392. [Crossref] [PubMed]