Mycoplasma pneumoniae: delayed re-emergence after COVID-19 pandemic restrictions

Mycoplasma pneumoniae is a common cause of respiratory tract infections with community-acquired pneumonia as the major disease-related burden. Compared with other pathogens, M pneumoniae is atypical in many ways: it is one of the smallest self-replicating organisms, has a reduced and highly stable genome (0·8 Mbp), lacks a cell wall, grows slowly (generation time 6 h), requires close contact for transmission, and has a distinct disease presentation (atypical pneumonia), the pathogenesis of which might involve host cell-mediated immunity.1Reimann HA An acute infection of the respiratory tract with atypical pneumonia: a disease entity probably caused by a filtrable virus.JAMA. 1938; 111: 2377-2384Crossref Google Scholar, 2Waites KB Talkington DF Mycoplasma pneumoniae and its role as a human pathogen.Clin Microbiol Rev. 2004; 17: 697-728Crossref PubMed Scopus (974) Google Scholar, 3Pánisová E Unger WWJ Berger C Meyer Sauteur PM Mycoplasma pneumoniae-specific IFN-gamma-producing CD4(+) effector-memory T cells correlate with pulmonary disease.Am J Respir Cell Mol Biol. 2021; 64: 143-146Crossref Scopus (7) Google Scholar Infections occur year-round in many different climates worldwide, with epidemics every few years.4Uldum SA Bangsborg JM Gahrn-Hansen B et al.Epidemic of Mycoplasma pneumoniae infection in Denmark, 2010 and 2011.Euro Surveill. 2012; 1720073Crossref PubMed Scopus (69) Google Scholar,5Beeton ML Zhang XS Uldum SA et al.Mycoplasma pneumoniae infections, 11 countries in Europe and Israel, 2011 to 2016.Euro Surveill. 2020; 251900112Crossref PubMed Scopus (18) Google Scholar Previously obtained data indicated an interval of 1–3 years between M pneumoniae epidemics in Europe and Israel.5Beeton ML Zhang XS Uldum SA et al.Mycoplasma pneumoniae infections, 11 countries in Europe and Israel, 2011 to 2016.Euro Surveill. 2020; 251900112Crossref PubMed Scopus (18) Google Scholar Several factors, including waning herd immunity or introduction of new subtypes into the population, account for the periodic occurrence of epidemics. The most recent epidemic occurred in late 2019–early 2020 simultaneously across multiple nations, predominantly in Europe and Asia.6Meyer 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; 272100746Crossref PubMed Scopus (9) Google Scholar In March, 2020, the introduction of non-pharmaceutical interventions (NPIs) against COVID-19 resulted in an abrupt ending of these epidemics and a marked decline in M pneumoniae detection worldwide.6Meyer 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; 272100746Crossref PubMed Scopus (9) Google Scholar Compared with the pre-pandemic incidence of M pneumoniae (8·61%, 2017–20), a significant reduction was observed in the first year after the implementation of NPIs (1·69%, 2020–21),6Meyer 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; 272100746Crossref PubMed Scopus (9) Google Scholar similar to the incidence of other respiratory pathogens.7Brueggemann AB Jansen van Rensburg MJ Shaw D et al.Changes in the incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis during the COVID-19 pandemic in 26 countries and territories in the Invasive Respiratory Infection Surveillance Initiative: a prospective analysis of surveillance data.Lancet Digit Health. 2021; 3: e360-e370Summary Full Text Full Text PDF PubMed Google Scholar A further unprecedented, yet substantial, reduction in the incidence of M pneumoniae was observed in the second year (0·70%, 2021–22),8Meyer Sauteur PM Chalker VJ Berger C et al.Mycoplasma pneumoniae beyond the COVID-19 pandemic: where is it?.Lancet Microbe. 2022; 3: e897Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar when other respiratory pathogens resurged as an indicator of community transmission.8Meyer Sauteur PM Chalker VJ Berger C et al.Mycoplasma pneumoniae beyond the COVID-19 pandemic: where is it?.Lancet Microbe. 2022; 3: e897Summary Full Text Full Text PDF PubMed Scopus (3) Google Scholar,9Clark SA Campbell H Ribeiro S et al.Epidemiological and strain characteristics of invasive meningococcal disease prior to, during and after COVID-19 pandemic restrictions in England.J Infect. 2023; 87: 385-391Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar The first global prospective surveillance study of M pneumoniae (ESGMAC MAPS study)10Meyer Sauteur PM Beeton ML ESGMAC and the ESGMAC MAPS study groupMycoplasma pneumoniae: gone forever?.Lancet Microbe. 2023; 4: e763Summary Full Text Full Text PDF Scopus (0) Google Scholar was initiated in April 2022 to allow for rapid notification regarding the geographical location of any substantial increase in activity via monthly website updates alerting clinicians. First data from this surveillance yielded a sustained very low incidence of M pneumoniae in the third year from April, 2022, to March, 2023 (0·82%).10Meyer Sauteur PM Beeton ML ESGMAC and the ESGMAC MAPS study groupMycoplasma pneumoniae: gone forever?.Lancet Microbe. 2023; 4: e763Summary Full Text Full Text PDF Scopus (0) Google Scholar However, though at very low levels, an increase in case numbers was noted in some countries in the last months of the third year (January to March, 2023),10Meyer Sauteur PM Beeton ML ESGMAC and the ESGMAC MAPS study groupMycoplasma pneumoniae: gone forever?.Lancet Microbe. 2023; 4: e763Summary Full Text Full Text PDF Scopus (0) Google Scholar which subsequently warranted increased vigilance. Here, we report on the further course in the fourth year after the introduction of NPIs, from April 1 to September 30, 2023 (6-month period). Prospective surveillance data were obtained from 45 sites in 24 countries from the four UN regions: Europe, Asia, the Americas, and Oceania. Laboratory information of participating sites has been previously described.10Meyer Sauteur PM Beeton ML ESGMAC and the ESGMAC MAPS study groupMycoplasma pneumoniae: gone forever?.Lancet Microbe. 2023; 4: e763Summary Full Text Full Text PDF Scopus (0) Google Scholar M pneumoniae was detected by PCR in all four UN regions (appendix 2). The mean incidence of M pneumoniae as detected by PCR during the 6-month period was 4·12% (SD 7·94; appendix 2). The incidences of M pneumoniae as detected by PCR were significantly higher in Europe and Asia than in America and Oceania and higher than those observed in previous testing periods in the same UN regions since the start of the prospective surveillance (appendix 3). Overall, M pneumoniae was detected by PCR in 1067 (0·71%) of 149 980 tests during the 6-month period (appendix 2). The most frequent detections in Europe were from Denmark (n=436), Sweden (n=145), Switzerland (n=132), Wales (n=49), and Slovenia (n=41), and in Asia from Singapore (n=172) (appendix 4). Positive test numbers (but not the total number of tests) were also reported from Belgium by PCR (n=136) and from Finland using combined serology and PCR with no distinction possible between the detection methods (n=129) (appendix 2). Detections by IgM serology were 158 (6·58%) of 2403 and by IgG serology were 292 (12·35%) of 2364 (appendix 2).See Online for appendix 2See Online for appendix 3See Online for appendix 4 See Online for appendix 2 See Online for appendix 3 See Online for appendix 4 These global prospective surveillance data show the re-emergence of M pneumoniae in Europe and Asia more than 3 years after the introduction of COVID-19 pandemic restrictions. This delayed re-emergence is striking because it occurred long after NPIs were discontinued, and because it is, to our knowledge, a phenomenon unique to this pathogen. Other respiratory pathogens with a sustained reduction in incidence but earlier resurgence than M pneumoniae were Mycobacterium tuberculosis and Bordetella pertussis, for which increased notifications were not reported until 2021 and 2022, respectively.11Burrell R Saravanos G Britton PN Unintended impacts of COVID-19 on the epidemiology and burden of paediatric respiratory infections.Paediatr Respir Rev. 2023; (published online Aug 3)https://doi.org/10.1016/j.prrv.2023.07.004Crossref Scopus (0) Google Scholar,12Izu A Nunes MC Solomon F et al.All-cause and pathogen-specific lower respiratory tract infection hospital admissions in children younger than 5 years during the COVID-19 pandemic (2020-22) compared with the pre-pandemic period (2015-19) in South Africa: an observational study.Lancet Infect Dis. 2023; 23: 1031-1041Summary Full Text Full Text PDF PubMed Scopus (0) Google Scholar Why is M pneumoniae also atypical in this respect? Numerous theories exist for the altered epidemiology of infections surrounding the COVID-19 pandemic. Most do not apply to M pneumoniae after the severe reduction in incidences long after the discontinued NPIs.6Meyer 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; 272100746Crossref PubMed Scopus (9) Google Scholar The possibility of a viral-bacterial interaction as was observed for Streptococcus pneumoniae, when the temporal suppression of respiratory syncytial virus, influenza viruses, and human metapneumovirus was associated with a decline in pneumococcal disease in young children,13Danino D Ben-Shimol S van der Beek BA et al.Decline in pneumococcal disease in young children during the coronavirus disease 2019 (COVID-19) pandemic in Israel associated with suppression of seasonal respiratory viruses, despite persistent pneumococcal carriage: a prospective cohort study.Clin Infect Dis. 2022; 75: e1154-e1164Crossref PubMed Scopus (56) Google Scholar could be excluded given the much earlier resurgence of respiratory viruses while M pneumoniae was still absent. As postulated for the occurrence of M pneumoniae epidemics, waning herd immunity could also account for the delayed re-emergence. Transient herd immunity from the last epidemic period in several countries in late 2019–early 2020 could have led to the delayed re-emergence considering an interval of up to 3 years between M pneumoniae epidemics in these UN regions.5Beeton ML Zhang XS Uldum SA et al.Mycoplasma pneumoniae infections, 11 countries in Europe and Israel, 2011 to 2016.Euro Surveill. 2020; 251900112Crossref PubMed Scopus (18) Google Scholar However, we have not yet observed a re-emergence in countries where the last epidemic was reported earlier (eg, Germany, Finland, and Norway; all in 2017–18).6Meyer 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; 272100746Crossref PubMed Scopus (9) Google Scholar In addition, no re-emergence was detected by PCR, but a further decline in detections of M pneumoniae-specific IgM and IgG antibodies indicative of waning immunity was observed at sites that reported data separately for PCR and serology (eg, Homburg, Germany; and Rotterdam, The Netherlands). As this delayed re-emergence is atypical and probably unique for M pneumoniae, the atypical characteristics that distinguish M pneumoniae from other pathogens should be strongly considered. Among those, the slow generation time (6 h), long incubation period (1–3 weeks), and relatively low transmission rate could be factors leading to a longer time interval required for the re-establishment of M pneumoniae infection within a population. In countries where M pneumoniae has re-emerged, case numbers are comparable to pre-pandemic (endemic) numbers. The further development of the re-emergence should be monitored to evaluate whether case numbers will escalate to epidemic levels or result in an exceptionally large wave of infections as was observed for the resurgence of other pathogens.11Burrell R Saravanos G Britton PN Unintended impacts of COVID-19 on the epidemiology and burden of paediatric respiratory infections.Paediatr Respir Rev. 2023; (published online Aug 3)https://doi.org/10.1016/j.prrv.2023.07.004Crossref Scopus (0) Google Scholar The progression and severity of the re-emergence are difficult to predict and whether it will lead to an increase in rare cases of severe disease2Waites KB Talkington DF Mycoplasma pneumoniae and its role as a human pathogen.Clin Microbiol Rev. 2004; 17: 697-728Crossref PubMed Scopus (974) Google Scholar and extrapulmonary manifestations14Meyer Sauteur PM Theiler M Buettcher M Seiler M Weibel L Berger C Frequency and clinical presentation of mucocutaneous disease due to Mycoplasma pneumoniae infection in children with community-acquired pneumonia.JAMA Dermatol. 2020; 156: 144-150Crossref PubMed Scopus (0) Google Scholar,15Narita M Classification of extrapulmonary manifestations due to Mycoplasma pneumoniae infection on the basis of possible pathogenesis.Front Microbiol. 2016; 7: 23Crossref PubMed Google Scholar because of the previously reduced exposure remains unknown. However, the global prospective surveillance will alert clinicians to the magnitude and severity of re-emerging infections, thereby allowing a prompt response with adequate management. We declare no competing interests. All data collected and analysed in this study are included in the appendices. Monthly updates of the ESGMAC MAPS study are published on the ESGMAC website (https://www.escmid.org/research-projects/study-groups/study-groups-g-n/mycoplasma-and-chlamydia/esgmac-maps-study). Download .pdf (.42 MB) Help with pdf files Supplementary appendix