Comment

Mycoplasma pneumoniae: delayed re-emergence after COVID-19

pandemic restrictions
Mycoplasma pneumoniae is a common cause of respira- on the further course in the fourth year after the intro- Lancet Microbe 2023
tory tract infections with community-acquired pneu- duction of NPIs, from April 1 to September 30, 2023 Published Online
https://doi.org/10.1016/
monia as the major disease-related burden. Compared (6-month period).
S2666-5247(23)00344-0
with other pathogens, M pneumoniae is atypical in many Prospective surveillance data were obtained from
ways: it is one of the smallest self-replicating organisms, 45 sites in 24 countries from the four UN regions:
has a reduced and highly stable genome (0⋅8 Mbp), lacks Europe, Asia, the Americas, and Oceania. Laboratory
a cell wall, grows slowly (generation time 6 h), requires information of participating sites has been previously
close contact for transmission, and has a distinct disease described.10 M pneumoniae was detected by PCR in all four
presentation (atypical pneumonia), the pathogenesis of UN regions (appendix 2). The mean incidence of See Online for appendix 2

which might involve host cell-mediated immunity.1–3 M pneumoniae as detected by PCR during the 6-month
Infections occur year-round in many different climates period was 4⋅12% (SD 7⋅94; appendix 2). The incidences
worldwide, with epidemics every few years.4,5 Previously of M pneumoniae as detected by PCR were significantly
obtained data indicated an interval of 1–3 years higher in Europe and Asia than in America and Oceania and
between M pneumoniae epidemics in Europe and Israel.5 higher than those observed in previous testing periods in
Several factors, including waning herd immunity or the same UN regions since the start of the prospective
introduction of new subtypes into the population, surveillance (appendix 3). Overall, M pneumoniae was See Online for appendix 3
account for the periodic occurrence of epidemics. The detected by PCR in 1067 (0⋅71%) of 149 980 tests during
most recent epidemic occurred in late 2019–early 2020 the 6-month period (appendix 2). The most frequent
simultaneously across multiple nations, predominantly detections in Europe were from Denmark (n=436), Sweden
in Europe and Asia.6 (n=145), Switzerland (n=132), Wales (n=49), and Slovenia
In March, 2020, the introduction of non-pharmaceutical (n=41), and in Asia from Singapore (n=172) (appendix 4). See Online for appendix 4

interventions (NPIs) against COVID-19 resulted in an Positive test numbers (but not the total number of tests)
abrupt ending of these epidemics and a marked decline were also reported from Belgium by PCR (n=136) and
in M pneumoniae detection worldwide.6 Compared with from Finland using combined serology and PCR with no
the pre-pandemic incidence of M pneumoniae (8⋅61%, distinction possible between the detection methods
2017–20), a significant reduction was observed in the first (n=129) (appendix 2). Detections by IgM serology were
year after the implementation of NPIs (1⋅69%, 2020–21),6 158 (6⋅58%) of 2403 and by IgG serology were
similar to the incidence of other respiratory pathogens.7 292 (12⋅35%) of 2364 (appendix 2).
A further unprecedented, yet substantial, reduction in the These global prospective surveillance data show the
incidence of M pneumoniae was observed in the second year re-emergence of M pneumoniae in Europe and Asia more
(0⋅70%, 2021–22),8 when other respiratory pathogens than 3 years after the introduction of COVID-19 pandemic
resurged as an indicator of community transmission.8,9 restrictions. This delayed re-emergence is striking because
The first global prospective surveillance study of it occurred long after NPIs were discontinued, and because
M pneumoniae (ESGMAC MAPS study)10 was initiated in it is, to our knowledge, a phenomenon unique to this
April 2022 to allow for rapid notification regarding the pathogen. Other respiratory pathogens with a sustained
geographical location of any substantial increase in reduction in incidence but earlier resurgence than
activity via monthly website updates alerting clinicians. M pneumoniae were Mycobacterium tuberculosis and
First data from this surveillance yielded a sustained very Bordetella pertussis, for which increased notifications were
low incidence of M pneumoniae in the third year from not reported until 2021 and 2022, respectively.11,12 Why is
April, 2022, to March, 2023 (0⋅82%).10 M pneumoniae also atypical in this respect?
However, though at very low levels, an increase in case Numerous theories exist for the altered epidemiology
numbers was noted in some countries in the last months of infections surrounding the COVID-19 pandemic. Most
of the third year (January to March, 2023),10 which sub- do not apply to M pneumoniae after the severe reduction
sequently warranted increased vigilance. Here, we report in incidences long after the discontinued NPIs.6 The

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 Comment

possibility of a viral-bacterial interaction as was observed are published on the ESGMAC website (https://www.escmid.org/research-
projects/study-groups/study-groups-g-n/mycoplasma-and-chlamydia/esgmac-
for Streptococcus pneumoniae, when the temporal sup- maps-study).
pression of respiratory syncytial virus, influenza viruses, Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open
and human metapneumovirus was associated with a Access article under the CC BY-NC-ND 4.0 license

decline in pneumococcal disease in young children,13 *Patrick M Meyer Sauteur, Michael L Beeton, on behalf of the
could be excluded given the much earlier resurgence of European Society of Clinical Microbiology and Infectious
Diseases (ESCMID) Study Group for Mycoplasma and
respiratory viruses while M pneumoniae was still absent.
Chlamydia Infections (ESGMAC), and the ESGMAC
As postulated for the occurrence of M pneumoniae Mycoplasma pneumoniae Surveillance (MAPS) study group†
epidemics, waning herd immunity could also account for [email protected]
the delayed re-emergence. Transient herd immunity †For the members of the ESGMAC MAPS study group, see appendix 1
from the last epidemic period in several countries in late Division of Infectious Diseases and Hospital Epidemiology, University Children’s
2019–early 2020 could have led to the delayed Hospital Zurich, Zurich CH-8032, Switzerland (PMMS); Microbiology and Infection
Research Group, Department of Biomedical Sciences, Cardiff Metropolitan
re-emergence considering an interval of up to 3 years University, Cardiff, UK (MLB)
between M pneumoniae epidemics in these UN regions.5 1 Reimann HA. An acute infection of the respiratory tract with atypical
However, we have not yet observed a re-emergence in pneumonia: a disease entity probably caused by a filtrable virus. JAMA
1938; 111: 2377–84.
countries where the last epidemic was reported earlier 2 Waites KB, Talkington DF. Mycoplasma pneumoniae and its role as a human
pathogen. Clin Microbiol Rev 2004; 17: 697–728.
(eg, Germany, Finland, and Norway; all in 2017–18).6 In
3 Pánisová E, Unger WWJ, Berger C, Meyer Sauteur PM. Mycoplasma
addition, no re-emergence was detected by PCR, but a pneumoniae-specific IFN-gamma-producing CD4(+) effector-memory
T cells correlate with pulmonary disease. Am J Respir Cell Mol Biol 2021;
further decline in detections of M pneumoniae-specific 64: 143–46.
IgM and IgG antibodies indicative of waning immunity 4 Uldum SA, Bangsborg JM, Gahrn-Hansen B, et al. Epidemic of Mycoplasma
pneumoniae infection in Denmark, 2010 and 2011. Euro Surveill 2012;
was observed at sites that reported data separately 17: 20073.
for PCR and serology (eg, Homburg, Germany; and 5 Beeton ML, Zhang XS, Uldum SA, et al. Mycoplasma pneumoniae infections,
11 countries in Europe and Israel, 2011 to 2016. Euro Surveill 2020;
Rotterdam, The Netherlands). 25: 1900112.
As this delayed re-emergence is atypical and probably 6 Meyer Sauteur PM, Beeton ML, Uldum SA, et al. Mycoplasma pneumoniae
detections before and during the COVID-19 pandemic: results of a global
unique for M pneumoniae, the atypical characteristics that survey, 2017 to 2021. Euro Surveill 2022; 27: 2100746.
distinguish M pneumoniae from other pathogens should be 7 Brueggemann AB, Jansen van Rensburg MJ, Shaw D, et al. Changes in the
incidence of invasive disease due to Streptococcus pneumoniae, Haemophilus
strongly considered. Among those, the slow generation influenzae, and Neisseria meningitidis during the COVID-19 pandemic
time (6 h), long incubation period (1–3 weeks), and rela- in 26 countries and territories in the Invasive Respiratory Infection
Surveillance Initiative: a prospective analysis of surveillance data.
tively low transmission rate could be factors leading to Lancet Digit Health 2021; 3: e360–70.
8 Meyer Sauteur PM, Chalker VJ, Berger C, et al. Mycoplasma pneumoniae
a longer time interval required for the re-establishment of beyond the COVID-19 pandemic: where is it? Lancet Microbe 2022; 3: e897.
M pneumoniae infection within a population. 9 Clark SA, Campbell H, Ribeiro S, et al. Epidemiological and strain
characteristics of invasive meningococcal disease prior to, during and after
In countries where M pneumoniae has re-emerged, case COVID-19 pandemic restrictions in England. J Infect 2023; 87: 385–91.
numbers are comparable to pre-pandemic (endemic) 10 Meyer Sauteur PM, Beeton ML, ESGMAC and the ESGMAC MAPS study
group. Mycoplasma pneumoniae: gone forever? Lancet Microbe 2023;
numbers. The further development of the re-emergence 4: e763.
should be monitored to evaluate whether case numbers 11 Burrell R, Saravanos G, Britton PN. Unintended impacts of COVID-19
on the epidemiology and burden of paediatric respiratory infections.
will escalate to epidemic levels or result in an excep- Paediatr Respir Rev 2023; published online Aug 3. https://doi.org/10.1016/
tionally large wave of infections as was observed for the j.prrv.2023.07.004.
12 Izu A, Nunes MC, Solomon F, et al. All-cause and pathogen-specific lower
resurgence of other pathogens.11 The progression and respiratory tract infection hospital admissions in children younger than
severity of the re-emergence are difficult to predict and 5 years during the COVID-19 pandemic (2020-22) compared with the
pre-pandemic period (2015-19) in South Africa: an observational study.
whether it will lead to an increase in rare cases of severe Lancet Infect Dis 2023; 23: 1031–41.
disease2 and extrapulmonary manifestations14,15 because 13 Danino D, Ben-Shimol S, van der Beek BA, et al. Decline in pneumococcal
disease in young children during the coronavirus disease 2019 (COVID-19)
of the previously reduced exposure remains unknown. pandemic in Israel associated with suppression of seasonal respiratory
viruses, despite persistent pneumococcal carriage: a prospective cohort
However, the global prospective surveillance will alert study. Clin Infect Dis 2022; 75: e1154–64.
clinicians to the magnitude and severity of re-emerging 14 Meyer Sauteur PM, Theiler M, Buettcher M, Seiler M, Weibel L, Berger C.
Frequency and clinical presentation of mucocutaneous disease due to
infections, thereby allowing a prompt response with Mycoplasma pneumoniae infection in children with community-acquired
adequate management. pneumonia. JAMA Dermatol 2020; 156: 144–50.
15 Narita M. Classification of extrapulmonary manifestations due to
We declare no competing interests. All data collected and analysed in this study Mycoplasma pneumoniae infection on the basis of possible pathogenesis.
are included in the appendices. Monthly updates of the ESGMAC MAPS study Front Microbiol 2016; 7: 23.

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