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. 2022 May 12;27(19):2100746. doi: 10.2807/1560-7917.ES.2022.27.19.2100746

Mycoplasma pneumoniae detections before and during the COVID-19 pandemic: results of a global survey, 2017 to 2021

Patrick M Meyer Sauteur 1, Michael L Beeton 2, Søren A Uldum 3, Nathalie Bossuyt 4, Melissa Vermeulen 4, Katherine Loens 5, Sabine Pereyre 6, Cécile Bébéar 6, Darja Keše 7, Jessica Day 8, Baharak Afshar 8, Victoria J Chalker 8, Gilbert Greub 9, Ran Nir-Paz 10,11, Roger Dumke 12; ESGMAC–MyCOVID Study Team13; ESGMAC–MyCOVID Study Team, Noémie Wagner, Corinne Andreutti, Philipp K A Agyeman, Christoph Aebi, Michael Buettcher, Lisa Kottanattu, Valeria Gaia, Frank Imkamp, Reinhard Zbinden, Christoph Berger, Anita Niederer-Loher, Florence Barbey, Adrian Egli, Hanna Schmid, Ulrich Heininger, Cihan Papan, Malte Kohns Vasconcelos, Birgit Henrich, Colin Mackenzie, Gerlinde Schneider, Mireille van Westreenen, Nelianne J Verkaik, Annemarie MC van Rossum, Hanne-Dorthe Emborg, Ville Peltola, Marjo Renko, Terhi Tapiainen, Santtu Heinonen, Henrik Døllner, Fernanda Rodrigues, Minos Matsas, Eleni Kalogera, Evangelia Petridou, Ioannis Kopsidas, Theoklis E Zaoutis, Ayelet Michael-Gayego, Kazunobu Ouchi, Ho Namkoong, Yu-Chia Hsieh, Matthias Maiwald, Liat Hui Loo, Rama Chaudhry, Larry K Kociolek, Nadia Rodríguez, David Lorenz, Mary De Almeida
PMCID: PMC9101966  PMID: 35551702

Abstract

Background

Mycoplasma pneumoniae respiratory infections are transmitted by aerosol and droplets in close contact.

Aim

We investigated global M. pneumoniae incidence after implementation of non-pharmaceutical interventions (NPIs) against COVID-19 in March 2020.

Methods

We surveyed M. pneumoniae detections from laboratories and surveillance systems (national or regional) across the world from 1 April 2020 to 31 March 2021 and compared them with cases from corresponding months between 2017 and 2020. Macrolide-resistant M. pneumoniae (MRMp) data were collected from 1 April 2017 to 31 March 2021.

Results

Thirty-seven sites from 21 countries in Europe, Asia, America and Oceania submitted valid datasets (631,104 tests). Among the 30,617 M. pneumoniae detections, 62.39% were based on direct test methods (predominantly PCR), 34.24% on a combination of PCR and serology (no distinction between methods) and 3.37% on serology alone (only IgM considered). In all countries, M. pneumoniae incidence by direct test methods declined significantly after implementation of NPIs with a mean of 1.69% (SD ± 3.30) compared with 8.61% (SD ± 10.62) in previous years (p < 0.01). Detection rates decreased with direct but not with indirect test methods (serology) (–93.51% vs + 18.08%; p < 0.01). Direct detections remained low worldwide throughout April 2020 to March 2021 despite widely differing lockdown or school closure periods. Seven sites (Europe, Asia and America) reported MRMp detections in one of 22 investigated cases in April 2020 to March 2021 and 176 of 762 (23.10%) in previous years (p = 0.04).

Conclusions

This comprehensive collection of M. pneumoniae detections worldwide shows correlation between COVID-19 NPIs and significantly reduced detection numbers.

Keywords: Face masks, nonpharmaceutical interventions (NPIs), personal protective equipment (PPE), pneumonia, Mycoplasma pneumoniae, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)

Introduction

Non-pharmaceutical interventions (NPIs) were suggested to reduce the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the worldwide coronavirus disease (COVID-19) pandemic [1]. Many countries introduced NPIs in March 2020, which included physical distancing measures, personal protective measures (e.g. the use of masks, improved hand hygiene, respiratory etiquette), stay-at-home orders, school and day-care closures, closing borders and travel restrictions. The NPIs have been temporally associated with a global unprecedented suppression of influenza epidemics and other viral respiratory infections, such as respiratory syncytial virus (RSV) [2-8]. COVID-19 vaccinations were available as measures in addition to NPIs since December 2020 [9].

Data from some countries during the first months in 2020 indicated that the introduction of NPIs also coincided with a reduction in Mycoplasma pneumoniae detections [2,6,10]. Mycoplasma pneumoniae is a major bacterial cause of respiratory tract infections in children and adults [11]. These infections occur both endemically in many different climates across the world and epidemically every few years. Previous epidemics in Europe were reported in 2010–2012, 2014–2015 and 2015–2017 [12-15]. Mycoplasma pneumoniae is transmitted by aerosol particles and respiratory droplets through close contacts within families, schools, military bases, institutions (residential care and nursing homes, homes for cognitively disabled people etc.) and among closed communities [15-17].

Diagnostic tests for M. pneumoniae include nucleic acid amplification tests (NAAT) such as PCR, antigen tests and culture from respiratory specimens (direct test methods) or serology (indirect test method) with varying sensitivities and specificities [11,18,19]. Real-time PCR applications are the most commonly used approach for detection of M. pneumoniae in clinical settings [20]. However, real-time PCR is not yet standardised across laboratories [20], and there are no internationally defined guidelines on the requirements for M. pneumoniae testing and surveillance [14]. Some countries collect laboratory reports on M. pneumoniae detections through national reference laboratories (e.g. England), but only few countries have a national surveillance (e.g. Denmark) [14]. To our knowledge, no analysis on the M. pneumoniae incidence from several United Nations (UN) regions has been published so far.

In this study, we used survey data on laboratory M. pneumoniae testing and detection before and during the COVID-19 pandemic across the world to assess the impact of NPIs on the global incidence of M. pneumoniae in the first year after the implementation of NPIs. Of particular interest was the impact of children returning to schools on M. pneumoniae incidence while maintaining other NPIs during the course of the pandemic, as children are believed to be the main drivers of M. pneumoniae transmission [16] and have greater difficulty adhering to physical distancing and personal protective measures. In this context, was also analysed the proportion of females in particular because of their assumed closer vicinity with children.

Methods

Study design

Survey development

A structured survey was developed by a group of members from the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Study Group for Mycoplasma and Chlamydia Infections (ESGMAC), according to guidelines for survey research [21,22]. The survey consisted of six items, covering (i) details of the survey participant, (ii) information on laboratory and area, (iii) local information on stay-at-home orders and school closures during the first year of the pandemic, (iv) detailed information on the test method for M. pneumoniae detection (technique, product and company or reference), (v) M. pneumoniae test numbers (total tests, positive tests, positive tests by month, proportion of children/adolescents younger than 18 years and of females of any age) for the first 12-month period after the worldwide implementation of NPIs (1 April 2020 to 31 March 2021) and for the same period in the preceding 3 years (1 April 2017 to 31 March 2020), and (vi) macrolide-resistant M. pneumoniae (MRMp) testing and detection during the same periods. The survey was only administered in English and built in the SurveyMonkey online survey platform [23]. A pilot test was performed with 10 individuals (infectious diseases specialists and microbiologists) to ensure that the questions were understood and interpreted consistently and that collection of requested data was feasible within the survey time period. Details of the survey are shown in Supplementary Table S1.

Survey administration

Dissemination of the survey to invite participation was mixed-mode through societies (ESCMID, ESGMAC, International Organisation for Mycoplasmology (IOM) and national societies for infectious diseases and microbiology via newsletter or email distribution lists), social media (ESCMID, ESGMAC, IOM and personal accounts of authors), and through in-person contact to potential participants by one of the authors (P.M.M.S). Potential participants were defined as authors of publications about M. pneumoniae epidemiology (PubMed search terms: “Mycoplasma pneumoniae” [title] and “epidemiology” [all fields], 1 January 2000 to 30 March 2021; search results: 439), and more than 300 corresponding authors were approached via email. The email was accompanied by a one-page study description on behalf of the ESGMAC, the survey in PDF and Word format and the link to the online survey. Close attention was paid to ensure that all UN regions were represented during dissemination of the survey. Participation was voluntary and without compensation. There was no mechanism in place to acknowledge receipt of the survey if a laboratory did not provide information. Consent to publish the data and be listed as a participant was declared on the first page of the questionnaire. The survey was launched on 30 March 2021. Reminders were sent out after 4 and 6 weeks via social media and email. The survey was closed on 31 May 2021.

Data collection

Quality control

Entries were included if they met the following quality control criteria for valid datasets: (i) verification of the participant, laboratory and institution via provided link and/or references in PubMed, (ii) validation of the information and/or references about the test method, and (iii) data check for multiple entries from the same institutions (double reporting), invalid or incomplete data, and inconsistent entries. In case of inconsistency or multiple entries from the same institutions, participants were contacted by email to request clarification and/or adapt entries to exclude double reporting. Criteria for de-duplication and exclusion criteria are listed in Supplementary Table S2.

Case definition

Because of local variation in the definition of M. pneumoniae infection, absence of clinical data and the difficulty to differentiate between M. pneumoniae infection and carriage [24], this study collated information on M. pneumoniae detections and not infections. A case was defined as M. pneumoniae detection in an individual with currently available test methods. Detailed information about microbiological detection methods (technique, product and company or reference) is listed in Table 1. A positive IgM, IgG or IgA serology was defined as antibody level above the cut-off of the test, as indicated by the manufacturer (Table 1). Participants were asked whether a positive serology was confirmed by a fourfold increase in IgG levels measured in convalescent samples (as serological gold standard for M. pneumoniae infection [11]).

Table 1. Demographic characteristics and laboratory information of participating sites, by United Nations (UN) region, global survey of Mycoplasma pneumoniae detections, April 2017–March 2021.
UN region and country City or region National pandemic lockdown (days, period)a School closure duration (days)b Laboratory and/or systemc Test method (technique; product) Company or reference Macrolide resistance determination
Europe
Western Europe
France Bordeaux 102 days
(17 Mar–11 May 2020; 28 Oct–14 Dec 2020)
43 Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [47] Yes [48]
Switzerland Geneva 41 days
(16 Mar–26 Apr 2020)
31 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; BioGX Sample-Ready BD MAX System) BD Diagnostics No
Lausanne Hospital / clinical laboratory (secondary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
Bernd Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; Anyplex II RB5 Detection) Seegene Inc. No
Lucerned Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
Bellinzona Surveillance system (regional; 0.4 million population) e NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel)f bioMérieux/BioFire Diagnostics No
Zurich (A) Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [49] Yes [50]
Zurich (B)d Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house)g [49] Yes [50]
St. Gallend Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; Allplex Respiratory Panel) Seegene Inc. No
Aarau Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
ELISAh (ImmunoWELL Mycoplasma IgM/IgG) Thermo Fisher Scientific Remel Inc.
Basel (A) Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
Basel (B)d Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel)i bioMérieux/BioFire Diagnostics No
Germany Homburg 161 days
(17 Mar–5 May 2020; 19 Dec 2020–end of survey period)
92 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; AID CAP Bac PCR Kit) Autoimmun Diagnostika GmbH (AID) No
CLIAh (Mycoplasma pneumoniae Virclia IgM/IgG Monotest) Vircell, S.L.
Düsseldorf Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [51] No
ELISAh (EIA Mycoplasma IgM/IgG/IgA) DIAsource ImmunoAssays SA
Saxonyj Surveillance system (regional; 4.1 million population) k Combination of direct and indirect test methods (different techniques)k [12] No
Belgium Antwerp, Leuven (national reference laboratory) 52 days
(18 Mar–9 May 2020)
76 Hospital / clinical laboratory (tertiary centre) and national reference laboratory l NAAT (PCR, real-time; in-house) [52] Yes [48]
National surveillancej Surveillance system (national; 60% of all Belgian microbiology laboratories) m Direct test methods (different techniques)m [53] No
The Netherlands Rotterdam 99 days
(16 Mar–6 Apr 2020; 15 Dec 2020–2 Mar 2021)
74 Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [54] No
Northern Europe
England National reference laboratoryn 72 days
(14 Mar– 9 May 2020; 5 Nov–1 Dec 2020)
102 National reference laboratory NAAT (multiplex PCR, real-time; in-house) [20] Yes [55]
Denmark National surveillance 99 days
(12 Mar–13 Apr 2020; 25 Dec–1 Mar 2020)
76 Surveillance system (national; 5.8 million population) NAAT (PCR, different techniques)o [56] No
Finland Turku 98 days
(16 Mar–22 Jun 2020)
42 Hospital / clinical laboratory (tertiary centre) Combination of direct and indirect test methods (different techniques)p [57] No
National surveillancej Surveillance system (national; 5.5 million population) Combination of direct and indirect test methods (different techniques)q [6] No
Norway Trondheim 81 days
(12 Mar–1 Jun 2020)
32 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; in-house) NA No
Southern Europe
Portugal Coimbrad 103 days
(19 Mar–2 May 2020; 15 Jan–15 Mar 2021)
67 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
Greece Athens (A)d 179 days
(23 Mar–4 May 2020; 7 Nov 2020–22 Mar 2021)
114 Hospital / clinical laboratory (tertiary centre) ELISA (DRG Mycoplasma pneumoniae ELISA IgM/IgG) DRG International, Inc. No
Athens (B)d Hospital / clinical laboratory (tertiary centre) ELISA (NovaLisa Mycoplasma pneumoniae IgM/IgG) Novatec Immundiagnostica GmbH No
Slovenia Ljubljana 46 days
(19 Mar–4 May 2020)
46 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, real-time; Chla/Myco pneumo R-GENE) bioMérieux/ARGENE No
Asia
Western Asia
Israel Jerusalem 52 days
(12 Mar–3 May 2020)
139 Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [20] No
Eastern Asia
Japan Kurashiki City (Okayama)d 0 days
(no national lockdown)
51 Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [58] Yes [58]
Tokyo Hospital / clinical laboratory (secondary centre) Rapid antigen test (SAI; FUJI DRI-CHEM IMMUNO AG) Fujifilm, Kanagawa, Japan No
Taiwan Taoyuand 0 days
(no national lockdown)
0 (no official school closures) Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; in-house) [59] Yes [59]
South-eastern Asia
Singapore Singapored 55 days
(7 Apr–1 Jun 2020)
57 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
South Asia
India New Delhi 74 days
(25 Mar–7 Jun 2020)
235 Hospital / clinical laboratory (tertiary centre) ELISA (NovaLisa Mycoplasma pneumoniae IgM) Novatec Immundiagnostica GmbH NO
America
Northern America
United States Chicagod 70 days
(21 Mar–30 May 2020)
192 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel) bioMérieux/BioFire Diagnostics No
Caribbean
Cuba National surveillance 240 days
(20 Mar–18 Jun 2020; 1 Nov 2020–end of survey period)
121 Surveillance system (national; 11.3 million population) NAAT (PCR, real-time; in-house) [60] Yes [60]
Oceania
Australia Darlinghurst (Sydney) 53 days
(23 Mar–15 May 2020)
125 Hospital / clinical laboratory (tertiary centre) NAAT (PCR, real-time; EasyScreen Respiratory Pathogen Detection Kit) Genetic Signatures No
New Zealand Auckland 78 days
(national: 23 Mar–13 May 2020; Auckland: 12–18 Aug 2020; 15–17 Feb 2021; 28 Feb–7 Mar 2021)
40 Hospital / clinical laboratory (tertiary centre) NAAT (multiplex PCR, microarray; FilmArray Respiratory Panel)r bioMérieux/BioFire Diagnostics No

CLIA: chemiluminescent immunoassay; ELISA: enzyme-linked immunosorbent assay; Ig, immunoglobulin; NA: not available; NAAT: nucleic acid amplification test; SAI: silver amplification immunochromatography; UN: United Nations.

a Stay-at-home orders for the general population (referred to as lockdown) according to an ECDC document [25] for Europe and to Wikipedia [26] for other UN regions, with adjustments made by the local participating author and considered until the end of the study period (31 March 2021).

b Full and partial school closure duration in days according to [27] until 2 March 2021 (last update before end of study period).

c More detailed information including reporting characteristics, de-duplication and exclusion criteria are provided in Supplementary Table S2.

d ≥ 90% of data are from children and adolescents < 18 years of age.

e Data from several hospitals in the region of Ticino.

f Additional use of a specific in-house PCR [52].

g From 12 October 2020 to the end of the survey period additional testing with the FilmArray Respiratory Panel (bioMérieux/BioFire Diagnostics).

h In addition to PCR also serological data separately reported.

i Multiplex PCR testing before 2020 using the Respifinder (Pathofinder), and single PCR testing over the total survey period with a specific in-house PCR, as described previously [61].

j Exclusively positive test numbers (and no total test numbers) available and/or reported.

k Data from the federal state of Saxony detected by the Landesuntersuchungsanstalt Sachsen based on combined direct and indirect test methods, but predominantly on serology (no information on isotypes) [12].

l National reference laboratory data from the two related hospitals (Antwerp, Leuven; 86–98%) and across the country (2–14%).

m Data collected through the Belgian Sentinel Network of Laboratories (SNL), a network of ca 95 microbiology laboratories (i.e. 60% of all Belgian microbiology laboratories) [53], based on direct test methods such as NAAT, antigen test, culture, microscopy, 'unknown' or 'other' (cases based on serology were excluded).

n Period of enhanced surveillance from 1 October 2019 to 30 March 2020.

o Different PCR assays, of which some are published [56] or commercial kits, but most are unpublished but validated in-house assays.

p Predominantly by serology (ca 75%; no information on isotypes), partly by multiplex PCR (Allplex Respiratory Panel, Seegene Inc.; ca 25%).

q Predominantly by PCR.

r Additional use of an in-house multiplex PCR (www.labplus.co.nz).

Entries in bold signify national and/or regional surveillances.

Stay-at-home order and school closure periods

Periods of stay-at-home orders for the general population (referred to as lockdowns) in Europe were obtained from the Response Measures Database (RMD) of the European Centre for Disease Prevention and Control (ECDC) [25] and those in other UN regions from a collection of pandemic lockdown dates in Wikipedia [26], with adjustments made by the participants. The total duration in days until the end of the study period was calculated for each site. School closure duration in days (full and partial closure in total) was determined according to the United Nations Children’s Fund (UNICEF) global school closures database until 2 March 2021 (last update before the end of the study period) [27].

Statistical analysis

Incidence was defined as the number of new cases over a specified period of time within a community [28]. Given the missing population denominators we were not able to report incidence rates. We compared M. pneumoniae detections between April 2020 and March 2021 with total numbers observed from April 2017 to March 2020. Fisher's exact test was used to compare proportions with corrections for multiple testing. Spearman rank correlation coefficient (R, rho) was used for analyses of correlation. All reported p values are two-tailed with statistical significance defined as p < 0.05. Data were analysed using R software (version 4.0.5) [29].

Results

Survey entries and detection methods

We received entries from 48 sites, of which 29 were entered via the online survey and 19 via email to authors. Of the 12 experts collating laboratory detections of M. pneumoniae in Europe and Israel for the ESGMAC in a previous study (January 2011–April 2016) [14], eight provided information for this survey. An overall response rate could not be calculated because the survey was widely disseminated through societies, social media and further dissemination among participants themselves. We excluded 11 entries because of invalid or incomplete data (n = 7), inconsistent data (n = 2; positive test numbers by month did not match with total numbers per year) or double reporting (n = 2; congruent data from same institutions). Thus, 37 valid datasets from separate sites in 21 countries from four UN regions were eligible for inclusion (Europe: n = 12; Asia: n = 5; America: n = 2; Oceania: n = 2), 29 from hospital laboratories, two from national reference laboratories and six from national and/or regional surveillance systems (Figure 1).

Figure 1.

Study profile, global survey of Mycoplasma pneumoniae detections, April 2017–March 2021

UN: United Nations.

a Three sites provided serological data in addition to PCR.

b No distinction possible between detection methods, but predominantly serological data included.

Figure 1

Demographic characteristics and laboratory information of participating sites are shown in Table 1. The detection method varied between sites: 29 (78.38%) sites reported exclusively PCR (n = 17 multiplex); three sites used exclusively serology (enzyme-linked immunosorbent assay (ELISA)), three sites reported combined PCR and serology (no distinction possible between detection methods, but predominantly serology), one site used a combination of direct test methods (i.e. PCR, antigen test or culture) and one site used exclusively rapid antigen testing. Three sites reported only the number of positive tests over the entire study period (Saxony (Germany) and national surveillance systems of Belgium and Finland), and another three sites provided serological data in addition to PCR.

Detections before and after the introduction of non-pharmaceutical interventions

A total of 631,104 tests were performed during the study period from April 2017–March 2021 (three sites did not have data about total test numbers available). Overall, 30,617 M. pneumoniae detections were confirmed from participating sites. Among those with available information on age/sex, 54.92% (n = 11,029/20,081) were reported in children/adolescents younger than 18 years of age and 52.90% (n = 12,794/24,184) in females. The greatest number of positive tests were obtained with direct test methods (n = 19,102; 62.39%; predominantly PCR) followed by a combination of PCR and serology (n = 10,483; 34.24%; no information on isotypes) or serology alone (n = 1,032; 3.37%; only IgM was considered if all isotypes were reported). Information about convalescent samples for serological testing was not available. No routine testing for a fourfold increase in IgG levels was reported. De-duplication data were determined at site level (Supplementary Table S2 lists the reporting characteristics per site).

There was a significant reduction of M. pneumoniae detections after the introduction of NPIs (Figure 2). Among total detections, 1,714 (5.60%) derived from April 2020 to March 2021 compared with 28,903 (94.40%) from April 2017 to March 2020 (Table 2). Mycoplasma pneumoniae testing and detection in children/adolescents and females per year is shown in Table 3. The annual proportion of children/adolescents and females with detections before and during the COVID-19 pandemic was 55.16% vs 49.77% (p < 0.01) and 53.01% vs 50.86% (p = 0.15), respectively. Detailed graphs for each site and country are shown in Supplementary Figures S1–S6. The difference in detections before and during the COVID-19 pandemic was more obvious for direct test methods (Figure 2A) than indirect test methods (Figure 2B). This is supported by a direct comparison of detections with PCR and single-sample serology (IgM, IgG and IgA) from the three sites that reported data separately for each method, which did not show any correlation between those two test methods (Figure 3).

Figure 2.

Global detection of Mycoplasma pneumoniae, April 2017–March 2021 (n = 30,617)

Ig: immunoglobulin.

Data from combined serology and PCR tests are shown under indirect test methods (no distinction possible between detection methods, but predominantly serology; Table 1). For serology, only total test numbers of IgM considered. The grey backgrounds indicate the presence of non-pharmaceutical interventions during the COVID-19 pandemic. Detailed graphs separately for each site and country with corresponding local lockdown periods are shown in Supplementary Figures S1–S6.

Figure 2

Table 2. Mycoplasma pneumoniae testing and detection rates per year, April 2017–March 2021 (n = 631,104).

UN region and country City or region Test method April 2017–March 2018 April 2018–March 2019 April 2019–March 2020 April 2020–March 2021
(COVID-19 pandemic)
Difference in detection rate (%)
pre-pandemic vs COVID-19 pandemica
Pb
Total tests
(N)
Positive tests
(n)
Detection rate
(%)
Total tests
(N)
Positive tests
(n)
Detection rate
(%)
Total tests
(N)
Positive tests
(n)
Detection rate
(%)
Total tests
(N)
Positive test
(n)
Detection rate
(%)
Europe
Western Europe
France Bordeaux PCR 619 16 2.58 625 22 3.52 530 41 7.74 466 4 0.86 –80.72 <0.01
Switzerland Geneva PCR 1,347 30 2.23 1,622 76 4.69 2,119 76 3.59 1,193 7 0.59 –83.60 <0.01
Lausanne PCR 388 6 1.55 406 4 0.99 592 20 3.38 246 0 0.00 –100.00 0.02
Bernc PCR 134 17 12.69 175 43 24.57 191 29 15.18 41 0 0.00 –100.00 <0.01
Lucernec PCR NA 7 NA 229 10 4.37 215 21 9.77 129 1 0.78 –88.90 <0.01
Bellinzona PCR 701 10 1.43 1,104 76 6.88 1,540 43 2.79 804 0 0.00 –100.00 <0.01
Zurich (A) PCR 1,067 17 1.59 1,361 41 3.01 1,620 50 3.09 1,823 11 0.60 –77.38 <0.01
Zurich (B)c PCR 104 21 20.19 123 22 17.89 201 54 26.87 1,659 6 0.36 –98.40 <0.01
St. Gallenc PCR 20 7 35.00 18 5 27.78 19 6 31.58 8 1 12.50 –60.42 0.42
Aarau PCR 1,431 36 2.52 1,586 55 3.47 1,955 77 3.94 1,601 10 0.62 –81.51 <0.01
IgM ELISA 220 14 6.36 229 19 8.30 191 23 12.04 183 13 7.10 18.81 0.55
IgG ELISA 220 43 19.55 229 50 21.83 191 48 25.13 183 46 25.14 + 14.10 0.37
Basel (A) PCR 1,535 9 0.59 2,212 12 0.54 5,028 53 1.05 3,061 2 0.07 –92.25 <0.01
Basel (B)c PCR 870 10 1.15 845 6 0.71 1,050 19 1.81 634 6 0.95 –25.24 0.69
Germany Homburg PCR 2,321 10 0.43 2,395 19 0.79 2,773 17 0.61 2,570 1 0.04 –93.67 <0.01
IgM ELISA 486 67 13.79 492 70 14.23 544 71 13.05 588 70 11.90 12.89 0.31
IgG ELISA 486 277 57.00 492 291 59.15 544 341 62.68 588 331 56.29 5.75 0.15
Düsseldorf PCR 1,515 27 1.78 1,530 18 1.18 1,283 16 1.25 1,011 12 1.19 –15.79 0.65
IgM ELISA 398 18 4.52 446 78 17.49 585 148 25.30 538 134 24.91 + 45.87 <0.01
IgG ELISA 530 298 56.23 491 288 58.66 561 307 54.72 522 315 60.34 + 6.90 0.13
IgA ELISAd NA NA NA 241 95 39.42 560 195 34.82 521 142 27.26 24.72 <0.01
Saxony PCR or serologye NA 2,013 NA NA 1,044 NA NA 927 NA NA 303 NA NA NA
Belgium Antwerp, Leuven (national reference laboratory) PCR 2,698 30 1.11 1,150 15 1.30 1220 32 2.62 864 3 0.35 –77.15 <0.01
National surveillance Direct test methods (different techniques) NA 1,151 NA NA 548 NA NA 833 NA NA 230 NA NA NA
The Netherlands Rotterdam PCR NA NA NA 240 36 15.00 407 56 13.76 444 36 8.11 –42.98 <0.01
Northern Europe
England National reference laboratoryf PCR 138 19 13.77 110 11 10.00 263 118 44.87 155 10 6.45 –77.72 <0.01
Denmark National surveillance PCR 100,257 5,303 5.29 80,965 1,371 1.69 100,879 4,383 4.34 58,716 177 0.30 –92.31 < 0.01
Finland Turku PCR or serologye NA NA NA NA NA NA 5,413 211 3.90 3,462 70 2.02 48.13 <0.01
National surveillance PCR or serologye NA 2,420 NA NA 1,728 NA NA 1,312 NA NA 455 NA NA NA
Norway Trondheim PCR 3,306 230 6.96 2,330 56 2.40 2,014 48 2.38 1,263 0 0.00 –100.00 <0.01
Southern Europe
Portugal Coimbrac PCR 803 5 0.62 924 90 9.74 1,084 19 1.75 161 0 0.00 –100.00 <0.01
Greece Athens (A)c IgM ELISA 212 19 8.96 236 51 21.61 250 65 26.00 167 35 20.96 + 8.36 0.66
IgG ELISA 212 44 20.75 236 29 12.29 250 37 14.80 167 41 24.55 + 55.79 <0.01
Athens (B)c IgM ELISA 185 9 4.86 181 15 8.29 231 27 11.69 172 14 8.14 4.72 1.00
IgG ELISA 185 59 31.89 181 88 48.62 231 92 39.83 172 44 25.58 36.10 <0.01
Slovenia Ljubljana PCR 1,604 22 1.37 1,887 153 8.11 2,639 495 18.76 1,241 20 1.61 –85.26 <0.01
Asia
Western Asia
Israel Jerusalem PCR 1,364 45 3.30 1,299 62 4.77 1,637 53 3.24 666 0 0.00 –100.00 <0.01
Eastern Asia
Japan Kurashiki City (Okayama)c PCR 30 4 13.33 64 14 21.88 34 3 8.82 5 0 0.00 –100.00 1.00
Tokyof Rapid antigen test 346 56 16.18 140 36 25.71 600 36 6.00 120 4 3.33 –71.72 <0.01
Taiwan Taoyuanc PCR 116 20 17.24 159 63 39.62 204 131 64.22 44 5 11.36 –74.56 <0.01
South-eastern Asia
Singapore Singaporec PCR 4,212 387 9.19 8,765 307 3.50 15,860 613 3.87 8,835 33 0.37 –91.76 <0.01
South Asia
India New Delhi IgM ELISA 245 19 7.76 320 18 5.63 205 19 9.27 153 16 10.46 + 43.79 0.19
America
Northern America
United States Chicagoc PCR 4,221 10 0.24 4,199 25 0.60 4,990 42 0.84 1,695 2 0.12 –79.45 0.01
Caribbean
Cuba National surveillance PCR 902 18 2.00 62 4 6.45 844 20 2.37 4 0 0.00 –100.00 1.00
Oceania
Australia Darlinghurst (Sydney) PCR 15,751 60 0.38 12,187 55 0.45 21,086 168 0.80 70,807 19 0.03 –95.35 <0.01
New Zealand Auckland PCR 543 21 3.87 993 26 2.62 858 41 4.78 2,723 4 0.15 –96.00 <0.01
Total (global, participating countries)g Direct test methods (PCR or rapid antigen test considered only) 148,343 6,453 4.35 129,705 2,733 2.11 173,735 6,780 3.90 162,989 374 0.23 –93.51 <0.01
Indirect test methods (IgM considered only) 1,746 146 8.36 1,904 251 13.18 2,006 353 17.60 1,801 282 15.66 + 18.08 0.01

COVID-19: coronavirus disease; ELISA: enzyme-linked immunosorbent assay; Ig: immunoglobulin; NA: not available; UN: United Nations.

a Difference in detection rate between April 2017 and March 2020 (mean positive/total tests across the 3 years) and between April 2020 and March 2021 (absolute number positive/total tests). Percentages showing a reduction in detection rate are indicated in bold.

b Proportions of positive/total tests from April 2020 to March 2021 were compared with total numbers from April 2017 to March 2020 by Fisher's exact test. p values < 0.05 are indicated in bold.

c ≥ 90% of data are from children and adolescents < 18 years of age.

d IgA ELISA introduced in November 2018.

e Data from combined serology and PCR tests (no distinction possible between detection methods; Table 1).

f Period of enhanced surveillance from 1 October 2019 to 30 March 2020.

g These numbers include only data from PCR or rapid antigen test (for direct test methods) and IgM serology (for indirect test methods).

Entries in italics signify serological data (± PCR).

Table 3. Mycloplasma pneumoniae testing and detection in children/adolescents and females per year, April 2017–March 2021 (n = 154,241 children/adolescents and 285,238 females).

UN region and country City or region Test method April 2017–March 2018 April 2018–March 2019 April 2019–March 2020 April 2020–March 2021
(COVID-19 pandemic)
Children/
adolescents
Females Children/
adolescents
Females Children/
adolescents
Females Children/
adolescents
Females
N n % N n % N n % N n % N n % N n % N n % N n %
Europe
Western Europe
France Bordeaux PCR 335 9 2.69 236 11 4.66 282 15 5.32 280 11 3.93 272 28 10.29 248 17 6.85 220 2 0.91 193 0 0.00
Switzerland Geneva PCR 201 8 3.98 579 17 2.94 301 43 14.29 704 39 5.54 354 45 12.71 392 34 8.67 161 2 1.24 449 3 0.67
Lausanne PCR 42 1 2.38 226 5 2.21 18 1 5.56 200 1 0.50 36 4 11.11 325 9 2.77 2 0 0.00 123 0 0.00
Berna PCR 134 17 12.69 65 8 12.31 175 43 24.57 74 18 24.32 191 29 15.18 78 14 17.95 41 0 0.00 16 0 0.00
Lucernea PCR NA 7 NA NA 3 NA 229 10 4.37 NA 3 NA 215 21 9.77 NA 5 NA 129 1 0.78 NA 1 NA
Bellinzona PCR 155 6 3.87 315 2 0.63 471 66 14.01 500 41 8.20 354 22 6.21 661 19 2.87 118 0 0.00 328 0 0.00
Zurich (A) PCR 29 2 6.90 NA 43 6 13.95 NA 44 8 18.18 NA 35 1 2.86 NA
Zurich (B)a PCR 104 21 20.19 NA 123 22 17.89 NA 201 54 26.87 NA 1,659 6 0.36 NA
St. Gallena PCR 20 7 35.00 14 4 28.57 18 5 27.78 12 5 41.67 19 6 31.58 7 3 42.86 8 1 12.50 4 1 25.00
Aarau PCR 441 13 2.95 603 14 2.32 392 22 5.61 723 24 3.32 484 26 5.37 891 38 4.26 287 4 1.39 658 6 0.91
IgM ELISA 25 4 16.00 91 10 10.99 20 8 40.00 99 7 7.07 33 8 24.24 77 10 12.99 16 3 18.75 69 9 13.04
IgG ELISA 25 3 12.00 91 15 16.48 20 6 30.00 99 19 19.19 33 9 27.27 77 15 19.48 16 1 b 6.25 69 18 26.09
Basel (A) PCR 4 0 0.00 644 6 0.93 5 0 0.00 937 7 0.75 9 0 0.00 2,201 25 1.14 1 0 0.00 1,251 2 0.16
Basel (B)a PCR 863 10 1.16 404 5 1.24 845 6 0.71 NA 1 NA 1,050 19 1.81 NA NA NA 634 6 0.95 NA NA NA
Germany Homburg PCR 53 2 3.77 NA 4 NA 75 3 4.00 NA 8 NA 111 4 3.60 NA 7 NA 88 0 0.00 NA 1 NA
IgM ELISA NA NA NA NA NA NA NA NA
IgG ELISA NA NA NA NA NA NA NA NA
Düsseldorf PCR 1,003 21 2.09 618 10 1.62 1,026 16 1.56 649 5 0.77 882 15 1.70 523 6 1.15 621 10 1.61 471 4 0.85
IgM ELISA 264 12 4.55 179 9 5.03 246 36 14.63 173 24 13.87 246 52 21.14 182 37 20.33 253 47 18.58 161 29 18.01
IgG ELISA 307 168 54.72 237 142 59.92 255 141 55.29 187 118 63.10 226 98 43.36 174 96 55.17 238 132 55.46 157 103b 65.61
IgA ELISA NA NA 120 36 30.00 80 26 32.50 226 37 16.37 174 46 26.44 237 17b 7.17 156 24 15.38
Saxony PCR or serology NA NA NA NA NA NA NA NA
Belgium Antwerp, Leuven (national reference laboratory) PCR 748 16 2.14 1,132 17 1.50 208 4 1.92 486 9 1.85 240 15 6.25 510 17 3.33 100 2 2.00 356 0 0.00
National surveillance Direct test methods (different techniques) NA 740 NA NA 639 NA NA 362 NA NA 285 NA NA 493 NA NA 433 NA NA 86b NA NA 140b NA
The Netherlands Rotterdam PCR NA NA 47 11 23.40 119 22 18.49 89 26 29.21 163 23 14.11 54 12 22.22 176 19 10.80
Northern Europe
England National reference laboratory PCR 39 8 20.51 63 7 11.11 34 2 5.88 45 9 20.00 84 51 60.71 102 50 49.02 58 7 12.07 49 5 10.20
Denmark National surveillance PCR 15,879 2,374 14.95 55,874 2,843 5.09 9,121 515 5.65 44,132 768 1.74 14,307 1,854 12.96 55,356 2,374 4.29 2,650 68 2.57 27,693 83 0.30
Finland Turku PCR or serology NA NA NA NA 1,488 138 9.27 NA 804 51 6.34 NA
National surveillance PCR or serology NA NA 1,344 NA NA NA 997 NA NA NA 699 NA NA NA 265 NA
Norway Trondheim PCR 3,306 230 6.96 1,556 113 7.26 2,330 56 2.40 1,041 26 2.50 2,014 48 2.38 920 22 2.39 1,263 0 0.00 486 0 0.00
Southern Europe
Portugal Coimbraa PCR 803 5 0.62 374 4 1.07 924 90 9.74 460 38 8.26 1,084 19 1.75 469 8 1.71 161 0 0.00 69 0 0.00
Greece Athens (A)a IgM ELISA 212 19 8.96 92 9 9.78 236 51 21.61 125 32 25.60 250 65 26.00 118 28 23.73 167 35 20.96 73 15 20.55
IgG ELISA 212 44 20.75 92 19 20.65 236 29 12.29 125 13 10.40 250 37 14.80 118 16 13.56 167 41 24.55 73 19 26.03
Athens (B)a IgM ELISA 185 9 4.86 90 3 3.33 181 15 8.29 87 6 6.90 231 27 11.69 106 14 13.21 172 14 8.14 90 8 8.89
IgG ELISA 185 59 31.89 90 25 27.78 181 88 48.62 87 46 52.87 231 92 39.83 106 46 43.40 172 44 25.58 90 20 22.22
Slovenia Ljubljana PCR 530 19 3.58 708 7 0.99 745 119 15.97 857 75 8.75 1,326 402 30.32 1,382 218 15.77 320 14 4.38 528 8 1.52
Asia
Western Asia
Israel Jerusalem PCR 256 17 6.64 573 19 3.32 337 39 11.57 610 33 5.41 364 29 7.97 760 25 3.29 216 0 0.00 275 0 0.00
Eastern Asia
Japan Kurashiki City (Okayama)a PCR 30 4 13.33 16 2 12.50 64 14 21.88 26 5 19.23 34 3 8.82 15 1 6.67 5 0 0.00 5 0 0.00
Tokyo Rapid antigen test 25 NA NA 52 33 63.46 80 25 31.25 60 9 15.00 420 22 5.24 180 14 7.78 60 3 5.00 60 1 1.67
Taiwan Taoyuana PCR 116 20 17.24 56 11 19.64 159 63 39.62 77 31 40.26 204 131 64.22 113 71 62.83 44 5 11.36 16 0b 0.00
South-eastern Asia
Singapore Singaporea PCR 4,212 387 9.19 NA 8,765 307 3.50 NA 15,860 613 3.87 NA 8,835 33 0.37 NA
South Asia
India New Delhi IgM ELISA 159 12 7.55 30 7 23.33 207 7 3.38 105 8 7.62 113 14 12.39 67 7 10.45 84 13 15.48 49 5 10.20
America
Northern America
United States Chicagoa PCR 3,818 10 0.26 1,892 3 0.16 3,873 21 0.54 1,814 15 0.83 4,653 39 0.84 2,258 21 0.93 1,589 2 0.13 735 0 0.00
Caribbean
Cuba National surveillance PCR 535 12 2.24 398 6 1.51 38 1 2.63 25 0 0.00 497 15 3.02 385 6 1.56 0 NA NA 0 NA NA
Oceania
Australia Darlinghurst
(Sydney)
PCR 3,975 35 0.88 8,303 36 0.43 3,050 30 0.98 6,241 22 0.35 4,784 111 2.32 11,242 82 0.73 9,487 10 0.11 36,408 10 0.03
New Zealand Auckland PCR 154 11 7.14 252 10 3.97 167 8 4.79 475 13 2.74 226 22 9.73 401 21 5.24 561 3 0.53 1,219 3 0.25

COVID-19: coronavirus disease; ELISA: enzyme-linked immunosorbent assay; Ig: immunoglobulin; NA: not available; UN: United Nations.

a ≥ 90% of data are from children and adolescents < 18 years of age.

b Statistically significant difference in proportions of children/adolescents or females with positive tests between April 2020 and March 2021 and between April 2017 and March 2020 (Fisher's exact test, p < 0.05).

For serology only total test numbers of IgM considered. Entries in italics signify serological data (± PCR).

Figure 3.

Detection of Mycoplasma pneumoniae at sites that provided single-sample serological data in addition to PCR, April 2017–March 2021 (n = 14,702a)

a For serology only total test numbers of IgM considered.

Grey backgrounds indicate local stay-at-home order (lockdown) periods. Another site from Germany (Homburg) did also provide PCR and serological data separately but numbers by month were not available.

Figure 3

Following the introduction of NPIs, the M. pneumoniae incidence by direct test methods decreased significantly from 8.61% ± 10.62 (mean of incidences from each site ± standard deviation) during April 2017 to March 2020 to 1.69% ± 3.30 in April 2020 to March 2021 (p < 0.01). The detection rates decreased with direct but not with indirect test methods (−93.51% vs +18.08%; p < 0.01) (Table 2). Although 27 sites reported also a reduction in total number of tests (–44.52% ± 24.61) in April 2020 to March 2021, seven sites showed an increase in total test numbers during the COVID-19 pandemic (because SARS-CoV-2 PCR was included in a multiplex panel that also contained M. pneumoniae PCR) (Table 2). In the year before the introduction of NPIs (April 2019 to March 2020), direct M. pneumoniae detections were significantly increased in several countries across UN regions compared with the period April 2018 to March 2019, which was indicative of an M. pneumoniae epidemic (Figure 2A).

Total duration of lockdown (82.80 days ± 55.73; range: 0–240) and school closure periods (84.05 days ± 56.33; range: 0–235) varied widely across countries. There was no correlation of the duration of lockdown or school closure periods with direct M. pneumoniae detection rates from April 2020 to March 2021. Several sites reported a longer duration of lockdown than school closure periods, which suggested that children returned to schools while lockdown continued for some time (Table 1). The re-opening of schools had no observable impact on the incidence of M. pneumoniae as direct detections remained remarkably low throughout the period April 2020 to March 2021. Detections were very low or absent even in countries where no school closures or official lockdowns were enforced (e.g. Japan, Taiwan; see Supplementary Figure S3 for M. pneumoniae detections in Asia).

Macrolide resistance

As a consequence of the significant decrease in M. pneumoniae detections after the introduction of NPIs, only few cases were investigated for macrolide resistance. In total, seven sites from Europe, Asia and America reported MRMp rates from April 2017 to March 2021 (Table 4). Macrolide resistance determination was reported as part of national surveillance of positive samples (Japan, Cuba) or only on positive samples identified at the reference laboratory and/or upon physician request. The MRMp detections among investigated cases are shown as absolute numbers in Figure 4A and as percentages in Figure 4B. The highest MRMp rate was found in Taiwan from April 2018 to March 2019 with 42 of 53 isolates. The national surveillance from Japan contributed the greatest number of strains investigated for macrolide resistance. Overall, MRMp was detected in one of 22 investigated cases from April 2020 to March 2021 and in 176 of 762 (23.10%) from April 2017 to March 2020 (p = 0.04).

Table 4. Macrolide-resistant Mycoplasma pneumoniae testing and detection rates per year, April 2017–March 2021 (n = 784).

UN region and country City or region Macrolide resistance determination (reference) April 2017–March 2018 April 2018–March 2019 April 2019–March 2020 April 2020–March 2021
(COVID-19 pandemic)
Difference in detection rate (%)
pre-pandemic vs COVID-19 pandemica
P b
Total tests (N) Positive tests (n) Detection rate (%) Total tests (N) Positive tests (n) Detection rate (%) Total tests (N) Positive tests (n) Detection rate (%) Total tests (N) Positive tests (n) Detection rate (%)
Europe
Western Europe
France Bordeaux [48] 10 0 0.00 15 2 13.33 30 3 10.00 3 0 0.00 –100.00 1.00
Switzerland Zurich (A + Bc)d [50] 0 NA NA 2 2 100.00 10 7 70.00 3 1 33.33 55.56 0.24
Belgium Antwerp, Leuven (national reference laboratory) [48] 26 1 3.85 15 0 0.00 30 0 0.00 2 0 0.00 –100.00 1.00
England National reference laboratorye [55] 19 3 15.79 11 0 0.00 104 1 0.96 6 0 0.00 –100.00 1.00
Asia
Eastern Asia
Japan National surveillance [58] 103 20 19.42 97 5 5.15 124 18 14.52 8 0 0.00 –100.00 0.60
Taiwan Taoyuan c [59] 10 6 60.00 53 42 79.25 80 62 77.50 0 NA NA NA NA
America
Caribbean
Cuba National surveillance [60] 14 2 14.29 0 NA NA 9 2 22.22 0 NA NA NA NA

COVID-19: coronavirus disease; SD: standard deviation; MRMp: macrolide-resistant Mycoplasma pneumoniae; NA: not applicable; UN: United Nations.

a Difference in detection rate between April 2017 and March 2020 (mean positive/total tests across the 3 years) and April 2020 and March 2021 (absolute number positive/total tests). Percentages showing a reduction in detection rate are indicated in bold.

b Proportions of positive/total tests from April 2020 to March 2021 were compared with total numbers from April 2017 to March 2020 by Fisher's exact test.

c ≥ 90% of data are from children and adolescents < 18 years of age.

d Macrolide resistance determination only upon physician's request in case of clinically suspected MRMp infection. Data reported for both sites from Zurich (A + B).

e Period of enhanced surveillance from 1 October 2019 to 30 March 2020.

Entries in italics signify macrolide resistance determination only upon physician’s request in case of clinically suspected MRMp infection.

Figure 4.

Macrolide-resistant Mycoplasma pneumoniae testing and detection in different countries across the world, April 2017–March 2021 (n = 784)

MRMp: Macrolide-resistant Mycoplasma pneumoniae.

The coloured parts of the bar graph with numbers represent absolute numbers or proportions of MRMp detection (the colours correspond with colours for sites in Figure 2). Data derived from the COVID-19 pandemic (April 2020–March 2021) are indicated by a grey background. Japan and Cuba reported national MRMp surveillance data (Table 4). Macrolide resistance determination in Switzerland was performed only upon request from a physician (in case of clinically suspected MRMp infection).

Figure 4

Discussion

This global survey showed that all countries experienced a decrease in M. pneumoniae incidence by direct test methods in April 2020–March 2021, relative to the previous three years. This decline corresponded with the timing of the implementation of NPIs against COVID-19 in March 2020 in each country. We also observed a decrease in MRMp rates in April 2020 to March 2021. The MRMp rates before the COVID-19 pandemic were lower in Europe than in America or Asia, consistent with previous reports [11].

A reduction in M. pneumoniae detections after the introduction of NPIs was observed with direct test methods such as PCR but not with serology. This effect could be explained by the long-lasting nature of antibodies against M. pneumoniae. Mycoplasma pneumoniae-specific antibodies (IgM and IgG) persist for months to years after infection, and significantly longer than M. pneumoniae DNA in the upper respiratory tract [30,31]. Based on these kinetics, we would expect a decline in positive IgM serology in the second year of the COVID-19 pandemic, but not necessarily in IgG serology as M. pneumoniae-specific IgG antibodies can persist lifelong [30]. There is also the possibility of false-positive results caused by limited assay performance [32] as serological detections are reported from single-sample serology, which was in most cases not confirmed by the detection of a significant antibody level change in convalescent sera. In addition, PCR and serology (IgM and IgG) can be positive in asymptomatic carriers [11]. The detection of specific antibody-secreting cells by enzyme-linked immunospot (ELISpot) assay may allow for differentiation between infection and carriage [24], and a combination of clinical features and biomarkers can help identify patients at high risk for M. pneumoniae community-acquired pneumonia [15]. However, no clinical features were reported in this study and cases were defined by local practice.

Our findings are in line with several reports about a worldwide reduction in infections with respiratory and gastrointestinal pathogens after the introduction of NPIs [2,3,5-7,33-37]. The incidence of invasive bacterial diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis that are transmitted via the respiratory route were also considerably reduced during the early months of the COVID-19 pandemic [38]. The interruption of direct person-to-person transmission was suspected to be the most plausible explanation for the reduction in respiratory infections. These remained low even after the re-opening of schools, except for rhinovirus [6,39-41].

Direct detections of M. pneumoniae between April 2020 and March 2021 were significantly below levels of non-epidemic periods of M. pneumoniae across countries despite widely differing lockdown or school closure periods, and even in countries where no official lockdowns or school closures were enforced. This suggests that the observed low M. pneumoniae incidence may be explained by the continuation of NPIs such as personal protective and physical distancing measures. Other factors that may be involved in restricting M. pneumoniae transmission are behavioural responses to the pandemic (e.g. limited mobility related to COVID-19) and change in healthcare utilisation (e.g. telemedicine visits). After the re-opening of schools, direct M. pneumoniae detections remained low. This was also observed at sites where lockdown and restrictions for the adult population continued while children returned to schools. Children have greater difficulty adhering to physical distancing and personal protective measures so that M. pneumoniae transmission may be less effectively prevented in schools than in the adult population. Unfortunately, we did not have information on the age distribution in children to look at the pre-school and school age groups separately. The low incidence despite the re-opening of schools might suggest that adults play a more important role in transmission of M. pneumoniae than previously thought. This is supported by the observed decrease in the proportion of children and adolescents with M. pneumoniae detection during the COVID-19 pandemic. Notably, there was no change in the proportion of females with M. pneumoniae infection before and during the COVID-19 pandemic. Reduced transmission by shielding of adults (regardless of school closures) was also discussed as possible reason for the decrease in invasive pneumococcal disease [38]. Interestingly, nasopharyngeal pneumococcal carriage in children was only slightly reduced during the first year of the COVID-19 pandemic and the reduction in invasive pneumococcal disease was therefore attributed to the suppression of specific respiratory viruses such as RSV and influenza, which are often implicated as co-pathogens with S. pneumoniae [42]. Mycoplasma pneumoniae is also frequently detected with other viruses in the upper respiratory tract [15,43-45], but the role of co-detections in M. pneumoniae respiratory disease remains unclear [44]. A direct biological effect of SARS-CoV-2 on M. pneumoniae by interference or interaction could be another explanation. To our knowledge, data supporting this hypothesis do not exist so far. Further, transient herd immunity from the recent epidemic period in April 2019–March 2020 in several countries in Europe and Asia could have led to a decreased M. pneumoniae incidence during the COVID-19 pandemic [12]. However, the incidence was also reduced in countries that had not experienced a recent epidemic (e.g. Norway).

The study has a number of limitations. Firstly, because of the variable reporting methods and testing criteria at each site, conclusions based on the analysis across countries must be considered with caution. Data obtained from a single hospital laboratory from a specific region may not be fully representative of the country as a whole. No information about catchment area and numbers of laboratories within regions were available. The study also lacks representation from Africa and South America (no survey response and/or no testing for M. pneumoniae reported). Secondly, defining study-wide case definitions and de-duplication criteria was not feasible given the heterogeneous nature of data collection between sites. De-duplication methodologies were therefore set at site level. Thirdly, as mentioned previously, serological detections were not confirmed by antibody changes in paired sera in most cases. Fourthly, analysis of the local clinical testing pathway for M. pneumoniae was not possible within this study. Decision-making to test or not to test with specific methodologies during the COVID-19 pandemic may have impacted which individuals and sites offered testing at which time. The number of tests increased in one fifth of the sites during the period April 2020 to March 2021 and also the incidence was significantly lower compared with the pre-pandemic period; hence, we do not believe that the overall reduction in M. pneumoniae detections can solely be accounted for by reduced testing. Nor was there an indication that M. pneumoniae testing was reduced because of shifting laboratory resources towards SARS-CoV-2 testing during the whole first year after the introduction of NPIs covered by this study. Finally, an overall survey response rate could not be calculated because of the widespread dissemination of the survey. Incomplete response to a survey can introduce a bias related to differences in incidence between the responders and the non-responders [21,46]. However, this risk seems minimal as our survey dealt with microbiological laboratory data and generated a large and varied sample [46].

This study is another example of how pandemic-focused public health measures may have prevented infections caused by other respiratory pathogens. The COVID-19 pandemic resulted in restrictive NPIs such as lockdowns and school closures, which are unsustainable in the longer term. The results of this study suggest that even less restrictive NPIs such as personal protective and physical distancing measures might have prevented transmission of M. pneumoniae in the community.

The study also highlights the importance of establishing international working groups to investigate pathogen epidemiology where surveillance systems are lacking. It underlines the need for an international case definition for infection with M. pneumoniae (detection method and clinical criteria). The influence of the detection method for epidemiological surveillance of M. pneumoniae is shown in the discrepancy between PCR and single-sample serology in this study. Serological surveillance of M. pneumoniae may be only accurate by using paired sera in order to detect a fourfold increase in IgG levels [11]. However, such procedures are time-consuming and are not useful for acute patient care. A more rapid response to public health measures may be obtained by surveillance of M. pneumoniae using PCR.

Finally, epidemiological surveillance should also include antimicrobial resistance testing of M. pneumoniae. This study represents the most comprehensive estimate of global resistance documented to date and is important for clinicians and infectious disease surveillance considering that macrolides remain the main global treatment option for children with M. pneumoniae infection.

Conclusion

The results of this study from diverse geographical locations and healthcare settings suggest that the implementation of NPIs against COVID-19 probably restricted transmission of M. pneumoniae, leading to a significant reduction in M. pneumoniae infections in many countries across the world from April 2020 to March 2021. The retention of some NPIs after the COVID-19 pandemic e.g. improved hand hygiene, respiratory etiquette or physical distancing in the community, or the use of masks in health care institutions may help reduce the burden of M. pneumoniae infections. The large collaborative network established for this study allows to assess the resurgence of M. pneumoniae infections at a later time.

Funding statement

PMMS was supported by a Walter und Gertrud Siegenthaler Fellowship and the career development program “Filling the Gap” of the University of Zurich, outside of this study. The ESGMAC covered costs for the survey development and administration.

Ethical statement

This study collected aggregated and anonymized data. The need for ethics approval for this study varied by country, and was administered by participants if required (Supplementary Table S2).

Acknowledgements

We are very grateful to all those who helped with the study: Laure F. Pittet (Department of Pediatrics, Division of General Pediatrics, Children’s Hospital, Faculty of Medicine, University of Geneva Hospitals, Geneva, Switzerland); Petra Zimmermann (Faculty of Science and Medicine, University of Fribourg, Fribourg, Switzerland); Jan Fehr (Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland); Lucas M. Bachmann (Medignition Inc. Research Consultants, Zurich, Switzerland); Semjon Sidorov (Division of Infectious Diseases and Hospital Epidemiology, University Children’s Hospital Zurich, Zurich, Switzerland); Wendy W.J. Unger (Division of Infectious Diseases and Immunology, Department of Pediatrics, Erasmus MC University Medical Center–Sophia Children's Hospital, Rotterdam, The Netherlands); Samuel Rhedin (Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden); Todd A. Florin (Feinberg School of Medicine, Northwestern University, Chicago, IL, USA); Lilliam Ambroggio (Sections of Emergency Medicine and Hospital Medicine, Department of Pediatrics, Children’s Hospital Colorado, University of Colorado, Denver, CO, USA); Asha C. Bowen (Department of Infectious Diseases, Perth Children's Hospital, Perth, Western Australia, Australia); ESCMID: William Caddy (executive office), Patrick Kudyba (science coordinator); Swiss Society for Infectious Diseases (SSI): Pierre-Yves Bochud (president); Pediatric Infectious Disease Group of Switzerland (PIGS): Andrea Duppenthaler (secretary); Swiss Society for Microbiology (SSM): Nathalie Mermoud (general secretary).

Supplementary Data

Supplement

Conflict of interest: None declared.

Authors’ contributions: Study conceptualisation and lead: PMMS. Study design: PMMS, MLB, RNP, RD. Acquisition of data: all authors including all ESGMAC–MyCOVID Study Team members. Analysis and interpretation of data: PMMS, MLB, SAU, NB, MV, KL, SP, CB, DK, JD, BA, VJC, GG, RNP, RD. Writing of the original manuscript draft: PMMS. Formal analysis: PMMS, MLB, RNP, RD. All authors, including all ESGMAC–MyCOVID Study Team members, contributed to the work, reviewed and approved the manuscript.

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