Invasive Group A Streptococcal Infections in Europe After the COVID-19 Pandemic

Background: The incidence of airborne respiratory infections fell as a result of the protective measures taken during the COVID-19 pandemic and rose again when these were stopped. In 2022, there was a notable rise in invasive group A streptococcal (iGAS) infections in many countries, including Germany. This rise was also reflected in the data of the university otorhinolaryngology department in Ulm, Germany.

Methods: This review is based on publications retrieved by a selective literature search on the rise of iGAS infections in Europe, with particular attention to the timing of disease onset, clinical presentation, pathogenic strains, and potential causes and risk factors.

Results: The rise in infections after the pandemic was especially marked among children up to age 10 and in older adults; in Germany, it affected all age groups equally, but predominantly persons older than 65. Rising prevalence figures were seen in Germany and elsewhere as early as the fall of 2022, outside the usual season, and peaked mainly in the first and second quarters of 2023. The increased incidence of iGAS-associated pneumonia was paralleled by that of viral airway infections and led to greater use of intensive-care measures for children. The main bacterial strain identified was emm1; a new variant (M1_DK) played a role in Denmark, and an emm4 variant (M4_NL22) became increasingly important in the Netherlands. In Germany, initial evidence suggested the predominance of M1_UK. Increased antibiotic resistance was not found.

Conclusion: The reduced confrontation of the immune system with pathogens during the pandemic, along with the increased incidence of viral airway infections immediately after it, apparently accounted for the exceptionally high post-pandemic rise in iGAS infections and the increase in invasive pulmonary diseases in Europe. Consistent vaccination programs against coincident respiratory viruses could reduce the burden of iGAS infections. The further extension of multinational surveillance programs with obligatory participation could aid in the detection of factors affecting the course of disease and the spread of new bacterial strains.

In early December 2022, the UK reported a particularly high and early incidence of infections with invasive group A streptococci in children (iGAS) and older adults compared with the years before the COVID-19 pandemic (1). At almost exactly the same time, the European Centre for Disease Control and Prevention (ECDC) and the World Health Organization (WHO) warned of an increase in iGAS infections in several European countries (2, 3). In the university otorhinolaryngology department in Ulm, Germany, which looks after patients from a catchment area of around 100 km diameter (about 3.5 million population), a rapid increase in cases of mastoiditis was observed, primarily caused by Streptococcus pyogenes (group A streptococci, GAS) (Figure, eFigure). Such infections were especially marked in children. In Germany, an increase in iGAS cases was observed in all age groups but older people were predominantly affected (4). The national reference center for streptococci did not see any association with the emergence of a new bacterial strain (4).

Figure

Isolates of causative pathogens in acute mastoiditis, Department for Diseases of Ear, Nose and Throat medicine, head and neck surgery, of the University Hospital Ulm, 2017–2023

eFigure

Proportion of pathogenic isolates in acute mastoiditis of the total number of cases per year, Department for Diseases of Ear, Nose and Throat medicine, head and neck surgery, of the University Hospital Ulm, 2017–2023

Case fatality rates of iGAS infections vary depending on the geographical location, income per head, and clinical symptoms: in industrialized countries they were between 5% and 23% and in countries in the global South between 3% and 50% (5). Socioeconomic factors and a genetic predisposition seem to have an influence on the development of invasive group A streptococcal disease (e1). The international increase in iGAS infections was the more important because beforehand, when pandemic measures were established in early 2020, a substantial fall was observed in viral and bacterial disorders transmitted by the respiratory route, including iGAS infections (6, 7, 8, 9). Different host related and pathogen related factors have been discussed as triggers. Box 1 and eBox 1 provide a brief overview of GAS and the virulence factors that are responsible for the development of invasive infections.

Box 1

Profile: group A streptococci (GAS)* (5, 26, 30, 36, e2, e3, e7, e8, e9, e10, e11, e12, e13, e14, e15, e16, e17)

eBox 1

Group A streptococci (GAS) and virulence factors

Methods

We carried out a selective literature search in PubMed, regarding the increase in iGAS infections at the end of the COVID-19 pandemic from January 2022 compared with pre-pandemic years. We searched primarily for national surveillance data from European countries and for large prospective and retrospective studies that wherever possible included all age groups and an analysis of the causative bacterial strains. We did not include case reports and case series from individual hospitals. Since postpandemic data for Germany are largely lacking to date, we included prepandemic publications on the epidemiology of iGAS infections.

The epidemiologic situation in Europe 2022/2023

We analyzed 13 studies from six countries (Table) (10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22). The data were collected mainly through compulsory or voluntary surveillance programs (10, 11, 13, 14, 15, 17, 20, 21) and partly by different laboratories or hospitals/clinics joining forces (12, 16, 19, 22).

Table

Overview of evaluated publications on the increase in invasive

Progress and dynamic

In the UK, Denmark, and Spain, above average steep and high increases were observed from October/November 2022 (10, 16, 17, 21), whereas in the Netherlands, Belgium, and Portugal, case numbers were already higher from spring 2022 onwards and rose again notably at the end of 2022 to reach a maximum in the first half of 2023 (11, 14, 15, 18). Dutch surveillance data showed differences in the annual maximum values for the different clinical pictures (11). In Belgium, case numbers remained high until August 2023 (14).

Age distribution

In the 2022/2023 season, the UK, the Netherlands, and Denmark noted a particularly steep rise in iGAS infections in children compared with prepandemic years (10, 11, 21). Children up to 5 years of age were typically most affected (10, 11, 18). A study in a pediatric population in Spain found a fourfold increase in iGAS infections in December 2022 compared with 2019 (16). By contrast, another Spanish study reported the most infections in older adults (17). In Denmark, incidence rates were highest in persons older than 85 but the relative increase compared with children younger than 5 was notably lower (10). In Belgium during the rise in iGAS infections from 2022 onwards, no age group was more markedly affected than before the pandemic.

Clinical manifestations and association with viral infections

Of note was the increase in invasive pneumonias with or without empyema in children in the Netherlands, the UK, Spain, and Portugal (12, 15, 16, 18, 21). In the UK, and especially in central Scotland, the increase in pulmonary iGAS infections was evident (21, 22). Prior respiratory infections or those existing in parallel were associated in 18–60% of cases (12, 16, 18, 21, 22) (Table). In Belgium, much as in the preceding years, sepsis was the pathology most often triggered by iGAS in all age groups (74–82% of all iGAS infections from 2018 to 2023) (14). In the Netherlands, necrotizing fasciitis (NF) occurred frequently in the first six months of 2022 (11); six cases were in children, all of whom showed an association with prior infection with the Varicella zoster virus (VZV) (18). This pathology was not seen in children in the comparison period 2018/2019 (18). Prior VZV infections were observed in Portugal in 24.6% of pediatric cases without any association with a specific pathology (15). Nielsen et al did a time series analysis of national surveillance data in Denmark and showed a 23-fold increase in the incidence of iGAS meningitis in adults compared with the preceding seven years (13). A time series analysis of national specimens of cerebrospinal fluid from the Netherlands also showed a cluster of meningitis cases compared with earlier years (20).

Severity of illness and case fatality rates

In the 2022/2023 season, death rates in most countries remained unchanged (10, 17, 21, 22) (Table). An increase in the case fatality rate in children from 3% to 9% was observed only in the Netherlands, but this was primarily due to cases of necrotizing fasciitis, which did not occur in the comparison season (18). The iGAS outbreak did not increase the probability for intensive care in adults (13, 22). In pediatric collectives with mainly pulmonary infections, the need for intensive care rose compared with the pre-COVID season from 30.4% (24 of 79 cases, 2019) to 48.6% (51 of 105 cases, 2022) in Spain (16) and from 21% (8 of 39 cases, 2018/2019) to 32% (18 of 57 cases, 2021/2022) in the Netherlands (18).

Bacterial strains

Group A streptococci are typed at the molecular level by the emm genes coding for the M protein. The M protein, which is located on the cellular surface, is a crucial virulence factor of these bacteria (Box 1, eBox 1)

eBox 2

Measures aiming to prevent increases in iGAS infections

Independently of age, emm1 was detected most often, followed by emm12 (10, 11, 12, 13, 14, 15, 17, 20, 21, 22) (Table). Variants of the emm1 gene were more frequently associated with intensive care (10, 15). Only in one pediatric study from the Netherlands (18) was emm12 confirmed more often than emm1. Furthermore, a relative increase in emm4 isolates was observed particularly in young children (11, 18). A selective analysis of these cases detected independently of age and clinical picture a new bacterial strain M4_NL22 in 85% (19). Cases of meningitis were not associated with emm4. They were caused by M1 (especially M1_UK) in 86% (20). Studies from England, Belgium, and Portugal also reported a dominance of M1_UK (14, 15, 22). In Denmark, where M1_UK was the most common bacterial strain responsible for iGAS infections before the pandemic, a new M1_DK strain was confirmed in August 2022, which in 2023 caused 30% of all iGAS infections (10). M1_DK differs from the original M1_UK and M1_global variants thanks to the exotoxin SpeC, which is also typical for M12 (10, 23). While for M1_DK an association with iGAS infections was seen, M12 was much more commonly detected in non-invasive group A streptococcal (nGAS) infections (10). Possible relevance also applies to the emm49 variant, which to date has been confirmed only in the US and since 2021 for the first time in Spain (17).

Antibiotic resistance

Currently available surveillance data do not provide any indication of increased resistance development as a cause of the postpandemic rise in iGAS infections, especially not in the confirmed new variant M4_NL22 (14, 15, 19). Only in the Netherlands have increasing rates of resistance to clindamycin (from 4% to 9%) and erythromycin (from 6% to 11%) been described between 2017 and 2021 (11).

The situation in Germany

For Germany, only limited national data exist regarding the postpandemic increase in iGAS infections. The surveillance of iGAS infections via the national reference center is carried out on a voluntary basis. To date, whole genome sequencing of specimens is not yet standard procedure. The analysis of routine data to identify pathogens causing invasive bacterial infections between 2017 and the first quarter of 2023 showed a strong and early rise in infections with S. pyogenes from the fourth quarter of 2022 in all age groups (24). The study did not provide any more detailed information about the clinical course or the case fatality rate of the infections, nor about the confirmed bacterial strains. A first single center study of iGAS isolates (10/2022–03/2023) confirmed M1_UK for the first time in Germany as the dominant M1 strain (14 of 17 emm isolates, 30% of all isolates) (25). The isolates emm12 and emm89 were detected as the second most common variants (25). The single center study did not include any information on the kind of clinical presentation, its extent, or the therapeutic measures employed.

A national analysis of German iGAS specimens from 2009 to 2014 found that emm28 and emm29 were the most common strains (26). The comparison with earlier analyses showed apart from an increase in emm89 since 1996 no relevant change regarding the emm variants (26). Rates of resistance rates to macrolides and clindamycin were low in the international comparison (27, 28). The most common clinical diagnoses were sepsis (59.4%), erysipelas (7.6%), and pneumonia (7%) (26). Most iGAS infections affected children up to 5 years of age and adults older than 70 (24, 26). The most recent data regarding the lethality of iGAS infections in Germany were collected for the time period 1996–2002 in a collective of 165 cases. Case fatality rates were notably lower in children and young adults (11.1–20.8%) than in older people (42.1–65.2%) (e2).

Discussion

Analyzing studies of the increase in iGAS infections in Europe since 2022 provides only partial answers to the question about causes and future effects. Because of heterogeneous approaches to data collection and processing, international comparisons and general conclusions are possible only to a limited extent.

Crucial observations relate to the shift in the usual periods of infection (earlier and higher rise in absolute case numbers) (11, 14, 15, 18), changes in the age distribution of infected patients (10, 11, 16, 18, 21), and a shift in clinical presentations towards invasive pneumonias with empyema (12, 15, 16, 18, 22).

Reports about the increase in iGAS infections in children at the end of 2022 coincided in many countries with the end of pandemic measures, which makes an association seem obvious (2, 3). But in many countries a continuous increase in infections with scarlet fever and iGAS was observed years before the COVID-19 pandemic, whose causes have thus far not been sufficiently explained (17, 29, 30). As our own data for acute mastoiditis show (Figure, eFigure), repeated high case numbers every 4–7 years are typical for iGAS infections (e3). It is possible that the pandemic only interrupted this periodic event and, in principle, the high case numbers of nGAS and iGAS infections after the pandemic are not unusual. The markedly high increase in case numbers after the pandemic could have been triggered by factors we list in what follows.

The effectiveness of diverse hygiene measures and contact restrictions on the transmission of respiratory pathogens was shown as early as during the Spanish flu (e4) and was also evident during the COVID-19 pandemic (6, 9). The lifting of certain restrictions (such as the wearing of protective face masks) resulted in different countries as early as in 2021 in an increase in viral and bacterial infections outside the usual season (7, 9, 10, 14), long before the WHO declared the pandemic over in 2023 (e5). The different time points of the observed increase in iGAS infections in the individual European countries are bound to be associated with different management of restrictions and lifting of restrictions. More precise conclusions cannot be drawn because of the poor data. Bacterial respiratory infections can be reduced by means of protective measures (7, 8), but certain pathogens will still persist as colonization pathogens in the nasopharynx (31). Even though no concrete data are available for GAS it seems possible that after the pandemic restrictions were lifted, group A streptococci spread more easily as colonization pathogens in the context of viral infections of the upper respiratory tract. Because of low test rates, the current data relating to a coincidence between viral and iGAS infections probably do not reflect the actual postpandemic incidence rates. A relevant association was seen in the UK, the Netherlands, Portugal, and Spain (12, 15, 16, 18, 21, 22). Of interest, coinfection with SARS-CoV-2 was reported only in individual cases (21). The analyses imply that the coincidence with viral infection stimulates especially pulmonary infections and could be responsible for the observed shift towards more cases of pneumonia and empyema. Viral infections enable bacterial superinfection by directly injuring the mucosal barrier of the respiratory tract and the lung, thus enabling easier adhesion and invasion of the bacteria and, on the other hand, triggering changes to the host’s protective immune response (32). The complex interaction of viral, bacterial, and host related factors remains insufficiently understood (33).

During the 2022/2023 season, children in some countries were particularly affected by scarlet fever and iGAS infections (10, 11, 21). The suspected cause, among others, lies in immunologic factors. The increased susceptibility to airborne respiratory pathogens is partly explained with the reduced peripandemic exposure—among others, because of the closure of educational institutions (“immunity debt or gap”) (6, 10, 11, 15, 21, 34). The general fall in standard vaccinations during the pandemic and the lacking recommendation for vaccination against pathogens that enable iGAS infections (for example, influenza virus IV and VZV), should be discussed as a possible cause (6). Infection with VZV can increase the risk for developing iGAS infections by a factor of almost 60 (23, e6). The presumed cause is—in addition to the weakened immune system—the penetration of pathogenic bacteria through the damaged skin barrier, which could explain the clusters of NF (5, 18, 23). The Netherlands and the UK reported a particularly high incidence of VZV in 2022 (18, 21). An association between iGAS and VZV infections in younger children was observed in the Netherlands and also in Portugal (11, 15, 18). As in the UK, Belgium, Spain, and Denmark, no general recommendation for vaccination exists here: the risk for coinfection could, however, crucially depend on mandatory vaccination recommendations and vaccination rates (34, 35).

The postpandemic rise in iGAS infections in Europe cannot be explained with the expansion and selection of a specific new bacterial strain. For most infections, strains were responsible that were widespread before the pandemic, especially emm1 variants (26, 36, 37). The M1_UK variant, which is currently dominant in Belgium (14), the UK (21, 22), the Netherlands (20), and Portugal, was already dominant before the COVID-19 pandemic in Denmark (10), the UK (30), and the Netherlands (38). Even though emm1 variants bore a higher risk for treatment in intensive care (10, 15), this was not the case for M1_UK and M1_DK specially (10, 14). For the first time, M1_UK was also confirmed in German specimens (25). Further work-up of data from the prepandemic years may enable insights into the relevance during the observed rise in infections in Germany. In the increase of iGAS infections, colonization advantages of certain variants in association with certain special genes may play a role; for the new variants M1_DK and M4_NL22 this will have to be investigated in molecular genetic studies in larger (inter)national collectives (10, 15, 19).

An increase in antibiotic resistance in Europe has not been noticed to date, which means that standard treatment (Box 2) will work (11, 14, 15, 19). In the autumn/winter season 2022/2023, reported bottlenecks in the supply of oral antibiotics, especially penicillins (39), and additionally the rapidly increasing consumption of antibiotics in some countries after the pandemic (4) will in future have to be considered risk factors for the increasing development of resistance and need to be stringently monitored.

Box 2

Treating group A streptococcal infections (27, 28, e18, e19, e20)

Despite gaps in the data, which cannot completely explain the remarkably early and steep rise in iGAS infections, observations to date can be used to deduct general recommendations to prevent further relevant increases in iGAS infections in the future. These recommendations are summed up in Box 2.

Conflict of interest statement
The authors declare that no conflict of interest exists.

Manuscript received on 1 January 2024, revised version accepted on 11 June 2024.

Translated from the original German by Birte Twisselmann, PhD.

Corresponding author
PD Dr. med. Eva Goldberg-Bockhorn
Universitätsklinikum Ulm, Klinik für Hals-Nasen-
Ohrenheilkunde, Kopf- und Halschirurgie
Frauensteige 12, 89075 Ulm

Cite this as
Goldberg-Bockhorn E, Hagemann JB, Furitsch M, Hoffmann TK: Invasive group A streptococcal infections in Europe after the COVID-19 pandemic. Dtsch Arztebl Int 2024; 121: 673–80. DOI: 10.3238/arztebl.m2024.0127

References

1. UK Health Security Agency (UKHSA): Group A streptococcal infections: report on seasonal activity in England, 2022 to 2023. 2022. www.gov.uk/government/publications/group-a-streptococcal-infections-activity- during-the-2022-to-2023-season/group-a-streptococcal- infections-report-on-seasonal-activity-in-england-2022-to-2023 (last accessed on 17 December 2023).

2. World Health Organization (WHO): Disease outbreak news: Increased incidence of scarlet fever and invasive group A streptococcus infection—multi-country. 2022. www.who.int/emergencies/disease-outbreak-news/item/2022-DON429 (last accessed on 22 December 2023).

3. European Centre for Disease Prevention and Control (ECDC): Increase in invasive group A streptococcal infections among children in Europe, including fatalities. European Centre for Disease Prevention and Control 2022. www.ecdc.europa.eu/en/news-events/increase-invasive-group-streptococcal-infections-among-children-europe-including (last accessed on 22 December 2023).

4. Robert Koch Institut (RKI): Update: Anstieg bakterieller Infektionen durch Gruppe-A-Streptokokken, Pneumokokken und Haemophilus influenzae in Deutschland seit Ende 2022. Vol. 8, Epidemiologisches Bulletin. 2023; 45. www.rki.de/DE/Content/Infekt/EpidBull/Archiv/2023/Ausgaben/08_23.pdf?__blob=publicationFile (last accessed on 19 August 2023).

5. Steer AC, Lamagni T, Curtis N, Carapetis JR: Invasive group A streptococcal disease: epidemiology, pathogenesis and management. Drugs 2012; 72: 1213–27

6. Oh KB, Doherty TM, Vetter V, Bonanni P: Lifting non-pharmaceutical interventions following the COVID-19 pandemic—the quiet before the storm? Expert Rev Vaccines 2022; 21: 1541–53

7. Shaw D, Abad R, Amin-Chowdhury Z, et al.: Trends in invasive bacterial diseases during the first 2 years of the COVID-19 pandemic: analyses of prospective surveillance data from 30 countries and territories in the IRIS consortium. Lancet Digit Health 2023; 5: e582–93.

8. Amarsy R, Fournier S, Trystram D, et al.: Decrease of hospital- and community-acquired bloodstream infections due to Streptococcus pneumoniae and Streptococcus pyogenes during the first year of the COVID-19 pandemic: a time-series analysis in Paris region. Am J Infect Control 2023; 51: 475–7

9. 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

10. Johannesen TB, Munkstrup C, Edslev SM, et al.: Increase in invasive group A streptococcal infections and emergence of novel, rapidly expanding sub-lineage of the virulent Streptococcus pyogenes M1 clone, Denmark, 2023. Euro Surveill 2023; 28: 2300291

11. de Gier B, Marchal N, de Beer-Schuurman I, et al.: Increase in invasive group A streptococcal (Streptococcus pyogenes) infections (iGAS) in young children in the Netherlands, 2022. Euro Surveill 2023; 28: 2200941

12. Holdstock V, Twynam-Perkins J, Bradnock T, et al.: National case series of group A Streptococcus pleural empyema in children: clinical and microbiological features. Lancet Infect Dis 2023; 23: 154–6

13. Nielsen H, Storgaard M, Helweg-Larsen J, et al.: Group A streptococcus meningitis in adults, Denmark. Emerg Infect Dis 2023; 29: 1937–9

14. Rodriguez-Ruiz JP, Lin Q, Lammens C, et al.: Increase in bloodstream infections caused by emm1 group A Streptococcus correlates with emergence of toxigenic M1 UK , Belgium, May 2022 to August 2023. Euro Surveill 2023; 28: 2300422

15. Gouveia C, Paula Bajanca-Lavado M, Mamede R, et al.: Sustained increase of paediatric invasive Streptococcus pyogenes infections dominated by M1 UK and diverse emm12 isolates, Portugal, September 2022 to May 2023. Euro Surveill 2023; 28: 2300427

16. Cobo-Vázquez E, Aguilera-Alonso D, Carrasco-Colom J, et al.: Increasing incidence and severity of invasive group A streptococcal disease in Spanish children in 2019–2022. Lancet Reg Heal Eur 2023; 27: 100597

17. Bellés-Bellés A, Prim N, Mormeneo-Bayo S, et al.: Changes in group A Streptococcus emm types associated with invasive infections in adults, Spain, 2023. Emerg Infect Dis 2023; 29: 2390–2

18. van Kempen EB, Bruijning-Verhagen PCJ, Borensztajn D, et al.: Increase in invasive group a streptococcal infections in children in the Netherlands, a survey among 7 hospitals in 2022. Pediatr Infect Dis J 2023; 42: e122–4

19. van der Putten BCL, Bril-Keijzers WCM, Rumke LW, et al.: Novel emm4 lineage associated with an upsurge in invasive group A streptococcal disease in the Netherlands, 2022. Microb Genom 2023; 9: mgen001026

20. van der Putten BCL, Vlaminckx BJM, De Gier B, Freudenburg-De Graaf W, Van Sorge NM: Group A streptococcal meningitis with the M1 UK variant in the Netherlands. JAMA 2023; 329: 1791–2

21. Guy R, Henderson KL, Coelho J, et al.: Increase in invasive group A streptococcal infection notifications, England, 2022. Euro Surveill 2023; 28: 2200942

22. Davies PJB, Russell CD, Morgan AR, et al.: Increase of severe pulmonary infections in adults caused by M1 UK Streptococcus pyogenes, central Scotland, UK. Emerg Infect Dis 2023; 29: 1638–42

23. Imöhl M, van der Linden M, Reinert RR, Ritter K: Invasive group A streptococcal disease and association with varicella in Germany, 1996–2009. FEMS Immunol Med Microbiol 2011; 62: 101–9

24. Singer R, Abu Sin M, Tenenbaum T, et al.: The increase in invasive bacterial infections with respiratory transmission in Germany, 2022/2023. Dtsch Arztebl Int 2024; 121: 114–20

25. Wolters M, Berinson B, Degel-Brossmann N, et al.: Population of invasive group A streptococci isolates from a German tertiary care center is dominated by the hypertoxigenic virulent M1 UK genotype. Infection 2024; 52: 667–71

26. Imöhl M, Fitzner C, Perniciaro S, Van Der Linden M: Epidemiology and distribution of 10 superantigens among invasive Streptococcus pyogenes disease in Germany from 2009 to 2014. PLoS One 2017; 12: e0180757

27. Imöhl M, Van Der Linden M: Antimicrobial susceptibility of invasive Streptococcus pyogenes isolates in Germany during 2003–2013. PLoS One 2015; 10: e0137313

28. Silva-Costa C, Friães A, Ramirez M, Melo-Cristino J: Macrolide-resistant Streptococcus pyogenes: prevalence and treatment strategies. Expert Rev Anti Infect Ther 2015; 13: 615–28

29. Venkatesan P: Rise in group A streptococcal infections in England. Lancet Respir Med 2023; 11: e16

30. Lynskey NN, Jauneikaite E, Li HK, et al.: Emergence of dominant toxigenic M1T1 Streptococcus pyogenes clone during increased scarlet fever activity in England: a population-based molecular epidemiological study. Lancet Infect Dis 2019; 19: 1209–18

31. Rybak A, Levy C, Angoulvant F, et al.: Association of nonpharmaceutical interventions during the COVID-19 pandemic with invasive pneumococcal disease, pneumococcal carriage, and respiratory viral infections among children in France. JAMA Netw Open 2022; 5: e2218959

32. Herrera AL, Huber VC, Chaussee MS: The association between invasive group A streptococcal diseases and viral respiratory tract infections. Front Microbiol 2016; 7: 342

33. Okamoto S, Nagase S: Pathogenic mechanisms of invasive group A Streptococcus infections by influenza virus–group A Streptococcus superinfection. Microbiol Immunol 2018; 62: 141–9

34. 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

35. Abo YN, Oliver J, McMinn A, et al.: Increase in invasive group A streptococcal disease among Australian children coinciding with northern hemisphere surges. Lancet Reg Health West Pac 2023; 41: 100873

36. Luca-Harari B, Darenberg J, Neal S, et al.: Clinical and microbiological characteristics of severe Streptococcus pyogenes disease in Europe. J Clin Microbiol 2009; 47: 1155–65

37. Jespersen MG, Lacey JA, Tong SYC, Davies MR: Global genomic epidemiology of Streptococcus pyogenes. Infect Genet Evol 2020; 86: 104609

38. Rümke LW, de Gier B, Vestjens SMT, et al.: Dominance of M1 UK clade among Dutch M1 Streptococcus pyogenes. Lancet Infect Dis 2020; 20: 539–40

39. Bundesinstitut für Arzneimittel und Medizinprodukte (BfArM): Informationen zur Verfügbarkeit von Antibiotikasäften und Empfehlungen zur Abmilderung möglicher Engpässe—Stand: 07.12.2023. www.bfarm.de/DE/Arzneimittel/Arzneimittelinformationen/Lieferengpaesse/Antibiotika.html (last accessed on 30 December 2023).

40. Ventura-Gabarró C, Leung VH, Vlahović-Palčevski V, Machowska A, Monnet DL, Högberg LD: Rebound in community antibiotic consumption after the observed decrease during the COVID-19 pandemic, EU/EEA, 2022. Euro Surveill 2023; 28: 2300604

e1. Parks T, Elliott K, Lamagni T, et al.: Elevated risk of invasive group A streptococcal disease and host genetic variation in the human leucocyte antigen locus. Genes Immun 2020; 21: 63–70

e2. Wahl RU, Lütticken R, Stanzel S, van der Linden M, Reinert RR: Epidemiology of invasive Streptococcus pyogenes infections in Germany, 1996–2002: results from a voluntary laboratory surveillance system. Clin Microbiol Infect 2007; 13: 1173–8

e3. Lynskey NN, Lawrenson RA, Sriskandan S: New understandings in Streptococcus pyogenes. Curr Opin Infect Dis 2011; 24: 196–202

e4. Bootsma MCJ, Ferguson NM: The effect of public health measures on the 1918 influenza pandemic in U.S. cities. Proc Natl Acad Sci USA 2007; 104: 7588–93

e5. Lenharo M: WHO declares end to COVID-19’s emergency phase. Nature 2023; DOI: 10.1038/d41586–023–01559-z (online ahead of print)

e6. Patel RA, Binns HJ, Shulman ST: Reduction in pediatric hospitalizations for varicella-related invasive group A streptococcal infections in the varicella vaccine era. J Pediatr. 2004; 144: 68–74

e7. Lannes-Costa PS, Oliveira JSS, Silva Santos G, Nagao PE: A current review of pathogenicity determinants of Streptococcus sp. J Appl Microbiol 2021; 131: 1600–20

e8. Walker MJ, Barnett TC, McArthur JD, et al.: Disease manifestations and pathogenic mechanisms of group A Streptococcus. Clin Microbiol Rev 2014; 27: 264–301

e9. Metzgar D, Zampolli A: The M protein of group A Streptococcus is a key virulence factor and a clinically relevant strain identification marker. Virulence 2011; 2: 402–12

e10. Boeddha NP, Atkins L, de Groot R, et al.: Group A streptococcal disease in paediatric inpatients: a European perspective. Eur J Pediatr 2023; 182: 697–706

e11. Gale AH: A century of changes in the mortality and incidence of the principal infections of childhood. Arch Dis Child 1945; 20: 2–21

e12. Gaworzewska E, Colman G: Changes in the pattern of infection caused by Streptococcus pyogenes. Epidemiol Infect 1988; 100: 257–69

e13. Lamagni T, Guy R, Chand M, et al.: Resurgence of scarlet fever in England, 2014–16: a population-based surveillance study. Lancet Infect Dis 2018; 18: 180–7

e14. Avire NJ, Whiley H, Ross K: A review of Streptococcus pyogenes: public health risk factors, prevention and control. Pathogens 2021; 10: 248

e15. Brouwer S, Rivera-Hernandez T, Curren BF, et al.: Pathogenesis, epidemiology and control of group A Streptococcus infection. Nat Rev Microbiol 2023; 21: 431–47

e16. Commons RJ, Smeesters PR, Proft T, Fraser JD, Robins-Browne R, Curtis N: Streptococcal superantigens: categorization and clinical associations. Trends Mol Med 2014; 20: 48–62

e17. Li HK, Zhi X, Vieira A, et al.: Characterization of emergent toxigenic M1 UK Streptococcus pyogenes and associated sublineages. Microb Genom 2023; 9: mgen000994

e18. Yu D, Guo D, Zheng Y, Yang Y: A review of penicillin binding protein and group A Streptococcus with reduced-β-lactam susceptibility. Front Cell Infect Microbiol 2023; 13: 1117160

e19. Carapetis JR, Jacoby P, Carville K, Ang SJJ, Curtis N, Andrews R: Effectiveness of clindamycin and intravenous immunoglobulin, and risk of disease in contacts, in invasive group A streptococcal infections. Clin Infect Dis 2014; 59: 358–65

e20. Johnson AF, LaRock CN: Antibiotic treatment, mechanisms for failure, and adjunctive therapies for infections by group A Streptococcus. Front Microbiol 2021; 12: 760255

e21. Miller KM, Lamagni T, Cherian T, et al.: Standardization of epidemiological surveillance of invasive group A streptococcal infections. Open Forum Infect Dis 2022; 9: S31–40

e22. Institut für medizinische Mikorbiologie: Referenzlabor für Streptokokken: www.ukaachen.de/kliniken-institute/institut-fuer-medizinische-mikrobiologie/forschung/nationales-referenzzentrum-fuer-streptokokken/ (last accessed on 10 June 2024).