Investigators in Canada have discovered that molecular changes to an infectious bacterium (Group A Streptococcus pyogenes [GAS]) underlie a post-pandemic surge of coinfections with a respiratory diagnosis, prompting one expert to suggest lockdowns during the pandemic might have created an immunity deficiency in hosts while at the same time helping the bacteria create newly virulent clones.
The members of the Toronto Invasive Bacterial Diseases Network led by Halima Dabaja-Younis, MD, MPH, tracked the pediatric incidence rate of invasive GAS (iGAS) infections over 32 years in southern Ontario.
The group found that the rates of iGAS infection snaked upward before the pandemic, then downward during the pandemic, then shot up significantly post-pandemic suggesting that lockdowns led to a genetic bottleneck of iGAS, subsequently triggering adaptive iGAS clones.
“Transmission bottlenecks play a critical role in shaping pathogen genetic diversity and evolutionary trajectories,” Anthony R. Flores, MD, MPH, PhD, professor and chair of the pediatric infectious disease unit at Vanderbilt University Medical Center, Nashville, Tennessee, wrote in an editorial that accompanied the study.
Both were published online in JAMA Network Open.
The bottleneck potentially allows the establishment of specific clones that “are better adapted to the conditions imposed by public health measures,” according to Flores.
Population Study Results
To describe the epidemiology of iGAS in pediatric populations, the investigators reviewed population-based surveillance data for iGAS in pediatric cases in metropolitan Toronto from 1992 through 2023. They found there were 498 documented cases of infection, 300 (60.2%) of them in male children. The median age of all those infected was 5.1 years.
Between the periods 1992-2011 and 2012-2019, the rates of infection went from 1.8 events per 100,000 population per year to 2.4 events per 100,000 population per year (incidence rate ratio [IRR],1.3; 95% CI,1.1-1.6). The increase in iGAS was in respiratory tract infections, the authors wrote.
During the pandemic, infection rates declined to 1.2 events per 100,000 population per year in 2020, and 0.5 events per 100,000 population per year in 2021, before rocketing to 6.0 events per 100,000 population per year in 2023.
Nearly a third of all cases studied (151, 30.7%) had comorbidities. Soft tissue infection (140 cases, 28.1%) was the most common, followed by bacteremia without focus (131 cases, 26.3%). Bone and joint infections were also common (97 cases, 19.5%), as was pneumonia (66 cases, 13.3%).
During the period 2022-2023, 18 of 56 children with iGAS had a viral respiratory coinfection. From 2005 onward, pneumonia occurred more frequently than in previous years: In 60 of 323 cases (18.6%) compared with 6 of 175 cases (3.4%) from 1992 to 2004 (odds ratio [OR], 6.43; 95% CI, 2.72-15.20). iGAS infections of the upper respiratory tract were a significantly more common presentation during 2022-2023 than in prior time periods.
Meanwhile, varicella-associated iGAS cases dropped from 23 of 137 children in 1992-2001 to there being such infections in only 2 of 223 children in 2012-2023 (P < .001). Notably, universal varicella vaccination implementation began in Canada in 2004.
Serotype Associated With Pneumonia, Intensive Care Unit (ICU) Admissions
A spike in the detection of iGAS emm1 serotype cases in 2023 was evident compared with that in previous years. More than any other serotype, emm1 was more likely to be associated across the study with diagnosis of pneumonia (33 of 182 cases [18.1%] vs 29 of 289 cases [10.0%]; OR,1.99; 95% CI,1.16-3.40).
In their study, Dabaja-Younis and colleagues found the incidence of disease due to iGAS emm1 was 0.64 events per 100,000 population per year from 1992 to 2001. From 2002 to 2011, the rate was 0.57 events per 100,000 population per year (IRR, 0.9; 95% CI, 0.6-1.4).
From 2012 to 2019, the rate of emm1-related disease was 1.0 event per 100,000 population per year (IRR,1.7; 95% CI,1.2-2.4). During the pandemic, the incidence declined sharply, with a single case identified between February 2020 and November 2022.
Serotype emm1 was associated with a higher risk for ICU admission than any other of the nine emm serotypes (41 of 179 children [22.9%] vs 43 of 284 children [15.1%]; OR,1.67; 95% CI, 1.03-2.68).
The investigators found that the hypertoxic M1UK variant of emm1, identified in 2019, comprised 32 of 46 emm1 isolates (70%) from 2019 to 2023. Serotype emm12, meanwhile, was uncommon during the study up until 2022.
‘Epidemiological Shift’
Except for the correlation between emm1 and ICU admission, the investigators did not find associations between specific emm serotypes and severity of disease.
“Importantly, the genomic evolution of emm types and the virulence factors they acquire over time can contribute to severe disease manifestations, which are thus not necessarily determined by the specific emm type alone,” the study authors wrote.
“That multiple GAS emm types became more prominent in the post-pandemic iGAS surge, suggests a more complex epidemiological shift than simple clonal expansion,” Flores wrote in the editorial.
As to observed increases in iGAS infections, “Of note, consistent with [lockdown protocols for] reducing transmission, recent evidence points to decreased antibody levels to major respiratory pathogens during the pandemic supporting an immunity debt that may contribute to many of the described surges in disease,” Flores wrote.
Differs From Other Population Studies
The resurgence of iGAS post-pandemic occurred later in the Canadian study than was seen in population studies conducted in the United Kingdom and in the Netherlands.
The authors concluded that their study also illuminates “the importance of considering age-specific factors in the clinical presentation of iGAS infections, reinforces the value of varicella vaccination in preventing iGAS, and highlights the potential for both respiratory viral and GAS vaccines to alleviate the burden of iGAS infections.”
Flores issued a call to action in his editorial. “The post-pandemic surges in GAS infections and our lack of understanding of the associated pathogen molecular changes should serve as a clarion call for a renewed emphasis on inactive pathogen surveillance, the study of transmission dynamics, and pathogen emergence,” he wrote.
This study was supported by contracts from the Centers for Disease Control and Prevention (1992-1998) and a grant from the Canadian Bacterial Diseases Network (1995-2000). The authors had no relevant financial conflicts of interest. Flores reported receiving grants from the National Institutes of Health, National Institute of Allergy and Infectious Diseases, and GlycosBio and personal fees from UpToDate outside the submitted work.
