By Rochita R. Kadam, MD, and Philip R. Fischer, MD, DTM&H
Rochita Kadam is a senior pediatric resident at Sheikh Shakhbout Medical City in Abu Dhabi, United Arab Emirates. Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN; Department of Pediatrics, Sheikh Shakhbout Medical City, Abu Dhabi, United Arab Emirates.
SYNOPSIS: Around the world, rates of severe illness due to group A Streptococcus are increasing. Possible explanations for the increase include immunity-altering post-pandemic changes in exposure to respiratory pathogens, as well as the emergence of new pathogenic M strains of Streptococcus.
SOURCE: Iro MA, Goldacre MJ, Morris EJ, Goldacre R. Hospital admissions for group A streptococcal infections in England: Current rates and historical perspective. Lancet Infect Dis 2023; Jul 19:S1473-3099(23)00428-0. [Online ahead of print].
Media reports in Europe this year have called attention to increasing rates of illness due to group A Streptococcus. Since most of those reports have been based on legally required epidemiological reporting of scarlet fever and invasive streptococcal infection, and realizing that these reports might be prone to reporting bias, Iro and colleagues sought to corroborate the findings by reviewing hospital admission data for severe illness due to group A streptococcal (GAS) infection.
Iro and colleagues used data from England’s national Hospital Episode Statistics to analyze admission rates from January 2000 through December 2022, focusing on admissions associated with GAS condition diagnoses in children younger than 18 years of age. Numbers of admissions were compared to national age-specific monthly population data to determine rates of infection over time periods.
From 2000 through the 2019 end of the pre-pandemic era, there was a gradual increase in GAS infection cases requiring admission from 2000 (0.52 per 100,000 population) to 2019 (2.36 per 100,000 population), with admission rates usually peaking in the spring season and easing up in the fall and winter. GAS admission rates dropped precipitously in April 2020 to 0.62 per 100,000 population and stayed at that lower level until the spring of 2022. Then, rates rose again (as happened during springtime in the pre-pandemic era) but kept rising throughout the year to reach 4.32 per 100,000 population by December 2022. Most of this unprecedented winter increase in GAS admissions was due to high rates in children younger than 15 years of age who had 16.16 admissions per 100,000 population. Among the total pediatric population, pre-school-age children were the most likely to be admitted. Similar patterns were noted for the various presentations of GAS disease, including scarlet fever and streptococcal sepsis. Case fatality rates due to GAS disease reached 0.17 per 100,000 population in December 2022.
The authors pointed out that the dramatic rise in hospitalizations and deaths from GAS disease could be due to either a truly increased incidence or to increased antigen testing and increased specificity of diagnostic coding in medical documentation. They explained that the post-pandemic rise in GAS hospitalization rates might stem from consequences of personal and group protection measures during the pandemic that left younger individuals without the previous usual exposures that would stimulate streptococcal immunity, while leaving older individuals with less repeated streptococcal exposure prompting a waning of previously established anti-streptococcal immunity. At the same time, the increased hospitalization rates could be because of changes in the streptococci themselves instead of just because of human changes; indeed, there has been emergence of the emm1 (M1UK) streptococcal sublineage, which is known to be highly transmissible and markedly toxigenic.
COMMENTARY
Concern for increasing rates of severe GAS disease is not limited to England. Similar reports have emerged from various parts of Europe and parts of the United States. There was a reported four-fold increase in the incidence of GAS infections in children during the winter of 2022 in Spain, compared to previous seasons.1 A similar rise in invasive GAS infections was noted in children in Colorado and Minnesota between October and December 2022.2
Group A streptococci are prevalent in communities, with up to 20% of school children being colonized.3 Beyond the common occurrence of streptococcal pharyngitis, group A streptococci can lead to invasive infections, including sepsis, streptococcal shock syndrome, meningitis, necrotizing fasciitis, and osteoarticular infections. Additionally, infections with group A streptococci can cause post-infectious immunological sequelae in the form of rheumatic fever and post-streptococcal glomerulonephritis due to antigenic mimicry with the streptococcal M protein in association with an abnormal immune response. Thus, accurate diagnosis and timely management are crucial in reducing both invasive disease and serious immune-mediated complications.
Overtesting and overtreatment of GAS leads to unnecessary costs and unpleasant adverse effects of antimicrobial agents. For children with pharyngitis, testing can be limited to those older than the age of 3 years with strong suspicion of GAS pharyngitis who do not display other signs of viral respiratory infections such as rhinorrhea, cough, hoarseness, or oral ulcerations. Testing can be performed by using either a rapid antigen detecting test or a bacterial throat culture. As rapid tests can have varying sensitivities, negative results should be corroborated with bacterial culture in children with strong suspicion of streptococcal infection for a more accurate diagnosis. This is crucial so that children with true group A streptococcal infections do not go undiagnosed and untreated, because as the authors of this paper from the United Kingdom demonstrated, GAS can cause severe invasive disease with devastating consequences far beyond the throat. This also would help in antimicrobial stewardship by reducing the use of antibiotics in children who do not require treatment. Appropriate detection and treatment also help decrease transmission of the bacteria from person to person, thus ultimately reducing the burden of the disease.4
The increasing trend of pediatric invasive GAS infections during the fall of 2022 is crucial in understanding the emerging trend and epidemiology of invasive GAS infections. There are two plausible theories that have emerged in various studies over the past year. The first one relates to the impact of lockdowns imposed during the COVID-19 pandemic, resulting in a surge due to decreased immunity to GAS and increased exposure to viruses and GAS post lifting of lockdowns worldwide. A report in January 2023 illustrated an increasing incidence of invasive GAS infections among children, particularly osteoarticular infections requiring surgical management.5 Out of those diagnosed with osteoarticular infections in the fall of 2022, a greater percentage of children had preceding varicella or upper respiratory tract infections, compared to previous years.5 A more extensive retrospective study done in France summarized the trends of GAS infections requiring admissions over the past 15 years in children younger than 18 years of age.6 It was observed that there was a dramatic rise in invasive GAS infections per 1,000 admissions per three months, in comparison to the pre-pandemic years.6 Interestingly, the study observed that the peak of infection rates happened concomitantly with a major influenza outbreak in the region.6
A second possible theory attributes the rising infections to the emergence of newer strains of GAS like the M1UK, specifically in the United Kingdom, which has been found to be more immunogenic and displays higher rates of transmission among children.5 Earlier this year, the emergence of a more virulent emm4 lineage of GAS was reported from the Netherlands.7
There is progress, slowly, toward developing a GAS vaccine. The Strep A Vaccine Global Consortium was established in 2019 to consolidate efforts and expedite Streptococcus pyogenes vaccine development globally. Currently, there are eight vaccine candidates in various phases of trials.8 In the meantime, vaccination against influenza and varicella can help reduce those two risk factors that have predisposed some individuals to severe GAS disease.
REFERENCES
- 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 Health Eur 2023;27:100597.
- Barnes M, Youngkin E, Zipprich J, et al. Notes from the field: Increase in pediatric invasive group A streptococcus infections - Colorado and Minnesota, October-December 2022. MMWR Morb Mortal Weekly Rep 2023;72:256-267.
- Oliver J, Malliya Wadu E, Pierse N, et al. Group A Streptococcus pharyngitis and pharyngeal carriage: A meta-analysis. PLoS Negl Trop Dis 2018;12:e000633.
- Thompson TZ, McMullen AR. Group A Streptococcus testing in pediatrics: The move to point-of-care molecular testing. J Clin Microbiol 2020;58:e01494-19.
- Pigeolet M, Haumont E, Rubinsztajn R, et al. Increase in paediatric group A streptococcal infections. Lancet Infect Dis 2023;23:282.
- Lassoued Y, Assad Z, Ouldali N, et al. Unexpected increase in invasive group A streptococcal infections in children after respiratory viruses outbreak in France: A 15-year time-series analysis. Open Forum Infect Dis 2023;10:ofad188.
- 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.
- Walkinshaw DR, Wright MEE, Mullin AE, et al. The Streptococcus pyogenes vaccine landscape. NPJ Vaccines 2023;8:16.