Increase in Invasive Group a Streptococcal Infections in Children in the Netherlands, A Survey Among 7 Hospitals in 2022

Abstract

Following an increase in notifiable invasive group A streptococcal (iGAS) infections in the Netherlands, we conducted a survey among 7 hospitals. Pediatric iGAS case numbers were 2-fold higher between July 2021 and June 2022 versus pre-COVID-19. A sharp increase occurred early 2022, most pronounced in <5 years old and for diagnoses empyema and necrotizing fasciitis. This recent pediatric iGAS surge warrants investigation and vigilance.

Since early 2022, pediatricians in the Netherlands have been alerted about a rise in pediatric cases of severe invasive group A streptococcal (iGAS) disease, including at least 7 deaths.^1,2 This coincided with an increase in the number of notifiable iGAS cases in national surveillance.³ However, this national surveillance only captures necrotizing fasciitis, toxic shock syndrome and puerperal fever/sepsis, whereas other clinical presentations of iGAS, such as (complicated) pneumonia or sepsis, are not systematically recorded. We performed a survey regarding pediatric iGAS cases in 7 Dutch hospitals to determine whether case numbers were indeed elevated compared with pre-COVID-19 and to gain more insight into the clinical presentation and severity of these cases. Furthermore, we assessed the emm-type of invasive Streptococcus pyogenes isolates from pediatric iGAS cases that were received by the Netherlands Reference Laboratory for Bacterial Meningitis (NRLBM) for 2021–2022 as part of routine bacteriological surveillance.

METHODS

Hospital Survey

Clinicians from 7 hospitals jointly set-up a survey to collect data on pediatric iGAS cases that were admitted to their hospital or that deceased upon arrival at their emergency department. Cases were defined as: patients 0–18 years with S. pyogenes positive culture or polymerase chain reaction from an otherwise sterile body site, or a clinical diagnosis of toxic shock syndrome or necrotizing fasciitis supported by S. pyogenes detection from a body site. Cases were included between July 1, 2021, and June 30, 2022, to capture recent trends, and compared with cases from a reference period defined as the most recent pre-COVID-19 years, that is, January 1, 2018, until December 31, 2019.

The participating hospitals were a convenience sample from a previous research network and included 3 university hospitals with pediatric intensive care unit (PICU) and 4 regional hospitals. The geographic location of the participating hospitals, as well as total number of hospitals with a PICU in the Netherlands is depicted in Figure (Supplemental Digital Content 1, https://links.lww.com/INF/E908).

The survey collected anonymous, aggregated data on the total number of iGAS cases per age category (<5; 5–9 and ≥10 years) and per year-quarter, clinical diagnosis on admission and outcome (mortality and/or PICU admission). For cases that occurred in 2021/2022, data on coinciding or preceding (within 14 days) polymerase chain reaction-confirmed influenza and anamnestic evidence of recent varicella infection were also collected.

Emm-typing of iGAS Isolates

To monitor the distribution of circulating emm-types, the NRLBM performs emm-typing of invasive S. pyogenes isolates since 2019. The NRLBM routinely receives isolates from (1) notifiable cases of iGAS, (2) from other non-notifiable clinical iGAS presentations from 9 sentinel hospitals covering ~28% of the population and (3) any hospital interested in typing invasive S. pyogenes isolates. The number and emm-(sub)types of S. pyogenes isolates received from hospitals participating in the survey and obtained from pediatric iGAS cases (not at patient level) were assessed. As surveillance started in 2019, no emm-types of iGAS isolates were available for the 2018–2019 reference period.

RESULTS

Between July 1, 2021, and June 30, 2022 (ie, 12 months), a total of 61 pediatric iGAS cases were reported (5.1/month) versus 56 cases between January 2018 and December 2019 (ie, 24 months, 2.3/month). The highest numbers were reported during Q1 and Q2 of 2022. Age distribution and clinical presentation were available for 6 of 7 hospitals. Period of presentation by annual quarter and outcome were available for 6 hospitals in the year 2021/2022 and 5 in 2018–2019. Data on preceding varicella or influenza infection was reported by 5 hospitals. Number of cases by year-quarter are presented in Figure 1.

FIGURE 1.: Quarterly number of pediatrics cases of iGAS infections (iGAS) in 2018–2019 and between July 2021 and June 2022. Quarterly number of pediatric iGAS infections in 2018–2019 and between July 2021 and June 2022. The in-between period was characterized by COVID-19 restrictions and not taken into account. Cases per time period (quarter) for both periods were available from 5/7 hospitals.

Most cases occurred in children 0–5 years old in both periods (70% in 2021–2022 vs. 50% in 2018–2019). Comparing the number of cases per age group by period, we observed the biggest increase in cases in children <5 years of age (21 vs. 38 cases in 2018–2019 and the epidemiologic year 2021/2022, respectively).

The dominant clinical presentation of iGAS was sepsis (n = 14, 26%) in 2018–2019 and pneumonia with empyema in 2021/2022 (n = 16, 28%). In 2018–2019, no cases of necrotizing fasciitis were reported. This clinical presentation represented, however, 11% (n = 6) of diagnoses in 2021/2022.

With regard to outcome, PICU admission occurred in 8 of 39 cases (21%) in 2018–2019 and in 18 of 57 (32%) in 2021/2022. One death was reported in 2018–2019 (1/39; 3%) versus 5/57 (9%) in 2021/2022 (see Table, Supplemental Digital Content 2, https://links.lww.com/INF/E909).

A preceding varicella infection was documented in 16 of 49 cases (33%) and involved necrotizing fasciitis (n = 6), sepsis (n = 2) septic arthritis (n = 2), pneumonia with empyema (n = 1), erysipelas (n = 3), other (n = 1) and not specified (n = 1). Preceding influenza infection was documented in 9 of 49 cases (18%) and involved pneumonia with empyema (n = 4), Streptococcal toxic shock syndrome (n = 1), sepsis (n = 1), other (n = 1) and not specified (n = 2).

Emm-types

In 2021/2022, the NRLBM received 32 isolates from children from the participating institutes. Twelve of 32 (38%) isolates were emm 12.0, 8 of 32 (25%) emm 1.0, and 4 of 32 (13%) emm 4.0, indicating that this increase is likely not explained by a single highly virulent emm-type (see Figure, Supplemental Digital Content 3, https://links.lww.com/INF/E910).

DISCUSSION

This survey among 7 hospitals in The Netherlands suggests that the total number of pediatric iGAS infections in 2021/2022 was increased compared with the reference pre-COVID-19 period (2018–2019). In particular, a sharp increase was observed starting early 2022 with a peak of 28 cases in the 2nd quartile of 2022. These numbers reflect a 3-fold and 14-fold increase in comparison to the same quarters in 2019 and 2018, respectively. The rise in pediatric iGAS cases is most pronounced in the age group 0–5 years. Moreover, there seems to be a shift in most common diagnoses, with pneumonia with empyema as most frequent diagnosis in 2021/2022 and 6 cases of pediatric necrotizing fasciitis, a clinical condition not observed in the pre-COVID-19 reference period. Mortality was 9% among cases in 2021/2022, occurring in both young and older children, which seems higher than the reported 2%–3% in children with iGAS infection from high-income countries.^4–6

The underlying causes for this iGAS surge in children are not yet fully understood. Recently, the UK Health Security Agency also reported an increase in iGAS disease in 2022, particularly in children under 10, and issued an alert on December 2, 2022, to warn parents and clinicians.⁷ In the 1–4 years age group, the iGAS rate was 2.3 of 100,000 population compared with 0.5 of 100,000 in the prepandemic period.⁷ A hypothesis is that mitigation measures during the COVID-19 pandemic have reduced exposure to S. pyogenes leading to a decreased development of protective immunity in children and an increased susceptibility to (severe) infection.⁸ Indeed, the UKSHA reported a concurrent rise in cases of scarlet fever. In the Netherlands, however, data from sentinel surveillance in Dutch primary care do not suggest this specific trend.⁹ Another contributing mechanism may be that postpandemic increased activity of other viral infections in combination with heightened activity of S. pyogenes predispose to secondary bacterial infections. In our survey, influenza infection was confirmed in 18% of iGAS cases and varicella infection, a known risk factor for iGAS, preceded all cases of necrotizing fasciitis.^4,6 In the Netherlands, varicella vaccination is not part of the national immunization program and the 2022 varicella epidemic in the Netherlands was exceptionally high.¹⁰ A third hypothesis is the evolution of more pathogenic emm-types or new iGAS clones. We were unable to compare current circulating emm-types to pre-COVID-19 cases because surveillance only started since 2019. Similar to our findings, UK Health Security Agency reported emm 12 (39%) and emm 1 (35%) as being dominant in pediatric iGAS cases in 2022. The current findings do not suggest one particular emm-type is responsible for the increase in case numbers.

The survey as study design has some limitations. Limited patient data could be collected. Therefore, we are not able to characterize the full epidemiology and clinical spectrum of the current pediatric iGAS wave. Although our survey used a convenience sample of hospitals, we feel the observed increase in iGAS is representative of the national situation, as we used the same hospitals as historical controls and our findings are in line with an increase in notifiable pediatric iGAS cases on a national level.³ This observation of iGAS surge in children in the Netherlands has implications for parents and clinicians and warrants increased vigilance for invasive disease. Early recognition and prompt initiation of therapy for children with iGAS infection may be life-saving. Future studies should focus on characterizing early predictive signs and symptoms and patient risk factors that predict a severe disease course. Moreover, further investigation should clarify whether the distribution of S. pyogenes strains has changed to more easily transmissible and/or more invasive emm-types and whether the increase in iGAS disease is also observed in more European countries.

CONCLUSIONS

Based on a rapid hospital-based survey, there are signs of a substantial surge in severe pediatric iGAS cases in the Netherlands since early 2022, some with fatal outcome that requires further evaluation. Clinicians and parents should be vigilant and aware of unusual pediatric presentations such as necrotizing fasciitis. Our findings urgently warrant future studies to investigate the full impact of iGAS in Europe post-COVID.

ACKNOWLEDGMENTS

The authors thank the members of the Dutch Study Group on Invasive Group A Streptococcal Infections in Children for their ongoing support and work.