Recurrence following invasive GAS infections in adults: Triumph of virulence or failure of immunity?

Abstract

Since late 2022, an increase in Streptococcus pyogenes (Group A Streptococcus, GAS) infections, both non-invasive and invasive (iGAS), has been reported globally. This study investigates iGAS cases complicated by recurrent infection (rGAS). From January to September 2023, four adults with severe iGAS suffered from rGAS. Clinical and whole-genome sequencing data were analysed. All patients required ICU admission and surgical debridement during their initial iGAS. The median interval between the initial iGAS and rGAS was 25.5 days, with a median duration of antibiotic treatment of 25 and 17.5 days, respectively. Patients A (female, age 69) and B (male, age 46) had upper limb necrotising fasciitis complicated by a subsequent cellulitis at the exact location. GAS emm1.3 (M1_UK) was isolated in both patients, but patient A´s isolates carried a type-IV secretion system (T4SS), and this patient had a more severe course of infection. Patient C (male, age 66) had two episodes of bacteremia caused by GAS emm89.0 carrying T4SS and GAS emm12.37 with a frameshift in the rocA gene. Patient D (female, age 69) had upper limb cellulitis with bacteremia during the initial iGAS and upper limb cellulitis with septic gonitis as two concurrent manifestations of rGAS. All three isolates were identical, belonging to emm12.0 and carrying a 79 amino acid deletion in the SclA. Patients B and C had a reduced function of the complement lectin pathway and CD19+ lymphocyte deficiency. A combination of strain virulence factors and host immune deficiencies may predispose patients with iGAS to recurrence.

Keywords: CD19+ deficiency; Streptococcus pyogenes; cellulitis; lectin pathway complement deficiency; necrotizing fasciitis; sepsis.

Figure 1.

A–D: Timeline of management of patients with recurrent GAS infection.

Figure 2.

A: Genome comparison of Streptococcus pyogenes emm1.3 isolates from patients A and B. The grey regions between the genome maps indicate the similarity range of the nucleotide sequence. B: schematic representation of the identified insert (50.2 kb) in GAS10 isolate from Patient a carrying a T4SS-type integrative conjugative element with the ermB gene. The functional categories of genes are colour-coded, as shown in the legend.

Figure 3.

Pairwise linear comparison of the predicted T4SS-type ICEs found in GAS10 (emm1) and GAS63 (emm89.0) isolates. The grey regions indicate nucleotide sequence similarities ranging between 70% and 100%.

Figure 4.

Core-genome maximum-likelihood phylogenetic tree inferred with GTR+G model with 500 bootstrap replicates. Green and red squares indicate the initial and recurrent episode isolates. The presence of virulence genes predicted with the VFDB database is classified into four categories and is shown as colored squares.