The recent issue of JPIDS featured a notable study by Hysmith et al which makes us rethink our approach of differentiating between “harmless” pharyngeal carriage of group A streptococcus (GAS) versus actual infection. The study longitudinally assesses the human immune response to natural infection with GAS [1], and as Shulman et al point out in their accompanying editorial, the findings challenge our current understanding of pharyngeal colonization versus infection with GAS, and the immunologic responses associated with colonization versus infection [2].

Taking a subset of subjects from a larger study conducted at multiple U.S. academic centers, they looked at 41 children who experienced 51 new pharyngeal acquisitions of GAS during a two year study period [3, 4]. They defined a new acquisition as a throat culture that was positive for an emm type of GAS that had not been isolated previously, with a subsequent immune response to 1 or more of the antigens studied. The 31 GAS antigens studied included 18 M peptides and 13 other shared GAS antigens, chosen based on previous studies that indicated their immunogenicity and potential as vaccine candidates, and included streptolysin O (SLO) and deoxyribonuclease B (DNaseB). They evaluated serial throat cultures and 195 serum samples obtained on enrollment and at scheduled intervals throughout the study and when subjects had signs or symptoms of pharyngitis. Salient results included the following:

  • 32 (63%) of the 51 episodes produced an antibody response to the homologous M peptide (i.e. the M type of the strain cultured from the throat produced an antibody response to the same M type in the serum).
  • No subjects had a new acquisition of an M type against which they had preexisting antibodies to the homologous M type.
  • 65% of subjects with new acquisition of GAS were asymptomatic, but mounted immune responses to 1 or more (average 3.7) antigens.
  • 67% of new GAS acquisitions elicited an immune response to SLO and/or DNaseB.
  • 8 (20%) subjects had persistently positive throat culture results (>12 weeks) despite immune responses to homologous M peptides and/or shared antigens.
  • No shared antigen consistently evoked an immune response after a new GAS acquisition.

Given their observation that 65% of subjects had asymptomatic GAS acquisition, yet mounted an immune response to the acquisition, the majority of infections would not be detected based on symptoms alone, and therefore could cause missed opportunities for antimicrobial treatment and prevention of rheumatic fever and rheumatic heart disease. In addition, not all patients actually mount a response to SLO and/or DNaseB, the most commonly used commercially available GAS antibody tests used in the evaluation of patients with suspected acute rheumatic fever or post-streptococcal glomerulonephritis. This means that a negative ASO and/or DNaseB test does not necessarily prove a patient did not have a prior GAS infection and suggests a need to expand the panel of tests available for the clinical evaluation of patients for post-streptococcal nonsuppurative complications.

Shulman et al point out that the study gives us some answers, but also raises important questions that “challenge long standing dogma” for us in how to best prevent the sequelae of GAS [2]. They highlight the bottom line that “(1) anti-M protein protects against a new acquisition of GAS in a type-specific fashion; (2) our previous concepts about a significant GAS acquisition requiring demonstrable increases in antibodies to non-M protein antigens and/or to M protein antigens may not be true and (3) whether or not a new GAS acquisition is significant—risk for post-streptococcal sequelae, whether or not a new GAS acquisition is significant appears to be unrelated to symptomatic or symptomatic acquisition status, whether or not antibiotics were administered promptly, and whether there was or was not a clear immune response to classical streptococcal antigens.”

So perhaps to answer “Where do we go from here?” the first step is for clinicians to be aware of these important findings in their management of patients and assessment of post-streptococcal sequelae. It remains to be seen how these findings and the work that comes after will impact the availability of other GAS serologic tests, changes in GAS treatment guidelines, and the development of a GAS vaccine.

References:

  1. Hysmith ND, Kaplan E, Cleary PP, et al. Prospective Longitudinal Analysis of Immune Responses in Pediatric Subjects After Pharyngeal Acquisition of Group A Streptococci. Journal of the Pediatric Infectious Diseases Society 2017;6(2):187–96.
  2. Shulman ST, Tanz RR. Strep: Where Do We Go From Here? Journal of the Pediatric Infectious Diseases Society 2017;6 (2):197–8.
  3. Kurlan R, Johnson D, Kaplan EL. Streptococcal infection and exacerbations of childhood tics and obsessive-compulsive symptoms: a prospective blinded cohort study. Pediatrics 2008; 121:1188–97.
  4. Leckman JF, King RA, Gilbert DL, et al. Streptococcal upper respiratory tract infections and exacerbations of tic and obsessive-compulsive symptoms: a prospective longitudinal study. J Am Acad Child Adolesc Psychiatry 2011; 50:108–18 e3.