The recent report by Hysmith et al (JPIDS March 2017) of unpredictable immune responses to symptomatic and asymptomatic pharyngeal acquisition creates 4 clinical circumstances, a GAS “Tetradigm:” (1) Symptoms/Immune Response (IR); (2) Symptoms/no IR; (3) no Symptoms/IR; (4) no Symptoms/no IR. Symptoms/IR corresponds to bona fide classic GAS pharyngitis. No Symptoms/no IR is consistent with chronic carriage; carriers are not routinely identified or treated.
Classically, ARF follows bona fide GAS pharyngitis but probably not chronic carriage. Symptomatic patients can be identified and treated for GAS, the current approach to ARF prevention. Patients with Symptoms/no IR are not distinguished clinically from those with Symptoms/IR; their risk for recurrent infection and GAS sequelae is unknown. Development of IR without Symptoms might explain ARF in patients without history of pharyngitis but the extent of risk is unknown and identification before ARF occurs is problematic. Confirming antecedent GAS illness requires identifying IR to GAS, but Hysmith’s report highlights the unpredictability of IR.
Conundrums and Challenges: 1. M protein-specific IR protects against homologous M type acquisition but is variable and may not develop; 2. Non-M IRs are unpredictable and their role in protection against infection and sequelae is unclear; 3. Identifying GAS IR supports the diagnosis of ARF and/or evidence of vaccine response, but which IRs protect against, or create risk for, ARF?; 4. What is the meaning of GAS acquisition without anti-M IR: is there risk for ARF? Studies are needed to clarify unpredictable immune responses to GAS pharyngitis and subsequent risk for ARF.