PIMS-TS and Kawasaki Disease: The Mystery Deepens

To the Editors: On the basis of the review of clinical and laboratory features, the Royal College of Paediatrics and Child Health have provisionally coined the term pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) to describe a novel severe Kawasaki-like disease in children related to coronavirus disease 2019. The recognition of this disease late in the first pandemic wave might relate to its rarity and the difficulty of recognizing uncommon syndromes. The term suggests that the mechanism for the Kawasaki-like disease described might represent a postinfectious inflammatory syndrome, which might be antibody or immune-complex mediated, particularly because in the Italian cohort there was little evidence of viral replication. For prospective studies, measuring antibody at the time of presentation will be essential to elucidate the mechanism of this syndrome.1 Intuitively, we can hypothesize that an aberrant immunologic response is at play. But, where do we start looking for the clues? Kawasaki disease (KD) is an inflammatory disease in children associated with vasculitis affecting predominantly the coronary arteries and is now the most common cause of acquired heart disease in children in developed countries. The 50-year-old mystery as to the cause of KD still remains to be solved. We still do not know whether it is caused by an infectious organism, a toxin, a chemical substance or other agent. But, what we do know is that immune complexes seem to be important in the etiopathogenesis of KD and may provide a clue to the triggering antigen.2 But, we are no closer to determining this antigen. Rowley et al3 hypothesized that the KD pathogen was a (yet) unidentified respiratory infectious agent, likely a virus, which infected ciliated bronchial epithelium and macrophages. The authors proposed that antigen processing in local respiratory lymphoid tissues gave rise to clonal expansion of IgA B lymphocytes and CD8 T lymphocytes. They further hypothesized the bloodstream spread of the agent during symptomatic infection, potentially within macrophages, with migration to the target tissues of KD, particularly the coronary arteries.3 Could then the subsequent pre-existing antibodies from asymptomatic initial infections exacerbate SARS-CoV2 infection through antibody-dependent enhancement? It has been shown in previous studies of animal models that in SARS-CoV infection, neutralizing antibodies to the S protein potentially augmented severe lung injury by exacerbating inflammatory responses.4 Are there analogies that can be drawn with PIMS-TS? Understanding this inflammatory phenomenon in children might provide vital information about immune responses to SARS-CoV-2 and possible correlates of immune protection that might have relevance both for adults and children.1 It was suggested that children’s antibody responses against respiratory syncytial virus are matured over months and years in at least 5 stages.5 It can be hypothesized that during one of these stages (in response to an early respiratory viral infection), in a small subset of infected children, an aberrant response had evolved. Similarly, recent findings point to an inadequate innate immune handling of single-stranded RNA viruses as a risk for transient asthma development.6 In conclusion, this correspondence, in conjunction with deliberations of Cristiani et al,7 who opined that age-related receptor expression, lymphocyte count and trained immunity might be the keystone to reveal children’s secret in the coronavirus dilemma, we can only surmise that we are far from knowing the magnitude of this mystery given the latest developments. Dhamend Lutchman, MPharmSLR, Melbourne, Australia