The Conundrum of Differentiating MIS-C from Dengue and Other Tropical Infections

Multisystem inflammatory syndrome in children (MIS-C) or Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is probably the most dramatic manifestation of COVID-19 in children. Soon after its recognition, the WHO and other Societies published diagnostic guidelines for this new entity [1]. Central to all these guidelines was exclusion of an infectious cause particularly staphylococcal and streptococcal toxic shock syndromes. However in India, other tropical infections including dengue, malaria, enteric fever, chikungunya, leptospira and rickettsial infections are commoner differentials as compared to the toxic shock syndromes. While the under diagnosis of MIS-C was an issue in the early days of the pandemic, over diagnosis became common later. This was partly due to previous clinical experience, heightened discussion of MIS-C in media/ scientific literature/ conferences and also high prevalence of SARS-CoV-2 antibodies in the population. Fortunately, cases of MIS-C have dramatically declined since the emergence of Omicron [2].

The dengue virus causes 12 million cases every year in India and is a common cause of hospitalization in children during the monsoon season [3]. It shares several clinical/ laboratory features with MIS-C, and thus differentiating it from MIS-C is crucial. The study by Randhawa et al. published in this issue of the Journal, compared hospitalized dengue patients with MIS-C patients [4]. They reported significantly higher prevalence of rash, mucocutaneous changes, conjunctival injection and gallop rhythm in MIS-C while dengue patients had higher prevalence of petechiae, hepatomegaly, headache and myalgia. When laboratory features were compared, MIS-C patients had significantly higher C-reactive protein (CRP) and interleukin-6 (IL-6) levels while patients with dengue had higher haemoglobin (Hb), aspartate aminotransferase/alanine transaminase (AST/ ALT) levels and lower platelet counts. Surprisingly, the prevalence of rash (22%) was lower and the mean white cell count (4900) was higher in the study dengue patients than usually seen in clinical practice. Though not reported in the study, capillary leak phenomena such as pleural effusion and ascites may be seen in both (due to congestive cardiac failure in MIS-C). While the authors measured IL-6, it is now not considered necessary in diagnosis or management of COVID-19. The SARS-CoV-2 antibody positivity was similar in both dengue and MIS-C patients highlighting the fact that this parameter is no longer useful for diagnosis of MIS-C in the setting of high rates of natural infection with SARS-CoV-2. While the study observations are useful pointers, dengue serology is the most specific test for differentiating dengue from MIS-C or other tropical infections. NS-1 antigen is more specific than IgM as the latter may also be positive due to past/recent infection [5].

There are tropical infections other than dengue which are even harder to differentiate from MIS-C. Chikungunya, with its high CRP and lack of an antigen based test poses diagnostic challenges. Enteric fever with its gastrointestinal manifestations and high CRP has often been confused with the febrile inflammatory variant of MIS-C. Rickettsial infections characterized by rash, shock, multiorgan dysfunction, high CRP, leucocytosis, thrombocytopenia, and coagulopathy are a close mimic. The situation is further complicated by limited availability of serologic/ molecular tests for rickettsial infections.

The conundrum caused by these tropical mimics of MIS-C highlights the importance of developing locally adapted diagnostic algorithms such as that published by the Indian Academy of Paediatrics [6].

Declarations

Conflict of Interest

None.