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Overdiagnosis of MIS-C poses challenges: Paediatricians

14 Dec 2021

  • Note MIS-C needs better definition to determine best clinical/therapeutic approach and true prognosis
BY Ruwan Laknath Jayakody A challenge faced by the healthcare community in low-resource countries is the overdiagnosis of the multisystem inflammatory syndrome in children (MIS-C) among sick, hospitalised children. This concern was raised by India’s Teerthanker Mahaveer Medical College and Research Centre Professor in Paediatrics Baljeet Maini in a correspondence on “MIS-C: Danger of overdiagnosis” to the Editor of the Sri Lanka Journal of Child Health, which was published in the journal’s Volume 50, Issue 4 in December 2021. Covid-19 has caused many direct and indirect effects on the paediatric population, and though the virus is not so damaging to children, unlike adults, MIS-C is a known, uncommon but potentially lethal complication in children. The defining criteria for MIS-C, as per the Centres for Disease Control and Research’s “Information for healthcare providers about MIS-C” and the World Health Organisation’s (WHO) “MIS-C and adolescents temporally related to Covid-19” include evidence of a recent Covid-19 infection, like Covid-19 antibody or reverse transcription polymerase chain reaction (RT-PCR) and even a clinical history of Covid-19, in cases presenting with fever and multiorgan (over two organ systems) dysfunction, with no other possible explanation. The issue is that, as noted by R. Viswanathan, A.K. Singh, C. Ghosh, S. Dasgupta, S. Mukherjee, and S. Basu in the “Profile of neonatal septicaemia (when bacteria enter the bloodstream and cause blood poisoning, which triggers sepsis, which is an overwhelming and life-threatening response to infection that can lead to tissue damage, organ failure, and death) at a district-level sick, newborn care unit”, in developing countries, many children get complications with multiorgan involvement due to other causes – in particular, those of a bacterial nature – and often investigations like cultures take a backseat, or even when performed, due to various reasons, in clinical septicaemia cases, cultures are, as per A. Lever and I. Mackenzie’s “Sepsis: Definition, epidemiology, and diagnosis”, negative. Moreover, Prof. Maini explained that aetiological agents like scrub typhus (disease caused by a bacteria which is spread through the bites of infected chiggers or larval mites, with the most common symptoms being fever, headache, body aches, and sometimes rash), which are notorious for causing systemic involvement, also do not grow in cultures, and their specific lab diagnosis is not widely available in an easy fashion even today, as acknowledged by J.A.J. Prakash in “Scrub typhus: Risks, diagnostic issues, and management challenges”. Prof. Maini noted that all over the developing world, many children have already been infected with Covid-19 and demonstrate antibodies on testing. As a result, a challenge for the healthcare community is the overdiagnosis of MIS-C in sick, hospitalised children in low-resource countries. Possible fallouts are, Prof. Maini explained, more expense-borne for investigations, increased demand for expensive medicines such as immunoglobulin, the overlooking of basic morbidity in many of the cases, unwanted psychological trauma to the parents, and mostly, the wrong labelling of MIS-C in many affected children. “It is high time, therefore, that the scientific community thinks about redefining MIS-C in low-resource situations with high Covid-19 positivity, in a way that is actually reflective of MIS-C, and helps avoid any negative impact due to the overdiagnosis of the same,” Prof. Maini emphasised. In an editorial published in the same journal’s same Volume and Issue, in the same month, on “MIS-C associated with severe acute respiratory syndrome coronavirus two (SARS-CoV-2) infection in children”, which is authored by G.N. Lucas, S. Esposito and N. Principi’s “MIS-C related to SARS-CoV-2” is quoted to note that the available literature on the knowledge of MIS-C is largely incomplete and that it is highly likely that the criteria currently used to diagnose MIS-C are too broad, meaning that children with different diseases are included, and that as there is some lack of clarity on the pathogenesis of MIS-C, different therapeutic approaches have been used as no specific therapy is currently available. Hence, Lucas too pointed out that further study is urgently required in order to better define MIS-C and its real impact on child health, and also to determine the best clinical and therapeutic approach and its true prognosis. In April 2020, reports from the UK documented a presentation of SARS-CoV-2 infection in children, in some with features similar to incomplete Kawasaki disease (KD – inflammation of the coronary arteries) or toxic shock syndrome (S. Riphagen, X. Gomez, C. Gonzalez-Martinez, N. Wilkinson, and P. Theocharis’ “Hyper-inflammatory shock in children during the Covid-19 pandemic”). This presentation was subsequently called MIS-C (N.A. Nakra, D.A. Blumberg, A. Herrera-Guerra, and S. Lakshminrusimha’s “MIS-C following SARS-CoV-2 infection: Review of clinical presentation, hypothetical pathogenesis, and proposed management”). MIS-C is defined by P. Taffarel, F.C. Baron, A.P. Rodriguez, J. Widmer, and C. Meregallia in “MIS-C related to Covid-19: An update regarding the presentation of two critically ill patients” as the presence of persistent fever, inflammation, and multiorgan dysfunction, with evidence of a past or recent temporarily associated SARS-CoV-2 infection, and the exclusion of other microbial causes. In certain documented cases, Lucas observed, the syndrome has presented late, around two to six weeks after the onset of the index illness. According to R. Pawar, V. Gavade, N. Patil, V. Mali, A. Girwalkar, V. Tarkasband, S. Loya, A. Chavan, N. Nanivadekar, R. Shinde, U. Patil, and S. Lakshminrusimha’s “Neonatal multisystem inflammatory syndrome (MIS-N) associated with prenatal maternal SARS-CoV-2: A case series”, maternal SARS-CoV-2 may potentially cause a similar hyper-MIS-N due to the trans-placental transfer of antibodies. In Pawar et al.’s study, 18 (90%) neonates had cardiac involvement, 40% had respiratory failure, 10% had fever, 30% had feeding intolerance, 10% had melaena (the production of dark sticky faeces containing partly digested blood, as a result of internal bleeding or the swallowing of blood), and 5% had renal failure; all infants had elevated inflammatory biomarkers and were given steroids and intravenous immunoglobulin (IVIG), but two died (low mortality).
  1. Sood, S. Sharma, I. Sood, K. Sharma, and A.A. Kaushik’s “Emerging evidence on MIS-C associated with SARS-CoV-2 infection: A systematic review with meta analysis” found that fever (95%) was the most common clinical manifestation of MIS-C followed by the involvement of the gastrointestinal system (78%), cardiovascular system (75.5%), and respiratory system (55.3%). Some features of MIS-C, according to Nakra et al. and Sood et al., resemble KD, toxic shock syndrome, and secondary hemophagocytic lymphohistiocytosis (HLH – aggressive and life-threatening syndrome of excessive immune activation) or macrophage activation syndrome (MAS – a life-threatening complication of a rheumatic disease), while the relationship of MIS-C to SARS-CoV-2 infection suggests that the pathogenesis involves some post-infectious immune dysregulation.
Since rapid clinical deterioration may occur, patients with MIS-C should, Nakra et al. maintained, ideally be managed in a paediatric intensive care unit (PICU), with Sood et al. noting that specific immune-modulatory therapy depends on the clinical presentation. Sood et al. found that 49% had shock, 32% had myocarditis (inflammation of the heart muscle), 18% had coronary vessel abnormalities, and 9% had congestive cardiac failure; 63% of the patients were admitted to the PICU, 63% received IVIG, 58% received corticosteroids (type of anti inflammatory drug), and 19% received alternate agents like immunosuppressive drugs, as per Pawar et al. A multicentric prospective national registry, including 47 PICUs, compared the clinical, laboratory and therapeutic features between MIS-C and non-MIS-C patients (A. Garcia-Salido, J.C.D.C. Vicente, S.B. Hofheinz, J.B. Ramirez, M.S. Barrio, I.L. Gordillo, A.H. Yuste, C.G. Pardellans, M.C.M. Tejedor, B.H. Labarga, J.L.V. Martinez, M.G. Jimeno, I. Oulego-Erroz, J.T. Quintela, C.M. Monzon, L.M. Ramos, M.S.H. Pena, J. Gil-Anton, C.S. Orti, J.C.F. Gonzalez, R.M.H. Palomo, I.S.Ganfornina, E.F. Romero, M. Garcia-Besteiro, J.L.H. Cid, R.G. Cortes, and the Spanish paediatric intensive care society working group on SARS-CoV-2 infection’s “Severe manifestations of SARS-CoV-2 in children and adolescents: From Covid-19 pneumonia [infection that inflames the lungs air sacs] to MIS: A multicentre study in PICUs in Spain”) found that MIS-C was the most frequent presentation among critically ill children with SARS-CoV-2 infection; that MIS-C patients were older and usually healthy; and that they showed a higher prevalence of gastrointestinal symptoms and shock and were more likely to receive vaso-active (affecting the diameter of blood vessels and thereby blood pressure) drugs and immune-modulators and less likely to need mechanical ventilation than non-MIS-C patients.

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