Abstract
Dear Editor,
Introduction
The incidence and severity of illness due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection showed more severe illness in adults and the elderly compared to children. But a clinical manifestation characterized by a multisystem inflammatory syndrome is described in children (Multisystem inflammatory syndrome in children (MIS-C)). MIS-C was first described in April 2020. MIS-C is due to a dysregulated immune response. The mechanism by which SARS-CoV-2 triggers the abnormal immune response is unknown. This abnormal immune response has similarities with Kawasaki and macrophage activation syndrome (MAS). Initially, due to a lack of awareness, MIS-C was underdiagnosed. At present, with increased awareness among pediatricians and due to a lack of characteristic clinical features and specific laboratory investigations, MIS-C has been overdiagnosed.
Clinical Features
The clinical presentation may vary from simple febrile illness to Kawasaki-like illness to shock. Gastrointestinal symptoms are more common. There are some case reports of laparotomy done for abdominal pain suspecting acute appendicitis in a case of MIS-C.
Diagnosis
The World Health Organization, the Center for Disease Control and Prevention (CDC), 1 and the UK health department proposed criteria for the diagnosis of the syndrome. They all have common criteria, such as persistent fever, multi-organ involvement, laboratory evidence of inflammation, and a confirmed current or recent infection with COVID-19.
CDC criteria:
1) Age <21 years
2) Clinical criteria:
Fever > 38C° for ≥ 24 h, or report of fever lasting ≥ 24 h AND
Involvement of two or more systems (i.e., cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic, neurological)
3) Evidence of inflammation:
An elevated CRP/ESR/fibrinogen/procalcitonin/D-dimer/ferritin/LDH or IL-6; elevated neutrophils, reduced lymphocytes
4) Laboratory or epidemiologic evidence of SARS-CoV-2 infection:
Evidence for current or recent SARS-CoV-2 infection by RT-PCR, serology or antigen test
Exposure to a suspected or confirmed COVID-19 case within the 4 weeks previous to the onset of symptoms
5) No alternative diagnoses
Diagnostic Dilemma
MIS-C is a diagnosis of exclusion. There are no specific clinical features or laboratory investigations to diagnose MIS-C. The existing criteria used to diagnose MIS-C are non-specific and too broad, that is, children with different conditions are diagnosed as having MIS-C.
All laboratory investigations mentioned above are indicators of inflammation. They can be elevated in any inflammatory condition, including sepsis. But in MIS-C, these parameters are extremely high in a relatively stable patient, unlike in other diseases where they correlate with the clinical picture.
Most of the children who were treated for MIS-C tested IgG positive for COVID with negative RT-PCR. IgG positivity just indicates that the patient was infected with the virus, not the time of infection, that is, whether it was in the past few weeks or several months ago.
Coronary artery involvement is characteristic of MIS-C, like Kawasaki disease. Coronary artery Z score cutoff 2 has a specificity of 95% and a sensitivity of 32%. A coronary artery Z score above 2.5 has a specificity of 98% and a sensitivity of 20%. Thus, coronary artery involvement helps in distinguishing MIS-C from other febrile patients.
If there is coronary involvement, the Kawasaki-like illness spectrum of MIS-C should be differentiated from Kawasaki disease. GI symptoms are present in only 30% of Kawasaki patients, less than half of that in cases with MIS-C. Other systems involvement is also uncommon in Kawasaki. Cardiac manifestations like ventricular dysfunction and ischemic insult are rare in Kawasaki, 2 whereas coronary artery aneurysms are more prevalent in KD.
Treatment
IVIG (2 g/kg) and aspirin (80−100 mg/day) in four divided doses (6 hourly) are the first treatment choices for patients with KD-like illnesses. The aspirin dose is decreased to the antiplatelet dose, that is, 5 mg/kg, once the inflammatory markers are normalized. High-risk cases (CRP > 100, coronary involvement) should be treated with IVIG (2 g/kg) and 3-day pulse methylprednisolone. 3
Immunomodulatory agents like infliximab, anakinra, and tocilizumab are third-line drugs reserved for those children who do not respond to IVIG and methylprednisolone.
Patients with coronary aneurysms should have regular follow-up. The frequency of the visits is based on the severity of the aneurysms. Small to moderate aneurysms may regress in a few months. Giant aneurysms are unlikely to regress. Giant aneurysms pose a risk of thrombosis in the acute stage and stenosis later.
In the case of a thrombus, the patient should undergo emergency thrombolysis or coronary angioplasty. Because of the non-availability of hardware and lack of expertise in pediatric coronary interventions, thrombolysis remains the treatment of choice.
On follow-up, children with signs of ischemia in non-invasive investigations like stress ECG or Echo, CT angiogram should undergo a conventional angiogram. Based on the findings of the angiogram, coronary angioplasty or coronary artery bypass grafting can be planned.
Conclusion
MIS-C with the clinical presentation of fever, rash, and organ dysfunction may pose diagnostic difficulty with sepsis and other tropical infections.
Overdiagnosis may lead to unwarranted use of steroids, IVIG, and other immunomodulators, which may worsen an infective febrile illness.
Underdiagnosis and a delayed diagnosis may lead to a delay in initiating immunomodulatory therapy, a persistent inflammatory state, and worsening organ dysfunction.
Footnotes
Declaration of Conflicting Interests
The author declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author received no financial support for the research, authorship, and/or publication of this article.
