A small proportion of children can develop a hyper-inflammatory condition 2 to 4 weeks following an infection or exposure to SARS-CoV2 virus termed interchangeably as multisystem inflammatory syndrome in children (MISC) or Pediatric Inflammatory Multisystem Syndrome temporally associated with SARS-CoV-2 virus (PIMS-TS) [1]. The patho-genesis of this novel condition remains elusive and treatment protocols are predominantly empirical. Intravenous immuno-globulin (IVIG) alone or with corticosteroids are the suggested first line agents [2,3]. In those with refractory disease (defined by the presence of persistent fever and/or significant end-organ involvement despite initial immunomodulation), second line treatment options include IL-1, IL-6, and tumor necrosis factor (TNF) blockers [2,3]. The PIMS-TS arm of the RECOVERY trial is currently evaluating tocilizumab and anakinra for refractory disease [5]. The experience with use of anakinra in India is sparse due to non-availability of the drug. We report our experience with the use of anakinra in two children with refractory MISC.

Case 1: A 11-year-old boy was referred for fever, abdominal pain and diarrhea of 5 days duration. At presentation he was hypotensive (BP 70/40 mm Hg) with bilateral non purulent conjunctival suffusion and an erythematous maculopapular rash over his trunk. Investigations revealed lymphopenia (total white blood cell count (WBC) 4,350/ìL, lymphocytes 4%), elevated inflammatory markers (CRP 170 mg/L, ESR 72 mm/hour, LDH 359 U/L, ferritin 1,200ng/mL, d-Dimer 12,500ng/mL), hyponatremia (130mEq/L) and increased NT-proBNP levels (>20,000pg/mL). Serology was positive for IgG SARs-CoV-2 antibodies (Chemiluminescence, titer 74.9 AU/mL). An echocardiogram showed decreased left ventricular function (LVEF, 40%). A diagnosis of MIS-C was considered, and he was given IVIG (2 g/kg) with intravenous methylprednisolone (IVMP) (2 mg/kg). Noradrenaline infusion (0.15 µg/kg/min) for hypotension and empirical antibiotics were commenced simultaneously. The dose of methylprednisolone was increased (10 mg/kg, once daily for three days), and adrenaline infusion (0.15 µg/kg/min) was started for persistent hypotension. He continued to be febrile and hypotensive with elevated inflammatory markers (Fig. 1a). Considering refractory disease, anakinra (5 mg/kg/day in two divided doses, subcutaneously) was initiated. There was a dramatic improvement in his clinical status with abrupt cessation of fever and normalization of blood pressure within 12 hours. LVEF increased subsequently (60%). Anakinra was discontinued after 48 hours, and he was discharged on a tapering dose of steroids and aspirin. On follow up at two- and six weeks, LVEF continued to be normal.

IVIG- intravenous immunoglobulin (2 g/kg), IVMP- intravenous methylprednisolone (10mg/kg once daily) Fig. 1 Trend of inflammatory markers and therapeutic interventions in (a) Case 1 and (b) Case 2.

Case 2: A 9-year-old boy presented with fever and diarrhea of five days. On examination, he had bilateral conjunctival suffusion, red lips, strawberry tongue, erythematous maculo-papular rash, and pedal edema. Investigations revealed lymphopenia (WBC count 9,230/µL, lymphocyte 6%), elevated acute phase reactants (CRP 140 mg/L, ESR 60 mm/hr, ferritin 596 ng/mL, d-Dimer 9120 ng/mL), and hyponatremia (127 mEq/L). He tested positive for IgG SARs-CoV-2 anti-bodies (Biomerieux, Index 10.95). An echocardiogram showed dilatation of the right coronary artery (RCA, z-score 2.19). His presentation was consistent with Kawasaki disease like phenotype of MISC and he was given IVIG (2 g/kg) with IVMP (2 mg/kg/day). On day 3 of admission, fever recurred, and he developed hypotension necessitating inotropic support (noradrenaline, 0.15 µg/kg/min). Inflammatory markers and NT-proBNP levels had further increased (Fig. 1b). Repeat echocardiogram showed a decrease in LVEF (35%) and progression of RCA involvement (z-score 3.5). The dose of methylprednisolone was increased to 10 mg/kg once daily for 3 days. On day 5 of admission, his inotropic requirement (adrenaline, 0.5 µg/kg/min) and inflammatory markers progressively increased. Anakinra (6 mg/kg/day in two divided doses, subcutaneously) was commenced for refractory disease. Within 48 hours, he was off inotropic support with defervescence of fever, down trending inflammatory markers and normal LVEF (60%). He was discharged on a slow taper of oral steroids and aspirin. On follow up at two- and six weeks, coronary vessels and LVEF were within normal limits.

1. Bhat CS, Gupta L, Balasubramanian S, Singh S, Ramanan AV. Hyperinflammatory syndrome in children associated with COVID-19: Need for awareness. Indian Pediatr. 2020;57: 929-35.

2. Fouriki A, Fougère Y, De Camaret C, et al. Case series of children with multisystem inflammatory syndrome following SARS-CoV-2 infection in Switzerland. Front Pediatr. 2021;8:594127.　

3. Harwood R, Allin B, Jones CE, et al. PIMS-TS National Consensus Management Study Group. A National Consensus Management Pathway For Paediatric Inflammatory Multisystem Syndrome Temporally Associated With COVID-19 (PIMS-TS): Results of a National Delphi Process. Lancet Child Adolesc Health. 2021;5:133-41.

4. Henderson LA, Canna SW, Friedman KG, et al. American College of Rheumatology Clinical Guidance for Multisystem Inflammatory Syndrome in Children Associated With SARS-CoV-2 and Hyperinflammation in Pediatric COVID-19: Version 2. Arthritis Rheumatol. 2021;73:e13-e29.　

5. Nuffield Department of Population Health. Information for site staff 2020.　Accessed June 21, 2021. Available from: https://www.recoverytrial .net/for-site-staff　

6. Shakoory B, Carcillo JA, Chatham WW, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: Re-analysis of a prior phase III trial. Crit Care Med. 2016;44:275-28.