Multisystem Inflammatory Syndrome in Children
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An overview of MIS- C post- COVID- 19 infection in children.
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Multisystem Inflammatory Syndrome in Children
- 1. Multisystem Inflammatory Syndrome in Children (MIS-C & COVID- 19) Fatima Farid Ped Resident Year 3 Cardiology Block
- 3. Overview • MIS- C is a diagnosis of growing frequency, more common among pediatric rather than adult population • It was first recognized in April 2020 in the UK & has since been reported from many countries world- wide • Our information is incomplete, constantly changing and further studies are still underway 3
- 4. Other Names Pediatric multisystem inflammatory syndrome [PMIS] Pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 [PIMS-TS] Pediatric hyperinflammatory syndrome Pediatric hyperinflammatory shock 4
- 5. Epidemiology • MIS- C has been observed with greatest frequency in: • School aged children & adolescents • Previously healthy • African & Hispanic ethnicity • China and other Asian regions with high incidence of COVID- 19 at the start of the pandemic have LOW to NO reports of MIS- C • Studies have shown the peak of MIS- C in the population occurs 3- 4 weeks after the spike of COVID- 19 cases, hinting to an immune mediated pathology 5
- 7. Pathogenesis • The exact cause of MIS- C is unknown so far, but suspected to be distinct from that of Kawasaki disease & MAS • The likeliest mechanism is a delayed antibody- mediated dysregulated host immune response to COVID- 19 virus infection • Disease presentations fall on a wide spectrum of severity, some studies have shown the risk of cardiac involvement is considerable at any degree of MIS- C • There are several theories attempting to explain the pathogenesis of MIS- C, some are shown in the next slides 7
- 11. Pathogenesis Heart involvement in MIS- C may be explained by: • Systemic inflammation • Acute viral myocarditis • Hypoxia • Stress cardiomyopathy • Coronary artery involvement 11
- 12. Subtypes (based on a limited study) • MIS-C without concurrent acute COVID- 19 or KD picture: • These children are more likely to develop shock, highly elevated inflammatory markers & heart disease • MIS- C with acute COVID- 19 • Prominent respiratory symptoms and HIGHEST mortality rate • MIS- C with overlapping KD picture • Younger age group, prominent mucocutaneous features 12
- 13. 13
- 14. Case Definition 14 • There are 2 guides to diagnose a child with MIS- C: CDC & WHO • Both are similar containing these basic points: 1. Age younger than 19- 21 years 2. Clinical features consistent with MIS- C: fever + multisystem involvement (at least 2) + lab evidence of inflammation +/ - severe illness requiring hospitalization 3. No other plausible diagnosis 4. Evidence of COVID- 19 infection
- 16. MIS- C & COVID- 19 • To diagnose MIS- C, the child must have any evidence of COVID- 19 infection (past, current & even close contact with proven cases are considered) • Both PCR swab and blood serology for COVID- 19 are collected to diagnose MIS-C, studies have shown: • 60% had positive serology & negative PCR • 34% had both positive serology & PCR • 5% had both negative serology & PCR 16
- 17. Presentation • Data has been obtained over time using different case definitions for MIS- C, hence there is a wide spectrum of possible presentations: 17 Persistent fever (100%) GI symptoms (60- 100%) Rash (45- 76%) Conjunctivitis & mucus membrane involvement (30- 80%) Respiratory symptoms (21- 65%) Neurocognitive symptoms (29- 58%) Lymphadenopathy (6- 16%) Sore throat (10- 16%) Myalgia (8- 17%) Swollen hands/ feet (9- 16%)
- 18. Others • Shock, arrhythmia • Acute kidney injury • Encephalopathy, seizure, coma, meningoencephalitis • Serositis, hepatitis, hepatomegaly 18
- 20. DDx Sepsis Kawasaki disease Toxic shock syndrome Appendicitis Viral infections: EBV, CMV, adenovirus & enterovirus Hemophagocytic lymphohistiocytosis Macrophage activation syndrome 20
- 21. Investigations • For mild presentation, the following labs are collected: • CBC • CRP • Urea electrolytes • Renal function testing • If these are abnormal, then to proceed for more extensive investigations 21
- 23. Investigations • If a child has moderate to severe presentation, labs can be prioritized as below: 23 Core Additional • FBC, renal function, LFT • Blood group & save • CRP, ESR, Procalcitonin • Blood and urine cultures • Ferritin, triglycerides, LDH • Interleukin 6 • Troponin T, NT- proBNP, CK • PT/ PTT, fibrinogen, D- dimer • Immunoglobulin level • Chest x- ray • Consider abdominal x- ray if clinically relevant • COVID- 19 virus PCR on nasopharyngeal secretions • COVID- 19 serology test • Standard respiratory viral panel • Respiratory culture • Serum EBV, CMV and Adenovirus DNA PCR • Blood film • Vitamin D • Amylase Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 24. Imaging • Chest x- ray, abdomen USS and CT chest may be indicated & reported abnormal depending on the clinical indication • CXR: consolidation, effusion, atelectasis • Abdomen USS: ascites, mesenteric lymphadenitis, bowel inflammation • CT chest: similar to CXR & rarely ground glass appearance • The most important imaging in proven MIS- C is echocardiography 24
- 25. Cardiac assessment In children with MIS- C, a full cardiac assessment is crucial Components include: • Blood tests: troponin, NT- pro BNP • 12 lead ECG • Echocardiography 25
- 26. Heart involvement • ECG may show arrhythmia or heart block • Echocardiography features: • LV/ biventricular impairment • Diastolic dysfunction • Pericardial effusion • Mitral or tricuspid valve dysfunction • Coronary artery dilation, including giant coronary artery aneurysms 26
- 27. Treatment – 4 main components Infection control (prevent spread to others) Stabilization & monitoring as per usual Medications specific for MIS- C Echocardiographic re- assessments 27
- 28. Initial Management • Examination: • Exclude potential septic foci • Careful cardiac examination: liver, JVP, cardio- thoracic ratio on CXR • Resuscitation: • If signs of shock: fluid resuscitation (10 ml/kg NS) with re- evaluation after each bolus, discuss with PICU • If no improvement with fluids: start inotropes (Dopamine 5- 10 mcg/kg/min) until central line access obtained (then consider Epinephrine infusion) • Ceftriaxone and Clindamycin as sepsis is impossible to exclude. Add broader spectrum antibiotic (i.e Vancomycin) if hospital- acquired/ drug resistant organisms suspected. Keep Clindamycin to reverse toxins release. • Early IVIG 2 g/kg once over 10- 12 hours, max dose 100 grams 28 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 29. Classification of Clinical Severity • Mild: 1. No vasoactive requirement 2. Minimal to no respiratory support 3. Minimal organ injury • Moderate: 1. Vasoactive- inotrope score (VIS) </= 10 2. Significant supplemental oxygen requirement 3. Mild or isolated organ injury 29 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 30. Classification of Clinical Severity • Severe: 1. VIS > 10 2. Non- invasive or invasive ventilator support 3. Moderate or severe organ injury, including moderate to severe ventricular dysfunction 30 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 31. 31 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 32. 32 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 33. PICU Care • Patient to be managed as COVID positive even if PCR negative (full PPE and room in appropriate area) • Central line access: femoral line preferred in awake, self- ventilating patients (as most would require Epinephrine) • Temperature control: regular paracetamol & active cooling if ventilated • Ensure IVIG was administered, otherwise give dose as mentioned, monitor for fluid overload during infusion • Methylprednisolone as detailed previously • Proton pump inhibitor: Esomeprazole 1 mg/kg/day, max dose 40 mg/day • Aspirin & anticoagulation as detailed previously 33 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 34. Cardiac Management • Clinical course is unpredictable with rapid deterioration observed in some • 12- lead ECG required – arrhythmias reported in some • Urgent echocardiogram • Low threshold for Milrinone infusion • Severe cases consider Levosimendan • VA ECMO for refractory shock 34 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 35. Immunomodulatory Therapy • Severe refractory cases should be discussed with a pediatric rheumatologist/ specialist prior to starting higher treatment modalities • Medications: • Repeat IVIG dose • Pulse steroid therapy • Anakinra (IL- 1 receptor antagonist) • Infliximab (monoclonal antibody) • Tocilizumab (IL- 6 receptor antibody) 35 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 36. Recommended Doses for Biologics 36 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 37. Monitoring Urgent echo upon admission to PICU, then repeat as clinically indicated 12- lead ECG at admission, repeat daily or if clinical concerns If oxygen requirement, repeat CXR Regular blood gas - measure lactate Repeat core investigations 12 hourly – if rising inflammatory markers, discuss with ID team 37 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 38. Therapy Complications • Fluid overload: risk with IVIG infusion, consider diuretic administration • Hypertension: high dose methylprednisolone is associated with severe hypertension and PRESS (posterior reversible encephalopathy syndrome). Treatment with calcium channel blockade or SNP if severe cardiac dysfunction. • Hyperglycemia: may require insulin infusion • Gastritis: patient should all receive a high dose PPI • Salicylate complications: acute kidney injury, respiratory alkalosis 38 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 39. Good Treatment Response Normalization of vital signs Improvement in inflammatory markers Resolution of symptoms and signs 39 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 40. Continuity of Care 40 Source: National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021)
- 41. Outcomes • The prognosis of MIS-C is uncertain, given that it is a relatively new clinical entity and long-term follow-up studies are lacking • Though MIS-C has many similarities to Kawasaki disease and toxic shock syndrome, the disease course in MIS-C can be more severe, with many children requiring intensive care interventions • Most children survive, but there have been several deaths reported • The nature and frequency of long-term complications from MIS-C are unknown as post- discharge follow-up data are not yet available 41
- 42. References • UpToDate: • Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) clinical features, evaluation, and diagnosis • Coronavirus disease 2019 (COVID-19): Multisystem inflammatory syndrome in children (MIS-C) management and outcome • National Guidelines for Clinical Management and Treatment of COVID-19 (Version 5.1, February 18th, 2021) • Nakra NA, Blumberg DA, Herrera-Guerra A, Lakshminrusimha S. Multi-System Inflammatory Syndrome in Children (MIS-C) Following SARS-CoV-2 Infection: Review of Clinical Presentation, Hypothetical Pathogenesis, and Proposed Management. Children. 2020; 7(7):69. https://doi.org/10.3390/children7070069 • Rowley, A.H. Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children. Nat Rev Immunol 20, 453–454 (2020). https://doi.org/10.1038/s41577-020-0367-5 • https://www.nejm.org/doi/pdf/10.1056/NEJMc2026136?articleTools=true 42
- 43. Thank you 43