Introduction
Definition of MIS-C
Royal College of Paediatrics and Child Health, UK | Centers for Disease Control and Prevention (CDC), USA | World Health Organization (WHO) |
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A child presenting with persistent fever (> 38.5 °C), inflammation (neutrophilia, elevated CRP, and lymphopenia) and evidence of single or multiorgan dysfunction (shock, cardiac, respiratory, kidney, gastrointestinal, or neurological disorder) with additional features*. This may include children fulfilling full or partial criteria for KD. Exclusion of any other microbial cause, including bacterial sepsis, staphylococcal or streptococcal shock syndromes, infections associated with myocarditis such as enterovirus (waiting for results of these investigations should not delay seeking expert advice). SARS-CoV-2 RT-PCR test results may be positive or negative. *Additional features: Clinical: Most: oxygen requirement, hypotension Some: abdominal pain, confusion, conjunctivitis, cough, diarrhea, headache, lymphadenopathy, mucus membrane changes, neck swelling, rash, respiratory symptoms, sore throat, swollen hands and feet, syncope vomiting; Laboratory: All: abnormal fibrinogen, high D-dimers, high ferritin, hypoalbuminemia; Some: acute kidney injury, anemia, thrombocytopenia, coagulopathy, high IL-10, high IL-6, proteinuria, high CK, high LDH, high TG, high troponin, transaminitis; Imaging: Echo and ECG: myocarditis, valvulitis, pericardial effusion, coronary artery dilation; CXR: patchy symmetrical infiltrates, pleural effusion; Abdo USS: colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly; CT chest: as for CXR. May demonstrate coronary artery abnormalities if with contrast. | An individual aged < 21 years presenting with fever*, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (≥ 2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological); AND No alternative plausible diagnoses; AND Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test, or COVID-19 exposure within 4 weeks prior to the onset of symptoms. *Fever ≤ 38 °C for ≥ 24 h, or report of subjective fever lasting ≥ 24 h. **Including, but not limited to, one or more of the following: an elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, ferritin, LDH, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin. Additional comments: Some individuals may fulfill or partial criteria for KD but should reported if they meet the case definition for MIS-C; Consider MIS-C in any pediatric death with evidence of SARS-Cov-2 infection. | Children and adolescents 0–19 years of age with fever ≥ 3 days; AND two of the following: 1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet). 2. Hypotension or shock. 3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including echo findings or elevated troponin/NT-proBNP), 4. Evidence of coagulopathy (by PT, PTT, elevated d-dimers). 5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain). AND Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin. AND No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes. AND Evidence of COVID-19 (RT-PCR, antigen test or serology positive), or likely contact with patients with COVID-19. Consider this syndrome in children with features of typical or atypical KD or toxic shock syndrome |
Clinical presentation
Clinical symptoms
Author, year | Study design, setting, and period | N | Age, gender | Other patients’ baseline characteristics | Symptoms | Cardiac involvement | SARS-CoV-2 test | |||||
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Ventricular function | Coronary involvement | Arrhythmia/ECG changes | Troponin | proBNP/BNP | RT-PCR | Serology | ||||||
Jones 2020 | Case report, Palo Alto, USA, April 2020 | 1 | 6 months, F | Previously healthy | Persistent fever, rash, conjunctivitis, mucosal changes, peripheral edema, minimal respiratory symptoms, irritability | Normal | Normal coronary arteries | - | - | - | Pos | - |
Riphagen 2020 | Case series, London, UK, April 2020 | 8 | Range 4–14 years, 5M, 3F | 6/8 previously healthy, 1/8 allergic rhinitis and alopecia areata, 1/8 autism, 6/8 Afro-Caribbean | Persistent fever, 7/8 GI symptoms, 5/8 conjunctivitis, 4/8 rash, 3/8 odynophagia, 2/8 headache, 1/8 myalgia, 8/8 Hypotension/shock | 6/8 (4/8 mild to severe LV dysfunction, 1/8 RV dysfunction, 1/8 BiV dysfunction) | 8/8 echobright coronary vessels, 1/8 giant aneurysm | 1/8 in context of refractory shock, requiring ECMO; other ECGs non-specific | ↑ | ↑ proBNP | 2/8 Pos | - |
Rivera-Figueroa 2020 | Case report, Jackson, USA, April 2020 | 1 | 5 years, M | Previously healthy, African-American | Persistent fever, GI symptoms, rash, conjunctivitis, mucosal changes, peripheral edema, shock | Normal | Normal coronary arteries | ↑ | Pos | - | ||
Balasubramanian 2020 | Case report, Chennai, India, April 2020 | 1 | 8 years, M | Previously healthy, Indian | Persistent fever, odynophagia, rash, conjunctivitis, mucosal changes, peripheral edema, mild respiratory distress, hypotension | Normal | Normal coronary arteries | - | - | - | Pos | - |
Verdoni 2020 | Case-control study, Bergamo, Italy, 2015–2020 | 10 | Mean 7.5 years (SD 3.5), 7M, 3F | Previously healthy, Caucasian | Persistent fever, rash, conjunctivitis, peripheral edema, 6/10 GI symptoms, 4/10 mucosal changes, 4/10 meningeal signs, hypotension | 5/10 LVEF < 50% | 2/10 coronary aneurysms (> 4 mm) | - | ↑ 5/9 | ↑ proBNP 10/10 | 2/10 Pos | 3/10 IgM+ 8/10 IgG+ |
Belhadjer 2020 | Case series, France and Switzerland (14 centers), March–April 2020 | 35 | Median 10 years (range 1–16 years), 18 M, 17F | 31/35 previously healthy, 3/35 asthma, 1/35 SLE, 6/35 overweight (BMI > 25) | Persistent fever, asthenia, 28/35 (80%) GI symptoms, 23/35 respiratory distress, 20/35 rash, mucosal changes, 11/35 meningeal signs, 6/35 chest pain, 35/35 hypotension/shock | 35/35 LVEF < 50% (inclusion criteria), 10/35 LVEF < 30%, 31/35 global LV hypokinesis, 3/35 segmental wall hypokinesis, 1/35 Takotsubo | 6/35 mild coronary dilatation (z score > 2), no aneurysms | 1/35 ST elevation at onset, 1/35 ventricular arrhythmia | ↑ | ↑ 35/35 proBNP or BNP | 14/35 Pos | 30/35: 28/35 IgG+ 2/35 IgM+ |
Licciardi 2020 | Case report, Turin, Italy, April 2020 | 2 | 7 years, M, 12 years, M | Previously healthy, 1/2 PFAPA syndrome | Persistent fever, GI symptoms, rash, conjunctivitis, peripheral edema, hypotension/shock | 2/2 Ventricular dysfunction | Normal coronary arteries | Normal ECG | ↑ 2/2 | ↑ 1/2 proBNP | Neg | IgM+, IgG+ |
Deza Leon 2020 | Case report, Detroit, USA, April 2020 | 1 | 6 years, F | Previously healthy | Fever, rash, conjunctivitis, peripheral edema odynophagia, respiratory distress, cardiogenic shock | Mildly diminished LVEF at onset, severe dysfunction requiring ECMO | Normal coronary arteries | Junctional cardiac rhythm | ↑ | - | Pos | - |
Dolinger 2020 | Case report, New York, USA, May 2020 | 1 | 14 years, M | Crohn disease | Persistent fever, GI symptoms, rash, hypotension | - | - | - | - | - | Pos | –- |
Labé 2020 | Case report, Argenteuil, France, May 2020 | 2 | 6 years, M 3 years, M | Previously healthy | Rash, conjunctivitis, mucosal changes;1/2 persistent fever, cervical lymphadenopathy | - | - | - | - | - | 1/2 Pos | - |
Rauf 2020 | Case report, Kerala, India, April 2020 | 1 | 5 years, M | Previously healthy | Persistent fever, GI symptoms, pyuria, conjunctivitis, peripheral edema, hypotension | Moderate LV dysfunction (FE = 35%), LV global hypokinesia | Normal coronary arteries | ↑ | ↑proBNP | Neg | - | |
Chiotos 2020 | Case series, Philadelphia, USA, April–May 2020 | 6 | Range 5–14 years, 1M, 5F | Previously healthy, 2/6 African-American, 2/6 Caucasian | Persistent fever, 5/6 GI symptoms, 2/6 rash, 2/6 conjunctivitis, 3/6 mucosal changes, 1/6 peripheral edema, 1/6 headache, 2/6 irritability, 4/6 respiratory failure, 6/6 shock | 4/6 Mild-Moderate LV dysfunction | 1/6 diffuse dilation right coronary artery (z score 3.15); 1/6 echobright coronaries | - | ↑ 3/5 | ↑BNP | 3/6 Pos | - |
Waltuch 2020 | Case series, New York, USA, April 2020 | 4 | Range 5–13, 3M, 1F | 2/4 previously healthy, 1/4 hypothyroidism, 1/4 asthma | Persistent fever, GI symptoms, 3/4 conjunctivitis, 2/4 rash, 2/4 cough, 2/4 fatigue, 1/4 myalgia, hypotension | Moderately depressed LV function | 1/4, dilated coronary arteries, 1/4 slight ectasia, 1/4 mildly dilated coronary arteries | - | ↑ 1/4 | ↑BNP | 0/3 Pos | 4/4 IgG+ |
Wolfler 2020 | Case series, Milan, Italy, March–April 2020 | 5 | Mean 84 m, range 2–168, 2M, 3F | Previously healthy | Persistent fever, GI symptoms, 3/4 rash, 1/5 conjunctivitis, 1/5 respiratory distress, 5/5 hypotension/shock | 5/5 Mild-moderate heart dysfunction, 3/5 LVEF < 50% | Normal coronary arteries | ST,T waves anomalies, 1/5 atrial fibrillation | ↑ | ↑proBNP | 5/5 Pos | - |
Grimaud 2020 | Case series, Paris, France (4 centers), April 2020 | 20 | Median 10 years (IQR 3–15), 10M, 10F | - | Persistent fever, GI symptoms, 10/20 rash, 6/20 conjunctivitis, 5/20 mucosal changes, 2/10 lymphadenopathy, 20/20 hypotension/shock | 20/20 Cardiogenic/vasoplegic shock (inclusion criteria), LVEF 35% (IQR 25–55) | Normal coronary arteries | - | ↑ | ↑BNP | 10/20 Pos, others neg | 15/20 IgG+ |
Toubiana 2020 | Case series, Paris, France, April–May 2020 | 21 | Median 8y (range 4–17), 9M, 12F | 12/21 African ancestry | Persistent fever, GI symptoms, 16/21 rash, 17/21 conjunctivitis, 16/21 mucosal changes, 12/21 cervical lymphadenopathy, 12/21 irritability, 12/21 serous effusion, 15/21 hypotension/shock | 16/21 myocarditis | 5/21 moderately dilated coronary arteries (z score 2–2.5), 3/21 echobright coronaries | 2/16 increased QT interval, ventricular arrhythmias or diffuse ST segment elevation | ↑ 17/21 | ↑14/18 | 8/21 Pos | 19/21 IgG+ |
Whittaker 2020 | Case series, UK (8 centers), March–May 2020 | 58 | Median 9 years (IQR 6–14), 25M, 33F | 7/58 comorbid: 3/58 asthma, 1/58 neuro-disability, 1/58 epilepsy, 1/58 sickle cell trait, 1/58 alopecia; 22/58 Black 18/31 Asian | Persistent fever, GI symptoms, 30/58 rash, 26/58 conjunctivitis, 17/58 mucosal changes, 12/58 respiratory symptoms, 9/58 peripheral edema, 9/58 lymphadenopathy, 6/58 odynophagia, 5/58 confusion, 29/58 shock | 18/29 LV dysfunction | 8/58 coronary artery dilatation (z score > 2), 7/58 z score > 2.5, giant aneurysm 2/58 | 4/58: 1/58 1st-degree AV block, 1/58 intractable broad complex tachycardia, requiring ECMO; 1/58 atrial fibrillation, 1/58 2nd-degree AV block | N-↑ | ↑ proBNP 29/29 | 15/58 Pos | 40/46 IgG+ |
Blondiaux 2000 | Case series, Paris, April | 4 | Median 9 y (range 6–12), 1M, 3F | No history of cardiovascular disease | Persistent fever, GI symptoms, rash, conjunctivitis | 4/4 transient systolic disfunction, 1/4 LVEF < 30% | Normal coronary arteries | 1/4 ST depression, 1/4 T waves abnormalities | ↑4/4 | ↑4/4 | 0/4 Pos | 4/4 IgG+, 1/4 IgM+ |
Cheung 2020 | Case series, New York, April–May 2020 | 17 | Median 8 years (range 2–16) 8M, 9F | Previously healthy, 3/17 mild asthma; 6/17 Ashkenazi Jewish, 4/17 Asian | Persistent fever, 14/17 GI symptoms,12/17 rash, 11/17 conjunctivitis, 9/17 mucosal changes, 3/17 respiratory symptoms, 13/17 shock | 11/17 normal-mild LV dysfunction 6/17 moderate-severe LV dysfunction | 7/17 echobright coronaries, 1/17 medium-sized aneurysm (z score 5.2) | 10/17 Non-specific ST/T-wave abnormalities, 1/17 attenuated QRS voltage. 3/17 dysrhythmias: premature ventricular contractions, non-sustained VT, sinus bradycardia | ↑14/17 | ↑ proBNP 15/29 | 8/17 Pos | 9/17 IgM/IgG + |
Ramcharan 2020 | Case series, Birmingham, April–May 2020 | 15 | Median 9 (IQR 7–11), 11M, 4 F | 6/15 African/Afro-Caribbean, 6/15 Asian | Persistent fever, 13/15 GI symptoms, 8/15 Kawasaki-like symptoms, 4/15 myalgia, 4/15 lethargy | 8/15 Reduced LV fractional shortening, 12/15 LVEF < 55% | 14/15 coronary artery abnormalities: 1 aneurysm, 6 ectasia, 7 prominent | 9/15 abnormal PR interval, abnormal T waves | ↑15/15 | ↑ proBNP 15/15 | 2/15 Pos | 12/12 IgM/IgG/IgA+ |
Pouletty 2020 | Case series, Paris (multicenter), April–May 2020 | 16 | Median 10 years (IQR 5–12), 8 M, 8F | 10/16 Previously healthy, 2/16 asthma, 4/16 overweight | Persistent fever, 13/16 GI symptoms, 13/16 rash, 15/16 conjunctivitis, 14/16 mucosal changes, 9/16 neurological signs, 6/16 lymphadenopathy, 2/16 respiratory symptoms, 1/16 arthritis, 1/16 anosmia 11/16 shock | 7/16 Myocarditis, LVEF 35% (IQR 32–46) | 3/16 coronary dilation, median z score 2.6 (IQR 1.7–3.7) | – | ↑11/16 | ↑ proBNP 11/16 | 11/16 Pos | 7/8 IgG+ |
Kaushik 2020 | Case series, New York (3 centers), April–May 2020 | 33 | Median 10 years (IQR 6–13), 20M, 13F | 17/33 Previously healthy, 5/33 asthma, 4/33 overweight, 15/33 Hispanic or Latino, 13/33 black | Persistent fever, 23/33 GI symptoms, 14/33 rash, 12/33 conjunctivitis, 11/33 respiratory symptoms, 7/33 mucosal changes, 4/33 neurologic involvement 21/33 hypotension | 21/32 LVEF < 50%, 4/32 LVEF < 30% | 6/21 prominent coronary arteries, 2/21 coronary ectasia | - | N-↑ | ↑BNP, proBNP | 11/33 Pos | 27/33 IgM/IgG+ |
Greene 2020 | Case report, New York, May 2020 | 1 | 11 years, F | Previously healthy | Persistent fever, GI symptoms, sore throat, rash, leg pain, malaise, shock | Decreased LV function | Normal coronary arteries | - | ↑ | ↑ | Pos | - |
Dufort 2020 | Case series, New York (multicenter), March–May 2020 | 99 | 31/99 0–5 years, 42/99 6–12 years, 26/99 13–20 years; 53M, 46F | 36/95 pre-existing condition, 29 of them obesity; 31/78 black, 31/78 Hispanic, 29/78 white | Persistent fever or chills, 79/99 GI symptoms, 59/99 rash, 60/99 mucosal change, 40/99 lower respiratory symptoms, 30/99 neurologic symptoms, 27/99 upper respiratory, 11/99 chest pain, 61/99 hypotension, 10/99 shock | 51/99 some degree of ventricular dysfunction, 52/99 myocarditis | 9/99 coronary artery aneurysm (4/99 z score > 2.5) | - | ↑ 63/89 | ↑ 74/82 | 50/94 Pos | 76/77 IgG+, 3/77 IgM+ |
Feldstein 2020 | Case-series, United States (multicenter), March–May 2020 | 186 | Median 8 years (IQR 3–12), 115M, 71F | 135 previously healthy, 51/186 at least one underlying condition excluding obesity (resp 33/186, cardiac 5/186, immunocompromising or autoimmune 10/186, 45/153 BMI-based obesity; 46/186 Black, 57/186 Hispanic or Latino) | Persistent fever, 171/186 GI symptoms, 110/186 rash, 103/55 conjunctivitis, 78/186 oral mucosal changes, 37/186 peripheral edema, 18/186 lymphadenopathy, 131/186 respiratory symptoms, 149/186 cardiovascular symptoms | 90/186 Myocardial dysfunction | 15/170 Coronary artery aneurysm (z score ≥ 2.5) | 12/186 Arrhythmia | ↑ 50/128 | ↑73/153 | 73/186 Pos | 85/186 IgM/IgG+ |
Author, year | Cardiac support treatment | Anti-inflammatory/immunomodulatory treatments | Antiplatelet/anticoagulation treatment | Outcomes | |||||
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Inotropes/vasopressors | ECMO | IVIG | Steroids | Biologic drugs | Aspirin | Heparin | At discharge | Follow-up | |
Jones 2020 | No | No | 2 g/kg | No | No | 20 mg/kg ×4/day, then 3 mg/kg/day | No | Complete recovery | Planned at 2 weeks after discharge |
Riphagen 2020 | 8/8 | 1/8 | 8/8 | 5/8 | 1/8 infliximab | 6/8 50 mg/kg | 1/8 | Complete recovery, ICU after 4–6 days | 1/8 developed 1 giant coronary aneurysm 1 week after discharge, 1/8 died for large cerebrovascular infarct; ongoing surveillance for coronary arteries |
Rivera-Figueroa 2020 | No | No | 1.8 g/kg | Premed only | No | 40 mg/kg/day | No | Complete recovery, discharged at day 6 | Complete recovery confirmed at 2 weeks |
Balasubramanian 2020 | No | No | 2 g/kg | No | Tocilizumab 8 mg/kg | 75 mg ×1/day | No | Complete recovery | - |
Verdoni 2020 | 2/10 | No | 10/10 2 g/kg | 8/10 MTPD 2 mg/kg/day × 5 | - | 10/10 3/10 50–80 mg/kg/day, 7/10 30/mg/day; then 3–5 mg/kg/day | No | Complete recovery | Planned at 8 weeks, including echocardiogram |
Belhadjer 2020 | 28/35 | 10/35 | 25/35 (1/25 s dose) | 12/35 | 3/35 anakinra | 28/35 | 23/35 Therapeutic dosage | Recovery, 7/35 residual LV dysfunction | 5/35 residual mild-moderate LV systolic dysfunction at last follow-up (median 12 days) |
Licciardi 2020 | 1/2 | No | 1/2 2 g/kg | 2/2 MTPD 2/mg/kg/die | No | - | No | Recovery | - |
Deza Leon 2020 | 1/1 | 1/1 | 2 g/kg | No | No | 1/1 | 1/1 on ECMO | ECMO decannulation at day 6, organs recovery day 12 | - |
Dolinger 2020 | No | No | No | No | Infliximab 10 mg/kg | No | No | Complete recovery | Complete recovery confirmed at 2 weeks |
Labé 2020 | No | No | 2 g/kg | No | No | - | No | 1/2 discharged at day 14 | - |
Rauf 2020 | 1/1 | No | 2 g/kg | MTPD 30/mg/kg/day ×3 | No | 1/1 | No | Complete recovery | - |
Chiotos 2020 | 5/6 | No | 4/6 2 g/kg, 2/6 s dose 2 g/kg | 5/6 MTPD 2 mg/kg/day, 2/6 MTPD 30/mg/kg/day ×3 | 1/10 anakinra 4/mg/kg/day | 3/6 “low dose” | No | 5/6 complete recovery discharged at day 8–17, 1/6 still in PICU at moment of submission | - |
Waltuch 2020 | 3/4 | No | 3/4 | No | 2/4 tocilizumab, 1/4 tocilizumab and anakinra | - | No | - | - |
Wolfler 2020 | 4/5 | No | 4/5 2 g/kg | 1/5 | 1/5 tocilizumab | - | 4/5 LMWH prophylaxis | Complete recovery | - |
Grimaud 2020 | 19/20 | No | 20/20 2 g/kg | 2/20 | 1/20 tocilizumab, 1/20 anakinra | - | No | Full left ventricular function recovery | - |
Toubiana 2020 | 15/21 | No | 21/21 2 g/kg, 5/21 s dose 2 g/kg | 10/21 steroids 2–10 mg/kg/day | No | 21/21 3–5 mg/kg/day | No | Complete recovery, discharged at day 5–17 | - |
Whittaker 2020 | 27/58 | 3/58 | 41/58 | 37/58 | 3/58 anakinra, 8/58 infliximab | - | - | 1/58 died | - |
Blondiaux 2000 | 3/4 | No | 4/4 | 3/4 | - | - | - | Complete recovery, discharged at day 13–23 | - |
Cheung 2020 | 10/17 | No | 13/17 2–4 g/kg | 14/17 MTPN 2–30 mg/kg/day, HC 2 mg/kg/day | 1/17 tocilizumab | 4/17 | Enoxaparin 10/17 prophylaxis, 1/17 treatment | Most patients had improved LV function at day 2–18. 1/17 mildly decreased function | At day 3–18 of follow up, all patients at home, no fatalities |
Ramcharan 2020 | 10/15 | 10/15, 3/15 s dose | 5/15 MTPN | - | 2/15 high dose, 11/15 low dose | No | All patients discharged home with normal/improving cardiac parameters | Planned at 1 week, including ECG and echocardiogram | |
Pouletty 2020 | 6/16 | No | 15/16, 5/16 s dose | 4/16 | 1/1 tocilizumab, 1/1 anakinra | 15/16 (7/16 30–50 mg/kg/day, 8/16 antiaggregant dose) | - | Complete recovery, all discharged at median follow-up of 14 days | - |
Kaushik 2020 | 17/33 | 1/33 | 18/33 | 17/33 | 12/33 tocilizumab, 4/33 anakinra | 8/24 | 28/33 therapeutic UHF/enoxaparin, 5/33 prophylactic enoxaparin | 32/33 complete recovery, discharged at day 6–10, 20/21 complete LV function recovery, 1/33 died on ECMO | - |
Greene 2020 | 1/1 | No | 1/1 | 1/1 | Tocilizumab | - | Therapeutic dose enoxaparin | Complete recovery | Planned at 2 weeks |
Dufort 2020 | 61/99 | 4/99 | 69/99 | 63/99 | No | - | - | 76/99 discharged, 21/99 still hospitalized as of May 15, 2020, 2/99 died | - |
Feldstein 2020 | 90/186 | 8/186 | 144/186 2 g/kg, 39/186 s dose 2 g/kg | 91/186 | 14/186 tocilizumab or siltuximab, 24/186 anakinra | - | 87/186 (heparin, enoxaparin, bivalirudin, warfarin, argatroban) | 130/186 discharged, 4/186 died as of May 20, 2020 | - |