Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children
Abstract
:1. Introduction
2. Materials and Methods
- Mild MIS-C patients are those who did not require significant fluid resuscitation, vasopressor medications, or positive pressure ventilation. Patients in this category received IVIG 2 g/kg once and were monitored for 36–48 h to determine if a low dose glucocorticoid course (prednisone or methylprednisolone 1–2 mg/kg/day tapered over 2–3 weeks) was needed for continued signs of inflammation.
- Moderate MIS-C patients are those who required significant fluid resuscitation (up to 60 mL/kg) to maintain normotension and/or required a short course of low-dose vasopressor medications without requiring ventilation or suffering from organ failure. These patients received IVIG 2 g/kg and glucocorticoids at 1–2 mg/kg/day started on presentation, with glucocorticoids tapered over 2–3 weeks.
- Severe MIS-C patients are those who required significant fluid resuscitation and high-dose/multiple vasopressor medications to maintain normotension, required positive pressure ventilation due to respiratory failure, had neurologic involvement with encephalopathy or seizures, and/or had organ failure on presentation. Severe patients were given IVIG 2 g/kg on admission and treated with high dose methylprednisolone (10–30 mg/kg/day, max 1000 mg daily) for 3–5 days with de-escalation thereafter to 1–2 mg/kg/day tapered over 2–3 weeks.
3. Results
3.1. Demographics and Hospitalization Characteristics
3.2. Treatment
3.3. Laboratory Abnormalities and Improvement Trend
3.4. Cardiac Outcomes
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
- Reiff, D.D.; Cron, R.Q. Who Would Have Predicted Multisystem Inflammatory Syndrome in Children? Curr. Rheumatol. Rep. 2022, 24, 1–11. [Google Scholar] [CrossRef] [PubMed]
- Centers for Disease Control and Prevention: Multisystem Inflammatory Syndrome. Available online: https://www.cdc.gov/mis/index.html (accessed on 11 November 2022).
- Cattalini, M.; Della Paolera, S.; Zunica, F.; Bracaglia, C.; Giangreco, M.; Verdoni, L.; Meini, A.; Sottile, R.; Caorsi, R.; Zuccotti, G.; et al. Defining Kawasaki disease and pediatric inflammatory multisystem syndrome-temporally associated to SARS-CoV-2 infection during SARS-CoV-2 epidemic in Italy: Results from a national, multicenter survey. Pediatr. Rheumatol. 2021, 19, 29. [Google Scholar] [CrossRef] [PubMed]
- Feldstein, L.R.; Tenforde, M.W.; Friedman, K.G.; Newhams, M.; Rose, E.B.; Dapul, H.; Soma, V.L.; Maddux, A.B.; Mourani, P.M.; Bowens, C.; et al. Characteristics and Outcomes of US Children and Adolescents with Multisystem Inflammatory Syndrome in Children (MIS-C) Compared with Severe Acute COVID-19. JAMA 2021, 325, 1074–1087. [Google Scholar] [CrossRef] [PubMed]
- Henderson, L.A.; Canna, S.W.; Friedman, K.G.; Gorelik, M.; Lapidus, S.K.; Bassiri, H.; Behrens, E.M.; Kernan, K.F.; Schulert, G.S.; Seo, P.; 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 3. Arthritis Rheumatol. 2022, 74, e1–e20. [Google Scholar] [CrossRef] [PubMed]
- Ouldali, N.; Toubiana, J.; Antona, D.; Javouhey, E.; Madhi, F.; Lorrot, M.; Léger, P.-L.; Galeotti, C.; Claude, C.; Wiedemann, A.; et al. Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone with Course of Fever in Multisystem Inflammatory Syndrome in Children. JAMA 2021, 325, 855–864. [Google Scholar] [CrossRef] [PubMed]
- Feldstein, L.R.; Rose, E.B.; Horwitz, S.M.; Collins, J.P.; Newhams, M.M.; Son, M.B.F.; Newburger, J.W.; Kleinman, L.C.; Heidemann, S.M.; Martin, A.A.; et al. Multisystem Inflammatory Syndrome in U.S. Children and Adolescents. N. Engl. J. Med. 2020, 383, 334–346. [Google Scholar] [CrossRef] [PubMed]
- Valverde, I.; Singh, Y.; Sanchez-De-Toledo, J.; Theocharis, P.; Chikermane, A.; Di Filippo, S.; Kuciñska, B.; Mannarino, S.; Tamariz-Martel, A.; Gutierrez-Larraya, F.; et al. Acute Cardiovascular Manifestations in 286 Children with Multisystem Inflammatory Syndrome Associated With COVID-19 Infection in Europe. Circulation 2021, 143, 21–32. [Google Scholar] [CrossRef] [PubMed]
- Chang, J.C.; Matsubara, D.; Morgan, R.W.; Diorio, C.; Nadaraj, S.; Teachey, D.T.; Bassiri, H.; Behrens, E.M.; Banerjee, A. Skewed Cytokine Responses Rather Than the Magnitude of the Cytokine Storm May Drive Cardiac Dysfunction in Multisystem Inflammatory Syndrome in Children. J. Am. Heart Assoc. 2021, 10, e021428. [Google Scholar] [CrossRef] [PubMed]
- Rodriguez-Smith, J.J.; Verweyen, E.L.; Clay, G.M.; Esteban, Y.M.; de Loizaga, S.R.; Baker, E.J.; Do, T.; Dhakal, S.; Lang, S.M.; A Grom, A.; et al. Inflammatory biomarkers in COVID-19-associated multisystem inflammatory syndrome in children, Kawasaki disease, and macrophage activation syndrome: A cohort study. Lancet Rheumatol. 2021, 3, e574–e584. [Google Scholar] [CrossRef] [PubMed]
- Farooqi, K.M.; Chan, A.; Weller, R.J.; Mi, J.; Jiang, P.; Abrahams, E.; Ferris, A.; Krishnan, U.S.; Pasumarti, N.; Suh, S.; et al. Longitudinal Outcomes for Multisystem Inflammatory Syndrome in Children. Pediatrics 2021, 148, e2021051155. [Google Scholar] [CrossRef] [PubMed]
- Penner, J.; Abdel-Mannan, O.; Grant, K.; Maillard, S.; Kucera, F.; Hassell, J.; Eyre, M.; Berger, Z.; Hacohen, Y.; Moshal, K.; et al. 6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: A retrospective cohort study. Lancet Child Adolesc. Health 2021, 5, 473–482. [Google Scholar] [CrossRef] [PubMed]
- Riphagen, S.; Gomez, X.; Gonzalez-Martinez, C.; Wilkinson, N.; Theocharis, P. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet 2020, 395, 1607–1608. [Google Scholar] [CrossRef] [PubMed]
- Haghighi Aski, B.; Manafi Anari, A.; Abolhasan Choobdar, F.; Zareh Mahmoudabadi, R.; Sakhaei, M. Cardiac abnormalities due to multisystem inflammatory syndrome temporally associated with Covid-19 among children: A systematic review and meta-analysis. Int. J. Cardiol. Heart Vasc. 2021, 33, 100764. [Google Scholar] [CrossRef] [PubMed]
- Capone, C.A.; Subramony, A.; Sweberg, T.; Schneider, J.; Shah, S.; Rubin, L.; Schleien, C.; Epstein, S.; Johnson, J.C.; Kessel, A.; et al. Characteristics, cardiac involvement, and outcomes of multisystem infammatory syndrome of childhood associated with severe acute respiratory syndrome coronavirus 2 Infection. J. Pediatr. 2020, 224, 141–145. [Google Scholar] [CrossRef] [PubMed]
- Bartoszek, M.; Małek, Ł.A.; Barczuk-Falęcka, M.; Brzewski, M. Cardiac Magnetic Resonance Follow-Up of Children After Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 with Initial Cardiac Involvement. J. Magn. Reason. Imaging 2022, 55, 883–891. [Google Scholar] [CrossRef] [PubMed]
All n = 137 | Mild n = 52 | Moderate n = 44 | Severe n = 41 | |
---|---|---|---|---|
Demographics | ||||
Age, years—median (IQR) | 9 (5–12) | 8 (4–11.3) | 9.5 (6–13) | 11 (7–12) |
Male sex—no. (%) | 88 (64%) | 33 (63%) | 28 (64%) | 27 (66%) |
Race/Ethnicity—no. (%) | ||||
White, non-Hispanic | 48 (35%) | 25 (48%) | 13 (30%) | 10 (24%) |
Black, non-Hispanic | 75 (55%) | 21 (40%) | 27 (61%) | 27 (66%) |
Hispanic | 12 (9%) | 6 (12%) | 3 (7%) | 3 (7%) |
Other | 2 (1%) | 0 (0%) | 1 (2%) | 1 (2%) |
BMI percentile–median (IQR) | 84 (41–97) | 79.5 (27.3–96.3) | 87.5 (56–97.3) | 89 (66–98) |
Co-morbidities—no. (%) | ||||
None | 101 (74%) | 36 (69%) | 31 (70%) | 34 (83%) |
Any | 36 (26%) | 16 (31%) | 13 (30%) | 7 (17%) |
Asthma | 25 | 12 | 9 | 4 |
Autism | 3 | - | 3 | - |
Congenital Heart Disease | 2 | 1 | 1 | - |
Hypertension | 2 | 1 | - | 1 |
Leukemia/Lymphoma in remission | 1 | 1 | - | - |
Precocious Puberty | 1 | 1 | - | - |
Ex-29 wga w/chronic lung dx | 1 | - | - | 1 |
Type 1 Diabetes | 1 | - | - | 1 |
Symptoms on Presentation—no. (%) | ||||
Fever | 134 (98%) | 52 (100%) | 44 (100%) | 38 (93%) |
Respiratory Symptoms | 27 (20%) | 15 (29%) | 6 (14%) | 6 (15%) |
Cough | 23 (17%) | 14 (27%) | 5 (11%) | 4 (10%) |
Shortness of Breath | 10 (7%) | 3 (6%) | 3 (7%) | 4 (10%) |
Gastrointestinal Symptoms | 124 (91%) | 43 (83%) | 41 (93%) | 40 (98%) |
Nausea/Vomiting | 92 (67%) | 32 (62%) | 28 (64%) | 32 (78%) |
Diarrhea | 62 (45%) | 17 (33%) | 22 (50%) | 23 (56%) |
Abdominal Pain | 84 (61%) | 25 (48%) | 33 (75%) | 26 (63%) |
Rash | 73 (53%) | 32 (62%) | 23 (52%) | 18 (44%) |
Conjunctivitis | 86 (63%) | 35 (67%) | 26 (59%) | 25 (61%) |
Mucosal Changes | 54 (39%) | 19 (37%) | 17 (39%) | 18 (44%) |
Neck pain/Cervical Lymphadenopathy | 46 (34%) | 15 (29%) | 17 (39%) | 14 (34%) |
Headache | 40 (29%) | 16 (31%) | 12 (27%) | 12 (29%) |
AMS or Encephalopathy | 10 (7%) | 3 (6%) | 1 (2%) | 6 (15%) |
Level of Admission—no. (%) | ||||
Intensive Care | 55 (40%) | 0 (0%) | 20 (45%) | 35 (85%) |
ICU step-down unit | 26 (19%) | 13 (25%) | 10 (23%) | 3 (7%) |
Acute Care | 56 (41%) | 39 (75%) | 14 (32%) | 3 (7%) |
Length of stay, days—median (IQR) | 5 (4–6) | 4 (4–6) | 5 (4.8–6) | 6 (5–8) |
SARS-CoV-2 Positivity | ||||
PCR—no./total no. (%) | 42/135 (31%) | 14/50 (28%) | 16 (36%) | 12 (29%) |
IgG Antibodies—no./total no. (%) | 130/135 (96%) | 49 (94%) | 42 (95%) | 39/39 (100%) |
Vasopressor Requirement—no. (%) | ||||
Yes | 51 (37%) | 0 (0%) | 13 (30%) | 38 (93%) |
No | 86 (63%) | 52 (100%) | 31 (70%) | 3 (7%) |
Respiratory Support—no. (%) | ||||
None | 77 (56%) | 47 (90%) | 21 (48%) | 9 (22%) |
Oxygen—Nasal Cannula | 40 (29%) | 4 (8%) | 20 (45%) | 16 (39%) |
Oxygen—High-Flow Nasal Cannula | 10 (7%) | 1 (2%) | 3 (7%) | 6 (15%) |
Positive pressure ventilation | 10 (7%) | 0 (0%) | 0 (0%) | 10 (24%) |
Survival—no. (%) | 137 (100%) | 52 (100%) | 44 (100%) | 41 (100%) |
All n = 137 | Mild n = 52 | Moderate n = 44 | Severe n = 41 | |
---|---|---|---|---|
Initial Therapy | ||||
Glucocorticoids—no. (%) | 117 (85%) | 34 (65%) | 43 (98%) | 40 (98%) |
Initial dose, mg/kg/day-median (IQR) | 2 (2–12.5) | 2 (1.7–2) | 2 (2–13.75) | 2 (2–20) |
Maximum dose, mg/kg/day—median (IQR) | 2 (2–15) | 2 (2–2) | 2 (2–15.5) | 10 (2–20) |
Intravenous Immunoglobulin—no. (%) | 133 (97%) | 50 (96%) | 44 (100%) | 39 (95%) |
Second-line Therapy | ||||
Anakinra—no. (%) | 7 (5%) | 1 (2%) | 0 (0%) | 6 (15%) |
Infliximab-—no. (%) | 6 (4%) | 4 (8%) | 2 (5%) | 0 (0%) |
Anticoagulation/Antiplatelet Therapy | ||||
Enoxaparin—no. (%) | 45 (33%) | 1 (2%) | 18 (41%) | 26 (63%) |
Aspirin—no. (%) | 134 (98%) | 52 (100%) | 44 (100%) | 38 (93%) |
Max/Min Value | 1-2-Week f/u | p-Value | |||
---|---|---|---|---|---|
n | Median | n | Median | ||
Sodium (mmol/L) | 136 | 132 | 98 | 137 | <0.00001 |
Creatinine (mg/dL) | 136 | 0.685 | 98 | 0.465 | <0.00001 |
Albumin (g/dL) | 136 | 2.5 | 98 | 3.9 | <0.00001 |
AST (U/L) | 133 | 47 | 97 | 27 | <0.00001 |
ALT (U/L) | 133 | 41.3 | 97 | 30.8 | 0.00857 |
White Blood Cell count (103/uL) | 134 | 18.04 | 98 | 7.35 | <0.00001 |
Absolute Lymphocyte count (103/uL) | 133 | 0.86 | 98 | 2.47 | <0.00001 |
Hemoglobin (g/dL) | 134 | 8.95 | 98 | 11.7 | <0.00001 |
Platelet count (103/uL) | 134 | 174 (Min) | 98 | 400 | <0.00001 |
Brain Natriuetic Peptide (pg/mL) | 118 | 798.1 | 81 | 10 | <0.00001 |
Troponin (ng/mL) | 97 | 0.13 | 60 | 0.01 | <0.00001 |
Fibrinogen (mg/dL) | 95 | 591 (Max) | 61 | 292 | <0.00001 |
D-Dimer DDU (ng/mL) | 93 | 1915 | 75 | 245 | <0.00001 |
CRP (mg/dL) | 135 | 20.25 | 97 | 0.1 | <0.00001 |
ESR (mm/hr) | 121 | 51 (Initial) | 59 | 30 | 0.00003 |
Ferritin (ng/mL) | 133 | 693 | 93 | 143.7 | <0.00001 |
Admission | Discharge | 1–2 Month Follow-Up | |||||||
---|---|---|---|---|---|---|---|---|---|
n | Percent Abnormal | Median (IQR) | n | Percent Abnormal | Median (IQR) | n | Percent Abnormal | Median (IQR) | |
Decreased Ejection Fraction-(normal > 55%) | |||||||||
ALL | 137 | 26% n = 36 | 60% (53.3–68%) n = 137 | 80 | 13% n = 10 | 63.5% (58.8–68%) n = 80 | 103 | 0% n = 0 | 67% (63.5–71%) n = 103 |
Mild | 52 | 6% n = 3 | 65% (60–69%) n = 52 | 20 | 0% n = 0 | 66% (63.5–69%) n = 20 | 41 | 0% n = 0 | 68% (63–72%) n = 41 |
Moderate | 44 | 25% n = 11 | 59% (54.5–65%) n = 44 | 30 | 10% n = 3 | 60.5% (57.8–67.3%) n = 30 | 35 | 0% n = 0 | 67% (65–70.3%) n = 35 |
Severe | 41 | 54% n = 22 | 52% (45–66%) n = 41 | 30 | 23% n = 7 | 63% (56–67%) n = 30 | 27 | 0% n = 0 | 66.5% (62.5–69%) n = 27 |
p-value—3-group comparison | 1.24 × 10-6 | 0.044 | N/A | ||||||
Coronary Artery dilation/aneurysm-max z-score | |||||||||
ALL | 137 | 6% n = 8 | 2.38 (2.16–2.91) n = 8 | 80 | 10% n = 8 | 2.18 (2.10–2.50) n = 8 | 103 | 0% n = 0 | - |
Mild | 52 | 8% n = 4 | 2.81 (2.34–3.28) n = 4 | 20 | 2% n = 1 | 2.36 n = 1 | 41 | 0% n = 0 | - |
Moderate | 44 | 7% n = 3 | 2.35 (2.23–2.58) n = 3 | 30 | 3% n = 1 | 2.12 n = 1 | 35 | 0% n = 0 | - |
Severe | 41 | 2% n = 1 | 2.15 n = 1 | 30 | 20% n = 6 | 2.17 (2.09–2.74) n = 6 | 27 | 0% n = 0 | - |
p-value—3-group comparison | 0.532 | 0.068 | N/A |
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Reiff, D.D.; Cron, R.Q. Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children. Viruses 2023, 15, 94. https://doi.org/10.3390/v15010094
Reiff DD, Cron RQ. Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children. Viruses. 2023; 15(1):94. https://doi.org/10.3390/v15010094
Chicago/Turabian StyleReiff, Daniel D., and Randy Q. Cron. 2023. "Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children" Viruses 15, no. 1: 94. https://doi.org/10.3390/v15010094
APA StyleReiff, D. D., & Cron, R. Q. (2023). Timely Resolution of SARS-CoV-2-Related Multi-System Inflammatory Syndrome in Children. Viruses, 15(1), 94. https://doi.org/10.3390/v15010094