Epidemiology, Clinical Features, and Outcomes of Multisystem Inflammatory Syndrome in Children (MIS-C) and Adolescents—a Live Systematic Review and Meta-analysis
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Abstract
Purpose of Review
A multisystem inflammatory condition occurring in children and adolescents with COVID-19
has become increasingly recognized and widely studied globally. This review aims to
investigate and synthesize evolving evidence on its clinical characteristics, management,
and outcomes in pediatric patients.
Recent Findings
We retrieved data from PubMed, EMBASE, Cochrane Library, WHO COVID-19 Database, Google
Scholar, and preprint databases, covering a timeline from December 1, 2019, to July
31, 2021. A total of 123 eligible studies were included in the final descriptive and
risk factor analyses. We comprehensively reviewed reported multisystem inflammatory
syndrome in children (MIS-C) cases from published and preprint studies of various
designs to provide an updated evidence on epidemiology, clinical, laboratory and imaging
findings, management, and short-term outcomes. Latest evidence suggests that African
black and non-Hispanic white are the two most common ethnic groups, constituting 24.89%
(95% CI 23.30–26.48%) and 25.18% (95% CI 23.51–26.85%) of the MIS-C population, respectively.
Typical symptoms of MIS-C include fever (90.85%, 95% CI 89.86–91.84%), not-specified
gastrointestinal symptoms (51.98%, 95% CI 50.13–53.83%), rash (49.63%, 95% CI 47.80–51.47%),
abdominal pain (48.97%, 95% CI 47.09–50.85%), conjunctivitis (46.93%, 95% CI 45.17–48.69%),
vomiting (43.79%, 95% CI 41.90–45.68%), respiratory symptoms (41.75%, 95% CI 40.01–43.49%),
and diarrhea (40.10%, 95% CI 38.23–41.97%). MIS-C patients are less likely to develop
conjunctivitis (OR 0.27, 95% CI 0.11–0.67), cervical adenopathy (OR 0.21, 95% CI 0.07–0.68),
and rash (OR 0.44, 95% CI 0.26–0.77), in comparison with Kawasaki disease patients.
Our review revealed that the majority of MIS-C cases (95.21%) to be full recovered
while only 2.41% died from this syndrome. We found significant disparity between low-
and middle-income countries and high-income countries in terms of clinical outcomes.
Summary
MIS-C, which appears to be linked to COVID-19, may cause severe inflammation in organs
and tissues. Although there is emerging new evidence about the characteristics of
this syndrome, its risk factors, and clinical prognosis, much remains unknown about
the causality, the optimal prevention and treatment interventions, and long-term outcomes
of the MIS-C patients.
Supplementary Information
The online version contains supplementary material available at 10.1007/s40124-022-00264-1.
South Thames Retrieval Service in London, UK, provides paediatric intensive care support and retrieval to 2 million children in South East England. During a period of 10 days in mid-April, 2020, we noted an unprecedented cluster of eight children with hyperinflammatory shock, showing features similar to atypical Kawasaki disease, Kawasaki disease shock syndrome, 1 or toxic shock syndrome (typical number is one or two children per week). This case cluster formed the basis of a national alert. All children were previously fit and well. Six of the children were of Afro-Caribbean descent, and five of the children were boys. All children except one were well above the 75th centile for weight. Four children had known family exposure to coronavirus disease 2019 (COVID-19). Demographics, clinical findings, imaging findings, treatment, and outcome for this cluster of eight children are shown in the table . Table Demographics, clinical findings, imaging findings, treatment, and outcome from PICU Age; weight; BMI; comorbidities Clinical presentation Organ support Pharmacological treatment Imaging results Laboratory results Microbiology results PICU length of stay; outcome Initial PICU referral Patient 1 (male, AfroCaribbean) 14 years; 95 kg; BMI 33 kg/m2; no comorbidities 4 days >40°C; 3 days non-bloody diarrhoea; abdominal pain; headache BP 80/40 mmHg; HR 120 beats/min; RR 40 breaths per min; work of breathing; SatO2 99% NCO2 MV, RRT, VA-ECMO Dopamine, noradrenaline, argipressin, adrenaline milrinone, hydroxicortisone, IVIG, ceftriaxone, clindamycin RV dysfunction/elevate RVSP; ileitis, GB oedema and dilated biliary tree, ascites, bilateral basal lung consolidations and diffuse nodules Ferritin 4220 μg/L; D-dimers 13·4 mg/L; troponin 675 ng/L; proBNP >35 000; CRP 556 mg/L; procalcitonin>100 μg/L; albumin 20 g/L; platelets 123 × 109 SARS-CoV-2 positive (post mortem) 6 days; demise (right MCA and ACA ischaemic infarction) Patient 2 (male, AfroCaribbean) 8 years; 30 kg; BMI 18 kg/m2; no comorbidities 5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis; rash BP 81/37 mmHg; HR 165 beats/min; RR 40 breaths/min; SVIA MV Noradrenaline, adrenaline, IVIG, infliximab, methylprednisolone, ceftriaxone, clindamycin Mild biventricular dysfunction, severely dilated coronaries; ascites, pleural effusions Ferritin 277 μg/L; D-dimers 4·8 mg/L; troponin 25 ng/L; CRP 295 mg/L; procalcitonin 8·4 μg/L; albumin 18 g/L; platelets 61 × 109 SARS-CoV-2 negative; likely COVID-19 exposure from mother 4 days; alive Patient 3 (male, Middle-Eastern) 4 years; 18 kg; BMI 17 kg/m2; no comorbidities 4 days >39°C; diarrhoea and vomiting; abdominal pain; rash; conjunctivitis BP 90/30 mmHg; HR 170 beats/min; RR 35 breaths/min; SVIA MV Noradrenaline, adrenaline, IVIG ceftriaxone, clindamycin Ascites, pleural effusions Ferritin 574 μg/L; D-dimers 11·7 mg/L; tropinin 45 ng/L; CRP 322 mg/L; procalcitonin 10·3 μg/L; albumin 22 g/L; platelets 103 × 109 Adenovirus positive; HERV positive 4 days; alive Patient 4 (female, AfroCaribbean) 13 years; 64 kg; BMI 33 kg/m2; no comorbidities 5 days >39°C; non-bloody diarrhoea; abdominal pain; conjunctivitis BP 77/41 mmHg; HR 127 beats/min; RR 24 breaths/min; SVIA HFNC Noradrenaline, milrinone, IVIG, ceftriaxone, clindamycin Moderate-severe LV dysfunction; ascites Ferritin 631 μg/L; D-dimers 3·4 mg/L; troponin 250 ng/L; proBNP 13427 ng/L; CRP 307 mg/L; procalcitonin 12·1 μg/L; albumin 21 g/L; platelets 146 × 109 SARS-CoV-2 negative 5 days; alive Patient 5 (male, Asian) 6 years; 22 kg; BMI 14 kg/m2; autism, ADHD 4 days >39°C; odynophagia; rash; conjunctivitis BP 85/43 mmHg; HR 150 beats/min; RR 50 breaths/min; SVIA NIV Milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone Dilated LV, AVVR, pericoronary hyperechogenicity Ferritin 550 μg/L; D-dimers 11·1 mg/L; troponin 47 ng/L; NT-proBNP 7004 ng/L; CRP 183 mg/L; albumin 24 g/L; platelets 165 × 109 SARS-CoV-2 positive; likely COVID-19 exposure from father 4 days; alive Patient 6 (female, AfroCaribbean) 6 years; 26 kg; BMI 15 kg/m2; no comorbidities 5 days >39°C; myalgia; 3 days diarrhoea and vomiting; conjunctivitis BP 77/46 mmHg; HR 120 beats/min; RR 40 breaths/min; SVIA NIV Dopamine, noradrenaline, milrinone, IVIG, methylprednisolone, aspirin, ceftriaxone, clindamycin Mild LV systolic impairment Ferritin 1023 μg/L; D-dimers 9·9 mg/L; troponin 45 ng/L; NT-proBNP 9376 ng/L; CRP mg/L 169; procalcitonin 11·6 μg/L; albumin 25 g/L; platelets 158 SARS-CoV-2 negative; confirmed COVID-19 exposure from grandfather 3 days; alive Patient 7 (male, AfroCaribbean 12 years; 50kg; BMI 20 kg/m2; alopecia areata, hayfever 4 days >39°C; 2 days diarrhoea and vomiting; abdominal pain; rash; odynophagia; headache BP 80/48 mmHg; HR 125 beats/min; RR 47 breaths/min; SatO2 98%; HFNC FiO2 0.35 MV Noradrenaline, adrenaline, milrinone, IVIG, methylprednisolone, heparin, ceftriaxone, clindamycin, metronidazole Severe biventricular impairment; ileitis, ascites, pleural effusions Ferritin 958 μg/L; D-dimer 24·5 mg/L; troponin 813 ng/L; NT-proBNP >35 000 ng/L; CRP 251 mg/L; procalcitonin 71·5 μg/L; albumin 24 g/L; platelets 273 × 109 SARS-CoV-2 negative 4 days; alive Patient 8 (female, AfroCaribbean) 8 years; 50 kg; BMI 25 kg/m2; no comorbidities 4 days >39°C; odynophagia; 2 days diarrhoea and vomiting; abdominal pain BP 82/41 mmHg; HR 130 beats/min; RR 35 breaths/min; SatO2 97% NCO2 MV Dopamine, noradrenaline, milrinone, IVIG, aspirin, ceftriaxone, clindamycin Moderate LV dysfunction Ferritin 460 μg/L; D-dimers 4·3 mg/L; troponin 120 ng/L; CRP 347 mg/L; procalcitonin 7·42 μg/L; albumin 22 g/L; platelets 296 × 109 SARS-CoV-2 negative; likely COVID-19 exposure from parent 7 days; alive ACA= anterior cerebral artery. ADHD=attention deficit hyperactivity disorder. AVR=atrioventricular valve regurgitation. BMI=body mass index. BP=blood pressure. COVID-19=coronavirus disease 2019. CRP=C-reactive protein. FiO2=fraction of inspired oxygen. HERV=human endogenous retrovirus. HFNC=high-flow nasal canula. HR=heart rate. IVIG=human intravenous immunoglobulin. LV=left ventricle. MCA=middle cerebral artery. MV=mechanical ventilation via endotracheal tube. NIV=non-invasive ventilation. PICU=paediatric intensive care unit. RA=room air. RR=respiratory rate. RRT=renal replacement therapy. RV=right ventricle. RVSP=right ventricular systolic pressure. SARS-CoV-2=severe acute respiratory syndrome coronavirus 2. SatO2=oxygen saturation. SVIA=self-ventilating in air. VA-ECMO=veno-arterial extracorporeal membrane oxygenation. Clinical presentations were similar, with unrelenting fever (38–40°C), variable rash, conjunctivitis, peripheral oedema, and generalised extremity pain with significant gastrointestinal symptoms. All progressed to warm, vasoplegic shock, refractory to volume resuscitation and eventually requiring noradrenaline and milrinone for haemodynamic support. Most of the children had no significant respiratory involvement, although seven of the children required mechanical ventilation for cardiovascular stabilisation. Other notable features (besides persistent fever and rash) included development of small pleural, pericardial, and ascitic effusions, suggestive of a diffuse inflammatory process. All children tested negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on broncho-alveolar lavage or nasopharyngeal aspirates. Despite being critically unwell, with laboratory evidence of infection or inflammation 3 including elevated concentrations of C-reactive protein, procalcitonin, ferritin, triglycerides, and D-dimers, no pathological organism was identified in seven of the children. Adenovirus and enterovirus were isolated in one child. Baseline electrocardiograms were non-specific; however, a common echocardiographic finding was echo-bright coronary vessels (appendix), which progressed to giant coronary aneurysm in one patient within a week of discharge from paediatric intensive care (appendix). One child developed arrhythmia with refractory shock, requiring extracorporeal life support, and died from a large cerebrovascular infarct. The myocardial involvement 2 in this syndrome is evidenced by very elevated cardiac enzymes during the course of illness. All children were given intravenous immunoglobulin (2 g/kg) in the first 24 h, and antibiotic cover including ceftriaxone and clindamycin. Subsequently, six children have been given 50 mg/kg aspirin. All of the children were discharged from PICU after 4–6 days. Since discharge, two of the children have tested positive for SARS-CoV-2 (including the child who died, in whom SARS-CoV-2 was detected post mortem). All children are receiving ongoing surveillance for coronary abnormalities. We suggest that this clinical picture represents a new phenomenon affecting previously asymptomatic children with SARS-CoV-2 infection manifesting as a hyperinflammatory syndrome with multiorgan involvement similar to Kawasaki disease shock syndrome. The multifaceted nature of the disease course underlines the need for multispecialty input (intensive care, cardiology, infectious diseases, immunology, and rheumatology). The intention of this Correspondence is to bring this subset of children to the attention of the wider paediatric community and to optimise early recognition and management. As this Correspondence goes to press, 1 week after the initial submission, the Evelina London Children's Hospital paediatric intensive care unit has managed more than 20 children with similar clinical presentation, the first ten of whom tested positive for antibody (including the original eight children in the cohort described above).
Background An epidemic of Coronavirus Disease 2019 (COVID-19) began in December 2019 and triggered a Public Health Emergency of International Concern (PHEIC). We aimed to find risk factors for the progression of COVID-19 to help reducing the risk of critical illness and death for clinical help. Methods The data of COVID-19 patients until March 20, 2020 were retrieved from four databases. We statistically analyzed the risk factors of critical/mortal and non-critical COVID-19 patients with meta-analysis. Results Thirteen studies were included in Meta-analysis, including a total number of 3027 patients with SARS-CoV-2 infection. Male, older than 65, and smoking were risk factors for disease progression in patients with COVID-19 (male: OR = 1.76, 95% CI (1.41, 2.18), P 40U/L, creatinine(Cr) ≥ 133mol/L, hypersensitive cardiac troponin I(hs-cTnI) > 28pg/mL, procalcitonin(PCT) > 0.5ng/mL, lactatede hydrogenase(LDH) > 245U/L, and D-dimer > 0.5mg/L predicted the deterioration of disease while white blood cells(WBC) 40U/L:OR=4.00, 95% CI (2.46, 6.52), P 28 pg/mL: OR = 43.24, 95% CI (9.92, 188.49), P 0.5 ng/mL: OR = 43.24, 95% CI (9.92, 188.49), P 245U/L: OR = 43.24, 95% CI (9.92, 188.49), P 0.5mg/L: OR = 43.24, 95% CI (9.92, 188.49), P < 0.00001; WBC < 4 × 109/L: OR = 0.30, 95% CI (0.17, 0.51), P < 0.00001]. Conclusion Male, aged over 65, smoking patients might face a greater risk of developing into the critical or mortal condition and the comorbidities such as hypertension, diabetes, cardiovascular disease, and respiratory diseases could also greatly affect the prognosis of the COVID-19. Clinical manifestation such as fever, shortness of breath or dyspnea and laboratory examination such as WBC, AST, Cr, PCT, LDH, hs-cTnI and D-dimer could imply the progression of COVID-19.
[1
]GRID grid.42327.30, ISNI 0000 0004 0473 9646, Centre for Global Child Health, , Hospital for Sick Children, ; Toronto, Canada
[2
]GRID grid.12527.33, ISNI 0000 0001 0662 3178, Vanke School of Public Health, , Tsinghua University, ; Beijing, China
[3
]GRID grid.11135.37, ISNI 0000 0001 2256 9319, Department of Pharmacy Administration and Clinical Pharmacy, School of Pharmaceutical,
, Peking University, ; Beijing, China
[4
]GRID grid.7147.5, ISNI 0000 0001 0633 6224, Institute for Global Health & Development, , the Aga Khan University, ; Karachi, Pakistan
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