Reported cases of multisystem inflammatory syndrome in children aged 12–20 years in the USA who received a COVID-19 vaccine, December, 2020, through August, 2021: a surveillance investigation

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Abstract

Background Multisystem inflammatory syndrome in children (MIS-C) is a hyperinflammatory condition associated with antecedent SARS-CoV-2 infection. In the USA, reporting of MIS-C after vaccination is required under COVID-19 vaccine emergency use authorisations. We aimed to investigate reports of individuals aged 12–20 years with MIS-C after COVID-19 vaccination reported to passive surveillance systems or through clinician outreach to the US Centers for Disease Control and Prevention (CDC). Methods In this surveillance activity, we investigated potential cases of MIS-C after COVID-19 vaccination reported to CDC's MIS-C national surveillance system, the Vaccine Adverse Event Reporting System (co-administered by CDC and the US Food and Drug Administration), and CDC's Clinical Immunization Safety Assessment Project. A multidisciplinary team adjudicated cases by use of the CDC MIS-C definition. Any positive SARS-CoV-2 serology test satisfied case criteria; although anti-nucleocapsid antibodies indicate previous SARS-CoV-2 infection, anti-spike protein antibodies indicate either past or recent infection or COVID-19 vaccination. We describe the demographic and clinical features of cases, stratified by laboratory evidence of SARS-CoV-2 infection. To calculate the reporting rate of MIS-C, we divided the count of all individuals meeting the MIS-C case definition, and of those without evidence of SARS-CoV-2 infection, by the number of individuals aged 12–20 years in the USA who received one or more COVID-19 vaccine doses up to Aug 31, 2021, obtained from CDC national vaccine surveillance data. Findings Using surveillance results from Dec 14, 2020, to Aug 31, 2021, we identified 21 individuals with MIS-C after COVID-19 vaccination. Of these 21 individuals, median age was 16 years (range 12–20); 13 (62%) were male and eight (38%) were female. All 21 were hospitalised: 12 (57%) were admitted to an intensive care unit and all were discharged home. 15 (71%) of 21 individuals had laboratory evidence of past or recent SARS-CoV-2 infection, and six (29%) did not. As of Aug 31, 2021, 21 335 331 individuals aged 12–20 years had received one or more doses of a COVID-19 vaccine, making the overall reporting rate for MIS-C after vaccination 1·0 case per million individuals receiving one or more doses in this age group. The reporting rate in only those without evidence of SARS-CoV-2 infection was 0·3 cases per million vaccinated individuals. Interpretation Here, we describe a small number of individuals with MIS-C who had received one or more doses of a COVID-19 vaccine before illness onset; the contribution of vaccination to these illnesses is unknown. Our findings suggest that MIS-C after COVID-19 vaccination is rare. Continued reporting of potential cases and surveillance for MIS-C illnesses after COVID-19 vaccination is warranted. Funding US Centers for Disease Control and Prevention.

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Multisystem Inflammatory Syndrome in U.S. Children and Adolescents

Leora Feldstein, Erica Rose, Steven M. Horwitz … (2020)

Abstract Background Understanding the epidemiology and clinical course of multisystem inflammatory syndrome in children (MIS-C) and its temporal association with coronavirus disease 2019 (Covid-19) is important, given the clinical and public health implications of the syndrome. Methods We conducted targeted surveillance for MIS-C from March 15 to May 20, 2020, in pediatric health centers across the United States. The case definition included six criteria: serious illness leading to hospitalization, an age of less than 21 years, fever that lasted for at least 24 hours, laboratory evidence of inflammation, multisystem organ involvement, and evidence of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) based on reverse-transcriptase polymerase chain reaction (RT-PCR), antibody testing, or exposure to persons with Covid-19 in the past month. Clinicians abstracted the data onto standardized forms. Results We report on 186 patients with MIS-C in 26 states. The median age was 8.3 years, 115 patients (62%) were male, 135 (73%) had previously been healthy, 131 (70%) were positive for SARS-CoV-2 by RT-PCR or antibody testing, and 164 (88%) were hospitalized after April 16, 2020. Organ-system involvement included the gastrointestinal system in 171 patients (92%), cardiovascular in 149 (80%), hematologic in 142 (76%), mucocutaneous in 137 (74%), and respiratory in 131 (70%). The median duration of hospitalization was 7 days (interquartile range, 4 to 10); 148 patients (80%) received intensive care, 37 (20%) received mechanical ventilation, 90 (48%) received vasoactive support, and 4 (2%) died. Coronary-artery aneurysms (z scores ≥2.5) were documented in 15 patients (8%), and Kawasaki’s disease–like features were documented in 74 (40%). Most patients (171 [92%]) had elevations in at least four biomarkers indicating inflammation. The use of immunomodulating therapies was common: intravenous immune globulin was used in 144 (77%), glucocorticoids in 91 (49%), and interleukin-6 or 1RA inhibitors in 38 (20%). Conclusions Multisystem inflammatory syndrome in children associated with SARS-CoV-2 led to serious and life-threatening illness in previously healthy children and adolescents. (Funded by the Centers for Disease Control and Prevention.)

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Hyperinflammatory shock in children during COVID-19 pandemic

Shelley Riphagen, Xabier Gómez, Carmen González-Martínez … (2020)

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).

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Rapid Decay of Anti–SARS-CoV-2 Antibodies in Persons with Mild Covid-19

F. Ibarrondo, Jennifer A. Fulcher, David Goodman-Meza … (2020)

To the Editor: A recent article suggested the rapid decay of anti–SARS-CoV-2 IgG in early infection, 1 but the rate was not described in detail. We evaluated persons who had recovered from Covid-19 and referred themselves to our institution for observational research. Written informed consent was obtained from all the participants, with approval by the institutional review board. Blood samples were analyzed by enzyme-linked immunosorbent assay (ELISA) to detect anti–SARS-CoV-2 spike receptor-binding domain IgG. 2 The ELISA was further modified to precisely quantify serum anti–receptor-binding domain activity in terms of equivalence to the concentration of a control anti–receptor-binding domain monoclonal IgG (CR3022, Creative Biolabs). Infection had been confirmed by polymerase-chain-reaction assay in 30 of the 34 participants. The other 4 participants had had symptoms compatible with Covid-19 and had cohabitated with persons who were known to have Covid-19 but were not tested because of mild illness and the limited availability of testing. Most of the participants had mild illness; 2 received low-flow supplemental oxygen and leronlimab (a CCR5 antagonist), but they did not receive remdesivir. There were 20 women and 14 men. The mean age was 43 years (range, 21 to 68) (see the Supplementary Appendix, available with the full text of this letter at NEJM.org). A total of 31 of the 34 participants had two serial measurements of IgG levels, and the remaining 3 participants had three serial measurements. The first measurement was obtained at a mean of 37 days after the onset of symptoms (range, 18 to 65), and the last measurement was obtained at a mean of 86 days after the onset of symptoms (range, 44 to 119). The initial mean IgG level was 3.48 log10 ng per milliliter (range, 2.52 to 4.41). On the basis of a linear regression model that included the participants’ age and sex, the days from symptom onset to the first measurement, and the first log10 antibody level, the estimated mean change (slope) was −0.0083 log10 ng per milliliter per day (range, −0.0352 to 0.0062), which corresponds to a half-life of approximately 36 days over the observation period (Figure 1A). The 95% confidence interval for the slope was −0.0115 to −0.0050 log10 ng per milliliter per day (half-life, 26 to 60 days) (Figure 1B). The protective role of antibodies against SARS-CoV-2 is unknown, but these antibodies are usually a reasonable correlate of antiviral immunity, and anti–receptor-binding domain antibody levels correspond to plasma viral neutralizing activity. Given that early antibody decay after acute viral antigenic exposure is approximately exponential, 3 we found antibody loss that was quicker than that reported for SARS-CoV-1, 4,5 and our findings were more consistent with those of Long et al. 1 Our findings raise concern that humoral immunity against SARS-CoV-2 may not be long lasting in persons with mild illness, who compose the majority of persons with Covid-19. It is difficult to extrapolate beyond our observation period of approximately 90 days because it is likely that the decay will decelerate. 3 Still, the results call for caution regarding antibody-based “immunity passports,” herd immunity, and perhaps vaccine durability, especially in light of short-lived immunity against common human coronaviruses. Further studies will be needed to define a quantitative protection threshold and rate of decline of antiviral antibodies beyond 90 days.