10. COVID-associated Kawasaki Disease

We’re talking about the little adults today! In particular, we’re diving into the reported Multi-System Inflammatory Syndrome/Kawasaki Disease that has been reported in association with COVID-19 in kids.

 

COVID in Peds: what we know

Epidemiology Infection rates are generally low: children seem to account for 1-5% of confirmed cases1 Only about 1% of cases in Canada seem to be in those < 19 years2 (though testing was previously not available to those with mild illness) Seems to be distributed reasonably evenly among age groups3 Presentations Symptoms are similar to adults; cases are generally mild3,4,5 Fever and cough are most commonly reported3,4,5 Reports of causing isolated fever in young infants6 Investigations Lab data seems variable; only 3.5% had lymphopenia in one study7 CXR: similar to adults; may be normal or may demonstrate patchy consolidations4 POCUS: similar to adults à irregular pleura, patchy B-lines8 Treatment Supportive care! Antivirals generally recommended only in the context of clinical trials9 For severe/critical disease, if used, panel recommends remdesivir over others9 Severity and outcomes Most children have mild disease and do well: in one case series of over 700 pediatric cases from China, 55% were mild or asymptomatic, 40% were moderate, 5% were severe, and <1% were critical10 Small number of children have been identified who develop a significant systemic inflammatory response This has features that overlap with other paediatric inflammatory conditions including Kawasaki disease, staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis and macrophage activation syndrome

 

Kawasaki Disease11

KD: childhood vasculitis characterized by systemic inflammation and fever Classic KD Fever for > 5 days PLUS 4 of 5: conjunctival injection, peripheral extremity changes such as desquamation, edema, or erythema; mucous membrane changes such as strawberry tongue or injected pharynx; polymorphous rash; cervical lymphadenopathy Complications Primarily cardiac, including coronary artery aneurysm Can rarely be associated with macrophage activation syndrome and shock Treatment IVIG and ASA Cause? Association with respiratory viruses? A retrospective chart review of 222 patients with KD found that 42% tested positive for a viral respiratory infection; most commonly rhinovirus or enterovirus12 No differences in presenting features or clinical outcomes in this compared to those who did not test positive

  

MIS-C and COVID-associated KD?

There is very little published research on this topic One case report of a 6-month old girl presenting with classic KD, without respiratory symptoms, whose swab was positive for COVID. She was treated with IVIG and high-dose ASA (standard KD Tx)13 One series of infographics from out of NYC14 A couple guideline statements and media releases on the basis on expert anecdotal experience15,16 A couple recent case series: one from the UK, one from Bergamo17,18 This is what we seem to know from guideline statements: There has been a small rise in the number of cases of critically ill children presenting with an unusual clinical picture Many of these children had tested positive for COVID-19 previously, and are now presenting with common overlapping features of toxic shock syndrome, Kawasaki disease, and MAS Presenting symptoms Prolonged fever (>5 days, >38.5 degrees) GI symptoms: severe abdominal pain, nausea, diarrhea, vomiting Conjunctival injection Maculopapular rash Other: cyanosis or pallor, dysphagia, dyspnea, palpitations, tachycardia, chest pain, lethargy, irritability, confusion Lab abnormalities Inflammatory markers: high CRP, ESR, ferritin; hypoalbuminemia High IL-6 and IL-10 (if available) Lymphopenia Coagulopathy: high D-dimer, high fibrinogen Cardiac involvement: elevated troponin/BNP (sometimes) May be present: AKI, high CK, transaminitis, high trigs Imaging features (may be present in some cases) EKG: changes consistent with myopericarditis Echo: coronary artery dilation; pericardial effusion CXR: patchy symmetrical infiltrates; may have pleural effusion Abdo US: HSMG, ileitis, colitis, ascites Treatment recommendations Early consultation with multiple specialists (peds ID, Rheum, Cardio, Crit Care) Early antibiotics if appropriate in accordance with sepsis protocols IVIG if meets KD or toxic shock criteria ASA if meets KD criteria COVID-specific: Supportive care Antivirals only in the context of clinical trials Immunomodulatory therapy in discussion with subspecialists More details from the NYC media releases: 82 cases on day of release (May 13)14 Relationship to COVID 60% of kids test positive for COVID PCR, 40% test positive for COVID antibodies (and 14% are positive for both) Severity of illness: 71% admitted to ICU, 19% intubated 71% admitted to ICU 19% intubated Seen in most age groups: few cases < 1yr; most in age 5-9 and 10-14 UK series17 8 children with overlapping features of KD/KD shock syndrome/TSS 1 death from a large cerebral infarct while on ECMO; others discharged All previously well All had no respiratory symptoms, but 7 required mechanical ventilation for cardiovascular stabilization All initially tested negative for COVID; 2 tested positive post-discharge Bergamo series18 Retrospective review of KD cases before vs after COVID Found that the monthly incidence was 30x greater than the historical average since the COVID pandemic (0.3 vs 10 cases per month) 10 cases identified; compared to historical cases (19 in previous 5-year period) Older on average (7yrs vs 3.5yrs) More cardiac involvement (60% vs 10%) More severe disease: 50% met criteria for KD-shock syndrome or MAS (compared to 0% of controls) More were treated with adjunctive steroid therapy (80% vs 16%) Relationship to COVID 2 had positive RT-PCR, but 8 had positive IgG to COVID – previous exposure Overall, there have still been very few cases of critically unwell children with COVID-19

  

Sources

Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088. doi:10.1111/apa.15270 Canada COVID-19 situational awareness dashboard. Ottawa, ON: Public Health Agency of Canada; 2020. Available from: https://phac-aspc.maps.arcgis.com/apps/opsdashboard/index.html#/e968bf79f4694b5ab290205e05cfcda6. Accessed 2020 May 17. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422. Apr 2020. doi:10.15585/mmwr.mm6914e4 Lu X, Zhang L, Du H et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663. Mar 2020. doi:10.1056/NEJMc2005073 Parri N, Lenge M, Buonsenso D et al. Children with Covid-19 in Pediatric Emergency Departments in Italy. New Eng J Med, May 2020. doi:10.1056/NEJMc2007617 Paret M, Lighter J, Pellett Madan R et al. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress. Clin Infect Dis, Apr 2020. doi:10.1093/cid/ciaa452 Jiang M, Guo Y, Luo Q et al. T cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of COVID-19. J Infect Dis, May 2020. doi:10.1093/infdis/jiaa252 Denina M, Scolfaro C, Silvestro E et al. Lung Ultrasound in Children With COVID-19. Pediatrics, May 2020. doi:10.1542/peds.2020-1157 Chiotos K, Hayes M, Kimberlin DW et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc, Apr 2020. doi:10.1093/jpids/piaa045 Dong Y, Mo X, Hu Y et al. Epidemiology of COVID-19 Among Children in China. Pediatrics, Mar 2020. doi:10.1542/peds.2020-0702 Kawasaki disease: clinical features and diagnosis. UpToDate. Updated Dec 2019. Turnier JL, Anderson MS, Heizer HR et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics, 2015 Sep;136(3):e609-14. doi:10.1542/peds.2015-0950 Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi:10.1542/hpeds.2020-0123 Twitter, @MarkLevineNYC. May 13 2020. https://twitter.com/MarkLevineNYC/status/1260579970138636289 Paediatric Intensive Care Society (PICS) Statement. Increased number of reported cases of novel presentation of multisystem inflammatory disease. Apr 2020. https://picsociety.uk/news/pics-statement-regarding-novel-presentation-of-multi-system-inflammatory-disease/ Royal College of Paediatrics and Child Health (RCPH). Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. May 2020. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 Riphagen S, Gomez X, Gonzalez-Martinez C et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet, May 2020. doi:10.1016/S0140-6736(20)31094-1 Verdoni, L., Mazza, A., Gervasoni A et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet, May 2020. doi:10.1016/ S0140-6736(20)31129-6

We’re talking about the little adults today! In particular, we’re diving into the reported Multi-System Inflammatory Syndrome/Kawasaki Disease that has been reported in association with COVID-19 in kids.

 

COVID in Peds: what we know

Epidemiology Infection rates are generally low: children seem to account for 1-5% of confirmed cases1 Only about 1% of cases in Canada seem to be in those < 19 years2 (though testing was previously not available to those with mild illness) Seems to be distributed reasonably evenly among age groups3 Presentations Symptoms are similar to adults; cases are generally mild3,4,5 Fever and cough are most commonly reported3,4,5 Reports of causing isolated fever in young infants6 Investigations Lab data seems variable; only 3.5% had lymphopenia in one study7 CXR: similar to adults; may be normal or may demonstrate patchy consolidations4 POCUS: similar to adults à irregular pleura, patchy B-lines8 Treatment Supportive care! Antivirals generally recommended only in the context of clinical trials9 For severe/critical disease, if used, panel recommends remdesivir over others9 Severity and outcomes Most children have mild disease and do well: in one case series of over 700 pediatric cases from China, 55% were mild or asymptomatic, 40% were moderate, 5% were severe, and 5 days PLUS 4 of 5: conjunctival injection, peripheral extremity changes such as desquamation, edema, or erythema; mucous membrane changes such as strawberry tongue or injected pharynx; polymorphous rash; cervical lymphadenopathy Complications Primarily cardiac, including coronary artery aneurysm Can rarely be associated with macrophage activation syndrome and shock Treatment IVIG and ASA Cause? Association with respiratory viruses? A retrospective chart review of 222 patients with KD found that 42% tested positive for a viral respiratory infection; most commonly rhinovirus or enterovirus12 No differences in presenting features or clinical outcomes in this compared to those who did not test positive

  

MIS-C and COVID-associated KD?

There is very little published research on this topic One case report of a 6-month old girl presenting with classic KD, without respiratory symptoms, whose swab was positive for COVID. She was treated with IVIG and high-dose ASA (standard KD Tx)13 One series of infographics from out of NYC14 A couple guideline statements and media releases on the basis on expert anecdotal experience15,16 A couple recent case series: one from the UK, one from Bergamo17,18 This is what we seem to know from guideline statements: There has been a small rise in the number of cases of critically ill children presenting with an unusual clinical picture Many of these children had tested positive for COVID-19 previously, and are now presenting with common overlapping features of toxic shock syndrome, Kawasaki disease, and MAS Presenting symptoms Prolonged fever (>5 days, >38.5 degrees) GI symptoms: severe abdominal pain, nausea, diarrhea, vomiting Conjunctival injection Maculopapular rash Other: cyanosis or pallor, dysphagia, dyspnea, palpitations, tachycardia, chest pain, lethargy, irritability, confusion Lab abnormalities Inflammatory markers: high CRP, ESR, ferritin; hypoalbuminemia High IL-6 and IL-10 (if available) Lymphopenia Coagulopathy: high D-dimer, high fibrinogen Cardiac involvement: elevated troponin/BNP (sometimes) May be present: AKI, high CK, transaminitis, high trigs Imaging features (may be present in some cases) EKG: changes consistent with myopericarditis Echo: coronary artery dilation; pericardial effusion CXR: patchy symmetrical infiltrates; may have pleural effusion Abdo US: HSMG, ileitis, colitis, ascites Treatment recommendations Early consultation with multiple specialists (peds ID, Rheum, Cardio, Crit Care) Early antibiotics if appropriate in accordance with sepsis protocols IVIG if meets KD or toxic shock criteria ASA if meets KD criteria COVID-specific: Supportive care Antivirals only in the context of clinical trials Immunomodulatory therapy in discussion with subspecialists More details from the NYC media releases: 82 cases on day of release (May 13)14 Relationship to COVID 60% of kids test positive for COVID PCR, 40% test positive for COVID antibodies (and 14% are positive for both) Severity of illness: 71% admitted to ICU, 19% intubated 71% admitted to ICU 19% intubated Seen in most age groups: few cases < 1yr; most in age 5-9 and 10-14 UK series17 8 children with overlapping features of KD/KD shock syndrome/TSS 1 death from a large cerebral infarct while on ECMO; others discharged All previously well All had no respiratory symptoms, but 7 required mechanical ventilation for cardiovascular stabilization All initially tested negative for COVID; 2 tested positive post-discharge Bergamo series18 Retrospective review of KD cases before vs after COVID Found that the monthly incidence was 30x greater than the historical average since the COVID pandemic (0.3 vs 10 cases per month) 10 cases identified; compared to historical cases (19 in previous 5-year period) Older on average (7yrs vs 3.5yrs) More cardiac involvement (60% vs 10%) More severe disease: 50% met criteria for KD-shock syndrome or MAS (compared to 0% of controls) More were treated with adjunctive steroid therapy (80% vs 16%) Relationship to COVID 2 had positive RT-PCR, but 8 had positive IgG to COVID – previous exposure Overall, there have still been very few cases of critically unwell children with COVID-19

  

Sources

Ludvigsson JF. Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults. Acta Paediatr. 2020;109(6):1088. doi:10.1111/apa.15270 Canada COVID-19 situational awareness dashboard. Ottawa, ON: Public Health Agency of Canada; 2020. Available from: https://phac-aspc.maps.arcgis.com/apps/opsdashboard/index.html#/e968bf79f4694b5ab290205e05cfcda6. Accessed 2020 May 17. CDC COVID-19 Response Team. Coronavirus Disease 2019 in Children - United States, February 12-April 2, 2020. MMWR Morb Mortal Wkly Rep. 2020;69(14):422. Apr 2020. doi:10.15585/mmwr.mm6914e4 Lu X, Zhang L, Du H et al. SARS-CoV-2 Infection in Children. N Engl J Med. 2020;382(17):1663. Mar 2020. doi:10.1056/NEJMc2005073 Parri N, Lenge M, Buonsenso D et al. Children with Covid-19 in Pediatric Emergency Departments in Italy. New Eng J Med, May 2020. doi:10.1056/NEJMc2007617 Paret M, Lighter J, Pellett Madan R et al. SARS-CoV-2 infection (COVID-19) in febrile infants without respiratory distress. Clin Infect Dis, Apr 2020. doi:10.1093/cid/ciaa452 Jiang M, Guo Y, Luo Q et al. T cell subset counts in peripheral blood can be used as discriminatory biomarkers for diagnosis and severity prediction of COVID-19. J Infect Dis, May 2020. doi:10.1093/infdis/jiaa252 Denina M, Scolfaro C, Silvestro E et al. Lung Ultrasound in Children With COVID-19. Pediatrics, May 2020. doi:10.1542/peds.2020-1157 Chiotos K, Hayes M, Kimberlin DW et al. Multicenter initial guidance on use of antivirals for children with COVID-19/SARS-CoV-2. J Pediatric Infect Dis Soc, Apr 2020. doi:10.1093/jpids/piaa045 Dong Y, Mo X, Hu Y et al. Epidemiology of COVID-19 Among Children in China. Pediatrics, Mar 2020. doi:10.1542/peds.2020-0702 Kawasaki disease: clinical features and diagnosis. UpToDate. Updated Dec 2019. Turnier JL, Anderson MS, Heizer HR et al. Concurrent Respiratory Viruses and Kawasaki Disease. Pediatrics, 2015 Sep;136(3):e609-14. doi:10.1542/peds.2015-0950 Jones VG, Mills M, Suarez D et al. COVID-19 and Kawasaki disease: novel virus and novel case. Hosp Pediatr. 2020; doi:10.1542/hpeds.2020-0123 Twitter, @MarkLevineNYC. May 13 2020. https://twitter.com/MarkLevineNYC/status/1260579970138636289 Paediatric Intensive Care Society (PICS) Statement. Increased number of reported cases of novel presentation of multisystem inflammatory disease. Apr 2020. https://picsociety.uk/news/pics-statement-regarding-novel-presentation-of-multi-system-inflammatory-disease/ Royal College of Paediatrics and Child Health (RCPH). Paediatric multisystem inflammatory syndrome temporally associated with COVID-19. May 2020. https://www.rcpch.ac.uk/resources/guidance-paediatric-multisystem-inflammatory-syndrome-temporally-associated-covid-19 Riphagen S, Gomez X, Gonzalez-Martinez C et al. Hyperinflammatory shock in children during COVID-19 pandemic. Lancet, May 2020. doi:10.1016/S0140-6736(20)31094-1 Verdoni, L., Mazza, A., Gervasoni A et al. An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study. Lancet, May 2020. doi:10.1016/ S0140-6736(20)31129-6