COVID-19-associated multisystem inflammatory syndrome
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. ; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D. José Eduardo Riceto Loyola Junior, M.D. Sahar Memar Montazerin, M.D. Aisha Adigun, B.Sc., M.D.
Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)
COVID-19-associated multisystem inflammatory syndrome (also known as PIMS-TS - pediatric inflammatory multisystem syndrome temporally with SARS-CoV2 infection or MIS-C - multisystem inflammatory syndrome in children) is an uncommon clinical entity caused by SARS-CoV2 and seen mostly on children. It presents with: fever > 3 days and elevated markers of inflammation and 2 of the following 5 criteria: rash or conjunctivitis; hypotension or shock; myocardial dysfunction, pericarditis, valvulitis or coronary abnormalities; evidence of coagulopathy and/or acute gastrointestinal problems along with evidence of COVID-19. It seems to be a severe form of COVID-19 in children presenting with symptoms that can be challenging to differentiate from other pediatric infectious diseases such as toxic shock syndrome and Kawasaki disease. The pathophysiology of this form of SARS-CoV2 infection remains unknown.
- COVID-19-associated multisystem inflammatory syndrome was first reported as a new febrile pediatric entity, which began to appear in late April 2020 during the COVID-19 pandemic in Western Europe.
- Cases of children with such symptoms were quickly identified in the New York City area, which was at that time the most heavily affected city in the U.S. by the COVID-19 pandemic;
- A report of 8 cases from Evelina London Children's Hospital was published on 6 May 2020, showing very prominent markers of inflammation such as ferritin, D-dimers, triglycerides, elevated cardiac enzymes, high NT-pro-BNP levels and troponin, being empirically treated with IVIG;
- On May 22, an article from the Journal of Pediatric Infectious Diseases Society addressed some of the similarities and differences of this new entity with Kawasaki's disease, noting that the demographics affected were significantly different, as it was not seen in Asia despite the pandemic also affecting such countries, but it was affecting mostly children of African ethnicity. The author also differentiated some of the laboratory findings, resembling the macrophage activation syndrome and not Kawasaki's disease.
Classification of Disease Severity of COVID-19-associated multisystem inflammatory syndrome
- There is no established system for the classification of COVID-19-associated multisystem inflammatory syndrome.
- The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear;
- It is thought that COVID-19-associated multisystem inflammatory syndrome is caused by either IgG antibody-mediated enhancement of the disease, an acute viral presentation, or due to cytokine storm.
- Since there is a lag time between COVID-19-associated multisystem inflammatory syndrome appearance and COVID-19 infection (median time: 25 days) it is suspected to be a post-infectious phenomenon related to IgG antibody-mediated enhancement of disease. There are two arguments that support this theory: the presence of IgG antibodies against SARS-CoV2 and the presence of the lag time between COVID-19 symptoms and COVID-19-associated multisystem inflammatory syndrome.
- There is, however, another theory that states that it is still an acute viral presentation of the disease due to the fact that children presenting with such symptoms undergone exploratory laparotomy which found mesenteric adenitis, supporting GI infection. SARS-CoV2 is also known to easily infect enterocytes. Another interesting point to consider is that the worsening of illness has not been observed in patients with COVID-19 who are treated with convalescent plasma, which could have occurred if it was an antibody-mediated enhancement.
- There is another hypothesis for the cytokine storm seen on children with COVID-19-associated multisystem inflammatory syndrome is originated from the known ability of coronaviruses to block type I and type III interferon responses, delaying the cytokine storm in patients that could not control the viral replication on earlier phases of the disease.
Differentiating COVID-19-associated multisystem inflammatory syndrome Disease from other disease
- For further information about the differential diagnosis, click here.
- To view the differential diagnosis of COVID-19, click here.
Epidemiology and Demographics
- Children aged 5 years and older seem to have a worse prognosis than children less than 5 years old.
- A recent study published in the Journal of American Medical Associated reported that children with this disease had a median age of 9 years.
- Clinical evidence of the association with underlying diseases is still undetermined.
Natural History, Complications, and Prognosis
Complications of COVID-19-associated multisystem inflammatory syndrome include:
- Ventricular dysfunction
- Coronary artery changes
- Atrioventricular valve regurgitation
- Pericardial eﬀusions
- Venous thromboembolic events
- Cytokine storm syndrome
Factors associated with poor prognosis in COVID-19-associated multisystem inflammatory syndrome include:
- Children younger than 1 month
- Children older than 5 years old (age 10-14years)
- A ferritin level of higher than 1400 µg/L
- Black ethnicity
The table below describes various diagnostic criteria for COVID-19-associated multisystem inflammatory syndrome:
|Features||World Health Organization
|Royal College of Paediatrics and Child Health
(United Kingdom) Criteria
|Centers for Disease Control and Prevention
(United States) Criteria
|1. Rash or non-purulent conjunctival injection or mucocutaneous involvement||
|2. Low blood pressure/Shock|
|3. Findings consistent with myocarditis, pericarditis, valvulitis or coronary involvement|
|4. Acute gastrointestinal symptoms|
|Laboratory Findings||5. Laboratory evidence of coagulopathy||
|Diagnosis of SARS-CoV-2||
History and Symptoms
COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:
- Fever lasting 24 hours or longer.
- Abdominal pain
- Difficulty Breathing
- Chest pain
- Sore throat
- New onset confusion
COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:
- Skin rash
- Redness or swelling of the lips and tongue
- Redness or swelling of the hands or feet
COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:
Less common laboratory findings include:
- Abnormal fibrinogen
- Elevated creatiine kinase (CK)
- Elevated LDH
- Elevated triglycerides
Elevation of inflammatory markers including erythrocyte sedimentation rate, reactive protein, and procalcitonin are usually seen in MIS-C. Increased level of Interleukin-6 (IL-6), Interleukin-10 (IL-10) d-dimer, serum ferritin, prothrombin time have also been seen in MIS-C.
Elevation of cardic enzymes including cardiac troponins (cardiac troponin I(cTnI) and cardiac troponin T (cTnT)) and Brain natriuretic peptide (BNP)) has been observed in MIS-C patients.
- To view the complete physical examination in COVID-19, click here.
- To view the laboratory findings on COVID-19, click here.
X-ray of patients with COVID-19 associated multiorgan system inflammatory syndrome may be normal. When abnormal, findings may include the followings:
- Peribronchial cuffing
- Perihilar interstitial thickening
- Perihilar opacification
- Perihilar consolidation
- Low volume pleural effusion affecting both lungs
- Left lower lobe atelectasis
Echocardiography or Ultrasound
Abdominal ultrasound imaging of patients with COVID-19 associated multiorgan system inflammatory syndrome may include the following findings:
- Localised inflammatory change within the right iliac fossa
- A combination of echogenic expanded mesenteric fat and enlarged lymph nodes
- Bowel wall thickening of parts of ileum and cecum
- Gall bladder wall thickening and edema
To view the echocardiographic findings on COVID-19, click here.
Chest CT scan of patients with COVID-19-associated multisystem inflammatory syndrome includes the following patterns:
- Consolidation and collapse of the lung bases
- Pleural effusions
- Diffuse bilateral ground-glass opacities with dense, patchy consolidation
Abdominal CT scan may show the following abnormalities:
- Intestinal wall thickening particularly in the terminal ileum and cecum
To view the CT scan findings on COVID-19, click here.
- To view the MRI findings on COVID-19, click here.
Other Imaging Findings
- To view other imaging findings on COVID-19, click here.
Other Diagnostic Studies
- To view other diagnostic studies for COVID-19, click here.
Treatment of patients with COVID-19-associated multisystem inflammatory syndrome includes:
- Antibiotics: broad-spectrum antibiotics are recommended initially.
- If the symptoms are mild, ceftriaxone may be sufficient.
- If the gastrointestinal symptoms are predominant, then metronidazole is recommended.
- In case of severe symptoms including shock the following antibiotics have been recommended:
- Vancomycin, clindamycin, and cefepime
- Vancomycin, meropenem, and gentamicin
- Remdesivir is indicated in children with PCR positive COVID-19 and/or with a presentation consistent with typical COVID-19.
- It should be administered 5 mg/kg loading dose IV once (max dose 200 mg) on day 1, then 2.5 mg/kg (100 mg max dose) IV daily for nine days.
- Cardiac and respiratory support is recommended for patients presenting with shock.
- IVIG and aspirin for Kawasaki-like disease
Patients with KD-like illness in high-risk categories should receive IVIG with other agents.The high-risk category includes:
- Those with KD shock syndrome
- Those with CRP > 130 g/dL
- Those with admission echo Z score > 2.5 or aneurysms
- Asian race
The following treatment regimen is recommended for patients with KD-like illness in high-risk categories:
- IVIG 2 g/kg as a single infusion with three-day pulse methylprednisolone. If fails, then:
- The second dose of IVIG or inﬂiximab (a Tumor necrosis factor (TNF)-alpha inhibitor)
- Venous thromboembolism prophylaxis may be indicated as well.
- Few studies have reported that interleukin-1 inhibitors may be effective in the treatment of severe cases.
- Tocilizumab (interleukin-6 inhibitor) is another agent that has been used in some cases.
- MIS-C can be prevented by reducing the risk of a child's exposure to COVID-19 infection.
- ↑ 1.0 1.1 1.2 1.3 Shulman ST (2020). "Pediatric Coronavirus Disease-2019-Associated Multisystem Inflammatory Syndrome". J Pediatric Infect Dis Soc. 9 (3): 285–286. doi:10.1093/jpids/piaa062. PMC 7313948 Check
|pmc=value (help). PMID 32441751 Check
- ↑ 2.0 2.1 2.2 2.3 Rowley AH (2020). "Understanding SARS-CoV-2-related multisystem inflammatory syndrome in children". Nat Rev Immunol. doi:10.1038/s41577-020-0367-5. PMC 7296515 Check
|pmc=value (help). PMID 32546853 Check
- ↑ Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF; et al. (2020). "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents". N Engl J Med. doi:10.1056/NEJMoa2021680. PMC 7346765 Check
|pmc=value (help). PMID 32598831 Check
- ↑ Cheung EW, Zachariah P, Gorelik M, Boneparth A, Kernie SG, Orange JS; et al. (2020). "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City". JAMA. doi:10.1001/jama.2020.10374. PMC 7281352 Check
|pmc=value (help). PMID 32511676 Check
- ↑ 5.0 5.1 5.2
- ↑ 6.0 6.1 Riphagen S, Gomez X, Gonzalez-Martinez C, Wilkinson N, Theocharis P (2020). "Hyperinflammatory shock in children during COVID-19 pandemic". Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. PMC 7204765 Check
|pmc=value (help). PMID 32386565 Check
- ↑ "World Health Organization - Multisystem inflammatory syndrome in children and adolescents temporally related to COVID-19". WHO. 07/13/2020. Check date values in:
- ↑ Riphagen, Shelley; Gomez, Xabier; Gonzalez-Martinez, Carmen; Wilkinson, Nick; Theocharis, Paraskevi (2020). "Hyperinflammatory shock in children during COVID-19 pandemic". The Lancet. 395 (10237): 1607–1608. doi:10.1016/S0140-6736(20)31094-1. ISSN 0140-6736.
- ↑ DeBiasi, Roberta L.; Song, Xiaoyan; Delaney, Meghan; Bell, Michael; Smith, Karen; Pershad, Jay; Ansusinha, Emily; Hahn, Andrea; Hamdy, Rana; Harik, Nada; Hanisch, Benjamin; Jantausch, Barbara; Koay, Adeline; Steinhorn, Robin; Newman, Kurt; Wessel, David (2020). "Severe COVID-19 in Children and Young Adults in the Washington, DC Metropolitan Region". The Journal of Pediatrics. doi:10.1016/j.jpeds.2020.05.007. ISSN 0022-3476.
- ↑ Verdoni, Lucio; Mazza, Angelo; Gervasoni, Annalisa; Martelli, Laura; Ruggeri, Maurizio; Ciuffreda, Matteo; Bonanomi, Ezio; D'Antiga, Lorenzo (2020). "An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study". The Lancet. 395 (10239): 1771–1778. doi:10.1016/S0140-6736(20)31103-X. ISSN 0140-6736.
- ↑ Belhadjer, Zahra; Méot, Mathilde; Bajolle, Fanny; Khraiche, Diala; Legendre, Antoine; Abakka, Samya; Auriau, Johanne; Grimaud, Marion; Oualha, Mehdi; Beghetti, Maurice; Wacker, Julie; Ovaert, Caroline; Hascoet, Sebastien; Selegny, Maëlle; Malekzadeh-Milani, Sophie; Maltret, Alice; Bosser, Gilles; Giroux, Nathan; Bonnemains, Laurent; Bordet, Jeanne; Di Filippo, Sylvie; Mauran, Pierre; Falcon-Eicher, Sylvie; Thambo, Jean-Benoît; Lefort, Bruno; Moceri, Pamela; Houyel, Lucile; Renolleau, Sylvain; Bonnet, Damien (2020). "Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic". Circulation. doi:10.1161/CIRCULATIONAHA.120.048360. ISSN 0009-7322.
- ↑ Klok, F.A.; Kruip, M.J.H.A.; van der Meer, N.J.M.; Arbous, M.S.; Gommers, D.; Kant, K.M.; Kaptein, F.H.J.; van Paassen, J.; Stals, M.A.M.; Huisman, M.V.; Endeman, H. (2020). "Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis". Thrombosis Research. 191: 148–150. doi:10.1016/j.thromres.2020.04.041. ISSN 0049-3848.
- ↑ 13.0 13.1 13.2 Hennon, Teresa R.; Penque, Michelle D.; Abdul-Aziz, Rabheh; Alibrahim, Omar S.; McGreevy, Megan B.; Prout, Andrew J.; Schaefer, Beverly A.; Ambrusko, Steven J.; Pastore, John V.; Turkovich, Stephen J.; Gomez-Duarte, Oscar G.; Hicar, Mark D. (2020). "COVID-19 associated Multisystem Inflammatory Syndrome in Children (MIS-C) guidelines; a Western New York approach". Progress in Pediatric Cardiology. 57: 101232. doi:10.1016/j.ppedcard.2020.101232. ISSN 1058-9813.
- ↑ Pouletty, Marie, et al. "Paediatric multisystem inflammatory syndrome temporally associated with SARS-CoV-2 mimicking Kawasaki disease (Kawa-COVID-19): a multicentre cohort." Annals of the Rheumatic Diseases (2020).
- ↑ 15.0 15.1 "Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study | The BMJ".
- ↑ 16.0 16.1 16.2 16.3 Feldstein, Leora R.; Rose, Erica B.; Horwitz, Steven M.; Collins, Jennifer P.; Newhams, Margaret M.; Son, Mary Beth F.; Newburger, Jane W.; Kleinman, Lawrence C.; Heidemann, Sabrina M.; Martin, Amarilis A.; Singh, Aalok R.; Li, Simon; Tarquinio, Keiko M.; Jaggi, Preeti; Oster, Matthew E.; Zackai, Sheemon P.; Gillen, Jennifer; Ratner, Adam J.; Walsh, Rowan F.; Fitzgerald, Julie C.; Keenaghan, Michael A.; Alharash, Hussam; Doymaz, Sule; Clouser, Katharine N.; Giuliano, John S.; Gupta, Anjali; Parker, Robert M.; Maddux, Aline B.; Havalad, Vinod; Ramsingh, Stacy; Bukulmez, Hulya; Bradford, Tamara T.; Smith, Lincoln S.; Tenforde, Mark W.; Carroll, Christopher L.; Riggs, Becky J.; Gertz, Shira J.; Daube, Ariel; Lansell, Amanda; Coronado Munoz, Alvaro; Hobbs, Charlotte V.; Marohn, Kimberly L.; Halasa, Natasha B.; Patel, Manish M.; Randolph, Adrienne G. (2020). "Multisystem Inflammatory Syndrome in U.S. Children and Adolescents". New England Journal of Medicine. doi:10.1056/NEJMoa2021680. ISSN 0028-4793.
- ↑ "Guidance - Paediatric multisystem inflammatory syndrome temporally associated with COVID-19 (PIMS) | RCPCH".
- ↑ Cheung, Eva W.; Zachariah, Philip; Gorelik, Mark; Boneparth, Alexis; Kernie, Steven G.; Orange, Jordan S.; Milner, Joshua D. (2020). "Multisystem Inflammatory Syndrome Related to COVID-19 in Previously Healthy Children and Adolescents in New York City". JAMA. doi:10.1001/jama.2020.10374. ISSN 0098-7484.
- ↑ 20.0 20.1 20.2 Hameed, Shema; Elbaaly, Heba; Reid, Catriona E. L.; Santos, Rui M. F.; Shivamurthy, Vinay; Wong, James; Jogeesvaran, K. Haran (2020). "Spectrum of Imaging Findings on Chest Radiographs, US, CT, and MRI Images in Multisystem Inflammatory Syndrome in Children (MIS-C) Associated with COVID-19". Radiology: 202543. doi:10.1148/radiol.2020202543. ISSN 0033-8419.
- ↑ Shah, Satish K.; Munoz, Alvaro Coronado (2020). "Multisystem Inflammatory Syndrome in Children in COVID-19 Pandemic". The Indian Journal of Pediatrics. doi:10.1007/s12098-020-03440-7. ISSN 0019-5456.