COVID-19-associated multisystem inflammatory syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Harmeet Kharoud M.D.[2] José Eduardo Riceto Loyola Junior, M.D.[3]

Synonyms and keywords: Multisystem Inflammatory Syndrome in Children (MIS-C)

Overview

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.

Historical Perspective

• Reports of a new febrile pediatric entity began to appear in late April 2020 during the COVID-19 pandemic in the Western Europe, characterized by systemic hyperinflammation, abdominal pain with gastrointestinal symptoms and multiorgan involvement affecting especially the myocardium causing cardiogenic shock which reminded the physicians of Kawasaki disease;
• Cases of children with such symptoms were quickly identified in the New York City area, which was then 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;
• In 22 May, 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 was 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.

Pathophysiology

• The exact pathophysiological mechanism of COVID-19-associated multisystem inflammatory syndrome is unclear.
• 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 seen 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 Any Disease from other disease

• Children who met criteria for COVID-19-associated multisystem inflammatory syndrome presented features that overlapped with the ones seen on Kawasaki's disease and toxic shock syndrome, such as conjunctival injection, oropharyngeal findings (red and/or cracked lips, strawberry tongue), rash, swollen and/or erythematous hands and feet, and cervical lymphadenopathy.
• PCR tests for SARS-CoV-2 were positive in the minority of cases (26%), while the IgG antibody was positive in most patients (87%) and it remains as the preferred laboratory test for differentiating such diseases;
• The first cases of COVID-19-associated multisystem inflammatory syndrome presented with: unrelenting fever (38–40°C), conjunctivitis, cutaneous rash, peripheral edema, extremity pain and remarkable gastrointestinal symptoms. Most didn't have any respiratory symptoms, and all progressed to warm vasoplegic shock, refractory to volume resuscitation demanding vasopressors for hemodynamic support.
• Serum IL-6 level was elevated in most patients. IL-2R, IL-18, and CXCL 9 levels were elevated in all patients of a cohort and mildly increased IFN-γ and IL-8 levels in some.
• TNF-α, IL-1b, IL-2, IL-4, IL-5, and IL-13 levels remained normal in one in a series of cases from New York City.

Summary of laboratory parameters of a COVID-19-associated multisystem inflammatory syndrome cohort compared with the historic cohorts of Kawasaki Disease, Kawasaki Disease Shock Syndrome and Toxic Shock Syndrome

Parameters	COVID-19-associated multisystem inflammatory syndrome (PIMS-TS)	Kawasaki Disease (KD)	Kawasaki Disease Shock (KDS)	Toxic Shock Syndrome (TSS)
Age (median, IQR)	9 (5.7-14)	2.7 (1.4-4.7)	3.8 (0.2-18)	7.38 (2.4-15.4)
Total white cell count (*10^9/L)	17 (12-22)	13.4 (10.5-17.3)	12.1 (7.9-15.5)	15.6 (7.5-20)
Neutrophil count (*10^9/L)	13 (10-19)	7.2 (5.1-9.9)	5.5 (3.2-10.3)	16.4 (12-22)
Lymphocyte count (*10^9/L)	0.8 (0.5-1.5)	2.8 (1.5-4.4)	1.6 (1-2.5)	0.63 (0.41, 1.13)
Hemoglobin (g/L)	92 (83-103)	111.0 (105-119)	107 (98-115)	114 (98-130)
Platelet number (10^9/L)	151 (104-210)	365.0 (288-462)	235 (138-352)	155 (92- 255)
C-reactive protein (mg/L)	229 (156-338)	67.0(40-150)	193 (83-237)	201 (122, 317)
ALT (IU/L)	42 (26-95)	42.0 (24-112)	73 (34-107)	30.00 (22.10, 49.25)
Albumin (g/L)	24 (21-27)	38.0 (35-41)	30 (27-35)	27.00 (21.00, 31.00)
Ferritin (ug/L)	610 (359-1280)	200 (143-243)	301 (228-337)	-
NT-Pro-BNP (pg/ml)	788 (174-10548)	41 (12-102)	396 (57-1520)	-
Troponin (ng/L)	45 (8-294)	10.0 (10-20)	10 (10-30)	-
D-dimer (ng/ml)	3578 (2085- 8235)	1650 (970-2660)	2580 (1460- 2990)	-

• Most patients presented with the following findings: elevated erythrocyte sedimentation rate or C-reactive protein level, elevated ferritin level, lymphocytopenia, hypoalbuminemia, neutrophilia, elevated alanine aminotransferase level, anemia, thrombocytopenia prolonged INR, elevated d-dimer level, or elevated fibrinogen level.

Epidemiology and Demographics

• Poor prognostic factors include age over 5 years and ferritin larger than 1400 µg/L.

Age

• Children aged age over 5 years seem to have a worse prognosis than younger ones.
• The median age found out in a study published by JAMA was 9 years.

Gender

• Most of the cases, estimated in two thirds, seem to happen in boys.

Race

• It seems to affect predominantly blacks and asians.

Comorbidities

• Clinical evidence of association with underlying diseases is still scarce since it is a rare presentation of COVID-19 in children and teenagers.

Complications and Prognosis

Complications

• Severe myocardial infarction
• Cardiac failure/arrest
• ARDS
• Hypervolemia
• Acute Kidney Injury
• Peritonitis
• Thrombotic complications.

Diagnosis

Diagnostic Criteria

In May 2020, the Centers for Disease Control and Prevention (CDC) set the criteria for multisystem inflammatory syndrome in children (MIS-C):

• Severe disease course leading to hospitalization
• Individuals younger than 21 years old
• Fever (body temperature, >38.0°C) or report of subjective fever present at least 24 hours
• Laboratory evidence of inflammation
• Multisystem organ involvement (at least two systems)
• Laboratory-confirmed SARS-CoV-2 infection

History and Symptoms

COVID-19 associated multisystem inflammatory syndrome is associated with the following symptoms:

• Fever lasting 24 hours or longer.
• Vomiting
• Diarrhea
• Abdominal pain
• Difficulty Breathing
• Chest pain
• Headache
• Sore throat
• New onset confusion

Physical Examination

COVID-19 associated multisystem inflammatory syndrome is associated with the following physical examination findings:

• Skin rash
• Conjuctivitis
• Redness or swelling of the lips and tongue
• Redness or swelling of the hands or feet
• Lymphadenopathy
• Lethargy
• Cyanosis

Laboratory Findings

COVID-19 associated multisystem inflammatory syndrome is associated with the following laboratory findings:

• High ESR
• Lymphopenia
• Neutrophilia
• Anemia
• Thrombocytopenia

Less common laboratory findings include:

• Abnormal fibrinogen
• Hypoalbuminaemia
• Elevated creatiine kinase (CK)
• Elevated LDH
• Elevated triglycerides

Inflammatory biomarkers

Elevation of inflammatory markers including ESR, C 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.

Cardiac biomarkers

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

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

CT scan

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

To view the CT scan findings on COVID-19, click here.

Treatment

Medical Therapy

• All the children with MIS-C are treated as suspected COVID-19.
• Mild to Moderate cases of MIS-C are managed supportively.
• Supplemental oxygen is required in children with low oxygen saturation.
• Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.
• Anti-inflammatory treatments with Intravenous immunoglobulin(IVIG) with or without corticosteroids have shown a good response rate.
• Aspirin has been used primarily for its antiplatelet effect. It is recommended in all patients with MIS-C.
• Anakinra is considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
• Tocilizumab is also considered if fevers last more than 24 hours post steroids/IVIG or in the moderate or severe presentation.
• Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours.

Presentation	Treatment
Mild Disease	Symptomatic Treatment
Severe Disease	Symptomatic Treatment IVIG(IV) Corticosteroids(IV/PO) Consider adding Anakinra or Tocilizumab if fever persist for more than 24 hours post steroids and IVIG use.

Prevention of MIS-C

• MIS-C can be prevented by reducing the risk of child exposure to COVID-19 infection.