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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]

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

Overview

Multisystem Inflammatory Syndrome in Children (MIS-C) is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes. According to recent evidence, it is suggested that children with MIS-C had antibodies against COVID-19 suggesting children had COVID-19 infection in the past. This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes.

Classification of Disease Severity of MIS-C

• Mild Disease
• Children with MIS-C fall under this category who-
  • require minimal to no respiratory support.
  • minimal to no organ injury
  • normotensive
  • Do not meet the criteria for ICU admission.
• Severe Disease
• Children with MIS-C fall under this category who-
  • have significant oxygen requirements (HFNC, BiPAP, mechanical ventilation).
  • have a mild-severe organ injury and ventricular dysfunction.
  • have a vasoactive requirement.
  • meet the criteria for ICU admissions

Pathophysiology

• The excat pathophysiological mechanism of MIS-C is unclear. Since there is a lag time between MIS-C appearance and COVID-19 infection it is suspected to be causing by antibody dependent enhancement.
• Another hypothesis is that since coronavirus block type1 and type III interferons, it results in delayed cytokine response in children with initially high viral load or whose immune response is unable to control infections causing MIS-C. Therefore, IFN responses result in viral clearance when the viral load is low resulting in mild infection. However, when the viral load is high and /or immune system is not able to clear the virus, the cytokine storm result in multisystem inflammatory syndrome in children (MIS-C).
• It is also suspected that since MIS-C presents predominantly with gastrointestinal manifestations, it replicates predominantly in the gastrointestinal tract.

Differentiating Any Disease from other disease

It should be differentiated from following diseases

• Bacterial sepsis
• Staphylococcal and streptococcal toxic shock syndrome
• Kawasaki disease.
• More information about the differential diagnosis could be found here.

Epidemiology and Demographics

• According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
• 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
• 4% of the children required extracorporeal membrane oxygenation.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <1yr-7%
  • 1-4yr-28%
  • 5-9yr-25%
  • 10-14yr-24%
  • 15-20yr-16%.

Gender

• Among the 186 children with MIS-C

Comorbidities

• Children with MIS-C had following underlying comorbidities.
  • Clinically diagnosed Obesity-8%
  • BMI-Based Obesity-29%
  • Cardiovascular diasease-3%
  • Respiratory disease-18%
  • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

• 71% of children had involvement of at least four organ systems.

The most common organ system involved in MIS-C children among a total of 186 children were.

• Gastrointestinal(92%)
• Cardiovascular(80%)
• Hematologic(76%)
• Mucocutaneous(74%)
• Pulmonary(70%)
• Historical perspective

Complications and Prognosis

Complications

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

Diagnosis

Diagnostic Criteria

Preliminary WHO case definition: Children and adolescents

• 0–19 years of age with fever >3 days

AND

• Two of the following:

1. Rash or bilateral non-purulent conjunctivitis or mucocutaneous inflammation signs (oral, hands or feet)
2. Hypotension or shock
3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
4. Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)

AND

• Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin

AND

• No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes

AND

• Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19

CDC Case Definition for MIS-C

• An individual aged <21 years presenting with fever, laboratory evidence of inflammation**, and evidence of clinically severe illness requiring hospitalization, with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological);

AND

No alternative plausible diagnoses;

AND

Positive for current or recent SARS-CoV-2 infection by RT-PCR, serology, or antigen test; or exposure to a suspected or confirmed COVID-19 case within the 4 weeks prior to the onset of symptoms.

Signs and Symptoms

• Fever lasting 24 hours or longer.
• Vomiting
• Diarrhea
• Abdominal pain
• Skin rash
• Conjuctivitis
• High ESR
• Redness or swelling of the lips and tongue
• Lethargy
• Redness or swelling of the hands or feet
• Confusion
• Headache
• Sore throat
• Syncope
• Lymphadenopathy

Emergency Warning Signs

• Difficulty Breathing
• Chest pain
• New onset confusion
• Lethargy
• Cyanosis
• Abdominal pain

Physical Examination

Blood Investigations

• Lymphopenia, Neutrophilia, Anemia, Thrombocytopenia have been seen in MIS-C pateints. Abnormal fibrinogen, Hypoalbuminaemia, elevated creatiine kinase (CK), LDH, triglycerides have been observed in MIS-C patients.

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.

Radiological Findings

• Following Radiological Findings are observed in MIS-C patients.

Test	Findings
Chest Xray	patchy symmetrical infiltrates, pleural effusion
Echocardiogram and EKG	myocarditis, valvulitis, pericardial effusion, coronary artery dilatation
Abdominal USG	colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly

Blood Culture, Viral PCR

• Absence of other potential causative organisms. IgG levels and IgM levels of SARS-CoV-2 are detected.

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.

Presentations

• Presentation of COVID-19 is less severe in children as compared to adults. Most of the children are asymptomatic.
• According to CDC, as of April 2, 2020, 1.7% confirmed cases of COVID-19 were reported in children aged <18 years age among the total number of confirmed cases of COVID-19.
• COVID-19 in children could range from asymptomatic presentation to mild to severe disease.
• The incubation period of SARS-CoV-2 varies from 2 to 14 days with most patients developing symptoms 3 to 7 days after exposure.

Symptoms

• Fever and Cough are one of the most common symptoms reported in children. One study showed fever is prevalent in 47.5% of children and cough in 41.5% among the 1124 children with COVID-19. According to the CDC, fever, and cough was reported in 56% and 54% of children with COVID 19
• Dyspnea, nasal congestion, pharyngeal erythema, and sore throat are also common presentations in children.
• Gastrointestinal symptoms-The gastrointestinal manifestation in COVID-19 positive children are diarrhea, vomiting, abdominal pain, nausea, and anorexia. Children can present with gastrointestinal symptoms in the absence of respiratory symptoms.
• Cutaneous Findings- The cutaneous findings in COVID-19 positive children range from petechiae to papulovesicular rashes to diffuse urticaria. These appear early in the course of COVID-19 and result secondary to viral replication or circulating cytokines. Many patients with COVID-19 are presenting with chilblains like lesions unrelated to cold. Chilblains are painful or itchy swellings of the toes and fingers, caused by small-vessel inflammation from repeated exposure to cold. A retrospective case series presented 22 children and adolescents with COVID-19 who presented with chillblains lesions.
• Neurological manifestation- The presentation of neurological manifestation in children is rare. However, a case report described a rare case of a 6-week old infant with COVID-19 who had 10-15 seconds episodes of upward gaze and bilateral leg stiffening.

• Neonates and Infants with COVID-19 are often asymptomatic or present with fever with or without mild cough and congestion.

Severity of Disease in Children with COVID-19

• Asymptomatic presentation-
  • A large number of children with COVID-19 are asymptomatic.
  • According to one study 14.2% of children were asymptomatic. Another study showed 18% of asymptomatic children with COVID-19.
• Mild Disease
  • Few numbers of children also present with mild manifestations of COVID-19.
  • A study showed 36.3% of children present with a mild form of the disease.

Moderate

• Severe
  • 2.1% of children present with a severe form of COVID-19 disease.
  • Children with underlying comorbidities are more susceptible to getting severe COVID-19 disease.

===Complication 1===

Multisystem Inflammatory Syndrome in Children (MIS-C)

• It is a condition that causes inflammation of some parts of the body like heart, blood vessels, kidneys, digestive system, brain, skin, or eyes.
• According to recent evidence, it is suggested that children with MISC had antibodies against COVID-19 suggesting children had COVID-19 infection in the past.
• This syndrome appears to be similar in presentation to Kawasaki disease, hence also called Kawasaki -like a disease. It also shares features with staphylococcal and streptococcal toxic shock syndromes, bacterial sepsis, and macrophage activation syndromes. "www.rcpch.ac.uk" (PDF).

Epidemiology and Demographics

• According to a recent study among the 186 children with MIS-C, the rate of hospitalization was 12% between March 16 and April 15 and 88% between April 16 and May 20.
  • 80% of the children were admitted to the intensive care unit and 20% of the children required mechanical ventilation.
  • 4% of the children required extracorporeal membrane oxygenation.
• The mortality rate among 186 children with MIS-C was 2%.

Age

• Among the 186 children with MIS-C distribution of age group was
  • <1yr-7%
  • 1-4yr-28%
  • 5-9yr-25%
  • 10-14yr-24%
  • 15-20yr-16%.

Gender

• Among the 186 children with MIS-C

Comorbidities

• Children with MIS-C had following underlying comorbidities.
  • Clinically diagnosed Obesity-8%
  • BMI-Based Obesity-29%
  • Cardiovascular diasease-3%
  • Respiratory disease-18%
  • Autoimmune disease or immunocompromising condition-5%

Organ System Involved

• 71% of children had involvement of at least four organ systems.

The most common organ system involved in MIS-C children among a total of 183 children were.

• Gastrointestinal(92%)
• Cardiovascular(80%)
• Hematologic(76%)
• Mucocutaneous(74%)
• Pulmonary(70%).

Pathophysiology

• Exact cause of MIS-C is unclear. It is suspected that it is caused by a delayed immune response to the SARS-CoV-2, causing inflammation of organs."Multisystem Inflammatory Syndrome in Children (MIS-C) | Boston Children's Hospital".
• It is also suspected that it is occurring due to antibody-mediated reaction."Multisystem Inflammatory Syndrome in Children (MIS-C) | Boston Children's Hospital".

Symptoms"www.rcpch.ac.uk" (PDF).

• Fever lasting 24 hours or longer(78%)
• Vomiting
• Diarrhea
• Abdominal pain
• Skin rash
• Conjuctivitis
• Redness or swelling of the lips and tongue
• Lethargy
• Redness or swelling of the hands or feet
• Confusion
• Headache
• Sore throat
• Syncope
• Lymphadenopath

Emergency Warning Signs

• Difficulty Breathing
• Chest pain
• New onset confusion
• Lethargy
• Cyanosis
• Abdominal pain

Laboratory Findings"www.rcpch.ac.uk" (PDF).

• Abnormal fibrinogen
• High CRP
• High D Dimer
• High Ferritin
• Hypoalbuminaemia
• Lymphopenia
• Neutrophilia
• Absence of other potential causative organisms.
• Anemia
• High IL-10
• High IL-6
• Raised CK
• Raised LDH
• Raised triglycerides
• Raised troponin
• Thrombocytopenia

Radiological Findings"www.rcpch.ac.uk" (PDF).

*Evaluation of Child for MIS-C.

Stable Child Fever(≥ 38.0°C) for ≥ 3 days. Presence of clinical features

Unstable Child(Sepsis) Fever(≥ 38.0°C) for ≥ 1 day Presence of signs/symptom Evidence of myocardial dysfunction or hypotension

{{{ C01 }}}

D01

D02

D03

E01

E02

E03

F01

F02

Test	Findings
Chest Xray	patchy symmetrical infiltrates, pleural effusion
Echocardiogram and EKG	myocarditis, valvulitis, pericardial effusion, coronary artery dilatation
Abdominal USG	colitis, ileitis, lymphadenopathy, ascites, hepatosplenomegaly

Diagnosis

Preliminary WHO case definition: Children and adolescents

• 0–19 years of age with fever >3 days

AND

• Two of the following:

1. Rash or bilateral non-purulent conjunctivitis or muco-cutaneous inflammation signs (oral, hands or feet)
2. Hypotension or shock
3. Features of myocardial dysfunction, pericarditis, valvulitis, or coronary abnormalities (including ECHO findings or elevated Troponin/NT-proBNP)
4. Evidence of coagulopathy (by PT, PTT, elevated D-Dimers)
5. Acute gastrointestinal problems (diarrhea, vomiting, or abdominal pain)

AND

• Elevated markers of inflammation such as ESR, C-reactive protein, or procalcitonin

AND

• No other obvious microbial cause of inflammation, including bacterial sepsis, staphylococcal or streptococcal shock syndromes

AND

• Evidence of COVID-19 (RT-PCR, antigen test or serology-positive), or likely contact with patients with COVID-19

Treatment

• All the children with MIS-C are treated as suspected COVID-19.
• Mild to Moderate cases of MIS-C are managed supportively.
• 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.
• The antiviral therapy where required are only given in the context of clinical trials(Eg RECOVERY TRIAL).
• Empiric antibiotics like vancomycin, ceftriaxone, and clindamycin are given for community-acquired shock presentation until cultures are negative for 48 hours."www.childrensmn.org" (PDF).
• Fluid resuscitation in 10 ml/kg aliquots with reevaluation after each bolus. Maintain euvolemia. Avoid hypervolemia.

Prevention of MIS-C

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

Complications of MIS-C

• Severe myocardial infarction"www.childrensmn.org" (PDF).
• Cardiac failure/arrest
• ARDS
• Fluid Overload
• Acute Kidney Injury
• Peritonitis
• Thrombotic complications.

Acute Heart Failure

• Acute Cardiac decompensation have been reported in children due to severe inflammatory state following COVID-19 infection. A case series describe 35 children in 14 centers admitted to PICU for cardiogenic shock, left ventricular dysfunction, and severe inflammatory state.

COVID-19 and HIV

Overview

• An observational prospective study found out that the incidence of HIV-infected individuals to be affected by SARS-CoV-2 was similar to the general population.
• Specific antiretroviral therapy did not affect COVID-19 severity.
• Immunosuppression(low CD4 cell counts) was associated with COVID-19 severity.
• Patients with HIV infection often have other comorbidities(lung disease, cardiovascular disease) therefore, increasing the risk for severe-COVID-19 disease.

Risk

• At present people with HIV who are at greatest risk of Severe COVID-19 infection are people -
  • who have lowCD4 cell count.
  • not on antiretroviral therapy.

Presentation

• There hasn't been any observable difference in clinical presentation among people with HIV infection as compared to the general population.
• Common symptoms for COVID-19 are
  • Fever or chills
  • Cough
  • Shortness of Breath or difficulty breathing
  • Fatigue
  • Muscle or Body aches
  • Headache
  • New loss of taste or smell
  • Sore Throat
  • Congestion or runny nose
  • Nausea or vomiting
  • Diarrhea

Recommendations for Patients with HIV

• Maintain the supply for antiretroviral therapy for a minimum of 30 days.
• Virtual visit and telemedicine should be considered for non-urgent care and non-adherence counseling
• People with suppressed HIV viral load and in stable health, should postpone their routine medical care and laboratory visits to the extent possible.
• If they develop symptoms of COVID-19 like fever, cough, shortness of breath, etc they should seek medical advice.
• They should make sure their vaccination status is uptodate.

Specific Populations with HIV

Pregnant Patients

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