Pediatric Multisystem Inflammatory Syndrome related to COVID-19

Pandemic COVID-19 (Corona Virus Disease- 19) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome- Corona Virus- 2) was first identified in December 2019 in Wuhan, China. Since then, news coverage of COVID-19 and its impact on the human population have dominated the headlines. It was usually thought that children were not significantly affected by COVID-19, rather most of the time they carry the virus without any symptoms; most children who become infected with coronavirus have only a mild illness. This misconception has changed after there were reports from the United Kingdom of a small number of cases related to critically ill children presenting with unusual symptoms. The symptoms mimic Kawasaki Disease and are called Pediatric Multisystem Inflammatory Syndrome (PMIS). PMIS is a serious condition that appears to be linked with COVID -19.

What is Kawasaki Disease (KD)?

The disease derived its name from a Japanese pediatrician, Tomisaku Kawasaki, who reported the first case in 1961 in a four years old boy.

It is primarily an acquired heart disease in children. It is widely thought to be due to an infection or an abnormal immune response to an infection, although the actual reason behind the disease is still unknown. Researchers speculated that a mixture of genetics and environmental factors can cause Kawasaki disease.

Kawasaki disease is commonly characterized by a high fever for more than three days, diarrhea or vomiting, skin rashes, bloodshot eyes, etc., at an early stage. In the late stages, there may be inflammation of medium-sized blood vessels (vasculitis). It also affects lymph nodes, skin, and mucous membranes.

Pediatric Multisystem Inflammatory Syndrome (MIS-C)

After the first-ever diagnosis of MIS-C or Pediatric Multisystem Inflammatory Syndrome, it was identified to be slightly different from Kawasaki Disease; immediately the news spread out everywhere, clusters of sick children were reported to be admitted in different countries with the same symptoms. For most of the admitted children, there were 2-4 weeks of the lag period for the appearance of MIS-C symptoms from COVID-19 infection, and it happened not only due to the post-COVID-19 infection but also appeared in children who had close exposure to COVID-19 patients.

In medical terms, MIS-C is a postinfectious abnormal immune response with an outburst of the interferon response, macrophage activation, and cytokine storm inside the body. The inflammatory response occurs when tissues are injured by microorganisms. The damaged cells of the tissue release various chemicals which cause blood vessels to leak fluid into the tissues and resulting in swelling. Inflammatory mediators mainly include cytokines as the proinflammatory factor.

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Difference Between Kawasaki Disease (KD) And Pediatric Multisystem Inflammatory Syndrome (MIS-C)

There are more similarities than differences between the symptoms of KD and MIS-C. The similarities include high fever, skin rash, splash red eye-white, diarrhea, red swollen tongue, swollen lymph nodes, inflammation of blood vessels. For these similar characteristics, KD and MIS-C appear to be the same at first recognition.

The major differences between MIS-C and KD are listed below:

MIS-C renders more rapid and serious advancement of symptoms, especially multisystem organ problems like cardiac and respiratory problems due to current or recent exposure to SARS-CoV-2.
Kawasaki Disease generally appears in children less than 5 years old, whereas the common age barrier of MIS- C is extended further up to12 years or even more (most common in the age range of 5-12).
Without early diagnosis and appropriate management and treatment, MIS-C can lead to severe problems and inflammation in multiple organs, such as the heart, lungs, gastrointestinal tract, or kidneys; in comparison, long-term effects of KD include heart problems and coronary artery abnormalities.
Thrombocytopenia, lymphopenia, and hypoalbuminemia are more common in MIS-C, which are relatively less common in the case of KD.
The C-reactive protein, ferritin, troponin, d-dimer, and fibrinogen are higher in MIS-C than those in Kawasaki Disease.
Ventricular dysfunction, respiratory failure requiring mechanical ventilators/ intensive care unit are more common in MIS-C in comparison to Kawasaki Disease.

These shreds of evidence suggest that MIS-C renders more severe and elaborate inflammation in multiple organs having elevated levels of inflammatory markers and cytokine storm in the circulation.

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Multisystem Inflammatory Syndrome In Adult (MIS-A)

Besides children, MIS also appear in adult, who usually require intensive care and can have more fatal outcomes than that of MIS-C. Most adult cases reported are younger than 50 years. The presence of antibodies for SARS-CoV-2 in most affected adults suggests a postinfectious syndrome, probably the product of an overexuberant immunologic response that affects multiple organs. Coronavirus attacks multiple organs, compared with the primarily pulmonary effects of influenza, perhaps because the receptors (ACE-2) for SARS-CoV-2 are ubiquitous. The massive destruction caused by COVID-19 may be considered a major reason for MIS-A.

Noteworthy, MIS-A can leave long-term effects than MIS-C.

Link Between COVID-19 AND MIS-C

Various reports from many countries of children with fever and inflammation without an obvious cause in the time of COVID-19 pandemic hinted towards the possible link between SARS-CoV-2 and MIS-C. Though the actual cause of MIS-C is not known, various reports suggest that exposure to infectious microorganisms and certain genes can trigger MIS in children.

Some MIS-C-affected children produced negative results for the COVID-19 test that often suggest no recent infection by the coronavirus. Yet evidence indicated that many of these children were infected in the recent past, as shown by positive antibody test results. Sometimes this positive blood test was the only indication that the child was ever infected with the virus, might not show any symptoms of COVID-19 infection.

Altough MIS-C is linked to COVID-19, still, scientists believe that it is not contagious from person to person.

What To Do As A Parent?

As we speculate, Pediatric Multisystem Inflammatory Syndrome is somehow related to COVID-19, so the first aim for you (the parents and seniors) should be to stay safe and keep your child safe from the novel coronavirus.

Parents have to go outside for work and can unwillingly carry the virus. It’s very usual that children love to stay close to their parents and thus anytime may be exposed to the virus. They may not show any symptoms for COVID-19 but after 2-4 weeks may become severely ill showing Inflammatory symptoms. So, the basic precaution for MIS is the same as COVID-19.

As a parent you have to do the followings:

  • Physical distancing
  • Wear a mask with proper maintenance
  • Keep rooms well ventilated
  • Clean hands in regular intervals
  • Avoid crowds
  • Cough into a bent elbow or tissue
  • After outdoor activity, wash yourself perfectly before touching the children.
  • If symptoms of skin rash, diarrhea, red eyes, persistent high fever, or strawberry tongue are shown by children consult a doctor immediately.

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Symptoms Of Multisystem Inflammatory Syndrome In Children

In this pandemic situation every parent need to stay alert if any of the following initial symptoms is visible in a child:

  • Fever for more than 3 days. Temperature rise around 102°F.
  • Red rashes with skin peeling.
  • Abdominal and joint pain.
  • Diarrhea, vomiting.
  • Eyes with bilateral non-purulent conjunctivitis and irritation.
  • Red palms and feet.
  • Chapped lips.
  • Strawberry tongue.
  • Swollen lymph nodes.

Children in critical conditions show heterogeneous inflammatory involvement. Besides several symptoms appear as listed below:

  • Cardiac dysfunction.
  • Low blood pressure.
  • Swollen reddish palms, feet.
  • Elevated inflammatory markers in the blood, presenting inflammation in arteries and other vital organs.
  • Oral mucosal swelling and redness.

Cytokine Storm In MIS-C

“Cytokine storm” (CS) indicates a sudden acute elevation in the levels of different pro-inflammatory circulating cytokines. This happens as a result of continuous activation and expansion of immune cells which produce an immense amount of cytokines.

Cytokines

Cytokines are an essential part of the inflammatory process and produced by several immune cells including the innate macrophages, dendritic cells, natural killer cells, and the adaptive T and B lymphocytes.

There are many types of cytokines such as, interleukins, lymphokines, monokines, interferons (IFN), etc. Three of the most important pro-inflammatory cytokines of the innate immune response are IL-1, IL-6 (IL = Interleukin), and TNF-alpha (Tumour Necrosis Factor).

Cytokine Storm (CS)

CS is characterized by a clinical presentation of overwhelming systemic inflammation, hyperferritinemia, hemodynamic instability, multiorgan failure, and death if left untreated. This increase in cytokines results in an influx of various immune cells such as macrophages, neutrophils, and T cells into the site of infection with destructive effects on human tissue resulting from the destabilization of endothelial barrier function, damage of vascular barrier, capillary damage, diffuse alveolar damage and multiorgan failure. Lung injury is one consequence of the cytokine storm that can progress into acute lung injury if it is not treated.

Normal anti-viral immune response requires the activation of the inflammatory pathways of the immune system. But in the case of Multisystem Inflammatory Syndrome, an aberrant response of the immune system cause severe inflammation in multiple organs.

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School Opening In The Pandemic Situation

Children below five years are not advised to wear masks by the World Health Organization. Children, more than 5 years of age can wear masks. Even the ones who can use, may not be very comfortable with it.

Schools open in many regions are advised to maintain proper guidelines for the pandemic. Thermal checking and hand sanitizing are advised while entering a school. School authorities need to confirm that all the employees and students are wearing masks, maintain physical distance, sanitize or wash their hands at regular intervals. In addition, the authority should keep a watch on little children that they should not inhale sanitizers as these are poisonous.

All these and other behavioral adaptations in children would not be easy to come by; thus school opening for younger students (up to 14 years of age) under this COVID situation is still not a wise step. The online class option is much better from such perspectives.

If school is already open for your children, as a parent, you have to keep a thorough watch on them whether they are feeling uncomfortable or sick after returning from school.

Treatment For Pediatric Multisystem Inflammatory Syndrome

Among the children admitted with the symptoms of MIS-C, as many as 63% of cases required admission in pediatric intensive care units (PICU). The median length of hospitalization was about 6 days. Treatment depends on the type and severity of symptoms and which organs or parts of the body are affected by inflammation.

Treatment to reduce swelling and inflammation include the followings:

The use of intravenous immunoglobulins (IVIG) is an effective treatment to create an artificial immune response. If this method doesn’t work at the first attempt and fever returns then this method is repeated.
Implementation of steroid treatment is another way to treat MIS-C. Administration of immunoglobulin is comparatively higher in cost than a steroid treatment which is relatively cheaper.
Antibiotics are common medication that is used to restrict bacteria infection.
Other types of treatment include targeted therapies aimed at reducing high levels of proteins called cytokines, which can cause inflammation.

Besides, there are some supportive care measures such as:

Application of fluid to support dehydration.
Application of oxygen to help with breathing.
Blood pressure medications to normalize low blood pressure.
Use of artificial breathing machine, the ventilator.
Medications that reduce the risk of blood clots, like aspirin or heparin.
Other types of care may be needed depending on the health condition.

In addition to anti-viral therapies that can directly target the virus, anti-inflammatory therapies that diminish the cytokine responses are suggested to decrease mortality in COVID-19 patients.

As the final words I like to relay, the first thing is to stay cautious and superclean in this corona age to keep your children away from any exposure to coronavirus. In case, any symptom of Pediatric Multisystem Inflammatory Syndrome (PMIS/MIS-C) is observed in your children you should take immediate action. It is very urgent to diagnose MIS-infected children correctly and treat them as early as possible for better outcomes.

Stay safe and keep your children safe.

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Ms. Subhra Das is a biology teacher in high school by profession. Besides she is a passionate science writer and nature lover.

As a teacher, she never restricts herself within the four walls of the classroom, rather she loves exploring the crude science behind the natural facts that include human and animal health, critical diseases, typical characteristics of wildlife, and mother nature.

Ms. Subhra Das is also a passionate traveler and explorer; she always tries to uncover natural flora and fauna at every destination she travels.

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