Multisystem Inflammatory Syndrome in Children (MIS-C)
Review by Kenneth Lyen
INTRODUCTION
On 31 December 2019, China announced to the World Health Organisation they had a new coronavirus illness that affected the city of Wuhan. Children were infrequently affected, and if they were, the illness was usually quite mild. The virus rapidly spread worldwide, and children continued to be less frequently and less severely affected compared to adults.
However, in March 2020, some children in England were found to have a severe illness requiring hospitalisation and intensive care. Initially this condition was described as a "mysterious disease". The children had high fever, abdominal pain, vomiting, skin rash and red eyes. A few went into shock, and organ failure. Later, some paediatricians recognised this combination of high fever, skin rash, red eyes, red tongue (see image above), to suggest an uncommon disease affecting children, namely Kawasaki Disease.
The British paediatricians tried to identify the causative agent, and using the nose swab test of Reverse Transcriptase Polymerase Chain Reaction for the coronavirus (SARS-CoV-2) RNA, most children tested negative. So it was uncertain whether this disease had anything to do with the raging COVID-19 pandemic, at least in the early stages of this mysterious disease. Later, using another test, the blood antibody test to to SARS-CoV-2, they found that many of these children who were initially negative, became positive to the coronavirus.
This led the doctors to ask the question: "Are we dealing with a new disease, or a new manifestation of COVID-19?" To try to answer this question, first, let us look at the clinical presentation of this condition. The picture below show the skin rash, the red eyes, and the skin peeling from the tips of the fingers.
The presenting symptoms were high fever, about 50% of the children complained of abdominal pain, vomiting, diarrhoea, red eyes and skin rash. Although there were some respiratory symptoms such as fast breathing and coughing, this was milder than that seen in older adult cases of COVID-19. The age of the children affected ranged from 2 to 17 years.
Investigations showed raised C-reactive protein, erythrocyte sedimentation rate, ferritin, D-dimer and procalcitonin levels. These test results were raised quite high in many of these children, and it pointed to a severe inflammatory response.
Early in the course of onset of this outbreak, an 8-year old boy whose mother was recently tested positive for Covid-19, was admitted to a London hospital. He had a fast heart and breathing rate. Initially he tested negative for SARS-CoV-2 but a few days later, the antibody test became positive. Ultrasound of the heart showed a coronary aneurysm (see below), which suggested a diagnosis of Kawasaki Disease:
Other Covid-19 positive children suddenly collapsed and were found to have heart systolic dysfunction affecting the left ventricle, and their troponin levels were elevated, indicating heart muscle damage.
The unexpected onset of this frightening disease raised a number of questions. Is it a new disease? How do we diagnose it? What is the differential diagnosis, meaning what are the similar diseases that need to be excluded, before we can conclude that this condition can be considered a unique disease? The original name given to this disease was Paediatric Multisystem Inflammatory Syndrome, but the USA and WHO have decided on the name Multisystem Inflammatory Syndrome in Children (MIS-C).
DIFFERENTIAL DIAGNOSIS
The first diagnosis to exclude is Kawasaki Disease.
KAWASAKI DISEASE
Several of the early cases of this new variation of COVID-19, now referred to as Multisystem Inflammatory Syndrome in Children (MIS-C), were initially diagnosed as Kawasaki or Kawasaki-like Disease. The problem with ruling out Kawasaki disease is that there are no definitive diagnostic tests, and we rely almost exclusively on classical clinical features of this disease.
Symptoms and signs of MIS-C and Kawasaki disease overlap. Both have high fevers, a red skin rash, peeling skin from the tips of the fingers and toes, red eyes (conjunctivitis), red tongue, and involvement of the heart and coronary arteries (coronary aneurysm).
And until recently, there were no biochemical tests to diagnose Kawasaki Disease. However, recently two urine proteins have been identified as potential biomarkers of Kawasaki Disease: meprin A and filamin C. Meprin A is an immune regulator, and filamin C is associated with endothelial and myocardial cell injury. It is too early to say whether or not these tests are diagnostic.
TOXIC SHOCK SYNDROME
Toxic shock syndrome is caused by a severe infection by staphylococcal aureus or group A streptococcus. They are detected by blood or tissue culture, and streptococcus can also be diagnosed by an immunoassay which is a rapid antigen detection test (RADT). There will usually be evidence of liver and renal failure.
MACROPHAGE ACTIVATION SYNDROME
The patients shown above have the Macrophage Activation Syndrome. This is a severe potentially life-threating disease in childhood, and may be a complication of systemic juvenile idiopathic arthritis or systemic lupus erythematosis. The diagnosis is confirmed by finding markedly elevated ferritin, D-dimer and cytokine levels in the blood, and they point to a strong inflammatory response. The platelets, white cell count, and clotting factors, are low, and there may be abnormal liver and kidney function tests. Although not widely available, gene expression profiling, and determination of sIL-2R alpha and sCD163 concentration in peripheral blood, can be useful for the early detection of macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis.
CASE DEFINITION OF MULTISYSTEM INFLAMMATORY SYNDROME IN CHILDREN (MIS-C)
37 children from 8 British hospitals were systematically reviewed in order to rule out the diseases that form the differential diagnosis. The doctors concluded that this was indeed a new disease, and they originally named it Paediatric Multisystem Inflammatory Syndrome. A case definition of this condition was drafted and on 24 April 2020, the UK National Health Service was alerted. In the meantime, the US Centers for Disease Control and Prevention (CDC) and the World Health Organisation (WHO) also formed their own separate committees, and they came to the same conclusions, that there was a unique condition, and they followed suit with a set of case definitions. They both named the new disease, Multisystem Inflammatory Syndrome in Children (MIS-C). Below is the WHO Preliminary Case Definition of MIS-C.
ARE WE DEALING WITH ONE DISEASE OR SEVERAL DIFFERENT DISEASES?
The definition of the Multisystem Inflammatory Syndrome in Children (MIS-C) by the British National Health Service, the US CDC, and the WHO, overlapped slightly, but in essence they had many common features. Professor Michael Levin suggested that different researchers from different countries were probably looking at the same disease elephant from their individual perspective.
COMPARE AND CONTRAST MIS-C & KAWASAKI DISEASE
Looking at the list of differential diagnoses, the disease that most resembles the new MIS-C, and the one that needs to be differentiated, is Kawasaki Disease.
MIS-C can affect both young and older children, with a mean age of 10-11 years. In contrast, Kawasaki Disease tends to affect younger children with a mean age of 2 years. There are also ethnic differences, with more African heritage experiencing MIS-C, while Kawasaki Disease tends to affect Asians more frequently. Gastrointestinal symptoms and acute renal injury are also more prevalent in MIS-C. Coronary artery abnomalities like aneurysms are more common in Kawasaki Disease. As for blood investigations, troponin, ferritin, triglycerides and CRP levels are significantly higher in MIS-C, while platelets and lymphocytes are lower when compared to Kawasaki Disease. The cause of MIS-C is the SARS-CoV-2 virus, whereas the cause of Kawasaki Disease is still unknown.
Below are illustrations and a table outlining the major differences between MIS-C and Kawasaki Disease:
HOW DOES MIS-C PRESENT CLINICALLY?
With larger numbers of patients meeting the definition of MIS-C, Elizabeth Whittaker and colleagues were able to divide the patients into three main groups:
1. Febrile and Inflammation
This group of children had mild symptoms of fever, but had persistently raised CRP and white blood cell count.
2. Shock and Myocarditis
Many of these patients were in shock and required admission to an intensive care unit, and needed treatment of their low blood pressure.
3. Kawasaki-like
These children met the definition of Kawasaki Disease.
All three groups had evidence of coronary artery aneurysm. This is interesting, because Kawasaki Disease is also strongly associated with coronary artery aneurysms. However, the laboratory features of MIS-C are quite different (higher CRP and lower lymphocytes) from Kawasaki Disease, and other febrile bacterial and viral diseases.
WHAT IS THE RELATIONHIP BETWEEN MIS-C AND SARS-CoV-2?
In London, MIS-C (shown in the orange line below) only appeared about one month after the onset of COVID-19 (shown in the blue line). Similar data are obtained from the USA and France.
Most cases of MIS-C are negative for the RT-PCR test of the virus, but are positive for antibodies against SARS-CoV-2.
PROGRESSION OF MIS-C
As the prevalence of COVID-19 fell in several countries, so did the numbers of MIS-C. Hence the public health measures that were effective in preventing COVID-19 could also prevent MIS-C.
TREATMENT
The treatment of MIS-C began by following the standard treatment of Kawasaki Disease. This included the administration of intravenous immunoglobulins (IVIG) sometimes with the addition of steroids. Anti-platelets and anticoagulants were also used in Kawasaki to prevent coronary thrombosis and embolism, and so these were added to the MIS-C regimen.
Some of the adults with COVID-19 were seriously ill, and they were given anti-inflammatory drugs, such as anti-tumour necrosis factor (Anti-TNF), and anti-interleukins (Anti-IL-1 and Anti-IL6). Some paediatricians have tried out a few of these biological medicines to treat severe MIS-C
Currently it is still not certain which treatment works best, because no double-blind controlled trials have been carried out.
MECHANISMS OF ACTION
The exact mechanisms of action how the coronavirus can cause such serious inflammatory reactions, is still being investigated. Below are some theories on how the virus can trigger off such a toll on our body.
(For a more detailed account of the mechanisms by which coronavirus is postulated to cause MIS-C, please refer to the Lancet article cited below by Li Jiang, Kun Tang, Mike Levin, et al.)
CONCLUSIONS
COVID-19 has spread throughout our planet, infecting over 300 million people, and taking away 1 million lives. It affects older adults more severely, but the young are not spared. In recent months, a new disease has emerged, resembling several diseases including Kawasaki Disease, toxic shock syndrome, and macrophage activation syndrome. It has been given the name Multisystem Inflammatory Syndrome in Children (MIS-C).
This life-threatening disease can lead to shock, heart failure, coronary aneurysms, respiratory failure, acute kidney injury, and serious blood clots in the arteries and veins.
Treatment is available, but the long-term effects of this disease remain uncertain. One should be cautious in trying not to over-reassure the patients or their relatives of the long-term outcomes. If we look at the examples taken from severely affected adults, one cannot be too complacent predicting their prognosis. Some of these adults appear to have fully recovered from the initial onslaught of the virus, only to later discover a serious unexpected complication, like a serious blood clot, or breathlessness, fatigue, persistent loss of smell and taste, or damage to the lungs, heart, kidneys, or brain.
While we are waiting for an effective and safe vaccine, we can prevent COVID-19 by wearing masks, safe-distancing, and washing our hands. If you do not get COVID-19, then you will not pass it onto the children. Our philosophy is to err on the side of caution: prevention is better than cure!
On a final note, we must thank all the health care workers and many others, who have worked tirelessly to prevent and save the lives of so many from the consequences of the COVID-19 pandemic.
Written by Kenneth Lyen
30 Sept 2020, Revised 7 May 2021
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REFERENCES
Multisystem Inflammatory Syndrome in Children.
https://en.wikipedia.org/wiki/Multisystem_inflammatory_syndrome_in_children
Michael Levin. Childhood Multisystem Inflammatory Syndrome.
https://www.nejm.org/doi/full/10.1056/NEJMe2023158
Riphagen S, Gomez X, Gonzales-Martinez C, Wilkinson N, Theocharis P. Hyperinflammatory shock in children during COVID-19 pandemic Lancet 2020; May 7. doi: 10.106/S0140-6736(20)31094-1.
Kawasaki disease. https://emedicine.medscape.com/article/965367-overview#showall
Lyen K. Kawasaki Disease. https://kenlyen.wixsite.com/website/kawasaki
Toxic shock syndrome. https://emedicine.medscape.com/article/169177-overview
Macrophage activation syndrome. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124446/
WHO Case Definition of MIS-C: https://www.who.int/docs/default-source/coronaviruse/final--misc-crf-18-may-2020-who.pdf?sfvrsn=8839181a_4
CDC Case Definition of MIS-C: https://www.uptodate.com/contents/image?imageKey=PEDS%2F128201&topicKey=ID%2F127454&source=outline_link
Whittaker E et al Clinical Characteristics of 58 Children With a Pediatric Inflammatory Multisystem Syndrome Temporally Associated With SARS-CoV-2. https://jamanetwork.com/journals/jama/fullarticle/2767209
Li Jiang, Kun Tang, Mike Levin et al. COVID-19 and multisystem inflammatory syndrome in children and adolescents. (This article describes the mechanisms of action of coronavirus causing MIS-C).
https://doi.org/10.1016/S1473-3099(20)30651-4
Vanessa Sancho-Shimizu, Petter Brodin, Aurelie Cobat et al. SARS-CoV-2–related MIS-C: A key to the viral and genetic causes of Kawasaki disease? J Exp Med 2021; 218: 1-16. https://doi.org/10.1084/jem.20210446
Lyen K. Cytokine Storm. https://kenlyen.wixsite.com/website/cytokine-storm