August 31, 2020

Multisystem Inflammatory Syndrome in Children (MIS-C) vs Kawasaki Disease

Case Presentation: A 4-year-old previously healthy Hispanic female presented to the ED with a diffuse rash and facial swelling, concerning for an apparent allergic reaction. She was rushed into the treatment area for evaluation of possible anaphylaxis and respiratory assessment. She was tachycardic with a heart rate in the 130s, tachypneic, and borderline hypotensive for her age. Initial exam was negative for wheezing or stridor, but she had edema to the face and neck with a red raised rash covering her face. Epinephrine, Benadryl, and Solumedrol were ordered STAT given concern for airway compromise secondary to a severe anaphylactic reaction.

Additional information from mom revealed no prior history of anaphylaxis, no new food/medication ingestions or topical exposures, no known allergies, and no significant past medical history. Of note, she had been seen in the ED three days earlier, diagnosed with Strep Pharyngitis, and discharged after treatment with IM Penicillin G. The patient was tearful, ill appearing, and withdrawn. On a quick review of systems, mom reports that over the last five days she initially had a high fever (102o F) and sore throat, followed by anterior neck swelling on day 2, with vomiting, diarrhea, and the rash presenting on day 4. On secondary examination, she was noted to be febrile in the ED, and physical exam was significant for diffuse blanching maculopapular rash, tender cervical lymphadenopathy, dry lips, conjunctivitis, and bilateral hand and foot edema and erythema. While her presentation was most consistent with Kawasaki disease, given the current pandemic required Multisystem Inflammatory Syndrome in Children following COVID-19 exposure (MIS-C) was also high on the list of differential diagnoses. Other diagnoses considered included: other viral exanthems (EBV, CMV, measles, adenovirus), Scarlet Fever, Toxic Shock Syndrome, Staphylococcal Scalded Skin Syndrome, Stevens-Johnson Syndrome, allergic reaction, and sepsis.

ED Course:

Considering MIS-C as a likely alternative diagnosis, a slower approach to fluid resuscitation was utilized instead of the traditional 20 cc/kg bolus used in sepsis/septic shock to better monitor her fluid status given the potential for fluid overload and the rapid development of acute heart failure. Initial resuscitation was started with a 10 cc/kg bolus of NS. Her vital signs and repeat physical exam were essentially unchanged following the first bolus, so an additional 10 cc/kg bolus was administered. Ceftriaxone and Vancomycin were also initiated in the ED with blood and urine cultures pending at the time of admission. EKG showed sinus tachycardia and Chest XR in ED was negative for pneumonia or any other acute cardiopulmonary findings. Additional laboratory workup is seen below. She was admitted to the Pediatric ICU for further management of Kawasaki Disease vs MIS-C.

Discussion:

Although this patient was negative for COVID antigens and antibodies, it is possible that she may have cleared the infection by the time she developed KD symptoms. Furthermore, it is important to note that the novelty of the virus leads to uncertainties regarding the sensitivity and specificity of COVID-19 RT-PCR testing and antibody detection and interpretation. Many recent studies, although limited by size and duration, have shown that these Kawasaki-like symptoms can develop weeks after exposure to COVID-19, and the majority of patients are not acutely infected with the virus at the time of presentation (5). On the one hand, antibodies are generally fairly reliable four weeks post infection, though there are some cases that have shown that even in patients with positive RT-PCR results, almost 19% may be IgG seronegative at four weeks following exposure and up to 40% after eight weeks (3).

There is also significant overlap in symptomatology and pathophysiology of the two disease processes. Initial studies have provided strong evidence showing that COVID preferentially targets the protein angiotensin-converting-enzyme 2 (ACE2) on endothelial cells resulting in a systemic vasculitis similar to that seen in KD (6). This evidence is further supported by the fact that MIS-C generally presents with physical exam findings consistent with a diagnosis of atypical KD. Additionally, in both severe MIS-C and KD Shock Syndrome, there may be associated left heart systolic dysfunction and significant hypotension requiring vasoactive medications for hemodynamic support (1). It is also known that KD has been associated with multiple viruses, including the seasonal coronavirus strain linked to the common cold. With this knowledge and understanding, it may be more appropriate to describe this disease process as COVID-19 associated KD instead of trying to differentiate between MIS-C and KD (2). It is very possible that MIS-C has been improperly classified as a separate entity from KD, when perhaps it is the same post-viral process, we have been studying for years with Kawasaki Disease, simply with the addition of a newly identified “Pathogen X.” The major difference in this case is that SARS-Cov-2 would be the first virus simultaneously linked to Kawasaki Disease and a global pandemic.

Considering these factors, in combination with the high prevalence of asymptomatic COVID carriers within the population, the presence of GI symptoms, and lab results that were consistent with an acute inflammatory syndrome, MIS-C remained high in the list of differential diagnoses.

Figure 1. Possible Link Between COVID-19 and KD

Diagnosis:

There is no single test that provides a definitive diagnosis of KD. The diagnosis is based on clinical presentation and supported by characteristic laboratory abnormalities. According to the AHA, in order to make a diagnosis of Typical KD, a child must have a fever for at least five days AND have four of the five additional physical exam findings:

  • Conjunctivitis (bilateral, painless, non-purulent)
  • Mucocutaneous changes (cracked lips, strawberry tongue, erythema, pharyngitis)
  • Polymorphous rash (diffuse, macular, may be scarlatiniform)
  • Extremity changes (erythema, edema, desquamation)
  • Lymphadenopathy (generally cervical and unilateral)

Patients with fewer than 4 of the above findings are considered to have Atypical KD.

Regarding the laboratory evaluation, almost all inflammatory markers and acute phase reactants are elevated given the disease’s association with acute inflammatory process.  CRP > 3 and ESR > 40 are seen in both typical and atypical KD. More severe disease, termed Kawasaki Shock Syndrome, often requires the use of vasopressors for hemodynamic support and is associated with increasingly high levels of CRP, Procalcitonin, d-dimer, and IL-6 (8). Leukocytosis and thrombocytosis are also common findings. Hypoalbuminemia is associated with increased disease severity due to microvascular permeability and resultant peripheral edema. Elevations in NT-proBNP and troponin reflect cardiac inflammation and edema as opposed to myocardial ischemia (1). Other findings of undefined significance include lymphopenia, elevated LFTs, hyponatremia, hyperbilirubinemia, and sterile pyuria.

Future options for testing include the use of serum and urinary biomarkers that have been found to be directly elevated in response to KD and later improve with IVIG administration (7).

Case Conclusion:

She received treatment with IVIG upon admission and had an uncomplicated inpatient course. Transthoracic echocardiogram showed normal cardiac structure and function with no evidence of proximal coronary artery aneurysm or ectasia. Initial urinalysis was consistent with UTI but repeat urinalysis the day following admission was negative. Stool PCR studies were positive for Enteropathogenic E. coli (EPEC). She continued to improve and was transferred to the floor after two days in the Pediatric ICU. Blood and urine cultures were also negative after 48 hours and antibiotics were discontinued. Parotid gland ultrasound showed cervical LAD. She was discharged on hospital day #4 with a diagnosis of Kawasaki Disease based on her negative COVID studies and relatively quick recovery. Her parents were instructed to continue giving her aspirin daily for continued prevention of complications related to coronary artery aneurysm. She is scheduled to follow up with pediatric cardiology in two weeks for repeat echocardiogram.

 Guest Post By

C. Blair Gaines, MD
Emergency Medicine, PGY-3
Jackson Memorial Hospital
Miami, FL

References:

  1. Belhadjer Z et al. Acute Heart Failure in Multisystem Inflammatory Syndrome in Children (MIS-C) in the Context of Global SARS-CoV-2 Pandemic. Circulation 2020. PMID: 32418446
  2. Calabri GB et al. COVID-19 and Kawasaki Disease: A Glimpse at the Past for a Predictable Future. Pediatric Cardiology 2020. PMID: 32462467
  3. Long QX et al. Clinical and Immunological Assessment of Asymptomatic SARS-CoV-2 Infections. Nature Medicine 2020. [Link is HERE]
  4. Ramphul K et al. Kawasaki Disease: A Comprehensive Review. Archives of Medical Science – Atherosclerotic Diseases 2018. PMID: 30775588
  5. Sandhaus H et al. Association Between COVID-19 and Kawasaki Disease: Vigilance Required From Otolaryngologists. Otolaryngology – Head and Neck Surgery 2020. PMID: 32423291
  6. Sardu C et al. Hypertension, Thrombosis, Kidney Failure, and Diabetes: Is COVID-19 an Endothelial Disease? A Comprehensive Evaluation of Clinical and Basic Evidence. Journal of Clinical Medicine 2020. PMID: 32403217
  7. Seaton K et al. Evidence-Based Management of Kawasaki Disease in the Emergency Department. Pediatric Emergency Medicine Practice 2015. [Link is HERE]
  8. Toubiani J et al. Kawasaki-Like Multisystem Inflammatory Syndrome in Children During the COVID-19 Pandemic in Paris, France: Prospective Observational Study. BMJ 2020. PMID: 32493739
  9. Xu S et al. COVID-19 and Kawasaki Disease in Children. Pharmacological Research 2020. PMID: 32464327

Post Peer Reviewed By: Mizuho Morrison, DO (Twitter: @mizuhomorrison) and Salim R. Rezaie, MD (Twitter: @srrezaie)

Cite this article as: C. Blair Gaines, MD, "Multisystem Inflammatory Syndrome in Children (MIS-C) vs Kawasaki Disease", REBEL EM blog, August 31, 2020. Available at: https://rebelem.com/multisystem-inflammatory-syndrome-in-children-mis-c-vs-kawasaki-disease/.
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C. Blair Gaines, MD

Emergency Medicine, PGY-3, Jackson Memorial Hospital, Miami, FL
3 Comments
  • Robin Whittle
    Posted at 10:51h, 02 September Reply

    Please read this research from Italy, which seems most doctors are unaware of: Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities? Stefano Stagi et al. Clinical Rheumatology volume 35, pages 1865–1872 (2015) https://link.springer.com/article/10.1007/s10067-015-2970-6 (Paywalled.)
    https://sci-hub.tw/10.1007/s10067-015-2970-6 .

    The patients were 21 girls and 58 boys, average age 5.8 years. Their average 25OHD levels were 9.2ng/ml, while age-matched healthy controls averaged 23.3ng/ml. In the patients who developed coronary artery abnormalities, the average 25OHD level was 4.9ng/ml.

    The best indication of the 25OHD levels of our ancestors comes from research into traditionally living Maasai pastoralists and Hadzabe hunter gatherers, who average 46ng/ml: https://www.ncbi.nlm.nih.gov/pubmed/22264449 .

    This accords with recent research recommending a 40 to 60ng/ml target range (Immunologic Effects of Vitamin D on Human Health and Disease, Charoenngam & Holick Nutrients 2020, 12(7), 2097 https://doi.org/10.3390/nu12072097) and the same recommendation of four dozen MDs and researchers since 2008: https://www.grassrootshealth.net/project/our-scientists/ .

    25OHD is an essential input for the autocrine signaling systems of many cell types, including especially immune system cells for the purposes of direct defense against pathogens and for regulating such immune responses. Another recent article makes the same recommendation. (Vitamin D status: a key modulator of innate immunity and natural defense from acute viral respiratory infections, A. Fabbri et al. https://www.europeanreview.org/article/20876), stating that 40ng/ml 25OHD (AKA calcifediol & calcidiol) is the minimum required to keep the CYP27B1 enzyme inside the cells busy converting it to 1,25OHD (AKA calcitriol) which activates the vitamin D receptors there. “We also believe that maintenance of circulating 25-hydroxyvitamin D levels of 40 – 60ng/ml would be optimal, since it has been suggested that concentrations amounting to 40ng/ml represent the beginning point of the plateau where the synthesis of the active form calcitriol becomes substrate-independent.”

    Numerous researchers report that COVID-19 severe symptoms correlate with low 25OHD levels. See my site https://aminotheory.com/cv19/#lr for the latest research. There are no doubt other nutritional deficiencies which contribute to the weak and dysregulated (overly aggressive, hyper-inflammatory) immune responses which drive COVID-19 endothelial destruction and so the hypercoagulative state which can damage all parts of the body. These include inadequate omega 3 fatty acids, boron, vitamin C, several B vitamins and, according to one report, vitamin K: https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaa1258/5898121 . However, vitamin D is the best researched and least expensive of these, with the lowest quantities required for repletion.

    It is reasonable to assume that this child had very low 25OHD levels and that this, combined with a viral infection trigger, and probably one or more genetic proclivities lead to the intense inflammatory immune system dysregulation which is the central feature of KD / MIS-C – and of severe COVID-19. While the latter usually manifests as viral and immune-system driven destruction of the pulmonary endothelium and the others as similar processes in other parts of the vasculature, the differences between these conditions are minor. The problem is extreme immune system dysregulation greatly exacerbating what might otherwise be a swiftly controlled viral infection.

    The real puzzle is why so many doctors do not immediately think of vitamin D deficiency when treating such conditions, including ARDS and sepsis. Perhaps they do not understand the need for robust 25OHD levels for immune cell autocrine signalling. This article is pertinent: An autocrine Vitamin D-driven Th1 shutdown program can be exploited for COVID-19 Reuben McGregor et al. 2020-07-19 https://www.biorxiv.org/content/10.1101/2020.07.18.210161v1

    Th1 lymphocytes isolated from the lungs of patients with severe COVID-19 symptoms have an autocrine signaling pathway which should be activated, to turn the cells off their hyper-inflammatory program which produces pro-inflammatory IL-17 and instead make them produce the anti-inflammatory cytokine IL-10. However, this anti-inflammatory pathway is not working due to lack of 25OHD. Similar cells from healthy controls have no such problem. Unfortunately no blood 25OHD levels are reported.

    While the various medications given no-doubt helped this child, no nutrients were given which might improve her immune system regulation. Perhaps hospital food and/or IVIG eventually improved her 25OHD levels enough for her immune cell autocrine signaling systems to work a lot better. However, this is a long process during which suffering and harm continues.

    The most obvious alternative, or additional, approach would be oral or parenteral D3 cholecalciferol. However, hepatic conversion to 25OHD takes some days, and there may be problems oral absorption and liver function in the child’s distressed state.

    Oral 25OHD (calcifediol AKA Rayaldee) is better absorbed than D3 (PMC6566727) and would lead to vitamin D repletion within an hour or so. Perhaps parenteral calcifediol is also an option.

    The etiology of KD is widely regarded as a mystery. The Stagi et al. research, together with all that is known about vitamin D deficiency driving immune system dysregulation makes it clear that low vitamin D is the single most important, easily correctable deficiency driving KD / MIS-C – as it is with severe COVID-19.

    Considering that 0.125mg (5000IU) D3 a day will raise average weight adults’ 25OHD levels to about 50ng/ml, that this is a gram every 22 years, and that pharma grade D3 costs USD$2.50 a gram ex-factory it is difficult for me to understand why this safe nutrient is is not more widely supplemented. There is little vitamin D in food or multivitamins. High elevation sunlight exposure is not available for many people all year round – and pigmented skin and the risk of skin cancer raise further difficulties. (BTW, I am an electronic technician and computer programmer.)

  • Robin Whittle
    Posted at 05:43h, 05 September Reply

    I was hoping someone else would comment, since KD / MIS-C is more prevalent due to COVID-19.

    Thanks for publishing my detailed comment. After writing it I found an article concerning oral 250HD calcifediol supplementation for hospitalised adult COVID-19 patients in Cordoba, Spain. All patients were treated with hydroxychloroquine and azithromycin. https://www.sciencedirect.com/science/article/pii/S0960076020302764 .

    The supplementation group of 50 patients received 0.532mg (21,280IU) calcifideol on day 1, 0.26mg (10,640IU) on days 3 and 7, and then 0.26mg every week until discharge.

    Of the 26 patients in the control group, 13 (50%) needed intensive care – and 2 of them (8%) died.

    In the supplementation group only one required intensive care (2%) and none died.

    25OHD levels were not measured. The control group had more patients with hypertension and diabetes, but overall comorbidities (BMI / obesity was not considered) were about the same in the two groups.

    This stark, successful outcome demonstrates the effectiveness of immediately available oral 25OHD calcifediol. A little more than one cubic millimetre of the form of vitamin D required for good autocrine signalling made a far greater difference to ICU admission and death rates than any treatment I have heard of, for COVID-19 or other acute immune dysregulatory conditions.

    Randomisation lead to 13 patients needing intensive care who would probably have recovered faster and not needed this if they had been given this fast-acting vitamin D supplement. Two of them died when they almost certainly would have survived with the supplement.

    There is a plenty of research on the importance of circulating 25OHD as the feedstock for conversion to 1,25OHD in the autocrine signalling pathways of immune system cells.

    Vitamin D is not a drug. It is a safe, very well researched, nutrient – almost ubiquitously deficient without supplementation by standard of the 40 to 60ng/ml ancestral levels and target range for immune system health.

    Is there any reason why doctors would delay repleting patients’ consistently low 25OHD levels, given the results of this trial?

    Are some doctors inclined to wait for another RCT, with more control arm patients suffering and dying, while they their own patients’ deficiencies remain uncorrected in the months or years this will take?

    Why would a doctor, knowing the research and the results of this trial hesitate to supplement vitamin D – or in a hospital setting use D3 or D2 if they could use 25OHD calcifediol instead?

    Most patients have low 25OHD levels. Very few people have levels above the 150ng/ml level about which toxicity might be a problem. This can only occur due to long-term supplementation with quantities far beyond those required to achieve 40 to 60ng/ml. Even if their levels were above the 100ng/ml “high end of normal” range, the quantities used in this trial, over a few weeks, would have little effect on such levels.

    25OHD blood test results are typically not available for days or a week. The patient could decompensate and die in that time if vitamin D repletion is withheld due to an over-abundance of caution regarding an extremely remote chance of them already having potentially toxic levels.

    Sarcoidosis is regarded as a contraindication for vitamin D supplementation. Several types of immune cells are squabbling amongst themselves, clumping together all over the body, and releasing 1,25OHD into the circulation, potentially leading to hypercalcemia. However, according to Calcium and Vitamin D in Sarcoidosis: Is Supplementation Safe? Lieke S Kamphuis et al, 2014
    https://sci-hub.tw/https://doi.org/10.1002/jbmr.2262 patients with this particular immune dysregulatory disorder also do better with vitamin D and calcium supplementation.

    Some articles on vitamin D toxicity: https://doi.org/10.1359/jbmr.07s221 , https://doi.org/10.1016/j.mayocp.2015.03.015 , https://doi.org/10.1016/j.mayocp.2015.02.012 , https://doi.org/10.3389/fendo.2018.00550 .

    • Salim Rezaie
      Posted at 09:06h, 05 September Reply

      Appreciate your thoughtful and detailed comment. 50 patients is hardly enough of a sample size to base any type of clinical decision making on. Many physicians are already using Via D supplementation without checking levels. The evidence for things like Vitamin C, Zinc, and Vitamin D are far from robust, but with minimum side effect profiles and the want to help patients, many are already using.

      Salim

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