CASE

A 6-month-old vaccinated, previously healthy boy presented to the ED with fever, rash, and irritability. He had fever for four days (Tmax 102°F).  Three days prior, he also developed a red non-pruritic rash and oral lesions. The rash started on his face and progressed to the rest of his body, sparing his palms and soles. His eyes have been red and irritated. He had decreased oral intake and poor urine output. His mother had been giving acetaminophen and ibuprofen. There had been no known sick or COVID-19 contacts.

Vital signs in the ED were notable for blood pressure of 96/79, heart rate of 200, temporal temperature of 38.1 °C (100.6 °F), respiratory rate of 70, and oxygen saturation of 99%.

Physical exam was notable for an irritable but active boy. He has conjunctival injection, dry mucous membranes, erythematous tongue with prominent papillae, and cracked erythematous lips. No lymphadenopathy was present. Heart and breath sounds were normal. Skin exam was notable for diffuse blanching erythematous coalescing patches on face, trunk, extremities and GU area sparing palms and soles. Hands and feet were swollen. Capillary refill was less than 2 seconds. 

 Laboratory evaluation was notable for elevated CRP (136.9 mg/L) and elevated D-dimer (724 ng/mL). Compete metabolic panel was notable only for mildly elevated ALT (76 IU/L). CBC was normal.  Troponin was normal and BNP was mildly elevated at 55.8 pg/mL. Urinalysis with 31 WBC’s, trace leukocyte esterase, no nitrites (catharized specimen). Blood and urine cultures and a respiratory pathogen panel (includes COVID-19 testing) were sent.

DIAGNOSIS

This child presented with four days of a febrile illness. His exam was notable for tachycardia, rash, conjunctivitis. The differential diagnosis for this patient was broad and included: Kawasaki disease, multisystem inflammatory syndrome in children (MIS-C), staphylococcal or streptococcal toxic shock syndrome, bacteremia, viral infection, pneumonia, UTI. The patient continued to have fevers after admission and was diagnosed with Kawasaki disease. 

DISCUSSION

Kawasaki Disease

Kawasaki Disease (KD) is an acute, self-limited vasculitis that can lead to coronary artery aneurysm and cardiovascular shock. It is the most common cause of acquired heart disease in developed countries. KD is typically seen in children younger than 5 years old, most commonly in children of Asian descent and least commonly in Caucasian children. [1] It is postulated that an infectious agent enters the respiratory tract and triggers an inflammatory cascade. [2] This hyper-inflammatory state affects cardiac tissue leading to myocarditis, arteritis, and coronary aneurysm, resulting in reduced ejection fraction and cardiogenic shock. [1]

Children typically present with multiple days of fever and malaise, which can last 1-2 weeks. Cardiac involvement usually occurs 4-6 weeks after initial symptoms. [1]

Criteria for KD published by the American Heart Association (AHA) are as follows [2]:

• Fever for 5 days or more.

• At least 4 of the following criteria:

• Bilateral painless, nonexudative conjunctival injection, with limbic sparing (figure 3).

• Erythematous mouth, strawberry tongue or red, cracked lips

• Polymorphous exanthem

• Swelling of hands and feet with erythema of the palms and soles

• Cervical lymphadenopathy

 Atypical Kawasaki Disease

The criteria for KD above does not identify all affected children. The diagnosis of atypical KD should be considered in children with prolonged unexplained fever, less than 4 of the AHA criteria, compatible laboratory findings, or concerning echocardiographic findings (such as coronary artery aneurysm or reduced EF) (Figure 4). [2]

Treatment

Treatment is targeted at suppressing the inflammatory response and preventing cardiac involvement. Patients should receive high dose IVIG as well as high dose aspirin until the patient becomes afebrile. [1] Corticosteroids may decrease risk of developing cardiac abnormalities and duration of hospitalization. Most studies have shown no harm to adding steroids. [1, 3, 4]

Treatment of KD in the emergency department should be targeted at stabilization with intravenous fluids, vasopressors, and antipyretics. While inpatient, cardiology and infectious disease consultation is recommended. 

MISC-C

Presentation/Pathophysiology

Since April 2020, several cases of hyperinflammatory shock linked to COVID-19 in children have been reported. This syndrome has many overlapping features with KD, but is defined as Multisystem Inflammatory Syndrome in Children (MIS-C). [5] As the name suggests, it is characterized by multi-organ involvement which typically includes fever, rash, conjunctivitis, gastrointestinal symptoms, and elevated markers of inflammation. MIS-C is a hyperinflammatory shock state that occurs typically 2-4 weeks after COVID-19 infection. [5] Though many of the symptoms between COVID-19 MIS-C and KD overlap, age of the patient and the presence of COVID-19 antibodies are distinguishing features. MIS-C is usually seen in older children and adolescents, whereas KD is often seen in children under 5 years. [6] An increased prevalence of MIS-C in children of African and Hispanic descent was noted in several studies. [5,6]

The CDC provides the following definition for MISC-C [7]:

• Patient aged <21 years

• Fever >24 hours

• Laboratory evidence of inflammation (elevated CRP, ESR, fibrinogen, procalcitonin, d-dimer, ferritin, LDH, or IL-6, elevated neutrophils, reduced lymphocytes and low albumin)

• evidence severe illness requiring hospitalization with multisystem (>2) organ involvement (cardiac, renal, respiratory, hematologic, gastrointestinal, dermatologic or neurological)

AND

• No alternative plausible diagnosis

AND

• Positive for recent COVID-19 infection or COVID-19 exposure within four weeks of symptom onset. 

There is a wide array in the severity of illness for MIS-C, ranging from clinically stable to decompensated shock. In one study of 33 cases, reduced ejection fraction was seen in 63% of patients. [6] It is thought that MIS-C is an antibody-mediated cytokine storm that results in myocardial injury, including coronary aneurysms, similar to KD [8, 9, 10].  

Treatment

Though there is much still to learn about MIS-C, elevated inflammatory markers suggest a role of immunomodulatory therapies. In several studies, IVIG and corticosteroids were given to patients. [6, 12] Tocilizumab, a humanized monoclonal antibody against the IL-1 and IL-6 receptors, was also used as these patients often had high levels of these cytokines. [6, 11, 12] IVIG and Tocilizumab may take time to be prepared and may not have immediate effect. As such, the emergency physician’s priority is to stabilize the patient. Patients may require mechanical ventilation, pressor support, and even ECMO in some cases. [6] All emergency physicians typically have access to steroids, and there should be strong consideration for administration in concerning cases. With supportive and immunomodulatory care, most patients do well with normalization of cardiac function. [5]

CASE RESOLUTION

The patient’s presentation, specifically four days of fever, conjunctival injection, cracked lips, and rash raised concern for the diagnosis of KD. Given the COVID-19 pandemic, MIS-C was also in the differential. Given initial tachycardia, bedside echocardiogram was performed, which was normal. IV fluids and antipyretics were administered in the ED and the patient’s hemodynamics improved. While admitted to the floor, he continued to have up to 5 days of fever, fulfilling the criteria for KD. He was started on IVIG, high dose ASA, and steroids. COVID-19 antibody testing was negative. After 4 days of treatment and monitoring, he was discharged in good condition with aspirin and a steroid taper. 

AUTHOR: Camila Tyminski, MD is a second year emergency medicine resident at Brown University/Rhode Island Hospital.

FACULTY REVIEWERS: Meghan Beucher, MD and Alicia E. Genisca, MD are pediatric emergency medicine physicians at Hasbro Children’s Hospital

REFERENCES

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7. Centers for Disease Control and Prevention Emergency preparedness and response. https://emergency.cdc.gov/han/2020/han00432.asp

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9. Tunuguntla H., Jeewa A., Denfield S.W. Acute myocarditis and pericarditis in children. Pediatr Rev. 2019;40:14–25

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