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Am Fam Physician. 2021;104(2):244-252

Published online August 12, 2021.

This clinical content conforms to AAFP criteria for CME.

Author disclosure: No relevant financial affiliations.

Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) are inflammatory conditions that present diagnostic and therapeutic challenges to the physician. Although many of their features overlap, they are two distinct conditions. KD is a febrile illness most commonly affecting children younger than five years. It manifests with prolonged fever and at least four of the following features: bilateral bulbar conjunctivitis, mucositis, diffuse maculopapular rash, extremity changes, and cervical lymphadenopathy of 1.5 cm or more in diameter. Patients with MIS-C may have many of the same manifestations but tend to have higher rates of gastrointestinal and neurocognitive symptoms and signs of shock on presentation. Both conditions are associated with cardiac sequelae, including coronary artery aneurysms, although children with MIS-C are at high risk of developing ventricular dysfunction and depressed cardiac output. Lymphocytopenia, thrombocytopenia, elevated troponin, and elevated B-type natriuretic peptide are key laboratory findings of MIS-C that can help distinguish it from KD. The use of intravenous immune globulin is well established in KD and also appears to have a role in the treatment of MIS-C. Aspirin has been used in KD for an anti-inflammatory effect, and low-dose aspirin is recommended for MIS-C to reduce the risk of thrombosis. In addition to supportive care, patients with MIS-C may benefit from immunomodulatory medications, although data on this topic are evolving.

First described in Japan in 1967, Kawasaki disease (KD) is a vasculitis affecting small- and medium-sized vessels; it is predominantly seen in children younger than five years.1 This febrile illness is characterized by systemic inflammation and is the most common cause of acquired coronary artery disease in children.2 With the emergence of multisystem inflammatory syndrome in children (MIS-C), a new inflammatory syndrome associated with COVID-19, KD has received increased attention because features of the diseases overlap.

Clinical recommendationEvidence ratingComments
A diagnosis of classic KD is made in the presence of prolonged fever (five or more days) and four or more of the following principal features: oral mucosal inflammation; bilateral bulbar conjunctivitis; a diffuse maculopapular rash; extremity changes, including erythema and edema of the hands and feet; and cervical lymphadenopathy of 1.5 cm or more in diameter.2 CConsensus opinion, society guidelines
For patients with a suspected diagnosis of KD or MIS-C, echocardiography should be performed promptly but should not delay treatment.2,7 CExpert guidelines that included studies in limited populations and with few randomized controlled trials; benefits greatly outweigh risks
Physicians concerned about MIS-C should pursue a diagnostic workup that includes complete blood count, complete metabolic panel, erythrocyte sedimentation rate, C-reactive protein, and SARS-CoV-2 polymerase chain reaction and/or serologies; additional workup may be necessary, including B-type natriuretic peptide, troponin, ferritin, prothrombin time, partial thromboplastin time, d dimer, fibrinogen, lactate dehydrogenase, cytokine panel, electrocardiography, and chest radiography.19 CExpert opinion, society guidelines
Patients with KD should receive IVIG (2 g per kg given as a single dose).2,2024 CMultiple randomized controlled trials and meta-analyses looking at coronary artery abnormalities
Suspected cases of MIS-C should be referred promptly to the hospital. Management of MIS-C requires a multidisciplinary team of specialists including, but not limited to, pediatric critical care physicians, pediatric cardiologists, pediatric hospitalists, pediatric rheumatologists, pediatric infectious disease specialists, and pediatric hematologists.19 CExpert opinion
Patients with MIS-C should receive IVIG (2 g per kg given as a single dose), and concurrent corticosteroids should be considered.19 CExpert opinion, observational studies

Epidemiology

Although the underlying cause of KD remains unknown, the epidemiology and pathophysiology suggest that it is an inflammatory response in a genetically susceptible host to an infectious or other exogenous trigger. A number of viruses have been implicated as potential triggers for KD, including coronaviruses (non–COVID-19 strains).3,4 KD is an illness predominantly occurring in toddlers, with a mean age of three years in the United States (76% of cases occur in children younger than five years).5 There is a predilection for children of Asian and Pacific Islander descent,5 and boys are affected slightly more often than girls (1.5:1).6

In contrast, MIS-C affects a wider age range, from one week to 20 years with a median age of seven to nine years.711 In the United States, 62% of patients are Hispanic or Latino (32%) or non-Hispanic Black (30%)—the ethnic groups disproportionately affected by COVID-19.7 Similarly to KD, MIS-C occurs more often in boys (60%) than in girls.7

Symptoms

The clinical features of classic KD are shown in Table 1.2 A diagnosis of classic KD is made in patients with prolonged fever (five or more days) and four or more of the following principal features: oral mucosal inflammation; bilateral bulbar conjunctivitis; a diffuse maculopapular rash; extremity changes, including erythema and edema of the hands and feet; and cervical lymphadenopathy of 1.5 cm or more in diameter.2 Incomplete KD is a diagnosis made when a patient has fewer than four of the major criteria but has sufficient laboratory features or suggestive changes on echocardiography. The 2017 American Heart Association KD guidelines provide a diagnostic algorithm to assist with this often challenging diagnosis2 (Table 2).

Classic KD
Children with at least five days of fever and at least four of the following clinical features*:
 Oral mucous membrane changes, including any of the following:
Erythema, dryness, and/or cracking of the lips
Tongue erythema with prominent fungiform papillae (“strawberry tongue”)
Diffuse oropharyngeal mucosal erythema
 Bilateral, nonexudative bulbar conjunctivitis, often sparing the limbus
 Diffuse, erythematous, maculopapular rash primarily affecting the trunk and extremities
 Extremity changes: hand and foot edema, erythema, and/or painful induration of the palms and soles (acute phase) or periungual desquamation (subacute phase, two to three weeks after fever onset)
 Unilateral cervical lymphadenopathy (≥ 1.5 cm in diameter)
Suspected incomplete KD
Children with at least five days of fever and at least two to three of the criteria for classic KD or infants with prolonged, unexplained fever (≥ 7 days) who have the following findings:
 Elevated erythrocyte sedimentation rate (≥ 40 mm per hour) and/or elevated C-reactive protein (≥ 3 mg per dL [30 mg per L]), and
 A positive echocardiography§or three or more of the following laboratory findings:
Anemia for age
Thrombocytosis (platelet count ≥ 450,000 per μL [450 × 109 per L]) after day 7 of fever
Hypoalbuminemia (albumin ≤ 3 g per dL [30 mg per L])
Elevated alanine transaminase level
Leukocytosis (white blood cell count ≥ 15,000 per μL [15 × 109 per L])
Sterile pyuria (≥ 10 white blood cells per high-power field)
Additional comments
Because the clinical features of KD are nonspecific, physicians should consider other diagnoses with similar findings; alternative diagnoses should be sought, particularly in patients with conjunctival or pharyngeal exudates, oral ulcers, a bullous or vesicular rash, generalized lymphadenopathy, or splenomegaly.
Patients with KD can have a concurrent viral infection; therefore, identification of a viral pathogen does not preclude the diagnosis of KD.
Given the potential for a missed KD diagnosis and/or higher risk of coronary abnormalities, physicians should consider KD in the differential diagnosis for the following:
 Infants younger than 6 months with prolonged, unexplained fever and irritability or with prolonged fever and unexplained aseptic meningitis
 Patients with prolonged fever and unexplained shock that is ultimately culture-negative
 Patients with prolonged fever and cervical lymphadenopathy or retro-/parapharyngeal phlegmon whose course does not respond to appropriate antibiotic treatment
American Heart Association guidelines on Kawasaki disease
https://www.ahajournals.org/doi/10.1161/CIR.0000000000000484
Centers for Disease Control and Prevention: Multisystem Inflammatory Syndrome in Children
https://www.cdc.gov/mis/hcp/index.html
American College of Rheumatology: Multisystem Inflammatory Syndrome in Children
https://www.rheumatology.org/Portals/0/Files/ACR-COVID-19-Clinical-Guidance-Summary-MIS-C-Hyperinflammation.pdf

When diagnosing KD, physicians must have a strong understanding of the features of each major symptom. The conjunctivitis of KD is bilateral, nonexudative, and affects the bulbar conjunctiva but classically spares the limbus (Figure 1). The rash of KD is typically diffuse and maculopapular, often accentuated in the perineal region (Figure 2). The oral mucous membrane changes of KD can manifest as erythema of the oropharyngeal mucosa or lips; dryness, cracking, and/or peeling of the lips (Figure 3); or a “strawberry” appearance of the tongue. Anterior cervical lymphadenopathy is typically unilateral and involves at least one node larger than 1.5 cm in diameter. In contrast to bacterial lymphadenitis, the lymphadenopathy of KD is typically not associated with marked erythema of the overlying skin and is not exquisitely painful to palpation. Rarely, painful lymphadenopathy is the presenting feature of KD and may be misdiagnosed as bacterial lymphadenitis.12 The extremity changes of KD manifest as erythema and edema of the palms and soles and, at times, refusal to walk because of painful induration. Subacute extremity changes include periungual desquamation and deep transverse grooves across the nail lines, termed Beau lines. Outside of the major diagnostic criteria, profound irritability is commonly described. Children may also have arthritis or arthralgia, gastrointestinal complaints such as diarrhea and vomiting, or rhinorrhea and cough. Symptoms, physical examination findings, and laboratory evidence of viral infection should not exclude the diagnosis of KD because studies have reported that 30% to 40% of children who meet the diagnostic criteria of KD are also positive for at least one respiratory virus.3,13

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