
Am Fam Physician. 2021;104(2):244-252
Published online August 12, 2021.
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.
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.7–11 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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