Author
Robert Sundel, MD
Section Editors
Marisa Klein-Gitelman, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2013. | This topic last updated: jul 27, 2012.
INTRODUCTION — Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood [1]. KD also occurs rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy [2]. However, complications such as coronary artery aneurysms, depressed myocardial contractility and heart failure, myocardial infarction, arrhythmias, and peripheral arterial occlusion may develop and lead to significant morbidity and mortality. (See "Cardiovascular sequelae of Kawasaki disease".)
The clinical manifestations and diagnosis of KD are discussed in this review. The epidemiology, etiology, treatment, and complications, including cardiac sequelae, of Kawasaki disease are presented separately. Incomplete (atypical) KD and unique features in infants and adults are also reviewed separately. (See "Kawasaki disease: Epidemiology and etiology" and "Kawasaki disease: Initial treatment and prognosis" and "Cardiovascular sequelae of Kawasaki disease" and "Incomplete (atypical) Kawasaki disease" and
"Kawasaki disease: Complications".)
CLINICAL MANIFESTATIONS — The clinical features of KD reflect widespread inflammation of medium- and small-sized blood vessels. Diagnosis is based upon evidence of systemic inflammation, as evidenced by fever, in association with signs of mucocutaneous inflammation. The characteristic bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and lymphadenopathy typically develop after a brief nonspecific prodrome of respiratory or gastrointestinal
symptoms [3-8]. These clinical signs are the basis for the diagnostic criteria for KD (table 1) [9].
TABLE 1. Diagnostic criteria for Kawasaki disease
| The diagnosis of Kawasaki disease requires the presence of fever lasting at least five days without any other explanation combined with at least four of the five following criteria: |
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Mucous membrane findings are seen in approximately 90 percent of cases of KD, polymorphous rash in 70 to 90 percent, extremity changes in 50 to 85 percent, ocular changes in >75 percent, and cervical lymphadenopathy in 25 to 70 percent [7,10-12].
These findings are often not present at the same time. As an example, some patients have only developed fever and cervical lymphadenopathy by the time of admission (so-called KD with isolated cervical lymphadenopathy, KDiL) [13]. In one case series, these patients tended to be older and to have a more severe course, with increased risk of coronary artery disease and lack of response to intravenous immune globulin. Thus, repeated histories and physical examinations are important both for making a timely diagnosis of KD in children who fail to meet diagnostic criteria, as well as for appropriate consideration of alternative
diagnoses. (See 'Diagnosis' below.)
Fever — Fever is the most consistent manifestation of KD. It reflects elevated levels of proinflammatory cytokines, such as tumor necrosis factor and interleukin-6, which are thought to mediate the underlying vascular inflammation [14]. Fever is minimally responsive to antipyretic agents, and it typically remains above 38.5ºC during most of the illness. The diagnosis of KD should be considered in all children with prolonged
unexplained fever ≥five days. (See "Incomplete (atypical) Kawasaki disease".)
Conjunctivitis — Bilateral nonexudative conjunctivitis is present in more than 90 percent of patients. A predominantly bulbar injection typically begins within days of the onset of fever, and the eyes often have a brilliant erythema, which spares the limbus (picture 1).
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| Picture 1: Conjunctivitis in Kawasaki disease |
Children also are frequently photophobic, and anterior uveitis may develop [12,15]. Slitlamp examination may be helpful in ambiguous cases; the presence of uveitis provides further evidence for the diagnosis of KD, since it is more commonly seen in KD than in other diseases with similar presentations. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)
Mucositis — Mucositis often becomes evident as KD progresses. Cracked, red lips (picture 2) and a strawberry tongue (picture 3) are characteristic; the latter is a result of sloughing of filiform papillae and denuding of the inflamed glossal tissue. Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate, are suggestive of a disease process other than KD.
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| Picture 2.Cracked, red lips seen in Kawasaki disease |
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| Picture 3.Strawberry tongue |
Rash — The cutaneous manifestations of KD are polymorphous. The rash typically begins as perineal erythema and desquamation, followed by macular, morbilliform, or targetoid skin lesions of the trunk and extremities. Vesicular or bullous lesions are rare, but KD may trigger a psoriasiform eruption in children not previously recognized to have psoriasis [16- 19].
Extremity changes — Changes in the extremities are generally the last manifestation to appear. Children develop an indurated edema of the dorsum of their hands and feet (picture 4), and a diffuse erythema of their palms and soles.
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| Picture 4. Indurated edema of the dorsum of the hands as seen in Kawasaki disease (acute phase) |
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| Picture 5 |
The convalescent phase of KD is often characterized by sheet-like desquamation that begins in the periungual region of the hands and feet (picture 5), and by linear nail creases (Beau's lines). The prevalence of periungual desquamation in patients with KD has been reported to vary from 98 to 68 percent [20]. The lowest rate was documented in a retrospective review of patients treated at a tertiary center in the United States from 2003 to 2007. Factors that might have contributed to this lower prevalence than was seen in earlier reports include uniform treatment with high dose IVIG, and ethnic differences from Asian case series
[3,4,21,22].
Arthritis has been reported in 7.5 to 25 percent of patients [23,24]. The prevalence of arthritis was 7.5 percent in a retrospective Canadian study of 414 consecutive patients diagnosed with KD [23]. The large joints (ie, knee, ankle, and hip) were primarily involved. Oligoarticular involvement (arthritis of four or fewer joints) occurred in 16 patients and polyarticular involvement (arthritis of five or more joints) in 15 patients. Patients with arthritis were more likely to have increased levels of inflammatory markers (C-reactive protein [CRP], or erythrocyte sedimentation rate [ESR]) and neutrophils. Otherwise, there were no differences in clinical features, response to therapy, or clinical outcome between patients with or without arthritis.
Lymphadenopathy — Cervical lymphadenopathy is the least consistent feature of KD, absent in as many as half to three-quarters of children with the disease [11]. When present, lymphadenopathy tends to involve primarily the anterior cervical nodes overlying the sternocleidomastoid muscles [25]. Diffuse lymphadenopathy or other signs of reticuloendothelial involvement (eg, splenomegaly) should prompt a search for alternative diagnoses.
Cardiovascular findings — Cardiac manifestations during the first week to 10 days of illness may include tachycardia out of proportion to the degree of fever, gallop sounds, and muffled heart tones [2]. Severely ill patients, particularly young infants, may develop fusiform aneurysms of the brachial arteries that are easily palpable or visible in the axillae. In addition, young infants may have cold, pale, or cyanotic digits of the hands and feet due to reduced blood perfusion. Gangrene may, in rare cases, cause loss of fingers or toes
during this acute period. Cardiovascular findings are not part of the classical diagnostic criteria.
Other findings — The following nonspecific symptoms commonly occur in children within the first 10 days before diagnosis of KD, but are not included in the diagnostic criteria [5]:
· Diarrhea, vomiting, or abdominal pain — 61 percent
· Irritability — 50 percent
· Vomiting alone — 44 percent
· Cough or rhinorrhea — 35 percent
· Decreased intake — 37 percent
· Weakness — 19 percent
· Joint pain — 15 percent
LABORATORY FINDINGS — No laboratory studies are included among the diagnostic criteria for typical KD. However, certain findings may support the diagnosis of KD, particularly in ambiguous cases [1] (see 'Diagnosis' below and "Incomplete (atypical) Kawasaki disease", section on 'Laboratory tests'):
· Systemic inflammation is characteristic of KD. Typical manifestations include elevation of acute phase reactants (eg, C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]), leukocytosis, and a left-shift in the white blood cell count. Platelet counts generally rise by the second week of illness and may reach 1,000,000/mm3 (reactive thrombocytosis) in the most severe cases.
· Children with KD often present with a normocytic, normochromic anemia. Hemoglobin concentrations more than two standard deviations below the mean for age are noted in one-half of patients within the first two weeks of illness (table 2).
· Urinary microscopy commonly reveals white blood cells [26]. Pyuria is often of urethral origin and therefore may be missed on urinalyses obtained by bladder tap or catheterization [27]. In addition, white cells are mononuclear, and are not detected by dipstick tests for leukocyte esterase. Thus, children with suspected KD should have a clean voided or bagged urine specimen collected for microscopic
examination.
· In one retrospective series of 259 patients, 45 percent had at least one abnormal liver function test [28]. In a case-control series approximately 30 percent of 280 patients with KD had mild to moderate elevation of transaminases (eg, serum alanine aminotransferase >50 U/L) because of intrahepatic congestion [6]. In
addition, a minority of children develop obstructive jaundice from hydrops of the gallbladder.
· Cerebrospinal fluid (CSF) may display a mononuclear pleocytosis without hypoglycorrhachia or elevation of CSF protein. In a retrospective review, 46 of 520 children with KD underwent lumbar puncture [29]. In this subset of patients, 39 percent had elevated CSF white cell counts. The median count was 22.5 cells/mm3 with 6 percent neutrophils and 92 percent mononuclear cells, although cell counts as high as 320/mm3 with up to 79 percent neutrophils were reported. In a small case series of 10 children with KD, elevated CSF inflammatory cytokines (ie, IL-6 and sTNFR1) were reported in addition to CSF pleocytosis [30].
· Similarly, arthrocentesis of involved joints typically demonstrates a pleocytosis, with 125,000 to 300,000 white cells/mm3, primarily neutrophils [31].
· Children with KD develop significant perturbations in serum lipid profiles, including elevated triglycerides and low density lipoproteins, and depressed high density lipoproteins [2,32-34]. A return to normal may take years in untreated children, but generally occurs within weeks or months following IVIG therapy.
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DIAGNOSIS — Guidelines for the diagnosis of KD were established by Tomisaku Kawasaki in 1967. Diagnosis of KD according to these criteria requires the presence of fever lasting ≥five days, combined with at least four of the five following physical findings, without an alternative explanation (table 1) [1,36]:
· Bilateral bulbar conjunctival injection (picture 1)
· Oral mucous membrane changes, including injected or fissured lips (picture 2), injected pharynx, or strawberry tongue (picture 3)
· Peripheral extremity changes, including erythema of palms or soles, edema of hands or feet (acute phase) (picture 4), and periungual desquamation (convalescent phase) (picture 5)
· Polymorphous rash
· Cervical lymphadenopathy (at least one lymph node >1.5 cm in diameter)
Redness or crust formation at the site of Bacille Calmette-Guerin (BCG) inoculation is also suggested as a useful sign in several diagnostic guidelines [2,9]. In one series of 15,524 patients with KD and a history of BCG vaccination, 50 percent had this finding, compared with none of the 53 children admitted with respiratory syncytial virus or rotavirus infection who served as the control group [37].
As with all clinical criteria, these are imperfect guidelines with less than 100 percent sensitivity and specificity. Children who do not meet the criteria may have an incomplete or atypical form of KD; algorithms published in 2004 form the basis for identifying such cases [2]. In addition, Dr. Kawasaki published his guidelines before cardiac involvement was recognized in this disease, so they were never intended to identify children at risk for developing coronary artery abnormalities. Thus, it is not surprising that at least 10 percent of children who develop coronary artery aneurysms never meet criteria for KD [38]. (See "Incomplete (atypical) Kawasaki disease".)
Conversely, some patients who manifest five or six signs of KD may have other conditions.
One study of patients referred for possible KD found that the standard clinical diagnostic criteria for KD were fulfilled in 18 of 39 patients (46 percent) in whom other diagnoses were established [6]. (See 'Differential diagnosis' below.)
Delayed diagnosis — Treatment with IVIG within the first 10 days of illness reduces the prevalence of coronary artery aneurysms fivefold compared with children not treated with IVIG [39,40]. Thus, it is desirable to diagnose KD as soon as possible after the criteria are met (ie, not before the fifth day of illness), in order to initiate treatment and reduce the risk of coronary artery lesions. However, timely identification is challenging because the diagnosis is based upon nonspecific clinical signs and there is no definitive diagnostic test.
In a retrospective study of 562 patients diagnosed with KD at eight North American centers, 92 cases (16 percent) were diagnosed after the first 10 days of illness (ie, late diagnosis) [41]. Predictors of a delay in diagnosis of KD included age below six months, clinical presentation of incomplete KD, greater distance from a tertiary center, and variability between clinical centers. In contrast, socioeconomic status was not associated with a delay in diagnosis.
These findings suggest that practice variation in confirming a diagnosis of KD may in part contribute to a delayed diagnosis. The results of this study underscore the need for a high index of suspicion of KD, especially in young infants and patients who present with incomplete KD, in order to identify and treat patients in a timely manner. (See "Incomplete (atypical) Kawasaki disease".)
DIFFERENTIAL DIAGNOSIS — KD is most commonly confused with infectious exanthems of childhood [2,42,43].
Infectious diseases and other mimics of KD may have the following clinical features not commonly found in KD [2]:
· Exudative conjunctivitis
· Exudative pharyngitis
· Discrete intraoral lesions
· Bullous or vesicular rash
· Generalized lymphadenopathy
The presence of any of these findings and/or the absence of fever should suggest a diagnosis other than KD. Of note, concurrent infections are common in patients with KD, found in up to 40 percent of patients in one study [44]. In this review of 129 consecutive children seen with KD in Toronto, infection at the time of diagnosis did not affect response to therapy or outcome. However, another series found that concomitant viral infection was associated with a higher frequency of coronary artery dilatation [45]. In any event, diagnosis of an infectious condition does not preclude a concurrent diagnosis of KD.
The differential diagnosis of KD includes (table 3):
· Measles, echovirus, adenovirus, and Epstein-Barr virus. These viral illnesses may share many of the signs of mucocutaneous inflammation, but they typically have less evidence of systemic inflammation and generally lack the extremity changes seen in KD. (See "Clinical presentation and diagnosis of measles" and "Clinical
manifestations and diagnosis of enterovirus and parechovirus infections" and "Epidemiology and clinical manifestations of adenovirus infection" and "Clinical manifestations and treatment of Epstein-Barr virus infection".)
· Toxin-mediated illnesses, especially group A streptococcal infections (eg, scarlet fever and toxic shock syndrome). These usually lack the ocular and articular involvement typical of KD, though patients with staphylococcal toxic shock syndrome occasionally may have conjunctival hemorrhage. (See "Epidemiology,
clinical manifestations, and diagnosis of streptococcal toxic shock syndrome" and "Staphylococcal toxic shock syndrome" and "Group A streptococcal (Streptococcus pyogenes) bacteremia in children", section on 'Clinical manifestations'.)
· Rocky Mountain spotted fever and leptospirosis. Headache and gastrointestinal complaints typically are prominent features of these infections. (See "Clinical manifestations and diagnosis of Rocky Mountain spotted fever" and "Microbiology, epidemiology, clinical manifestations, and diagnosis of leptospirosis".)
· Drug reactions such as Stevens-Johnson syndrome or serum sickness. These may mimic KD, but with subtle differences in the ocular and mucosal manifestations. (See "Stevens-Johnson syndrome and toxic epidermal necrolysis: Clinical manifestations; pathogenesis; and diagnosis".)
· Systemic onset juvenile idiopathic arthritis. Children with this condition generally lack the conjunctival and oral findings of KD. Lymphadenopathy also is generalized, unlike in KD. (See "Systemic onset juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
· Mercury hypersensitivity reaction (acrodynia). In particular, this shares certain clinical features with KD, including fever, rash, swelling of the palms and feet, desquamation, and photophobia. However, treatment of a child with possible KD should not be delayed while awaiting mercury levels, unless there is a convincing
history of exposure to mercury, because of the rarity of acrodynia in the developed world. (See "Epidemiology and toxicity of mercury", section on 'Acrodynia'.)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, “The Basics” and “Beyond the Basics.” The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want
in-depth information and are comfortable with some medical jargon. Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on “patient info” and the keyword(s) of interest.)
· Basics topics (see "Patient information: Kawasaki disease (The Basics)")
SUMMARY
· Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. KD also occurs rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. (See 'Introduction' above.)
· Kawasaki disease is characterized by systemic inflammation manifested by fever and mucocutaneous involvement, including bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and lymphadenopathy (table 1). These findings are often not present at the same time.
Thus, repeated histories and physical examinations are important in making a timely diagnosis of KD in children with fever and signs of mucocutaneous inflammation. (See 'Clinical manifestations' above.)
· No laboratory studies are included among the diagnostic criteria for typical KD.
However, certain findings may support the diagnosis of KD in ambiguous cases.
(See 'Laboratory findings' above.)
· The diagnosis of KD according to classical criteria requires the presence of fever ≥five days, combined with at least four of the other five signs of mucocutaneous inflammation, without any other explanation (table 1). Incomplete KD, representing 20 to 60 percent of cases, is identified on the basis of additional clinical and
laboratory features supportive of the diagnosis. (See 'Diagnosis' above and "Incomplete (atypical) Kawasaki disease".)
· KD is most commonly confused with infectious exanthems of childhood. The presence of clinical features not commonly found in KD, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, and/or generalized lymphadenopathy, suggest another diagnosis (table 3).
Nonetheless, KD is sufficiently pleomorphic that none of these findings can definitively exclude the diagnosis. In addition, many children with KD also have concurrent infections. (See 'Differential diagnosis' above.)
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