ARTICULO MEDICO:Incomplete (atypical) Kawasaki disease

Incomplete (atypical) Kawasaki disease
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: jun 18, 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 11 days without therapy [2]. However, complications such as coronary artery aneurysms may develop and lead to significant
morbidity and mortality.
Children suspected of having KD who do not fulfill diagnostic criteria (ie, have less than four signs of mucocutaneous inflammation) may have incomplete or atypical KD [1-3].
"Incomplete" KD is the preferred term, since these patients do not appear to differ from those with classic KD in any way except that they lack a sufficient number of criteria to fulfill the epidemiologic case definition [2]. Children with incomplete KD are also at risk for cardiovascular sequelae.
The clinical manifestations, diagnosis, and criteria for treatment of incomplete KD are discussed in this review. Unique features in infants and adults are also presented. Other aspects of Kawasaki disease are reviewed separately. (See "Kawasaki disease: Epidemiology and etiology" and "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis" and "Kawasaki disease:
Complications" and "Cardiovascular sequelae of Kawasaki disease".)

EPIDEMIOLOGY — The incidence of incomplete KD is unknown [4,5]. In a retrospective report of 242 Japanese children with KD treated at a single center over a nine-year period, 10 percent of patients were diagnosed with incomplete KD [4]. The incidence appears to be greater in infants younger than six months of age [5,6]. This was illustrated in a retrospective review of 44 children with KD; 5 of 11 infants (45 percent) had incomplete disease compared with 4 of 33 (12 percent) older children [5].

CLINICAL PRESENTATION OF TYPICAL VERSUS INCOMPLETE KD — Signs and symptoms appear to parallel those in children who fulfill diagnostic criteria for typical disease (table 1) when clinical judgment of reliable observers is used to define incomplete KD. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations' and 'Infants' below.)
One report studied 242 patients hospitalized for KD in Japan during a nine-year period and found that 25 (10 percent) ultimately failed to meet diagnostic criteria [4]. Three criteria were met in 17 of the 25 patients (68 percent), and 7 (28 percent) met only two criteria.
Only one patient ultimately developed transient dilatation of a coronary artery. In this review, comparison of physical findings among patients with typical and incomplete KD revealed the following:
· Cervical lymphadenopathy was the cardinal manifestation most often absent in children with either complete or incomplete KD. Adenopathy was missing in up to 90 percent of children with incomplete disease versus 40 to 50 percent of those who met criteria for KD.
· Rash was not present in 50 percent of children with incomplete disease compared with 7 to 10 percent of children with typical KD.
· Peripheral extremity changes were absent in approximately 40 percent of incomplete KD cases. In comparison, only 15 percent of those with typical KD failed to develop palmar erythema, dorsal edema, or periungual desquamation.
· Mucous membrane changes were most characteristic of KD and were present in more than 90 percent of children with either typical or incomplete disease.

EVALUATION OF INCOMPLETE KD — The diagnosis of incomplete KD is problematic because the correct diagnosis rests upon clinical judgment and supportive laboratory findings, but remains uncertain unless the child develops coronary artery abnormalities. Other illnesses associated with fever, rash, and marked laboratory abnormalities must be carefully excluded before the label of incomplete KD is applied. Children with a variety of inflammatory and infectious conditions, including sarcoid, polyarteritis nodosa, and
systemic onset juvenile idiopathic arthritis have been mislabeled as having incomplete KD prior to establishment of the correct diagnosis. The main diagnoses to exclude in adults are drug hypersensitivity reactions and toxic shock syndrome [7]. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis' and "Kawasaki disease: Clinical features and diagnosis", section on 'Laboratory findings'.)
The American Heart Association (AHA) and the American Academy of Pediatrics (AAP) have established guidelines for the diagnosis, treatment, and management of KD (table 1) [2]. These guidelines are based upon recommendations of an expert panel using data summarized above. They include an algorithm for the evaluation of incomplete KD (algorithm 1). The goal of adding this category of patients was to help providers identify children at risk of developing coronary artery abnormalities who would benefit from treatment for KD regardless of whether they meet diagnostic criteria. The guidelines use laboratory studies and echocardiography to aid in the diagnosis of patients whose clinical presentation is consistent with KD, but who do not meet diagnostic criteria (table 1). At any point in the evaluation, consultation with an expert is recommended if assistance is required or the diagnosis is in question.
Laboratory tests — Laboratory evaluation is recommended for the following patients with suspected incomplete KD:
· Patients less than six months of age with unexplained fever ≥seven days, even if they have no clinical findings of KD.
· Patients of any age with unexplained fever >five days and fewer than three clinical criteria (table 1).
The AHA/AAP recommended laboratory evaluation includes the following tests:
· Acute phase reactants (CRP or ESR)
· Complete blood count (CBC) with differential white blood cell count (WBC)
· Urinalysis (U/A), preferably clean catch
· Serum alanine aminotransferase level
· Serum albumin
Laboratory findings suggestive of KD include the following:
· Elevated acute phase reactants (CRP ≥3.0 mg/dL or ESR ≥40 mm/hr)
· White cell count ≥15,000/microL
· Normocytic, normochromic anemia for age (table 2)
· Pyuria (≥10 white blood cells/high-power field)
· Serum alanine aminotransferase level >50 U/L
· Serum albumin ≤3 g/dL
· Platelet cell count ≥450,000/microL after seven days of illness
Echocardiography — The presence of cardiac abnormalities detected by echocardiography, although not included in the diagnostic criteria for KD, provides support in ambiguous (incomplete) cases of KD. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Echocardiography' and "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis'.)
The recommendation for echocardiography depends upon the clinical course and initial laboratory findings. Echocardiography is recommended in the following circumstances when a diagnosis of KD is under consideration:
· Elevation of CRP and/or ESR and less than three supplemental abnormal laboratory findings. KD is unlikely if the echocardiogram is normal and the fever abates.
Repeat echocardiography and consultation with a clinician who has expertise in KD are recommended if fever persists.
· Periungual desquamation after resolution of the fever in someone not meeting epidemiologic criteria for KD. The diagnosis is unlikely if the echocardiogram is normal.
Echocardiographic abnormalities suggestive of KD include aneurysms (rare before 10 days of disease), findings consistent with coronary arteritis (eg, perivascular brightness, ectasia, and lack of tapering of the coronary arteries), decreased left ventricular contractility, mild valvular regurgitation (primarily mitral valve), and pericardial effusion. However, none of these findings, including coronary artery dilatation, is pathognomonic for KD. A prospective study of echocardiograms in febrile children found that conditions other than KD can be associated with some degree of coronary artery dilatation [8]. However, only children with KD had coronary artery z-scores more than 2.5, suggesting that significant coronary artery enlargement is indeed a reliable marker of probable KD.

CRITERIA FOR TREATMENT — The AHA/AAP criteria to diagnose incomplete KD and initiate treatment in a child with features compatible with KD include:
· Elevated CRP and/or ESR and three or more abnormal supplemental laboratory findings (See 'Laboratory tests' above.) OR
· Abnormal echocardiography (See 'Echocardiography' above.)
Treatment of KD is discussed in greater detail separately. (See "Kawasaki disease: Initial treatment and prognosis".)
It is important to recognize that as long as the diagnosis of KD is based upon clinical criteria, it will remain an imperfect undertaking. Although the above recommendations reflect the consensus of experts in the field, they are not based upon firm data, and they have not been validated. Ultimately, they reflect the bias in favor of treatment in uncertain cases that has developed as a result of having an effective and safe therapy. Children with a variety of other febrile conditions may receive IVIG treatment using these guidelines. Thus, these recommendations should be applied only as intended, in cases in which an experienced clinician considers KD to be a probable diagnosis.
Treating children at risk even though the diagnosis is uncertain should result in fewer children with incomplete KD subsequently developing coronary artery aneurysms. This was demonstrated in a study that evaluated the performance of the 2004 AHA/AAP criteria in 195 children at four centers, 58 of whom developed coronary artery aneurysms despite failing to meet criteria for KD [9]. Fifty-three of these children had atypical KD and would have received IVIG at presentation according to the algorithm. Two of the remaining five patients would have received IVIG after further monitoring. Overall, application of the 2004 AHA/AAP guidelines would have led to IVIG treatment of 97 percent of the children who developed aneurysms. The corresponding number of children without KD who would have received unnecessary IVIG treatment was not calculated. In any event, as long as the disadvantages of undertreating appear to outweigh the disadvantages of overtreating, some children who have a condition that mimics KD will receive unnecessary intravenous immune globulin (IVIG). Thus, continued consideration of alternative diagnoses in “atypical cases” is essential despite initial response to IVIG. This is particularly important in children who fail to respond or respond only incompletely to IVIG.

PROGNOSIS — Earlier reports suggested a poor prognosis for infants and children with incomplete KD [5,10,11]. One review cited a 41 percent mortality, although only children with coronary artery aneurysms were included in this series [10]. However, subsequent studies have indicated that outcomes in children with incomplete KD may be comparable to those of children with complete disease [12]. Nonetheless, the overall data continue to suggest that children with incomplete KD are more likely to develop coronary artery
abnormalities, probably because they are less likely to be diagnosed expeditiously [13,14].
In fact, the goal of the AHA/AAP guidelines cited above is to remove precisely this obstacle to early diagnosis.

INFANTS — Infants are more likely to present with incomplete KD, occasionally even presenting only with fever and no other clinical features of KD. Infants are also at increased risk of coronary artery (CA) aneurysms, possibly in part because of delay in treatment due to their lack of complete diagnostic criteria. Thus, infants six months of age or less with unexplained fever for at least seven days should be evaluated for KD regardless of whether they have signs of mucocutaneous inflammation, since early diagnosis and timely
intervention can reduce their risk of cardiac sequelae.
The following studies are illustrative of the presentation and cardiovascular outcome in infants:
· In a retrospective Canadian study of 44 children with KD, 5 of 11 infants (45 percent) had atypical disease compared with 4 of 33 (12 percent) older children [5].
In addition, all five infants with incomplete disease developed coronary artery aneurysms.
· In a Japanese nationwide survey of 2221 children younger than five years of age with KD from 1995 to 1996, approximately one-third of the group were infants younger than one year of age. These infants had an increased risk of developing cardiac aneurysms compared with children older than one year of age (15 versus 10 percent, respectively) [15].
· In a retrospective survey of North American patients with KD, 4 of 47 children younger than 12 months of age (8.5 percent) developed cardiac abnormalities compared with 5 of 272 patients 12 months or older (1.8 percent) [16].
· In a retrospective Taiwanese study of 120 patients with KD, the 20 infants (defined as six months of age or less) were more likely to present with incomplete KD than patients older than six months of age (35 versus 12 percent), have coronary involvement (65 versus 19 percent), and receive late immunoglobulin therapy [17].
ADULTS — KD occurs rarely in adults and presents in an incomplete form more often than in children [7,18-23]. About one-fourth of adult KD cases have occurred in patients with HIV infection [20]. One review found that cervical lymphadenopathy, hepatitis, and arthralgia were all more common in adults with KD than in children, and meningitis, thrombocytosis, and coronary artery aneurysms were less common [22]. Splenomegaly and elevated serum ferritin levels were reported in one adult patient [23].

SUMMARY
· Kawasaki disease is typically a self-limited condition, but cardiac complications can lead to significant morbidity and mortality. Timely diagnosis and initiation of appropriate therapy minimize cardiac sequelae and improve clinical outcome. (See 'Introduction' above and "Cardiovascular sequelae of Kawasaki disease".)
· KD is a systemic illness characterized by fever, conjunctivitis, mucositis, rash, extremity changes, and cervical lymphadenopathy. These findings are the basis for the diagnostic criteria for KD (table 1). Patients who lack a sufficient number of findings to fulfill the classic criteria may have incomplete KD (algorithm 1). (See 'Clinical presentation of typical versus incomplete KD' above and "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations'.)
· No laboratory or cardiac studies are included among the diagnostic criteria for typical KD, but certain findings characteristic of KD may support the diagnosis in ambiguous cases. (See 'Evaluation of incomplete KD' above and "Kawasaki disease:
Clinical features and diagnosis", section on 'Laboratory findings' and "Cardiovascular sequelae of Kawasaki disease", section on 'Echocardiography'.)
· The criteria to diagnose incomplete KD and initiate treatment in a child with features compatible with KD include elevated C-reactive protein and/or erythrocyte sedimentation rate and three or more abnormal supplemental laboratory findings OR abnormal echocardiography. (See 'Criteria for treatment' above.)
· Infants and adults are more likely to present with incomplete KD. Infants are at greater risk for cardiovascular sequelae, possibly due in part to a delay in diagnosis and intervention. Thus, infants six months of age or less with unexplained fever for at least seven days should be evaluated for KD, even if they have no clinical findings of KD. (See 'Infants' above and 'Adults' above.)