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Article
May 2000

The Differentiation of Classic Kawasaki Disease, Atypical Kawasaki Disease, and Acute Adenoviral InfectionUse of Clinical Features and a Rapid Direct Fluorescent Antigen Test

Author Affiliations

From the Department of Pediatrics, North Shore University Hospital, New York University School of Medicine, Manhasset.

Arch Pediatr Adolesc Med. 2000;154(5):453-456. doi:10.1001/archpedi.154.5.453
Abstract

Objective  To compare the clinical and laboratory features of children with Kawasaki disease with those with acute adenoviral infection, which may mimic Kawasaki disease.

Design  We retrospectively compared the medical records of children with Kawasaki disease and atypical Kawasaki disease with those of children with acute adenoviral infection. All children included were initially evaluated because their primary care physicians were concerned that they might have Kawasaki disease. The utility of a rapid direct fluorescent antigen test for adenovirus was evaluated. Thirty-six children with Kawasaki disease (23 with classic and 13 with atypical presentations) and 7 patients with acute adenoviral infection were studied.

Setting  A tertiary care pediatric hospital.

Results  Children with Kawasaki disease were more likely to have conjuctivitis (36 of 36 vs 4 of 7), strawberry tongues (23 of 36 vs 1 of 7), perineal peeling (19 of 36 vs 0 of 7), and distal extremity changes (22 of 36 vs 0 of 7) than those with acute adenoviral infection. Children with acute adenoviral infection were more likely to have purulent conjuctivitis (3 of 7 vs 1 of 36) and exudative pharyngitis (3 of 7 vs 1 of 35). In addition to pyuria (13 of 26 vs 0 of 6), patients with Kawasaki disease had higher mean white blood cell counts (15.3 ± 3.5 vs 11.5 ± 6.0 ×109/L), erythrocyte sedimentation rates (56 vs 42 mm/h), platelet counts (426 vs 259 × 109/L), and levels of alanine aminotransferase (101 vs 18 U/L) than those with acute adenoviral infection. Children with Kawasaki disease had lower mean albumin levels (32 vs 36 g/L). A rapid antigen test for adenovirus had a specificity and sensitivity of 100% compared with viral culture.

Conclusions  Kawasaki disease and acute adenoviral infection can present with many of the same clinical characteristics. A rapid direct fluorescent antigen assay for adenovirus may be a helpful adjunctive test for distinguishing acute adenoviral infection from Kawasaki disease.

KAWASAKI DISEASE is an acute systemic vasculitis of infancy and childhood. Despite extensive investigation, the cause(s) of this disease remains a mystery. As there is no specific laboratory test for this illness, a diagnosis of Kawasaki disease is established on clinical grounds. Diagnostic criteria1 are as follows:

  • Fever lasting for at least 5 days.

  • Presence of 4 of the following 5 conditions: bilateral conjunctival injection; changes of the mucosae of the oropharynx, including injected pharynx, injected and/or dry fissured lips, or strawberry tongue; changes in the peripheral extremities, such as edema and/or erythema of hands and/or feet, desquamation usually beginning periungally; polymorphous, but nonvesicular, rash; cervical lymphadenopathy greater than 1.5 cm.

  • Illness not explained by other known disease processes.

Most experienced clinicians have no problem making the diagnosis of Kawasaki disease when it presents in its classic form; however, many times its presentation is subtle. This is especially true when it presents atypically. The term "atypical Kawasaki disease" was initially coined to describe patients with coronary artery abnormalities whose illness did not meet the strict criteria for classic Kawasaki disease. Sonobe and Kawasaki2 proposed that the diagnosis of atypical Kawasaki disease be restricted to those children who have 3 or 4 of 5 of the clinical criteria plus coronary artery vasculitis. However, many authors believe that this definition is too restrictive. They cite examples of children who developed coronary artery abnormalities when physicians relied too heavily on strict criteria.3 It is critical that we identify these children and institute appropriate therapy before they develop coronary artery damage. Therefore, most clinicians today use the term "atypical Kawasaki disease" to describe children who fail to meet the case definition for classic Kawasaki disease but have compatible laboratory findings and no other explanation for their illness. This approach allows for the prompt initiation of immunoglobulin therapy and, hopefully, a decrease in the occurrence of coronary artery complications.

On the other hand, we do not want to give children immunoglobulin therapy unnecessarily. Disorders that are frequently cited in the differential diagnosis of Kawasaki disease include presumed viral infections, group A streptococcal infections, Epstein-Barr virus infections, measles, collagen vascular disorders, and drug reactions. In our experience, acute adenoviral infections pose the greatest diagnostic dilemma. Many of these children present with features suggestive of classic Kawasaki disease or atypical Kawasaki disease. We compared the clinical and laboratory features of these 3 conditions, with particular emphasis on the use of a rapid direct fluorescent antigen (DFA) test for adenovirus.

PATIENTS AND METHODS

We reviewed all cases of Kawasaki disease diagnosed at North Shore University Hospital (Manhasset, NY) from January 1, 1996, to May 31, 1998. We selected January 1, 1996, as the starting date because this is the date a rapid DFA test for adenovirus (Imagen; Dako Diagnostics Ltd, Ely, England) became available for use at our institution. Children with Kawasaki disease were identified through a review of hospital records. A subset of these children were further categorized as having atypical Kawasaki disease if they did not meet the strict criteria for classic Kawasaki disease but nevertheless were thought to have sufficient likelihood of Kawasaki disease based on clinical and laboratory features to merit treatment with intravenous immunoglobulin therapy and aspirin. This definition is broader than the initial description of atypical Kawasaki disease, but is consistent with current usage in clinical practice. All patients treated for Kawasaki disease were seen by 1 of 2 experienced pediatric infectious disease physicians (S.R.B., L.R.K.). A child was considered to have an acute adenoviral infection if he or she had a positive culture for adenovirus as part of the infectious disease service evaluation for possible Kawasaki disease. We did not include patients diagnosed as having acute adenoviral infections who presented with other clinical syndromes such as fever of unknown origin or pneumonia. The following data were recorded for each patient: age, sex, race, duration of fever, number of physician visits before hospitalization, ill contacts, temperature on arrival in the emergency department, conjunctival changes, mucous membrane changes, exanthema, adenopathy, peripheral extremity changes, and the time course of specific symptoms. A review of other nonspecific symptoms was also recorded. These included arthragia, arthritis, vomiting, diarrhea, otitis media, pharyngeal complaints, abdominal pain, irritability, hepatomegaly, splenomegaly, cough, and upper respiratory symptoms. Laboratory data, which were analyzed, included white blood cell count, hemoglobin level, platelet count, erythrocyte sedimentation rate, electrolyte count, liver function tests, and urinalysis. These evaluations were obtained prior to the use of intravenous immunoglobulin therapy. We also recorded the results of ophthalmologic examinations. It was also noted if a child had a rapid DFA test for adenovirus performed on his or her nasopharyngeal secretions. These secretions were also cultured for adenovirus by routine laboratory methods. A χ2 or Fisher exact test was used for the analysis of categorical variables and Mann-Whitney tests were used for comparison of continuous variables.

RESULTS

Forty-three children met criteria for inclusion in this study. Thirty-six children were diagnosed as having Kawasaki disease and received intravenous immunoglobulin therapy. Thirteen of these 36 children were classified as having atypical Kawasaki disease. Seven children, who were initially referred to the pediatric infectious disease service for Kawasaki disease, were diagnosed as having acute adenoviral infection and did not receive immunoglobulin therapy. The features of the 7 patients with an acute adenoviral infection are listed in Table 1. Three children with adenoviral infections met diagnostic criteria for Kawasaki disease. The 4 other children met some, but not all, of the criteria for Kawasaki disease.

Table 1. 
Clinical Characteristics of the 7 Children With Adenoviral Infections*
Clinical Characteristics of the 7 Children With Adenoviral Infections*

When children with Kawasaki disease (both classic and atypical) were compared with those with acute adenoviral infections, there were no significant differences in their ages (46 ± 26 vs 64 ± 33 months). Additionally, there was no difference between the 2 groups with regard to the duration of fever (6.3 ± 3.4 vs 5.3 ± 1.1 days), number of physician visits prior to diagnosis (1.7 ± 0.8 vs 1.7 ± 0.5), or report of exposure to ill contacts (6 of 36 vs 3 of 7). Differences with regard to clinical characteristics are shown in Table 2. The only differences that were statistically significant between the 2 groups were the presence or absence of conjunctivitis and changes in the peripheral extremities. There were no differences with regard to the presence of absence of a rash, cervical adenopathy, or mucous membrane changes. The conjunctivitis was more likely to be purulent and the pharyngitis was more likely to be exudative in children with adenoviral infections. Children with Kawasaki disease were more likely to have a perineal accentuation of their rash.

Table 2. 
Comparison of Children With Kawasaki Disease vs Acute Adenoviral Infection*
Comparison of Children With Kawasaki Disease vs Acute Adenoviral Infection*

When children with atypical Kawasaki disease were compared with those with adenoviral infections, the differences between the groups were less striking (Table 2). With regard to age, there was no significant difference (39 ± 22 vs 64 ± 33 months) between the 2 groups. There was no difference with respect to the duration of fever (7.0 ± 4.7 vs 5.3 ± 1.1 days), number of physician visits prior to diagnosis (1.4 ± 0.8 vs 1.7 ± 0.5), or report of exposure to ill contacts (1 of 13 vs 3 of 7). The only difference between the 2 groups, based on the 5 Kawasaki criteria, was an increase in the number of children with conjunctivitis in the atypical Kawasaki group. There were no statistical differences with regard to presence or absence of a rash, cervical adenopathy, mucous membrane changes, or changes in the peripheral extremities. The rash associated with atypical Kawasaki disease was both more likely to be accentuated and more likely to have peeled in the perineal area.

Although no diagnostic test for Kawasaki disease is currently available, there are several nonspecific abnormalities often seen in patients with this syndrome. When children with Kawasaki disease were compared (Table 2) with those with an adenoviral infection, they had higher mean white blood cell counts, platelet counts, and erythrocyte sedimentation rates. In contrast, their hemoglobin and albumin levels were lower. Children with Kawasaki disease also had higher mean alanine aminotransferase levels. No child with an acute adenoviral infection had increased transaminase levels, compared with 14 of 34 children with Kawasaki disease (P<.05).

When children with atypical Kawasaki disease are analyzed separately, there is very little difference in their laboratory values compared with all children diagnosed as having Kawasaki disease (Table 2).

Another feature of Kawasaki disease that may be helpful in distinguishing this disease from others is the presence of sterile pyuria. Of those children who underwent a urinalysis, no child with an acute adenoviral infection (0 of 6) had pyuria (defined as >10 white blood cells per high-powered field), compared with 13 of 27 (P<.05) and 4 of 11 (P<.05) children with Kawasaki disease or atypical Kawasaki disease, respectively.

A slitlamp examination of the eyes was used in several cases to help differentiate atypical Kawasaki disease and adenoviral infection. Eleven of the 20 children with either atypical Kawasaki disease or adenoviral infection underwent an ophthalmologic examination. Anterior uveitis was found in 6 of 9 children with atypical Kawasaki disease vs 0 of 2 with an adenoviral infection.

Children diagnosed as having Kawasaki disease underwent echocardiographic evaluations of their hearts. All patients had normal coronary arteries. One patient with an adenoviral infection underwent an evaluation, which also did not reveal any abnormal findings.

All children who had a DFA test positive for adenovirus subsequently had a positive adenoviral culture. Eighteen children with either classic or atypical Kawasaki disease had a rapid DFA test and viral culture performed. All of these children had negative results. Eighteen additional children with Kawasaki disease were not tested. In general, the DFA test was used in the cases that were more challenging to diagnose. This is demonstrated by the fact that of the 18 children with Kawasaki disease tested, 9 were subsequently diagnosed as having an atypical case. The turnaround time for results from the DFA test was usually 4 to 6 hours and almost always within 24 hours. No child who had a DFA test positive for adenovirus received immunoglobulin therapy.

COMMENT

Since the initial description of Kawasaki disease almost 30 years ago,4 a great deal has been learned about its epidemiology, clinical characteristics, and management. However, without a definitive cause(s) or diagnostic test, recognition of the disease and the decision to initiate therapy rests solely on the clinical presentation. Although certain laboratory tests may suggest the diagnosis, they are by no means definitive. Experienced clinicians or infectious disease experts may have no difficulty making the diagnosis of Kawasaki disease when the child has the classic symptoms. However, the most astute pediatrician can find the decision of whether to treat difficult when a patient has atypical symptoms. Nevertheless, these children need to be identified because they are at risk for coronary artery abnormalities.5

Group A streptococcal infections, Epstein-Barr virus infections, measles, collagen vascular disorders, and drug reactions are often cited as manifesting with symptoms similar to those found in Kawasaki disease.6,7 In our opinion, most of these conditions can be differentiated by an experienced pediatrician either on clinical grounds or with the use of specific laboratory tests. Acute adenoviral infections, however, can present with many features suggestive of Kawasaki disease. These include prolonged fever, rash, conjunctivitis, mucous membrane changes, and adenopathy. Our study demonstrates some subtle differences between the 2 diseases. The adenoviral conjunctivitis is more likely to be purulent. The adenoviral pharyngitis is more likely to be exudative. The rash of Kawasaki disease, as reported previously by others, tends to be accentuated in the perineal area.8 Many of these features may overlap in both conditions. Cases of atypical Kawasaki disease are particularly troublesome, as they can present with only a few of the necessary diagnostic features.

An ophthalmologic examination can be helpful in atypical cases if the characteristic anterior uveitis of Kawasaki disease can be demonstrated.9 Another diagnostic test that may be helpful is a rapid DFA test for adenovirus. A DFA test positive for adenovirus in a child with signs and symptoms suggestive of atypical Kawasaki disease may supply the clinician with an alternative diagnosis and prevent a child from receiving unnecessary treatment with immunoglobulin therapy and aspirin. The specimen can easily be collected from the nasopharynx and analyzed in a viral laboratory. The Imagen adenovirus test has an excellent sensitivity (86%), specificity (100%), positive predictive value (100.0%), and negative predictive value (98.6%) when interpreted by an experienced technologist.10 In our study, both the sensitivity and specificity of the Imagen adenovirus test, as compared with viral isolation, was 100%.

Our review of Kawasaki disease suggests that, in addition to a thorough history, physical examination, and laboratory evaluation, testing a child's nasopharyngeal secretions for adenovirus by use of a DFA test may be helpful in distinguishing Kawasaki disease from acute adenoviral infection. Although the DFA test should not be relied on solely, it can be used as an adjunctive test to provide the clinician with a plausible alternative diagnosis. We believe that a DFA test for adenovirus should be considered when the diagnosis of Kawasaki disease is in question.

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Article Information

Accepted for publication November 5, 1999.

Presented at the 36th Annual Meeting of the Infectious Disease Society, Denver, Colo, November 13, 1998.

Corresponding author: Stephen R. Barone, MD, 865 Northern Blvd, Suite 101, Great Neck, NY 11021.

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