PURIFIED PROTEIN DERIVATIVE ANERGY IN KAWASAKI DISEASE

It was previously reported from Italy that all patients with Kawasaki disease had a positive tuberculin intradermal test. In this study from Seattle, WA, nine patients with Kawasaki disease showed no reaction to intradermal tuberculin. The difference in results might be caused by the different tuberculin products. Kawasaki disease (KD) has replaced rheumatic fever as the leading cause of acquired heart disease in children in the United States. Its etiology is unknown and a specific diagnostic test is not available. Although intravenous immunoglobulin (IVIG) has proved effective in most cases if given early in the disease, some cases are still missed and not treated, especially those that do not fulfill the clinical criteria necessary to make the diagnosis (atypical KD). 1 In addition others may be treated with IVIG though it might later be discovered that there is a cause for their symptoms other than KD. From Italy Bertotto et al. 2, 3 reported that the tuberculin skin test was positive in all KD patients tested during the acute phase of the illness. None of the children in that study had been given the Calmette-Guérin bacillus (BCG) vaccine or had history of exposure to tuberculosis. The authors postulated that the tuberculin skin test might be a simple and reliable adjunct in the diagnosis of KD, especially in atypical cases. We set out to test this hypothesis in our patient population. Methods. Eligible patients included any child admitted to Children’s Hospital and Regional Medical Center in Seattle, WA, for evaluation and treatment of KD from April, 1999, through April, 2000. All patients had fever without an obvious source. They also had variable combinations of bulbar conjunctivitis, oropharyngeal changes such as erythema or scaling, changes on the extremities such as induration, erythema or scaling, a polymorphous rash and cervical lymphadenopathy (defined as at least one lymph node larger than 1.5 cm). Patients with possible typical and atypical KD were included. Patients were excluded if they had known hypersensitivity to purified protein derivative (PPD) or mumps, a previously positive PPD, a history of tuberculosis or contact with an active tuberculosis patient or had received the BCG vaccination. Patients were also excluded if they had a known immunodeficiency disorder, had received a recent (<4 weeks) live virus vaccination, were receiving chemotherapy or had a chronic disease that put them at risk to be anergic (e.g. diabetes mellitus). After informed consent was obtained, PPD and controls (Candida and diphtheria/tetanus or mumps) were placed intradermally. PPD skin test reaction of >15 mm induration in diameter at 48 h was considered positive. For the control antigens a reaction of >5 mm induration at 48 h was considered positive. This study was approved by the hospital Institutional Review Board. Results. Nine KD patients were enrolled in our study starting in April, 1999. The ages of patients ranged from 8 months to 8 years (median, 2.9 years). Eight were males, and one was female; there were one Asian, one Hispanic, three African-Americans and four Caucasians. Eight had typical KD and one had atypical KD proven by coronary aneurysm on echocardiography. On initial echocardiogram, most had changes consistent with acute carditis, such as pericardial effusion, mitral and tricuspid regurgitation and subnormal left ventricular function. All patients had 5 IU of PPD (Aventis Pasteur, Toronto, Ontario, Canada) and two controls placed intradermally. Candida and diphtheria antigens were used in patients <1 year of age;Candida and mumps antigens were used in patients older than 1 year. Skin tests were read 48 to 72 h later by one of the investigators. None of our nine KD patients reacted to PPD. Only two patients (22%) reacted to controls (both with 5-mm reactions to Candida antigen). No patients reacted to any of the other controls. This is a lower rate than that of other children without KD tested at our institution during a similar time period. Forty-three percent of all children tested at our institution had a positive reaction to at least one of the control antigens, although only 20% of children <2 years old tested had a positive reaction to at least one of the control antigens. All patients were treated with IVIG and aspirin. In only the one atypical case were coronary artery abnormalities documented by echocardiography. Follow-up studies in that patient showed improvement. None of the other patients had cardiac abnormalities on follow-up echocardiography. Discussion. In 1996 and 1997 Bertotti et al. in Perugia, 2, 3 Italy, reported that the tuberculin skin test was a highly sensitive and specific diagnostic test for KD. Their investigation followed the observation that children with acute KD often had swelling at the site of a previous BCG vaccination or a crusting erythematous reaction at current BCG inoculation sites if given during acute KD. 4 The Italian group investigated 11 typical KD patients and 41 non-KD patients who had other febrile illnesses. All KD patients but none of the non-KD patients had a positive tuberculin skin test (>15 mm). The reactivity waned, and 2 months after the acute phase of KD none of their subjects had a positive tuberculin reaction. They hypothesized an autoimmune cross-reaction between mycobacterial heat shock proteins and human mitochondrial heat shock proteins as the underlying basis. 2, 3 In contrast to the findings of Bertotti et al., none of our KD patients had a positive tuberculin skin reaction, including our one proven atypical case. One of the possibilities to explain this discrepancy could be the different ethnic backgrounds of the two study populations. We do not have data on the makeup of the Italian population, but our group consisted of several ethnic backgrounds. This would argue against a major histocompatibility complex difference as the reason. More intriguing to us is the possibility of variations in the PPD preparation. The Italian group used tuberculin manufactured by Sclavo in Italy; we used a preparation made by Aventis Pasteur. Sclavo, in 1992, recalled all of its biologic products distributed in the United States. The firm had made unapproved manufacturing changes, and the Food and Drug Administration revoked its product licenses. 5 It is possible that Sclavo’s tuberculin preparation contained substances causing the positive skin reaction in the Italian KD patients. Because our patients did not react to tuberculin made by a different supplier, the positive skin reaction reported by Bertotto et al. is unlikely to have been caused by PPD. A comparative analysis of Aventis Pasteur’s and Sclavo’s tuberculin preparations might shed some light on this issue. If the differences include specific components, Sclavo’s tuberculin might hold the key to identifying a causative agent for KD or to the development of a diagnostic test for KD. In any case PPD is not the exciting new adjunct for the diagnosis of KD. Acknowledgments. This study was supported by an unrestricted educational grant from Aventis Pasteur.

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