Kawasaki disease (KD) is an acute, self-limited vasculitis with unknown etiology. Recurrent KD usually occurs within 2 years after the first episode, but multiple recurrent KD is an exceedingly rare occurrence. The literature on recurrent Kawasaki disease was searched in PubMed and limited articles was published. Multiple recurrent KD is only 3 reported cases in literature. Falcini et al5 reported a child with recurrence of KD for 4 times in a period of 33 months, each time presented typical KD and were successfully treated without any cardiac sequels. Hamada et al6 described a 1-year-old male with 4 recurrent episodes of KD within a single year, and his recurrence may be associated with Streptococcus spp, and the third case involved a 10-year-old girl with recurrent KD for 3 episodes, about 4 years apart. In her third episode, because of her older age and atypical presentation led to a delay in diagnosis, she was treated with IVIG until day 13 of illness and was found to have aneurysms of right and left coronary arteries7. Our patient, a 5-year-old child presented as much as 5 episodes during 41 months, and his recurrent symptoms were atypical, and was each episode successfully treated with intravenous immunoglobulin and (or) aspirin without any cardiovascular damage.
Factors associated with recurrent KD have been pursued, but the results were not inconsistence. The latest Japan Nationwide Survey8 reported that the incidence rate for recurrence was higher among males, patients under the age of 3 years and those who received IVIG or steroid therapy at the initial episode, while cardiovascular complications during the first episode did not affect the recurrence incidence. In a previous retrospective study, Chahal et al showed a lack of association between age at first episode and risk of recurrent KD9. Hirata et al10 associated cardiac sequels during the initial episode to be significant risk for recurrent KD. Treatment of IVIG before the fifth day of the disease had been reported to be one of the risk factor for recurrence in children with KD and may be correlated with higher retreatment rate3,11. The increased correlation between arterial injury and recurrent KD suggests that more aggressive treatment combines with IVIG may be indicated for the next episode of KD3. During the first and third episode, our patient was treated before the fifth day of illness, which may be one of the reasons for his relapses.
The diagnosis of KD is made according to the criteria of the American Heart Association1. The diagnosis of recurrent KD is difficult to establish because of the atypical or incomplete clinical features, and usually requires a combination of cardiac ultrasonography and biological criteria12. In our case, he presented complete forms of KD in his first and third episodes, and all of the other 3 relapse episodes were incomplete KD. Incomplete Kawasaki disease we need to be careful to distinguish it from other diseases, such as infectious diseases. In his 3 relapse episodes, our patients who presented 2 or 3 principal symptoms combined with high level biological data (ESR༞40mm/hr, CRP༞3.0mg/dl, platelet count of ≥450, 000 after the 7th day of fever, elevated ALAT level, WBC count of ≥15,000/mm3), and was invalid by anti-infective treatment, were diagnosed as incomplete KD. The multiple recurrent KD also should distinguish from the periodic fever syndrome13. The common periodic fever syndrome in children mainly includes Familial Mediterranean Fever (FMF) and High Immunoglobulin-D Syndrome (HIDS). FMF is the most common single-gene mutant recurrent fever syndrome, presenting with episodic fever lasting for about 1-3 days, mostly with a family history14.The case in our report was not consistent with FMF. The onset of HIDS occurred in more than 2/3 of the patients within 1 year after birth, with clinical manifestations of periodic fever, growth retardation, and hepatosplenomegaly, and most patients showed elevated IgD and IgA levels15. The case in our report was inconsistent with HIDS as well. These diseases are often confusing and need to be carefully identified. It is likely to omit some of these features as the recurrence is often milder and transient than the initial episode, and both the parents and treating doctors may ignore the evolving disease. So physicians need to be aware of the differential diagnosis of relapsing KD should be kept in mind while treating a patient with a history of KD.
High-dose IVIG remains the cornerstone of management, reducing the risk of coronary complications from about 25–4%16, But approximately 10–20% of patients did not respond to initial high-dose IVIG, which increased the risk of coronary complications to varying degrees11. Study has shown that IVIG is more likely to be unresponsive when treating recurrent KD3. However, the strategies for prediction of potential IVIG non-responders and the optimal regime for IVIG-resistant patients remain to be determined17. Many experts recommend the second dose IVIG, and retrospective series had suggested safety and efficacy18. During the third episode, our patient was still suffering from persistent high fever at least 36 hours following completion of the first dose of IVIG, so he was treated with additional dose IVIG infusion, and he had a slight dilation (3.1mm) of the left coronary artery. Fortunately, he returned to normal at the time of follow-up.
To the best of our knowledge, this is a rare case of recurrent KD occurring five times with episodes during 41 months. This case and our literature review should raise awareness that KD can still recur two years after the first episode, often presenting atypically. Recognizing recurrent KD and taking appropriate treatment can result in resolution of symptoms and may decrease the risk of cardiac complications. Hence, the differential diagnosis of relapsing KD should be kept in mind while treating a patient with a history of KD, even if it's more than 2 years since his initial episodes, as aforementioned in the 3 of 4 multiple recurrence patients remaining relapsed after two years of first episodes. Therefore, it is important for every clinician to follow KD patients carefully, even more than 2 years after the first episode.