A Five-time-recurring Kawasaki Disease : A Case Report and Literature Review


 BackgroundFive-time-recurring Kawasaki Disease without any cardiovascular complications is relatively rare and was first described in 2021.Case presentationWe describe a case of five-time-recurring Kawasaki disease (KD) in a 6-year-old boy who had been diagnosed with typical KD without cardiac involvement at age 25 months. Subsequently, the child was hospitalized with KD other 4 times when he was 40, 47, 59, and 66-month-old respetively. In each episode, the boy was characterized by an abrupt intermittently high fever but typical cutaneous and mucosal manifestations were not always presented. Clinical improvement was successfully obtained after intravenous immunoglobulin and (or) aspirin in each time without any cardiovascular damage. Diagnosis was difficult to establish because of the incomplete clinical features and the recurrence of the disease.ConclusionPhysicians 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. Five-time-recurring Kawasaki Disease is infrequent and will increase the likelihood of poor clinical outcomes if not diagnosed and managed promptly.

intermittently high fever, when he was 2 years and 1month old. Fever was combined with unexplained irritability, chapped lips, mucositis, conjunctivitis, rash, stiff edema of both hands and feet and cervical lymphadenopathy on the left. When he was hospitalized, local doctors gave empirical anti-infective treatment for 3 days, but there was no sign of fever abatement. Blood tests showed the following: white blood cell count (WBC) 7,850/mm 3 , hemoglobin (Hb) 11.7 g/dl, C-reactive protein (CRP, n.v. 10mg/l) 152mg/l, erythrosedimentation rate (ESR) 105mm/hr. A nal diagnosis of KD was established, and treated by intravenous immunoglobulin (IVIG) / aspirin with usual dosages on 4 day. Defervescence was reached after one day at the end of IVIG infusion and typical Kawasaki-like peeling around the extremities (Fig. 1) and anus developed after 10 days, while in ammatory markers were negative. The child was then discharged with that his echocardiographic picture was silent.
15 months later, he was hospitalized again for bellyache and vomiting with increased in ammatory parameters (WBC, 13,740/mm 3 ; CRP, 161.6mg/l; ESR, 95mm/hr). The next day he developed intermittent high fever which lasted for 7 days. During the course of this episode he only presented cervical lymphadenopathy and transient conjunctivitis. He was treated with penicillin and cephalosporin successively, with poor results. Until the 8th day of the illness the patient was diagnosed as incomplete KD and was treated with aspirin without IVIG. Because his fever had been resolved, and laboratory values had normalized, and echocardiogram was normal. He developed typical Kawasaki-like peeling around the extremities, when he followed up 7 days after discharge. 7 months later, the patient presented again a febrile episode with typical manifestations of KD, accompany with abdominal pain and irritability. Blood tests revealed the following: WBC 19,310/mm 3 , Hb 12.4g/dl, CRP 107.5mg/l, ESR 102mm/hr. The child was again hospitalized and treated with IVIG / aspirin following a diagnosis of KD on day 4 of his illness. But fever still persisted at the end of IVIG infusion more than 48h, so he needed the second dose of IVIG infusion and fever has resolved at the end of the second dose of IVIG infusion. An echocardiography revealed a slight dilation (3.1mm) (Fig. 2)of the left coronary artery on day 4, but it soon returned to normal at follow-up without any cardiovascular sequelae.
12 months later, He had intermittent high fever again combined with conjunctivitis, chapped lips, mucositis, and cervical lymph node enlargement. Laboratory tests showed increased in ammatory parameters (WBC, 18,180/mm 3 ; CRP, 135mg/l; ESR, 56mm/hr). So another hospitalization was required. The treatment of antibiotics is ineffective, due to the suspicion of a relapsing KD on day 8 and treated with IVIG/aspirin following a diagnosis of incomplete KD. His cardiological assessment remained normal. 7 months later, when the child was 5.5 years old, He was hospitalized again for persistent fever with increased in ammatory parameters (WBC, 14,540/mm 3 ; CRP, 135mg/l; ESR, 60mm/hr). After 8 days, he was diagnosed incomplete KD ful lled with 3 of 5 principal symptoms and successfully treated with IVIG / aspirin at the usual dosages. Without any cardiovascular abnormality could be detected on echocardiography. Other infectious diseases were excluded in every KD episode. The patient has remained clinically healthy without growth retardation at 29 moths after the last hospitalization.

Discussion And Conclusion
Kawasaki disease (KD) is an acute, self-limited vasculitis with unknown etiology. Recurrent KD usually occurs within 2 years after the rst 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 al 5 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 al 6 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 arteries 7 . 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 Survey 8 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 rst episode did not affect the recurrence incidence. In a previous retrospective study, Chahal et al showed a lack of association between age at rst episode and risk of recurrent KD 9 . Hirata et al 10 associated cardiac sequels during the initial episode to be signi cant risk for recurrent KD. Treatment of IVIG before the fth 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 rate 3,11 . 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 KD 3 . During the rst and third episode, our patient was treated before the fth 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 Association 1 . The diagnosis of recurrent KD is di cult to establish because of the atypical or incomplete clinical features, and usually requires a combination of cardiac ultrasonography and biological criteria 12 . In our case, he presented complete forms of KD in his rst 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/mm 3 ), and was invalid by anti-infective treatment, were diagnosed as incomplete KD. The multiple recurrent KD also should distinguish from the periodic fever syndrome 13 . 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 history 14 .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 levels 15 . The case in our report was inconsistent with HIDS as well. These diseases are often confusing and need to be carefully identi ed. 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 degrees 11 . Study has shown that IVIG is more likely to be unresponsive when treating recurrent KD 3 . However, the strategies for prediction of potential IVIG non-responders and the optimal regime for IVIG-resistant patients remain to be determined 17 . Many experts recommend the second dose IVIG, and retrospective series had suggested safety and e cacy 18 . During the third episode, our patient was still suffering from persistent high fever at least 36 hours following completion of the rst 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 ve times with episodes during 41 months. This case and our literature review should raise awareness that KD can still recur two years after the rst 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 rst episodes. Therefore, it is important for every clinician to follow KD patients carefully, even more than 2 years after the rst episode.