Kawasaki Disease Open Access Articles and Journals
KD studies on long term effects:
Diagnosis, Treatment, and Long-Term Management of Kawasaki Disease, A Scientific Statement for Health Professionals From the American Heart Association
BACKGROUND: Kawasaki disease is an acute vasculitis of childhood that leads to coronary artery aneurysms in ≈25% of untreated cases. It has been reported worldwide and is the leading cause of acquired heart disease in children in developed countries.
METHODS AND RESULTS: To revise the previous American Heart Association guidelines, a multidisciplinary writing group of experts was convened to review and appraise available evidence and practice-based opinion, as well as to provide updated recommendations for diagnosis,
treatment of the acute illness, and long-term management. Although the cause remains unknown, discussion sections highlight new insights into the epidemiology, genetics, pathogenesis, pathology, natural history, and longterm outcomes. Prompt diagnosis is essential, and an updated algorithm defines supplemental information to be used to assist the diagnosis when
classic clinical criteria are incomplete. Although intravenous immune globulin is the mainstay of initial treatment, the role for additional primary therapy in selected patients is discussed. Approximately 10% to 20% of patients do not respond to initial intravenous immune globulin, and
recommendations for additional therapies are provided. Careful initial management of evolving coronary artery abnormalities is essential, necessitating an increased frequency of assessments and escalation of thromboprophylaxis. Risk stratification for long-term management is based primarily on maximal coronary artery luminal dimensions, normalized as Z scores, and is calibrated to both past and current involvement. Patients with aneurysms require life-long and uninterrupted cardiology follow-up.
CONCLUSIONS: These recommendations provide updated and best evidence-based guidance to healthcare providers who diagnose and manage Kawasaki disease, but clinical decision making should be individualized to specific patient circumstances.
Kawasaki disease is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children. If not treated early with high-dose intravenous immunoglobulin, 1 in 5 children develop coronary artery aneurysms; this risk is reduced 5 fold if intravenous immunoglobulin is administered within 10 days of fever onset. Coronary artery aneurysms evolve dynamically over time, usually reaching a peak dimension by 6 weeks after illness onset. Almost all the morbidity and mortality occur in patients with giant aneurysms. Risk of myocardial infarction from coronary artery thrombosis is greatest in the first 2 years after illness onset. However, stenosis and occlusion progress over years. Indeed, Kawasaki disease is no longer a rare cause of acute coronary syndrome presenting in young adults. Both coronary artery bypass surgery and percutaneous intervention have been used to treat Kawasaki disease patients who develop myocardial ischemia as a consequence of coronary artery aneurysms and stenosis.
Prospective study of Kawasaki disease complications: review of 115 cases
OBJECTIVE: To draw attention to complications that might arise in any Kawasaki disease (KD) stage, risk factors contributing to the onset of complications and possible transient or permanent disease sequelae.
METHODS: Prospective study (clinical cohort) conducted between April 2002 and April 2009 of 115 patients with KD admitted to the Pediatric Rheumatology Clinic of the General Hospital of the Federal District, Brazil. All patients were sequentially assessed with clinical and laboratory examinations, Doppler echocardiography, imitanciometry, auditory evoked potentials, psychological evaluation, ophthalmologic examination and, in one patient with chorea, cerebral magnetic resonance angiography. In all patients, a questionnaire assessing the possible presence of cognitive, emotional, behavioral and social disorders was applied.
RESULTS: Twenty-five patients (21.7%) had coronary aneurisms. Thirty-eight patients (33%) had a sensorineural auditory loss during the acute and subacute phases of the disease and 13 patients (11.3%) maintained the auditory loss six months after the first assessment. Other complications observed were as follows: facial palsy in one patient (0.9%), ataxia in acute and subacute phases in 11 (9.5%); 15 patients had ophthalmologic complications (13.2%), with uveitis in 13, papilledema in one patient, and conjunctival hemorrhage in another patient. One patient experienced chorea (0.9%), with a magnetic resonance angiography showing changes consistent with cerebral ischemia. In one patient, a thoracic aorta aneurism was found (0.9%) and another patient had a necrotizing vasculitis progressing to peripheral gangrene and tongue tip loss (0.9%). Behavioral changes over convalescence were observed in 23 children.
CONCLUSION: KD may progress with several complications even within months of the disease acute phase, eventually resulting in permanent sequelae. The earlier the diagnosis and therapeutic intervention with IV IgG administration are, the lower will be the occurrence of complications; the presence of thrombocytosis, anemia and elevated and extended inflammatory activity are risk factors for complication arising.
Long-Term Outcome of Kawasaki Disease
Kawasaki disease was first reported in 1967 by Japanese pediatrician Tomisaku Kawasaki as an acute febrile syndrome mainly affecting the skin, mucosa, and lymph nodes. Although initially recognized as benign, this syndrome was subsequently acknowledged to have a serious complication of coronary artery aneurysm, and it has gained the worldwide interest of pediatricians and pediatric cardiologists. The importance of and interest in this disease can be seen in the existence of the unusual publication of the English translation of the first report in Japanese. Because Japan is the country where the disease was first observed and the largest numbers of new patients are diagnosed each year, researchers there have been making outstanding efforts to uncover the mystery of this disease. Scientists from other countries have also contributed greatly in this regard despite the underlying difficulties in conducting research due to the limited number of cases compared with Japan. The present review article covers such longstanding efforts and their fruits, with a special focus on the long-term outcome of Kawasaki disease. Although data on the epidemiology, origin, pathophysiology, and treatment of this disease are important for a better understanding of the outcome, they have been reviewed extensively by several previous publications. Nevertheless, key data on these topics are summarized briefly herein.
Coronary Artery Aneurysms: A Review of the Epidemiology, Pathophysiology, Diagnosis, and Treatment
Coronary artery aneurysms (CAAs) are uncommon and describe a localized dilatation of a coronary artery segment more than 1.5-fold compared with adjacent normal segments. The incidence of CAAs varies from 0.3 to 5.3%. Ever since the dawn of the interventional era, CAAs have been increasingly diagnosed on coronary angiography. Causative factors include atherosclerosis, Takayasu arteritis, congenital disorders, Kawasaki disease (KD), and percutaneous coronary intervention. The natural history of CAAs remains unclear; however, several recent studies have postulated the underlying molecular mechanisms of CAAs, and genome-wide association studies have revealed several genetic predispositions to CAA. Controversies persist regarding the management of CAAs, and emerging findings support the importance of an early diagnosis in patients predisposed to CAAs, such as in children with KD. This review aims to summarize the present knowledge of CAAs and collate the recent advances regarding the epidemiology, etiology, pathophysiology, diagnosis, and treatment of this disease.
Long-term Management of Kawasaki Disease: Implications for the Adult Patient
Coronary artery complications from Kawasaki disease (KD) range from no involvement to giant coronary artery aneurysms (CAA). Current long-term management protocols are calibrated to the degree of maximal and current coronary artery involvement reflecting the known likelihood of severe long-term cardiac complications. It has recently been suggested that all KD patients may be at potential risk of severe long-term cardiac complications. If this assertion was to be confirmed, current follow-up protocols would need to be extensively modified, with important implications both for the growing adult population with a previous history of KD and for the healthcare system. Based on the available evidence, patients with multiple large and/or giant CAA are at substantial risk of severe long-term cardiac complications and should have regular specialized follow-up. Patients with transient or no CAA have not been reported to be at risk of severe long-term cardiac complications. The influence of KD on the atherosclerotic process remains suboptimally defined, and should be the focus of future studies. Heightened cardiovascular risk factor surveillance and management is recommended regardless of coronary artery involvement. Based on the currently available evidence, existing long-term management protocols seem to be appropriately calibrated to the level of risk. Revised long-term management protocols should incorporate newer, noninvasive imaging methods and intensive management of atherosclerotic risk. There is insufficient evidence at this time to mandate long-term specialized follow-up and invasive testing for patients who have not had CAA.
Long-term Cardiovascular Outcomes in Survivors of Kawasaki Disease
BACKGROUND AND OBJECTIVE: Kawasaki disease (KD) may result in coronary aneurysm formation, but there is incomplete knowledge regarding its long-term effects. Our objective was to quantify the longer-term rates of adverse cardiac events in a modern North American KD cohort.
METHODS: Using the Kaiser Permanente Northern California population, we performed a retrospective cohort study in patients with a history of KD versus matched patients without KD. Chart review was used to confirm the diagnosis of KD and all outcomes of interest, including acute coronary syndrome, coronary revascularization, heart failure, ventricular arrhythmia, valve disease, aortic aneurysm, and all-cause mortality. All outcomes occurring at age ≥15 years were included in the primary analysis. Outcome rates were compared between the 2 groups by using Cox proportional hazards analysis.
RESULTS: The study included 546 KD patients and 2218 matched patients without KD. Seventy-nine percent of the KD patients received intravenous immunoglobulin and 5% had persistent coronary aneurysm. The average follow-up time was 14.9 years. Only 2 KD patients experienced outcomes after age 15 (0.246 events per 1000 person-years) compared with 7 events in the non-KD group (0.217 events per 1000 person-years), a nonsignificant difference (hazard ratio: 0.81; 95% confidence interval: 0.16–4.0). Within the KD subgroup, persistent coronary aneurysm predicted the occurrence of adverse events (P = .007).
CONCLUSIONS: This is the largest US study of longer-term cardiac outcomes after KD and reveals a low rate of adverse cardiovascular events through age 21. Additional validation studies, including studies with longer-term follow-up, should be performed.
Cardiovascular status after Kawasaki disease in the UK
Objective Kawasaki disease (KD) is an acute vasculitis that causes coronary artery aneurysms (CAA) in young children. Previous studies have emphasised poor long-term outcomes for those with severe CAA. Little is known about the fate of those without CAA or patients with regressed CAA. We aimed to study long-term cardiovascular status after KD by examining the relationship between coronary artery (CA) status, endothelial injury, systemic inflammatory markers, cardiovascular risk factors (CRF), pulse-wave velocity (PWV) and carotid intima media thickness (cIMT) after KD.
Methods Circulating endothelial cells (CECs), endothelial microparticles (EMPs), soluble cell-adhesion molecules cytokines, CRF, PWV and cIMT were compared between patients with KD and healthy controls (HC). CA status of the patients with KD was classified as CAA present (CAA+) or absent (CAA−) according to their worst-ever CA status. Data are median (range).
Results Ninety-two KD subjects were studied, aged 11.9 years (4.3–32.2), 8.3 years (1.0–30.7) from KD diagnosis. 54 (59%) were CAA−, and 38 (41%) were CAA+. There were 51 demographically similar HC. Patients with KD had higher CECs than HC (p=0.00003), most evident in the CAA+ group (p=0.00009), but also higher in the CAA− group than HC (p=0.0010). Patients with persistent CAA had the highest CECs, but even those with regressed CAA had higher CECs than HC (p=0.011). CD105 EMPs were also higher in the KD group versus HC (p=0.04), particularly in the CAA+ group (p=0.02), with similar findings for soluble vascular cell adhesion molecule 1 and soluble intercellular adhesion molecule 1. There was no difference in PWV, cIMT, CRF or in markers of systemic inflammation in the patients with KD (CAA+ or CAA−) compared with HC.
Conclusions Markers of endothelial injury persist for years after KD, including in a subset of patients without CAA.
Persistence of endothelial cell damage late after Kawasaki disease in patients without coronary artery complications
Recent studies proposed an increased risk of atherosclerosis in patients with a history of Kawasaki disease. This study aimed to investigate the persistence of vascular injury after an acute phase of the Kawasaki disease.
Materials and Methods:
We determined the number of circulating endothelial cells (CEC) in the peripheral blood of 13 patients with a history of Kawasaki disease within four to ten years, in comparison with 13 healthy relative controls. The CECs were counted as CD146+/CD34 + cells by the standard flow cytometry technique, and the independent t-test was employed to compare the mean number of CECs in the two groups.
The mean number of CECs was significantly higher in patients than in controls (12 ± 3.03 vs. 2.38 ± 0.87, respectively, P < 0.001).
This study elucidates the persistence of vascular injury late after Kawasaki disease. This finding suggests that prolonged administration of vascular anti-inflammatory agents might be beneficial for preventing atherosclerosis in the subsequent years, in these patients.
Circulating endothelial cells in Kawasaki disease
Recent reports have demonstrated that circulating endothelial cells (CECs) are observed in several diseases with vascular injury. Because Kawasaki disease (KD) is one type of systemic vasculitis, we hypothesized that an increased number of CECs may be associated with the appearance of complicated coronary artery lesions (CAL). In the present study we investigated the enumeration and origin of CECs in 20 patients with KD, using an immunohistochemical method with monoclonal antibodies: clone P1H12 against ECs and clone AC133 against endothelial progenitor cells (EPCs), which were derived from the bone marrow. The mean number of CECs increased significantly (P < 0·05) from the acute through the subacute phases of KD compared with both the convalescent phase of KD and healthy children. The mean number of CECs was significantly (P < 0·05) higher in six KD patients with CAL than in 14 KD patients without CAL. The population of EPCs in the total CECs in KD was 4·4 ± 1·2% (range 0–18%). The number of EPCs during the subacute phase was also significantly higher (P < 0·05) in KD patients with CAL than in those without CAL. Our findings indicate that the number of CECs increase in KD vasculitis and suggest that the increased numbers of CECs and EPCs may reflect the EC damage of this disease.
Progression of coronary artery calcification at the crossroads: sign of progression or stabilization of coronary atherosclerosis?
Abstract: Coronary artery calcification (CAC) has been strongly established as an independent predictor of adverse events, with a significant incremental prognostic value over traditional risk stratification algorithms. CAC progression has been associated with a higher rate of events. In parallel, several randomized studies and meta-analysis have shown the effectiveness of statins to slow progression and even promote plaque regression. However, evidence regarding the effect of routine medical therapy on CAC has yielded conflicting results, with initial studies showing significant CAC regression, and contemporaneous data showing rather the opposite. Accordingly, there is currently a great controversy on whether progression of CAC is a sign of progression or stabilization of coronary artery disease (CAD). The finding of inexorable CAC progression despite the implementation of intensive contemporaneous medical therapy suggests that further understanding of this phenomenon should be undertaken before the implementation of CAC as a surrogate endpoint for longitudinal studies, or for prospective follow-up of patients under routine medical treatment.
Assessing Vascular Health After Kawasaki Disease
Kawasaki disease (KD) is a self-limited, systemic vasculitis of children with the most profound effect on the coronary arterial bed. Without timely diagnosis and treatment with intravenous immunoglobulin, coronary artery aneurysms will develop in 1 in 4 children with the attendant risks of thrombotic occlusion, myocardial infarction, and sudden death. Two major areas of controversy are emerging as this patient population ages. The first is whether patients will have longterm cardiovascular sequelae after KD, and the second is whether accelerated atherosclerotic changes in the coronary arteries will develop in these patients as a direct consequence of the arterial wall inflammation during their acute disease.
Arterial stiffness in patients after Kawasaki disease without coronary artery involvement: Assessment by performing brachial ankle pulse wave velocity and cardio-ankle vascular index
A B S T R A C T
Background: It remains unclear whether systemic arterial beds other than the coronary arteries are truly healthy in patients without coronary artery lesions (CAL) after Kawasaki disease (KD). We tested the hypothesis that patients with KD without echocardiographic evidence of CAL during the acute phase of the disease have abnormal mechanical properties in systemic arteries later.
Methods and results: We studied 201 consecutive patients with KD (age 2–23 years, mean 10 4 years; 109 male, 92 female) without CAL during the acute phase. Data were compared with those in 129 control subjects (age 2–25 years, mean 10 4 years; 73 male, 56 female; control group). We examined arterial stiffness by using the brachial–ankle pulse wave velocity (baPWV) and the cardio-ankle vascular index (CAVI). The baPWV in the KD group was significantly higher than that in the control group (913 121 cm/s vs. 886 135 cm/s, p = 0.04). In contrast, there was no significant difference in CAVI (4.0 1.0 vs. 4.2 1.0, p = 0.9) between the two groups. Multivariate analysis indicated a highly significant difference in baPWV (higher baPWV in patients with KD than in controls, p = 0.004), after controlling for age, gender, body height and weight, and systolic and diastolic blood pressure, but no difference in CAVI between the groups.
Conclusion: Years after KD occurs in patients without apparent CAL during the acute phase, there is a small but significant change in systemic arterial properties, characterized by increased wall stiffness. The clinical importance of these findings must be clarified by performing long-term follow-up studies.
Severe vitamin D deficiency in patients with Kawasaki disease: a potential role in the risk to develop heart vascular abnormalities?
Twenty-five-hydroxyvitamin D (25(OH)-vitamin D) is crucial in the regulation of immunologic processes, but-although its deficiency has been reported in patients with different rheumatological disorders-no data are available for Kawasaki disease (KD). The goals of this study were to assess the serum levels of 25(OH)-vitamin D in children with KD and evaluate the relationship with the eventual occurrence of KD-related vascular abnormalities. We evaluated serum 25(OH)-vitamin D levels in 79 children with KD (21 females, 58 males, median age 4.9 years, range 1.4-7.5 years) in comparison with healthy sex-/age-matched controls. A significantly higher percentage of KD patients (98.7 %) were shown to have reduced 25(OH)-vitamin D levels (<30 ng/mL) in comparison with controls (78.6 %, p < 0.0001). Furthermore, KD patients had severely low levels of 25(OH)-vitamin D than controls (9.17 ± 4.94 vs 23.3 ± 10.6 ng/mL, p < 0.0001), especially the subgroup who developed coronary artery abnormalities (4.92 ± 1.36 vs 9.41 ± 4.95 ng/mL, p < 0.0001). In addition, serum 25(OH)-vitamin D levels correlated not only with erythrosedimentation rate (p < 0.0001), C-reactive protein (p < 0.0001), hemoglobin level at KD diagnosis (p < 0.0001) but also with both coronary artery aneurysms (p = 0.005) and non-aneurysmatic cardiovascular lesions (p < 0.05). Low serum concentrations of 25(OH)-vitamin D might have a contributive role in the development of coronary artery complications observed in children with KD.
Vitamin K Status and Vascular Calcification: Evidence from Observational and Clinical Studies
Vascular calcification occurs when calcium accumulates in the intima (associated with atherosclerosis) and/or media layers of the vessel wall. Coronary artery calcification (CAC) reflects the calcium burden within the intima and media of the coronary arteries. In population-based studies, CAC independently predicts cardiovascular disease (CVD) and mortality. A preventive role for vitamin K in vascular calcification has been proposed based on its role in activating matrix Gla protein (MGP), a calcification inhibitor that is expressed in vascular tissue. Although animal and in vitro data support this role of vitamin K, overall data from human studies are inconsistent. The majority of population-based studies have relied on vitamin K intake to measure status. Phylloquinone is the primary dietary form of vitamin K and available supplementation trials, albeit limited, suggest phylloquinone supplementation is relevant to CAC. Yet observational studies have found higher dietary menaquinone, but not phylloquinone, to be associated with less calcification. Vascular calcification is highly prevalent in certain patient populations, especially in those with chronic kidney disease (CKD), and it is plausible vitamin K may contribute to reducing vascular calcification in patients at higher risk. Subclinical vitamin K deficiency has been reported in CKD patients, but studies linking vitamin K status to calcification outcomes in CKD are needed to clarify whether or not improving vitamin K status is associated with improved vascular health in CKD. This review summarizes the available evidence of vitamin K and vascular calcification in population-based studies and clinic-based studies, with a specific focus on CKD patients.
Long-term outcome of coronary artery dilatation in Kawasaki disease
Kawasaki disease (KD) is an acute systemic vasculitis syndrome with a high incidence of coronary aneurysms in untreated children. The majority of aneurysms resulting from KD are known to regress with time.
This study aimed to determine the course and outcome of coronary artery dilatation in patients with KD and ascertain whether there are any differences in the outcomes in the different branches.
Setting and Design:
This is a retrospective cohort study of patients diagnosed with KD with midterm follow-up data.
Serial echocardiography was performed in all KD patients with coronary dilatation for 1–10½ years. The Kaplan–Meier curve was used for statistical analysis.
There were 154 patients with coronary dilatation studied. The frequency of coronary dilatation in acute phase was 33.3% and decreased to 7.9% 6–8 weeks later. Each patient could have dilatations at more than one branch, so the total number of dilatations was 245. The median time needed for regression was 2.6 months (mean: 10.5 months) while the median of follow-up duration was 41 months (mean: 23 months). Small- and medium-sized dilatations had more favorable outcomes compared to the giant ones. Location of dilatation did not influence the outcome.
The majority (77.4%) of small- and medium-sized dilatations regress within 2 years, but giant aneurysms tend to persist. The outcome of coronary dilatation is determined by the diameter and not by the location. Regression rate is faster in smaller dilatations. Left main coronary artery is the most frequent location for dilatation.
When children with Kawasaki disease grow up: Myocardial and vascular complications in adulthood
Kawaski disease (KD) is an acute, self-limited vasculitis that typically occurs in young children and was first described by Japanese pediatrician Tomisaku Kawasaki in 1967. Although originally thought to be a rare condition, KD has become the most common cause of acquired heart disease in the pediatric age group in developed countries. The majority of patients with KD appear to have a benign prognosis but a subset of patients with coronary artery aneurysms are at risk for ischemic events and require lifelong treatment. In the four decades that have passed since the initial recognition of KD, the number of patients reaching adulthood has continued to grow. Adult cardiologists will be increasingly involved in the management these patients. Currently, there are no established guidelines for the evaluation and treatment of adult patients who have had KD. We review here the current literature that may be helpful to clinicians who care for adults who suffered from KD in childhood.
KD studies on hearing loss:
Sensorineural Hearing Loss and Kawasaki Disease: A Prospective Study
Purpose: Kawasaki disease (KD) is an acute, self-limited vasculitis of infants and children that is now the most common cause of acquired heart disease in the pediatric age group in the United States and Japan. Reports have documented the association of acute KD with sensorineural hearing loss. To assess the prevalence of hearing loss following acute KD in a geographically and ethnically diverse population, a prospective, multicenter study of hearing loss in patients with KD was conducted.
Materials and Methods: Patients with acute KD were enrolled in 7 clinical centers and underwent a primary audiologic evaluation within 30 days of the onset of fever. Patients were subsequently reevaluated after resolution of the acute phase of the disease. A questionnaire assessing risk factors for hearing loss was also administered.
Results: A total of 62 patients were evaluated during the 29-month study period. At the first audiologic evaluation, 19 patients (30.6%) had sensorineural hearing loss, 6 patients (9.7%) had conductive hearing loss, 17 patients (27.4%) had normal hearing, and 20 patients (32.3%) had inconclusive studies. Overall, 2 of 36 patients (5.5%) had sensorineural hearing loss documented on their second audiologic evaluation. No risk factors for hearing loss were identified by the questionnaire.
Conclusions: Transient sensorineural hearing loss (20 to 35 dB) is a frequent complication of acute KD and may be related to salicylate toxicity in some patients. Persistent sensorineural hearing loss is uncommon. Parents and primary care providers should be made aware of the potential for persistent sensorineural hearing loss following resolution of KD, but routine audiologic screening of this patient population does not appear to be warranted.
Sensorineural hearing loss associated with Kawasaki disease
In five children who met the diagnostic criteria for Kawasaki Disease, sensorineural hearing loss developed in association with the acute illness. The children, aged 7 months to 13 years, had deficits ranging from mild to profound bilateral sensorineural hearing loss. There were no associated neurologic abnormalities, and immunologic investigations and magnetic resonance imaging failed to reveal a cause. Treatment regimens differed among the children, but none had high salicylate levels (>20 mg/dl) or received other ototoxic medications. Anti-inflammatory therapy was not obviously beneficial in any case, and four of the children have persistent hearing deficits. We conclude that auditory involvement may be a complication of Kawasaki disease; screening of clinically affected children should be considered. (J PEDIATR 1990;117:371-7)
Audiologic profiles of children with Kawasaki disease
Kawasaki disease (KD) is an idiopathic vasculitis associated with systemic inflammation and profound immunoregulatory changes. Recent reports from Japan and the United States have documented the association of sensorineural hearing loss (SNHL) with acute KD. To further characterize the nature and prevalence of this complication, we prospectively evaluated the hearing of 40 consecutive patients with acute KD at a single institution. Standard audiometric procedures were used, including visual reinforcement audiometry and play audiometry. Auditory brainstem response (ABR) testing using clicks and tone pips (1000-4000 Hz) was performed in patients with abnormal or unreliable results on behavioral audiometry. Acoustic immittance measurements were obtained on all patients. Of the 23 males and 17 females (mean age 3.2 +/- 2.3 years, range 0.6-11.1 years), all but three were evaluated and treated with aspirin and intravenous gama globulin within 1 month of onset of fever. Seven children had test results suggesting sensorineural threshold shifts, 16 had normal hearing, and 14 had inconclusive hearing evaluations. Laboratory data in patients with hearing threshold shifts revealed significantly longer duration of fever (4.1 +/- 1.0 versus 1.9 +/- 0.5 days), and a tendency for higher temperatures and white blood cell counts at diagnosis compared to those with normal hearing. Results suggest that transient as well as persistent SNHL may be associated with the acute vasculitis of KD, and may be associated with laboratory markers indicating more severe systemic inflammation. Audiologic screening should be considered for all patients following KD.
KD studies on recurrent skin peeling:
Recurrent skin peeling following Kawasaki disease
Long term follow up of 259 cases of Kawasaki disease led to the observation that 11% of children have episodes of recurrent peeling of the skin for several years after their recovery. These events were usually associated with an upper respiratory tract infection and were distinct from a recurrence of Kawasaki disease. Repeeling was significantly less frequent in children who had suffered coronary artery dilatation and was more frequently seen in those with nasal staphylococcal colonisation. The mechanism for this phenomenon is unclear, but it has been observed in a number of other conditions caused by infectious agents and their toxins. Paediatricians need to be aware of this phenomenon which is distinct from recurrence of Kawasaki disease.
KD studies on recurrent cases of Kawasaki disease:
Cardiac sequelae of Kawasaki disease among recurrent cases
OBJECTIVE This study was undertaken to clarify whether cardiac sequelae due to Kawasaki disease are more frequent among recurrent cases than initial onset cases.
STUDY DESIGN A cross sectional study using data from nationwide surveys of Kawasaki disease in Japan was conducted. A total of 33 976 patients reported were divided into two groups: initial onset cases (32 923 patients) and recurrent cases (1053 patients). Proportions of cardiac sequelae such as coronary aneurysms/dilatation, coronary stenosis/narrowing, myocardial infarction, and valvular lesions were compared between the two groups.
RESULTS The proportions of patients with the sequelae were significantly more common among recurrent cases. In men 25.5% of the recurrent cases had the sequelae in comparison with 14.9% for initial onset cases, and in women 16.1% of recurrent cases had the sequelae compared with 9.8% of initial onset cases. Giant coronary aneurysms were twice as likely in men in whom the disease was recurring than in initial onset cases, and 1.5 times more likely in women in whom the disease was recurring than in initial onset cases.
CONCLUSION Cardiac sequelae of Kawasaki disease are more likely to appear on recurrent case patients.
Management and Outcome of Persistent or Recurrent Fever After Initial Intravenous Gamma Globulin Therapy in Acute Kawasaki Disease
To determine differences in clinical characteristics, laboratory findings, and cardiac complications between patients with acute Kawasaki disease who received additional treatment for persistent or recurrent fever vs those who did not.
Nonconcurrent case series; medical record review.
Tertiary care pediatric hospital.
One hundred eighty-five consecutive patients diagnosed as having acute Kawasaki disease at The Hospital for Sick Children, Toronto, Ontario, from 1995 to 1997.
Measure Prevalence of cardiac complications.
Twenty-one patients (11%) received additional treatment with intravenous gamma globulin (IVGG) with or without intravenous methylprednisolone for persistent fever lasting for more than 48 hours or recurrent fever after initial treatment with IVGG. Patients who received additional treatment did not differ significantly from other patients regarding age, sex, race, or diagnostic criteria. Compared with the patients who did not receive additional therapy, the patients who received additional treatment had shorter median interval from fever onset to initial dose of IVGG (5 vs 6 days; P=.006) and longer total days of fever (9 vs 6 days; P<.001). Initial laboratory investigations did not differ significantly. On initial echocardiography, patients who received additional therapy were significantly more likely to have pericardial effusion (33% vs 15%; P=.04), ventricular dysfunction (14% vs 2%; P=.002), and coronary artery ectasia (76% vs 43%; P=.004) but not aneurysms (10% vs 5%; P=.47). At 12 months after diagnosis, there were no significant differences between the 2 groups regarding the prevalence of coronary artery ectasia or aneurysms.
Patients receiving additional treatment for persistent or recurrent fever have similar demographic and clinical characteristics, greater initial cardiac involvement, and similar overall outcomes.
KAWASAKI DISEASE is the leading cause of acquired heart disease in children in the developed world, with coronary artery aneurysms occurring in 20% to 25% of untreated cases.1,2 Treatment with intravenous gamma globulin (IVGG) within 10 days of onset of fever has been shown in clinical trials to reduce the risk of coronary artery aneurysms to 4% to 8%.2,3 However, 10% to 30% of children treated with IVGG are refractory to treatment and are febrile for at least 3 days after treatment initiation.3,4
Additional treatment with IVGG appears to be safe,4 but a number of children continue to have persistent or relapsing fever despite the additional courses of IVGG.4,5 In contrast, although IV corticosteroids have been found to be efficacious in resolving fever,1,6 Kato et al1 reported that the use of steroids was associated with an increased prevalence of coronary artery aneurysms as high as 65%. Other studies have found no increased risk.5-7 Thus, the appropriate management of children with persistent or relapsing fever despite standard therapy remains controversial.
The purpose of this study was to determine differences in clinical characteristics, laboratory findings, and cardiac complications between patients with acute Kawasaki disease who received additional treatment with IVGG and/or IV corticosteroids for persistent or recurrent fever and patients who did not.
Cardiac Sequelae in Recurrent Cases of Kawasaki Disease: A Comparison Between the Initial Episode of the Disease and a Recurrence in the Same Patients
Objective. Cardiac sequelae develop more frequently after recurrent Kawasaki disease than from the initial onset of the disease. The purpose of this study was to observe the existence of the sequelae at the initial and second onsets of the disease simultaneously with a large cohort.
Materials and Methods. From the database of patients with Kawasaki disease prepared by the Japanese Kawasaki Disease Research Committee, 559 cases with recurrences recorded between 1989 through 1994 and their initial occurrence listed in the database were selected. Their proportions of cardiac sequelae after the initial and second onsets of Kawasaki disease were compared.
Results. Of the 68 patients with cardiac sequelae after the initial onset, 32 (47%) suffered the sequelae after the second onset, whereas 78 (16%) of the 491 who were without cardiac sequelae after the initial onset developed the sequelae after the recurrence. Both proportions were higher than proportions in all patients with Kawasaki disease. In addition to the sex (male) and the existence of the sequelae after the initial onset, age at the second onset (older age) and the interval between the two episodes (longer period) were suspected to be risk factors for sequelae attributable to recurrent Kawasaki disease.
Conclusion. Linked data of the initial and second episodes of Kawasaki disease showed that the risk of developing cardiac sequelae attributable to recurrent Kawasaki disease is high among both those with and without the sequelae at the initial episode.
Recurrent Kawasaki disease
Kawasaki disease (mucocutaneous lymph node syndrome) is a disease of unknown aetiology characterised by vasculitis which may affect the coronary arteries. Young children are most commonly affected although the disease has been described in adults. We report a case of recurrent Kawasaki disease which presented to an oral medicine clinic, where early recognition prompted appropriate management.
Kawasaki disease (mucocutaneous lymph node syndrome) was first described by Dr Tomisaku Kawasaki in 1967.1 Since then, more than 100,000 cases have been reported worldwide, the majority occuring in Japan.2 The disease predominantly affects young children and it is now the commonest cause of acquired heart disease in children in developed countries.3 The diagnosis is based on the presence of at least five of the following six clinical features: 1) persistent fever, 2) polymorphous rash, 3) characteristic changes in the extremities (erythema of the hands and feet followed by desquamation of the fingers and toes), 4) bilateral conjunctivitis, 5) cervical lympha- denopathy, 6) oropharyngeal changes including ‘strawberry’ tongue (prominent lingual papillae); dry, erythematous or cracked lips, and erythema of the oropharyngeal mucosa.2 The oral changes are a prominent feature of this serious disease and it is quite possible that some cases will present to dentists or dental departments in the first instance. Despite this, there appears to be little awareness of the condition in the dental community and the condition has received little attention in the dental literature.4 Since early diagnosis and treatment is important, the condition should be considered in children presenting with any of the oral features of the disease.
A 6-year-old boy of mixed Afro-Caribbean and Caucasian heritage presented to the oral medicine clinic with a 3-day history of lethargy, mild pyrexia, and a sore tongue. His past medical history was unremarkable apart from an episode of Kawasaki disease 15 months previously, which had been treated with intravenous immunoglobulin and oral aspirin. There had been no cardiac sequelae. At presentation in the oral medicine clinic, systemic and oral examination was unremarkable apart from the presence of a brightly erythematous tongue with prominent lingual papillae (fig. 1). This ‘strawberry’ tongue appearance produced a differential diagnosis including recurrent Kawasaki disease and scarlet fever. There was no history of sore throat or evidence of tonsillar exudate and scarlet fever was thought to be unlikely. Arrangements were made for the child to be reviewed by his paediatrician. Within 2 days he had developed conjunctivitis, generalised lymphadenopathy and desquamation of his finger tips. A clinical diagnosis of recurrent Kawasaki disease was made and treatment with a single dose of 2 g/kg of intravenous immunoglobulin and regular daily aspirin was initiated. Streptococcal serology was negative and no other explanation of his signs and symptoms became apparent. Examination of his cardiovascular system including echocardiography revealed no abnormalities. The patient was discharged 3 days after admission and within a month the original signs and symptoms had resolved. Further follow-up including echocardiography has been uneventful.
Kawasaki Disease: A Brief History
Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan. Although an infectious agent is suspected, the cause remains unknown. However, significant progress has been made toward understanding the natural history of the disease and therapeutic interventions have been developed that halt the immune-mediated destruction of the arterial wall. We present a brief history of KD, review progress in research on the disease, and suggest avenues for future study.
Kawasaki saw his first case of KD in January 1961 and published his first report in Japanese in 1967. Whether cases existed in Japan before that time is currently under study. The most significant controversy in the 1960s in Japan was whether the rash and fever sign/symptom complex described by Kawasaki was connected to subsequent cardiac complications in a number of cases. Pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that KD was a self-limited illness with no sequelae. This controversy was resolved in 1970 when the first Japanese nationwide survey of KD documented 10 autopsy cases of sudden cardiac death after KD. By the time of the first English-language publication by Kawasaki in 1974, the link between KD and coronary artery vasculitis was well-established.