P A Brogan, A Bose, D Burgner, D Shingadia, R Tulloh, C Michie, N Klein, R Booy, M Levin, M J Dillon
Arch Dis Child 2002;86:286-290
Fever duration of 5 days or more plus 4 of the following:
Kawasaki's disease (KD) may be diagnosed with fever and only 3 of these features if coronary artery aneurysms (CAAs) are detected. "Incomplete" cases have fewer criteria than required. Irritability is an important sign, which is virtually universally present, although not included as one of the diagnostic criteria. Another clinical sign not incorporated into the diagnostic criteria, but relatively specific to KD, is the development of erythema and induration at sites of BCG immunisation. The mechanism is cross reactivity of T cells between specific epitopes of mycobacterial and human heat shock proteins. An important point is that the criteria may present sequentially such that a so called "incomplete" case can evolve with time into a "complete" case. Thus the diagnosis of KD must be considered in any child with a febrile exanthemaous illness, particularly if it persists longer than 4-5 days.
Other relatively common clinical findings in KD include:
Relatively uncommon abnormalitis include hydrops of the gallbladder, gastrointestinal ischaemia, jaundice, petechial rash, febrile confusions and encephalopathy or ataxia. Cardiac complications other than coronary arterial abnormalities include cardiac tamponade, cardiac failure, myocarditis, and pericarditis.
Non specific. Acute phase proteins, neutrophils, ESR are usually increased. Thrombocytosis occurs towards the end of the second week of the illness and therefore may not be helpful diagnostically. Liver function may be deranged. Sterile pyuria is occasionally observed, and also CSF pleocytosis (predominantly lymphocytes) representing aseptic meningitis.
Treatment of KD is aimed at reducing inflammation, and preventing the occurrence of CAA and arterial thrombosis. The optimal doses of aspirin and IVIG are discussed, and the treatment of refractory KD is considered.
It is worthy of note that treatment of KD with aspirin alone has never been subject to a randomised controlled trial, although aspirin versus aspirin plus IVIG has been studied. Aspirin is given in the acute phase of the illness at relatively high "anti-inflammatory" doses (30-100 mg/kg/day). Following defervescence of the disease aspirin is given as an antiplatelet agent in a dose of 2-5 mg/kg once daily, the duration being dependent on findings on echocardiography.
Recent reviews have recommended the higher antiinflammatory dose of 100 mg/kg/day in the acute phase of the illness3 on the basis of reducing duration of fever and length of hospitalisation compared with low dose aspirin (3-8 mg/kg/day).8 No such comparative data on fever and hospitalisation exists regarding high dose aspirin versus moderate doses (30-50 mg/kg/day).
Meta-analysis comparing moderate anti-inflammatory doses of aspirin (30-50 mg/kg/day) with IVIG versus high dose aspirin (80-120 mg/kg/day) with IVIG found no signifi- cant difference in the incidence of CAA between the groups.9 Currently, it is our practice to administer aspirin at a dose of 30 mg/kg/day during the acute phase of the illness, as this may be better tolerated in terms of gastrointestinal and other side effects.10 Some have advocated the use of dipyridamole in addition to moderate dose aspirin as a synergistic antiplatelet agent. The evidence for the effectiveness of this in this situation is, however, lacking.
Early recognition and treatment of KD with aspirin and IVIG has been shown unequivocally by meta-analysis to reduce the occurrence of CAA.9 11 Moreover, the prevalence of coronary artery abnormalities in KD is highly dependent on total IVIG dose, but independent of aspirin dose.9 Treated with aspirin alone, 20-40% of children develop CAA.2 9 11 Combined therapy with aspirin and high dose IVIG given as a single infusion reduces the occurrence of CAA to 9% at 30 days, and 4% at 60 days after the onset of the illness.11 The prevalence of CAA is inversely related to the total dose of IVIG,9 2 g/kg of IVIG being the optimal dose, usually given as a single infusion.9 11 Meta-analysis of randomised controlled trials comparing divided lower doses of IVIG (400 mg/kg/day for four consecutive days) versus a single infusion of high dose IVIG (2 g/kg over 10 hours) has clearly shown the therapeutic benefits in the prevention of CAA with the latter regimen.11 One important practical point, however, is that infants who have cardiac compromise may not be able to tolerate the fluid challenge associated with the high dose single infusion, and consideration of divided doses given over several days may be appropriate for this patient group.
IVIG treatment should be started early in the disease, preferably within the first 10 days of the illness.9 11Importantly, however, clinicians should not hesitate to give IVIG to patients who present after 10 days if there are signs of persisting inflammation. Not all patients respond to a single dose of IVIG, and some require a second dose. It has been observed that those children who received IVIG very early in the illness may require a second infusion of IVIG for primary treatment failure or disease recrudescence.12 Thus, the timing of IVIG administration appears to be important, although this latter point should not dissuade clinicians from giving IVIG before day 5 of fever if the diagnosis of KD is suspected. Lastly, one question that remains unanswered is whether the type of IVIG administered is important, perhaps as a result of the presence of antibodies to epitopes derived from different donor pools. There are currently no data to suggest that any particular preparation is superior.
The use of corticosteroids in KD remains controversial. Unlike other vasculitic conditions, where corticosteroid remains the mainstay of treatment, an early study suggested that the incidence of CAA was greater in those treated with prednisolone compared with those treated with aspirin alone.13 Other workers have suggested that the use of pulsed methylprednisolone is effective in treating patients with KD resistant to IVIG.14 We believe that there is a role for corticosteroids in patients with KD refractory to treatment with IVIG,15 and also for those patients who may refuse IVIG because of religious beliefs, such as Jehovah’s Witnesses. We suggest, however, that treatment of refractory KD with corticosteroids should be undertaken in specialised centres.
Echocardiographic and cardiac angiographic data indicate that 20-40% of untreated KD patients develop coronary artery abnormalities. Approximately 50% of these lesions regress within five years, and in most with mild CAA (3-4 mm) regression occurs within two years.2 Giant aneurysms (>8 mm) are unlikely to resolve, and some may develop stenosis with risk of coronary thrombosis, myocardial infarction, and death. In 1993, a report from the British Paediatric Surveillance Unit indicated a mortality rate of 3.7% in the UK for KD.19 Current mortality rates reported from Japan are much lower at 0.14%.3 The reasons for this difference include improved therapy, and better case recognition. Long term sequelae may include the early development of coronary atherosclerosis.20
All patients with KD should undergo echocardiography on diagnosis and six to eight weeks after the onset of the disease.2 We also advocate an intermediate echocardiograph at 10-14 days of disease onset to pick up any missed pathology. Additionally, it is our practice to perform echocardiography at least weekly (and occasionally 48 hourly in the acute stages with ongoing active inflammation) for those who develop CAA to monitor aneurysm size progression, or the development of thrombus formation. Long term aspirin at 2-5 mg/kg/ day is recommended for those with persisting aneurysms on echocardiography.3 This can be discontinued if the aneurysms resolve. Depending on the size of the aneurysms, electrocardiography, and echocardiography performed 6-12 monthly is recommended.
Patients with aneurysms greater than 8 mm may require stress testing and possibly coronary angiography to identify stenotic lesions. Most experts recommend the addition of warfarin to aspirin therapy for those with giant (greater than 8 mm) coronary aneurysms,21 although randomised controlled trials supporting this practice are lacking. If warfarin is to be commenced, it is imperative to cover the initial warfarinisation period with intravenous heparin to counteract the paradoxical prothrombotic state which can occur soon after starting warfarin in some patients.22 More recently, it has been suggested that platelet glycoprotein IIb/IIIa receptor blockade therapy may be a useful addition to the therapeutic armamentarium for those with giant aneurysms.23 Limitation of strenuous activity is recommended in all patients with giant coronary aneurysms and/or stenoses. Some patients with coronary artery stenoses may require surgical revascularisation. In those patients who develop myocardial infarction, treatment with streptokinase or tissue plasminogen activator is indicated.2 A rare but serious complication of KD is the development of peripheral ischaemia and gangrene.2 This particular complication is associated with peripheral arterial aneurysm formation, particularly axillary aneurysms. Treatment with thrombolytic agents, anticoagulants, and intravenous prostacyclin may be indicated in such patients.2
Based on the evidence available to date, we recommend the clinical guideline shown in fig 1 for the management of KD in the UK. We propose that complete cases are treated, and additionally incomplete cases are treated at the discretion of the admitting clinician. We suggest, however, that clinicians should have a lower threshold for treatment of incomplete cases under the age of 1 year. For older children with incomplete KD, the decision to treat will be influenced by factors such as the small but theoretical risk of blood borne virus infection from IVIG. Lastly, we recommend yearly lifelong follow up of all children following an episode of KD. The purpose of this is to document the blood pressure, and provide general advice regarding other cardiac risk factors.
Seek expert advice to consider:
There are two important issues relating to vaccination following an episode of KD. Firstly, IVIG can block replication of live viral vaccines and subsequent actively acquired immunity.16 17 Consequently it is currently recommended that live vaccines be deferred for at least three months following treatment with IVIG.18 Secondly, an important question remaining unanswered is the safety of live or other vaccines in children recovering from KD. It has been our observation that some autoimmune disease states, including the systemic vasculitides, flare in response to live and non-live vaccine preparations. It is therefore our policy to defer immunisation with all vaccines for at least three months following an episode of KD.
The KDRG is made up of the principle research groups with an interest in KD in the London area. The main objectives of the group are to examine the aetiopathogenesis and changing epidemiology of KD in the UK. Specific areas of research will include: (1) the epidemiology including incidence, management, complication rate, and case fatality rate; (2) investigation of superantigen dependent or independent pathways of T cell activation in the acute and convalescent phases of the illness24-26; (3) the investigation of a viral aetiopathogenesis, in particular herpes viruses, using degenerate polymerase chain reaction methodology27; (4) investigation of host genetic determinants of susceptibility and outcome in KD5; (5) correlation of coronary and/or peripheral arterial involvement with clinical presentation; (6) evaluation of the potential of circulating endothelial microparticles as a laboratory diagnostic test and predictor of those at risk of coronary arterial aneurysm formation28 29; (7) the examination of B lymphocyte homing receptor expression of circulating antibody secreting B lymphocytes in acute and convalescent KD.
Multiregional and local research ethical committee approval has been granted in the London area. If clinicians wish to enrol a patient for research, the first step is to contact amember of the KDRG (see below). If not previously received, the appropriate information and consent forms will be faxed to the referring clinician, and advice given regarding the collection and handling of blood specimens and swabs. Samples must be collected prior to administration of IVIG, hence the KDRG bleep holder is available 24 hours/day, including weekends. A secondary aim of the group is to provide a centralised advisory service for general paediatricians, initially within the London area, but ultimately nationwide. Clinicians are therefore invited to contact key nominated clinical representatives of the KDRG with suspected complete or incomplete cases of KD, prior to commencement of therapy with IVIG. Permission to enrol the patient into the KDRG study will be sought, and telephonic advice given if requested. The aircall number to contact (24 hours) is: 08700 555500; ask for pager number 845031 and leave a message.