Primary vasculitis - classified by size of vessel affected (although a degree of overlap often exists):
Secondary vasculitis - SLE, mixed CT, infective esp streptococcus.
Differential: hyperlipidaemia, coagulopathy, fibromuscular dysplasia (familial).
May present with rash esp purpuric, pernio (swelling of subcutaneous tissue), ischaemia eg infarction (brain, gut, digits), nephritis, asthma.
The Chapel Hill system provides definitions for 10 different forms of adult vasculitis but is of debatable utility. Recent EULAR consensus criteria look pretty good Annals of the Rheumatic Diseases. 65(7):936-41, 2006. PMID 16322081.
pANCA seen in microscopic polyangiitis, cANCA (anti-MPO) in Wegener's granulomatosis (should be Wanca?!) but in children these are not very sensitive and in any case no evidence that distinction influences treatment or prognosis. The type of ANCA seems to be related to the population rather than the disease! Also associated with Churg Strauss. Probably has direct toxic effect. Untreated, these diseases have 90% 2 yr mortality...
Various subtypes:
In Ozen's study, skin features and musculoskeletal symptoms were common, as was CNS involvement. Overall, none had positive ANCA titres, and only a few had positive ANCA stains. 64% resolved with treatment, usually cyclophosphamide, often changed to azathioprine.
Journal of Pediatrics. 145(4):517-22, 2004 Oct. PMID 15480378
Standard induction therapy for vasculitis is high dose corticosteroids and either daily oral or pulsed IV cyclophosphamide. Pulsed therapy is less toxic but has a slightly higher risk of disease relapse. Then taper over 1 year.
Methotrexate is as effective as oral CYP in early, less severe vasculitis (ie without pulmonary/renal involvement). Methotrexate has higher relapse rate. Azathioprine seems to be equivalent to cyclophosphamide. Rituximab has been effective in 23 out of 24 patients, with no side effects. Relapse is associated with return of B cells. RCT in progress. Infliximab has had a rough ride: as adjuvant therapy, it has been associated with high incidence of infections and one lymphoma, and has not always produced any obvious benefit. Etanercept in relapsed Wegener's was as good as standard therapy but high incidence of side effects and death in both groups, plus 6 solid tumours all in Etanercept group... See Rheumatology drugs for more.
Antiphospholipid syndrome seen in 6% of primary vasculitis (not all studies have confirmed association) - high risk of thrombosis so consider anticoagulation.
A syndrome of unknown cause, characterised by persistent fever, conjunctivitis and mucosal changes eg strawberry tongue in a young child who has often been treated empirically with antibiotics without improvement, and is invariably miserable. Potentially complicated by coronary aneurysms, which may be fatal. Kawasaki's is the leading cause of acquired heart disease after rheumatic fever.
It is a vasculitis affecting medium sized arteries, and other arterial vessels down to capillary size. Probably a superantigen disorder with no specific infectious agent - coronary aneurysms have been seen in other superantigen diseases eg toxic shock, has also been reported in meningococcal septicaemia. Clustering has been shown (Knox test significant within the space-time interval of 3 km and 3-5 days) which suggests an infectious trigger PIDJ 27(11):981-985, Nov 2008). TNF alpha seems important, in an animal model, knock out mice or anti TNF treatment prevents aneurysm development. The underlying pathology is a vasculitis, and although coronary disease is the best recognized there is increasing evidence that other medium sized arteries are affected with descriptions in the literature of peripheral gangrene and cerebral infarction.
Archives Guideline for standard diagnosis and treatment.
More common in males, peak age 18-24 months, more common in Japanese children.
Standard case definition (American Heart Association) is:
Kawasaki disease may be diagnosed with fever and only 3 of these features if coronary artery aneurysms are detected. Lymphadenopathy is the least common feature (?easy to miss) - esp uncommon in younger children. Perineal desquamation is also quite characteristic.
There may also be abdominal pain, diarrhoea, arthralgia/arthritis, and headache. Aseptic meningitis, pneumonitis (with or without pulmonary nodules) have also been described. There may be a murmur of mitral incompetence, but this is rarely severe; myocarditis occurs but rarely leads to cardiac failure. Many of the clinical features of the disease are outbreak dependent with a different spectrum of clinical findings in one mini-outbreak compared with another, and with cases having similar clinical phenotypes clustering temporally.
So consider echo in any young child with persistent fever.
The term atypical or incomplete Kawasaki disease is used for cases without the required number of features. Whether this is the same disease or not is unclear; there will undoubtedly be some cases that overlap with other systemic vasculitides eg polyarteritis nodosa (PAN). In PAN, mucocutaneous changes are uncommon, whereas renal disease is common. Gall bladder hydrops appears to be unique to Kawasaki's. On the other hand, having a rigid case definition is perhaps unhelpful since incomplete cases are often seen, particularly in infants, and are associated with a delay in diagnosis and worse prognosis. Under the age of 3 months, the majority of cases with coronary aneurysms have atypical presentations.
Differential diagnosis:
Investigations mainly help exclude alternative diagnoses. Typically with the disease itself they simply indicate systemic inflammation and can be useful for monitoring response to treatment. Hence there are usually elevated white cells, platelets, ESR and CRP. Liver function tests are often mildly deranged. Low sodium and albumin suggest vascular leak. The ECG may have PR interval changes, and ST segment or T wave changes. Echocardiography may reveal dilated, ectatic coronary arteries or frank aneurysms.
Treatment is with intravenous immunoglobulin (IVIG) 2gm/kg over 8-12 hours, ideally within the first 7-10 days of the illness, and with aspirin 80-100 mg/kg/day orally during the acute phase. This combination reduces the risk of aneurysm formation from 25% to 9%. A recent New England Journal of Medicine RCT showed no significant benefit from adding steroids (although fever settled slightly more quickly). NEJM 2007;356(7):663-75. Most will respond to a single dose, but about 20% will require a second dose. Of these, about half will then defervesce.
Once defervescence has occurred, the aspirin dose can be reduced to an anti-platelet dose of 3-5mg/kg/day.
Duration of fever is the most powerful predictor of poor coronary outcome (one additional day of fever increasing the odds of aneurysm development by 3-5x). Delayed diagnosis is usually a reflection of slow evolution of criteria rather than atypical presentation. Outcome also relates to level of inflammation eg platelet count, high % neutrophils, high CRP (a rise in platelet count by 100/fL increasing the odds 8x). In Japan, the Harada score was developed - in addition to the clinical factors already described it includes male sex and age under 12 months. Age over 7yrs, abnormally low platelet count, failure to respond to IVIG, markers of vascular leak (eg low serum sodium, albumin) would also appear to be related to a worse outcome.
Pediatrics. 115(4):e428-33, 2005. PMID 15805345
Most aneurysms will resolve over time, unless they are giant (>8mm). Serial echocardiography should be done to monitor resolution. Warfarin should be considered for giant aneurysms, although its potential for complications in young children is significant. Stress testing and angiography may be appropriate. Aspirin can be discontinued if aneurysms resolve, but it is likely that the atherosclerosis risk remains high and life long follow up to address other risk factors is sensible.
In refractory cases where defervescence does not occur after 2 doses of IVIG, treatment becomes more complicated and evidence of effective strategies becomes more scarce.
Firstly, the diagnosis must be reviewed. Consider other forms of systemic vasculitis.
Pulsed methylprednisolone 30mg/kg (max 1g) once daily for 3 days is effective in achieving defervescence in at least 75% of patients, but historically has not prevented progression to aneurysms. A wide range of other immunosuppressant agents has been used including cyclophosphamide, ciclosporin, and methotrexate. Case reports and small case series have reported success with all of these agents. Plasmapheresis has also been used. There is a good theoretical basis for the use of the TNF alpha antagonist infliximab, and in a series from the US it was effective in 13 of 16 patients. J pediatrics 2005;146(5):662-7. Using IVMP after 1st dose IVIG in KD is effective, perhaps more effective than a 2nd dose IVIG (not randomized). However, there was a tendency for fever to recur later in IVMP-resistant patients, which could potentially delay the therapeutic decision-making process.Arch Dis Child. 2008 PMID 17962370
Mortality in the UK has been as high as 3.7%, but is much lower in Japan.
Lancet Volume 369, January 2007, Pages 85-87
1 study of 6 patients divided into:
1 died of pulmonary vasculitis during the first month of therapy. All of the survivors in group 2 entered remission (12-18 months). Other treatments included aortic bypass, aortorenal bypass, balloon dilatation. J Pediatrics Volume 150, 1 January 2007, 72-76
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