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Atypical and incomplete Kawasaki disease
Best Practice & Research Clinical Rheumatology 23 (2009) 689–697
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Atypical and incomplete Kawasaki disease R. Cimaz, MD Head, Rheumatology Department a, *, R. Sundel, MD Head, Rheumatology Department b,1 a b
AOU Meyer and University of Florence, Viale Pieraccini 24, 50139 Florence, Italy Children’s Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA
Keywords: Kawasaki disease coronary artery aneurysms vasculitis diagnosis atypical incomplete
Kawasaki disease (KD) is the most common systemic vasculitis in childhood after Henoch–Schonlein purpura, and the most common cause of acquired heart disease among children living in Western countries. Its diagnosis relies on clinical findings; laboratory tests are useful to rule out other causes of unexplained fever but are not specific for the diagnosis of KD. Numerous efforts to produce a diagnostic algorithm have been made, but without success. Expert opinion is therefore required in doubtful cases, especially those that lack classical criteria (the so-called atypical or incomplete cases). Renal, gastrointestinal, neurologic, pulmonary and ocular involvements have all been described. Infants may be at higher risk of complications since recognising manifestations of the disease might be more difficult in this group. Approaches to treatment and followup of KD are changing in parallel with changes in concepts of what constitutes classical and incomplete KD. Guiding this evolution is the probability that the diagnosis is actually KD, the duration of the child’s illness and the desired effects of therapy. Until a gold standard for diagnosing KD is available, these therapeutic decisions will continue to be made on an individual basis. Ó 2009 Elsevier Ltd. All rights reserved.
What is ‘typical’ Kawasaki disease? The Japanese paediatrician Tomisaku Kawasaki has given his name to the febrile illness that he called ‘mucocutaneous lymph node syndrome’ in his seminal 1967 report of 50 patients. As with all ‘new’ diseases, Kawasaki disease (KD) appears to have affected children long before this early
* Corresponding author. Tel.: þ39 055 5662924; Fax: þ39 055 5662400. E-mail address: [email protected] (R. Cimaz). 1 Tel.: þ617 355 6524; Fax: þ617 730 0249. 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.08.010
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description. Dr. Kawasaki indeed was perceptive and astute enough to detect the common features among patients whose diagnoses were until then elusive. Descriptions of children with similar findings dot the medical literature of the early 1900s, however, and in fact, a heart bearing the pathologic and clinical hallmarks of KD was preserved in the Guy’s Hospital, London, in the late 19th century. Even more tantalising is the potential relationship between KD and infantile polyarteritis nodosa (IPN), a uniformly fatal condition that sporadically struck down children during the 1920s, 1930s, and 1940s. Nothing about IPN distinguishes it from severe KD; therefore, upon weighing the available data, it seems that IPN was likely an early example of atypical KD with fatal coronary vasculitis. In any event, Dr. Kawasaki’s case series first appeared in English in 1974 [1]. Since then, Kawasaki disease (KD) has become the second most common systemic paediatric vasculitis (after Henoch– Schonlein purpura), and the most common cause of acquired heart disease among children living in Western countries. Kawasaki disease is also among the most thoroughly investigated inflammatory disorders in children, yet many fundamental questions remain unanswered. Most notable among this list of unresolved mysteries is the aetiology of KD, the reason that intravenous immunoglobulin (IVIG) is an effective therapy for KD and the variable susceptibility of different populations to the disease and its sequelae. More clinically relevant is the additional fact that there is still no diagnostic test for KD; rather, the diagnosis continues to rely upon the same clinical criteria that Dr. Kawasaki proposed 45 years ago. Fever of at least 5 days’ duration in addition to four of five signs of mucocutaneous inflammation (bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash and cervical lymphadenopathy) are required to meet the classical criteria for KD. Alternatively, fewer clinical signs of mucocutaneous inflammation in the presence of fever and coronary artery aneurysms (CAAs) are also deemed sufficient to diagnose KD [2]. Recently, an international committee has proposed perineal erythema, a useful clinical hint, as an additional diagnostic criterion [3]. Shortcomings of traditional diagnostic criteria–definition of atypical and incomplete KD A major impediment to diagnosing, treating and studying KD has been the absence of a ‘gold standard’ for defining the condition. Initially, Dr. Kawasaki proposed diagnostic criteria in response to a controversy about whether KD truly represented a condition discrete from Stevens–Johnson syndrome and erythema multiforme [4]. The subsequent discovery of cardiac involvement in KD largely resolved this controversy, but led to another in its place: Did children with coronary artery aneurysms (CAAs) necessarily have KD? With few exceptions, the answer to this question seems to be positive; although CAA may occur in systemic-onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus (SLE) and polyarteritis nodosa (PAN), they are generally regarded as confirmation of a diagnosis of KD if there is no evidence of another chronic inflammatory disease. This provides an unambiguous and convincing marker of KD in the 20–25% of children who develop CAA, but leaves the remainder at the mercy of subjective diagnostic criteria and clinical impressions. Children without coronary artery changes and not fulfilling the diagnostic criteria represent a particularly vexing subset of patients presenting with suspected KD. Such children often have been diagnosed as having ‘incomplete’ or ‘atypical’ KD. Early reports suggested a grave prognosis for children with atypical or incomplete KD, including a sobering mortality rate of 41% among children with CAAs in one review [5]. This death rate is at least partially due to inherent bias, in that by definition if there are less than the required criteria, coronary abnormalities have traditionally been required to confirm the diagnosis. Moreover, diagnostic delays are more common if the clinical phenotype is not typical; delayed treatment results in poorer outcomes [6]. One group requiring particular care is infants. Incomplete features of KD are more common in children younger than 6 months or older than 5 years of age, and particularly in the younger group the percentage demonstrating full diagnostic criteria is lower and the incidence of coronary arteritis higher [7]. In the past, there has been some confusion about the terms atypical and incomplete. The American Heart Association (AHA) and the American Academy of Pediatrics [2] (AAP) state: ‘‘The term ‘incomplete’ may be preferable to ‘atypical’ because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features.’’ For example, a Japanese study of 242 patients hospitalised for KD identified 25 who failed to meet the diagnostic criteria [8].
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Seventeen of these children had three clinical criteria for the diagnosis, seven had two criteria and only one patient ultimately developed transient coronary artery dilatation. The AHA and AAP recommend that the phrase ‘atypical Kawasaki disease’ be reserved for patients who have a problem, such as renal impairment, that generally is not seen in KD. Incomplete KD should be considered in all children with prolonged unexplained fever associated with even a few of the principal clinical features of KD. Nonetheless, in the absence of coronary abnormalities, the diagnosis of incomplete KD may be subject to criticism, since many other illnesses can have a similar clinical presentation. In fact, the differential diagnosis of KD is wide and includes entities such as viral infections (e.g., measles, adenovirus, enterovirus and Epstein–Barr virus), scarlet fever, staphylococcal scalded skin syndrome, toxic shock syndrome, bacterial cervical lymphadenitis, drug hypersensitivity reactions, Stevens–Johnson syndrome, systemic-onset juvenile idiopathic arthritis, Rocky Mountain spotted fever, leptospirosis and mercury hypersensitivity reaction (acrodynia). Interestingly, in a study of patients referred for evaluation for KD, over 40% of those in whom an alternative diagnosis was ultimately confirmed nonetheless met the criteria for the diagnosis of KD [9]. Most had Group A streptococcal disease or measles. SOJIA also may be difficult to distinguish from KD [10], particularly in some children who appear to develop KD as a prodrome of SOJIA [11]. In general, the pattern of the two types of fever (spiking in SOJIA and persistent in KD), and the more persistent arthritis in most cases of SOJIA, are sufficiently characteristic to allow distinction of atypical KD from typical SOJIA. Details of the rashes in these two conditions are also useful hints for differentiating between KD and SOJIA. In KD the rash is usually described as a polymorphous exanthem, meaning that it can take various forms, the most common being a non-specific, diffuse erythematous maculopapular eruption. Occasionally, it can also be urticarial, scarlatiniform, it can look like erythroderma or erythema-multiforme, and more rarely can be micropustular. Early and accentuated involvement of the groin and perineum are also typical. On the contrary, the rash of systemic JIA is usually maculopapular, pink-salmon and mostly concentrated in the warmer areas of the body such as the thighs, axillae and trunk. Important is the fact that while in KD the rash is persistent during the acute phase of illness, in SOJIA it is evanescent and usually flares during temperature spikes, only to fade or disappear when fever resolves. It is also important to note that in the clinical setting cardinal manifestations often do not appear simultaneously, and this can render the diagnosis difficult. Echocardiography should be considered in the presence of fever that does not respond to antibiotics associated with laboratory evidence of systemic inflammation, even if classical criteria are not present [2]. The so-called atypical forms of KD should include those patients who present with clinical manifestations that have been described rarely in the syndrome. This is also an evolving consideration, since as more experience is accumulated, manifestations formerly considered to be atypical may be noted more commonly than previously and no longer considered to be atypical. On the other hand, some features may not be recognised if clinically not apparent, or may be overlooked. Using these definitions, a single patient with coronary abnormalities might at the same time have both ‘‘incomplete’’ and ‘‘atypical’’ KD, if he or she shows less than the required criteria, accompanied by some unusual manifestations. Therefore, nomenclature and definitions in this context may be subject to pitfalls and confusion. In any case, the following summary of clinical manifestations not typical among classical cases of KD may be useful for clinical decision making; the interpretation of each finding in the context of definitions of atypical or incomplete is left to clinical researchers. Organ system involvement not included in the classic criteria Descriptions of gastrointestinal involvement are frequent, even at disease onset, and consist mainly of vomiting, diarrhoea and liver function abnormalities; hydrops of the gallbladder is also often found [12–14]. Unusual complications were described by Ravinder et al. in 2007 [15], with duodenal ulcer in one case and a retroperitoneal mass (lymphoid tissue at pathology report) in another child. Abdominal manifestations may sometimes be so acute and severe to mimic appendicitis or pancreatitis, leading to surgical interventions [16]. An Italian report described 10 children, most of whom did not have the required classical criteria, who had their disease onset with severe gastrointestinal complaints (acute abdominal pain and distension, vomiting, hepatomegaly and
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jaundice). Haematemesis was present in one case; toxic shock syndrome requiring care in the intensive care unit occurred in four. Five patients had laparotomy, three had percutaneous transhepatic biliary drainage and one had a gastrointestinal endoscopy. Postoperative diagnosis was gallbladder hydrops with cholestasis in five, paralytic ileus in three, appendicular vasculitis in one and haemorrhagic duodenitis in one [17]. Lymphadenopathy is classically cervical, mainly unilateral, with large nodes (>1.5 cm). However, it can also be mediastinal [18] or even multicentric [19]. In the neck it may not only be laterocervical but may also be located in the retropharyngeal space, mimicking an abscess [20,21]; torticollis may therefore be a presenting sign. The nervous system is rarely involved in KD, but occasional reports of nerve palsy exist [22,23]. Brain involvement is however exceptional and would raise questions about the diagnosis. Seizures may occur but they are most likely due to metabolic derangements in the context of an acute inflammatory disease. Aseptic meningitis may be more common than thought (lumbar puncture is performed only in a minority of cases) and could explain the extreme irritability that is present in practically all children with KD [24]. Finally, transient high-frequency sensorineural hearing loss can occur during the acute phase, but persistent sensorineural hearing loss is rare [25–27]. Pulmonary [28–30] and renal/genitourinary [31–34] involvement have also been described, but they appear to be rare. BCG (Bacillus Calmette-Gue´rin) reactivation is a useful diagnostic hint: in some countries, vaccination against tuberculosis is still required, and the occurrence of erythema and induration at the site of the previous scar may be diagnostically useful in doubtful cases [35,36]. Ocular manifestations, apart from conjunctivitis, more commonly consist of uveitis, and ocular evaluation with slit-lamp examination should be included as a part of the work-up in doubtful cases. Other ocular manifestations that have been described include punctate keratitis, vitreous opacities, optic disc swelling, retinal ischaemia, vascular occlusion and periorbital vasculitis [37–41]. Other unusual complications that have been recently described in KD involve symptoms consistent with a cytokine storm. As in systemic JRA and some viral infections, children with KD might develop fever, hepatitis and disseminated intravascular coagulopathy, the so-called macrophage activation syndrome (MAS) (or reactive haemophagocytosis) [42–44]. Similarly, Jane Burns’ group in San Diego published a series of 13 patients (out of a prospective cohort of 187) in whom KD presented as systolic hypotension or clinical signs of inadequate perfusion [45]. As with the children who developed MAS, evidence of consumptive coagulopathy was common. All patients required fluid resuscitation, and seven required infusions of vasopressors. On the basis of their study, the authors concluded that KD shock syndrome is associated with more severe laboratory markers of inflammation and greater risk of coronary artery abnormalities, mitral regurgitation and prolonged myocardial dysfunction. These patients may be resistant to immunoglobulin therapy and require additional anti-inflammatory treatment. Finally, some authors have included the presence of viral infections as a feature of atypical KD [46–48]. Conversely, the group at the Hospital for Sick Children in Toronto reported that 33% of their patients who met the criteria for a diagnosis of KD had evidence of at least one infection at the time of diagnosis [49]. The relationship between a coincident infection and KD thus is ambiguous; it may just as convincingly be argued that viral infections may co-exist with KD, trigger KD or be misdiagnosed as KD. Indeed, the fact that KD often occurs in epidemics and that household contacts of children with KD are at increased risk for developing the disease in Japan, all point to a transmissible agent being involved in its pathogenesis. Nonetheless, although many putative aetiologies have been proposed during the past 4 decades, suggestions that various viruses or bacterial toxins account for the majority of cases have not been substantiated. Thus, many researchers now believe that KD represents a final common pathway of immune-mediated vascular inflammation in genetically susceptible children triggered by any one of a variety of common infections [50]. Can diagnostic problems be solved with algorithms and/or protocols? A new tool that would facilitate the diagnosis of KD, taking into account clinical and laboratory values, is certainly needed and would be most welcome [51]. The main problem is that as long as KD
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remains a clinical diagnosis, it will always be subject to bias, misjudgement and second-guessing. Conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis, but may result in failure to recognise incomplete forms of illness. The laboratory findings of incomplete cases appear to be similar to those of classic cases. Several risk scores and algorithms have been developed in order to improve diagnostic accuracy in patients with incomplete manifestations. Unfortunately, these attempts have all been imperfect and no two have been identical, largely due to the absence of a gold standard for diagnosing KD and to the pitfalls of diagnostic classification in a pleomorphic syndrome like KD. In an attempt to develop such a tool, a large multicentre survey within the Pediatric Rheumatology European Society led to the identification through chart review of approximately 1500 children in 11 countries who had a discharge diagnosis of KD [52,53]. Of those, 225 (15%) did not fulfil American Heart Association (AHA) criteria for classical KD (172 had incomplete KD and 53 had atypical disease). The study compared clinical and laboratory variables between these two groups, and with a third group of 55 patients with other illnesses characterised by fever and rash (viral infections, systemic JIA, staphylococcal scalded skin syndrome). There were some statistical differences between groups when comparing atypical and incomplete KD (grouped together) with other febrile illnesses distinguishable from KD: platelet count and erythrocyte sedimentation rate (ESR) were higher in KD, while oral and extremity changes were more common children with other illnesses. Interestingly, lymphadenopathy was more frequent in the group with febrile diseases than among those with atypical or incomplete KD. An algorithm published by the American Academy of Pediatrics and the American Heart Association [2] suggests measuring CRP and ESR on day 5 of fever in children with 2 or 3 of the clinical criteria. Children with CRP 3 mg/dl and/or an ESR 40 mm/h should be considered for further diagnostic evaluation. Albumin 3.0 g/dl, anaemia, elevated aminotransferase levels, platelet count after 7 days 450,000/mm3, WBC 15,000 per mm3, and sterile pyuria all may be useful for distinguishing KD from its mimics. This and other similar studies will continue to provide interesting fodder for debates on the diagnosis of KD. Nonetheless, we believe that without a gold standard for diagnosing KD, no clinical criteria have a high enough positive predictive value to ensure foolproof treatment decisions. Ultimately, whether to give or not give intravenous (i.v.) gammaglobulin in doubtful cases is still a difficult decision, and expert opinion will be required until more specific diagnostic markers are identified. Who should be treated? Questions regarding therapy of KD overlap debates concerning classification and diagnosis, though they are not identical. The standards for diagnosing KD may be stricter or more lenient than the standards for using IVIG in a particular case. Nonetheless, given the expanding view of what KD and incomplete KD may be, approaches to treatment and follow-up are changing, too. Since 20–60% of children who develop CAAs never meet classic criteria for the diagnosis of KD, it is clear that the major goal of treatment – preventing coronary artery sequelae – cannot be met by limiting treatment to children with classical KD. One alternative was the development of an algorithm for identifying all children thought to be at risk for developing CAAs by a blue-ribbon panel of KD experts from North America [2]. This approach too has limitations, since conditions other than KD, including systemic JIA, EBV, PAN and SLE, also cause coronary artery dilatation. Further, it is not known whether children with other viral or febrile illnesses might develop transient coronary artery dilatation during the course of their illness. Of course, whether children such as these might also benefit from IVIG therapy is similarly not known. Clearly, treating all children with fever of more than 7 days with IVIG for possible KD is not a viable option. Rather, identifying those at risk of developing aneurysms appears to be the more practical approach for further decreasing the cardiac morbidity of atypical or incomplete KD. Interestingly, attempts at identifying risk factors for the development of CAAs significantly antedate the current discussion. As early as 1983, only 8 years after initial reports of cardiac involvement in KD [54], Asai offered a system for assessing the severity of KD [55]. Even after researchers recognised the efficacy of IVIG in treating KD, the prevailing opinion was that it was impractical to give such an expensive and potentially toxic therapy to everyone with KD in the hope of preventing aneurysms in no more than 20–25% [56]. Initially, researchers identified age under 1 year, male gender and prolonged fever as markers of increased likelihood of
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developing CAAs. Since that time, additional risk factors have been identified, including presence of axillary aneurysms, hypoalbuminaemia, hyponatraemia, elevated CRP and elevated ALT [57,58]. Treatment decisions regarding children with atypical or incomplete KD are based upon the probability that the diagnosis is actually KD, the duration of the child’s illness and the desired effects of therapy. In turn, these are predicated on the natural history of the disease and the risk–benefit calculations of therapy. These factors are incorporated into the treatment algorithm recommended by Newburger et al. [2], though the quality of data driving the recommendations vary considerably. Thus, these guidelines provide a framework for what is ultimately a subjective decision best made by clinicians with expertise in the care of children with suspected KD. While relief of the discomfort and irritability that accompany KD is an important goal, recommendations for the management of KD are predicated on the ability of IVIG to prevent long-term sequelae and, most importantly, coronary artery abnormalities. The consequences of failure to expeditiously treat a child with KD are sufficient grave, and the repercussions of using IVIG in a child who does not have KD sufficiently benign, to dictate a general bias in favour of treating ambiguous cases. Nonetheless, IVIG is not entirely without side effects, and it is quite expensive, so every attempt is made to minimise the inappropriate use of IVIG. Treatment strategies also depend on the implications of coronary artery dilatation. Long-term outcome studies are incompletely reassuring. Fifty percent of CAAs regress angiographically, and among such children, at least one study demonstrated no increase in morbidity or mortality rates up to 2 decades after a diagnosis of KD [59]. On the other hand, children with persistent cardiac sequelae of KD have a twofold risk of mortality after 20 years [60]. Further, functional [61] and histological [62] abnormalities of more subtle markers of endothelial health are demonstrable even in children with healed or consistently normal coronary arteries following KD. Similarly, acute-phase reactants and platelet counts may not return to normal for up to 2 months after apparently successful treatment, suggesting that vasculitis and endothelial inflammation may not fully resolve even when fever is controlled. On the basis of these and similar data, today there is very little debate that all children diagnosed with KD should be treated with IVIG. Even if some are not destined to develop coronary artery dilatation, all children may have some degree of cardiac involvement, including functional endothelial changes and myocarditis. Regardless, absent infallible ways of identifying all children at risk of developing CAAs, withholding a benign therapy like IVIG and allowing some children to develop CAA is not acceptable. On the horizon is also the possibility that children’s risk at presentation will be stratified to determine who might benefit from combination therapy beyond the routine IVIG [63]. More complicated are determinations of when to treat children who fail to meet criteria for KD, but in whom the disease cannot be ruled out. Risk factors formerly used to decide in which children IVIG could be safely withheld are now used to identify children not meeting criteria for KD, but who may nonetheless be at risk of developing aneurysms, and therefore warranting therapy with IVIG. The most widely used system for identifying children with incomplete KD who should receive IVIG is that of Newburger et al. [2]. Children in whom KD is being considered, but who do not meet clinical criteria for the diagnosis by day 7 of fever, are further evaluated with laboratory studies, slit-lamp examinations and/or echocardiograms. Certain arbitrary cut-offs for treatment are proposed; these are based upon clinical studies, but extrapolation beyond available data is necessary in order to provide practical guidelines for real-life situations. Prolonged fever is still the cardinal manifestation of KD under the AHA algorithm. Children with 5 or more days of fever and two or three clinical criteria should be evaluated further for incomplete KD. This starts with a full assessment for possible characteristics suggesting KD, including those noted above. Characteristics suggestive of an alternative diagnosis are considered as well, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash and generalised adenopathy. If KD appears unlikely, watchful waiting with ongoing re-assessment is employed to integrate additional clinical data. If the clinical picture is consistent with KD, the next step is obtaining laboratory tests. If inflammatory markers are minimally abnormal (CRP <3.0 mg dl1, ESR <40 mm h1), this is less suggestive of KD, though the child should be followed daily and formally re-assessed if fevers persist. Even in children with unimpressive inflammatory markers whose fever resolves, an echocardiogram is recommended if typical peeling of the skin develops, despite the fact that this appears to be an insensitive marker of KD [64].
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In those children with a clinical picture consistent with KD and significantly elevated inflammatory markers (CRP 3.0 mg/dl, ESR 40 mm/h), supplemental laboratory criteria are taken into consideration. These include albumin 3.0 g/dl, anaemia for age, elevated alanine aminotransferase, platelets 450,000/mm3 after 7 days of illness, white blood cell count 15,000/mm3 and urine 10 white blood cells/high-power field. If a child with suspected incomplete KD has three or more supplemental lab criteria, treatment for KD is recommended, and it may be started before an echocardiogram is performed. In children with fewer than three supplemental lab criteria, an echocardiogram is recommended, with treatment to follow if the echocardiogram is suggestive of KD; treatment is recommended even if the child is past day 10 of fever if there are clinical and laboratory signs of continued inflammation. If the echocardiogram is negative and the fever subsides, KD is considered to have been unlikely. If the echocardiogram is negative and unexplained fever persists, a repeat echo and consultation with a KD expert are recommended. Febrile infants aged 6 months or younger are treated with particular caution. Because even those infants who do have KD tend to present with minimal evidence of mucocutaneous inflammation, yet their risk of developing aneurysms is up to 35% even with IVIG treatment, guidelines for use of empiric therapy are more lenient. It is recommended that these young infants should have laboratory studies if febrile for 7 days or more, even if there are no other clinical manifestations of KD present. If systemic inflammation is found, it is recommended that such infants undergo echocardiogram and be treated if the echocardiogram is positive. In conclusion, KD will remain a clinical diagnosis until specific and reliable disease markers are discovered. The ultimate decision of whether or not to treat an individual patient will continue to be the responsibility of the clinician in charge. Existing data and decision algorithms provide support and guidance, but physicians who are uncomfortable with the need to make therapeutic decisions in the absence of certainty should avoid KD, In summary, as long as KD remains a clinical syndrome, diagnostic uncertainty and fallability are unavoidable. Conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis, but may result in failure to recognise incomplete forms of illness. The laboratory findings of incomplete cases appear to be similar to those of classic cases. Several risk scores and algorithms have been developed to improve diagnostic accuracy in patients with incomplete manifestations, but none of these identifies all children who ultimately develop CAAs nor excludes everyone with a different condition that mimics KD. Ultimately, whether to give or not give i.v. gammaglobulin in doubtful cases is a difficult decision, improved but not perfected by experience and expertise.
Practice points KD is a clinical diagnosis; markers of the illness are fever and associated signs and symptoms of mucocutaneous inflammation. Conventional diagnostic criteria should be viewed as guidelines, not prerequisites, since cardiac complications can occur even in children lacking the classic criteria. In children with suspected incomplete KD and significantly elevated inflammatory markers, supplemental laboratory criteria (low albumin, anaemia, elevated ALT, thrombocytosis, leucocytosis, pyuria) are taken into consideration. With three or more supplemental lab criteria, treatment may be recommended. Febrile infants aged 6 months or younger are treated with particular caution, and should have laboratory studies if febrile for 7 days or more, even if there are no other clinical manifestations of KD present, and if systemic inflammation is found, it is recommended that such infants undergo echocardiogram. Treatment should be instituted as soon as the diagnosis of classical or incomplete KD is made because prolonged fever is the strongest risk factor for development of coronary artery aneurysms.
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Research agenda Research at a basic science level (particularly the search for an aetiology of the disease) is the only path that will ultimately lead to a gold standard for the diagnosis of KD. In the absence of fuller knowledge of the cause and pathogenesis of KD, diagnostic algorithms based on clinical and laboratory parameters will continue to assist clinicians with therapeutic decision making. Studies on risk factor stratification will also be useful, both for primary treatment decisions in doubtful cases, and to determine who might benefit from combination therapy beyond the routine IVIG alone.
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[28] Uziel Y, Hashkes PJ, Kassem E, et al. ‘‘Unresolving pneumonia’’ as the main manifestation of atypical Kawasaki disease. Arch Dis Child 2003;88:940–2. [29] Falcini F, Vitale A, La Torre F, et al. Refractory pneumonia and high fever. Lancet 2009;373:1818. [30] Freeman AF, Crawford SE, Finn LS, et al. Inflammatory pulmonary nodules in Kawasaki disease. Pediatr Pulmonol 2003; 36:102–6. [31] Papadodima SA, Sakelliadis EI, Goutas ND, et al. Atypical Kawasaki disease presenting with symptoms from the genitourinary system: an autopsy report. J Trop Pediatr 2009;55:55–7. [32] Kabani A, Joffe A, Jadavji T. Hydrocele in Kawasaki disease: importance in early recognition of atypical disease. Am J Dis Child 1991;145:1349–51. [33] Wu CY, Hsieh KS, Chiou YH, et al. Prolonged fever and pyuria: a urinary tract infection presentation of incomplete Kawasaki disease. Acta Paediatr 2005;94:375–7. [34] Falcini F, Calabri GB, Simonini G, et al. Bilateral renal artery stenosis in Kawasaki disease: a report of two cases. Clin Exp Rheumatol 2006;24:719–21. [35] Sinha R, Balakumar T. BCG reactivation: a useful diagnostic tool even for incomplete Kawasaki disease. Arch Dis Child 2005;90:891. [36] Yamazaki-Nakashimada MA, Ramırez-Vargas N, De Rubens-Figueroa J. Chronic granulomatous disease associated with atypical Kawasaki Disease. Pediatr Cardiol 2008;29:169–71. [37] Kadayan A, Choi J, Headon MP. Disciform keratitis and optic disc swelling in Kawasaki disease: an unusual presentation. Eye 2006;20:976–7. [38] Anand S, Yang YC. Optic disc changes in Kawasaki disease. J Pediatr Ophtalmol Strabismus 2004;41:177–9. [39] Purvin V, Kawasaki A, Jacobson DM. Optic perineuritis: clinical and radiographic features. Arch Ophtalmol 2001: 1299–306. [40] Ohono S, Miyajima T, Higuci M, et al. Ocular manifestations of Kawasaki disease. Am J Ophthalmol 1982;93:713–7. [41] Blatt AN, Vogler L, Tychsen L. Incomplete presentations in a series of 37 children with Kawasaki disease: the role of the pediatric ophthalmologist. J Pediatr Ophthalmol Strabismus 1996;33:114–9. [42] Cummings C, McCarthy P, van Hoff J, Porter Jr G. Kawasaki disease associated with reactive hemophagocytic lymphohistiocytosis. Pediatr Infect Dis J 2008;27:1116–8. [43] Muise A, Tallett SE, Silverman ED. Are children with Kawasaki disease and prolonged fever at risk for macrophage activation syndrome? Pediatrics 2003;112:e495. [44] Palazzi DL, McClain KL, Kaplan SL. Hemophagocytic syndrome after Kawasaki disease. Pediatr Infect Dis J 2003;22: 636–66. *[45] Kanegaye JT, Wilder MS, Molkara D, et al. Recognition of a Kawasaki Disease Shock Syndrome. Pediatrics 2009;123: e783–9. [46] Usta Guc B, Cengiz N, Yildirim SV, Uslu Y. Cytomegalovirus infection in a patient with atypical Kawasaki disease. Rheumatol Int 2008;28:387–9. [47] Catalano-Pons C, Quartier P, Leruez-Ville M, et al. Primary cytomegalovirus infection, atypical Kawasaki disease, and coronary aneurysms in 2 infants. Clin Infect Dis 2005;41:53–6. [48] Kanegane H, Tsuji T, Seki H, et al. Kawasaki disease with a concomitant primary Epstein-Barr virus infection. Acta Paaediatr Jpn 1994;36:713–6. [49] Benseler SM, McCrindle BW, Silverman ED, et al. Infections and Kawasaki disease: implications for coronary artery outcome. Pediatrics 2005;116:e760–6. [50] Burgner D, Harnden A. Kawasaki disease: what is the epidemiology telling us about the etiology? Int J Infect Dis 2005;9: 185–94. [51] Simonini G, Rose` CD, Vierucci A, et al. Diagnosing Kawasaki syndrome: the need for a new clinical tool. Rheumatology 2005;44:959–61. [52] Falcini F, Simonini G, De Simone L, et al. Atypical and incomplete Kawasaki disease: a challenge for pediatricians. Clin Exp Rheumatol 2004;22:535 [abstract]. [53] Falcini F, Simonini G, Vitale A, et al. Facing the atypical/incomplete Kawasaki disease: what’s the purpose? Clin Exp Rheumatol 2005;23:S55 [abstract]. [54] Kato H, Koike S, Yamamoto M, et al. Coronary aneurysms in infants and young children with acute febrile mucocutaneous lymph node syndrome. J Pediatr 1975;86:892. [55] Asai T. Evaluation method for the degree of seriousness in Kawasaski disease. Acta Pediatr Jpn 1983;25:170–5. *[56] Feigin RD, Barron KD. Treatment of Kawasaki syndrome. New Engl J Med 1986;315:388–90. [57] Song D, Yeo Y, Ha K, et al. Risk factors for Kawasaki disease-associated coronary abnormalities differ depending on age. Eur J Pediatr 2009 Jan 22 [Epub ahead of print]. [58] Uehara R, Belay ED, Maddox RA, et al. Analysis of potential risk factors associated with nonresponse to initial intravenous immunoglobulin treatment among Kawasaki disease patients in Japan. Pediatr Infect Dis J 2008;27:155–60. *[59] Kato H, Sugimura T, Akagi T, et al. Long-term consequences of Kawasaki disease. A 10- to 21-year follow-up study of 594 patients. Circulation 1996;94:1379–85. [60] Nakamura Y, Yanagawa H, Harada K, et al. Mortality among persons with a history of Kawasaki disease in Japan: the fifth look. Arch Pediatr Adolesc Med 2002;156:162–5. [61] Furuyama H, Odagawa Y, Katoh C, et al. Assessment of coronary function in children with a history of Kawasaki disease using (15)O-water positron emission tomography. Circulation 2002;105:2878–84. [62] Tanaka N, Naoe S, Masuda H, Ueno T. Pathological study of sequelae of Kawasaki disease (MCLS) with special reference to the heart and coronary arterial lesions. Acta Pathol Jpn 1986;36:1513–27. *[63] Kobayashi T, Inoue I, Otani T, et al. Risk stratification in the decision to include prednisolone with intravenous immunoglobulin in primary therapy in Kawasaki disease. Pediatr Infect Dis J 2009;28:498–502. [64] Wang S, Best BM, Burns JC. Periungual desquamation in patients with Kawasaki disease. Pediatr Infect Dis J 2009;28: 538–9.
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9
Atypical and incomplete Kawasaki disease R. Cimaz, MD Head, Rheumatology Department a, *, R. Sundel, MD Head, Rheumatology Department b,1 a b
AOU Meyer and University of Florence, Viale Pieraccini 24, 50139 Florence, Italy Children’s Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston MA 02115, USA
Keywords: Kawasaki disease coronary artery aneurysms vasculitis diagnosis atypical incomplete
Kawasaki disease (KD) is the most common systemic vasculitis in childhood after Henoch–Schonlein purpura, and the most common cause of acquired heart disease among children living in Western countries. Its diagnosis relies on clinical findings; laboratory tests are useful to rule out other causes of unexplained fever but are not specific for the diagnosis of KD. Numerous efforts to produce a diagnostic algorithm have been made, but without success. Expert opinion is therefore required in doubtful cases, especially those that lack classical criteria (the so-called atypical or incomplete cases). Renal, gastrointestinal, neurologic, pulmonary and ocular involvements have all been described. Infants may be at higher risk of complications since recognising manifestations of the disease might be more difficult in this group. Approaches to treatment and followup of KD are changing in parallel with changes in concepts of what constitutes classical and incomplete KD. Guiding this evolution is the probability that the diagnosis is actually KD, the duration of the child’s illness and the desired effects of therapy. Until a gold standard for diagnosing KD is available, these therapeutic decisions will continue to be made on an individual basis. Ó 2009 Elsevier Ltd. All rights reserved.
What is ‘typical’ Kawasaki disease? The Japanese paediatrician Tomisaku Kawasaki has given his name to the febrile illness that he called ‘mucocutaneous lymph node syndrome’ in his seminal 1967 report of 50 patients. As with all ‘new’ diseases, Kawasaki disease (KD) appears to have affected children long before this early
* Corresponding author. Tel.: þ39 055 5662924; Fax: þ39 055 5662400. E-mail address: [email protected] (R. Cimaz). 1 Tel.: þ617 355 6524; Fax: þ617 730 0249. 1521-6942/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2009.08.010
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description. Dr. Kawasaki indeed was perceptive and astute enough to detect the common features among patients whose diagnoses were until then elusive. Descriptions of children with similar findings dot the medical literature of the early 1900s, however, and in fact, a heart bearing the pathologic and clinical hallmarks of KD was preserved in the Guy’s Hospital, London, in the late 19th century. Even more tantalising is the potential relationship between KD and infantile polyarteritis nodosa (IPN), a uniformly fatal condition that sporadically struck down children during the 1920s, 1930s, and 1940s. Nothing about IPN distinguishes it from severe KD; therefore, upon weighing the available data, it seems that IPN was likely an early example of atypical KD with fatal coronary vasculitis. In any event, Dr. Kawasaki’s case series first appeared in English in 1974 [1]. Since then, Kawasaki disease (KD) has become the second most common systemic paediatric vasculitis (after Henoch– Schonlein purpura), and the most common cause of acquired heart disease among children living in Western countries. Kawasaki disease is also among the most thoroughly investigated inflammatory disorders in children, yet many fundamental questions remain unanswered. Most notable among this list of unresolved mysteries is the aetiology of KD, the reason that intravenous immunoglobulin (IVIG) is an effective therapy for KD and the variable susceptibility of different populations to the disease and its sequelae. More clinically relevant is the additional fact that there is still no diagnostic test for KD; rather, the diagnosis continues to rely upon the same clinical criteria that Dr. Kawasaki proposed 45 years ago. Fever of at least 5 days’ duration in addition to four of five signs of mucocutaneous inflammation (bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, changes in the extremities, rash and cervical lymphadenopathy) are required to meet the classical criteria for KD. Alternatively, fewer clinical signs of mucocutaneous inflammation in the presence of fever and coronary artery aneurysms (CAAs) are also deemed sufficient to diagnose KD [2]. Recently, an international committee has proposed perineal erythema, a useful clinical hint, as an additional diagnostic criterion [3]. Shortcomings of traditional diagnostic criteria–definition of atypical and incomplete KD A major impediment to diagnosing, treating and studying KD has been the absence of a ‘gold standard’ for defining the condition. Initially, Dr. Kawasaki proposed diagnostic criteria in response to a controversy about whether KD truly represented a condition discrete from Stevens–Johnson syndrome and erythema multiforme [4]. The subsequent discovery of cardiac involvement in KD largely resolved this controversy, but led to another in its place: Did children with coronary artery aneurysms (CAAs) necessarily have KD? With few exceptions, the answer to this question seems to be positive; although CAA may occur in systemic-onset juvenile idiopathic arthritis (SOJIA), systemic lupus erythematosus (SLE) and polyarteritis nodosa (PAN), they are generally regarded as confirmation of a diagnosis of KD if there is no evidence of another chronic inflammatory disease. This provides an unambiguous and convincing marker of KD in the 20–25% of children who develop CAA, but leaves the remainder at the mercy of subjective diagnostic criteria and clinical impressions. Children without coronary artery changes and not fulfilling the diagnostic criteria represent a particularly vexing subset of patients presenting with suspected KD. Such children often have been diagnosed as having ‘incomplete’ or ‘atypical’ KD. Early reports suggested a grave prognosis for children with atypical or incomplete KD, including a sobering mortality rate of 41% among children with CAAs in one review [5]. This death rate is at least partially due to inherent bias, in that by definition if there are less than the required criteria, coronary abnormalities have traditionally been required to confirm the diagnosis. Moreover, diagnostic delays are more common if the clinical phenotype is not typical; delayed treatment results in poorer outcomes [6]. One group requiring particular care is infants. Incomplete features of KD are more common in children younger than 6 months or older than 5 years of age, and particularly in the younger group the percentage demonstrating full diagnostic criteria is lower and the incidence of coronary arteritis higher [7]. In the past, there has been some confusion about the terms atypical and incomplete. The American Heart Association (AHA) and the American Academy of Pediatrics [2] (AAP) state: ‘‘The term ‘incomplete’ may be preferable to ‘atypical’ because these patients lack sufficient clinical signs of the disease to fulfill the classic criteria; they do not demonstrate atypical clinical features.’’ For example, a Japanese study of 242 patients hospitalised for KD identified 25 who failed to meet the diagnostic criteria [8].
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Seventeen of these children had three clinical criteria for the diagnosis, seven had two criteria and only one patient ultimately developed transient coronary artery dilatation. The AHA and AAP recommend that the phrase ‘atypical Kawasaki disease’ be reserved for patients who have a problem, such as renal impairment, that generally is not seen in KD. Incomplete KD should be considered in all children with prolonged unexplained fever associated with even a few of the principal clinical features of KD. Nonetheless, in the absence of coronary abnormalities, the diagnosis of incomplete KD may be subject to criticism, since many other illnesses can have a similar clinical presentation. In fact, the differential diagnosis of KD is wide and includes entities such as viral infections (e.g., measles, adenovirus, enterovirus and Epstein–Barr virus), scarlet fever, staphylococcal scalded skin syndrome, toxic shock syndrome, bacterial cervical lymphadenitis, drug hypersensitivity reactions, Stevens–Johnson syndrome, systemic-onset juvenile idiopathic arthritis, Rocky Mountain spotted fever, leptospirosis and mercury hypersensitivity reaction (acrodynia). Interestingly, in a study of patients referred for evaluation for KD, over 40% of those in whom an alternative diagnosis was ultimately confirmed nonetheless met the criteria for the diagnosis of KD [9]. Most had Group A streptococcal disease or measles. SOJIA also may be difficult to distinguish from KD [10], particularly in some children who appear to develop KD as a prodrome of SOJIA [11]. In general, the pattern of the two types of fever (spiking in SOJIA and persistent in KD), and the more persistent arthritis in most cases of SOJIA, are sufficiently characteristic to allow distinction of atypical KD from typical SOJIA. Details of the rashes in these two conditions are also useful hints for differentiating between KD and SOJIA. In KD the rash is usually described as a polymorphous exanthem, meaning that it can take various forms, the most common being a non-specific, diffuse erythematous maculopapular eruption. Occasionally, it can also be urticarial, scarlatiniform, it can look like erythroderma or erythema-multiforme, and more rarely can be micropustular. Early and accentuated involvement of the groin and perineum are also typical. On the contrary, the rash of systemic JIA is usually maculopapular, pink-salmon and mostly concentrated in the warmer areas of the body such as the thighs, axillae and trunk. Important is the fact that while in KD the rash is persistent during the acute phase of illness, in SOJIA it is evanescent and usually flares during temperature spikes, only to fade or disappear when fever resolves. It is also important to note that in the clinical setting cardinal manifestations often do not appear simultaneously, and this can render the diagnosis difficult. Echocardiography should be considered in the presence of fever that does not respond to antibiotics associated with laboratory evidence of systemic inflammation, even if classical criteria are not present [2]. The so-called atypical forms of KD should include those patients who present with clinical manifestations that have been described rarely in the syndrome. This is also an evolving consideration, since as more experience is accumulated, manifestations formerly considered to be atypical may be noted more commonly than previously and no longer considered to be atypical. On the other hand, some features may not be recognised if clinically not apparent, or may be overlooked. Using these definitions, a single patient with coronary abnormalities might at the same time have both ‘‘incomplete’’ and ‘‘atypical’’ KD, if he or she shows less than the required criteria, accompanied by some unusual manifestations. Therefore, nomenclature and definitions in this context may be subject to pitfalls and confusion. In any case, the following summary of clinical manifestations not typical among classical cases of KD may be useful for clinical decision making; the interpretation of each finding in the context of definitions of atypical or incomplete is left to clinical researchers. Organ system involvement not included in the classic criteria Descriptions of gastrointestinal involvement are frequent, even at disease onset, and consist mainly of vomiting, diarrhoea and liver function abnormalities; hydrops of the gallbladder is also often found [12–14]. Unusual complications were described by Ravinder et al. in 2007 [15], with duodenal ulcer in one case and a retroperitoneal mass (lymphoid tissue at pathology report) in another child. Abdominal manifestations may sometimes be so acute and severe to mimic appendicitis or pancreatitis, leading to surgical interventions [16]. An Italian report described 10 children, most of whom did not have the required classical criteria, who had their disease onset with severe gastrointestinal complaints (acute abdominal pain and distension, vomiting, hepatomegaly and
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jaundice). Haematemesis was present in one case; toxic shock syndrome requiring care in the intensive care unit occurred in four. Five patients had laparotomy, three had percutaneous transhepatic biliary drainage and one had a gastrointestinal endoscopy. Postoperative diagnosis was gallbladder hydrops with cholestasis in five, paralytic ileus in three, appendicular vasculitis in one and haemorrhagic duodenitis in one [17]. Lymphadenopathy is classically cervical, mainly unilateral, with large nodes (>1.5 cm). However, it can also be mediastinal [18] or even multicentric [19]. In the neck it may not only be laterocervical but may also be located in the retropharyngeal space, mimicking an abscess [20,21]; torticollis may therefore be a presenting sign. The nervous system is rarely involved in KD, but occasional reports of nerve palsy exist [22,23]. Brain involvement is however exceptional and would raise questions about the diagnosis. Seizures may occur but they are most likely due to metabolic derangements in the context of an acute inflammatory disease. Aseptic meningitis may be more common than thought (lumbar puncture is performed only in a minority of cases) and could explain the extreme irritability that is present in practically all children with KD [24]. Finally, transient high-frequency sensorineural hearing loss can occur during the acute phase, but persistent sensorineural hearing loss is rare [25–27]. Pulmonary [28–30] and renal/genitourinary [31–34] involvement have also been described, but they appear to be rare. BCG (Bacillus Calmette-Gue´rin) reactivation is a useful diagnostic hint: in some countries, vaccination against tuberculosis is still required, and the occurrence of erythema and induration at the site of the previous scar may be diagnostically useful in doubtful cases [35,36]. Ocular manifestations, apart from conjunctivitis, more commonly consist of uveitis, and ocular evaluation with slit-lamp examination should be included as a part of the work-up in doubtful cases. Other ocular manifestations that have been described include punctate keratitis, vitreous opacities, optic disc swelling, retinal ischaemia, vascular occlusion and periorbital vasculitis [37–41]. Other unusual complications that have been recently described in KD involve symptoms consistent with a cytokine storm. As in systemic JRA and some viral infections, children with KD might develop fever, hepatitis and disseminated intravascular coagulopathy, the so-called macrophage activation syndrome (MAS) (or reactive haemophagocytosis) [42–44]. Similarly, Jane Burns’ group in San Diego published a series of 13 patients (out of a prospective cohort of 187) in whom KD presented as systolic hypotension or clinical signs of inadequate perfusion [45]. As with the children who developed MAS, evidence of consumptive coagulopathy was common. All patients required fluid resuscitation, and seven required infusions of vasopressors. On the basis of their study, the authors concluded that KD shock syndrome is associated with more severe laboratory markers of inflammation and greater risk of coronary artery abnormalities, mitral regurgitation and prolonged myocardial dysfunction. These patients may be resistant to immunoglobulin therapy and require additional anti-inflammatory treatment. Finally, some authors have included the presence of viral infections as a feature of atypical KD [46–48]. Conversely, the group at the Hospital for Sick Children in Toronto reported that 33% of their patients who met the criteria for a diagnosis of KD had evidence of at least one infection at the time of diagnosis [49]. The relationship between a coincident infection and KD thus is ambiguous; it may just as convincingly be argued that viral infections may co-exist with KD, trigger KD or be misdiagnosed as KD. Indeed, the fact that KD often occurs in epidemics and that household contacts of children with KD are at increased risk for developing the disease in Japan, all point to a transmissible agent being involved in its pathogenesis. Nonetheless, although many putative aetiologies have been proposed during the past 4 decades, suggestions that various viruses or bacterial toxins account for the majority of cases have not been substantiated. Thus, many researchers now believe that KD represents a final common pathway of immune-mediated vascular inflammation in genetically susceptible children triggered by any one of a variety of common infections [50]. Can diagnostic problems be solved with algorithms and/or protocols? A new tool that would facilitate the diagnosis of KD, taking into account clinical and laboratory values, is certainly needed and would be most welcome [51]. The main problem is that as long as KD
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remains a clinical diagnosis, it will always be subject to bias, misjudgement and second-guessing. Conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis, but may result in failure to recognise incomplete forms of illness. The laboratory findings of incomplete cases appear to be similar to those of classic cases. Several risk scores and algorithms have been developed in order to improve diagnostic accuracy in patients with incomplete manifestations. Unfortunately, these attempts have all been imperfect and no two have been identical, largely due to the absence of a gold standard for diagnosing KD and to the pitfalls of diagnostic classification in a pleomorphic syndrome like KD. In an attempt to develop such a tool, a large multicentre survey within the Pediatric Rheumatology European Society led to the identification through chart review of approximately 1500 children in 11 countries who had a discharge diagnosis of KD [52,53]. Of those, 225 (15%) did not fulfil American Heart Association (AHA) criteria for classical KD (172 had incomplete KD and 53 had atypical disease). The study compared clinical and laboratory variables between these two groups, and with a third group of 55 patients with other illnesses characterised by fever and rash (viral infections, systemic JIA, staphylococcal scalded skin syndrome). There were some statistical differences between groups when comparing atypical and incomplete KD (grouped together) with other febrile illnesses distinguishable from KD: platelet count and erythrocyte sedimentation rate (ESR) were higher in KD, while oral and extremity changes were more common children with other illnesses. Interestingly, lymphadenopathy was more frequent in the group with febrile diseases than among those with atypical or incomplete KD. An algorithm published by the American Academy of Pediatrics and the American Heart Association [2] suggests measuring CRP and ESR on day 5 of fever in children with 2 or 3 of the clinical criteria. Children with CRP 3 mg/dl and/or an ESR 40 mm/h should be considered for further diagnostic evaluation. Albumin 3.0 g/dl, anaemia, elevated aminotransferase levels, platelet count after 7 days 450,000/mm3, WBC 15,000 per mm3, and sterile pyuria all may be useful for distinguishing KD from its mimics. This and other similar studies will continue to provide interesting fodder for debates on the diagnosis of KD. Nonetheless, we believe that without a gold standard for diagnosing KD, no clinical criteria have a high enough positive predictive value to ensure foolproof treatment decisions. Ultimately, whether to give or not give intravenous (i.v.) gammaglobulin in doubtful cases is still a difficult decision, and expert opinion will be required until more specific diagnostic markers are identified. Who should be treated? Questions regarding therapy of KD overlap debates concerning classification and diagnosis, though they are not identical. The standards for diagnosing KD may be stricter or more lenient than the standards for using IVIG in a particular case. Nonetheless, given the expanding view of what KD and incomplete KD may be, approaches to treatment and follow-up are changing, too. Since 20–60% of children who develop CAAs never meet classic criteria for the diagnosis of KD, it is clear that the major goal of treatment – preventing coronary artery sequelae – cannot be met by limiting treatment to children with classical KD. One alternative was the development of an algorithm for identifying all children thought to be at risk for developing CAAs by a blue-ribbon panel of KD experts from North America [2]. This approach too has limitations, since conditions other than KD, including systemic JIA, EBV, PAN and SLE, also cause coronary artery dilatation. Further, it is not known whether children with other viral or febrile illnesses might develop transient coronary artery dilatation during the course of their illness. Of course, whether children such as these might also benefit from IVIG therapy is similarly not known. Clearly, treating all children with fever of more than 7 days with IVIG for possible KD is not a viable option. Rather, identifying those at risk of developing aneurysms appears to be the more practical approach for further decreasing the cardiac morbidity of atypical or incomplete KD. Interestingly, attempts at identifying risk factors for the development of CAAs significantly antedate the current discussion. As early as 1983, only 8 years after initial reports of cardiac involvement in KD [54], Asai offered a system for assessing the severity of KD [55]. Even after researchers recognised the efficacy of IVIG in treating KD, the prevailing opinion was that it was impractical to give such an expensive and potentially toxic therapy to everyone with KD in the hope of preventing aneurysms in no more than 20–25% [56]. Initially, researchers identified age under 1 year, male gender and prolonged fever as markers of increased likelihood of
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developing CAAs. Since that time, additional risk factors have been identified, including presence of axillary aneurysms, hypoalbuminaemia, hyponatraemia, elevated CRP and elevated ALT [57,58]. Treatment decisions regarding children with atypical or incomplete KD are based upon the probability that the diagnosis is actually KD, the duration of the child’s illness and the desired effects of therapy. In turn, these are predicated on the natural history of the disease and the risk–benefit calculations of therapy. These factors are incorporated into the treatment algorithm recommended by Newburger et al. [2], though the quality of data driving the recommendations vary considerably. Thus, these guidelines provide a framework for what is ultimately a subjective decision best made by clinicians with expertise in the care of children with suspected KD. While relief of the discomfort and irritability that accompany KD is an important goal, recommendations for the management of KD are predicated on the ability of IVIG to prevent long-term sequelae and, most importantly, coronary artery abnormalities. The consequences of failure to expeditiously treat a child with KD are sufficient grave, and the repercussions of using IVIG in a child who does not have KD sufficiently benign, to dictate a general bias in favour of treating ambiguous cases. Nonetheless, IVIG is not entirely without side effects, and it is quite expensive, so every attempt is made to minimise the inappropriate use of IVIG. Treatment strategies also depend on the implications of coronary artery dilatation. Long-term outcome studies are incompletely reassuring. Fifty percent of CAAs regress angiographically, and among such children, at least one study demonstrated no increase in morbidity or mortality rates up to 2 decades after a diagnosis of KD [59]. On the other hand, children with persistent cardiac sequelae of KD have a twofold risk of mortality after 20 years [60]. Further, functional [61] and histological [62] abnormalities of more subtle markers of endothelial health are demonstrable even in children with healed or consistently normal coronary arteries following KD. Similarly, acute-phase reactants and platelet counts may not return to normal for up to 2 months after apparently successful treatment, suggesting that vasculitis and endothelial inflammation may not fully resolve even when fever is controlled. On the basis of these and similar data, today there is very little debate that all children diagnosed with KD should be treated with IVIG. Even if some are not destined to develop coronary artery dilatation, all children may have some degree of cardiac involvement, including functional endothelial changes and myocarditis. Regardless, absent infallible ways of identifying all children at risk of developing CAAs, withholding a benign therapy like IVIG and allowing some children to develop CAA is not acceptable. On the horizon is also the possibility that children’s risk at presentation will be stratified to determine who might benefit from combination therapy beyond the routine IVIG [63]. More complicated are determinations of when to treat children who fail to meet criteria for KD, but in whom the disease cannot be ruled out. Risk factors formerly used to decide in which children IVIG could be safely withheld are now used to identify children not meeting criteria for KD, but who may nonetheless be at risk of developing aneurysms, and therefore warranting therapy with IVIG. The most widely used system for identifying children with incomplete KD who should receive IVIG is that of Newburger et al. [2]. Children in whom KD is being considered, but who do not meet clinical criteria for the diagnosis by day 7 of fever, are further evaluated with laboratory studies, slit-lamp examinations and/or echocardiograms. Certain arbitrary cut-offs for treatment are proposed; these are based upon clinical studies, but extrapolation beyond available data is necessary in order to provide practical guidelines for real-life situations. Prolonged fever is still the cardinal manifestation of KD under the AHA algorithm. Children with 5 or more days of fever and two or three clinical criteria should be evaluated further for incomplete KD. This starts with a full assessment for possible characteristics suggesting KD, including those noted above. Characteristics suggestive of an alternative diagnosis are considered as well, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash and generalised adenopathy. If KD appears unlikely, watchful waiting with ongoing re-assessment is employed to integrate additional clinical data. If the clinical picture is consistent with KD, the next step is obtaining laboratory tests. If inflammatory markers are minimally abnormal (CRP <3.0 mg dl1, ESR <40 mm h1), this is less suggestive of KD, though the child should be followed daily and formally re-assessed if fevers persist. Even in children with unimpressive inflammatory markers whose fever resolves, an echocardiogram is recommended if typical peeling of the skin develops, despite the fact that this appears to be an insensitive marker of KD [64].
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In those children with a clinical picture consistent with KD and significantly elevated inflammatory markers (CRP 3.0 mg/dl, ESR 40 mm/h), supplemental laboratory criteria are taken into consideration. These include albumin 3.0 g/dl, anaemia for age, elevated alanine aminotransferase, platelets 450,000/mm3 after 7 days of illness, white blood cell count 15,000/mm3 and urine 10 white blood cells/high-power field. If a child with suspected incomplete KD has three or more supplemental lab criteria, treatment for KD is recommended, and it may be started before an echocardiogram is performed. In children with fewer than three supplemental lab criteria, an echocardiogram is recommended, with treatment to follow if the echocardiogram is suggestive of KD; treatment is recommended even if the child is past day 10 of fever if there are clinical and laboratory signs of continued inflammation. If the echocardiogram is negative and the fever subsides, KD is considered to have been unlikely. If the echocardiogram is negative and unexplained fever persists, a repeat echo and consultation with a KD expert are recommended. Febrile infants aged 6 months or younger are treated with particular caution. Because even those infants who do have KD tend to present with minimal evidence of mucocutaneous inflammation, yet their risk of developing aneurysms is up to 35% even with IVIG treatment, guidelines for use of empiric therapy are more lenient. It is recommended that these young infants should have laboratory studies if febrile for 7 days or more, even if there are no other clinical manifestations of KD present. If systemic inflammation is found, it is recommended that such infants undergo echocardiogram and be treated if the echocardiogram is positive. In conclusion, KD will remain a clinical diagnosis until specific and reliable disease markers are discovered. The ultimate decision of whether or not to treat an individual patient will continue to be the responsibility of the clinician in charge. Existing data and decision algorithms provide support and guidance, but physicians who are uncomfortable with the need to make therapeutic decisions in the absence of certainty should avoid KD, In summary, as long as KD remains a clinical syndrome, diagnostic uncertainty and fallability are unavoidable. Conventional diagnostic criteria should be viewed as guidelines that are particularly useful in preventing overdiagnosis, but may result in failure to recognise incomplete forms of illness. The laboratory findings of incomplete cases appear to be similar to those of classic cases. Several risk scores and algorithms have been developed to improve diagnostic accuracy in patients with incomplete manifestations, but none of these identifies all children who ultimately develop CAAs nor excludes everyone with a different condition that mimics KD. Ultimately, whether to give or not give i.v. gammaglobulin in doubtful cases is a difficult decision, improved but not perfected by experience and expertise.
Practice points KD is a clinical diagnosis; markers of the illness are fever and associated signs and symptoms of mucocutaneous inflammation. Conventional diagnostic criteria should be viewed as guidelines, not prerequisites, since cardiac complications can occur even in children lacking the classic criteria. In children with suspected incomplete KD and significantly elevated inflammatory markers, supplemental laboratory criteria (low albumin, anaemia, elevated ALT, thrombocytosis, leucocytosis, pyuria) are taken into consideration. With three or more supplemental lab criteria, treatment may be recommended. Febrile infants aged 6 months or younger are treated with particular caution, and should have laboratory studies if febrile for 7 days or more, even if there are no other clinical manifestations of KD present, and if systemic inflammation is found, it is recommended that such infants undergo echocardiogram. Treatment should be instituted as soon as the diagnosis of classical or incomplete KD is made because prolonged fever is the strongest risk factor for development of coronary artery aneurysms.
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Research agenda Research at a basic science level (particularly the search for an aetiology of the disease) is the only path that will ultimately lead to a gold standard for the diagnosis of KD. In the absence of fuller knowledge of the cause and pathogenesis of KD, diagnostic algorithms based on clinical and laboratory parameters will continue to assist clinicians with therapeutic decision making. Studies on risk factor stratification will also be useful, both for primary treatment decisions in doubtful cases, and to determine who might benefit from combination therapy beyond the routine IVIG alone.
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