Incomplete (atypical) Kawasaki disease
Author
Robert Sundel, MD
Section Editors
Marisa Klein-Gitelman, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
All topics are updated as new evidence becomes available and our peer review process is
complete.
Literature review current through: May 2013. | This topic last updated: jun 18, 2012.
INTRODUCTION — Kawasaki disease (KD, also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood [1]. KD also occurs rarely in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 11 days without therapy [2]. However, complications such as coronary artery aneurysms may develop and lead to significant
morbidity and mortality.
Children suspected of having KD who do not fulfill diagnostic criteria (ie, have less than four signs of mucocutaneous inflammation) may have incomplete or atypical KD [1-3].
"Incomplete" KD is the preferred term, since these patients do not appear to differ from those with classic KD in any way except that they lack a sufficient number of criteria to fulfill the epidemiologic case definition [2]. Children with incomplete KD are also at risk for cardiovascular sequelae.
The clinical manifestations, diagnosis, and criteria for treatment of incomplete KD are discussed in this review. Unique features in infants and adults are also presented. Other aspects of Kawasaki disease are reviewed separately. (See "Kawasaki disease: Epidemiology and etiology" and "Kawasaki disease: Clinical features and diagnosis" and "Kawasaki disease: Initial treatment and prognosis" and "Kawasaki disease:
Complications" and "Cardiovascular sequelae of Kawasaki disease".)
EPIDEMIOLOGY — The incidence of incomplete KD is unknown [4,5]. In a retrospective report of 242 Japanese children with KD treated at a single center over a nine-year period, 10 percent of patients were diagnosed with incomplete KD [4]. The incidence appears to be greater in infants younger than six months of age [5,6]. This was illustrated in a retrospective review of 44 children with KD; 5 of 11 infants (45 percent) had incomplete disease compared with 4 of 33 (12 percent) older children [5].
CLINICAL PRESENTATION OF TYPICAL VERSUS INCOMPLETE KD — Signs and symptoms appear to parallel those in children who fulfill diagnostic criteria for typical disease (table 1) when clinical judgment of reliable observers is used to define incomplete KD. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations' and 'Infants' below.)
One report studied 242 patients hospitalized for KD in Japan during a nine-year period and found that 25 (10 percent) ultimately failed to meet diagnostic criteria [4]. Three criteria were met in 17 of the 25 patients (68 percent), and 7 (28 percent) met only two criteria.
Only one patient ultimately developed transient dilatation of a coronary artery. In this review, comparison of physical findings among patients with typical and incomplete KD revealed the following:
· Cervical lymphadenopathy was the cardinal manifestation most often absent in children with either complete or incomplete KD. Adenopathy was missing in up to 90 percent of children with incomplete disease versus 40 to 50 percent of those who met criteria for KD.
· Rash was not present in 50 percent of children with incomplete disease compared with 7 to 10 percent of children with typical KD.
· Peripheral extremity changes were absent in approximately 40 percent of incomplete KD cases. In comparison, only 15 percent of those with typical KD failed to develop palmar erythema, dorsal edema, or periungual desquamation.
· Mucous membrane changes were most characteristic of KD and were present in more than 90 percent of children with either typical or incomplete disease.
EVALUATION OF INCOMPLETE KD — The diagnosis of incomplete KD is problematic because the correct diagnosis rests upon clinical judgment and supportive laboratory findings, but remains uncertain unless the child develops coronary artery abnormalities. Other illnesses associated with fever, rash, and marked laboratory abnormalities must be carefully excluded before the label of incomplete KD is applied. Children with a variety of inflammatory and infectious conditions, including sarcoid, polyarteritis nodosa, and
systemic onset juvenile idiopathic arthritis have been mislabeled as having incomplete KD prior to establishment of the correct diagnosis. The main diagnoses to exclude in adults are drug hypersensitivity reactions and toxic shock syndrome [7]. (See "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis' and "Kawasaki disease: Clinical features and diagnosis", section on 'Laboratory findings'.)
The American Heart Association (AHA) and the American Academy of Pediatrics (AAP) have established guidelines for the diagnosis, treatment, and management of KD (table 1) [2]. These guidelines are based upon recommendations of an expert panel using data summarized above. They include an algorithm for the evaluation of incomplete KD (algorithm 1). The goal of adding this category of patients was to help providers identify children at risk of developing coronary artery abnormalities who would benefit from treatment for KD regardless of whether they meet diagnostic criteria. The guidelines use laboratory studies and echocardiography to aid in the diagnosis of patients whose clinical presentation is consistent with KD, but who do not meet diagnostic criteria (table 1). At any point in the evaluation, consultation with an expert is recommended if assistance is required or the diagnosis is in question.
Laboratory tests — Laboratory evaluation is recommended for the following patients with suspected incomplete KD:
· Patients less than six months of age with unexplained fever ≥seven days, even if they have no clinical findings of KD.
· Patients of any age with unexplained fever >five days and fewer than three clinical criteria (table 1).
The AHA/AAP recommended laboratory evaluation includes the following tests:
· Acute phase reactants (CRP or ESR)
· Complete blood count (CBC) with differential white blood cell count (WBC)
· Urinalysis (U/A), preferably clean catch
· Serum alanine aminotransferase level
· Serum albumin
Laboratory findings suggestive of KD include the following:
· Elevated acute phase reactants (CRP ≥3.0 mg/dL or ESR ≥40 mm/hr)
· White cell count ≥15,000/microL
· Normocytic, normochromic anemia for age (table 2)
· Pyuria (≥10 white blood cells/high-power field)
· Serum alanine aminotransferase level >50 U/L
· Serum albumin ≤3 g/dL
· Platelet cell count ≥450,000/microL after seven days of illness
Echocardiography — The presence of cardiac abnormalities detected by echocardiography, although not included in the diagnostic criteria for KD, provides support in ambiguous (incomplete) cases of KD. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Echocardiography' and "Kawasaki disease: Clinical features and diagnosis", section on 'Diagnosis'.)
The recommendation for echocardiography depends upon the clinical course and initial laboratory findings. Echocardiography is recommended in the following circumstances when a diagnosis of KD is under consideration:
· Elevation of CRP and/or ESR and less than three supplemental abnormal laboratory findings. KD is unlikely if the echocardiogram is normal and the fever abates.
Repeat echocardiography and consultation with a clinician who has expertise in KD are recommended if fever persists.
· Periungual desquamation after resolution of the fever in someone not meeting epidemiologic criteria for KD. The diagnosis is unlikely if the echocardiogram is normal.
Echocardiographic abnormalities suggestive of KD include aneurysms (rare before 10 days of disease), findings consistent with coronary arteritis (eg, perivascular brightness, ectasia, and lack of tapering of the coronary arteries), decreased left ventricular contractility, mild valvular regurgitation (primarily mitral valve), and pericardial effusion. However, none of these findings, including coronary artery dilatation, is pathognomonic for KD. A prospective study of echocardiograms in febrile children found that conditions other than KD can be associated with some degree of coronary artery dilatation [8]. However, only children with KD had coronary artery z-scores more than 2.5, suggesting that significant coronary artery enlargement is indeed a reliable marker of probable KD.
CRITERIA FOR TREATMENT — The AHA/AAP criteria to diagnose incomplete KD and initiate treatment in a child with features compatible with KD include:
· Elevated CRP and/or ESR and three or more abnormal supplemental laboratory findings (See 'Laboratory tests' above.) OR
· Abnormal echocardiography (See 'Echocardiography' above.)
Treatment of KD is discussed in greater detail separately. (See "Kawasaki disease: Initial treatment and prognosis".)
It is important to recognize that as long as the diagnosis of KD is based upon clinical criteria, it will remain an imperfect undertaking. Although the above recommendations reflect the consensus of experts in the field, they are not based upon firm data, and they have not been validated. Ultimately, they reflect the bias in favor of treatment in uncertain cases that has developed as a result of having an effective and safe therapy. Children with a variety of other febrile conditions may receive IVIG treatment using these guidelines. Thus, these recommendations should be applied only as intended, in cases in which an experienced clinician considers KD to be a probable diagnosis.
Treating children at risk even though the diagnosis is uncertain should result in fewer children with incomplete KD subsequently developing coronary artery aneurysms. This was demonstrated in a study that evaluated the performance of the 2004 AHA/AAP criteria in 195 children at four centers, 58 of whom developed coronary artery aneurysms despite failing to meet criteria for KD [9]. Fifty-three of these children had atypical KD and would have received IVIG at presentation according to the algorithm. Two of the remaining five patients would have received IVIG after further monitoring. Overall, application of the 2004 AHA/AAP guidelines would have led to IVIG treatment of 97 percent of the children who developed aneurysms. The corresponding number of children without KD who would have received unnecessary IVIG treatment was not calculated. In any event, as long as the disadvantages of undertreating appear to outweigh the disadvantages of overtreating, some children who have a condition that mimics KD will receive unnecessary intravenous immune globulin (IVIG). Thus, continued consideration of alternative diagnoses in “atypical cases” is essential despite initial response to IVIG. This is particularly important in children who fail to respond or respond only incompletely to IVIG.
PROGNOSIS — Earlier reports suggested a poor prognosis for infants and children with incomplete KD [5,10,11]. One review cited a 41 percent mortality, although only children with coronary artery aneurysms were included in this series [10]. However, subsequent studies have indicated that outcomes in children with incomplete KD may be comparable to those of children with complete disease [12]. Nonetheless, the overall data continue to suggest that children with incomplete KD are more likely to develop coronary artery
abnormalities, probably because they are less likely to be diagnosed expeditiously [13,14].
In fact, the goal of the AHA/AAP guidelines cited above is to remove precisely this obstacle to early diagnosis.
INFANTS — Infants are more likely to present with incomplete KD, occasionally even presenting only with fever and no other clinical features of KD. Infants are also at increased risk of coronary artery (CA) aneurysms, possibly in part because of delay in treatment due to their lack of complete diagnostic criteria. Thus, infants six months of age or less with unexplained fever for at least seven days should be evaluated for KD regardless of whether they have signs of mucocutaneous inflammation, since early diagnosis and timely
intervention can reduce their risk of cardiac sequelae.
The following studies are illustrative of the presentation and cardiovascular outcome in infants:
· In a retrospective Canadian study of 44 children with KD, 5 of 11 infants (45 percent) had atypical disease compared with 4 of 33 (12 percent) older children [5].
In addition, all five infants with incomplete disease developed coronary artery aneurysms.
· In a Japanese nationwide survey of 2221 children younger than five years of age with KD from 1995 to 1996, approximately one-third of the group were infants younger than one year of age. These infants had an increased risk of developing cardiac aneurysms compared with children older than one year of age (15 versus 10 percent, respectively) [15].
· In a retrospective survey of North American patients with KD, 4 of 47 children younger than 12 months of age (8.5 percent) developed cardiac abnormalities compared with 5 of 272 patients 12 months or older (1.8 percent) [16].
· In a retrospective Taiwanese study of 120 patients with KD, the 20 infants (defined as six months of age or less) were more likely to present with incomplete KD than patients older than six months of age (35 versus 12 percent), have coronary involvement (65 versus 19 percent), and receive late immunoglobulin therapy [17].
ADULTS — KD occurs rarely in adults and presents in an incomplete form more often than in children [7,18-23]. About one-fourth of adult KD cases have occurred in patients with HIV infection [20]. One review found that cervical lymphadenopathy, hepatitis, and arthralgia were all more common in adults with KD than in children, and meningitis, thrombocytosis, and coronary artery aneurysms were less common [22]. Splenomegaly and elevated serum ferritin levels were reported in one adult patient [23].
SUMMARY
· Kawasaki disease is typically a self-limited condition, but cardiac complications can lead to significant morbidity and mortality. Timely diagnosis and initiation of appropriate therapy minimize cardiac sequelae and improve clinical outcome. (See 'Introduction' above and "Cardiovascular sequelae of Kawasaki disease".)
· KD is a systemic illness characterized by fever, conjunctivitis, mucositis, rash, extremity changes, and cervical lymphadenopathy. These findings are the basis for the diagnostic criteria for KD (table 1). Patients who lack a sufficient number of findings to fulfill the classic criteria may have incomplete KD (algorithm 1). (See 'Clinical presentation of typical versus incomplete KD' above and "Kawasaki disease: Clinical features and diagnosis", section on 'Clinical manifestations'.)
· No laboratory or cardiac studies are included among the diagnostic criteria for typical KD, but certain findings characteristic of KD may support the diagnosis in ambiguous cases. (See 'Evaluation of incomplete KD' above and "Kawasaki disease:
Clinical features and diagnosis", section on 'Laboratory findings' and "Cardiovascular sequelae of Kawasaki disease", section on 'Echocardiography'.)
· The criteria to diagnose incomplete KD and initiate treatment in a child with features compatible with KD include elevated C-reactive protein and/or erythrocyte sedimentation rate and three or more abnormal supplemental laboratory findings OR abnormal echocardiography. (See 'Criteria for treatment' above.)
· Infants and adults are more likely to present with incomplete KD. Infants are at greater risk for cardiovascular sequelae, possibly due in part to a delay in diagnosis and intervention. Thus, infants six months of age or less with unexplained fever for at least seven days should be evaluated for KD, even if they have no clinical findings of KD. (See 'Infants' above and 'Adults' above.)
jueves, 13 de junio de 2013
ARTICULO MEDICO: Kawasaki disease: Initial treatment and prognosis
Kawasaki disease: Initial treatment and prognosis
Author
Robert Sundel, MD
Section Editors
Marisa Klein-Gitelman, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2013. | This topic last updated: may 2, 2012.
INTRODUCTION — Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood [1]. It is typically a self-limited condition with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy.
However, cardiovascular complications, particularly coronary artery (CA) aneurysms, which can lead to occlusion and cardiac ischemia, may develop and lead to significant morbidity and mortality. (See "Cardiovascular sequelae of Kawasaki disease".)
The frequency of CA aneurysm development and associated morbidity and mortality, have been dramatically decreased as a result of intravenous immune globulin (IVIG) therapy. This therapy is most effective for preventing coronary artery abnormalities, but the benefits in children who have already developed CA aneurysms are more equivocal. Thus, expeditious diagnosis and timely treatment are critical to achieve the optimal clinical outcome. The initial treatment of KD is discussed in this review.
The treatment of refractory KD, diagnosis, clinical manifestations, and cardiovascular sequelae are reviewed elsewhere. (See "Treatment of refractory Kawasaki disease" and "Kawasaki disease: Clinical features and diagnosis" and "Cardiovascular sequelae of Kawasaki disease".)
initial IVIG infusion, as fever before this time may represent a reaction to the medication.
Nonetheless, it is extremely important not to dismiss mild temperature elevations in children with KD
because persistent or recrudescent fever is the single strongest risk factor for the development of CA
aneurysms [43]. As a result, additional therapy is indicated in any patient with KD who does not
respond fully to initial therapy. Treatment of refractory KD is discussed in detail separately. (See
"Treatment of refractory Kawasaki disease".)
OVERVIEW — Theoretically, it should be possible to stratify therapy for KD according to disease severity defined by the likelihood of developing CA aneurysms. While many risk scores have been proposed, none are validated across different populations [2,3]. Since no criteria have been developed that can reliably identify children most at risk for severe disease at the time of initial presentation, all children diagnosed with KD or incomplete KD are treated at the time of diagnosis [1]. (See "Treatment of refractory Kawasaki disease", section on 'Risk factors'.)
In 2004, guidelines by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) were developed for the treatment of patients who fulfill the diagnostic criteria for KD (table 1) and for those who do not (so-called incomplete KD) (algorithm 1) [4,5]. The recommended initial therapy includes IVIG (2 gm/kg) administered as a single infusion over 8 to 12 hours and aspirin (initial dose of 80 to 100 mg/kg daily divided into four doses). Additional agents are used only for children who fail to respond to standard therapy. (See "Kawasaki disease: Clinical features and diagnosis" and "Treatment of refractory Kawasaki disease".)
A retrospective review of 195 patients with KD treated at four centers in the United States from 1981 to
2006 showed application of the AHA/AAP guidelines would result in the administration of IVIG therapy in almost all affected children (97 percent) [6].
INTRAVENOUS IMMUNE GLOBULIN — Since the first report of intravenous immune globulin
(IVIG) therapy in patients with KD in 1983 [7], randomized controlled studies and meta-analyses have
confirmed that IVIG plus aspirin compared to aspirin alone reduces the risk of CA aneurysms [5,8-13].
Although aspirin does not appear to affect aneurysm formation, all trials of IVIG treatment have included aspirin as well, since it was the treatment of choice at the time IVIG was introduced. (See 'Aspirin' below.)
The mechanism of the beneficial effect of IVIG remains unknown. IVIG appears to have a generalized
antiinflammatory effect with reduction of fever and acute markers of inflammation [12]. Possible mechanisms include modulating cytokine levels and production, neutralizing bacterial superantigens or other etiologic agents, augmenting T-cell suppressor activity, down-regulating antibody synthesis, and providing anti-idiotypic antibodies [5].
Cost-benefit analysis reveals that IVIG treatment of KD is one of the most cost-effective medical therapies available, leading to tremendous short- and long-term savings [14]. The AHA and the AAP recommend its use for the treatment of acute KD [4,5].
Efficacy and dosing — The efficacy of IVIG and aspirin compared with aspirin alone, and the benefits of higher doses of IVIG with aspirin were illustrated in a review of 1629 patients with KD from six randomized controlled studies [12]. These studies utilized blinded echocardiographic assessment to detect CA aneurysms. The prevalence of CA aneurysms at respective subacute (30 days) and convalescent (more than 60 days) timepoints based upon IVIG dose was as follows:
· Aspirin alone, 26 and 18 percent
· IVIG dose of less than 1gm/kg and aspirin, 18 and 14 percent
· IVIG dose of 1.6 gm/kg and aspirin, 9 and 6 percent
· IVIG dose of 2 gm/kg and aspirin, 4 and 4 percent
A meta-analysis reported similar findings of decreasing risk of CA aneurysms with increasing doses of IVIG [13]. The duration of fever also decreased with increasing IVIG dosing. The relative risks of developing CA aneurysms 30 days after receiving varying doses of IVIG plus aspirin, compared with aspirin alone, were:
· IVIG dose of 1 gm/kg, RR 0.81, 95% CI 0.43 to 1.50
· IVIG dose of 1.2 gm/kg, RR 0.51, 95% CI 0.29 to 0.92
· IVIG dose of 1.6 gm/kg, RR 0.35, 95% CI 0.15 to 0.83
The dose response effect of IVIG implies that additional modifications of this treatment regimen might lead to further improvement in outcome. There are no data, however, documenting effects of treating patients with doses greater than 2 gm/kg. Increasing the dose is limited by the cost and availability of IVIG, as well as by concern for the large volume that is administered to patients who may not be able to tolerate the fluid load. The potential for additional benefit with the prevalence rate for CA complications already reduced five-fold with the current standard therapy also is not clear.
Nevertheless, the dose response to IVIG provides the theoretical basis for the current practice of IVIG
retreatment of patients who have persistent or recrudescent fever after initial IVIG therapy. (See "Treatment of refractory Kawasaki disease".)
There are no randomized controlled studies comparing IVIG therapy alone to combined IVIG and aspirin therapy. In one retrospective report from Taiwan, IVIG was administered initially to patients without concomitant aspirin treatment [15]. Low-dose aspirin (as an antiplatelet agent) was subsequently prescribed following resolution of fever. In 128 of 162 patients (80 percent), fever resolved within 24 hours of completion of IVIG therapy. At the time of diagnosis, 10 percent of patients had CA aneurysms. Subsequent CA aneurysms formed in 3 percent of patients whose fever normalized within 24 hours of completing IVIG therapy. These results are comparable to those seen in studies of children treated initially with both IVIG and aspirin.
The beneficial effects of IVIG are not limited to the prevention of CA aneurysms. Abnormalities in serum lipoprotein profiles may persist for years in untreated patients with KD [16]; IVIG therapy leads to normalization of these abnormalities within months [17]. Similarly, echocardiographic data suggest that another common manifestation of KD, depressed myocardial contractility, may be more rapidly
reversed by IVIG [18].
Based upon these results, we recommend that a total IVIG dose of 2 gm/kg be given to children who are newly diagnosed with KD to reduce the risk of CA aneurysms.
Administration — IVIG is most effective when administered in a single infusion. This is illustrated by the following studies:
· In the previously mentioned meta-analysis, two studies demonstrated that a single infusion of IVIG (2 gm/kg) compared to a regimen of 400 mg/kg per day for five days was more effective at reducing the frequency of CA aneurysms (RR 0.22, 95% CI 0.8 to .65) [13]. In addition, the duration of fever and the length of hospital stay also were decreased.
· A randomized controlled study of 549 patients with KD demonstrated that a single dose of IVIG (2 gm/kg) compared with a four-day treatment regimen (400 mg/kg for four consecutive days) led to a more rapid resolution of fever, normalization of laboratory evidence of acute inflammation, and lower risk of CA abnormalities [10]. Based upon these results, we recommend that the total IVIG dose of 2 gm/kg be given as a single infusion over 8 to 12 hours.
Timing of therapy — The effectiveness of IVIG therapy is best established for patients treated within the first 7 to 10 days of illness [5]. Two retrospective studies reported a lower incidence of cardiac sequelae and a shorter duration of clinical symptoms (eg, fever) for patients treated before day 5 or 6 of illness [19,20]. On the other hand, in the nationwide surveys of KD in Japan, there was no difference in the incidence of CA aneurysms between the 4731 patients treated early (≤day 4 of illness) and 4020 patients treated between days 5 and 9. However, patients treated early were more likely to require retreatment with IVIG [21]. (See "Treatment of refractory Kawasaki disease".)
There are few data on the efficacy of IVIG therapy administered more than 10 days after the onset of KD in preventing CA aneurysms. In one report of 16 children with CA aneurysms, patients treated after a mean of 17 days of illness appeared to benefit, with improvement in echocardiographic abnormalities already present at the time of treatment [22]. A case-control study of 150 children treated with IVIG 10 to 20 days (cases) or 4 to 8 days (controls) after the onset of illness found that the rate of CA lesions (dilatation or aneurysm) during the convalescent period was significantly higher in cases (27 percent) versus controls (1 percent) [23]. However, the effectiveness of IVIG treatment after 10 days was unclear, because approximately half of patients in the late group had already developed coronary artery lesions (CAL) before receiving IVIG. In fact, among patients without CAL before treatment with IVIG, the percentage developing CAL after treatment during the acute phase was 8 percent in both groups. The AHA and AAP guidelines recommend that IVIG be administered to children with KD within the first 10 days of illness, and if possible, within the first seven days of illness. IVIG also should be administered to patients who present after the 10th day of illness if they have persistent fever without another explanation, aneurysms, or evidence of ongoing systemic inflammation (eg, elevated Creactive protein [CRP] or erythrocyte sedimentation rate [ESR]) [5].
Type of IVIG — IVIG is a biological product pooled from donor plasma that undergoes a number of
manufacturing procedures including different methods of sterilization. As a result, these processes may result in variation of effects among the different brands of IVIG. This potential for disparity has raised concerns that different brands may differ in regard to their efficacy in treating patients with KD.
In the previously mentioned meta-analysis, subset analyses compared the risk of developing CA aneurysms with different brands of IVIG [13].
· In two studies, intact IVIG compared to pepsin-treated IVIG (both administered at a dose of 100 mg/kg per day) appeared to decrease the rate of CA aneurysms at 30 days (RR 0.84, 95% CI 0.71 to 1.01), but there was no difference between the two preparations at 60 days.
· In two studies, there was no difference in the rate of CA aneurysms or duration of fever between a freeze-dried sulfonated IVIG and polyethylene glycol treated IVIG.
In a retrospective study from Taiwan, four different brands of IVIG were used in treating KD during the time period from 1994 to 2003 [24]. All brands were administered as a single dose of 2 gm/kg. One brand of IVIG, prepared with beta-propiolactone, had a greater rate of CA aneurysms at convalescence (defined as four to six weeks after onset of disease) and a higher rate of unresponsiveness (defined as persistent fever >2 days after completion of IVIG therapy) compared to the other three brands. Using univariate analysis, administration of this brand of IVIG was the factor most associated with CA aneurysms at convalescence (OR 4.7, 95% CI 1.7 to 12.7). In addition, the only cases of giant aneurysms were in 3 of 93 patients treated with this brand of IVIG, compared to no giant CA aneurysms in the 344 patients treated with the other three bands.
In a retrospective study from Canada, two different brands of IVIG (2 g/kg dose) were used to treat KD
between 1990 and 2007, one with low IgA content and stabilized with glucose and the other with higher IgA content and stabilized through acidification [25]. Coronary artery outcomes and median duration of hospital stay favored the low IgA containing, glucose stabilized IVIG, although treatment failure with the initial IVIG dose was more likely and median duration of fever was higher with this preparation. The overall clinical significance of these findings is uncertain.
Although data are not sufficient to recommend a brand of IVIG that is most efficacious in the treatment of KD, it appears that the brand of IVIG may impact clinical outcome.
Adverse effects — Despite its advantages, IVIG is an expensive and potentially toxic intervention. The greatest long-term concern is transmission of bloodborne pathogens. As an example, more than 100 cases of hepatitis C occurred in recipients of a single brand of IVIG in 1994 (none were in children with KD) [26]. Since that time, manufacturers have introduced a variety of elaborate sterilization procedures including lyophilization, pasteurization, and addition of solvent detergents. These are generally effective in rendering the product free of at least lipid soluble viruses, so that transmission of hepatitis C is no longer a risk. However, other pathogens such as parvovirus might escape neutralization by these procedures.
Significant toxicity is nonetheless rare, and the benefits outweigh risks in children with confirmed KD.
The adverse effects of IVIG are discussed in detail separately. (See "Immune globulin therapy in
primary immunodeficiency".)
ASPIRIN — Aspirin is used for treatment of KD because of its antiinflammatory and anti-platelet effects [27]. The dose of aspirin used during the acute phase of illness to achieve an antiinflammatory effect is relatively high, with a recommended range of 30 to 100 mg/kg per day in four divided doses [1,5,28]. Subsequently, aspirin is administered in low doses (3 to 5 mg/kg per day) for its antiplatelet action. Alternative antiinflammatory agents, such as ibuprofen, may be used for prolonged episodes of arthritis.
Although the AHA and AAP guidelines recommend the initial use of high-dose aspirin (80 to 100 mg/kg per day) to maximize its antiinflammatory effects (eg, reduce the duration of fever), there are no randomized controlled studies comparing high-dose (>80 mg/kg per day) with moderate-dose (≤50 mg/kg per day) aspirin in resolving the signs and symptoms of inflammation in KD [28]. It is also unclear whether aspirin is needed when high-dose IVIG is used. In the previously mentioned retrospective study of 162 children with KD, 80 percent of patients who received a single dose of IVIG (2 gm/kg) with no concomitant aspirin therapy had resolution of fever within 24 hours of completing IVIG therapy [15].
Not only is it unclear if the addition of aspirin provides greater antiinflammatory effects than does IVIG alone, but it also seems that aspirin has no effect on the subsequent development of CA aneurysms.
· In the previously mentioned retrospective review, the incidence of subsequent CA aneurysms was 3 percent in the patients who received IVIG therapy alone [15]. This is similar to the rates seen in studies of patients treated with combined therapy of IVIG 2 gm/kg and aspirin [12]. (See 'Intravenous immune globulin' above.)
· The previously mentioned review of six randomized controlled studies, which evaluated varying doses of IVIG and aspirin, demonstrated no difference in the prevalence of CA aneurysms between patients receiving moderate-dose aspirin (30 to 50 mg/kg per day) and those receiving high-dose aspirin (80 to 120 mg/kg) [12]. The risk of CA aneurysms was only dependent upon IVIG dose. For each IVIG dose, the risk of CA aneurysms was the same in each of the aspirin subgroups when evaluated at 30 days (subacute) and 60 days (convalescent) after diagnosis.
The risks of aspirin therapy appear to be similar to those reported in other settings, including chemical hepatitis with elevated transaminases, transient hearing loss, and rarely Reye syndrome. However, these risks may be increased in patients with KD. Aspirin-binding studies have suggested that the hypoalbuminemia of children with KD predisposes them to toxic free salicylate levels despite measured (total) values within the therapeutic range [29]. Several cases of Reye syndrome have been documented after aspirin therapy for KD [30,31]. Thus, clinicians should be aware of the potential side effects of aspirin therapy and in particular should not disregard the risk of Reye syndrome. Aspirin should be rapidly discontinued upon exposure to or signs of varicella or influenza, as there is an increased risk of Reye syndrome with aspirin therapy in children with these diseases. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome' and "Clinical features and diagnosis of seasonal influenza in children", section on 'Clinical features'.)
The question of whether the benefits of aspirin warrant its continued use in KD cannot be answered. All
prospective studies that have demonstrated the effectiveness of IVIG in treating KD also employed conventional doses of aspirin. Consequently, despite the potential risks and lack of obvious benefits of very high dose regimens, we continue to use aspirin as recommended by the AHA and AAP, 80 to 100 mg/kg per day. The initial dose of aspirin should be no higher than 100 mg/kg per day, and the maximum dose should not exceed 4 gm per day. Once fever has been absent for 48 hours, patients are generally switched to a low dose of aspirin, 3 to 5 mg/kg per day, for its antiplatelet effect. This lowdose aspirin regimen is continued until laboratory markers of acute inflammation (eg, platelet count and C-reactive protein) return to normal. Aspirin therapy typically is complete within two months of the onset of disease in children with no CA abnormalities detected by echocardiography. Alternate regimens, such as treatment with aspirin for 14 days, are used by other practitioners.
GLUCOCORTICOIDS — Glucocorticoids (also called corticosteroids) have reported benefits in
patients with KD who fail to respond to IVIG [5,32]. (See "Treatment of refractory Kawasaki disease",
section on 'Glucocorticoid therapy'.)
The role of glucocorticoids in initial therapy is controversial. A meta-analysis of clinical trials found that glucocorticoids in addition to IVIG significantly reduced the duration of fever and the rate of initial treatment failure compared with IVIG alone, but did not significantly alter the incidence of CA aneurysms [33]. As an example, a large randomized trial comparing standard initial therapy with standard therapy plus a single dose of intravenous methylprednisolone (IVMP) failed to demonstrate any benefit from the glucocorticoids [34]. However, post hoc analysis suggested that patients refractory to initial therapy with IVIG seemed to have a lower risk of developing CA aneurysms if they had received pretreatment with IVMP.
Disease stratification — Stratification of patients' risk of developing CA aneurysm at presentation with KD may allow selection of those children who are at high risk of developing CA aneurysm and/or developing recurrent fever after initial therapy. This is the group of children most likely to benefit from adjuvant therapy in addition to routine IVIG.
A randomized, open-label, blinded endpoints trial of 248 patients with severe Kawasaki disease who were predicted to have IVIG resistance (based upon the Kobayashi score [2]) found that CA abnormalities were significantly decreased in those treated with prednisolone in addition to IVIG and aspirin compared with IVIG and aspirin alone (3 versus 23 percent) [35]. The IVIG dose was 2 g/kg given over 24 hours. Aspirin was dosed at 30 mg/kg/day until the patient was afebrile and then decreased to a dose of 3 to 5 mg/kg/day until at least 28 days after fever onset. Glucocorticoids were given as methylprednisolone 2 mg/kg/day (maximum 60 mg/day) in three divided daily doses for five days, after which patients were switched to oral prednisolone. The dose was tapered over 15 days once the C-reactive protein level normalized (≤5 mg/L).
A nonblinded trial [36] and a prospective observational study [37] reported similar findings of decreased rates of CA abnormalities in patients at high risk for refractory disease who were treated with glucocorticoids in addition to conventional therapy, although the courses of glucocorticoids were shorter than in the randomized trial discussed above. In a retrospective observational study, a higher rate of response to initial therapy and a lower rate of treatment failure were seen in those treated with both IVIG and prednisolone, although no difference was seen in the risk of coronary artery aneurysm at one month after diagnosis between the two groups [38].
Further studies are needed to prospectively validate criteria for identifying high-risk patients [39]. Once such validated markers are available, additional clinical trials are required to demonstrate whether a combination of methylprednisolone and IVIG is beneficial in these patients. Only then might it be possible to recommend the addition of glucocorticoid therapy to initial standard therapy with IVIG and aspirin in certain groups of patients. (See "Treatment of refractory Kawasaki disease", section on 'Risk factors'.)
TNF INHIBITION — Reports from several small studies suggest that anti-tumor necrosis factor-alpha
(TNF-alpha) agents such as etanercept or infliximab are beneficial in KD, especially in view of the very elevated levels of TNF that characterize KD. (See "Treatment of refractory Kawasaki disease", section on 'TNF inhibition'.)
The utility of these agents as an adjuvant to initial IVIG therapy is also under study. In a small openlabel study, 17 patients with KD and fever ≤10 days were treated with IVIG and high-dose aspirin plus etanercept immediately after IVIG and then weekly for two doses [40]. None of the 15 patients who completed the study required retreatment with IVIG for persistent or recurrent fever, nor did they have worsening coronary artery involvement/cardiac dysfunction compared with baseline measurements. No serious drug-related adverse events were reported. Such small trials, however, are inadequately powered to determine whether combined therapy actually offers improved safety or efficacy compared with conventional treatment.
A large randomized trial of IVIG plus intravenous methylprednisolone or placebo found that children treated optimally for KD with IVIG alone had a <1 accordingly="" addition="" agents="" aneurysms="" are="" artery="" available.="" br="" coronary="" data="" do="" further="" incidence="" inhibitors="" initial="" ivig="" kd="" not="" of="" or="" other="" percent="" recommend="" routine="" tnf="" to="" treatment="" until="" we="">OTHER THERAPIES — Ulinastatin is a urinary trypsin inhibitor that has antiinflammatory effects and
may prevent tissue and organ damage, particularly neutrophil-mediated injury that is suspected to play a role in refractory KD. Ulinastatin was less effective than IVIG as monotherapy in a small randomized trial [41]. A retrospective study suggests that it may have some benefit when used with IVIG and aspirin for initial therapy, but further studies are needed [42].
REFRACTORY KD — Fever persists or returns in 10 to 15 percent of patients with KD who are initially treated with IVIG and aspirin [1,4]. Persistent fever of any magnitude usually indicates ongoing vasculitis, although other causes of fever should be excluded. Barring extenuating circumstances, children are not usually retreated until at least 36 hours after the completion of their initial IVIG infusion, as fever before this time may represent a reaction to the medication.
Nonetheless, it is extremely important not to dismiss mild temperature elevations in children with KD because persistent or recrudescent fever is the single strongest risk factor for the development of CA aneurysms [43]. As a result, additional therapy is indicated in any patient with KD who does not respond fully to initial therapy. Treatment of refractory KD is discussed in detail separately. (See "Treatment of refractory Kawasaki disease".)
COMPLICATIONS — Complications in patients with KD primarily result from cardiovascular involvement. In the following section, a brief review of these complications is presented, and a more complete discussion including management of cardiac sequelae is found elsewhere. (See "Cardiovascular sequelae of Kawasaki disease" and "Kawasaki disease: Complications".)
Heart failure may rarely complicate the acute phase of KD. If the cause of heart failure is myocardial inflammation, routine treatment with IVIG and aspirin generally results in rapid clinical improvement.
Although IVIG therapy involves infusion of large volumes of isotonic solution (2 g/kg of 5 percent IVIG delivers 40 mL/kg over 8 to 12 hours), improvements in myocardial contractility compensate for the volume delivered, and treatment rarely leads to circulatory deterioration.
Ischemia or infarction must be excluded as causes of new myocardial dysfunction, particularly during the second week of illness in patients with coronary artery (CA) abnormalities. Characteristic electrocardiographic and echocardiographic changes allow this distinction to be made rapidly in most patients. A more complete description of these findings is discussed separately. (See "Cardiovascular
sequelae of Kawasaki disease", section on 'Evaluation'.) Children with severe KD who develop coronary occlusion may experience myocardial infarction and/or arrhythmias, and those with peripheral artery disease may develop ischemia or gangrene [44]. The rare fatal outcomes from severe cardiac involvement in KD are generally the result of either myocardial infarction or arrhythmias.
Various therapies have been attempted to maintain and restore circulation, although control of vascular
inflammation with sufficient IVIG is an essential prerequisite to arterial reperfusion. If arterial thrombosis (either central or peripheral) is present, additional treatment may include antiplatelet, anticoagulant, and/or thrombolytic therapy (such as urokinase, streptokinase, or tissue type plasminogen). Although one report suggested that heparin might be beneficial for treating children with ischemia following KD [45], without any other confirmation of the efficacy of anticoagulants, we continue to recommend treatment with anticoagulants only for children at risk of development or expansion of thrombosis [46].
In severe cases of coronary artery occlusion, percutaneous coronary intervention (PCI), coronary artery
bypass graft surgery, or cardiac transplantation may be required. In settings where tissue viability is primarily threatened by vasospasm, therapy includes vasodilators. A more complete discussion of these therapeutic modalities is presented separately. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Coronary revascularization procedures'.)
PROGNOSIS
Mortality — The reported mortality rate of KD is low (0.1 to 0.3 percent) [47,48]. In Japan, a registry of 6576 patients with KD has been established for longitudinal evaluation of ongoing morbidity and mortality [47]. Standardized mortality rates based upon Japanese vital statistics data demonstrated an increased mortality rate within the first two months of the disease, but after the acute phase, the mortality rate was not increased compared to the general population.
Long-term morbidity — The long-term morbidity for patients following KD depends on the severity of
coronary artery involvement.
· Children without cardiovascular abnormalities detected in the acute and subacute phase (up to eight weeks after onset of disease) appear to be clinically asymptomatic 10 to 21 years later [49]. However, the long-term effect on cardiovascular health is unknown, and it is unclear whether these patients will be at increased risk for atherosclerotic heart disease as adults compared to those who never had KD.
· CA dilatation smaller than 8 mm generally regresses over time, and most smaller aneurysms 6 mm in diameter fully resolve by echocardiogram [50]. Healing is by fibrointimal proliferation, often accompanied by calcification, and vascular reactivity does not return to normal despite grossly normal appearance [51]. Children should thus be followed indefinitely after KD, a point highlighted by a report of sudden death in a three-and-a-half-year-old child three months after dilated coronary arteries had regained a normal echocardiographic appearance [52]. Autopsy revealed obliteration of the lumen of the left anterior descending CA because of fibrosis, with evidence of ongoing active inflammation in the epicardial arteries. (See "Cardiovascular
sequelae of Kawasaki disease", section on 'Coronary artery aneurysm'.)
Patients with giant aneurysms (maximum diameter ≥8 mm) are at the greatest risk for myocardial infarction resulting from CA occlusion [53]. In these lesions, thrombosis is promoted by the combination of sluggish blood flow through the massively dilated vessel and the frequent development of stenoses at the proximal and/or distal ends of the aneurysms.
Recurrence — There appears to be a low rate of recurrence for KD as illustrated by data from the 13th and 14th nationwide surveys of Kawasaki disease in Japan. After three years of follow-up, 2 percent of patients were reported to have a recurrence of KD with a rate of 6.9 per 1000 person-years [54]. The highest incidence was in children less than three years of age who had cardiac sequelae during the first episode. Recurrences most commonly occurred within the first 12 months after the initial episode of KD.
In this report, however, a recurrent episode was defined as a rehospitalization of a patient who satisfied the diagnostic criteria for KD. In order to determine a true recurrence rate, follow-up studies must use a more precise definition of recurrence: a separate episode fulfilling KD criteria after an earlier occurrence has fully resolved, typically at least two months later. Episodes that occur sooner may well represent recrudescent or resistant KD and not truly recurrent disease.
In patients with recurrent disease, particularly aggressive treatment is recommended because these
patients appear to be at increased risk for cardiac sequelae [55].
FOLLOW-UP — An echocardiogram should be obtained early in the acute phase of illness (ie, within two weeks of the onset of fever) in order to evaluate for coronary artery involvement, and four to six weeks later in order to confirm the efficacy of treatment [5]. Patients also should have repeated clinical evaluations during the first two months following diagnosis of KD to detect arrhythmias, heart failure, valvular insufficiency, or myocarditis.
The relative risk for myocardial infarction based upon CA abnormalities detected by echocardiogram can be assessed at six to eight weeks [5]. Based upon this risk, guidelines have been developed by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) for medical therapy, physical activity, and the schedule and content of follow-up visits (table 2). Children with CA abnormalities generally receive antithrombotic therapy with aspirin, warfarin, or other agents, as well as regular cardiac evaluation. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Management'.)
Physical activity — Children generally do not feel completely well for several weeks after KD, and they therefore tend to limit their own activity level. Restrictions are dependent on the risk of myocardial infarction and should be imposed only in children with increased risk of thrombosis during the convalescent stage of disease, particularly those with giant coronary artery (CA) aneurysms (table 2). The restrictions should be determined in consultation with the child's cardiologist.
Vaccinations — The administration of live virus vaccines, including measles and varicella, should be postponed for at least 11 months in children who have been treated with IVIG. Passively acquired antibodies persist for an extended period of time (up to 11 months) following IVIG administration, and may interfere with vaccine immunogenicity [4]. Patients may be vaccinated during a measles outbreak or after a varicella exposure as long as the vaccine is repeated at least 11 months after the administration of IVIG (unless there is serologic evidence of adequate immunity). Schedules for other routine childhood vaccinations do not need to be altered. (See "Post-exposure prophylaxis against varicella-zoster virus infection" and "Standard immunizations for children and adolescents", section on 'Overview'.)
Influenza immunization, recommended in all children over six months of age, is particularly important in those who require long-term aspirin therapy, because of the possible increased risk of Reye syndrome [4,56]. They should receive the inactivated vaccine. In addition, patients receiving long-term aspirin therapy also should be considered for the varicella vaccine even if they have received IVIG in the past 11 months, because varicella infection also may increase the risk of Reye syndrome. They should be revaccinated at least 11 months following completion of IVIG treatment unless serologic immunity is demonstrated. (See "Seasonal influenza vaccination in children", section on 'Overview' and "Prevention of varicella-zoster virus infection: Chickenpox".)
Author
Robert Sundel, MD
Section Editors
Marisa Klein-Gitelman, MD, MPH
Sheldon L Kaplan, MD
Deputy Editor
Elizabeth TePas, MD, MS
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: May 2013. | This topic last updated: may 2, 2012.
INTRODUCTION — Kawasaki disease (KD), formerly called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood [1]. It is typically a self-limited condition with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy.
However, cardiovascular complications, particularly coronary artery (CA) aneurysms, which can lead to occlusion and cardiac ischemia, may develop and lead to significant morbidity and mortality. (See "Cardiovascular sequelae of Kawasaki disease".)
The frequency of CA aneurysm development and associated morbidity and mortality, have been dramatically decreased as a result of intravenous immune globulin (IVIG) therapy. This therapy is most effective for preventing coronary artery abnormalities, but the benefits in children who have already developed CA aneurysms are more equivocal. Thus, expeditious diagnosis and timely treatment are critical to achieve the optimal clinical outcome. The initial treatment of KD is discussed in this review.
The treatment of refractory KD, diagnosis, clinical manifestations, and cardiovascular sequelae are reviewed elsewhere. (See "Treatment of refractory Kawasaki disease" and "Kawasaki disease: Clinical features and diagnosis" and "Cardiovascular sequelae of Kawasaki disease".)
initial IVIG infusion, as fever before this time may represent a reaction to the medication.
Nonetheless, it is extremely important not to dismiss mild temperature elevations in children with KD
because persistent or recrudescent fever is the single strongest risk factor for the development of CA
aneurysms [43]. As a result, additional therapy is indicated in any patient with KD who does not
respond fully to initial therapy. Treatment of refractory KD is discussed in detail separately. (See
"Treatment of refractory Kawasaki disease".)
OVERVIEW — Theoretically, it should be possible to stratify therapy for KD according to disease severity defined by the likelihood of developing CA aneurysms. While many risk scores have been proposed, none are validated across different populations [2,3]. Since no criteria have been developed that can reliably identify children most at risk for severe disease at the time of initial presentation, all children diagnosed with KD or incomplete KD are treated at the time of diagnosis [1]. (See "Treatment of refractory Kawasaki disease", section on 'Risk factors'.)
In 2004, guidelines by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) were developed for the treatment of patients who fulfill the diagnostic criteria for KD (table 1) and for those who do not (so-called incomplete KD) (algorithm 1) [4,5]. The recommended initial therapy includes IVIG (2 gm/kg) administered as a single infusion over 8 to 12 hours and aspirin (initial dose of 80 to 100 mg/kg daily divided into four doses). Additional agents are used only for children who fail to respond to standard therapy. (See "Kawasaki disease: Clinical features and diagnosis" and "Treatment of refractory Kawasaki disease".)
A retrospective review of 195 patients with KD treated at four centers in the United States from 1981 to
2006 showed application of the AHA/AAP guidelines would result in the administration of IVIG therapy in almost all affected children (97 percent) [6].
INTRAVENOUS IMMUNE GLOBULIN — Since the first report of intravenous immune globulin
(IVIG) therapy in patients with KD in 1983 [7], randomized controlled studies and meta-analyses have
confirmed that IVIG plus aspirin compared to aspirin alone reduces the risk of CA aneurysms [5,8-13].
Although aspirin does not appear to affect aneurysm formation, all trials of IVIG treatment have included aspirin as well, since it was the treatment of choice at the time IVIG was introduced. (See 'Aspirin' below.)
The mechanism of the beneficial effect of IVIG remains unknown. IVIG appears to have a generalized
antiinflammatory effect with reduction of fever and acute markers of inflammation [12]. Possible mechanisms include modulating cytokine levels and production, neutralizing bacterial superantigens or other etiologic agents, augmenting T-cell suppressor activity, down-regulating antibody synthesis, and providing anti-idiotypic antibodies [5].
Cost-benefit analysis reveals that IVIG treatment of KD is one of the most cost-effective medical therapies available, leading to tremendous short- and long-term savings [14]. The AHA and the AAP recommend its use for the treatment of acute KD [4,5].
Efficacy and dosing — The efficacy of IVIG and aspirin compared with aspirin alone, and the benefits of higher doses of IVIG with aspirin were illustrated in a review of 1629 patients with KD from six randomized controlled studies [12]. These studies utilized blinded echocardiographic assessment to detect CA aneurysms. The prevalence of CA aneurysms at respective subacute (30 days) and convalescent (more than 60 days) timepoints based upon IVIG dose was as follows:
· Aspirin alone, 26 and 18 percent
· IVIG dose of less than 1gm/kg and aspirin, 18 and 14 percent
· IVIG dose of 1.6 gm/kg and aspirin, 9 and 6 percent
· IVIG dose of 2 gm/kg and aspirin, 4 and 4 percent
A meta-analysis reported similar findings of decreasing risk of CA aneurysms with increasing doses of IVIG [13]. The duration of fever also decreased with increasing IVIG dosing. The relative risks of developing CA aneurysms 30 days after receiving varying doses of IVIG plus aspirin, compared with aspirin alone, were:
· IVIG dose of 1 gm/kg, RR 0.81, 95% CI 0.43 to 1.50
· IVIG dose of 1.2 gm/kg, RR 0.51, 95% CI 0.29 to 0.92
· IVIG dose of 1.6 gm/kg, RR 0.35, 95% CI 0.15 to 0.83
The dose response effect of IVIG implies that additional modifications of this treatment regimen might lead to further improvement in outcome. There are no data, however, documenting effects of treating patients with doses greater than 2 gm/kg. Increasing the dose is limited by the cost and availability of IVIG, as well as by concern for the large volume that is administered to patients who may not be able to tolerate the fluid load. The potential for additional benefit with the prevalence rate for CA complications already reduced five-fold with the current standard therapy also is not clear.
Nevertheless, the dose response to IVIG provides the theoretical basis for the current practice of IVIG
retreatment of patients who have persistent or recrudescent fever after initial IVIG therapy. (See "Treatment of refractory Kawasaki disease".)
There are no randomized controlled studies comparing IVIG therapy alone to combined IVIG and aspirin therapy. In one retrospective report from Taiwan, IVIG was administered initially to patients without concomitant aspirin treatment [15]. Low-dose aspirin (as an antiplatelet agent) was subsequently prescribed following resolution of fever. In 128 of 162 patients (80 percent), fever resolved within 24 hours of completion of IVIG therapy. At the time of diagnosis, 10 percent of patients had CA aneurysms. Subsequent CA aneurysms formed in 3 percent of patients whose fever normalized within 24 hours of completing IVIG therapy. These results are comparable to those seen in studies of children treated initially with both IVIG and aspirin.
The beneficial effects of IVIG are not limited to the prevention of CA aneurysms. Abnormalities in serum lipoprotein profiles may persist for years in untreated patients with KD [16]; IVIG therapy leads to normalization of these abnormalities within months [17]. Similarly, echocardiographic data suggest that another common manifestation of KD, depressed myocardial contractility, may be more rapidly
reversed by IVIG [18].
Based upon these results, we recommend that a total IVIG dose of 2 gm/kg be given to children who are newly diagnosed with KD to reduce the risk of CA aneurysms.
Administration — IVIG is most effective when administered in a single infusion. This is illustrated by the following studies:
· In the previously mentioned meta-analysis, two studies demonstrated that a single infusion of IVIG (2 gm/kg) compared to a regimen of 400 mg/kg per day for five days was more effective at reducing the frequency of CA aneurysms (RR 0.22, 95% CI 0.8 to .65) [13]. In addition, the duration of fever and the length of hospital stay also were decreased.
· A randomized controlled study of 549 patients with KD demonstrated that a single dose of IVIG (2 gm/kg) compared with a four-day treatment regimen (400 mg/kg for four consecutive days) led to a more rapid resolution of fever, normalization of laboratory evidence of acute inflammation, and lower risk of CA abnormalities [10]. Based upon these results, we recommend that the total IVIG dose of 2 gm/kg be given as a single infusion over 8 to 12 hours.
Timing of therapy — The effectiveness of IVIG therapy is best established for patients treated within the first 7 to 10 days of illness [5]. Two retrospective studies reported a lower incidence of cardiac sequelae and a shorter duration of clinical symptoms (eg, fever) for patients treated before day 5 or 6 of illness [19,20]. On the other hand, in the nationwide surveys of KD in Japan, there was no difference in the incidence of CA aneurysms between the 4731 patients treated early (≤day 4 of illness) and 4020 patients treated between days 5 and 9. However, patients treated early were more likely to require retreatment with IVIG [21]. (See "Treatment of refractory Kawasaki disease".)
There are few data on the efficacy of IVIG therapy administered more than 10 days after the onset of KD in preventing CA aneurysms. In one report of 16 children with CA aneurysms, patients treated after a mean of 17 days of illness appeared to benefit, with improvement in echocardiographic abnormalities already present at the time of treatment [22]. A case-control study of 150 children treated with IVIG 10 to 20 days (cases) or 4 to 8 days (controls) after the onset of illness found that the rate of CA lesions (dilatation or aneurysm) during the convalescent period was significantly higher in cases (27 percent) versus controls (1 percent) [23]. However, the effectiveness of IVIG treatment after 10 days was unclear, because approximately half of patients in the late group had already developed coronary artery lesions (CAL) before receiving IVIG. In fact, among patients without CAL before treatment with IVIG, the percentage developing CAL after treatment during the acute phase was 8 percent in both groups. The AHA and AAP guidelines recommend that IVIG be administered to children with KD within the first 10 days of illness, and if possible, within the first seven days of illness. IVIG also should be administered to patients who present after the 10th day of illness if they have persistent fever without another explanation, aneurysms, or evidence of ongoing systemic inflammation (eg, elevated Creactive protein [CRP] or erythrocyte sedimentation rate [ESR]) [5].
Type of IVIG — IVIG is a biological product pooled from donor plasma that undergoes a number of
manufacturing procedures including different methods of sterilization. As a result, these processes may result in variation of effects among the different brands of IVIG. This potential for disparity has raised concerns that different brands may differ in regard to their efficacy in treating patients with KD.
In the previously mentioned meta-analysis, subset analyses compared the risk of developing CA aneurysms with different brands of IVIG [13].
· In two studies, intact IVIG compared to pepsin-treated IVIG (both administered at a dose of 100 mg/kg per day) appeared to decrease the rate of CA aneurysms at 30 days (RR 0.84, 95% CI 0.71 to 1.01), but there was no difference between the two preparations at 60 days.
· In two studies, there was no difference in the rate of CA aneurysms or duration of fever between a freeze-dried sulfonated IVIG and polyethylene glycol treated IVIG.
In a retrospective study from Taiwan, four different brands of IVIG were used in treating KD during the time period from 1994 to 2003 [24]. All brands were administered as a single dose of 2 gm/kg. One brand of IVIG, prepared with beta-propiolactone, had a greater rate of CA aneurysms at convalescence (defined as four to six weeks after onset of disease) and a higher rate of unresponsiveness (defined as persistent fever >2 days after completion of IVIG therapy) compared to the other three brands. Using univariate analysis, administration of this brand of IVIG was the factor most associated with CA aneurysms at convalescence (OR 4.7, 95% CI 1.7 to 12.7). In addition, the only cases of giant aneurysms were in 3 of 93 patients treated with this brand of IVIG, compared to no giant CA aneurysms in the 344 patients treated with the other three bands.
In a retrospective study from Canada, two different brands of IVIG (2 g/kg dose) were used to treat KD
between 1990 and 2007, one with low IgA content and stabilized with glucose and the other with higher IgA content and stabilized through acidification [25]. Coronary artery outcomes and median duration of hospital stay favored the low IgA containing, glucose stabilized IVIG, although treatment failure with the initial IVIG dose was more likely and median duration of fever was higher with this preparation. The overall clinical significance of these findings is uncertain.
Although data are not sufficient to recommend a brand of IVIG that is most efficacious in the treatment of KD, it appears that the brand of IVIG may impact clinical outcome.
Adverse effects — Despite its advantages, IVIG is an expensive and potentially toxic intervention. The greatest long-term concern is transmission of bloodborne pathogens. As an example, more than 100 cases of hepatitis C occurred in recipients of a single brand of IVIG in 1994 (none were in children with KD) [26]. Since that time, manufacturers have introduced a variety of elaborate sterilization procedures including lyophilization, pasteurization, and addition of solvent detergents. These are generally effective in rendering the product free of at least lipid soluble viruses, so that transmission of hepatitis C is no longer a risk. However, other pathogens such as parvovirus might escape neutralization by these procedures.
Significant toxicity is nonetheless rare, and the benefits outweigh risks in children with confirmed KD.
The adverse effects of IVIG are discussed in detail separately. (See "Immune globulin therapy in
primary immunodeficiency".)
ASPIRIN — Aspirin is used for treatment of KD because of its antiinflammatory and anti-platelet effects [27]. The dose of aspirin used during the acute phase of illness to achieve an antiinflammatory effect is relatively high, with a recommended range of 30 to 100 mg/kg per day in four divided doses [1,5,28]. Subsequently, aspirin is administered in low doses (3 to 5 mg/kg per day) for its antiplatelet action. Alternative antiinflammatory agents, such as ibuprofen, may be used for prolonged episodes of arthritis.
Although the AHA and AAP guidelines recommend the initial use of high-dose aspirin (80 to 100 mg/kg per day) to maximize its antiinflammatory effects (eg, reduce the duration of fever), there are no randomized controlled studies comparing high-dose (>80 mg/kg per day) with moderate-dose (≤50 mg/kg per day) aspirin in resolving the signs and symptoms of inflammation in KD [28]. It is also unclear whether aspirin is needed when high-dose IVIG is used. In the previously mentioned retrospective study of 162 children with KD, 80 percent of patients who received a single dose of IVIG (2 gm/kg) with no concomitant aspirin therapy had resolution of fever within 24 hours of completing IVIG therapy [15].
Not only is it unclear if the addition of aspirin provides greater antiinflammatory effects than does IVIG alone, but it also seems that aspirin has no effect on the subsequent development of CA aneurysms.
· In the previously mentioned retrospective review, the incidence of subsequent CA aneurysms was 3 percent in the patients who received IVIG therapy alone [15]. This is similar to the rates seen in studies of patients treated with combined therapy of IVIG 2 gm/kg and aspirin [12]. (See 'Intravenous immune globulin' above.)
· The previously mentioned review of six randomized controlled studies, which evaluated varying doses of IVIG and aspirin, demonstrated no difference in the prevalence of CA aneurysms between patients receiving moderate-dose aspirin (30 to 50 mg/kg per day) and those receiving high-dose aspirin (80 to 120 mg/kg) [12]. The risk of CA aneurysms was only dependent upon IVIG dose. For each IVIG dose, the risk of CA aneurysms was the same in each of the aspirin subgroups when evaluated at 30 days (subacute) and 60 days (convalescent) after diagnosis.
The risks of aspirin therapy appear to be similar to those reported in other settings, including chemical hepatitis with elevated transaminases, transient hearing loss, and rarely Reye syndrome. However, these risks may be increased in patients with KD. Aspirin-binding studies have suggested that the hypoalbuminemia of children with KD predisposes them to toxic free salicylate levels despite measured (total) values within the therapeutic range [29]. Several cases of Reye syndrome have been documented after aspirin therapy for KD [30,31]. Thus, clinicians should be aware of the potential side effects of aspirin therapy and in particular should not disregard the risk of Reye syndrome. Aspirin should be rapidly discontinued upon exposure to or signs of varicella or influenza, as there is an increased risk of Reye syndrome with aspirin therapy in children with these diseases. (See "Acute toxic-metabolic encephalopathy in children", section on 'Reye syndrome' and "Clinical features and diagnosis of seasonal influenza in children", section on 'Clinical features'.)
The question of whether the benefits of aspirin warrant its continued use in KD cannot be answered. All
prospective studies that have demonstrated the effectiveness of IVIG in treating KD also employed conventional doses of aspirin. Consequently, despite the potential risks and lack of obvious benefits of very high dose regimens, we continue to use aspirin as recommended by the AHA and AAP, 80 to 100 mg/kg per day. The initial dose of aspirin should be no higher than 100 mg/kg per day, and the maximum dose should not exceed 4 gm per day. Once fever has been absent for 48 hours, patients are generally switched to a low dose of aspirin, 3 to 5 mg/kg per day, for its antiplatelet effect. This lowdose aspirin regimen is continued until laboratory markers of acute inflammation (eg, platelet count and C-reactive protein) return to normal. Aspirin therapy typically is complete within two months of the onset of disease in children with no CA abnormalities detected by echocardiography. Alternate regimens, such as treatment with aspirin for 14 days, are used by other practitioners.
GLUCOCORTICOIDS — Glucocorticoids (also called corticosteroids) have reported benefits in
patients with KD who fail to respond to IVIG [5,32]. (See "Treatment of refractory Kawasaki disease",
section on 'Glucocorticoid therapy'.)
The role of glucocorticoids in initial therapy is controversial. A meta-analysis of clinical trials found that glucocorticoids in addition to IVIG significantly reduced the duration of fever and the rate of initial treatment failure compared with IVIG alone, but did not significantly alter the incidence of CA aneurysms [33]. As an example, a large randomized trial comparing standard initial therapy with standard therapy plus a single dose of intravenous methylprednisolone (IVMP) failed to demonstrate any benefit from the glucocorticoids [34]. However, post hoc analysis suggested that patients refractory to initial therapy with IVIG seemed to have a lower risk of developing CA aneurysms if they had received pretreatment with IVMP.
Disease stratification — Stratification of patients' risk of developing CA aneurysm at presentation with KD may allow selection of those children who are at high risk of developing CA aneurysm and/or developing recurrent fever after initial therapy. This is the group of children most likely to benefit from adjuvant therapy in addition to routine IVIG.
A randomized, open-label, blinded endpoints trial of 248 patients with severe Kawasaki disease who were predicted to have IVIG resistance (based upon the Kobayashi score [2]) found that CA abnormalities were significantly decreased in those treated with prednisolone in addition to IVIG and aspirin compared with IVIG and aspirin alone (3 versus 23 percent) [35]. The IVIG dose was 2 g/kg given over 24 hours. Aspirin was dosed at 30 mg/kg/day until the patient was afebrile and then decreased to a dose of 3 to 5 mg/kg/day until at least 28 days after fever onset. Glucocorticoids were given as methylprednisolone 2 mg/kg/day (maximum 60 mg/day) in three divided daily doses for five days, after which patients were switched to oral prednisolone. The dose was tapered over 15 days once the C-reactive protein level normalized (≤5 mg/L).
A nonblinded trial [36] and a prospective observational study [37] reported similar findings of decreased rates of CA abnormalities in patients at high risk for refractory disease who were treated with glucocorticoids in addition to conventional therapy, although the courses of glucocorticoids were shorter than in the randomized trial discussed above. In a retrospective observational study, a higher rate of response to initial therapy and a lower rate of treatment failure were seen in those treated with both IVIG and prednisolone, although no difference was seen in the risk of coronary artery aneurysm at one month after diagnosis between the two groups [38].
Further studies are needed to prospectively validate criteria for identifying high-risk patients [39]. Once such validated markers are available, additional clinical trials are required to demonstrate whether a combination of methylprednisolone and IVIG is beneficial in these patients. Only then might it be possible to recommend the addition of glucocorticoid therapy to initial standard therapy with IVIG and aspirin in certain groups of patients. (See "Treatment of refractory Kawasaki disease", section on 'Risk factors'.)
TNF INHIBITION — Reports from several small studies suggest that anti-tumor necrosis factor-alpha
(TNF-alpha) agents such as etanercept or infliximab are beneficial in KD, especially in view of the very elevated levels of TNF that characterize KD. (See "Treatment of refractory Kawasaki disease", section on 'TNF inhibition'.)
The utility of these agents as an adjuvant to initial IVIG therapy is also under study. In a small openlabel study, 17 patients with KD and fever ≤10 days were treated with IVIG and high-dose aspirin plus etanercept immediately after IVIG and then weekly for two doses [40]. None of the 15 patients who completed the study required retreatment with IVIG for persistent or recurrent fever, nor did they have worsening coronary artery involvement/cardiac dysfunction compared with baseline measurements. No serious drug-related adverse events were reported. Such small trials, however, are inadequately powered to determine whether combined therapy actually offers improved safety or efficacy compared with conventional treatment.
A large randomized trial of IVIG plus intravenous methylprednisolone or placebo found that children treated optimally for KD with IVIG alone had a <1 accordingly="" addition="" agents="" aneurysms="" are="" artery="" available.="" br="" coronary="" data="" do="" further="" incidence="" inhibitors="" initial="" ivig="" kd="" not="" of="" or="" other="" percent="" recommend="" routine="" tnf="" to="" treatment="" until="" we="">OTHER THERAPIES — Ulinastatin is a urinary trypsin inhibitor that has antiinflammatory effects and
may prevent tissue and organ damage, particularly neutrophil-mediated injury that is suspected to play a role in refractory KD. Ulinastatin was less effective than IVIG as monotherapy in a small randomized trial [41]. A retrospective study suggests that it may have some benefit when used with IVIG and aspirin for initial therapy, but further studies are needed [42].
REFRACTORY KD — Fever persists or returns in 10 to 15 percent of patients with KD who are initially treated with IVIG and aspirin [1,4]. Persistent fever of any magnitude usually indicates ongoing vasculitis, although other causes of fever should be excluded. Barring extenuating circumstances, children are not usually retreated until at least 36 hours after the completion of their initial IVIG infusion, as fever before this time may represent a reaction to the medication.
Nonetheless, it is extremely important not to dismiss mild temperature elevations in children with KD because persistent or recrudescent fever is the single strongest risk factor for the development of CA aneurysms [43]. As a result, additional therapy is indicated in any patient with KD who does not respond fully to initial therapy. Treatment of refractory KD is discussed in detail separately. (See "Treatment of refractory Kawasaki disease".)
COMPLICATIONS — Complications in patients with KD primarily result from cardiovascular involvement. In the following section, a brief review of these complications is presented, and a more complete discussion including management of cardiac sequelae is found elsewhere. (See "Cardiovascular sequelae of Kawasaki disease" and "Kawasaki disease: Complications".)
Heart failure may rarely complicate the acute phase of KD. If the cause of heart failure is myocardial inflammation, routine treatment with IVIG and aspirin generally results in rapid clinical improvement.
Although IVIG therapy involves infusion of large volumes of isotonic solution (2 g/kg of 5 percent IVIG delivers 40 mL/kg over 8 to 12 hours), improvements in myocardial contractility compensate for the volume delivered, and treatment rarely leads to circulatory deterioration.
Ischemia or infarction must be excluded as causes of new myocardial dysfunction, particularly during the second week of illness in patients with coronary artery (CA) abnormalities. Characteristic electrocardiographic and echocardiographic changes allow this distinction to be made rapidly in most patients. A more complete description of these findings is discussed separately. (See "Cardiovascular
sequelae of Kawasaki disease", section on 'Evaluation'.) Children with severe KD who develop coronary occlusion may experience myocardial infarction and/or arrhythmias, and those with peripheral artery disease may develop ischemia or gangrene [44]. The rare fatal outcomes from severe cardiac involvement in KD are generally the result of either myocardial infarction or arrhythmias.
Various therapies have been attempted to maintain and restore circulation, although control of vascular
inflammation with sufficient IVIG is an essential prerequisite to arterial reperfusion. If arterial thrombosis (either central or peripheral) is present, additional treatment may include antiplatelet, anticoagulant, and/or thrombolytic therapy (such as urokinase, streptokinase, or tissue type plasminogen). Although one report suggested that heparin might be beneficial for treating children with ischemia following KD [45], without any other confirmation of the efficacy of anticoagulants, we continue to recommend treatment with anticoagulants only for children at risk of development or expansion of thrombosis [46].
In severe cases of coronary artery occlusion, percutaneous coronary intervention (PCI), coronary artery
bypass graft surgery, or cardiac transplantation may be required. In settings where tissue viability is primarily threatened by vasospasm, therapy includes vasodilators. A more complete discussion of these therapeutic modalities is presented separately. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Coronary revascularization procedures'.)
PROGNOSIS
Mortality — The reported mortality rate of KD is low (0.1 to 0.3 percent) [47,48]. In Japan, a registry of 6576 patients with KD has been established for longitudinal evaluation of ongoing morbidity and mortality [47]. Standardized mortality rates based upon Japanese vital statistics data demonstrated an increased mortality rate within the first two months of the disease, but after the acute phase, the mortality rate was not increased compared to the general population.
Long-term morbidity — The long-term morbidity for patients following KD depends on the severity of
coronary artery involvement.
· Children without cardiovascular abnormalities detected in the acute and subacute phase (up to eight weeks after onset of disease) appear to be clinically asymptomatic 10 to 21 years later [49]. However, the long-term effect on cardiovascular health is unknown, and it is unclear whether these patients will be at increased risk for atherosclerotic heart disease as adults compared to those who never had KD.
· CA dilatation smaller than 8 mm generally regresses over time, and most smaller aneurysms 6 mm in diameter fully resolve by echocardiogram [50]. Healing is by fibrointimal proliferation, often accompanied by calcification, and vascular reactivity does not return to normal despite grossly normal appearance [51]. Children should thus be followed indefinitely after KD, a point highlighted by a report of sudden death in a three-and-a-half-year-old child three months after dilated coronary arteries had regained a normal echocardiographic appearance [52]. Autopsy revealed obliteration of the lumen of the left anterior descending CA because of fibrosis, with evidence of ongoing active inflammation in the epicardial arteries. (See "Cardiovascular
sequelae of Kawasaki disease", section on 'Coronary artery aneurysm'.)
Patients with giant aneurysms (maximum diameter ≥8 mm) are at the greatest risk for myocardial infarction resulting from CA occlusion [53]. In these lesions, thrombosis is promoted by the combination of sluggish blood flow through the massively dilated vessel and the frequent development of stenoses at the proximal and/or distal ends of the aneurysms.
Recurrence — There appears to be a low rate of recurrence for KD as illustrated by data from the 13th and 14th nationwide surveys of Kawasaki disease in Japan. After three years of follow-up, 2 percent of patients were reported to have a recurrence of KD with a rate of 6.9 per 1000 person-years [54]. The highest incidence was in children less than three years of age who had cardiac sequelae during the first episode. Recurrences most commonly occurred within the first 12 months after the initial episode of KD.
In this report, however, a recurrent episode was defined as a rehospitalization of a patient who satisfied the diagnostic criteria for KD. In order to determine a true recurrence rate, follow-up studies must use a more precise definition of recurrence: a separate episode fulfilling KD criteria after an earlier occurrence has fully resolved, typically at least two months later. Episodes that occur sooner may well represent recrudescent or resistant KD and not truly recurrent disease.
In patients with recurrent disease, particularly aggressive treatment is recommended because these
patients appear to be at increased risk for cardiac sequelae [55].
FOLLOW-UP — An echocardiogram should be obtained early in the acute phase of illness (ie, within two weeks of the onset of fever) in order to evaluate for coronary artery involvement, and four to six weeks later in order to confirm the efficacy of treatment [5]. Patients also should have repeated clinical evaluations during the first two months following diagnosis of KD to detect arrhythmias, heart failure, valvular insufficiency, or myocarditis.
The relative risk for myocardial infarction based upon CA abnormalities detected by echocardiogram can be assessed at six to eight weeks [5]. Based upon this risk, guidelines have been developed by the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) for medical therapy, physical activity, and the schedule and content of follow-up visits (table 2). Children with CA abnormalities generally receive antithrombotic therapy with aspirin, warfarin, or other agents, as well as regular cardiac evaluation. (See "Cardiovascular sequelae of Kawasaki disease", section on 'Management'.)
Physical activity — Children generally do not feel completely well for several weeks after KD, and they therefore tend to limit their own activity level. Restrictions are dependent on the risk of myocardial infarction and should be imposed only in children with increased risk of thrombosis during the convalescent stage of disease, particularly those with giant coronary artery (CA) aneurysms (table 2). The restrictions should be determined in consultation with the child's cardiologist.
Vaccinations — The administration of live virus vaccines, including measles and varicella, should be postponed for at least 11 months in children who have been treated with IVIG. Passively acquired antibodies persist for an extended period of time (up to 11 months) following IVIG administration, and may interfere with vaccine immunogenicity [4]. Patients may be vaccinated during a measles outbreak or after a varicella exposure as long as the vaccine is repeated at least 11 months after the administration of IVIG (unless there is serologic evidence of adequate immunity). Schedules for other routine childhood vaccinations do not need to be altered. (See "Post-exposure prophylaxis against varicella-zoster virus infection" and "Standard immunizations for children and adolescents", section on 'Overview'.)
Influenza immunization, recommended in all children over six months of age, is particularly important in those who require long-term aspirin therapy, because of the possible increased risk of Reye syndrome [4,56]. They should receive the inactivated vaccine. In addition, patients receiving long-term aspirin therapy also should be considered for the varicella vaccine even if they have received IVIG in the past 11 months, because varicella infection also may increase the risk of Reye syndrome. They should be revaccinated at least 11 months following completion of IVIG treatment unless serologic immunity is demonstrated. (See "Seasonal influenza vaccination in children", section on 'Overview' and "Prevention of varicella-zoster virus infection: Chickenpox".)
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