Kawasaki disease (KD), previously called mucocutaneous lymph node syndrome, is one of the most common vasculitides of childhood, particularly in East Asia. KD rarely occurs in adults. It is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days if not treated (Sundel, 2020a). The underlying etiology is unknown.
KD can cause a variety of cardiovascular complications, particularly coronary artery (CA) aneurysms. These, in turn, can lead to coronary occlusion and cardiac ischemia and result in significant morbidity or even mortality. The frequency of CA aneurysm development and associated morbidity and mortality has dramatically decreased due to treatment with intravenous immune globulin (IVIG). This therapy effectively prevents CA abnormalities, but the benefits in children who have already developed CA aneurysms are more equivocal (Sundel, 2020d). Other cardiovascular complications include cardiomyopathy with depressed myocardial contractility and heart failure, myocardial infarction (MI), arrhythmias, and peripheral arterial occlusion. These complications may cause significant morbidity and mortality, particularly in children who are inadequately treated (Sundel, 2020c). Thus, early diagnosis and timely treatment are critical to achieving the optimal clinical outcome.
Children suspected of having KD who do not fulfill diagnostic criteria (i.e., have fever ≥five days but less than four signs of mucocutaneous inflammation) may have incomplete or atypical KD. "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 (Sundel, 2020b). Children with incomplete KD are also at risk for cardiovascular sequelae.
KD is second only to immunoglobulin A (IgA) vasculitis (Henoch-Schönlein purpura) as the most common vasculitis of childhood.
The incidence of KD is greatest in children who live in East Asia or are of Asian ancestry living in other parts of the world. The incidence in underdeveloped countries is largely unknown, and ascertainment is likely to be incomplete. KD is particularly difficult to diagnose in areas where measles is still prevalent because the presentation is similar. Many nations worldwide have demonstrated an increase in the number of children diagnosed with KD since the early to mid-2000s. However, it is not clear whether this represents an actual increase in the incidence of the disease, increased awareness of the condition, or a greater tendency to classify children with incomplete clinical features as having KD.
The following studies illustrate the geographic and ethnic variation in the incidence of KD:
The epidemiology of the illness is illustrated by analyzing data from the Pediatric Health Information System (PHIS) that identified 4,811 patients treated in 27 hospitals in the U.S. between 2001 and 2006.
In Japan, there is a reported 10-fold increased risk of KD for children with an affected sibling and a twofold increased risk for those with a previously affected parent. In North America, there are case reports of families with multiple affected members, but data are insufficient to determine whether there is an increased familial risk for developing KD.
The incidence of incomplete KD is unknown. In a retrospective report of 242 Japanese children with KD treated at a single center over nine years, 10% of patients were diagnosed with incomplete KD. The incidence appears to be greater in infants younger than six months of age. This incidence was illustrated in a retrospective review of 44 children with KD. Five of 11 infants (45%) had incomplete KD compared with 4 of 33 (12%) older children. KD rarely occurs in adults and presents in an incomplete form more often than in children.
The etiology of KD remains unknown. A variety of theories have been proposed based upon pathologic, epidemiologic, and demographic data. Infection by one or more agents that usually cause an asymptomatic or nonvasculitic condition in most children but results in KD in genetically predisposed individuals fits the epidemiologic data well. Various case series over many years have reported localized outbreaks of KD, each associated with a different bacterial or viral pathogen such as parvovirus B19, Propionibacterium, human bocavirus, and numerous others.
The major debate concerns whether KD is caused by a single, previously unidentified agent or an immunologic response to various triggers. This point remains unresolved, although the possibility of a unique KD infection seems less likely with each negative serologic, genetic, and immunologic study or case series.
KD is a systemic, inflammatory illness that particularly affects medium-sized arteries, especially the CAs. Pathologic studies indicate that multiple organs and tissues are involved, but long-term sequelae appear only in the arteries. Blood vessel damage appears to result from inflammatory cell infiltration into vascular tissues. The stimulus for this infiltration is unknown, but it is most profound in the CAs. It can involve the destruction of luminal endothelial cells, elastic lamina, and medial smooth muscle cells in severe cases. The destruction of elastin and collagen fibers and the loss of the arterial wall's structural integrity led to dilatation and aneurysm formation. Inflammatory cells infiltrating the CAs may include neutrophils, T cells (particularly CD8 T cells), eosinophils, plasma cells (particularly IgA producing), and macrophages. Macrophages are not prominent participants in any other type of vasculitis.
A neutrophilic infiltrate is observed in the arterial wall in KD fatalities that occur within the first two weeks after fever onset and may represent an innate immune response. A study of gene expression patterns in acute KD peripheral blood using DNA microarrays reflects the predominance of neutrophils early in the course of KD. Expression of genes associated with neutrophils and inflammatory processes, including adrenomedullin, grancalcin, and granulin, was high during the acute phase of the illness. These transcripts' levels tended to decrease over time, while gene expression in CD8 T cells and natural killer (NK) cells increased as the illness evolved. CD8 T cells were prevalent in the arterial wall in fatalities that occurred after two weeks in another study, consistent with developing an acquired immune response. Gene expression in the peripheral blood from individual patients tended to be more consistent than were transcript levels in different subjects on the same day of illness. This suggests the possibility that DNA polymorphisms affected individuals' gene expression.
Plasma cells producing oligoclonal IgA antibodies are found in the arteries and respiratory tract of children with KD. A synthetic monoclonal antibody derived from prevalent IgA sequences in the KD arterial wall identified intracytoplasmic inclusion bodies consistent with aggregates of proteins and nucleic acids in 85% of KD cases but not in infant control tissues. Immune complexes are sometimes detected in the peripheral blood in KD, but they are not observed to form deposits in affected tissues. They do not appear to correlate with the development of CAD.
Many epidemiologic data suggest that KD is caused or triggered by a transmissible agent or agents. Support for this theory is derived from the following similarities between KD and other pediatric infectious conditions:
The cause(s) of KD remain(s) unknown despite clinical and epidemiologic data suggesting a relationship to infections.
Coronavirus disease 2019 (COVID-19) is associated with hyperinflammatory syndromes.
Genetic factors appear to contribute to this disorder's pathogenesis, as suggested by the increased frequency of the disease in Asian and Asian-American populations and family members of an index case.
Variants or polymorphisms of the following genes are associated with increased susceptibility to KD:
Genome-wide association studies have revealed other potential susceptibility loci, including a functional polymorphism in the immunoglobulin G receptor gene (FCGR2A). ITPKC is associated with an increased risk of CA aneurysms in addition to being a putative susceptibility factor.
Environmental factors have also been proposed as the triggers of KD. The overlap between the cutaneous and acral manifestations of KD to acrodynia, a disease caused by mercury toxicity, led to proposals that mercury might play a causative role in KD. Similarly, the frequent association between KD and atopy, particularly atopic dermatitis, has inspired a common immune susceptibility search. This has led to various hypotheses involving dust mites, rug shampoo, and pollen release in the etiology of KD. However, once again, additional data accrued over time have not provided support to these theories. Analysis of seasonal variations in epidemics of KD suggested that cases are linked to largescale wind currents from Central Asia, potentially carrying an airborne antigenic trigger in the troposphere.
Despite these and numerous other theories' plausibility, it is difficult to understand how a single environmental factor could account for a ubiquitous disease such as KD that occurs at all times of the year and in virtually every country on Earth. Thus, like other pediatric vasculitides such as IgA vasculitis (Henoch-Schönlein purpura), KD may occur in genetically susceptible individuals following exposure to any of a variety of infectious or environmental triggers.
The clinical features of KD reflect widespread inflammation of primarily medium-sized muscular arteries. Diagnosis is based upon evidence of systemic inflammation (e.g., fever) in association with signs of mucocutaneous inflammation. The characteristic bilateral nonexudative conjunctivitis, erythema of the lips and oral mucosa, rash, extremity changes, and cervical lymphadenopathy typically develop after a brief nonspecific prodrome of respiratory or gastrointestinal symptoms. These characteristic clinical signs are the basis for the diagnostic criteria for KD. (Table 1).
|The diagnosis of KD requires fever lasting at least five days without any other explanation combined with at least 4 of the five following criteria. A significant proportion of children with KD have a concurrent infection. Consequently, ascribing the fever to such an infection or KD requires clinical judgment.|
|If ≥4 of the above criteria are present, a diagnosis of KD can be made on day 4 of illness|
Variations in age have the greatest impact on a patient's likelihood of developing mucocutaneous manifestations of KD. For examples:
These findings are often not present simultaneously, and there is no typical order of appearance. For examples:
An elevated body temperature is the most consistent manifestation of KD. Fever is minimally responsive to antipyretic agents, and it typically remains above 38.5ºC (101.3ºF) during most of the illness. Alternately, fever may be intermittent and may be missed by parents who use tympanic, temporal, axillary, or similar temperature measurement methods that are less reliable than oral or rectal methods. Thus, the diagnosis should be considered in all children with prolonged, unexplained fever ≥five days but should still be considered in seemingly afebrile children who have other findings consistent with KD.
Bilateral nonexudative conjunctivitis is present in more than 90% of patients. A predominantly bulbar injection typically begins within days of the onset of fever, and the eyes often have brilliant erythema, which characteristically spares the limbus. (Image 1)
Image 1: Conjunctivitis in KD
Children also are frequently photophobic. Also, anterior uveitis may develop in up to 70% of children with ocular findings. Therefore, a slit-lamp examination may be helpful in ambiguous cases. The presence of uveitis provides further evidence for the diagnosis of KD since it is more commonly seen in KD than in other diseases with similar presentations.
Mucositis often becomes evident as KD progresses. Cracked, red lips (Image 2), and a "strawberry tongue" (Image 3) are characteristic.
Image 2: Cracked, Red Lips Seen in KD
Image 3: Strawberry Tongue
“Strawberry tongue” results from sloughing of filiform papillae and denuding of the inflamed glossal tissue. The bumps on the "strawberry" are the remaining fungiform papillae. These manifestations of oral mucositis may occur singly, in a very mild form, or not at all. Discrete oral lesions, such as vesicles or ulcers, and tonsillar exudate suggest a disease process other than KD.
The cutaneous manifestations of KD are polymorphous. The rash usually begins during the first few days of illness, typically as perineal erythema and desquamation, followed by macular, morbilliform, or targetoid skin lesions of the trunk and extremities. Vesicular or bullous lesions generally are not observed, but KD may trigger a psoriasiform eruption in children not previously recognized to have psoriasis. Patients may also have redness or crust formation at the site of Bacille Calmette-Guérin (BCG) inoculation. This finding is more useful for increasing the suspicion for KD in countries where the BCG vaccine is routinely given.
Changes of the extremities are generally the last manifestation to appear. Children develop an indurated edema of the dorsum of their hands and feet (Image 4) and diffuse erythema of their palms and soles.
Image 4: Indurated Edema the Hands as seen in KD (Acute Phase)
The erythema overlying the metacarpophalangeal and proximal interphalangeal joints indicates arthritis of the small joints of the hand.
The convalescent phase of KD is often characterized by sheet-like desquamation that begins in the periungual region of the hands and feet (Image 5A and B) and linear nail creases (Beau's lines). The prevalence of periungual desquamation in patients with KD has been reported to vary from 68% to 98%.
Image 5: Characteristic Periungual Desquamation of the Hands and Feet seen in KD
Skin peeling usually begins under the nails during the second week of illness. Peeling of large sheets of skin progresses proximally over the next several days.
Cervical lymphadenopathy is the least consistent feature of KD, absent in as many as one-half to three-quarters of children with the disease, especially those under one year of age.
Cardiovascular findings are not part of the diagnostic criteria of KD, but they support the diagnosis since most conditions that mimic KD do not involve the heart.
Arthritis is not included in the diagnostic criteria but has been reported in 7.5% to 25% of KD patients.
With only very rare exceptions, the arthritis is self-limited and nondeforming.
Patients with arthritis were more likely to have increased levels of inflammatory markers (C-reactive protein [CRP] or erythrocyte sedimentation rate [ESR]) and neutrophils. Otherwise, there were no differences in clinical features, response to therapy, or clinical outcomes between patients with or without arthritis.
The following nonspecific symptoms commonly occur during the prodrome of the illness, 7 to 10 days before the typical mucocutaneous features develop:
Patients with gastrointestinal involvement often have pseudo-obstruction on radiologic studies. The presentation of gastrointestinal symptoms before typical KD features may delay the diagnosis and lead to unnecessary invasive procedures, including surgery.
Infants are at increased risk of CA aneurysms, possibly because of delay in treatment due to their lack of complete diagnostic criteria.
Even in infants diagnosed and treated before the 10th day of illness, CA abnormalities are significantly higher than in older patients.
Approximately one-fourth of adult KD cases have occurred in patients with human immunodeficiency virus (HIV) infection.
Signs and symptoms appear to parallel those in children who fulfill diagnostic criteria for complete KD (see Table 1 above) when a clinical judgment of reliable observers is used to define incomplete KD.
One report studied 242 patients hospitalized for KD in Japan for nine years and found that 25 (10%) ultimately failed to meet diagnostic criteria. Three criteria were met in 17 of the 25 patients (68%), and 7 (28%) met only two criteria. Only one patient ultimately developed transient dilatation of a CA. In this review, a comparison of physical findings among patients with complete and incomplete KD revealed the following:
No laboratory studies are included among the diagnostic criteria for complete KD. However, certain findings may support the diagnosis of KD, particularly in incomplete cases.
Diagnosis of KD according to the criteria established by Tomisaku Kawasaki in 1967 requires the presence of fever lasting ≥five days, combined with at least four of the five following physical findings, without an alternative explanation:
Approximately 40% of children with KD have a concurrent infection. Ascribing the fever to such an infection or KD requires clinical judgment.
Redness or crust formation at the Bacille Calmette-Guérin (BCG) inoculation site is also suggested as a useful sign in several diagnostic guidelines.
Rash and conjunctival injection are seen with many illnesses. Still, other KD features, such as red, cracked lips and redness and swelling of the hands and feet, are unusual in the illnesses in the differential diagnosis and should increase the suspicion for KD.
As with all clinical criteria, these are imperfect guidelines with less than 100% sensitivity and specificity. Also, Dr. Kawasaki published his guidelines before cardiac involvement was recognized in this disease, so they were never intended to identify children at risk for developing CA abnormalities. Thus, it is not surprising that at least 10% of children who develop CA aneurysms never meet complete KD criteria. Incomplete KD should be suspected in patients less than six months of age with unexplained fever ≥seven days, even if they have no clinical findings of KD. In patients of any age with unexplained fever ≥, five days and only two or three clinical criteria. An algorithmic approach can help identify such cases and significantly decrease the number of children who develop CA abnormalities despite not meeting the disease criteria.
As noted above, Dr. Kawasaki identified the first 50 cases of "mucocutaneous lymph node syndrome" based on clinical findings rather than laboratory or imaging studies. Thus, no laboratory values are included in the classical diagnostic criteria, but they nonetheless may support a diagnosis of KD in ambiguous cases. Some laboratory tests are explicitly included in the algorithm for the diagnosis of incomplete KD.
The following blood tests are typically obtained on children in whom a diagnosis of KD is being considered:
Elevated WBC and platelet counts, transaminases, acute-phase reactants, and anemia and pyuria suggest KD.
Also, when specific mimics of KD are strongly suspected, studies that are more specific for these alternative diagnoses may help confirm the diagnosis. These can include:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is associated with an emerging syndrome (MIS-C) comprised of persistent fever, systemic inflammation, and multiorgan failure mimicking children with some features of KD. Polymerase chain reaction (PCR) testing for SARS-CoV-2 should be performed in children who present with MIS-C features, particularly if there is evidence of coronavirus disease 19 (COVID-19) exposure.
Echocardiography should be performed in all patients with KD as soon as the diagnosis is suspected of establishing a reference point for longitudinal follow-up and treatment efficacy. Additionally, initial CA diameter is a factor in identifying patients at high risk of developing a CA aneurysm and therefore warranting augmentation of initial IVIG therapy. Finally, CA diameters are useful for identifying patients treated with IVIG despite failing to meet classical diagnostic criteria for KD.
KD is most commonly confused with infectious exanthems of childhood. Early in the course, KD is often mistaken for more routine childhood illnesses, such as viral gastroenteritis, viral upper respiratory tract infection, or pneumonia, depending upon the other presenting symptoms, such as vomiting or cough. Concurrent viral infections are common, and, therefore, the presence of respiratory symptoms or positive respiratory viral PCR testing does not exclude the diagnosis of KD. Meningitis is sometimes suspected due to irritability.
Infectious diseases and other mimics of KD may have the following clinical features not commonly found in KD:
The presence of any of these findings or the absence of fever should suggest a diagnosis other than KD. Of note, concurrent infections (both viral and bacterial) are common in patients with KD, found in up to 33% of children in one study. In this retrospective analysis of 129 consecutive children seen with KD in Toronto, infection at the time of diagnosis did not affect response to therapy or outcome. In any event, the diagnosis of an infectious condition does not preclude a concurrent diagnosis of KD.
The differential diagnosis of KD includes:
Treatment with IVIG within the first ten days of illness reduces the prevalence of CA aneurysms fivefold compared with children not treated with IVIG. Consequently, it is desirable to diagnose KD as soon as possible after the onset of symptoms to initiate treatment and reduce CA lesions' risk. However, timely identification is challenging because the diagnosis is based on nonspecific clinical signs, and there is no definitive diagnostic test. Thus, the clinicians in a medical facility with the most experience taking care of patients with KD should be consulted as early as possible to evaluate suspected KD. These clinicians may include pediatric rheumatologists, infectious disease specialists, cardiologists, or hospitalists, depending upon the institution.
In a retrospective study of 562 patients diagnosed with KD at eight North American centers, 92 cases (16%) were diagnosed after the first ten days of illness (i.e., late diagnosis). Predictors of a delay in diagnosis of KD included:
In contrast, socioeconomic status was not associated with a delay in diagnosis.
These findings suggest that practice variation in confirming a KD diagnosis may contribute to a delayed diagnosis. This study's results underscore the need for a high KD suspicion index, especially in young infants and patients who present with incomplete KD, to identify and treat patients promptly.
Complete KD diagnosis is problematic because the correct diagnosis rests upon clinical judgment and supportive laboratory findings but remains uncertain unless the child develops CA abnormalities. However, the goal of adding this category of patients was to help providers identify children at risk of developing CA abnormalities, which would benefit from treatment for KD regardless of whether they meet diagnostic criteria. As such, the American Heart Association (AHA) and the American Academy of Pediatrics (AAP) have created an algorithm for the evaluation of incomplete KD that uses 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. Patients who do not initially meet diagnostic criteria for complete or incomplete KD should be reevaluated if they have a persistent fever. At any point in the evaluation, consultation with an expert is recommended if assistance is required or the diagnosis is in question.
Incomplete KD should be suspected and laboratory evaluation performed in patients less than six months of age with unexplained fever ≥seven days, even if they have no clinical findings of KD. In patients of any age with unexplained fever ≥, five days and only two or three clinical criteria. Other illnesses associated with fever, rash, and similar laboratory abnormalities must be carefully excluded before the label of incomplete KD is applied. Children with various inflammatory and infectious conditions, including adenovirus, atypical measles, sarcoid, polyarteritis nodosa, and systemic JIA, have been mislabeled as having incomplete KD before establishing the correct diagnosis. The main diagnoses to exclude in adults are drug hypersensitivity reactions and toxic shock syndrome.
The AHA/AAP-recommended laboratory evaluation includes the following tests:
Laboratory findings suggestive of KD include the following:
Although not included in the diagnostic criteria for KD, the presence of cardiac abnormalities detected by echocardiography provides support in ambiguous (incomplete) cases of KD. Echocardiographic abnormalities suggestive of KD include:
None of these findings are pathognomonic for KD, but significantly dilated CAs are unusual in other conditions. Mild CA dilatation is sometimes observed in children with other febrile illnesses.
The recommendation for echocardiography depends upon the clinical course and initial laboratory findings. Echocardiography is helpful when KD is suspected in a child who does not meet classical criteria for KD but who has the following features:
The AHA and the AAP criteria to diagnose incomplete KD and initiate treatment include clinical features compatible with KD. Such children commonly have a fever for at least five days, two or three additional clinical criteria, and elevated CRP or ESR. IVIG therapy should not be withheld when KD is the most likely diagnosis, even without any additional disease manifestations.
Features increasing the likelihood that such a child has incomplete KD that would benefit from IVIG therapy include any of the following:
This determination is best made by a clinician experienced in diagnosing KD to avoid misdiagnosis and unnecessary treatment. The above recommendations are based upon clinical criteria and reflect the consensus of experts in the field, although they are not based upon firm data and have not been validated. Ultimately, they reflect a bias in favor of treatment in uncertain cases that have developed due to the availability of effective and safe therapy. As such, children with a variety of other febrile conditions may end up receiving IVIG treatment using these guidelines. However, the presence of a concurrent infection does not exclude the diagnosis of KD since up to 33% of children with KD have a concurrent infection.
Even though the diagnosis is uncertain, treating children at risk should result in fewer children with incomplete KD, subsequently developing CA 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 CA aneurysms despite failing to meet criteria for KD.
Earlier reports suggested a poor prognosis for infants and children with incomplete KD.
Nonetheless, children with incomplete KD features are more likely to be diagnosed later in the illness, and prolonged fever is the strongest predictor of CA aneurysm formation. Thus, children will be best served if KD is considered in any case of unexplained fever lasting five or more days. The AHA's goal and the AAP guidelines cited above are to precisely remove this obstacle to early diagnosis and treatment.
Once the KD diagnosis has been made, the next step is to determine the risk of IVIG resistance since it is associated with a higher risk of CA abnormalities. Patients who do not respond to IVIG treatment may benefit from more aggressive initial therapy for KD.
The first retrospective study to look at risk factors for refractory KD used the database of the 2003 to 2004 nationwide survey of KD in Japan. Of the 15,940 patients with KD, 20% did not respond to initial IVIG therapy. These nonresponders had a dramatically higher risk for CA aneurysms and giant CA aneurysms compared with responders. One of the risk factors identified was initial treatment at or before the fifth day of illness. However, a review of data from 1997 to 2004 nationwide KD surveys suggests that earlier initial treatment might have reflected more clear-cut and, therefore, more severe disease at presentation. Thus, the high incidence of retreatment among children initially treated before the sixth day of illness could support the impression that severe vasculitis requires more aggressive therapy.
No single risk factor identifies most children likely to have an incomplete response to IVIG's initial dose. Scoring models based upon combinations of risk factors have been developed to predict initial response to IVIG therapy. However, most such attempts have been inadequate to be clinically used, with sensitivities ranging from 86% to 33% and specificities from 87% to 62%. Also, risk factors are not necessarily transferable between populations. For example, the Kobayashi score effectively-identified 95% of Japanese children in Japan likely to respond incompletely to IVIG's initial dose. However, when used in the U.S., 64% of patients who were resistant to IVIG were not flagged as high risk by the Kobayashi score. Three other Japanese risk scores sensitive and specific for identifying children in Japan at high risk of being resistant to the first IVIG dose are similarly insensitive in American patients with KD.
Risk stratification has proven useful in identifying Japanese children treated in Japan for KD who are at high risk of IVIG resistance. Further studies are needed to validate criteria for identifying high-risk patients in other populations prospectively. The Japanese studies have led to the augmentation of initial therapy with glucocorticoids or other agents in certain patients at high risk for IVIG resistance (refractory KD). Extrapolating the data from Japanese children in Japan to other populations, including children of Japanese ethnicity in other countries, is increasingly common because of the strength of the benefit in Japan.
The risk of IVIG resistance in Japanese children with KD can be ascertained using the Kobayashi score or similar validated scores. These scores can be used to determine which patients might benefit from augmented initial therapy. The data are strongest for administering glucocorticoids to initial IVIG treatment in children at high risk of failing to respond to IVIG alone.
The Kobayashi score includes the following risk factors:
Additional risk factors for nonresponsiveness to initial IVIG therapy identified in retrospective studies include:
Non-Japanese children are also at increased risk of failing to respond to initial therapy with IVIG alone when they fulfill risk scores (such as the Kobayashi score). Still, these scores have low sensitivity and poor negative predictive value outside of Japan. In non-Japanese populations, different risk factors can identify children in whom significant CA dilatation is likely to occur despite treatment with IVIG. Extrapolating from the RAISE trial, some centers elect to treat such children with adjunct glucocorticoids because they believe that the potential benefits outweigh potential risks. However, it is important to stress that limited data are available, demonstrating that such an extrapolation is valid.
One risk model appears to successfully predict risk factors for developing CA aneurysms despite initial treatment with IVIG in children in the U.S. with KD. The development database retrospectively analyzed 903 patients with KD from Boston and San Diego. The validation cohort consisted of 185 well-characterized subjects in a Pediatric Heart Network clinical trial at eight North American centers. The final score used several of the same risk factors central to the Japanese models, with the unique addition of enlarged CAs at presentation (Z-score >2). Predictors of CA aneurysms at two to eight weeks were:
Each variable is given 1 point, except 2 points for baseline Z-score of left anterior descending or right CA >2.0. Patients are grouped into low (0 to 1 point), moderate (2 points), or high (3 to 5 points) risk. The odds of developing aneurysms (Z-score >2.5) two to eight weeks after the onset of KD was 40-fold greater in high- than low-risk groups in the validation cohort.
The treatment of patients who are diagnosed with KD is consistent with the AHA and AAP guidelines. The recommended initial therapy includes:
Children who meet partial criteria for incomplete KD are treated no differently from children who fulfill diagnostic criteria for KD.
A review of almost 16,000 cases enrolled in the 17th Japanese nationwide survey of KD found that 16.1% of children with CA abnormalities had incomplete KD, meeting fewer than five diagnostic criteria. A retrospective review evaluated 195 patients with KD who developed CA aneurysms at four centers in the U.S. from 1981 to 2006, 53 (27%) of whom were not treated for KD because they did not fulfill diagnostic criteria. Application of the 2004 AHA/AAP guidelines4 would have resulted in IVIG therapy administration to all but three of these children (98%).
Patients are usually observed for 24 hours (minimum 12 hours) following completion of initial IVIG therapy to confirm fever resolution. Recommendations concerning the timing of follow-up of children discharged after responding to IVIG depend upon whether CAs are normal or dilated and the patient's risk factors for ultimately failing to respond to IVIG. Refractory KD is defined as persistent or recurrent fever of any magnitude between 36 hours to approximately two weeks after the start of treatment.
Theoretically, it should be possible to stratify therapy for KD according to disease severity defined by the likelihood of developing CA aneurysms. However, no criteria have been developed that can reliably distinguish children who are not at risk of developing the severe disease at the time of initial presentation. Thus, all children diagnosed with complete or incomplete KD are treated with IVIG and also aspirin, unless contraindicated, at the time of diagnosis.
Patients at high risk for IVIG resistance are at increased risk for CA abnormalities and are usually treated with additional therapy.
Fever persists or returns in 10% to 15% of patients with KD who are initially treated with IVIG and aspirin. 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 starting their initial IVIG infusion. A fever before this time may represent a reaction to the medication or a slow response to therapy. In children with severe CA involvement or other signs of active vasculitis and inflammation, rescue therapy need not be postponed for more than 18 to 24 hours after the first dose of IVIG.
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 developing CA aneurysms. Additional therapy is indicated in any patient with KD who does not respond fully to initial therapy. Indeed, this is the reason that researchers are focusing on augmented initial therapy for patients at high risk of failing to respond to the initial dose of IVIG.
Persistent or recurrent fever of any magnitude between 36 hours to approximately two weeks after the start of treatment in patients with KD is generally assumed to be the result of failure to abort the disease process. Patients who have persistent or recurrent fever more than 24 hours after completing the initial treatment should also be assessed for intercurrent infection. The diagnosis of KD should be re-evaluated. However, these patients should be retreated for presumed recrudescence of KD unless there is clear evidence of another explanation for fever since numerous studies have confirmed an association between prolonged fever and the development of CA abnormalities. Fever within 36 hours of the start of intravenous IVIG therapy does not warrant retreatment because it may represent a reaction to the medication or a slow response to therapy.
The clinician needs to remain alert to mild temperature elevations in children treated for KD. In one study of 378 patients, those who remained febrile had an almost ninefold increased risk of developing CA abnormalities than those who responded to initial IVIG (12.2% versus 1.4%). Accurate core temperature measurements are important for KD patients' optimal management because of the strong association between elevated temperatures and CA abnormalities. Temperatures should be taken orally or rectally. Inaccurate temperature measurement may explain the rare reports of CA abnormalities after children became afebrile based upon axillary temperature measurement.5 Thus, the most prudent approach to a child recovering from KD is regular follow-up during the convalescent period regardless of whether there are any signs of smoldering vasculitis.
Fever persists or returns within 48 hours in approximately 10% to 15% of patients with KD who are initially treated with IVIG and aspirin. For unclear reasons, however, this fraction can vary significantly. In 2006, the incidence of refractory KD in Boston was 8%. In contrast, the likelihood of having KD refractory to initial IVIG therapy in San Diego increased to 38% in 2006 from a range of 10% to 20% between 1998 and 2005. This increase was not associated with any changes in the formulations of IVIG used. The same IVIG brands and lots administered in San Diego to treat KD patients were also used in Boston.
Just as IVIG's KD mechanism is not understood, some patients with KD fail initial IVIG therapy is also not clear. Retrospective studies have identified potential factors that predict which patients will require further therapy for refractory disease. The presence of one or more of these risk factors for treatment failure should alert clinicians to an increased likelihood that the patient may not respond adequately to the initial IVIG therapy. Scoring models based upon these risk factors have been developed to predict the initial response to IVIG therapy. Still, their sensitivity (range from 86% to 33%) and specificity (range from 87 to 62) are not adequate for identifying all children who would potentially benefit from augmented initial therapy. Also, risk scores useful for identifying children in Japan who will have IVIG resistance are less effective in predicting which children are at risk for refractory KD in other populations. Nonetheless, many centers add glucocorticoids or other agents to initial IVIG for children at high risk of failing to respond to initial IVIG, even as ongoing studies seek to improve the sensitivity and specificity of algorithms for identifying such high-risk patients. Studies are ongoing to determine whether patients with these risk factors may benefit from more aggressive initial therapy.
Fever that occurs during or within 36 hours after the IVIG infusion may be due to a medication's reaction. Intercurrent infection or MAS (a form of hemophagocytic lymphohistiocytosis) is another potential cause of recurrent or prolonged fever in KD patients. Alternative diagnoses, such as systemic JIA or chronic vasculitis (e.g., polyarteritis nodosa), should be considered when KD findings are prolonged beyond three to four weeks. In general, a child diagnosed with KD who has persistent or recurrent fever plus the reappearance of one or more of the presenting signs of mucocutaneous inflammation 36 hours after the start of the IVIG infusion is likely to have IVIG resistance. However, an absence of signs of KD other than fever, or the appearance of manifestations of infection, MAS, or other conditions, should lead to evaluation for other causes of fever.
Children who are febrile more than 24 to 36 hours after completing the initial intravenous IVIG infusion require additional therapy unless an alternative explanation for persistent or recurrent fever is unambiguously demonstrated. Children are generally re-treated with persistent fever after an initial IVIG dose with a single infusion of IVIG (2 g/kg) for a total cumulative IVIG dose of 4 g/kg because of the apparent dose-response effect of IVIG and its general safety.
There are no prospective trials evaluating approaches to salvage therapy in children who fail initial treatment for KD. Observational studies suggest that most patients with persistent fever after initial IVIG therapy will resolve their fever after retreatment with IVIG. It also appears that retreatment with IVIG (resulting in a higher total cumulative dose of IVIG) decreases CA aneurysms' risk. However, some clinicians prefer to use alternative salvage agents such as infliximab, even though data demonstrating beneficial effects on CAs are minimal.
IVIG carries a dose-related risk of causing hemolytic anemia, with up to 15% of children receiving 4 g/kg requiring transfusions. The hemolysis is due to antibodies against major blood types in IVIG. Children with type AB blood are at the highest risk, while those with type O do not develop hemolysis. Thus, in some children with non-type O blood, glucocorticoids may be used instead of a second IVIG dose for resistant KD. Cumulative doses of IVIG above 4 g/kg are typically not beneficial in KD, so this amount is usually not exceeded during the acute phase of KD. Overall, at least 5% of children remain febrile despite multiple doses of IVIG.
Even multiple doses of intravenous IVIG may not completely control recalcitrant cases of KD. These patients are at high risk of developing CA abnormalities and long-term sequelae of the disease. The greatest risk factor is prolonged fever. Ideally, such patients should be identified prospectively before CA abnormalities develop, allowing supplemental therapy to prevent or ameliorate vascular damage. One systematic review and meta-analysis of 16 controlled studies involving 2,746 patients treated with IVIG plus glucocorticoids versus IVIG alone concluded that glucocorticoid's efficacy in providing CA abnormality protection was inversely related to the duration of illness before glucocorticoids were administered. Evidence is strong that glucocorticoids' addition to initial IVIG treatment decreases the likelihood that high-risk patients will develop CA aneurysms. However, analysis of rescue therapy with glucocorticoids does not provide statistically significant evidence of a benefit on CA outcomes. Unfortunately, risk scores are insufficiently sensitive or specific to identify high-risk patients reliably. Instead, many patients wind up failing to respond to IVIG fully and then are candidates for salvage therapy. The ultimate goal, both with initial IVIG treatment and salvage therapy with glucocorticoids or other agents, is to prevent or minimize dilatation of the CAs. Still, no salvage agent unequivocally has been shown to achieve this goal in children who have failed to respond to IVIG.
Therapeutic options for rescue therapy are based upon agents that have demonstrated effectiveness in other vasculitides, including glucocorticoids, TNF inhibitors, other immunosuppressive agents, and plasmapheresis. These rescue therapies have not been compared in controlled studies, and all have been used in small numbers of children who are refractory to IVIG. While many second-line agents appear to control fever in children with KD, none have demonstrated a protective effect on CAs in prospective clinical trials. Also, fever in KD is self-limiting, and apparent response to therapy reported in uncontrolled studies may represent abatement of the disease process that is not directly related to the therapy administered. Thus, while a wide variety of salvage agents are reported to be safe and effective in small, uncontrolled studies, their therapeutic utility remains unproven. Clinicians are thus left with numerous imperfect options and inadequate data to make a fully informed choice when their patient remains febrile and is at high risk of developing CA abnormalities.
A regimen of methylprednisolone (30 mg/kg per day) for up to three consecutive days in patients who demonstrate ongoing signs suggestive of active vasculitis (e.g., persistent or recurrent fever) despite two doses of IVIG (total 4 g/kg) or whose risk of hemolysis with a second dose of IVIG warrants use of an alternate agent may be employed. Methylprednisolone is administered over two hours once daily until a full response (i.e., resolution of fever and clinical manifestations of mucocutaneous inflammation) is obtained or the patient has received three doses of methylprednisolone. At that point, children who continue to have evidence of active vasculitis should be treated with one of the less-studied salvage therapies (e.g., an anti-TNF agent or plasmapheresis).
As a result of experience with glucocorticoids for treating a broad range of vasculitides, glucocorticoids were the first agents used as salvage therapy for children with KD who failed to respond to two courses IVIG. Several case reports, series, and uncontrolled clinical trials have reported the benefits of a short course of systemic glucocorticoids in patients with KD resistant to IVIG therapy. Most found that many patients had a good clinical response, with a persistent resolution of fevers. One retrospective study found daily prednisolone rescue therapy for more than 15 days was effective in preventing CA abnormalities. However, not all found a difference in the incidence of CA aneurysms in those treated with systemic glucocorticoids versus an additional dose of IVIG. One systematic review and meta-analysis concluded that salvage therapy with glucocorticoids might be ineffective in protecting CAs because too much time has passed, and damage has occurred. Until a randomized trial comparing the efficacy of glucocorticoids and other medications for salvage therapy provides high-quality data, clinicians will continue to have to rely on extrapolations from imperfect studies.
Various glucocorticoid regimens are used in patients who fail to respond to IVIG therapy, generally paralleling glucocorticoid regimens for augmented initial therapy of KD. In North America, the first prospective trial of augmented primary treatment used IV pulsed-dose methylprednisolone (30 mg/kg per day) for up to three consecutive days. This is the agent most often used to treat children who remain febrile after initial IVIG therapy. In Japan, children with KD are typically hospitalized longer than in the U.S., and salvage therapy is based upon the RAISE protocol, with daily doses of prednisolone 1 to 2 mg/kg/day IV or orally (PO) for at least 15 days.
The following studies are illustrative:
The increased risk of CA aneurysms in children who fail IVIG and glucocorticoid therapy has led to a search for alternative therapy in these patients. Several agents with the potential for causing more serious toxicity than either IVIG or glucocorticoids are discussed below. These agents are reserved for children with severe refractory KD who have failed initial standard therapy and at least one repeat infusion of IVIG and a course of glucocorticoid therapy. These therapies should also be given under the supervision of a clinician with expertise in treating children with KD. The most commonly used of these agents is the TNF-alpha inhibitor infliximab.
Complications in patients with KD primarily result from cardiovascular involvement and include:
Noncardiac complications are generally uncommon and include:
Patients with KD shock syndrome or MAS are at higher risk of failing to respond to IVIG and are often given augmented initial therapy.
Mortality due to KD is rare among children treated with IVIG. Long-term morbidity is primarily related to the degree of CA involvement. The recurrence of KD is uncommon.
The reported mortality rate of KD is low (0.1% to 0.3%) since the advent of IVIG therapy. The rare fatal outcomes from severe cardiac involvement in KD are generally the result of either MI or arrhythmias, although aneurysm rupture can also occur. Mistaken or late diagnosis, or complete lack of IVIG treatment, is associated with potentially fatal outcomes.
In Japan, a registry of 6,576 patients with KD has been established for longitudinal evaluation of ongoing morbidity and mortality. As of 1998, standardized mortality rates based upon Japanese vital statistics data demonstrated an increased mortality rate within the first two months of the disease. After the acute phase, the mortality rate was not increased compared with the general population. A subsequent follow-up of this cohort was published in 2013. At that time, subjects were 17 to 39 years of age, representing a follow-up of 17 to 27 years. Overall age-adjusted mortality remained no higher than in the general Japanese population, and subjects with no cardiac sequelae decreased the standardized mortality rate (SMR). However, the SMR was 1.86 for those with cardiac sequelae of KD, including 7 of 14 deaths among those with sequelae of KD definitely or presumptively ascribed to late effects of KD.
Long-term morbidity for patients following KD depends upon the severity of CA involvement.
There appears to be a low rate of recurrence for KD, as illustrated by data from the 13th and 14th nationwide surveys of KD in Japan. After three years of follow-up, 2% of patients were reported to have a recurrence of KD with a rate of 6.9 per 1000 person-years. 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 the rehospitalization of a patient who satisfied the diagnostic criteria for KD. To determine a true recurrence rate, follow-up studies must use a more precise definition of recurrence, i.e., 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 persistent KD and not truly a recurrent disease. Nonetheless, patients with recurrent disease appear to be at increased risk for cardiac sequelae. Consequently, practitioners should adopt a more conservative approach to possible recurrences of KD, including a lower threshold for using IVIG if the diagnosis is uncertain and earlier use of salvage therapy for incomplete responses to IVIG.
Follow-up after discharge includes monitoring for recurrence of fever and repeat echocardiograms to assess for cardiac involvement. Live-virus vaccines are postponed due to decreased immunogenicity in children who have received IVIG treatment.
Caregivers are typically instructed to:
Such heightened vigilance should be continued until the next outpatient follow-up visit, which usually occurs 7 to 10 days after discharge. Any child who develops fever should be evaluated for recurrence of other manifestations of inflammation, interval CA dilatation on echocardiogram, and other fever causes. These patients should be retreated for presumed recrudescence of KD unless there is clear evidence of another explanation for fever.
After the baseline echocardiogram is obtained at diagnosis, echocardiography is usually repeated at approximately two and six weeks of illness to evaluate CA involvement. Children who remain clinically well following IVIG therapy and have a normal echocardiogram at two weeks seldom develop new abnormalities. Conversely, those with CA aneurysms, or those at higher risk for developing CA dilatation, warrant more frequent echocardiograms. Patients should also have repeated clinical evaluations during the first one to two months following KD's diagnosis to detect arrhythmias, heart failure, valvular insufficiency, or myocarditis.
The relative risk for MI-based upon CA abnormalities detected by echocardiogram can be assessed six to eight weeks after illness onset. Based on this risk, the AHA and the AAP guidelines have been developed for medical therapy, physical activity, and the schedule and content of follow-up visits. Children with CA abnormalities generally receive antithrombotic therapy with aspirin, warfarin, or other agents and regular cardiac evaluation.
Children generally do not feel completely well for several weeks after KD, and they, therefore, tend to limit their activity level. Restrictions are dependent upon the risk of MI. They should be imposed only in children with increased risk of thrombosis during the disease's convalescent stage, particularly those with giant CA aneurysms. The restrictions should be determined in consultation with the child's cardiologist.
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. Passive-acquired antibodies persist for an extended time (up to 11 months) following IVIG administration and may interfere with vaccine immunogenicity. 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 administering IVIG (unless there is serologic evidence of adequate immunity). Schedules for other routine childhood vaccinations do not need to be altered.
Influenza immunization, recommended in all children over six months of age, is particularly important in those who require long-term high-dose aspirin therapy because of the possible increased risk of Reye syndrome. Additionally, we suggest giving the varicella vaccine to patients receiving long-term low-dose aspirin therapy, even though epidemiologic data only implicate high- and medium-dose aspirin in the development of Reye syndrome. As of 2017, no Reye syndrome cases had been reported in children receiving influenza or varicella vaccines while on long-term low-dose aspirin therapy.
John Samuels, a four-year-old Japanese/Caucasian male, is transported to the Emergency Room via EMS on August 3, 2020, at 0700, accompanied by his mother, Zhua Samuels, and father, William Samuels. His mother states that he spiked a temperature the previous Friday, July 31, 2020, to 102.5° Fahrenheit (oral). The child had been being given Children’s Tylenol and Children’s Motrin every four hours, but the lowest temperature ever got was 100.5°. Last Children’s Tylenol was given at 2400.
The child has been eating and drinking little since the previous Friday. He also has been sleeping a lot, and when awake, he is very fussy and irritable. He also has “bloodshot” eyes since Saturday and a rash “between his upper legs and buttocks” since Sunday. His mother states that his cheeks, hands, and feet are red.
Current Medical History:
Past Medical History:
Past Surgical History:
IV access (left forearm): 1000 ml 0.9 NS hung at 50 ml/hr.
Blood was drawn:
Other labs sent:
Other imaging studies were done:
Emergency physician obtained an initial physical examination:
Echocardiogram ordered stat.
Cardiology consult ordered stat.
Infectious disease consults ordered stat.
Awaiting results of laboratory tests
Notified PICU concerning the need for bed in the isolation room or negative pressure with airborne precautions room.
In the ED, John Samuels was monitored, awaiting echocardiogram results, cardiology and infectious disease recommendations, and laboratory results. Tentative diagnoses: Incomplete Kawasaki disease versus MIS-C.
John Samuels’s health history and physical examination were performed quickly with appropriate orders written. Appropriate interventions implemented.
KD (also called mucocutaneous lymph node syndrome) is one of the most common vasculitides of childhood. The incidence of KD is greatest in children who live in East Asia (e.g., Japan, Korea, Taiwan) or are of Asian ancestry living in other parts of the world. Other risk factors include male sex, age between six months and five years, and family history of KD. KD occurs only rarely in adults.
KD is typically a self-limited condition, with fever and manifestations of acute inflammation lasting for an average of 12 days without therapy. Still, cardiac complications can lead to significant morbidity and mortality. Timely diagnosis and initiation of appropriate therapy minimize cardiac sequelae and improve clinical outcomes.
The etiology of KD remains unknown. Inflammatory cell infiltration into KD vascular tissue leads to vascular damage, but the inflammatory infiltration stimulus has not been identified.
The similarities between KD and other pediatric infectious conditions suggest that a transmissible agent causes KD. However, no studies have convincingly identified a specific virus, bacterium, or bacterial toxin, or other pathogen-associated with KD. The etiology may be a previously unidentified infectious agent. An alternative theory to a specific inciting agent is that KD represents a final common pathway of immune-mediated vascular inflammation following various inciting infections or environmental antigens.
Genetic factors appear to contribute to this disorder's pathogenesis, as suggested by the increased frequency of the disease in Asian and Asian-American populations and family members of an index case. Several gene polymorphisms are associated with increased susceptibility to KD, and some of these variants are also associated with coronary artery lesions and aneurysm formation.
KD is characterized by systemic inflammation manifested by fever and mucocutaneous involvement, including:
These findings are the basis for the diagnostic criteria for KD. Patients who lack a sufficient number of findings to fulfill the classic criteria may have incomplete KD.
These findings are often not present at the same time. Thus, repeated histories and physical examinations are important in making a timely diagnosis of KD in children with fever and signs of mucocutaneous inflammation.
Infants and possibly adults are more likely to present with incomplete KD. Infants are at greater risk for cardiovascular sequelae, possibly due 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.
No laboratory studies are included among the diagnostic criteria for complete KD. But certain findings characteristic of KD may support the diagnosis in ambiguous cases. However, the presence of compatible laboratory features strongly supports the diagnosis.
According to classical criteria, the diagnosis of KD requires the presence of fever ≥five days, combined with at least four of the other five signs of mucocutaneous inflammation, without any other explanation. A significant proportion of children with KD have a concurrent infection. Therefore, ascribing the fever to such an infection or KD requires clinical judgment.
Additional clinical and laboratory features are often used to guide diagnosis in children who have fewer than five KD criteria (incomplete KD). The criteria to diagnose incomplete KD and initiate treatment in a child in whom an experienced clinician believes that KD is the probable diagnosis include elevated CRP or ESR and three or more abnormal supplemental laboratory findings OR abnormal echocardiography. A child with incomplete KD whose diagnosis is delayed is more likely to develop CA abnormalities. Thus, KD should be in the differential diagnosis of any child with unexplained fever lasting five or more days.
KD is most commonly confused with infectious exanthems of childhood. The presence of clinical features not commonly found in KD, including exudative conjunctivitis, exudative pharyngitis, discrete intraoral lesions, bullous or vesicular rash, splenomegaly, or generalized lymphadenopathy, suggest another diagnosis. Nonetheless, KD is sufficiently pleomorphic that none of these findings can definitively exclude the diagnosis. Children with KD can have concurrent infections, particularly with viruses circulating in the community at their diagnosis.
Patients who fulfill the criteria for complete KD or incomplete KD require treatment because of the risk of cardiovascular complications that may result in significant morbidity and even mortality.
A single IVIG dose (2 g/kg administered over 8 to 12 hours) is recommended in patients with KD. IVIG is most effective if administered within the first ten days of illness before aneurysms typically develop. Nonetheless, IVIG should be administered even beyond this 10-day window in patients with evidence of persistent vasculitis or systemic inflammation (e.g., persistent fever, elevated acute-phase reactants).
In patients with KD, aspirin should be administered during the acute phase of the illness. The AAP and AHA have recommended a broad range of aspirin doses (30 to 100 mg/kg/day), but it is not clear that any amount of aspirin has long-term benefits. A total daily aspirin dose of 30 to 50 mg/kg/day in four divided doses (maximum dose 4 g per day) is advised. Still, it should be held for any contraindication, particularly exposure to varicella or influenza. The aspirin dose is decreased to 3 to 5 mg/kg/day 48 hours after fever resolution. Aspirin is continued until laboratory markers of ongoing inflammation (e.g., platelet count and ESR) return to normal unless CA abnormalities are detected by echocardiography, in which case aspirin therapy is continued.
For Japanese children, well-validated criteria, such as the Kobayashi criteria or similar, can be used to select patients at increased risk of IVIG resistance. Such high-risk patients are most likely to benefit from adjuvant treatment with glucocorticoids in addition to IVIG.
For non-Japanese patients, the criteria for identifying at-risk children are not well validated. In these patients, the following may be used to select those who are most likely to benefit from augmented treatment with glucocorticoids in addition to initial IVIG:
In children with KD who are determined to be at increased risk of IVIG resistance, glucocorticoids should be added to initial IVIG therapy. A total of 15 days of prednisone/prednisolone (five days each of 2 mg/kg, 1 mg/kg, and 0.5 mg/kg), starting with an intravenous formulation and switching to oral glucocorticoids 12 to 24 hours before expected discharge, is suggested. A reasonable alternative, particularly in non-Japanese patients, is to treat with IVIG and aspirin alone since most children with KD recover with standard therapy and have a low risk of CA aneurysms or other complications.
Prognosis is based upon the severity of CA involvement as a marker of risk for MI. After the baseline echocardiogram is obtained at diagnosis, echocardiography is usually repeated at approximately two and six weeks of illness to evaluate CA involvement. Examinations and echocardiograms are repeated more frequently in children with CA abnormalities. Children also should be monitored carefully for any signs of persistent illness during the first two weeks after treatment, as those with ongoing inflammation, particularly fever of any degree, are at the highest risk of developing CA abnormalities.
The AHA and AAP have developed guidelines for subsequent therapy, physical activity, and follow-up visits (schedule and content) based on MI's relative risk.
Patients without any cardiovascular abnormalities appear to be clinically healthy at long-term follow-up (range, 10 to 21 years). However, it is unknown whether they are at increased risk for atherosclerotic heart disease.
Administration of live-virus vaccines (e.g., measles, varicella) for at least 11 months in children who have been treated with IVIG should be postponed because passively acquired antibodies can interfere with vaccine immunogenicity. One exception to this postponement is in children residing in communities experiencing an outbreak of a vaccine-preventable disease. Another exception is children on long-term aspirin therapy. Children who are ≥12 months of age and are on long-term, moderate- or high-dose aspirin therapy (30 to 100 mg/kg/day) should receive the varicella vaccine because of the increased risk of Reye syndrome. In situations where vaccination is not postponed, the vaccine should be repeated at least 11 months after administering IVIG. Influenza immunization, recommended in all children over six months of age, is also particularly important in those who require long-term high-dose aspirin therapy because of the possible increased risk of Reye syndrome.
Some patients with KD have persistent or recurrent fever despite treatment with IVIG and aspirin. Prolonged fever is a risk factor for CA sequelae in KD. In these patients, other causes of fever should be considered. Risk factors for failing to respond to a single dose of IVIG include:
Patients with refractory KD are at increased risk of developing CA aneurysms.
Additional therapy is recommended in children with KD who have persistent fever 24 hours after completing initial therapy or whose fever returns after an afebrile period (up to two weeks after starting treatment). Retreatment is suggested with a single dose of IVIG (2 g/kg). Additional dose(s) of IVIG may be administered before considering other medications in those who remain febrile. However, the benefits of a total dose of more than 4 g/kg of IVIG have not been demonstrated.
For patients who do not respond to retreatment with IVIG, treatment with glucocorticoids is suggested. Pulsed-dose methylprednisolone (30 mg/kg per day administered on one to three consecutive days) once daily until a full response (e.g., resolution of fever) is obtained or the patient has received three doses is suggested. A 15- to 30-day course of twice or thrice daily oral prednisone (total daily dose 1 to 2 mg/kg) may be equally or more effective than IV methylprednisolone in children with KD who are resistant to IVIG.
Therapeutic alternatives, which have demonstrated effectiveness for other vasculitis forms, include TNF-alpha inhibitors, other immunosuppressive agents, and plasmapheresis. However, there are limited data concerning these agents' risks and benefits for refractory KD and only a few small trials to evaluate them. The most commonly used of these agents is infliximab, a monoclonal antibody against TNF-alpha. In multiple trials, it effectively lowers fever, laboratory markers of inflammation, and signs of mucocutaneous inflammation, but there is minimal evidence that it improves CA outcomes. Infliximab (5 mg/kg) is typically given to children who have evidence of active vasculitis despite receiving two IVIG courses (total 4 mg/kg) and one to three IV doses of methylprednisolone.
CEUFast, Inc. is committed to furthering diversity, equity, and inclusion (DEI). While reflecting on this course content, CEUFast, Inc. would like you to consider your individual perspective and question your own biases. Remember, implicit bias is a form of bias that impacts our practice as healthcare professionals. Implicit bias occurs when we have automatic prejudices, judgments, and/or a general attitude towards a person or a group of people based on associated stereotypes we have formed over time. These automatic thoughts occur without our conscious knowledge and without our intentional desire to discriminate. The concern with implicit bias is that this can impact our actions and decisions with our workplace leadership, colleagues, and even our patients. While it is our universal goal to treat everyone equally, our implicit biases can influence our interactions, assessments, communication, prioritization, and decision-making concerning patients, which can ultimately adversely impact health outcomes. It is important to keep this in mind in order to intentionally work to self-identify our own risk areas where our implicit biases might influence our behaviors. Together, we can cease perpetuating stereotypes and remind each other to remain mindful to help avoid reacting according to biases that are contrary to our conscious beliefs and values.
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