salicylates and Mucocutaneous-Lymph-Node-Syndrome

Kawasaki disease is the most common cause of acquired heart disease in children in developed countries. The coronary arteries supplying the heart can be damaged in Kawasaki disease. The principal advantage of timely diagnosis is the potential to prevent this complication with early treatment. Salicylate (acetyl salicylate acid (ASA), aspirin) and intravenous immunoglobulin (IVIG) are widely used for this purpose. Salicylate is largely otherwise avoided in children because of concerns about serious side effects, particularly the risk of Reyes syndrome.. The objective of this review was to evaluate the effectiveness of salicylate in treating and preventing cardiac consequences of Kawasaki disease in children.. The Cochrane Peripheral Vascular Disease Group searched their trials register (last searched July 2006) and the Cochrane Central Register of Controlled Trials (CENTRAL) (last searched Issue 3, 2006). We searched MEDLINE (January 1966 to July 2006), EMBASE (January 1980 to July 2006), and CINAHL (1982 to July 2006), and reference list of articles. In addition we contacted experts in the field.. Randomised controlled trials (RCTs) of salicylate to treat Kawasaki disease in children were eligible for inclusion.. Two authors independently assessed trial quality and extracted data. Study authors were contacted for additional information.. We found one trial involving 102 children which was described as randomised, but it was not possible to confirm the method of treatment allocation. A second comparative study, possibly with a randomised treatment allocation, was also identified. The one randomised trial reported no association between the addition of ASA to IVIG treatment on the rate of coronary artery abnormalities at follow up, but with wide confidence limits. The second, possibly randomised trial did demonstrate a reduction in duration of fever with high dose ASA compared to low dose ASA, but was insufficiently powered to establish the effect on coronary artery abnormalities at follow up.. Until good quality RCTs are carried out, there is insufficient evidence to indicate whether children with Kawasaki disease should continue to receive salicylate as part of their treatment regimen.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Child; Humans; Immunoglobulins, Intravenous; Mucocutaneous Lymph Node Syndrome; Salicylates

Kawasaki disease is a childhood vasculitis of medium-sized vessels, affecting the coronary arteries in particular. We have treated a therapy-resistant child who met all diagnostic criteria for Kawasaki disease. After the boy was given intravenous immunoglobulins and salicylates, as well as several courses of pulsed methylprednisolone, disease recurred and coronary artery lesions became progressively detectable. Cyclosporin A was started and seemed clinically effective. In contrast to the positive effect on inflammatory parameters, ie, C-reactive protein and white blood cell counts, a novel plasma marker for cytotoxicity (granzyme B) remained elevated. Coronary disease progressed to fatal obstruction and myocardial infarction. Echocardiography, electrocardiograms, and myocardial creatine phosphokinase did not predict impending death. At autopsy an obliterative panarteritis was observed resulting from massive fibrointimal proliferation, affecting the aorta and several large and medium-sized arteries. Immunophenotypic analysis of the inflammatory infiltrates in arteries revealed mainly granzyme-positive cytotoxic T cells and macrophages in the intima and media, as well as nodular aggregates of T cells, B cells, and plasma cells in the adventitia of affected arteries. These findings further endorse the role of specific cellular and humoral immunity in Kawasaki disease. Unremitting coronary arteritis and excessive smooth muscle hyperplasia resulted in coronary occlusion despite the use of cyclosporin A.

Topics: Aneurysm; C-Reactive Protein; Coronary Disease; Cyclosporine; Cytokines; Drug Resistance; Fatal Outcome; Humans; Immunoglobulins, Intravenous; Immunosuppressive Agents; Infant; Male; Methylprednisolone; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Salicylates; Serine Endopeptidases

Topics: Adolescent; Child; Child, Preschool; Coronary Aneurysm; Female; Humans; Immunization, Passive; Incidence; Infant; Male; Mucocutaneous Lymph Node Syndrome; Salicylates; Thrombocytosis

Topics: Aspirin; Biological Availability; Blood Proteins; Child; Child, Preschool; Clinical Trials as Topic; Humans; Liver; Mucocutaneous Lymph Node Syndrome; Protein Binding; Salicylates

Salicylate is the basic therapy for Kawasaki disease, however its optimal dose is controversial. We investigated the therapeutic efficacy of high dose (100 mg/kg per day, n = 30) versus low dose (30 mg/kg per day, n = 30) salicylate. Duration of fever, SGPT, serum salicylate, plasma thromboxane B2 (TxB2) and 6-keto-prostaglandin F1 alpha (PGF1 alpha) levels were compared before enrollment and on days 4, 7 and 14 of treatment. In the high dose group, duration of fever was significantly shorter than that of the low dose group (3.2 +/- 0.3 versus 5.4 +/- 0.8 days, P less than 0.05), however, SGPT levels were significantly elevated (157 +/- 34 versus 48 +/- 11 IU/1, P less than 0.05). No differences in the incidence of coronary artery lesions were observed (5/30 versus 7/30). Plasma TxB2 production was completely blocked in both groups, and plasma 6-keto-PGF1 alpha levels in the high dose group on day 14 was lower than that in the low dose group (39 +/- 8 versus 159 +/- 65 pg/ml, P less than 0.05). SGPT and plasma 6-keto-PGF1 alpha correlated with serum salicylate concentration. These data suggest that high dose salicylate therapy may be disadvantageous as anti-thrombotic therapy, and supports the notion that low dose therapy is safe in the acute stage of Kawasaki disease.

Topics: 6-Ketoprostaglandin F1 alpha; Alanine Transaminase; Child, Preschool; Dose-Response Relationship, Drug; Female; Fever; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Salicylates; Salicylic Acid; Thromboxane B2

Topics: Aspirin; Biological Availability; Blood Proteins; Child; Child, Preschool; Clinical Trials as Topic; Humans; Liver; Mucocutaneous Lymph Node Syndrome; Protein Binding; Salicylates

Orgun A, Karagöl C, Pamuk U, Gürsu HA, Çetin İ. A rare cause of facial nerve palsy in a young infant: Kawasaki disease. Turk J Pediatr 2018; 60: 433-435. Kawasaki disease (KD) is a vasculitis in which the most common complication is development of coronary aneurysms. Neurological complications rarely occur in KD patients such as facial nerve palsy (FNP). FNP associated with KD may indicate increased risk of coronary artery aneurysm. Infants with facial nerve paralysis and unexplained-prolonged febrile period should be evaluated with echocardiography. Here in, we present a 4-month-old female with FNP and unexplained fever who was diagnosed KD due to echocardiographic findings.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antihypertensive Agents; Coronary Aneurysm; Echocardiography; Enalapril; Facial Paralysis; Female; Fever; Humans; Immunoglobulins, Intravenous; Infant; Mucocutaneous Lymph Node Syndrome; Salicylates

Kawasaki disease (KD) is a multisystem vasculitis affecting children and is characterized by immune activation in the acute stage of disease. Systemic inflammation eventually subsides, although coronary arteritis persists, resulting in aneurysm formation. KD is the leading cause of acquired heart disease among children in North America. Accepted treatment guidelines include high-dose intravenous immunoglobulin (IVIG) and aspirin in the acute phase. Although this therapy is effective, the cellular and molecular mechanisms involved are not clear. The aim of this study was to examine the effect of IVIG and salicylate at each stage of disease development.. Using a murine model of KD, we established and validated several in vitro techniques to reflect 3 key steps involved in disease pathogenesis, as follows: thymidine incorporation to evaluate T cell activation, enzyme-linked immunosorbent assay to measure tumor necrosis factor alpha (TNFalpha) production, and real-time polymerase chain reaction to examine TNFalpha-mediated expression of matrix metalloproteinase 9 (MMP-9).. At therapeutic concentrations, IVIG, but not salicylate, effectively reduced the immune response leading to TNFalpha expression. Unexpectedly, pharmacologic doses of salicylate were not able to inhibit TNFalpha production and in fact enhanced its production. Neither drug directly regulated MMP-9 expression but did so only indirectly via modulating TNFalpha. TNFalpha activity was a prerequisite for local expression of MMP-9 at the coronary artery.. Therapeutic concentrations of IVIG and salicylate differentially modulate the expression of TNFalpha and its downstream effects. Further dissection of the biologic effects of aspirin in acute KD is necessary for the rational design of therapy.

Topics: Animals; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Immunoglobulins, Intravenous; Immunologic Factors; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Knockout; Mucocutaneous Lymph Node Syndrome; NF-kappa B; Receptors, Tumor Necrosis Factor, Type I; Salicylates; T-Lymphocytes; Tumor Necrosis Factor-alpha; Vascular Diseases

Topics: Humans; Mucocutaneous Lymph Node Syndrome; Salicylates

The authors report on the case history of a three-month-old infant with Kawasaki-syndrome. The course of the disease was atypical, the various symptoms (antibiotic resistant high fever, urticariform rash, meningitis serosa, steril pyuria, coronaria aneurysma, thrombocytosis, high sedimentation rate) developed slowly during a period of several weeks. The authors intend to point out that Kawasaki-syndrome may appear in early infancy, frequently in an atypical way.

Topics: Age Factors; Blood Sedimentation; Coronary Aneurysm; Coronary Angiography; Dose-Response Relationship, Drug; Follow-Up Studies; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Salicylates

Serum salicylate concentrations were measured in 60 patients with acute phase Kawasaki disease (KD), who were treated with intravenous aspirin (IVASP), to evaluate its anti-inflammatory effect in the treatment of KD. Patients with serum salicylate concentrations > or = 150 micrograms/ml showed shorter durations of fever (7.1 +/- 2.0 vs 10.4 +/- 6.6 days; P < 0.05), shorter durations of positive serum C-reactive protein (14.6 +/- 4.5 vs 22.3 +/- 10.6 days; P < 0.01) and lower incidences of coronary arterial involvements (0/10 vs 6/24; P < 0.05) than did patients with serum salicylate concentrations < 150 micrograms/ml. Significant linear correlations were recognized between daily IVASP dosage and serum salicylate concentrations (r = 0.73; P < 0.01), and between serum salicylate concentrations and serum free salicylate concentrations (r = 0.82; P < 0.01). These correlations did not differ between the presence and absence of coronary arterial involvements. Based on these findings we concluded that a beneficial anti-inflammatory effect in the treatment of KD is achieved when the serum salicylate concentration is > or = 150 micrograms/ml, and that such concentrations could be achieved by increasing the daily IVASP dosage to 100 mg/kg per day or more.

Topics: Acute Disease; Aspirin; Child; Child, Preschool; Coronary Disease; Female; Humans; Infant; Inflammation; Infusions, Intravenous; Male; Mucocutaneous Lymph Node Syndrome; Retrospective Studies; Salicylates; Treatment Outcome

From 1974 through 1991, a total of 583 children with Kawasaki disease were seen at the Hospital for Sick Children, in Toronto, of whom 80 (13.7%) had coronary artery involvement. There were 55 boys and 25 girls, whose mean age at onset was 2.9 +/- 2.5 years, followed for a mean period of 4.0 +/- 3.6 years. Giant aneurysms (maximum diameter > or = 8 mm) were found in 22 children, moderate-sized aneurysms (> or = 4 to < 8 mm) in 44, and dilation lesions (< 4 mm) in 14. Myocardial infarction occurred in 9 (1.5%), all of whom had giant aneurysms. The persistence rate for aneurysms was 72% at 1 year and 41% at 5 years of follow-up. In multivariate analysis, the regression of an aneurysm was significantly related to the severity of coronary artery lesions, initial treatment, and gender. Although > 80% of small or moderate-sized aneurysms regressed within 5 years, giant aneurysms did not regress during the follow-up period. In patients who received immune globulin therapy, coronary lesions tended to resolve more rapidly than in those treated with salicylate therapy alone, because 91% of the lesions in the former were small or moderate. These findings suggest that the severity of coronary artery involvement during the initial stages of Kawasaki disease influences the regression of these lesions, and that immune globulin treatment may improve outcome by reducing the incidence of severe lesions.

Topics: Adolescent; Child; Child, Preschool; Coronary Aneurysm; Female; Follow-Up Studies; Humans; Immunoglobulins, Intravenous; Infant; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Prognosis; Salicylates

We described the pharmacokinetics of acetylsalicylic acid and salicylic acid in 5 children with prior Kawasaki disease receiving buffered aspirin tablets or intravenous aspirin DL-lysine. Oral aspirin is characterized by its longer mean residence time in the body (MRT), an indicator for duration of exposure, than intravenous aspirin (1.18 vs. 0.37 h). The apparent elimination half-life (t1/2) of acetylsalicylic acid was also longer after oral than after intravenous administration of aspirin (40 vs. 17 min). The mean absorption time was calculated to be as long as 0.8 h. In contrast, the two modes of administration gave virtually identical results regarding MRT of salicylic acid proper and its t1/2. After oral administration of aspirin, 51% of the dose is absorbed intact as acetylsalicylic acid while 23% is converted to salicylic acid presystemically, indicating that 74% of aspirin is actually absorbed. Our data suggest that an equivalent intravenous aspirin dose to achieve the same salicylic acid concentration is about 70% of the oral dose. However, the area under the curve of acetylsalicylic acid itself, a more potent cyclooxygenase inhibitor than salicylic acid, would be about 1.5 times higher than that following oral administration. The clinical consequences of this exposure difference remain uncertain.

Topics: Absorption; Administration, Oral; Aspirin; Biological Availability; Buffers; Child, Preschool; Drug Administration Schedule; Half-Life; Humans; Infusions, Intravenous; Mucocutaneous Lymph Node Syndrome; Salicylates; Salicylic Acid

Because patients with Kawasaki disease have low serum concentrations of salicylates despite high doses, and because the free (unbound) drug is responsible for the pharmacologic effects of salicylates, we assessed salicylate protein binding in patients with Kawasaki disease. During the acute phase of the disease, protein binding of salicylate in 36 children with Kawasaki disease was 73 +/- 12%, significantly lower than during the subacute phase (90.4 +/- 8.7%; p less than 0.0005). Mean serum albumin concentration was 29.2 +/- 6.4 gm/L during the acute phase and 36.7 +/- 7.8 gm/L during the subsequent subacute phase (p less than 0.005). Salicylate protein binding was affected independently by both serum albumin and total salicylate levels. During the acute phase of Kawasaki disease, children had an average twofold increase in free salicylate compared with normoalbuminemic control subjects. A nomogram has been devised to derive free salicylate levels from the known total salicylate and serum albumin concentrations.

Topics: Acute Disease; Adult; Carbon Radioisotopes; Child; Humans; Mucocutaneous Lymph Node Syndrome; Protein Binding; Salicylates; Serum Albumin; Ultrafiltration

Topics: Child, Preschool; gamma-Globulins; Humans; Mucocutaneous Lymph Node Syndrome; Salicylates

The mechanisms leading to the previously reported difficulties in achieving therapeutic serum concentrations of salicylates in Kawasaki disease were studied in eight children, once during the acute (febrile) phase and again during the nonfebrile (subacute) phase of the disease. Salicylate bioavailability was impaired during the acute phase of the disease (47.7% +/- 6.6%), and increased significantly thereafter to 75.1% +/- 9.3%. During the febrile phase there was a significant correlation between salicylate bioavailability and steady-state serum concentrations. Salicylate renal clearance was significantly higher during the febrile phase (14.45 +/- 2.5 mL/kg.h), compared with the nonfebrile phase (7 +/- 1.6 mL/kg.h, P less than 0.05). The change in salicylate clearance could be explained by decreased protein binding in the acute phase (82.5% +/- 1.9%) with substantially more free salicylates caused by significantly lower serum albumin concentrations. Changes in urine metabolites during the acute and subacute phases were consistent with the changes in dose administered (100 mg/kg in the acute phase vs 10 mg/kg in the subacute phase). The pattern of metabolites excreted in the urine of children with Kawasaki disease receiving 100 mg/kg was similar to that in children with juvenile rheumatoid arthritis receiving the same dose.

Topics: Arthritis, Juvenile; Biological Availability; Child; Fever; Humans; Kidney; Metabolic Clearance Rate; Mucocutaneous Lymph Node Syndrome; Salicylates

Paired sera from 30 patients with muco-cutaneous lymph node syndrome (Kawasaki disease) were studied for possible effects on human vascular endothelial cells growth in vitro. The majority of sera from acute phase muco-cutaneous lymph node syndrome patients significantly enhanced endothelial cell proliferation more than those from convalescent phase patients, infectious diseases patients, and age-matched normal controls. This stimulation was considered to be specific for EC since muco-cutaneous lymph node syndrome sera did not enhance fibroblast growth more than normal sera. Fractionation of the serum with gel filtration failed to clearly detect the molecular properties of this effect, although both heavy and light material possessed this activity. Extensive search for circulating immune complex in muco-cutaneous lymph node syndrome sera were negative, suggesting that the enhanced endothelial cell proliferation was due to serum components other than immune complexes.

Topics: Antigen-Antibody Complex; Cell Division; Cells, Cultured; Chemical Fractionation; Child; Child, Preschool; Chromatography, Gel; Endothelial Growth Factors; Endothelium; Female; Growth Substances; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Prednisolone; Salicylates

Between June 1, 1979, and May 31, 1984, at The Hospital for Sick Children in Toronto, Kawasaki disease was diagnosed in 163 patients (112 boys, 51 girls, P less than 0.001). Fifteen percent of the children had coronary artery aneurysms. Prior to diagnosis, 24% had been given low doses of aspirin, and 50% acetaminophen. Children with coronary aneurysms had significantly higher temperature during days 10 to 13 of the disease. The febrile phase of the disease was also significantly longer in these children. Coronary artery involvement occurred with equal frequency in boys and girls. There was no significantly greater incidence of coronary artery involvement in infants younger than 1 year of age than in older children. Duration of fever (greater than or equal to 14 days vs less than 14 days) was equally as predictive of the eventual occurrence of coronary aneurysms as the modified Asai score.

Topics: Acetaminophen; Age Factors; Aneurysm; Child; Child, Preschool; Coronary Disease; Female; Fever; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Probability; Retrospective Studies; Risk; Salicylates; Seasons; Sex Factors; Time Factors

Topics: Child; Humans; Mucocutaneous Lymph Node Syndrome; Salicylates

We investigated 49 children (33 boys), mean (+/- SD) age 2.6 +/- 1.8 years (range 8 months to 8 years), who had Kawasaki disease treated with acetylsalicylic acid (ASA) 30 to 180 mg/kg. There was good correlation between salicylate doses and serum concentrations (r = 0.69, P less than 0.01); however, large variability existed. With doses less than 80 mg/kg/day there was not a single therapeutic salicylate serum concentration (greater than 20 mg/dl). In children receiving 100 to 110 mg/kg/day 55% of the serum concentrations were subtherapeutic. The same pattern persisted with doses greater than 120 mg/kg/day; however, 28% of levels were in the toxic range (greater than 30 mg/dl). There was no evidence of salicylate poisoning in the group; three children receiving greater than 100 mg/kg/day had aspirin-induced gastritis. An additional four children, studied prospectively, received ASA 80 to 180 mg/kg/day. The fraction absorbed was 14% to 60%, which may be compared to a normal 85% to 90% absorption. Salicylate renal clearance in these children (7.3 to 21 ml/kg/hr) was lower than in hyperthermic children. Their steady-state serum salicylate concentrations were subtherapeutic (7 to 11.5 mg/dl). The high ASA dose needed to overcome the impaired absorption should be accompanied by frequent monitoring of levels because of the unpredictable changes in absorption.

Topics: Aspirin; Child; Child, Preschool; Dose-Response Relationship, Drug; Female; Humans; Infant; Male; Mucocutaneous Lymph Node Syndrome; Prospective Studies; Retrospective Studies; Salicylates; Salicylic Acid

We studied gallbladder involvement in 19 patients with Kawasaki syndrome who presented over a 4-year period from 1979 to 1982. Diagnosis and follow-up of gallbladder disease were defined by real-time ultrasound. Complete spontaneous resolution of abdominal symptomatology related to the hydropic gallbladder occurred without complication and did not require surgical intervention. We suggest that the incidence of hydrops of the gallbladder in mucocutaneous lymph node syndrome is higher than commonly appreciated, since diagnosis may be missed unless ultrasound is performed.

Topics: Acute Disease; Child; Child, Preschool; Edema; Female; Fluid Therapy; Gallbladder Diseases; Humans; Male; Mucocutaneous Lymph Node Syndrome; Salicylates; Ultrasonography

Kawasaki disease, mucocutaneous lymph node syndrome, thought to be rare in the continental United States, occurred in epidemic form in New York City and adjacent New York and New Jersey in November-December, 1977. Aspirin and corticosteroids, reported to be ineffective treatment, were found to completely control the illness in affected children, provided adequate doses to achieve therapeutic blood levels were administered. Patients were found to malabsorb aspirin (and perhaps also to destroy it) and so required extraordinarily high doses during the acute phase; during recovery, doses had to be lowered to the usual range to avoid toxicity. The need for hospitalization and morbidity were reduced and, hopefully, mortality will also be reduced. The importance of not judging a drug ineffective in a disease without demonstrating adequate serum levels was again shown.

Topics: Aging; Aspirin; Child; Child, Preschool; Disease Outbreaks; Feces; Humans; Infant; Lymphatic Diseases; Mucocutaneous Lymph Node Syndrome; New York City; Salicylates

Since October 1978, four cases of mucocutaneous lymph node syndrome, a disease previously not yet described in our country were observed in our childrens hospital. This particular disease has been described quite frequently in Japan since 1967. It has a characteristic manifestation being mostly benign and self limited. In a few cases however acute cardiac arrest has been described. The first case we observed expired as a result of acute coronary infarction on the twentyfifth day of illness although clinical improvement had been previously noted. At post mortem examination the coronary arteries showed changes consistent with arteriitis. The following three cases presented the more typical benign course of this disease one of them with deformities of the coronary arteries. The clinical synopsis describes the above mentioned cases.

Topics: Adrenal Cortex Hormones; Arteritis; Austria; Child, Preschool; Coronary Vessels; Electrocardiography; Humans; Infant; Lymphatic Diseases; Male; Mucocutaneous Lymph Node Syndrome; Myocardial Infarction; Salicylates