John F. Bastian

A Single Intravenous Infusion of Gamma Globulin as Compared with Four Infusions in the Treatment of Acute Kawasaki Syndrome

BACKGROUND Treatment of acute Kawasaki syndrome with a four-day course of intravenous gamma globulin, together with aspirin, has been demonstrated to be safe and effective in preventing coronary-artery lesions and reducing systemic inflammation. We hypothesized that therapy with a single, very high dose of gamma globulin would be at least as effective as the standard regimen. METHODS We conducted a multicenter, randomized, controlled trial involving 549 children with acute Kawasaki syndrome. The children were assigned to receive gamma globulin either as a single infusion of 2 g per kilogram of body weight over 10 hours or as daily infusions of 400 mg per kilogram for four consecutive days. Both treatment groups received aspirin (100 mg per kilogram per day through the 14th day of illness, then 3 to 5 mg per kilogram per day). RESULTS The relative prevalence of coronary abnormalities, adjusted for age and sex, among patients treated with the four-day regimen, as compared with those treated with the single-infusion regimen, was 1.94 (95 percent confidence limits, 1.01 and 3.71) two weeks after enrollment and 1.84 (95 percent confidence limits, 0.89 and 3.82) seven weeks after enrollment. Children treated with the single-infusion regimen had lower mean temperatures while hospitalized (day 2, P less than 0.001; day 3, P = 0.004), as well as a shorter mean duration of fever (P = 0.028). Furthermore, in the single-infusion group the laboratory indexes of acute inflammation moved more rapidly toward normal, including the adjusted serum albumin level (P = 0.004), alpha 1-antitrypsin level (P = 0.007), and C-reactive protein level (P = 0.017). Lower IgG levels on day 4 were associated with a higher prevalence of coronary lesions (P = 0.005) and with a greater degree of systemic inflammation. The two groups had a similar incidence of adverse effects (including new or worsening congestive heart failure in nine children), which occurred in 2.7 percent of the children overall. All the adverse effects were transient. CONCLUSIONS In children with acute Kawasaki disease, a single large dose of intravenous gamma globulin is more effective than the conventional regimen of four smaller daily doses and is equally safe.

Oral Viscous Budesonide Is Effective in Children With Eosinophilic Esophagitis in a Randomized, Placebo-Controlled Trial

BACKGROUND & AIMS Eosinophilic esophagitis (EoE) is caused by immunologic reactions to ingested/inhaled allergens. The diagnosis is considered if >or=15 eosinophils per high-powered field (eos/hpf) are detected in mucosal biopsies. Placebo-controlled studies have not been conducted to evaluate the safety and efficacy of oral viscous budesonide (OVB). METHODS Children with EoE were randomly assigned to groups that were given OVB (n=15) or placebo (n=9). Patients<5 feet and >or=5 feet tall received 1 mg and 2 mg OVB daily, respectively. All patients received lansoprazole. Duration of treatment was 3 months, followed by repeat endoscopy and biopsies. Patients were classified as responders if their peak eosinophil counts were <or=6 eos/hpf, partial responders were 7-19 eos/hpf, and nonresponders were >or=20 eos/hpf. Baseline and post-treatment symptoms and endoscopic and histologic features were scored. RESULTS Thirteen (86.7%) children given OVB (P<.0001) and none who received placebo (P=.3) were classified as responders. Mean pre-/post-treatment peak eosinophil counts were 66.7 and 4.8 eos/hpf, respectively, in the group given OVB (P<.0001); they were 83.9 and 65.6 eos/hpf, respectively, in the group given placebo (P=.3). In the group given OVB, there were significant reductions from baseline values in proximal (P=.002), mid (P=.0003), and distal (P=.001) esophageal eosinophilia. After OVB therapy, compared with baseline, the mean symptom (P=.0007), endoscopy (P=.0005), and histology scores improved (P=.0035) significantly. CONCLUSIONS OVB is an effective treatment of pan-esophageal disease in children with EoE. OVB improves symptoms and endoscopic and histologic features. Proton pump inhibitor single therapy did not significantly improve esophageal eosinophilia or symptoms of EoE.

Resolution of remodeling in eosinophilic esophagitis correlates with epithelial response to topical corticosteroids

Background:  Esophageal remodeling occurs in eosinophilic esophagitis (EE) patients but whether the components of remodeling in the subepithelium are reversible by administration of topical oral corticosteroids is unknown.

Oral Viscous Budesonide: A Potential New Therapy for Eosinophilic Esophagitis in Children

BACKGROUND:Eosinophilic esophagitis (EE) is a disorder characterized typically by pan-esophageal eosinophilia. We evaluate a palatable, long-acting topical corticosteroid preparation for the treatment of EE.STUDY DESIGN:This is a retrospective analysis of symptoms, endoscopic and histologic findings, efficacy, and safety of treatment in children with EE receiving oral viscous budesonide. Response to therapy was determined histologically by the number of eos/hpf. Patients were classified by histology into responders (0–7 eos/hpf), partial responders (8–23 eos/hpf), and nonresponders (≥24 eos/hpf). A symptom score (max. 14) and an EE endoscopy score (max. 8) were used to compare data.RESULTS:In 20 children (mean age 5.5 yr, median age 4.1 yr) the mean highest eosinophil count was 87 eos/hpf (range 30–170) before and 7 eos/hpf (range 0–50, P < 0.0001) after therapy. There were 16 (80%) responders, 1 partial responder, and 3 nonresponders. Commonest pretreatment symptoms were nausea, vomiting, pain, and heartburn. The mean symptom score fell from 4.4 to 0.8 (P < 0.0001) and the mean endoscopy score from 3.6 to 0.8 (P < 0.0001). No significant adverse events were reported. Morning cortisol levels were within normal limits.CONCLUSIONS:Topical viscous budesonide is a safe and effective therapy for EE in young children.

Mast cells infiltrate the esophageal smooth muscle in patients with eosinophilic esophagitis, express TGF-β1, and increase esophageal smooth muscle contraction

BACKGROUND Increased numbers of mast cells are present in the esophageal epithelium in patients with eosinophilic esophagitis (EE). However, mast cell infiltration into the esophageal lamina propria (LP) and smooth muscle (SM) and the effects of their products on SM function has not been determined. OBJECTIVE We investigated mast cell localization and characterization in esophageal SM, the functional significance of mast cell TGF-β1 expression to contraction of human esophageal smooth muscle (HESM) cells in vitro, and the effect of topical corticosteroids on the number of tryptase-positive (MC(T)) and chymase-positive (MC(C)) mast cells in patients with EE. METHODS MC(T)- and MC(C)-positive mast cell numbers were quantitated in the epithelium, the LP before and after topical corticosteroid therapy, and the muscularis mucosa in patients with EE and control subjects by using immunohistology. Double immunofluorescence was used to assess mast cell production of TGF-β1. The ability of TGF-β1 to influence HESM cell contractility was assessed in vitro. RESULTS In the SM in patients with EE, significantly increased numbers of MC(T)- and TGF-β1-positive cells (but only low levels of eosinophils) were detected compared with those seen in control subjects. MC(T) expressed TGF-β1, which increased the contractility of cultured primary HESM cells in vitro. Topical corticosteroid therapy in patients with EE significantly reduced epithelial MC(T) numbers but not LP tryptase-chymase-positive mast cell numbers. CONCLUSIONS MC(T) numbers, rather than eosinophil numbers, are increased in the SM in patients with EE, express TGF-β1, and increase the contractility of HESM cells in vitro. As such, mast cells localized to SM in patients with EE might modulate esophageal contractility.

Kawasaki Disease: A Brief History

Tomisaku Kawasaki published the first English-language report of 50 patients with Kawasaki disease (KD) in 1974. Since that time, KD has become the leading cause of acquired heart disease among children in North America and Japan. Although an infectious agent is suspected, the cause remains unknown. However, significant progress has been made toward understanding the natural history of the disease and therapeutic interventions have been developed that halt the immune-mediated destruction of the arterial wall. We present a brief history of KD, review progress in research on the disease, and suggest avenues for future study. Kawasaki saw his first case of KD in January 1961 and published his first report in Japanese in 1967. Whether cases existed in Japan before that time is currently under study. The most significant controversy in the 1960s in Japan was whether the rash and fever sign/symptom complex described by Kawasaki was connected to subsequent cardiac complications in a number of cases. Pathologist Noboru Tanaka and pediatrician Takajiro Yamamoto disputed the early assertion of Kawasaki that KD was a self-limited illness with no sequelae. This controversy was resolved in 1970 when the first Japanese nationwide survey of KD documented 10 autopsy cases of sudden cardiac death after KD. By the time of the first English-language publication by Kawasaki in 1974, the link between KD and coronary artery vasculitis was well-established. KD was independently recognized as a new and distinct condition in the early 1970s by pediatricians Marian Melish and Raquel Hicks at the University of Hawaii. In 1973, at the same Hawaiian hospital, pathologist Eunice Larson, in consultation with Benjamin Landing at Los Angeles Childrens Hospital, retrospectively diagnosed a 1971 autopsy case as KD. The similarity between KD and infantile periarteritis nodosa (IPN) was apparent to these pathologists, as it had been to Tanaka earlier. What remains unknown is the reason for the simultaneous recognition of this disease around the world in the 1960s and 1970s. There are several possible explanations. KD may have been a new disease that emerged in Japan and emanated to the Western World through Hawaii, where the disease is prevalent among Asian children. Alternatively, KD and IPN may be part of the spectrum of the same disease and clinically mild KD masqueraded as other diseases, such as scarlet fever in the preantibiotic era. Case reports of IPN from Western Europe extend back to at least the 19th century, but, thus far, cases of IPN have not been discovered in Japan before World War II. Perhaps the factors responsible for KD were introduced into Japan after the World War II and then reemerged in a more virulent form that subsequently spread through the industrialized Western world. It is also possible that improvements in health care and, in particular, the use of antibiotics to treat infections caused by organisms including toxin-producing bacteria reduced the burden of rash/fever illness and allowed KD to be recognized as a distinct clinical entity. Itsuzo Shigematsu, Hiroshi Yanagawa, and colleagues have conducted 14 nationwide surveys in Japan. These have indicated that: 1) KD occurred initially in nationwide epidemics but now occurs in regional outbreaks; 2) there are ∼5000 to 6000 new cases each year; 3) current estimates of incidence rates are 120 to 150 cases per 100 000 children <5 years old; 4) KD is 1.5 times more common in males and 85% of cases occur in children <5 years old; and 5) the recurrence rate is low (4%). In 1978, David Morens at the Centers for Disease Control and Prevention published a case definition based on Kawasakis original criteria. The Centers for Disease Control and Prevention developed a computerized database in 1984, and a passive reporting system currently exists in 22 states. Regional investigations and national surveys suggest an annual incidence of 4 to 15 cases per 100 000 children <5 years of age in the United States. The natural history of KD reveals that coronary artery aneurysms occur as a sequela of the vasculitis in 20% to 25% of untreated children. Echocardiography can be successfully used to detect coronary artery dilatation and aneurysms in virtually all patients. Patients with no acute phase coronary artery changes detected by echocardiogram are clinically asymptomatic at least 10 years later. The Japanese Ministry of Health has established a registry of 6500 children who will be followed longitundinally to determine the natural history of the illness. No similar registry of patients exists in the United States. Studies of KD pathogenesis show a progression of arterial lesions accompanying KD vasculitis and a number of immunoregulatory changes, including a deficiency of circulating CD8+ suppressor/cytotoxic T cells; an abundance of circulating B cells spontaneously producing immunoglobulins; and circulating, activated monocytes. Biochemical and immunologic evidence suggests endothelial cell activation and injury. Although the cause of KD remains unknown, clinical trials have established effective therapies, despite the absence of a proven cause. Intravenous immunoglobulin (IVIG) plus aspirin lowers the rate of coronary artery aneurysms from 20% to between 3% and 5%. In 1988, the Committee on Infectious Diseases of the American Academy of Pediatrics endorsed IVIG treatment as recommended therapy for KD. Questions remain regarding treatment of patients who fail to respond to an initial dose of IVIG. The role of steroids or other antiinflammatory agents in the treatment of KD is controversial. Areas for further research include: 1) a more sensitive case definition that includes laboratory and echocardiographic data, as well as clinical signs and symptoms; 2) development of a diagnostic test based on the biology of inflammation and acute endothelial cell damage that, in the absence of the causative agent, could be used to identify children with KD; 3) studies of index cases and their families to identify relevant genetic factors; and 4) long-term follow-up of patients into their third and fourth decades with monitoring for late cardiovascular sequelae.

Clinical and epidemiologic characteristics of patients referred for evaluation of possible Kawasaki disease

Study objectives (1) To determine those diseases that most often mimic Kawasaki disease (KD) in the United States. (2) To examine the physical findings and laboratory studies that influenced experienced clinicians to exclude the diagnosis of KD. (3) To compare epidemiologic features of patients with KD and patients referred for evaluation of possible KD in whom alternative diagnoses were established. Design: Case comparison study. Setting: Seven pediatric tertiary care centers. Patients: Consecutive sample of 280 patients with KD and 42 comparison patients examined within the first 14 days after onset of fever. Measurements and main results: (1) Infectious diseases, particularly measles and group A β-hemolytic streptococcal infection, most closely mimicked KD and accounted for 35 (83%) of 42 patients in the comparison group. (2) The standard diagnostic clinical criteria for KD were fulfilled in 18 (46%) of 39 patients in whom other diagnoses were established. (3) Patients with KD were significantly less likely to have exudative conjunctivitis or pharyngitis, generalized adenopathy, and discrete intraoral lesions, and more likely to have a perineal distribution of their rash. The patients with KD were also more likely to have anemia and elevated erythrocyte sedimentation rate; leukocyte count 3 /mm 3 and platelet count 3 /mm 3 were significantly less prevalent in patients with KD. (4) Residence within 200 yards of a body of water was more common among KD patients. Conclusions: (1) Measles and streptococcal infection should be excluded in patients examined for possible KD. (2) Laboratory studies that may be useful in discriminating patients with KD from those with alternative diagnoses include hemoglobin concentration, erthyrocyte sedimentation rate, and serum alanine aminotransferase activity. (3) Residence near a body of water may be a risk factor for the development of KD.

Distinguishing eosinophilic esophagitis in pediatric patients: clinical, endoscopic, and histologic features of an emerging disorder.

Goals To determine the clinical, endoscopic, and histologic criteria that distinguish children with eosinophilic esophagitis (EE) from those with non-EE diagnoses. Background EE is a disease of escalating incidence. Distinguishing children with EE from those with non-EE diagnosis can be difficult before endoscopy. Study A retrospective case-control study was performed for children with any degree of esophageal eosinophilic inflammation who underwent esophageal biopsy at Childrens Hospital San Diego from January 1998 to December 2002. A database containing children who met histologic criteria for EE and an equivalent number of children who had milder esophageal eosinophilia (non-EE patients) was created to compare the 2 groups. Results The number of EE cases increased from 15 in 1998 to 35 in 2002. EE patients were predominantly school-aged boys; 5 of 102 were suspected to have EE before biopsy. Although EE and non-EE patients complained of vomiting and abdominal pain at equivalent rates, EE patients were 3 times more likely to complain of dysphagia [odds ratio (OR)=3.11, 95% confidence interval (CI) 1.55-6.65] and twice as likely to have stricture formation (OR=2.43, 95% CI 0.72-11.75). On endoscopy, patients with EE were 19-times more likely than non-EE patients to have endoscopic abnormalities (OR=19, 95% CI 9.0-45.88). Histologically, EE patients were more likely to have basal zone hyperplasia and degranulated eosinophils (OR=45 and 157, respectively). Conclusions We demonstrate that school-aged children, particularly boys, who complain of dysphagia should raise the index of suspicion for EE. We also suggest that EE-associated strictures are more common than peptic strictures in children.

Prediction of persistent immunodeficiency in the DiGeorge anomaly

To assess the natural history of the immune defect in DiGeorge anomaly, we reviewed serial immunologic studies in 18 patients. The diagnosis was made with criteria based on the concept of the DiGeorge anomaly as a field defect. Initial or early follow-up laboratory examination suggested moderate to normal T cell function in 14 patients. None of these patients have lost T cell capability; they have never had infections characteristic of T cell deficiency. Four patients had clinical and laboratory evidence of profound immunodeficiency. A decreased number of CD4+ cells (less than 400/microliters) and a decrease in phytohemagglutinin responsiveness (stimulation index less than 10) may be useful in discriminating patients with immunodeficiency; absolute lymphocyte count and immunoglobulin values were not informative. At the time of surgery, the thymus was not found in 11 of 14 patients; however, only two of these patients had immunodeficiency. Patients with a persistently low number of CD4+ cells and decreased phytohemagglutinin response are candidates for immunologic reconstitution.

A symptom scoring tool for identifying pediatric patients with eosinophilic esophagitis and correlating symptoms with inflammation.

BACKGROUND Eosinophilic esophagitis (EE) is an increasingly recognized allergic disease entity that is difficult to distinguish clinically from other causes of esophagitis, especially gastroesophageal reflux disease (GERD). To our knowledge, there are no prospectively analyzed or validated symptom scoring tools for pediatric patients with EE and no prospective evaluation correlating symptoms with tissue inflammation. OBJECTIVES To prospectively analyze a symptom scoring tools ability to distinguish pediatric patients with EE from those with GERD and from control patients with and without allergies and to correlate symptoms with tissue inflammation. METHODS A prospective study of a symptom scoring tool given to patients with EE (n = 35 not receiving EE targeted therapy), patients with GERD (n = 27 not undergoing acid suppression), allergic control patients (n = 24), and nonallergic control patients (n = 14) at an academic pediatric hospital. Histology and endoscopy scores were correlated with symptom complaints. RESULTS The total symptom score was higher among patients with EE (mean, 6.51; 95% confidence interval [CI], 5.50-7.53) and GERD (mean, 5.44; 95% CI, 4.64-6.25) than in allergic (mean, 0.92; 95% CI, 0.28-1.55) and nonallergic (mean, 1.00; 95% CI, 0.40-1.60) patients (P < .001). Patients with EE and GERD complained of more nausea/vomiting, abdominal pain, heartburn/regurgitation, and nocturnal awakening than control groups (P < .001). Only dysphagia (mean, 0.9 [95% CI, 0.7-1.2] in EE patients vs 0.4 [95% CI, 0.2-0.7] in GERD patients) and anorexia/early satiety (mean, 1.4 [95% CI, 1.2-1.6] in EE patients vs 0.8 [95% CI, 0.5-1.1] in GERD patients) discriminate EE from GERD (P < .01). These symptoms also correlated with the severity of histologic and endoscopic findings (P < .05). CONCLUSION Dysphagia and anorexia/early satiety identify pediatric patients with EE and correlate symptoms with tissue inflammation.