Hodgkin's and non-Hodgkin's lymphomas occurring in two brothers with Wiskott-Aldrich syndrome and review of the literature.

Approximately 13% of patients with Wiskott-Aldrich syndrome (WAS), a primary immune deficiency, develop malignant tumors, the predominant form being non-Hodgkin's lymphoma. Previously, only 4 cases of Hodgkin's lymphoma have been reported in WAS patients. Herein, we review the literature of WAS-related lymphomas and report 2 brothers with WAS who both developed lymphomas; one developed Epstein-Barr virus (EBV)-driven diffuse large B-cell lymphoma, and one developed EBV-negative classical Hodgkin's lymphoma. In contrast to many of the previously reported lymphomas in WAS patients, these lymphomas were extensively evaluated by means of molecular, flow cytometric, and immunohistochemical methods. Both brothers died shortly after diagnosis, despite aggressive therapy. The occurrence of 2 distinct forms of lymphomas in these brothers underscores the interplay between genetic susceptibility and environmental exposure in lymphoma pathogenesis.

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=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.

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 Children's 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.

Esophageal remodeling in pediatric eosinophilic esophagitis.

BACKGROUND: Eosinophils are associated with airway remodeling in asthma, but studies have not yet determined whether eosinophilic esophagitis (EE) is associated with esophageal remodeling. OBJECTIVE: We performed quantitative immunohistochemical analysis of remodeling changes in esophageal biopsy specimens from children with and without EE to evaluate if there were changes in the esophagus of pediatric patients with EE akin to airway remodeling. In addition, we determined whether the esophagus of patients with EE had increased levels of expression of TGF-beta(1) and its signaling molecule, phosphorylated SMAD2/3 (phospho-SMAD2/3). METHODS: To determine esophageal levels of eosinophilic inflammation, fibrosis, and vascular activation, endoscopically obtained esophageal biopsy specimens from 7 patients with EE (5 strictured, 2 nonstrictured), 7 with gastroesophageal reflux disease, and 7 normal patients were processed for immunohistology, trichrome staining, and assessment of levels of expression of TGF-beta(1), phospho-SMAD2/3, and vascular cell adhesion molecule 1. RESULTS: Esophageal biopsies in patients with EE demonstrated increased levels of subepithelial fibrosis and increased expression of TGF-beta(1) and its signaling molecule phospho-SMAD2/3 compared with gastroesophageal reflux disease and normal control patients. In addition, esophageal biopsies in patients with EE demonstrated an increased vascular density and an increased expression of the vascular endothelial adhesion molecule, vascular cell adhesion molecule 1. CONCLUSION: Previously unrecognized esophageal remodeling changes analogous to aspects of airway remodeling are detectable in the subepithelial region of the esophagus in pediatric patients with EE. CLINICAL IMPLICATIONS: Pediatric patients with EE demonstrate increased fibrosis, vascularity, and vascular activation in the esophagus that may contribute to stricture formation and potentially provide a basis for stratifying patients with EE on the basis of disease severity and/or prognosis.

Immunodeficiency in childhood.

Primary immunodeficiency disorders (PIDs) continue to illuminate mechanisms of human immunity and hypersensitivity. New discoveries in common variable immunodeficiency, the most enigmatic of PID syndromes, reveal molecular pathways of importance in human antibody production. FOXP3 mutations demonstrate the essential role that T-regulatory cells play in controlling autoantibody formation and disease. Interleukin-1 receptor-associated kinase 4 deficiency emphasizes the key role that innate immunity plays in the defense of bacterial disease occurring early in life. With respect to therapy, subcutaneous immunoglobulin treatment may indeed be a better treatment than intravenous immunoglobulin for many patients with antibody deficiency. Finally, PIDs remain in the vanguard for the treatment of inherited disorders by gene therapy. Gene therapy has cured patients with chronic granulomatous disease and severe combined immunodeficiency, but not without morbidity and mortality. Into the 21st century, PIDs continue to instruct us in human health and disease.

Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID).

Adenosine deaminase (ADA)-deficient Severe Combined Immunodeficiency (ADA-deficient SCID) is characterized by impaired lymphocyte development and function resulting from the adenosine metabolism defect. Enzyme replacement therapy with polyethylene glycol-conjugated adenosine deaminase (PEG-ADA) minimizes infectious complications of ADA-deficient patients who have not received bone marrow transplantation. In PEG-ADA therapy, enzymatically active ADA continuously circulates to act as a metabolic sink, detoxifying the adenosine and deoxyadenosine metabolites that accumulate to high levels in the absence of ADA. Studies have shown that upon the initiation of PEG-ADA therapy, the absolute numbers of circulating T and B lymphocytes and NK cells increase and protective immune function develops. However, the long-term efficacy is unknown. This retrospective study was designed to assess the long-term effectiveness of PEG-ADA treatment, based on evaluation of the immune function of nine ADA-deficient SCID patients (age 5-15) treated over the past decade. The results showed that the lymphocyte counts of all of the PEG-ADA treated patients were below the normal range at all times, despite initial improvements. A gradual decline of mitogenic proliferative responses occurred after a few years of treatment and normal antigenic response occurred less than expected. To this date, these low numbers and functions of lymphocytes had been adequate to provide protective immunity. These patients should be followed closely to detect a premature decline in immune function with aging in future decades of PEG-ADA therapy.

Staphylococcus aureus golden pigment impairs neutrophil killing and promotes virulence through its antioxidant activity.

Golden color imparted by carotenoid pigments is the eponymous feature of the human pathogen Staphylococcus aureus. Here we demonstrate a role of this hallmark phenotype in virulence. Compared with the wild-type (WT) bacterium, a S. aureus mutant with disrupted carotenoid biosynthesis is more susceptible to oxidant killing, has impaired neutrophil survival, and is less pathogenic in a mouse subcutaneous abscess model. The survival advantage of WT S. aureus over the carotenoid-deficient mutant is lost upon inhibition of neutrophil oxidative burst or in human or murine nicotinamide adenine dinucleotide phosphate oxidase-deficient hosts. Conversely, heterologous expression of the S. aureus carotenoid in the nonpigmented Streptococcus pyogenes confers enhanced oxidant and neutrophil resistance and increased animal virulence. Blocking S. aureus carotenogenesis increases oxidant sensitivity and decreases whole-blood survival, suggesting a novel target for antibiotic therapy.

Infliximab treatment for refractory Kawasaki syndrome.

OBJECTIVE: To evaluate the use of tumor necrosis factor (TNF)-alpha blockade for treatment of patients with Kawasaki syndrome (KS) who fail to become afebrile or who experience persistent arthritis after treatment with intravenous gamma globulin (IVIG) and high-dose aspirin. STUDY DESIGN: Cases were retrospectively collected from clinicians throughout the United States who had used infliximab, a chimeric murine/human immunoglobulin (Ig)G1 monoclonal antibody that binds specifically to human TNF-alpha-1, for patients with KS who had either persistent arthritis or persistent or recrudescent fever > or =48 hours following infusion of 2 g/kg of IVIG. RESULTS: Response to therapy with cessation of fever occurred in 13 of 16 patients. C-reactive protein (CRP) level was elevated in all but one patient before infliximab infusion, and the level was lower following infusion in all 10 patients in whom it was re-measured within 48 hours of treatment. There were no infusion reactions to infliximab and no complications attributed to infliximab administration in any of the patients. CONCLUSION: The success of TNF-alpha blockade in this small series of patients suggests a central role of TNF-alpha in KS pathogenesis. Controlled, randomized clinical trials are warranted to determine the role of anti-TNF-alpha therapy in KS.

Chronic granulomatous disease caused by a deficiency in p47(phox) mimicking Crohn's disease.

We describe 2 cases of autosomal recessive chronic granulomatous disease (CGD) in 2 sisters presenting with a picture consistent with inflammatory bowel disease. The index case is a 10-year-old girl with a history of refractory Crohn's colitis treated with aggressive immunosuppressive therapy whose course subsequently was complicated by central nervous system aspergillosis. Additional evaluation showed a diagnosis of CGD, an underlying immunodeficiency in which phagocytes fail to produce microbicidal reactive oxygen intermediates because of inherited defects in the reduced form of nicotinamide-adenine phosphate dinucleotide (NADPH) oxidase. The diagnosis of a typically X-linked inherited disease in our female patient suggested that she had 1 of the 3 less common autosomal recessive forms of the disease. This was confirmed by studies showing the absence of the p47(phox) subunit of NADPH oxidase in her neutrophils and the presence of a homozygous dinucleotide deletion in the neutrophil cytosolic factor 1 gene that encodes p47(phox). Additional analyses of members of the patient's immediate family showed the same homozygous mutation in 2 siblings, 1 of whom also developed chronic colitis consistent with a diagnosis of Crohn's disease. These 2 cases emphasize the importance of high clinical suspicion for an alternative diagnosis of immune deficiency in the setting of presumed inflammatory bowel disease and opportunistic infection.