Anaphylaxis in Israel: experience with 92 hospitalized children.

Little is known about the courses, causes, and clinical features of anaphylaxis in children outside the USA and Europe. Our objective was to evaluate the events of anaphylaxis in children admitted to the Schneider Children's Medical Center of Israel, a major tertiary facility, over a 12-year period. Ninety-two children with anaphylaxis (50 boys, 42 girls) aged 14 days to 18 yr (mean, 7.4 yr) were hospitalized during the study period. The event occurred at home in 52 children (56%), in a medical institution in 24 (26%), outdoors in 13 (15%), at school in 2 (2%), and in an unspecified location in 1 (1%). The main causes were foods (43%), mainly milk and nuts, medications (22%), and hymenoptera venom (11%); in five children, anaphylaxis occurred during general anesthesia, and in 5, the causative agent could not be determined. Food-induced anaphylaxis tended to occur in younger children. Forty-eight children (52%) had a history of atopy (mainly asthma). Hospital treatment consisted of corticosteroids (85%), antihistamines (75%), epinephrine (72%), and ß2 agonists (42%). Seven patients were admitted to intensive care units. There were no fatalities. EpiPen was used by only one of the 16 patients with more than one episode of anaphylaxis, indicating that patient and parent education in the application of the EpiPen needs to be improved.

Proinflammatory cytokines in a mouse model of central retinal artery occlusion.

PURPOSE: To analyze cytokines in the retina and serum in an experimental model of central retinal artery occlusion (CRAO) in mice. METHODS: CRAO was induced by laser activation of intravenously injected rose bengal, a photosensitive dye, in 60 C57Bl/6 mice. mRNA and protein levels of macrophage inhibitory protein-2 (MIP-2), interleukin-6 (IL-6), and tumor necrosis factor- alpha (TNF-alpha) were analyzed using real-time polymerase chain reaction, and western blot, respectively. Cytokine levels in serum were measured by ELISA. Analysis was performed at various time intervals from CRAO induction. RESULTS: In the retina, MIP-2 and IL-6 mRNA expression decreased 3 h after induction of CRAO and increased thereafter, peaking at 12-24 h. By 7 days, levels were again mostly undetectable. TNF-alpha mRNA expression increased at 3 h and decreased to control levels at 7 days. At the protein level, all cytokines were present at 3 h, following similar patterns to their respective gene expression thereafter. In serum, MIP-2 and TNF-alpha levels peaked early, and decreased to control levels at 12 h, with a second late rise of TNF-alpha. IL-6 levels increased between 3 and 12 h and decreased at 24 h. CONCLUSIONS: Temporal variations in cytokines were observed following the induction of CRAO, both at the retinal mRNA expression and protein levels. These temporal changes, and the variable effects of the cytokines at the different time intervals, should be taken into account during the formulation of therapeutic strategies.

C-reactive protein levels do not correlate with retinal artery occlusion but with atherosclerosis.

PURPOSE: To determine C-reactive protein (CRP) levels in acute retinal artery occlusion (RAO) and their association with atherosclerotic risk factors. METHODS: CRP levels in 16 patients with RAO were compared with levels in 16 age-matched controls at risk of atherosclerosis and 16 young volunteers. Repeated CRP testing was performed 6 years later. RESULTS: Elevated CRP levels (>3 mg/l) and risk factors for atherosclerosis were detected in seven patients in the study group (44%) and nine at-risk controls (56%). On follow-up, CRP levels were reduced in all seven retested patients. Six patients died of vascular events within 5 years, of whom four had high CRP levels during RAO. CONCLUSIONS: CRP level correlates with atherosclerosis but it is not significantly elevated in patients with RAO.

Serum cytokine levels in active uveitis and remission.

Serum levels of interleukin(IL)-8, IL-6, and (TNF)-alpha were measured in 25 patients during active uveitis and uveitis in remission and compared to age-matched controls. Levels of IL-8 and IL-6 were significantly elevated in patients with active disease and were decreased during remission. IL-8 levels were highest in patients with anterior uveitis, with greatest difference between active disease and remission. No consistent pattern was observed for TNF-alpha. In conclusion, serum cytokine levels are elevated in active noninfectious uveitis. The rise in IL-8 may suggest innate immune mechanisms in the acute disease, while IL-6 participates in modulation of inflammation in the chronic disease.

Anti-Saccharomyces cerevisiae antibodies in Behçet's disease--a familial study.

OBJECTIVE: To evaluate the rate and clinical correlations of antibodies against saccharomyces cerevisiae (ASCA) among healthy family members of patients with Behçet's disease (BD). METHODS: Twenty-one BD patients and 52 healthy family members (HFM) were studied. Data from medical files and from patients' interviews was collected, regarding the entire spectrum of disease manifestations. Each family member was personally interviewed and a questionnaire composed of BD symptoms and their temporal relation was compiled. IgA- and IgG-ASCA levels, determined by ELISA, were studied in all BD patients and their family members, the results were compared to a group of 23 healthy controls (HC). RESULTS: Eight (38.1%) BD patients were ASCA positive, compared to five among HFM (9.6%) and none among healthy unrelated controls (p=0.001). Mean IgG and IgA-ASCA levels were significantly higher in BD patients compared with HFM and HC groups (p = 0.002 and p = 0.03, respectively). No correlation was found between positive ASCA tests and any of BD-related manifestations. Mean IgG-ASCA levels were significantly lower in HFM compared to BD patients (p = 0.03), yet IgA-ASCA levels were similar in HFM and BD. Mean IgG and IgA-ASCA levels were higher in HFM compared with healthy unrelated controls (p=0.09 and p=0.03). No difference was found in ASCA rates between relatives of BD patients who had positive or negative ASCA tests, or between spouses of BD patients and genetically related relatives. In HFM with recurrent oral ulcers there was a positive correlation between titers of IgA-ASCA and the yearly number of oral ulcers episodes (p = 0.01), and mean ulcers healing time (p = 0.01). IgG-ASCA titers correlated with yearly number of aphtae episodes (p = 0.03). CONCLUSION: The results of this study confirm our previous observation on a high prevalence of ASCA in BD. ASCA levels are also increased in healthy family members of BD patients, and are probably influenced by genetic as well as environmental factors. ASCA in HFM were significantly associated with a more severe oral ulcer disease. The role of ASCA as a marker for predisposition to develop future BD remains to be evaluated.

Changes in autoimmune markers of the anti-cardiolipin syndrome on days of extreme geomamagnetic activity.

UNLABELLED: The possible relation between various biological or medical phenomena and changes in environmental physical activity, such as Solar, Geomagnetic Activity (GMA); Cosmic Ray; Proton, and other particle flux, have been reported. These phenomena seem to be reflected, among others, in the immune system, resulting in changes in immunoglobulin (Ig) levels or outbursts of epidemics. AIM: to examine a possible association of GMA with another aspect of the immune system--autoimmunity. Fluctuations of levels of anticardiolipin (IgG; IgM, IgA subtypes) and lupus anticoagulant (Kaulin clotting time and Dilute Russell's viper venom time) autoantibodies, serving as anticardiolipin syndrome (ACLS) markers, were monitored during days of severe GMA storms and compared with those of lowest/quiet GMA days. Cosmophysical data were obtained from the NOAA National Space Service Center and the National Geophysical Data Center, USA. RESULTS: A significant rise in the levels of anti beta2Gp1-IgA (p = 0.0001); and KCT (p = 0.019) was observed on days of the GMA storms. CONCLUSION: On days of major GMA storms, significant changes in the autoimmune marker levels of ACLS were observed compared with quiet days. An involvement of those changes in clinical events related to GMA storms is possible.

Elevated plasma levels of interleukin 8 in patients with acute anterior ischaemic optic neuropathy.

BACKGROUND/AIM: Alterations of the immune system may have a role in thrombogenesis. Artery sites occluded with thrombi apparently release pro-inflammatory cytokines. Non-arteritic anterior ischaemic optic neuropathy (NAION) results from occlusion of the blood supply to the optic nerve. The aim of this study was to analyse levels of pro-inflammatory cytokines in patients with acute event of NAION. METHODS: Study participants included 10 patients (12 eyes) with NAION and 20 age matched controls with the same risk factors for atherosclerosis disease. Peripheral blood samples were obtained immediately at the acute onset of NAION. Plasma interleukin 8 (IL-8), IL-6, and tumour necrosis factor alpha (TNF-alpha) levels were measured immediately following diagnosis and during the follow up intervals. RESULTS: The plasma levels of IL-8 were significantly higher in NAION patients at the time of diagnosis in comparison to the control group (p = 0.002), and decreased during the follow up period (6-12 months) (p = 0.05). There were no differences in plasma levels of IL-6 and TNF-alpha between NAION patients and controls, either in the acute phase or during the follow up period. CONCLUSION: Plasma levels of IL-8 are elevated during the acute phase of NAION, but not IL-6 and TNF-alpha. These elevated levels are in accordance with other acute vascular thrombosis. The clinical significance of these findings should be further evaluated.

Primary anetoderma: a cutaneous sign of antiphospholipid antibodies.

Although a few reports in recent years have suggested that patients with antiphospholipid antibodies (aPL) are prone to developing primary anetoderma (PA), it is still unclear how often aPL are detected in unselected PA patients. We studied nine consecutive PA patients for the presence of autoimmune antibodies and disorders in general and the presence of aPL in particular. Six of the nine patients had clinical evidence of associated autoimmune disorders (Graves'disease and autoimmune haemolysis in one, systemic scleroderma in one, Hashimoto's thyroiditis in one, alopecia areata in one) and/or signs of hypercoagulability (recurrent fetal loss in two, recurrent stokes in one, recurrent deep vein thrombosis in one). In four ofthese six patients the onset of PA preceded these signs. Positive aPL was found in all: anticardiolipin (aCL) in six, anti-beta2-glycoprotein-I (a(beta)2GPI) in six and lupus anticoagulant (LAC) in four. The most frequent isotype was IgA. Among other autoantibodies found the most frequently was antinuclear antibodies. Four ofthe nine patients fulfilled the criteria for antiphospholipid syndrome (APS). It is concluded that PA is an important cutaneous sign for autoimmune disorders in general and the presence of aPL in particular. Hence, the work-up of these patients should include testing for LAC as well as for all different isotypes ofaCL and a(beta)2GPI. We recommend that PA be added to the list of the cutaneous manifestations of APS.

Anti-Saccharomyces cerevisiae antibodies--a novel serologic marker for Behçet's disease.

OBJECTIVE: To evaluate the prevalence and clinical correlations of antibodies against Saccharomyces cerevisiae (ASCA) among patients with BD. METHODS: Twenty-seven BD patients were studied. Data from medical files and from patients' interviews was collected, regarding the entire spectrum of disease manifestations, and a severity score was calculated for each patient. IgA- and IgG-ASCA levels, determined by ELISA, were studied in all BD patients and in three control groups: patients with recurrent aphthous stomatitis (RAS), systemic lupus erythematosus (SLE) and healthy volunteers. RESULTS: Thirteen BD patients (48.1%) were ASCA-positive, compared to one patient in each control group (10%, p = 0.01). The mean value of IgG-ASCA in the BD patients was 20.7 +/- 12.3 units, significantly higher than in patients with RAS (10.0 +/- 5.5, p < 0.001), SLE (11.8 +/- 9.3, p < 0.03) or healthy volunteers (10.8 +/- 9.8, p < 0.02). Mean IgA-ASCA level was 16.8 +/- 8.8 units in the BD patients, significantly higher compared to healthy volunteers (11.0 +/- 5.0, p = 0.02) but similar to patients with RAS (17.0 +/- 5.3). No correlation was found between ASCA and any BD-associated clinical manifestation nor the presence of HLA-B5. No difference was found in the rate of major oral ulcers nor in the systemic disease severity score between positive- and negative-ASCA patients (27.3% vs. 30.8%, and 7.31 +/- 1.80 vs. 7.28 +/- 2.27 respectively, NS). CONCLUSION: The results of our study associate, for the first time, the presence of a distinct antibody, i.e. ASCA, with BD. ASCA were not linked to a specific clinical manifestation of the disease and probably do not pose an increased risk for a more severe disease course.

Urinary soluble VCAM-1 in systemic lupus erythematosus: a clinical marker for monitoring disease activity and damage.

OBJECTIVE: To determine the urinary levels of soluble vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) in patients with systemic lupus erythematosus (SLE) and to assess their relationship with clinical and laboratory features and the degree of activity and damage associated with the disease. METHODS: The study sample included 24 consecutive patients with SLE. 24-hour urine samples were collected for the determination of soluble VCAM-1 and ICAM-1 levels by ELISA. Disease activity was defined by the SLE Disease Active Index (SLEDAI) and disease outcome by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ ACR) damage index. RESULTS: The urinary soluble VCAM-1 level was significantly higher in patients with SLE compared to normal controls (32.35+/-34.27 vs. 4.66+/-3.8 ng/mg creatinine, p = 0.0005) and statistically significantly correlated with disease activity (SLEDAI), a low serum C3 level, decreased creatinine clearance and albuminuria, as well as with disease damage (SLICC/ACR damage index). In contrast, the urinary soluble ICAM-1 level was not significantly higher in the patients' group compared with the controls (4.5+/-5.19 vs. 2.72+/-2.31 ng/mg creatinine, p=0.2), but was statistically significantly correlated with hematuria and albuminuria. CONCLUSION: Our data suggest that the urinary level of soluble VCAM-1 significantly correlates with overall disease activity and damage scores, but not with nephritis in SLE.

The hypereosinophilic syndrome associated with CD4+CD3- helper type 2 (Th2) lymphocytes.

We describe herein the clinical and laboratory manifestations of a unique group of patients (pts) presenting with hypereosinophilic syndrome (HES) who were treated in our medical centers for 4-13 years. Skin biopsies, flow cytometry of peripheral blood mononuclear cells (PBMC), assays for cytokines and immunoglobulin (Ig) production in vitro, and Southern blots of T-cell receptor (TCR) genes were performed. All four pts had a persistent hypereosinophilia (> 1.9 x 10(9)/L) and chronic skin rash. Three of four had elevated IgE, thrombotic manifestations and lung involvement (asthma and/or infiltrates), and one had deforming sero-negative arthritis of the hands. 66-95% of their peripheral T-cells expressed CD4 but not CD3 or TCR molecules on the cell surface membrane. Activated CD4+CD3- cells secreted interleukin (IL)-4 and/or 5, and were required for maximal IgE secretion by autologous B-cells. Two pts had evidence of rearrangement of TCR genes of the CD4+CD3- cells, one of whom died of anaplastic lymphoma. In conclusion, HES with CD4+CD3- lymphocytosis may be associated with high serum IgE, dermatological, pulmonary, thrombotic and rheumatic manifestations which may be due to Th2 effects of CD4+CD3- cells migrating to end organs. Fatal systemic lymphoid malignancy may also develop in some pts with monoclonal expansion of the CD4+CD3- T-cells.

Soluble CD14 in children with status asthmaticus.

BACKGROUND: Inflammation is a major component in the pathogenesis of asthma. CD14 is an endotoxin (lipopolysaccharide) receptor, and is expressed mainly on monocytes and macrophages. Binding of LPS to CD14 activates the monocyte or macrophage and causes the release of different cytokines. The soluble form of CD14 is present in serum, and its concentration increases in several clinical conditions, including infections, autoimmune disorders, allergic disorders, and lung diseases. The possible role of CD14/sCD14 in asthma has been investigated in a few adult patients only. OBJECTIVES: To measure serum concentrations of sCD14 in children with status asthmaticus. METHODS: We compared serum concentration of sCD14 in 10 children with status asthmaticus measured within 24 hours of admission and after recovery from the acute episode. RESULTS: Levels of sCD14 were significantly higher during acute asthma attacks than at recovery. CONCLUSIONS: The elevated serum levels of sCD14 during status asthmaticus may be the result of the activation of monocytes, macrophages or other cells. The influence of medications on serum sCD14 cannot be ruled out. The possible use of sCD14 as a marker of lung inflammation in asthma warrants further investigation.

Syncytial giant-cell hepatitis due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant hepatitis.

Giant cell hepatitis (GCH) in adults is a rare event. The diagnosis of GCH is based on findings of syncytial giant hepatocytes. It is commonly associated with either viral infection or autoimmune hepatitis type I. A patient with GCH due to autoimmune hepatitis type II (LKM1+) is described, a combination that has not been previously reported. Corticosteroid therapy was effective in decreasing serum liver enzymes; however, the patient deteriorated rapidly and developed subfulminant hepatic failure. Although an emergency orthotopic liver transplantation was performed, the patient died because of reperfusion injury. Interestingly, only a few giant hepatocytes were noted in the explanted liver. This case stresses the association of GCH with autoimmune disorders, the possible immune mechanism involved in the formation of giant cell hepatocytes, and illustrates the rapidly progressive course and unfavorable prognosis that these patients can develop.

Role of gamma/delta T cells in a patient with CD4+CD3- lymphocytosis, hypereosinophilia, and high levels of IgE.

BACKGROUND: CD4+CD3- T cells have previously been shown to play a pathogenic role in the hypereosinophilic syndrome by secreting IL-5 and IL-4. OBJECTIVES: The goal of this study was to study the role of CD4+CD3- and other T-cell subsets in a patient with eosinophilia, dermatitis, and a high level of IgE (100,000 IU/mL) in the serum. METHODS: We isolated PBMCs and performed flow cytometry, cell cultures, and in vitro assays of Ig, lymphokine production, and cell-mediated cytotoxicity. RESULTS: Flow cytometric and immunohistochemical analysis of the PBMCs revealed a major population (consisting of approximately 85% of the CD4+ T cells) that lacked expression of CD3 and T-cell receptors on the cell surface (CD4+CD3- T cells), but did express CD3 peptides in the cytoplasm. Activation of the PBMCs in vitro resulted in a 100-fold greater than normal release of IL-4, whereas IFN-gamma production was less than normal, suggesting a predominantly type 2 helper functional phenotype of the CD4+CD3- T cells. Importantly, both CD4-CD8(low) Vdelta1+ T-cell receptor gammadelta+ and CD4+CD3- T cells were cultured from the PBMCs. The former secreted IFN-gamma exclusively, whereas the latter secreted both IL-4 and IFN-gamma. Furthermore, only the T-cell receptor gammadelta+ lymphocytes were cytotoxic to autologous B-lymphoblastoid cells and specifically inhibited IgE production in cultures of autologous polyclonally stimulated PBMCs. CONCLUSIONS: The results suggest that CD8(low) Vdelta1+ T-cell receptor gammadelta+ clones functionally counteract IgE-inducing effects of type 2 CD4+CD3- helper cells in this patient with hypereosinophilic syndrome.