Ben-Zion Garty

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo.

Invasive pediatric Kingella kingae infections: a nationwide collaborative study.

Background: Kingella kingae is a gram-negative coccobacillus, increasingly recognized as an invasive pediatric pathogen. To date, only few small series of invasive K. kingae infections have been published, mostly from single medical centers. A nationwide multicenter study was performed to investigate the epidemiologic, clinical, and laboratory features of children with culture-proven K. kingae infections. Methods: Clinical microbiology laboratories serving all 22 medical centers in Israel were contacted in a search for children aged 0 to 18 years from whom K. kingae was isolated from a normally sterile site, dating from as far back as possible until December 31, 2007. Medical records of identified patients were reviewed using uniform case definitions. Results: A total of 322 episodes of infection were identified in 321 children, of which 96% occurred before the age of 36 months. The annual incidence in children aged <4 years was 9.4 per 100,000. Infections showed a seasonal nadir between February and April. Skeletal system infections occurred in 169 (52.6%) children and included septic arthritis, osteomyelitis, and tenosynovitis. Occult bacteremia occurred in 140 children (43.6%), endocarditis in 8 (2.5%), and pneumonia in 4 (1.2%). With the exception of endocarditis cases, patients usually appeared only mildly ill. About one-quarter of children had a body temperature <38°C, 57.1% had a blood white blood cell count <15,000/mm3, 22.0% had normal C-reactive protein values, and 31.8% had nonelevated erythrocyte sedimentation rate. Conclusions: K. kingae infections usually occur in otherwise healthy children aged 6 to 36 months, mainly causing skeletal system infections and bacteremia, and occasionally endocarditis and pneumonia. Clinical presentation is usually mild, except for endocarditis, necessitating a high index of suspicion.

Invasive Kingella kingae Infections in Children: Clinical and Laboratory Characteristics

OBJECTIVE. Kingella kingae, a Gram-negative coccobacillus, is being increasingly recognized as an invasive pathogen in children, causing mainly bacteremia and arthritis; however, there have been only a few studies on K kingae infections to date, mostly small-scale series. The aim of this study was to report our experience with invasive K kingae infections in children who were hospitalized at a major tertiary medical center in Israel. METHODS. The medical charts of 62 children with proven invasive K kingae infections were reviewed: 42 with positive blood culture results and 20 with positive synovial fluid culture results. RESULTS. Most infections occurred among previously healthy children aged 5 to 22 months. Eighty percent had a mild concurrent illness of the respiratory or gastrointestinal tract. A chronic underlying disease was documented in 19% of the 1- to 15-year-old children with bacteremia. Three patients had persistent bacteremia, identified by 2 positive blood cultures drawn 1 to 4 days apart. Four (10%) patients from the bacteremia group had endocarditis, and 2 required emergency cardiac surgery. Only a mild-to-moderate elevation of serum inflammatory markers was noted except for patients with endocarditis or a prolonged course of arthritis. Patients with bacteremia received a diagnosis significantly later than those with arthritis, with no other between-group differences in age, month of disease onset, and inflammatory marker levels. All K kingae isolates were resistant to vancomycin and clindamycin. CONCLUSIONS. Our large series indicates that invasive K kingae infections occur in previously healthy children, mostly during the first 2 years of life; affected older children usually have an underlying medical condition. The infection generally elicits only a mild inflammatory response unless accompanied by endocarditis. Despite its low virulence, K kingae might cause a life-threatening heart disease that requires emergent, aggressive treatment.

A Fast Procedure for the Detection of Defects in Toll-like Receptor Signaling

OBJECTIVES. Inborn defects in Toll-like receptor signaling are recently described primary immunodeficiencies that predispose affected children to life-threatening infections. Patients with interleukin-1 receptor-associated kinase-4 deficiency are prone to invasive pneumococcal disease, and patients with UNC-93B deficiency are prone to herpes simplex virus encephalitis. These genetic disorders are underdiagnosed, partly because diagnosis currently requires expensive and time-consuming techniques available at only a few specialized centers worldwide. We, therefore, aimed to develop a cheap and fast test for the detection of defects in Toll-like receptor signaling. PATIENTS AND METHODS. We used flow cytometry to evaluate the cleavage of membrane-bound L-selectin on granulocytes in 38 healthy controls and in 7 patients with genetically defined Toll-like receptor signaling defects (5 patients with interleukin-1 receptor-associated kinase-4 deficiency and 2 patients with UNC-93B deficiency), on activation with various Toll-like receptor agonists. RESULTS. Impaired L-selectin shedding was observed with granulocytes from all of the interleukin-1 receptor-associated kinase-4-deficient patients on activation with agonists of Toll-like receptors 1/2, 2/6, 4, 7, and 8 and with granulocytes from all of the UNC-93B-deficient patients on activation with agonists of Toll-like receptors 7 and 8. All of the healthy controls responded to these stimuli. CONCLUSIONS. The assessment of membrane-bound L-selectin cleavage on granulocytes by flow cytometry may prove useful for the detection of primary immunodeficiencies in the Toll-like receptor pathway, such as interleukin-1 receptor-associated kinase-4 deficiency and UNC-93B deficiency. This procedure is cheap and rapid. It may, therefore, be suitable for routine testing worldwide in children with invasive pneumococcal disease and in patients with herpes simplex encephalitis.

Leukocyte Adhesion Deficiency Type II: Long-Term Follow-Up and Review of the Literature

IntroductionLeukocyte adhesion deficiency (LAD) is a group of rare inherited disorders characterized by immune deficiency and peripheral neutrophilia. There are only seven reported cases of LAD type II worldwide, and no long-term follow-up data.Case ReportWe reviewed the medical file of a 20-year-old man with LAD II. Clinical characteristics included short stature, severe mental retardation, and autistic features. He had had no severe infections since infancy, and his current immunological status was stable. The last laboratory work-up revealed mild leukocytosis and neutrophilia. Genetic analysis of the Golgi GDP-fucose transporter (GFTP) sequence yielded a point mutation resulting in Y337C amino acid transition in the tenth transmembrane domain.ConclusionIn conclusion, in LAD II, the main clinical countenance shifts from frequent infections due to immunodeficiency in the early years to the metabolic consequences of the defect in fucose metabolism, i.e., retarded growth and mental retardation, in the later years. A novel mutation in the GFTP loci associated with LAD II is described.

Lessons from the clinical course of IgE-mediated cow milk allergy in Israel

Cow milk and milk products are the most common food products consumed in Israel; rates of allergy to cow milk exceed those of peanuts in infants and children. The aim of the present study was to evaluate retrospectively the clinical features and natural course of immunoglobulin (Ig) E‐mediated cow milk allergy (CMA) in Israel. Data of children diagnosed with CMA from 1995 to 2003, were collected regarding age at first and most recent reactions, symptoms and signs, family history of atopy, other allergic diseases, emergency department visits, hospitalizations, and treatment. Patients with transient CMA were compared to those with persistent CMA (≥3 yr old). The study group consisted of 105 patients, 43 with transient CMA (age range: 0.48–11 yr). The remaining 62 patients (age range: 3–16.5 yr) did not achieve tolerance to cow milk during the follow‐up period. No differences were found between the groups in mean age and symptoms and signs at the first allergic reaction and family history of atopy. Patients with persistent CMA had a higher rate of asthma than patients with transient CMA (61.2% vs. 18.6%, p < 0.001). Fifty patients with persistent CMA had 137 subsequent allergic reactions after diagnosis, 25% of the reactions were due to oral milk challenge at the clinic and 75% due to accidental exposure, of which 13% required an emergency department visit and 8%, hospitalization. Only 19% of the reactions were treated with epinephrine injection. In conclusion, in our experience, less than half of the children diagnosed with IgE‐mediated CMA during 9 yr, outgrew it. The patients with persistent CMA have a higher prevalence of asthma compared with the general population or to children with transient CMA. The high number of recurrent allergic reactions due to accidental exposure and the low rate of epinephrine usage in these patients point to a need for better education of patients and their families.

Anaphylaxis in Israel: Experience with 92 hospitalized children

To cite this article: Hoffer V, Scheuerman O, Marcus N, Levy Y, Segal N, Lagovsky I, Monselise Y, Garty BZ. Anaphylaxis in Israel: Experience with 92 hospitalized children. Pediatr Allergy Immunol 2011; 22:172–177.

Effect of Melatonin on Seizure Frequency in Intractable Epilepsy: A Pilot Study

Melatonin is effective for treating sleep–wake cycle disturbances and has been reported occasionally to decrease epileptic seizure frequency, with no long-term side effects. In this pilot study, the investigators examined the effect of melatonin on seizures, sleep quality, and behavior in 10 patients aged 9 to 32 years with intractable epilepsy. Patients were randomized to receive melatonin (10 mg daily at bedtime) followed by placebo or placebo followed by melatonin for 3 weeks each, with a 1-week washout period in between. Seizure frequency was monitored by daily diaries and actigraphy recordings; behavioral and sleep parameters were rated by caregivers. Diurnal seizures decreased significantly with melatonin compared with placebo (P = .034, Wilcoxon test). Maximal number of seizures, seizure duration, sleep efficiency or latency, and behavioral parameters remained unchanged. No major side effects or seizure aggravation were documented. It is concluded that melatonin could be effective and safe for decreasing daytime seizure frequency in patients with intractable epilepsy.

A randomized, double-blind study comparing cefixime and trimethoprim-sulfamethoxazole in the treatment of childhood shigellosis

We compared the clinical and bacteriologic response of 5-day treatment with cefixime, 8 mg/kg per day, with the response to trimethoprim-sulfamethoxazole (TMP-SMX), 10-50 mg/kg per day, the currently recommended therapy. Of the assessable children with acute, culture-proven shigellosis, 38 received cefixime and 39 received TMP-SMX. Pretreatment data on the two study groups were similar. In the first group, all isolates were susceptible to cefixime; in the TMP-SMX group, 32 isolates were resistant and 7 were susceptible to TMP-SMX. Clinical response (day 5) showed cure, improvement, and failure in 89%, 8%, and 3%, respectively, of the cefixime group, and in 25%, 44%, and 31%, respectively, of the TMP-SMX-resistant group (p < 0.001). Bacteriologic cure (day 3) occurred in 78% and 23% of the cefixime and TMP-SMX-resistant groups, respectively (p < 0.001). Clinical or bacteriologic relapse (day 12) was infrequent in both groups. The response to treatment of the cefixime and the TMP-SMX-susceptible groups was similar. No significant side effects were noted. We conclude that cefixime is superior to TMP-SMX in the treatment of suspected shigellosis in areas with a high rate of resistance to TMP-SMX.

Expression of the Complement Receptors CR1 and CR3 and the Type III Fcγ Receptor on Neutrophils from Newborn Infants and from Fetuses with Rh Disease

ABSTRACT: Developmental defects in neutrophil function, including diminished expression of plasma membrane receptors, may play an important role in the susceptibility of the newborn infant to infection. We used monoclonal antibodies and flow cytometry to study the expression of complement receptor type one (CR1), complement receptor type three (CR3), and Fcγ receptor type three (FcRIII) on neutrophils from six fetuses with Rh disease, 10 preterm infants, nine term infants, and nine adults. Expression of the complement receptors on unstimulated cells was similar for all groups, but significant diffences in complement receptor expression were observed after stimulation with N-formyl-methionyl-leucyl-phenylalanine (FMLP). Fetal, preterm, and term infant neutrophils expressed less CR3 than FMLP-stimulated neutrophils of adults [61 ± 2, 48 ± 4, and 66 ± 4% (mean ± SEM) of the mean for adults, p < 0.05]. FMLP-stimulated CR1 expression for these groups was 61 ± 6, 73 ± 6, and 91 ± 9% of the adult mean (p < 0.05, fetal versus term infant and adult). Expression of both CR3 and CR1 increased with postconceptional age in the infants (r2 = 0.49, p < 0.001 for CR3; r2 = 0.23, p < 0.05 for CR1). Neutrophils of the preterm and term infants expressed less FcRIII than adult neutrophils (68 ± 10 and 77 ± 7% of the adult mean, p < 0.05, for FMLP-stimulated cells), whereas fetal neutrophil FcRIII expression did not differ from that of the adult. The fluorescence distributions showed a peak for eosinophils that was distinct from the FMLP-stimulated neutrophil peak, allowing separate analysis for the two cell types. Eosinophils constituted an unexpectedly large proportion of granulocytes in fetuses with Rh disease, averaging 61% of granulocytes in seven specimens at 20 to 26 wks gestation and 37% in 11 specimens at 28 to 34 wks.