Genotype-phenotype correlations in chronic granulomatous disease: insights from a large national cohort.

ABSTRACT: Neutrophils are the first line of defense against invading pathogens. Neutrophils execute and modulate immune responses by generating reactive oxygen species (ROS). Chronic granulomatous disease (CGD) is a primary immune deficiency disorder of phagocytes, caused by inherited mutations in the genes of the nicotinamide adenine dinucleotide phosphate reduced oxidase enzyme. These mutations lead to failure of ROS generation followed by recurrent bacterial and fungal infections, frequently associated with hyperinflammatory manifestations. We report a multicenter cumulative experience in diagnosing and treating patients with CGD. From 1986 to 2021, 2918 patients experiencing frequent infections were referred for neutrophil evaluation. Among them, 110 patients were diagnosed with CGD: 56 of Jewish ancestry, 48 of Arabic ancestry, and 6 of non-Jewish/non-Arabic ancestry. As opposed to other Western countries, the autosomal recessive (AR) CGD subtypes were predominant in Israel (71/110 patients). Thirty-nine patients had X-linked CGD, in most patients associated with severe infections (clinical severity score ≥3) and poor outcomes, presenting at a significantly earlier age than AR-CGD subtypes. The full spectrum of infections and hyperinflammatory manifestations is described. Six patients had hypomorphic mutations with significantly milder phenotype, clinical severity score ≤2, and better outcomes. Hematopoietic stem cell transplantation was implemented in 39 of 110 patients (35.5%). Successful engraftment was achieved in 92%, with 82% long-term survival and 71% full clinical recovery. CGD is a complex disorder requiring a multiprofessional team. Early identification of the genetic mutation is essential for prompt diagnosis, suitable management, and prevention.

Association of post-transplantation anellovirus viral load with kidney transplant rejection in children.

BACKGROUND: Post-transplantation immunosuppressive therapy reduces the risk of graft rejection but raises the risk of infection and malignancy. A biomarker of the level of immunosuppression can be helpful in monitoring immunosuppressive therapy. Inverse correlation between Torque teno virus (TTV) from the Anelloviridae (AV) family load and immune competence was described in previous studies. The aim of this study was to analyze the association between AV family viruses' kinetics and the risk for graft rejection in the first year after kidney transplantation in children. METHODS: The titers of three genera (TTV, TTMDV, and TTMV) from the AV family were monitored by real-time PCR in consecutive samples from children before and after kidney transplantation. RESULTS: Twenty-one children who underwent kidney transplantation were enrolled. Five out of 21 patients experienced acute graft rejection within a year from transplantation. We found that in patients who experienced graft rejection, the median titers of TTV and total AV titers at 5-6 months post-transplantation were lower than in those who did not. Using a threshold determined by ROC analysis, significant differences in TTV and total AV load were found between patients who had or did not have graft rejection (p = 0.002 and 0.004, respectively). No association was found between the dominance of any AV genus titer and the likelihood of rejection. CONCLUSION: This pilot study suggests that children after kidney transplantation with low TTV and total AV titers 5-6 months post-transplantation are at increased risk for graft rejection within a year after transplantation. A higher resolution version of the Graphical abstract is available as Supplementary information.

SARS-CoV-2 antibodies started to decline just four months after COVID-19 infection in a paediatric population.

AIM: We evaluated the prevalence of paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections using antibody testing and characterised antibody titres by time from exposure. METHODS: This was a single-centre, prospective, cross-sectional cohort study. Patients under 18 years old were eligible to participate if they attended the paediatric emergency department at the tertiary Shaare Zedek Medical Center, Jerusalem, Israel, from 18 October 2020 to 12 January 2021 and required blood tests or intravenous access. SARS-CoV-2 seropositivity and antibody levels were tested by a dual-assay model. RESULTS: The study comprised 1138 patients (56% male) with a mean age of 4.4 years (interquartile range 1.3-11.3). Anti-SARS-CoV-2 antibodies were found in 10% of the patients. Seropositivity increased with age and 41% of seropositive patients had no known exposure. Children under 6 years of age had higher initial antibody levels than older children, followed by a steeper decline. The seropositivity rate did not vary during the study, despite schools re-opening. The findings suggest that children's immunity may start falling 4 months after the initial infection. CONCLUSION: Immunity started falling after just 4 months, and re-opening schools did not affect infection rates. These findings could aid decisions about vaccinating paediatric populations and school closures.

Chronic granulomatous disease: Clinical, functional, molecular, and genetic studies. The Israeli experience with 84 patients.

Chronic granulomatous disease (CGD) is an innate immunodeficiency with a genetic defect of the nicotinamide adenosine dinucleotide phosphate, reduced, oxidase components. This leads to decreased reactive oxygen species (ROS) production, which renders patients susceptible to life-threatening infections. Over the course of 30 years, we diagnosed CGD in 84 patients from 61 families using functional, molecular, and genetic studies. The incidence of CGD in Israel is 1.05 per 100,000 live-births in the Jewish population and 1.49 in the Israeli Arab population. We diagnosed 52 patients (62%) with autosomal recessive inheritance (AR-CGD) and 32 (38%) with X-linked recessive inheritance (XLR-CGD). Consanguinity was detected in 64% of AR-CGD families (14% in Jews and 50% in Israeli Arabs). We found 36 different mutations (23 in XLR-CGD and 13 in AR-CGD patients), 15 of which were new. The clinical spectrum of CGD varied from mild to severe disease in both XLR and AR forms, although the AR subtype is generally milder. Further, residual ROS production correlated with milder clinical expression, better prognosis and improved overall survival. Patients with recurrent pyogenic infections developed fibrosis and hyperinflammatory states with granuloma formation. The management of CGD has progressed substantially in recent years, evolving from a fatal disease of early childhood to one of long-term survival. Our present cohort displays an encouraging 81% overall long term survival. Early hematopoietic stem cell transplantation is advisable before tissue damage is irreversible. Successful transplantation was performed in 18/21 patients. Therapeutic gene modification could become an alternative cure for CGD. Am. J. Hematol. 92:28-36, 2017. © 2016 Wiley Periodicals, Inc.

Fever survey highlights significant variations in how infants aged ≤60 days are evaluated and underline the need for guidelines.

AIM: To assess the common practices for evaluating and treating febrile infants aged ≤60 days in a nationwide survey. METHODS: Questionnaires were administrated to inpatient paediatric departments in all 25 hospitals in Israel. RESULTS: Of the 25 centres surveyed (100% response rate), only 36% had written protocols concerning the approach to young febrile infants. The existence of a written protocol was significantly associated with the level of medical centre (tertiary versus primary and secondary, p = 0.041) and with the number of local paediatric infectious disease specialists (p = 0.034). In 13 (52%) hospitals, a normal white blood cell count was defined as 5000-15 000 cells/mL and 20 (80%) centres use C-reactive protein. Hospitalisation was mandatory in most (96%) centres for all neonates aged ≤28 days. Low-risk infants aged 29-60 days were hospitalised in 68.4% of the primary and secondary hospitals, compared with 33.3% tertiary centres. Ampicillin and gentamicin was the routine empiric antibiotic treatment for febrile infant in 92% of centres. CONCLUSION: Significant differences exist among centres in the evaluation of febrile infants aged ≤60 days exist. These differences reflect the lack of, and highlight the need for, national or international guidelines for the evaluation of fever in this age group.

Jerusalem's CoVID-19 Experience-The Effect of Ethnicity on Disease Prevalence and Adherence to Testing.

BACKGROUND: The management of the SARS-CoV-2 pandemic depends amongst other factors on disease prevalence in the general population. The gap between the true rate of infection and the detected rate of infection may vary, especially between sub-groups of the population. Identifying subpopulations with high rates of undetected infection can guide authorities to direct resource distribution in order to improve health equity. METHODS: A cross-sectional epidemiological survey was conducted between April and July 2021 in the Pediatric Emergency Department of the Shaare Zedek Medical Center, Jerusalem, Israel. We compared three categories: unconfirmed disease (UD), positive serology test result with no history of positive PCR; confirmed disease (CD), history of a positive PCR test result, regardless of serology test result; and no disease (ND), negative serology and no history of PCR. These categories were applied to local prevailing subpopulations: ultra-orthodox Jews (UO), National Religious Jews (NRJ), secular Jews (SJ), and Muslim Arabs (MA). RESULTS: Comparing the different subpopulations groups, MAs and UOs had the greatest rate of confirmed or unconfirmed disease. MA had the highest rate of UD and UO had the highest rate of CD. UD significantly correlated with ethnicity, with a low prevalence in NRJ and SJ. UD was also associated with larger family size and housing density defined as family size per number of rooms. CONCLUSION: This study highlights the effect of ethnicity on disease burden. These findings should serve to heighten awareness to disease burden in weaker populations and direct a suitable prevention program to each subpopulation's needs. Early awareness and possible intervention may lower morbidity and mortality.

Neurologic manifestations of Fusobacterium infections in children.

UNLABELLED: Fusobacterium necrophorum causes various clinical syndromes, ranging from otitis media to life-threatening Lemierre's syndrome. The purpose of this study was to review our experience with pediatric Fusobacterium infections. The medical records of all children aged 0 to 18 years who were diagnosed between 1999 and 2011 with Fusobacterium infection were reviewed. Fusobacterium was isolated from clinical samples of 27 children: blood cultures (n = 16), abscesses (n = 8), joint fluids (n = 2), and cerebrospinal fluid (n = 1). The median age at admission was 3.5 years (range, 7 months to 17 years). Eight children (30 %) had seizures at presentation. Ten children (37 %) underwent lumbar puncture. Fifteen children (56 %) underwent brain imaging, and in seven of these children, a thrombus was identified either in a sinus vein or in an internal jugular vein. The most common source of infection was otogenic in 19 (70 %) of the children. Six of the children presented in 2011. All patients recovered. CONCLUSIONS: Neurologic manifestations are common at presentation of children with Fusobacterium infections. In young children, the most common source of infection is otogenic. Thrombotic complications are common, and imaging should be considered in all children with Fusobacterium infections arising from the head or neck region. There was a recent increase in the isolation of this bacterium, either because of better culturing techniques and increased awareness to this entity or a true increase in infections due to this organism.

Inducible clindamycin resistance in ß-hemolytic streptococci and Streptococcus pneumoniae.

BACKGROUND: Resistance to macrolides in beta-hemolytic streptococci and Streptococcus pneumoniae arises primarily due to Erm(B) or Mef(A). Erm(B) typically confers high level resistance to macrolides, lincosamides and streptogramin B (MLSB phenotype), whereas Mef(A) confers low level resistance to macrolides only (M phenotype). OBJECTIVES: To investigate the incidence of macrolide resistance mechanisms in isolates of beta-hemolytic streptococci and pneumococci in Israel, with particular emphasis on inducible MLSB phenotype. METHODS: We collected 316 clinical isolates of streptococci during May-August 2010. Erythromycin resistance mechanism was determined by the erythromycin-clindamycin double disk diffusion method. RESULTS: Erythromycin and clindamycin resistance rates were 19.4% and 13.4% for S. pneumoniae, 4.7% and 1.6% for group A Streptococcus (GAS), 17% and 17% for group B Streptococcus (GBS), and 38.8% and 27.8% for group G Streptococcus (GGS) respectively. The most common resistance mechanism for all streptococci was constitutive MLSB (cMLSB). Inducible MLSs (iMLSB) mechanism was found in 3% of all strains and represented 25% of resistance mechanisms. CONCLUSIONS: The prevalence of macrolide resistance and the distribution of resistance mechanisms differ among beta-hemolytic streptococci and S. pneumoniae, with GBS, GGS and S. pneumoniae showing the highest resistance rate. Macrolide or lincosamide cannot be empirically used for severe streptococcal infections before strains are proved to be susceptible. Continuous surveillance of erythromycin and clindamycin resistance patterns among streptococci is needed.

Cytomegalovirus (CMV) seroprevalence among women at childbearing age, maternal and congenital CMV infection: policy implications of a descriptive, retrospective, community-based study.

BACKGROUND: Maternal CMV infection during pregnancy, either primary or non-primary, may be associated with fetal infection and long-term sequelae. While guidelines recommend against it, screening for CMV in pregnant women is a prevalent clinical practice in Israel. Our aim is to provide updated, local, clinically relevant, epidemiological information about CMV seroprevalence among women at childbearing age, the incidence of maternal CMV infection during pregnancy and the prevalence of congenital CMV (cCMV), as well as to provide information about the yield of CMV serology testing. METHODS: We performed a descriptive, retrospective study of women at childbearing age who were members of Clalit Health Services in the district of Jerusalem and had at least one gestation during the study period (2013-2019). We utilized serial serology tests to determine CMV serostatus at baseline and at pre/periconception and identified temporal changes in CMV serostatus. We then conducted a sub-sample analysis integrating inpatient data on newborns of women who gave birth in a single large medical center. cCMV was defined as either positive urine CMV-PCR test in a sample collected during the first 3 weeks of life, neonatal diagnosis of cCMV in the medical records, or prescription of valganciclovir during the neonatal period. RESULTS: The study population Included 45,634 women with 84,110 associated gestational events. Initial CMV serostatus was positive in 89% women, with variation across different ethno-socioeconomic subgroups. Based on consecutive serology tests, the detected incidence rate of CMV infection was 2/1000 women follow-up years, among initially seropositive women, and 80/1000 women follow-up years, among initially seronegative women. CMV infection in pregnancy was identified among 0.2% of women who were seropositive at pre/periconception and among 10% of women who were seronegative. In a subsample, which included 31,191 associated gestational events, we identified 54 newborns with cCMV (1.9/1000 live births). The prevalence of cCMV among newborns of women who were seropositive at pre/periconception was lower than among newborns of women who were seronegative (2.1 vs. 7.1/1000). Frequent serology tests among women who were seronegative at pre/periconception detected most primary CMV infections in pregnancy that resulted in cCMV (21/24). However, among women who were seropositive, serology tests prior to birth detected none of the non-primary infections that resulted in cCMV (0/30). CONCLUSIONS: In this retrospective community-based study among women of childbearing age characterized by multiparity and high seroprevalence of CMV, we find that consecutive CMV serology testing enabled to detect most primary CMV infections in pregnancy that led to cCMV in newborns but failed to detect non-primary CMV infections in pregnancy. Conducting CMV serology tests among seropositive women, despite guidelines' recommendations, has no clinical value, while it is costly and introduces further uncertainties and distress. We thus recommend against routine CMV serology testing among women who were seropositive in a prior serology test. We recommend CMV serology testing prior to pregnancy only among women known to be seronegative or women whose serology status is unknown.

Inhaled Nitric Oxide for the Treatment of Acute Bronchiolitis: A Multicenter Randomized Controlled Clinical Trial to Evaluate Dose Response.

Rationale: Inhaled nitric oxide (iNO) has potential antiinflammatory, antimicrobial, and antiviral properties for patients with lower respiratory tract infections. Objectives: We compared the safety and efficacy of iNO administered in two concentrations in addition to standard supportive treatment (SST) compared with SST alone with the aim of improving clinical outcomes of infants with bronchiolitis. Methods: In this prospective, multicenter, double-blind, randomized controlled study, 89 infants hospitalized with moderate to severe bronchiolitis were randomly assigned to three treatment groups: 150 ppm NO plus SST (group 1), 85 ppm NO plus SST (group 2), and the control treatment (O2/air plus SST) (group 3). Treatment was given for 40 minutes, four times each day, for up to 5 days. The primary endpoint was time to reach "fit for discharge." This was a composite endpoint composed of both reaching a sustained oxygen saturation ≥92% on room air and reaching a clinical score ⩽5. Secondary endpoints included time to reach sustained oxygen saturation ≥92% on room air, time to clinical score ⩽5, and time to hospital discharge. Safety was assessed by the number of treatment-related adverse events (AEs) or serious AEs. Time-to-event efficacy outcomes were analyzed using a Cox proportional hazards regression model. Hazard ratios (HR) describe how many times more likely an individual is to experience an event, if such an individual receives NO rather than the control treatment during the observational period. Results: Group 1 demonstrated significant efficacy for time to reach fit to discharge compared with groups 2 (HR, 2.11; P = 0.041) and 3 (HR, 2.32; P = 0.049). Group 1 also demonstrated significant efficacy for time to hospital discharge compared with groups 2 (HR, 2.01; P = 0.046) and 3 (HR, 2.28; P = 0.043). No significant differences were observed between groups 2 and 3 for either endpoint. There were no differences between treatment groups in time to reach a clinical score ⩽5. The iNO therapy was well tolerated, with no treatment-related serious AEs. Conclusions: Treatment with high-dose intermittent iNO at 150 ppm showed reduced time to clinical improvement compared with 85 ppm or control treatment of hospitalized infants with acute bronchiolitis. The 150-ppm iNO dose is well tolerated, with significant benefit compared with both standard therapy and 85 ppm iNO, improving respiratory outcomes and reducing length of stay. Clinical trial registered with www.clinicaltrials.gov (NCT04060979).

Haemophilus influenzae activity in a single medical center in Israel in the post-vaccine era.

BACKGROUND: The incidence of invasive disease due to Haemophilus influenzae has decreased since the implementation of vaccination against serotype B. OBJECTIVES: To describe the epidemiological, clinical and microbiological characteristics of patients with H. influenzae meningitis or bacteremia in the vaccine era in Israel. METHODS: We reviewed the medical records of all patients admitted to Shaare Zedek Medical Center between 1997 and 2010 who had blood or cerebrospinal fluid culture positive for H. influenzae. RESULTS: The study group comprised 104 patients - 57 children and 47 adults. Overall, 21 (20%) of the infections were due to serotype b. The children had shorter hospitalizations (6vs. 12 days, P = 0.005) and lower mortality rate (5% vs. 28%, P = 0.003) as compared to the adults. Bacteremic pneumonia was the most common diagnosis in adults (45% vs. 28% in children, P = 0.08) while meningitis was more common in children (17% vs. 3.5%, P = 0.09). There was a seasonal pattern, with infections being more common during the winter and spring. CONCLUSIONS: Invasive H. influenzae disease is uncommon but still exists in both children and adults. The disease course tends to be more severe in adults. Even in the global vaccination era, serotype b constitutes a significant portion of invasive disease.

A costly covenant: ritual circumcision and urinary tract infection.

BACKGROUND: Ritual circumcision in neonates may cause a urinary tract infection within 2 weeks of the procedure. OBJECTIVES: To evaluate the prevalence of urinary tract infection among Jewish male circumcised neonates < or = 28 days old) evaluated for fever in the emergency room. METHODS: All available medical records of neonates presenting to the pediatric emergency room for evaluation of fever over a 10 year period were reviewed. Data included gender, ethnic background, age (in days) on presentation to the emergency room, age (in days) when circumcision was performed (in males > or = 8 days of age), and results of urine, blood and cerebrospinal fluid cultures. Families of males older than 8 days of age who had a UTI were contacted by telephone to verify the circumcision status when the infant presented to the ER, to ascertain whether the circumcision had been performed ritually by a mohel* or by a physician, and, if not recorded in the chart, to verify the day of life on which circumcision was performed. RESULTS: Among neonates older than 8 days of age, 60 (24.7%) of the 243 febrile Jewish males had a UTI, as compared to 12 (8.4%) of 143 females (P < 0.0001). In 39 of 54 male neonates (72%) for whom circumcision was performed ritually on the eighth day of life, UTI occurred within 9 days of the circumcision. For females, there was no such clustering of UTI cases in the second week of life, nor during any other time period. CONCLUSIONS: Febrile male neonates who have undergone ritual circumcision have a high prevalence of UTI and must be evaluated and treated accordingly.

Age-related immunoglobulin G seroprevalence of human parvovirus B-19 in Israeli children.

BACKGROUND: Human parvovirus B19 is a global and common infectious pathogen in humans, particularly in children. OBJECTIVES: To assess the immunoglobulin G3 seroprevalence of B19 in children in Israel. METHODS: Overall, 128 previously healthy children (1.5-17 years old) hospitalized for various diseases other than acute human parvovirus B19 infection were assessed for IgG to the virus by enzyme-linked immunosorbent assay. RESULTS: The IgG seroprevalence increased from 22% in children aged 1.5-9 years to 52% in older children (P = 0.001). CONCLUSIONS: Our data suggest that most acute parvovirus B19 infections in Israel occur in the early school years, and that by 18 years of age 50% of Israeli children have been infected by the virus.

Longitudinal quantification of Ehrlichia canis in experimental infection with comparison to natural infection.

Ehrlichia canis is a major tick-borne bacterial pathogen of dogs. Quantitative real-time PCR was evaluated for the detection of E. canis in naturally (NI) and experimentally infected (EI) dogs. DNA was extracted from blood, spleen and conjunctival swabs of experimentally infected dogs pre- and post-infection (PI), and during doxycycline therapy, and from blood and conjunctivas of naturally infected dogs. The primers and probe were designed to amplify a 93bp fragment of the single copy E. canis 16S rRNA gene with the TaqMan system. All EI dogs were positive for E. canis DNA by 7d PI and developed clinical ehrlichiosis by 9-12d PI. A rapid increase in ehrlichial DNA in EI dogs correlated with the appearance of severe clinical signs of disease. The mean spleen and blood DNA copies significantly increased by more than 10-folds from 7d PI to 10 and 12d PI (p<0.05). E. canis DNA was undetectable in the blood by day 9 post-treatment. Although the spleen was more frequently positive than blood (15/15 specimens vs. 13/15), no significant differences were found between the mean ehrlichial DNA copies in the spleen and blood on each day of examination. In 12 naturally infected dogs, the mean blood DNA copies was similar to the number found in EI 7d PI, but significantly lower than the means of 10 and 12d PI (p<0.0001). Although the conjunctivas of all EI dogs were positive by 12d PI, only 3/5 (60%) NI dogs were positive also by conjunctival PCR. In conclusion, the kinetics of E. canis during acute experimental infection with complete pathogen clearance following doxycyline treatment was demonstrated for the first time by real-time PCR. The value of real-time PCR was shown in NI dogs as well as in EI dogs with spleen and blood sampling more sensitive than non-invasive conjunctival PCR.

Cefuroxime for empiric treatment of community-acquired pneumococcal pneumonia: is there a generation gap?

BACKGROUND: Streptococcus pneumoniae infection is an important cause of morbidity and mortality. The recommendations to use expanded-spectrum beta-lactam drugs for patients with community-acquired pneumonia derived from the growing prevalence of penicillin-resistant pneumococci. Controversy exists regarding the use of second generation cephalosporins for empirical treatment of community-acquired pneumonia. METHODS: In a retrospective study, 31 adult patients with pneumococcal pneumonia and bacteremia caused by S. pneumoniae that was intermediately resistant to penicillin were compared with 31 control patients with similar infection caused by penicillin-susceptible pneumococci. All patients were treated empirically with cefuroxime, alone or in combination with other antibiotics. Morbidity and mortality were studied. RESULTS: All unsusceptible pneumococci isolates were intermediately resistant to penicillin. No cases of fully resistant pneumococci were isolated from blood cultures in our hospital. Two factors were significantly associated with non-susceptibility to penicillin: hematologic malignancy and immunosuppression. No significant difference in morbidity or mortality was detected between the 2 groups, and penicillin minimum inhibitory concentration was not found to be a factor associated with mortality. CONCLUSIONS: Patients with pneumococcal pneumonia caused by intermediately resistant pneumococci can be empirically treated with cefuroxime. In regions where fully resistant pneumococci are rare, the use of a second generation cephalosporin for empiric treatment of community-acquired pneumonia may be appropriate.

[Gastrointestinal carriage of Pseudomonas aeruginosa in children residing in chronic care institutes in Jerusalem: high prevalence and high rates of antibiotic resistance].

BACKGROUND: Pseudomonas aeruginosa carriage in the gastrointestinal tract is uncommon in healthy children. Children living in chronic care institutions are often carriers of P. aeruginosa in the respiratory tract, but data is lacking regarding gastrointestinal carriage in these children. AIMS: To examine the carriage rate of P. aeruginosa in children living in chronic care institutions in Jerusalem and to assess resistance rates of the bacteria to different classes of antibiotics. METHODS: Rectal swabs were taken from all children residing in two chronic care institutions in Jerusalem: "St. Vincent" and "Aleh". The swabs were examined for presence of Pseudomonas aeruginosa. The authors used disk diffusion technique and E Test to assess resistance for different antibiotics. RESULTS: Gastrointestinal carriage of P. aeruginosa was detected in 37 out of 125 of the children (30%); 16% of the P. aeruginosa isolates were resistant to carbapenems; 16% were resistant to aminoglycosides, 14% to ureidopenicillins and 11% to quinolones. All isolates were sensitive to ceftazidime and colistin. In 84% of the isolates, the minimal inhibitory concentration (MIC) for meropenem was significantly lower than the MIC for imipenem. SUMMARY: P. aeruginosa is a common colonizer of the gastrointestinal tract of children living in chronic care institutions. Empiric antibiotic treatment against P. aeruginosa should be considered when treating children with acute gastrointestinal pathologies. Antibiotic resistance, and particularly carbapenem resistance, is common in this population. There is a significant difference between the MICs for imipenem and meropenem. Future studies are needed to understand the clinical significance of this finding.

[Vibrio vulnificus infection outside of the fish ponds in northern Israel: acquisition in the "Einot Tzukim" springs near the Dead Sea].

Vibrio vulnificus is a Gram-negative bacterium that may cause severe skin and systemic infection after exposure of open wounds to contaminated water, especially in patients with underlying disease such as immune-deficiency, iron overload or end stage liver or renal disease. The V. vulnificus infection has been reported in Israel almost exclusively after exposure to Tilapia fish cultivated in fresh water fish ponds in northern Israel. The authors report the first case of V. vulnificus infection acquired in a nature reserve in southeastern Israel, with no connection to fish handling. A 14.5-years-old girl with transfusion-dependant thalassemia major presented with high fever and a rapidly progressive bullous cellulitis of the ankle. The infection occurred around a cut on the left lateral malleolus, after bathing in the fresh water ponds of Einot Tzukim (Ein Feshcha) in south-eastern Israel, and progressed despite the use of broad-spectrum antibiotics. Blood and wound cultures eventually yielded Vibrio vulnificus and appropriate treatment was commenced. The fever subsided after a few days but resolution of the local findings was very gradual and lasted for weeks. The presence of V. vulnificus in natural springs far from the northern artificial fish ponds broadens the danger of this infection. We find it prudent to advise people at risk for V. vulnificus infection, such as those suffering from immunedeficiency, iron overload and end stage liver or renal disease, to refrain from bathing in natural ponds whilst injured.

Chronic granulomatous disease in Israel: clinical, functional and molecular studies of 38 patients.

Chronic granulomatous disease (CGD) is an innate immunodeficiency due to a genetic defect in one of the NADPH-oxidase components. In the course of 21 years, 38 Israeli CGD patients were diagnosed with 17 gene mutations, seven of which were new. Clinical, functional, and molecular studies were accomplished. Although X-linked recessive (XLR)-CGD is worldwide the most common genotype of the disease (~70%), in our study only 11 patients (29%) suffered from XLR-CGD. In Israel, the higher incidence of the autosomal recessive (AR) form of CGD (63%) may be related to consanguineous marriages. In three patients (8%), all four proteins of the NADPH oxidase were present. Severe clinical expression was found both in the XLR and AR forms, but in general a milder disease was evident in AR-CGD, particularly in patients with p47(phox) deficiency. Despite early and aggressive therapy, a mortality rate of 26% was noted. Given that bone-marrow transplantation was successful in five of seven patients, it is recommended to perform it as early as possible before tissue damage is irreversible.