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.

COVID-19 in a Subset of Hospitalized Children in Israel.

BACKGROUND: Most pediatric coronavirus disease 2019 (COVID-19) is mild. We assessed nationally severe COVID-19, including pediatric inflammatory multisystem syndrome (PIMS), in hospitalized children. METHODS: An ongoing, prospective, national surveillance was conducted from March 2020 through March 2021, at 20 hospitals treating children <18 years across Israel (~75% of Israeli hospitals). RESULTS: Overall, 1007 cases (439 outpatients and 568 hospitalized) identified represent 0.35% of pediatric COVID-19 nationwide (n = 291 628). Of hospitalized cases, 464 (82%), 48 (8%), and 56 (10%) had mild, moderate/severe, and PIMS disease, respectively. The mean ± SD age was 5.6 ± 6.4 years. In mild, moderate/severe, and PIMS disease, 55%, 23%, and 4% of patients were <1 year old, respectively. Obesity was reported in 1%, 4%, and 13% of patients, respectively (P < .001). The most common symptom was fever in 67%, 60%, and 100%, respectively, whereas respiratory symptoms were documented in 33%, 41%, and 38% of patients, respectively. Lymphopenia was recorded in 25%, 60%, and 86% of cases, respectively. PIMS diagnosis was mainly serology-based (in 59%). Gastrointestinal symptoms, cardiovascular involvement, rash, and conjunctivitis were noted in 82%, 61%, 57%, and 34% of PIMS episodes, respectively. Elevated C-reactive protein (100%), ferritin, troponin, D-dimer, low albumin, and thrombocytopenia were common in PIMS. Echocardiography revealed pathological findings in 33% of patients. PIMS mainstay treatment included corticosteroids (77%) and intravenous immunoglobulin (53%). No mortality was recorded. CONCLUSIONS: At a national level, pediatric COVID-19 is mild, even in hospitalized cases, with only a third presenting with respiratory involvement. PIMS is rare, but necessitates a high index of suspicion, and with suitable treatment prognosis is favorable.

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.

Diminished selection for thymidine-analog mutations associated with the presence of M184V in Ethiopian children infected with HIV subtype C receiving lamivudine-containing therapy.

BACKGROUND: We retrospectively studied the effect of the lamivudine-induced reverse transcription mutation M184V on selection of thymidine analog mutations (TAMs) in HIV subtype C-infected children and on clinical outcome. METHODS: We genotyped 135 blood samples from 55 children. TAMs accumulation, viral load and clinical outcome were compared in children maintained on zidovudine/stavudine + lamivudine + protease inhibitor/nonnucleoside reverse transcriptase inhibitor (PI/NNRTI) despite loss of viral suppression and in children treated with, or switched to, other nucleoside reverse transcriptase inhibitors (NRTIs). Drug susceptibility and replication capacity of selected samples were measured. RESULTS: M184V developed in 18 of 22 of children who had received only zidovudine/stavudine + lamivudine + PI/NNRTI during a mean of 23.2 +/- 3.2 months versus in 3 of 14 children treated with other drugs and/or having multiple regimen changes (P = 0.001). TAMs appeared, respectively, in 2 of 22 versus 12 of 14 (P < 0.0001). The 2 groups did not differ significantly in baseline HIV-RNA or CD4 count, sampling time, and follow-up period. In M184V-containing samples, we found large reductions in susceptibility to lamivudine and emtricitabine but not to other NRTIs. When T215Y was present without M184V, susceptibility to zidovudine was reduced 8-fold. When both M184V + T215Y occurred, susceptibility to zidovudine was substantially increased. Average inhibition concentration 50 values were similar to those documented in the Stanford database for subtype B HIV with these mutation patterns. CONCLUSIONS: Maintaining a thymidine analog + lamivudine-based regimen reduced accumulation of TAMs and increased zidovudine susceptibility. This is likely the result of an increased susceptibility to thymidine analog (zidovudine) in the context of M184V documented here for the first time in subtype C-infected children. This retrospective study supports the strategy of maintaining lamivudine-containing therapy in subtype C-infected children. This strategy may be beneficially applied in the treatment of children in Africa, where thymidine analog + lamivudine-based regimen became available recently but further options are limited.

The Clinical Spectrum of Zika Virus in Returning Travelers.

INTRODUCTION: The clinical spectrum of Zika virus had, to date, been described in small series from endemic/epidemic countries and is not well established. METHODS: We describe the clinical manifestations of laboratory-proven Zika virus infection in Israeli travelers during December 2015-February 2016, and review all published cases of travel-related Zika virus. RESULTS: During the study period, 8 returning Israeli travelers were diagnosed with Zika virus infection. In addition, 41 published cases were included, mostly from Latin America to Europe and North America. Overall, 65.3% were diagnosed by polymerase chain reaction. Rash was the most frequent symptom, present in 95.7% of cases, followed by fever and arthralgia. Conjunctivitis was present in 53.1%; however, only 40.3% presented with a triad of conjunctivitis, fever, and rash. Less frequent symptoms included dysgeusia and nightmares, which, together with arthralgia, persisted for several weeks in some travelers. CONCLUSIONS: Zika virus clinical picture in travelers is diverse. Prolonged symptoms may occur.

Differential impact of pneumococcal conjugate vaccines on bacteremic pneumonia versus other invasive pneumococcal disease.

BACKGROUND: Bacteremic pneumonia (BP) accounts for ~35% of invasive pneumococcal disease (IPD) in young children. Our aims were to compare age, seasonal and serotype distribution of BP versus non-BP IPD and to determine whether the impact of the sequential 7/13-valent pneumococcal conjugate vaccine (PCV7/PCV13) introduction on disease incidence differed between BP and non-BP IPD in children <5 years of age. METHODS: A nationwide, prospective, population-based, active surveillance (July 2004-June 2013) was conducted. All IPD episodes were included. PCV7 was introduced to the Israeli National Immunization Plan in July 2009 and has been replaced by PCV13 since November 2010. RESULTS: In all, 983 (36.8%) BP and 1687 (63.2%) non-BP IPD episodes were recorded. A higher proportion of BP than that of non-BP IPD episodes (42.0% vs. 20.7%; P < 0.001) occurred in children >24 months old. Seasonality differed between BP and non-BP IPD, with yearly earlier peaks of non-BP IPD. The proportion of the 5 additional PCV13 serotypes (1, 3, 5, 7F and 19A) was higher in children with BP versus non-BP IPD (39.6% vs. 23.6%; P < 0.01). Shortly after PCV7 introduction, non-BP IPD rate was significantly reduced but that of BP was not. However, PCV13 introduction resulted in rapid reduction of BP rate, with a further reduction of non-BP IPD. CONCLUSION: The differences in age distribution, seasonality and serotype distribution between BP and non-BP IPD suggest that the pathogenesis of these 2 entities is not identical and resulted in different impact rate dynamics after PCV7 and PCV13 introduction.

[Acute acquired non-traumatic torticollis in hospitalized children].

BACKGROUND: The inflammatory process in torticollis involves the cervical muscles, nerves, and/or the vertebral synovia causing painful and abnormal head position. Most cases of acute acquired non-traumatic torticollis are of benign etiology, but some patients may suffer from a serious disease requiring thorough investigation and hospitalization. OBJECTIVES: To describe the epidemiology, clinical features and the etiology of acute acquired non-traumatic torticollis in our center. METHODS: A retrospective chart review of 45 hospitalized children in the Sapir Medical Center over a 10 year period. RESULTS: We studied 45 children; 23 girls and 22 boys. Their mean age was 6 years (range 6 months to 16 years). All patients reported marked neck pain as their main complaint. Local infection was the most frequent etiology, and 33 (73%) patients were hospitalized during the fall-winter season. Twenty six patients underwent x-ray imaging, and of these, ten (38%) had pathology. The main findings were some degree of atlanto-axial subluxation, and widening of the prevertebral space. Treatment included analgesic and antibiotics for suspected bacterial infections. Two patients required surgical drainage. Cervical neck traction was performed on 15 patients. Mean admission time was 4.1 days and was shorter in the pediatric department compared to the ENT and orthopedic departments. CONCLUSIONS: Careful clinical and radiological evaluation for the wide spectrum of clinical entities should be done. Local infections of the respiratory tract are the most common etiology. Conservative treatment usually leads to complete resolution in a short time.

Actinobacillus actinomycetemcomitans endocarditis in a 1.5 year old toddler.

The authors report a 1.5-year-old girl who developed Actinobacillus actinomycetemcomitans (AA) endocarditis involving the pulmonic valve. She had a congenital cardiac abnormality, but no history of dental manipulation. The case illustrates an uncomplicated course with three unique features; the youngest reported infant with endocarditis caused by AA with vegetation on the pulmonic valve. She underwent a benign course with complete recovery. The authors report a 1.5-year-old girl who developed AA endocarditis involving the pulmonic valve. She had a congenital cardiac abnormality, but no history of dental manipulation. The case illustrates an uncomplicated course with three unique features; the youngest reported infant with endocarditis caused by AA with vegetation on the pulmonic valve. She underwent a benign course with complete recovery.

Comparative performance of the Amplicor HIV-1 Monitor Assay versus NucliSens EasyQ in HIV subtype C-infected patients.

In facing global programs for treating HIV-infected patients in the developing countries, there is a real need for viral load assays that are accurate for the local subtypes. The present study was designed to evaluate viral load measurements using the newer version of the NASBA assay in subtype C-infected patients. The performances of this new version, a real-time nucleic acid sequence-based amplification HIV-1 assay (NucliSens EasyQ), were compared to Amplicor HIV-1 Monitor Assay version 1.5 in 79 samples of subtype C-infected patients originating from Ethiopia. Twenty HIV-1 subtype B-infected patients served as a control group. Blood samples from patients in both groups were tested by both assays. The results were compared by a paired, two-tailed Student's t-test. The disparity between the results of the two viral load assays was highly significant in subtype C samples (P = 0.005), such that in the vast majority, higher values of viral load were obtained by the Amplicor assay. However, no differences between the two assays were found in subtype B samples (P = 0.77). CD4 measurements were available for 78 samples of subtype C-infected patients. Of these, a CD4-to-viral load discrepancy (CD4

Bacillus species sepsis in the neonatal intensive care unit.

OBJECTIVES: In 2002 there was an increase in the incidence of Bacillus species sepsis in our NICU that was almost completely resolved in 2003-2004 after the NICU was relocated. Our aims were to identify the source, the risk factors, and to characterize the clinical features of these infections. METHODS: The epidemiological investigation commenced during the outbreak and thereafter. The patient's data were collected retrospectively and a case control study was used to analyze the risk factors. RESULTS: There were eight cases of Bacillus species sepsis: five during 2002, two in 2003, and one in 2004. All infants recovered and salvaging percutaneous central venous catheter (PCVC) was successful in 4/6 of the cases. A case control study identified necrotizing enterocolitis (NEC) and PCVC as risk factors in univariate analysis but only NEC in multivariate analysis. No focal source of Bacillus bacteria was identified, but a high load of bacteria was found in the NICU's air before it was relocated. CONCLUSION: The risk factors for Bacillus species sepsis in our NICU were NEC and PCVC. The clinical course was milder than previously described, and PCVC was successfully salvaged in most cases. The increase in the incidence could be related to the construction work connected with NICU's relocation.

Severe Coxsackie virus B infection in preterm newborns treated with pleconaril.

UNLABELLED: Four preterm newborn infants with severe multisystem Coxsackie virus B infection were treated with an oral suspension of pleconaril (5 mg/kg per day). The patients had myocarditis, fulminant hepatitis, meningoencephalitis and disseminated intravascular coagulopathy. All four infants recovered, and no adverse effects of the treatment were noted. CONCLUSION: pleconaril needs to be comprehensively evaluated in this population.

Enteroaggregative Escherichia coli serotype O126:H27, Israel.

Enteroaggregative Escherichia coli (EAEC) is a newly diarrheagenic agent wherein several predominant serotypes are reported. We studied the association between those serotypes, as clonal indicators, and the trait of enteroaggregative adherence to host cells, tested by polymerase chain reaction. We also evaluated the clinical manifestations of infection in 17 hospitalized children by our most common EAEC serotype, O126:H27.

Measurement of HIV RNA in patients infected by subtype C by assays optimized for subtype B results in an underestimation of the viral load.

Quantitation assays of HIV-1 RNA used currently were designed and optimized for subtype B viruses. However, infection with non-B HIV viruses has become more common worldwide. Unfortunately, little information is available regarding the suitability of these assays for measurement of viral load in specific non-B subtypes. The performance of two commercial HIV-1 RNA quantitation assays was evaluated in 82 HIV subtype C-infected patients and in 43 HIV-1 subtype B-infected patients. Blood samples were tested by the Amplicor HIV-1 Monitor Assay, Version 1.5, and by the nucleic acid sequence-based amplification HIV-1 assay (NucliSens). The results were compared by using a paired, two-tailed Student's t-test; the difference between the assays was found to be significant only for subtype C. Discordant results (>0.5 log difference) between the two assays were detected in 39% of subtype C samples, compared to 23.2% of subtype B samples. In all cases in which a discordant result was detected, the lower results were obtained by the NucliSens assay. Discordant results between CD4 and viral load (CD4 < 200 cells/ml with a viral load <5,000 copies/ml) were observed in eight of the subtype C-infected patients when a viral load was measured by NucliSens (9.7%), compared to three patients (3.6%) when measured by the Amplicor assay. In conclusion, in patients with HIV subtype C infection, measurement of HIV RNA by the NucliSens assay resulted in a significant underestimation of the viral load as compared to the Amplicor assay. As a consequence, such an underestimation may result in sub-optimal care of patients infected with HIV subtype C.