Epidemiological and clinical characteristics of hospitalized human metapneumovirus patients in Israel, 2015-2021: A retrospective cohort study.

This study evaluated the epidemiological and clinical characteristics of human metapneumovirus (hMPV) infection among hospitalized patients with acute respiratory infections during 2015-2021 and assessed the impact of the coronavirus disease 2019 pandemic on hMPV infection. A single-center, retrospective cohort study was performed, including pediatric and adult patients with laboratory-confirmed hMPV. Of a total of 990 patients, 253 (25.6%), 105 (10.6%), 121 (12.2%), and 511 (51.6%) belonged to age groups 0-2, 3-17, 18-59, and ≥60 years, respectively. The highest percentage (23.0%) of patients were hospitalized during 2019 and the lowest (4.7%) during 2020. Patients < 18 years experienced high rates of comorbidities (immunodeficiencies: 14.4% and malignancies: 29.9%). Here, 37/39 (94.9%) of all bronchiolitis cases were diagnosed in patients < 2 years, whereas more patients in older age groups were diagnosed with pneumonia. A greater proportion of hMPV patients diagnosed with viral coinfection (mostly respiratory syncytial virus and adenovirus) were <18 years. The highest percentages of intensive care unit admissions were recorded among patients < 18 years. Our findings demonstrate that hMPV is an important cause of morbidity in young children and a possibly underestimated cause of morbidity among older adults.

Risk Factors and Characteristics of Candidemia After Cardiac Surgery in Pediatric Patients in Central Israel.

BACKGROUND: Candidemia is a serious complication in pediatric patients with congenital heart defects (CHD) after cardiac surgery. Information about the epidemiology, clinical characteristics and risk factors for candidemia in this vulnerable population remains limited. METHODS: This retrospective case-control study was conducted in 2 pediatric intensive care units between 2004 and 2019. All patients <18 years old who developed candidemia following cardiac surgery were included. Each case was matched with 2 control patients based on age and date of surgery. Multivariable logistic regression analysis was conducted to determine the risk factors for postoperative candidemia. RESULTS: Thirty-five candidemia cases were identified and matched to 70 control cases. The incidence of candidemia was 6.3 episodes per 1000 admissions. The median age for candidemia cases was 4 months. The attributable mortality was 28.5%. The predominant (54%) pathogens isolated were non- albicans Candida species, of which C. parapsilosis isolates demonstrated high resistance to fluconazole (70%). Independent risk factors associated with candidemia included cumulative antibiotic exposure for ≥4 days [OR: -4.3; 95% confidence interval (CI): 1.3-14.6; P = 0.02], the need for total parenteral nutrition or peritoneal dialysis (OR: -6.1; 95% CI: 2-18.8; P = 0.001), male sex (OR: 6.2; 95% CI: 1.9-20.3; P = 0.002) and delayed sternal closure≥2 days (OR: -3.2; 95% CI: 1-11.2; P = 0.05). CONCLUSIONS: Postoperative candidemia in children with CHD is an uncommon but severe complication. Our study revealed an unexpectedly high frequency of fluconazole-resistant C. parapsilosis as the main cause of non- albicans candidemia. In addition to confirming previously recognized risk factors, our results reveal new potential risk factors such as delayed sternal closure and male sex.

Treatment of severe Kaposiform lymphangiomatosis positive for NRAS mutation by MEK inhibition.

BACKGROUND: Kaposiform lymphangiomatosis (KLA) is a complex lymphatic anomaly involving most commonly the mediastinum, lung, skin and bones with few effective treatments. In recent years, RAS-MAPK pathway mutations were shown to underlie the pathogenesis of several complex lymphatic anomalies. Specifically, an activating NRAS mutation (p.Q61R) was found in the majority of KLA patients. Recent reports demonstrated promising results of treatment with the MEK inhibitor, Trametinib, in patients with complex lymphatic anomalies harboring gain of function mutations in ARAF and SOS1, as well as loss of function mutation in the CBL gene, a negative regulator of the RAS-MAPK pathway. We present a 9-year-old child with a severe case of KLA harboring the typical NRAS (p.Q61R) mutation detected by plasma-derived cell free DNA, responsive to trametinib therapy. METHODS: The NRAS somatic mutation was detected from plasma cfDNA using droplet digital PCR. Concurrent in-vitro studies of trametinib activity on mutant NRAS affected lymphatic endothelial cells were performed using a three-dimensional spheroid sprouting assay. RESULTS: Trametinib treatment lead to resolution of lifelong thrombocytopenia, improvement of pulmonary function tests and wellbeing, as well as weaning from prolonged systemic steroid treatment. Concurrent studies of mutant NRAS-expressing cells showed enhanced lymphangiogenic capacity along with over activation of the RAS-MAPK and PI3K-AKT-mTOR pathways, both reversed by trametinib. CONCLUSIONS: Trametinib treatment can substantially change the prognosis of patients with RAS pathway associated lymphatic anomalies. IMPACT: This is the first description of successful trametinib treatment of a patient with KLA harboring the most characteristic NRAS p.Q61R mutation. Treatment can significantly change the prognosis of patients with RAS pathway-associated lymphatic anomalies. We devised an in vitro model of KLA enabling a reproducible method for the continued study of disease pathogenesis. Mutated NRAS p.Q61R cells demonstrated increased lymphangiogenic capacity.

Human enterovirus D68 in clinical and sewage samples in Israel.

BACKGROUND: Since mid-August 2014, North America experienced a wide outbreak of Enterovirus D68 (EV-D68) associated with severe respiratory illness in children. Several other countries also reported cases of EV-D68 in 2014. OBJECTIVES: The aim of this study was to determine whether EV-D68 circulated in Israel in 2014, caused severe respiratory illness in children and was the causative agent of Acute Flaccid Paralysis. STUDY DESIGN: Archived clinical respiratory samples from a cohort of 710 hospitalized pediatric patient's (<10years old) with respiratory illness were screened for clade B specific EV-D68 by real-time PCR. The patients were seen at four medical centers covering the entire country between August and November 2014. We also evaluated 49 patient stool samples from 26 AFP cases during 2014 for presence of EV-D68. In addition, RNA from sewage samples collected throughout Israel during the same study period was also tested for EV-D68. Partial VP1 sequencing was performed on all positive samples. RESULTS: Of the 710 clinical samples evaluated, 7 (1%) were positive for EV-D68. Two patients were from the central part of Israel, while the rest was from the southern part. The majority of the patients did not have any underlying disease. Not only that, but, none of the 26 suspected AFP cases had EV-D68 nucleic acid in their stool samples. EV-D68 RNA was detected in 9 out of 93 sewage samples, mainly from Southern Israel. Sequence analysis of EV-D68 VP1 gene from both sewage and clinical samples indicated that the Israeli EV-D68 RNA belonged to Clade B which was genetically similar to 2014 circulating European and North American EV-D68 virus. CONCLUSIONS: EV-D68 circulated in Israel during the 2014 summer-fall season and caused hospitalization of a small percent of the patients with respiratory illness.

Human metapneumovirus (hMPV) infection in immunocompromised children.

BACKGROUND: Human metapneumovirus (hMPV) is a major cause of upper and lower respiratory tract infection (URTI, LRTI) in children. The prognosis of hMPV is unclear in immunocompromised patients. OBJECTIVES: To describe the characteristics of hMPV infection in immunocompromised pediatric patients and to review the literature. STUDY DESIGN: This retrospective study included 39 immunocompromised children (age 0-18 years) with proven hMPV infection attending two tertiary pediatric medical centers in 2004-2014. Demographic, clinical, laboratory, and radiological data were collected from the medical files. RESULTS: Median age was 6 years. Seven patients had primary immune deficiency and 32, secondary immune deficiency, including 9 patients who underwent hematopoietic stem cell transplantation (HSCT). Most cases (92%) occurred in January-May. Twenty patients (51%) had lower respiratory tract infection and 17 (44%), upper respiratory tract infection; 2 patients (5%) had fever only. Presenting symptoms were fever (70%), cough (54%), and rhinorrhea (35%). Severe lymphopenia (<1000lymphocytes/mL) was noted in 64% of patients and elevated liver enzyme levels in 49%. Seventeen patients had pneumonia: bilateral and alveolar in 13 patients, each. HSCT was not associated with more severe disease. Respiratory failure occurred in 6 patients, of whom 4 died (10% of cohort). All children who died had severe lymphopenia. On multivariate analysis, bacterial or fungal co-infection was the only major risk factor for death. Review of the literature showed variable clinical presentations and severity in pediatric patients with hMPV infection. CONCLUSIONS: Infection with hMPV may be associated with relatively high morbidity and mortality in immunocompromised children. Death was associated with bacterial and fungal co-infection.

Universal neonatal cytomegalovirus screening using saliva - report of clinical experience.

OBJECTIVES: To analyze the results of a neonatal universal screen for congenital cytomegalovirus (CMV) using saliva real-time polymerase chain reaction (rt-PCR). STUDY DESIGN: During one year (15/5/2011-15/5/2012), saliva was collected from 9845 infants (97% of 10,137 newborns). Viral DNA was extracted by Magna-Pure LC (Roche) and was tested for the presence of CMV IE and gB genes. Urine culture was collected from positive infants for confirmation. For all infants with congenital CMV maternal data were collected and head ultrasound, blood count, liver enzymes, retinal examination and auditory brainstem response testing were performed. Parents were notified in advance and had the option to avoid screening. The ethical committee approved retrospective analysis of the data. RESULTS: Fifty six infants (0.57%) had a positive saliva assay. Of these, 47 were confirmed by urine rt-PCR and culture, in another one maternal sero-conversion was documented during pregnancy (48 infants). Twenty-eight mothers (28/47, 60%) had primary infection during pregnancy, 14 (30%) had non-primary infection, and no serological data were obtained from five (10%). Four infants (8.5%), two with prenatal diagnosis of CMV and normal fetal brain imaging and two born to mothers sero-positive before pregnancy, exhibited symptoms related to CMV and were offered antivirals. Hearing impairment was diagnosed in two infants (late onset HI in one case). CONCLUSIONS: Saliva rt-PCR assay is a feasible and effective means of universal neonatal CMV screening that can detect affected infants who might benefit from treatment and follow-up. The long-term clinical significance of screening and its cost effectiveness are yet to be determined.

[Combination antifungal therapy in hematopoietic stem cell transplantation patients].

Invasive fungal infections are a major cause of morbidity and mortality in hematopoietic stem cell transplantation patients. In recent years, new resistant fungal strains have emerged, requiring physicians to use new generation antifungal drugs or drug combinations. We report a case of invasive Fusarium infection involving the nasopharynx, skin and lungs, following haploidentical hematopoietic stem cell transplantation in an 8-year old patient with recurrent leukemia. The patient was treated with combination antifungal treatment of amphotericin B and voriconazole, as well as supportive care, with the improvement of his symptoms and home discharge. We reviewed the history of combination antifungal therapy. Combination antifungal treatment has been used since 1979, especially in immunocompromised patients. Although randomized controlled trials are lacking, reports favoring combination, especially for invasive mold infections, are increasingly published.