Efficacy of preexposure prophylaxis with monoclonal-antibody tixagevimab-cilgavimab against emerging SARS-CoV-2 resistant variants in patients with chronic lymphocytic leukemia.

Introduction Pre exposure prophylaxis with monoclonal antibodies (mAbs) were developed in addition to COVID19 vaccine for immunocompromised and those with insufficient immune response, among them patients with CLL. Omicron variant and its sublineages evolved mutations that escape mAbs neutralizing effect, yet the extent of which was not studied. Methods We evaluated anti-spike titters and neutralization activity of COVID-19 wild type (WT) , Delta , Omicron, BA2, BA4 and BA5 before and after tixagevimab-cilgavimab (TGM/CGM) dose of 150/150mg or 300/300mg in patients with CLL. Results 70 patients were tested 2 weeks before and 4 weeks after receiving TGM/CGM mAbs. After TGM/CGM anti-spike ab level increased 170 folds from 13.6 BAU/ml (IQR, 0.4-288) to 2328 BAU/ml (IQR, 1681-3500). Neutralization activity increased in all variants, and was 176 folds higher in WT and 55 folds higher in Delta compared to 10 folds higher in Omicron and its sublineages (BA2 x11, BA4 x4 , BA5 x18). Over follow-up period of 3 months, 20 patients (29%) with CLL acquired COVID-19 infection, all recovered uneventfully. In a multivariate analysis anti-spike antibody titer was found a significant predictor for post TGM/CGM COVID19 infection. Conclusion Efficacy of preexposure prophylaxis with TGM/CGM in patients with CLL is significantly reduced in era of Omicron and its sublineages BA2, BA4 and BA5.

High CCL2 Levels Detected in CSF of Patients with Pediatric Pseudotumor Cerebri Syndrome.

Pseudotumor cerebri (PTC) is a disorder characterized by increased intracranial pressure in the absence of a structural lesion or other identifiable cause. Cytokines, which are involved in the regulation of immune responses and inflammation, have been implicated in the pathogenesis of PTC. In a prospective, cross-sectional study at three centers in Israel, we analyzed cerebrospinal fluid (CSF) samples from 60 children aged 0.5-18 years, including 43 children with a definitive diagnosis of PTC and a control group of 17 children. Levels of IL-4, IL-10, IL-17, CCL2, CCL7, CCL8, CCL13, BDNF, and IFN-γ were measured using ELISA kits. Levels of CCL2 were significantly higher in the PTC group compared to the control group (p < 0.05), with no other significant differences in the measured cytokines between the two groups. The groups did not differ significantly in clinical presentation, imaging, treatment, or ophthalmic findings. Our findings provide preliminary evidence that CCL2 may be involved in the pathogenesis of PTC and may serve a potential target for therapy in PTC.

Prospective, Cross-Sectional Study Finds No Common Viruses in Cerebrospinal Fluid of Children with Pseudotumor Cerebri.

Pseudotumor cerebri (PTC) in children is a rare condition whose underlying cause remains largely unknown. No study has yet systematically examined viral infection as a cause of PTC. The current study aimed to characterize PTC in children and investigate the possible role of acute viral infection of the central nervous system in its pathogenesis. A prospective, cross-sectional study was conducted in three centers in Israel. Participants were 50 children aged 0.5-18 years, of whom 27 had a definitive diagnosis of pseudotumor cerebri (the study group) and 23 comprised a control. Data collected included clinical presentation, imaging, treatment, ophthalmic findings, and cerebrospinal fluid (CSF) analysis. Using the ALLPLEXTM meningitis panel, real-time polymerase chain reaction (PCR) was used to test for the presence of 12 common viruses. PTC patients (mean age 12 ± 4.3 years; 14 males, 13 females) had mean opening pressure of 41.9 ±10.2 mmH2O. All PTC patients had papilledema, and 25 (93%) had PTC symptoms. No viruses were found in the PTC group, while in the control group, one patient tested positive for Epstein-Barr virus and another for human herpesvirus type 6. Overall, in our study, PTC was not found to be associated with the presence of viruses in CSF.

Pooled saliva CMV DNA detection: A viable laboratory technique for universal CMV screening of healthy newborns.

BACKGROUND: Most infants with congenital cytomegalovirus (cCMV) have no overt manifestations at birth, yet may later develop CMV-related sensorineural hearing loss (SNHL). With targeted screening, many asymptomatic neonates are missed and lose the opportunity for timely anti-viral treatment to ameliorate SNHL. Saliva is the preferred screening specimen given its ease of collection. OBJECTIVES: Assess a pooled saliva CMV DNA detection technique for cCMV screening of healthy full-term neonates. STUDY DESIGN: We conducted a prospective laboratory CMV PCR screening study in a secondary hospital from March-June 2019. Saliva specimens were obtained from 1000 newborns two-four hours after birth. Specimens were analyzed for CMV DNA with a real-time PCR platform (Altona) in pools of 10 and individually (40 µL and 400 µL, respectively). Neonates with positive saliva CMV DNA detection required urine CMV PCR testing to confirm cCMV diagnosis. RESULTS: From the 1000 saliva samples, there were 6 urine-confirmed cCMV cases, yielding a prevalence rate of 0.6 %. The specificity was high for both pooled and individual saliva sampling (99.9 % and 98.1 %, respectively). The positive predictive value of the pooled sample was 85.7 %, compared to 24.0 % for a single saliva sample. CONCLUSIONS: Pooling saliva of healthy newborns appears to be a reliable method to identify asymptomatic cCMV infection when positive results are confirmed by urine CMV DNA. Pooling in sizes appropriate to the cCMV prevalence rate may improve the laboratory workflow and decrease costs. Further studies should evaluate the clinical implications of this widespread cCMV pooled screening technique.

The yield of CSF molecular testing in febrile neonates.

We retrospectively examined the yield of a cerebrospinal fluid (CSF) multiplex real-time PCR assay of febrile young infants undergoing a full sepsis work-up. Eighty infants were included in the study: Forty-nine (61%) neonates and 31 (39%) 29-90 day-old patients were included in the study. A viral pathogen was detected in 59% (47/80) of the samples, human enterovirus in 53% (42/80) and Human parechovirus in 6% (5/80). The CSF of nearly half of the subjects with CNS infection was without pleocytosis; all CSF cultures were negative. Multiplex PCR CSF testing enhances the diagnosis of pathogen-specific viral CNS infection among febrile young infants.

Respiratory Viruses Frequently Mimic Pertussis in Young Infants.

Bordetella pertussis is prevalent among infants, but its diagnosis is complicated by the fact that its signs and symptoms overlap with respiratory viruses. Indeed, when evaluating the etiology of infants less than 1 year of age suspected of having pertussis, we found that respiratory viruses frequently mimic B. pertussis and are more likely to be the causative agent.

Does Herpes 6 Infection Have a Role in Bell's Palsy Among Children and Adolescents?

BACKGROUND: Bell's palsy is a peripheral paralysis of the seventh cranial nerve, whose etiology is unknown. Using polymerase chain reaction technology, it is possible to sample accessible body fluids and identify possible viral factors. The purpose of this research is to investigate its connection to the herpes virus family by testing for the presence of the virus in the saliva and tear fluid of Bell's palsy patients. METHODS: Saliva and tears were collected from 42 children and adolescents suffering from idiopathic facial nerve paralysis. Polymerase chain reaction was used to test for the presence of the viruses Epstein-Barr virus, cytomegalovirus, herpes simplex virus 1 and 2, varicella zoster virus and human herpes virus 6 (HHV-6). Samples were also taken from a control group without paralysis. A second specimen was taken from patients who tested positive for HHV-6 several months after their recovery. RESULTS: Of the 42 patients in the study group, 71% (30 patients) tested positive for HHV-6, compared with only 37% of the control group (P = 0.001). The prevalence of the other 5 viruses tested was low-herpes simplex virus 1: 9.5%, Epstein-Barr virus: 9.5%, cytomegalovirus: 4.8%, varicella zoster virus: 2.3% and herpes simplex virus 2: 0%. Twenty-four of the 30 patients who were HHV-6-positive during their illness were reexamined following recovery. Only 13 patients (54.2%) excreted the virus after recovery from the paralysis. CONCLUSIONS: Herpes 6 virus appears to play some role in the etiology of facial nerve paralysis. The virus was detected in the saliva of children during acute illness and decreased with resolution. Our research opens new insights linking HHV-6 to the etiology of Bell's palsy in children.

Validation of a Novel Assay to Distinguish Bacterial and Viral Infections.

BACKGROUND: Reliably distinguishing bacterial from viral infections is often challenging, leading to antibiotic misuse. A novel assay that integrates measurements of blood-borne host-proteins (tumor necrosis factor-related apoptosis-inducing ligand, interferon γ-induced protein-10, and C-reactive protein [CRP]) was developed to assist in differentiation between bacterial and viral disease. METHODS: We performed double-blind, multicenter assay evaluation using serum remnants collected at 5 pediatric emergency departments and 2 wards from children ≥3 months to ≤18 years without (n = 68) and with (n = 529) suspicion of acute infection. Infectious cohort inclusion criteria were fever ≥38°C and symptom duration ≤7 days. The reference standard diagnosis was based on predetermined criteria plus adjudication by experts blinded to assay results. Assay performers were blinded to the reference standard. Assay cutoffs were predefined. RESULTS: Of 529 potentially eligible patients with suspected acute infection, 100 did not fulfill infectious inclusion criteria and 68 had insufficient serum. The resulting cohort included 361 patients, with 239 viral, 68 bacterial, and 54 indeterminate reference standard diagnoses. The assay distinguished between bacterial and viral patients with 93.8% sensitivity (95% confidence interval: 87.8%-99.8%) and 89.8% specificity (85.6%-94.0%); 11.7% had an equivocal assay outcome. The assay outperformed CRP (cutoff 40 mg/L; sensitivity 88.2% [80.4%-96.1%], specificity 73.2% [67.6%-78.9%]) and procalcitonin testing (cutoff 0.5 ng/mL; sensitivity 63.1% [51.0%-75.1%], specificity 82.3% [77.1%-87.5%]). CONCLUSIONS: Double-blinded evaluation confirmed high assay performance in febrile children. Assay was significantly more accurate than CRP, procalcitonin, and routine laboratory parameters. Additional studies are warranted to support its potential to improve antimicrobial treatment decisions.

Pertussis Resurgence Associated with Pertactin-Deficient and Genetically Divergent Bordetella Pertussis Isolates in Israel.

The Bordetella pertussis polymerase chain reaction positivity rate changed after additional diphtheria-tetanus-acellular pertussis boosters in 2005 and 2008, 9.8%, 13.4%, 22% and 15.2% in 2010, 2011, 2012 and 2013, P < 0.001, respectively. New pulsed-field gel electrophoresis profiles were detected between 2009 and 2012. The proportion of pertactin-deficient isolates increased over time, 6.6% versus 7.1% versus 33.3% during 2005-2006, 2011-2012 and 2013-2014, P < 0.03, respectively.

Heat-shock protein 70: expression in monocytes of patients with sleep apnoea and association with oxidative stress and tumour necrosis factor-alpha.

Obstructive sleep apnoea (OSA) is associated with a variety of nightly stresses, including intermittent hypoxaemia, oxidative stress and sleep fragmentation. Heat-shock proteins (HSPs) are upregulated in response to an array of environmental and metabolic stresses. We hypothesized that the OSA-related stresses would affect the expression of HSP70 in monocytes. Basal (30 min, at 37 degrees C), heat stress-induced HSP70 (30 min, at 43 degrees C) and basal tumour necrosis factor-alpha (TNF-alpha) were determined by flow cytometry in monocytes of 10 patients with OSA and 10 controls matched by age, gender and body mass index. Oxidative stress was determined by thiobarbituric acid-reactive substances (TBARS) and antioxidant paraoxonase-1 activity. Basal HSP70 expression was 1.8-fold higher in patients with OSA as compared with controls (P < 0.0005) and was significantly positively correlated with TBARS (r = 0.56, P < 0.009). However, induction of HSP70 in response to heat stress treatment was lower by 40% in OSA monocytes as compared with controls (P < 0.0003). Furthermore, heat stress-induced HSP70 expression was significantly negatively correlated with basal HSP70 expression independently of apnoea severity (r = -0.69, P < 0.0006). Also, basal intracellular TNF-alpha expression was inversely correlated with heat-shock-induced HSP70 (r = -0.78, P < 0.015) in OSA monocytes but not in controls. In conclusion, basal HSP70 overexpression that is a protective mechanism indicative of disease-associated stress was significantly higher in patients with OSA and was correlated with oxidative stress. On the other hand, in response to a defined heat-stress treatment, the induction of HSP70 was lower in patients with OSA, indicative of a possible maladaptive response to an acute stress. Correlations with oxidative stress and TNF-alpha further support this conclusion.