Don't rash it! The clinical significance of positive Varicella zoster virus PCR in cerebrospinal fluid of patients with neurological symptoms.

BACKGROUND: Varicella zoster virus (VZV) is among the leading pathogens causing meningitis and encephalitis. While VZV-PCR-positive CSF is considered a gold-standard for diagnosis, it is not-uncommon to detect VZV-DNA in CSF of patients with other acute or chronic illness. Our goal was to determine the clinical relevance of VZV-PCR-positive CSF when investigating patients with neurological symptoms. METHODS: In this retrospective cohort from the largest hospital in Israel, we collected demographic, clinical and laboratory data of patients with VZV-PCR-positive CSF, analyzing the significance of various parameters. RESULTS: During a 5-years study, 125 patient-unique VZV-PCR-positive CSFs were recorded, in which only 9 alternative diagnoses were noted. The commonest symptoms were headache (N = 104, 83 %) and rash (N = 96, 76 %). PCR-cycle-threshold (Ct), a surrogate of viral burden, did not significantly vary across the clinical manifestations; however, patients with rash and Ct<35 were prone to develop stroke in the following year (N = 6, 7 %). Empiric nucleoside-analogue treatment was not associated with a better outcome compared to treatment administered upon a positive-PCR result. DISCUSSION: Our findings suggest that in patients with neurological symptoms, detection of VZV-DNA in CSF renders VZV the probable culprit. Nevertheless, a systematic evaluation of treatment and follow-up algorithms of patients with suspected or proved VZV meningitis and encephalitis is needed. The benefits of a prompt treatment should be weighed against the potential complications of nucleoside-analogue. Conversely, the propensity for stroke in patients with higher viral-burden, necessitates further studies assessing VZV causal role, directing additional workup, treatment and monitoring policy.

Multi-center nationwide comparison of seven serology assays reveals a SARS-CoV-2 non-responding seronegative subpopulation.

BACKGROUND: An Israeli national taskforce performed a multi-center clinical and analytical validation of seven serology assays to determine their utility and limitations for SARS-CoV-2 diagnosis. METHODS: Serology assays from Roche, Abbott, Diasorin, BioMerieux, Beckman-Coulter, Siemens, and an in-house RBD ELISA were included. Negative samples from 2391 individuals representative of the Israeli population, and 698 SARS-CoV-2 PCR positive patients, collected between March and May 2020, were analyzed. FINDINGS: Immunoassays sensitivities between 81.5%-89.4% and specificities between 97.7%-100% resulted in a profound impact on the expected Positive Predictive Value (PPV) in low (<15%) prevalence scenarios. No meaningful increase was detected in the false positive rate in children compared to adults. A positive correlation between disease severity and antibody titers, and no decrease in antibody titers in the first 8 weeks after PCR positivity was observed. We identified a subgroup of symptomatic SARS-CoV-2 positive patients (~5% of patients), who remained seronegative across a wide range of antigens, isotypes, and technologies. INTERPRETATION: The commercially available automated immunoassays exhibit significant differences in performance and expected PPV in low prevalence scenarios. The low false-positivity rate in under 20's suggests that cross-reactive immunity from previous CoV strains is unlikely to explain the milder disease course in children. Finding no decrease in antibody titers in the first 8 weeks is in contrast to some reports of short half-life for SARS-CoV-2 antibodies. The ~5% who were seronegative non-responders, using multiple assays in a population-wide manner, represents the proportion of patients that may be at risk for re-infection. FUNDING: Israel Ministry of Health.

Diagnosing congenital cytomegalovirus by saliva on Guthrie paper.

BACKGROUND: In recent years, interest in universal newborn screening for congenital cytomegalovirus (cCMV) has intensified. consequently, reliable and simple methods of mass screening for cCMV, are essential. Herein, we present a novel approach of using polymerase chain reaction (PCR) in saliva with direct inoculation onto Guthrie paper. Our aim was to determine the diagnostic accuracy of real- time PCR in saliva rolled directly onto Guthrie paper in diagnosing cCMV infection. OBJECTIVES: To evaluate the diagnostic accuracy of real-time PCR analysis of dried saliva on Guthrie paper as a future approach for mass screening of newborns in diagnosing cCMV infection. STUDY DESIGN: This prospective, blinded study was performed in a tertiary cytomegalovirus (CMV) clinic from May 2018 through January 2019. Forty-two cCMV positive newborns and 41 without cCMV, were enrolled and tested for CMV using PCR from their saliva placed onto Guthrie paper and from their saliva using standard methods. Specificity and sensitivity of dried saliva PCR versus gold-standard methods were analyzed. RESULTS: Forty-two out of 42 (100 %) CMV positive infants showed positive PCR in the dried saliva on the Guthrie paper. All (100 %) controls exhibited negative PCR results. Congenital CMV infection was identified with a sensitivity of 100 % (95 % C.I. = 91.4%-100.00%) and specificity of 100 % (95 % C.I. = 91.4%-100.00%). DISCUSSION: CMV testing with saliva real-time PCR on Guthrie paper displayed a high sensitivity and specificity, rendering it a powerful screening test. The accuracy, simplicity of sampling, storage and transportation and the potential reliance on existing logistic resources, establishes this method as a candidate for cCMV universal screening programs.

Cytomegalovirus positive ulcerative colitis: A single center experience and literature review.

AIM: To compare the clinical outcome of cytomegalovirus (CMV)-positive ulcerative colitis (UC) patients with and without antiviral therapy. METHODS: This was a retrospective case-controlled study. The database of UC patients in our institution was scanned for documented presence of CMV on colonic biopsies. Demographics, clinical data, endoscopy findings and pathology reports were extracted from the patients' charts and electronic records. When available, the data from colonoscopies preceding and following the diagnosis of colonic CMV infection were also extracted. The primary outcomes of the study were colectomy/death during hospitalization and the secondary outcomes were colectomy/death through the course of the follow-up. RESULTS: Thirteen patients were included in the study, 7 (53.5%) of them were treated with gancyclovir and 6 (46.5%) were not. Patients treated with antivirals presented with a more severe disease and 57% of them were treated with cyclosporine or infliximab before initiation of gancyclovir, while none of the patients without antivirals required rescue therapy. One patient died and another patient underwent urgent colectomy during hospitalization, both of them from the gancyclovir-treatment group. For the entire follow-up time (13 ± 13 mo), a total of 3 colectomies and one death occurred, all among the antiviral-treated patients (for colectomy: 3/7 vs 0/6 patients, P = 0.19; for combined adverse outcome: 4/7 vs 0/6 patients, P = 0.07). In 9/13 patients, immunohistochemistry for CMV was performed on biopsies obtained during a subsequent colonoscopy and was positive in one patient only. CONCLUSION: Gancyclovir-treated patients had a more severe disease and outcome, probably unrelated to antiviral therapy. Immunohistochemistry-CMV-positive patients with mild disease may recover without antiviral therapy.