Congenital Cytomegalovirus Infection: A Narrative Review of the Issues in Screening and Management From a Panel of European Experts.

Maternal primary and non-primary cytomegalovirus (CMV) infection during pregnancy can result in in utero transmission to the developing fetus. Congenital CMV (cCMV) can result in significant morbidity, mortality or long-term sequelae, including sensorineural hearing loss, the most common sequela. As a leading cause of congenital infections worldwide, cCMV infection meets many of the criteria for screening. However, currently there are no universal programs that offer maternal or neonatal screening to identify infected mothers and infants, no vaccines to prevent infection, and no efficacious and safe therapies available for the treatment of maternal or fetal CMV infection. Data has shown that there are several maternal and neonatal screening strategies, and diagnostic methodologies, that allow the identification of those at risk of developing sequelae and adequately detect cCMV. Nevertheless, many questions remain unanswered in this field. Well-designed clinical trials to address several facets of CMV treatment (in pregnant women, CMV-infected fetuses and both symptomatic and asymptomatic neonates and children) are required. Prevention (vaccines), biology and transmission factors associated with non-primary CMV, and the cost-effectiveness of universal screening, all demand further exploration to fully realize the ultimate goal of preventing cCMV. In the meantime, prevention of primary infection during pregnancy should be championed to all by means of hygiene education

Interferon-Gamma Release Assays Differentiate Between Mycobacterium avium Complex and Tuberculous Lymphadenitis in Children

OBJECTIVES: To assess the performance of interferon-gamma release assays (IGRAs) in the differential diagnosis between Mycobacterium avium complex (MAC) and tuberculosis (TB) in children affected with subacute/chronic submandibular/cervical lymphadenitis. STUDY DESIGN: Multicenter observational study comparing children with microbiologically-confirmed MAC lymphadenitis from the European NontuberculouS MycoBacterial Lymphadenitis in childrEn (ENSeMBLE) study with children with TB lymphadenitis from the Spanish Network for the Study of Pediatric TB (pTBred) database. RESULTS: Overall, 78 patients with MAC and 34 with TB lymphadenitis were included. Among MAC cases, 44/74 (59.5%) had positive tuberculin skin test (TST) results at the 5 mm cutoff, compared with 32/33 (97%) TB cases (p<0.001); at the 10 mm cutoff TST results were positive in 23/74 (31.1%) vs. 26/31 (83.9%), respectively (P < .001). IGRA results were positive in only 1/32 (3.1%) MAC cases who had undergone IGRA testing, compared with 21/23 (91.3%) TB cases (p<0.001). Agreement between TST and IGRA results was poor in MAC (23.3%;κ=0.017), but good in TB cases (95.6%;κ=0.646). IGRAs had a specificity of 96.9% (95%CI:84.3-99.8%), positive predictive value (PPV) of 95.4% (95%CI:78.2-99.8%), and negative predictive value (NPV) of 93.9% (95%CI:80.4-98.9%) for TB lymphadenitis. CONCLUSIONS: In contrast to TST, IGRAs have high specificity, NPV and PPV for TB lymphadenitis in children with subacute/chronic lymphadenopathy, and consequently can help to discriminate between TB and MAC disease. Therefore, IGRAs are useful tools in the diagnostic work-up of children with lymphadenopathy, particularly when culture- and PCR-results are negative

Clinical Outcomes of a Zika Virus Mother-Child Pair Cohort in Spain

BACKGROUND: Zika virus (ZIKV) infection has been associated with congenital microcephaly and other neurodevelopmental abnormalities. There is little published research on the effect of maternal ZIKV infection in a non-endemic European region. We aimed to describe the outcomes of pregnant travelers diagnosed as ZIKV-infected in Spain, and their exposed children. METHODS: This prospective observational cohort study of nine referral hospitals enrolled pregnant women (PW) who travelled to endemic areas during their pregnancy or the two previous months, or those whose sexual partners visited endemic areas in the previous 6 months. Infants of ZIKV-infected mothers were followed for about two years. RESULTS: ZIKV infection was diagnosed in 163 PW; 112 (70%) were asymptomatic and 24 (14.7%) were confirmed cases. Among 143 infants, 14 (9.8%) had adverse outcomes during follow-up; three had a congenital Zika syndrome (CZS), and 11 other potential Zika-related outcomes. The overall incidence of CZS was 2.1% (95%CI: 0.4-6.0%), but among infants born to ZIKV-confirmed mothers, this increased to 15.8% (95%CI: 3.4-39.6%). CONCLUSIONS: A nearly 10% overall risk of neurologic and hearing adverse outcomes was found in ZIKV-exposed children born to a ZIKV-infected traveler PW. Longer-term follow-up of these children is needed to assess whether there are any later-onset manifestations

Discrepancies in Management of Congenital Cytomegalovirus in Preterm Infants: An International Survey.

We performed an international survey regarding management of infants with congenital cytomegalovirus (cCMV) born at less than 32 weeks gestation or with birth weight under 1500 g. Replies from 51 level 3 neonatal intensive care units across 13 countries demonstrated striking discrepancies in screening practices, testing for cCMV, further investigations of confirmed cases, indications for initiation, and duration of treatment

Maternal type of CMV infection and sequelae in infants with congenital CMV: Systematic review and meta-analysis

Cytomegalovirus (CMV) is the most common congenital infection. Intrauterine transmission may occur following primary (PI) or non-primary (NPI) maternal infection and result in both neonatal symptomaticdisease and long-term complications.The aim of the present systematic review and meta-analysis was the qualitative and quantitative comparison of neonatal symptomatic disease and long-term sequelae of congenitally CMV infected children born following maternal PI or NPI. Articles from MEDLINE and SCOPUS databases were systematically reviewed. Articles describing neonatal symptoms and/or long-term sequelae in infants and children with cCMV born to mothers following PI and NPI were eligible.From eligible articles, data on the prevalence of neonatal symptoms, sensorineural hearing loss (SNHL) or neurologic sequelae in children born following PI and NPI were extracted and statistically analyzed. Maternal infection status did not influence neonatal symptomatic disease (pooled Odds Ratio (OR) 0.83, 95 % CI [0.55; 1.27], p=0.397). Additionally, the two groups of cCMV infected children had similar risk of developing SNHL, bilateral SNHL or other neurologic outcomes. Importantly, these findings remained as such, when newborns identified through universal screening were separately analyzed. Finally, when data on symptomatic and/or asymptomatic newborns were evaluated alone, maternal type was not associated with outcomes examined. Considering available data, the universal screening of all newborns for CMV infection may be discussed as a perspective. The systematic review and meta-analysis were registered in PROSPERO (Prospero registration number: CRD42019125179). © 2020 Elsevier B.V

Performance of immune-based and microbiological tests in children with tuberculosis meningitis in Europe: A multicentre paediatric tuberculosis network european trials group (ptbnet) study

Introduction: Tuberculous meningitis (TBM) is often diagnostically challenging. Only limited data exist on the performance of interferon-ã release assays (IGRA) and molecular assays in children with TBM in routine clinical practice, particularly in the European setting. Methods: Multicentre, retrospective study involving 27 healthcare institutions providing care for children with tuberculosis (TB) in nine European countries. Results: Of 118 children included, 54 (45.8%) had definite, 38 (32.2%) probable and 26 (22.0%) possible TBM; 39 (33.1%) had TBM grade 1, 68 (57.6%) grade 2 and 11 (9.3%) grade 3. Of 108 patients who underwent cranial imaging 90 (83.3%) had at least one abnormal finding consistent with TBM. At the 5-mm cut-off the tuberculin skin test had a sensitivity of 61.9% (95% CI 51.2-71.6%) and at the 10-mm cut-off 50.0% (95% CI 40.0-60.0%). The test sensitivities of QuantiFERON-TB and T-SPOT.TB assays were 71.7% (95% CI 58.4-82.1%) and 82.5% (95% CI 58.2-94.6%), respectively (p=0.53). Indeterminate results were common, occurring in 17.0% of QuantiFERON-TB assays performed. Cerebrospinal fluid (CSF) cultures were positive in 50.0% (95% CI 40.1-59.9%) of cases, and CSF PCR in 34.8% (95% CI 22.9-43.7%). In the subgroup of children who underwent tuberculin skin test, IGRA, CSF culture and CSF PCR simultaneously, 84.4% had at least one positive test result (95% CI 67.8%-93.6%). Conclusions: Existing immunological and microbiological TB tests have suboptimal sensitivity in children with TBM, with each test producing false-negative results in a substantial proportion of patients. Combining immune-based tests with CSF culture and CSF PCR results in considerably higher positive diagnostic yields, and should therefore be standard clinical practice in high-resource settings. Copyright © 2020 ERS

Congenital Cytomegalovirus: A European Expert Consensus Statement on Diagnosis and Management.

Molecular basis of virus replication, viral pathogenesis and antiviral strategie