Postnatal cytomegalovirus infection and pulmonary vascular disease in extremely premature infants: A case series.

BACKGROUND: Pulmonary vascular disease (PVD) is a major determinant of both morbidity and mortality in extremely low birth weight infants. It is biologically plausible that postnatal cytomegalovirus (pCMV) infection may lead to PVD in premature infants secondary to pneumonitis or via derangement of pulmonary vascular development directly through endothelial dysfunction. Uncertainty remains, however, regarding thresholds for intervention in premature infants with cardiorespiratory instability and presumed CMV infection likely secondary to the limited understanding of the natural history of the disease. METHODS/RESULTS: We describe four cases of premature infants with clinical and echocardiography features of PVD, in the setting of postnatally acquired CMV. All patients had atypical PVD trajectories, refractory to vasodilator treatment, which improved after initiation of CMV treatment. CONCLUSION: We highlight the need to consider postnatally acquired CMV infection in patients with PVD non-responsive to standard pulmonary vasodilator therapies or disease severity which is out of proportion of the usual clinical trajectory. Treatment of extremely premature infants with CMV-associated PVD may have positive impact on cardiorespiratory health, although duration of therapy remains uncertain.

Evaluation of suspected neonatal herpes simplex virus infection in preterm versus term newborns in the neonatal intensive care unit.

BACKGROUND: While national guidelines are available for the evaluation and management of term infants at risk for herpes simplex virus (HSV) infection, such guidelines are lacking for preterm infants. We sought to determine the risk factors and clinical characteristics of preterm vs. term infants who were evaluated and treated empirically for HSV infection in the neonatal intensive care unit (NICU). METHODS: In a retrospective cohort study, medical records of all infants who were admitted to our NICU (2009-2016) and who were evaluated and empirically treated for HSV were reviewed for mothers' and infants' demographics, clinical characteristics, and laboratory findings. RESULTS: During the study period 4.2% (103/2,471) of all preterm infants, and 6.0% (112/1,865) of all term infants were evaluated and treated empirically for neonatal HSV. Among all infants who were evaluated and treated for HSV, 5.5% (12/215) had neonatal HSV disease, of whom 83.3% (10/12) were preterm infants. In comparison to term, preterm infants were more likely to be evaluated and treated, if they had a maternal history of HSV [OR 2.51 (95% CI: 1.41-4.48)], prolonged rupture of membranes [2.64 (1.221-5.73)], leukopenia [3.65 (1.94-6.87)] and thrombocytopenia [2.25 (0.85-5.89)]. HSV disease was associated with a higher mortality compared to those without disease [25% (3/12) vs. 4.4% (9/203) respectively; p = <0.05]. CONCLUSION: Preterm infants evaluated and empirically treated for HSV have a higher burden of HSV infection than term infants. HSV should be considered in the management of preterm infant with a maternal history of HSV, prolonged rupture of membranes, and thrombocytopenia.

Comparison of health care resource utilization among preterm and term infants hospitalized with Human Respiratory Syncytial Virus infections: A systematic review and meta-analysis of retrospective cohort studies.

INTRODUCTION: Data on the variation in the medical resource utilization rate of Human Respiratory Syncytial Virus (HRSV) infected children by gestational age have recently been made available. This review aimed to determine whether prematurity is independently associated with the use of medical resources in hospitalized children for HRSV infections. METHODS: We conducted this systematic review on cohort studies published on the medical resources use in preterm and full-term patients hospitalized for confirmed HRSV infections. We searched PubMed, Embase, and Global Index medicus for eligible studies. The standardized mean difference (SMD) and Risk Ratio (RR) with their 95% confidence intervals (95% CI) were estimated as summary statistics with random effects meta-analysis. The overall results were adjusted to the common confounders by stratified analyses. RESULTS: A total of 14 articles (20 studies) were included. Compared to full-term, preterm hospitalized with HRSV infections had more frequent intensive care unit admission (RR = 2.6, 95% CI = 1.9-3.5), increased length of stay in hospital (SMD = 0.6, 95% CI = 0.5-0.8) and intensive care unit (SMD = 0.6, 95% CI = 0.4-0.8) and increased case fatality rate (RR = 6.9, 95% CI = 2.0-23.8). Mechanical ventilation utilization was more frequent in preterm children ≤ 2 years (RR = 15.5, 95% CI = 8.9-26.4) and those who did not receive prophylaxis against HRSV (RR = 15.9, 95% CI = 9.1-27.9)] than in full-term children. No differences were identified in the frequency of emergency department visits, oxygen utilization, and the age at the first HRSV episode between preterm and full-term infants. CONCLUSIONS: Regardless of gestational age, preterm infants hospitalized for HRSV infections, especially those ≤ 2 years, have an increased frequency of use of health resources and poor outcomes compared to full-term infants. HRSV vaccine development programs for pregnant women should be accelerated. CLINICAL TRIALS REGISTRATION: Review registration PROSPERO, CRD42019124375.

Microwave treatment of breast milk for prevention of cytomegalovirus infection.

BACKGROUND: Breast milk (BM) is the best nutrition for very preterm infants (VPI), except when provided by human cytomegalovirus (HCMV)-seropositive mothers. Given that VPI are at high risk of developing a sepsis-like syndrome or cholestasis, methods for prevention of HCMV infection via BM have been investigated. Although Holder pasteurization (HP) is the gold standard, HP needs special instruments. Microwave (MW) is available anywhere, therefore, we performed this study to determine whether MW can be used for HCMV prevention. METHODS: Human cytomegalovirus Towne strain was added to formula, followed by heating procedure using HP or MW (at 500 W for 20, 30, 40, or 60 s). HFL-III cells were seeded in culture dishes. Aliquots of HCMV-milk samples after heating were inoculated onto susceptible cell monolayers. The number of plaques was counted to determine the viral titer. The determination of HCMV-DNA copies was also performed. RESULTS: Addition of HCMV for a viral load of 5.0 × 103 plaque-forming units (p.f.u.)/mL achieved 772 p.f.u./mL at baseline, with a decrease to 257 p.f.u./mL after MW radiation for 20 s. No plaque was detected after HP or MW for 30, 40, and 60 s. The temperature of the breast milk reached 60°C after MW radiation for 40 s. The number of HCMV-DNA copies did not change with MW. CONCLUSIONS: Microwave at 500 W for 40 s can be used as a prevention strategy for HCMV transmission. Further research including the loss of bioactive properties in BM is required prior to clinical application.

Predicting healthcare outcomes in prematurely born infants using cluster analysis.

AIMS: Prematurely born infants are at high risk of respiratory morbidity following neonatal unit discharge, though prediction of outcomes is challenging. We have tested the hypothesis that cluster analysis would identify discrete groups of prematurely born infants with differing respiratory outcomes during infancy. METHODS: A total of 168 infants (median (IQR) gestational age 33 (31-34) weeks) were recruited in the neonatal period from consecutive births in a tertiary neonatal unit. The baseline characteristics of the infants were used to classify them into hierarchical agglomerative clusters. Rates of viral lower respiratory tract infections (LRTIs) were recorded for 151 infants in the first year after birth. RESULTS: Infants could be classified according to birth weight and duration of neonatal invasive mechanical ventilation (MV) into three clusters. Cluster one (MV ≤5 days) had few LRTIs. Clusters two and three (both MV ≥6 days, but BW ≥or <882 g respectively), had significantly higher LRTI rates. Cluster two had a higher proportion of infants experiencing respiratory syncytial virus LRTIs (P = 0.01) and cluster three a higher proportion of rhinovirus LRTIs (P < 0.001) CONCLUSIONS: Readily available clinical data allowed classification of prematurely born infants into one of three distinct groups with differing subsequent respiratory morbidity in infancy.

Burden, Etiology, and Risk Factors of Respiratory Virus Infections Among Symptomatic Preterm Infants in the Tropics: A Retrospective Single-Center Cohort Study.

Background: The burden of respiratory viral infections (RVIs) among preterm infants in the first few years of life, especially those living in the tropics with year-long transmissions of respiratory viruses, remains unknown. We aimed to describe the clinical epidemiology and associated risk factors for RVIs among symptomatic preterm infants ≤32 weeks up to 2 years of life. Methods: We performed a data linkage analysis of clinical and hospital laboratory databases for preterm infants born at KK Women's and Children's Hospital, Singapore, from 2005 to 2015. RVI episodes during initial admission and subsequent hospital readmissions were included. Results: Of 1854 infants in the study, 270 (14.5%) infants were diagnosed with at least 1 RVI. A total of 285 (85.3%) episodes were diagnosed postdischarge, with the highest risk for RVIs being from 3 to 5 months of age. The incidence of RVI in this population was 116 per 1000 infant-years and respiratory syncytial virus was the main overall causative pathogen. Infants with RVIs were more likely to be born at ≤27 weeks' gestational age (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.2-2.3), to have received postnatal steroids (OR, 1.5; 95% CI, 1.0-2.1), and to be diagnosed with bronchopulmonary dysplasia (OR, 1.7; 95% CI, 1.2-2.4). Conclusions: The burden of RVIs is high in preterm infants in the tropics, affecting >1 of 10 infants born at ≤32 weeks' gestation before 2 years of age. Respiratory syncytial virus was the main causative pathogen identified. Risk factors for RVI included extremely low gestational age, receipt of postnatal steroids, and bronchopulmonary dysplasia.

Palivizumab administration in preterm infants in France: EPIPAGE-2 cohort study.

BACKGROUND: Several countries, including France, have restricted the indications for monoclonal antibodies directed against respiratory syncytial virus (RSV) compared to the marketing authorization (MA). No new data concerning use of palivizumab on a national scale have been published since the 2007 update of the national guidelines. OBJECTIVES: To describe palivizumab administration for RSV prophylaxis during the first RSV season in infants born prematurely in France in 2011. METHODS: Infants from the national population-based cohort EPIPAGE-2 born at≤34 weeks' gestation, discharged home before 31 March 2012 and followed-up at 1year were included. The RSV season ran from 1 October 2011 to 31 March 2012. Prophylaxis was deemed "initiated" if the infant had received at least one dose of palivizumab during this period and "complete" if it had received at least five doses or as many doses as the number of exposed months. The reference documents were the MA and French Transparency Committee guidelines (TC). RESULTS: Prophylaxis was indicated in 3586 of 3608 infants (99.7%) according to the MA and 1315 of 3608 (16.7%) according to the TC. A total of 1906 infants (26.6%) received at least one dose of palivizumab. The overall rate of conformity with TC indications was 85%, but was lower for infants born at 27-32 weeks' gestation. The rate of complete prophylaxis was 77.2%. The factors associated with prophylaxis initiation were low gestational age, low birthweight, high maternal educational level, type of neonatal unit, and date at discharge. Factors associated with complete prophylaxis were respiratory impairment, high educational level, and characteristics related to living conditions (absence of siblings at home, type of childcare). CONCLUSIONS: Palivizumab administration in France generally conformed with TC guidelines, but could be further improved for infants born at 27-32 weeks' gestation without bronchopulmonary dysplasia.

Persistent intestinal bleeding due to severe CMV-related thrombocytopenia in a preterm newborn.

The optimal threshold for neonatal platelet transfusions in sick newborns is still uncertain. We report a congenital cytomegalovirus (CMV) infection in a premature neonate with severe thrombocytopenia who subsequently presented with necrotizing enterocolitis and intestinal bleeding. The baby recovered after platelet transfusions were discontinued and the therapy was switched from intravenous ganciclovir to oral valganciclovir. We discuss both measures, speculating on the key role of platelet transfusions.

Neonatal gastrointestinal involvement and congenital cytomegalovirus.

Cytomegalovirus (CMV) is the most common cause of congenital viral infection, affecting 0.2 to 2.3% of all live births in developed countries. Very low birth weight and extremely low birth weight newborns are at higher risk of symptomatic CMV infection, most commonly secondary and acquired through breast milk. Gastrointestinal involvement is rare in acquired CMV infections, but it could be an important manifestation of postnatal infection in preterm infants admitted to neonatal intensive care units. Early onset of CMV gastrointestinal signs/symptoms is very rare. In a review of the literature it is described in 5 newborns in the first 24 hours of life, and 6 considering the onset in the first week of life. This review describes also a case report of congenital CMV in an immunocompetent newborn with onset of gastrointestinal signs immediately after birth: a possible association between viral infection and enteric manifestations was considered in the differential diagnosis. A review of the literature of the different case reports found has done, with description and comparison of the different patients and clinical presentations.

Respiratory Syncytial Virus Hospitalizations in Healthy Preterm Infants: Systematic Review.

BACKGROUND: Studies have explored the risk for and impact of respiratory syncytial virus (RSV) infection requiring hospitalization among healthy preterm infants born at 29-35 weeks of gestational age not given RSV immunoprophylaxis. We performed a systematic review and qualitative synthesis of these studies. METHODS: Two experienced reviewers used prespecified inclusion/exclusion criteria to screen titles/abstracts and full-text studies using MEDLINE, Embase, BIOSIS and Cochrane Library (January 1, 1985, to November 6, 2014). We abstracted data on risk factors for RSV hospitalization, incidence and short- and long-term outcomes of RSV hospitalization. Using standard procedures, we assessed study risk of bias and graded strength of evidence (SOE). RESULTS: We identified 4754 records and reviewed 27. Important risk factors for RSV hospitalization included young age during the RSV season, having school-age siblings and day-care attendance, with odds ratios >2.5 in at least one study (high SOE). Incidence rates for RSV hospitalizations ranged from 2.3% to 10% (low SOE). Length of hospital stays ranged from 3.8 to 6.1 days (low SOE). Recurrent wheezing rates ranged from 20.7% to 42.8% 1 to 2 years after RSV hospitalization (low SOE). CONCLUSIONS: Young chronological age and some environmental risk factors are important clinical indicators of an increased risk of RSV hospitalization in healthy preterm infants 32 to 35 weeks of gestational age. SOE was low for estimates of incidence of RSV hospitalizations, in-hospital resource use and recurrent wheezing in this population. Studies were inconsistent in study characteristics, including weeks of gestational age, age during RSV season and control for confounding factors.

Cytomegalovirus and other common enteric viruses are not commonly associated with NEC.

AIM: Changes in gut microbiota may contribute to NEC, but most studies focus on bacteria. Case reports suggest a link between cytomegalovirus (CMV) or other enteric viruses and NEC, but there are few case series systematically looking at common potential viral causes. We aimed to assess the presence of candidate viruses in blood or stool of a case series of infants with NEC managed in one surgical centre. METHODS: We identified 22 infants diagnosed with NEC (from November 2011 to March 2014): 17 had suitable blood stored, of whom 14 also had suitable stool samples stored. Blood was analysed with polymerase chain reaction (PCR) for CMV, Epstein-Barr virus (EBV) and adenovirus, and stool by PCR for norovirus, sappovirus, astrovirus, adenovirus and rotavirus. RESULTS: All samples were negative. CONCLUSION: Although case reports indicate an episodic association of enteric viruses in NEC, the inability to detect any of these viruses in our 17 NEC infants suggests that a viral aetiology is unlikely to be causative for most sporadic forms of NEC.

Revised recommendations concerning palivizumab prophylaxis for respiratory syncytial virus (RSV).

Respiratory Syncytial Virus infections are one of the leading causes of severe respiratory diseases that require hospitalization and, in some cases, intensive care. Once resolved, there may be respiratory sequelae of varying severity. The lack of effective treatments for bronchiolitis and the lack of vaccines for RSV accentuate the role of prevention in decreasing the impact of this disease. Prevention of bronchiolitis strongly relies on the adoption of environment and the hygienic behavior measures; an additional prophylactic effect may be offered, in selected cases, by Palivizumab, a humanized monoclonal antibody produced by recombinant DNA technology, able to prevent RSV infection by blocking viral replication.After many years the Italian Society of Neonatology, on the basis of the most recent scientific knowledge, has decided to revise recommendations for the use of palivizumab in the prevention of RSV infection.

Long-Term Burden and Respiratory Effects of Respiratory Syncytial Virus Hospitalization in Preterm Infants-The SPRING Study.

The health status of premature infants born 321-350 weeks' gestational age (wGA) hospitalized for RSV infection in the first year of life (cases; n = 125) was compared to that of premature infants not hospitalized for RSV (controls; n = 362) through 6 years. The primary endpoints were the percentage of children with wheezing between 2-6 years and lung function at 6 years of age. Secondary endpoints included quality of life, healthcare resource use, and allergic sensitization. A significantly higher proportion of cases than controls experienced recurrent wheezing through 6 years of age (46.7% vs. 27.4%; p = 0.001). The vast majority of lung function tests appeared normal at 6 years of age in both cohorts. In children with pulmonary function in the lower limit of normality (FEV1 Z-score [-2; -1]), wheezing was increased, particularly for cases vs. controls (72.7% vs. 18.9%, p = 0.002). Multivariate analysis revealed the most important factor for wheezing was RSV hospitalization. Quality of life on the respiratory subscale of the TAPQOL was significantly lower (p = 0.001) and healthcare resource utilization was significantly higher (p<0.001) in cases than controls. This study confirms RSV disease is associated with wheezing in 32-35 wGA infants through 6 years of age.

An atypical course of coxsackievirus A6 associated hand, foot and mouth disease in extremely low birth weight preterm twins.

The incidence of coxsackievirus A6 (CV-A6) associated hand, foot and mouth disease (HFMD) has reportedly increased since 2008 with sometimes severe complications. We here describe an atypical course of CV-A6-associated HFMD in extremely low birth weight twins. The CV-A6-strains are genetically closely related to international strains isolated from HFMD outbreaks.

[Universal cytomegalovirus infection screening in premature newborns less than 1500 g]. / Cribado universal de infección por citomegalovirus en prematuros de menos de 1.500 g.

INTRODUCTION: Cytomegalovirus (CMV) infection is endemic, and children who attend day care are the most important source of infection. OBJECTIVE: To establish recommendations based on the medical evidence on the vertical transmission of cytomegalovirus in preterm infants weighing less than 1500g at birth. BACKGROUND: Infection in pregnant women may be primary or secondary. Although there is fetal infection, 85% of newborn infants are asymptomatic. Symptoms of infection include low birth weight, hepatosplenomegaly, thrombocytopenia, microcephaly and neurological disorders. The prognosis of symptomatic children is very poor, with high mortality and neurological disorders. The virus can be reactivated during breast feeding, and early infection is possible through breast milk, probably with little impact in term infants, although the long-term neurological outcome worsens in preterm infants. The diagnostic method of choice is the identification of CMV in urine; the determination in the first two weeks of life suggests congenital infection; later it can be acquired at birth or through breast milk or contaminated blood transfusion. CONCLUSION AND RECOMMENDATION: Determine viral DNA at 4-6 weeks of life by protease chain reaction. If it is positive, monitoring of samples from the first days of life and breast milk are mandatory. This should allow the newborn to be classified into three states: "Without CMV infection", "Congenital CMV infection", "Acquired CMV infection".