Burden of sequelae and healthcare resource utilization in the first year of life in infants born with congenital cytomegalovirus (cCMV) infection in Germany: A retrospective statutory health insurance claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can have a broad range of manifestations. This study aimed to assess cCMV-associated sequelae and healthcare resource utilization (HCRU) in infants during the first year of life in Germany. METHODS: A retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database was conducted. cCMV-associated sequelae and HCRU during the first year of life were assessed by matching (1:60) infants with at least one inpatient/outpatient cCMV diagnosis (ICD-10-GM: P35.1) ≤90 days after birth (cCMV90 cohort) and infants with at least one inpatient cCMV diagnosis plus specific sequelae ≤21 days after birth (cCMV21-S) to infants without cCMV or CMV (ICD-10-GM: B25) diagnosis (control group), respectively. Outcomes were analyzed during the first 365 days of life. RESULTS: Between 2014-2018, we identified 54 newborns for cCMV90 and 24 newborns for cCMV21-S cohort. Compared to the 3,240 and 1,440 controls, respectively, more cCMV90 infants (83.3% vs. 41.9%, p<0.01) presented with at least one sequela during the first year of life, including intrauterine growth retardation (42.6% vs. 5.3%, p<0.01), sensorineural hearing loss (SNHL) to deafness (38.9% vs. 2.2%, p<0.01), and motor development disorders (33.3% vs. 10.9%, p<0.01). Further, 13.0% of cCMV90 infants (vs. 2.3%, p<0.01) suffered from visual impairment. In cCMV21-S cohort, intrauterine growth retardation (79.2% vs. 6.0%, p<0.01), prematurity (54.2% vs. 7.3%, p<0.01), and motor development disorders (50.0% vs. 11.0%, p<0.01) were the most frequent sequelae. Infants in the cCMV90 and cCMV21-S cohort had, on average, 7.3 times and 9.5 times more hospitalizations and 2.0 times and 2.1 times more outpatient physician visits than their respective controls (p<0.01). Hospitalized infants with cCMV stayed, on average, significantly longer in hospital compared to their controls (cCMV90 cohort: 30.3 days vs. 9.0 days, p<0.01; cCMV21-S cohort: 46.5 days vs. 9.3 days, p<0.01). CONCLUSIONS: cCMV-infection shows a considerable disease and healthcare burden during the first year of life. More than 80% of the identified newborns with cCMV suffered from at least one associated sequela during the first year of life, including long-term sequelae such as SNHL (40%) and visual impairment (13%). Additional steps for prevention of cCMV infection and associated sequelae as well as a comprehensive monitoring of disease burden are needed.

Reduced structural connectivity in non-motor networks in children born preterm and the influence of early postnatal human cytomegalovirus infection.

Introduction: Preterm birth is increasingly recognized to cause lifelong functional deficits, which often show no correlate in conventional MRI. In addition, early postnatal infection with human cytomegalovirus (hCMV) is being discussed as a possible cause for further impairments. In the present work, we used fixel-based analysis of diffusion-weighted MRI to assess long-term white matter alterations associated with preterm birth and/or early postnatal hCMV infection. Materials and methods: 36 former preterms (PT, median age 14.8 years, median gestational age 28 weeks) and 18 healthy term-born controls (HC, median age 11.1 years) underwent high angular resolution DWI scans (1.5 T, b = 2 000 s/mm2, 60 directions) as well as clinical assessment. All subjects showed normal conventional MRI and normal motor function. Early postnatal hCMV infection status (CMV+ and CMV-) had been determined from repeated screening, ruling out congenital infections. Whole-brain analysis was performed, yielding fixel-wise metrics for fiber density (FD), fiber cross-section (FC), and fiber density and cross-section (FDC). Group differences were identified in a whole-brain analysis, followed by an analysis of tract-averaged metrics within a priori selected tracts associated with cognitive function. Both analyses were repeated while differentiating for postnatal hCMV infection status. Results: PT showed significant reductions of fixel metrics bilaterally in the cingulum, the genu corporis callosum and forceps minor, the capsula externa, and cerebellar and pontine structures. After including intracranial volume as a covariate, reductions remained significant in the cingulum. The tract-specific investigation revealed further reductions bilaterally in the superior longitudinal fasciculus and the uncinate fasciculus. When differentiating for hCMV infection status, no significant differences were found between CMV+ and CMV-. However, comparing CMV+ against HC, fixel metric reductions were of higher magnitude and of larger spatial extent than in CMV- against HC. Conclusion: Preterm birth can lead to long-lasting alterations of WM micro- and macrostructure, not visible on conventional MRI. Alterations are located predominantly in WM structures associated with cognitive function, likely underlying the cognitive deficits observed in our cohort. These observed structural alterations were more pronounced in preterms who suffered from early postnatal hCMV infection, in line with previous studies suggesting an additive effect.

Good handling practice of parenterally administered medicines in neonatal intensive care units - position paper of an interdisciplinary working group.

This position paper, developed by an interdisciplinary expert group of neonatologists, paediatric infectious disease physicians, clinical pharmacists and specialists for the prevention and control of nosocomial infections, describes the "Good handling practice of medicines parenterally administered to patients on NICUs". It takes equal account of patient safety and the specialties of neonatal intensive care regarding feasibility and proportionality. The overall concept is perceived as a "learning system", in which open communication within the health-care team relating to medication errors and critical incidents enables continuous development and improvement to ensure patient safety. In our opinion, pharmacists, who are responsible for the supply of ready-to-administer parenteral medicinal products for neonatal intensive care patients, as well as the hygiene staff responsible on site are integral parts of the interdisciplinary treatment team. Risks of the current clinical practice of parenteral treatment of NICU patients are discussed in detail and recommendations for safety-relevant procedures are given.

Healthcare costs of congenital cytomegalovirus (cCMV) disease in infants during the first two years of life: a retrospective German claims database analysis.

BACKGROUND: Congenital cytomegalovirus (cCMV) infection can cause severe neurological damage, growth retardation, hearing loss, and microcephaly in infants. We aimed at assessing healthcare costs of infants with recorded cCMV diagnosis in an administrative claims database in the first 2 years of life. METHODS: We conducted a retrospective, controlled cohort study using German claims data from the Institute for Applied Health Research Berlin (InGef) database. Incremental healthcare costs during the first and second year of life were assessed by matching (1:60) infants with cCMV diagnoses ≤ 90 days after birth (cCMV90 cohort) to infants without cCMV diagnosis ("representative" controls) and infants with cCMV diagnoses ≤ 21 days after birth plus specific symptoms (cCMV21-S) to infants without cCMV and any ICD-10-GM records (besides Z00-Z99) until 4th preventive health check-up ("healthy" controls). Due to missing data, mean imputation was applied for aids and remedies costs. RESULTS: We identified 54 and 24 infants born 2014-2018 for the cCMV90 and cCMV21-S cohorts, respectively. During the first year, mean (median) healthcare costs were significantly higher in cCMV90 cases vs. "representative" controls (€22,737 (€9759) vs. €3091 (€863), p < 0.001), with 87.2% inpatient costs. Healthcare costs for cCMV21-S cases compared to "healthy" controls were €34,498 (€20,924) vs. €680 (€569), p < 0.001. Differences decreased for both comparisons in the second year but remained statistically significant. CONCLUSIONS: cCMV comprises a considerable economic burden for the German healthcare system (€19,646 to €33,818 higher mean costs for infants with recorded cCMV diagnosis in the first year of life). Attempts should be made to reduce this burden.

Frequencies of activated T cell populations increase in breast milk of HCMV-seropositive mothers during local HCMV reactivation.

Background: Human cytomegalovirus (HCMV) can reactivate in the mammary gland during lactation and is shed into breast milk of nearly every HCMV-IgG-seropositive mother of a preterm infant. Dynamics of breast milk leukocytes during lactation, as well as blood leukocytes and the comparison between both in the context of HCMV reactivation is not well understood. Methods: Here, we present the BlooMil study that aimed at comparing changes of immune cells in blood and breast milk from HCMV-seropositive- vs -seronegative mothers, collected at four time ranges up to two months post-partum. Viral load was monitored by qPCR and nested PCR. Multiparameter flow cytometry was used to identify leukocyte subsets. Results: CD3+ T cell frequencies were found to increase rapidly in HCMV-seropositive mothers' milk, while they remained unchanged in matched blood samples, and in both blood and breast milk of HCMV-seronegatives. The activation marker HLA-DR was more strongly expressed on CD4+ and CD8+ T cells in all breast milk samples than matched blood samples, but HCMV-seropositive mothers displayed a significant increase of HLA-DR+ CD4+ and HLA-DR+ CD8+ T cells during lactation. The CD4+/CD8+ T cell ratio was lower in breast milk of HCMV-seropositive mothers than in the blood. HCMV-specific CD8+ T cell frequencies (recognizing pp65 or IE1) were elevated in breast milk relative to blood, which might be due to clonal expansion of these cells during local HCMV reactivation. Breast milk contained very low frequencies of naïve T cells with no significant differences depending on serostatus. Conclusion: Taken together, we conclude that the distribution of breast milk leukocyte populations is different from blood leukocytes and may contribute to the decrease of breast milk viral load in the late phase of HCMV reactivation in the mammary gland.

Safely Inserting Neonatal Chest Drains.

BACKGROUND: Inserting a chest drain for a left-sided neonatal pneumothorax carries a risk of penetrating the pericardium. We identified reference ranges for the chest wall thickness (CWT) and distance between the pericardium and parietal pleura to improve safety of chest tube insertion. METHOD: We prospectively measured the CWT using ultrasound in 20 neonates (body weight [BW] 640-2,700 g, age <10 days) at the usual site of puncture in the 4th and 5th intercostal space (ICS). Furthermore, we measured the minimal distance between the parietal pleura and the cardiac silhouette in 131 neonatal chest X-rays (birth weight, 420-4,930 g [divided into 11 weight groups]; age <10 days). Both data sets were transformed into weight-dependent percentiles (Ps). We considered the difference between the sum of P 2.5 for the CWT plus P 2.5 for pleura-heart distance minus P 97.5 for the CWT as a safe corridor for placing the tip of the needle. RESULTS: At both ICSs, curves for the above metrics did not cross, indicating a narrow but safe corridor for each BW with at least 97.5% probability. This safety corridor was 4.6-5.2 mm wide for the 4th and 2.8-3.4 mm for the 5th ICS. CONCLUSION: These data offer a reference for left-sided chest drain insertion for BW <2,700 g, which may help to improve safety of the procedure.

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome: two-year outcomes.

OBJECTIVE: To assess at 24 months corrected age (CA) the neurological, respiratory, and general health status of children born prematurely from 27+0 to 33+6 weeks' gestation who were treated in a first-in-human study with a new fully synthetic surfactant (CHF5633) enriched with SP-B and SP-C proteins. OUTCOME MEASURES: Children were assessed using Bayley Scales of Infant Development (BSID), with a score below normal defined as BSID-II Mental Development Index score <70, or BSID-III cognitive composite score <85. In addition, a health status questionnaire was used to check for functional disability including respiratory problems and related treatments, sensory and neurodevelopment assessments, communication skills as well as the number of hospitalizations. RESULTS: 35 of 39 survivors had a neurodevelopmental assessment, 24 infants being evaluated by Bayley's Scales and 11 by health status questionnaires only. 23 children had scores within normal limits and one had BSID-III <85. The remaining 11 were judged clinically to have normal development. Health status questionnaires detected only issues that would normally be expected in preterm-born children. CONCLUSIONS: This assessment offers reassurance that treatment with CHF5633 surfactant was not associated with adverse neurodevelopmental, respiratory, or health outcomes by two years corrected age.

Immunomonitoring of Human Breast Milk Cells During HCMV-Reactivation.

Background: Breast milk leukocytes may play a role in protecting the infant from pathogens. The dynamics and the role of lymphocytes in human cytomegalovirus (HCMV)-seropositive mothers shedding HCMV into breast milk during the first months postpartum (p.p.) are mostly unclear. Methods: Breast milk cells were analyzed by Pappenheim panoptic and alpha-naphthyl acetate esterase staining as well as by imaging and polychromatic flow cytometry to simultaneously establish their morphological and phenotypic properties. The latter were characterized in HCMV-seropositive and seronegative mothers´ breast milk cells at different time points p.p. Results: Panoptic staining of breast milk cells revealed the presence of monocytes/macrophages, granulocytes and lymphocytes. Imaging flow cytometry data combining phenotypic and morphological analysis identified NKT-like cells, NK cells, epithelial cells, T cells and monocytes/macrophages. HCMV-seropositive but not -seronegative mothers had significantly higher T cell frequencies in mature milk. Conclusions: The presence of lymphocyte subsets in breast milk may be more influenced by the HCMV-seropositivity of the mother than previously recognized.

Optimizing Early Neonatal Nutrition and Dietary Pattern in Premature Infants.

Providing adequate amounts of all essential macro- and micronutrients to preterm infants during the period of extraordinarily rapid growth from 24 to 34 weeks' postmenstrual age to achieve growth as in utero is challenging yet important, since early growth restriction and suboptimal neonatal nutrition have been identified as risk factors for adverse long-term development. Along with now well-established early parenteral nutrition, this review emphasizes enteral nutrition, which should be started early and rapidly increased. To minimize the side effects of parenteral nutrition and improve outcomes, early full enteral nutrition based on expressed mothers' own milk is an important goal. Although neonatal nutrition has improved in recent decades, existing knowledge about, for example, the optimal composition and duration of parenteral nutrition, practical aspects of the transition to full enteral nutrition or the need for breast milk fortification is limited and intensively discussed. Therefore, further prospective studies on various aspects of preterm infant feeding are needed, especially with regard to the effects on long-term outcomes. This narrative review will summarize currently available and still missing evidence regarding optimal preterm infant nutrition, with emphasis on enteral nutrition and early postnatal growth, and deduce a practical approach.

Human Cytomegalovirus Genome Diversity in Longitudinally Collected Breast Milk Samples.

Reactivation and shedding of human cytomegalovirus (HCMV) in breast milk during lactation is highly frequent in HCMV-seropositive mothers. This represents a key transmission route for postnatal HCMV infection and can lead to severe disease in preterm neonates. Little is known about HCMV strain composition or longitudinal intrahost viral population dynamics in breast milk from immunocompetent women. We performed HCMV-specific target enrichment and high-throughput sequencing of 38 breast milk samples obtained in Germany between days 10 and 60 postpartum from 15 mothers with HCMV DNA lactia, and assembled HCMV consensus sequences de novo. The genotype distribution and number of HCMV strains present in each sample were determined by quantifying genotype-specific sequence motifs in 12 hypervariable viral genes, revealing a wide range of genotypes (82/109) for these genes in the cohort and a unique, longitudinally stable strain composition in each mother. Reactivation of up to three distinct HCMV strains was detected in 8/15 of mothers, indicating that a representative subset of the woman's HCMV reservoir might be locally reactivated early during lactation. As described previously, nucleotide diversity of samples with multiple strains was much higher than that of samples with single strains. Breast milk as a main source of postnatal mother-to-infant transmission may serve as a repository for viral diversity and thus play an essential role in the natural epidemiology of HCMV.

Living-Donor Uterus Transplantation: Pre-, Intra-, and Postoperative Parameters Relevant to Surgical Success, Pregnancy, and Obstetrics with Live Births.

Uterus transplantation (UTx) can provide a route to motherhood for women with Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS), a congenital disorder characterized by uterovaginal aplasia, but with functional ovaries. Based on our four successful living-donor transplantations and two resulting births, this analysis presents parameters relevant to standardizing recipient/donor selection, UTx surgery, and postoperative treatment, and their implementation in routine settings. We descriptively analyzed prospectively collected observational data from our four uterus recipients, all with MRKHS, their living donors, and the two newborns born to two recipients, including 1-year postnatal follow-ups. Analysis included only living-donor/recipient pairs with completed donor/recipient surgery. Two recipients, both requiring ovarian restimulation under immunosuppression after missed pregnancy loss in one case and no pregnancy in the other, each delivered a healthy boy by cesarean section. We conclude that parameters crucial to successful transplantation, pregnancy, and childbirth include careful selection of donor/recipient pairs, donor organ quality, meticulous surgical technique, a multidisciplinary team approach, and comprehensive follow-up. Surgery duration and blood vessel selection await further optimization, as do the choice and duration of immunosuppression, which are crucial to timing the first embryo transfer. Data need to be collected in an international registry due to the low prevalence of MRKHS.

Nasal insertion depths for neonatal intubation.

AIM: Data on the depth of nasal intubation in neonates are rare, although this is the preferred route in some countries. Therefore, recommendations on optimal nasal intubation depths based on gestational age (GA) and weight are desirable. METHODS: We determined the distances between the middle of thoracic vertebrae 2 (T2) and the tip of the endotracheal tube in 116 X-rays from nasally intubated neonates. The intubation depth (tip to nostril distance) that was documented in the digital patient's file was then corrected for this distance to reach an optimal nasal insertion depth. Results were plotted against the infant's GA and weight. RESULTS: GA-based and birthweight-based charts and formulas for the nasal intubation depth in infants with a GA between 24 and 43 weeks and body weight between 400 and 4500 g were created. CONCLUSIONS: Generated data may help in predicting optimal insertion depths for nasal intubation in neonates.

Human Cytomegalovirus Reactivation During Lactation: Impact of Antibody Kinetics and Neutralization in Blood and Breast Milk.

Human cytomegalovirus (HCMV) is shed into breast milk in nearly every seropositive woman during lactation. This reactivation shows mostly a self-limited, unimodal course. The dynamics and functional role of HCMV-specific-IgG in breast milk and in plasma during reactivation are unknown. Milk whey viral loads were monitored with real-time PCR in 18 HCMV-seropositive mothers over two months postpartum. HCMV-antibody binding assays (ECLIA) and antigen-specific immunoblotting were performed from plasma and corresponding milk samples. Epithelial-cell-specific neutralization was used to analyze functional antibodies in plasma- and whey-pools. Viral loads in milk whey showed unimodal courses in 15 of 18 mothers with peak viral loads around one month postpartum. HCMV-specific-IgG-antibodies increased significantly in plasma and milk whey during reactivation. The mean levels of plasma IgG were about 275-fold higher than in whey. Only antibodies against tegument protein p150 were continuously expressed in both compartments. Anti-glycoprotein-B1 IgG-antibodies were variably expressed in whey, but continuously in plasma. Neutralization assays showed 40-fold higher NT-50 values in plasma compared to whey at two months postpartum. During reactivation, HCMV-specific-IgG reactivities and neutralizing capacities are much lower in whey than in plasma. Therefore, their specific role in the decrease and discontinuation of virus-shedding in milk remains unclear.

Human Cytomegalovirus (HCMV) Reactivation in the Mammary Gland Induces a Proinflammatory Cytokine Shift in Breast Milk.

A locally restricted human cytomegalovirus (HCMV) reactivation in the mammary gland commonly occurs in nearly every IgG-seropositive breastfeeding mother. This unique phenomenon can therefore be used to study the reactivation process in an immunocompetent healthy host. Breast milk contains a variety of immunoactive compounds, including immune cells, antibodies, growth factors, and cytokines supporting the newborn's immature immune system. To characterize the impact of HCMV reactivation on breast milk cytokines, we analyzed longitudinal breast milk samples of four IgG-seropositive and three IgG-seronegative mothers of preterm infants using Proximity Extension Assay (PEA) technology (Olink Proteomics, Uppsala, Sweden). Cytokine profiling revealed elevated cytokine levels in IgG-seropositive mothers' milk whey. Reactivating mothers showed higher levels of CC-chemokines (MCP-2, CCL19, and CCL20) and CXC-chemokines (IL-8, CXCL9, CXCL10, and CXCL11), such as the proinflammatory cytokine IL-17C, glycoprotein CD5, and TNFSF14. HCMV reactivation seems to influence the cytokine profile in human breast milk. This work could open the door for further studies analyzing distinct relations of the cytokine network as well as phenotypical and functional T cell properties in background of HCMV DNA dynamics in early lactation.

New short-term heat inactivation method of cytomegalovirus (CMV) in breast milk: impact on CMV inactivation, CMV antibodies and enzyme activities.

OBJECTIVES: Breast milk (BM) is the primary source of cytomegalovirus (CMV) transmission to premature infants with potentially harmful consequences. We therefore wanted to evaluate temperature and duration of short-term BM pasteurisation with respect to CMV inactivation, effect on CMV-IgG antibodies and BM enzyme activities. METHODS: 116 artificially CMV-spiked BM and 15 wild-type virus-infected samples were subjected for 5 s to different temperatures (55°C-72°C). CMV-IE-1 expression in fibroblast nuclei was assessed using the milk whey fraction in short-term microculture. BM lipase and alkaline phosphatase (AP) activities and CMV binding using CMV-recomLine immunoblotting and neutralising antibodies using epithelial target cells were analysed before and after heating. RESULTS: A minimum of 5 s above 60°C was necessary for CMV inactivation in both CMV-AD-169 spiked and wild-type infected BM. Lipase was very heat sensitive (activities of 54% at 55°C, 5% at 60°C and 2% at 65°C). AP showed activities of 77%, 88% and 10%, respectively. CMV-p150 IgG antibodies were mostly preserved at 62°C for 5 s. CONCLUSION: Our results show that short-term pasteurisation of BM at 62°C for 5 s might be efficient for CMV inactivation and reduces loss of enzyme activities, as well as CMV binding, and functional CMV antibodies.

Short-term Pasteurization of Breast Milk to Prevent Postnatal Cytomegalovirus Transmission in Very Preterm Infants.

BACKGROUND: Postnatally acquired cytomegalovirus (pCMV) infection through breast milk (BM) may cause severe illness and even death, yet BM is advantageous for preterm infants. Therefore, effective methods to prevent CMV transmission are needed. METHODS: To assess the effectiveness of short-term pasteurization (62°C for 5 seconds) in preventing CMV transmission via BM in preterm infants. Design: Prospective interventional bicentric cohort study with infant enrollment between 6/2010 and 1/2012. A cohort from the Tuebingen neonatal intensive care unit (NICU) from 1995-1998 served as historical controls. Differences in CMV transmission were compared with reference to the cumulative time at risk for CMV transmission. Setting: Two German level-3 NICUs. Eighty-seven preterm infants of 69 CMV immunoglobulin G-positive mothers with birth weight <1500 g or gestational age <32 weeks and 83 historical controls were included. Intervention: BM samples were short-term pasteurized from postnatal day 4 to discharge. Primary endpoint: CMV status at discharge, evaluated by polymerase chain reaction and short-term microculture from urine. RESULTS: Two of 87 (2.3%) study infants had a pCMV transmission. This compared to 17 of 83 (20.5%) controls. Total time under risk for infection was 9.6 years vs 10.0 years in controls, yielding an incidence of 0.21/year (95% confidence interval [CI], 0.03 to 0.75/year) vs 1.70/year (95% CI, 0.99 to 2.72/year), respectively. The risk ratio controls vs study infants was 8.3 (95% CI, 2.4 to 52.4) according to Cox proportional hazard model (P = .0003). CONCLUSIONS: Short-term pasteurization significantly reduces the incidence of pCMV infection through BM in the NICU. CLINICAL TRIALS REGISTRATION: NCT01178905.

Comparison of quantitative real-time PCR and short-term (18-hour) microculture in diagnosis of fetal cytomegalovirus infection: Impact of hyperimmunoglobulin treatment.

OBJECTIVE: The prognostic value of human cytomegalovirus detection (HCMV) DNA levels from amniotic fluid (AF) for the outcome of the infected newborn is still a matter of debate, especially if the onset of maternal primary infection at amniocentesis is unknown. The objective of this study was to investigate the analytical performance in short-term (18-hour) microculture from preconcentrated samples and quantitative real-time PCR (rtPCR) for diagnosis of fetal HCMV infection. METHODS: A retrospective diagnostic study was conducted on 51 AF samples taken from women that transmitted HCMV prenatally. Amniocentesis was performed around 22-week gestation. The samples were tested for HCMV viral load via quantitative rtPCR and additionally with quantitative short-term (18-hour) microculture following preconcentration via a 50 000 g centrifugation step prior to inoculation to fibroblast monolayers. RESULTS: Both methods show correlating results (ρ = 0.903). In 25 samples, the women received intravenous hyperimmunoglobulin prior to amniocentesis resulting in a lower correlation of both quantitative methods (ρ = 0.445), in reduced median copy numbers of HCMV DNA (P = .037) and reduced viral infectivity in short-term microculture (P = .025). CONCLUSION: Both methods lead to correlating results using AF samples from HIG-naïve women. Human cytomegalovirus viral load and infectivity in cell culture are reduced in samples following maternal hyperimmunoglobulin treatment.

Granulocytic Myeloid-Derived Suppressor Cells (GR-MDSC) in Breast Milk (BM); GR-MDSC Accumulate in Human BM and Modulate T-Cell and Monocyte Function.

Nosocomial bacterial infections (NBI) and necrotizing enterocolitis (NEC) are among the main reasons for death in preterm infants. Both are often caused by bacteria coming from the infected infant's gut and feeding with breast milk (BM) seems beneficial in their pathogenesis. However, mechanisms causing the protective effect of BM are only incompletely understood. Myeloid-derived suppressor cells (MDSC) are myeloid cells with suppressive activity on other immune cells, recently described to play a role in mediating maternal-fetal tolerance during pregnancy and immune adaptation in newborns. Until now, nothing is known about occurrence and function of MDSC in BM. We analyzed MDSC in BM and peripheral blood of breastfeeding mothers and found that granulocytic MDSC, but not monocytic MDSC, accumulate in BM, exhibit an activated phenotype and increased suppressive activity and modulate TLR-expression on monocytes. Furthermore, we found that the lactotrophic hormones prolactin and oxytocin do not induce MDSC from peripheral blood. This is the first study to describe MDSC with immune-modulatory properties in human BM. Our results point toward a role for MDSC in local immune modulation in the gut possibly protecting infants from NBI and NEC.

Incidence and Severity of Prescribing Errors in Parenteral Nutrition for Pediatric Inpatients at a Neonatal and Pediatric Intensive Care Unit.

OBJECTIVES: Pediatric inpatients are particularly vulnerable to medication errors (MEs), especially in highly individualized preparations like parenteral nutrition (PN). Aside from prescribing via a computerized physician order entry system (CPOE), we evaluated the effect of cross-checking by a clinical pharmacist to prevent harm from PN order errors in a neonatal and pediatric intensive care unit (NICU/PICU). METHODS: The incidence of prescribing errors in PN in a tertiary level NICU/PICU was surveyed prospectively between March 2012 and July 2013 (n = 3,012 orders). A pharmacist cross-checked all PN orders prior to preparation. Errors were assigned to seven different error-type categories. Three independent experts from different academic tertiary level NICUs judged the severity of each error according to the National Coordinating Council for Medication Error Reporting and Prevention (NCC MERP) Index (categories A-I). RESULTS: The error rate was 3.9% for all 3,012 orders (118 prescribing errors in 111 orders). 77 (6.0%, 1,277 orders) errors occurred in the category concentration range, all concerning a relative overdose of calcium gluconate for peripheral infusion. The majority of all events (60%) were assigned to categories C and D (without major harmful consequences) while 28% could not be assigned due to missing majority decision. Potential harmful consequences requiring interventions (category E) could have occurred in 12% of assessments. CONCLUSION: Next to systematic application of clinical guidelines and prescribing via CPOE, order review by a clinical pharmacist is still required to effectively reduce MEs and thus to prevent minor and major adverse drug events with the aim to enhance medication safety.

A first-in-human clinical study of a new SP-B and SP-C enriched synthetic surfactant (CHF5633) in preterm babies with respiratory distress syndrome.

OBJECTIVE: CHF5633 (Chiesi Farmaceutici S.p.A., Parma, Italy) is the first fully synthetic surfactant enriched by peptide analogues of two human surfactant proteins. We planned to assess safety and tolerability of CHF5633 and explore preliminary efficacy. DESIGN: Multicentre cohort study. PATIENTS: Forty infants from 27+0 to 33+6 weeks gestation with respiratory distress syndrome requiring fraction of inspired oxygen (FiO2) ≥0.35 were treated with a single dose of CHF5633 within 48 hours after birth. The first 20 received 100 mg/kg and the second 20 received 200 mg/kg. OUTCOME MEASURES: Adverse events (AEs) and adverse drug reactions (ADRs) were monitored with complications of prematurity considered AEs if occurring after dosing. Systemic absorption and immunogenicity were assessed. Efficacy was assessed by change in FiO2 after dosing and need for poractant-alfa rescue. RESULTS: Rapid and sustained improvements in FiO2 were observed in 39 (98%) infants. One responded neither to CHF5633 nor two poractant-alfa doses. A total of 79 AEs were experienced by 19 infants in the 100 mg/kg cohort and 53 AEs by 20 infants in the 200 mg/kg cohort. Most AEs were expected complications of prematurity. Two unrelated serious AEs occurred in the second cohort. One infant died of necrotising enterocolitis and another developed viral bronchiolitis after discharge. The single ADR was an episode of transient endotracheal tube obstruction following a 200 mg/kg dose. Neither systemic absorption, nor antibody development to either peptide was detected. CONCLUSIONS: Both CHF5633 doses were well tolerated and showed promising clinical efficacy profile. These encouraging data provide a basis for ongoing randomised controlled trials. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01651637.