Illness In Infants Research Articles

LB19. Progress Toward a Vaccine for Maternal Immunization to Prevent Respiratory Syncytial Virus (RSV) Lower Respiratory Tract Illness (LRTI) in Infants

BackgroundRSV is the leading cause of infant LRTI and hospitalization worldwide. The greatest burden of severe disease is in term infants <5 months old. Novavax is developing an aluminum-adjuvanted RSV F nanoparticle vaccine for use in the third trimester of pregnancy, with the goal of preventing medically significant infant RSV LRTI in the first 3–6 months of life via transplacental transfer of maternal antibodies.MethodAfter dose-finding studies in 1,050 women, we studied vaccine safety and immunogenicity in a Phase 2 trial in 50 healthy third trimester pregnant women. Safety was assessed in mothers and infants, focusing on pregnancy and peri-partum outcomes. We measured binding and functional RSV antibodies in mothers at baseline, day 14, delivery, and days 35 and 180 post-partum, in cord blood, and in infant sera on days 14, 35, 60, and 180 of life. Anti-F antibody specificities were probed with biolayer interferometry and monoclonal antibodies (mabs) to known epitopes.ResultIn Phase 2, RSV F nanoparticle vaccine was immunogenic, safe, and well-tolerated in pregnant women. Anti-F IgG and neutralizing antibodies were elicited. Increases in antibodies competitive with mabs to neutralizing epitope sites Ø, VIII, II, and IV, and also the p27 domain displayed by the pre-fusogenic F protein, were present in maternal and infant sera of vaccinated subject pairs. Transplacental transfer of RSV antibodies was more efficient (110 to 120%) in women immunized >30 days before delivery compared with those vaccinated later; RSV antibody t1/2 ranged from 30 to 41 days in infants. We have subsequently enrolled 4,636 pregnant women and their infants in a global observer-blind, randomized, placebo-controlled Phase 3 trial assessing efficacy against medically significant RSV LRTI. In November 2017, an informational analysis performed by an independent statistician, the sponsor remaining blinded, yielded a posterior probability of ≥90% that efficacy was >0%.ConclusionRSV F nanoparticle vaccine is immunogenic in pregnancy, and neutralizing antibodies, including those competing for pre-and post-fusion F epitopes, are transferred efficiently transplacentally. An analysis of Phase 3 efficacy against medically signifcant infant RSV LRTI is projected for Q1, 2019.Disclosures L. Fries, Novavax: Employee and Shareholder, Salary. D. N. Thomas, Novavax: Employee, Salary. G. Smith, Novavax: Employee and Shareholder, Salary. J. Plested, Novavax: Employee, Salary. P. Piedra, Novavax: Collaborator, Consultant, Research Contractor and Scientific Advisor, Consulting fee, contract fees for immunologic assays and Research support. N. Patel, Novavax: Employee and Shareholder, Salary. I. Cho, Novavax: Employee and Shareholder, Salary. G. Glenn, Novavax: Employee and Shareholder, Salary.

117. Effect of Nasopharyngeal Pneumococcal Carriage on RSV and hMPV Illness Severity in Infants in Nepal

BackgroundPneumococcal pneumonia after a preceding respiratory viral illness is associated with morbidity and mortality in infants. Our study sought to determine how pneumococcal carriage impacted illness severity due to respiratory syncytial virus (RSV) or human metapneumovirus (hMPV) in infants 0–6 months in a low resource setting in South Asia without pneumococcal vaccination. Previous studies in this population found an overall 79.4% prevalence of pneumococcal carriage in ages 1–36 months with higher rates of carriage among healthy controls when compared with those with respiratory illness.MethodsInfants were enrolled at the time of birth in a maternal influenza immunization trial conducted in rural Nepal from 2011 to 2014. Weekly household-based active surveillance was performed from birth to 6 months to assess for infant respiratory illness, defined as fever, cough, difficulty breathing, wheeze, or otorrhea. Mid-nasal swabs were collected and tested by PCR for RSV, hMPV, and streptococcus pneumoniae with inclusion of first illness episode in the surveillance period. Disease severity was defined using the World Health Organization Integrated Management of Childhood Illness criteria.ResultsAltogether, 247 (73.5%) of 336 infants with RSV and 154 (83.7%) of 184 infants with hMPV had S. pneumoniae detected. Mean age at RSV illness with concurrent pneumococcal carriage was 97.0 days (91.3–102.6) versus 72.8 days (63.3–82.4) for infants without carriage (P < 0.001). Mean age at hMPV illness with concurrent pneumococcal carriage was 101.3 days (93.9–108.7) versus 77.2 days (56.5–98.0) for infants without carriage (P = 0.01). Frequency of reported lower respiratory tract infection did not differ with or without carriage (RSV: 64.4% vs. 65.2% respectively; P = 0.89, hMPV: 52.6% vs. 50.0% P = 0.79). S. pneumoniae PCR cycle threshold value did not differ by duration or severity of RSV or hMPV illness episode.ConclusionHigh rates of pneumococcal carriage were observed with RSV and hMPV illness episodes in a birth cohort of infants in rural Nepal. The majority of infants with RSV or hMPV illness had pneumococcus detected at the time of first observed illness. However, no increase in RSV or hMPV illness severity or duration was seen with pneumococcal carriage. Disclosures H. Y. Chu, sanofi pasteur: Grant Investigator, Grant recipient. Novavax: Grant Investigator, Grant to co-investigator’s institution.

613. Transmission of Influenza Virus in Mother and Infant Transmission Events in Nepal

BackgroundInfluenza immunization of pregnant women provides protection of the infant against influenza disease. A potential mechanism of protection is prevention of maternal illness that may result in secondary transmission to infants. We aim to characterize influenza transmission in mother–infant pairs.MethodsPregnant mothers were enrolled in a randomized controlled trial of influenza immunization in rural Nepal from April 2011 to April 2013. Mothers and infants were surveyed weekly until 180 days post-partum for respiratory illness and mid-nasal swabs were collected at time of illness and tested for influenza virus by reverse-transcriptase polymerase chain reaction (RT-PCR). We defined a transmission episode as a mother–infant pair with an influenza-positive illness within 14 days of each other. Influenza viruses were strain-typed by RT-PCR and/or mass spectrometry.ResultsSeventeen mother–infant transmission episodes occurred with maternal illness preceding infant illness in 12 (70.6%). Of transmission pairs, 12 (70.6%) were influenza B, three (17.6%) H3N2 influenza A, one (5.9%) H1N1 influenza A, and one (5.9%) unspecified influenza A. Five (29.4%) mothers received the influenza vaccine. Successful strain-typing with RT-PCR/mass spectrometry of 11 pairs revealed that 10 (90.9%) were synonymous strains. Figure 1 shows the start of respiratory symptoms and virus type associated with influenza illness in the 17 mother–infant pairs.ConclusionMothers are an important source of infant influenza infection. Transmission was confirmed with nearly all paired transmissions demonstrating a similar strain. The majority of transmission events occurred in nonvaccinated mother–infant pairs. Figure 1: Influenza transmission events in mother–infant pairs. Symbols represent first day of respiratory symptoms associated with influenza-positive illness.Disclosures J. Englund, GlaxoSmithKline: Investigator, Research grant. MedImmune: Investigator, Research grant. Gilead: Investigator, Research grant. Novavax: Investigator, Research grant. Chimerix: Investigator, Research grant. Alios: Investigator, Research grant. H. Chu, Sanofi-Pasteur: Grant Investigator, Grant recipient.

Informing randomized clinical trials of respiratory syncytial virus vaccination during pregnancy to prevent recurrent childhood wheezing: A sample size analysis

BackgroundEarly RSV illness is associated with wheeze-associated disorders in childhood. Candidate respiratory syncytial virus (RSV) vaccines may prevent acute RSV illness in infants. We investigated the feasibility of maternal RSV vaccine trials to demonstrate reductions in recurrent childhood wheezing in general paediatric populations. MethodsWe calculated vaccine trial effect sizes that depended on vaccine efficacy, allocation ratio, rate of early severe RSV illness, risk of recurrent wheezing at age 3, and increased risk of RSV infection on recurrent wheezing. Model inputs came from systematic reviews and meta-analyses. For each combination of inputs, we estimated the sample size required to detect the effect of vaccination on recurrent wheezing. ResultsThere were 81 scenarios with 1:1 allocation ratio. Risk ratios between vaccination and recurrent wheezing ranged from 0.9 to 1.0 for 70% of the scenarios. Among the 57 more plausible scenarios, the lowest sample size required to detect significant reductions in recurrent wheezing was 6196 mother-infant pairs per trial arm; however, 75% and 47% of plausible scenarios required >31,060 and >100,000 mother-infant pairs per trial arm, respectively. Studies with asthma endpoints at age 5 will likely need to be larger. DiscussionClinical efficacy trials of candidate maternal RSV vaccines undertaken for licensure are unlikely to demonstrate an effect on recurrent wheezing illness due to the large sample sizes likely needed to demonstrate a significant effect. Further efforts are needed to plan for alternative study designs to estimate the impact of maternal RSV vaccine programs on recurrent childhood wheezing in general populations.

The Efficacy and Safety Of Using Hydrochlorothiazide As Adjuvant Therapy In Pediatric Urinary Tract Infections

Background: Acute urinary tract infection is a common bacterial infection causing illness in infants and children. At age of seven, 8% of girls and 2% of boys will have at least one episode. Although drinking water and using home remedies are known to help to flush away bacteria and keeps them from sticking to the bladder wall, researches to test the efficacy and safety of hydrochlorothiazide's diuretic effect as adjuvant to the antibiotics in pediatric age groups are lacking, and so this research was to address this subject.&#x0D; Objectives: To assess the effectiveness and the safety of hydrochlorothiazide as adjuvant therapy to the antibiotics in treating acute urinary tract infection in pediatric age group.&#x0D; Type of the study: Case-control prospective study.&#x0D; Methods: The study was done including eight hundred sixty five patients ((In_ &amp; Out_ patients)): The patients included were aged from few hours (neonates) to 16 years old, Those who attended three pediatric hospitals- department of nephrology of:The Central Child Teaching Hospital,Al- Elwyia Pediatric Hospital andIbn Al-Baladi Hospital&#x0D; Results: 215 patients in group 1 ((97.3%)) presented with cystitis and 6 patients ((2.7%)) with pyelonephritis, And In group 2, 243 ((96.4%)) with cystitis and 9 patients ((3.6%)) with pyelonephritis.The urine cultures were negative in ((76.4, 80.1, 85.9,95.0 percentages of patients)) after ((10 days, 1 month, 3 months and 6 months respectively)) in group1 vs. ((60.3, 68.60,75.8,85.3 )) after the same periods in group 2 ((p-value=0.04 at 10 days, 0.03 at 1month, 0.04 at 3 month and 0.02 at 6month)).&#x0D; Conclusions: This research had concluded that 5 days of treatment with antibiotics and hydrochlorothiazide were effective and safe to treat children with urinary tract infection. Hydrochlorothiazide (as a diuretic and hypocalciuric agent) adjuvant to the antibiotics in pediatrics was safe and effective to: Decrease duration of treatment and hospitalization days, Improve clinical responses to antibiotics and Decrease risk of complications of UTI.&#x0D;

FUT2 Genetic Variants and Reported Respiratory and Gastrointestinal Illnesses During Infancy.

Fucosyltransferase 2 (FUT2) controls the production of digestive and respiratory epithelia of histo-blood group antigens involved in the attachment of pathogens. The aim of our study was to relate FUT2 variants to reported gastrointestinal and respiratory illnesses in infancy. In the Southampton Women's Survey, FUT2 genetic variants (single-nucleotide polymorphisms [SNPs] rs601338 and rs602662) were genotyped in 1831 infants and related to infant illnesses, after adjustment for sex, breastfeeding duration, and potential confounders. For FUT2 SNP rs601338, the risk ratios for ≥1 bout of diarrhea during ages 6-12 months and ages 12-24 months per additional risk (G) allele were 1.23 (95% confidence interval [CI], 1.08-1.4; P = .002) and 1.41 (95% CI, 1.24-1.61; P = 1.7 × 10-7), respectively; the risk ratio for ≥1 diagnosis of a lower respiratory illness (ie, pneumonia or bronchiolitis) during ages 12-24 months per additional G allele was 2.66 (95% CI, 1.64-4.3; P = .00007). Similar associations were found between rs602662 and gastrointestinal and respiratory illnesses, owing to the high linkage disequilibrium with rs601338 (R2 = 0.92). Longer breastfeeding duration predicted a lower risk of diarrhea, independent of infant FUT2 genotype. We confirmed that FUT2 G alleles are associated with a higher risk of infant gastrointestinal illnesses and identified novel associations with respiratory illnesses. FUT2 locus variants need consideration in future studies of gastrointestinal and respiratory illnesses among infants.

Antibodies in lymphocyte supernatants can distinguish between neutralising antibodies induced by RSV vaccination and pre-existing antibodies induced by natural infection

IntroductionRespiratory syncytial virus (RSV) is the single most important cause of severe respiratory illness in infants. There is no effective vaccine and the only effective treatment available is the monoclonal antibody palivizumab which reduces the risk of severe RSV disease in prematurely born infants. However, palivizumab is too costly to allow for wide implementation and thus treatment is restricted to supportive care. Despite extensive efforts to develop a vaccine, progress has been hindered by the difficulty in measuring and assessing immunological correlates of RSV vaccine efficacy in the presence of high levels of pre-existing RSV antibodies. MethodsHere we describe a new method for measuring the functional activity of antibodies induced by vaccination distinct from pre-existing antibodies. Antibodies in lymphocyte supernatants (ALS) from the cultured peripheral blood mononuclear cells (PBMCs) of young adults who had recently been vaccinated with a novel RSV candidate vaccine were directly assayed for virus neutralising activity. An ELISA method was used to measure antibodies in nasal and serum samples and then compared with the adapted ALS based method. ResultsThere was a wide background distribution of RSV-specific antibodies in serum and nasal samples that obscured vaccine-specific responses measured two weeks after vaccination. No RSV-specific antibodies were observed at baseline in ALS samples, but a clear vaccine-specific antibody response was observed in ALS seven days after the administration of each dose of vaccine. These vaccine-specific antibodies in ALS displayed functional activity in vitro, and quantification of this functional activity was unperturbed by pre-existing antibodies from natural exposure. The results demonstrate a promising new approach for assessing functional immune responses attributed to RSV vaccines.

“Cheerful Angels Looking Down on Us”: Parental Emotions in Diaries about the Illness and Death of Infants and Young Children (1780-1880)

A Festschrift for Philippe Lejeune

Breast Milk Prefusion F Immunoglobulin G as a Correlate of Protection Against Respiratory Syncytial Virus Acute Respiratory Illness.

BackgroundTransplacental respiratory syncytial virus (RSV) antibody transfer has been characterized, but little is known about the protective effect of breast milk RSV-specific antibodies. Serum antibodies against the prefusion RSV fusion protein (pre-F) exhibit high neutralizing activity. We investigate protection of breast milk pre-F antibodies against RSV acute respiratory infection (ARI).MethodsBreast milk at 1, 3, and 6 months postpartum and midnasal swabs during infant illness episodes were collected in mother–infant pairs in Nepal. One hundred seventy-four infants with and without RSV ARI were matched 1:1 by risk factors for RSV ARI. Pre-F immunoglobulin A (IgA) and immunoglobulin G (IgG) antibody levels were measured in breast milk.ResultsThe median breast milk pre-F IgG antibody concentration before illness was lower in mothers of infants with RSV ARI (1.4 [interquartile range {IQR}, 1.1–1.6] log10 ng/mL) than without RSV ARI (1.5 [IQR, 1.3–1.8] log10 ng/mL) (P = .001). There was no difference in median maternal pre-F IgA antibody concentrations in cases vs controls (1.7 [IQR, 0.0–2.2] log10 ng/mL vs 1.7 [IQR, 1.2–2.2] log10 ng/mL, respectively; P = .58).ConclusionsLow breast milk pre-F IgG antibodies before RSV ARI support a potential role for pre-F IgG as a correlate of protection against RSV ARI. Induction of breast milk pre-F IgG may be a mechanism of protection for maternal RSV vaccines.

Identification and Characterization of Human Monoclonal Antibodies for Immunoprophylaxis against Enterotoxigenic Escherichia coli Infection.

Enterotoxigenic Escherichia coli (ETEC) causes diarrheal illness in infants in the developing world and travelers to countries where the disease is endemic, including military personnel. ETEC infection of the host involves colonization of the small intestinal epithelium and toxin secretion, leading to watery diarrhea. There is currently no vaccine licensed to prevent ETEC infection. CFA/I is one of the most common colonization factor antigens (CFAs). The CFA/I adhesin subunit, CfaE, is required for ETEC adhesion to host intestinal cells. Human antibodies against CfaE have the potential to block colonization of ETEC and serve as an immunoprophylactic against ETEC-related diarrhea. Mice transgenic for human immunoglobulin genes were immunized with CfaE to generate a panel of human monoclonal IgG1 antibodies (HuMAbs). The most potent IgG1 antibodies identified in the in vitro functional assays were selected and isotype switched to secretory IgA (sIgA) and tested in animal colonization assays via oral administration. Over 300 unique anti-CfaE IgG1 HuMAbs were identified. The lead IgG1 anti-CfaE HuMAbs completely inhibited hemagglutination and blocked adhesion of ETEC to Caco-2 cells. Epitope mapping studies revealed that HuMAbs recognized epitopes in the N-terminal domain of CfaE near the putative receptor binding site. Oral administration of anti-CfaE antibodies in either IgG or sIgA isotypes inhibited intestinal colonization in mice challenged with ETEC. A 2- to 4-log decrease in CFU was observed in comparison to mice challenged with irrelevant isotype controls. We identified fully human monoclonal antibodies against the CfaE adhesion domain that can be potentially employed as an immunoprophylactic to prevent ETEC-related diarrhea.

Design and rationale of the “Sedation strategy and cognitive outcome after critical illness in early childhood” study

There is increasing concern that sedatives commonly used during critical illness may be neurotoxic during the period of early brain development. The Sedation strategy and cognitive outcome after critical illness in early childhood (RESTORE-cognition) study is a prospective cohort study designed to examine the relationships between sedative exposure during pediatric critical illness and long-term neurocognitive outcomes. We assess multiple domains of neurocognitive function 2.5–5 years post-hospital discharge, at a single time point and depending on participant and clinician availability, in up to 500 subjects who had normal baseline cognitive function, were aged 2 weeks to 8 years at pediatric intensive care unit admission, and were enrolled in a cluster randomized controlled trial of a sedation protocol (the RESTORE trial; U01 HL086622 and HL086649). In addition, to provide comparable data on an unexposed group with similar baseline biological characteristics and environment, we are studying matched, healthy siblings of RESTORE patients. Our goal is to increase understanding of the relationships between sedative exposure, critical illness, and long-term neurocognitive outcomes in infants and young children by studying these subjects 2.5 to 5 years after their index hospitalization. This paper highlights the design challenges in conducting comprehensive neurocognitive assessment procedures across a broad age span at multiple testing centers across the United States. Our approach, which includes building interprofessional teams and novel cohort retention strategies, may be of help in future longitudinal trials.

Factors associated with delayed initiation of breastfeeding: a cross-sectional study in South Sudan

BackgroundThe global breastfeeding recommendation states that all infants should be put to the breast within one hour of birth, which is defined as timely initiation or early initiation of breastfeeding. Early initiation of breastfeeding is associated with reduced risk in infant illness and death. Understanding the determinants of delay in initiation of breastfeeding might spur health staff and policy makers to foster timely breastfeeding. We assessed the prevalence and determinants of delay in initiation of breastfeeding among mothers in Juba Teaching Hospital.MethodsThe present study enrolled 806 mother-infant pairs within 24 hrs of birth in Juba Teaching Hospital in 2017. The mothers were interviewed about the time of initiation of breastfeeding, sociodemographic and birth characteristics. The independent variables associated with delay in initiation of breastfeeding were identified using multivariable logistic regression analysis.ResultsIn the current study, 52% (418/806) of the mothers initiated breastfeeding later than one hour after birth. Birth by Caesarean section (Adjusted Odds Ratio [AOR] 41; 95% Confidence Interval [CI] 12.21, 138), discarding of colostrum (AOR 9.89; 95% CI 4.14, 23.62), unmarried mothers (AOR 3.76; 95% CI 1.53, 9.24), exposure to infant formula advertisement (AOR 1.82; 95% CI 1.09, 3.02) and no house ownership (AOR 1.52; 95% CI 1.11, 2.09) were independent factors associated with delay in initiation of breastfeeding.ConclusionWe found that more than half of the mothers delayed the initiation of breastfeeding. Therefore, we recommend training on best breastfeeding practices and counselling skills for health staff in Juba Teaching Hospital. Policy dialogue, with the relevant ministries and departments on the promotion and protection of early initiation of breastfeeding is crucial.

A Prospective Study of Causes of Illness and Death in Preterm Infants in Ethiopia: The SIP Study Protocol

BackgroundWith nearly 15 million annual preterm births globally, preterm birth is the most common cause of neonatal death. Forty to 60 % of neonatal deaths are directly or indirectly associated with preterm mortality. As countries aim to meet the Sustainable Development Goals to reduce neonatal mortality, significant reductions in preterm mortality are needed. This study aims to identify the common causes of preterm illness and their contribution to preterm mortality in low-resource settings. This article will describe the methods used to undertake the study.MethodsThis is a prospective, multi-centre, descriptive clinical study. Socio-demographic, obstetric, and maternal factors, and clinical and laboratory findings will be documented. The major causes of preterm mortality will be identified using clinical, laboratory, imaging, and autopsy methods and use the national Ethiopian guidelines on management of preterm infants including required investigations to reach final diagnoses. The study will document the clinical and management protocols followed in these settings. The approach consists of clinical examinations and monitoring, laboratory investigations, and determination of primary and contributory causes of mortality through both clinical means and by post-mortem examinations. An independent panel of experts will validate the primary and contributory causes of mortality.To obtain the estimated sample size of 5000 preterm births, the study will be undertaken in five hospitals in three regions of Ethiopia, which are geographically distributed across the country. All preterm infants who are either born or transferred to these hospitals will be eligible for the study. Three methods (last menstrual period, physical examination using the New Ballard Score, and ultrasound) will be used to determine gestational age.All clinical procedures will be conducted per hospital protocol and informed consent will be taken from parents or caretakers prior to their participation in the study as well as for autopsy if the infant dies.DiscussionThis study will determine the major causes of death and illness among hospitalized preterm infants in a low-resource setting. The result will inform policy makers and implementers of areas that can be prioritized in order to contribute to a significant reduction in neonatal mortality.

Cost effectiveness of mHealth intervention by community health workers for reducing maternal and newborn mortality in rural Uttar Pradesh, India

BackgroundA variety of mobile-based health technologies (mHealth) have been developed for use by community health workers to augment their performance. One such mHealth intervention—ReMiND program, was implemented in a poor performing district of India. Despite some research on the extent of its effectiveness, there is significant dearth of evidence on cost-effectiveness of such mHealth interventions. In this paper we evaluated the incremental cost per disability adjusted life year (DALY) averted as a result of ReMiND intervention as compared to routine maternal and child health programs without ReMiND.MethodsA decision tree was parameterized on MS-Excel spreadsheet to estimate the change in DALYs and cost as a result of implementing ReMiND intervention compared with routine care, from both health system and societal perspective. A time horizon of 10 years starting from base year of 2011 was considered appropriate to cover all costs and effects comprehensively. All costs, including those during start-up and implementation phase, besides other costs on the health system or households were estimated. Consequences were measured as part of an impact assessment study which used a quasi-experimental design. Proximal outputs in terms of changes in service coverage were modelled to estimate maternal and infant illnesses and deaths averted, and DALYs averted in Uttar Pradesh state of India. Probabilistic sensitivity analysis was undertaken to account for parameter uncertainties.ResultsCumulatively, from year 2011 to 2020, implementation of ReMiND intervention in UP would result in a reduction of 312 maternal and 149,468 neonatal deaths. This implies that ReMiND program led to a reduction of 0.2% maternal and 5.3% neonatal deaths. Overall, ReMiND is a cost saving intervention from societal perspective. From health system perspective, ReMiND incurs an incremental cost of INR 12,993 (USD 205) per DALY averted and INR 371,577 (USD 5865) per death averted.ConclusionsOverall, findings of our study suggest strongly that the mHealth intervention as part of ReMiND program is cost saving from a societal perspective and should be considered for replication elsewhere in other states.

Coupling between mean blood pressure and EEG in preterm neonates is associated with reduced illness severity scores.

Hypotension or low blood pressure (BP) is a common problem in preterm neonates and has been associated with adverse short and long-term neurological outcomes. Deciding when and whether to treat hypotension relies on an understanding of the relationship between BP and brain functioning. This study aims to investigate the interaction (coupling) between BP and continuous multichannel unedited EEG recordings in preterm infants less than 32 weeks of gestational age. The EEG was represented by spectral power in four frequency sub-bands: 0.3–3 Hz, 3–8 Hz, 8–15 Hz and 15–30 Hz. BP was represented as mean arterial pressure (MAP). The level of coupling between the two physiological systems was estimated using linear and nonlinear methods such as correlation, coherence and mutual information. Causality of interaction was measured using transfer entropy. The illness severity was represented by the clinical risk index for babies (CRIB II score) and contrasted to the computed level of interaction. It is shown here that correlation and coherence, which are linear measures of the coupling between EEG and MAP, do not correlate with CRIB values, whereas adjusted mutual information, a nonlinear measure, is associated with CRIB scores (r = -0.57, p = 0.003). Mutual information is independent of the absolute values of MAP and EEG powers and quantifies the level of coupling between the short-term dynamics in both signals. The analysis indicated that the dominant causality is from changes in EEG producing changes in MAP. Transfer entropy (EEG to MAP) is associated with the CRIB score (0.3–3 Hz: r = 0.428, p = 0.033, 3–8 Hz: r = 0.44, p = 0.028, 8–15 Hz: r = 0.416, p = 0.038) and indicates that a higher level of directed coupling from brain activity to blood pressure is associated with increased illness in preterm infants. This is the first study to present the nonlinear measure of interaction between brain activity and blood pressure and to demonstrate its relation to the initial illness severity in the preterm infant. The obtained results allow us to hypothesise that the normal wellbeing of a preterm neonate can be characterised by a nonlinear coupling between brain activity and MAP, whereas the presence of weak coupling with distinctive directionality of information flow is associated with an increased mortality rate in preterms.

Increased detection of human parechovirus infection in infants in England during 2016: epidemiology and clinical characteristics

BackgroundHuman parechovirus (HPeV), like enteroviruses, usually causes mild self-limiting respiratory and gastrointestinal symptoms. In infants, HPeV can occasionally cause serious illnesses, including sepsis-like syndrome and encephalitis. In summer 2016, Public...

Interleukin-13 associates with life-threatening rhinovirus infections in infants and young children.

Delineate risk factors associated with severe hypoxemia (O2 sat ≤87%) in infants and children younger than 2 years hospitalized with single pathogen HRV infection. Prospective study in a yearly catchment population of 56 560 children <2 years old between 2011 and 2013 in Argentina. All children with respiratory signs and O2 sat <93% on admission were included. HRV infections were identified by reverse transcriptase-polymerase chain reaction. Epidemiologic, clinical, viral, and immunological risk factors were assessed. Among 5012 hospitalized patients, HRV was detected as a single pathogen in 347 (6.92%) subjects. Thirty-two (9.2%) had life-threatening disease. Traditional risk factors for severe bronchiolitis did not affect severity of illness. HRV viral load, HRV groups, and type II and III interferons did not associate with severe hypoxemia. Interleukin-13 Levels in respiratory secretions at the time of admission (OR = 7.43 (3-18.4); P < 0.001 for IL-13 >10 pg/mL) predisposed to life-threatening disease. Targeted interventions against IL-13 should be evaluated to decrease severity of HRV illness in infancy and early childhood.

Human Parainfluenza Virus Type 3 Matrix Protein Reduces Viral RNA Synthesis of HPIV3 by Regulating Inclusion Body Formation.

Human parainfluenza virus type 3 is one of the main causes of lower respiratory illness in newborns and infants. The role of the matrix protein (M) in viral budding is extensively studied, but the effect of M on viral replication remains to be determined. Using an HPIV3 minigenome assay, we found that M reduced HPIV3 mingenome-encoded reporter activity even though it had an unspecific effect on the expression of cellular genes. Furthermore, the inhibition effect of M on viral RNA synthesis was proven to be independent of its virus-like particles (VLPs)’ release ability. A VLP’s defective mutant (ML302A) decreased the expression of minigenome reporter as wild type M did. Using an immunofluorescence assay, we found that M weakened the formation of inclusion bodies (IBs), although it did not co-localize with the IBs. Moreover, using another mutant, ML305A , which is defective in M-nucleoprotein (N) interaction, we found that ML305A had no effect on reporter activity and IB formation as the wild type of M did. Taken together, we conclude that M reduces the replication of HPIV3 and IB formation by M–N interaction.

Cognitive Development One Year After Infantile Critical Pertussis.

Pertussis can cause life-threatening illness in infants. Data regarding neurodevelopment after pertussis remain scant. The aim of this study was to assess cognitive development of infants with critical pertussis 1 year after PICU discharge. Prospective cohort study. Eight hospitals comprising the Eunice Kennedy Shriver National Institute for Child Health and Human Development Collaborative Pediatric Critical Care Research Network and 18 additional sites across the United States. Eligible patients had laboratory confirmation of pertussis infection, were less than 1 year old, and were admitted to the PICU for at least 24 hours. The Mullen Scales of Early Learning was administered at a 1-year follow-up visit. Functional status was determined by examination and parental interview. Of 196 eligible patients, 111 (57%) completed the Mullen Scales of Early Learning. The mean scores for visual reception, receptive language, and expressive language domains were significantly lower than the norms (p < 0.001), but not fine and gross motor domains. Forty-one patients (37%) had abnormal scores in at least one domain and 10 (9%) had an Early Learning Composite score 2 or more SDs below the population norms. Older age (p < 0.003) and Hispanic ethnicity (p < 0.008) were associated with lower mean Early Learning Composite score, but presenting symptoms and PICU course were not. Infants who survive critical pertussis often have neurodevelopmental deficits. These infants may benefit from routine neurodevelopmental screening.

Epidemiology of Sepsis-like Illness in Young Infants: Major Role of Enterovirus and Human Parechovirus.

Sepsis-like illness is a main cause for hospital admission in young infants. Our aim was to investigate incidence, epidemiology and clinical characteristics of enterovirus (EV) and human parechovirus (HPeV) infections in young infants with sepsis-like illness. This is a prospective observational cohort study in which infants younger than 90 days of age, presenting with sepsis-like symptoms in a secondary care children's hospital, underwent a full sepsis work-up. Clinical signs and infectious indices were recorded. EV or HPeV RNA was detected by polymerase chain reaction in plasma and/or cerebrospinal fluid (CSF). Infants were diagnosed with EV, HPeV, fever of unknown origin or severe infection. EV and HPeV were detected in 132 of 353 (37%) and 52 of 353 (15%) of cases, respectively. EV and HPeV have distinct seasonability. Some differences in clinical signs and symptoms occurred between children with EV and HPeV infection but were of limited clinical value. CSF pleocytosis occurred in 44% of EV positive infants, and only in 13% of those with HPeV infection. EV and HPeV infections are major causes of sepsis-like illness in infants < 90 days of age. Neither clinical characteristics nor laboratory indices were predictive for EV/HPeV infection. CSF pleocytosis occurs, but not in all patients. Testing for EV and HPeV in all young infants with sepsis-like illness is strongly advised.