ABSTRACT
OBJECTIVE: The objective of this study was to determine if valganciclovir initiated after 1 month of age improves congenital cytomegalovirus-associated sensorineural hearing loss. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled phase 2 trial of 6 weeks of oral valganciclovir at US (n = 12) and UK (n = 9) sites. Patients of ages 1 month through 3 years with baseline sensorineural hearing loss were enrolled. The primary outcome was change in total ear hearing between baseline and study month 6. Secondary outcome measures included change in best ear hearing and reduction in cytomegalovirus viral load in blood, saliva, and urine. RESULTS: Of 54 participants enrolled, 35 were documented to have congenital cytomegalovirus infection and were randomized (active group: 17; placebo group: 18). Mean age at enrollment was 17.8 ± 15.8 months (valganciclovir) vs 19.5 ± 13.1 months (placebo). Twenty (76.9%) of the 26 ears from subjects in the active treatment group did not have worsening of hearing, compared with 27 (96.4%) of 28 ears from subjects in the placebo group (P = .09). All other comparisons of total ear or best ear hearing outcomes were also not statistically significant. Saliva and urine viral loads decreased significantly in the valganciclovir group but did not correlate with change in hearing outcome. CONCLUSIONS: In this randomized controlled trial, initiation of antiviral therapy beyond the first month of age did not improve hearing outcomes in children with congenital cytomegalovirus-associated sensorineural hearing loss. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01649869.
Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Ganciclovir , Hearing Loss, Sensorineural , Valganciclovir , Humans , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/complications , Valganciclovir/therapeutic use , Valganciclovir/administration & dosage , Hearing Loss, Sensorineural/drug therapy , Hearing Loss, Sensorineural/virology , Hearing Loss, Sensorineural/etiology , Antiviral Agents/therapeutic use , Antiviral Agents/administration & dosage , Male , Female , Double-Blind Method , Infant , Administration, Oral , Ganciclovir/analogs & derivatives , Ganciclovir/therapeutic use , Ganciclovir/administration & dosage , Child, Preschool , Treatment Outcome , Viral Load , Infant, NewbornABSTRACT
Respiratory syncytial virus (RSV) infection results in millions of hospitalizations and thousands of deaths each year. Variations in the adaptive and innate immune response appear to be associated with RSV severity. To investigate the host response to RSV infection in infants, we performed a systems-level study of RSV pathophysiology, incorporating high-throughput measurements of the peripheral innate and adaptive immune systems and the airway epithelium and microbiota. We implemented a novel multi-omic data integration method based on multilayered principal component analysis, penalized regression, and feature weight back-propagation, which enabled us to identify cellular pathways associated with RSV severity. In both airway and immune cells, we found an association between RSV severity and activation of pathways controlling Th17 and acute phase response signaling, as well as inhibition of B cell receptor signaling. Dysregulation of both the humoral and mucosal response to RSV may play a critical role in determining illness severity.
Subject(s)
Genomics/methods , Respiratory Syncytial Virus Infections , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Infant , Machine Learning , Microbiota/immunology , Nasal Cavity/cytology , Nasal Cavity/immunology , Nasal Cavity/metabolism , RNA-Seq , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus Infections/immunology , Respiratory Syncytial Virus Infections/metabolism , Respiratory Syncytial Virus Infections/physiopathology , Severity of Illness IndexABSTRACT
BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. METHODS: We carried out 16S rRNA microbiota profiling of infants in the first year of life from (1) a cross-sectional cohort of 89 RSV-infected infants sampled during illness and 102 matched healthy controls, and (2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. RESULTS: We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs infected than of disease severity. CONCLUSIONS: Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.
Subject(s)
Dysbiosis , Microbiota , Nose/microbiology , Respiratory Syncytial Virus Infections , Cross-Sectional Studies , Dysbiosis/etiology , Humans , Infant , RNA, Ribosomal, 16S/genetics , Respiratory Syncytial Virus Infections/complications , Respiratory Syncytial Virus, Human , Severity of Illness IndexABSTRACT
BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. The causes and correlates of severe illness in the majority of infants are poorly defined. METHODS: We recruited a cohort of RSV-infected infants and simultaneously assayed the molecular status of their airways and the presence of airway microbiota. We used rigorous statistical approaches to identify gene expression patterns associated with disease severity and microbiota composition, separately and in combination. RESULTS: We measured comprehensive airway gene expression patterns in 106 infants with primary RSV infection. We identified an airway gene expression signature of severe illness dominated by excessive chemokine expression. We also found an association between Haemophilus influenzae, disease severity, and airway lymphocyte accumulation. Exploring the time of onset of clinical symptoms revealed acute activation of interferon signaling following RSV infection in infants with mild or moderate illness, which was absent in subjects with severe illness. CONCLUSIONS: Our data reveal that airway gene expression patterns distinguish mild/moderate from severe illness. Furthermore, our data identify biomarkers that may be therapeutic targets or useful for measuring efficacy of intervention responses.
Subject(s)
Microbiota , Respiratory Syncytial Virus Infections , Respiratory System/metabolism , Transcriptome , Humans , Infant , Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus, Human , Respiratory System/virology , Severity of Illness IndexABSTRACT
The coronavirus disease 2019 (COVID-19) pandemic has highlighted the challenges inherent to the serological detection of a novel pathogen such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Serological tests can be used diagnostically and for surveillance, but their usefulness depends on their throughput, sensitivity, and specificity. Here, we describe a multiplex fluorescent microsphere-based assay, 3Flex, that can detect antibodies to three major SARS-CoV-2 antigens-spike (S) protein, the spike ACE2 receptor-binding domain (RBD), and nucleocapsid (NP). Specificity was assessed using 213 prepandemic samples. Sensitivity was measured and compared to that of the Abbott Architect SARS-CoV-2 IgG assay using serum samples from 125 unique patients equally binned (n = 25) into 5 time intervals (≤5, 6 to 10, 11 to 15, 16 to 20, and ≥21 days from symptom onset). With samples obtained at ≤5 days from symptom onset, the 3Flex assay was more sensitive (48.0% versus 32.0%), but the two assays performed comparably using serum obtained ≥21 days from symptom onset. A larger collection (n = 534) of discarded sera was profiled from patients (n = 140) whose COVID-19 course was characterized through chart review. This revealed the relative rise, peak (S, 23.8; RBD, 23.6; NP, 16.7 [in days from symptom onset]), and decline of the antibody response. Considerable interperson variation was observed with a subset of extensively sampled intensive care unit (ICU) patients. Using soluble ACE2, inhibition of antibody binding was demonstrated for S and RBD, and not for NP. Taking the data together, this study described the performance of an assay built on a flexible and high-throughput serological platform that proved adaptable to the emergence of a novel infectious agent.
Subject(s)
COVID-19 Serological Testing/methods , COVID-19/diagnosis , Microspheres , SARS-CoV-2/isolation & purification , Aged , Aged, 80 and over , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/blood , COVID-19/pathology , Coronavirus Nucleocapsid Proteins/immunology , Female , Fluoroimmunoassay , Humans , Immunoglobulin G/blood , Kinetics , Male , Middle Aged , Phosphoproteins/immunology , SARS-CoV-2/immunology , Sensitivity and Specificity , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/metabolismABSTRACT
OBJECTIVE: To develop a novel predictive model using primarily clinical history factors and compare performance to the widely used Rochester Low Risk (RLR) model. STUDY DESIGN: In this cross-sectional study, we identified infants brought to one pediatric emergency department from January 2014 to December 2016. We included infants age 0-90 days, with temperature ≥38°C, and documented gestational age and illness duration. The primary outcome was bacterial infection. We used 10 predictors to develop regression and ensemble machine learning models, which we trained and tested using 10-fold cross-validation. We compared areas under the curve (AUCs), sensitivities, and specificities of the RLR, regression, and ensemble models. RESULTS: Of 877 infants, 67 had a bacterial infection (7.6%). The AUCs of the RLR, regression, and ensemble models were 0.776 (95% CI 0.746, 0.807), 0.945 (0.913, 0.977), and 0.956 (0.935, 0.975), respectively. Using a bacterial infection risk threshold of .01, the sensitivity and specificity of the regression model was 94.6% (87.4%, 100%) and 74.5% (62.4%, 85.4%), compared with 95.5% (87.5%, 99.1%) and 59.6% (56.2%, 63.0%) using the RLR model. CONCLUSIONS: Compared with the RLR model, sensitivities of the novel predictive models were similar whereas AUCs and specificities were significantly greater. If externally validated, these models, by producing an individualized bacterial infection risk estimate, may offer a targeted approach to young febrile infants that is noninvasive and inexpensive.
Subject(s)
Bacterial Infections/diagnosis , Clinical Decision Rules , Fever/microbiology , Medical History Taking/methods , Bacterial Infections/complications , Cross-Sectional Studies , Emergency Service, Hospital , Female , Humans , Infant , Infant, Newborn , Linear Models , Logistic Models , Machine Learning , Male , Retrospective Studies , Risk Assessment , Sensitivity and SpecificityABSTRACT
There is now reliable evidence that early psychosocial stress exposures are associated with behavioral health in children; the degree to which these same kinds of stress exposures predict physical health outcomes is not yet clear. We investigated the links between economic adversity, family and caregiving stress in early childhood and several markers of immune function in early adolescence. The sample is derived from the Family Life Project, a prospective longitudinal study of at-risk families. Socio-demographic and psychosocial risks have been assessed at regular intervals since the children were first assessed at 2â¯months of age. When the children were early adolescents, we conducted an in-depth health assessment of a subsample of families; blood samples were collected from venipuncture for interleukin(IL)-6, Tumor Necrosis Factor (TNF)-alpha, and C-reactive protein (CRP), as well as glucocorticoid resistance. Results indicated limited but reliable evidence of an association between early risk exposure and inflammation in adolescence. Specifically, caregiver depressive symptoms in early childhood predicted elevated CRP almost a decade later, and the prediction was significant after accounting for multiple covariates such as socio-economic adversity, health behaviors and body mass index. Our findings provide strong but limited evidence that early stress exposures may be associated with inflammation, suggesting one mechanism linking early stress exposure to compromised behavioral and somatic health.
Subject(s)
Adverse Childhood Experiences , Caregivers/psychology , Depression , Domestic Violence , Family Health , Inflammation/etiology , Stress, Psychological , Adolescent , C-Reactive Protein/analysis , Child , Child, Preschool , Female , Humans , Infant , Interleukin-6/blood , Longitudinal Studies , Male , Prospective Studies , Risk Factors , Tumor Necrosis Factor-alpha/bloodABSTRACT
OBJECTIVE: To develop a valid research tool to measure infant respiratory illness severity using parent-reported symptoms. STUDY DESIGN: Nose and throat swabs were collected monthly for 1 year and during respiratory illnesses for 2 years in a prospective study of term and preterm infants in the Prematurity, Respiratory Outcomes, Immune System and Microbiome study. Viral pathogens were detected using Taqman Array Cards. Parents recorded symptoms during respiratory illnesses using a Childhood Origins of Asthma (COAST) scorecard. The COAST score was validated using linear mixed effects regression modeling to evaluate associations with hospitalization and specific infections. A data-driven method was also used to compute symptom weights and derive a new score, the Infant Research Respiratory Infection Severity Score (IRRISS). Linear mixed effects regression modeling was repeated with the IRRISS illness data. RESULTS: From April 2013 to April 2017, 50 term, 40 late preterm, and 28 extremely low gestational age (<29 weeks of gestation) infants had 303 respiratory illness visits with viral testing and parent-reported symptoms. A range of illness severity was described with 39% of illness scores suggestive of severe disease. Both the COAST score and IRRISS were associated with respiratory syncytial virus infection and hospitalization. Gestational age and human rhinovirus infection were inversely associated with both scoring systems. The IRRISS and COAST scores were highly correlated (r = 0.93; P < .0001). CONCLUSIONS: Using parent-reported symptoms, we validated the COAST score as a measure of respiratory illness severity in infants. The new IRRISS score performed as well as the COAST score.
Subject(s)
Infant, Premature, Diseases/diagnosis , Respiratory Tract Diseases/diagnosis , Severity of Illness Index , Female , Follow-Up Studies , Humans , Infant, Newborn , Infant, Premature , Male , Prospective StudiesABSTRACT
Background: Maternally derived serum antibody and viral load are thought to influence disease severity in primary respiratory syncytial virus (RSV) infection. As part of the AsPIRES study of RSV pathogenesis, we correlated various serum antibody concentrations and viral load with disease severity. Methods: Serum neutralizing antibody titers and levels of immunoglobulin G (IgG) to RSV fusion protein (F), attachment proteins of RSV group A and B, the CX3C region of G, and nasal viral load were measured in 139 full-term previously healthy infants with primary RSV infection and correlated with illness severity. Results: Univariate analysis showed no relationship between measures of serum antibody and severity. However, a multivariate model adjusting for age at the time of infection found a significant 0.56 decrease in severity score for each 2-fold increase in antibody concentration to RSV F. The benefit of antibody was greatest in infants ≤ 2 months of age. Additionally, estimated antibody titer at birth was correlated with age at infection, suggesting that higher antibody titers delay infection. Viral load did not differ by illness severity. Conclusion: Our data support the concept of maternal immunization with an RSV vaccine during pregnancy as a strategy for reducing the burden of RSV infection in full-term healthy infants exposed to RSV during their first winter.
Subject(s)
Antibodies, Viral/blood , Respiratory Syncytial Virus Infections/pathology , Respiratory Syncytial Virus Infections/virology , Respiratory Syncytial Virus, Human/immunology , Respiratory Syncytial Virus, Human/isolation & purification , Viral Load , Antibodies, Neutralizing/blood , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Nasal Mucosa/virology , Respiratory Syncytial Virus Infections/immunology , Serum/immunology , Severity of Illness IndexABSTRACT
BACKGROUND: Human herpesvirus-6A and -6B (HHV-6) are betaherpesviruses that reach > 90% seroprevalence in the adult population. Unique among human herpesviruses, HHV-6 can integrate into the subtelomeric regions of human chromosomes; when this occurs in germ line cells it causes a condition called inherited chromosomally integrated HHV-6 (iciHHV-6). Only two complete genomes are available for replicating HHV-6B, leading to numerous conflicting annotations and little known about the global genomic diversity of this ubiquitous virus. RESULTS: Using a custom capture panel for HHV-6B, we report complete genomes from 61 isolates of HHV-6B from active infections (20 from Japan, 35 from New York state, and 6 from Uganda), and 64 strains of iciHHV-6B (mostly from North America). HHV-6B sequence clustered by geography and illustrated extensive recombination. Multiple iciHHV-6B sequences from unrelated individuals across the United States were found to be completely identical, consistent with a founder effect. Several iciHHV-6B strains clustered with strains from recent active pediatric infection. Combining our genomic analysis with the first RNA-Seq and shotgun proteomics studies of HHV-6B, we completely reannotated the HHV-6B genome, altering annotations for more than 10% of existing genes, with multiple instances of novel splicing and genes that hitherto had gone unannotated. CONCLUSION: Our results are consistent with a model of intermittent de novo integration of HHV-6B into host germline cells during active infection with a large contribution of founder effect in iciHHV-6B. Our data provide a significant advance in the genomic annotation of HHV-6B, which will contribute to the detection, diversity, and control of this virus.
Subject(s)
Gene Expression Profiling/methods , Genomics/methods , Herpesvirus 6, Human/genetics , Herpesvirus 6, Human/metabolism , Roseolovirus Infections/virology , Viral Proteins/analysis , Adolescent , Adult , Aged , Child , Child, Preschool , Cohort Studies , Female , Genome, Viral , Global Health , Herpesvirus 6, Human/isolation & purification , Humans , Infant , Infant, Newborn , Male , Middle Aged , Proteomics/methods , Young AdultABSTRACT
BACKGROUND: The treatment of symptomatic congenital cytomegalovirus (CMV) disease with intravenous ganciclovir for 6 weeks has been shown to improve audiologic outcomes at 6 months, but the benefits wane over time. METHODS: We conducted a randomized, placebo-controlled trial of valganciclovir therapy in neonates with symptomatic congenital CMV disease, comparing 6 months of therapy with 6 weeks of therapy. The primary end point was the change in hearing in the better ear ("best-ear" hearing) from baseline to 6 months. Secondary end points included the change in hearing from baseline to follow-up at 12 and 24 months and neurodevelopmental outcomes, with each end point adjusted for central nervous system involvement at baseline. RESULTS: A total of 96 neonates underwent randomization, of whom 86 had follow-up data at 6 months that could be evaluated. Best-ear hearing at 6 months was similar in the 6-month group and the 6-week group (2 and 3 participants, respectively, had improvement; 36 and 37 had no change; and 5 and 3 had worsening; P=0.41). Total-ear hearing (hearing in one or both ears that could be evaluated) was more likely to be improved or to remain normal at 12 months in the 6-month group than in the 6-week group (73% vs. 57%, P=0.01). The benefit in total-ear hearing was maintained at 24 months (77% vs. 64%, P=0.04). At 24 months, the 6-month group, as compared with the 6-week group, had better neurodevelopmental scores on the Bayley Scales of Infant and Toddler Development, third edition, on the language-composite component (P=0.004) and on the receptive-communication scale (P=0.003). Grade 3 or 4 neutropenia occurred in 19% of the participants during the first 6 weeks. During the next 4.5 months of the study, grade 3 or 4 neutropenia occurred in 21% of the participants in the 6-month group and in 27% of those in the 6-week group (P=0.64). CONCLUSIONS: Treating symptomatic congenital CMV disease with valganciclovir for 6 months, as compared with 6 weeks, did not improve hearing in the short term but appeared to improve hearing and developmental outcomes modestly in the longer term. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT00466817.).
Subject(s)
Antiviral Agents/administration & dosage , Cytomegalovirus Infections/congenital , Cytomegalovirus Infections/drug therapy , Ganciclovir/analogs & derivatives , Hearing Loss, Sensorineural/prevention & control , Antiviral Agents/adverse effects , Audiometry , Child Development , Cytomegalovirus Infections/complications , Double-Blind Method , Drug Administration Schedule , Evoked Potentials, Auditory, Brain Stem , Ganciclovir/administration & dosage , Ganciclovir/adverse effects , Gestational Age , Hearing Loss, Sensorineural/virology , Humans , Infant, Newborn , Neutropenia/chemically induced , ValganciclovirABSTRACT
Background: Nearly all children are infected with respiratory syncytial virus (RSV) within the first 2 years of life, with a minority developing severe disease (1%-3% hospitalized). We hypothesized that an assessment of the adaptive immune system, using CD4+ T-lymphocyte transcriptomics, would identify gene expression correlates of disease severity. Methods: Infants infected with RSV representing extremes of clinical severity were studied. Mild illness (n = 23) was defined as a respiratory rate (RR) < 55 and room air oxygen saturation (SaO2) ≥ 97%, and severe illness (n = 23) was defined as RR ≥ 65 and SaO2 ≤ 92%. RNA from fresh, sort-purified CD4+ T cells was assessed by RNA sequencing. Results: Gestational age, age at illness onset, exposure to environmental tobacco smoke, bacterial colonization, and breastfeeding were associated (adjusted P < .05) with disease severity. RNA sequencing analysis reliably measured approximately 60% of the genome. Severity of RSV illness had the greatest effect size upon CD4 T-cell gene expression. Pathway analysis identified correlates of severity, including JAK/STAT, prolactin, and interleukin 9 signaling. We also identified genes and pathways associated with timing of symptoms and RSV group (A/B). Conclusions: These data suggest fundamental changes in adaptive immune cell phenotypes may be associated with RSV clinical severity.
Subject(s)
Respiratory Syncytial Virus Infections/genetics , Respiratory Syncytial Virus, Human/immunology , Transcriptome , CD4-Positive T-Lymphocytes/immunology , Cohort Studies , Female , Humans , Infant , Infant, Newborn , Male , Respiratory Syncytial Virus Infections/virology , Severity of Illness Index , Tobacco Smoke PollutionABSTRACT
Background: Respiratory syncytial virus (RSV) infection in infants has recognizable clinical signs and symptoms. However, quantification of disease severity is difficult, and published scores remain problematic. Thus, as part of a RSV pathogenesis study, we developed a global respiratory severity score (GRSS) as a research tool for evaluating infants with primary RSV infection. Methods: Previously healthy infants <10 months of age with RSV infections representing the spectrum of disease severity were prospectively evaluated. Clinical signs and symptoms were collected at 3 time points from hospitalized infants and those seen in ambulatory settings. Data were also extracted from office, emergency department, and hospital records. An unbiased data-driven approach using factor analysis was used to develop a GRSS. Results: A total of 139 infants (84 hospitalized and 55 nonhospitalized) were enrolled. Using hospitalization status as the output variable, 9 clinical variables were identified and weighted to produce a composite GRSS. The GRSS had an area under the receiver operator curve of 0.961. Construct validity was demonstrated via a significant correlation with length of stay (r = 0.586, P < .0001). Conclusions: Using routine clinical variables, we developed a severity score for infants with RSV infection that should be useful as an end point for investigation of disease pathogenesis and as an outcome measure for therapeutic interventions.
Subject(s)
Respiratory Syncytial Virus Infections/diagnosis , Respiratory Syncytial Virus Infections/epidemiology , Severity of Illness Index , Female , Gestational Age , Hospitalization , Humans , Infant , Infant, Newborn , Length of Stay , Linear Models , Male , Prospective Studies , Reproducibility of Results , Respiratory Syncytial Virus, Human , Risk FactorsABSTRACT
OBJECTIVE: To determine the burden of viral respiratory infections in preterm infants both during and subsequent to neonatal intensive care unit (NICU) hospitalization and to compare this with term infants living in the community. STUDY DESIGN: From March 2013 through March 2015, we enrolled 189 newborns (96 term and 93 preterm) into a prospective, longitudinal study obtaining nose/throat swabs within 7 days of birth, weekly while hospitalized and then monthly to 4 months after hospital discharge. Taqman array cards were used to identify 16 viral respiratory pathogens by real-time polymerase chain reaction. Demographic, clinical, and laboratory data were gathered from electronic medical records, and parent interview while hospitalized with interval histories collected at monthly visits. The hospital course of all preterm infants who underwent late-onset sepsis evaluations was reviewed. RESULTS: Over 119 weeks, we collected 618 nose/throat swabs from at risk preterm infants in our level IV regional NICU. Only 4 infants had viral respiratory infections, all less than 28 weeks gestation at birth. Two infants were symptomatic with the infections recognized by the clinical team. The daily risk of acquiring a respiratory viral infection in preterm infants in the NICU was significantly lower than in the full term cohort living in the community. Once discharged from the hospital, viral respiratory infections were common in all infants. CONCLUSIONS: Viral respiratory infections are infrequent in a NICU with strict infection prevention strategies and do not appear to cause unrecognized illness. Both preterm and term infants living in the community quickly acquire respiratory viral infections.
Subject(s)
Hospitalization/statistics & numerical data , Intensive Care Units, Neonatal/statistics & numerical data , Respiratory Tract Infections/epidemiology , Virus Diseases/epidemiology , Female , Humans , Infant , Infant, Newborn , Infant, Premature , Infant, Premature, Diseases , Length of Stay , Longitudinal Studies , Male , Prospective Studies , Real-Time Polymerase Chain Reaction , Respiratory Tract Infections/virologyABSTRACT
There is now a clear focus on incorporating, and integrating, multiple levels of analysis in developmental science. The current study adds to research in this area by including markers of the immune and neuroendocrine systems in a longitudinal study of temperament in infants. Observational and parent-reported ratings of infant temperament, serum markers of the innate immune system, and cortisol reactivity from repeated salivary collections were examined in a sample of 123 infants who were assessed at 6 months and again when they were, on average, 17 months old. Blood from venipuncture was collected for analyses of nine select innate immune cytokines; salivary cortisol collected prior to and 15 min and 30 min following a physical exam including blood draw was used as an index of neuroendocrine functioning. Analyses indicated fairly minimal significant associations between biological markers and temperament at 6 months. However, by 17 months of age, we found reliable and nonoverlapping associations between observed fearful temperament and biological markers of the immune and neuroendocrine systems. The findings provide some of the earliest evidence of robust biological correlates of fear behavior with the immune system, and identify possible immune and neuroendocrine mechanisms for understanding the origins of behavioral development.
Subject(s)
Cytokines/blood , Hydrocortisone/analysis , Temperament/physiology , Female , Humans , Infant , Longitudinal Studies , Male , Saliva/chemistryABSTRACT
BACKGROUND: Quality of the parent-child relationship is a robust predictor of behavioral and emotional health for children and adolescents; the application to physical health is less clear. METHODS: We investigated the links between observed parent-child relationship quality in an interaction task and antibody response to meningococcal conjugate vaccine in a longitudinal study of 164 ambulatory 10-11 year-old children; additional analyses examine associations with cortisol reactivity, BMI, and somatic illness. RESULTS: Observed Negative/Conflict behavior in the interaction task predicted a less robust antibody response to meningococcal serotype C vaccine in the child over a 6 month-period, after controlling for socio-economic and other covariates. Observer rated interaction conflict also predicted increased cortisol reactivity following the interaction task and higher BMI, but these factors did not account for the link between relationship quality and antibody response. CONCLUSIONS: The results begin to document the degree to which a major source of child stress exposure, parent-child relationship conflict, is associated with altered immune system development in children, and may constitute an important public health consideration.
Subject(s)
Antibody Formation , Emotions , Meningococcal Vaccines/immunology , Parent-Child Relations , Vaccination/psychology , Child , Female , Humans , Male , Mental HealthABSTRACT
Experimental animal and adult human data suggest that stress exposure is associated with alterations in immune system function that may underlie increased susceptibility to disease and behavioral disorders. The implications of these data for child psychology and psychiatry are not yet clear. The current review seeks to distil and translate the relevant animal and adult human work to children to advance a developmental model of psychoneuroimmunology. In addition to reviewing key specific findings, we consider biological/conceptual models and technical aspects of psychoneuroimmunology work in pediatric populations, and outline the rationales and advantages of integrating hypotheses concerning neuroinflammation in developmental studies of psychopathology.
Subject(s)
Brain/immunology , Child Development/physiology , Mental Disorders/immunology , Neuroimmunomodulation/immunology , Stress, Psychological/immunology , HumansABSTRACT
Research findings in psychoneuroimmunology document reliable, bidirectional linkages among psychological processes, the nervous system, and the immune system. However, available data are based almost entirely on animal and adult human studies; the application to children and adolescents is uncertain. We capitalized on the experimental leverage provided by a routine vaccination to examine the link between mood symptoms and the immune response to a vaccine challenge in early adolescence. One hundred twenty-six 11-year-olds for whom vaccine response data were available were assessed at prevaccination and 4 weeks, 3 months, and 6 months following vaccination; self-report ratings of depression and anxiety as well as measures of psychosocial and somatic risk were assessed prior to vaccine response. Analyses indicated that children's internalizing mood symptoms were associated with elevated and persistently higher antibody responses, with evidence extending to two of the four serogroups. The associations remained after controlling for multiple possible confounders (social class, body mass index, sleep, psychosocial risk, and pubertal status). The observed enhanced vaccine response associated with depressive and anxious symptoms in early adolescence may reflect an important developmental difference in immune system-brain interplay between adults and children, and it underscores the need for further developmental studies of psychoneuroimmunology.
Subject(s)
Anxiety/immunology , Depression/immunology , Meningococcal Vaccines/immunology , Child , Female , Humans , MaleABSTRACT
BACKGROUND: Children <2 years of age are at high risk of influenza-related mortality and morbidity. However, the appropriate dose of oseltamivir for children <2 years of age is unknown. METHODS: The National Institute of Allergy and Infectious Diseases Collaborative Antiviral Study Group evaluated oseltamivir in infants aged <2 years in an age-de-escalation, adaptive design with a targeted systemic exposure. RESULTS: From 2006 to 2010, 87 subjects enrolled. An oseltamivir dose of 3.0 mg/kg produced drug exposures within the target range in subjects 0-8 months of age, although there was a greater degree of variability in infants <3 months of age. In subjects 9-11 months of age, a dose of 3.5 mg/kg produced drug exposures within the target range. Six of 10 subjects aged 12-23 months receiving the Food and Drug Administration-approved unit dose for this age group (ie, 30 mg) had oseltamivir carboxylate exposures below the target range. Virus from 3 subjects developed oseltamivir resistance during antiviral treatment. CONCLUSIONS: The appropriate twice-daily oral oseltamivir dose for infants ≤8 months of age is 3.0 mg/kg, while the dose for infants 9-11 months old is 3.5 mg/kg.
Subject(s)
Drug Resistance, Viral , Influenza, Human/drug therapy , Influenza, Human/virology , Orthomyxoviridae/drug effects , Orthomyxoviridae/isolation & purification , Oseltamivir/administration & dosage , Oseltamivir/pharmacokinetics , Administration, Oral , Female , Humans , Infant , Infant, Newborn , Male , Oseltamivir/pharmacologyABSTRACT
BACKGROUND: Respiratory Syncytial Virus (RSV) disease in young children ranges from mild cold symptoms to severe symptoms that require hospitalization and sometimes result in death. Studies have shown a statistical association between RSV subtype or phylogenic lineage and RSV disease severity, although these results have been inconsistent. Associations between variation within RSV gene coding regions or residues and RSV disease severity has been largely unexplored. METHODS: Nasal swabs from children (< 8 months-old) infected with RSV in Rochester, NY between 1977-1998 clinically presenting with either mild or severe disease during their first cold-season were used. Whole-genome RSV sequences were obtained using overlapping PCR and next-generation sequencing. Both whole-genome phylogenetic and non-phylogenetic statistical approaches were performed to associate RSV genotype with disease severity. RESULTS: The RSVB subtype was statistically associated with disease severity. A significant association between phylogenetic clustering of mild/severe traits and disease severity was also found. GA1 clade sequences were associated with severe disease while GB1 was significantly associated with mild disease. Both G and M2-2 gene variation was significantly associated with disease severity. We identified 16 residues in the G gene and 3 in the M2-2 RSV gene associated with disease severity. CONCLUSION: These results suggest that phylogenetic lineage and the genetic variability in G or M2-2 genes of RSV may contribute to disease severity in young children undergoing their first infection.