Infections In Early Life Research Articles

Respiratory viral infections in infants: causes, clinical symptoms, virology, and immunology.

In global terms, respiratory viral infection is a major cause of morbidity and mortality. Infancy, in particular, is a time of increased disease susceptibility and severity. Early-life viral infection causes acute illness and can be associated with the development of wheezing and asthma in later life. The most commonly detected viruses are respiratory syncytial virus (RSV), rhinovirus (RV), and influenza virus. In this review we explore the complete picture from epidemiology and virology to clinical impact and immunology. Three striking aspects emerge. The first is the degree of similarity: although the infecting viruses are all different, the clinical outcome, viral evasion strategies, immune response, and long-term sequelae share many common features. The second is the interplay between the infant immune system and viral infection: the immaturity of the infant immune system alters the outcome of viral infection, but at the same time, viral infection shapes the development of the infant immune system and its future responses. Finally, both the virus and the immune response contribute to damage to the lungs and subsequent disease, and therefore, any prevention or treatment needs to address both of these factors.

Maternal Infection with Trypanosoma cruzi and Congenital Chagas Disease Induce a Trend to a Type 1 Polarization of Infant Immune Responses to Vaccines

BackgroundWe previously showed that newborns congenitally infected with Trypanosoma cruzi (M+B+) display a strong type 1 parasite-specific T cell immune response, whereas uninfected newborns from T. cruzi-infected mothers (M+B−) are prone to produce higher levels of proinflammatory cytokines than control neonates (M−B−). The purpose of the present study was to determine if such fetal/neonatal immunological environments could alter the response to standard vaccines administered in early life.MethodologyInfants (6–7 months old) living in Bolivia, an area highly endemic for T. cruzi infection, and having received Bacillus Calmette Guerin (BCG), hepatitis B virus (HBV), diphtheria and tetanus vaccines, were enrolled into the M+B+, M+B−, M−B− groups mentioned above. The production of IFN-γ and IL-13, as markers of Th1 and Th2 responses respectively, by peripherical blood mononuclear cells stimulated with tuberculin purified protein derivative of Mycobacterium tuberculosis (PPD) or the vaccinal antigens HBs, diphtheria toxoid (DT) or tetanus toxoid (TT), as well as circulating levels of IgG antibodies against HBsAg, DT and TT were analyzed in infants. Cellular responses to the superantigen SEB were also monitored in M+B+, M+B−, M−B−infants and newborns.Principal FindingsM+B+ infants developed a stronger IFN-γ response to hepatitis B, diphtheria and tetanus vaccines than did M+B− and M−B− groups. They also displayed an enhanced antibody production to HBsAg. This was associated with a type 1-biased immune environment at birth, since cells of M+B+ newborns produced higher IFN-γ levels in response to SEB. M+B− infants produced more IFN-γ in response to PPD than the other groups. IL-13 production remained low and similar in all the three groups, whatever the subject's ages or vaccine status.ConclusionThese results show that: i) both maternal infection with T. cruzi and congenital Chagas disease do not interfere with responses to BCG, hepatitis B, diphtheria and tetanus vaccines in the neonatal period, and ii) the overcoming of immunological immaturity by T. cruzi infection in early life is not limited to the development of parasite-specific immune responses, but also tends to favour type 1 immune responses to vaccinal antigens.

Early-life EBV infection protects against persistent IgE sensitization

Infection with EBV has previously been implicated in influencing allergic disorders, but its precise role remains contradictory. The timing of primary infection may contribute to the discrepancies. This study aimed at investigating whether the time-point of primary EBV infection during childhood could be of importance in modulating the risk of developing IgE sensitization. A total of 219 Swedish infants were followed prospectively to 5 years of age with clinical examinations, skin prick testing, specific IgE analyses, and determination of serostatus against EBV. After analysis of the children's EBV serostatus, we found that 5-year-olds who were infected with EBV before the age of 2 years were at a significantly lower risk of being persistently IgE-sensitized-that is, sensitized at both 2 and 5 years of age (adjusted odds ratio, 0.34; 95% CI, 0.12-0.94). In contrast, contraction of EBV after 2 years of age was highly associated with late-onset IgE sensitization (adjusted odds ratio, 4.64; 95% CI, 1.57-13.69). Persistently sensitized 5-year-olds had higher specific-IgE levels than children with late-onset IgE sensitization (P < .01). Our data support the value of early-life microbial exposure for protection against the development of IgE sensitization and underscore the proximate postnatal years as an important period during which EBV could contribute to an allergo-protective immune profile.

Possible environmental determinants of juvenile idiopathic arthritis

Like other autoimmune diseases, including adult RA, risk of developing juvenile idiopathic arthritis (JIA) is thought to be determined by a complex combination of genetic and environmental factors. Although some predisposing JIA genes are now being identified, research aimed at identifying environmental influences lags behind most other autoimmune conditions. Here we review research to date, from which some evidence has been generated to support a role for breastfeeding, infection and maternal smoking in determining JIA risk. We also propose further hypotheses worthy of testing, based on knowledge acquired for other autoimmune diseases. These include the role of vitamin D and sun exposure, and the role of early-life infection ('the hygiene hypothesis') in determining risk. Finally, we discuss future directions including practical study designs to more comprehensively test hypotheses and provide new insight into this important area of research.

The Level and Duration of RSV-Specific Maternal IgG in Infants in Kilifi Kenya

BackgroundRespiratory syncytial virus (RSV) is the major cause of lower respiratory tract infection in infants. The rate of decay of RSV-specific maternal antibodies (RSV-matAb), the factors affecting cord blood levels, and the relationship between these levels and protection from infection are poorly defined.MethodsA birth cohort (n = 635) in rural Kenya, was studied intensively to monitor infections and describe age-related serological characteristics. RSV specific IgG antibody (Ab) in serum was measured by the enzyme linked immunosorbent assay (ELISA) in cord blood, consecutive samples taken 3 monthly, and in paired acute and convalescent samples. A linear regression model was used to calculate the rate of RSV-matAb decline. The effect of risk factors on cord blood titres was investigated.ResultsThe half-life of matAb in the Kenyan cohort was calculated to be 79 days (95% confidence limits (CL): 76–81 days). Ninety seven percent of infants were born with RSV-matAb. Infants who subsequently experienced an infection in early life had significantly lower cord titres of anti-RSV Ab in comparison to infants who did not have any incident infection in the first 6 months (P = 0.011). RSV infections were shown to have no effect on the rate of decay of RSV-matAb.ConclusionMaternal-specific RSV Ab decline rapidly following birth. However, we provide evidence of protection against severe disease by RSV-matAb during the first 6–7 months. This suggests that boosting maternal-specific Ab by RSV vaccination may be a useful strategy to consider.

Spatiotemporal Trends of Incidence Rates of Ulcerative Colities and Crohnʼs Disease

ISEE-0105 Background and Objective: Ulcerative colitis and Crohn's disease are assumed to be caused by a dysregulation in the immune system due to the commensal bacteria flora in genetically susceptible individuals. Incidence rates of the diseases, however, show large geographic and temporal variability. The temporal increase is often explained by the “hygiene hypothesis”, stating that reduced number of infections in early life will increase the likelihood for developing autoimmune diseases in adulthood, but this hypothesis is less likely to explain differences between countries. We will therefore decompose worldwide incidence rates of ulcerative colitis and Crohn's disease and correlate the incidence values to latitude, temperature, time, and economic conditions. Methods: We used published incidence studies of both Crohn's disease and ulcerative colitis from 1966 to 2007. The incidence rates were modelled as functions of latitude, mean annual temperature for the study areas, year of the study, and gross national product per capita. Results: Incidence rates of both diseases increase with increased gross national product per capita (P<0.001 and P = 0.046 for UC and CD). Incidence rates of ulcerative colitis were significantly related to latitude (P = 0.028). For Crohn's disease incidence rates were associated to both latitude and mean annual temperature (P = 0.016, P<0.001). Conclusions: Incidence rates for both diseases are related to economic changes and either latitude and/or mean annual temperature. Mean annual temperature is also assumed to reflect latitudinal change. We postulate that both economic and latitudinal variability are aspects of the same phenomena: microbial diversity. Improved economic conditions are related to a reduced microbial load. Species diversity is also known to be larger closer to equator than far from equator–the latitudinal diversity gradient. Reduced contact with commensal flora or “old friends”, due to reduced microbial load or ecological conditions could therefore explain the worldwide trends in incidence rates.

IL‐12 and type I IFN response of neonatal myeloid DC to human CMV infection

Following congenital human CMV (HCMV) infection, 15-20% of infected newborns develop severe health problems whereas infection in immunocompetent adults rarely causes illness. The immaturity of neonatal antigen presenting cells could play a pivotal role in this susceptibility. Neonatal myeloid DC were shown to be deficient in IFN-beta and IL-12 synthesis in response to TLR triggering. We studied the response of cord and adult blood-derived myeloid DC to HCMV infection. Neonatal and adult DC were equally susceptible to in vitro HCMV infection. Among immunomodulatory cytokines, IL-12, IFN-beta and IFN-lambda1 were produced at lower levels by neonatal as compared with adult DC. In contrast, neonatal and adult DC produced similar levels of IFN-alpha and IFN-inducible genes. Microarray analysis indicated that among the more than thousand genes up- or down-regulated by HCMV infection of myeloid DC, 88 were differently regulated between adult and neonatal DC. We conclude that neonatal and adult DC trigger a partly different response to HCMV infection. The deficient IL-12 and mature IFN-alpha production by neonatal DC exposed to HCMV are likely to influence the quality of the T lymphocyte response to HCMV infection in early life.

Neonatal immunization with Listeria monocytogenes induces T cells with an adult-like avidity, sensitivity, and TCR-Vβ repertoire, and does not adversely impact the response to boosting

Listeria monocytogenes ( Lm) holds promise as a neonatal vaccine vehicle. Here we show that Lm immunized neonatal mice reached maximal Ag-specific CD8 + T cell expansion after only a single immunization, while adults required two doses. Ag-specific CD4 + T cell expansion in both age groups required a boost to reach its peak. Neither functional avidity, sensitivity, nor the TCR-Vβ repertoire of the Ag-specific T cells differed between mice immunized as neonates or adults. Lastly, neonatal immunization did not decrease protection or preclude a booster response. Overall, our data provide further evidence in support of immunization at birth as a feasible public health strategy to combat early life infections.

Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain

Systemic infection with Escherichia coli on postnatal day (P) 4 in rats results in significantly altered brain cytokine responses and behavioral changes in adulthood, but only in response to a subsequent immune challenge with lipopolysaccharide [LPS]. The basis for these changes may be long-term changes in glial cell function. We assessed glial and neural cell genesis in the hippocampus, parietal cortex (PAR), and prefrontal cortex (PFC), in neonates just after the infection, as well as in adulthood in response to LPS. E. coli increased the number of newborn microglia within the hippocampus and PAR compared to controls. The total number of microglia was also significantly increased in E. coli-treated pups, with a concomitant decrease in total proliferation. On P33, there were large decreases in numbers of cells coexpressing BrdU and NeuN in all brain regions of E. coli rats compared to controls. In adulthood, basal neurogenesis within the dentate gyrus (DG) did not differ between groups; however, in response to LPS, there was a decrease in neurogenesis in early-infected rats, but an increase in controls to the same challenge. There were also significantly more microglia in the adult DG of early-infected rats, although microglial proliferation in response to LPS was increased in controls. Taken together, we have provided evidence that systemic infection with E. coli early in life has significant, enduring consequences for brain development and subsequent adult function. These changes include marked alterations in glia, as well as influences on neurogenesis in brain regions important for cognition.

Neonatal bacterial infection alters fever to live and simulated infections in adulthood

Fever is a critical component of the host immune response to infection. An emerging literature demonstrates that experience with infectious organisms early in life, during the perinatal period, may permanently program immune responses later in life, including fever. We explored the influence of neonatal infection with Escherichia coli on fever responses to lipopolysaccharide (LPS) and E. coli in adulthood. Fever to a low dose of LPS in adulthood did not significantly differ as a consequence of early-life infection. Eight days after the LPS injection, the same group of rats received a high dose of live E. coli. This time, neonatally infected rats exhibited a markedly longer fever than controls. In a subsequent experiment, fever to a single high dose of E. coli without prior LPS in adulthood did not differ by group, suggesting that the previous difference was a lack of tolerance to the dual challenges in early-infected rats. Finally, both groups exhibited decreased tumor necrosis factor (TNF)-alpha and toll-like-receptor (TLR) 4 production to dual LPS challenges in isolated splenocytes, whereas only rats infected as neonates exhibited increased cyclooxygenase-2 within the hypothalamus in response to adult infection, suggesting that early infection-induced changes in fever regulation may involve a change in central mechanisms. Taken together, these data indicate that early-life infection is associated with marked changes in host temperature regulation in adulthood.

Neonatal infection with neurotropic influenza A virus induces the kynurenine pathway in early life and disrupts sensorimotor gating in adult Tap1−/− mice

Epidemiological studies suggest that early life infections may contribute to the development of neuropsychiatric disorders later in life. Experimental studies employing infections during neonatal life support this notion by reporting persistent changes in the behaviour of adult animals, including deficits in sensorimotor gating. We have previously described an induction of the kynurenine pathway in neonatal wild-type (WT) mice following a systemic infection with neurotropic influenza A/WSN/33 virus. Here, we use the same model of infection in both WT and Tap1-/- mice (expressing reduced levels of MHC class I) and study long-term effects of the infection on sensorimotor gating, as determined by measuring prepulse inhibition (PPI). Moreover, transcription of genes encoding enzymes in the kynurenine pathway and levels of kynurenic acid (KYNA), in the brain of Tap1-/- mice were investigated. In mice infected on postnatal day (P)3 or P4, the levels of several transcripts in the kynurenine pathway were altered at P7, P13 and P24. Transcripts encoding indoleamine-pyrrole 2,3-dioxygenase (IDO), degrading tryptophan in the first step of the kynurenine pathway were consistently up-regulated at all time-points investigated. The changes in transcript levels were accompanied by a transient elevation of KYNA in the brain of infected mice at P13. At age 5-6 months, neonatally infected Tap1-/-, but not WT, mice exhibited a reduction in PPI. The present data show that a neonatal infection targeting the brain can induce the kynurenine pathway and that such an infection can disrupt sensorimotor gating in adulthood in genetically vulnerable mice.

12. Learning-induced increases in immune and plasticity-related genes: Modulation by cytokines and early-life infection

12. Learning-induced increases in immune and plasticity-related genes: Modulation by cytokines and early-life infection

Long-term airway morbidity following viral LRTI in early infancy: recurrent wheezing or asthma?

Episodes of lower respiratory illnesses (LRIs) in the first years of life have been associated with recurrent wheeze in studies of high-risk and community-based cohorts. Respiratory syncytial virus (RSV) is an agent especially associated with severe cases of bronchiolitis affecting young infants in winter months and has a typical seasonal pattern. Data from the Children's Respiratory Study from Arizona and a hospital-based Swedish study have been interpreted as evidence that severe RSV bronchiolitis is associated with a 30-40% likelihood of subsequent asthma. Other respiratory viruses, especially Rhinovirus, have been identified to be importantly associated with recurrent wheeze in children at risk for asthma. A case-control study of palivizumab given in the first year of life to preterm infants has shown a 50% reduction in the occurrence of recurrent wheeze even after controlling for potential confounding variables. Prospective trials with anti-viral strategies, including potential new vaccines, should give us better understanding of the role of viral infections in early life in the causation of childhood asthma.

Lung function at 10 yr is not impaired by early childhood lower respiratory tract infections

The causal relationship between lower respiratory tract infections (LRIs) in early life and reduced lung function later in childhood is unsettled. Therefore, we assessed whether LRIs the first 2 yr of life influenced lung function development from birth to school age. In the prospective Oslo birth cohort, 'the Environment and Childhood Asthma (ECA) study' lung function was measured at birth in 802 infants by tidal flow volume loops and in 664 infants by passive respiratory mechanics and half yearly questionnaires, including LRI questions, were completed until 2 yr of age. The present study includes 607 children with information about LRIs the first 2 yr of life and successfully forced expiratory flow (FEF) volume measurements at the 10-yr follow-up assessment. At 10 yr of age, FEF at 50% of forced vital capacity (FEF(50)) (mean 95% confidence interval) was reduced in children with at least one bronchiolitis (85.0, 80.6-89.5, p = 0.020) or bronchitis (86.2, 82.6-89.8, p = 0.030) or > or =3 LRIs (83.4, 78.1-88.8, p = 0.017) when compared with no LRIs (90.6, 88.8-92.5) by 2 yr of life. The effects were significant in girls only when stratifying for gender. Among girls with later bronchiolitis compliance of the respiratory system (3.64, 3.17-4.10 vs. 4.18, 3.98-4.37, p = 0.031) and the ratio of time to peak tidal expiratory flow to total expiratory time (t(PTEF)/t(E)) measured at birth was significantly reduced (0. 26, 0.23-0.29 vs. 0.32, 0.30-0.33, p = 0.005) when compared with children with no LRIs. Change in lung function from birth (by t(PTEF)/t(E)) to 10 yr of age was not significantly associated with LRIs the first 2 yr of life, and LRIs by 2 yr of life were not significantly associated with lung function at 10 yr of age in regression analyses including lung function at birth and other possible predictors of lung function at 10 yr. In our study, LRIs during the first 2 yr of life did not impair lung function development from birth until 10 yr of age.

Neonatal infection with neurotropic influenza A virus affects working memory and expression of type III Nrg1 in adult mice

Epidemiological studies suggest that early life infections may contribute to the development of psychiatric disorders characterized by cognitive deficits. Here, we studied the effects of a neonatal influenza A/WSN/33 virus infection on locomotor activity, working memory and emotional behavior in adult mice. In addition to wild type mice, immunodeficient (Tap1−/−) mice lacking functional CD8+ T cells, were included in the study to model the potential influence of a genetic deficit relating to virus clearance. Three to four months after the infection, infected Tap1−/− mice, but not wild type mice, exhibited deficits in working memory as well as increased rearing activity and anxiety. In the medial prefrontal cortices of these infected Tap1−/− mice reduced levels of type III Nrg1 transcripts were observed supporting a role for neuregulin 1 signaling in neuronal circuits involved in working memory. Virus replication, distribution or clearance did not differ between the two genotypes. The lack of CD8+ T cells, however, appeared to contribute to a more pronounced glia response in Tap1−/− than in wild type mice. Thus, the present study suggest that the risk of developing deficits in cognitive and emotional behavior following a CNS infection during brain development is influenced by genetic variation in genes involved in the immune response.

Early life chlamydial infection enhances allergic airways disease through age-dependent differences in immunopathology (79.20)

Abstract Chlamydial respiratory tract infections are associated with the development and exacerbation of asthma in both children and adults, but the mechanisms underpinning this association remain unknown. We investigated the effect of the age of chlamydial infection on key features of asthma in later life using mouse models of Ovalbumin-induced allergic airways disease (AAD). Neonatal and infant, but not adult infection resulted in differential and permanent alterations in airway eosinophils, T-cell cytokines and dendritic cells (DCs). Infection of neonates suppressed eosinophil influx into the airways and reduced T-cell cytokine release which correlated with a significant reduction in the number and activation of DCs. In stark contrast, infant infection augmented eosinophil influx and increased T-cell cytokine release which correlated with increased DC numbers and activation. Importantly, both neonatal and infant infections enhanced physiological (mucus secreting cell hyperplasia and airways hyper-responsiveness) responses in AAD in later life, which correlated with enhanced IL-13 expression in the lung. Furthermore, neonatal infection induced substantial alterations in lung structure which was linked with increased TGF-β in lung tissue. Thus, early life infection enhances pivotal features of AAD through age dependent, differential affects on immune responses and lung structure.

Infections in early life and risk of childhood ALL

Sir, Cardwell et al (2008) report that a survey of GP records, detailing recorded infections in the first year of life, finds no evidence to support the hypothesis by Greaves (2006) that deficient infectious exposure in infancy may be a risk factor for developing the common form of childhood acute lymphoblastic leukaemia (ALL). This study therefore confirms the earlier report by Roman et al (2007). These data indeed provide no support for the hypothesis. However, the authors' underlying premise bears examination. Nowhere in the ‘Greaves' (‘delayed infection') hypothesis does it state or predict that the relevant ‘protective', infectious exposures in infancy or early childhood will necessarily elicit overt symptoms or pathology that prompt GP visitations. It is perfectly plausible that only particular, albeit common, infections are, for historical/evolutionary reasons (Greaves, 2006), competent to appropriately modulate the neonatal immune system network, and these could be essentially innocuous or ‘invisible' infections as in the parallel ‘Old Friends' hypothesis proposed by Rook (2007) for risk of allergies. We suspect that a large proportion of infections in infancy and early childhood are asymptomatic. Has anyone done a careful study of this? A biological measure might be more relevant for an evaluation of the hypothesis than querying GP records. The authors (Cardwell et al, 2008) also ignore a conflict of data that requires resolution. The lack of protection afforded by infectious episodes recorded in GP records is at odds with a large and growing body of data from case–control studies that indicate that attendance at playgroups in infancy is protective for childhood ALL. This latter conclusion is a consistent finding from the largest studies designed to address the question (Gilham et al, 2005; Ma et al, 2005; Kamper-Jorgensen et al, 2007). Day care attendance is an accepted surrogate indicator for all types of infections transmitted through personal contact and is currently the best test of the ‘Greaves' hypothesis as it makes no assumptions about microbial species or associated pathology/symptoms. The authors of the recent reports (Roman et al, 2007; Cardwell et al, 2008) are correct to conclude that their data provide no support for the ‘delayed infection' hypothesis, but neither do they negate it.

Associations between Early-life Infections, Antibiotic Use, and Asthma

Associations between Early-life Infections, Antibiotic Use, and Asthma

Allergen and Endotoxin Exposure, Infection, and Breastfeeding in Early Life, and Recurrent Wheezing in Children: 48-month Follow-up of a Cohort Study

RATIONALE: Exposure to environmental factors early in life may have a critical role in subsequent development of sensitization and asthma.METHODS: One-hundred and four newborns were enrolled at birth in this cohort study. Children belonged to low-income families and were at high risk for asthma. Recurrent wheezing was defined as three or more wheezing episodes in the past year. Infection of the upper or lower respiratory tract requiring antibiotics was recorded. Dust samples were collected from bedding and floor of the infants' bedroom within six months after birth. Endotoxin content was determined by Limulus Amebocyte Lysate assay, and major allergens from mites, cockroach, cat, dog, mouse and rat were quantitated by ELISA in dust extracts. Serum IgE antibodies were quantitated by ImmunoCAP.RESULTS: At age 48 months, 35/98 (35.7%) children presented with recurrent wheezing. Multivariate analysis revealed that respiratory infection in the first 12 months of life was associated with recurrent wheezing, OR (95% CI) 3.94 (1.29-11.98), p = 0.016, whereas allergen exposure, exclusive breast feeding for at least four months, male gender, and high levels of exposure to endotoxin had no effect. Sensitization to D. pteronyssinus (CAP score≥2) was found in 25/90 (27%) children, with no association with recurrent wheezing.CONCLUSIONS: Respiratory infection in the first 12 months of life was associated with recurrent wheezing at age 4, whereas exposure to allergen and high levels of endotoxin in early life and exclusive breastfeeding for at least four months showed no effect in development of asthma. RATIONALE: Exposure to environmental factors early in life may have a critical role in subsequent development of sensitization and asthma. METHODS: One-hundred and four newborns were enrolled at birth in this cohort study. Children belonged to low-income families and were at high risk for asthma. Recurrent wheezing was defined as three or more wheezing episodes in the past year. Infection of the upper or lower respiratory tract requiring antibiotics was recorded. Dust samples were collected from bedding and floor of the infants' bedroom within six months after birth. Endotoxin content was determined by Limulus Amebocyte Lysate assay, and major allergens from mites, cockroach, cat, dog, mouse and rat were quantitated by ELISA in dust extracts. Serum IgE antibodies were quantitated by ImmunoCAP. RESULTS: At age 48 months, 35/98 (35.7%) children presented with recurrent wheezing. Multivariate analysis revealed that respiratory infection in the first 12 months of life was associated with recurrent wheezing, OR (95% CI) 3.94 (1.29-11.98), p = 0.016, whereas allergen exposure, exclusive breast feeding for at least four months, male gender, and high levels of exposure to endotoxin had no effect. Sensitization to D. pteronyssinus (CAP score≥2) was found in 25/90 (27%) children, with no association with recurrent wheezing. CONCLUSIONS: Respiratory infection in the first 12 months of life was associated with recurrent wheezing at age 4, whereas exposure to allergen and high levels of endotoxin in early life and exclusive breastfeeding for at least four months showed no effect in development of asthma.

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