Asthma In Later Life Research Articles

Anti-viral agents: potential utility in exacerbations of asthma

Asthma is the most common chronic respiratory disease and its prevalence is on the increase. Respiratory viral infections in early life have been suggested to increase the risk of development of asthma in later life and virus infection remains the single greatest precipitant of asthma exacerbations. The development of effective anti-viral treatments remains a key target for therapeutic intervention. Here we discuss the role of respiratory viral infection in asthma exacerbation and highlight current and potential anti-viral agents and their mechanisms of action.

Osteopontin receptor expression on immune effector cells in neonatal RSV infection (P3232)

Abstract Respiratory Syncitial Virus (RSV)-induced bronchiolitis-pneumonia during early infancy predisposes asthma in later life. Augmented Th2 response and skewed polarization of Dendritic cells (DC) towards plasmacytoid DC (pDC) are associated. In addition, Osteopontin (OPN) serves as an immunomodulator, which is relatively deficient in RSV- infected neonatal lungs. Exogenous OPN inhibits skewed pDC polarization in RSV- infected neonatal mice. In the present study, we examined the expression of OPN receptors (CD44 and CD51/61) by flowcytometry on pDC, myeloid DC (mDC), T and B cells in response to RSV infection in the presence and absence of NKT cells using wild type (WT) and NKT cell KO (NKT-/-) mouse models. Neonates and adults are shown to exhibit NKT and NK dominant responses, respectively, in RSV infections. Expression of CD44 and CD51/61 decreased on mDC, pDC, T and B cells in RSV infected WT pups compared to the uninfected pups particularly early on infection (day 2 and 4 post-infection). On the other hand, expression OPN receptors on DC, T and B cells were increased in the RSV-infected NKT-/- pups compared to the infected WT and uninfected NKT-/- pups. This augmented expression was abolished by day 10 post-infection. Increased expression of OPN receptors in absence of NKT cells signifies their inhibitory role. Further studies examining the roles of NKT cells in OPN treatment would help understand the underlying mechanisms for developing new therapeutic strategies.

Respiratory Syncytial Virus Infection. Pathogenesis Peculiarities, Prevention and Treatment Strategies

Respiratory syncytial virus (RSV) is a most important cause of viral acute respiratory tract illness especially in infants and young children. In industrialized countries RSV infections account for 42–63% of hospital admissions with lower respiratory tract infections in children younger than 3 years of age. Risk factors for increased mortality and morbidity during RSV infection were prematurity, young age below 12 months as well old age, blood and cardiopulmonary diseases, immunocompromised conditions. In children hospitalized with RSV infections mortality is estimated to be approximately 1%, although it is increased up to 37% in patients with burdened anamnesis. Among respiratory viruses, RSV is the most common cause of airway obstruction, particularly in children below 1 year of age. RSVassociated infection in infancy is associated with distant harmful consequences: increased risk for developing bronchial obstruction during following respiratory diseases, systemic allergic sensitization and asthma in later life. Despite its importance, there is no safe vaccine as well as no effective medicines to protect against RSV infection. This brief report describes the mechanisms contributing to immunopathology of RSV infection and present status of treatment and prevention of this disease.

Childhood Infections and the Risk of Asthma: A Longitudinal Study Over 37 Years

Few studies have examined common childhood infections and adult asthma. We examined associations between childhood infectious diseases, childhood pneumonia, and current, persisting, and incident asthma to middle age. We analyzed data from the Tasmanian Longitudinal Health Study (TAHS). A history of pneumonia was ascertained from their parents when the TAHS participants were 7 years old. Measles, rubella, mumps, chickenpox, diphtheria, and pertussis were identified from school medical records. Associations with current, persisting, or incident asthma were examined using regression techniques. Greater infectious diseases load was negatively associated with persisting asthma at all ages. Individually, pertussis (adjusted OR [aOR], 0.53; 95% CI, 0.28-1.00) was negatively associated with asthma persisting to age 13 years, chickenpox (aOR, 0.58; 95% CI, 0.38-0.88) was negatively associated with asthma persisting to age 32 years, and rubella was negatively associated with asthma persisting to ages 32 (aOR, 0.61; 95% CI, 0.31-0.96) and 44 years (aOR 0.53; 95% CI, 0.35-0.82). Pertussis was associated with preadolescent incident asthma (adjusted hazard ratio [aHR], 1.80; 95% CI, 1.10-2.96), whereas measles was associated with adolescent incident asthma (aHR, 1.66; 1.06-2.56). Childhood pneumonia was associated with current asthma at ages 7 (aOR, 3.12; 95% CI, 2.61-3.75) and 13 years (aOR, 1.32; 95% CI, 1.00-1.75), an association stronger in those without than those with eczema (aOR, 3.46; 95% CI, 2.83-4.24 vs aOR, 2.08; 95% CI, 1.38-3.12). Overall, childhood infectious diseases protected against asthma persisting in later life, but pertussis and measles were associated with new-onset asthma after childhood. Measles and pertussis immunization might lead to a reduction in incident asthma in later life.

Understanding the evidence for and against the role of breastfeeding in allergy prevention

The relationship between breastfeeding and allergic disease risk has been controversial. This article reviews the current evidence for the role of breastfeeding in the prevention of allergic disease. We found considerable methodological limitations inherent in most studies evaluating the effect of breastfeeding in allergic disease. Nevertheless, since randomized control trials in breast feeding research would be considered unethical, the evidence remains limited to poorer quality observational studies where participation and recall bias can severely affect the objectivity of the data collected. Furthermore, reporting of type of breastfeeding (exclusive, full or partial) may be biased by a participant's inherent belief system of what they think they should be doing. Current evidence is inconclusive regarding the effect of breastfeeding on the development of eczema, with the most recent systemic review reporting no protective effect. There is insufficient data regarding the effects of breastfeeding on objective measures of food allergy at any age. Studies show a paradoxical effect of breastfeeding on the prevention of asthma, with an apparent protective effect against early wheezing illness in the first years of life yet an increased risk of asthma in later life; however, these findings must be interpreted with caution. Existing studies fail to adequately adjust for confounders, including the critical issues of protection against early life respiratory illnesses and reverse causation. Therefore, it is possible that the effect of breastfeeding on early wheezing illness reflects protection against respiratory infection, the predominant trigger of wheezing in early childhood, rather than a true reduction in risk of asthma. In summary, future research that takes into account the potential contribution of confounding factors and effect modifiers is needed to clarify the role of breastfeeding in development of allergic disease and to inform current clinical guidelines on the prevention of allergic disease.

Vitamin D Deficiency as a Strong Predictor of Asthma in Children

Background: Epidemiological studies suggest a link between vitamin D deficiency in early life and development of asthma in later life. Aim: The aim of this study was to measure serum vitamin D levels in asthmatic children and to compare these to healthy non-asthmatic controls. Methods: Asthmatic (n = 483) and healthy control (n = 483) children were recruited from the Pediatric Allergy-Immunology Clinics of Hamad General Hospital and the Primary Health Care Clinics in Qatar from October 2009 to July 2010. All children were below 16 years of age and asthma was diagnosed by a physician. Parents of all children completed extensive questionnaires documenting demographics, child’s feeding practice and vitamin D intake. Serum vitamin D (25-hydroxyvitamin D), calcium, phosphorus, alkaline phosphatase, magnesium, creatinine and parathyroid hormone assays were performed. Subjects with serum containing less than 20 ng/ml vitamin D were deemed deficient. Results: Asthmatic children had significantly reduced serum vitamin D levels compared to non-asthmatic children (p < 0.001); 68.1% of all asthmatics were vitamin D deficient. Asthmatic children had significantly higher degrees of moderate (41.8 vs. 25.1%) and severe (26.3 vs. 11.0%) vitamin D deficiency compared to healthy controls (p < 0.001). Positive familial history of vitamin D deficiency (35.6%, p = 0.005) and asthma (36.4%, p = 0.009) were significantly higher in asthmatic children. Along with vitamin D deficiency, asthmatics also had reduced phosphorus (p < 0.001) and magnesium (p = 0.001) levels but elevated serum alkaline phosphatase (p < 0.001) and IgE (p < 0.001). The majority of asthmatic children had less exposure to sunlight (66.7%, p = 0.006) and less physical activity (71.3%, p < 0.001). Vitamin D deficiency was the strongest predictor of asthma in this population (OR 4.82; 95% CI 2.41–8.63, p < 0.001). Conclusion: The present study revealed that the majority of asthmatic children had vitamin D deficiency compared to control children. Vitamin D deficiency was the major predictor of asthma in Qatari children.

Osteopontin induced inhibition of dendritic cell polarization towards pDC cells is not exclusively mediated by NKT cells (147.28)

Abstract Pediatric post-RSV infection associated bronchial asthma is known to be mediated via an enhanced pulmonary Th2 response. However, adult RSV infection is not known to be associated with this pathology. Further, osteopontin and NKT cell have been reported to be involved with induction of Th1 and Th2 type host-immune responses, respectively. The effect of NKT cells on naïve T helper cells is suggested to be a result of NKT cells’ subsequent modulation of naïve dendritic cells (DCs) towards plasmacytoid DCs (pDCs). So, in our present studies, using an NKT cell KO (CD1d-/-) mouse model, we have studied the role of osteopontin and NKT cells in modulating the polarization of DCs towards pDC in RSV-infected neonatal lungs. Flowcytometry analysis determined that there was an enhanced NKT cell (CD19-CD4+CD1d+) response in the RSV-infected neonatal lungs compared to that in the infected adult lungs. There was a decrease in the NKT cell response to RSV infection in the neonatal lungs upon concomitant administration of exogenous osteopontin as compared to those without osteopontin. Furthermore, in the absence of NKT cells (CD1d-/-), the administration of exogenous osteopontin induced inhibition of DC polarization towards pDC. Thus, differential pDC responses to RSV infection in neonates with exogenous osteopontin administration, even in the absence of NKT cells, warrants investigation into involvement of other factors in the development of RSV-induced bronchial asthma in later life.

Respiratory Syncytial Virus infection induces alternatively activated macrophages in the lung (158.3)

Abstract Asthma is a chronic inflammatory disease of the airways characterized by a heightened response to normally harmless antigens. Respiratory Syncytial Virus (RSV) infections in children have been associated with predisposition to asthma in later life. However, the underlying molecular mechanisms are not well understood. RSV infection was recently shown to induce Th2 type cytokines such as IL-13 within 6 days after infection. Given this early induction of IL-13, we hypothesized that the source of RSV-induced IL-13 is a cell of the innate immune system. Our ongoing studies show rapid induction of alternatively activated macrophages (AAMs) in the lung following RSV infection. RSV induces expression of Arginase I (Arg I), a characteristic marker of AAMs and stimulates secretion of the Th2 cytokines IL-5 and IL-13 from the alveolar macrophages as early as 48 hours after infection. This was found to continue on day 5 after infection, being detectable in the lung tissue as well. These observations suggest that RSV, directly or indirectly, alters gene expression in alveolar macrophages very early after infection, which we hypothesize plays an important role in promoting an allergic immune response in the infected lungs.

RSV-induced polarization of lung DCs towards plasmacytoid DCs with an associated Th2 response is dependent on NKT cells in the neonatal lungs (37.46)

Abstract RSV bronchiolitis and pneumonia during early infancy is associated with increased susceptibility to asthma; and is characterized by a hyper-responsiveness airway and a predominant Th2 response. Using a BALB/C neonatal mouse model we have observed a skewed polarization of DCs towards plasmacytoid DCs (pDCs: CD11blo CD11clo CD45R+) over myeloid DC (mDCs: CD11blo CD11chi/med CD45R-), as determined by flow cytometry (FACS). This was associated with increased and decreased production of Th2 (IL-10) and Th1 (IFN-g) cytokines, respectively, in the alveolar spaces, as measured by ELISA. A temporal observation of enhanced NKT (CD3-CD19-CD1d+) cell response was also determined by FACS. In addition, FACS revealed that RSV infection of NKT cell knock out (CD1d-/-) neonatal mouse had lower proportions of pDCs and a higher proportions of mDCs compared to the wild type (WT) mouse of same age. Amount of IL-10 in bronchoalveolar lavage fluid was lower in the CD1d-/- mouse than that in the WT mouse. This data suggests that NKT cells are instrumental in skewed polarization of DC in response to RSV infection, which in turn may influence the T cell responses and hence, development of susceptibility to asthma in later life.

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.

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.

Enhanced NKT cell response and skewed polarization of DC in RSV infection and susceptibility to asthma (131.6)

Abstract RSV infection in early infancy makes individuals susceptible to develop asthma in later life due to airway hyper-responsiveness (AHR) to innocuous antigens, which is characterized by enhanced Th2 responses. Using a neonatal mouse model, we investigated whether differential NKT cell responses and skewed polarization of DC are involved in the underlying mechanism. Flow cytometry revealed a significant increase in the proportions of NKT cells (CD3-CD19-CD1d+) in RSV-infected 5 days old lungs compared to that of 7 and 34 days old lungs. A comparable increase in the proportions of plasmacytoid DCs (pDCs; CD11blo CD11clo CD45R+) to myeloid DC (mDCs; CD11blo CD11chi/med CD45R-) was also determined by flow cytometry. To note, DC phenotypes involved in antigen presentation influence the outcomes of the immune responses. In support of this notion, RSV infection induced a significantly higher production of Th2 cytokines than Th1 cytokines in the lungs of younglings. In contrast, RSV-infected adult lungs produced significantly higher amount of Th1 cytokines. Furthermore, NK cell response was not enhanced in the young lungs as opposed to that in the adult lungs in response to RSV infection. Thus, enhanced NKT cell and reduced NK cell responses to RSV infection in the neonatal lungs, along with an enhanced Th2 response, may have induced a skewed polarization of DCs to pDCs leading to development of AHR and susceptibility to asthma.

Infection of mice with respiratory syncytial virus during neonatal life primes for enhanced antibody and T cell responses on secondary challenge

Primary neonatal immune responses to infection or vaccines are weak when compared with those of adults. In addition, memory responses of neonatally primed animals may be absent, weak or T helper type 2 (Th2)-biased. Respiratory syncytial virus (RSV) is an important pathogen of human infants and infection during the neonatal period has been linked to the development of asthma in later life. Here we report that acute intranasal infection of neonatal mice with RSV induces significant RSV-specific antibody and CD8 T cell responses. These responses were boosted after RSV rechallenge during adulthood, demonstrating the establishment of memory after neonatal priming. Primary infection during neonatal life was associated, following rechallenge, with limited viral replication in the lung. Recall responses of both spleen and lymph node cells from neonatally primed and adult-primed mice were associated with interferon-gamma secretion, indicative of a Th1-type response. However, interleukin (IL)-4 and IL-5 secretion were enhanced only in spleen and lymph node cells from neonatally primed mice. Rechallenge of neonatally primed mice was also associated with increased concentrations of chemokines monocyte chemoattractant protein-1, macrophage inflammatory protein-1alpha and regulated upon activation normal T cell expressed and secreted in the lung. These may play a role in the enhanced inflammatory cell recruitment and immunopathology induced following RSV reinfection. Our results demonstrate therefore that immunity to RSV can be established during neonatal life and, importantly, that the quality of the subsequent response is dependent upon the age of first infection.

Childhood eczema and asthma incidence and persistence: A cohort study from childhood to middle age

The association between eczema and asthma is well documented, but the temporal sequence of this association has not been closely examined. To examine the association between childhood eczema and asthma incidence from preadolescence to middle age, and between childhood eczema and asthma persisting to middle age. A further aim was to examine any effect modification by nonallergic childhood exposures on the association between childhood eczema and both childhood asthma and later life incident asthma. Data were gathered from the 1968, 1974, and 2004 surveys of the Tasmanian Longitudinal Health Study. Multivariable logistic regression examined the association between childhood eczema and childhood asthma. Cox regression examined the association between childhood eczema and asthma incidence in preadolescence, adolescence, and adult life. Binomial regression examined the association between childhood eczema and childhood asthma persisting to age 44 years. Childhood eczema was significantly associated with childhood asthma and with incident asthma in preadolescence (hazard ratio [HR], 1.70; 95% CI, 1.05-2.75), adolescence (HR, 2.14; 95% CI, 1.33-3.46), and adult life (HR, 1.63; 95% CI, 1.28-2.09). Although childhood eczema was significantly associated with asthma persisting from childhood to middle age (relative risk, 1.54; 95% CI, 1.17-2.04), this association was no longer evident when adjusted for allergic rhinitis. Childhood eczema increased the likelihood of childhood asthma, of new-onset asthma in later life and of asthma persisting into middle age.

Skewed polarization of pulmonary dendritic cells in RSV-infection and susceptibility to asthma (39.2)

Abstract Respiratory syncytial virus (RSV) infection accounts for significant morbidity in young infants. The survivors become susceptible to develop asthma later in life. Studies have shown increased airway responsiveness in these individuals and a concomitant Th2 response in their lungs. However, the underlying mechanism (s) responsible for this pulmonary Th2 response in post- RSV infection period is not well understood. In this study, using a mouse model, we examined whether differentiation of lung dendritic cells (DCs) was skewed due to RSV infection and whether a Th2 cytokine response was associated. Neonatal mice were sensitized with intraperitoneal ovalabumin (ova) and infected with intranasal RSV followed by subsequent challenge with intranasal ova. Flowcytometric analysis of lung parenchymal cells determined the proportions of CD11bloCD11chiCD45R- myeloid DCs (mDCs) and CD11blo CD11chi CD45Rhi plasmacytoid DCs (pDCs). An increase in the numbers of pDCs was observed in the lungs of RSV-infected as well as RSV-infected and ova-exposed mice. To mention, pDCs are reported to downregulate Th1 responses. Consistent to this, augmentation of Th2 cytokine responses was observed in the RSV-infected and ova-exposed mice. Thus, polarization of lung DCs towards pDC due to RSV infection may modulate lung cytokine responses leading to susceptibility to asthma in later life. Reversal or inhibition of this skewed polarization may be considered as a clinical strategy in the post-RSV infection asthma. In this connection, we have reported that GMCSF and IL4 treatment expands lung dendritic cell population with enhanced Th1 responses.

Childhood adiposity predicts adult-onset current asthma in females: a 25-yr prospective study

Few data exist on associations between childhood adiposity and incident asthma in later life. The present authors examined the relationship between childhood body mass index (BMI) and incident asthma beginning in adolescence or in adult life. All subjects included in the study were participants in the Tasmanian Asthma Survey, a large population-based cohort study, and were asthma free at 7 yrs of age. Weight, height and lung function were measured at 7 yrs of age. Asthma status at 7 and 32 yrs of age was ascertained by questionnaire. Odds ratios were calculated for the association between childhood adiposity, expressed as "overweight" or as BMI z-score quartiles at 7 yrs of age, and asthma development after that age. In females, but not in males, there was a significant association between adiposity at 7 yrs of age and current asthma at 32 yrs of age that developed after the age of 21 yrs. The association was not explained by childhood lung function or age at menarche. There was no association between adiposity at 7 yrs of age and asthma that developed after that age and remitted at 32 yrs of age in either sex. Higher body mass index in nonasthmatic young females at 7 yrs of age predicts risk of current asthma developing in adult life.

Lack of long-term effects of respiratory syncytial virus infection on airway function in mice

Epidemiological data suggests lower respiratory infections (LRI) with respiratory syncytial virus (RSV) are capable of causing long-term abnormalities in airway function. To directly test the effects of RSV LRI, we infected adult and weanling BALB/c mice with RSV (A2) or vehicle. Respiratory system impedance was used to assess baseline airway function and responses to iv methacholine (MCh) at 4, 8, 24 and 34 weeks post infection. In vitro airway responses were measured 24 weeks post infection using electrical field stimulation and MCh. Mice infected as adults showed no alterations in airway function. Mice infected as weanlings had increased MCh responses 24 weeks post infection. However, the increased response was not present 34 weeks post infection nor accompanied by alterations in in vitro responses or airway morphometry. This study did not detect long-lasting changes in airway function following RSV infection in mice. These data do not provide support for alterations in airway structure or function being responsible for the observed relationship between RSV infection in infants and asthma in later life.

The Sensitization of House Dust Mite(HDM) and Food Allergen of Atopic Dermatitis in Korean Infants and Young Children

RATIONALE: Early exposure to HDM allergen can increase the risk of allergic sensitization and the development of asthma in later life. The aim of this study was to evaluate the prevalence of HDM and food sensitization in infants and children, association with sensitization of allergen and age, clinical severity and family allergic history.

REPLY

We thank Sears et al. for their comments on our annotation.1 They point out that they have never suggested that the children should not be breast-fed on the basis of their findings and neither did we suggest that they had recommended such a course. Indeed, we were well aware of, and referred to, their previous statement on this issue.2 A point of concern is that others who are less well informed might misinterpret the conclusion in their Lancet paper3 that breast-feeding ‘may even increase the risk’ of atopy and asthma. There is considerable community concern concerning allergic disease and such statements have the potential to influence mothers and practitioners to make a decision not to breast-feed. Sears et al. agree that there are protective effects against allergic disease in early life quote, ‘studies with outcomes examined over the first few years of life generally indicate that breast-feeding protects against early childhood wheezing and to some extent atopic dermatitis’. We also agree with their conclusion that breast-feeding has not been shown to have preventative effects on asthma and atopy in later life. Thus, the issue is whether one regards those positive benefits on allergic disease in early life as one rationale for recommending breast-feeding as we have done, or emphasize the lack of a proven protective effect in later life as advocated by Sears et al. It is perhaps not surprising that any benefits from breast-feeding with regard to allergic disease are most prominent in early life as in later life, other environmental considerations come into play. However, a significant issue from their Lancet paper was their suggestion that breast-feeding might increase the risk of atopic disease. This controversial suggestion obviously demands close examination. Sears et al. address possible discrepancies between the data provided in their original Lancet publication3 and that provided on the same cohort in their article in the New England Journal of Medicine.4 The fact remains that the statistic (P for trend) that they chose to examine influences on severity of asthma in the latter publication did not show any adverse effect of breast-feeding. In their list of the independent risk factors for persistent asthma in adulthood, they listed allergy to house dust mites, smoking, airway hyperresponsiveness and female sex but not breast-feeding.4 In this correspondence, they provide additional analysis of their New England Journal of Medicine figures stating that the prevalence of breast-feeding was significantly higher among those with persistent, relapsing or remitting asthma (56.8% vs 48.3%, P = 0.038) at 26 years of age. However, when examining whether breast-feeding protects against or promotes the development of long-term asthma, it seems illogical to include the category of asthma in remission in the persisting category, particularly as from their paper the remission may have occurred from 11 years of age. Examination of their data on the effect of breast-feeding on persisting, relapsing and intermittent asthma as compared to transient asthma never wheezed, and asthma in remission indicates that the prevalence of breast-feeding in the group with ongoing symptoms is 50.7% and in the remission, transient or never wheezed group 52.6% (P = 0.67). On face value this does not support the suggestion that breast-feeding may increase the risk of asthma in adult life. With respect to some of the additional points raised by Sears et al., they again refer to the Tucson cohort,5 which suggests that breast-feeding may exacerbate asthma outcomes in later life, without acknowledging the very small numbers involved. The issue as to whether mothers who have children with atopic eczema in early life, and thus choose to prolong breast-feeding, is not resolved by their statement that ‘as atopic eczema is very rare before age 4 weeks, this should not have impacted the decision to breast-feed’. A recent population-based study indicates that, of those infants who manifest eczema by 6 months of age, eczema was present in 40% at 4 weeks of age.6 The importance of studies such as that of Sears et al., which have examined the long-term influence of breast-feeding on atopic disease, should be acknowledged and we did so in the final paragraph of our annotation.1 However, the suggestion that breast-feeding may increase the risk of atopy or asthma in later life is far from proven.

Acute and long-term effects of infection by the respiratory syncytial virus in children with congenital cardiac malformations

All newborn infants have limited pulmonary reserve compared with older children. This puts them at increased risk of respiratory complications, such as those associated with infection by the respiratory syncytial virus. Young children with congenital cardiac disease are particularly likely to suffer severe disease related to infection by the virus. In these children, the extreme vulnerability of the lung to pulmonary oedema is compounded by the additional burden caused by the respiratory syncytial virus. In addition to the well-documented acute pulmonary effects of infection with the respiratory syncytial virus, there may also be consequent long-term respiratory morbidity. Clinical studies have shown that infection by the virus in infancy is associated with a higher risk of developing subsequent bronchial obstructive disease. Much debate surrounds the mechanisms underlying this association. It is thought that a combined immunological and neurogenic response mechanism is likely. Prevention of severe respiratory disease in infants and young children with congenital heart disease due to infection by the virus may, therefore, offer both immediate and long-term benefits. Indeed, an increasing body of evidence supports this hypothesis, indicating a clinical rationale for prophylaxis against the virus in infancy, in order to reduce the chance of developing reactive airways disease and asthma in later life.