© 2006 American Thoracic Society doi: 10.1164/rccm.2601002
Update in Pediatrics 2005Imperial School of Medicine, National Heart and Lung Institute; and Royal Brompton Hospital, London, United Kingdom Correspondence and requests for reprints should be addressed to Andrew Bush, M.D., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: a.bush{at}rbh.nthames.nhs.uk GENERAL RESEARCH ISSUES The future of pediatric research was the focus of an American Thoracic Society (ATS) document last year (1). Particular issues highlighted included the following: First, the much greater diversity of pediatric versus adult disease (and one only has to consider the field of interstitial lung disease, the subject of a number of recent important reports and reviews [2–8, summarized in Reference 9] to realize this). The second is the paucity of knowledge of normal human growth and development. The third was the ethical and technical difficulties in researching young children; these were not discussed in very great depth, but the reader is referred to a recent British ethical statement (10). Finally, the small workforce (a staggering 15-fold less than adult pulmonology, with trainees spending only 8% of the time in research) and the resultant necessary inefficiencies of scale in studies were highlighted. Importantly, much research was by integration into existing clinical and basic adult programs, which means topics are often largely focused on subjects of interest to adults, such as asthma and cystic fibrosis (CF), rather than normal airway development. Pediatricians will need to find ways of having more pediatrically integrated research centers. One area where there has been valuable advances in improving research, along the lines suggested by the general ATS consensus statement, has been in infant lung function testing, where joint ATS/European Respiratory Society initiatives have been leading to the production of detailed methodologic and standardization position papers. The first of these has been in the raised-volume forced expiratory technique in infants (11). This technique involves the sedated infant being ventilated by one operator using a bag and mask. When ventilation has been taken over, a full inspiratory breath to total lung capacity is given, and then a rapid squeeze applied. This produces an expiratory flow volume curve similar to that voluntarily produced by older children and adults, as compared with the conventional rapid thoracoabdominal compression technique, in which the thoracic squeeze is applied at the end of a passive inspiration. The raised-volume technique has been shown to be more discriminatory between health and disease (12). This review gives a scholarly series of recommendations, and encouragingly shows that normal values obtained from three reputable laboratories are comparable, not merely providing the basis for centile charts for this technique but also showing that it is robust and transferable. This report has set a high standard against which the future consensus statements, which will be coming out in 2006, will inevitably be measured (11). A recent editorial in the Journal inadvertently highlighted where pediatricians have perhaps failed to follow the adult lead, which close proximity of research facilities should have permitted (13). Endobronchial biopsy is a standard and routine research technique in adult pulmonology (14, 15). An increasing number of studies have demonstrated the safety of this technique, even in small children, and investigators have also used endobronchial biopsy in research. There are published safety data on endobronchial biopsy in at least 150 children (16–18), and endobronchial biopsy has been used for research purposes in more than 150 other children (19–23). Although the overwhelming evidence is that, when properly performed in the context of a clinically indicated bronchoscopy, endobronchial biopsy is both safe and ethical, there remains reluctance in some circles to embrace the technique. Perhaps we need to be more ready to believe evidence, as well as increase the research culture in pediatric pulmonology. LUNG GROWTH AND REPAIR Of all the issues fundamental to pediatric pulmonology, normal and abnormal lung growth must take precedence. The two processes involved, branching morphogenesis (setting the pattern of the bronchial tree) and septation (creation of the terminal gas-exchanging lung), were recently comprehensively reviewed (24). A better understanding of these processes is clearly fundamental to improving lung growth and maturation, which are important not only to perinatologists but to all pediatricians faced with a child with airway or parenchymal damage. Another excellent review that focused on growth factors and vascular adaptation at birth also underscored the complexity of the subject and the gaps in our knowledge (25). The authors identified nitric oxide (NO), vascular endothelial growth factor (VEGF), endothelin (ET) receptors, and KATP channels as being among the key players in these complex processes. The complexities of the interplay between mediators and their receptors remain in large part obscure, often because of lack of the development of a focused hypothesis before starting the study. Padela and colleagues selected hepatocyte growth factor (HGF) for study in the developing lung because of its known involvement in intrauterine lung growth, in ischemia-reperfusion injury, and in situations in the adult lung where there is alveolar neogenesis (26). They hypothesized that a mediator that is up-regulated in the context of neonatal or other lung injury was likely important in normal alveolar development, and determined the role of HGF and its c-Met receptor in a hyperoxia-induced lung injury model in rats. After exposure to 60% oxygen, there was up-regulation of mRNA and immunoreactive HGF and c-Met. DNA synthesis was inhibited in the alveoli-forming secondary crests by intraperitoneal injection of either neutralizing antibody to HGF or a truncated soluble c-Met receptor, with corresponding reduction in alveolar numbers. The interest of this study was as much for the use of other models to generate hypotheses as for the delineation of the role of HGF and c-Met in secondary septation and alveologenesis. A vital area in which lung growth (or lack of it) is crucial to prognosis is congenital diaphragmatic hernia (CDH). Both ipsilateral and contralateral bronchial trees show reduced branching and failure of normal alveolar development. Surgical developments, including the use of extracorporeal membrane oxygenation and in utero surgery, have not prevented many deaths from this condition. Cyclic strain is known to be essential for normal release of growth factors and organ growth, in a number of contexts. Nelson and coworkers (27) exploited this in a lamb model of diaphragmatic hernia in which they placed an endotracheal balloon occlusion catheter into the fetuses. Three regimes were compared: continuous occlusion, analogous to the procedure that has been tried without success in humans; occlusion for cycles of 47 h occluded, 1 h released; and cycles of 23 h occluded, 1 h released. Consistent with previous reports, complete occlusion resulted in lung hyperplasia but poor differentiation. The 47-h cycle animals had significantly better lung development than the 23-h cycle lambs, even though fetal lung volume and tracheal occlusion pressure did not change during the longer occlusion. There are two major implications of these data, which require testing in humans. The first is that these interventions were performed much later in gestation than conventional fetal tracheal occlusion, corresponding to around 21 to 38 wk of human gestation. Second is that some form of cycling is much better than continuous occlusion of the fetal trachea. The optimal cycling times, and whether there is synergy with other forms of alveolar rescue strategy such as maternal corticosteroid therapy, remain to be determined. Nonetheless, this fascinating model demands further study. A recent study proposed another mechanism in addition to pulmonary alveolar–capillary hypoplasia for pulmonary hypertension in CDH (28). This group proposed that ET-1 dysregulation may play a significant role in the pathophysiology of persistent pulmonary hypertension of the newborn (PPHN). ET-1 acts through binding to type A (ETA) and type B (ETB) receptors, and so ETA and ETB receptor protein expression was studied using immunohistochemistry in 10 lung specimens obtained from newborns with CDH and in four normal lung specimens to explore whether dysregulation of ETA and ETB expression contributes to PPHN. ETA and ETB mRNAs were then quantified using real-time reverse transcriptase–polymerase chain reaction (RT-PCR) in laser-microdissected pulmonary resistive arteries. In the lungs of newborns with CDH, immunohistochemistry of both ETA and ETB receptors demonstrated overexpression in the thickened media of pulmonary arteries. Using laser microdissection and real-time RT-PCR, higher levels of ETA and ETB mRNA were found in CDH pulmonary arteries than in controls: this increase was more pronounced for ETA mRNA. This study provided the first demonstration of ET-1 receptor dysregulation in association with structural alteration of pulmonary arteries in newborns with CDH and PPHN preferentially affecting the ETA receptor; this dysregulation might contribute to PPHN associated with CDH. However, the presence of mRNA is not the same as functional receptors being synthesized. For example, organ bath work would help clarify if there is a functional, as well as a molecular, abnormality. If these studies were confirmatory, clinical studies with ET receptor antagonists (see below) in the context of CDH would be justified, to assess whether this mechanism is of real pathophysiologic significance and could be modulated favorably therapeutically. The preservation of alveolar structure in the setting of the administration of known toxic strategies, such as positive- pressure ventilation and oxygen-enriched mixtures, is paramount, and so a means of measuring alveolar size would be very valuable. Ridsdale and coworkers suggested that phosphatidylcholine measurements may present just such a marker (29). They performed rat and human studies and, in the human, used bronchopulmonary dysplasia (BPD) and emphysema as models of alveolar dysfunction. They used palmitoylmyristoyl phosphatidylcholine content (16:0/14:0 phosphatidylcholine) measured in rodent lavage fluid, and showed that during normal lung maturation, it rose, but was specifically reduced in two animal models of BPD. It was decreased in human BPD and emphysema, but not in patients without alveolar pathology. It was suggested on the basis of laser capture microdissection that the source of these changes was the alveolar type 2 cell. Clearly, longitudinal studies in humans are now required to validate these findings, together with comparisons with other markers of alveolar size, such as magnetic resonance imaging/hyperpolarized helium. However, the potential clinical use of this sort of measurement is large, and will be even greater if we can devise strategies for regrowing new alveoli, and we will therefore wish to measure efficacy. One possible candidate for regrowing alveoli therapeutically would be recombinant human (rh) VEGF, which has been shown in neonatal rats recovering from acute hyperoxia to enhance vessel growth and alveolarization (30). These authors also speculated that impaired VEGF signaling may be important in disordered lung growth. PULMONARY HYPERTENSION
An example of where pediatric and adult issues, although superficially similar, are widely divergent is in the area of pulmonary hypertension. PPHN is very difficult to treat, and the pathophysiology is very different, with a temporarily or permanently reduced pulmonary vascular bed, and increased arterial muscularization and distal extension. In the context of PPHN, hyperoxic gas mixtures are lifesaving, but toxic, to the developing lung. Superoxide dismutase (SOD) is one of the body's major antioxidant defenses, and SOD3 (extracellular SOD) is the only known defense against the free radical There is an increasing realization that the treatment of pulmonary hypertension requires not merely vasodilatation but also alteration of the structural changes in the pulmonary vasculature. In the context of neonatal lung disease, this challenge is extended into the preservation of normal lung growth. The effects of two agents widely used for the treatment of pulmonary hypertension, NO and sildenafil, have now been studied in the context of the growing lung. Eight preterm lambs were ventilated; four were also treated with NO (33). NO had minimal effects on pulmonary vascular resistance and arterial muscularization, but reduced bronchial smooth muscle and increased alveolar numbers. The implication is that NO may favorably modulate alveolar growth, independent of any vasodilator actions. An agent used in pulmonary hypertension in older children and adults is the selective phosphodiesterase V inhibitor sildenafil. Rats exposed to hyperoxia have large primitive alveolar spaces, with reduced vascularization and evidence of pulmonary hypertension, akin to the structural changes in severe human BPD (34). However, Ladha and coworkers showed that administration of sildenafil led to preservation of normal alveolar growth and vascularization, and abrogation of the pulmonary hypertensive changes (35). This work is important not only on theoretic grounds, implying a central role of the NO–guanosine monophosphate (GMP) pathway in lung growth but also as a pointer that sildenafil may have a therapeutic role in disorders characterized by iatrogenic or congenital pulmonary alveolar–capillary hypoplasia. However, there are species differences; for example the effects of NO reported in lambs and rats were not seen in baboons. However, in this context, a case report of a child with impaired alveolarization and plexiform arteriopathy who was treated with sildenafil with apparent resolution of pulmonary hypertension and good long-term benefit is of interest (36). This is another promising area where more work is needed, including potential studies combining sildenafil with ET receptor antagonists. Bosentan is an oral ET combined ETA and ETB receptor antagonist, which improves hemodynamics and exercise capacity in adults with pulmonary arterial hypertension (PAH). An important pediatric study investigated the long-term outcome of children with PAH treated with bosentan, with or without concomitant prostanoid treatment (37). In this retrospective study, 86 children with PAH (idiopathic, associated with congenital heart or connective tissue disease) started bosentan with or without concomitant intravenous epoprostenol or subcutaneous treprostinil therapy. Median exposure to bosentan was 14 mo. In 90% of the patients (n = 78), World Health Organization functional class improved (46%) or was unchanged (44%) with bosentan treatment. Mean pulmonary artery pressure and pulmonary vascular resistance decreased. Kaplan-Meier survival estimates at 1 and 2 yr were 98 and 91%, respectively. These results suggested that bosentan, with or without concomitant prostanoid therapy, is safe and effective for the treatment of PAH in children. NEONATAL LUNG DISEASE There has been increasing focus on the role of chorioamnionitis in preterm delivery and its consequences, and two recent articles from the same group have moved our understanding forward. In the first article, Kramer and colleagues (38) compared cord blood monocytes from neonatal sheep with adult sheep peripheral blood monocytes. Endotoxin stimulation in vitro resulted in greater production of interleukin 6 (IL-6) and hydrogen peroxide, and more Toll-like receptor (TLR)–4 expression in the adult monocytes. In the preterm sheep that had been exposed to intraamniotic endotoxin, there was a major reduction in response to further in vitro LPS challenge 3 d later, with reduced production of IL-6, hydrogen peroxide, CD14, and class 2 major histocompatibility complex. However, 14 d later, there was evidence of augmented response to LPS, similar to an adult monocyte pattern. Two intrauterine challenges a week apart resulted in prolonged reduction in cord blood monocyte function, suggesting tolerance to LPS. It is unclear whether this is a specific tolerance to LPS, or a more generalized monocyte immune paresis, or what pattern of endotoxin exposure best mimics the natural model of chorioamnionitis. It is also not yet clear whether the changes seen in peripheral blood monocytes are found also in fetal alveolar macrophages, which might be more relevant to respiratory failure and chronic lung disease of prematurity.
A second article from the same group explored the seemingly paradoxic observation that chorioamnionitis results in accelerated fetal lung maturation (39). In a series of interlocking experiments, they induced lung inflammation in preterm sheep with intraamniotic injections of either LPS or IL-1. They determined the effect of intramuscular anti-CD18 antibody on white cell recruitment. Inhibition of CD18, an important subfamily of There are some puzzling features of the lamb endotoxin model. When the same group tried to mimic chronic chorioamnionitis using prolonged intraamniotic endotoxin, surprisingly, neither continuous infusions of endotoxin nor repeated intermittent boluses caused any changes in lung structure or function in near-term lambs (40). They did have mild inflammation, but no alteration in endothelial protein synthesis. Preterm lambs given continuous intraamniotic endotoxin had lung inflammation, fewer saccules, and decreased endothelial proteins, including endothelial NO synthase and VEGF receptor 2 expression, compared with control animals. It seems counterintuitive that prolonged fetal exposure to intraamniotic endotoxin caused such trivial changes in the lungs of near-term gestation lambs. Further work is needed to determine if there is some protective maturational effect and, more importantly, whether that protective mechanism can be activated in preterm lambs and, ultimately, infants. Continuous positive airway pressure (CPAP) is commonly used in the neonatal nursery to improve gas exchange, and the benefits of this were previously and clearly established in an animal model (41). Another article from the same group explored the interactions between level of CPAP to maintain gas exchange, and surfactant function (42). Comparisons were between 5 and 8 cm of water, and surfactant function was determined as the level of saturated phosphatidylcholine. The investigators found that gas exchange was more effective at the higher level of CPAP, but that some residual surfactant function was needed for this mode of respiratory support to work. As stated, there are other important variables that need to be dissected out, such as the effects of maternal betamethasone and exogenous surfactant administration, both of which are routine in human neonatal practice. The role of fluid overload and pulmonary edema in the development of BPD is still debated. Closure of the arterial duct by ligation or nonsteroidal antiinflammatory agents is widely practiced in the neonatal nursery. McCurnin and colleagues have used a baboon model of BPD to try to dissect out the contribution (if any) made by ligation of the arterial duct to the prevention of BPD (43). Baboons were delivered at 125 d of gestation (60 d prematurely) and randomized to ligation or no ligation on Day 6 of life. Duct ligation had the predictable cardiorespiratory beneficial effects in the short term, but there was no benefit on lung histology or proinflammatory cytokine release. The authors noted that, to some extent, the model is artificial, in that neither maternal steroids nor exogenous surfactant was administered. Clearly, this study is hypothesis-generating, rather than immediately practice-changing, but it does raise questions about the rightness of any policy of routine closure of the arterial duct in the neonatal nursery. Chronic lung consequences of prematurity encompass a range of problems, from severe and prolonged oxygen dependency, to minor degrees of asymptomatic airflow obstruction in midchildhood. It should be noted that low birth weight is a risk factor for impaired lung function, even if there are no requirements for neonatal critical care; therefore, for example, better ventilation strategies will not get rid of the problem. Hence, unless premature delivery is abolished altogether, we will still have cohorts of children with impaired lung health reaching adult life, and very likely with accelerated lung aging, as has been seen in other contexts. However, this does not mean that novel treatments should not be assessed in long-term studies to ensure that, for example, a new mode of ventilation does not cause major long-term problems (44). In general, however, novel strategies are needed, and one such strategy may be the prevention of oxidant stress. This is logical because even the preterm fetus breathing room air is exposing the developing lung to higher oxygen tensions than it would receive in utero. Lee and colleagues have looked at the potential roles of p66Shc in normal lung development and the development of BPD (45). p66Shc mediates oxidative stress–induced apoptosis. It is expressed throughout gestation in the mouse lung. These authors studied two baboon models of BPD, the "old," heavily fibrotic disease and the "new" BPD, in which alveolar–capillary hypoplasia is more of a feature. They also had access to human postmortem tissue. In summary, they found that p66Shc, cell proliferation, and apoptosis were altered concurrently during normal lung development, and during the evolution of BPD. p66Shc decreased between Days 125 and 175, then doubled after term delivery. In the "new" BPD model, p66Shc persisted and shifted from the epithelium to the mesenchyme. Interestingly, treatment with an antibombesin antibody attenuated BPD, reduced cell proliferation, and preserved the normal p66Shc distribution. Mild BPD was characterized more by epithelial, not mesenchymal p66Shc distribution. Human fetal lungs also showed a reduction in p66Shc with advancing gestation. These data are descriptive and hypothesis-generating, and a long way from coming into the clinical field, but study of the basic mechanisms of antioxidant defenses are surely an important way toward future improvements in the outcomes of neonatal intensive care. One of the spin-offs of the increasing success of neonatal intensive care units in salvaging ever tinier and more premature infants has been the survival of a population with respiratory morbidity, the nature of which has yet to be determined. Indeed, babies of birth weights of less than 501 g should expect to have full intensive care with good survival rates (46, 47). An important cohort study reported on 107 preterm infants with birth weights of less than 501 g born in three tertiary perinatal centers, with mean gestational age of 25.2 wk, and mean birth weight of 435 g. Twenty-nine were stillborn. Twenty-nine of the 48 infants with immediate life support (60%) survived (95% confidence interval, 46–75%). Forty-two of these 48 (88%) infants were small for gestational age. No infant without immediate life support survived (0/30). Twenty-three (79%) survivors developed chronic lung disease (CLD) and eight (28%) received photocoagulation for retinopathy of prematurity. The data support the increasing use of immediate life support after birth in preterm infants with birth weights of less than 501 g. This is clearly a very different population compared with the bigger (> 1,000 gm) preterm infants of 20 yr ago, and their long-term outcome must be studied carefully. The goal posts are clearly moving constantly; the surviving babies of today are much smaller, and have been treated very differently, compared with those preterm survivors who have now reached adult life. Follow-up data in such groups have been summarized (48). Generally, in the survivors of preterm delivery from years ago, there is an excess of respiratory symptoms, which improve with age; and variable airway obstruction. There is no evidence that these symptoms and disturbed physiology are affected by inhaled steroid therapy (49). Now, Baraldi and coworkers (50) have looked at fractional exhaled NO (FeNO) in a group of survivors of preterm birth. Their mean birth weights were greater than 1,000 g, and so the findings may not be relevant to the new cohort of very preterm survivors. They found that in survivors with BPD, but not preterm control infants who did not have BPD, FeNO was reduced. When compared with term control infants, and subjects with asthma with a comparable degree of airflow obstruction, FeNO was still reduced in the BPD survivors. The mechanisms are speculative, but the article serves to remind us that success in one field may bring problems in others and also that human activities may challenge our previous knowledge of airway processes. The same is true of another article, discussed in a subsequent section, on smoking, baseline lung function, and airway reactivity (51). VIRUSES IN CHILDREN Worldwide, viral diseases are probably the major respiratory issues. Respiratory syncytial virus (RSV) is ubiquitous, and exposure is almost universal by age 3 yr. Seasonal acute bronchiolitis fills pediatric wards and intensive care units, but postbronchiolitic morbidity may continue for many years. There is compelling evidence that one factor determining severity is premorbid lung function (52). The acute cellular inflammation is neutrophilic, not eosinophilic, and IL-9 may be an important factor (53). Both the acute and long-term symptoms are poorly responsive to inhaled steroids (54, 55), and the pathophysiology of the chronic morbidity is doubtful. There have been studies in rats that suggest that chronic neurogenic inflammation is the key mechanism. Early-life infection with RSV is associated with increased expression of nerve growth factor (NGF) and up-regulation of its high (TrkA) and low (p75) affinity receptors. The relevance of these rat findings has been explored recently in a human model (56). Levels of NGF and brain-derived neurotrophic factor (BDNF) were measured in non–bronchoscopically obtained lavage fluid from infants ventilated with RSV bronchiolitis. Immunofluorescence was used to detect TrkA expression in airway cells. Compared with RSV-negative bronchiolitics and postsurgical patients with no evidence of an acute infection, NGF and BDNF levels were higher in bronchoalveolar lavage (BDNF by one to two orders of magnitude more than NDF) but not in serum; TrkA was also overexpressed only in the RSV group. Lavage cellularity was similar in the RSV and non-RSV groups. It is a long step to go from these fascinating observations to attributing long-term morbidity to neurogenic inflammation after RSV, but nonetheless, they open up a number of potential possibilities for therapy in this condition. Rhinovirus (RV) infection is also very common, but usually less severe than RSV bronchiolitis. Xatzipsalti and colleagues (57) sought to determine whether RV viremia was a feature of this common childhood infection, based on previous occasional reports. They were able to detect RV cDNA by seminested RT-PCR in 10 of 88 children who were positive for RV on nasopharyngeal wash, 7 of 28 children with an asthma exacerbation, 2 of 26 with a simple cold, 1 of 25 with bronchiolitis, and 0 of 9 with pneumonia. Thirty-one RV-negative control subjects had no RV viremia. The authors speculated that RV viremia may be implicated in asthma exacerbations. More work is needed, but perhaps the defects in innate immunity, which have been implicated in the pathophysiology of asthma, may also render the subject more vulnerable to viremia. Viral exacerbations of asthma are difficult to treat, and their relationship with loss of asthma control hotly debated (58). An important study evaluated the relationship between atopy and postviral airway hyperresponsiveness (AHR) (59). Twenty-five children (13 atopic) with intermittent virus-induced asthma were studied. Clinical evaluation, skin-prick tests, methacholine bronchoprovocation, questionnaires, and a nasal wash specimen were obtained at baseline. A nasal wash specimen was obtained during their first reported cold, and methacholine provocation was performed 10 d and 5, 7, 9, and 11 wk later. Unsurprisingly, viruses were detected in 17 (68%) of 25 patients during their first cold, with RV being the most common (82%). AHR increased significantly 10 d after the upper respiratory infection, and the duration of AHR in subjects experiencing a single upper respiratory infection ranged from 5 to 11 wk, with no significant difference between groups. In the 9 mo of the study, interestingly, atopic children experienced more colds and asthma exacerbations than nonatopic children. Thus, in atopic children, there is considerable cumulative prolongation of AHR. The reason that the atopic children had more colds is unclear, and for future studies, it would be nice to know about allergen sensitization and exposure, which in adults have been shown to interact with viral infection to produce symptoms in some (60) but not other studies (61). This study is a welcome step forward in an attempt to dissect out viral colds from other asthmogenic stimuli, which may have both different mechanisms and different optimal treatment strategies. Overlapping with the next section is a study that looked at determinants of severity of RSV bronchiolitis in more than 200 infants (< 1 yr) (62). This study has the disadvantage of not having premorbid lung function data (52), but it nonetheless has useful insights. Severity of bronchiolitis was based on the lowest recorded oxygen saturation and the length of hospital stay. Environmental factors studied included the child's and family's demographics, presence of household allergens (dust mite, cat, dog, and cockroach), peripheral blood eosinophil count, IgE level, infant feeding, prior illnesses, exposure to intrauterine and postnatal cigarette smoke, and family history of atopy. Unsurprisingly, the younger the infant, the more severe was the infection. Infants exposed to maternal postnatal cigarette smoke had a lower oxygen saturation during their bronchiolitis than those not exposed. However, there was no significant difference in RSV bronchiolitis severity between infants exposed only to intrauterine smoke and those infants never exposed to cigarette smoke. This is surprising given the findings in many studies that intrauterine smoke exposure reduces infant lung function (63–66) and that impaired lung function is a risk factor for bronchiolitis in at least one excellent prospective study (52). Black infants had less severe RSV bronchiolitis than their white counterparts in the current study (62). Multivariate analysis revealed age, race, maternal atopy, and smoking to be associated with severity of RSV bronchiolitis, but there was no effect of levels of allergens in the home environment. GENES, PASSIVE SMOKING, AND CHILDREN AHR is a concept that may have different meanings at different ages. Two studies have shown that airway reactivity in infancy is predictive of lung function in midchildhood (67, 68). The suggestion was that AHR at this age relates to anatomy (a smaller airway constricted by the same percentage as a larger airway will give a bigger obstructive signal), rather than atopy and eosinophilic airway inflammation, as in older children and adults. A study by Tepper and colleagues looked at the effect of passive smoke exposure on baseline lung function and AHR (51). They found that smoke exposure led to a reduction in baseline lung function, as described many times before, but that there was less airway reactivity in the smoke-exposed children. An excellent feature of this study is the use of objective measurements by measuring cotinine levels in the infants' hair. The data are impressive, and clear cut, and consistent with some animal data (63). However, they are quite difficult to understand; given the known effects of smoke exposure on airway caliber (64–66) and alveolar tether points (69), why are these airways not more reactive? Is there some undescribed protective structural change that prevents the airways from constricting? More work is needed to address these issues. The indoor environment in childhood is another important theme. All pediatricians know that early life events are pivotal, and to most adult physicians, childhood is a closed book. Environmental smoke exposure in childhood has effects extending well into adulthood (70). Childhood environmental tobacco smoke exposure in relation to chronic cough, phlegm, and asthma diagnosis was studied in never-smokers from a cohort of Singaporeans of Chinese ethnicity aged 45 to 74 yr at enrollment. Subjects were interviewed regarding environmental tobacco smoke exposure before and after the age of 18 and the presence and duration of current symptoms of chronic cough and phlegm production and asthma diagnosis. Staggeringly, nearly two-thirds reported living with a daily smoker before the age of 18 yr. Living with a smoker before the age of 18 increased the odds of chronic dry cough and, to a lesser extent, phlegm, after adjustment for age, sex, dialect group, and current and past exposure to smokers at home and at work after the age of 18. Associations strengthened with higher numbers of smokers in childhood. There was no association with asthma or chronic bronchitis. In summary, for lifetime nonsmokers who lived with a smoker in childhood, there was an association with chronic dry cough and phlegm in adulthood, independent of later exposures to environmental tobacco smoke. The purpose of a second study was to determine the association between level of lung function in preadolescence and indoor air quality in the postnatal period in a retrospective cohort study (71). The authors reported on 1,036 preadolescent schoolchildren (9 yr of age) in Poland. Indoor air quality was based on reported environmental tobacco smoke and type of household heating. In addition, the number of winter months that occurred during the first 6 mo of life was included as a key independent variable. Findings were adjusted for potential confounders such as maternal smoking during pregnancy and parental education as a proxy of social class. The results of this study suggested that a lower level of lung function in preadolescent children can be related to postnatal exposure to indoor emissions in the winter. The findings must be extrapolated cautiously to communities with different indoor heating exposures, but they do underscore the importance of the air that we breathe in our homes for future outcomes.
One very important theme of the past year has been the appreciation that genes work their effects in the environment, and merely collecting DNA, plugging it into a computer, and hoping for the best is not a good strategy for the 21st century. This was illustrated in an article looking for modifier genes in CF (72). Although prognosis is determined to some extent by the class of mutation at the CF locus (73), it is clear that mutation class is a poor predictor of prognosis in many individuals. Various candidate modifier genes have been proposed, including in genes encoding proinflammatory cytokines and alternative ion channels. However, as with so-called asthma genes, studies have been remarkable for their inconsistency. A large number of patients with CF were genotyped at potential loci, and importantly, the findings were verified in a second, quite similar population. Only transforming growth factor-
A European group has published a study bringing this into sharp focus. CD14 is a molecule involved in the responses to LPS, and is as such a likely candidate "asthma gene." Previous studies have implicated CD14 in the process of immune switching from T-helper type 1 (Th1) to Th2, and in responses to viral infections (75, 76). However, results from other previous epidemiologic studies were inconclusive, and indeed a meta-analysis, illustrating the principle that the best meta-analysis is only as good as the data on which it is based, declared CD14 was not relevant to asthma (77). This more recent study (78) looked at the CD14/–260 C In this context, a study of genetic interactions with passive smoking is particularly timely (79). The effect of glutathione S-transferase (80, 81) polymorphisms on the effects on the fetus of maternal smoking in pregnancy has previously been determined; only babies born to mothers with the null polymorphisms (i.e., cannot detoxify cigarette smoke) have evidence of airflow obstruction. Wenten and colleagues (79) studied the effect of tumor necrosis factor (TNF)-308 variants on a marker of respiratory illness, respiratory-related school absences, in healthy children. They found that the combination of exposure to second-hand smoke doubled the risk of respiratory-related school absences in children with the TNF-308A compared with the TNF-308G variant, and led to a fourfold increased risk of lower respiratory tract infections causing school absence. The mechanisms are still speculative, but this study again makes clear that genetic association studies neglecting the environment, in the hope that environmental effects will cancel themselves out, are not a good approach. A GLOOMY ENDPIECE These last few studies discussed here lead to the question, who actually out there cares about the findings of research? How depressing to have to end this review on our failure to implement effective tobacco control measures. Why isn't there a total worldwide ban on advertising tobacco, and a total ban on smoking in public places? This would do more good than all the pediatric research papers published this year or in any other year. Our pusillanimous failure to control the tobacco industry is likely to be matched by our equally abject failure to tackle the next epidemic that is already upon us, childhood obesity, with its attendant respiratory and other morbidity (82). Perhaps we should remember the ancient Romans; they forged a great empire, not by forming committees but by killing everyone who disagreed with them. Maybe a similar approach would be more effective in the field of public health. FOOTNOTES Conflict of Interest Statement: A.B. does not have a financial relationship with a commercial entity that has an interest in the subject of the manuscript. Received in original form January 3, 2006; accepted in final form January 3, 2006 REFERENCES
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2. A previous article (
2-integrins expressed on leukocytes and important in endothelial binding and thus leukocyte recruitment, had no effect on IL-1 leukocyte recruitment, but significantly reduced the effects of LPS. There were corresponding effects on lung physiology; none in the IL-1 anti-CD18 model, worsening in the LPS anti-CD18 model. The important main conclusion is that white cells are somehow at least in part modulating lung maturation. The next key steps, which would be of enormous clinical benefit, are to dissect out which factors are responsible, and try to obtain their benefit therapeutically, without the deleterious effect of infection. 
T polymorphism in the CD14 promoter. For these authors' total population, there was no association with any manifestation of atopic sensitisation, but this masked significant findings in a hypothesis-driven subgroup analysis. The promotor polymorphism was associated with higher levels of both total and specific IgE to aeroallergens in children in regular contact with domestic pets, but the opposite relationship, not explained by endotoxin levels, in children in contact with stable animals. Hence, a gene could produce exactly opposite effects depending on the environment, so-called phenotypic plasticity, which is well described in lower organisms. The important point is that neglect of the environment may well account for conflicting results in different genetic studies, and that the way forward is focused hypotheses encompassing the environment as well as genetics. 
production and soluble CD14 levels in early life predict recurrent wheezing by 1 year of age. Am J Respir Crit Care Med 2004;169:70–76.
