© 2007 American Thoracic Society doi: 10.1164/rccm.200701-018UP
Update in Pediatric Lung Disease 20061 Imperial School of Medicine at National Heart and Lung Institute, London, United Kingdom; and 2 Royal Brompton Hospital, London, United Kingdom Correspondence and requests for reprints should be addressed to Andrew Bush, M.D., F.R.C.P., Department of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. E-mail: a.bush{at}rbh.nthames.nhs.uk The corresponding 2005 Pulmonary and Critical Care Update on pediatrics, published in 2006 (1), covered general research issues (2), lung growth and repair (3–5), pulmonary hypertension (6–8), neonatal lung disease (9–15), viruses and children (16, 17), and important aspects of gene–environment interactions (18). This update takes some of these themes forward in the light of research published in 2006, particularly emphasizing normal and abnormal lung growth and its consequences, with an additional focus on important papers in the fields of childhood infection and pediatric interstitial lung disease (ILD). NORMAL LUNG DEVELOPMENT
Before birth, the human lung secretes a staggering 5 ml/kg/hour of fluid; at birth, this secretory capacity must be switched off, and the lung become an absorptive organ, if the baby is to survive. There is much evidence that the mechanisms of this switch involve the epithelial sodium channel (ENaC); for example, rodents with
ENaC may be a key molecule in other diseases, such as the cystic fibrosis (CF) lung phenotype.
Lung development requires not only cell proliferation but also apoptosis. Yi and colleagues studied the role of the fibroblast growth factor (FGF) family in newborn rats (30). They used a soluble recombinant decoy sFGF-R1 Two important articles described imaging techniques with which lung growth may be followed sequentially in humans (37, 38). de Jong and associates (37) used computed tomography (CT) scanning to determine normative data for airway wall and luminal size, and arterial and parenchymal dimensions. Whether CT will be more useful in monitoring the effects of disease or its treatment than, for example, indices of gas mixing remains to be seen (39–42). In the second article (38), estimates of alveolar size were reported using hyperpolarized helium magnetic resonance imaging. This will almost certainly be far superior to current physiological techniques, such as carbon monoxide transfer. The approach of harnessing modern imaging technology to longitudinal measurements of lung growth will undoubtedly be important in the future. ABNORMAL LUNG DEVELOPMENT Despite advances in neonatal intensive care allowing better lung protection, prematurity and its iatrogenic consequences set the scene for disordered lung growth, and long-term cardiopulmonary impairment (see below). Attempting to understand and modulate these processes is likely to be an important research theme for many years to come. An obvious candidate suite of molecules involved in modulation of lung development are the proteases and their corresponding antiproteases, because of their potential roles in affecting lung tissue destruction. There are three families: serine proteases (e.g., neutrophil elastase and trypsin); matrix metalloproteinases (MMPs); and the papain family (the cathepsins B, H, K, L, and S), the subject of a recent report (43). The levels of mRNA of cathepsins, and their natural inhibitors cystatin B and C, were determined in a baboon model of "new" bronchopulmonary dysplasia (BPD). In animals with BPD, compared with control animals, levels of cystatin B and C mRNA were unchanged, but all cathepsin levels were increased. There were corresponding increases in cathepsin functional activity in bronchoalveolar lavage fluid and lung tissue homogenates. Levels of cathepsin B, H, S, and K decreased with advancing gestational age. The cathepsins were localized to macrophages in the main, but also to other lung cells. The authors intriguingly hypothesized that a neutrophil-to-macrophage switch may lead to increasing importance of cathepsins over MMPs. Recent work implicating protease–antiprotease imbalance in BPD studied the role of serine protease inhibitor B1 (SERPINB1) (44). This study had the merit of comparing "old" and "new" BPD models. Neutrophil elastase was elevated in old, but not new BPD, and SERPINB1 increased with advancing gestation and in new, but not old BPD. The higher levels of SERPINB1 in new BPD may be protective against the effects of neutrophil elastase. Further work is needed to determine the relative roles of the macrophage and neutrophil in the pathophysiology of new BPD. We also need to remember that, as neonatal intensive care unit practice changes, so may disease pathophysiology. It is wrong to assume that what is relevant in one human disease will remain relevant when new therapies are introduced. It is not merely the airway that has to cope with the challenges of prematurity but the immune system as well. There is intriguing evidence of the importance of pulmonary bombesin-like peptides in BPD (45). Little is known about T-cell function in BPD, even though T-cell function is pivotal in airway structural wall changes in diseases such as asthma. Rosen and colleagues studied thymic architecture and T-cell function in the baboon model of new BPD, some of which were given the bombesin blocking antibody 2A11 intravenously (46). The principal findings of this study were as follows: that bombesin-like peptide accelerates the maturation of the thymus; that the loss of thymic nurse cells leads to the release of autoreactive T lymphocytes into the circulation; and that, in the lung parenchyma, there are abundant CD4+ lymphocytes (but not CD8+ T cells, or dendritic cells) in animals not treated with 2A11. Thus, BPD baboons have acquired immunodeficiency and autoreactive T cells, probably modulated by bombesin. It should be remembered that, in asthma, mucosal T-lymphocyte numbers appear to be important in determining lung function (47, 48), and the host of growth factors and cytokines that they can produce make them attractive candidates as effector cells in BPD. The challenge will be to explore this in the airway in infants with BPD. Given the ethical and technical challenges of performing airway biopsy in infants (49), however, it would seem that, for the foreseeable future, studies will be confined to autopsy material. Pulmonary vascular hypoplasia has long been believed to be an important feature of BPD. Thus, it was refreshing to see this paradigm challenged by De Paepe and coworkers (50). The pulmonary vasculature was studied using antiplatelet endothelial cell adhesion molecule (PECAM)–1 immunohistochemistry, quantitative stereology, analysis of endothelial cell proliferation, and Western blot of PECAM-1 protein levels. The results showed that long-term ventilated children had a twofold expansion of the pulmonary microvasculature, related in part to endothelial cell proliferation. However, as the authors point out, this may not relate to a functional gas-exchanging membrane, if branching organization is incorrect. Indeed, compared with the apoptosis studies described above, one could speculate that a failure of endothelial apoptosis may be important. This is a relatively small study, and the techniques used are fraught with methodological issues, and so the findings need confirmation, but it is always refreshing to see a very sacred cow dispatched briskly to the abattoir. The strength of the study includes the use of multiple techniques to support the conclusions. The regulation of vasculogenesis is another key to BPD, and an unelucidated puzzle; vascular endothelial growth factor (VEGF) is believed to be important (51–53). The nature of the growth factors driving the development of the lymphatic system is unclear, but it seems that VEGF may also have a role here (54, 55). VEGF–/+ and VEGF–– knockout mice exhibit lymphatic dysplasia as part of the pulmonary phenotype (56). The VEGF family comprises molecules identified A through D (57), with VEGF-C and VEGF-D being known lymphangiogenic growth factors (54, 55). A recent study investigated VEGF-C and its receptor, VEGFR-3, which is situated on sprouting lymphatic cells during development (58). VEGF-C was measured in tracheal aspirates of preterm infants, and VEGF-C and VEGFR-3 were localized using immunohistochemistry in fetal lungs. Staining showed bronchial and alveolar localization, the latter mostly in fetuses. VEGF3-R staining was localized to the developing lymphatics. These data, combined with those from animals, and the finding of VEGF3-R mutations in Milroy's disease (hereditary lymphedema), make a persuasive case for the importance of VEGF-C and VEGFR-3 in lymphatic development (59). It would be of interest to study the VEGF family and its receptors in the lymphangiectatic and lymphangiomatous syndromes of childhood, in the hope of finding novel therapies for these very refractory problems. The role of VEGF in acute lung injury has also been reviewed in 2006 (60). Could viral colds be good for you? The putative role of viral infections in driving a Th1 phenotype has been suggested by the "hygiene hypothesis" (61); this hypothesis was supported by recent data (62). A challenging report suggested that, in vitro, human rhinoviruses induce VEGF secretion by human bronchial epithelial cells, and culture supernatants were able to induce angiogenesis (63). This could indicate a role in airway remodeling for viral infections. However, could human rhinoviruses be useful therapeutically in disease states in which there is alveolar–capillary hypoplasia? There are no data, but perhaps this is a question that might be pursued in the future.
Many pregnant women smoke and are unable to prevent themselves from abusing their unborn child. However, it is not merely via the mothers' own actions that fetuses are abused; environmental tobacco smoke inhaled by the pregnant mother is also harmful to the baby. In a recent article, which has mechanistic as well as pathophysiological interest, pregnant rhesus monkeys were exposed to filtered air or diluted sidestream tobacco smoke, the latter as a surrogate for environmental smoke exposure (64). The nuclear transcription factor nuclear factor (NF)– LONG-TERM CONSEQUENCES OF PREMATURE BIRTH The spectrum of adult chronic lung disease is expanding, as children who previously would have died are surviving into adult life. The obvious example is CF, which has gone from being a fatal pediatric lung and digestive disease to a multisystem adult disease, affecting virtually every organ system in the body, and including such important but previously little considered complications such as stress incontinence, osteopenia, insulin deficiency, chronic renal failure, and epithelial cancer (66). Although pediatric services for CF are well developed, it is worrisome that adult centers have often lagged behind (67). The best are superb, but in many parts of the world, they are nonexistent. Thus, it is particularly disturbing to contemplate what may be happening in a disease where pediatricians may have failed to grasp the long-term issues, and, after a honeymoon period, problems may recrudesce in adult life. The long-term pulmonary consequences of prematurity and its treatment have recently been reviewed (68), and two further important articles were published in the AJRCCM in 2006 (69, 70). The adverse effects of positive-pressure ventilation, oxygen therapy, and parenteral steroids on alveolar–capillary development are well known. However, it is becoming increasingly apparent that prematurity itself may be a cause of impaired pulmonary function. This is important, because it means that, even if neonatal intensive care reaches the point of salvaging extremely preterm infants, without inducing iatrogenic complications (a goal to be wished for), in the distant future there will still be long-term problems with which the adult physician will have to contend. Indeed, two articles (71, 72) have suggested that there are similar and persisting decrements in lung function, or at least spirometry, in successive cohorts of preterm survivors, despite the advent of surfactant therapy and new ventilator strategies. Furthermore, Friedrich and associates tested 62 preterm babies (< 37 wk of gestation), none of whom had received positive-pressure ventilation or required oxygen-enriched mixtures for more than 48 hours, and compared the results with 27 term control infants (69). They used the raised volume, rapid thoracoabdominal compression technique, and showed that there was evidence of airway obstruction, with impairment of flow rates and expired volumes of around 30% in the preterm group. Male sex, gestational age, and weight were important predictors of lung function. It is hoped that the authors will report follow-up measurements at 1 year of age; previous workers have shown that preterm ventilated neonates (73, 74), and even nonventilated preterm infants, may show actual deterioration of lung function in the first year of life (75). Thus, the complacency in some circles—that if the preterm baby has not needed oxygen, or no longer requires it, all is well—is not tenable. A more reassuring article looked at the long-term effects on lung function of infants whose mothers were given betamethasone antenatally (76). There is no question that giving mothers betamethasone before the preterm delivery of the baby has had major beneficial effects in terms of survival and less chronic lung disease of prematurity. The steroid accelerates the maturing of the fetal lungs, including the production of surfactant. Dalziel and colleagues followed up on 534 babies whose mothers had been entered into an early double-blind, randomized, controlled trial of a single dose of antenatal betamethasone. They found that, at age 30 years, there was no effect of betamethasone on spirometry or diagnosed asthma. Whether multiple doses are equally safe remains to be seen; however, the arguments for repeating the dose are at best contentious. The nature of the long-term deficit in lung function associated with prematurity was highlighted by a study that followed up 32 survivors of preterm delivery, 19 years later (70). The mean birth weight was 1,246 g, so this is a very different cohort from the survivors of today, whose birth weight may be below 500 g, who may be treated with artificial surfactant, and who may be recipients of ventilatory strategies not available in the past. The authors performed spirometry and plethysomography, measured carbon monoxide transfer, and performed an exercise test using cycle ergometry. They recruited 48 healthy term control subjects. There were reductions in spirometry and carbon monoxide transfer, although the means for the preterm group remained within the normal range; there was a reduced exercise load, but similar maximal oxygen consumption between the two groups. The ex-preterm group appeared to have a lower anaerobic threshold, and reduced exercise efficiency. The study population was too small to make a significant comparison between those who did and did not have a history of BPD. The changes were reassuringly minor at the time of testing, but they may have long-term significance (see below), and it may be that the modern survivors may have a worse functional result. Early impairment of lung function associated with prematurity may have short- and long-term consequences. In the short term, it is clear that premorbid reductions in lung function predispose to respiratory syncytial virus bronchiolitis (77, 78). Longer term, do these minor changes have any consequence? Most information about the evolution of lung function changes comes from cohort studies of wheeze. There is no cohort study that has run from before birth to old age, but a series of cohorts of overlapping time periods have established that pulmonary function tracks from age 3 years into late middle age (79–83). More importantly, in late middle age, those who had viral-associated wheeze, and thus presumably airflow obstruction in the preschool years, similar to ex-preterm and ex-BPD babies, showed an accelerated rate of decline in lung function, and are presumably a high-risk group for chronic obstructive pulmonary disease (COPD) (84). Hence, it is likely that the survivors of preterm birth, with or without iatrogenic complications, are at risk for what might be termed "new COPD"; "new" refers to the fact that these patients may well have long-standing pulmonary parenchymal disease as well as airway disease. Furthermore, the patterns of disease will be changing over time, as smaller and more preterm babies survive, with new iatrogenic complications. A related issue is the effect of neonatal surgery for congenital malformations, in particular diaphragmatic hernia (CDH), on long-term functional status. Here, too, the goal posts are moving, as pediatric surgeons and neonatal intensivists salvage ever-sicker babies. Trachsel and colleagues (85) reported on 23 CDH survivors aged 10 to 16 years. Reassuringly, there was no evidence of pulmonary hypertension, and there were normal cardiorespiratory responses to exercise. However, we await to see the effects of CDH on lung aging in adult life. It follows that pediatricians must not be complacent about any preterm baby but must maximize efforts to preserve optimal airway function; and adult respiratory physicians need to become increasingly aware of the cohort of childhood preterm survivors who are reaching adult life. The importance of the inclusion of modules on normal lung development for the adult physician has been stressed elsewhere (86); and this "new respiratory medicine" underscores the need for close interactions of academic and clinical medicine between adult and pediatric respiratory physicians. RESPIRATORY COMPLICATIONS OF NEUROLOGICAL DISEASE IN CHILDHOOD Children with neuromuscular disease are also surviving into adult life. The use of noninvasive nasal mask ventilation (NIV) has transformed the outlook for boys with Duchenne muscular dystrophy (DMD) (87). This technique is being used increasingly in more severe neuromuscular diseases, such as spinal muscular atrophy (SMA) type 1 and SMA with respiratory disease (SMARD) (88, 89). There is an increasing willingness to resort to tracheostomy ventilation for some of these babies. The success of NIV, which essentially rests the inspiratory muscles, has to some extent led to a loss of focus on the expiratory muscles, which are pivotal in cough clearance. Indeed, cough failure leading to respiratory infection is the likeliest cause of death in these children, and recent work has started to address this. Clearly, the realization that both inspiratory and expiratory muscle function is important is pivotal to the successful management of these children, and particularly those with conditions with early-onset respiratory muscle failure but with relatively well preserved limb muscle function, such as in some cases of Nemaline rod myopathy and minicore myopathy. If children with neuromuscular disease are to be managed correctly, then objective measurements of respiratory muscle function are essential. Such testing can be volitional (and therefore attendant on motivation), or nonvolitional. The techniques used need ideally to be noninvasive, and thus acceptable as a routine and repeated clinical tool. Nicot and colleagues studied 41 children and young adults with a variety of neuromuscular conditions (90). These subjects had gastric and esophageal balloons placed and sniffing (volitional) and magnetic coil phrenic nerve stimulation (nonvolitional) transdiaphragmatic pressures (Pdi) were compared. There was, perhaps surprisingly, a good correlation between the two. Of more clinical use was the correlation between percent-predicted forced vital capacity (FVC) and sniff Pdi in the patients with DMD and those with congenital myopathy. It would have been interesting to compare the change between sitting and supine FVC, which is less than 25% in normal subjects, although measuring postural drop in an overweight, wheelchair-bound patient may not be practical. However, from these data, if FVC is less than 40% predicted, inspiratory muscle dysfunction is likely. The same group also reported on how many sniffs were needed for accuracy, conventionally said to be 10, and found that better results were obtained if 20 sniffs were requested (91), which represents an important, practical finding. The act of coughing involves sensing that there is material within the airway to be cleared (not usually a problem in neuromuscular disease), taking a full inspiration, then glottal closure, a forced expiration, and finally, glottal opening to produce an expulsive force. Kang and coworkers (92) looked at factors predicting weak cough in boys with DMD, and found that both inspiratory and expiratory mouth pressures correlated significantly with unassisted peak cough flow. They found that combined manual and volume assisted cough was better than either alone. The utility of artificial insufflation to high lung volume to augment cough was highlighted in another article (93). The importance of cough in protecting against respiratory infections was investigated in another study (94), which showed that, in children and adolescents with a variety of neuromuscular disorders, a vital capacity of less than 1.1 L and/or a peak cough flow of less than 160 L/minute were specific and sensitive markers of patients who had had chest infections requiring hospital admissions. This was a retrospective study, which needs confirming prospectively, but these two relatively simple markers should be part of the routine assessment of the child with neuromuscular disease. It should be noted that patients become clever at trick maneuvers to confuse unwary doctors! Breath stacking using "frog breathing" to produce a vastly exaggerated vital capacity is well known; this requires integrity of glottal muscle function. Bach and colleagues (95) report on what they term "dart flows," confounding lip and tongue propulsive efforts, which significantly exceeded peak flows and cough peak flows. They commented on the need not to confuse the three measurements. Another problem of the neuromuscular patient, in particular during puberty, is the development of scoliosis, and a common dilemma for clinicians is to balance the perioperative risks of major spinal surgery against the long-term adverse effects on respiratory function if nothing is done. Di Pietro and associates adopted the interesting approach of studying normal patients undergoing spinal surgery for a variety of indications (96). They found that vital capacity, tidal volume, and peak inspiratory and expiratory mouth pressures were reduced, and respiratory rate increased, by between 10 and 20% on the first 2 postoperative days. Of relevance to the neuromuscular patient, risk factors for reductions in respiratory function were surgical time of more than 4 hours, and cervicothoracic surgical access. It seems intuitively likely that the changes in lung function will likely be greater in those with preexisting neuromuscular disease. Another group looked at the benefits of supramaximal inflation on lung compliance in amyotrophic lateral sclerosis, and demonstrated that the reduced lung compliance typical of these patients was improved after 5 minutes of positive pressure via a mouthpiece (97). They hypothesized that this reversed atelectasis or increased alveolar surface forces, thus reducing the work of breathing. This might be another mechanism of benefit of positive pressure, in addition to inspiratory muscle rest and augmentation of cough. INFECTIONS IN CHILDHOOD Tuberculosis (TB) remains a worldwide scourge, but it is also an ever-present problem in developed countries, and disseminated childhood TB is becoming more common, at least in the United Kingdom (98). The simple case of TB is simple indeed; established diagnostic tests and protocol-driven management will result in a cure. With the emergence of multidrug-resistant and extremely drug-resistant TB, comorbidities such as HIV, and the problems of the delivery of care in poverty-stricken circumstances to often itinerant patients, the nonsimple case of TB is taxing even to the greatest experts. Thus, it is easy to recommend a recent review article, coming out of Texas, and one of the epicenters of world TB, South Africa (99). This article covers all the most important aspects of childhood TB, including diagnosis, treatment, and drug resistance, and the role of concomitant HIV infection. The incidence of pleural empyema is increasing, at least in the United Kingdom (100, 101). Increasingly, severe cavitating pneumonia is being seen with empyema (102). It is unclear whether this reflects a change in the virulence of community-acquired organisms, an increased reluctance to prescribe antibiotics blindly for childhood febrile illness, or other factors. Treatment options include combinations of intravenous antibiotics (and a proportion will get better with antibiotic therapy alone [103]), needle aspiration, tube thoracocentesis, intrapleural instillation of thrombolytics and/or human recombinant DNase, video-assisted thoracoscopy (VATS), minithoractomy, or open decortication. Until recently, much of the literature consisted of medical papers extolling the virtues of conservative treatment, and surgical papers lauding the results of early and aggressive operations (104–106), with a complete absence of randomized controlled trial data comparing the two approaches, on each of which views were held with almost religious fervor. This changed with a British randomized trial, which showed, in marked distinction to the situation in adults, that intrapleural urokinase shortened hospital stay in children with empyema (107). The difference between outcomes in children and adults (108) may relate in part to the comorbidities common in adults, but underscores the need for proper pediatric trials, and the danger of blindly extrapolating from adult data. Kalfa and colleagues (109) reported on whether clinical features or pleural ultrasound predicted prognosis in childhood empyema. Neither did, and the authors found that their VATS procedures were technically more difficult if there was a delay between diagnosis and surgery of more than 4 days. There is reason to believe that early VATS is not indicated (see below), but this study provides useful confirmation that detection of loculations by pleural ultrasound, the optimal imaging technique in empyema, is not a good predictor of outcome, and should not be used as such. It would seem logical that using early VATS to debride the pleural space, and place chest tubes precisely, would be preferable to blind tube placement and thrombolysis. This was studied in a randomized controlled trial, which demonstrated yet again that medicine is a graveyard for what appear to be good ideas but in fact turn out to be no such thing (110). The authors randomized 60 children, and showed no difference in outcome between blind tube placement with urokinase administration and primary VATS. Specifically, length of stay was unaltered, and even if one takes the extreme of the 95% confidence intervals in favor of VATS, the cost of the possible 2 extra days saved would be outweighed by the greater costs of the VATS arm. This latter procedure was associated with extra health costs of more than $2,000, $15 million/year if extrapolated to the United States! There is also an increased radiation burden: all VATS patients had CT scans, whereas for chest tube placement, pleural ultrasound is the investigation of choice. This paper means that the onus is on the proponents of VATS to prove that this actually offers any benefit at all, let alone one commensurate with the health costs, in most cases of pleural empyema. By contrast, the opposite conclusions concerning treatment of empyema were reached in a study from Taiwan (111). Surprisingly, the authors found that ultrasound was useful in determining the stage of empyema, and hence prognosis, and that early VATS was recommended in those with a septated (late) effusion. However, it is unclear that this distinction can truly be made by ultrasound scanning, and whether this was a preplanned or post hoc analysis. Although interesting, I believe that methodologically this study is inferior to that of Sonnappa and colleagues (110), not least because it was a retrospective review, and far fewer children were in the VATS versus chest drain comparison. It cannot be used to unseat the conclusion that, for the majority of patients with empyema, early VATS has no advantage. PEDIATRIC ILD ILD is rare in childhood, with a prevalence at least an order of magnitude less than adult ILD, and a far greater range of disease. This makes ILD in children much harder to study, and it is appropriate to welcome the establishment of the chILD Network in the United States, which will surely contribute to the understanding of these diseases. The importance of childhood ILD is not just to the individuals concerned and their families, but because investigation of this problem sheds light on fundamental processes. Indeed, studies in pediatric ILD have demonstrated an important genetic component (surfactant protein [SP]-C deficiency) to cases of adult ILD with histology that is not seen in childhood (usual interstitial pneumonia) (112). A further important insight is provided by the study of pulmonary alveolar proteinosis. This disease, which is characterized on light microscopy by alveolar filling with periodic acid-Schiff–positive material, can be divided into at least four types: adult onset, due to anti–granulocyte-macrophage colony–stimulation factor (GM-CSF) autoantibodies (this may also occur in childhood, and respond to inhaled GM-CSF [113]); adult type, secondary to macrophage blockade (e.g., silicosis or lymphoma); juvenile onset due to congenital SP-B deficiency; and juvenile onset due to mutations in the GM-CSF receptor (114). A basic question arose in the context of the inherited disease: What is the mechanism of what appears to be a disease caused by a gene mutation, if in fact there is no mutation in that gene (in this case, SP-B)? The answer lies in the complex post-transcriptional processing required to convert cytoplasmic pre–pro-SP-B to extracellular mature SP-B (115). In theory, a loss-of-function mutation in any protein that is critical to this process would result in a disease that closely resembles a deficiency in the original gene. Such a condition is ABCA3 deficiency, the subject of recent important new work (see below). However, the principle that many more than one gene can be deficient to produce the same disease picture extends outside pediatric ILD. Cases of phenotypic CF with a completely normal CF gene sequence have been described (28); some may be due to mutations in the ENaC gene (see previously) (29). However, as a conservative estimate, more than 20 proteins are required to get CFTR to traverse the cell to the apical membrane, and on arrival, CFTR interacts with at least 10 different proteins (116). It is possible to speculate that such cases of CF with a normal CFTR gene sequence may be due to mutations in some of these other proteins. Brasch and colleagues studied ABCA3 mutations in 14 full-term infants from eight families with unexplained newborn respiratory distress (117). In six of the families, there was parental consanguinity. Mutations in the ABCA3 gene, and reduced levels of ABCA3 protein, were found in 10 infants. Novel mutations of ABCA3 were described in this report. Inheritance was consistent with an autosomal recessive pattern. The authors discovered ultrastructural abnormalities of the lamellar bodies, and defects in processing of SP-B and SP-C, such that there were high levels of pro–SP-B and pro–SP-C, but levels of mature SP-B were reduced, and SP-C absent. All but one child died quickly; one survived to undergo double lung transplant at 21 months of age, dying subsequently of a (presumably post-transplant) lymphoproliferative disease. The histology of the lung disease was a mixture of desquamative interstitial pneumonitis, nonspecific interstitial pneumonitis, and infant-type pulmonary alveolar proteinosis; the appearances fit well for chronic pneumonitis of infancy. It is intriguing to speculate on the nature of the problem in the four infants in whom ABCA3 problems could not be found; no doubt they are the subject of further work, and new publications can be anticipated. Garmany and coworkers (118) provided further evidence of the mechanisms whereby ABCA3 mutations cause human disease, by comparing the composition of surfactant obtained by bronchoalveolar lavage from SP-B–deficient infants, infants with ABCA3 mutations, and control infants. Surface tension was greater in the two disease groups compared with control group, and in ABCA3 deficiency, there were reduced phosphatidyl choline levels, confirming a role for ABCA3 in surfactant homeostasis. Furthermore, Cheong and associates (119), in an in vitro study, showed that wild-type, but not mutant, ABCA3 localized to membranes of both lysosomes and lamellar bodies, and that the use of siRNA to knock out ABCA3 expression resulted in the production of lamellar bodies similar in morphology to those of the human disease, and reduced vesicular uptake of the surfactant lipids phosphatidyl choline, sphingomyelin, and cholesterol, but not phosphatidylethanolamine. Intriguing data relating to the embryological functions of ABCA3 have recently been published (120). Although, as expected, the highest levels of staining were in the type 2 epithelial cells of the lung, staining was also reported in liver, stomach, kidney, adrenal glands, pancreas, trachea, and brain. The role of ABCA3 in extrapulmonary tissues is unknown. Because ABCA3 deficiency is dominated by the lethal pulmonary phenotype, it may be that death supervenes before there is a chance to develop an extrapulmonary phenotype. Within the lung, ABCA3 staining and mRNA increased prior to birth, but was not normally seen except in pathological states before 22 to 23 weeks' gestation, and was induced by thyroid transcription factor-1, and by inflammation (tying up with the effects of chorioamnionitis in maturing the preterm lung). Postnatally, ABCA3 is found in the hyperplastic epithelial cells lining the airway of infants with chronic lung disease. Matsumura and colleagues (121) have further refined our understanding of the consequences of ABCA3 deficiency. They have defined two types on the basis of studies of mutations known to cause the human disease: abnormal intracellular localization (type 1) and normal localization with decreased ATP binding or hydrolysis (type 2). This sort of study is likely to be increasingly important, as the long-held concept of genotype-specific therapy in CF spreads to other diseases (122). There is a further reason why the study of obscure early-lethal gene muations is important also to adult physicians. Although SP-B deficiency is usually fatal early in life, mild cases with prolonged survival have been described, and SP-C deficiency presenting in adult life as usual interstitial pneumonitis is well described. SP-C deficiency may cause different histological appearances in the same family at different age groups (112). Increasingly, genetic studies of the SP-B, SP-C, and ABCA3 genes will become part of the workup of ILD at any age; and it is likely that further surfactant-processing genes may be added to the list. With regard to CF mutations, a higher that expected number is found in non-CF patients with allergic bronchopulmonary aspergillosis, idiopathic (nonalcoholic) pancreatitis, and other CF-related phenotypes (123–125), implying that CFTR carrier status may be a cofactor in the development of these conditions. It is also tempting to speculate that perhaps SP gene mutation carrier status confers increased susceptibility to ILD in the presence of a second stimulus. Two articles (126, 127) drew attention to other differential diagnoses of pediatric ILD. Chest radiography, CT scans, and pulmonary function tests were compared in 53 patients, aged 7 to 65 years, with type B Niemann-Pick disease (126). CT showed predominantly basilar predominance; six patients had pulmonary nodules, one of which calcified. There were no correlations between CT appearances and any lung function test. Pulmonary Langerhans cell histiocytosis is usually part of a multisystem disease in childhood, whereas it is typically a single-organ disease in adults, and associated with smoking. Odame and colleagues reviewed the records of 178 children with Langerhans cell histiocytosis, and found no case of isolated lung involvement (127). When the lungs were involved, it was always in the context of a multisystem disease, often asymptomatic, and probably had no effect on prognosis; a timely reminder that diseases called by the same name in different age groups may bear no resemblance to each other. AFTERWORD I ended my last Update (1) with a rant at the pusillanimous lack of public health measures to combat second-hand smoke exposure and obesity. Nothing has changed significantly during the year. The potential for effective public health measures remains high, the obstruction by vested interests continues. When will there be a total ban on all smoking in public places? When will there be a ban on advertisements for food that glorify the vast quantities on offer, without giving clear guidance on the fat and calorie content? When will the school health services identify the young, obese child, and set in place a program of weight reduction, and monitor him or her carefully, to prevent the child becoming a large, fat adult? There are plenty of ways of doing this, including the use of incentives and financial penalties for persistent overeaters, but very little will, it would seem, to put this into practice. 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 this manuscript. Received in original form January 3, 2007; accepted in final form January 3, 2007 REFERENCES
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B, but not AP-1, akt, or p53, was down-regulated in the smoke-exposed monkeys. The consequences were down-regulation of antiapoptotic genes, and up-regulation of caspases, cleavage of cellular death substrates, and an increased rate of lung parenchymal apoptosis. The fact that smoke is bad for the lungs is not new, but it is depressing that we as a community continue to be so criminally complacent about the health of future generations by allowing the continued widespread peddling and consumption of tobacco, with effects not only on the individual smoker but also on those in the vicinity. What is novel in this study is the implication of NF-
