European Respiratory Society
Respiratory Diseases in Infants and Children

Respiratory disorders in infants and children are challenging problems for every clinician involved in the management of these patients. This book summarises recent advances in paediatric pulmonology. The scholarly contributions of the distinguished contributors represent a careful and comprehensive synthesis of current knowledge in pathogenesis, diagnosis and treatment.

  • European Respiratory Society Monographs
  1. Page viii
  2. Page ix
  3. Page 1
    Correspondence: E. von Mutius, Dr von Haunersches Kinderspital, Ludwig-Maximilian-Universität München, Lindwurmstrasse 4, D-80337 München, Germany. Fax: 49 8951604452; e-mail:

    The application of epidemiological methods in the investigation of paediatric respiratory disease has greatly contributed to the understanding of these illnesses. In childhood asthma and allergies, results of longitudinal cohort studies have pointed towards the developmental aspect of paediatric diseases which arise, become manifest and disappear at various ages. Several wheezing phenotypes have been confirmed in a number of studies.

    First, transient wheeze in infancy must be regarded as a separate condition being associated with risk factors, such as maternal smoking, premature birth and low birth weight. There is good evidence to suggest that reduced lung function after birth, before any wheezing illness has occurred, contributes to the underlying mechanisms. Viral infections are potent triggers of symptoms among children with this phenotype. The prognosis is good as children outgrow their symptoms between 2–3 yrs of age.

    Secondly, nonatopic wheezing after toddler and school age has been documented. This phenotype is characterised by the lack of detectable immunoglobulin E antibodies, allergic comorbidities, and often by the absence of airway hyperresponsiveness. Children with nonatopic wheeze are likely to lose their symptoms around school age and retain normal lung function. In contrast, children with the atopic wheezing phenotype are most likely to develop a chronic course of the illness with significant impairment in lung function and the development of airway hyperresponsiveness.

    Over adolescence, a significant proportion of these children lose their symptoms, but new onset of illness, particularly among females, is also seen at that age. Risk factors for the persistence of asthma and wheeze during puberty include the severity of atopy and airway hyperresponsiveness.

  4. Page 8
    Correspondence: P.J.F.M. Merkus, Division of Respiratory Medicine, Dept of Paediatrics, Erasmus Medical Centre, Sophia Children's Hospital, P.O. Box 2060, 3000 CB, Rotterdam, the Netherlands. Fax: 31 104636801; E-mail:

    Since the 1980s, it has become increasingly clear that conditions during foetal life and early childhood are of paramount importance for optimal growth and development of the respiratory system. The development of the pulmonary vasculature interacts with that of the bronchial tree, and this has important clinical consequences for premature infants and children with congenital cardiovascular abnormalities. Therapeutic options for preventing abnormal development have been lacking until now. The anatomical and functional development of the lung appears especially vulnerable to a whole range of insults during gestation and the first few years of life, and a significant proportion of adult lung disease probably has its origin in utero or in early infancy. Many conditions and treatment modalities may affect lung maturation and growth, including the drugs administered during early life. The magnitude of these effects in humans needs to be studied further.

    Promoting or facilitating optimal lung growth in foetuses and infants and reducing the incidence of respiratory tract illness in infancy may reduce the incidence of chronic adult lung disease in future generations.

    There is a need for improved or new imaging techniques suitable for monitoring the development of the peripheral airways, vasculature and lung parenchyma noninvasively and without radiation, and there remains a need for standardised histological morphometric studies of paediatric lungs throughout childhood. By combining functional, histological, biochemical and genetic studies, progress will be made in understanding mechanisms of lung growth and their relative importance in contributing to the function of the respiratory system.

  5. Page 22
    Correspondence: M. Gappa, Paediatric Pulmonology and Neonatology, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-30625 Hannover, Germany.Fax: 49 5115329125; E-mail:

    During the first years of life, the lung undergoes a period of most rapid growth and development of all structures involved, making this period of life particularly susceptible to adverse environmental and disease-related factors. Lung function testing allows indirect noninvasive assessment of the functional consequences reflecting this developmental process. Measurements of respiratory function can now be carried out at most ages, with methodological guidelines being available for most infant lung function techniques. Published studies incorporating functional assessment of the lung and the airways appear to support current pathophysiological concepts, such as early programming of lung function or tracking. However, direct assessment of alveolar and vascular development is currently not feasible using conventional methods. In addition, the complex interaction between airway dimensions, airway wall characteristics, chest wall and tissue mechanics, all influencing airway function, are not yet fully understood. The dynamic behaviour of the respiratory system has only recently received attention with regard to the paediatric population. A variety of newer techniques are being explored in order to clarify these issues, including low-frequency forced oscillation and new imaging techniques.

  6. Page 41
    Correspondence: A. Bush, Dept of Paediatric Respiratory Medicine, 4th Floor, Chelsea Wing, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Fax: 44 2073518763; E-mail:

    Remodelling is the collective term used to describe the structural changes seen in the lungs of patients with respiratory disease. Structural changes have been reported in a number of conditions, although they are most commonly described in the airways of patients with asthma, with changes recently described in children similar to those seen in adults. As a result, these findings in children have led investigators to challenge the previously held assumptions that remodelling develops as a result of persistent airway inflammation and that structural changes are associated with progressive impairment of lung function. Prioritising this area of research will be beneficial as the limited data available suggest that remodelling occurs early, with significant long-term consequences. However, this is not an easy area to research, in view of ethical and practical constraints. Efforts therefore need to be made to maximise the opportunities for obtaining airway tissue from controls and subjects with disease. In addition, a better understanding of normal airway development is essential in order to interpret the changes in disease accurately.

  7. Page 60
    Correspondence: B. Schaub, Pediatric Pulmonary Division, University Children's Hospital Muni, LMU Munich, Lindwurmstr. 4, 80337 Munich, Germany. Fax: 49 8951604764;

    The ontogenetic development of the immune system is the result of an interaction between the host's genetic background and its environment. It is proposed that an individual organism's immune system is shaped by the interaction between its genetic background and environmental influences. With regard to the immune system, microbes are the most relevant constituent of the environment. The innate immune response is not only the first response to microbial molecules, but it also modulates any subsequent antigen-specific adaptive immune response. Thus, a host's immune response is not only modulated by gene–environment interactions, but rather by interaction between the host's genetic background, environmental factors and the host's age. Mucosal and epithelial surfaces of the body are the sites of the first contact between microbes and the host, and the place where initial immune responses take place. The gut occupies a particularly important role, given the exposure of the gut-associated immune system to microbes. The immunological effects of exposure to microbes, however, are not limited to the site of exposure, but rather may manifest at distant sites, as suggested, for example, by data showing an association between gut microflora and the development of atopic airway diseases in children. More detailed insights into the mechanisms governing the modulation of immune responses by exposure of the immune system to microbes may lead to novel approaches both for therapy as well as for prevention of immunologically mediated diseases of the lung. The art of putting into practice such new approaches will be to induce the desired control mechanisms of the immune system without suppressing antimicrobial or antitumour defence mechanisms and without inducing inflammatory reactions.

  8. Page 79
    Correspondence: K.C. Lødrup Carlsen, Dept of Paediatrics, Ullevål University Hospital, NO-0407 Oslo, Norway. Fax: 47 22118663; E-mail: and

    The clinical entities of asthma, atopic eczema and allergic rhinitis may appear alone or in any combination. The link between the developing and growing lung and these clinical diseases is not clear, although several risk factors for asthma are similar to risk factors for reduced lung function in early life. Even less is known about possible associations between environmental exposure, allergic sensitisation and lung function in early life, and whether patho-physiological mechanisms related to allergic sensitisation also play a role in lung development and growth in the young child.

    In recent years, the availability of equipment for measuring various aspects of lung function from birth through infancy, preschool age into school age and adolescence has increased greatly. This will increase the possibility of unravelling some of the current questions in years to come.

  9. Page 93
    Correspondence: M. Kabesch, University Children's Hospital, Ludwig Maximilians University Munich, Lindwurmstrasse 4, D-80337 Munich, Germany. Fax: 49 8951604764; E-mail:

    Few lung diseases are caused by monogenetic disorders. However, respiratory health and the development of lung diseases are strongly influenced by genes that modify pulmonary development and the capability to react to environmental challenges. Genetic variation, a driving force of evolution and an important guarantee of a broad range of adaptive potential on the population level to increase survival of the species, may turn into a burden when changes accumulate in certain individuals, thus leading to disease. Genetic variations in genes that modify pulmonary health have now been identified in many cases. Some of these common alterations affect genes involved in pulmonary structure, detoxification and inflammation, but may also affect immunity genes, which in turn may have profound effects on pulmonary health. In this context, genetic susceptibility determines the potential of the organism to interact with the environment and it is only recently that some of these interactions have been identified. Smoke exposure seems to be of particular importance as it interacts with a multitude of genetically determined mechanisms, aggravating immunological as well as respiratory problems.

  10. Page 108
    Correspondence: J. Gerritsen, University Medical Center Groningen, Beatrix Children's Hospital, P.O. Box 30.001, 9700 RB Groningen, The Netherlands. Fax: 31 503614235; E-mail:

    The exact genetic aetiology of asthma is complex. The reasons are that in asthma more than one gene is involved, there is interaction between genetic (host) and environmental factors, and there is wide heterogeneity of asthma phenotypes. The present chapter discusses gene–gene interaction, gene–environment interaction, the influence of the in utero environment, and the role of sex. The overall conclusion is that the environment plays a pivotal role in the development and severity of asthma and allergy, although the role of the environment in disease development and progression is still to be unravelled. Collaborative studies of different genetic centres with a large number of subjects are needed to extensively increase the power. However, new techniques offer the opportunity to identify genes in asthma and the related phenotypes. With this approach it can be expected that the links between asthma, and allergy genes, environmental factors will be uncovered.

  11. Page 120
    Correspondence: J.C. de Jongste, Dept of Paediatrics, Erasmus University Medical Center, Sophia Children’s Hospital, PO Box 2060, 3000 CB Rotterdam, The Netherlands. Fax: 31 104636811; E-mail:

    A brief overview of tests that are relevant to the detection of lung disease in children is presented in this chapter. Exhaled nitric oxide (NO) is a noninvasive and well-validated marker of eosinophilic airway inflammation and is useful in asthma diagnosis and management. Elevated exhaled NO fraction is characteristic for atopic asthma andresponds dose-dependently to steroid treatment. Nasal NO is a highly specific and sensitive screening test for primary ciliary dyskinesia. Exhaled breath condensate (EBC) may in part reflect the composition of airway lining fluid. The lack of standardisation of EBC collection and analysis is currently the primary limitation of this technique and is likely to explain most of the variability of the results. Eosinophils and their products play an important role in allergic inflammation and asthma. However, serum or urinary eosinophil cationic protein and eosinophil protein X are too variable for diagnostic use in individual patients. Pulmonary function tests play an important role in the diagnosis and monitoring of paediatric lung disease. Bronchial challenge tests with spasmogens (methacholine) may be helpful in ruling out asthma when negative, but are not diagnostic if positive. The value of infant lung function tests as diagnostic or monitoring tools in routine clinical practice is limited by the demanding methodology and need for sedation. Computed tomography (CT) is superior to lung function for the assessment of progression of lung disease in cystic fibrosis. Development of new magnetic resonance imaging techniques to replace CT scanning would solve the problem of radiation dose, and is a promising alternative for the future.

  12. Page 142
    Correspondence: A. Schibler, Queensland Paediatric Intensive Care Service, Paediatric Intensive Care Unit, Mater Children’s Hospital, South Brisbane 41010 QLD, Australia. Fax: 41 738401642; E-mail:

    Predicting outcome and potential lung disease for any child suffering from severe respiratory failure in the paediatric intensive care unit is difficult. The causes of the acute respiratory failure are diverse and still not well understood. In simple terms, it may be concluded that high pressures and supplementary oxygen in the phase of acute respiratory failure increase the likelihood that complications and subsequent death may occur. As a simple rule of thumb, if the oxygenation index after intubation exceeds 15–20 and there follows prolonged mechanical ventilation, a poor outcome is likely.

  13. Page 153
    Correspondence: J. Grigg, Academic Division of Paediatrics, Queen Mary’s School of Medicine and Dentistry, 4 Newark Street, London, E1 2AT, UK. Fax: 44 1162523282; E-mail:

    Wheeze is a symptom with a complex physiological basis. This leads to the possibility that, within the spectrum of wheezing disorders in young children, several different disorders or phenotypes exist, each with its own aetiology, pathophysiology and prognosis. If so, this has important therapeutic implications. Evidence for at least two clearly distinct phenotypes, exclusive viral wheeze, an illness resembling classical chronic asthma, is strong. Clinical and epidemiological observations supported by studies of airway inflammation, pulmonary physiology and randomised controlled trials support the existence of these two phenotypes. However, new statistical techniques, falling broadly within clustering methodology, may lead to more subtle classifications. The prognosis of early wheezing disorders, and in particular their role in chronic obstructive pulmonary disease in adult life, remains to be studied in detail.

  14. Page 170
    Correspondence: J.L.L. Kimpen, Wilhelmina Children’s Hospital, University Medical Center Utrecht, POB 85090, 3508 AB Utrecht, The Netherlands. Fax: 31 302505346; E-mail:

    Bronchiolitis is a common clinical syndrome in infancy. It is caused most often by respiratory syncytial virus, although recently other causative respiratory viruses have been identified. Bronchiolitis is followed in a considerable number of cases by recurrent episodes of wheezing in the first years of life, but probably has no relation to the development of atopy later in childhood. Although there is no effective treatment for bronchiolitis, disease progression after infection can be attenuated by prophylactic administration of humanised monoclonal antibodies. The pathogenesis of viral bronchiolitis is the subject of intensive research because it is clear that the immune response initiated by the viral infection is partially responsible for the damage of the airways. The cells that have been implicated in this process are virus-specific cytotoxic and T-helper cells, as well as antigen-presenting cells, such as dendritic cells.

  15. Page 191
    Correspondence: J.H. Wildhaber, University Children’s Hospital Zürich, Steinwiesstrasse 75, 8032 Zürich, Switzerland. E-mail:

    Although inhaled corticosteroids have become the key aspect of maintenance therapy in childhood asthma, it is not clear at what point such treatment should begin and indeed whether anti-inflammatory therapy can influence the natural course of the disease.

    A further complication is the fact that, in many cases, anti-inflammatory drugs are not taken as prescribed. Thus, idealised asthma guidelines do not reflect the reality of asthma management.

    As understanding of the underlying mechanisms of, and individual responses to, anti-inflammatory treatment improves, it is likely that treatment strategies will evolve towards more individualised, bespoke plans based upon this new information.

    With this in mind, clinicians need to work closely with children with asthma, as well as with their families, to develop an understanding of individual cases and to educate patients about their treatment. In this way, short- and long-term outcomes can be improved.

  16. Page 217
    Correspondence: A. Greenough, Regional Neonatal Intensive Care Centre supported by the WellChild Trust, 4th Floor Golden Jubilee Wing, King’s College Hospital, Denmark Hill, London SE5 9RS, UK. Fax: 44 2073468284; E-mail:

    Bronchopulmonary dysplasia (BPD) is a common adverse outcome of very premature birth. BPD infants suffer prolonged oxygen dependency, troublesome respiratory symptoms, lung function abnormalities at follow-up and related problems, including pulmonary and systemic hypertension, neurodevelopmental delay and conductive hearing loss. There are many risk factors for BPD development, including oxygen toxicity, volutrauma and infection, as well as prematurity. Studies in animal models have demonstrated that these factors lead to the inflammatory pulmonary response seen in infants with BPD. In addition, it has been highlighted that abnormal vascular development may lead to impaired lung growth. Nowadays, infants are described as having “new” BPD, with abnormalities of lung growth being more prominent than the fibrosis and smooth muscle augmentation of the airways seen previously in severe or classical BPD. Preventative strategies have largely been aimed at preventing or minimising lung injury and have had limited success. Despite many randomised trials, the optimum ventilation mode with regard to preventing BPD has not been identified, and, although systemically administered corticosteroids in the first 96 h after birth are efficacious, concerns regarding serious adverse effects preclude their use. Supplementary oxygen is the mainstay of treatment for BPD infants, but further work is necessary to identify the optimum oxygen saturation level, particularly in infants with pulmonary hypertension. On current evidence, the use of medications in BPD infants should be individualised and only continued whilst there is evidence of a clinically important response. Research areas regarding prevention of BPD that merit further investigation are antioxidant supplementation, resolution of lung injury by neutrophil apoptosis, treatment of antenatally acquired infection and prophylactic administration of nitric oxide to promote angiogenesis and alveolarisation.

  17. Page 234
    Correspondence: A. Bush, Dept of Paediatric Respiratory Medicine, Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK. Fax: 44 2073518763; E-mail:,

    Twenty years ago, cystic fibrosis was considered a disease mainly of children, affecting the lungs and the digestive systems, diagnosed using the sweat test. Since then, the gene for CF has been discovered, leading to great increases in the knowledge about the fundamental molecular and cellular biology of the airway; the diagnostic spectrum has also been expanded to mild and atypical cases, requiring more sophisticated diagnostic testing, with mild cases presenting in adult life. Specialist care has lead to an increase in survival, so that shortly there will be more adults than children with the disease. The nature of the disease is now appreciated to affect nearly all systems in the body, including the bones and the genitourinary system. Psychosocial issues of living with a chronic disease have become increasingly important. These new complications have lead to searches for new preventative strategies in childhood and have posed novel treatment challenges in adults. The expectation for treatment has switched from the reactive and symptomatic, to curative strategies, including gene therapy and phenotype-specific treatments, such as aminoglycosides, to overcome premature stop codons. There remain many unanswered questions about basic pathophysiology and much treatment is not evidence-based. The ongoing challenge for clinicians is to establish a firm evidence base for therapy; for basic scientists, it is to understand the crucial steps leading from an absent or dysfunctional protein to the clinical disease, and to target those functions that are crucially disease-producing.

  18. Page 291
    Correspondence: S.L. Brody, Dept of Internal Medicine, Washington University School of Medicine, Box 8052, 660 South Euclid Avenue, Saint Louis, MO 63110, USA. Fax: 1 3143628987; E-mail:

    Primary ciliary dyskinesia (PCD) is a genetic disorder resulting from dysfunction of motile cilia. Epithelial cells containing motile cilia are localised in the respiratory tree, ventricles of the brain, oviduct, sperm and the embryonic node. In these epithelial cells, dysfunction accounts for the major symptoms of PCD, including otitis media, sinusitis and bronchiectasis, Situs inversus (in half of the patients) and, more rarely, infertility and hydrocephalus. While the understanding of cellular and molecular mechanisms responsible for these symptoms has recently progressed, genetic analysis has identified mutations in only two axonemal dynein genes that can account for abnormal cilia ultrastructure and beat frequency in a subpopulation of individuals. Thus, investigations are directed towards expanding understanding of the genetic basis of PCD by identification of proteins with roles in ciliogenesis, and increasing the scope of genes and populations subject to genetic analyses. To support the diagnosis of PCD, efforts are currently directed toward the optimal use of cilia ultrastructure and beat analysis, and interpretation of low levels of exhaled nasal nitric oxide. While there is no specific therapy for PCD, maintenance of mucociliary clearance and culture-directed antibiotic therapy are current cornerstones of therapy. The establishment of new methodologies for PCD diagnosis and therapies will require evaluation of relationships between specific genetic mutations, disease phenotypes and therapeutic responses to be carried out in multicentre cooperative trials.

  19. Page 314
    Correspondence: K.G. Tantisira, Channing Laboratory, Brigham and Women’s Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, , MA 02115, USA. Fax: 1 6175250958; E-mail:

    The incidence and prevalence of obesity are increasing rapidly in children throughout many parts of the world. Among the many sequelae of childhood obesity, respiratory complications have been largely underappreciated. Body mass index (BMI) remains the primary means of evaluating obesity in children and adults, although some criticisms have been directed at this measure. Epidemiological and human physiological studies have noted associations between childhood obesity and lung function. Although morbid obesity is associated with the traditional restrictive defect, increases in BMI have been associated with decrements in the forced expiratory volume in one second/forced vital capacity ratio. Obese children also show decrements in functional residual capacity and the diffusing capacity of the lung for carbon monoxide, this latter observation has not been noted in obese adults. Obesity has been associated with incident and prevalent asthma. Although obesity has also been associated with increased airways responsiveness in adults, studies in children have yielded conflicting results. Obesity remains a major risk factor for obstructive sleep apnoea in adults. Although mechanical effects have been traditionally thought of as the pathophysiological basis for the obesity–respiratory disease link, there is increasing evidence that obesity may influence the lung via inflammatory, genetic, sex-specific, developmental and dietary mechanisms. Of greatest current interest to the research community is the diverse array of inflammatory processes that accompany increased adiposity. Given the evidence from both human association studies and the literature surrounding the mechanisms behind these associations, it is becoming evident that adequate prevention and treatment of respiratory disorders in children will include community, national and global strategies for addressing the obesity epidemic.

  20. Page 345
    Correspondence: U. Frey, Paediatric Respiratory Medicine, Dept of Paediatrics, University Hospital of Bern, Inselspital, 3010 Bern, Switzerland. Fax: 41 316329484; E-mail:

    Despite recent advances in the understanding of chronic respiratory diseases, such as bronchial asthma, the complexity of such diseases has made it difficult to obtain a comprehensive picture of the multiple mechanisms involved. With regard to asthma, a large variety of genetic factors, environmental triggers, interactions between inflammatory and repair mechanisms, structural alterations of the airways and changes in the immune system are involved in the disease process. Several strategies have been used to target problems related to asthma. They are mainly based on phenomenologically characterising subgroups of patients with similarities in disease conditions, or based on mechanisms linking genetic or pathophysiological abnormalities to clinical phenotypes. This reductionist approach can help in the understanding of individual components or the interaction of single components of the disease system; however, this approach often fails to cope with the overall complexity and temporal pattern of the disease. There are still a number of unexplained phenomena in asthma, such as unexpected fatal attacks, the persistence of symptoms after removal of the trigger in occupational asthma or the persistence of bronchial hyperactivity following a bronchial challenge with an allergen or viral infections. These phenomena, including the lack of a well-defined relationship between trigger and symptoms (attacks), point to the existence of a nonlinear relationship among the subcomponents of the system. Additionally, bronchial hyperactivity, allergic sensitisation or remodelling phenomena are consistent with memory effects in the system. The analysis of nonlinear dynamic systems with memory effects has been a challenge for several decades. This chapter demonstrates how the techniques borrowed from statistical physics can be applied to fluctuations in physiological variables in order to better understand asthma. It is proposed that the next steps in understanding and treating chronic diseases in general need to utilise tools from complex systems analysis, which should find their way into life sciences and medicine.