Bombesin and vasoactive intestinal polypeptide in the developing lung: marked changes in acute respiratory distress syndrome

The quantitative distribution of bombesin- and vasoactive intestinal polypeptide (VIP)-like immunoreactivities was determined by RIA and immunocytochemistry in regions of trachea, bronchus, and whole lung at various stages of human fetal development and in neonates, children, and adults. In addition, these two immunoreactivities were studied in infants that had died of the acute respiratory distress syndrome. The concentration of bombesin-like immunoreactivity in the whole respiratory tract steadily increased during gestation, reaching a plateau at birth. In the lung, the bombesin concentration remained almost unchanged during childhood, but decreased to one tenth in the adult. In neonates with the acute respiratory distress syndrome, there was a significantly lower bombesin content in all regions of the respiratory tract compared to either normal full-term infants or 24- to 28-week-old fetuses. Immunocytochemistry localized bombesin immunoreactivity within mucosal neuroendocrine cells present in the airway epithelium throughout the respiratory tract and particularly in the intrapulmonary airways. The number of cells increased throughout gestation, reflecting the pattern found by RIA, and were greatly decreased in acute respiratory distress syndrome patients. VIP concentrations were much lower than those of bombesin and did not change significantly with gestational age. In contrast to bombesin, VIP was mainly concentrated in the upper respiratory tract. In infants with the respiratory distress syndrome, the VIP content was not different from normal. These results are compatible with the possibility that bombesin-like peptides may have a role in the normal development of the human lung.     

Pulmonary mucus: Pediatric perspective

Airway mucus hypersecretion is a clinical feature of a number of childhood diseases, including asthma and bronchitis-associated conditions. However, compared with adults, there is relatively scarce information concerning mucus pathophysiology in respiratory diseases in children. The available evidence indicates many similarities between adult and childhood respiratory hypersecretory conditions, including goblet-cell hyperplasia and submucosal gland hypertrophy, and airway mucus plugging in asthma. Consequently, it is likely that treatments that are effective in adults would be effective in children. Numerous therapeutic targets are linked to the pathophysiology of airway mucus hypersecretion in experimental models and adults with respiratory disease. Whether or not these same targets are relevant in children is for the most part unclear. These targets include the inflammatory cells mediating the inflammatory response that generates the hypersecretory phenotype, and highly specific cellular elements such as epidermal growth factor receptor tyrosine kinase and calcium-activated chloride (CACL) channels. Identification of these factors is linked with the development of different classes of pharmacotherapeutic molecules directed at these targets. Compounds with a broader spectrum of anti-inflammatory activity are likely to be more effective than compounds with restricted activity. However, certain highly specific targets, such as human CACL1 channels, appear to be strongly associated with the development of an airway hypersecretory phenotype. Data from current clinical trials in adults with blockers of these specific targets are awaited with great interest. The hope is that, if effective, pediatric trials with these compounds could be initiated with a view to alleviation of the clinical impact of airway mucus hypersecretion in children. A significant challenge to the therapeutic progression of these new compounds is effective delivery to the airways in children, with the research effort into development of new compounds matched by advances in inhaler design.     

Childhood antecedents of adult respiratory disease

Abstract This review examines the relations between early childhood lower respiratory symptoms and adult respiratory disease. The problems associated with investigating potential associations between respiratory disease in children and adults are discussed. Some studies have limitations because they are retrospective and early childhood respiratory symptoms have not been accurately diagnosed. Therefore, in this review, particular attention is paid to longitudinal studies (some from birth) that have used strict diagnostic criteria for respiratory episodes. These studies provide unique insights into the risk factors for the development of childhood respiratory problems and for persistence of symptoms into adulthood. Although cross-sectional studies have indicated that early childhood respiratory disease is more frequent in adults with respiratory disease, evidence from longitudinal studies suggests that respiratory symptoms such as wheezing, are transient in the majority of infants and result from developmentally small airways. These longitudinal investigations have also indicated that persistence of symptoms into later childhood is associated with atopy. The important role of cigarette-smoke exposure as a risk factor for abnormal pulmonary development, persistence of respiratory disease and reduction in lung function is discussed. The discovery of genetic markers associated with respiratory syndromes such as asthma, should facilitate studies that investigate the childhood antecedents of adult respiratory disease. Future longitudinal studies using genetic markers, will allow relations between specific genotypes and phenotypic outcomes to be examined.     

The use of filters with small infants

The use of breathing system filters may be particularly beneficial in small infants, compared with older children and adults, because of their greater need for warming and humidification of inspired gases as well as their increased susceptibility to lower respiratory tract contamination. The only evidence available regarding the safety and efficacy of breathing system filters in small infants comes from a few small studies conducted on intensive care patients, however. These studies have suggested that the use of HME filters may be effective in preserving body temperature and airway humidity while decreasing fluid build-up in the breathing system and therefore reducing breathing system contamination. Nonetheless, the use of filters has not been shown to decrease the incidence of VAP in small infants. In contrast,their use in adult intensive care patients, particularly those requiring prolonged ventilation, has been associated with a decrease in the infection rate. The use of breathing system filters is not associated with a statistically significant increase in the rate of complications, despite the potentially greater hazards associated with their use in small infants compared with older children and adults. In practice the use of breathing system filters, even in small infants, rarely causes any major clinical problems that cannot be prevented with a high degree of vigilance and appropriate monitoring. This vigilance is particularly important to prevent the serious morbidity and even mortality that may result from filter occlusion; when subjected to excessive loading, smaller filters are more prone to obstruction than are their larger counterparts. The increased resistance provided by smaller filters should not translate into a clinically significant increase in the work of breathing during general anesthesia, because it is common practice to ventilate small infants for all but the shortest of surgical procedures. An increase in the work of breathing may, however, become more significant when spontaneous ventilation is established at the end of a surgical case. It remains unclear whether the use of filters allows the safe reuse of breathing systems in small infants. None of the breathing system filters tested by the MHRA had a zero-percent penetrance to sodium chloride particles, and pediatric filters generally had a higher penetrance than their adult counterparts. This finding suggests that there is a potential, albeit small, risk of cross-contamination. The exact risk depends on the type of filter used and on the particular patient undergoing anesthesia or ventilation in the ICU. Although no evidence has been published showing cross-infection occurring when any filter has been used in the anesthesia breathing system for adults or small infants, the level of filtration performance required to allow the safe reuse of anesthesia breathing systems in small infants remains unanswered. Because the incidence of lower respiratory tract colonization is low in unselected small infants, a study with sufficient power to answer accurately the questions regarding the safety of breathing system reuse in small infants would be very difficult to conduct. The effect of filters on post operative infection rates may in fact be of less significance than the adoption of adequate standards of hygiene (eg, hand washing and the use of gloves).Further research is needed to determine if the variations in filtration efficiency demonstrated by the MHRA have any effects on patient outcome.This research might allow setting an effective minimal level of filtration performance for breathing system filters for use in small infants. On a practical note, the publication of the MHRA assessments of breathing system filters provides a useful tool for objective comparison of the different filters available for use in small infants, even though the relevance of the flow used to test pediatric filters has been criticized. Individual institutions will need to formulate policies for the use of breathing system filters for clinical reasons as well as for cost containment or logistical reasons. These policies should be within the frameworks set out by their regulatory agencies. Any problems arising from policies that are in breach of these frame works will remain the responsibility of the individual clinicians caring for these small infants.     

Colorectal cancer in children: Epidemiologic aspects

Summary Despite many similarities to colorectal cancer in adults, the rare childhood form has some peculiarities. Childhood mortality is greater among Negroes than Caucasians, particularly in boys, reflecting the rising incidence of this tumor in the young Negro population. In addition, the percentage of childhood cases with precancerous diseases (polyposis, colitis) appears greater than in adults. Most striking is the high percentage of mucin-producing tumors in young people with colorectal cancer. The mucoid tumors tend to occur after the age of 10 years, whereas younger children are more likely to develop non-mucoid carcinoma in an adenomatous polyp.     

Special considerations in pediatric lung transplantation

More than 1300 lung or heart-lung transplants have been performed in children to date, resulting in many years of improved quality of life. Increasing experience has demonstrated that this therapy is unique and differs from adult lung transplantation in terms of indications, complications, pharmacokinetics, and monitoring. Unlike adult lung transplant recipients, cystic fibrosis and pulmonary vascular disease are very common indications. Complications such as graft dysfunction and bronchiolitis obliterans occur similarly in children as in adults, but others such as posttransplant lymphoproliferative disorders, growth retardation, respiratory tract infections, and medical nonadherence appear to be more common in pediatric lung transplant recipients. In addition, infants and adolescents are two very distinct populations that require special attention. Although the new lung allocation system grants some preference to children, donor shortage remains a limiting factor. Living donor lobar transplantation is an alternative for select candidates. Survival rates are similar between adult and pediatric transplant recipients. Support for collaborative studies is critical if we are to improve long-term outcomes for our young patients.     

Respiratory syncytial virus infection in adults

Respiratory syncytial virus (RSV), an enveloped RNA virus in the Paramyxovirus family, is the most important cause of lower respiratory tract infection in infants and young children, accounting for ~100,000 pediatric hospitalizations and 250 deaths annually in the United States. Despite primarily being recognized as a pediatric pathogen, RSV reinfection causes substantial disease in all adult populations, including healthy young persons, old and frail individuals, those with chronic obstructive pulmonary disease and immunocompromised patients. Most illnesses are mild in adults, but significant morbidity and mortality can develop. In contrast to infants, diagnosis of RSV infections is difficult due to low virus shedding, and optimal diagnosis requires molecular tests. Unfortunately, antiviral therapy is of limited benefit. Ribavirin and palivizumab are the only approved pharmacological agents for RSV treatment and prophylaxis, respectively, and are primarily used in infants; data regarding their usefulness in adults are limited. Currently, specific antiviral therapy is generally reserved for severely immunocompromised patients or severe respiratory failure. The greatest promise for reducing the impact of RSV in adults may be through immunization. However, an effective vaccine for RSV is not currently available.     

Long-term respiratory outcome of babies born prematurely

Chronic respiratory morbidity is a common adverse outcome of premature birth, particularly in infants who develop bronchopulmonary dysplasia (BPD). Prematurely born infants who had BPD may require supplementary oxygen at home for many months, but few remain oxygen dependent beyond 2 years of age. Readmission to hospital is common, particularly for those who had BPD, but only in the first 2 years after birth. The readmissions are usually for respiratory problems, particularly respiratory syncytial virus lower respiratory infections. Recurrent respiratory symptoms requiring treatment are common, particularly in those who had BPD, even at school age and in adolescence. Affected children have evidence of airways obstruction. Pulmonary function does improve with age, but children with BPD may have ongoing airflow limitation. Computed tomography of the chest gives helpful information at follow up of patients with ongoing respiratory problems who had BPD.     

Modulating airway defenses against microbes

Prevention and treatment of respiratory infections remain an important health care challenge as the US population ages, contains more susceptible or high-risk people, and encounters new pathogens or antibiotic resistant bacteria. Reasonably protective vaccines against very common microbes are available for childhood and adult immunization, but, generally, these are underutilized. A broader definition of higher risk individuals is evolving, which will include more for immunization. Different approaches to vaccine development through design of new component vaccines are necessary. This review has updated host defense mechanisms at three levels in the human respiratory tract: naso-oropharynx (upper airways), conducting airways, and alveolar space. Examples of representative pathogenic microbes have been inserted at the respective airway segment where they may colonize or create infection (influenza, measles virus, Porphyromonas gingivalis causing periodontitis, Bordetella pertussis, Chlamydia pneumoniae, Streptococcus pneumoniae, and Bacillus anthracis ). Hopefully, microbe-host interactions will suggest new approaches for preventing these kinds of infections.     

Progress in the diagnosis,prevention, and treatment of pertussis

Pertussis (“whooping cough”), caused by the gramnegative pleomorphic bacillus Bordetella pertussis, is a highly contagious, potentially life-threatening respiratory tract illness that has re-emerged worldwide as a cause of substantial morbidity and mortality in infants, children, and adolescents, even in countries with high vaccination rates. Waning immunity after immunization during childhood has been associated with a growing pool of susceptible adolescents and adults who are capable of transmitting pertussis to vulnerable unvaccinated or incompletely vaccinated infants. The use of acellular pertussis vaccine boosters in adolescents has been proposed and is likely to be recommended. Active immunization and improved methods for early diagnosis are key in the management of pertussis, and represent the most rapidly evolving aspects of this disease.     

Maxwell Finland lecture: the influenza viruses and the human respiratory tract

This paper has reviewed evidence concerning the changes brought about in the structure and function of the lower airways by influenza virus infections. Disposal of inhaled bacteria is believed to be hindered by the mechanical damage to the epithelium of the respiratory tract caused by the virus infection, and phagocytosis is inhibited as well. Alteration in the ventilation, particularly of the peripheral small airways, which has been found in previously healthy persons during and after influenza, may add to the obstruction of the airways in those with chronic bronchitis and emphysema during influenza and may be important in the genesis of these disorders. The immunological defense of the respiratory tract against the influenza viruses has been discussed briefly with reference to the best available means of enhancing this defense, particularly in individuals with chronic pulmonary disease.     

IL-8 and neutrophil elastase levels in the respiratory tract of infants with RSV bronchiolitis.

The aim of this study was to determine whether interleukin (IL)-8 is released within the upper respiratory tract of infants during respiratory syncytial virus (RSV) bronchiolitis and whether the large number of polymorphonuclear neutrophils (PMNs) present in the respiratory tract of these infants are contributing to the inflammation through release of inflammatory mediators. Twenty-seven infants with acute bronchiolitis were recruited during one winter epidemic and 20 infant control subjects were recruited from a cohort participating in a community-based vaccine study. Samples of airways fluid were obtained using nasal lavage. The lavage fluid was spun to remove the cells, and the supernatant was stored at -70 degrees C. The supernatants were subsequently assayed for the presence of IL-8, total human neutrophil elastase (HNE) and neutrophil elastase activity. In the children with bronchiolitis compared with control infants, elevated levels of IL-8 (median (range) 1.53 (0-153) versus 0 (0-5.6) ng x mL(-1)) HNE (136 (32-694) versus 14 (0-516) ng x mL(-1)) and elastase activity (4 (1-220) versus 1 (0-339) mU x mL(-1)) were found. These results indicate that interleukin-8 is released in the upper respiratory tract in response to respiratory syncytial virus infection and suggest that polymorphonuclear neutrophil products are playing an important role in the inflammatory response to respiratory syncytial virus infection in infants with acute bronchiolitis. This contrasts with the predominantly eosinophilic response evident in atopic upper and lower respiratory tract disease.     

Latent adenoviral infection in the pathogenesis of chronic airways obstruction.

Childhood infection of the respiratory tract has been proposed as an independent risk factor in the pathogenesis of the chronic obstructive pulmonary disease (COPD) that develops in cigarette smokers. The present study examines adult lung tissue for latent adenoviral DNA because many of its 41 serotypes cause childhood respiratory disease and the virus is known to persist in other tissues in a latent form. Lung tissue resected for solitary nodules from 20 patients with airways obstruction and 20 patients without airways obstruction, matched for age, sex, and smoking history, were compared to determine whether adenoviral DNA is more commonly found in patients with COPD. The polymerase chain reaction (PCR) was used to examine two widely separated segments of the adenoviral genome. In situ hybridization (ISH) was performed using a probe covering the entire viral genome to determine the types of cell infected by the virus. The PCR analysis showed that a 675 base pair target sequence of the E1A region of the adenovirus was present in most of the lungs studied with greater copy numbers in the smokers with airways obstruction in both paraffin-embedded (p less than 0.002) and frozen lung tissue (p less than 0.016), whereas the E3/19K region showed no difference between the groups. When sufficient copy numbers were present to localize the DNA by ISH it was found in epithelial cells of the smokers who had airways obstruction. These data are consistent with a current model of adenoviral integration into host DNA and suggest that the E1A region of the adenovirus may contribute to the pathogenesis of COPD.     

Predictive value of measurements of respiratory mechanics in preterm infants with HMD

Conventional methods for measuring respiratory mechanics model the respiratory system as a single compartment. The interrupter technique allows the respiratory system to be considered as a two compartment model with “flow resistance” of the conducting airways (Pinit), calculated from the initial pressure drop (Pinit), considered separately from Pdiff, as a measure of the viscoelastic properties of the lung and chest wall and any pendelluft present. The pulmonary mechanics of 50 intubated and mechanically ventilated preterm infants (≤1500 g) were studied during the first week of life using conventional methods and the interrupter technique to determine whether it was possible to predict which infants would develop bronchopulmonary dysplasia (BPD). Pulmonary mechanics of preterm infants intubated and ventilated for apnea of prematurity were also studied. The dynamic compliance of the respiratory system (C_rsdyn) was significantly lower on day 1 (P<0.001) and during the first week of life in the infants with HMD who developed BPD (ANOVA, P<0.0001). There was no significant difference in the respiratory system resistance (R_rs), Rinit, or Pdiff between BPD and no-BPD groups. However, Pdiff was significantly higher in infants with HMD, regardless of the outcome, when compared to the infants ventilated for apnea of prematurity. This suggests that the pathology of HMD is distal to the conducting airways and significantly alters the viscoelastic properties of the lung on day 1. Using stepwise logistic regression, C_rsdum on day 1 and birth weight or gestational age were significant independent predictors of the development of BPD, correctly classifying 92% of infants. Due to the correlation between birth weight and gestational age (r = 0.72, P<0.0001). only one of these variables was necessary in the prediction model. In conclusion, C_rsdyn is a better independent predictor of the development of BPD in preterm infants with HMD than gestational age or birth weight. Pediatr Pulmonol. 1993; 16:116–123. © 1993 Wiley-Liss, Inc.     

Quantitative assessment of intrathoracic airway collapse in infants and children with tracheobronchomalacia

Tracheobronchomalacia (TBM) is increasingly recognized in infants, children, and adults with acquired chronic lung diseases as the use of flexible bronchoscopy has become widely established in spontaneously breathing patients. However, the lack of a reliable method to quantify the severity of the airway collapse has made serial studies, evaluation of therapies, and comparisons between patients difficult. The purpose of this study was to describe a method of quantifying airway collapse in TBM. The degree of airway collapse was quantitated by measuring the ratio of the smallest to the largest airway area during a respiratory cycle. The videotape of flexible bronchoscopy was run through a video monitor and frozen at the appropriate times. The airway circumference was then traced onto plastic overlays and the area measured. The videotapes of seven infants and children with TBM and eight with normal airways were reviewed by investigators who did not know the diagnosis. Intra-observer variability was 2.2%, and inter-observer variability was 1.4%. The mean smallest/largest airway ratio was 0.34 ± 0.14 (SD) in the subjects with known TBM, compared with a ratio of 0.82 ± 0.08 (SD) in children with a normal airway (P < 0.0001). The range in the children with TBM was 0.22–0.61, whereas for the control children it was 0.73–0.93. In this series, there was no overlap in the ratios between affected and unaffected patients. In addition to the manual method of calculating airway area ratios, a computer-assisted method is described that could be adapted to real-time use. This way of analyzing the degree of airway collapse could be used to assess patients with TBM quantitatively and reproducibly. Pediatr Pulmonol. 1996; 21:241–245. © 1996 Wiley-Liss, Inc.     

Development of Bronchial Hyperresponsiveness During Childhood

Bronchial hyperresponsiveness (BHR) produces the characteristic pathological abnormalities seen in asthma and clearly plays a central role in the pathophysiology of asthma. The presence of BHR has been demonstrated in infants with asthma, as has the possibility of BHR persisting through the childhood period. The level of BHR may not only reflect the state of the airways, as a marker of airway dysfunction, but may also predict the persistent prognosis of the disease. Thus, measurement of BHR may provide important information about the symptoms and lung function in children with asthma. In view of multiple pathophysiological mechanisms, BHR does not seem to have a single cause. Many potential confounding variables, such as age, gender, and genetic status, and some environmental factors, such as allergens, infections, and pollutants, could be responsible for the establishment of childhood BHR. There may be differences between the mechanisms that induce transient BHR and the mechanisms that induce persistent BHR. Also, there may be differences between the causes that induce BHR in the infantile period and the causes that maintain persistent BHR during childhood asthma. There is also disagreement as to the most suitable method to measure BHR in children, especially in infants. The assessment of BHR in young children has not been uniformly successful, and measurements of BHR changes over the childhood period are associated with a number of problems. To resolve these problems, there may be two ways to study childhood BHR. One is to use age-matched specific techniques to clarify the precise BHR in each age group; the other is to use simple techniques that can be performed over the childhood period on a large number of subjects. In studies of infantile respiratory dysfunction the ultimate goal is to establish a simple, noninvasive method by which measurements of respiratory function may be obtained in infants. Further investigations and acceptable methods will be needed to clarify the mechanisms involved in the establishment of asthma throughout the childhood period.     

Human metapneumovirus: a newly emerging respiratory pathogen

PURPOSE OF REVIEW: The present review focuses on the recent discovery, and clinical and epidemiological features of a virus associated with respiratory tract infections. RECENT FINDINGS: In June 2001, researchers in The Netherlands reported the discovery of a virus associated with respiratory tract disease in infants and children. Genetic studies of this newly discovered viral pathogen revealed that it was a paramyxovirus. This virus is the first human pathogen in the Genus Metapneumovirus and was called human metapneumovirus (hMPV). hMPV may be a common respiratory virus. Seroepidemiologic studies in The Netherlands suggested that, by age 5 years, nearly all individuals have been exposed to hMPV. The results of several studies suggest that hMPV may account for about 10% of respiratory tract infections in which a common respiratory virus, such as respiratory syncytial virus, or influenza or parainfluenza viruses, could not be detected. hMPV has been detected in patients with either upper or lower respiratory tract disease, or both. Symptoms associated with hMPV include cough, dyspnea, wheeze, and hypoxia. This newly recognized pathogen has been detected in children and adults. Epidemiological findings suggest that it may circulate worldwide and may have a seasonal distribution. SUMMARY: hMPV is a newly emerging respiratory pathogen and may be the cause of a significant proportion of both upper and lower respiratory tract infection in infants, children, and adults.