Pulmonary complications of esophageal disease. Mok J and Levison H. Wheezing and gastroesophageal reflux in infants. Gastroesophageal reflux-associated pulmonary disease in infants and children. Clinical expressions of immotile cilia syndrome. Pediatrics ; 67 — Greenstone M and Cole PJ. Ciliary function in health and disease. Chest ; 79 :9— IgG subclass deficiency in children with IgA deficiency presenting with recurrent or severe respiratory infections.
Respiratory dysfunction in patients with common variable hypogammaglobulinemia. Recurrent sinopulmonary infection and impaired antibody response to bacterial polysaccharide antigen in children with selective IgG-subclass deficiency. IgG4 deficiency in childhood: association of isolated IgG4 deficiency with recurrent respiratory tract infection.
IgG subclass deficiency and recurrent respiratory disease in childhood. Asthma Allergy Immunol. Selective defect in the antibody response to Haemophilus influenzae type b in children with recurrent infections and normal serum IgG subclass levels. IgG subclasses in non-allergic children with chronic chest symptoms. Asthma and selective immunoglobulin subclass deficiency: Improvement of asthma after immunoglobulin replacement therapy. Jefferis R, and Kumarartne DS. Selective IgG subclass deficiency: quantification and clinical relevance.
Psychogenic upper airway obstruction presenting as wheezing. Psychogenic upper airway obstruction. Pediatrics ; 81 — Geist R and Tallett SE. Diagnosis and management of psychogenic stridor caused by a conversion disorder. Pediatrics ; 86 — McFadden ER. Glottic function and dysfunction. Paradoxical vocal cord motion in presumed asthmatics. Hollinger LD.
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Chronic cough in infants and children. Laryngoscope ; 96 — Psychogenic cough. Pediatrics ; 87 — Slavin RG. Relationship of nasal disease and sinusitis to bronchial asthma. Allergy ; 49 — Chronic sinus disease with associated reactive airway disease in children. Pediatrics ; 73 — Sinusitis and its relationship to asthma. Postnasal drip causes cough and is associated with reversible upper airway obstruction.
Chest ; 85 — Prevalence of abnormalities found by sinus x-rays in childhood asthma: lack of relation to severity of asthma. Nasal-sinus-pulmonary reflexes and bronchial asthma. Surgical management of chronic sinusitis in childhood. Ferguson AC. With a predominantly infective stimulus, however, it is more difficult to separate site-specific effects of the provoking agent from underlying systemic processes. Our traditional understanding of COPD has focused on the presence of chronic airflow obstruction and, accordingly, therapy has been mainly directed to relieve this.
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More recently, it has been demonstrated that airflow limitation is associated with an abnormal inflammatory response and that the latter appears to be responsible for specific effects on mucociliary function, structural changes in the airways and lung parenchyma, and extrapulmonary effects the systemic effects of COPD, including impairments of metabolism and inflammation, that lead to comorbid conditions. At present, a combination of pharmacological and nonpharmacological approaches seems the most effective strategy for confronting this multicomponent disease.
As regards pharmacotherapy, bronchodilators and inhaled corticosteroids have shown complementary mechanisms of action, targeting different arms of the vicious cycle of COPD: A combination of the two types of drugs has the potential to address several major components of the disease, including airflow limitation, mucociliary dysfunction, and airway inflammation. Furthermore, since COPD is a progressive disease, with lung function worsening over time, a major target of the therapy is to modify its clinical course, in other words, slow down the evolution of lung damage to respiratory failure and improve survival.
Recent evidence suggests that appropriate pharmacological therapy can reduce the long-term decline of FEV1 in patients with moderate-to-severe COPD, thus slowing disease progression, and this has a favorable trend on survival. The current shift in the approach to respiratory diseases favors the hypothesis of a united airways disease, supported by the growing evidence of a systemic link between the upper and lower airways. Diseases that affect one part of the airway often impact other parts. The united airways disease hypothesis, in fact, maintains that upper and lower airways disease are both manifestations of a single inflammatory process within the respiratory tract, and a unified diagnostic approach to upper and lower airways disease will constitute a solid basis for a common therapeutic management.
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Latest Issue Archives. Lung Biology in Health and Disease. Volume Upper and Lower Respiratory Disease. New York: Marcel Dekker; Togias A. Rhinitis and asthma: evidence for respiratory system integration.
Lung Biology In Health Disease Vol 181 Upper And Lower Respiratory Disease
J Allergy Clin Immunol. Rimmer J, Ruhno JW. Rhinitis and asthma: united airway disease. Med J Aust. Comparison between nasal and bronchial inflammation in asthmatic and control subjects. Inflammatory features of nasal mucosa in smokers with and without COPD. Observational study of the natural history of eosinophilic bronchitis. Clin Exp Allergy. Prevalence of asthma and allergy in schoolchildren in Belmont, Australia: three cross sectional surveys over 20 years.
Rhinitis as an independent risk factor for adult-onset asthma. Childhood factors that predict asthma in young adulthood. Eur Respir J. Rhinosinusitis in severe asthma. Improvement of clinical and immunopathologic parameters in asthmatic children treated for concomitant chronic rhinosinusitis. As neutrophil elastase is a remarkably potent secretagogue, it has been proposed that the location of neutrophils within the epithelium is crucial for the activation of the secretory function of goblet cells in smokers. While airway obstruction may be induced by excessive mucus production from the numerous goblet cells in the peripheral airways, it remains controversial whether or not chronic bronchitis due to mucus hypersecretion in the bronchial glands of the central airways contributes to the development of functional abnormalities.
For many years, chronic bronchitis was considered irrelevant, but more recent studies have demonstrated an association between chronic mucus hypersecretion, FEV 1 decline and COPD morbidity [ 37 , 38 ], suggesting that this clinical condition, when present, should not be ignored. When the amount of smooth muscle is measured in the peripheral airways of smokers with or without COPD, an increased area occupied by smooth muscle is found in those with COPD.
Increase in smooth muscle correlates with the degree of airflow limitation; the greater the amount of smooth muscle, the lower the FEV 1 and the more severe the airway obstruction [ 25 ]. So, increased smooth-muscle mass is an important component of airway wall thickening, which can be due to several mechanisms including hypertrophy and hyperplasia, possibly due to the activity of inflammatory mediators, cytokines and growth factors.
The airways of smokers can react to nonspecific stimuli by constricting, and this results in increased resistance and decreased FEV 1. Whether hyperresponsiveness is a primary event that might contribute to the natural history of COPD or is a consequence of the already decreased airway dimensions is still an open question. Regardless of the mechanism, the abnormalities found in the airways of smokers, such as epithelial damage and chronic inflammation, could contribute to the constriction of even a normal airway smooth muscle [ 39 ].
The major functional consequence of the increase in smooth-muscle mass is that, in airways with thickened walls, the same degree of smooth-muscle shortening may cause considerably greater lumenal narrowing than in the normal airways [ 40 ]. Another important component of remodeling is fibrosis of the airway wall.
It has previously been reported that cigarette smoke induces oxidative stress in human lung fibroblasts, which may then initiate a process of repair and collagen deposition [ 41 ]. Furthermore, the interaction between fibroblasts and inflammatory cells may also play a role in fibrotic remodeling.
Along with this is the observation that mast cells, which have important profibrotic and prorepair properties, are increased in the airways of smokers with COPD, particularly in those with centrilobular emphysema [ 42 ].
Fibrosis, along with an increased airway smooth muscle and other inflammatory components, ought to increase the airway wall thickness and change the mechanical characteristics of the airway to decrease the luminal diameter. That this is indeed the case was shown by Wright et al. In the context of a disease such as COPD, it is well conceivable that the pathological changes observed in small airways are associated with an attempt to repair, resulting in fibrosis and thickening of the airway wall [ 45 ].
In line with this hypothesis, Hogg et al. Inflammation, fibrosis and smooth-muscle hypertrophy, by increasing the thickness of the airway wall, may facilitate uncoupling between airways and parenchyma, therefore promoting airway closure. In addition, airway wall inflammation could contribute to the destruction of alveolar attachments i. This hypothesis is supported by the observation that, in smokers, the destruction of alveolar attachments is correlated with the degree of inflammation in the peripheral airways [ 46 ].
This finding suggests a pathogenetic role for airway inflammation in inducing the destruction of alveolar attachments.
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It is possible that mediators released by inflammatory cells may weaken the alveolar tissue and facilitate its rupture, particularly at the point where the attachments join the airway wall and the mechanical stress is maximal. Note that the airway wall is thin, the lumen is wide open and that intact alveoli are attached along its circumference. The airway wall is thickened, with an important component of airway smooth muscle and fibrosis, and the majority of the alveolar attachments along its circumference are broken.
Once the pathological changes in the airways are established, the striking correlation between the progression of physiological impairment and the degree of small airway disease suggests that inflammation of the small airways makes an important contribution to the functional deterioration seen in COPD, even in the presence of emphysema. In patients with severe COPD, an amplification of the inflammatory response in the peripheral airways has been demonstrated, with a nearly 3-fold increase in the number of leukocytes, particularly of T lymphocytes and macrophages, suggesting that the inflammation initiated by cigarette smoking worsens as airflow deteriorates [ 47 , 48 ].
This worsening airway inflammatory process is correlated with the degrees of airflow limitation, lung hyperinflation, CO diffusion impairment and radiological emphysema, suggesting a role for this inflammatory response in the clinical progression of the disease [ 47 ]. A similar amplification of the inflammatory response was observed in the lung parenchyma of patients with severe emphysema by Retamales et al.
These results confirm the pioneer observations of Nagai et al. In their study, flow rates correlated with the degree of macroscopic emphysema, but also with the degree of deformity of respiratory bronchioles, indicating that decreases in flow were secondary to both emphysema and airway obstruction. Of note in that study is that, for the same degree of airflow limitation, smokers with lesser amounts of emphysema had more diseased small airways and vice versa , pointing to the heterogeneity of the pathophysiology of COPD, which is reflected in the heterogeneity in the clinical presentation.
Moreover, in patients in the most severe stages of COPD, inflammatory cells in the airway wall are observed in well-organized lymphoid follicles, that represent tertiary lymphoid structures specialized in antigen presentation [ 32 ]. Sequence analysis of rearranged immunoglobulin genes in individual B cell clones in these lymphoid follicles revealed the presence of clonally related B cells, suggesting an antigen-driven selection process.
Some authors suggested that these follicles represent an adaptive immune response which may develop in relation to microbial colonization and infection, which are a frequent occurrence in the later stages of COPD [ 32 ]. However, the absence of bacterial and viral products in the follicles prompts other authors to suggest that these oligoclonal B cells may arise in response to lung auto-antigens [ 52 ]. Indeed, there is increasing evidence that autoimmunity may play a role in the pathogenesis of COPD. This hypothesis was first raised based on the observation that lymphocytes are the predominant cells infiltrating the lung tissue of patients with COPD and that their numbers are strongly related to the apoptosis of structural cells and lung function impairment.
Currently, there is circumstantial, indirect and direct evidence of the involvement of cellular and humoral immune responses in the lung damage of COPD, possibly supported by the recognition of pulmonary self-antigens modified by cigarette smoking and the failure of mechanisms regulating immunological tolerance [ 19 ]. Nevertheless, no direct cause-effect relationship linking COPD to autoimmune damage has of yet been established, and further studies are required to investigate this important issue.
In conclusion, in this review we have seen how the normal structure of the small airways is reached through development, how it is affected by the insult from cigarette smoke and how it is further modified in parallel with the establishment and progression of airflow limitation. These observations highlight the complexity of COPD and its pathophysiology and points to the importance of studies correlating the morphology and function in COPD, the basis for our present understanding of the pathophysiology of the small airways.
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