Kristiina Malmström

The common cold: Effects of intranasal fluticasone propionate treatment ☆ ☆☆ ★ ★★

OBJECTIVE A double-blind, randomized, placebo-controlled trial was conducted to study the effect of the intranasal corticosteroid, fluticasone propionate (FP), in the naturally occurring common cold. METHODS One hundred ninety-nine young adults received high-dose FP (200 microg four times daily) or placebo beginning 24 to 48 hours after onset of the common cold for 6 days. All symptoms were recorded on diary cards on days 1 to 20, and clinical examinations were carried out on days 1, 7, and 21. Nasopharyngeal aspirates were collected on days 1 and 7 for detection of rhinoviruses (found in 105 subjects) and Streptococcus pneumoniae, Haemophilus influenzae, or Moraxella catarrhalis (found in 52 subjects) in the nasopharynx. RESULTS In general, FP treatment had no clinically recognizable effects on the symptoms of the common cold, although it significantly reduced nasal congestion and cough on some study days. After treatment, rhinoviruses were cultured more often in the FP treatment group (37% vs 14%, p < 0.001), but this had no effect on the symptoms of common cold. FP treatment produced no changes in the colonization of pathogenic bacteria in the nasopharynx. Some symptoms of common cold were significantly more severe during days 1 to 10 (p < 0.05) in subjects found to have positive cultures for S. pneumoniae, H. influenzae, or M. catarrhalis in the nasopharynx on day 1 (n = 33). CONCLUSION FP treatment does not have any marked effects on the symptoms of the common cold. FP treatment induced prolonged shedding of viable rhinoviruses. Some symptoms of the common cold were significantly more severe in subjects with pathogenic bacteria in the nasopharynx.

Repaired oesophageal atresia: respiratory morbidity and pulmonary function in adults

Although after oesophageal atresia (OA) repair in infancy, respiratory problems are common, their natural history remains unclear. We assessed morbidity, pulmonary function (PF), and bronchial hyperresponsiveness (BHR) in adults with repaired OA respiratory. 588 patients who underwent surgery for OA during 1947–1985 were identified and those 262 who were alive and had their native oesophagus were included. Respiratory symptoms and respiratory symptom-related quality of life (RSRQoL) were assessed by questionnaire and interview, and the patients underwent spirometry, a histamine challenge test, and an exhaled nitric oxide test. For the questionnaires, we added 287 carefully matched general population-derived controls. Among the 101 (58 male) patients, median age 36 yrs (range 22–56 yrs), respiratory morbidity was significantly increased compared to controls. Patients had more respiratory symptoms and infections, as well as asthma and allergies, and more often impaired RSRQoL (p<0.001 for all). PF tests revealed restrictive ventilatory defect in 21 (21%) patients, obstructive ventilatroy defect in 21 (21%) patients, and both in 36 (36%) patients. A total of 41 (41%) had BHR, and in 15 (15%), it was consistent with asthma. The most significant risk factors for restrictive ventilatory defect were thoracotomy-induced rib fusions (OR 3.4, 95% CI 1.3–8.7; p = 0.01) and oesophageal epithelial metaplasia (OR 3.0, 95% CI 1.0–8.9; p = 0.05). After repair of OA, respiratory-related morbidity, restrictive ventilatory defect and BHR extended into adulthood. Nearly half the patients had BHR and over half had a restrictive ventilatory defect. Thoracotomy-induced rib fusions and gastro-oesophageal reflux-associated oesophageal epithelial metaplasia were the strongest risk factors for restrictive ventilatory defect.

Ultrastructure of the reticular basement membrane in asthmatic adults, children and infants

Reticular basement membrane (RBM) thickening in asthma is considered to be the result of subepithelial fibrosis. Thus, the RBM in asthma should contain an excess of fibrils identified as interstitial collagen and the ratio of fibril to matrix should be increased above normal levels. Electron micrographs of the RBM were compared with those of interstitial collagen deeper in the bronchial wall using endobronchial biopsy specimens from adult asthmatics (aged 18–41 yrs (n = 10)), children with difficult asthma (aged 6–16 yrs (n = 10)), wheezy infants with reversible airflow limitation (aged 0.3–2 yrs (n = 10)) and age-matched nonasthmatic controls: 10 adults, nine children and nine symptomatic infants with normal lung function. Fibrils in the RBM were significantly thinner (median (range) width 39 (30–52) nm versus 59 (48–73) nm), and fewer fibrils were banded than in the interstitial collagen (ratio of banded to non-banded fibrils 0.08 (0–0.17) versus 0.22 (0–1.3)). The ratio of fibrils to matrix in the thickened RBM of asthmatics did not differ from that of their respective controls (1.34 (0.63–2.49) versus 1.18 (0.31–2.6)). The ratio of fibril to matrix in the thickened reticular basement membrane of asthmatics is normal, and, contrary to what is expected in fibrosis, the fibrils do not resemble those of interstitial collagen.

Lung function, airway remodelling and inflammation in symptomatic infants: outcome at 3 years

Background Relationships between early deficits of lung function, infant airway pathology and outcome in symptomatic infants are unclear. A study was undertaken to determine the associations between early lung function, airway histology and inflammation in symptomatic infants with the continuance of respiratory symptoms, lung function and subsequent use of inhaled asthma medication at the age of 3 years. Methods 53 children who underwent lung function measurements and bronchoscopy following referral to a specialist childrens hospital for recurrent lower respiratory symptoms at a mean age of 1 year were followed up at 3 years of age. Assessments were made of respiratory symptoms during the previous year, lung function by oscillometry and atopy by skin prick testing. Individual data on the purchase of asthma medications were obtained from the Social Insurance Institution for the 12 months preceding the follow-up visit. Results 50 children (94%) were re-evaluated, of whom 40 had ongoing airway symptoms. 11/39 (28%) who underwent successful oscillometry had reduced lung function, 31/50 (62%) used inhaled corticosteroids (ICS) regularly and 12/50 (24%) used ICS intermittently. Abnormal lung function at infancy was associated with ongoing airway symptoms (p<0.001) and with the purchase of ICS (p=0.009) and β agonists (p=0.002). Reticular basement membrane thickness in infancy and the numbers of mucosal mast cells, but not eosinophils, correlated significantly with the amount of ICS purchased at 3 years (p=0.003 and p=0.018, respectively). Conclusions Reduced lung function, thickening of the reticular basement membrane and increased density of mucosal mast cells in infancy are associated with respiratory morbidity and treatment needs at age 3 years in this highly selected group of children.

Bronchial response pattern of antigen presenting cells and regulatory T cells in children less than 2 years of age

Background: In early childhood, the ability to mount protective immune responses in the airways is impaired, with increased risk of allergic sensitisation to inhaled allergens. Antigen presenting cells (APC) and regulatory T cells (Treg) are important modifiers of T cell immunity but little is known about their distribution in bronchial mucosa at this age. Here the subset distribution of APC and the appearance of Foxp3+ Treg and bronchus associated lymphoid tissue (BALT) were examined immunohistochemically in children less than 2 years of age with chronic asthma-like symptoms of the lower airways. Methods: Immunophenotyping was performed in situ on bronchial biopsy specimens obtained from 45 infants, 4–23 months of age, under investigation for airway disease. Results: A well developed HLA-DR+ network of APC was present in all samples, approximately 50% of the cells being CD68+ macrophages and the remainder various subsets of dendritic cells. The density of HLA-DR+ cells increased significantly with age but was not related to atopy, clinical symptoms or lung function. Comparing the density of APC subsets and clinical parameters, only the number of intraepithelial CD1a+ dendritic cells was significantly increased in infants who had recently suffered a respiratory infection. BALT structures were identified in 22 children, with no relation to lung function, atopic status or human rhinovirus positivity. Plasmacytoid dendritic cells and Foxp3+ Treg were located primarily within these isolated lymphoid follicles. Conclusion: A bronchial network of dendritic cells and macrophages develops quite rapidly after birth, apparently independent of clinical symptoms or atopy. The high frequency of BALT structures containing putative tolerogenic dendritic cells and Treg suggests that these lymphoid follicles play an important role in bronchial immune homeostasis during infancy.

Acute childhood asthma in Finland:A retrospective review of hospital admissions from 1976 to 1995

The prevalence of childhood asthma has increased markedly in many Western societies during recent decades. We wanted to study whether the incidence and severity of childhood asthma in Finland had changed during the time‐period 1976–95. Hospital admission rates from 1976 to 1995 were obtained from the National Hospital Discharge Register and the individual intensive care unit (ICU) registers of the five university hospitals in Finland. The number and length of treatment periods for childhood asthma in all Finnish hospitals and at the ICUs of the five university hospitals were analyzed. The number of children receiving special reimbursement for asthma medication costs was obtained from the central register of the Social Insurance Institution. The data showed that during the time‐period investigated, hospital admissions as a result of asthma had increased by 2.8‐fold, but the mean length of hospital stay had more than halved (from 7.3 to 2.6 days). The increase in hospital admissions showed greatest significance in the 0–4‐year age‐group among both sexes (p < 0.001). In contrast, a significant reduction in hospital admissions was found among the 10–14‐year age‐group (p < 0.001). No discernible change in admission to ICUs was seen. During the same time‐period, the number of children receiving special reimbursement for asthma medication costs increased 7.5‐fold. Hence, a major increase has occured in the number of children diagnosed with asthma that has not been paralleled by a proportionate increase in the number of hospital admissions. While the prevalence of mild and moderate asthma has increased, the occurrence of severe asthma has remained essentially unchanged.

Remodeling, inflammation and airway responsiveness in early childhood asthma.

Purpose of reviewRemodeling and inflammation together with airway hyperresponsiveness are essential components of asthma but their role in development of the disease is still obscure. Recent findingsRecent data imply that remodeling can occur early in childhood, not necessarily subsequent to but rather, in parallel with inflammation. The assumption of thickening of the reticular basement membrane being a prerequirement for chronic asthma is questioned but development of airway responsiveness is a significant factor. Airway responsiveness is at least partially linked to bronchial inflammation but there are several other genes and pathways regulating airway responsiveness. Increased airway smooth muscle in early childhood is associated with later development of asthma and may be one link between inflammation and airway responsiveness. Novel findings on genetic variation in genes regulating lung growth and remodeling in early childhood shed light on the pathophysiological mechanisms leading to chronic asthma. SummaryEven young children with chronic asthma have detectable elements of airway remodeling, inflammation and increased airway responsiveness, which all contribute to impaired lung function.

Characterisation of bronchus-associated lymphoid tissue and antigen-presenting cells in central airway mucosa of children

Background Childhood represents an immunological window of vulnerability in which individuals are at increased risk for both serious infections and development of allergic diseases, particularly affecting the airways. However, little is known about how the airway mucosal immune system is organised and functions during early age. Here, the organisation of immune cells in bronchial mucosa of children was characterised. Methods Immunophenotyping was performed on mucosal samples obtained postmortem from nine children aged 2–15 years without any history of atopic manifestations or any signs of respiratory disease, who died from non-inflammatory causes. Results In all nine cases, isolated lymphoid follicles (ILFs), interpreted as bronchus-associated lymphoid tissue (BALT), were found, constituting an average frequency of 60 ILFs/cm2 of airway mucosal surface. Outside these ILFs, dense networks of CD11c+ myeloid dendritic cells (DCs), CD68+ macrophages and CD3+CD45RA− memory T cells were found. Plasmacytoid DCs occurred in low numbers. Importantly, intraepithelial antigen-presenting cells were found to extend cellular projections into the airway lumen. Conclusion The density and location of antigen-presenting cells and T cells in this age group are similar to those observed in adults. However, in contrast to adults, BALT appears to be a normal feature of the airway mucosa throughout childhood, suggesting that these structures contribute to regional immunity and homeostasis. This indicates that the local immune system in the airways of children has unique features which should be taken into account, not only when studying airway immunology and immunopathology, but also in the development of mucosal vaccines.

Neuroendocrine cell hyperplasia of infancy: a prospective follow-up of nine children

Neuroendocrine cell hyperplasia of infancy (NEHI) has recently been described as an obstructive airway disease that affects infants aged 1–24 months, and presents typically with tachypnoea, crackles and hypoxia. The pathogenesis of the disease is unknown. We describe the clinical course of nine infants with radiologically and histologically confirmed NEHI. Host or environmental factors were not associated with the disease development. All infants with lung function tests demonstrated findings consistent with severe irreversible peripheral airway obstruction, assessed with whole body plethysmography (6/6) or the rapid thoracoabdominal compression technique (5/5). While the symptoms abated in all infants, six infants developed a non-atopic asthma during the follow-up. Systemic or inhaled corticosteroid treatment did not affect the duration of the symptoms. NEHI may mimic severe asthma and thus this entity should be taken into account when evaluating infants with chronic respiratory symptoms.

Airway responsiveness: associated features in infants with recurrent respiratory symptoms

Increased airway responsiveness (AR) is one of the main pathophysiological manifestations of asthma. The present study aimed to define the clinical features associated with increased AR in infants with recurrent lower respiratory tract symptoms. AR was evaluated by performing a novel dosimetric methacholine challenge test. Increased AR to methacholine, defined as a methacholine dose of ≤0.90 mg producing a 40% fall (PD40) in the maximal flow at functional residual capacity (V′max,FRC), was associated with atopy (odds ratio (OR) 4.1; 95% confidence interval (CI) 1.3–13.3), a history of physician-confirmed wheezing with respiratory syncytial virus (OR 32.9; 95% CI 2.5–428.8) or of a nonspecified aetiology (OR 4.9; 95% CI 1.1–22.5), functional residual capacity z-score ≥2 (OR 36.8; 95% CI 2.9–472.6), and V′max,FRC z-score (OR 0.5; 95% CI 0.2–0.9) at baseline, when compared with infants with only mild or no responsiveness to methacholine (PD40 V′max,FRC >0.90 mg). In conclusion, in recurrently symptomatic infants, increased airway responsiveness is associated with reduced baseline lung function, an atopic trait of the child, a history of physician-confirmed wheeze and viral aetiology of wheeze. Future intervention studies are needed to confirm the role of airway responsiveness in respiratory morbidity during infancy.