Development Of Bronchial Hyperreactivity Research Articles

Beyond forced exhalation: impulse oscillometry as a promising tool for bronchial hyperresponsiveness evaluation

Introduction: The multiple forced expiratory maneuvers that must be performed during methacholine test require a high degree of collaboration and can lead to fatigue. However, impulse oscillometry (IOS) is a noninvasive test, quick and easy to perform, that does not require effort-dependent maneuvers. Objectives: The primary endpoint was to evaluate the relationship between IOS and spirometry during the methacholine test. The secondary endpoint was to study the predictive value of baseline IOS in the development of bronchial hyperreactivity. Methods: Observational, prospective, cross-sectional study, with recruitment of consecutive patients from the pulmonology department with clinical suspicion of bronchial asthma with negative bronchodilator test and normal FeNO. Results: Twenty-five patients were included, with a mean age of 49 ± 18 years. Thirteen patients (52%) had a positive methacholine test. The correlation between IOS indices and FEV1 was significant (p < 0.05) in all cases. The indices with the highest predictive power were R5-20 and AX. The optimal cutoff points were an increase of greater than 32.96% in R5, greater than 120.83% for X5, an increase of 30.30 [kPa l-1s-1] in R5-20, and an increase of 1.01 [kPa l−1] for AX. Baseline oscillometry demonstrated a strong predictive value in the development of bronchial hyperreactivity, with a sensitivity of 61.5% and a specificity of 91.7%, using the cut-off point of 160.0% for R5. Conclusions: IOS may be a valuable alternative to forced spirometry in detecting bronchial hyperreactivity during the methacholine test, showing a good correlation between both tests.

Changes in the cellular composition of guinea pig’s distal airways epithelium in the dynamics of experimental ovalbumin-induced allergic inflammation

The problem of studying the processes of restructuring of airways epithelium of humans and animals of adaptive nature under the influence of various factors on the body remains the subject of scientific discussions. The aim of this work is to study morphometric changes in the cellular composition guinea pig’s distal airways epithelium in the dynamics of experimental ovalbumin-induced allergic inflammation. We studied lung of 48 male guinea pigs, using histological, morphometric and statistical methods, under conditions of experimental ovalbumin-induced allergic inflammation, simulated by subcutaneous sensitization and subsequent intranasal inhalation with ovalbumin. The average number of epithelial cells of small bronchi and terminal bronchioles was determined: basal epithelium cells, ciliated cells, goblet cells and exocrine bronchiolar cells per unit area of 10000 μm2. We have shown the most significant reactive morphometric changes on the 23rd and 30th days of the experiment. We demonstrated a decrease of the number of basal cells (by 1.5 times compared to the control, p*/**&lt;0.01) and ciliated cells (by 1.6 times compared to the control, p*/**&lt;0.001) and an elevation of the average number of goblet cells (by 2.6 times compared to the control, p*/**&lt;0.01) in bronchioles, a decrease of the average number of exocrine bronchiolar cells (by 1.6 times compared to the control, p*/**&lt;0.01) in terminal bronchioles. These changes are the morphological confirmation of the development of bronchial hyperreactivity as a result of the action of the allergen. Sensitization and allergization with ovalbumin cause statistically significant morphological changes in the cellular composition of small bronchi and terminal bronchioles of an alterative nature in the early period and adaptive – in the late period of allergic inflammation, corresponding to the main morphological manifestations of allergic inflammation.

Hyperreactivity of the bronchi in children, whooping cough convalescents

Objective:to assess the presence and degree of bronchial hyperreactivity in convalescents of whooping cough based on the results of bronchial provocation tests.Materials and methods. Using bronchial provocative samples with a 0,02/0,33% histamine solution and 0,33% methacholine solution on a PROVOTEST-2 apparatus from PARI, bronchial hyperreactivity was studied in 12 pertussis convalescents aged 7 to 17 years. The level of endogenous nitrogen monoxide in exhaled air (FeNO) was measured using a portable NObreath electrochemical analyzer (from Bedfont Scientific Ltd.).The results.According to the results of BPP, 6 of 12 convalescents of whooping cough were found to have bronchial hyperreactivity of varying degrees. When conducting a breath test with a histamine solution, bronchial hyperreactivity was recorded in three children, in a sample with methacholine, in five. In 3 out of 6 children with revealed signs of bronchial hyperreactivity, the history of atopy was not burdened, which suggests a connection between the pertussis and the development of bronchial hyperreactivity. A significant increase in the level of endogenous nitric monoxide (above 16 ppb) was observed in 2 out of 10 patients. Follow-up observation showed that the duration of cough with whooping cough ranged from 3 to 6 months, and in patients with positive results of several tests it was maximum. Two out of three children with bronchial asthma showed elevated levels of FeNO and samples with methacholine. Follow-up observation showed that whooping cough aggravated bronchial asthma and demanded correction therapy.Conclusion. A pilot study on the evaluation of bronchial provocative tests suggests that the formation of bronchial hyperreactivity in convalescents of whooping cough is probable, including without a history of atopy, which increases the risk of developing bronchial asthma, however, additional studies are required for a final conclusion.

Модель нейтрофильной бронхиальной астмы у мышей как инструмент для тестирования персонализированных лекарственных средств

Bronchial asthma is a chronic inflammatory disease of the respiratory tract characterized by reversible bronchial obstruction and bronchial hyperreactivity. The neutrophilic endotype of bronchial asthma is associated with an aggressive course of the disease, severe tissue destruction and a low response to standard corticosteroid therapy. All of the above indicates the need to create new drugs for the treatment of neutrophilic asthma, which requires adequate animal models of this disease. We have proposed a protocol for the induction of experimental neutrophilic bronchial asthma in mice, which includes intraperitoneal immunization with a mixture of a model allergen of ovalbumin and Freund's adjuvant followed by aerosol challenge with the same allergen mixed with the lipopolysaccharide. This approach made it possible to reproduce the main manifestations of neutrophilic bronchial asthma: the production of IgE allergen-specific antibodies, the development of bronchial hyperreactivity, respiratory tract remodeling and the lung tissue infiltration with neutrophils. bronchial asthma, murine model, neutrophils The work was supported by the Grant of the President of the Russian Federation (no. MD-1578.2019.4).

Respiratory syncytial virus infection and bronchial hyperreactivity in children up to two years of age in correlation with atopy.

Bronchiolitis in early childhood caused by respiratory syncytial virus (RSV) is considered to be important risk factor of the recurrent wheezing and asthma development. The aim of this study was to examine the frequency of RSV infection and atopy in children up to two years of age and to determine their correlation with bronchial hyperreactivity. The study included 175 children aged 5-24 months. The presence of RSV infection was identified by serum levels of IgA and IgG determined by ELISA. Bronchial hyperreactivity (BHR) has been defined as the existence of chronic bronchial disease and/or three or more previous suspected diagnosis of acute bronchial disease. Atopy was confirmed by detection of the specific serum IgE using quantitative multitest Phadiatop infant (cut off 0.35 kUA/L). The children with atopy were more frequently infected with RSV (43.3%) than those without atopy (22.8%; p = 0.02). The higher frequency of RSV infection was found in children with BHR in comparison with those without it but only in the group who also had atopy (77.8% vs. 28.6%, p = 0.018). In the female children, BHR and RSV infection were associated in 62.5% of cases, regardless the atopy. In the male children with atopy, RSV infection was associated with BHR in 83.3% of the cases, while in those without atopy, RSV infection with BHR was found in only 17.4% of the cases. Children up to two years of age with atopy are more frequently infected with RSV (43.3%) than nonatopic children. Every third child with atopy develops BHR and 77.8% of them also have RSV infection. Atopic children are at higher risk for development of BHR when infected with RSV also.

Prevention of hyperoxia-induced bronchial hyperreactivity by sildenafil and vasoactive intestinal peptide: impact of preserved lung function and structure.

ObjectiveHyperoxia exposure leads to the development of lung injury and bronchial hyperreactivity (BHR) via involvement of nitric oxide (NO) pathway. We aimed at characterizing whether the stimulation of the NO pathway by sildenafil or vasoactive intestinal peptide (VIP) is able to prevent the hyperoxia-induced development of BHR. The respective roles of the preserved lung volume and alveolar architecture, the anti-inflammatory and anti-apoptotic potentials of these treatments in the diminished lung responsiveness were also characterized.Materials and methodsImmature (28-day-old) rats were exposed for 72 hours to room air (Group C), hyperoxia (>95%, Group HC), or hyperoxia with the concomitant administration of vasoactive intestinal peptide (VIP, Group HV) or sildenafil (Group HS). Following exposure, the end-expiratory lung volume (EELV) was assessed plethysmographically. Airway and respiratory tissue mechanics were measured under baseline conditions and following incremental doses of methacholine to assess BHR. Inflammation was assessed by analyzing the bronchoalveolar lavage fluid (BALF), while biochemical and histological analyses were used to characterize the apoptotic and structural changes in the lungs.ResultsThe BHR, the increased EELV, the aberrant alveolarization, and the infiltration of inflammatory cells into the BALF that developed in Group HC were all suppressed significantly by VIP or sildenafil treatment. The number of apoptotic cells increased significantly in Group HC, with no evidence of statistically significant effects on this adverse change in Groups HS and HV.ConclusionsThese findings suggest that stimulating the NO pathway by sildenafil and VIP exert their beneficial effect against hyperoxia-induced BHR via preserving normal EELV, inhibiting airway inflammation and preserving the physiological lung structure, whereas the antiapoptotic potential of these treatments were not apparent in this process.

Prevention of airway hyperresponsiveness induced by left ventricular dysfunction in rats

BackgroundThe effectiveness of strategies for treatment of the altered static lung volume and against the development of bronchial hyperreactivity (BHR) following a left ventricular dysfunction (LVD) induced by myocardial ischaemia was investigated in a rat model of sustained postcapillary pulmonary hypertension.MethodsAirway resistance (Raw) was identified from the respiratory system input impedance (Zrs) in four groups of rats. End-expiratory lung volume (EELV) was determined plethysmographically, and Zrs was measured under baseline conditions and following iv infusions of 2, 6 or 18 μg/kg/min methacholine. Sham surgery was performed in the rats in Group C, while the left interventricular coronary artery was ligated and Zrs and its changes following identical methacholine challenges were reassessed in the same rats 8 weeks later, during which no treatment was applied (Group I), or the animals were treated daily with a combination of an angiotensin enzyme converter inhibitor and a diuretic (enalapril and furosemide, Group IE), or a calcium channel blocker (diltiazem, Group ID). The equivalent dose of methacholine causing a 100% increase in Raw (ED50) was determined in each group. Diastolic pulmonary arterial pressure (PapD) was assessed by introducing a catheter into the pulmonary artery.ResultsThe sustained presence of a LVD increased PapD in all groups of rats, with variable but significant elevations in Groups I (p = 0.004), ID (p = 0.013) and IE (p = 0.006). A LVD for 8 weeks induced no changes in baseline Raw but elevated the EELV independently of the treatments. In Group I, BHR consistently developed following the LVD, with a significant decrease in ED50 from 10.0 ± 2.5 to 6.9 ± 2.5 μg/kg/min (p = 0.006). The BHR was completely abolished in both Groups ID and IE, with no changes in ED50 (9.5 ± 3.6 vs. 10.7 ± 4.7, p = 0.33 and 10.6 ± 2.1 vs. 9.8 ± 3.5 μg/kg/min p = 0.56, respectively).ConclusionsThese findings suggest that a LVD following coronary ischaemia consistently induces BHR. The more consistent efficacy of both treatment strategies in preventing BHR than in treating the adverse pulmonary vascular consequences suggests the benefit of both calcium channel blockade and ACE inhibition to counteract the airway susceptibility following a LVD.

Prevention of bronchial hyperreactivity in a rat model of precapillary pulmonary hypertension

BackgroundThe development of bronchial hyperreactivity (BHR) subsequent to precapillary pulmonary hypertension (PHT) was prevented by acting on the major signalling pathways (endothelin, nitric oxide, vasoactive intestine peptide (VIP) and prostacyclin) involved in the control of the pulmonary vascular and bronchial tones.MethodsFive groups of rats underwent surgery to prepare an aorta-caval shunt (ACS) to induce sustained precapillary PHT for 4 weeks. During this period, no treatment was applied in one group (ACS controls), while the other groups were pretreated with VIP, iloprost, tezosentan via an intraperitoneally implemented osmotic pump, or by orally administered sildenafil. An additional group underwent sham surgery. Four weeks later, the lung responsiveness to increasing doses of an intravenous infusion of methacholine (2, 4, 8 12 and 24 μg/kg/min) was determined by using the forced oscillation technique to assess the airway resistance (Raw).ResultsBHR developed in the untreated rats, as reflected by a significant decrease in ED50, the equivalent dose of methacholine required to cause a 50% increase in Raw. All drugs tested prevented the development of BHR, iloprost being the most effective in reducing both the systolic pulmonary arterial pressure (Ppa; 28%, p = 0.035) and BHR (ED50 = 9.9 ± 1.7 vs. 43 ± 11 μg/kg in ACS control and iloprost-treated rats, respectively, p = 0.008). Significant correlations were found between the levels of Ppa and ED50 (R = -0.59, p = 0.016), indicating that mechanical interdependence is primarily responsible for the development of BHR.ConclusionsThe efficiency of such treatment demonstrates that re-establishment of the balance of constrictor/dilator mediators via various signalling pathways involved in PHT is of potential benefit for the avoidance of the development of BHR.

Concentrations of plasminogen activator inhibitor-1 (PAI-1) and urokinase plasminogen activator (uPA) in induced sputum of asthma patients after allergen challenge.

Urokinase plasminogen activator (uPA) and its inhibitor (PAI-1) are involved in tiisue remodeling and repair processes associated with acute and chronic inflammation. The aim of the study was to evaluate the effect of allergen challenge on concentration of uPA and PAI-1 in induced sputum of house dust mite allergic asthmatics (HDM-AAs). Thirty HDM-AAs and ten healthy persons (HCs)were recruited for the study. In 24 HDM-AAs bronchial challenge with Dermatophagoides pteronyssinus (Dp) and in 6 HDM-AAs sham challenege with saline were performed. In HDM-AAs sputum was induced 24 hours before (T0) and 24 hours (T24) after the challenge. Concentration of uPA and PAI-1 in induced sputum were determined using immunoenzymatic assays. At T0 in HDM-AAs mean sputum uPA (151 ± 96 pg/ml) and PAI-1 (4341 ± 1262 pg/ml) concentrations were higher than in HC (18.8 ± 6.7 pg/ml; p=0.0002 and 596 ± 180 pg/ml; p<0.0001; for uPA and PAI-1 respectively). After allergen challenge further increase in sputum uPA (187 ± 144 pg/ml; p=0.03) and PAI-1 (6252 ± 2323 pg/ml; p<0.0001) concentrations were observed. Moreover, in Dp challenged, but not in saline challenged HDM-AAs the mean uPA/PAI-1 ratio decreased significantly at T24. No significant increase in the studied parameters were found in sham challenged patients. In HDM-AAs allergen exposure leads to activation of the plasmin system in the airways. Greater increase of the PAI-1 concentration than uPA concentration after allergen challenge may promote airway remodeling and play an important role in the development of bronchial hyperreactivity.

Airway responsiveness and bronchoalveolar lavage fluid profiling in individual rats: Effects of different ovalbumin exposures

We studied repeatedly the development of bronchial hyperreactivity (BHR) and bronchoalveolar lavage fluid (BALF) in rats undergoing different modes of ovalbumin exposures. Treatment was two intraperitoneal injections of ovalbumin in Groups 1-3, followed by one ovalbumin aerosolization in Groups 2 and 3, while rats in Group 4 received repeated ovalbumin aerosols after one single intraperitoneal injection. BHR was assessed longitudinally on day 0 (before treatment) and on day 14 (Groups 1 and 2) or 20 (Groups 3 and 4) and cellular influx was estimated from BALF. No BHR or change in BALF cellular profile was detected in Groups 1-3. However, the infiltration of inflammatory cells, associated with BHR (PC(100) 8.9+/-1.3 microg/kg vs. 4.2+/-1.1 microg/kg), was observed in Group 4. The BHR was always associated with increased number of eosinophils in the BALF. The substantial interindividual variability confirmed the need for a technique that permits follow-up of lung responsiveness and BALF profile. This approach evidenced strong associations between the severity of BHR and the eosinophilia.

Mechanical ventilation with high tidal volume or frequency is associated with increased expression of nerve growth factor and its receptor in rabbit lungs

Nerve growth factor (NGF), a neurotrophin, is induced in lung cells by proinflammatory cytokines, and has a role in bronchial hyperreactivity and lung tissue repair. Ventilation induced lung injury, on the other hand, is known to increase the levels of proinflammatory cytokines in the lungs. We investigated whether, and to what extent, various degrees of lung injury induced by short-term ventilation affect NGF levels in the lung tissue of adolescent rabbits. The rabbits were randomized to different modes of ventilation: (1) CON: normal ventilation for 30 min; (2) NVT: normal ventilation for 6 hr; (3) HFQ: ventilation for 6 hr at double frequency, but normal tidal volume (VT); and (4) HVT: 6 hr ventilation at double VT but normal frequency. NGF protein was detected in bronchoalveolar lavage fluid (BALF) and lung tissue in all animals. Ventilation for 6 hr significantly increased NGF levels, in both BALF and lung tissue, in the HFQ and HVT groups as compared to control (P < 0.05). The maximum increase in BALF NGF was seen in the HVT group (P = 0.02 vs. CON and NVT groups, and P = 0.05 vs. HFQ). A parallel increase in interleukin 1-beta (IL1-beta) was observed. Expression of the high-affinity NGF-receptor, tropomyosin-related kinase A (TrkA), was also upregulated in these two groups. Injurious modes of mechanical ventilation upregulate NGF and its receptor TrkA in rabbit lungs, and IL1-beta may be a mediator for this response. We speculate that this increase in NGF level may translate into the development of bronchial hyperreactivity.

Mechanisms of airway hyper-responsiveness after coronary ischemia

We explored the consequences of myocardial ischemia (MI) on the lung responsiveness and identified the pathophysiological mechanisms involved. Airway resistance (R(aw)) was identified from the respiratory system input impedance (Z(rs)) in rats. Z(rs) was determined under baseline conditions, and following iv boluses of 20 and 30 microg/kg serotonin. MI was then induced in the animals in Group I by ligating the left-interventricular coronary artery, while rats in Group C underwent sham surgery. Four weeks later, baseline Z(rs) and its changes following serotonin administration were reassessed. Lung morphological changes were assessed by histology, and alpha smooth muscle actin cells (alpha-SMA) were identified. MI induced no changes in baseline R(aw) but led to bronchial hyper-reactivity (BHR) with 2.7+/-0.5-times (p<0.05) greater responses in R(aw) to 30 microg/kg serotonin. Perivascular edema and alpha-SMA cell proliferation were observed after MI. The development of BHR following MI is a consequence of the expression of alpha-SMA, while the geometrical alterations caused by the pulmonary vascular engorgement have smaller impact.

Infection by Ascaris lumbricoides and bronchial hyper reactivity: An outstanding association in Venezuelan school children from endemic areas

Asthma and other respiratory diseases have increased in the last years among Venezuelan children from helminthic endemic areas where the infection by Ascaris lumbricoides has been associated to bronchial airway inflammation in parasitized individuals. The aim of this work was to investigate the possible associations between the development of bronchial hyper reactivity and the immune response against A. lumbricoides in urban and rural children. We evaluated 470 school children from rural and urban communities. Pulmonary function tests were performed and ≥20% PC 20 changes were considered as a positive diagnostic of bronchial hyper reactivity. The prevalence and intensity of A. lumbricoides infection was determined by faecal examination. Specific serum IgE levels using a modified ELISA and skin prick tests against A. lumbricoides and the common allergen Dermatophagoides pteronyssinus were done. The number of circulating lymphocyte sub populations was determined by flow cytometry analysis. In rural children, bronchial hyper reactivity was associated with increased specific levels of anti- A. lumbricoides IgE ( p < 0.0001) and skin test positivity for A. lumbricoides ( p < 0.0001). The percentage of FEV1 predictive values correlated inversely ( p < 0.0001) with anti- A. lumbricoides IgE levels. Elevated numbers of circulating CD3+CD4+ and CD20+CD23+ cells were found in rural children with bronchial hyper reactivity compared to their asymptomatic counterparts. They correlated positively with anti- A. lumbricoides IgE levels ( p < 0.005 and < 0.0001, respectively). In contrast, in urban children, bronchial hyper reactivity was associated with elevated anti- D. pteronyssinus IgE levels ( p = 0. 0089), skin hyper reactivity towards this aero allergen ( p = 0.003) and to an increase in the number of CD3+CD8+ ( p < 0.0001). Our results suggest that the IgE response against A. lumbricoides infection may be involved in the development of bronchial hyper reactivity among rural children from endemic areas and also that improved hygienic conditions in the urban environment is associated with increased responses to airborne allergens.

Plasminogen Activator Inhibitor-1 Plasma Concentration in Allergic Asthma Patients during Allergen Challenge

Background: The –675 4G/5G plasminogen activator inhibitor-1 (PAI-1) polymorphism is linked with asthma and bronchial hyperreactivity. The aim of this study was to evaluate the effect of allergen challenge on plasma PAI-1 concentration in relation to the –675 4G/5G PAI-1 gene polymorphism in house dust mite-allergic asthma patients (HDM-AAs). Materials and Methods: The study was performed in 54 HDM-AAs and 54 healthy nonatopic controls (HCs). Plasma samples were collected in HDM-AAs before, as well as 30 min, 6 h and 24 h after allergen challenge and at corresponding time points in sham-challenged HCs. Results: In subjects carrying the individual PAI-1 genotype, the mean baseline plasma PAI-1 concentration was greater in HDM-AAs than in HCs. At 30 min the mean increase in plasma PAI-1 concentration was significantly greater in HDM-AAs (14.4 ± 12.9 ng/ml) than in HCs (3.4 ± 3.2 ng/ml; p < 0.001). At 6 h, plasma PAI-1 concentration greater than before challenge was found in only 4 HCs (7.4%) but in 48 HDM-AAs (88.9%; p < 0.0001). An increase in plasma PAI-1 concentration at 6 h was found in all HDM-AAs carrying the 4G allele but only in 33.3% of the 5G homozygotes (p < 0.0001). The strongest correlation was found between log PC₂₀ and PAI-1 plasma concentration over the period of 24 h (r = –0.507; p = 0.0001). Conclusion: Changes in plasma PAI-1 concentration associated with allergen-induced bronchoconstriction are modulated by the –675 4G/5G polymorphism of the PAI-1 gene. Allergen-induced upregulation of PAI-1 synthesis may participate in the development of bronchial hyperreactivity in HDM-AAs.

Evaluation of the intraoesophageal pH patterns in patients with bronchial hyperreactivity (BHR)

Aims: Gastroesophageal reflux (GER) is considered a significant pathogenetical factor in the development of BHR. The aim of the study was to evaluate the intraoesophageal pH patterns in patients with BHR. Patients and methods: 43 consecutive patients (M/F 12/31) with recent diagnosis of BHR were prospectively studied. 20 patients with chronic cough, but without BHR were evaluated as controls. Patients were all submitted to reflux symptom analysis, upper gastrointestinal endoscopy, oesophageal manometry, and Bernstein-test. Proximal GER reflux was established by double channel intraoesophageal pH monitoring. The presence of oesophago-bronchial reflux (OBR) was studied by combined oesophageal acid (0.1N HCl) perfusion and metacholine test. Results: The studied patient groups had similar age, BMI, male-female ratio and were identical regarding their smoking habits. The prevalence of reflux and respiratory symptoms, the baseline lung function, the manometric parameters, the acid sensitivity and the endoscopic appearance of the oesophagus were not different. The double channel pH monitoring showed that patients with BHR had significantly more proximal acid reflux, than controls. On the contrary, similar pH patterns were observed in the distal oesophagus. The patient group with BHR was subdivided on the basis of the presence of OBR. Patients with OBR positivity were more likely to have an acid sensitive oesophagus and had more acid reflux – especially in the supine period – at the distal measurement point. Other studied parameters were not different. Conclusions: Proximal acid reflux may have a greater role in the development of BHR, than in chronic cough. The increased amount of supine acid reflux in patients with OBR positivity may indicate, that the effectiveness of the night time acid suppressive therapy can be important for the attenuation of the reflux to achieve clinical improvement.

Respiratory syncytial virus: the virus, the disease and the immune response.

RSV is the primary cause of hospitalisation in the first year of life for children in most parts of the world, and nearly 100% of children in the USA are infected with the virus by 2 to 3 years of age. The agent is an enveloped RNA virus with a non-segmented single-stranded negative-sense genome. The viral genome encodes 8 structural and 2 non-structural proteins. Important structural proteins include the fusion (F) protein and the attachment (G) protein which are essential for viral penetration and attachment to the host cells. Both proteins are important in development of immune responses. The virus is estimated to cause 3000 to 4000 deaths annually. Primary infections are as a rule symptomatic. The spectrum of clinical manifestations ranges from mild upper tract illness, infection in middle ear which progresses to acute otitis media, croup, to apnoea in premature infants, pneumonia and bronchiolitis. Premature babies born at 30–35 weeks of gestation, infants with cyanotic congenital heart disease, HIV-infected subjects, and patients on intensive immunosuppressive therapy especially after bone marrow transplant are considered to be at risk for increased mortality and morbidity during RSV infection. The virus does not normally replicate outside of the bronchopulmonary tree and the infection is exquisitely restricted to the respiratory mucosa. However, development of extrapulmonary disease has been observed in certain T and B cell immunodeficiency states. The association of RSV with asthma and reversible reactive airway disease in early childhood has attracted significant attention. Recurrent wheezing for up to 5 to 7 years of age and established airway disease has been observed in a significant number of children with a strong family history of allergy, after primary infection or reinfection with RSV. Immune response to primary infection is relatively small but on reinfection, a significant booster effect with sustained immunologic reactivity is observed in serum and respiratory mucosa. Both CD4- and CD8-specific as well as Th1- and Th2-cell specific immune responses have been observed during human infection. In addition, proinflammatory as well as immunoregulatory cytokines and chemokines are induced in the respiratory tract after natural and induced (in vitro) infection. Significant progress has been made in understanding the role of Th1 vs. Th2, IgE, viral induced cytokines and chemokines in the mechanisms of pathogenesis of the disease, development of wheezing and in the prevention and treatment of the infection and its sequelae. Respiratory syncytial virus (RSV) is one of the commonest human viral infections, and virtually every child is infected by the third birthday. Because of its restricted mucosal immunopathology, and frequent association with bronchial hyperreactivity and development of wheezing, RSV has served as an important model to investigate mechanisms of mucosal immune responses and development of mucosal disease following infection. The importance of RSV in bronchopulmonary disease and development of bronchial hyperreactivity has been the focus of several recent symposia [Kimpen JL, Simoes EAF. Am J Respir Crit Care Med 2001; 163:S1–S6]. This brief report will only summarise, based on selected references, the historical landmarks of its discovery and current understanding of the mechanisms of immunity, and their possible role in the pathogenesis of bronchopulmonary disease.

Lung CD25 CD4 regulatory T cells suppress type 2 immune responses but not bronchial hyperreactivity.

To study the effects of chronic Ag deposition in the airway mucosa on CD4(+) T cell priming and subsequent airway disease, transgenic mice were generated that expressed OVA under the control of the surfactant protein C promoter. CD4 T cells from these mice were tolerant to OVA but this was overcome among spleen CD4 T cells by crossing to OVA-specific DO11.10 TCR-transgenic mice. Lungs from the double-transgenic mice developed lymphocytic infiltrates and modest mucus cell hyperplasia. Infiltrating cells were unaffected by the absence of either Rag-1 or Stat6, although the latter deficiency led to the disappearance of mucus. In the lung of double-transgenic mice, a large number of Ag-specific CD4 T cells expressed CD25 and functioned as regulatory T cells. The CD25(+) CD4 T cells suppressed proliferation of CD25(-) CD4 T cells in vitro and inhibited type 2 immune responses induced by aerosolized Ags in vivo. Despite their ability to suppress allergic type 2 immunity in the airways, however, CD25(+) CD4 regulatory T cells had no effect on the development of bronchial hyperreactivity.

Molecular and cellular mechanisms of allergic disease

The molecular and cellular mechanisms mediating the allergic inflammatory cascade involve multiple mediators, cell types, and pathways. Of particular interest are the pathways regulated by the T H2 lymphocyte, which result in release of IL-4 (important to IgE synthesis) and IL-5 (important to eosinophil proliferation). IL-4 regulates differentiation of naïve T H0 cells to develop a T H2 phenotype and stimulates B cells to produce IgE. Cross-linking by allergen of IgE affixed to high-affinity receptors on mast cells and basophils triggers degranulation and the release of preformed inflammatory mediators (important to the early phase response), and subsequently initiates synthesis and the release of lipid mediators and cytokines (which may contribute to the late phase response). Eosinophils may also play a prominent role in the development of bronchial hyperreactivity. IL-5, which is a lineage-specific eosinophil growth factor, increases the formation of eosinophils from progenitor cells and, in concert with CCR3 active chemokines, increases their trafficking to sites of allergic inflammation. An improved understanding of the basic mechanisms of allergic inflammation has led to the discovery of molecular targets involved in the initial events of the inflammatory cascade. Potential targets for the development of novel therapies for allergic disease include IgE, the T H2 lymphocyte, and T H2–derived cytokines, IL-4 and IL-5. (J Allergy Clin Immunol 2001;108:S65-71.)

Eosinophil activity markers in peripheral blood have high predictive value for bronchial hyperreactivity in patients with suspected mild asthma.

The present study aimed to evaluate the predictive value of eosinophils and markers of their activity for bronchial hyperreactivity (BHR) in a population of patients with recently developed clinical symptoms of asthma. The activation of eosinophils was estimated by measuring eosinophil cationic protein (ECP) in serum. In addition, flow cytometry was used to measure the expression of the EG2-epitope on intracellular ECP in eosinophils from peripheral blood. Twenty-eight consecutive patients with clinical history of asthma were studied. Of the 28 patients, 18 had a positive bronchial challenge test measured as PD20 < or = 1600 micrograms histamine. A significantly higher concentration of eosinophils and a trend to higher ECP in the peripheral blood was found in the hyperreactive group than in the nonreactive group. However, the intracellular expression of ECP did not correlate with the PD20 value, and no significant difference between the groups was found. With one eosinophil activity marker, either serum ECP or EG2, BHR could be predicted in 70% of the patients. If we combined any two of the activity markers (serum ECP, EG2, or the percentage of eosinophils), the predictive value increased to 100%. We conclude that the blood eosinophil concentration, as well as, to some extent, serum ECP, has a high specificity for BHR in patients with recently developed clinical symptoms of asthma. Despite normal bronchial reactivity, some patients had signs of activated eosinophils, i.e., high serum ECP and increased EG2 expression. Thus, these markers may reflect early stages in the development of BHR. Our results also indicate that a combined evaluation of percentage of eosinophils and of eosinophil activity markers is of clinical value to predict BHR.

Development of bronchial hyperreactivity following transient absence of salivary IgA.

In a birth cohort of 114 normal children, this study examined the hypothesis that a transient absence of salivary IgA in the first year of life was associated with an increased risk of developing atopy, asthma, or bronchial hyperreactivity (BHR) later in life. Episodes of transient absence of IgA in saliva, of less than 1 mo, occurred in 18% of the study population in the first year of life. The children were assessed at age 7.5 to 12 yr for the presence of atopy (skin prick test to inhaled allergens), asthma (wheeze in the previous 12 mo), and BHR (histamine provocation). The transient absence of salivary IgA in the first year of life was associated with an increased risk of BHR (adjusted odds ratio [Adj OR]: 11.6; 95% confidence interval [CI]: 2.2 to 60.9) and a trend toward a lowered risk of atopy to inhaled allergens (raw OR: 0.35; CI: 0.11 to 1.11). There was no relationship between the transient absence of salivary IgA and a clinical diagnosis of asthma (Adj OR: 0.9; CI: 0.2 to 3.6). The inconsistency in the relationships between the transient absence of salivary IgA and atopy, asthma, and BHR supports the concept that atopy, wheeze, and bronchial hyperreactivity are independent clinical outcomes. One possible explanation for the relationships observed in this study is that the transient absence of IgA in saliva in the first year of life identifies a cohort with mucosal hypoimmunity. These subjects are thus less likely to develop atopy and less able to effectively respond to a mucosal infection. Presentation of a mucosal antigen in these subjects may subsequently be associated with an inappropriate inflammatory response, which conditions bronchial hyperreactivity, and which is independent of atopy.