Reticulation pattern without honeycombing on high-resolution CT is associated with the risk of disease progression in interstitial lung diseases.

BACKGROUND: The disease course of idiopathic pulmonary fibrosis (IPF) is progressive and occasionally, other types of interstitial lung disease (ILD) may progress similarly to IPF. This study aimed to evaluate risk factors for disease progression within 24 months in patients with various ILDs. METHODS: This prospective study obtained 97 patients with a suspected ILD who underwent a transbronchial lung cryobiopsy. The extent of several high-resolution computed tomography (HRCT) patterns was assessed. Due to the inclusion criteria the study population presented a low extent of honeycombing and definite usual interstitial pneumonia (UIP) pattern on HRCT suggesting an early stage of ILD. Disease progression within 24 months despite treatment was defined as a relative decline of ≥ 10% in forced vital capacity (FVC), or a relative decline in FVC of ≥ 5% and one of the three additional criteria: (1) a decline in diffusion capacity to carbon monoxide (DLCO) ≥ 15%; (2) increased fibrosis on HRCT; (3) progressive symptoms, or progressive symptoms and increased fibrosis on HRCT. The same definition was utilized in patients with IPF and other ILDs. Risk factors for disease progression were evaluated in a multivariable logistic regression model. RESULTS: Disease progression was revealed in 52% of the patients with ILD, 51% of the patients with IPF, and 53% of the patients with other types of ILD. A high extent of reticulation on HRCT (Odds ratio [OR] 3.11, 95% Confidence interval [CI] 1.21-7.98, P = 0.019) and never smoking (OR 3.11, CI 1.12-8.63, P = 0.029) were associated with disease progression whereas platelet count (OR 2.06 per 100 units increase, CI 0.96-4.45, P = 0.065) did not quite reach statistical significance. CONCLUSION: Higher extent of reticulation on HRCT and never smoking appeared to associate with the risk of disease progression within 24 months in ILD patients without honeycombing. Approximately half of the patients with ILD revealed disease progression, and similar proportions were observed in patients with IPF and in other types of ILD.

Risk factors of clinically significant complications in transbronchial lung cryobiopsy: A prospective multi-center study.

BACKGROUND: The use of a transbronchial lung cryobiopsy (TBLC) is increasing as a diagnostic method of interstitial lung diseases (ILD). This study aimed to evaluate risk factors associated with clinically significant complications of TBLC in ILD patients. METHODS: Patients referred to Kuopio or Tampere university hospitals, in Finland, for a suspected ILD were included. The TBLC was performed in an outpatient setting for 100 patients. Patients were mechanically ventilated in general anesthesia. Fluoroscopy guidance and prophylactic bronchial balloon were used. Complications, such as bleeding, pneumothorax, infections, and mortality were recorded. Moderate or serious bleeding, pneumothorax, or death ≤90 days were defined as clinically significant complications. A multivariable model was created to assess clinically significant complications. RESULTS: The extent of traction bronchiectasis (Odds ratio [OR] 1.30, Confidence interval [CI] 1.03-1.65, p = 0.027) and young age (OR 7.96, CI 2.32-27.3, p = 0.001) were associated with the risk of clinically significant complications whereas the use of oral corticosteroids ≤30 days before the TBLC (OR 3.65, CI 0.911-14.6, p = 0.068) did not quite reach statistical significance. A history of serious cough was associated with the risk of pneumothorax (OR 4.18, CI 1.10-16.0, p = 0.036). Procedure associated mortality ≤90 days was 1%. CONCLUSION: The extent of traction bronchiectasis on HRCT and young age were associated with the risk of clinically significant complications whereas oral corticosteroid use did not quite reach statistical significance. A history of serious cough was associated with the risk of clinically significant pneumothorax.

Single-cell characterization of dog allergen-specific T cells reveals TH2 heterogeneity in allergic individuals.

BACKGROUND: Allergen-specific type 2 CD4+ TH2 cells are critically involved in the pathogenesis of IgE-mediated allergic diseases. However, the heterogeneity of the TH2 response has only recently been appreciated. OBJECTIVE: We sought to characterize at the single-cell level the ex vivo phenotype, transcriptomic profile, and T-cell receptor (TCR) repertoire of circulating CD4+ T cells specific to the major dog allergens Can f 1, Can f 4, and Can f 5 in subjects with and without dog allergy. METHODS: Dog allergen-specific memory CD4+ T cells were detected ex vivo by flow cytometry using a CD154-based enrichment assay and single-cell sorted for targeted gene expression analysis and TCR sequencing. RESULTS: Dog allergen-specific T-cell responses in allergic subjects were dominantly of TH2 type. TH2 cells could be phenotypically further divided into 3 subsets, which consisted of TH2-like (CCR6-CXCR3-CRTH2-), TH2 (CCR6-CXCR3-CRTH2+CD161-), and TH2A (CCR6-CXCR3-CRTH2+CD161+CD27-) cells. All these subsets were nonexistent within the allergen-specific T-cell repertoire of healthy subjects. Single-cell transcriptomic profiling confirmed the TH2-biased signature in allergen-specific T cells from allergic subjects and revealed a TH1/TH17 signature in nonallergic subjects. TCR repertoire analyses showed that dog allergen-specific T cells were diverse and allergic subjects demonstrated less clonality compared to nonallergic donors. Finally, TCR and transcriptomic analyses revealed a close relationship between TH2-like, TH2, and TH2A cells, with the last ones representing the most terminally differentiated and highly polarized subtype. CONCLUSIONS: Our study demonstrates heterogeneity within allergen-specific TH2 cells at the single-cell level. The results may be utilized for improving immune monitoring after allergen immunotherapy and for designing targeted immunomodulatory approaches.

[Good specimens for the diagnosis and assessment of extent of lung cancer]. / Hyvä näytteenotto keuhkosyövän diagnostilkassa ja levinneisyyden arviossa.

In the diagnosis of lung cancer, tissue and cytologic specimens are needed for confirmation of the diagnosis, elucidation of the histologic type of lung cancer, determination of the extent of the cancer, and increasingly also for the molecular biological investigations required for the planning of drug therapy. The site and method of specimen collection are chosen multidisciplinarily on the basis of imaging studies, taking the clinical picture and patient safety into consideration. High-quality and quantitatively representative specimens are required for molecular biological analyses, and assessment of the response to drug therapy or modifying the treatment may require a new sample, which can be a tissue or cytologic specimen or a liquid biopsy.

Mild obstructive sleep apnea does not modulate baroreflex sensitivity in adult patients.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic and progressive disease. OSA is associated with increased cardiovascular morbidity and mortality, the risk being more frequently encountered with severe degrees of OSA. Increased sympathetic activation and impaired cardiac autonomic control as reflected by depressed baroreceptor reflex sensitivity (BRS) are possible mechanisms involved in the cardiovascular complications of OSA. However, it is not known at what stage of OSA that changes in BRS appear. The aim of this study was to evaluate BRS in patients with mild OSA. METHODS: The study population consisted of 81 overweight patients with mild OSA and 46 body weight-matched non-OSA subjects. BRS, apnea-hypopnea index, body mass index, and metabolic parameters were assessed. The phenylephrine test was used to measure BRS. RESULTS: Patients in the OSA group were slightly but significantly older than the non-OSA population (50.3±9.3 years vs 45.7±11.1 years, P=0.02). Body mass index, percentage body fat, blood pressure, fasting glucose, insulin, and lipid levels did not differ between the OSA patients and non-OSA subjects. Absolute BRS values in patients with mild OSA and non-OSA subjects (9.97±6.70 ms/mmHg vs 10.51±7.16 ms/mmHg, P=0.67) and BRS values proportional to age-related and sex-related reference values (91.4%±22.7% vs 92.2%±21.8%, P=0.84) did not differ from each other. BRS <50% of the sex-specific reference value was found in 6% of patients with mild OSA and in 2% of non-OSA subjects (P=0.29). CONCLUSION: Patients with mild OSA did not show evidence of disturbed BRS in comparison with weight-matched non-OSA controls.

Characterization of human memory CD4(+) T-cell responses to the dog allergen Can f 4.

BACKGROUND: The recently identified dog lipocalin allergen Can f 4 is an important respiratory allergen. OBJECTIVE: We sought to comprehensively characterize the memory CD4(+) T-cell responses of allergic and nonallergic subjects to Can f 4. METHODS: Can f 4-specific CD4(+)CD45RO(+) T-cell lines (TCLs) from allergic and healthy subjects were established and characterized by their functional and phenotypic properties. The epitope specificity of the TCLs was tested with 48 overlapping 16-mer peptides spanning the sequence of Can f 4. HLA restriction of the specific TCLs and the binding capacity of the epitope-containing peptides to common HLA class II molecules were studied. RESULTS: Can f 4-specific memory CD4(+) TCLs were obtained at an 8-fold higher frequency from allergic than from nonallergic subjects. Functionally, the TCLs of allergic subjects exhibited a higher T-cell receptor avidity and expression of CD25 and predominantly produced IL-4 and IL-5. The TCLs of nonallergic subjects mostly secreted IFN-γ and IL-10, with high CXCR3 expression. Several distinct T-cell epitope regions along the allergen were identified. Importantly, the peptides from the region between amino acids 43 and 67 showed promiscuous HLA-binding capacity and induced memory CD4(+) T-cell responses in 90% of the allergic donors. CONCLUSION: Productive TH2-deviated memory T-cell responses to Can f 4 are observed in allergic but not nonallergic subjects. A 19-mer peptide sequence covering the core of the immunodominant region of the allergen is a potential target for the development of peptide-based allergen immunotherapy.

IgE Reactivity of the Dog Lipocalin Allergen Can f 4 and the Development of a Sandwich ELISA for Its Quantification.

PURPOSE: Divergent results on the IgE reactivity of dog-allergic subjects to Can f 4 have been reported. The aim of this study was to evaluate the significance of Can f 4 in dog allergy and to develop an immunochemical method for measuring Can f 4 content in environmental samples. METHODS: We purified the natural dog allergen Can f 4 from a dog dander extract by monoclonal antibody-based affinity chromatography and generated its variant in a recombinant form. Sixty-three dog-allergic patients and 12 nonallergic control subjects were recruited in the study. The IgE-binding capacity of natural Can f 4 and its recombinant variant was assessed by ELISA, immunoblotting, and skin prick tests (SPT). RESULTS: Eighty-one percent of the dog-allergic patients showed a positive result to the immunoaffinity-purified natural Can f 4 in IgE ELISA, but only 46% in IgE immunoblotting. Respective results with the recombinant Can f 4 variant were 54% and 49%. SPT results reflected those obtained in ELISA and immunoblotting. The overall IgE reactivity of the immunoaffinity-purified natural Can f 4 was found to depend strongly on the integrity of the allergen's conformation. A sandwich ELISA based on monoclonal antibodies was found to be functional for measuring Can f 4 in environmental samples. CONCLUSIONS: Can f 4 is a major allergen of dog together with Can f 1 and Can f 5. In combination with other dog allergens, it improves the reliability of allergy tests in dog allergy.

Human CD4+ T cell responses to the dog major allergen Can f 1 and its human homologue tear lipocalin resemble each other.

Lipocalin allergens form a notable group of proteins, as they contain most of the significant respiratory allergens from mammals. The basis for the allergenic capacity of allergens in the lipocalin family, that is, the development of T-helper type 2 immunity against them, is still unresolved. As immunogenicity has been proposed to be a decisive feature of allergens, the purpose of this work was to examine human CD4+ T cell responses to the major dog allergen Can f 1 and to compare them with those to its human homologue, tear lipocalin (TL). For this, specific T cell lines were induced in vitro from the peripheral blood mononuclear cells of Can f 1-allergic and healthy dog dust-exposed subjects with peptides containing the immunodominant T cell epitopes of Can f 1 and the corresponding TL peptides. We found that the frequency of Can f 1 and TL-specific T cells in both subject groups was low and close to each other, the difference being about two-fold. Importantly, we found that the proliferative responses of both Can f 1 and TL-specific T cell lines from allergic subjects were stronger than those from healthy subjects, but that the strength of the responses within the subject groups did not differ between these two antigens. Moreover, the phenotype of the Can f 1 and TL-specific T cell lines, determined by cytokine production and expression of cell surface markers, resembled each other. The HLA system appeared to have a minimal role in explaining the allergenicity of Can f 1, as the allergic and healthy subjects' HLA background did not differ, and HLA binding was very similar between Can f 1 and TL peptides. Along with existing data on lipocalin allergens, we conclude that strong antigenicity is not decisive for the allergenicity of Can f 1.

The impact of weight reduction in the prevention of the progression of obstructive sleep apnea: an explanatory analysis of a 5-year observational follow-up trial.

BACKGROUND: Obstructive sleep apnea (OSA) is a chronic progressive disease, and it is well-documented that severe OSA is associated with an increased cardiovascular morbidity and mortality. Weight reduction has been shown to improve OSA; however, we need further evidence to determine if it may prevent the progression of OSA in the long term. The aim of our study was to assess the impact of weight change during a 5-year observational follow-up of an original 1-year randomized controlled trial. METHODS: The participants were divided into the two groups according to the weight change at 5-year follow-up using the 5% weight loss as a cutoff point, which was later referred to as the successful (n = 20) or unsuccessful groups (n = 27). The change in apnea-hypopnea index (AHI) was the main objective outcome variable. RESULTS: Fifty-seven patients participated in the 5-year follow-up. At 5 years from the baseline, the change in AHI between the groups was significant in the successful group (-3.5 [95% confidence interval {CI}, -6.1 to -0.9]) compared with the unsuccessful group (5.0 [95% CI, 2.0-8.5]) (P = .002). Successful weight reduction achieved an 80% reduction in the incidence of progression of OSA compared to the unsuccessful group (log-rank test, P = .016). CONCLUSIONS: A moderate but sustained weight reduction can prevent the progression of the disease or even cure mild OSA in obese patients.

Differential CD4+ T-cell responses of allergic and non-allergic subjects to the immunodominant epitope region of the horse major allergen Equ c 1.

The responses of allergen-specific CD4(+) T cells of allergic and healthy individuals are still incompletely understood. Our objective was to investigate the functional and phenotypic properties of CD4(+) T cells of horse-allergic and healthy subjects specific to the immunodominant epitope region of the major horse allergen Equ c 1. Specific T-cell lines (TCLs) and clones were generated from peripheral blood mononuclear cells with Equ c 1(143-160), the peptide containing the immunodominant epitope region of Equ c 1. The frequency, proliferative response, cytokine production and HLA restriction of the cells were examined. The frequency of Equ c 1-specific CD4(+) T cells was low (approximately 1 per 10(6) CD4(+) T cells) in both allergic and non-allergic subjects. The cells of allergic subjects had a stronger proliferative capacity than those of non-allergic subjects, and they predominantly emerged from the memory T-cell pool and expressed the T helper type 2 cytokine profile, whereas the cells of non-allergic subjects emerged from the naive T-cell pool and produced low levels of interferon-γ and interleukin-10. T-cell response to Equ c 1(143-160) was restricted by several common HLA class II molecules from both DQ and DR loci. As the phenotypic and functional properties of Equ c 1-specific CD4(+) T cells differ between allergic and non-allergic subjects, allergen-specific T cells appear to be tightly implicated in the development of diseased or healthy outcome. Restriction of the specific CD4(+) T-cell response by multiple HLA alleles suggests that Equ c 1(143-160) is a promising candidate for peptide-based immunotherapy.

Endothelial function is well preserved in obese patients with mild obstructive sleep apnea.

PURPOSE: Endothelial dysfunction is one of the early markers of cardiovascular complications in obstructive sleep apnea (OSA). The aim of our study was to evaluate whether overweight patients with mild OSA displayed endothelial dysfunction, and to assess the effect of 1-year lifestyle intervention with an early very low calorie diet in endothelial function. METHODS: At baseline, the study population consisted of 83 overweight patients with mild OSA and 46 weight-matched non-OSA subjects. OSA patients were further randomized into a 1-year supervised lifestyle intervention group or control group which received routine lifestyle counselling. Endothelial function measured by brachial artery flow-mediated dilatation (FMD), apnea-hypopnea index (AHI), body mass index (BMI), and metabolic parameters were assessed at baseline and 12 months. RESULTS: No correlations between endothelial function and mild OSA were detected. However, patients with impaired endothelial function had lower mean saturation and impaired endothelial function correlated significantly with glucose intolerance and dyslipidemia. After the lifestyle intervention and successful weight reduction, AHI, BMI, serum triglycerides and insulin improved significantly; however, no improvement in FMD was detected. CONCLUSIONS: Mild OSA was not observed to be associated with endothelial dysfunction. Although in mild OSA endothelial function is still preserved, lifestyle intervention with weight reduction did achieve an improvement in other obesity-related risk factors for cardiovascular diseases, thus highlighting the importance of early intervention.

Cholesterol metabolism and weight reduction in subjects with mild obstructive sleep apnoea: a randomised, controlled study.

To evaluate whether parameters of obstructive sleep apnoea (OSA) associate with cholesterol metabolism before and after weight reduction, 42 middle-aged overweight subjects with mild OSA were randomised to intensive lifestyle intervention (N = 23) or to control group (N = 18) with routine lifestyle counselling only. Cholesterol metabolism was evaluated with serum noncholesterol sterol ratios to cholesterol, surrogate markers of cholesterol absorption (cholestanol and plant sterols) and synthesis (cholestenol, desmosterol, and lathosterol) at baseline and after 1-year intervention. At baseline, arterial oxygen saturation (SaO2 ) was associated with serum campesterol (P < 0.05) and inversely with desmosterol ratios (P < 0.001) independently of gender, BMI, and homeostasis model assessment index of insulin resistance (HOMA-IR). Apnoea-hypopnoea index (AHI) was not associated with cholesterol metabolism. Weight reduction significantly increased SaO2 and serum cholestanol and decreased AHI and serum cholestenol ratios. In the groups combined, the changes in AHI were inversely associated with changes of cholestanol and positively with cholestenol ratios independent of gender and the changes of BMI and HOMA-IR (P < 0.05). In conclusion, mild OSA seemed to be associated with cholesterol metabolism independent of BMI and HOMA-IR. Weight reduction increased the markers of cholesterol absorption and decreased those of cholesterol synthesis in the overweight subjects with mild OSA.

Sustained improvement in mild obstructive sleep apnea after a diet- and physical activity-based lifestyle intervention: postinterventional follow-up.

BACKGROUND: Obesity is the most important risk factor for obstructive sleep apnea (OSA). Weight-reduction programs have been observed to represent effective treatment of overweight patients with OSA. However, it is not known whether beneficial changes remain after the end of the intervention. OBJECTIVE: The aim of the study was to assess the long-term efficacy of a lifestyle intervention based on a healthy diet and physical activity in a randomized, controlled, 2-y postintervention follow-up in OSA patients. DESIGN: Eighty-one consecutive overweight [body mass index (in kg/m(2)): 28-40] adult patients with mild OSA were recruited. The intervention group completed a 1-y lifestyle modification regimen that included an early 12-wk weight-reduction program with a very-low-calorie diet. The control group received routine lifestyle counseling. During the second year, no dietary counseling was offered. Change in the apnea-hypopnea index (AHI) was the main objective outcome variable, and changes in symptoms were used as a subjective measurement. RESULTS: A total of 71 patients completed the 2-y follow-up. The mean (± SD) changes in diet and lifestyle with simultaneous weight reduction (-7.3 ± 6.5 kg) in the intervention group reflected sustained improvements in findings and symptoms of OSA. After 2 y, the reduction in the AHI was significantly greater in the intervention group (P = 0.049). The intervention lowered the risk of OSA at follow-up; the adjusted odds ratio for OSA was 0.35 (95% CI: 0.12-0.97; P = 0.045). CONCLUSION: Favorable changes achieved by a 1-y lifestyle intervention aimed at weight reduction with a healthy diet and physical activity were sustained in overweight patients with mild OSA after the termination of supervised lifestyle counseling. This trial was registered at clinicaltrials.gov as NCT00486746.

Lifestyle intervention with weight reduction: first-line treatment in mild obstructive sleep apnea.

RATIONALE: Obesity is the most important risk factor for obstructive sleep apnea (OSA). However, although included in clinical guidelines, no randomized controlled studies have been performed on the effects of weight reduction on mild OSA. OBJECTIVES: The aim of this prospective, randomized controlled parallel-group 1-year follow-up study was to determine whether a very low calorie diet (VLCD) with supervised lifestyle counseling could be an effective treatment for adults with mild OSA. METHODS: Seventy-two consecutive overweight patients (body mass index, 28-40) with mild OSA were recruited. The intervention group (n = 35) completed the VLCD program with supervised lifestyle modification, and the control group (n = 37) received routine lifestyle counseling. The apnea-hypopnea index (AHI) was the main objectively measured outcome variable. Change in symptoms and the 15D-Quality of Life tool were used as subjective measurements. MEASUREMENTS AND MAIN RESULTS: The lifestyle intervention was found to effectively reduce body weight (-10.7 +/- 6.5 kg; body mass index, -3.5 +/- 2.1 [mean +/- SD]). There was a statistically significant difference in the mean change in AHI between the study groups (P = 0.017). The adjusted odds ratio for having mild OSA was markedly lowered (odds ratio, 0.24 [95% confidence interval, 0.08-0.72]; P = 0.011) in the intervention group. All common symptoms related to OSA, and some features of 15D-Quality of Life improved after the lifestyle intervention. Changes in AHI were strongly associated with changes in weight and waist circumference. CONCLUSIONS: VLCD combined with active lifestyle counseling resulting in marked weight reduction is a feasible and effective treatment for the majority of patients with mild OSA, and the achieved beneficial outcomes are maintained at 1-year follow-up.

Health risk assessment of indoor air pollution in Finnish ice arenas.

Poor indoor air quality and epidemic carbon monoxide (CO) and nitrogen dioxide (NO(2)) poisonings due to exhaust emissions from ice resurfacers have been continuously reported from enclosed ice arenas for over 30 years. The health risks in users of Finnish ice arenas were analysed in three ways: (1) evaluation of four cases of epidemic CO poisonings, (2) modelling the association between NO(2) exposure and respiratory symptoms among junior ice hockey players, and (3) estimation of the number of arena users at risk of breathing poor quality air due to non-compliance of ice arenas with recommended abatement measures. The common causes for the CO poisonings involving over 300 subjects were large emissions from propane-fuelled ice resurfacer, small arena volume, negligible ventilation, and very recent opening of the arena. Rhinitis (prevalence 18.3%) and cough (13.7%) during or after training or game were significantly associated with the estimated personal NO(2) exposure of young hockey players (n=793) to average concentrations ranging from 21 to 1176 microg/m(3) in their home arena. During a 6-year follow-up of an intensive information campaign the portion of electric resurfacers increased from 9% to 27%, and that of emission control technology on propane-fuelled resurfacers increased from 13% to 84%. The portion of inadequately ventilated arenas decreased from 34% to 25%. However, 48% of the investigated Finnish ice arenas (n=125) did not fully comply with the non-regulatory recommendations. Consequently, 20000 daily users of ice arenas were estimated to remain in 2001 at risk of breathing poor quality air. Modern small and inadequately ventilated ice arenas pose their users (mostly children and young adults) at risk of breathing poor quality air and suffering from acute adverse health effects. Governmental regulations are needed worldwide to ensure safe sports in enclosed ice arenas.

Short-term and seasonal variations of exhaled and nasal NO in healthy subjects.

Nitric oxide (NO) is an important biological mediator with a variety of cellular and tissue functions. Fractional exhaled (FE(NO)) and nasal NO (FN(NO)) are known to be altered in several respiratory tract disease and disorders. However, there are rather few studies into the reproducibility of FE(NO) or FN(NO) measurements in healthy subjects. The aim of this study was to examine both short- and long-term variations of FE(NO) and FN(NO). In addition to intraday, day-to-day and week-to-week variations, the seasonal variation was assessed. The data revealed that FE(NO) and FN(NO) levels were lower in the mornings compared to the afternoon values. There were clinically significant correlations in day-to-day (morning values 121.4+/-37.5 vs. 119.8+/-29.6, r=0.868, P=0.000), week-to-week (morning values 121.4+/-37.5 vs. 128.0+/-32.1, r=0.637, P=0.000) and seasonal (winter 133.5+/-29.7, summer 138.1+/-47.6, autumn 121.4+/-37.5, r=0.624, P=0.000) values of FN(NO). Day-to-day (morning values 14.6+/-6.7 vs. 14.2+/-5.1, r=0.784, P=0.000) week-to-week (morning values 14.6+/-6.7 vs. 15.4+/-7.3, r=0.738, P=0.000) and seasonal (autumn 14.6+/-7.2, winter 16.6+/-6.4, summer 17.4+/-8.0, r=0.709, P=0.000) levels of FE(NO) were also highly reproducible. Serial FE(NO) and FN(NO) measurements can be used in the monitoring of respiratory tract inflammation. Due to the diurnal variation of FE(NO) and FN(NO,) in long-term follow-up the measurements should be performed at the same time of day.

Interpretation of cough provoked by airway challenges.

STUDY OBJECTIVE: To analyze the cough response to three airway challenges in order to clarify whether the recording of the provoked coughs would be beneficial in the management of asthma. DESIGN: A prospective study. SETTING: University hospital. PARTICIPANTS: Fifteen healthy subjects, 16 steroid-naïve subjects with asthma, and 16 subjects with steroid-treated asthma. INTERVENTIONS: Inhalation challenges with isotonic histamine, hypertonic saline solution, and hypertonic histamine, using an ultrasonic nebulizer and 2-min tidal breathing method. MEASUREMENTS: Airflow parameters were measured with a spirometer, and the coughs were recorded manually. RESULTS: Coughing during the isotonic histamine challenge was associated with the degree of the bronchoconstriction induced. When this was taken into account, the healthy subjects coughed as frequently as the asthmatic subjects. During the two hypertonic challenges, the asthmatic subjects coughed more frequently than did the healthy subjects when the induced bronchoconstriction had not yet developed. At that stage of the hypertonic saline solution challenge, the mean coughing frequency was 0.7 coughs per minute (95% confidence interval [CI], 0.03 to 1.3 coughs per minute) for the healthy subjects, 2.7 coughs per minute (95% CI, 0.8 to 4.5 coughs per minute) for the steroid-naïve asthmatic subjects, and 1.3 coughs per minute (95% CI, 0.6 to 1.9 coughs per minute) for the steroid-treated asthmatic subjects (p = 0.018). For the hypertonic histamine challenge, the respective values were 0.8 coughs per minute (95% CI, 0.4 to 1.2 coughs per minute), 3.6 coughs per minute (95% CI, 2.4 to 4.9 coughs per minute), and 2.1 coughs per minute (95% CI, 1.0 to 3.1 coughs per minute; p = 0.001). This cough did not correlate with airway hyperresponsiveness. CONCLUSIONS: Coughing during isotonic histamine challenge seems to be a manifestation of bronchoconstriction, and recording of the coughs may not provide additional information to airflow measurements. Frequent coughing during hypertonic saline solution and hypertonic histamine challenges in the absence of bronchoconstriction is a pathologic phenomenon. Sensitivity to the cough-provoking effect of hypertonic challenges seems to be enhanced in patients with asthma but unrelated to airway hyperresponsiveness. Therefore, the recording of the provoked coughs during these challenges may add to the information obtained from airflow measurements.

Hypertonicity of the challenge solution may increase the diagnostic accuracy of histamine challenge.

There is significant overlap in the responsiveness to direct airway challenges, such as the histamine challenge, between asthmatic and non-asthmatic subjects, which decreases their accuracy in the diagnosis of asthma. To minimise this overlap, a new test, hypertonic histamine challenge, was developed. Fifteen healthy subjects, 16 subjects with steroid-naive asthma, and 16 asthmatic subjects undergoing inhaled corticosteroid treatment underwent inhalation challenges with hypertonic saline, isotonic histamine, and hypertonic histamine, using an ultrasonic nebuliser and 2-min tidal breathing method. The increase in histamine solution tonicity decreased the histamine PC20 values only in the steroid-naive asthmatic subjects (1.1 (0.5-2.7) vs. 0.5 (0.2-1.2) mg/ml, P = 0.047). Using 1mg/ml as the cut-off value, the sensitivity, specificity, and accuracy of the hypertonic histamine challenge to detect steroid-naive asthma was 81%, 100%, and 90%. The respective values for the isotonic histamine challenge were 56%, 100%, and 77%. Furthermore, there was a statistically significant difference in the hypertonic histamine PC20 between steroid-naive and steroid-treated asthmatic subjects, which could not be detected in the isotonic histamine PC20. The hypertonic histamine PC20 was highly repeatable, with a single determination 95% range of +/-1.35 doubling concentrations. The hypertonic histamine challenge was safe but provoked more cough and throat irritation than the other two challenges. In conclusion, compared with a conventional, isotonic histamine challenge, hypertonic histamine challenge may be more accurate in the diagnosis of asthma and also, more capable to detect the effects of inhaled corticosteroid treatment.

Nasal lavage method in the monitoring of upper airway inflammation: seasonal and individual variation.

A noninvasive and reliable method is needed to investigate causal relationship between exposure to bioaerosols in occupational and indoor environments and adverse health effects. As an essential part of the method development, the individual variation as well as seasonal and gender differences in the concentrations of inflammatory mediators in nasal lavage (NAL) fluid were studied. NAL was performed in 10 healthy volunteers every other week for a year. Concentrations of nitric oxide, assessed as nitrite, interleukin (IL)-1 beta, IL-4, IL-5, IL-6, and tumor necrosis factor alpha (TNF alpha) in NAL fluid were measured. The NAL sampling was minimally invasive and well tolerated and no side effects were observed among the studied subjects. Low concentrations of nitrite, TNFalpha, IL-1 beta, IL-4, and IL-6 were detected in the NAL samples of the studied subjects. Within-subject variation in the concentrations of inflammatory mediators in the NAL fluid was at its lowest during the wintertime. Moreover, differences between individuals and genders were statistically significant. In summary, the individual variation in the basal levels of measured inflammatory markers is low, whereas differences between individuals are considerable. Thus, in the studies evaluating upper airway effects of occupational or environmental exposure, the method is most suitable in settings where comparison can be made using test subjects as their own controls.