Re-evaluation of diagnostic parameters is crucial for obtaining accurate data on idiopathic pulmonary fibrosis.

BACKGROUND: The FinnishIPF registry is a prospective, longitudinal national registry study on the epidemiology of idiopathic pulmonary fibrosis (IPF). It was designed to describe the characteristics, management and prognosis of prevalent and incident IPF patients. The study was initiated in 2012. METHODS: We present here results limited to five university hospitals. Patients with IPF were screened from hospital registries using ICD-10 diagnosis codes J84.1 and J84.9. All patients who gave informed consent were included and evaluated using novel diagnostic criteria. Point prevalence on the 31(st) of December in 2012 was calculated using the reported population in each university hospital city as the denominator. RESULTS: Patients with ICD-10 codes J84.1 and J84.9 yielded a heterogeneous group - on the basis of patient records assessed by pulmonologists only 20-30 % of the cases were IPF. After clinical, radiological and histological re-evaluation 111 of 123 (90 %) of patients fulfilled the clinical criteria of IPF. The estimated prevalence of IPF was 8.6 cases/100 000. 60.4 % were men. Forty four percent of the patients were never-smokers. At diagnosis, the patients' mean age was 73.5 years and mean FVC was 80.4 % and DLCO 57.3 % of predicted. CONCLUSIONS: Our results suggest that hospital registries are inaccurate for epidemiological studies unless patients are carefully re-evaluated. IPF is diagnosed in Finland at a stage when lung function is still quite well preserved. Smoking in patients with IPF was less common than in previous reports.

Hypertonic saline cough provocation test with salbutamol pre-treatment: evidence for sensorineural dysfunction in asthma.

BACKGROUND: Cough is one of the most common symptoms of asthma. However, studies using capsaicin, citric acid, or tartaric acid to document cough threshold have repeatedly failed to show statistically significant differences between asthmatic and healthy subjects. The studies using hypertonic aerosols as the cough stimulant have suggested an enhanced sensitivity in asthmatic subjects but the induced bronchoconstriction has made the interpretation of the results difficult. OBJECTIVE: To determine the cough sensitivity to hypertonicity in healthy subjects, patients with chronic cough, and patients with asthma in a setting where the induction of bronchoconstriction is prevented. METHODS: Nineteen healthy subjects, 21 non-asthmatic patients with chronic cough, and 26 asthmatic patients with chronic cough underwent an incremental hypertonic saline challenge including a pre-treatment with 0.4 mg of salbutamol. Spirometry was performed before the challenge, after salbutamol, and after the challenge. The patients with cough also underwent skin testing, histamine challenge, exhaled nitric oxide measurement, ambulatory peak flow monitoring, kept cough diary, and filled in the Leicester Cough Questionnaire. Eighteen patients repeated the saline challenge. RESULTS: The challenge did not induce bronchoconstriction in any group. The osmolality to provoke 15 cumulative coughs was significantly smaller in the asthmatic patients than in the healthy subjects (P<0.001) and in the cough patients without asthma (P=0.04). According to multivariate analysis among all the 47 patients with cough, female sex (P<0.001) and large spontaneous peak flow variation in the ambulatory recording (P=0.001) were associated with high sensitivity to saline. The saline challenge response was well repeatable (intraclass correlation coefficient 0.90). CONCLUSION: The findings of the present study are not affected by induced bronchoconstriction. Asthma or, more specifically, spontaneous, reversible airway obstruction is associated with an enhanced sensitivity to the cough-provoking effect of hypertonic saline. This suggests a pathological function of the sensorineural apparatus in this disorder.

Aspergillus fumigatus challenge increases cytokine levels in nasal lavage fluid.

Several studies have shown an association between exposure in moisture-damaged buildings and adverse health effects. There are several indicator microbes of moisture damage, but Aspergillus fumigatus is one of the best-documented molds provoking health problems in different occupational conditions. We assessed whether inhalation of a commercial A. fumigatus solution would affect cytokine levels (tumor necrosis factor [TNF]-alpha, interleukin [IL]-1beta, IL-4, IL-6, interferon [IFN]-gamma) in nasal lavage fluid (NAL) compared with that evoked by placebo challenge. Twenty-seven subjects were studied: 13 had occupational exposure in a moisture-damaged building, 4 were atopic, and 10 were considered as controls. In all the subjects, the IL-1beta levels were increased significantly both at 6 (p = 0.013) and 24 h (p = .005) after the A. fumigatus challenge compared to placebo. In subjects with previous occupational exposure in a moisture-damaged building, IL-4 concentrations were increased significantly both at 6 (p =.046) and 24 h (p =.008) after the A. fumigatus challenge compared with placebo. Furthermore, in the control group, TNF-alpha levels were significantly increased at 6 h after the A. fumigatus challenge compared to placebo (p = .028). Thus, these data show a link between markers of inflammation in NAL and experimental A. fumigatus challenge.

The effects of Aspergillus fumigatus challenge on exhaled and nasal NO levels.

Several studies have previously shown that exposure to indoor air microbes from moisture-damaged buildings can cause adverse health effects. Aspergillus fumigatus is one of the best-documented moulds causing health problems to those exposed. In this study, inhalation of a commercial A. fumigatus solution was assessed, to establish if it would have effects on fractional exhaled (FeNO) and nasal (FnNO) nitric oxide levels and on lung function. The results were compared with placebo challenge. A total of 28 subjects were divided into three study groups: group 1 had been exposed to occupational mould; group 2 consisted of atopic subjects; and group 3 was a control group. Some 3 h after A. fumigatus challenge, there was a considerable increase in FeNO, and a significant difference was observed between the A. fumigatus and placebo inhalations. The difference was seen in all study groups. No such differences were found in the levels of FnNO or nitrite in nasal lavage fluid. Subjects reported significantly more frequent respiratory tract symptoms after the A. fumigatus inhalation compared with placebo challenge. In conclusion, it was shown here that inhalation challenge of Aspergillus fumigatus elevated fractional exhaled nitric oxide levels. An increase in fractional exhaled nitric oxide may serve as an indicator of respiratory inflammation of acute mould exposure.

Nitric oxide alone is an insufficient biomarker of exposure to microbes in a moisture-damaged building.

Several epidemiological studies have revealed a large variety of adverse health effects related to exposure to microbes in moisture damaged buildings. Recently some evidence has been reported for a biochemical linkage between microbial exposure and the respiratory symptoms suffered by the occupants. The objective of the current study was to evaluate the value of nitric oxide (NO) measurements in determining the inflammatory status of airways in inhabitants of problem buildings. NO was measured by a chemiluminescence analyzer from the exhaled air. In addition, NO was determined as its metabolite nitrite from nasal lavage (NL) and induced sputum (IS) samples and also via the expression of inducible nitric oxide synthase (iNOS) in the cells. Occupants of moisture-damaged and reference schools were studied. The sampling was performed at the end of the spring term, at the end of the summer vacation, during the winter term, and after a 1-wk winter holiday. No statistically significant differences in NO levels were detected between the studied groups or between exposure and vacation periods. iNOS was not detected from IS or NL samples of the exposed occupants. These results suggest that NO measurements alone are not sufficient to quantify airway inflammation when evaluating subjects exposed to microbes present in moisture-damaged buildings.

Comparison of inflammatory elements in nasal lavage and induced sputum following occupational exposure to moldy-building microbes.

Inflammatory processes in the nasal air passages may reflect corresponding processes in the lower airways due to the similarities in histology of nasal mucosa and bronchi. The objective of the current study was to determine whether the levels of inflammatory markers in nasal lavage fluid could be used as predictors of lower respiratory tract inflammation after exposure to microbes in indoor air of moisture-damaged buildings. Differential cell count, immunochemically measured concentrations of proinflammatory cytokines (Interleukins [IL] IL-1, IL-4, IL-6, and tumor necrosis factor alpha [TNFalpha]) and nitric oxide (NO), assessed as nitrite, were analyzed from nasal lavage (NL) and induced sputum (IS) samples of the occupants (n = 60) working in moisture-damaged and reference school buildings. The measurements of inflammation markers in NL and IS sample pairs, collected on the same day, were compared. Although the levels of NO (p =.026) and IL-4 (p =.014) in NL predicted their levels in IS in a statistically significant manner, their predictive values (6.9% and 7.8%, respectively) were low. There was no significant correlation between the concentrations of the studied proinflammatory cytokines or differential cell counts in NL and IS samples. Our results indicate that measurement of inflammatory mediators in NL is not per se a reliable method to evaluate the inflammatory status of the lower airways after exposure to indoor air pollutants of moisture damaged building. It is possible that NL is a more sensitive indicator of direct exposure to different irritants in inhaled air than is IS. This may be a reflection of the role of nasal mucosa as the primary physicochemical barrier to inhaled air.

Changes in pro-inflammatory cytokines in association with exposure to moisture-damaged building microbes.

Several epidemiological studies have described an association between adverse health effects and exposure to mould and microbes present in the indoor air of moisture-damaged buildings. However, the biochemical linkage between microbial exposure and the large variety of reported respiratory symptoms is poorly understood. In the present study, the authors compared the respiratory symptoms, the production of inflammatory mediators interleukin (IL)-1, IL-4, IL-6, tumour necrosis factor-alpha (TNF-alpha) and cell count in nasal lavage fluid and induced sputum samples of subjects working in moisture-damaged and control school buildings. The sampling was performed and the questionnaires were completed at the end of the spring term, at the end of the summer vacation (2.5 months), during the winter term and after a 1-week winter holiday. The authors found a significant elevation of IL-1, TNF-alpha and IL-6 in nasal lavage fluid and IL-6 in induced sputum during the spring term in the subjects from the moisture-damaged school building compared to the subjects from the control building. The exposed workers reported sore throat, phlegm, eye irritation, rhinitis, nasal obstruction and cough in parallel with these findings. The present data suggests an association between microbial exposure, and symptoms as well as changes in pro-inflammatory mediators detected from both the upper and lower airways.

Reproducibility of measurements of exhaled NO, and cell count and cytokine concentrations in induced sputum.

Sputum induction is a noninvasive, well-tolerated method for studying airway inflammation. When induction with hypertonic saline is repeated at short time-intervals (<24 h), the cell profile of sputum has not been reproducible. To determine the proper interval between sampling cell profiles and cytokine contents of sputum samples that had been induced 48 h apart, were compared. In addition, the inducible nitric oxide synthase (iNOS) expression of sputum cells was compared to the levels of exhaled nitric oxide (NO). Sputum induction and measurement of exhaled NO was performed in 31 healthy nonatopic volunteers. Cell differentials were counted. Concentrations of interleukin (IL)-4, IL-6, tumour necrosis factor (TNF)alpha, eosinophil cationic protein (ECP) were measured in sputum supernatant, and iNOS was determined. Reproducibility of cell counts was high (r=0.836 total cells, r=0.762 neutrophils, r=0.966 eosinophils, r=0.742 macrophages). IL-4 (r=0.398), IL-6 (r=0.566), TNFalpha (r=0.658) and ECP (r=0.501) were also less reproducible in healthy volunteers. Consistent with the low levels of NO in the exhaled air (18.5+/-2.6 ppb and 19.3+/-2.8 parts per billion (ppb) on the two study days, r=0.976, p=0.0000), expression of iNOS was not detected. In conclusion, in healthy subjects, induced sputum cell counts are reproducible. Even though the success rate in nonatopic populations is relatively low, sputum induction appears to be a valid method for detecting inflammatory changes within the airways, when being performed 48 h apart.