Treatment of idiopathic pulmonary fibrosis: a position paper from a Nordic expert group.

Idiopathic pulmonary fibrosis (IPF) is a fatal progressive lung disease occurring in adults. In the last decade, the results of a number of clinical trials based on the updated disease classification have been published. The registration of pirfenidone and nintedanib, the first two pharmacological treatment options approved for IPF, marks a new chapter in the management of patients with this disease. Other nonpharmacological treatments such as lung transplantation, rehabilitation and palliation have also been shown to be beneficial for these patients. In this review, past and present management is discussed based on a comprehensive literature search. A treatment algorithm is presented based on available evidence and our overall clinical experience. In addition, unmet needs with regard to treatment are highlighted and discussed. We describe the development of various treatment options for IPF from the first consensus to recent guidelines based on evidence from large-scale, multinational, randomized clinical trials, which have led to registration of the first drugs for IPF.

Increased microRNA-323-3p in IL-22/IL-17-producing T cells and asthma: a role in the regulation of the TGF-ß pathway and IL-22 production.

BACKGROUND: IL-22- and IL-17-producing T cells have important roles in allergic diseases. MicroRNAs (miRNAs) are posttranscriptional regulators of gene expression and modulate numerous biological processes. Little is known about the functions of miRNAs in IL-22/IL-17-producing T cells. MATERIAL AND METHODS: IL-22- and IL-17-positive T cells were sorted from human peripheral blood mononuclear cells (PBMCs) by intracellular staining and dual-secretion assay. miRNA expression profiles were detected with TaqMan array microfluidic cards. T cells were transfected with miRNA mimics. Gene expression was analyzed using RT-qPCR and/or enzyme-linked immunosorbent assay in T-cell subsets and PBMCs from patients with asthma and atopic dermatitis. RESULTS: The increased expression of miR-323-3p and noncoding RNA nc886 and reduced expression of miR-93, miR-181a, miR-26a, and miR-874 were detected in IL-22-producing T cells. The pathway analysis of the putative targets suggested that these differentially expressed miRNAs could impact the proliferation, differentiation, and effector functions of T cells. Further analyses showed the highest expression for miR-323-3p in IL-22- and IL-17-double-positive T cells and its capacity to suppress multiple genes from the transforming growth factor-ß pathway and the production of IL-22 in T cells. An increased expression of miR-323-3p in PBMCs from patients with asthma and reverse correlation between miR-323-3p levels and IL-22 production in PBMCs cultured in T-cell growth conditions was observed. CONCLUSIONS: Our data suggest that miR-323-3p acts in a negative feedback loop to control the production of IL-22 in IL-22/IL-17-producing T cells and might thus impact the T-cell responses in asthma.

Prospective evaluation of thin-layer agar colour test in routine diagnosis of multidrug-resistant TB.

This study evaluated the diagnostic performance of the thin-layer agar MDR/XDR-TB Colour Test (CT), a Mycobacterium tuberculosis complex (MTBC) detection and direct drug susceptibility testing (DST) method with routine sputum, bronchoalveolar lavage and pleural fluid specimen.In a prospective study, the time and rate of MTBC detection were compared between CT, Löwenstein-Jensen, and MGIT media. Times until DST result, sensitivities, and specificities were evaluated between CT and MGIT 960 indirect DST.The cultivation of 177 pulmonary specimens resulted in 83 MTBC-positive cultures. The sensitivity of CT for MTBC detection was 81.3% with a median time of 20 days compared to 13 days and 93.5% for MGIT. The sensitivity of CT for DST results was 100% for isoniazid and levofloxacin and 94.7% for rifampicin. The specificities for isoniazid and rifampicin DST were 97.3% and 98.0% for levofloxacin. The median time until a DST result was significantly shorter with CT than the BACTEC MGIT 960 system, 20 and 27 days, respectively, independent of the specimen type used.The CT is a highly accurate and fast initial diagnostic test for high-incidence settings and could also be used as a first culture and direct DST in peripheral settings..

Predictors of poor treatment outcome in multi- and extensively drug-resistant pulmonary TB.

Treatment outcome in multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) is often unsuccessful, but the particular determinants of poor treatment outcome have remained obscure. The present authors therefore analysed treatment effectiveness and predictors of poor treatment outcome in pulmonary MDR-TB and XDR-TB in Estonia, a European country with one of the highest MDR-TB and XDR-TB rates in the world. All culture-confirmed pulmonary MDR-TB and XDR-TB patients who started TB treatment in 2003-2005 were included. Multivariate analysis was performed on two models of predictors: 1) patients' HIV-status, demographic and socioeconomic characteristics; and 2) TB-related data. In the 235 MDR-TB patients, the proportion of overall successful treatment outcome was 60.4%, rising to 72.8% among adherent patients. Among the 54 XDR-TB patients, these proportions were 42.6% and 50.0%, respectively. Risk factors for poor treatment outcome in MDR-TB were HIV infection, previous TB treatment, resistance to ofloxacin and positive acid-fast bacilli (AFB) smear at the start of treatment. Predictors of poor treatment outcome in XDR-TB were urban residence and positive AFB smear. This country-wide study provides evidence that to improve treatment outcome in multidrug-resistant and extensively drug-resistant tuberculosis, special care should be taken to treat HIV-infected patients and urban residents, as well as to make efforts to diminish re-treatment cases by increasing patient adherence.

Rapid tests reduce the burden of tuberculosis in Azerbaijan prisons: special emphasis on rifampicin-resistance.

AIMS: To evaluate the impact of addition of rapid tests for tuberculosis (TB) to mass screening and passive case finding on the burden of TB in high-incidence prisons of Azerbaijan. MATERIALS AND METHODS: All new and relapse TB cases notified in 01.01.2009-31.12.2015 were retrospectively included. RESULTS: 2,315 TB patients were identified in 19 prisons. Implementation of the rapid tests to the case finding algorithms lead to 3-, 10- and 5-fold decrease in the annual rates of the notified, smear-positive and RIF-resistant TB cases, respectively. After introduction of rapid tests into the screening algorithms, there were significant linear trends towards decrease in the notified (p=0.009), smear-positive (p=0.011) and RIF-resistant TB cases (p=0.02) with the annual rates of decrease (95% confidence interval (CI)) being -435 (-614; -255), -356 (-517; -195), and -99 (-160; -38), respectively. Utilization of rapid tests also significantly increased treatment success with first-line drugs among all cases, cases detected by mass screening and those, detected by passive case finding [adjusted odds ratio (aOR)=2.38, 95% CI:1.86-3.05, aOR=4.56, 95% CI:2.64-7.89 and aOR=2.60, 95% CI:1.81-3.75, respectively]. CONCLUSIONS: Introduction of rapid tests into the screening lead to decline in the burden of TB and RIF-resistance, and improved outcomes of treatment with first-line drugs in prisons.

Factors related to health system delays in the diagnosis of pulmonary tuberculosis in Estonia.

OBJECTIVE: To estimate health system delays (HSD) in the diagnosis of pulmonary tuberculosis (PTB) and its risk factors after major social changes in Estonia, and to assess the ability of a completely reformed health care system to diagnose patients with PTB. METHODS: All newly detected symptomatic culture-positive patients with PTB aged > or = 16 years from Southern Estonia during 2002-2003 (n = 185) were interviewed. HSD was defined as the interval from a patient's first contact with a medical provider to the date of TB diagnosis. RESULTS: The factors significantly associated with HSD greater than the median (19 days) and the 75th percentile (40 days) were smear negativity, absence of cough among symptoms, absence of chest X-ray during the first visit and age > 60 years. A significantly shorter HSD was determined in non-Estonians and unemployed patients. HSD was not associated with the specialty of the doctor first contacted by the patient. CONCLUSION: This study in Southern Estonia shows that the health care system is still managing the diagnosis of PTB without significant delays, even after substantial modifications in the health care system resulting from social reform in a post-socialist country, and that family physicians can manage PTB patients successfully.

Antimicrobial susceptibility of common pathogens from community-acquired lower respiratory tract infections in Estonia.

Antimicrobial resistance among clinical isolates of Streptococcus pneumoniae (n = 49), Haemophilus influenzae (n = 66) and Moraxella catarrhalis (n = 25) from adults with community-acquired lower respiratory tract infections (CALRTI) was assessed in a national surveillance study in Southern Estonia during 2000-2003. In S. pneumoniae, no penicillin resistance and only 2.0% resistance to clarithromycin was present, although intermediate resistance to trimethoprim-sulphamethoxazole (TMP-SMX) reached 24.5%. Beta-lactamase production rate was 96.0% in M. catarrhalis, but only 3.0% in H. influenzae. Both Gram-negative strains lacked resistance to ciprofloxacin. Clarithromycin resistance was 12% in M. catarrhalis but lacking among H. influenzae (except for 18.2% intermediate resistance). Resistance to TMP-SMX was 12.0% and 24.2% in M. catarrhalis and H. influenzae, respectively. In summary, a favorable resistance pattern of the main CALRTI pathogens is preserved in Estonia to core antibacterials. Nevertheless, use of TMP-SMX in CALRTI is discouraged and clinical response should be carefully monitored, when clarithromycin is chosen against M. catarrhalis or H. influenzae.

Predictors of cure in rifampicin-resistant tuberculosis in prison settings with low loss to follow-up.

OBJECTIVE: To determine the factors predictive of cure among inmates with pulmonary rifampicin-resistant tuberculosis (R(R)-TB). DESIGN: A total of 444 new and previously treated patients with pulmonary R(R)-TB who started treatment with second-line anti-tuberculosis drugs in the penitentiary system of Azerbaijan during the period 1 April 2007-28 February 2013 were retrospectively subjected to multivariate logistic regression analysis. RESULTS: Of the 444 patients, 78.4% were cured. A higher number of effective bactericidal drugs in the regimen at months 7-12 and 13-18, normal chest X-ray and body mass index ⩾18.5 kg/m(2) at the treatment start significantly increased the chances of cure both in all cases (aOR 2.29, aOR 4.39, aOR 1.18, aOR 1.98 and aOR 1.97, respectively) and in retreatment cases (aOR 3.88, aOR 5.02, aOR 1.17, aOR 2.26 and aOR 1.90, respectively). There was no added benefit of using moxifloxacin (MFX) as compared to levofloxacin (LVX) in case of resistance to ofloxacin. CONCLUSION: The use of a higher number of effective bactericidal drugs after month 6 of treatment for R(R)-TB was found to be the main factor associated with cure. No added benefit of using MFX instead of LVX was found. High cure rates can be achieved among vulnerable population groups such as prisoners if comprehensive TB control measures are in place to ensure low loss to follow-up.

Airway inflammation and basement membrane tenascin in newly diagnosed atopic and nonatopic asthma.

Previous studies have shown both similar and distinct inflammatory changes in atopic and nonatopic asthma. This study was set to investigate the bronchial inflammatory cell infiltrate and subepithelial basement membrane (BM) tenascin deposition in subjects with newly diagnosed asthma and bronchial hyperresponsiveness (BHR). Seventy-nine asthmatic subjects (age 18-60 years) were recruited and 58 were atopic according to skin prick testing. The patients recorded asthma symptoms and peak flow measurements for 14 days. Lung function and BHR were measured by spirometry and histamine challenge. Serum eosinophil cationic protein (ECP) and blood eosinophils were assessed. Fiberoptic bronchoscopy was performed to obtain bronchial biopsies. Serum ECP was higher in the atopic group but eosinophil counts did not differ. There were no differences in inflammatory cells studied (activated eosinophils, T-lymphocytes, mast cells or macrophages) between nonatopic and atopic subjects. BM tenascin layer was significantly thicker in atopic compared with nonatopic subjects (7.6 vs 6.3 microm, P = 0.007). The thickness of tenascin correlated with eosinophil, T-lymphocyte, and macrophage counts, as well as with IL-4-positive cell counts and the correlation was seen only in atopic asthmatics. These findings suggest that inflammatory cells may have a regulatory role in tenascin expression in atopic asthma.

Regular albuterol or nedocromil sodium--effects on airway subepithelial tenascin in asthma.

Both albuterol and nedocromil sodium have been recognized to possess certain anti-inflammatory properties. However, there are no data on the impact of these drugs on the pathophysiology of the bronchial extracellular matrix in asthma characterized by enhanced tenascin (Tn) expression, known to occur proportional to the severity of asthma. This paper reports data from a morphometric study on the effects of regular treatment with inhaled albuterol or nedocromil sodium on the extent of bronchial subepithelial deposition of Tn, collagen types III, IV, and VII and mucosal infiltration with macrophages. Thirty-two patients (14 women) with chronic asthma, aged 38.7 years (median) with a median forced expiratory volume in 1 sec (FEV1) of 74.4% predicted, were selected to undergo fibre-optic bronchoscopy with bronchial biopsies before and after 12 weeks of treatment with either inhaled albuterol 0.2 mg or nedocromil sodium 4 mg four times daily according to a double-blind protocol. Cryostat sections of the biopsy specimens were studied by indirect immunostaining techniques using monoclonal antibodies and computer-assisted quantitative image analysis. Albuterol treatment significantly reduced the median thickness of subepithelial Tn expression from 9.7 to 6.3 microns (P = 0.023) and macrophage numbers in the epithelium (P = 0.034), lamina propria (P = 0.039) and entire mucosa (P = 0.033), whereas nedocromil sodium had no effect. Expression of the collagen types was not affected by either treatment. There was no identifiable statistical difference between the two treatments for any of the outcome variables measured. Nevertheless, the results demonstrate that even a short-acting beta 2-agonist may exert anti-inflammatory potential sufficient to interfere with the basic mechanisms of asthma as shown by reduction of subepithelial Tn content and mucosal macrophage count.

A four-year nationwide molecular epidemiological study in Estonia: risk factors for tuberculosis transmission.

SETTING: Estonia has a high proportion of multidrug-resistant tuberculosis (MDR-TB). It is important to link molecular and epidemiological data to understand TB transmission patterns. OBJECTIVE: To use 24-locus variable numbers of tandem repeat (VNTR) typing and national TB registry data in Estonia from 2009 to 2012 to identify the distribution of drug resistance patterns, Mycobacterium tuberculosis isolate clustering as an index for recent transmission, socio-demographic and clinical characteristics associated with recent transmission, and the distribution of transmission between index and secondary cases. DESIGN: A retrospective nationwide cross-sectional study. RESULTS: Of 912 cases with isolate and patient information, 39.1% of isolates were from the Beijing lineage. Cluster analysis identified 87 clusters encompassing 69.1% of isolates. The largest cluster comprised 178 isolates from the Beijing lineage, of which 92.1% were MDR- or extensively drug-resistant TB (XDR-TB). Factors associated with recent transmission were polyresistant TB, MDR- and XDR-TB, human immunodeficiency virus positivity, Russian ethnicity, non-permanent living situation, alcohol abuse and detention. XDR-TB cases had the highest risk of recent transmission. The majority of transmission cases involved individuals aged 30-39 years. CONCLUSION: Recent TB transmission in Estonia is high and is particularly associated with MDR- and XDR-TB and the Beijing lineage.

Overall and cause-specific mortality among patients with tuberculosis and multidrug-resistant tuberculosis.

OBJECTIVE: To assess overall and cause-specific mortality among patients with tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB) in Estonia. DESIGN: A total of 2449 patients diagnosed with active respiratory TB from 1 January 2002 to 31 December 2009 were followed up retrospectively until 31 December 2011. To estimate the risk of death, standardised mortality ratios (SMR) and mortality rate ratios (RR) were calculated. RESULTS: The SMR for all-cause mortality among those diagnosed with TB was 5.30 (95%CI 4.85-5.75) in males and 10.00 (95%CI 8.25-11.74) in females. The relative risk of death from TB was higher among MDR-TB patients (adjusted RR in males 2.98, 95%CI 2.00-4.44, and in females 3.26, 95%CI 1.42-7.50) than among non-MDR-TB patients. Among the cohort of successfully treated patients, the SMR for all-cause mortality was 3.46 (95%CI 3.08-3.84) in males and 6.24 (95%CI 4.86-7.88) in females. Lower education level and foreign ethnicity contributed to the higher risk of mortality. Previous history of successfully treated MDR-TB did not increase the risk of death compared to successfully treated non-MDR-TB. CONCLUSIONS: Mortality among successfully treated TB and MDR-TB patients remained higher than among the general population. It was influenced by foreign ethnicity and lower education but, importantly, not by previous history of MDR-TB.

Predictors of recurrence of multidrug-resistant and extensively drug-resistant tuberculosis.

OBJECTIVE: To assess the treatment outcome of the first Green Light Committee (GLC) approved countrywide management of multidrug-resistant (MDR-) and extensively drug-resistant tuberculosis (XDR-TB) in Estonia and to evaluate risk factors contributing to TB recurrence over 8 years of follow-up. DESIGN: Prospective assessment of MDR- and XDR-TB patients starting second-line anti-tuberculosis drug treatment between 1 August 2001 and 31 July 2003, with follow-up until 31 December 2010. RESULTS: In 211 MDR- and XDR-TB patients, treatment success was 61.1%; 22.3% defaulted, 8.5% failed and 8.1% died. TB recurrence among successfully treated patients was 8.5%, with no significant difference between XDR-TB and MDR-TB. TB recurrence was associated with resistance to all injectables (HR 2.27, 95%CI 1.16-5.06, P = 0.046), resistance to a greater number of drugs (HR 1.35, 95%CI 1.11-1.64, P = 0.003), and sputum smear positivity (HR 2.16, 95%CI 1.16-4.00, P = 0.016). A history of previous TB treatment was associated with TB recurrence among successfully treated patients (HR 4.28, 95%CI 1.13-16.15, P = 0.032). CONCLUSIONS: The internationally recommended Category IV treatment regimens are sufficiently effective to cure 75% of adherent MDR- and XDR-TB patients. A history of previous treatment, resistance to all injectable agents and resistance to a greater number of drugs increase the recurrence of MDR- and XDR-TB.

Countrywide management of pulmonary tuberculosis reverses increasing incidence.

OBJECTIVE: To evaluate the impact of countrywide management of tuberculosis (TB) and the availability of second-line drugs (SLDs) on the notification rates of pulmonary TB (PTB) overall and of multidrug-resistant TB (MDR-TB), taking into account human immunodeficiency virus (HIV) co-infection and the national economy in Estonia. DESIGN: Retrospective analysis of notification rates and treatment outcomes of PTB and MDR-TB during 1998-2006. RESULTS: The annual notification rates of both PTB and MDR-TB decreased significantly, by on average 3.3 (P = 0.007) and 1.7 (P = 0.008) cases per 100,000 population, respectively. The accelerating impact of SLD availability on the annual decline was significant for both PTB overall and MDR-TB (P = 0.003 and P = 0.025, respectively). During 1998-2006, an increase in TB-HIV co-infection (P = 0.009) significantly affected the notification rates of both PTB overall and MDR-TB (P < 0.001 and P < 0.001, respectively). The negative impact of TB-HIV co-infection was counterbalanced by the availability of SLDs, the decrease in the MDR-TB rate and the increase in gross domestic product (GDP) per capita, as confirmed by multivariate analysis. CONCLUSION: Countrywide access to SLDs and the coordinated effect of programmatic conditions can, in parallel with increasing GDP, reverse the increasing notification rates of PTB and MDR-TB in the context of an HIV epidemic.

Predictors and mortality associated with treatment default in pulmonary tuberculosis.

OBJECTIVE: To identify risk factors for default from pulmonary tuberculosis (TB) treatment and to assess mortality associated with default in Estonia. DESIGN: All patients with culture-confirmed pulmonary TB who started treatment during 2003-2005 were included in a retrospective cohort study. RESULTS: In 1107 eligible patients, the treatment success rate was 81.5% and the default rate 9.4% (respectively 60.4% and 17.0% in multidrug-resistant TB [MDR-TB]). Independent predictors of treatment default were alcohol abuse (OR 3.22, 95%CI 1.93-5.38), unemployment (OR 3.05, 95%CI 1.84-5.03), MDR-TB (OR 2.17, 95%CI 1.35-3.50), urban residence (OR 1.85, 95%CI 1.00-3.42) and previous incarceration (OR 1.78, 95%CI 1.05-3.03). Of the defaulters, 29.4% died during follow-up (median survival 342.0 days). Cox regression analysis revealed that unemployment was associated with all-cause and TB-related mortality among defaulters (respectively HR 4.58, 95%CI 1.05-20.1 and HR 11.2, 95%CI 1.58-80.2). HIV infection (HR 51.2, 95%CI 6.06-432), sputum smear positivity (HR 9.59, 95%CI 1.79-51.4), MDR-TB (HR 8.56, 95%CI 1.81-40.4) and previous TB (HR 5.15, 95%CI 1.64-16.2) were predictors of TB-related mortality. CONCLUSION: The main risk factors for treatment default can be influenced. Interventions to reduce default should therefore concentrate on socially disadvantaged patients and prevention of alcohol abuse, with special attention given to MDR-TB patients.

Histopathologic features of early and progressive asthma.

During the last decade, morphologic studies on bronchial biopsy specimens have led to our present understanding of asthma as an inflammatory airways disease. However, little knowledge exists about the sequence of cellular events during the disease or of possible mucosal changes early in asthma. So far the primary cause, the site of damage, and the mechanisms inducing the inflammatory reaction remain to be elucidated. A multifactorial genetic susceptibility may be important for the development of asthma. Suggested factors that may trigger changes in the cells' morphologic and functional phenotype are viral infections, allergen exposure, maternal factors, diet, and smoking. Current evidence has implied that interactions between epithelial cells and the subepithelial connective tissue in the mucosa are important for normal homeostatic balance. Changes in airway epithelial phenotype possibly resulting from altered gene expression in its lining cells may be very important even as a first line change in asthma.

Early interventions in asthma with inhaled corticosteroids.

We have earlier shown epithelial damage in the airway mucosa in patients with asthma. Later other structural changes have been recognized in asthma, such as deposition of collagen and tenascin in the subepithelial basement membrane and changes in the laminin subchain composition. These processes are modified by an inflammatory process in the airways. Both the United States National Institutes of Health and the British Thoracic Society guidelines on the management of asthma emphasize the need for early use of anti-inflammatory drugs. Many clinical studies that used airway biopsy specimens have shown a decrease in airway inflammatory cell numbers after inhaled corticosteroid therapy. However, there is very little information on the effects of asthma medication on the structural components of the airways. Both the synthesis and degradation of many extracellular matrix components may be affected by the disease process and the drugs resulting in altered remodeling and gene expression in the airways. Because there are only a few studies that try to identify early changes in asthma, it is not known whether the anti-inflammatory treatment of asthma proposed by the guidelines is started early enough.

Tenascin is increased in airway basement membrane of asthmatics and decreased by an inhaled steroid.

Tenascin and fibronectin are extracellular matrix glycoproteins expressed during morphogenesis and tissue repair. In the present study bronchial biopsies were studied by the morphometric method of immunocytochemistry to reveal the distribution of different tenascin and fibronectin isoforms as well as the presence of inflammatory cells in the airway mucosa of patients with chronic asthma (n = 32) and those with seasonal birch-pollen-sensitive asthma out of season (n = 17), both in comparison with healthy control subjects (n = 12). The results showed an increase in tenascin immunoreactivity in the bronchial subepithelial reticular basement membrane layer in patients with chronic asthma (p < 0.0001) and in those with seasonal asthma (p < 0.01) compared with control subjects. The tenascin immunoreactivity, appearing as an intense wide subepithelial band in asthma, was seen only occasionally in the basement membrane of control specimens. Instead, a diffuse immunoreaction against both total fibronectin and locally produced extradomain A fibronectin was similarly visible in the airway mucosa of both patients and control subjects. Despite the significant increase in the airway mucosa of eosinophils and lymphocytes in patients with chronic asthma (p < 0.0001 and p < 0.0001, respectively) and of eosinophils in patients with seasonal asthma (p < 0.001), there was no correlation between the number of these cell types and level of tenascin expression. In patients with birch-pollen-sensitive asthma during the birch-pollen season, inhaled corticosteroid treatment, budesonide 400 micrograms twice daily, decreased tenascin immunoreactivity, in comparison with effects of placebo (p = 0.01). Our results suggest that the higher amount of tenascin reflects disease activity in asthma and may be an indicator of a remodeling process rather than of injury itself.

Effect of regular nedocromil sodium or albuterol on bronchial inflammation in chronic asthma.

Nedocromil sodium is recommended for daily treatment of mild persistent asthma but its effect on cellular changes in asthmatic airways is poorly understood. We compared the antiinflammatory effects of nedocromil sodium and albuterol in 32 patients with asthma who received either nedocromil sodium 4 mg or albuterol 0.2 mg four times daily for 12 weeks according to a double-blind protocol. Patients underwent fiberoptic bronchoscopy, and lung function and bronchial responsiveness to histamine were measured. Numbers of inflammatory cells were studied by immunohistochemistry and image analysis. We were unable to identify any statistical differences between treatment groups for any of the variables measured. We conclude that our immunohistochemical study does not support the concept of nedocromil sodium as a potent/antiinflammatory drug.

Evidence of airway inflammation and remodeling in ski athletes with and without bronchial hyperresponsiveness to methacholine.

Asthma-like symptoms, methacholine hyperresponsiveness, and use of asthma medication are prevalent in elite cross-country skiers. We quantitated mucosal inflammatory cell infiltration and tenascin expression in the subepithelial basement membrane in endobronchial biopsy specimens of the proximal airways from 40 elite, competitive skiers (mean: 17.5; range: 16 to 20 yr) without a diagnosis of asthma, in 12 subjects with mild asthma, and in 12 healthy controls, through immunohistochemistry and indirect immunofluorescence, respectively. All of the subjects were nonsmokers. T-lymphocyte, macrophage, and eosinophil counts were, respectively, greater by 43-fold (p < 0.001), 26-fold (p < 0.001), and twofold (p < 0.001) in skiers, and by 70-fold (p < 0.001), 63-fold (p < 0.001), and eightfold (p < 0.001) in asthmatic subjects than in controls. In skiers, neutrophil counts were more than twofold greater than in asthmatic subjects, and mast cell counts were not significantly different than in controls. Tenascin expression (as measured through the thickness of the tenascin-specific immunoreactivity band in the basement membrane) was increased in skiers (median: 6.7 microm; interquartile range [IQR]: 5.3 to 8.5 microm, p < 0.001) and asthmatic subjects (mean: 8.8 microm; IQR: 7.2 to 10.8 microm, p < 0. 001) compared with controls (mean: 0.8 microm; IQR: 0 to 3.1 microm) and did not correlate with inflammatory cell counts. Inflammatory changes were present irrespective of asthmalike symptoms, hyperresponsiveness, or atopy. Prolonged repeated exposure of the airways to inadequately conditioned air may induce inflammation and remodeling in competitive skiers.