Interactions between SERPINA1 PiMZ genotype, occupational exposure and lung function decline.

OBJECTIVES: We evaluated interactions between SERPINA1 PiMZ genotype, associated with intermediate α1-antitrysin deficiency, with outdoor particulate matter ≤10 µm (PM10), and occupational exposure to vapours, dusts, gases and fumes (VGDF), and their effects on annual change in lung function. METHODS: Pre-bronchodilator spirometry was performed in 3739 adults of the Swiss Cohort Study on Air Pollution and Lung Disease in Adults (SAPALDIA) for whom SERPINA1 genotypes were available. At baseline in 1991, participants were aged 18-62 years; follow-up measurements were conducted from 2001 to 2003. In linear mixed regression models of annual change in lung function, multiplicative interactions were evaluated between PiMZ genotype (PiMM as reference) and change in PM10 (µg/m(3)), and VGDF exposure (high-level, low-level or no exposure as reference) during follow-up. RESULTS: Annual declines in forced expiratory flow at 25-75% of forced vital capacity (FEF25-75%) (-82 mL/s, 95% CI -125 to -39) and forced expiratory volume in 1 s over forced vital capacity (FEV1/FVC) (-0.3%, 95% CI -0.6% to 0.0%) in association with VGDF exposure were observed only in PiMZ carriers (Pinteraction<0.0001 and Pinteraction=0.03, respectively). A three-way interaction between PiMZ genotype, smoking and VGDF exposure was identified such that VGDF-associated FEF25-75% decline was observed only in ever smoking PiMZ carriers (Pinteraction=0.01). No interactions were identified between PiMZ genotype and outdoor PM10. CONCLUSIONS: SERPINA1 PiMZ genotype, in combination with smoking, modified the association between occupational VGDF exposure and longitudinal change in lung function, suggesting that interactions between these factors are relevant for lung function decline. These novel findings warrant replication in larger studies.

Diagnosis and management of chronic obstructive pulmonary disease: the Swiss guidelines. Official guidelines of the Swiss Respiratory Society.

The new Swiss Chronic Obstructive Pulmonary Disease (COPD) Guidelines are based on a previous version, which was published 10 years ago. The Swiss Respiratory Society felt the need to update the previous document due to new knowledge and novel therapeutic developments about this prevalent and important disease. The recommendations and statements are based on the available literature, on other national guidelines and, in particular, on the GOLD (Global Initiative for Chronic Obstructive Lung Disease) report. Our aim is to advise pulmonary physicians, general practitioners and other health care workers on the early detection and diagnosis, prevention, best symptomatic control, and avoidance of COPD as well as its complications and deterioration.

[Dyspnoea, cough and B symptoms in a 40-year-old woman]. / Husten, Atemnot und B-Symptome bei einer 40-jährigen Frau.

Multicentric Castleman's disease (MCD) is a rare polyclonal lymphoproliferative disorder that is typically accompanied by an overproduction of circulating cytokines (mainly interleukin-6). We here report the case of a 40-year-old HIV-negative woman with pulmonary manifestation of MCD. There is no standard treatment for MCD. In our patient, various treatment courses with immunomodulatory drugs were unsuccessful. Finally, treatment with the interleukin-6 receptor antibody tocilizumab has resulted in continual clinical improvement over the last 5 years.

Prevalence and prediction of exercise-induced oxygen desaturation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Previous studies with small sample sizes reported contradicting findings as to whether pulmonary function tests can predict exercise-induced oxygen desaturation (EID). OBJECTIVE: To evaluate whether forced expiratory volume in one second (FEV(1)), resting oxygen saturation (SpO(2)) and diffusion capacity for carbon monoxide (DLCO) are predictors of EID in chronic obstructive pulmonary disease (COPD). METHODS: We measured FEV(1), DLCO, SpO(2) at rest and during a 6-min walking test as well as physical activity by an accelerometer. A drop in SpO(2) of >4 to <90% was defined as EID. To evaluate associations between measures of lung function and EID univariate and multivariate analyses were used and positive/negative predictive values were calculated. Receiver operating characteristic curve analysis was performed to determine the most useful threshold in order to predict/exclude EID. RESULTS: We included 154 patients with COPD (87 females). The mean FEV(1) was 43.0% (19.2) predicted and the prevalence of EID was 61.7%. The only independent predictor of EID was FEV(1) and the optimal cutoff value of FEV(1) was at 50% predicted (area under ROC curve, 0.85; p < 0.001). The positive predictive value of a threshold of FEV(1) <50% was 0.83 with a likelihood ratio of 3.03 and the negative predicting value of a threshold of FEV(1) ≥80% was 1.0. The severity of EID was correlated with daily physical activity (r = -0.31, p = 0.008). CONCLUSIONS: EID is highly prevalent among patients with COPD and can be predicted by FEV(1). EID seems to be associated with impaired daily physical activity which supports its clinical importance.

Longitudinal change of prebronchodilator spirometric obstruction and health outcomes: results from the SAPALDIA cohort.

BACKGROUND: Understanding the prognostic meaning of early stages of chronic obstructive pulmonary disease (COPD) in the general population is relevant for discussions about underdiagnosis. To date, COPD prevalence and incidence have often been estimated using prebrochodilation spirometry instead of postbronchodilation spirometry. In the SAPALDIA (Swiss Study on Air Pollution and Lung Disease in Adults) cohort, time course, clinical relevance and determinants of severity stages of obstruction were investigated using prebronchodilator spirometry. METHODS: Incident obstruction was defined as an FEV(1)/FVC (forced expiratory volume in 1 s/forced vital capacity) ratio >or=0.70 at baseline and <0.70 at follow-up, and non-persistence was defined inversely. Determinants were assessed in 5490 adults with spirometry and respiratory symptom data in 1991 and 2002 using Poisson regression controlling for self-declared asthma and wheezing. Change in obstruction severity (defined analogously to the GOLD (Global Initiative for Chronic Obstructive Lung Disease) classification) over 11 years was related to shortness of breath and health service utilisation for respiratory problems by logistic models. RESULTS: The incidence rate of obstruction was 14.2 cases/1000 person years. 20.9% of obstructive cases (n = 113/540) were non-persistent. Age, smoking, chronic bronchitis and non-current asthma were determinants of incidence. After adjustment for asthma, only progressive stage I or persistent stage II obstruction was associated with shortness of breath (OR 1.71, 95% CI 0.83 to 3.54; OR 3.11, 95% CI 1.50 to 6.42, respectively) and health service utilisation for respiratory problems (OR 2.49, 95% CI 1.02 to 6.10; OR 4.17 95% CI 1.91 to 9.13, respectively) at follow-up. CONCLUSIONS: The observed non-persistence of obstruction suggests that prebronchodilation spirometry, as used in epidemiological studies, might misclassify COPD. Future epidemiological studies should consider both prebronchodilation and postbronchodilation measurements and take specific clinical factors related to asthma and COPD into consideration for estimation of disease burden and prediction of health outcomes.

HMOX1 and GST variants modify attenuation of FEF25-75% decline due to PM10 reduction.

Reduced exposure to particulate matter with a 50% cut-off aerodynamic diameter of 10 microm (PM(10)) attenuated age-related lung function decline in our cohort, particularly in the small airways. We hypothesised that polymorphisms in glutathione S-transferase (GST) and haem oxygenase-1 (HMOX1) genes, important for oxidative stress defence, modify these beneficial effects. A population-based sample of 4,365 adults was followed up after 11 yrs, including questionnaire, spirometry and DNA blood sampling. PM(10) exposure was estimated by dispersion modelling and temporal interpolation. The main effects on annual decline in forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%)) and interactions with PM(10) reduction were investigated for polymorphisms HMOX1 rs2071746 (T/A), rs735266 (T/A) and rs5995098 (G/C), HMOX1 (GT)(n) promoter repeat, GSTM1 and GSTT1 deletions, and GSTP1 p.Ile105Val, using mixed linear regression models. HMOX1 rs5995098, HMOX1 haplotype TTG and GSTP1 showed significant genetic main effects. Interactions with PM(10) reduction were detected: a 10 microg.m(-3) reduction significantly attenuated annual FEF(25-75%) decline by 15.3 mL.s(-1) only in the absence of HMOX1 haplotype ATC. Similarly, carriers of long (GT)(n) promoter repeat alleles or the GSTP1 Val/Val genotype profited significantly more from a 10 microg.m(-3) reduction (26.5 mL.s(-1) and 27.3 mL.s(-1) respectively) than non-carriers. Benefits of a reduction in PM(10) exposure are not equally distributed across the population but are modified by the individual genetic make-up determining oxidative stress defence.

Prevalence of airflow obstruction in smokers and never-smokers in Switzerland.

The aim of the present study was to measure age-specific prevalence of airflow obstruction in Switzerland in smokers and never-smokers using pulmonary function tests and respiratory symptoms from 6,126 subjects participating in the Swiss Cohort Study on Air Pollution and Lung Diseases in Adults. The lower limit of normal of the forced expiratory volume in 1 s/forced vital capacity ratio was used to define airflow obstruction. Severity of airflow obstruction was graded according to the recommendations of the Global Initiative for Chronic Obstructive Lung Disease. Prevalence of airflow obstruction ranged from 2.5% in subjects aged 30-39 yrs to 8.0% in those aged ≥ 70 yrs. In multivariate analysis, age (OR 2.8, ≥ 70 yrs versus 30-39 yrs), smoking (OR 1.8) and asthma (OR 6.7) were associated with airflow obstruction. Never-smokers constituted 29.3% of subjects with airflow obstruction. Never-smokers with airflow obstruction were younger, more likely to be male and reported asthma more frequently than obstructive smokers. Obstructive smokers and never-smokers had similar level of symptoms and quality of life impairment. The prevalence of airflow obstruction in Switzerland is similar to other developed countries. Never-smokers account for a third of the prevalence, which is higher proportion than elsewhere. Airflow obstruction in never-smokers deserves attention because of its frequency and its similar health impact to that in smokers.

Disability and survival in Duchenne muscular dystrophy.

BACKGROUND: Duchenne muscular dystrophy (DMD) leads to progressive impairment of muscle function, respiratory failure and premature death. Longitudinal data on the course of physical disability and respiratory function are sparse. OBJECTIVES: To assess prospectively physical impairment and disability, respiratory function and survival in patients with DMD over several years to describe the course of the disease with current care. METHODS: In 43 patients with DMD, aged 5-35 years, yearly assessments of physical disability by the Duchenne muscular dystrophy physical Impairment and Dependence on care (DID) score, ranging from 9 (no disability) to 80 (complete dependence), and forced vital capacity (FVC), were obtained over a mean time interval of 5.4 (SD 2.1) years. RESULTS: DID scores were correlated with age according to a hyperbolic function (f = 85.3 x age/(10.05+age), R = 0.62, p<0.0001). FVC declined exponentially with age (f = 139.1 x exp(-0.08 x age), R = 0.52, p<0.0001). Mean age at which patients lost their ambulation was 9.4 (SD 2.4) years and they became dependent on an electric wheelchair at 14.6 (4.0) years. Age at the beginning of assisted ventilation was 19.8 (3.9) years, Three patients died during the observation period. The estimated probability of survival to age 30 years was 85% (median survival was 35 years). CONCLUSIONS: Our detailed observations of the progression of physical disability, dependence on care and respiratory impairment in patients with DMD from childhood to adult life is valuable for predicting the clinical course with current medical care. Compared with historical data, survival has improved considerably.

Does oral alprazolam affect ventilation? A randomised, double-blind, placebo-controlled trial.

The respiratory effects of benzodiazepines have been controversial. This investigation aimed to study the effects of oral alprazolam on ventilation. In a randomised, double-blind cross-over protocol, 20 healthy men ingested 1 mg of alprazolam or placebo in random order, 1 week apart. Ventilation was unobtrusively monitored by inductance plethysmography along with end-tidal PCO(2) and pulse oximetry 60-160 min after drug intake. Subjects were encouraged to keep their eyes open. Mean +/- SD minute ventilation 120 min after alprazolam and placebo was similar (6.21 +/- 0.71 vs 6.41 +/- 1.12 L/min, P = NS). End-tidal PCO(2) and oxygen saturation did also not differ between treatments. However, coefficients of variation of minute ventilation after alprazolam exceeded those after placebo (43 +/- 23% vs 31 +/- 13%, P < 0.05). More encouragements to keep the eyes open were required after alprazolam than after placebo (5.2 +/- 5.7 vs 1.3 +/- 2.3 calls, P < 0.05). In a multiple regression analysis, higher coefficients of variation of minute ventilation after alprazolam were related to a greater number of calls. Oral alprazolam in a mildly sedative dose has no clinically relevant effect on ventilation in healthy, awake men. The increased variability of ventilation on alprazolam seems related to vigilance fluctuations rather than to a direct drug effect on ventilation.

Novel mutations in the folliculin gene associated with spontaneous pneumothorax.

Spontaneous pneumothorax is mostly sporadic but may also occur in families with genetic disorders, such as Birt-Hogg-Dubé syndrome, which is caused by mutations in the folliculin (FLCN) gene. The aim of the present study was to investigate the presence and type of mutation in a Swiss pedigree and in a sporadic case. Clinical examination, lung function tests and high-resolution computed tomography were performed. All coding exons and flanking intronic regions of FLCN were amplified by PCR and directly sequenced. The amount of FLCN transcripts was determined by quantitative real-time RT-PCR. Two novel mutations in FLCN were identified. Three investigated family members with a history of at least one spontaneous pneumothorax were heterozygous for a single nucleotide substitution (c.779G>A) that leads to a premature stop codon (p.W260X). Quantitative real-time RT-PCR revealed a reduction of FLCN transcripts from the patient compared with an unaffected family member. DNA from the sporadic case carried a heterozygous missense mutation (c.394G>A). Lung function of this patient was normal and computed tomography showed similar bilateral cysts, as observed in the two members of the unrelated Swiss family. Mutations in the folliculin gene are associated with cystic lung lesions in an otherwise morphological normal lung and predispose to spontaneous pneumothorax.

Periodic whole body acceleration: a novel therapy for cardiovascular disease.

BACKGROUND: Periodic whole body acceleration in the spinal axis (pGz) applied by a motion platform is a novel treatment modality that induced endothelial nitric oxide release into the circulation of animals, healthy subjects and patients with inflammatory diseases during single treatment sessions in previous studies. We hypothesized that patients with advanced arteriosclerotic diseases who are not candidates for a surgical intervention would clinically benefit from repeated pGz treatments over several weeks through improvement of endothelial function. PATIENTS AND METHODS: 11 patients, 5 men (37 to 71 y) with stable ischemic heart disease, LVEF < 35%, NYHA stage > II, and 6 patients (51 to 83 y, 1 woman) with intermittent leg claudication, Fontaine stage II, were enrolled after optimization of pharmacological therapy. PGz was applied for 40 min, 5 days/week during 5 weeks. Quality of life (SF-36 questionnaire), exercise performance, and endothelial function were assessed at baseline, during the treatment period, and 4 weeks after discontinuation of pGz. RESULTS: PGz was well tolerated. In heart failure paitents, pGz therapy improved quality of life, increased 6 min walking distance by a mean +/- SE of 105 +/- 24 m, and improved postischemic skin hyperemia (p < .05 in all instances). In 4 of 6 patients with intermittent claudication, quality of life, treadmill walking distance and post-ischemic skin hyperemia improved with pGz therapy (p < .05). Four weeks after discontinuation of pGz, most therapeutic effects had vanished in both patient groups. CONCLUSIONS: In patients with severe heart failure and with leg claudication who remain symptomatic despite maximal medical therapy and who were not candidates for surgery, periodic acceleration applied over several weeks improved quality of life and exercise capacity. The clinical benefits appear to be mediated through improved endothelial function.

[Physical examination of the lung--value and limits]. / Untersuchung der Lungen--Nutzen und Grenzen.

Sensitivity and specificity of clinical findings for the diagnosis of pulmonary diseases is often poor, or information on test characteristics of particular findings is even missing. Nevertheless, a meticulous clinical exam remains a cornerstone in clinical practice. Quite often clear-cut findings may provide valuable diagnostic information. Furthermore, history taking and painstaking physical examination foster the confidence between patients and physicians, which is urgently needed in a time of machine-dominated medical practice.

Shortcomings of chest radiography in detecting Pneumocystis carinii pneumonia.

The radiographic presentation of Pneumocystis carinii pneumonia (PCP) was studied in 93 consecutive patients to determine the frequency of normal findings on chest roentgenograms and possible correlations with clinical or laboratory findings. The roentgenograms were reviewed by two radiologists in an independent, blinded way and judged with a score distinguishing between none, interstitial, and acinar infiltrates. Discordance mainly between absent versus interstitial and interstitial versus acinar infiltrates occurred in 23% of roentgenograms and was settled by consensus. The majority of patients presented with moderate-to-mild symptoms; the combination of dyspnea, cough, and fever was present in 53%. Lactate dehydrogenase (LDH) was elevated in 63%, hypoxemia (PaO2 < 75 mm Hg) was present in 57%. Findings on chest roentgenograms were normal in 39%, whereas 36% showed interstitial and 25% acinar infiltrates. These three radiographic groups represented an increasingly severe PCP, indicated by higher LDH levels and hypoxemia (both p < 0.05). In a multivariate logistic regression, normal roentgenograms were predicted by low LDH and low peripheral blood granulocytes (p < 0.005). Mortality within 3 weeks was only 4% and correlated with the severity of infiltrates (p < 0.05). Normal roentgenograms thus corresponded to an oligosymptomatic, less severe PCP. In immunodeficient HIV-infected patients, a normal chest roentgenogram does not exclude PCP and should not distract from attaining a definite diagnosis by examination of induced sputum or bronchoalveolar lavage.

Osteonecrosis after lung transplantation: cystic fibrosis as a potential risk factor.

BACKGROUND: Osteonecrosis is a known complication after transplantation of solid organs. The incidence of osteonecrosis after lung transplantation is not well documented. METHODS: We investigated the incidence of symptomatic osteonecrosis in lung transplant recipients, transplanted between November 1992 and June 1998 at our institution. For the detection of osteonecrosis, all patients complaining of musculoskeletal pain underwent magnetic resonance imaging. Demographic characteristics, time after transplantation, etiology of underlying lung disease, and the number of steroid pulses for rejection episodes were compared for patients with and without osteonecrosis. RESULTS: Of 63 transplant recipients, all 49 with a follow-up of >3 months were included for analysis. Of seven symptomatic transplant recipients, five cases of osteonecrosis (10%) were detected at a median duration of 216 days (range 44-600) after transplantation. Patients with osteonecrosis have been treated with the same immunosuppressive regimen and with an equal number of steroid pulses for acute rejection episodes (1.4+/-1.1 vs. 1.4+/-1.5, P=0.69), but were younger (26+/-8 vs. 40+/-11 years, P<0.01) than other transplant recipients. Symptomatic osteonecrosis was detected in four of 14 patients (29%) with cystic fibrosis (CF), compared with one osteonecrosis among 35 patients (3%) with other underlying diseases (P<0.02). Within the group of CF patients, specific clinical and demographic characteristics correlating with the risk for subsequent osteonecrosis could not be found. CONCLUSION: In lung transplant recipients, CF may be a risk factor for the development of symptomatic osteonecrosis.

Comparative modification of antigen-induced bronchoconstriction by the calcium antagonists, nifedipine and verapamil.

We compared the effects of the two calcium antagonists, nifedipine and verapamil, on baseline airway function and antigen-induced bronchoconstriction in asymptomatic subjects with ragweed hypersensitivity and a history of bronchial asthma. Twelve subjects received a single oral dose of 20 mg of nifedipine or 160 mg of verapamil before inhalation with ragweed antigen. Mean specific airway conductance, a measurement of airway obstruction, was not affected by either agent; nifedipine caused bronchodilatation in two subjects, and verapamil was followed by slight bronchoconstriction in another subject. Nifedipine partially or completely blocked the antigen-induced bronchoconstriction in 67 percent (8/12) of the subjects (p less than 0.05). Two of the subjects who were protected by nifedipine were also protected by pretreatment with verapamil, while this drug was without effect in the others. This study demonstrates that both nifedipine and verapamil in a single oral dose may attenuate antigen-induced bronchoconstriction in some subjects with allergic bronchial asthma and that nifedipine may be more effective than verapamil.

Endobronchial lipomatous hamartoma: a rare cause of bronchial occlusion.

A 74-year-old man presented with shortness of breath and vague chest pain. A chest roentgenogram showed subtotal atelectasis of the upper lobe of the left lung and a CT scan revealed an occlusion of the bronchus of the upper lobe of the left lung by an intraluminal tumor. A well-circumscribed yellow tumor obstructing the bronchus of the upper lobe of the left lung was seen by fiberoptic bronchoscopy. Biopsies revealed mature fat tissue and small areas with bone consistent with the diagnosis of an endobronchial predominantly lipomatous hamartoma.

Lung volume reduction surgery: a survey on the European experience.

STUDY OBJECTIVE: To evaluate the activity and evolution in the field of lung volume reduction surgery (LVRS) performed at surgical centers in Europe. BACKGROUND: LVRS is a novel surgical therapy with the potential to improve lung function, exercise performance, and quality of life in selected patients suffering from severe pulmonary emphysema. METHODS: Questionnaire addressed to 75 European thoracic surgical centers presumed to perform LVRS, and review of the literature. RESULTS: Of 45 responding centers, 42 centers in 17 countries covering a population of 423 million reported performing LVRS. Until the end of 1998, 1,120 patients were reported to have undergone LVRS, corresponding to 2.6 patients/million inhabitants. Thirty-one of 40 centers (78%) perform the operation bilaterally. Most centers (83%) evaluate their activity prospectively. The average perioperative mortality rate of 4.1% is moderate. The most commonly utilized technique is video-assisted thoracoscopy, which is most frequently performed bilaterally. Two thirds of the centers treat patients with alpha(1)-antitrypsin deficiency, and half of the centers will consider patients with homogenous morphology of emphysema on CT scan for LVRS. Half of the centers also perform lung transplantation. The five largest centers have operated on 49% of all LVRS patients assessed by this survey. CONCLUSIONS: LVRS is performed at few thoracic surgical centers throughout Europe, with a large variation in the operative activity between different regions. Half of the centers also perform lung transplantation. Between 1995 and 1997, the number of LVRS procedures performed per year nearly tripled but has reached a plateau since then. As five centers perform nearly half the total number of operations, an optimal exchange of knowledge with smaller centers seems important.

Pulmonary hypertension five years after left pneumonectomy for adenoid cystic carcinoma.

We report the findings in a patient with shortness of breath due to pulmonary hypertension five years after left pneumonectomy. Mediastinal recurrence of an incompletely resected and slowly growing adenoid cystic carcinoma of the left main bronchus had encased the right main pulmonary artery.

Primary pulmonary hypertension in HIV infection.

A prospective evaluation of 74 human immunodeficiency virus (HIV)-infected patients with cardiopulmonary complaints revealed six patients (8.1 percent) with pulmonary hypertension with elevated right ventricular systolic over right atrial pressure of 58 +/- 8 mm Hg (range, 49 to 66 mm Hg), as documented by Doppler echocardiography. A thromboembolic cause was excluded by normal lung perfusion scans. Electrocardiographic and roentgenographic features of pulmonary hypertension were present in five patients. Two patients died three and nine months after diagnosis of pulmonary hypertension. Autopsy revealed plexogenic pulmonary arteriopathy in both. The observation of six patients with primary pulmonary hypertension (PPH) in a cohort of 1,200 HIV-infected subjects corresponding to an incidence of 0.5 percent is striking and suggests a possible association of PPH with HIV infection.

Whole-lung lavage in alveolar proteinosis by a modified lavage technique.

Whole-lung lavage is the only efficient treatment in pulmonary alveolar proteinosis. A 36-year-old woman with severe pulmonary alveolar proteinosis confirmed by video-assisted thoracoscopic lung biopsies underwent repetitive whole-lung lavages without improvement. A modified technique consisting of manual ventilation between instillation and aspiration of half the amount of saline used for conventional lavage was applied. Impressive clinical and functional improvement occurred and persisted for 1 year. We believe that the amelioration can be attributed to the technique described above.