Alpha1-antitrypsin deficiency in Greece: Focus on rare variants.

PURPOSE: A1Antitrypsin deficiency (AATD) pathogenic mutations are expanding beyond the PI*Z and PI*S to a multitude of rare variants. AIM: to investigate genotype and clinical profile of Greeks with AATD. METHODS: Symptomatic adult-patients with early-emphysema defined by fixed airway obstruction and computerized-tomography scan and lower than normal serum AAT levels were enrolled from reference centers all over Greece. Samples were analyzed in the AAT Laboratory, University of Marburg-Germany. RESULTS: Included are 45 adults, 38 homozygous or compound heterozygous for pathogenic variants and 7 heterozygous. Homozygous were 57.9% male, 65.8% ever-smokers, median (IQR) age 49.0(42.5-58.5) years, AAT-levels 0.20(0.08-0.26) g/L, FEV1(%predicted) 41.5(28.8-64.5). PI*Z, PI*Q0, and rare deficient allele's frequency was 51.3%, 32.9%,15.8%, respectively. PI*ZZ genotype was 36.8%, PI*Q0Q0 21.1%, PI*MdeficientMdeficient 7.9%, PI*ZQ0 18.4%, PI*Q0Mdeficient 5.3% and PI*Zrare-deficient 10.5%. Genotyping by Luminex detected: p.(Pro393Leu) associated with MHeerlen (M1Ala/M1Val); p.(Leu65Pro) with MProcida; p.(Lys241Ter) with Q0Bellingham; p.(Leu377Phefs*24) with Q0Mattawa (M1Val) and Q0Ourem (M3); p.(Phe76del) with MMalton (M2), MPalermo (M1Val), MNichinan (V) and Q0LaPalma (S); p.(Asp280Val) with PLowell (M1Val); PDuarte (M4), YBarcelona (p.Pro39His). Gene-sequencing (46.7%) detected Q0GraniteFalls, Q0Saint-Etienne, Q0Amersfoort(M1Ala), MWürzburg, NHartfordcity and one novel-variant (c.1A>G) named Q0Attikon.Heterozygous included PI*MQ0Amersfoort(M1Ala), PI*MMProcida, PI*Mp.(Asp280Val), PI*MOFeyzin. AAT-levels were significantly different between genotypes (p = 0.002). CONCLUSION: Genotyping AATD in Greece, a multiplicity of rare variants and a diversity of rare combinations, including unique ones were observed in two thirds of patients, expanding knowledge regarding European geographical trend in rare variants. Gene sequencing was necessary for genetic diagnosis. In the future the detection of rare genotypes may add to personalize preventive and therapeutic measures.

Evaluation of respiratory parameters in finswimmers regarding gender, swimming style and distance.

AIM: The purpose of our study was to investigate the differences in the finswimmers' physiological characteristics, as far as gender, the swimming style and the different swimming distance are concerned. METHODS: 52 finswimmers participated in our study (Age: 17.4 ±â€¯2.1yrs, BMI: 21.8 ±â€¯2.3, body fat: 12.2 ±â€¯4.7%) and were allocated into groups [Gender: Female vs. Male, swimming style: Bifin vs. Surface, and swimming distance: <200 m vs. ≥200 m]. Anthropometric characteristics, handgrip, estimated strength of inspiratory muscles (PImax) and pulmonary function parameters (FEV1, FVC and PEF) were measured. The Independent T-test was used for statistical comparisons between groups. Multivariate analyses were performed via binary logistic regression. RESULTS: The results showed differences between groups in gender in PEF (p < 0.05), PImax (p < 0.05) and handgrip (p < 0.001) in swimming style in handgrip (p < 0.05), FEV1 (p < 0.05) and FVC (p < 0.05) and in swimming distance (p < 0.05) in hours/day spent at the gym (p < 0.05) and FVC (p < 0.05). In multivariate analyses handgrip remained an independent predictor of style (OR: 1.154; 95%CI: 1.022-1.303, p = .021), and hours/day spent at the gym was retained as an independent predictor of distance (OR: 131.607; 95%CI: 3.655-4739.441, p = .008). CONCLUSION: The data from the present study reveal that handgrip was associated with style, and hours per day spent at the gym were associated with distance.

Prediction of particle deposition in the lungs based on simple modeling of alveolar mixing.

A simplified model of particle deposition in the lungs has been developed and implemented, based on the hypothesis that perfect mixing takes place in the alveolar volume of each airway generation. This key idea is combined with purely convective transport along airways, driven by steady alveolar expansion and contraction, and results in an analytically tractable model. Predictions of the model, and in particular pulmonary deposition, are found in very good agreement with detailed benchmark data in the literature for particle diameters d ≥ 0.1 µm. The success of this simple model provides indirect evidence in favor of the role of alveolar mixing in the deposition process.

Polymorphisms and haplotypes in MyD88 are associated with the development of sarcoidosis: a candidate-gene association study.

Sarcoidosis is considered as a disorder of protracted immune response to an as yet unidentified causative agent that leads to granuloma formation. Material from M. tuberculosis and P. acne has been repeatedly detected in the sarcoidosis lesions, implying the involvement of the Toll-like receptor2 (TLR2) gene that responds to these intracellular pathogens. Since TLR2 association studies have produced controversial results, we sought to investigate whether the downstream signalling molecule MyD88 could be linked to disease susceptibility. We analyzed a total of 93 cases with sarcoidosis and of 89 controls for the most common MyD88 SNPs: -938C>A (rs4988453) and 1944C>G (rs4988457). There is evidence that the genotype distributions of both variants are associated with the development of sarcoidosis (p = 0.038 for -938C>A and p = 0.026 for 1944C>G). In particular, -938A and 1944G carriers were associated with risk of sarcoidosis [OR = 2.48 (1.23-5.02) and OR = 0.33 (0.14-0.76)], respectively, indicating dominance of the mutant alleles; however, the adjustment of the effect size for age and sex diminished the significance. The haplotype analysis showed association for the -938A/1944G haplotype (p < 0.001). Since genetic association studies have linked MyD88 to Hodgkin's lymphoma it is tempting to speculate that MyD88 may contribute to the granuloma formation that characterizes sarcoidosis.

Work-related respiratory symptoms and airway disease in hairdressers.

BACKGROUND: Hairdressers are occupationally exposed to a number of agents in their workplace that result in respiratory symptoms and changes in pulmonary function. OBJECTIVE: To evaluate associations between occupational exposure and respiratory function and reported symptoms in a group of hairdressers compared to a control group. METHODS: A questionnaire on respiratory symptoms and workplace characteristics was completed by 94 hairdressers and 39 age- and sex-matched controls. Spirometry and exhaled nitric oxide (FeNO) measurements were also performed. RESULTS: Hairdressers reported more severe dyspnea (p=0.03) and eye (p=0.001) and throat (p=0.007) irritation, compared to the control group, at the workplace; no differences were noted at home. Lower FEV1/FVC (p<0.001) and higher FeNO values (p=0.012) were observed in hairdressers. A larger working area and presence of window ventilation were associated with better pulmonary function. CONCLUSION: Worsening of symptoms and pulmonary function at workplace, and alleviating the symptoms at home, indicate that they may be related to occupational exposure.

Prevalence of pulmonary hypertension in patients with idiopathic pulmonary fibrosis: correlation with physiological parameters.

The aim of this study was to prospectively evaluate the prevalence of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF). One hundred thirty-nine patients (101 male, mean age = 68.6 ± 9 years), with confirmed IPF and who were admitted to eight Pulmonary Departments in Greece between November 2005 and December 2006 were included in the study. Pulmonary artery systolic pressure (PASP) was estimated by echocardiography, and PH was defined as PASP > 36 mmHg. We compared demographics, pulmonary function tests, NYHA functional status, 6-min walk distance (6MWD), B-type natriuretic peptide (BNP), PaO(2), and P(A-a)O(2) at rest data between patients with PH and without PH (PASP ≤ 36 mmHg). Increased estimated right ventricular systolic pressure was present in 55% of patients (mean PASP = 47.1 ± 11.2 mmHg vs. 30.3 ± 3.8 mmHg, respectively). Patients with PH had a lower but not statistically significant DL(CO) (47.1 ± 18.8 vs. 52.5 ± 20.1), lower PaO(2) at rest (64.6 ± 12.2 vs. 71.1 ± 11.3, P = 0.004), and lower mean 6MWD (282 ± 118 vs. 338 ± 91, P = 0.007). Significant differences were also observed in the NYHA functional status between the two groups (P = 0.02). Statistically significant correlations were observed between PASP and PaO(2) at rest (r = -0.331, P = 0.00), P(A-a)O(2) at rest (r = 0.494, P = 0.00)(,) 6MWD (r = -0.264, P = 0.01), SpO(2) at rest (r = -0.293, P = 0.00), SpO(2) at the end of exercise (r = -0.364, P = 0.00), and also BNP values (r = 0.319, P = 0.01). Moreover, PaO(2) (P = 0.02), P(A-a)O(2) (P = 0.005), and SpO(2) at the end of exercise (P = 0.023) were independent predictors of the presence of estimated PH. Using Doppler echocardiography as a screening tool for the estimation of PH, we found that PH is common in patients with IPF. Gas exchange parameters at rest and exercise desaturation might indicate underlying PH in IPF.

Pulmonary hypertension in COPD: pathophysiology and therapeutic targets.

The incidence of mild to moderate pulmonary hypertension (PH) is highly prevalent, reaching to 50% in advanced chronic obstructive pulmonary disease (COPD). However, a subpopulation (1-4% in most studies) with grim prognosis despite moderate airflow limitation, present with "out-of-proportion" severe PH, is arbitrarily defined by a mean PH ≥ 40 mmHg, at rest. The sequence of changes that lead to PH in COPD begins at early disease stages by the impairment of endothelial function, which is associated with impaired release of endothelium-derived vasodilating (nitric oxide, prostacyclin) and vasoconstrictive agents (endothelin-1) and imbalance among them. PH in COPD is caused by vasoconstriction and remodelling of pulmonary arteries, which is characterized by the intimal proliferation of poorly differentiated smooth muscle cells and the deposition of elastic and collagen fibres. Hypoxia, inflammation and toxic effects of cigarette smoke, independently or additively interacting, are confirmed factors leading to PH. To date, long-term supplemental oxygen remains the primary treatment in COPD patients with PH. The administration of new vasodilators (prostanoids, endothelin-1 receptor antagonists and phosphodiesterase-5 inhibitors) dedicated to idiopathic pulmonary arterial hypertension in the disproportionate subgroup of patients with "out-of-proportion" PH may be considered in the setting of clinical trials. The use of these drugs in COPD patients with PH < 40 mmHg may worsen gas exchange, and to date, has no proven benefit. Future treatments must target more directly pathogenetic mechanisms. Therefore, novel agents have been proposed and are under active investigation, including 5-HT receptor antagonists, Rho-kinase inhibitors, statins and stem cell therapy.

Impact of dietary shift to higher-antioxidant foods in COPD: a randomised trial.

Chronic obstructive pulmonary disease (COPD) is characterised by increased oxidative stress. Dietary factors, such as ample consumption of foods rich in antioxidants, such as fruit and vegetables, might have beneficial effects in COPD patients. The association between dietary shift to foods rich in antioxidants and lung function in COPD was investigated in a 3-yr prospective study. A total of 120 COPD patients were randomised to follow either a diet based on increased consumption of fresh fruit and vegetables (intervention group (IG)) or a free diet (control group (CG)). The mean consumption of foods containing antioxidants was higher in the IG than in the CG throughout the study period (p<0.05). The relationship between consumption of foods rich in antioxidants and percentage predicted forced expiratory volume in 1 s was assessed using a general linear model for repeated measures; the two groups overall were different in time (p = 0.03), with the IG showing a better outcome. In investigating the effect of several confounders (sex, age, smoking status, comorbid conditions and exacerbation) of group response over time, nonsignificant interactions were found between confounders, group and time. These findings suggest that a dietary shift to higher-antioxidant food intake may be associated with improvement in lung function, and, in this respect, dietary interventions might be considered in COPD management.

Discrimination of exudative pleural effusions based on multiple biological parameters.

Pleural effusion is a common complication of various diseases. Conventional methods are not always capable of establishing the cause of pleural effusion, so alternative tests are needed. The aim of this study was to explore means of discriminating between different pleural effusion groups, malignant, parapneumonic and tuberculous, based on the combined function of seven biological markers. Adenosine deaminase (ADA), interferon-gamma, C-reactive protein (CRP), carcinoembryonic antigen, interleukin-6, tumour necrosis factor-alpha and vascular endothelial growth factor concentration levels were measured in pleural fluid from 45 patients with malignant, 15 with parapneumonic and 12 with tuberculous pleural effusion. Receiver operating characteristic curve analysis, multinomial logit modelling and canonical variate analysis were applied to discriminate the pleural effusion groups. The three groups could be discriminated successfully using the measured markers. The most important parameters for discrimination were ADA and CRP concentration levels. An individual with an ADA concentration level of >45 U.L(-1) and a CRP concentration of <4 mg.dL(-1) was more likely to belong to the tuberculous pleural effusion group, whereas one with an ADA concentration level of <40 U.L(-1) and a CRP concentration of >6 mg.dL(-1) was more likely to belong to the parapneumonic pleural effusion group, and one with a CRP concentration of <4 mg.dL(-1) to the malignant pleural effusion group. The combination of adenosine deaminase and C-reactive protein levels might be sufficient for discriminating between the three different groups of exudative pleural effusion: malignant, tuberculous and parapneumonic.

Pulmonary arterial hypertension in a patient with common variable immunodeficiency and unilateral bronchiectasis: Successful treatment with iloprost.

The present study describes a case of severe pulmonary arterial hypertension (PAH) associated with unilateral lung destruction due to bronchiectasis in a patient with common variable immunodeficiency (CVID). Initially, the patient's treatment included antibiotics, oral anticoagulants, diuretics, and immunoglobulin replacement therapy. However, the patient's condition improved significantly only after inhaled iloprost was administered. Three months later, his PAH was almost reversed. The hemodynamic response of our patient suggests that inhaled iloprost may have a role in the treatment of sustained PAH related to unilateral lung destruction.

Losartan controlled blood pressure and reduced left ventricular hypertrophy but did not alter arrhythmias in hypertensive men with preserved systolic function.

The effect of antihypertensive therapy on arrhythmias is controversial. An initial study in patients with chronic heart failure indicated that losartan, an angiotensin II receptor antagonist, may possess antiarrhythmic properties. However, the effect of AT1 receptor antagonists on arrhythmias of subjects with good systolic function has never been evaluated. Thirty-nine men with primary hypertension (18 without left ventricular hypertrophy [LVH], and 21 with LVH, aged 48.2 +/-8.6 and 50.5 +/-6.0 years, respectively), 15 healthy normotensive subjects (47.9 +/-8.5 years), and 14 highly trained athletes (34.1 +/-1.6 years) were studied. Transthoracic echocardiography and 24-hour Holter ambulatory monitoring were performed at baseline (without treatment). Hypertensive patients underwent the same examinations after 8 months of losartan administration. The prevalence and complexity of ventricular arrhythmias, and the frequency of supraventricular arrhythmias were increased in hypertensive patients with LVH compared to normotensive controls and athletes, at baseline. A similar significant reduction of blood pressure (BP) was noted in both groups of patients (p < 0.001). The LVH was reduced in hypertensives with LVH (the left ventricular mass index by 12%, the interventricular septum by 8.1%, the posterior wall by 7%, all p < 0.01). However, the arrhythmias did not change in either group of patients, even if all hypertensives were considered as 1 group. In conclusion, an 8-month course with losartan was effective in lowering BP and reducing LVH. However, the increased arrhythmias, which were registered in hypertensive patients with LVH at baseline, did not change.

Pulmonary hypertension, interstitial lung fibrosis, and lung iron deposition in thalassaemia major.

Although restrictive lung disease is the predominant abnormality of pulmonary function in patients with thalassaemia major (TM), its aetiology and its association with pulmonary hypertension (PH) detected in some patients with TM remains unknown. We report a patient with TM, iron overload, frequent pulmonary infections, and progressive severe precapillary PH over the previous 5 years. A severe restrictive pattern and interstitial lung fibrosis were revealed by pulmonary function tests and high resolution computed tomography, respectively. This presentation suggests that interstitial fibrosis may complicate lung involvement in TM and can significantly contribute to the development of PH.

Epidemiology of familial sarcoidosis in the UK.

BACKGROUND: The last comprehensive epidemiological studies on familial sarcoidosis in the UK were more than 25 years ago, reporting another affected family member in 1.7% of index cases. A significant proportion of like-sex over unlike-sex pairs, an excess of mother-child over father-child associations, and a preponderance of monozygous over dizygous twins was noted. Another study reported ethnic heterogeneity in familial disease. This study was undertaken to identify the risk ratio (lambda(S)) for siblings of familial sarcoidosis in the UK, to determine if the previous epidemiological findings have persisted, and to reassess whether ethnic heterogeneity prevails in familial disease. METHOD: Questionnaires were sent to 406 index patients. RESULTS: Two hundred and sixty eight replies (66%) were received. Twenty four of the original 406 index patients (5.91%) were found to have at least one other relative (first, second or third degree) with biopsy proven sarcoidosis. A lambda(S) value of 36-73 was calculated indicating significant familial clustering of the disease. Ethnically the families comprised 62.5% Caucasian, 29.2% Afro-Caribbean, and 8.3% Asian. Mean age at diagnosis was 39.8 years for women and 40.9 years for men with a male to female ratio of 1:1.7. This differed for the Asian families in which all the affected members were male. Three sets of female twins (two monozygous and one dizygous) were included. There was an equal distribution of like-sex (primarily female) and unlike-sex families as well as mother-child and father-child pairs. Pulmonary involvement was predominant irrespective of ethnicity, as was the need for corticosteroid treatment. CONCLUSIONS: These results support the theory that a shared determinant (either genetic or environmental) is operating in familial sarcoidosis and suggest that this determinant is similar for all ethnic groups.

The effect of lung biopsy on lung function in diffuse lung disease.

The aim of this study was to investigate the effect on lung function of lung biopsy used in the diagnosis of diffuse lung disease carried out by an open procedure or by video-assisted thoracoscopy. One hundred and sixteen patients with diffuse lung disease who attended the Royal Brompton Hospital were studied retrospectively. Thirty five patients underwent open lung biopsy, and 33 video-assisted thoracoscopic biopsy and 48 had their diagnosis made without biopsy. All patients underwent lung function tests before and after surgery, or at an interval of 3-6 months in those who did not undergo biopsy. No significant differences were found in changes in lung function between those who had and had not undergone biopsy, and the proportions of patients whose lung function improved or deteriorated were similar. Lung biopsy by an open procedure or by video-assisted thoracoscopy did not differ in its effects on lung function. The results for older patients, those with severe disease and those with fibrosing alveolitis were the same as for the whole group. Open lung biopsy for the diagnosis of diffuse lung disease does not deleteriously affect lung function whether carried out by an open or a minimally invasive procedure.

A histologic pattern of nonspecific interstitial pneumonia is associated with a better prognosis than usual interstitial pneumonia in patients with cryptogenic fibrosing alveolitis.

This study aimed to investigate whether there was a difference in outcome related to histologic pattern in cryptogenic fibrosing alveolitis (CFA) and to see whether there were correlations between clinical and radiologic findings and histology. One hundred thirteen lung biopsies from consecutive patients taken for the diagnosis of diffuse lung disease were reviewed and reclassified using the Katzenstein and Myers criteria for interstitial pneumonias. Patients lacking full investigational data at presentation and those with conditions predisposing to lung fibrosis were excluded, leaving 15 patients diagnosed with nonspecific interstitial pneumonia (NSIP) and 15 with usual interstitial pneumonia (UIP). Clinical and radiologic findings at presentation and serial lung function information and survival status in November 1998 were compared for the two groups. Survival was found to be significantly greater in the NSIP group compared with the UIP group (p < 0.001). This could not be explained by differences in treatment. Patients with UIP showed a progressive deterioration in lung function whereas those with NSIP remained stable. CT scans of patients with UIP showed more fibrosis than those of patients with NSIP (p < 0.011). A histologic diagnosis of NSIP is associated with a better prognosis than UIP. This subclassification of CFA is clinically useful.