The impact of alpha-1 antitrypsin deficiency alleles on lung cancer survival.

Different studies have shown that carrying an alpha-1 antitrypsin (AAT) deficiency allele is an independent risk factor for developing lung cancer (LC). However, to date, little is known regarding whether carrying a deficiency allele may be a prognostic factor in the evolution of LC. A prospective observational study was carried out which consecutively included patients diagnosed with LC in University Hospital "Nuestra Señora de Candelaria" between December 2017 and August 2020. A blood sample was taken from each of the patients in order to determine both AAT serum concentration and genotype. Based on AAT genotype, patients were divided into the deficiency (Pi*≠MM) or non-deficiency (Pi*=MM) group. One hundred and sixty-four patients were included. The average length of follow-up was 13±10 months. Patients were classified as stage I (4.2%), stage II (8.3%), stage III (31.2%) and stage IV (56.3%), according to tumour, node and metastasis (TNM) staging. Twenty-eight patients (17%) were carriers of a deficiency allele (6 Pi*MS, 1 Pi*MZ, 1 Pi*MMheerlen). No significant differences were found with respect to baseline characteristics between Pi*≠MM and Pi*=MM. Patients in the Pi*≠MM group had a higher risk of death in the first 6 months after the LC diagnosis compared to Pi*=MM subjects (HR =2.04; 95% CI: 1.04-4.0; P=0.038). The presence of an AAT deficiency genotype could be a potential prognostic marker in LC. However, larger studies that justify these findings are needed.

Severe COVID-19 Illness and α1-Antitrypsin Deficiency: COVID-AATD Study.

BACKGROUND: Epidemiologic studies have reported that the geographical distribution of the prevalence of allelic variants of serine protein inhibitor-A1 (SERPINA1) and severe cases of COVID-19 were similar. METHODS: A multicenter, cross-sectional, observational study to evaluate the frequency of alpha-1 antitrypsin deficiency (AATD) in patients with COVID-19 and whether it was associated with having suffered severe COVID-19. RESULTS: 2022 patients who had laboratory-confirmed SARS-CoV-2 infection. Mutations associated with AATD were more frequent in severe COVID versus non-severe (23% vs. 18.8%, p = 0.022). The frequency of Pi*Z was 37.8/1000 in severe COVID versus 17.5/1000 in non-severe, p = 0.001. Having an A1AT level below 116 was more frequent in severe COVID versus non-severe (29.5% vs. 23.1, p = 0.003). Factors associated with a higher likelihood of severe COVID-19 were being male, older, smoking, age-associated comorbidities, and having an A1AT level below 116 mg/dL [OR 1.398, p = 0.003], and a variant of the SERPINA1 gene that could affect A1AT protein [OR 1.294, p = 0.022]. CONCLUSIONS: These observations suggest that patients with AATD should be considered at a higher risk of developing severe COVID-19. Further studies are needed on the role of A1AT in the prognosis of SARS-CoV-2 infection and its possible therapeutic role.

Clinical and functional characteristics of individuals with alpha-1 antitrypsin deficiency: EARCO international registry.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare disease that is associated with an increased risk of pulmonary emphysema. The European AATD Research Collaboration (EARCO) international registry was founded with the objective of characterising the individuals with AATD and investigating their natural history. METHODS: The EARCO registry is an international, observational and prospective study of individuals with AATD, defined as AAT serum levels < 11 µM and/or proteinase inhibitor genotypes PI*ZZ, PI*SZ and compound heterozygotes or homozygotes of other rare deficient variants. We describe the characteristics of the individuals included from February 2020 to May 2022. RESULTS: A total of 1044 individuals from 15 countries were analysed. The most frequent genotype was PI*ZZ (60.2%), followed by PI*SZ (29.2%). Among PI*ZZ patients, emphysema was the most frequent lung disease (57.2%) followed by COPD (57.2%) and bronchiectasis (22%). Up to 76.4% had concordant values of FEV1(%) and KCO(%). Those with impairment in FEV1(%) alone had more frequently bronchiectasis and asthma and those with impairment in KCO(%) alone had more frequent emphysema and liver disease. Multivariate analysis showed that advanced age, male sex, exacerbations, increased blood platelets and neutrophils, augmentation and lower AAT serum levels were associated with worse FEV1(%). CONCLUSIONS: EARCO has recruited > 1000 individuals with AATD from 15 countries in its first 2 years. Baseline cross sectional data provide relevant information about the clinical phenotypes of the disease, the patterns of functional impairment and factors associated with poor lung function. Trial registration www. CLINICALTRIALS: gov (ID: NCT04180319).

Pulmonary Function and Respiratory Diseases in Different Genotypes of Alpha-1 Antitrypsin Deficiency.

OBJECTIVE: Respiratory disease is the major cause of morbidity and mortality in patients with alpha-1 antitrypsin deficiency, mainly in homozygous PI*ZZ individuals. However, this association is uncertain in subjects with other deficiency genotypes. The objective of this study was to assess, in the context of alpha-1 antitrypsin deficiency, the existence of further risk factors that have been associated with respiratory diseases. MATERIAL AND METHODS: Lung function was assessed by spirometry in a sample of 1334 patients with a known genotype for the SERPINA1 gene whose serum alpha-1 antitrypsin levels had been previously determined. Patients with a normal genotype (PI*MM) were compared to 389 patients carrying a deficiency allele. RESULTS: Statistically significant associations were detected between (i) PI*ZZ genotype and abnormal FEV1 values (χ2 = 26.45; P <.0002), FEV1/FVC (χ2 = 14.8; P < .02) or forced mid-expiratory flow 25%-75% (χ2 =22.66; P < .0009); (ii) chronic obstructive pulmonary disease and PI*ZZ odds ratio: 26.5; 95% CI: (2.6-265.9); P <.005 and or PI*SS genotype odds ratio: 9; 95% CI: (2-40.1); P < .004; (iii) prevalence of COPD in PI*MZ subjects and smoking habit (P < .01), low body weight (P < .01) or older age (P < .0001). CONCLUSION: The PI*ZZ and PI*SS genotypes seem to be associated with the prevalence of chronic obstructive pulmonary disease. Tobacco use, low body weight, and older age are risk factors that increase the probability of prevalence of chronic obstructive pulmonary disease by up to 70% in PI*MZ individuals.

Characteristics of patients referred to Canary Island pneumology outpatient services for chronic obstructive pulmonary disease: the EPOCan study.

OBJECTIVE: Assessing patients with chronic obstructive pulmonary disease (COPD) accounts for 30% of all pneumology outpatient evaluations. COPD is a heterogeneous disease and generates a massive public health problem. Overall morbidity, particularly cardiovascular disease, challenges patient management. This is an observational, multicentre study, performed at four hospitals in the Canary Islands (Spain), aimed at characterising patients with COPD referred to pneumology outpatient services. Demographic variables, lung function, and morbidity were assessed. RESULTS: Of the 877 included patients, 44.9% were active smokers with a mean (± SD) age of 68.2 ± 10.3 years. The median (IQR) score for the Charlson comorbidity index was 2 (2), and 70.6% of the patients were assigned high risk according to the Spanish Guidelines for COPD (GesEPOC) 2021. The degree of airflow obstruction defined by the GOLD 2021 stages 1, 2, 3, and 4 corresponded to 13.6%, 49%, 31%, and 6.3% of patients, respectively. The most frequently associated morbidities were arterial hypertension (59.5%), dyslipidaemia (54.3%), and type 2 diabetes mellitus (31.2%); 32% of the patients suffered heart disease. There is a high prevalence of active smoking, type 2 diabetes mellitus, and heart disease in patients referred for COPD to Canary Island pneumology outpatient services.

Improvement of the cystine measurement in granulocytes by liquid chromatograhy-tandem mass spectrometry.

BACKGROUND: Cystinosis is an autosomal recessive genetic disorder due to mutations in CTNS gene, which causes a defect of cystinosin, impairing the transport of free cystine out of lysosomes and causing irreversible damage to various organs, particularly the kidney. The diagnosis of Cystinosis is carried out by measuring the cystine content in leucocytes. Accurate quantification of cystine is of capital importance not only for the diagnosis, but also for monitoring the effectiveness of cysteamine treatment. Here we describe an improvement to measure cystine in granulocytes using high-pressure-liquid chromatography-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS). METHOD: Granulocytes were isolated from heparinized blood by isopycnic centrifugation. After lysis and deproteinization, the concentration of di-butylated cystine was measured by HPLC-ESI-MS/MS, using deuterium labelled, d6-cystine, as internal standard. RESULTS: The assay was linear to at least 50 µmol/L with a good precision. Within-day and between-day coefficients of variation were about 6%. The recovery was higher than 98%. Control values were clearly distinguishable from pathological levels, even if patients were under treatment. A good correlation was observed with cystine binding protein (CBP) assay, one of the most sensitive and specific methods. CONCLUSION: This method results in good analytical performance, and is useful for diagnosis and follow up of Cystinosis. This method offers several advantages over the CBP assay: it is less expensive, easier, quicker and it does not require radioactivity. In addition, when comparing with the HPLC-ESI-MS/MS method previously described by Chabli et al. 2006, our assay exhibits more sensitivity and is faster.

Treatment of complicated parapneumonic pleural effusion and pleural parapneumonic empyema.

BACKGROUND: We performed this observational prospective study to evaluate the results of the application of a diagnostic and therapeutic algorithm for complicated parapneumonic pleural effusion (CPPE) and pleural parapneumonic empyema (PPE). MATERIAL/METHODS: From 2001 to 2007, 210 patients with CPPE and PPE were confirmed through thoracocentesis and treated with pleural drainage tubes (PD), fibrinolytic treatment or surgical intervention (videothoracoscopy and posterolateral thoracotomy). Patients were divided into 3 groups: I (PD); II (PD and fibrinolytic treatment); IIIa (surgery after PD and fibrinolysis), and IIIb (direct surgery). The statistical study was done by variance analysis (ANOVA), χ2 and Fisher exact test. RESULTS: The presence of alcohol or drug consumption, smoking and chronic obstructive pulmonary disease (COPD) were strongly associated with a great necessity for surgical treatment. The IIIa group was associated with increased drainage time, length of stay and complications. No mortality was observed. The selective use of PD and intrapleural fibrinolysis makes surgery unnecessary in more than 75% of cases. CONCLUSIONS: The selective use of PD and fibrinolysis avoids surgery in more than 75% of cases. However, patients who require surgery have more complications, longer hospital stay, and more days on PD and they are more likely to require admittance to the Intensive Care Unit.

Screening for congenital disorders of glycosylation (CDG): transferrin HPLC versus isoelectric focusing (IEF).

OBJECTIVES: Transferrin isoelectrofocusing (Tf-IEF) is widely used to screen for Congenital Disorders of Glycosylation (CDG), but it is laborious, time-consuming, and not suitable for automation or accurate quantification. We present our experience and advantages of the implementation of Tf-HPLC. METHODS: Sera were iron saturated, lipid precipitated and filtrated on Microcon-YM10. Glycoforms were separated by HPLC on a SOURCE 15Q anion-exchange column. Detection was at 470 nm. RESULTS: We established reference values and validated the HPLC method by analysing samples with abnormal Tf-IEF. Comparison between both methods is described. CONCLUSIONS: HPLC is useful for CDG screening, especially for laboratories that deal with great number of samples, due to its easy sample processing, the possibility of performing long series of analysis and the advantage of peak quantification, which allows objective interpretations.