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.

An alternative method for measuring total respiratory resistance during quiet breathing: a feasibility and validation study.

OBJECTIVE: Determining the respiratory system's mechanical properties with minimal patient effort has been an important field of investigation addressing patients unable to perform pulmonary function testing and in light of the preventive measures due to the recent pandemic. The current study aimed to present an alternative method for total respiratory resistance measurement during tidal breathing, compare it with airway resistance (Raw), measured by body plethysmography, and validate the procedure in three groups of subjects with normal, constrictive and obstructive respiratory patterns in spirometry. PATIENTS AND METHODS: We developed an alternative method of assessing total respiratory resistance during quiet breathing. After manufacturing the appropriate hardware apparatus, we applied a steady extrinsic resistance (ΔR) for 100-200 m/s during tidal breathing. Α theoretical mathematical model allowed measurement of total respiratory resistance (Rtot) during inspiration (Rin) and expiration (Rex). To validate the method, 15 individuals were enrolled and assigned to the normal, obstructive and restrictive groups based on their spirometry patterns. All groups participated in two sets of measurements, the plethysmographic and novel method. Finally, respiratory resistance measurements were compared between groups and methods. RESULTS: The method was successfully developed, and Rtot measurements were recorded in five normal subjects and in five obstructive and restrictive subjects. Mean Rin and mean Rex were 4.99 cm H2O/L/sec and 4.42 cm H2O/L/sec in the healthy, 4.87 cm H2O/L/sec, and 6.63 cm H2O/L/sec in the obstructive and 5.97 cm H2O/L/sec and 4.12 cm H2O/L/sec in the restrictive group, respectively. Rex was notably higher than Rin in the obstructive group and was positively correlated with Raw (p<0.005, r=0.47). CONCLUSIONS: This method provides the theoretical background for a plausible alternative tool for accessing a mechanical parameter of the respiratory system, which is easy to perform and requires only passive patient cooperation while enabling rough differentiation between obstructive and restrictive disorders. The model's feasibility potential in a real-life setting was studied in a small sample, and additional implementation and validation of the method in a larger population are guaranteed.

CTPA imaging findings, beyond pulmonary embolism, in patients with Severe Acute Respiratory Syndrome Corona Virus-2 infection and their relation to clinical outcome - a single center experience.

OBJECTIVE: The aim of our study was to investigate a potential association between the severity of COVID-19 disease and related 28-day mortality, with the presence of mediastinal lymphadenopathy, the extension of lung parenchymal infiltrates, the presence of pulmonary embolism, the density and distribution of mediastinal and subcutaneous fat, the inflammatory markers and the direct and indirect radiological signs of right heart overload and strain. PATIENTS AND METHODS: We retrospectively included patients diagnosed with SARS-CoV-2 infection, who were admitted to the Departments of Internal and Respiratory Medicine of Patras University Hospital during the second pandemic wave (February 2021 up to July 2021) and underwent CTPA for routine diagnostic workup. Demographic characteristics, routine laboratory, radiological parameters and 28-day mortality were also recorded. RESULTS: Fifty-three consecutive patients were included. The mean age was 64.47±17.1 years and 64,1% (n=34) were males. Pulmonary embolism (PE) (p=0.019), Right Ventricle-to-Left Ventricle Diameter (RV/LV)  Ratio>1 (p<0.01), Reverse Flow in Hepatic Veins (RFHV) (p=0.019), higher density in subcutaneous fat (-99 HU vs. -104HU, p=0.016), increased Lactic Dehydrogenase (LDH), Polymorphonuclear cells (PMN), ferritin, and d-dimer levels (534 vs. 367 U/L, p=0.001, 9220 vs. 5660 Κ/µL, p=001, 956 vs. 360 ng/ml, p=0.005 and 2300 vs. 1040 µg/ml, p=0.003, respectively) were statistically significant related with worse 28-day mortality. Binomial multivariate regression analysis revealed that only RV/LV diameter>1, higher subcutaneous fat density and higher LDH values were independently associated with increased 28-day mortality (OR: 82.9, 95%CI: 1.334-5158, p=0.036, OR: 1.2, 95%CI: 1.016-1.426, p=0.032 and OR:1.016, 95% CI:1.004-1.029, p=0.011, respectively). Subgroup analysis revealed that mediastinal lymph node enlargement (EML) and PE were associated to increased Pulmonary Disease Severity Index (PDSI) score (p=0.042 and p=0.007, respectively), but not to mortality. CONCLUSIONS: Our study showed that right heart strain as depicted by a RV/LV diameter>1, higher subcutaneous fat density and higher LDH values are independently associated with an increased 28-day mortality in our SARS-COV2 patient group.

Effect of pulmonary rehabilitation on muscle remodelling in cachectic patients with COPD.

It is known that non-cachectic patients with chronic obstructive pulmonary disease (COPD) respond well to pulmonary rehabilitation, but whether cachectic COPD patients are capable of adaptive responses is both important and unknown. 10 cachectic and 19 non-cachectic COPD patients undertook high-intensity cycling training, at the same relative intensity, for 45 min x day(-1), 3 days x week(-1) for 10 weeks. Before and after rehabilitation vastus lateralis muscle biopsies were analysed morphologically and for the expression of muscle remodelling factors (insulin-like growth factor (IGF)-I, myogenic differentiation factor D (MyoD), tumour necrosis factor (TNF)-alpha, nuclear factor (NF)-kappaB and myostatin) and key components of ubiquitin-mediated proteolytic systems (muscle ring finger protein (MURF)-1 and Atrogin-1). Rehabilitation improved peak work-rate and the 6-min walk distance similarly in non-cachectic (18+/-3% and 42+/-13 m, respectively) and cachectic (16+/-2% and 53+/-16 m, respectively) patients, but quality of life only improved in non-cachectic COPD. Mean muscle fibre cross-sectional area increased in both groups, but significantly less in cachectic (7+/-2%) than in non-cachectic (11+/-2%) patients. Both groups equally decreased the proportion of type IIb fibres and increased muscle capillary/fibre ratio. IGF-I mRNA expression increased in both groups, but IGF-I protein levels increased more in non-cachectic COPD. MyoD was upregulated, whereas myostatin was downregulated at the mRNA and protein level only in non-cachectic patients. Whilst rehabilitation had no effect on TNF-alpha expression, it decreased the activation of the transcription factor NF-kappaB in both groups by the same amount. Atrogin-1 and MURF-1 expression were increased in cachectic COPD, but it was decreased in non-cachectic patients. Cachectic COPD patients partially retain the capacity for peripheral muscle remodelling in response to rehabilitation and are able to increase exercise capacity as much as those without cachexia, even if they exhibit both quantitative and qualitative differences in the type of muscle fibre remodelling in response to exercise training.

Exercise-induced skeletal muscle deoxygenation in O-supplemented COPD patients.

This study was designed to assess quadriceps oxygenation during symptom-limited and constant-load exercise in patients with chronic obstructive pulmonary disease (COPD) and healthy age-matched controls. Thirteen male COPD patients [FEV(1): 43 +/- 5% predicted (mean +/- SEM)] and seven healthy male controls performed an incremental exercise test at peak work rate (WR) and a constant-load test at 75% peak WR on a cycle ergometer. Quadriceps hemoglobin saturation (StO2) was measured by continuous-wave near-infrared spectrophotometry throughout both exercise tests. StO2 is the ratio of oxygenated hemoglobin to total hemoglobin and reflects the relative contributions of tissue O2 delivery and tissue O2 utilization. Oxygen was supplemented to all patients in order to maintain arterial O2 saturation normal (> 95%). The StO2 decreased during symptom-limited exercise, reaching the nadir at peak WR. The decrease in StO2 was greater (P < 0.05) in healthy subjects (from 74 +/- 2% to 38 +/- 6%) compared with that in COPD patients (from 61 +/- 5% to 45 +/- 4%). However, when StO2 was normalized relative to the WR, the slope of change in StO2 during exercise was nearly identical between COPD patients and healthy subjects (0.47 +/- 0.10%/W and 0.51 +/- 0.04%/W, respectively). During constant-load exercise, the kinetic time constant of StO2 desaturation after the onset of exercise (i.e., equivalent to time to reach approximately 63% of StO2 decrease) was not different between COPD patients and healthy subjects (19.0 +/- 5.2 and 15.6 +/- 2.5 s, respectively). In O2-supplemented COPD patients, peripheral muscle oxygenation for a given work load is similar to that in healthy subjects, thus suggesting that skeletal muscle O2 consumption becomes normal for a given O2 delivery in COPD patients

Chest wall volume regulation during exercise in COPD patients with GOLD stages II to IV.

The present study investigated how end-expiratory ribcage and abdominal volume regulation during exercise is related to the degree of dynamic chest wall hyperinflation in patients with different spirometric severity of chronic obstructive pulmonary disease (COPD) based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) classification. In total, 42 COPD patients and 11 age-matched healthy subjects were studied during a ramp-incremental cycling test to the limit of tolerance (W(peak)). Volume variations of the chest wall (at end expiration (EEV(cw)) and end inspiration) and its compartments (ribcage (V(rc)) and abdominal (V(ab))) were computed by optoelectronic plethysmography. At W(peak), only patients in GOLD stages III and IV exhibited a significant increase in EEV(cw) (increase of 454+/-509 and 562+/-363 mL, respectively). These patients did not significantly reduce end-expiratory V(ab), whereas patients in GOLD stage II resembled healthy subjects with significantly reduced end-expiratory V(ab) (decrease of 287+/-350 mL). In patients, the greater the increase in EEV(cw) at W(peak), the smaller the reductions in end-expiratory V(ab) and the greater the increase in end-expiratory V(rc). In chronic obstructive pulmonary disease patients with different spirometric disease severity, greater degrees of exercise-induced dynamic chest wall hyperinflation were accompanied by lower degrees of end-expiratory abdominal volume displacement and larger increases in end-expiratory ribcage volume.

Stenting allows weaning and extubation in ventilator- or tracheostomy dependency secondary to benign airway disease.

Central airway obstruction can cause severe respiratory insufficiency leading to mechanical ventilation (MV) or artificial airway (AA) dependency. Interventional bronchoscopic procedures have been reported to be of help in weaning patients with malignant airway stenoses from mechanical ventilation, whereas their use in benign disease is only anecdotal. The objectives of this study are to evaluate early, intermediate and long-term outcome of interventional bronchoscopy and stent placement in the treatment of MV/AA dependency due to benign airway obstruction. In a retrospective cohort analysis for the period 1999-2004, we evaluated 15 consecutive ICU patients with documented benign central airway obstruction, who were referred for bronchoscopic management of their condition after multiple failed attempts at weaning from MV or decannulation of the AA. Indications for bronchoscopic treatment were surgery refusal, medical or surgical inoperability, or absence of alternative treatment options. Malacia, post-intubation stenosis and goiter were the main causes of airway obstruction and MV/AA dependency. All patients were treated by means of rigid bronchoscopy, dilatation procedures and stent insertion. All but one patient (93.3%) were successfully and permanently extubated/decanulated immediately after the bronchoscopy. Minor complications occurred in 6 patients (40%) leading to a second intervention. All complications could be managed endoscopically and long-term follow up was uneventful. Interventional bronchoscopy with stent insertion can allow successful withdrawal from MV/AA and can offer longstanding airway patency in selected ventilator- or tracheostomy-dependant individuals with benign airway stenoses,when surgery in not feasable or contra-indicated.

Malignant triton tumour of the anterior mediastinum as incidental finding.

A rare case of malignant peripheral nerve sheath tumour with rhabdomyoblastic differentiation (malignant triton tumour) of the anterior mediastinum in a 30-year-old male is reported. The tumour was an incidental finding during the diagnostic work-up following a motor vehicle accident. The patient underwent median sternotomy with a tumour resection performed. Local relapse was suspected one month later, as per the chest CT-scan, and post-operative chemoradiation was applied, which produced a response. Twelve months later the patient is doing well while radiological findings remain invariable. Localization of a triton tumour in the anterior mediastinum is extremely rare, adjuvant treatment is necessary, recurrence frequently occurs and the prognosis is dismal.

Tracheoesophageal fistula managed with tracheal stent through flexible bronchoscopy without fluoroscopy.

Inoperable malignant tracheoesophageal fistula (TEF) is characterised by an extremely poor prognosis. Tracheal or double (tracheal-esophageal) stenting through rigid bronchoscopy has been suggested as a valuable therapeutic option. We report on a patient with a large TEF successfully sealed by deployment of a self-expandable stent through flexible bronchoscopy (FB) without fluoroscopy. Dramatically improved health status permitted him to undergo radiation, attaining further clinical improvement. Four months after stent placement no sequelae were observed. During the fifth month a new fistula developed distally to the stent finally leading to death from septic complication. Palliative management of inoperable malignant TEF by tracheal stent placement through FB without fluoroscopy, is feasible, safe and rewarding leading to important clinical improvement.

Adenosine deaminase activity and lysozyme levels in bronchoalveolar lavage fluid in patients with pulmonary tuberculosis.

SETTING: The estimations of adenosine deaminase (ADA) activity and lysozyme (LYS) levels in pleural fluid have been proved useful tools in the diagnosis of tuberculous pleural effusions. Little is known about their usefulness when estimated in bronchoalveolar lavage fluid (BALF). OBJECTIVE: To evaluate whether both ADA activity and LYS levels in BALF could be employed in the diagnosis of pulmonary tuberculosis, and especially in active but acid fast bacilli (AFB) smear negative cases. DESIGN: ADA activity and LYS levels were determined in BALF and serum obtained on the same day in 28 patients with tuberculosis, 21 with interstitial lung diseases, 14 with lung cancer and 13 with infectious diseases. RESULTS: Patients with pulmonary tuberculosis had significantly higher ADA activity in BALF than patients with non-tuberculous lung diseases (P < 0.001). High BALF ADA activity in pulmonary tuberculosis patients suggests increased local production. In contrast, in this group of patients BALF LYS levels were not significantly higher than in the other groups of patients, but were in the group with interstitial lung diseases. CONCLUSION: BALF ADA activity seems to be a useful tool in the differentiation of tuberculosis from other lung diseases. Its estimation can be restricted to the detection of cases with AFB negative smears.

Effects of rehabilitation on chest wall volume regulation during exercise in COPD patients.

In order to investigate underlying mechanisms, the present authors studied the effect of pulmonary rehabilitation on the regulation of total chest wall and compartmental (ribcage, abdominal) volumes during exercise in patients with chronic obstructive pulmonary disease. In total, 20 patients (forced expiratory volume in one second, mean +/- SEM 39 +/- 3% predicted) undertook high-intensity exercise 3 days x week(-1) for 12 weeks. Before and after rehabilitation, the changes in chest wall (cw) volumes at the end of expiration (EEV) and inspiration (EIV) were computed by optoelectronic plethysmography during incremental exercise to the limit of tolerance (W(peak)). Rehabilitation significantly improved W(peak) (57+/-7 versus 47+/-5 W). In the post-rehabilitation period and at identical work rates, significant reductions were observed in minute ventilation (35.1+/-2.7 versus 38.4+/-2.7 L x min(-1)), breathing frequency (26+/-1 versus 29+/-1 breaths x min(-1)) and EEV(cw) and EIV(cw) (by 182+/-79 and 136+/-37 mL, respectively). Inspiratory reserve volume was significantly increased (by 148+/-70 mL). Volume reductions were attributed to significant changes in abdominal EEV and EIV (by 163+/-59 and 125+/-27 mL, respectively). The improvement in W(peak) was similar in patients who progressively hyperinflated during exercise and those who did not (24 and 26%, respectively). In conclusion, pulmonary rehabilitation lowers chest wall volumes during exercise by decreasing the abdominal volumes. The improvement in exercise capacity following rehabilitation is independent of the pattern of exercise-induced dynamic hyperinflation.