A Comprehensive Update on Late-Onset Pompe Disease.

Pompe disease (PD) is an autosomal recessive disorder caused by mutations in the GAA gene that lead to a deficiency in the acid alpha-glucosidase enzyme. Two clinical presentations are usually considered, named infantile-onset Pompe disease (IOPD) and late-onset Pompe disease (LOPD), which differ in age of onset, organ involvement, and severity of disease. Assessment of acid alpha-glucosidase activity on a dried blood spot is the first-line screening test, which needs to be confirmed by genetic analysis in case of suspected deficiency. LOPD is a multi-system disease, thus requiring a multidisciplinary approach for efficacious management. Enzyme replacement therapy (ERT), which was introduced over 15 years ago, changes the natural progression of the disease. However, it has limitations, including a reduction in efficacy over time and heterogeneous therapeutic responses among patients. Novel therapeutic approaches, such as gene therapy, are currently under study. We provide a comprehensive review of diagnostic advances in LOPD and a critical discussion about the advantages and limitations of current and future treatments.

Juvenile-Onset Recurrent Rhabdomyolysis Due to Compound Heterozygote Variants in the ACADVL Gene.

Very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency is a rare autosomal recessive long-chain fatty acid oxidation disorder caused by mutations in the ACADVL gene. The myopathic form presents with exercise intolerance, exercise-related rhabdomyolysis, and muscle pain, usually starting during adolescence or adulthood. We report on a 17-year-old boy who has presented with exercise-induced muscle pain and fatigue since childhood. In recent clinical history, episodes of exercise-related severe hyperCKemia and myoglobinuria were reported. Electromyography was normal, and a muscle biopsy showed only "moth-eaten" fibers, and a mild increase in lipid storage in muscle fibers. NGS analysis displayed the already known heterozygote c.1769G>A variant and the unreported heterozygote c.523G>C change in ACADVL both having disease-causing predictions. Plasma acylcarnitine profiles revealed high long-chain acylcarnitine species levels, especially C14:1. Clinical, histopathological, biochemical, and genetic tests supported the diagnosis of VLCAD deficiency. Our report of a novel pathogenic missense variant in ACADVL expands the allelic heterogeneity of the disease. Since dietary treatment is the only therapy available for treating VLCAD deficiency and it is more useful the earlier it is started, prompt diagnosis is essential in order to minimize muscle damage and slow the disease progression.

Home-Based Adaptation to Night-Time Non-Invasive Ventilation in Patients with Amyotrophic Lateral Sclerosis: A Randomized Controlled Trial.

BACKGROUND: Initiation to Non-Invasive Ventilation (NIV) in amyotrophic lateral sclerosis (ALS) can be implemented in an inpatient or outpatient setting. AIMS: We aimed to evaluate the efficacy of adaptation (the number of needed sessions) to home-based NIV compared to an outpatient one in ALS in terms of arterial carbon dioxide (PaCO2) improvement. NIV acceptance (mean use of ≥5 h NIV per night for three consecutive nights during the adaptation trial), adherence (night-time NIV usage for ≥150 h/month), quality of life (QoL), and caregiver burden were secondary outcomes. METHODS: A total of 66 ALS patients with indications for NIV were involved in this randomized controlled trial (RCT): 34 underwent NIV initiation at home (home adaptation, HA) and 32 at multiple outpatient visits (outpatient adaptation, OA). Respiratory function tests were performed at baseline (the time of starting the NIV, T0) together with blood gas analysis, which was repeated at the end of adaptation (T1) and 2 (T2) and 6 (T3) months after T1. NIV adherence was measured at T2 and T3. Overnight cardiorespiratory polygraphy, Short Form Health Survey (SF-36), Caregiver Burden Inventory (CBI), Caregiver Burden Scale (CBS), and Zarit Burden Interview (ZBI) were performed at T0, T2, and T3. RESULTS: Fifty-eight participants completed the study. No differences were found between groups in PaCO2 at T1 (p = 0.46), T2 (p = 0.50), and T3 (p = 0.34) in acceptance (p = 0.55) and adherence to NIV at T2 and T3 (p = 0.60 and p = 0.75, respectively). At T2, the patients' QoL, assessed with SF-36, was significantly better in HA than in OA (p = 0.01), but this improvement was not maintained until T3 (p = 0.17). CONCLUSIONS: In ALS, adaptation to NIV in the patient's home is as effective as that performed in an outpatient setting regarding PaCO2, acceptance, and adherence, which emphasizes the need for further studies to understand the role of the environment concerning NIV adherence.

Mammalian Target of Rapamycin: Is It Relevant to COPD Pathogenesis or Treatment?

The mammalian target of rapamycin (mTOR) signalling pathway regulates fundamental metabolic processes such as inflammation, autophagy and apoptosis, all of which influence cell fate. Recent experimental data suggest that mTOR signalling is involved in many diseases, including lung diseases, but with contrasting data. Overexpression of mTOR and its signalling proteins have been linked to lung cell senescence and development of emphysema, pulmonary hypertension and inflammation. On the other hand, mTOR inhibitors, as rapamycin and/or its derivatives, restore corticosteroid sensitivity in peripheral blood mononuclear cells from chronic obstructive pulmonary disease (COPD) patients, and overexpression of mTOR suppresses cigarette smoke-induced inflammation and emphysema, suggesting that induction of mTOR expression/activity might be useful to treat COPD. This apparent discrepancy is due to complex and heterogenic enzymatic pathway of mTOR. Translation of pre-clinical positive data on the use of mTOR inhibitors to COPD therapy needs a more in-depth knowledge of mTOR signalling.

Lifestyle interventions in prevention and comprehensive management of COPD.

Chronic respiratory diseases are among the four major human chronic diseases. Tobacco smoke as well as environmental pollutants, infections, physical activity and nutritional status play a role in the prevalence, development and/or progression of chronic obstructive pulmonary disease (COPD). Changes in lifestyle are possible and may be beneficial in prevention and comprehensive management of COPD. Population-level interventions aimed at early diagnosis, promotion of vaccinations and prevention of infections, and reductions in smoking, environmental pollutants, physical inactivity, obesity and malnutrition may increase the number of life-years lived in good health. EDUCATIONAL AIMS: To improve awareness of the influence of lifestyle on natural history of COPD.To describe the effects of some interventions to modify lifestyle in prevention and management.To provide information on the main clinical results.To define recommendations and limitations.

Early initiation of night-time NIV in an outpatient setting: a randomized non-inferiority study in ALS patients.

BACKGROUND: In patients with amyotrophic lateral sclerosis (ALS), non-invasive ventilation (NIV) is usually initiated in an in-hospital regime. AIM: We investigated if NIV initiated in an outpatient setting can be as effective in terms of patients' acceptance/adherence. We also evaluated factors predicting NIV acceptance and adherence and disease progression. DESIGN: Prospective randomized study. SETTING: Outpatient versus inpatient rehabilitation. POPULATION: ALS patients. METHODS: ALS patients were randomized to two groups for NIV initiation: outpatients versus inpatients. At baseline (T0), end of NIV trial program (T1) and after 3 months from T1 (T2), respiratory function tests, blood gas analysis, and sleep study were performed. At T1, we assessed: NIV acceptance (>4 h/night), and dyspnea symptoms (day/night) by Visual analogue scale (VAS), staff and patients' experience (how difficult NIV was to accept, how difficult ventilator was to manage, satisfaction); at T2: NIV adherence (>120 h/month) and patients' experience. RESULTS: Fifty patients participated. There were no differences in acceptance failure (P=0.733) or adherence failure (P=0.529). At T1, outpatients had longer hours of nocturnal ventilation (P<0.02), at T2 this was similar (P=0.34). Female gender and spinal onset of the disease were predictors for NIV acceptance/adherence failure. There were no between-group differences in progression of respiratory impairment, symptoms and sleep quality. CONCLUSIONS: Early outpatient initiation of NIV in ALS is as effective as inpatient initiation.

Italian registry of patients with alpha-1 antitrypsin deficiency: general data and quality of life evaluation.

Alpha1-antitrypsin Deficiency (AATD) is a rare hereditary disorder with an estimated prevalence of about 1/5000 individuals in Italy. Deficient patients are at a higher risk of developing lung emphysema and chronic liver disease. The low estimated prevalence of AATD prompted the establishment of a registry with the aim of learning more about the natural history and the quality of care of these patients. The Italian registry for AATD was established in 1996. In this study, genetic and clinical findings of Italian AATD patients are presented. Moreover, we also evaluated the changes in health-related quality of life (HRQoL) in patients with COPD and AAT deficiency over a three-year period, in relation to augmentation therapy. In a period spanning 18 years (1996-2014) a total of 422 adult subjects with severe AATD were enrolled, namely 258 PI*ZZ, 74 PI*SZ, 4 PI*SS and 86 patients with at least one rare deficient allele. The 21.3% frequency for AATD patients with at least one deficient rare variant is the highest so far recorded in national registries of AATD. The registry data allow a detailed characterization of the natural course of the disease and the level of patient care, as well as confirm the usefulness of early AATD detection.

COPD management in primary care: is an educational plan for GPs useful?

BACKGROUND: GPs currently deal with COPD. The aim of this study was to review COPD management, data collection in medical records, and adherence to GOLD guidelines of 12 GPs from rural areas of Northern Italy and to assess changes after an educational program (EP). METHODS: From 2004 to 2008 medical records of patients, defined as COPD by GPs, were analyzed. Data collection in terms of tests prescription, Forced Expiratory Volume at first second (FEV1), smoking habits and actual drug treatment were reviewed at baseline and 1 year after EP. RESULTS: 437 patients were defined as COPD. GPs prescribed more chest X-rays than spirometry (99% vs. 74%, p<0.001), FEV1 was registered only in 50% of the population. GPs prescribed "correct" or "doubtful" (not related to FEV1) therapy in 38% and 56% of patients, respectively. Only smoking habit registration increased significantly (p<0.05) after EP. CONCLUSIONS: Adherence to COPD Guidelines is suboptimal and data collection is poor. The EP did not change significantly GPs' practice: i) COPD diagnosis is largely clinical, ii) usage of spirometry is poor, GPs prescribe more chest X-rays iii) a small proportion of patients receive respiratory therapy, iv) therapy is often incorrect or not related to FEV1, v) correct clinical practice is influenced by the number of COPD patients and number of dedicated visits.

Dose-response curve to salbutamol during acute and chronic treatment with formoterol in COPD.

BACKGROUND: Use of short-acting ß(2)-agonists in chronic obstructive pulmonary disease (COPD) during treatment with long-acting ß(2)-agonists is recommended as needed, but its effectiveness is unclear. The purpose of this study was to assess the additional bronchodilating effect of increasing doses of salbutamol during acute and chronic treatment with formoterol in patients with COPD. METHODS: Ten patients with COPD underwent a dose-response curve to salbutamol (until 800 µg of cumulative dose) after a 1-week washout (baseline), 8 hours after the first administration of formoterol 12 µg (day 1), and after a 12-week and 24-week period of treatment with formoterol (12 µg twice daily by dry powder inhaler). Peak expiratory flow, forced expiratory volume in one second (FEV(1)), forced vital capacity, and inspiratory capacity were measured at the different periods of treatment and at different steps of the dose-response curve. RESULTS: Despite acute or chronic administration of formoterol, maximal values of peak expiratory flow, FEV(1), and forced vital capacity after 800 µg of salbutamol were unchanged compared with baseline. The baseline FEV(1) dose-response curve was steeper than that at day 1, week 12, or week 24 (P < 0.0001). Within each dose-response curve, FEV(1) was different only at baseline and at day 1 (P < 0.001), when FEV(1) was still greater at 800 µg than at 0 µg (P < 0.02). In contrast, the forced vital capacity dose-response curves were similar at the different periods, while within each dose-response curve, forced vital capacity was different in all instances (P < 0.001), always being higher at 800 µg than at 0 µg (P < 0.05). CONCLUSION: In patients with stable COPD, the maximal effect of salbutamol on peak expiratory flow, FEV(1), and forced vital capacity was unchanged after either acute or chronic treatment with formoterol. With increasing doses of salbutamol, FEV(1) increased only after acute administration of formoterol. Forced vital capacity also significantly improved during long-term treatment with formoterol.

Population genetic screening for alpha1-antitrypsin deficiency in a high-prevalence area.

BACKGROUND: Current guidelines for α1-antitrypsin deficiency (AATD) state that adult population screening should only be done in high-risk areas. Up-to-date genetic methods are always recommended. OBJECTIVES: To determine the prevalence of AATD in a suspected high-risk area by population screening, applying new genetic analyses and comparing the prevalence of liver and lung abnormalities in subjects with or without AATD. METHODS: Adult residents of Pezzaze, a village in an Italian alpine valley, voluntarily participated in the screening, and were examined for: nephelometric α1-antitrypsin (AAT) serum level, DNA analysis (mutagenic polymerase chain reaction and restriction fragment length polymorphism tests for Z and S AATD causative mutations, and denaturing high-performance liquid chromatography and/or direct gene sequencing if needed), serum aspartate and alanine transaminases, a respiratory questionnaire and the Medical Research Council dyspnea index scale. The prevalence of AATD was compared with that expected in Italy (Hardy-Weinberg equilibrium), and transaminases and the prevalence of respiratory symptoms were compared between study groups. RESULTS: Of 1,353 residents, 817 (60.4%) participated; 67 (8.2%) had low AAT serum levels (<90 mg/dl); 118 were carriers of AATD-associated alleles, 4 (0.5%) homozygotes or compound heterozygotes (1 Z, 1 S, 2 ZP(brescia)), 114 (14%) heterozygotes (46 Z, 52 S, 9 P(brescia), 4 M(wurzburg), 2 I, 1 P(lowell)). The prevalence and frequency of all AATD-related alleles was higher than expected for Italy (p < 0.001). There were no differences in symptoms of respiratory disease and transaminases between individuals with normal and low serum AAT. CONCLUSION: The screening design is one of the main strengths of this study. The large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible. Early recognition of individuals at risk means primary or secondary prevention measures can be taken.

Tele-assistance in chronic respiratory failure: patients' characterization and staff workload of 5-year activity.

BACKGROUND: The issue of how to optimize the routine use of tele-assistance (TA) in the clinical care remains to be addressed. Skills and costs of human resources represent the major component to care for chronic patients with TA. METHODS: We investigated (1) the change in patient population, mortality, and staff utilization/cost during the first 5-year activity of a TA program (24-h availability of a call center, pulse oxygen device, and second medical opinion) dedicated to chronic respiratory failure patients and (2) the staff time dedicated to each new patient admitted to the service. RESULTS: Three-hundred and ninety-six patients (age 64 +/- 17 years; 296 men) were reviewed across 5 years of activity. Patients followed/year increased over time, particularly for amyotrophic lateral sclerosis subjects. Calls/month dramatically increased from 60 to 290, with a 5-year number of calls equal to 12.952. The doctor's time dedicated to TA decreased over time, whereas the nurse's time increased allowing a cost saving of 39% when compared with budgeted salary costs. The number of home ventilated patients did not change, remaining over 78%. The mortality rate increased over time (from 6% to 11%). Both chronic obstructive pulmonary disease (COPD) and No-COPD patients used the TA service more frequently during the winter, and COPD used it also in the summer. CONCLUSIONS: A stable TA service dedicated to chronic respiratory failure may be reached after 4 years. Across years, (1) number of patients increased, with COPD and ventilated subjects being the most representative; (2) calls varied during seasons; (3) doctor's workload decreased, saving salary costs; and (4) each new enrolled patient may require 73 and 27 min/month of nurse and doctor, respectively.

Short- and long-term effects of CPAP on upper airway anatomy and collapsibility in OSAH.

RATIONALE AND AIM: In obstructive sleep apnea hypopnea (OSAH) patients, an increase of upper airway (UA) collapsibility has been described together with a reduced UA caliber due to inflammation, edema, and fat accumulation in pharyngeal walls. CPAP is the main treatment of OSAH and acts mechanically by increasing pressure inside UA. The aim of this study was to assess the short- and long-term effects of CPAP on UA caliber and collapsibility in severe OSAH patients. PATIENTS AND METHODS: Ten obese patients (nine male, age 55+/- 9 yr, BMI 35.1 +/- 6.1, Epworth sleepiness scale 12.3 +/- 3.6 point, AHI 58.8 +/- 27.1) had measurements of oropharingeal junction area (OPJ), mean pharyngeal area (APmean), maximal pharyngeal area (APmax) by acoustic pharyngometry and determination of expired volume in the first 0.5 s after the application at the mouth of -5 cmH(2)O negative expiratory pressure (V,NEP(0.5)) during wakefulness in the supine position under basal conditions (baseline) and after 1 week and 6 months of CPAP treatment. RESULTS: OPJ was 0.74 +/- 0.28 cm(2) at baseline, 0.90 +/- 0.24 cm(2) after 1 week and 1.05 +/- 0.31 cm(2) after 6 months (1 week and 6 months vs baseline p < 0.05). APmax was 2.28 +/- 0.74 cm(2) at baseline, 2.79 +/- 0.90 cm(2) after 1 week and 2.94 +/- 0.33 cm(2) after 6 months (1 week and 6 months vs baseline p < 0.05). APmean was 1.43 +/- 0.46 cm(2) at baseline, 1.82 +/- 0.45 cm(2) after 1 week and 1.94 +/- 0.35 cm(2) after 6 months (1 week vs baseline p < 0.01; 6 months vs baseline; p < 0.05). V,NEP(0.5) was 290 +/- 73 mL at baseline, 291 +/- 65 mL after 1 week and 338 +/- 67 mL after 6 months (6 months vs baseline p < 0.05; 1 week vs 6 months p < 0.01). CONCLUSIONS: Our data suggest that CPAP treatment might be effective in OSAH patients not only by causing a mechanical splint of UA but also by inducing an improvement on anatomical (early) and functional (later on) aspects of UA that can be observed during wakefulness.

Inhaled corticosteroids as additional treatment in alpha-1-antitrypsin-deficiency-related COPD.

BACKGROUND: No consistent data are available regarding the effect of inhaled corticosteroids (ICS) in alpha(1)-antitrypsin-deficiency (AATD)-related COPD. Recent data report inflammatory effects of the polymers of alpha(1)-antitrypsin on the peripheral lung. OBJECTIVES: The aim of this study was to assess the effectiveness of an extra-fine ICS, hydrofluoroalkane-134a beclometasone dipropionate (HFA-BDP) with a mass median aerodynamic diameter of 1.1 microm, on lung function and exercise tolerance in COPD patients with AATD when added to long-acting bronchodilators (LABAs). METHODS: After a 1-week washout, 8 steroid-naïve COPD patients with AATD (ZZ genotype), within a double-blind randomized cross-over study, were assigned to one of the following 16-week treatments: (1) HFA-BDP 400 microg b.i.d., salmeterol 50 microg b.i.d. and oxitropium bromide 200 microg t.i.d. or (2) placebo, salmeterol 50 microg b.i.d. and oxitropium bromide 200 microg t.i.d; after a 2-week washout period they received the other treatment. In weeks 1, 17, 19 and 35, patients took a spirometry assessment (breathing air and heliox) and a shuttle walking test (SWT) with dyspnea assessed by the modified Borg scale. RESULTS: Significant differences in improvement were found in FEV(1), FVC, IC, distance covered and dyspnea perceived during SWT between the 2 treatments and baseline values (p < 0.05; Friedman's test). However, further analysis showed that only the LABAs + ICS condition showed significant increases in the FEV(1), FVC, IC, DeltaMEF(50%) and distance covered during SWT along with a reduction in maximum isostep exertional dyspnea (p < 0.05; Wilcoxon test). A greater distance was walked at the end of the SWT with LABA + ICS than LABAs alone (301 +/- 105 vs. 270 +/- 112 m; p < 0.05). CONCLUSIONS: In AATD-related COPD patients (ZZ genotype) the addition of extra-fine ICS to LABAs decreases airway narrowing, mostly in the small airways, further reducing dynamic hyperinflation with a marked improvement in exercise tolerance and dyspnea, suggesting that a peripheral inflammatory process contributes to airflow obstruction in these patients.

Diagnostic flow chart for targeted detection of alpha1-antitrypsin deficiency.

BACKGROUND: Alpha1-antitrypsin (AAT) deficiency is under-recognized, probably because many individuals affected show no clinical impairment. The targeted detection is a tool to increase its recognition. METHODS: We prospectively submitted to AAT serum levels determination, phenotyping and, if doubtful, genotyping: (i) patients with the early onset of emphysema, emphysema in absence of recognized risk or pneumothorax (path P), antineutrophil cytoplasm antibodies (ANCA) positive vasculitis (path V), cervical artery dissection (path A), Periodic acid-Schiff (PAS) positive bodies in the liver cell or unexplained abnormal transaminase level (Path L) [index cases: IC] and (ii) subjects with low-serum alpha1-globulin (path e) and close relatives of patients with AAT deficiency (path r) [non index cases: NIC]. We determined and compared gender, age, AAT serum levels values, the ratio between AAT deficiency subjects identified and all subjects examined (identified/examined). Receiver operating characteristic (ROC) curve was plotted to find the best threshold for AAT serum levels. RESULTS: Two hundred and eighty-five individuals were examined and 211 with AAT deficiency identified: 66 were IC and 145 NIC. The ratio identified/examined resulted 0.74. A serum level of 120 mg/dL was able to identify AAT deficiency with a specificity of 73% and a sensitivity of 97%. IC showed male prevalence (P=0.005), more advanced age (P=0.02), lower AAT serum levels (P=0.008). CONCLUSIONS: Our protocol is effective to detect AAT deficiency in a selected population. About 120 mg/dL (nephelometric method) is a reliable AAT serum level cut-off for selecting subjects/patients to submit to phenotype or genotype; as compared to NIC, IC are older, mostly male and with lower AAT serum levels.