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Many coronavirus disease 2019 (Covid-19) survivors show symptoms months after acute illness. The aim of this work is to describe the clinical evolution of Covid-19, one year after discharge. We performed a prospective cohort study on 238 patients previously hospitalized for Covid-19 pneumonia in 2020 who already underwent clinical follow-up 4 months post-Covid-19. 200 consented to participate to a 12-months clinical assessment, including: pulmonary function tests with diffusing lung capacity for carbon monoxide (DLCO); post-traumatic stress (PTS) symptoms evaluation by the Impact of Event Scale (IES); motor function evaluation (by Short Physical Performance Battery and 2 min walking test); chest Computed Tomography (CT). After 366 [363–369] days, 79 patients (39.5%) reported at least one symptom. A DLCO

Background Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated. Methods We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR. Results AATD-AT patients were younger but had similar spirometric and DLCO values compared to cigarette smoke-associated COPD, despite a lower burden of smoking history. Compared to cigarette smoke-associated COPD, AATD-noT and AATD-AT patients had lower sputum neutrophil levels (p=0.0446, p=0.0135), total bacterial load (16S) (p=0.0081, p=0.0223), M. catarrhalis (p=0.0115, p=0.0127) and S. pneumoniae (p=0.0013, p=0.0001). Sputum IL-27 was significantly elevated in CS and cigarette smoke-associated COPD. AATD-AT, but not AATD-noT patients, had IL-27 sputum levels (pg/ml) significantly lower than COPD (p=0.0297) and these positively correlated with FEV1% predicted values (r=0.578, p=0.0307). Conclusions Compared to cigarette smoke-associated COPD, AATD-AT (COPD) patients have a distinct airway inflammatory and microbiological profile. The decreased sputum bacterial load and IL-27 levels in AATD-AT patients suggests that augmentation therapy play a role in these changes.

The management of bronchial secretions is one of the main problems encountered in a wide spectrum of medical conditions ranging from respiratory disorders, neuromuscular disorders and patients undergoing either thoracic or abdominal surgery. The purpose of this review is illustrate to the reader the different ACTs currently available and the related evidence present in literature. Alongside methods with a strong background behind as postural drainage, manual techniques or PEP systems, the current orientation is increasingly aimed at devices that can mobilize and / or remove secretions. Cough Assist, Vacuum Techniques, systems that modulate airflow have more and more scientific evidence. Different principles combination is a new field of investigation that goes toward an increasing of clinical complexity that will facing us.

Objective The study aimed to evaluate whether high-flow oxygen therapy (HFOT) during training was more effective than oxygen in improving exercise capacity in hypoxemic chronic obstructive pulmonary disease (COPD). Methods A total of 171 patients with COPD and chronic hypoxemia were consecutively recruited in 8 rehabilitation hospitals in a randomized controlled trial. Cycle-ergometer exercise training was used in 20 supervised sessions at iso inspiratory oxygen fraction in both groups. Pre- and post-training endurance time (Tlim), 6-minute walking distance (6MWD), respiratory and limb muscle strength, arterial blood gases, Barthel Index, Barthel Dyspnea Index, COPD Assessment Test, Maugeri Respiratory Failure questionnaire, and patient satisfaction were evaluated. Results Due to 15.4% and 24.1% dropout rates, 71 and 66 patients were analyzed in HFOT and Venturi mask (V-mask) groups, respectively. Exercise capacity significantly improved after training in both groups with similar patient satisfaction. Between-group difference in post-training improvement in 6MWD (mean: 17.14 m; 95% CI = 0.87 to 33.43 m) but not in Tlim (mean: 141.85 seconds; 95% CI = −18.72 to 302.42 seconds) was significantly higher in HFOT. The minimal clinically important difference of Tlim was reached by 47% of patients in the V-mask group and 56% of patients in the HFOT group, whereas the minimal clinically important difference of 6MWD was reached by 51% of patients in the V-mask group and 69% of patients in the HFOT group, respectively. Conclusion In patients with hypoxemic COPD, exercise training is effective in improving exercise capacity. Impact Statement The addition of HFOT during exercise training is not more effective than oxygen through V-mask in improving endurance time, the primary outcome, whereas it is more effective in improving walking distance.

A autoimmune Pulmonary Alveolar Proteinosis (PAP) patient with persistent disease underwent 3 Whole Lung Lavages (WLLs), 10 plasmapheresis sessions and further 3 WLL, from October 2004 to May 2007.

Background: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder. Most of case of severe AAT are caused by Z and S mutations in the SERPINA1 gene, that reduces serum AAT concentrations till to 15% of normal levels. Mutations causing total absence of serum AAT (Null mutations) are very rare. Individuals homozygouse for Null mutations should be considered a subgroup at particularly high risk of emphysema, but their clinical phenotype is poorly described. Objectives: We would like to evaluate the differences between clinical history of AATD in subject with the most prevalent deficient genotype (PI*ZZ) and those with rare PI*Null/Null genotypes, and the different impact that the only available specific therapy for AATD (augmentation therapy with purified AAT) could have on them. Methods: We analyzed clinical and demographic characteristics of 8 PI*Null/Null patients in comparison to 338 PI*ZZ subjects from the Italian Registry of Severe AATD. Results: In comparison to PI*ZZ, PI*Null/Null patients have early respiratory symptoms (31.7 vs 45.2 years, p=0,006), and worse lung function at diagnosis (FEV1 41.5 vs 70.7, p=0.01; FVC 77.4 vs 87.57 %pred.) and obstruction (FEV1/FVC 0.6 vs 0.7). They are most frequently treated with augmentation therapy (100% vs 31.4%, p Conclusions: Early detection of PI*Null/Null subject is desirable for preventive and therapeutic interventions. PI*Null/Null subjects have great benefit from early augmentation therapy.

We compared in COPD with CRF undergoing training, HFOT (AIRVO2® FisherP all used the same high-intensity exercise program (1 session/day for ≥ 20 sessions) with different oxygen device. BMI, spirometry and co morbidities have been collected. Baseline and after training exercise tolerance (Constant Work Rate Exercise Test, CWERT + 6-min walk test, 6MWT), respiratory (MIP/MEP) and biceps/quadriceps muscle strength, blood gases, Barthel Index and Barthel Dyspnoea Index, CAT and MRF-26 were measured. Patients’ satisfaction has been evaluated. 71 and 66 patients were analysed for HFOT and V-mask respectively being 15% and 24% the rate of drop-out. All variables improved after training in both groups with similar satisfaction. Comparing the two groups, only meters at 6MWT resulted statistically higher in HFOT group (p=0.029). HFOT group performed 153 seconds more than V-mask at CWERT, without statistical significance (p=0.057). Improvers (gain > 150 sec at CWERT) were 44% and 56% for V-mask and HFOT, respectively. FEV1% prd higher than 30% (OR 2.44, p=0.025) and higher baseline endurance time (OR 1.15, p=0.024) predicted improvers. Low BMI (OR 0.9298, p=0.038) predicted drop-outs. CWERT improvement was positively related to comorbidities (p=0.025) and CAT (p=0.031), while negatively to PaO2/FiO2 (p=0.04). We have confirmed the strong indication to training program in advanced COPD with CRF; HFOT used during training may further increase exercise tolerance.

Adherence to CPAP therapy is effective when applying a standard protocol consisting of a diagnostic procedure, accurate pressure setting and mask choice, a group educational session on sleep disorders and 1-yr follow up visithttp://bit.ly/352XPBH

BACKGROUND: A recent study found that activation of disconnection and low-pressure alarms is common during mouthpiece ventilation and may represent a major limitation to its use. The aim of this bench study was: (1) to investigate the technical aspects that can influence the setting of the ventilator during mouthpiece ventilation and (2) to provide a practical setting strategy to avoid the alarm activation. METHODS: Eight life-support ventilators able to deliver volume controlled ventilation were tested in a bench study using a single-limb non-vented circuit configuration connected to a standard mouthpiece. Disconnection and apnea alarm were turned off or set at the least sensitive setting. The backup frequency was set at the lowest available level. Different tidal volumes (VT) (from 500 to 1,200 mL) were tested with the rectangular and descending flow shape. For each VT, we reported the maximum set inspiratory time (TI) that allowed preventing activation of the low-pressure alarm. The presence of auto-triggering was also surveyed. RESULTS: We found that a correct combination of VT and TI avoided the activation of disconnection and low-pressure alarms in all but 3 ventilators. One ventilator did not allow mouthpiece ventilation independently from the settings used. The inability to turn off the apnea alarm in two other ventilators led to the alarm going off in any tested conditions after 120 s without triggered breaths. Auto-triggering was seldom found and easily worked out, except for in one ventilator. CONCLUSIONS: An appropriate alarm setting and combination of VT and TI would allow the majority of the tested ventilators to be used for mouthpiece ventilation without alarm activation.

Rationale: PAP is a an ultra-rare disease where a perturbation in surfactant homeostasis results in its accumulation within airspaces, thus impairing gas transfer. WLL currently remains the therapeutic standard, even if it may induce complete resolution of the disorder only in 30% of patients. Aim: To characterize the gene network able to predict the outcome of the WLL, i.e. total resolution/persistent improvement vs transient resolution/progressive deterioration. Methods: We conducted a gene interaction network analysis, with web-based software (esyN), to calculate hub and bottleneck genes previously investigated by a microarray analysis (1), performed on the PBMCs of 16 PAP patients treated with WLL and followed for 24 months. Hub genes were identified by the number of interactions within the network. Bottleneck genes were identified by calculating the betweenness centrality index (BCI) for each gene in the network. BCI reflects the amount of control that a gene exerts over the interactions of other genes in the network. Results: We found that SMAD3, which acts as a mediator of the profibrotic signals initiated by TGF-β and SYNCRIP, which plays a role in multiple aspects of mRNA maturation, are top ranked hubs genes. Interestingly, SMAD3 is also the top ranked bottleneck gene. Conclusion: The SMAD3 transcription factor seems to be the central mediator and conductor of the gene network involved in the response to the WLL treatment in PAP patients. 1- M Zorzetto, et al. A gene network to predict the clinical response to whole lung lavage (WLL), in pulmonary alveolar proteinosis (PAP). ERS Annual Congress, Milano, Italy, September 9-13, 2017.

Rationale: PAP is a ultra-rare disease, where surfactant accumulation within alveolar spaces could lead to respiratory failure and death. WLL is the current standard treatment for PAP, nevertheless disease persistence after treatment is reported in 30% of cases. Aim: This work is aimed to identify a common gene co-expression network able to predict the outcome of the WLL: total resolution/persistent improvement vs transient resolution/progressive deterioration. Methods: We applied a weighted genes co-expression network analysis to transcriptional profiles of total RNA, collected from peripheral blood mononuclear cells (PBMC) of 16 PAP patients who underwent WLL. After a 24-month follow up, they were dichotomized in positive vs negative outcome and a microarray analysis, with around 20000 genes screened (SurePrint G3 Human Gene, Agilent) was performed. Finally Gene Ontology (GO), Reactome, KEGG, and Disease Ontology enrichment analysis was performed for differentially expressed genes (DEGs). Results: Four biologically meaningful modules of genes highly connected were identified. In particular, one of these (comprehending 111 genes with a p value Conclusion: For the first time we provide a modular profile of PAP which could explain the regulatory mechanism underlying the clinical outcome.

Pulmonary alveolar proteinosis (PAP) is a diffuse pulmonary disease, characterised by the accumulation of lipoproteinaceous material in the distal air spaces, which results in impaired gas transfer. Autoimmune PAP accounts for the vast majority of cases in humans and is caused by autoantibodies directed towards granulocyte-macrophage colony-stimulating factor (GM-CSF), which causes a defect in the function of alveolar macrophages linked to the disruption of surfactant homeostasis. Whole lung lavage (WLL) is the current standard of care for PAP patients and although it is effective in the majority of cases, disease persistence is not an unusual outcome, even if airspace accumulation is well controlled by WLL. Even though WLL remains the current standard therapy for PAP, in this review we focus on novel treatment approaches for autoimmune PAP.

Background: A patient with autoimmune PAP with persistent disease underwent 3 WLL, 10 plasmapheresis cycles and further 3 WLL, from October 2004 to May 2007. Despite a substantial clinical and functional benefit, the radiographic appearance showed a partial resolution of lung infiltrates(1). At the beginning of 2010, after a worsening of respiratory conditions, the patient was admitted to inhaled GM-CSF (Sagramostin) therapy as compassionate treatment. Methods: GM-CSF, dispensed byAkita 2 nebulizer (Vectura),was administered following:250 mcg/day every other week for 12 weeks, then 250 mcg/day on 2 consecutive days every 2 weeks for 6 months. Follow up visits were scheduled at 3, 10, 18, 30 months and after that once a year. Functional and HRCT data and PaO2 were collected. Results: From the start of the inhalatory therapy the patient no more required WLL. Furthermore we found a significant increase in DLCO%(p=0.013) and FVC%(p=0.023) while FEV1% show a positive trend(Fig.1). No substantial differences in blood gas analysis. The pulmonary involvement at HRCT shows a significant decrease of lung infiltrates(p=0.039) in terms of pathological segments. Conclusion: These data underscore the utility of inhaled GM-CSF not only in case of progressing disease but also in case of persistence/stabilization, in order to increase response rate. 1.Luisetti et al. Eur Respir J 2009; 33: 1220–1222.

Background: aPAP is a rare disease characterized by neutralizing GM-CSF autoantibodies and alveolar surfactant accumulation. WLL is the standard therapy but results in complete resolution only in 30% of patients. We hypothesized that the combination WLL and inhaled hGM-CSF (Sargramostim) is more effective than WLL alone. Methods: We conducted a phase II clinical trial:aPAP patients were randomized to receive either WLL alone (group A) or WLL followed by inhaled sargramostim (250 mcg/day every other week for 12 weeks followed by 250 mcg/day on 2 consecutive days every 2 weeks for 6 months) (group B). GM-CSF was administered by the Akita 2 nebulizer (Vectura). Here, we report interim results obtained 30 months after WLL. Results: 18 aPAP patients (7 females/11 males) were randomized (equally) into each group. 7 in the initial group A required re-randomization because of recurrence while only 1 in the initial group B required re-randomization. Compared to the group A, the group B had significant improvement in pulmonary function including increases in mean (95% CI) DLCO%(15.7, 10.0-21.4), FVC%(11.8, 7.4-16.3), TLC%(10, 6.4-13.8), FEV1%(9.6, 5.5-13.7) (P Conclusion: Interim results demonstrate that inhaled sargramostim was well tolerated and effective in aPAP and that combination therapy is more effective than WLL alone. Funding: AIFA(FARM7MCPK4).

PAP is a rare disorder characterized by the accumulation of lipoproteinaceous material within alveolar spaces. WLL is the current standard treatment for PAP patients and although it is effective in the majority of cases, disease persistence is not unusual. To identify blood biomarkers able to predict the outcome of the WLL: total resolution/persistent improvement (positive outcome) or transient resolution/progressive deterioration (negative outcome). We collected total RNA from peripheral mononuclear cells of 8 PAP patients who underwent WLL, at the baseline and 24 months from the lavage. After the 24-month follow up, they were dichotomized in positive vs negative outcome and a microarray analysis was performed. Co-expression eigengenes module search and Gene Ontology, Reactome, KEGG, and Disease Ontology enrichment analysis was performed for differentially expressed genes (DEGs). Our preliminary data show 86 significantly DEGs, between PAP patients with a positive vs negative outcome; whereas WLL seems not to induce difference in gene expression, in the same subject, at least after two years. The gene co-expression networks analysis, selected a module comprehending 764 genes, which showed a gene significance mean p value=0.04 and a strong relationship between pairwise gene connections and gene significance. The enrichment analysis showed a common predominance of the GO biological process and Reactome pathways. This preliminary study allows to identify key pathways whose different expression could discriminate between PAP patients with a positive outcome vs negative outcome. The validation of our results will lead us to select biomarkers useful to follow up the clinical response to WLL.

Rationale: Whole lung lavage (WLL) is the current standard of care for PAP; WLL is not a standardized procedure, moreover it is highly invasive and is performed under general anesthesia. During the lavage, chest wall percussion is added when the outflow, initially milky, becomes clear. Lavage and percussion are continued until the outflow fluid became completely clear, which may take 3 hrs and an average of 15L saline for a single lung. The complications are rare, consisting mostly of hypoxemia, hydropneumothorax, ARDS, and post-procedure infections. Aims: Our aim is to demonstrate that the efficacy of WLL remains unaltered by using a reduced volume of saline. Methods: Functional data (FEV1, FVC, TLC, FEV1/VC, DLCO) and PaO2 were collected from 15 PAP patients who underwent WLL, at the baseline and 1,3,6 months after the lavage. The amount of 15L saline for single lung was used in 8 patients. In order to optimize WLL procedure, in 7 patients the infusion was reduced to 8L and chest percussion was started in concomitance with the first aliquot infusion. Results: We compared the parameters at the baseline and 1,3,6 months after the lavage and we did not find any statistically significant difference, although we can identify a positive trend of all the functional parameters considered, in the patients group lavaged with 8L saline. Conclusions: Our preliminary data suggest the possibility to reduce the infusion volume (with an earlier clapping) and consequently the time of the procedure. Considering the complexity of the WLL and the risk of a prolonged anesthesia, it could be an advantage in terms of safety of the procedure.

Crack inhalation is known to cause a wide spectrum of acute and chronic pulmonary complications, along with imaging manifestations and lung function patterns. The diagnosis of these conditions is often delayed or mistaken. Only little information about the management and follow up of these pulmonary complications is available in literature. We present the case of a young patient referred to our clinic for symptoms mimicking an asthma exacerbation, not responsive to inhalant treatment. After investigations and the admission of crack abuse by the patient a final diagnosis of bronchiolitis crack-related was made. The patient was then followed for more than a year showing that lung function tests may be useful both for the diagnosis and follow up of such pulmonary complications.

Rationale: PAP is a rare disorder characterized by the accumulation of lipoproteinaceous material within alveolar spaces. The clinical course is variable, ranging from an asymptomatic presentation to respiratory failure and death. WLL is the current standard treatment for PAP patients and although it is effective in the majority of cases, disease persistence is not an unusual outcome. Although the introduction of the WLL has changed the natural history of PAP, little is known about the intimate mechanisms of action of WLL. Aims: Our aim is to identify blood biomarkers able to predict the outcome of the WLL: total resolution/persistent improvement (positive outcome) or transient resolution/progressive deterioration (negative outcome). Methods: We collected total RNA from peripheral mononuclear cells of 8 PAP patients who underwent WLL, at the baseline and 24 months from the lavage. After the 24-month follow up, they were dichotomized in positive vs negative outcome and a microarray analysis, with around 20000 genes screened (SurePrint G3 Human Gene, Agilent) was performed. Results: Our preliminary data show 86 genes significantly differentially expressed, between PAP patients with a positive outcome (n=4) vs negative outcome (n=4), which could be predictive of the response to the lavage; whereas WLL seems not to induce difference in gene expression, in the same subject, at least after two years. Conclusion: The identification of an expression signature, able to discriminate between PAP patients with a positive outcome vs negative outcome, will lead us to select biomarkers useful to follow up the clinical response to WLL. Funding: AIFA(FARM7MCPK4), eRARE(EuPAPNet).

The first step in laboratory diagnosis of alpha1-antitrypsin deficiency (AATD) is the determination of alpha1-antitrypsin (AAT) serum levels; these levels in turn are influenced by the inflammatory status. C reactive protein (CRP) has been proposed as a marker of systemic inflammation. Single nucleotide polymorphisms (SNPs) in the CRP gene have been associated with differences in baseline CRP levels. The purpose of this study was to investigate the relationship between CRP and AAT in the AATD diagnostic setting and to verify whether variations in the CRP gene could influence CRP. We determined AAT and CRP levels in 362 consecutive dried blood spot (DBS) samples submitted for AATD diagnosis and genotyped 3 CRP gene SNPs (rs1205, rs3093077, and rs3091244) associated with variations in serum CRP concentrations. To this aim, we developed a method to measure CRP in a DBS with a good correlation with CRP measurement in serum ( r 2 = 0.9927). We showed then that systemic inflammatory status parallels increased levels of AAT (80% of subjects with intermediate AATD and a CRP > 0.8 mg/dL had an AAT level above the cut-off of 113 mg/dL) and that this increase might mask the presence of AATD variants. No association was detected between CRP levels and the 3 CRP gene polymorphisms. Simultaneous determination of CRP and AAT is useful in the correct diagnosis of heterozygotes carrying intermediate AATD genotypes; their genetic influence on the CRP level is negligible.