Molecular characterization of macrolide resistance in Haemophilus influenzae and Haemophilus parainfluenzae strains (2018-21).

OBJECTIVES: This study aimed to explore the prevalence of macrolide resistance and the underlying resistance mechanisms in Haemophilus influenzae (n = 2556) and Haemophilus parainfluenzae (n = 510) collected between 2018 and 2021 from Bellvitge University Hospital, Spain. METHODS: Antimicrobial susceptibility was tested by microdilution. Whole-genome sequencing was performed using Illumina MiSeq and Oxford Nanopore technologies, and sequences were examined for macrolide resistance determinants and mobile genetic structures. RESULTS: Macrolide resistance was detected in 67 H. influenzae (2.6%) and 52 (10.2%) H. parainfluenzae strains and associated with resistance to other antimicrobials (co-trimoxazole, chloramphenicol, tetracycline). Differences in macrolide resistance existed between the two species. Acquired resistance genes were more prevalent in H. parainfluenzae (35/52; 67.3%) than in H. influenzae (12/67; 17.9%). Gene mutations and amino acid substitutions were more common in H. influenzae (57/67; 85%) than in H. parainfluenzae (16/52; 30.8%). Substitutions in L22 and in 23S rRNA were only detected in H. influenzae (34.3% and 29.0%, respectively), while substitutions in L4 and AcrAB/AcrR were observed in both species. The MEGA element was identified in 35 (67.3%) H. parainfluenzae strains, five located in an integrative and conjugative element (ICE); by contrast, 11 (16.4%) H. influenzae strains contained the MEGA element (all in an ICE). A new ICEHpaHUB8 was described in H. parainfluenzae. CONCLUSIONS: Macrolide resistance was higher in H. parainfluenzae than in H. influenzae, with differences in the underlying mechanisms. H. parainfluenzae exhibits co-resistance to other antimicrobials, often leading to an extensively drug-resistant phenotype. This highlights the importance of conducting antimicrobial resistance surveillance.

Treating sleep-disordered breathing of idiopathic pulmonary fibrosis patients with CPAP and nocturnal oxygen treatment. A pilot study : Sleep-disordered breathing treatment in IPF.

INTRODUCTION: Sleep-disordered breathing (SDB) is a major comorbidity in idiopathic pulmonary fibrosis (IPF) and is associated with a poor outcome. There is a lack of knowledge regarding the impact of SDB treatment on IPF. We assessed at one year: (1) the effect of CPAP and/or nocturnal oxygen therapy on IPF regarding lung function, blood mediators, and quality of life; (2) adherence to SDB treatment and SDB changes. METHODOLOGY: This is a prospective study of consecutive newly diagnosed IPF patients initiating anti-fibrotic treatment. Lung function, polysomnography, blood tests and quality of life questionnaires were performed at inclusion and after one year. Patients were classified as obstructive sleep apnoea (OSA), central sleep apnoea (CSA), and sleep-sustained hypoxemia (SSH). SDB therapy (CPAP and/or nocturnal oxygen therapy) was initiated if needed. RESULTS: Fifty patients were enrolled (36% had OSA, 22% CSA, and 12% SSH). CPAP was started in 54% of patients and nocturnal oxygen therapy in 16%. At one-year, polysomnography found improved parameters, though 17% of patients had to add nocturnal oxygen therapy or CPAP, while 33% presented SDB onset at this second polysomnography. CPAP compliance at one year was 6.74 h/night (SD 0.74). After one year, matrix metalloproteinase-1 decreased in OSA and CSA (p = 0.029; p = 0.027), C-reactive protein in OSA (p = 0.045), and surfactant protein D in CSA group (p = 0.074). There was no significant change in lung function. CONCLUSIONS: Treatment of SBD with CPAP and NOT can be well tolerated with a high compliance. IPF patients may exhibit SDB progression and require periodic re-assessment. Further studies to evaluate the impact of SDB treatment on lung function and serological mediators are needed.

Efficacy of Low-Dose versus High-Dose Continuous Cyclic Azithromycin Therapy for Preventing Acute Exacerbations of COPD.

BACKGROUND: Long-term azithromycin therapy significantly reduces the frequency of COPD exacerbations (ECOPD). However, previous studies have used different dosing regimens, and the efficacy of these regimens has not been compared. OBJECTIVE: Compare the efficacy of low-dose with high-dose continuous cyclic azithromycin (CC-A) in severe COPD. METHODS: Patients with severe COPD and repeated exacerbations (ECOPD ≥4 or ≥3 with at least 1 hospital admission in the previous year) were prospectively recruited (January 2017 to December 2019) as a multicenter cohort (from 3 university hospitals in the Barcelona area) and treated with low-dose CC-A: 250 mg 3 times per week (250-CC-A group). This cohort was compared with a historical (January 2007 to December 2013) single-center cohort of severe COPD with frequent ECOPD treated with high-dose CC-A: 500 mg 3 times per week (500-CC-A group). To assess differences in ECOPD prevention according to the administration of low-dose or high-dose CC-A, moderate-to-severe ECOPD was evaluated during the 12-month period before and after starting CC-A therapy. RESULTS: Fifty-eight patients with severe COPD were evaluated: 37 in the low-dose group and 21 in the high-dose group. The 250-CC-A therapy group achieved a mean reduction in moderate-to-severe ECOPD of 65.6% at 12 months after starting CC-A therapy (with a 61.5% reduction in hospitalizations), while the 500-CC-A group achieved a reduction of 60.5% (with a 44.8% reduction in hospitalizations). No significant differences between 250-CC-A and 500-CC-A dosages were observed in the mean annual reduction of moderate-to-severe ECOPD (p = 0.55) or hospitalizations (p = 0.07) with respect to the year prior to starting CC-A. CONCLUSIONS: Low-dose 250-CC-A therapy over a 1-year period is similar to high-dose 500-CC-A in reducing exacerbation frequency in severe COPD patients with frequent ECOPD despite maximal medical therapy.

Is the purinergic pathway involved in the pathology of COPD? Decreased lung CD39 expression at initial stages of COPD.

BACKGROUND: Extracellular adenosine triphosphate (ATP) is up-regulated in the airways of patients with chronic obstructive pulmonary disease (COPD), resulting in increased inflammation, bronchoconstriction, and cough. Although extracellular ATP levels are tightly controlled by nucleoside triphosphate diphosphohydrolase-1 (NTPDase1; also known as CD39) in the lungs, the role of CD39 in the pathology of COPD is unknown. We hypothesized that alterations in the expression and activity of CD39 could be part of the mechanisms for initiating and perpetuating the disease. METHODS: We analyzed CD39 gene and protein expression as well as ATPase enzyme activity in lung tissue samples of patients with COPD (n = 17), non-obstructed smokers (NOS) (n = 16), and never smokers (NS) (n = 13). Morphometry studies were performed to analyze pulmonary vascular remodeling. RESULTS: There was significantly decreased CD39 gene expression in the lungs of the COPD group (1.17 [0.85-1.81]) compared with the NOS group (1.88 [1.35-4.41]) and NS group (3.32 [1.23-5.39]) (p = 0.037). This attenuation correlated with higher systemic inflammation and intimal thickening of muscular pulmonary arteries in the COPD group. Lung CD39 protein levels were also lower in the COPD group (0.34 [0.22-0.92]) compared with the NOS group (0.67 [0.32-1.06]) and NS group (0.95 [0.4-1.1) (p = 0.133). Immunohistochemistry showed that CD39 was downregulated in lung parenchyma, epithelial bronchial cells, and the endothelial cells of pulmonary muscular arteries in the COPD group. ATPase activity in human pulmonary structures was reduced in the lungs of patients with COPD. CONCLUSION: An attenuation of CD39 expression and activity is presented in lung tissue of stable COPD patients, which could lead to pulmonary ATP accumulation, favoring the development of pulmonary inflammation and emphysema. This may be a mechanism underlying the development of COPD.

Effectiveness of a Respiratory Day Hospital Program to Reduce Admissions for Exacerbation in Patients with Severe COPD: A Prospective, Multicenter Study.

The respiratory Day Hospital (DH) is a care facility currently operating at various healthcare institutions. It monitors patients with severe chronic obstructive pulmonary disease (COPD) presenting repeated exacerbations with at least two hospital admissions per year. The main aim of the study was to evaluate the effectiveness of the DH program for controlling admissions for COPD exacerbations in this cohort of patients, and to identify clinical factors associated with hospitalizations and mortality. An observational prospective multicenter study was carried out at three hospitals. The sample comprised 150 consecutive patients (median age 70 [65-76] years, FEV1 33 [26-43]%, 97% males), included at the DH program. Over a one-year period, variables assessing effectiveness and use of healthcare resources were recorded. Factors associated with hospitalizations and mortality were identified. Patients made a median of 4[2-5] emergency visits due to COPD exacerbations with a median of 1[0-2] hospitalization(s)/year. Most of exacerbations (77%) were evaluated at the DH, but there were fewer hospitalizations from the DH than from the emergency department (21% vs. 81%, p < 0.001). In all, 29% of the patients had at least two admissions; these were the patients with the most severe disease. Age, readmission at 30-days and the presence of respiratory failure were the predictors of mortality. In conclusion, the DH program is an effective model for reducing hospitalizations in this cohort of patients. In all, 29% of the patients required two hospital admissions or more; these patients had more advanced disease and poorer prognosis, and would be most likely to benefit from additional care support.

Roflumilast added to triple therapy in patients with severe COPD: a real life study.

BACKGROUND: Roflumilast is used in severe chronic obstructive pulmonary disease (COPD) patients with frequent exacerbations. However, limited information is available on its impact in a "real-life" population that may be receiving triple therapy. OBJECTIVE: This study aimed to evaluate the effectiveness and safety of roflumilast in COPD patients already receiving triple therapy (long-acting ß-agonist/inhaled corticosteroids and long-acting muscarinic antagonist). METHODS: Prospective registry that included COPD patients who were prescribed roflumilast added to triple therapy. The yearly rate of all COPD exacerbations before and after roflumilast and side effects related to the drug were registered. RESULTS: Among 55 patients prescribed 500 mg of roflumilast. Only 50.9% (n = 28) completed 1 year of therapy (roflumilast group). A reduction of all exacerbations with roflumilast was observed (2.75 ± 0.29 vs. 3.57 ± 0.26; P = 0.022), with a particular benefit in patients with ≥4 exacerbations prior to initiating therapy (3.55 ± 0.51 vs. 5.00 ± 0.30; P = 0.034). Side effects (mainly gastrointestinal) and treatment discontinuation occurred in 69.1% and 49.1% of the overall population, respectively. CONCLUSIONS: Roflumilast, when added to triple therapy, reduces exacerbations in a "real-life" population of severe COPD patients with frequent exacerbations. However, side effects are more common and lead more frequently to discontinuation of therapy than has been reported in trials.

Gene and Protein Expression of Fibronectin and Tenascin-C in Lung Samples from COPD Patients.

PURPOSE: Fibronectin (Fn) and tenascin-C (TnC) are two extracellular matrix proteins associated with remodeling changes. Fn and TnC gene and protein expression in lung tissue, including their predominant location in bronchial and pulmonary artery structures, have not yet been fully evaluated. The aim of the present study was to assess: (1) gene expression of Fn and TnC in lung samples from chronic obstructive pulmonary disease (COPD) and non-COPD subjects; and (2) protein content and location of Fn and TnC in both groups. METHODS: Consecutive subjects requiring lung resection due to lung cancer surgery were included. Lung specimens were examined for gene expression by quantitative real-time PCR (values expressed as fold change ratio). The analysis of their protein content and location was performed by western blot and immunohistochemical studies, respectively. Patients were divided into two cohorts according to COPD status. RESULTS: A total of 41 patients (20 with COPD and 21 without COPD) were included. An enhanced Fn gene expression was observed in the COPD group compared to the non-COPD group (4.73 ± 0.54 vs. 2.65 ± 0.57; P = 0.012), whereas no differences in gene TnC expression were observed (2.91 ± 0.44 vs. 2.60 ± 0.48; P = 0.633). No differences in lung protein content and location were found between groups. Immunohistochemical evaluation showed a predominantly vascular and bronchial location of Fn and TnC in both groups. CONCLUSIONS: An enhanced lung gene expression of Fn was observed in COPD subjects compared to non-COPD subjects. No differences were found in Fn protein expression or in TnC gene or protein expression among groups.

Dynamics of the pneumococcal population causing acute exacerbations in COPD patients in a Barcelona hospital (2009-12): comparison with 2001-04 and 2005-08 periods.

BACKGROUND: Pneumococci are an important cause of acute exacerbations in patients with chronic obstructive pulmonary disease (COPD). In the last decade, the pneumococcal population has changed, mainly due to the introduction of the 7-valent conjugate vaccine (PCV7). METHODS: We analysed the antimicrobial susceptibility (microdilution), serotype (PCR) and genotype (PFGE/multilocus sequence typing) of pneumococci causing acute exacerbations during the period 2009-12. Results were compared with two previously published historic periods (2001-04 and 2005-08). RESULTS: A total of 206 pneumococci were collected from 162 COPD patients with acute exacerbations. Compared with previous periods, no significant changes in the rate of multidrug resistance were observed (36.2% in the 2001-04 period to 33.5% in the 2009-12 period, P = 0.644). The most frequent serotypes in the 2009-12 period were 15A (9.6%), 3 (8.1%), 19F (6.6%), 11A (6.1%) and 6C (5.6%), which accounted for 36.0%. A drastic decrease in PCV7 serotypes was observed throughout the study period (from 39.7% in 2001-04 to 10.9% in 2009-12, P < 0.001); non-PCV13 serotypes increased from 44.9% to 71.2%, especially 15A (from 2.2% to 9.6%) and 6C (from 0.0% to 5.6%) (P < 0.05). The most frequent genotypes (clonal complexes, CCs) in the 2009-12 period were CC63(15A,19F,15F) (9.1%), CC180(3) (4.5%), CC62(11A) (4.0%), CC97(10A) (4.0%), CC386(6C) (3.5%), CC260(3) (3.5%) and CC30(16F) (3.5%). Serotypes 19F, 19A, 6A and 6C were genetically diverse. CONCLUSIONS: PCV7 serotypes have decreased dramatically. In parallel, two non-PCV7 serotypes (15A and 6C) and their related genotypes (CC63 and CC386) showed a significant increase. Although resistance rates to ß-lactams decreased over time, multidrug resistance remained stable.

Lung fibrotic tenascin-C upregulation is associated with other extracellular matrix proteins and induced by TGFß1.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive parenchymal lung disease of unknown aetiology and poor prognosis, characterized by altered tissue repair and fibrosis. The extracellular matrix (ECM) is a critical component in regulating cellular homeostasis and appropriate wound healing. The aim of our study was to determine the expression profile of highlighted ECM proteins in IPF lungs. METHODS: ECM gene and protein expression was analyzed by cDNA microarrays, rt-PCR, immunohistochemistry and western-blot in lungs from idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), categorized as chronic (cHP) and subacute (saHP), and healthy lung tissue. Primary fibroblast cultures from normal subjects and fibrotic patients were studied to evaluate tenascin-C (TNC) synthesis. RESULTS: A total of 20 ECM proteins were upregulated and 6 proteins downregulated in IPF. TNC was almost undetected in normal lungs and significantly upregulated in fibrotic lungs (IPF and cHP) compared to saHP. Furthermore, it was located specifically in the fibroblastic foci areas of the fibrotic lung with a subepithelial gradient pattern. TNC levels were correlated with fibroblastic foci content in cHP lungs. Versican and fibronectin glycoproteins were associated with TNC, mainly in fibroblastic foci of fibrotic lungs. Fibroblasts from IPF patients constitutively synthesized higher levels of TNC than normal fibroblasts. TNC and α-sma was induced by TGF-ß1 in both fibrotic and normal fibroblasts. TNC treatment of normal and fibrotic fibroblasts induced a non-significant increased α-sma mRNA. CONCLUSIONS: The difference in ECM glycoprotein content in interstitial lung diseases could contribute to the development of lung fibrosis. The increase of TNC in interstitial areas of fibrotic activity could play a key role in the altered wound healing.

Risk of severe cardiovascular events following COPD exacerbations: results from the EXACOS-CV study in Spain.

INTRODUCTION AND OBJECTIVES: This real-world study-the first of its kind in a Spanish population-aimed to explore severe risk for cardiovascular events and all-cause death following exacerbations in a large cohort of patients with chronic obstructive pulmonary disease (COPD). METHODS: We included individuals with a COPD diagnosis code between 2014 and 2018 from the BIG-PAC health care claims database. The primary outcome was a composite of a first severe cardiovascular event (acute coronary syndrome, heart failure decompensation, cerebral ischemia, arrhythmia) or all-cause death following inclusion in the cohort. Time-dependent Cox proportional hazards models estimated HRs for associations between exposed time periods (1-7, 8-14, 15-30, 31-180, 181-365, and > 365 days) following an exacerbation of any severity, and following moderate or severe exacerbations separately (vs unexposed time before a first exacerbation following cohort inclusion). RESULTS: During a median follow-up of 3.03 years, 18 901 of 24 393 patients (77.5%) experienced ≥ 1 moderate/severe exacerbation, and 8741 (35.8%) experienced the primary outcome. The risk of a severe cardiovascular event increased following moderate/severe COPD exacerbation onset vs the unexposed period, with rates being most increased during the first 1 to 7 days following exacerbation onset (HR, 10.10; 95%CI, 9.29-10.97) and remaining increased > 365 days after exacerbation onset (HR, 1.65; 95%CI, 1.49-1.82). CONCLUSIONS: The risk of severe cardiovascular events or death increased following moderate/severe exacerbation onset, illustrating the need for proactive multidisciplinary care of patients with COPD to prevent exacerbations and address other cardiovascular risk factors.

Sildenafil to improve respiratory rehabilitation outcomes in COPD: a controlled trial.

Pulmonary hypertension is a serious complication of chronic obstructive pulmonary disease (COPD) that currently has no established pharmacological treatment. This study aimed to assess whether concomitant treatment with sildenafil would enhance the results of pulmonary rehabilitation in patients with COPD and increased pulmonary arterial pressure (PAP). In this double-blind, randomised controlled trial patients received 20 mg sildenafil or placebo three times daily and underwent pulmonary rehabilitation for 3 months. The primary end-point was the gain in the cycle endurance time at a constant work-rate. Secondary end-points included performance in the incremental exercise test, 6-min walk distance and quality of life. 63 patients with severe COPD and moderately increased PAP were randomised. Cycle endurance time increased by 149 s (95% CI 26-518 s) in the sildenafil group and by 169 s (95% CI 0-768 s) in the placebo group (median change difference -7 s, 95% CI -540-244 s; p=0.77). Gains in the incremental exercise test, 6-min walk distance and quality of life at the end of the study did not differ between groups. Measurements of arterial oxygenation and adverse events were similar in both groups. In patients with severe COPD and moderately increased PAP, concomitant treatment with sildenafil does not improve the results of pulmonary rehabilitation in exercise tolerance.

Systemic and functional effects of continuous azithromycin treatment in patients with severe chronic obstructive pulmonary disease and frequent exacerbations.

Background: Continuous treatment with azithromycin may lead to fewer acute exacerbations of chronic obstructive pulmonary disease (AECOPD), but little is known of its impact on systemic and functional outcomes in real-life settings. Methods: This was a multicenter prospective observational study of patients with severe COPD who started treatment with azithromycin. Tests were compared at baseline and after 3 and 12 months of treatment. These included lung function tests, a 6-min walking test (6MWT), and enzyme-linked immunosorbent assays of serum and sputum markers, such as interleukins (IL-6, IL-8, IL-13, IL-5), tumor necrosis factor receptor 2 (TNFR2), and inflammatory markers. Incidence rate ratios (IRR) and their 95% confidence intervals (95% CI) are reported. Results: Of the 478 eligible patients, the 42 who started azithromycin experienced reductions in AECOPDs (IRR, 0.34; 95% CI, 0.26-0.45) and hospitalizations (IRR, 0.39; 95% CI, 0.28-0.49). Treatment was also associated with significant improvement in the partial arterial pressure of oxygen (9.2 mmHg, 95% CI 1.4-16.9) at 12 months. While TNFR2 was reduced significantly in both serum and sputum samples, IL-13 and IL-6 were only significantly reduced in serum samples. Moreover, an elevated serum and sputum IL-8 level significantly predicted good clinical response to treatment. Conclusion: Continuous azithromycin treatment in a cohort of patients with severe COPD and frequent exacerbations can significantly reduce the number and severity of exacerbations and improve gas exchange. Treatment changes the pattern of microorganism isolates and decreases the inflammatory response. Of note, IL-8 may have utility as a predictor of clinical response to azithromycin treatment.

Genetic Adaptation and Acquisition of Macrolide Resistance in Haemophilus spp. during Persistent Respiratory Tract Colonization in Chronic Obstructive Pulmonary Disease (COPD) Patients Receiving Long-Term Azithromycin Treatment.

Patients with chronic obstructive pulmonary disease (COPD) benefit from the immunomodulatory effect of azithromycin, but long-term administration may alter colonizing bacteria. Our goal was to identify changes in Haemophilus influenzae and Haemophilus parainfluenzae during azithromycin treatment. Fifteen patients were followed while receiving prolonged azithromycin treatment (Hospital Universitari de Bellvitge, Spain). Four patients (P02, P08, P11, and P13) were persistently colonized by H. influenzae for at least 3 months and two (P04 and P11) by H. parainfluenzae. Isolates from these patients (53 H. influenzae and 18 H. parainfluenzae) were included to identify, by whole-genome sequencing, antimicrobial resistance changes and genetic variation accumulated during persistent colonization. All persistent lineages isolated before treatment were azithromycin-susceptible but developed resistance within the first months, apart from those belonging to P02, who discontinued the treatment. H. influenzae isolates from P08-ST107 acquired mutations in 23S rRNA, and those from P11-ST2480 and P13-ST165 had changes in L4 and L22. In H. parainfluenzae, P04 persistent isolates acquired changes in rlmC, and P11 carried genes encoding MefE/MsrD efflux pumps in an integrative conjugative element, which was also identified in H. influenzae P11-ST147. Other genetic variation occurred in genes associated with cell wall and inorganic ion metabolism. Persistent H. influenzae strains all showed changes in licA and hgpB genes. Other genes (lex1, lic3A, hgpC, and fadL) had variation in multiple lineages. Furthermore, persistent strains showed loss, acquisition, or genetic changes in prophage-associated regions. Long-term azithromycin therapy results in macrolide resistance, as well as genetic changes that likely favor bacterial adaptation during persistent respiratory colonization. IMPORTANCE The immunomodulatory properties of azithromycin reduce the frequency of exacerbations and improve the quality of life of COPD patients. However, long-term administration may alter the respiratory microbiota, such as Haemophilus influenzae, an opportunistic respiratory colonizing bacteria that play an important role in exacerbations. This study contributes to a better understanding of COPD progression by characterizing the clinical evolution of H. influenzae in a cohort of patients with prolonged azithromycin treatment. The emergence of macrolide resistance during the first months, combined with the role of Haemophilus parainfluenzae as a reservoir and source of resistance dissemination, is a cause for concern that may lead to therapeutic failure. Furthermore, genetic variations in cell wall and inorganic ion metabolism coding genes likely favor bacterial adaptation to host selective pressures. Therefore, the bacterial pathoadaptive evolution in these severe COPD patients raise our awareness of the possible spread of macrolide resistance and selection of host-adapted clones.

The 7 Cardinal Sins of COPD in Spain.

Chronic obstructive pulmonary disease (COPD) is a public health problem due to its high prevalence (11% in the adult population in Spain), increasing incidence, and great social and economic impact. Despite this, it is underdiagnosed (and, therefore, undertreated) at a rate of around 80%. In this paper, a group of respiratory physicians specializing in COPD discuss 7 fundamental problems ("cardinal sins") that contribute to this situation, with the explicit aim of proposing specific solutions that may help to improve this unfavorable state of affairs.

Telemedicine home CPAP titration and follow-up in the COVID-19 scenario.

Introduction: Continuous positive airway pressure (CPAP) titration was dramatically affected by the coronavirus disease 2019 (COVID-19) pandemic due to increased biological risk. This study aimed to compare successful CPAP adaptation and compliance with home telemedicine CPAP titration with the usual method based on face-to-face visits. Methodology: A prospective cohort using telemedicine home CPAP titration and follow-up during the COVID-19 pandemic (TC) was compared with a retrospective cohort receiving face-to-face pre-pandemic home titration (RC). The TC included a subgroup with a smartphone application (TC-APP). Successful CPAP adaptation and compliance at 1 month of follow-up were the main endpoints, while patient satisfaction and costs were secondary endpoints. Results: 210 consecutive patients were evaluated (80 RC and 130 TC). 36 patients were in the TC-APP subgroup. CPAP titration was successful in 90% in RC versus 95% in TC and 100% in TC-APP. No compliance differences between groups were found at 1  month (4.79 h·night-1 RC, 4.33  h·night-1 TC and 4.59 h·night-1 TC-APP). Mean±sd patient satisfaction out of 10 was 7.69±2.05 in RC versus 9.02±0.64 in TC (p<0.001). 64% of the TC-APP subgroup reported that their telemedicine strategy influenced an increase in CPAP use (p=0.011). CPAP adaptation with follow-up had an estimated direct staff cost per patient of EUR 19.61±8.61 in TC with no smartphone application used versus EUR 23.79±9.94 in TC-APP (p=0.048). Conclusions: Telemedicine in CPAP titration and early follow-up is equivalent to the usual care in terms of successful adaptation and compliance, while achieving greater patient satisfaction.

Patient-reported outcomes measures (PROMs) and patient-reported experience measures (PREMs) of COVID-19 telerehabilitation: Prospective pilot program.

Telemedicine is proving to be a useful tool in the telemonitoring of respiratory patients and telerehabilitation programs. The use of telemedicine has been proposed by the main medical societies because of the limited resources and the healthcare workers infection risk in the Coronavirus Disease 2019 (COVID-19) pandemic. The aim of this pilot program is to evaluate the feasibility of COVID-19 telerehabilitation program from the hospital to the home with clinical, functional and patient satisfaction outcomes. Rehabilitation was initiated in the hospital by a physiotherapist and complemented by "Estoi" (a mobile application), which was continued at home with telemonitoring and messaging with the medical team. Patients' habitual use of smartphones was not queried for inclusion. Sixteen patients were consecutively enrolled, 47% women with a mean age of 63 years old. 50% of patients completed ≥15 rehabilitation sessions. In total, 88% of patients referred that the mobile application incentive them to do more physical therapy, and 63% would choose telerehabilitation instead of center-based rehabilitation for new rehabilitation programs. Patient satisfaction (0-10) for the mobile application was 8.4 and 8.9 for the telerehabilitation program. Beginning telerehabilitation in the hospital could increase the efficacy and efficiency of physical therapy, which is safe for patients and healthcare workers. Following at home, this telerehabilitation program seems to encourage and empower patients who have reported high satisfaction. Further randomized studies with larger numbers of patients and multicenter studies are required to evaluate these results.

Radio-Histological Correlation of Lung Features in Severe COVID-19 Through CT-Scan and Lung Ultrasound Evaluation.

Background: Patients with coronavirus disease 2019 (COVID-19) can develop severe bilateral pneumonia leading to respiratory failure. Lung histological samples were scarce due to the high risk of contamination during autopsies. We aimed to correlate histological COVID-19 features with radiological findings through lung ultrasound (LU)-guided postmortem core needle biopsies (CNBs) and computerized tomography (CT) scans. Methodology: We performed an observational prospective study, including 30 consecutive patients with severe COVID-19. The thorax was divided into 12 explorations regions to correlate LU and CT-scan features. Histological findings were also related to radiological features through CNBs. Results: Mean age was 62.56 ± 13.27 years old, with 96.7% male patients. Postmortem LU-guided CNBs were performed in 13 patients. Thirty patients were evaluated with both thoracic LU and chest CT scan, representing a total of 279 thoracic regions explored. The most frequent LU finding was B2-lines (49.1%). The most CT-scan finding was ground-glass opacity (GGO, 29%). Pathological CT-scan findings were commonly observed when B2-lines or C-lines were identified through LU (positive predictive value, PPV, 87.1%). Twenty-five postmortem echo-guided histological samples were obtained from 12 patients. Histological samples showed diffuse alveolar damage (DAD) (75%) and chronic interstitial inflammation (25%). The observed DAD was heterogeneous, showing multiple evolving patterns of damage, including exudative (33.3%), fibrotic (33.3%), and organizing (8.3%) phases. In those patients with acute or exudative pattern, two lesions were distinguished: classic hyaline membrane; fibrin "plug" in alveolar space (acute fibrinous organizing pneumonia, AFOP). C-profile was described in 33.3% and presented histological signs of DAD and lung fibrosis. The predominant findings were collagen deposition (50%) and AFOP (50%). B2-lines were identified in 66.7%; the presence of hyaline membrane was the predominant finding (37.5%), then organizing pneumonia (12.5%) and fibrosis (37.5%). No A-lines or B1-lines were observed in these patients. Conclusion: LU B2-lines and C-profile are predominantly identified in patients with severe COVID-19 with respiratory worsening, which correspond to different CT patterns and histological findings of DAD and lung fibrosis.

Effects of Early Physical Therapy and Follow-Up in Acute Severe Coronavirus Disease 2019 Pneumonia: A Retrospective Observational Study.

Background: Rehabilitation in subjects with severe coronavirus disease 2019 (COVID-19) pneumonia has been widely recommended. However, data regarding the starting time of rehabilitation, subjects and healthcare workers' safety, as well as rehabilitation program features are limited. We aimed to assess the safety and characterize the effect of early and non-early physiotherapy on severe COVID-19 pneumonia subjects. Methods: A retrospective cohort study, including a consecutive sample of surviving subjects admitted to an acute care hospital due to severe COVID-19 pneumonia from March 13th to May 15th of 2020, is made. Subjects were separated into three groups: non-physical therapy, early physiotherapy (onset <7 days of admission), and non-early physiotherapy. Subject and therapist safety and length of hospital stay were the main evaluated outcomes. Results: A total of 159 subjects were included (72% men; median age 62 years). Rehabilitation was performed on 108 subjects (32 early and 76 non-early physiotherapies). The length of hospital stay was 19 [interquartile range (IQR) 36.25] and 34 days (IQR 27.25) (p = 0.001) for early and non-early physiotherapy groups, respectively. No physiotherapist was infected and no subject adverse effect was identified. Multivariate analysis of subjects receiving physiotherapy during admission identified obesity [odds ratio (OR) 3.21; p-value 0.028], invasive mechanical ventilation (OR 6.25; p-value <0.001), and non-early physiotherapy (OR 3.54; p-value 0.017) as independent factors associated with a higher risk of prolonged hospital stay. Survivors' follow-up after hospital discharge at 8 weeks was completed by 54% of subjects. Conclusion: Rehabilitation in acute severe COVID-19 pneumonia is safe for subjects and healthcare workers and could reduce the length of hospitalization stay, especially in those that may start early.

Outcomes of COVID-19 Patients Admitted to the Intermediate Respiratory Care Unit: Non-Invasive Respiratory Therapy in a Sequential Protocol.

The intermediate respiratory care units (IRCUs) have a pivotal role managing escalation and de-escalation between the general wards and the intensive care units (ICUs). Since the COVID-19 pandemic began, the early detection of patients that could improve on non-invasive respiratory therapies (NRTs) in IRCUs without invasive approaches is crucial to ensure proper medical management and optimize limiting ICU resources. The aim of this study was to assess factors associated with survival, ICU admission and intubation likelihood in COVID-19 patients admitted to IRCUs. Observational retrospective study in consecutive patients admitted to the IRCU of a tertiary hospital from March 2020 to April 2021. Inclusion criteria: hypoxemic respiratory failure (SpO2 ≤ 94% and/or respiratory rate ≥ 25 rpm with FiO2 > 50% supplementary oxygen) due to acute COVID-19 infection. Demographic, comorbidities, clinical and analytical data, and medical and NRT data were collected at IRCU admission. Multivariate logistic regression models assessed factors associated with survival, ICU admission, and intubation. From 679 patients, 79 patients (12%) had an order to not do intubation. From the remaining 600 (88%), 81% survived, 41% needed ICU admission and 37% required intubation. In the IRCU, 51% required non-invasive ventilation (NIV group) and 49% did not (non-NIV group). Older age and lack of corticosteroid treatment were associated with higher mortality and intubation risk in the scheme, which could be more beneficial in severe forms. Initial NIV does not always mean worse outcomes.