Persisting exercise ventilatory inefficiency in subjects recovering from COVID-19. Longitudinal data analysis 34 months post-discharge.

BACKGROUND: SARS-CoV-2 infection has raised concerns about long-term health repercussions. Exercise ventilatory inefficiency (EVin) has emerged as a notable long-term sequela, potentially impacting respiratory and cardiovascular health. This study aims to assess the long-term presence of EVin after 34 months and its association with cardiorespiratory health in post-COVID patients. METHODS: In a longitudinal study on 32 selected post-COVID subjects, we performed two cardiopulmonary exercise tests (CPETs) at 6 months (T0) and 34 months (T1) after hospital discharge. The study sought to explore the long-term persistence of EVin and its correlation with respiratory and cardiovascular responses during exercise. Measurements included also V̇O2peak, end-tidal pressure of CO2 (PETCO2) levels, oxygen uptake efficiency slope (OUES) and other cardiorespiratory parameters, with statistical significance set at p < 0.05. The presence of EVin at both T0 and T1 defines a persisting EVin (pEVin). RESULTS: Out of the cohort, five subjects (16%) have pEVin at 34 months. Subjects with pEVin, compared to those with ventilatory efficiency (Evef) have lower values of PETCO2 throughout exercise, showing hyperventilation. Evef subjects demonstrated selective improvements in DLCO and oxygen pulse, suggesting a recovery in cardiorespiratory function over time. In contrast, those with pEvin did not exhibit these improvements. Notably, significant correlations were found between hyperventilation (measured by PETCO2), oxygen pulse and OUES, indicating the potential prognostic value of OUES and Evin in post-COVID follow-ups. CONCLUSIONS: The study highlights the clinical importance of long-term follow-up for post-COVID patients, as a significant group exhibit persistent EVin, which correlates with altered and potentially unfavorable cardiovascular responses to exercise. These findings advocate for the continued investigation into the long-term health impacts of COVID-19, especially regarding persistent ventilatory inefficiencies and their implications on patient health outcomes.

Six-minute walk distance in healthy subjects: reference standards from a general population sample.

INTRODUCTION: The 6-min walking distance (6MWD) test is a useful tool to obtain a measure of functional exercise capacity. However, reference equations have been mainly based on selected populations or small samples. The purpose of this study was to determine the reference equations to predict the 6MWD in a large Italian population sample of healthy adults of a wide age range. METHODS: In the frame of the multi case-control population-based study Gene Environment Interaction in Respiratory Diseases (GEIRD), we studied 530 healthy subjects: 287 females ranging 21-76 and 243 males ranging 21-78 years of age. We measured 6MWD, demographic and anthropometric data and collected the reported physical activity. A multiple linear regression model for the 6MWD included age, age2, height, weight and physical activity for both sex equations. The two-way interaction age-height and age-weight and the quadratic terms of weight and height were also tested for inclusion separately in each model. RESULTS: The mean ± SD for 6MWD was 581.4 ± 66.5 m (range 383-800 m) for females and 608.7 ± 80.1 m (range 410-875 m) for males. The reference equations were 6MWD = 8.10*age + 1.61*heightcm-0.99*weightkg + 22.58*active-0.10*age2 + 222.55 for females (R squared = 0.238) and 6MWD = 26.80*age + 8.46*heightcm-0.45*weightkg-2.54*active-0.06*age2-0.13*age*heightcm-890.18 for males (R squared = 0.159), where "active" is 1 when the subject is physically active, 0 otherwise. CONCLUSION: This study is the first to describe the 6MWD in a large population sample of young, middle aged and elderly healthy Caucasian subjects, and to determine reference equations. These findings will help to improve the evaluation of Italian and European patients with diseases influencing their functional capacity.

Chronic fatigue syndrome: an emerging sequela in COVID-19 survivors?

SARS-CoV-2 survivors may report persistent symptoms that resemble myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We explored (a) ME/CFS-like symptom prevalence and (b) whether axonal, inflammatory, and/or lung changes may contribute to ME/CFS-like symptoms in SARS-CoV-2 survivors through clinical, neuropsychiatric, neuropsychological, lung function assessment, and serum neurofilament light chain, an axonal damage biomarker. ME/CFS-like features were found in 27% of our sample. ME/CFS-like group showed worse sleep quality, fatigue, pain, depressive symptoms, subjective cognitive complaints, Borg baseline dyspnea of the 6-min walking test vs. those without ME/CFS-like symptoms. These preliminary findings raise concern on a possible future ME/CFS-like pandemic in SARS-CoV-2 survivors.

Home-based unsupervised pulmonary rehabilitation program improves the respiratory disability in systemic sclerosis patients with dyspnea: an observational prospective study.

Dyspnea is a common symptom in Systemic Sclerosis (SSc) that considerably decreases patients' quality of life (QoL). Pulmonary Rehabilitation (PR) mitigates dyspnea impact on daily activities. The aim of this study is to evaluate the effect on respiratory disability of home-based PR in SSc patients with dyspnea. In this observational prospective monocentric study, we screened all dyspneic SSc consecutive patients attending the Rheumatological day hospital in the University hospital of Parma from January 2019 and June 2019. The aim of our study was to understand if a PR unsupervised home-based program could improve respiratory disability in this specific population. Dyspnea was evaluated with the self-administered questionnaires modified Medical Research Council (mMRC) and  Saint George's Respiratory Questionnaire (SGRQ).Patients also filled in Short Form 36 (SF36) and the Modified-Health Assessment Questionnaire for SSc (HAQ-MOD). Health Professionals assessed and trained the patients and collected data before PR and at the end of the program. PR consisted in 5 weekly unsupervised sessions for 8 weeks. Wilcoxon test for paired data evaluated the changes after PR. p<0.05 was considered statistically significant. 46 SSc patients were included (43 female). Only 31 (29 female) performed PR as planned (Adherent Group-AG) while the others gave up within the first week (Non-Adherent Group-NAG). All SGRQ domains (Symptoms: from 30 to 18; p=0.0055; Activity: from 47 to 35, p=0.23; Impact from 29 to 25, p=0.044) and SGRQ total score (from 35 to 29; p=0.022) improved in AG. SGRQ scores did not change in NAG as well as SF36 and HAQ-MOD in both groups. The home-based PR program dramatically decreased the effect, frequency and severity of respiratory symptoms. Conversely, it slightly changed the activities causing breathlessness and dyspnea-related social functioning disturbances. PR appears to be a useful tool in treatment strategies aiming to achieve a QoL improvement in SSc patients.

Pneumonic versus Nonpneumonic Exacerbations of Chronic Obstructive Pulmonary Disease.

Patients with chronic obstructive pulmonary disease (COPD) often suffer acute exacerbations (AECOPD) and community-acquired pneumonia (CAP), named nonpneumonic and pneumonic exacerbations of COPD, respectively. Abnormal host defense mechanisms may play a role in the specificity of the systemic inflammatory response. Given the association of this aspect to some biomarkers at admission (e.g., C-reactive protein), it can be used to help to discriminate AECOPD and CAP, especially in cases with doubtful infiltrates and advanced lung impairment. Fever, sputum purulence, chills, and pleuritic pain are typical clinical features of CAP in a patient with COPD, whereas isolated dyspnea at admission has been reported to predict AECOPD. Although CAP may have a worse outcome in terms of mortality (in hospital and short term), length of hospitalization, and early readmission rates, this has only been confirmed in a few prospective studies. There is a lack of methodologically sound research confirming the impact of severe AECOPD and COPD + CAP. Here, we review studies reporting head-to-head comparisons between AECOPD and CAP + COPD in hospitalized patients. We focus on the epidemiology, risk factors, systemic inflammatory response, clinical and microbiological characteristics, outcomes, and treatment approaches. Finally, we briefly discuss some proposals on how we should orient research in the future.

The value of high-resolution computed tomography (HRCT) to determine exercise ventilatory inefficiency and dynamic hyperinflation in adult patients with cystic fibrosis.

INTRODUCTION: In Cystic Fibrosis (CF), exercise ventilatory inefficiency and dynamic hyperinflation (DH) cause exercise limitation and induce poor exercise tolerance. High-resolution computed tomography (HRCT) of the lung can detect pulmonary abnormalities in CF patients. We aimed to identify the determinants of exercise ventilatory inefficiency and DH using HRCT-derived metrics. METHODS: Fifty-two adult CF patients were prospectively enrolled; all participants underwent cardio-pulmonary exercise test (CPET) and HRCT. Radiological impairment was evaluated by the Brody II scoring system. Slope and intercept of the minute ventilation/CO2 production (V'E/V'CO2) regression line and the ratio of inspiratory capacity/total lung capacity (IC/TLC) at rest and at peak of exercise were measured. RESULTS: Four groups of patients were identified based on the combination of ventilatory efficiency (Vef) or inefficiency (Vin) and the presence/absence of DH. Compared to other groups, CF adults with Vin and DH had worse functional status and higher total (T), bronchiectasis (B) and air trapping (AT) scores at HRCT. Significant correlations were found between V'E/V'CO2 intercept and V'E/V'CO2 slope (ρ - 0.455, p = 0.001) and between V'E/V'CO2 intercept and Δ inspiratory capacity (IC) (ρ - 0.334, p = 0.015). Regression analysis identified AT score (cut-off 7.9, odds ratio-OR 3.50) as the only independent predictor of Vin and T (cut-off 53.6, OR 4.98), B (cut-off 16.1, OR 4.88), airways wall thickening (AWT) (cut-off 13, OR 3.41), and mucous plugging (MP) scores (cut-off 11.7, OR 4.18) as significant predictors of DH. CONCLUSION: In adult CF cohort, values of HRCT metrics are determinants of Vin (AT) and DH (T, B, AWT, MP).

Clinical variables predicting the risk of a hospital stay for longer than 7 days in patients with severe acute exacerbations of chronic obstructive pulmonary disease: a prospective study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients may experience an acute exacerbation (AECOPD) that requires hospitalisation. The length of hospital stay (LHS) has a great economic impact on the health-care system. Knowing the predictors of prolonged LHS could help to identify possible interventions. METHODS: We performed a prospective study to identify the clinical predictors of prolonged LHS in patients hospitalised for AECOPD. We divided the study sample by LHS into normal (≤7 days) and prolonged LHS (> 7 days) groups. Outcomes were the need for non-invasive and invasive mechanical ventilation (NIMV and IMV), intensive care unit (ICU) admission, and the 3-year mortality. RESULTS: We enrolled 437 patients, of which 213 and 224 had normal LHS and prolonged LHS, respectively. Patients with a prolonged LHS had more prior hospitalisations for AECOPD, a worse mMRC (modified Medical Research Council) dyspnoea score, a higher prevalence of long-term oxygen therapy and a higher rate of congestive heart disease. During the current admission, this group also tended to require NIMV, IMV and ICU admission and the mortality risks at 6 months, 1 year and 3 years were higher. In the multivariate regression analysis, an mMRC dyspnoea score ≥ 2 (odds ratio-OR 2.24; 95% confidence interval-CI 1.34 to 3.74; p = 0.002) and the presence of acute respiratory acidosis (OR 2.75; 95% CI 1.49 to 5.05; p = 0.001) predicted a prolonged LHS at admission. CONCLUSIONS: The presence of an mMRC ≥2 and acute respiratory acidosis at admission independently increased the risk of a prolonged LHS for AECOPD.

Microorganisms resistant to conventional antimicrobials in acute exacerbations of chronic obstructive pulmonary disease.

BACKGROUND: Antimicrobial treatment for acute exacerbations of chronic obstructive pulmonary disease (AECOPD) remains controversial. In some cases AECOPD are caused by microorganisms that are resistant to treatments recommended by guidelines. Our aims were: 1) identify the risk factors associated with infection by microorganisms resistant to conventional treatment (MRCT), 2) Compare the clinical characteristics and outcomes of patients with AECOPD resulting from MRCT against those with AECOPD from other causes. METHODS: We prospective analysed a cohort of patients admitted with severe AECOPD (2009 to 2015) who were assigned to three groups: patients with MRCT (those patients with germs resistant to antibiotics recommended in guidelines), patients with microorganisms sensitive to conventional antimicrobial treatment (MSCT), and patients with negative microbiology results who had not previously received antibiotics. Multinomial logistic regression analyses were used to examine the associations between microbial aetiology groups and risk factors. The association between LOS and risk factors was also tested in simple and multiple analyses, and similar inclusion criteria were applied for the linear regression analysis. RESULTS: Of the 451 patients admitted, 195 patients (43%) were included. Respiratory cultures were positive in 86(44%) and negative in 109(56%). MRCT were isolated in 34 cases (40%) and MSCT in 52 (60%). Patients with MRCT had more AECOPD in the previous year, received more antibiotic treatment in the previous three months, had more severe disease, higher dyspnoea and a positive respiratory culture in the previous year (mainly for Pseudomonas aeruginosa). The following conditions were independent factors for MRCT isolation: non-current smoker (odds ratio [OR] 4.19 [95% confidence interval [CI] 1.29-13.67], p = 0.017), ≥ 2 AECOPD or ≥ 1 admission for AECOPD in the previous year (OR 4.13 [95% CI 1.52-11.17], p = 0.005), C-reactive protein < 5 mg/dL; (OR 3.58 [95% CI 1.41-9.07], p = 0.007). Mortality rates were comparable at 30-days, one year and 3 years; however, patients in the MRCT group had longer hospital stays. CONCLUSION: In conclusion, there are risk factors for resistant germs in AECOPD; however, the presence of these germs does not increase mortality. Patients with isolation of MRCT had longer length of stay.

When Two Drugs Are Better than Three: Re-Modulating the Therapeutic Plan of a Chronic Obstructive Pulmonary Disease Patient.

We present the case of a 77-year-old man diagnosed with chronic obstructive pulmonary disease (COPD) stage D with emphysema phenotype and treated with triple therapy (salmeterol, fluticasone propionate, and tiotropium) for 1 year without relevant improvements in exertional dyspnea and disease impact. After switching to combination therapy with a long-acting ß2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (indacaterol/glycopyrronium), we observed, in a 3-month period, a substantial reduction of the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) scores. Moreover, the patient reported a reduction of dynamic hyperinflation and an improvement of ventilatory response to exercise.

COPD 2017: A Year in Review.

In this review, we focused on original manuscripts published in the 2017 that provided additional information on the clinical and therapeutic features of the chronic obstructive pulmonary disease (COPD). We have chosen eight of these studies, collected in four topics concerning the pharmacological treatment (tiotropium) of mild-moderate patients, the pharmacological (fluticasone furoate/vilanterol/umeclidinium) and non-pharmacological treatment (non-invasive mechanical ventilation) of severe patients, the etiology of acute exacerbation of COPD involving seasonal airway pathogens and the role of eosinophils with particular interest to the monoclonal antibody directed against interleukin-5 (mepolizumab). For each topic, we report a brief description of studies, take-home messages, and brief comments.

Prevalence of Small-Airway Dysfunction among COPD Patients with Different GOLD Stages and Its Role in the Impact of Disease.

BACKGROUND: In chronic obstructive pulmonary disease (COPD) patients, small-airway dysfunction (SAD) is considered a functional hallmark of disease. However, the exact role of SAD in the clinical presentation of COPD is not yet completely understood; moreover, it is not known whether SAD may have a relationship with the impact of disease. OBJECTIVES: To evaluate the prevalence of SAD among COPD patients categorized by the old and the new GOLD classification and to ascertain whether there is a relationship between SAD and impact of disease measured by the COPD Assessment Test (CAT) questionnaire. METHODS: We prospectively enrolled COPD outpatients from the University Hospital of Parma. Using the impulse oscillometry system (IOS), we assessed the fall in resistance from 5 to 20 Hz (R5-R20), reactance at 5 Hz (X5), and resonant frequency (FRes) as markers of peripheral airway dysfunction. According to R5-R20 ≥0.07 or <0.07, the cohort was also categorized in patients with and without SAD, respectively. RESULTS: We studied 202 patients. In both GOLD classifications, a progressive increasing distribution of R5-R20 and FRes was reported with a decreasing of X5. Moreover, there was a significant correlation between R5-R20 and CAT (r = 0.527, p < 0.001). Finally, the presence of SAD (OR 11.96; 95% CI 4.53-31.58; p < 0.001) and use of ICS + LABA + LAMA (OR 5.31; 95% CI 1.88-15.02; p = 0.002) were independent predictors of higher impact (CAT score ≥10). CONCLUSION: In COPD patients, the presence of SAD, as assessed by IOS, progressively increases with GOLD classifications and it is closely related to the high impact of disease on health status.

Transthoracic Echocardiography and Chest Computed Tomography Arteriography in Patients with Acute Pulmonary Embolism: A Two-Year Follow-Up Study.

BACKGROUND: Pulmonary hypertension (PH) is frequently found at the time of diagnosis of pulmonary embolism (PE). An incomplete resolution of PE can lead to chronic thromboembolic pulmonary hypertension (CTPH). Transthoracic echocardiogram (TTE) is the first step to diagnose an abnormality of the pulmonary vasculature. Based on computed tomography (CT), the Qanadli vascular obstruction index has been extensively used to assess acute PE. OBJECTIVES: Our aim was to ascertain whether at the time of diagnosis of an acute PE episode TTE variables and a Qanadli CT index score may be associated with CTPH 2 years later. METHOD: Patients with PE were prospectively enrolled. TTE was performed and the Qanadli CT obstruction index was calculated on admission to the hospital, while only TTE was repeated at the 2-year follow-up. The NYHA (New York Heart Association) functional classification was evaluated. Correlation analyses were performed. RESULTS: Twenty patients (11 males, median age 69.5 years) were considered for the study. There was no significant correlation between TTE parameters and the Qanadli CT obstruction index. A significant distribution (χ2 = 5.69, p = 0.017) was found in the analysis among patients with CTPH at 24 months and the Qanadli CT index, categorized by a receiver operating characteristic curve cutoff value of 42.5%. Additionally, a significant distribution (χ2 = 4.09, p = 0.043) was found in the analysis among patients with CTPH at 24 months and right ventricular systolic pressure on admission, categorized as PH (>31 mm Hg). CONCLUSION: Our study demonstrates that in patients with acute PE there is no relationship between the Qanadli CT obstruction index and TTE parameters on admission to the hospital. However, the occurrence of CTPH at the 24-month follow-up is associated with PH and with a high Qanadli CT obstruction index score.

Predicting In-Hospital Treatment Failure (≤ 7 days) in Patients with COPD Exacerbation Using Antibiotics and Systemic Steroids.

Although pharmacological treatment of COPD exacerbation (COPDE) includes antibiotics and systemic steroids, a proportion of patients show worsening of symptoms during hospitalization that characterize treatment failure. The aim of our study was to determine in-hospital predictors of treatment failure (≤ 7 days). Prospective data on 110 hospitalized COPDE patients, all treated with antibiotics and systemic steroids, were collected; on the seventh day of hospitalization, patients were divided into treatment failure (n = 16) or success (n = 94). Measures of inflammatory serum biomarkers were recorded at admission and at day 3; data on clinical, laboratory, microbiological, and severity, as well data on mortality and readmission, were also recorded. Patients with treatment failure had a worse lung function, with higher serum levels of C-reactive protein (CRP), procalcitonin (PCT), tumour necrosis factor-alpha (TNF-α), interleukin (IL) 8, and IL-10 at admission, and CRP and IL-8 at day 3. Longer length of hospital stay and duration of antibiotic therapy, higher total doses of steroids and prevalence of deaths and readmitted were found in the treatment failure group. In the multivariate analysis, +1 mg/dL of CRP at admission (OR, 1.07; 95% CI, 1.01 to 1.13) and use of penicillins or cephalosporins (OR, 5.63; 95% CI, 1.26 to 25.07) were independent variables increasing risk of treatment failure, whereas cough at admission (OR, 0.20; 95% CI, 0.05 to 0.75) reduces risk of failure. In hospitalized COPDE patients CRP at admission and use of specific class of antibiotics predict in-hospital treatment failure, while presence of cough has a protective role.

C-Reactive Protein at Discharge, Diabetes Mellitus and ≥ 1 Hospitalization During Previous Year Predict Early Readmission in Patients with Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Recurrent hospitalizations in acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients have clinical and economic consequences; particularly those readmitted soon after discharge. The aim of our observational study was to determine predictors of early readmission to hospital (30 days from discharge). Prospective data on 125 hospitalized AECOPD patients were collected over a 30-month period at two Spanish university hospitals. Based on readmission after discharge, patients were divided into non-readmitted (n = 96) and readmitted (n = 29). Measures of serum inflammatory biomarkers were recorded on admission to hospital, at day 3 and at discharge; data on clinical, laboratory, microbiological and severity features were also recorded. In a multivariate model, C-reactive protein (CRP) at discharge ≥ 7.6 mg/L, presence of diabetes and ≥ 1 hospitalization for AECOPD during previous year were significant risk factors for predicting readmission. Presence of all 3 risk factors perfectly identified the readmitted patients (positive and negative predictive values of 1.000; 95% CI, 1.00-1.00). A combination of 3 readily available clinical and biochemical parameters is accurate in identifying hospitalized AECOPD patients at risk for early readmission.

Assessment of severity of ICU-acquired pneumonia and association with etiology.

OBJECTIVES: We evaluated the association between severity of illness and microbial etiology of ICU-acquired pneumonia to define if severity should be used to guide empiric antibiotic choices. DESIGN: Prospective observational study. SETTING: ICUs of a university hospital. PATIENTS: Three hundredy forty-three consecutive patients with ICU-acquired pneumonia clustered, according to the presence of multidrug resistant pathogens. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Two hundred eight patients had ventilator-associated pneumonia and 135 had nonventilator ICU-acquired pneumonia. We determined etiology in 217 patients (63%). The most frequent pathogens were Pseudomonas aeruginosa, Enterobacteriaceae, and methicillin-sensitive and methicillin-resistant Staphylococcus aureus. Fifty-eight patients (17%) had a multidrug-resistant causative agent. Except for a longer ICU stay and a higher rate of microbial persistence at the end of the treatment in the multidrug-resistant group, no differences were found in clinical and inflammatory characteristics, severity criteria, and mortality or survival between patients with and without multidrug-resistant pathogens, even after adjusting for potential confounders. Patients with higher severity scores (Acute Physiology and Chronic Health Evaluation II and Sepsis-related Organ Failure Assessment) and septic shock at onset of pneumonia had significantly lower 28- and 90-day survival and higher systemic inflammatory response. The results were similar when only patients with microbial diagnosis were considered, as well as when stratified into ventilator-associated pneumonia and nonventilator ICU-acquired pneumonia. CONCLUSIONS: In patients with ICU-acquired pneumonia, severity of illness seems not to affect etiology. Risk factors for multidrug resistant, but not severity of illness, should be taken into account in selecting empiric antimicrobial treatment.