Cardiopulmonary exercise testing complements both spirometry and nuclear imaging for assessing sarcoidosis stage and for monitoring disease activity.

BACKGROUND: Pulmonary sarcoidosis is a systemic disease that can confound established follow-up tools. Pulmonary function tests (PFTs) are recommended in initial and follow-up patient evaluations yet are imperfect predictors of disease progression. The cardiopulmonary exercise test (CPET) is another potentially useful monitoring tool, although previous studies report conflicting findings regarding which variables are altered by the disease. Nuclear imaging tests are also employed to assess inflammatory activity and may be predictive of functional deterioration. AIM: We asked whether PFTs or CPET are more diagnostic of disease stage, which subsets of functional variables are impacted by the disease, and how these relate to nuclear imaging signs of active inflammation. STUDY DESIGN AND METHODS: We collected retrospective data (spirometry, CPET, Gallium-67 scintigraphy, 18F-FDG PET/CT) from 48 patients and 10 controls. Disease severity was assessed following Scadding classification. First, we correlated individual PFTs and CPET parameters to Scadding stage and nuclear imaging data. Next, we performed Principal Component Analysis (PCA) on PFTs and CPET parameters, separated into respiratory, cardiovascular and metabolic subsets. Finally, we constructed multiple regression models to determine which variable subsets were the best predictors of Scadding stage and disease activity. RESULTS: The majority of PFTs and CPET single parameters were significantly correlated with patient stage, while only few correlated with disease activity. Nevertheless, multiple regression models were able to significantly relate PFTs and CPET to both disease stage and activity. Additionally, these analyses highlighted CPET cardiovascular parameters as the best overall predictors of disease stage and activity. CONCLUSIONS: Our results display how CPET and spirometry data complement each other for sarcoidosis disease staging, and how these tests are able to detect disease activity. Our findings suggest that CPET, a repeatable and non-invasive functional test, should be more routinely performed and taken into account in sarcoidosis patient follow-up.

Oscillometry Longitudinal Data on COVID-19 Acute Respiratory Syndrome Treated with Non-Invasive Respiratory Support.

Background: Oscillometry allows for the non-invasive measurements of lung mechanics. In COVID-19 ARDS patients treated with Non-Invasive Oxygen Support (NI-OS), we aimed to (1) observe lung mechanics at the patients' admission and their subsequent changes, (2) compare lung mechanics with clinical and imaging data, and (3) evaluate whether lung mechanics helps to predict clinical outcomes. Methods: We retrospectively analyzed the data from 37 consecutive patients with moderate-severe COVID-19 ARDS. Oscillometry was performed on their 1st, 4th, and 7th day of hospitalization. Resistance (R5), reactance (X5), within-breath reactance changes (ΔX5), and the frequency dependence of the resistance (R5-R19) were considered. Twenty-seven patients underwent computed tomographic pulmonary angiography (CTPA): collapsed, poorly aerated, and normally inflated areas were quantified. Adverse outcomes were defined as intubation or death. Results: Thirty-two patients were included in this study. At the first measurement, only 44% of them had an abnormal R5 or X5. In total, 23 patients had measurements performed on their 3rd day and 7 on their 7th day of hospitalization. In general, their R5, R5-R19, and ΔX decreased with time, while their X5 increased. Collapsed areas on the CTPA correlated with the X5 z-score (ρ = -0.38; p = 0.046), while poorly aerated areas did not. Seven patients had adverse outcomes but did not present different oscillometry parameters on their 1st day of hospitalization. Conclusions: Our study confirms the feasibility of oscillometry in critically ill patients with COVID-19 pneumonia undergoing NI-OS. The X5 z-scores indicates collapsed but not poorly aerated lung areas in COVID-19 pneumonia. Our data, which show a severe impairment of gas exchange despite normal reactance in most patients with COVID-19 ARDS, support the hypothesis of a composite COVID-19 ARDS physiopathology.

Theory and Practice of Glucocorticoids in COVID-19: Getting to the Heart of the Matter-A Critical Review and Viewpoints.

Prolonged, low-dose glucocorticoids (GCs) have shown the highest efficacy among pharmacological and non-pharmacological treatments for COVID-19. Despite the World Health Organization's recommendation against their use at the beginning of the pandemic, GCs at a dose equivalent to dexamethasone 6 mg/day for 10 days are now indicated in all COVID-19 cases who require respiratory support. However, the efficacy of the intervention depends on the timing of initiation, the dose, and other individual factors. Indeed, patients treated with similar GC protocols often experience different outcomes, which do not always correlate with the presence of comorbidities or with the severity of respiratory involvement at baseline. This prompted us to critically review the literature on the rationale, pharmacological principles, and clinical evidence that should guide GC treatment. Based on these data, the best treatment protocol probably involves an initial bolus dose to saturate the glucocorticoid receptors, followed by a continuous infusion to maintain constant plasma levels, and eventually a slow tapering to interruption. Methylprednisolone has shown the highest efficacy among different GC molecules, most likely thanks to its higher ability to penetrate the lung. Decreased tissue sensitivity to glucocorticoids is thought to be the main mechanism accounting for the lower response to the treatment in some individuals. We do not have a readily available test to identify GC resistance; therefore, to address inter-individual variability, future research should aim at investigating clinical, physiological, and laboratory markers to guide a personalized GC treatment approach.

Prolonged higher dose methylprednisolone versus conventional dexamethasone in COVID-19 pneumonia: a randomised controlled trial (MEDEAS).

BACKGROUND: Dysregulated systemic inflammation is the primary driver of mortality in severe coronavirus disease 2019 (COVID-19) pneumonia. Current guidelines favour a 7-10-day course of any glucocorticoid equivalent to dexamethasone 6 mg daily. A comparative randomised controlled trial (RCT) with a higher dose and a longer duration of intervention was lacking. METHODS: We conducted a multicentre, open-label RCT to investigate methylprednisolone 80 mg as a continuous daily infusion for 8 days followed by slow tapering versus dexamethasone 6 mg once daily for up to 10 days in adult patients with COVID-19 pneumonia requiring oxygen or noninvasive respiratory support. The primary outcome was reduction in 28-day mortality. Secondary outcomes were mechanical ventilation-free days at 28 days, need for intensive care unit (ICU) referral, length of hospitalisation, need for tracheostomy, and changes in C-reactive protein (CRP) levels, arterial oxygen tension/inspiratory oxygen fraction (P aO2 /F IO2 ) ratio and World Health Organization Clinical Progression Scale at days 3, 7 and 14. RESULTS: 677 randomised patients were included. Findings are reported as methylprednisolone (n=337) versus dexamethasone (n=340). By day 28, there were no significant differences in mortality (35 (10.4%) versus 41 (12.1%); p=0.49) nor in median mechanical ventilation-free days (median (interquartile range (IQR)) 23 (14) versus 24 (16) days; p=0.49). ICU referral was necessary in 41 (12.2%) versus 45 (13.2%) (p=0.68) and tracheostomy in 8 (2.4%) versus 9 (2.6%) (p=0.82). Survivors in the methylprednisolone group required a longer median (IQR) hospitalisation (15 (11) versus 14 (11) days; p=0.005) and experienced an improvement in CRP levels, but not in P aO2 /F IO2 ratio, at days 7 and 14. There were no differences in disease progression at the prespecified time-points. CONCLUSION: Prolonged, higher dose methylprednisolone did not reduce mortality at 28 days compared with conventional dexamethasone in COVID-19 pneumonia.

Monitoring respiratory mechanics by oscillometry in COVID-19 patients receiving non-invasive respiratory support.

BACKGROUND: Non-invasive ventilation (NIV) has been increasingly used in COVID-19 patients. The limited physiological monitoring and the unavailability of respiratory mechanic measures, usually obtainable during invasive ventilation, is a limitation of NIV for ARDS and COVID-19 patients management. OBJECTIVES: This pilot study was aimed to evaluate the feasibility of non-invasively monitoring respiratory mechanics by oscillometry in COVID-19 patients with moderate-severe acute respiratory distress syndrome (ARDS) receiving NIV. METHOD: 15 COVID-19 patients affected by moderate-severe ARDS at the RICU (Respiratory Intensive Care Unit) of the University hospital of Cattinara, Trieste, Italy were recruited. Patients underwent oscillometry tests during short periods of spontaneous breathing between NIV sessions. RESULTS: Oscillometry proved to be feasible, reproducible and well-tolerated by patients. At admission, 8 of the 15 patients showed oscillometry parameters within the normal range which further slightly improved before discharge. At discharge, four patients had still abnormal respiratory mechanics, not exclusively linked to pre-existing respiratory comorbidities. Lung mechanics parameters were not correlated with oxygenation. CONCLUSIONS: Our results suggest that lung mechanics provide complementary information for improving patients phenotyping and personalisation of treatments during NIV in COVID 19 patients, especially in the presence of respiratory comorbidities where deterioration of lung mechanics may be less coupled with changes in oxygenation and more difficult to identify. Oscillometry may provide a valuable tool for monitoring lung mechanics in COVID 19 patients receiving NIV.

Different Methods to Improve the Monitoring of Noninvasive Respiratory Support of Patients with Severe Pneumonia/ARDS Due to COVID-19: An Update.

The latest guidelines for the hospital care of patients affected by coronavirus disease 2019 (COVID-19)-related acute respiratory failure have moved towards the widely accepted use of noninvasive respiratory support (NIRS) as opposed to early intubation at the pandemic onset. The establishment of severe COVID-19 pneumonia goes through different pathophysiological phases that partially resemble typical acute respiratory distress syndrome (ARDS) and have been categorized into different clinical-radiological phenotypes. These can variably benefit on the application of external positive end-expiratory pressure (PEEP) during noninvasive mechanical ventilation, mainly due to variable levels of lung recruitment ability and lung compliance during different phases of the disease. A growing body of evidence suggests that intense respiratory effort producing excessive negative pleural pressure swings (Ppl) plays a critical role in the onset and progression of lung and diaphragm damage in patients treated with noninvasive respiratory support. Routine respiratory monitoring is mandatory to avoid the nasty continuation of NIRS in patients who are at higher risk for respiratory deterioration and could benefit from early initiation of invasive mechanical ventilation instead. Here we propose different monitoring methods both in the clinical and experimental settings adapted for this purpose, although further research is required to allow their extensive application in clinical practice. We reviewed the needs and available tools for clinical-physiological monitoring that aims at optimizing the ventilatory management of patients affected by acute respiratory distress syndrome due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection.

An Overview of Different Techniques for Improving the Treatment of Pulmonary Hypertension Secondary in Systemic Sclerosis Patients.

In systemic sclerosis (SSc) mortality is mainly linked to lung involvement which is characterized by interstitial lung disease (ILD) and pulmonary hypertension (PH). In SSc, PH may be due to different etiologies, including ILD, chronic thromboembolic disease, pulmonary veno-occlusive disease, and pulmonary arterial hypertension (PAH). The main tool to screen PAH is transthoracic echocardiography (TTE), which has a sensitivity of 90%, even if definitive diagnosis should be confirmed by right heart catheterization (RHC). The radiological evaluation (i.e., HRTC) plays an important role in defining the possible causes and in monitoring the evolution of lung damage. For PAH, identifying individuals who have borderline elevation of pulmonary arterial pressure needs to be appropriately managed and followed. In the past few years, the strategy for the management of PAH has significantly evolved and new trials are underway to test other therapies. This review provides an overview of the tools to evaluate PAH in SSc patients and on treatment options for these patients.

Correlation between Potential Risk Factors and Pulmonary Embolism in Sarcoidosis Patients Timely Treated.

BACKGROUND: Some studies with inconclusive results have reported a link between sarcoidosis and an increased risk of pulmonary embolism (PE). This study aimed at assessing a possible correlation between potential risk factors and PE in sarcoidosis patients. METHODS: A total of 256 sarcoidosis patients (84 males and 172 females; mean age at diagnosis 49 ± 13) were enrolled after giving written informed consent. Clinical evaluations, laboratory and radiology tests were performed to evaluate the presence of pulmonary embolism. RESULTS: Fifteen sarcoidosis patients with PE (4 males and 11 females; mean age at diagnosis 50 ± 11), diagnosed by lung scintigraphy and 241 sarcoidosis patients without PE (80 males and 161 females; mean age at diagnosis 47 ± 13), were observed. There was a statistically significant increase of the presence of antiphospholipid antibodies in the sarcoidosis group with pulmonary embolism. There was no statistically significant difference between the two groups as to smoking habit, obesity or hereditary thrombophilia frequency (p > 0.05, respectively). CONCLUSIONS: This study demonstrates a significant correlation between the presence of antiphospholipid antibody positivity and the pulmonary embolism events in our sarcoidosis patients. Furthermore, we propose screening for these antibodies and monitoring, aimed at timely treatment.

Dynamic pulmonary hyperinflation occurs without expiratory flow limitation in chronic heart failure during exercise.

To assess the occurrence of tidal expiratory flow limitation (EFL) and/or dynamic pulmonary hyperinflation (DH) in chronic heart failure (CHF) during exercise 15 patients with stable systolic CHF, aged 69 ± 6yr, underwent pulmonary function testing and incremental cardio-pulmonary exercise testing. They subsequently performed constant load exercise testing at 30, 60 and 90% of respective maximum workload. At each step the presence of EFL, by negative expiratory pressure technique, and changes in inspiratory capacity (IC) were assessed. Ejection fraction amounted to 36 ± 6% and VO2, peak (77 ± 19% pred.) was reduced. EFL was absent at any step during constant load exercise. In 6 patients IC decreased more than 10% pred. at highest step. Only in these patients TLC, FRC, RV FEF(25-75%) and DL(CO) were decreased at rest. VO2, peak correlated with DL(CO), TLC and IC at rest and with IC (r(2)=0.59; p<0.001) and decrease in IC (r(2)=0.44; p<0.001) at 90% of maximum workload. During exercise CHF patients do not exhibit EFL, but some of them develop DH that is associated with lower VO2, peak.

Inspiratory muscle training for diaphragm dysfunction after cardiac surgery.

OBJECTIVE: Diaphragm dysfunction is a complication of cardiac surgery with partial or absent spontaneous recovery in most cases. Surgical diaphragm plication represents the only option when symptoms persist. Because training improves functional nerve recovery after a nerve lesion, we hypothesized that early diaphragm muscle training may be beneficial. METHODS: A prospective, randomized at 2:1 ratio, controlled trial of diaphragm training using an adjustable pressure device (Threshold; Philips Respironics Inc, Murrysville, Pa) versus no training (sham device) was performed in patients with diaphragm paralysis after major cardiac surgery. This 1-year study recruited consecutive adult patients with sniff fluoroscopy-defined diaphragm paralysis after coronary bypass, valve replacement, or both. The outcome measures were diaphragm function recovery assessed by sniff fluoroscopy, maximum inspiratory and expiratory pressures, and lung function tests. RESULTS: A total of 69 patients were randomized. At 12 months, 52 patients completed the study assessments, 36 in the treatment group and 16 in the control group. Inspiratory muscle training produced a significant improvement of diaphragm mobility after 12 months (P < .001). Most patients in the training group (77.78%) experienced a partial improvement (41.67%) or achieved a complete improvement (36.11%) versus no improvement (87.5%) or partial recovery (12.5%) among controls. CONCLUSIONS: Inspiratory muscle training may improve inspiratory muscle strength and increases paralyzed diaphragm mobility.

Effect of training on airways inflammatory response and remodeling in a rat model.

Training has many beneficial effects, however few studies report its effects on the lungs. The aim of this study was to assess the effects of acute exercise and exercise training on inflammatory responses and remodeling in central and peripheral airways. Sixteen Sprague-Dawley rats trained for 10 weeks, while 14 rats served as controls. Before sacrifice, 8 trained (TR(AC)) and 8 untrained control (CON(AC)) rats underwent a single acute exercise bout, while 8 trained (TR) and 6 untrained control (CON) rats were sacrificed without acute exercise. The central and peripheral airways were morphologically examined for inflammatory cells and immunostained for decorin, collagen I, α-smooth muscle actin. No significant differences were found for morphometric analysis in central and peripheral airways, however CON(AC) showed a significant increase in polymorphonuclear cells in the central airways compared to CON. In contrast, TR(AC) did not show an inflammatory response different from TR. A similar trend was present in peripheral airways. Training did not induce differences in airways inflammation and remodeling as compared to CON. However, training seemed to limit the inflammatory response induced by acute exercise in the central airways.

Effects of decorin and biglycan on human airway smooth muscle cell proliferation and apoptosis.

Proteoglycans (PG) are altered in the asthmatic airway wall. Because PGs are known to affect cell proliferation and apoptosis, we hypothesized that alterations in PG might influence the airway smooth muscle (ASM) hyperplasia observed in the asthmatic airway. Human ASM cells were seeded on plastic or plates coated with decorin (Dcn), biglycan (Bgn), or collagen type I (Col I) (1, 3, and 10 microg/ml). Cells were stimulated with platelet-derived growth factor (PDGF), and cell number was assessed at 0, 48, and 96 h. Cell proliferation was measured by bromodeoxyuridine (BrdU) incorporation and apoptosis by annexin V and propidium iodide staining at 48 h post-PDGF stimulation. A significant decrease in cell number was observed with cells seeded on Dcn (10 microg/ml) at 0, 48, and 96 h (P < 0.01). Dcn induced both decreases in BrdU incorporation and increases in annexin V staining (P < 0.05). Bgn decreased cell number at time 0 only (P < 0.05) and affected neither proliferation nor apoptosis. Col I (10 mug/ml) caused a significant increase in cell number at 48 and 96 h (P < 0.01). Adding exogenous Dcn (1-30 microg/ml) to the medium had no effect on cell number. Exposing Dcn-coated matrices to chondroitinase ABC, an enzyme that degrades glycosaminoglycan side chains, reversed the Dcn-induced decrease in cell number. These studies demonstrate that different PGs have variable effects on ASM cell proliferation and apoptosis. Recently described decreases in Dcn in the asthmatic airway wall could potentially permit more exuberant ASM growth.

Airway remodeling in allergen-challenged Brown Norway rats: distribution of proteoglycans.

Proteoglycans (PG) have important effects on the mechanical properties of tissues and the phenotype of various structural cells. Little is known about changes in PG deposition in the airways in animal models of asthma. We studied changes in PG in the airway wall of Brown Norway rats sensitized to ovalbumin (OA) and exposed to repeated OA challenge. Control (Sal) animals were sensitized and challenged with saline. After the 3rd challenge, animals were killed and lungs fixed in formalin. Tissue sections were incubated with antibodies to the small, leucine-rich PG, decorin, and biglycan and collagen type I. Airways were classified according to basement membrane perimeter length (< or =0.99, 1-2.99, and > or =3 mm). Decorin, biglycan, and collagen type I were increased in the airways of OA vs. Sal rats. Remodeling was most prominent in central airways. The distribution of PG differed with respect to the subepithelial vs. airway smooth muscle (ASM) vs. adventitial layer. Whereas biglycan was readily detected within the ASM, decorin and collagen were detected outside the ASM and especially in the adventitial layer. Differences in the distribution of these molecules within the layers of the airway wall may reflect their specific functional roles.