Impact of Coronavirus Disease 2019-Related Infection Prevention and Control Measures on the Occurrence of COPD Exacerbations During Inpatient Pulmonary Rehabilitation.

Rationale: A significant reduction in hospitalizations for acute exacerbations of COPD (AECOPDs) has been reported during the coronavirus disease 2019 (COVID-19) pandemic. It remains unclear whether this reduction is the result of health care avoidance by patients, or of infection prevention and control (IPC) measures. Objectives: Our objective was to explore the impact of COVID-19-related IPC measures on the occurrence of AECOPD in a real-life inpatient pulmonary rehabilitation (PR) setting, thereby ruling out potential effects of health care avoidance. Methods: Patients with COPD admitted for 8 weeks of inpatient PR at Ciro (Horn, the Netherlands) between October 2020 and March 2021, the first winter with full COVID-19-related IPC measures,were compared to patients admitted during the same period in previous years (2017-2018, 2018-2019, and 2019-2020). Electronic medical records were retrospectively screened for the occurrence of moderate to severe AECOPDs, drop-out, and mortality. Results: A total of 501 patients with COPD (median age 66.6 [interquartile range (IQR) 60.3-71.9] years, 43.1% male, forced expiratory volume in 1 second [FEV1] 35.9 [26.8-50.6] % predicted) were analyzed. During 2020-2021, 22 patients (31.0%) experienced ≥1 AECOPD compared to 43 patients (33.6%) in 2019-2020, 55 patients (36.9%) in 2018-2019, and 83 patients (54.2%) in 2017-2018. This represents a 25.4% reduction in 2020-2021 compared to the average of the previous 3 periods, p=0.077. No differences in AECOPD severity, drop-out, or mortality were observed. Conclusions: COVID-19-related IPC measures did not significantly reduce the AECOPD rate during inpatient PR in a single-center setting. The current findings suggest that avoidance of health care may be an important factor in the observed reduction of AECOPD-related hospitalizations during the pandemic and that the value of the strict COVID-19-related IPC measures for the prevention of AECOPDs warrants further research.

Severe Fatigue in Long COVID: Web-Based Quantitative Follow-up Study in Members of Online Long COVID Support Groups.

BACKGROUND: Fatigue is the most commonly reported symptom in patients with persistent complaints following COVID-19 (ie, long COVID). Longitudinal studies examining the intensity of fatigue and differentiating between physical and mental fatigue are lacking. OBJECTIVE: The objectives of this study were to (1) assess the severity of fatigue over time in members of online long COVID peer support groups, and (2) assess whether members of these groups experienced mental fatigue, physical fatigue, or both. METHODS: A 2-wave web-based follow-up study was conducted in members of online long COVID peer support groups with a confirmed diagnosis approximately 3 and 6 months after the onset of infectious symptoms. Demographics, COVID-19 diagnosis, received health care (from medical professionals or allied health care professionals), fatigue (Checklist Individual Strength-subscale subjective fatigue [CIS-Fatigue]; 8-56 points), and physical and mental fatigue (self-constructed questions; 3-21 points) were assessed. Higher scores indicated more severe fatigue. A CIS-Fatigue score ≥36 points was used to qualify patients as having severe fatigue. RESULTS: A total of 239 patients with polymerase chain reaction/computed tomography-confirmed COVID-19 completed the survey 10 weeks (SD 2) and 23 weeks (SD 2) after onset of infectious symptoms, respectively (T1 and T2). Of these 239 patients, 198 (82.8%) were women; 142 (59.4%) had no self-reported pre-existing comorbidities; 208 (87%) self-reported being in good health before contracting COVID-19; and 62 (25.9%) were hospitalized during acute infection. The median age was 50 years (IQR 39-56). The vast majority of patients had severe fatigue at T1 and T2 (n=204, 85.4%, and n=188, 78.7%, respectively). No significant differences were found in the prevalence of normal, mild, and severe fatigue between T1 and T2 (P=.12). The median CIS-Fatigue score was 48 points (IQR 42-53) at T1, and it decreased from T1 to T2 (median change: -2 points, IQR -7 to 3; P<.001). At T1, a median physical fatigue score of 19 points (IQR 16-20) and a median mental fatigue score of 15 points (IQR 10-17) were reported; these scores were lower at T2 for physical but not for mental fatigue (median change for physical fatigue -1 point, IQR -3 to 0, P<.001; median change for mental fatigue 0 points, IQR -3 to 3, P=.52). At the time of completing the follow-up survey, 194/239 (81.2%) and 164/239 (68.6%) of all patients had received care from at least one medical professional and one allied health care professional, respectively. CONCLUSIONS: Fatigue in members of online long COVID support groups with a confirmed COVID-19 diagnosis decreases from 10 to 23 weeks after onset of symptoms. Despite this, severe fatigue remains highly prevalent. Both physical and mental fatigue are present. It remains unclear whether and to what extent fatigue will resolve spontaneously in the longer term. TRIAL REGISTRATION: Netherlands Trial Register NTR8705; https://www.trialregister.nl/trial/8705.

Understanding and Being Understood: Information and Care Needs of 2113 Patients With Confirmed or Suspected COVID-19.

To become a proactive and informed partner in postacute coronavirus disease 2019 (COVID-19) management, patients need to have the knowledge, skills, and confidence to self-manage COVID-19-related health challenges. Due to several restrictions and consequently social isolation, online platforms and forums where people can share information and experiences became more popular and influential. Therefore, this study aimed to identify perceived information needs and care needs of members of 2 Facebook groups for patients with COVID-19 and persistent complaints in the Netherlands and Belgium and patients with COVID-19 who registered at a website of the Lung Foundation Netherlands. Besides demographics and clinical characteristics, the degree of satisfaction with care during and after the infection as well as satisfaction with available information were assessed. Open text fields revealed specific information needs which were summarized. Patients with confirmed or suspected COVID-19 perceive various unmet needs varying from specific information needs (eg, information about permanent lung damage) to general needs (eg, being heard and understood). These data lead to several recommendations to improve care for patients with COVID-19 and justify further development of online platforms specifically addressing these unmet needs.

Recovery from COVID-19: a sprint or marathon? 6-month follow-up data from online long COVID-19 support group members.

BACKGROUND: It remains unknown whether and to what extent members of online "long COVID" peer support groups remain symptomatic and limited over time. Therefore, we aimed to evaluate symptoms in members of online long COVID peer support groups up to 6 months after the onset of coronavirus disease 2019 (COVID-19)-related symptoms. METHODS: Demographics, symptoms, health status, work productivity, functional status and health-related quality of life were assessed about 3 and 6 months after the onset of COVID-19-related symptoms in members of online long COVID peer support groups. RESULTS: Data from 239 patients with a confirmed COVID-19 diagnosis (83% women; median (interquartile range) age 50 (39-56) years) were analysed. During the infection, a median (interquartile range) of 15 (11-18) symptoms was reported, which was significantly lower 3 and 6 months later: 6 (4-9) and 6 (3-8), respectively (p<0.05). From 3 to 6 months follow-up, the proportion of patients without symptoms increased from 1.3% to only 5.4% (p<0.001). Patients also reported a significantly improved work productivity (work absenteeism and presenteeism: 73% versus 52% and 66% versus 60%, respectively), self-reported good health (9.2% versus 16.7%), functional status (mean±sd Post-COVID-19 Functional Status scale: 2.4±0.9 versus 2.2±1.0) and health-related quality of life (all p<0.05). CONCLUSION: Although patients with confirmed COVID-19, who were all members of online long COVID peer support groups, reported significant improvements in work productivity, functional status and quality of life between 3 and 6 months follow-up, these data clearly highlight the long-term impact of COVID-19, as approximately 6 months after the onset of COVID-19-related symptoms a large proportion still experienced persistent symptoms, a moderate-to-poor health, moderate-to-severe functional limitations, considerable loss in work productivity, and/or an impaired quality of life. Action is needed to improve the management and healthcare of these patients.

Persistent symptoms 3†months after a SARS-CoV-2 infection: the post-COVID-19 syndrome?

BACKGROUND: Many patients with COVID-19 did not require hospitalisation, nor underwent COVID-19 testing. There is anecdotal evidence that patients with "mild" COVID-19 may complain about persistent symptoms, even weeks after the infection. This suggests that symptoms during the infection may not resolve spontaneously. The objective of this study was to assess whether multiple relevant symptoms recover following the onset of symptoms in hospitalised and nonhospitalised patients with COVID-19. METHODS: A total of 2113 members of two Facebook groups for coronavirus patients with persistent complaints in the Netherlands and Belgium, and from a panel of people who registered on a website of the Lung Foundation Netherlands, were assessed for demographics, pre-existing comorbidities, health status, date of symptoms onset, COVID-19 diagnosis, healthcare utilisation, and the presence of 29 symptoms at the time of the onset of symptoms (retrospectively) and at follow-up (mean±sd 79±17 days after symptoms onset). RESULTS: Overall, 112 hospitalised patients and 2001 nonhospitalised patients (confirmed COVID-19, n=345; symptom-based COVID-19, n=882; and suspected COVID-19, n=774) were analysed. The median number of symptoms during the infection reduced significantly over time (median (interquartile range) 14 (11-17) versus 6 (4-9); p<0.001). Fatigue and dyspnoea were the most prevalent symptoms during the infection and at follow-up (fatigue: 95% versus 87%; dyspnoea: 90% versus 71%). CONCLUSION: In previously hospitalised and nonhospitalised patients with confirmed or suspected COVID-19, multiple symptoms are present about 3 months after symptoms onset. This suggests the presence of a "post-COVID-19 syndrome" and highlights the unmet healthcare needs in a subgroup of patients with "mild" or "severe" COVID-19.

An update on pulmonary rehabilitation techniques for patients with chronic obstructive pulmonary disease.

Introduction: Pulmonary rehabilitation (PR) is one of the core components in the management of patients with chronic obstructive pulmonary disease (COPD). In order to achieve the maximal level of independence, autonomy, and functioning of the patient, targeted therapies and interventions based on the identification of physical, emotional and social traits need to be provided by a dedicated, interdisciplinary PR team.Areas covered: The review discusses cardiopulmonary exercise testing in the selection of different modes of training modalities. Neuromuscular electrical stimulation as well as gait assessment and training are discussed as well as add-on therapies as oxygen, noninvasive ventilator support or endoscopic lung volume reduction in selected patients. The potentials of pulsed inhaled nitric oxide in patients with underlying pulmonary hypertension is explored as well as nutritional support. The impact of sleep quality on outcomes of PR is reviewed.Expert opinion: Individualized, comprehensive intervention based on thorough assessment of physical, emotional, and social traits in COPD patients forms a continuous challenge for health-care professionals and PR organizations in order to dynamically implement and adapt these strategies based on dynamic, more optimal understanding of underlying pathophysiological mechanisms.

A randomized study using functional respiratory imaging to characterize bronchodilator effects of glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler using co-suspension delivery technology in patients with COPD.

Background: Functional respiratory imaging (FRI) uses high-resolution computed tomography (HRCT) scans to assess changes in airway volume and resistance. Patients and methods: In this randomized, double-blind, 2-week, crossover, Phase IIIB study, patients with moderate-to-severe COPD received twice-daily glycopyrrolate/formoterol fumarate delivered by a metered dose inhaler (GFF MDI, 18/9.6 µg) and placebo MDI, formulated using innovative co-suspension delivery technology. Co-primary endpoints included the following: specific image-based airway volume (siVaw) and specific image-based airway resistance (siRaw) at Day 15, measured using FRI. Secondary and other endpoints included the following: change from baseline in post-dose forced expiratory volume in 1 second (FEV1) and inspiratory capacity (IC; spirometry) and ratio to baseline in post-dose functional residual capacity (FRC) and residual volume (RV; body plethysmography). Results: Twenty patients (46-78 years of age) were randomized and treated; of whom 19 completed the study. GFF MDI treatment increased siVaw by 75% and reduced siRaw by 71% vs placebo MDI (both P<0.0001). Image-based airway volume (iVaw) and image-based airway resistance (iRaw), without adjusting for lobe volume, demonstrated corresponding findings to the co-primary endpoint, as lobe volumes did not change with either treatment. Approximately 48% of the delivered dose of glycopyrronium and formoterol fumarate was estimated to be deposited in the lungs. Compared with placebo, GFF MDI treatment improved post-dose FEV1 and IC (443 mL and 454 mL, respectively; both P<0.001) and reduced FRC and RV (13% and 22%, respectively; both P<0.0001). There were no significant safety findings. Conclusion: GFF MDI demonstrated significant, clinically meaningful benefits on FRI-based airway volume and resistance in patients with moderate-to-severe COPD. Benefits were associated with improvements in FEV1, IC, and hyperinflation. Clinical trial registration: ClinicalTrials.gov: NCT02643082.

Functional respiratory imaging: heterogeneity of acute exacerbations of COPD.

Background: Exacerbations of COPD are a major burden to patients, and yet little is understood about heterogeneity. It contributes to the current persistent one-size-fits-all treatment. To replace this treatment by more personalized, precision medicine, new insights are required. We assessed the heterogeneity of exacerbations by functional respiratory imaging (FRI) in 3-dimensional models of airways and lungs. Methods: The trial was designed as a multicenter trial of patients with an acute exacerbation of COPD who were assessed by FRI, pulmonary function tests, and patient-reported outcomes, both in the acute stage and during resolution. Results: Forty seven patients were assessed. FRI analyses showed significant improvements in hyperinflation (a decrease in total volume at functional residual capacity of -0.25±0.61 L, p≤0.01), airway volume at total lung capacity (+1.70±4.65 L, p=0.02), and airway resistance. As expected, these improvements correlated partially with changes in the quality of life and in conventional lung function test parameters. Patients with the same changes in pulmonary function differ in regional disease activity measured by FRI. Conclusion: FRI is a useful tool to get a better insight into exacerbations of COPD, and significant improvements in its indices can be demonstrated from the acute phase to resolution even in relatively small groups. It clearly visualizes the marked variability within and between individuals in ventilation and resistance during exacerbations and is a tool for the assessment of the heterogeneity of COPD exacerbations.

Changes in ventilation-perfusion during and after an COPD exacerbation: an assessment using fluid dynamic modeling.

Introduction: Severe exacerbations associated with chronic obstructive pulmonary disease (COPD) that require hospitalization significantly contribute to morbidity and mortality. Definitions for exacerbations are very broad, and it is unclear whether there is one predominant underlying mechanism that leads to them. Functional respiratory imaging (FRI) with modeling provides detailed information about airway resistance, hyperinflation, and ventilation-perfusion (V/Q) mismatch during and following an acute exacerbation. Materials and methods: Forty-two patients with COPD participating in a multicenter study were assessed by FRI, pulmonary function tests, and self-reported outcome measures during an acute exacerbation and following resolution. Arterial blood gasses and lung function parameters were measured. Results: A significant correlation was found between alveolar-arterial gradient and image-based V/Q (iV/Q), suggesting that iV/Q represents V/Q mismatch during an exacerbation (p<0.05). Conclusion: Recovery of an exacerbation is due to decreased (mainly distal) airway resistance (p<0.05). Improvement in patient-reported outcomes were also associated with decreased distal airway resistance (p<0.05), but not with forced expiratory volume. FRI is, therefore, a sensitive tool to describe changes in airway caliber, ventilation, and perfusion during and after exacerbation. On the basis of the fact that FRI increased distal airway resistance seems to be the main cause of an exacerbation, therapy should mainly focus on decreasing it during and after the acute event.

Pathophysiological mechanism of long-term noninvasive ventilation in stable hypercapnic patients with COPD using functional respiratory imaging.

INTRODUCTION: Patients with severe COPD often develop chronic hypercapnic respiratory failure. Their prognosis worsens and they are more likely to develop exacerbations. This has major influence on the health-related quality of life. Currently, there is no information about the success of long-term noninvasive ventilation (NIV) among patients who receive NIV in acute settings. Also, little is known about the pathophysiological mechanism of NIV. METHODS: Ten Global Initiative for Obstructive Lung Disease stage III and IV COPD patients with respiratory failure who were hospitalized following acute exacerbation were treated with NIV using a Synchrony BiPAP device for 6 months. Arterial blood gases and lung function parameters were measured. Low-dose computed tomography of the thorax was performed and used for segmentation. Further analyses provided lobe volume, airway volume, and airway resistance, giving an overall functional description of the separate airways and lobes. Ventilation perfusion (VQ) was calculated. Patient-reported outcomes were evaluated. RESULTS: PaCO2 significantly improved from 50.03 mmHg at baseline to 44.75 mmHg after 1 month and 43.37 mmHg after 6 months (P=0.006). Subjects showed improvement in the 6-minute walk tests (6MWTs) by an average of 51 m (from 332 m at baseline to 359 m at 1 month and 383 m at 6 months). Patients demonstrated improvement in self-reported anxiety (P=0.018). The improvement in image-based VQ was positively associated with the 6MWT and the anxiety domain of the Severe Respiratory Insufficiency Questionnaire. CONCLUSION: Though previous studies of long-term NIV have shown conflicting results, this study demonstrates that patients can benefit from long-term NIV treatment, resulting in improved VQ, gas exchange, and exercise tolerance.

Pulmonary vascular effects of pulsed inhaled nitric oxide in COPD patients with pulmonary hypertension.

INTRODUCTION: Severe chronic obstructive pulmonary disease (COPD) is often associated with secondary pulmonary hypertension (PH), which worsens prognosis. PH can be lowered by oxygen, but also by inhaled nitric oxide (NO), which has the potential to improve the health status of these patients. NO is an important mediator in vascular reactions in the pulmonary circulation. Oral compounds can act through NO-mediated pathways, but delivering pulsed inhaled NO (iNO) directly to the airways and pulmonary vasculature could equally benefit patients. Therefore, a proof-of-concept study was performed to quantify pulmonary blood vessel caliber changes after iNO administration using computed tomography (CT)-based functional respiratory imaging (FRI). METHODS: Six patients with secondary PH due to COPD received "pulsed" iNO in combination with oxygen for 20 minutes via a nasal cannula. Patients underwent a high-resolution CT scan with contrast before and after iNO. Using FRI, changes in volumes of blood vessels and associated lobes were quantified. Oxygen saturation and blood pressure were monitored and patients were asked about their subjective feelings. RESULTS: Pulmonary blood vessel volume increased by 7.06%±5.37% after iNO. A strong correlation (Ω(2) 0=0.32, P=0.002) was obtained between ventilation and observed vasodilation, suggesting that using the pulsed system, iNO is directed toward the ventilated zones, which consequently experience more vasodilation. Patients did not develop oxygen desaturation, remained normotensive, and perceived an improvement in their dyspnea sensation. CONCLUSION: Inhalation of pulsed NO with oxygen causes vasodilation in the pulmonary circulation of COPD patients, mainly in the well-ventilated areas. A high degree of heterogeneity was found in the level of vasodilation. Patients tend to feel better after the treatment. Chronic use trials are warranted.

Efficacy of inhaled medications in asthma and COPD related to disease severity.

INTRODUCTION: The administration of medication by inhalation has become the most important route in treating airway diseases. The efficacy of this route depends on several factors like correct inhalation techniques, compliance and the size of the particles. The flow properties and internal flow distribution contribute to the deposition pattern. Areas covered: What has been less well studied is the effect of the internal flow distribution. We know from recent studies that using systemic anti-inflammatory compounds that open up the distal airways redistributes flow internally and enhances the deposition of inhaled particles to the active site of bronchoconstriction or airway inflammation. We discuss this in more detail in this paper, and also make reference to the use of functional respiratory imaging (FRI) that allows for the description of this flow pattern starting from chest CT followed by post processing with segmentation software and the application of fluid dynamics. Expert opinion: The method that was previously validated does show the importance of redistribution of flow in the final clinical results that could be obtained with inhaled medication, especially in more severe obstructive airway diseases. Based on these insights and novel diagnostic tools, patients in end stage respiratory failure would benefit from a personalized approach with inhaled medication.

Functional respiratory imaging to assess the interaction between systemic roflumilast and inhaled ICS/LABA/LAMA.

BACKGROUND: Patients with COPD show a significant reduction of the lobar hyperinflation at the functional residual capacity level in the patients who improved >120 mL in forced expiratory volume in 1 second (FEV1) after 6 months of treatment with roflumilast in addition to inhaled corticosteroids (ICSs)/long-acting beta-2 agonists (LABAs)/long-acting muscarinic antagonists (LAMAs). METHODS: Functional respiratory imaging was used to quantify lobar hyperinflation, blood vessel density, ventilation, aerosol deposition, and bronchodilation. To investigate the exact mode of action of roflumilast, correlations between lobar and global measures have been tested using a mixed-model approach with nested random factors and Pearson correlation, respectively. RESULTS: The reduction in lobar hyperinflation appears to be associated with a larger blood vessel density in the respective lobes (t=-2.154, P=0.040); lobes with a higher percentage of blood vessels reduce more in hyperinflation in the responder group. Subsequently, it can be observed that lobes that reduce in hyperinflation after treatment are better ventilated (t=-5.368, P<0.001). Functional respiratory imaging (FRI)-based aerosol deposition showed that enhanced ventilation leads to more peripheral particle deposition of ICS/LABA/LAMA in the better-ventilated areas (t=2.407, P=0.024). Finally, the study showed that areas receiving more particles have increased FRI-based bronchodilation (t=2.564, P=0.017), leading to an increase in FEV1 (R=0.348, P=0.029). CONCLUSION: The study demonstrated that orally administered roflumilast supports the reduction of regional hyperinflation in areas previously undertreated by inhalation medication. The local reduction in hyperinflation induces a redistribution of ventilation and aerosol deposition, leading to enhanced efficacy of the concomitant ICS/LABA/LAMA therapy. FRI appears to be a sensitive tool to describe the mode of action of novel compounds in chronic obstructive pulmonary disease. Future studies need to confirm the enhanced sensitivity and the potential of FRI parameters to act as surrogates for clinically relevant, but more difficult to measure, end points such as exacerbations.

Functional respiratory imaging (FRI) for optimizing therapy development and patient care.

Functional imaging techniques offer the possibility of improved visualization of anatomical structures such as; airways, lobe volumes and blood vessels. Computer-based flow simulations with a three-dimensional element add functionality to the images. By providing valuable detailed information about airway geometry, internal airflow distribution and inhalation profile, functional respiratory imaging can be of use routinely in the clinic. Three dimensional visualization allows for highly detailed follow-up in terms of disease progression or in assessing effects of interventions. Here, we explore the usefulness of functional respiratory imaging in different respiratory diseases. In patients with asthma and COPD, functional respiratory imaging has been used for phenotyping these patients, to predict the responder and non-responder phenotype and to evaluate different innovative therapeutic interventions.