Sex differences of post-Covid patients undergoing outpatient pulmonary rehabilitation.

BACKGROUND: Following years of pandemic severe acute respiratory syndrome coronavirus 2 infections labelled Covid-19, long lasting impairment summarized as post-Covid syndrome (PCS) challenges worldwide healthcare. Patients benefit from rehabilitation programs, but sex specific aspects of improvement remain little understood. The aim of the study was to assess whether women and men differ in response to outpatient pulmonary rehabilitation for PCS. METHODS: 263 (54.4% female) patients partaking in outpatient pulmonary rehabilitation (OPR) due to PCS between March 2020 and July 2022 were included in a prospective observational cohort study. Outcomes were assessed at baseline and before discharge from OPR and included six-minute walking distance (6MWD), 1-second forced expiratory volume (FEV1), diffusion capacity for carbon monoxide, maximal inspiratory pressure (MIP), dyspnea (medical research council scale), and post-Covid functional status scale (PCFS). Sexspecific changes in outcomes following OPR were assessed by linear mixed model and presented as mean differences (MD) with 95% confidence intervals. Linear regression was applied to test whether 6MWD correlates with PCFS and the minimal clinically important difference (MCID) in 6MWD regarding an improvement of at least one point in PCFS was computed with logistic regression. RESULTS: Significant improvement throughout OPR was observed for all outcomes (all p < 0.0001). Despite less severe Covid-19 infections, PCFS scores remained higher in females after OPR (p = 0.004) and only 19.4% of women compared to 38.5% of men achieved remission of functional impairment. At baseline as well as after OPR, females showed higher symptom load compared to men in dyspnea (p = 0.0027) and scored lower in FEV1 (p = 0.009) and MIP (p = 0.0006) assessment. Performance in 6MWD was comparable between men and women. An increase of 35 m in 6MWD was computed as minimal clinically important difference to improve functional impairment. CONCLUSION: Both subjective symptoms such as fatigue and dyspnea and objective impairment in performance in pulmonary function were more frequently observed among women. Despite improvement throughout OPR in both women and men, the sex-gap in symptom load could not be closed as women less often achieved remission from functional impairment due to PCS. Intensified treatment of these symptoms should be considered in women undergoing rehabilitation for PCS.

While female sex is protective during the acute infection of Covid-19, women are at increased risk of developing post-Covid syndrome (PCS) even after only mild Covid-19 infections. Severity and frequency of symptoms such as fatigue and shortness of breath are known to be higher in women compared to men. Many different rehabilitation protocols are used for PCS, but a knowledge gap regarding sex related differences in rehabilitation success remains.Both female and male patients with PCS undergoing outpatient pulmonary rehabilitation improved in the maximum walking distance achieved within 6 min and selfrated impairment in everyday living. Although women less frequently required inpatient treatment for acute Covid-19 infection, female patients with PCS showed higher impairment in everyday living, lower capacity of physical exercise and more frequent shortness of breath, fatigue and breathing muscle weakness. Only 19.4% of women compared to 38.5% of men achieved complete remission of impairment in everyday living. Our results show that women treated for PCS retain greater symptom burden and are at risk of unsuccessful rehabilitation, calling for more targeted treatment in female patients after Covid-19 infection.

[S1 guidelines for the management of postviral conditions using the example of post-COVID-19]. / Leitlinie S1 für das Management postviraler Zustände am Beispiel Post-COVID-19.

These S1 guidelines are an updated and expanded version of the S1 guidelines on long COVID differential diagnostic and management strategies. They summarize the state of knowledge on postviral conditions like long/post COVID at the time of writing. Due to the dynamic nature of knowledge development, they are intended to be "living guidelines". The focus is on practical applicability at the level of primary care, which is understood to be the appropriate place for initial access and for primary care and treatment. The guidelines provide recommendations on the course of treatment, differential diagnostics of the most common symptoms that can result from infections like with SARS-CoV-2, treatment options, patient management and care, reintegration and rehabilitation. The guidelines have been developed through an interdisciplinary and interprofessional process and provide recommendations on interfaces and possibilities for collaboration.

Echocardiography and Lung Ultrasound in Long COVID and Post-COVID Syndrome, a Review Document of the Austrian Society of Pneumology and the Austrian Society of Ultrasound in Medicine.

Lung ultrasound has the potential to enable standardized follow-up without radiation exposure and with lower associated costs in comparison to CT scans. It is a valuable tool to follow up on patients after a COVID-19 infection and evaluate if there is pulmonary fibrosis developing. Echocardiography, including strain imaging, is a proven tool to assess various causes of dyspnea and adds valuable information in the context of long COVID care. Including two-dimensional (2D) strain imaging, a better comprehension of myocardial damage in post-COVID syndrome can be made. Especially 2D strain imaging (left and the right ventricular strain) can provide information about prognosis.

Decreased phrenic nerve compound muscle action potential, inspiratory muscle strength, and exercise capacity after COVID-19.

Objectives: Respiratory muscle weakness with higher ventilatory demands were reported even in patients recovering from only mild COVID-19 symptoms. Aim of this study was to assess the function of phrenic nerve and inspiratory respiratory muscle as well as cardiopulmonary exercise capacity in patients with prolonged exertional dyspnea after COVID-19 infection. Methods: In this observational exploratory study, electrophysiological examination of the phrenic nerve, inspiratory muscle capacity as well as lung function test, 6-min walk distance (6MWD) and cardiopulmonary exercise test, have been performed in 22 patients post COVID-19 diagnosis (post-CoV). Results: Exercise capacity (peak workload, Wpeak % predicted and peak oxygen uptake, VO2peak % predicted) were significantly affected in the post-CoV patients (61.8 ± 23.3 Wpeak % and 70.9 ± 22.3 VO2peak %). Maximum inspiratory pressure (MIP) was reduced (60.1 ± 25.5 mbar). In 6 of the 22 patients the electrophysiological response of the phrenic nerve was pathologically decreased (reduced compound muscle action potential, CMAP), while nerve conduction velocity (NCV) was normal, which corresponds to reduced muscle fiber contraction capacity. Positive relationships were demonstrated between 6MWD and MIP (rs = 0.88) as well as quality of life questionnaire (CRQ) and MIP (rs = 0.71) only in patients with reduced CMAP. Discussion: Respiratory muscle weakness and exercise capacity is associated with reduced phrenic nerve CMAP without signs of neuropathy. This indicates that muscle fiber pathology of the diaphragm may be one pathophysiological factor for the prolonged respiratory symptoms after COVID-19 infections.

Performance Score (T2D)-A New Perspective in the Assessment of Six-Minute Walking Tests in Pulmonary Rehabilitation.

Because absolute changes in outcomes are difficult to interpret and the minimal clinically important difference (MCID) is not suitable to address this challenge, a novel method of classifying outcomes by relating changes to baseline values is warranted. We used the "performance score" (T2D), which reflects individual performance, enabling us to consider the functional status at the beginning of rehabilitation without dealing with the problems of mathematical coupling or regression effects, as encountered in ANCOVA. To illustrate the T2D, we retrospectively analyzed changes in the six-minute walking test (6MWT) in COPD patients undergoing outpatient pulmonary rehabilitation and compared the results with absolute differences related to a predetermined MCID. We evaluated a total of 575 COPD patients with a mean age of 61.4 ± 9.2 years. 6MWT improved significantly, with a mean change of 32.3 ± 71.2. A total of 105/311 participants who had reached the MCID were still classified as "below average" by the T2D. Conversely, 76/264 patients who had not reached the MCID were classified as "above average". This new performance measure accounts for the patient's current status and for changes over time, potentially representing a simple and user-friendly tool that can be used to quantify a patient's performance and response to rehabilitation.

Effectiveness of Outpatient Pulmonary Rehabilitation in Patients with Surgically Resected Lung Cancer: A Retrospective Real-World Analysis.

Patients with lung cancer frequently suffer from physical deconditioning, low exercise capacity, and reduced quality of life. There is little evidence on the effects of a structured outpatient pulmonary rehabilitation program (OPR) on exercise capacity and symptom load in these patients. We performed a retrospective, single-center analysis of surgically resected lung cancer patients, who underwent a multiprofessional 6-week OPR. The primary endpoint was a change in the six-minute walk test distance (6 MWT). Secondary endpoints included changes in maximal workload and constant work-rate test results during cycle-ergometry, upper and lower extremity strength, and inspiratory muscle strength. The COPD Assessment Test (CAT) was used to assess symptom burden. Fifty-seven patients were included. Of those, fifty-two (91.2%) completed the full 6 weeks of OPR. The mean age was 56.4 (SD 9.2) years, and 58% were female. At completion of OPR, there was a statistically significant mean of a 50 m (95% CI, 29.6−70.7; p < 0.001) increase in 6 MWT. Significant improvements were also seen in all other exercise and strength tests (p < 0.001), accompanied by a significant reduction in the CAT score (mean difference −3.1, p = 0.001). No adverse effects were reported. OPR for surgically resected lung cancer patients was safe and effective and showed high adherence in the current study.

Management of patients with SARS-CoV-2 infections with focus on patients with chronic lung diseases (as of 10 January 2022) : Updated statement of the Austrian Society of Pneumology (ASP).

The Austrian Society of Pneumology (ASP) launched a first statement on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in May 2020, at a time when in Austria 285 people had died from this disease and vaccinations were not available. Lockdown and social distancing were the only available measures to prevent more infections and the breakdown of the health system. Meanwhile, in Austria over 13,000 patients have died in association with a SARS-CoV­2 infection and coronavirus disease 2019 (COVID-19) was among the most common causes of death; however, SARS-CoV­2 has been mutating all the time and currently, most patients have been affected by the delta variant where the vaccination is very effective but the omicron variant is rapidly rising and becoming predominant. Particularly in children and young adults, where the vaccination rate is low, the omicron variant is expected to spread very fast. This poses a particular threat to unvaccinated people who are at elevated risk of severe COVID-19 disease but also to people with an active vaccination. There are few publications that comprehensively addressed the special issues with SARS-CoV­2 infection in patients with chronic lung diseases. These were the reasons for this updated statement. Pulmonologists care for many patients with an elevated risk of death in case of COVID-19 but also for patients that might be at an elevated risk of vaccination reactions or vaccination failure. In addition, lung function tests, bronchoscopy, respiratory physiotherapy and training therapy may put both patients and health professionals at an increased risk of infection. The working circles of the ASP have provided statements concerning these risks and how to avoid risks for the patients.

[Outpatient pulmonary rehabilitation]. / Ambulante pneumologische Rehabilitation.

Background: Outpatient pulmonary rehabilitation (PR) plays a central role in the integrative care of patients with pulmonary diseases. Material and methods: The article gives an overview of the recent evidence on outpatient PR in various diseases, in various settings including the cost-effectiveness. This is based on a selective literature search in the PubMed and Medline databanks, current expert opinions and clinical experiences. Results: Early rehabilitation after exacerbation in COPD patients leads to a reduction of rehospitalizations (hazard ratio 0.83) and to a reduction of mortality (hazard ratio 0.63) over a period of 12 months. Telerehabilitation is a promising future perspective in specific settings. Recent publications on bronchiectasis, interstitial lung diseases and pulmonary hypertension could confirm the safety and feasibility of outpatient PR and the cost-effectiveness could be demonstrated. Also, the evidence for inpatient as well as outpatient PR settings for patients with post-COVID and long COVID is growing. Conclusion: There is growing equivalence with respect to the evidence on PR, independent of whether it is carried out in an outpatient or inpatient setting.

Outpatient Pulmonary Rehabilitation in Patients with Long COVID Improves Exercise Capacity, Functional Status, Dyspnea, Fatigue, and Quality of Life.

BACKGROUND: COVID-19 survivors face the risk of long-term sequelae including fatigue, breathlessness, and functional limitations. Pulmonary rehabilitation has been recommended, although formal studies quantifying the effect of rehabilitation in COVID-19 patients are lacking. METHODS: We conducted a prospective observational cohort study including consecutive patients admitted to an outpatient pulmonary rehabilitation center due to persistent symptoms after COVID-19. The primary endpoint was change in 6-min walk distance (6MWD) after undergoing a 6-week interdisciplinary individualized pulmonary rehabilitation program. Secondary endpoints included change in the post-COVID-19 functional status (PCFS) scale, Borg dyspnea scale, Fatigue Assessment Scale, and quality of life. Further, changes in pulmonary function tests were explored. RESULTS: Of 64 patients undergoing rehabilitation, 58 patients (mean age 47 years, 43% women, 38% severe/critical COVID-19) were included in the per-protocol-analysis. At baseline (i.e., in mean 4.4 months after infection onset), mean 6MWD was 584.1 m (±95.0), and functional impairment was graded in median at 2 (IQR, 2-3) on the PCFS. On average, patients improved their 6MWD by 62.9 m (±48.2, p < 0.001) and reported an improvement of 1 grade on the PCFS scale. Accordingly, we observed significant improvements across secondary endpoints including presence of dyspnea (p < 0.001), fatigue (p < 0.001), and quality of life (p < 0.001). Also, pulmonary function parameters (forced expiratory volume in 1 s, lung diffusion capacity, inspiratory muscle pressure) significantly increased during rehabilitation. CONCLUSION: In patients with long COVID, exercise capacity, functional status, dyspnea, fatigue, and quality of life improved after 6 weeks of personalized interdisciplinary pulmonary rehabilitation. Future studies are needed to establish the optimal protocol, duration, and long-term benefits as well as cost-effectiveness of rehabilitation.

One-Year Follow-Up Lung Ultrasound of Post-COVID Syndrome-A Pilot Study.

(1) Background: Millions of people worldwide were infected with COVID-19. After the acute phase of the disease, many suffer from prolonged symptoms, the post-COVID syndrome, especially the phenotype with lung residuals. Many open questions regarding lung ultrasound (LUS) have to be answered. One essential question is the means for optimal following-up of patients with post-COVID-19 residuals with LUS; (2) Methods: A retrospective data analysis of patients after acute COVID-19 infection diagnosed with post-COVID syndrome in the state hospital of Steyr and the rehabilitation center of Hochegg was performed. LUS examinations following a 12-zone scanning protocol were performed, and the LUS score quantified comet tail artifacts. A total of 16 patients were evaluated twice with LUS from May 2020 until June 2021. (3) Results: All patients' reverberation artifacts were reduced over time. The initial LUS score of 17.75 (SD 4.84) points was decreased over the duration of the second rehabilitation to 8,2 (SD 5.94). The difference in the Wilcoxon test was significant (p < 0.001); (4) Conclusions: Lung ultrasound was a valuable tool in the follow-up of post-COVID-syndrome with lung residuals in the first wave of COVID-19. A reduction in reverberation artifacts was demonstrated. Further studies about the clinical significance have to follow.

Comparison of heart rates at fixed percentages and the ventilatory thresholds in patients with interstitial lung disease.

Heart rate (HR) responses to maximal exercise are commonly used for the prescription of training intensities in pulmonary rehabilitation. Those intensities are usually based on fixed percentages of peak HR (HRpeak), heart rate reserve (HRR), or peak work load (Wpeak), and rarely on HRs at the individual ventilatory thresholds (VT1 and VT2) derived from cardiopulmonary exercise testing (CPET). For patients suffering from interstitial lung disease (ILD), data on cardiorespiratory responses to CPET are scarce. Thus, the aim of this study was to record cardiorespiratory responses to CPET and to compare fixed HR percentages with HRs at VT1 and VT2 in ILD patients. A total of 120 subjects, 80 ILD patients and 40 healthy controls, underwent a symptom-limited CPET. From the ILD patient, 32 suffered from idiopathic pulmonary fibrosis (IPF), 37 from connective tissue disease (CTD), and 11 from sarcoidosis. HRs at fixed percentages, that is, at 70%HRpeak, at 70%Wpeak, and at 60%HRR were significantly lower in the ILD patients compared with the control group (p-values: 0.001, 0.044, and 0.011). Large percentages of HR values at 70%Wpeak and 60%HRR ranged between the HRs at VT1 and VT2 in ILD subgroups and controls as well. HRs at 70%HRpeak were lower than HRs at VT1 in 66% of the IPF patients, 54% of the CTD patients, and 55% of patients with sarcoidosis compared with 18% in the control group. Our findings demonstrate a considerable scattering of fixed HR percentages compared with HRs at the individual VTs derived from CPET in ILD patients. These findings may provide valuable information for the prescription of exercise intensity in pulmonary rehabilitation of ILD patients.

[Guideline S1: Long COVID: Diagnostics and treatment strategies]. / Leitlinie S1: Long COVID: Differenzialdiagnostik und Behandlungsstrategien.

This guideline comprises the state of science at the time of the editorial deadline. In view of the high turnover of knowledge the guideline is designed as a living guideline. The main objective was to provide a tool for the use in primary care, being considered well suited as a first point of entry and for the provision of care. The guideline gives recommendations on the differential diagnosis of symptoms following SARS-CoV­2 infection, on their therapeutic options, as well as for guidance and care of the patients concerned. It also offers advice concerning return to daily life and rehabilitation. Long COVID being a very variable condition, we chose an interdisciplinary approach.

[S1 Guideline Post-COVID/Long-COVID]. / S1-Leitlinie Post-COVID/Long-COVID.

The German Society of Pneumology initiated the AWMFS1 guideline Post-COVID/Long-COVID. In a broad interdisciplinary approach, this S1 guideline was designed based on the current state of knowledge.The clinical recommendation describes current post-COVID/long-COVID symptoms, diagnostic approaches, and therapies.In addition to the general and consensus introduction, a subject-specific approach was taken to summarize the current state of knowledge.The guideline has an expilcit practical claim and will be continuously developed and adapted by the author team based on the current increase in knowledge.

[Osteoporosis in pneumological diseases : Joint guideline of the Austrian Society for Bone and Mineral Research (ÖGKM) and the Austrian Society for Pneumology (ÖGP)]. / Osteoporose bei pneumologischen Erkrankungen : Gemeinsame Leitlinie der Österreichischen Gesellschaft für Knochen und Mineralstoffwechsel (ÖGKM) und der Österreichischen Gesellschaft für Pneumologie (ÖGP).

Chronic inflammation induces proinflammatory cytokine cascades. In addition to systemic inflammation, hypoxemia, hypercapnia, a catabolic metabolism, gonadal or thyroid dysfunction, musculoskeletal dysfunction and inactivity as well as vitamin D deficiency contribute to an increased risk of fragility fractures. Iatrogenic causes of osteoporosis are long-term use of inhaled or systemic glucocorticoids (GC). Inhalative GC application in asthma is often indicated in childhood and adolescence, but interstitial lung diseases such as chronic organizing pneumonia, COPD, sarcoid or rheumatic diseases with lung involvement are also treated with inhalative or oral GC. In patients with cystic fibrosis, malabsorption in the context of pancreatic insufficiency, hypogonadism and chronic inflammation with increased bone resorption lead to a decrease in bone structure. After lung transplantation, immunosuppression with GC is a risk factor.The underlying pneumological diseases lead to a change in the trabecular and cortical bone microarchitecture and to a reduction in osteological formation and resorption markers. Hypercapnia, acidosis and vitamin D deficiency can accelerate this process and thus increase the individual risk of osteoporotic fragility fractures.A bone mineral density measurement with a T­Score < -2.5 is a threshold value for the diagnosis of osteoporosis; in contrast the vast majority of all osteoporotic fractures occur with a T­Score > -2.5. A history of low-trauma fracture indicates osteological therapy.All antiresorptive or anabolic drugs approved in Austria for the treatment of osteoporosis are also indicated for pneumological patients with an increased fragility fracture risk of bone fractures in accordance with the national reimbursement criteria.

Outpatient Pulmonary Rehabilitation in Patients with Persisting Symptoms after Pulmonary Embolism.

Background: Patients with pulmonary embolism (PE) may suffer from long-term consequences, including decreased functional capacity. Data on pulmonary rehabilitation (PR) in patients with PE are scarce, and no data on outpatient PR are available so far. Methods: We analyzed data of 22 PE patients who attended outpatient PR due to exertional dyspnea. Patients underwent a multi-professional 6-week PR program. The primary outcome was change in 6-min walk test (6MWT). Secondary outcomes included changes in strength and endurance tests. To assess long-term benefits, follow-up was performed a median of 39 months after PR. Results: Patients started PR a median of 19 weeks after the acute PE event. Their median age was 47.5 years, 33% were women and all presented with NYHA (New York Heart Association) class II and higher. After PR, patients showed significant and clinically relevant improvements in 6MWT (mean difference: 49.4 m [95% CI 32.0-66.8]). Similarly, patients increased performance in maximum strength, endurance and inspiratory muscle strength. At long-term follow-up, 78% of patients reported improved health. Conclusion: We observed significant improvements in exercise capacity in PE patients undergoing outpatient PR. The majority of patients also reported a long-term improvement in health status. Prospective studies are needed to identify patients who would benefit most from structured PR.

Management of patients with SARS-CoV-2 infections and of patients with chronic lung diseases during the COVID-19 pandemic (as of 9 May 2020) : Statement of the Austrian Society of Pneumology (ASP).

The coronavirus disease 2019 (COVID-19) pandemic is currently a challenge worldwide. In Austria, a crisis within the healthcare system has so far been prevented. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV­2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic; however, COVID-19 specific adjustments are useful. The treatment of patients with chronic lung diseases has to be adapted during the pandemic but must still be guaranteed.

[Guidelines for outpatient pulmonary rehabilitation in Austria]. / Richtlinien für die ambulante pneumologische Rehabilitation in Österreich.

Pulmonary rehabilitation has become a standard of care for patients with chronic lung disease. It has been clearly demonstrated that pulmonary rehabilitation improves exercise capacity and quality of life in patients with chronic lung disease and reduces the number of hospital days and other measures of health-care utilization in patients with chronic obstructive pulmonary disease (COPD). This is an update of the guidelines in outpatient pulmonary rehabilitation in Austria, closely related to the official American Thoracic Society and European Respiratory Society Statement published in 2013.The guidelines represent standards of quality for requirements of structural and personal qualifications.

Disruption of STAT3 signalling promotes KRAS-induced lung tumorigenesis.

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased Kras(G12D)-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-κB-induced IL-8 expression by sequestering NF-κB within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3-NF-κB-IL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.

The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression.

Most preneoplastic lesions are quiescent and do not progress to form overt tumors. It has been proposed that oncogenic stress activates the DNA damage response and the key tumor suppressor p53, which prohibits tumor growth. However, the molecular pathways by which cells sense a premalignant state in vivo are largely unknown. Here we report that tissue-specific inactivation of the stress signaling kinase MKK7 in KRas(G12D)-driven lung carcinomas and NeuT-driven mammary tumors markedly accelerates tumor onset and reduces overall survival. Mechanistically, MKK7 acts through the kinases JNK1 and JNK2, and this signaling pathway directly couples oncogenic and genotoxic stress to the stability of p53, which is required for cell cycle arrest and suppression of epithelial cancers. These results show that MKK7 functions as a major tumor suppressor in lung and mammary cancer in mouse and identify MKK7 as a vital molecular sensor to set a cellular anti-cancer barrier.