Airway remodeling in COVID-19 lungs

Besides parenchymal changes that have been described extensively in COVID-19, bronchiectasis is also reported but detailed characterization of airway changes is lacking. Hence, we aimed to quantify the number of visible airways and their diameters in end-stage COVID-19 lungs. Explanted right lungs, obtained after lung transplantation (n=2) or autopsy (n=1) (65.3+/-26.7 days after symptom onset), were inflated to total lung capacity, frozen and scanned with whole lung microCT (155 mum). Airways were segmented using Mimics Innovation Suite (Materialise, Belgium) and airway count and diameter were assessed using Neuronstudio. Three discarded donor lungs were used as controls. Number of visible airways increased in COVID-19 lungs compared to controls (fig.1a) potentially caused by airway remodeling and bronchiectasis (fig.1b, red arrows) due to fibrotic rearrangement (fig. 1b). Small airway count (diameter 0-2 mm) in generation (G) 1-11 was lower in COVID-19 patients compared to controls, with a shift of small airways from lower generations (G1-11) to higher generations (G12-27) in COVID-19 patients. Simultaneously, airways with a diameter > 2 mm were increased in all generations in COVID-19 (present until G21 compared to G13 in controls). This study shows that COVID-19 causes a remodeling of the (small) airways, leading to an increase of visible airways and diameter of large and small airways, similar to that seen in idiopathic pulmonary fibrosis due to traction bronchiectasis. (Figure Presented).

The impact of the covid-19 pandemic on diabetes care: the perspective of healthcare providers across Europe.

AIMS: Covid-19 caused changes on the delivery of diabetes care. This study aimed to explore perceptions of healthcare providers across Europe concerning 1) the impact of covid-19 on delivery of diabetes care; 2) impact of changes in diabetes care on experienced workload; 3) experiences with video consultation in diabetes care. METHODS: Cross-sectional survey among healthcare providers in the Netherlands, United Kingdom, Turkey, Ukraine and Sweden, with a focus on primary care. RESULTS: The survey was completed by 180 healthcare providers. During the COVID-19 pandemic 57.1% of respondents provided less diabetes care and 72.8% observed a negative impact on people with diabetes. More than half of respondents (61.9%) expressed worries to some extent about getting overloaded by work. Although the vast majority considered their work meaningful (85.6%). Almost half of healthcare providers (49.4%) thought that after the pandemic video-consultation could be blended with face-to-face contact. CONCLUSIONS: Less diabetes care was delivered and a negative impact on people with diabetes was observed by healthcare providers. Despite healthcare providers' feeling overloaded, mental wellbeing seemed unaffected. Video consultations were seen as having potential. Given the remaining covid-19 risks and from the interest of proactive management of people with diabetes, these findings urge for further exploration of incorporating video consultation in diabetes care.

COVID-19 and Global Poverty and Food Security

The impacts of coronavirus disease 2019 (COVID-19) on food systems, poverty, and nutrition have been caused by generalized economic recession and disruptions in agrifood supply chains. This article reviews a growing empirical literature assessing those impacts. The review confirms that income shocks and supply disruptions have affected food security and livelihoods more where supply chains were poorly integrated and poverty where market informality had a greater presence before COVID-19. Yet, as the pandemic persists, outcomes remain uncertain and reliable data are still sparsely available. This review also reveals how methodological approaches have evolved during the pandemic, ranging from model-based scenario analyses, telephone survey evidence, case-study analyses, and data collection on policy responses and their effects. This review concludes that while we have good insight into the COVID-19 pandemic's impacts on food security, there is still much that we do not know, requiring much more rigorous hypothesis testing based on reliable and observed data.

Lung Transplantation for COVID-19: An International Registry

Purpose: SARS-CoV-2 can result in a range of infections from asymptomatic disease to progressive COVID-19 and death. In some patients with COVID-19 Lung Disease (C19LD), lung transplantation (LTx) may be lifesaving. Up to 10% of LTx in the US is currently for patients with C19LD. Understanding the characteristics and outcomes of these patients is critical. Method(s): A open-access electronic registry was established to collect de-identified data from pts who have undergone LTx for C19LD from centers globally. The study was IRB approved at Northwestern with a wavier for consent (no PHI is collected sites could submit data about pre-Tx, peri-Tx and post-Tx course). Follow-up for 1-yr post-LTx was collected. Result(s): To date, 23 patients with complete day 30 post-LTx data have been entered into the registry. Patient demographics and pre-Tx status are shown in Table 1. 3 patients required oxygen prior to COVID-19 infection. All sites required neg PCR tests prior to listing (22 (95.7%) require 2 neg PCRs). LTx occurred 150 days post-infection and none developed COVID-19 in the first 30 days. Post-Tx ICU LOS averaged 18.6 days with total post-tx hospitalization of 36.3 days (See Table 2). Most LTx experienced infectious and non-infectious morbidity. Most (47.8%) required an additional 36.8 days of rehab. 1 patient died within 30 days due to sepsis. Conclusion(s): The contribution of cases to this international registry is ongoing. While outcomes of LTx for C19LD are generally good, patients experience prolonged post-transplant hospitalization, rehabilitation and significant morbidity.

FEASIBILITY OF THE FOCUM STUDY, A PILOT OBSERVATIONAL COHORT STUDY ABOUT THE INFLUENCE OF MENOPAUSE ON THE DEVELOPMENT OF OSTEOARTHRITIS

Purpose: After the age of fifty years, the incidence of osteoarthritis (OA) increases rapidly in women, suggesting an effect of menopause on the development of OA. Because it is still unclear how menopause precisely influences the development of OA, we aim to investigate this in a novel human model: the Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM) model. This model consists of women between fifty and sixty years of age, who are currently using a combined oral contraceptive (OC) and aim to stop OC use at short term. When these women stop using OC, a rapid change in hormones is expected, modelling a “sudden menopause”. Therefore, this model provides an opportunity to study changes occurring during menopausal transition. Because the FOCUM model is new, it is unknown if women want to participate, are willing to stop OC use shortly, and will not start hormone replacement after stopping OC use. Therefore, we aim to investigate the feasibility of the FOCUM study. We define the study to be feasible when: 1) 50 participants are included within one year and received their baseline measurements (including questionnaires, blood samples and Magnetic Resonance Imaging (MRI) assessments), 2) the loss of follow-up at 6 weeks is less than 5%, and 3) no hormone replacement therapy is used by the participants at 6 weeks follow-up. Methods: For the inclusion of participants, pharmacies in and nearby Rotterdam were invited to participate. Pharmacies were asked to search in their information systems to identify all possible eligible subjects, based on age and OC use. All eligible subjects received an invitation letter with information about the study. Interested subjects were contacted by the researchers for more information. Inclusion criteria were: 1) woman, 2) between 50 and 60 years of age, 3) currently using a combined OC (with Anatomical Therapeutic Chemical (ATC) code G03AA or G03AB), and 4) started OC use before the age of 45. Exclusion criteria were: 1) already known with osteoarthritis (self-reported or registered by their general practitioner), 2) already known with another inflammatory rheumatic condition, 3) having a contra-indication for MRI assessment, 4) having a terminal or mental illness, and 5) not being able to give informed consent. In this study, measurements are performed at baseline, just before stopping OC use (T0 = 0 to 30 days), and after (T1 = 6 weeks;T2 = 6 months;T3 = 1 year;T4 = 2 years) stopping OC use. At every time point, a digital questionnaire is filled in and a blood sample is drawn. At T0 and T4, also an MRI of one of the knees is performed. Results: In January 2020, invitations were sent to 106 pharmacies of which 48 were willing to participate. Due to COVID restrictions, the first invitations to possible eligible subjects were sent in July 2020. Until April 2021, a total of 1037 invitation letters were sent. 206 subjects replied positively, of which 175 were screened by the researchers. After screening for in- and exclusion criteria, 85 subjects were eligible. The most common reason why subjects were not eligible, was because they did not use their OC anymore. Eventually, 54 subjects gave informed consent and were all seen for their baseline measurements between August 2020 and July 2021. All baseline questionnaires, blood samples and MRI assessments were available. At 6 weeks follow-up, all 54 subjects were still participating in the study. From one participant the blood sample has not been drawn at 6 weeks follow-up and one participant started hormone replacement therapy after baseline measurements (see flowchart 1). [Formula presented] Conclusions: We reached the number of 54 participants within one year, which is more than the initially targeted number of 50. All baseline measurements, including questionnaires, blood samples and MRI assessments, have been collected from these 54 participants. At 6 weeks follow-up, there was no loss of follow-up, of one participant no blood sample was available and one participant started hormone replacement therapy. Therefore, we conclude that the FOCUM study is feasible. The next step will be to investigate differences in cardiometabolic and inflammatory biomarkers, joint complaints and structural OA features between baseline and follow-up measurements.

The kallikrein-kinin system in bronchoalveolar lavage fluid from patients with COVID-19

Background : Markers of both inflammation and coagulation are linked to clinical outcome in coronavirus disease 2019 (COVID-19). Binding of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to the angiotensin-converting enzyme 2 receptor, which is involved in kinin breakdown, interferes with the kallikreinkinin pathway. This could result in increased vascular permeability, fluid excess in the lungs and pulmonary edema. Furthermore, the kallikrein-kinin pathway links coagulation and inflammation through its interactions with the contact activation pathway of coagulation via factor XII and with neutrophil extracellular traps (NETs). These insights could help to explain the clinical presentation of COVID-19 pneumonia with pulmonary coagulopathy and the high incidence of thromboembolic complications in COVID-19. Aims : Given the lack of clinical evidence to support this hypothesis, we studied the kallikrein-kinin system in bronchoalveolar lavage (BAL) fluid. Methods : In BAL fluid samples from patients with or without COVID-19, we performed in-depth analyses of kinin peptides (bradykinin, Lys-bradykinin, Lys-bradykinin-(1-8), bradykinin-(1-8), bradykinin-(1-7), and bradykinin-(1-5)) using a liquid chromatography with tandem mass spectrometry assay, along with measurements of plasma and tissue kallikrein hydrolytic activity and myeloperoxidase (MPO)-DNA complexes as a biomarker for NETs. Informed consent and ethical approval were obtained. Results : We observed higher levels of the most downstream kinin peptide bradykinin-(1-5) (Figure 1), higher tissue kallikrein activity (Figure 2), and higher levels of MPO-DNA complexes (699.0 ng/mL [66.0-142621.0], median [range], n = 21 vs 70.5 [9.9-960.0], n = 19;P < 0.001) in BAL fluid from patients with COVID-19 compared to those in BAL fluid from patients without COVID-19. Conclusions : Our data support the hypothesis that SARS-CoV-2 induces dysregulation of the kallikrein-kinin system, which contributes to thromboinflammation in COVID-19. These findings encourage the investigation of drugs that target the kallikrein-kinin system as a potential treatment option for patients with COVID-19.

Delivering physiotherapy outpatient assessment and treatment in a severe asthma clinic in the era of COVID-19

Introduction and ObjectivesThe global SARS-CoV-2 pandemic has forced clinicians to consider alternative methods of service provision to patients with respiratory conditions who were clinically vulnerable and/or advised to shield.Breathing pattern disorders (BPD) are a common comorbidity affecting approximately one third of patients with asthma. The respiratory physiotherapy team within the Portsmouth Severe Asthma Service (PSAS) recognised the need to continue to assess and deliver treatment for patients with BPD particularly at a time of heightened anxiety.Breathing retraining requires precise and highly specific assessment and treatment to ensure optimal outcomes and the decision to use a video conferencing platform was made to utilise the visual medium. To ensure quality service was being delivered, patients using the video conferencing platform to receive respiratory physiotherapy in the PSAS were asked for feedback.MethodsAt the end of every video consultation, written feedback was requested. Sixty-nine responses were received from July 2020-May 2021. Patients were asked to rate their physiotherapy consultation from very good to very poor;how they would prefer to receive treatment;if they would use this method of consultation again and the ease of use of the video consultation.ResultsOf the 69 responses:68/69 (98%) would use the service again58/69 (84%) rated the service as very good35/69 (51%) would choose video over face to face appointments23/69 (33%) would prefer to be seen face to face63/69 (91%) felt that accessibility of the video platform could be improvedQualitative feedback was also gathered from patients and included statements suchExcellent quality and a very thorough appointment.It was helpful to actually see a clinician face to face via video instead of a phone callConclusionsVideo consultations have proven to be a feasible and successful way of assessing BPD in asthma patients. Despite feedback regarding the ease of accessing the online platform being suboptimal, overarching positive responses to video consultations was received. With 51% favouring being seen via video consultation rather than face to face, this has wider implications for patients and the NHS including reduced travel time to appointments and reduced waiting room pressures.

Improving the accessibility of peak expiratory flow during the COVID-19 pandemic using a patient-friendly system

P78 Figure 1ConclusionThis electronic system re-vitalised the use of PEF in our asthma clinic;it is paper-light, patient-friendly and has increased our PEF diary responses, without additional cost or the requirement of a smart-phone. An average daily diurnal PEF variability >10% is valuable for the diagnosis of asthma and to assess asthma control. We continue to utilise PEF and have shared this resource across our local asthma networks. This is also likely to be beneficial in primary care to support annual asthma reviews and the requirement for at least two confirmatory diagnostic tests in the 2020/2021 NHS Quality and Outcomes Framework.

Poverty reduction through the development of inclusive food value chains. (Special Issue: Paths out of poverty.)

Propelled by urbanization, rising incomes, and changing diets, food markets have been expanding in Africa and South Asia, creating the vast potential for job and income opportunities along food supply chains and, hence, for poverty reduction. The novel coronavirus (COVID-19) that spread to a pandemic in early 2020 provokes enormous setbacks to this expansion. This, however, should provide lessons regarding the importance of resilient and inclusive food systems. Emergency responses to COVID-19 should consider interventions towards that end and leverage the opportunities provided by food markets growth as economies recover from the present economic recession. This paper assesses options of how this could be done by facilitating the better functioning and interconnectedness of the many small and medium-sized enterprises that are proliferating along the "hidden middle" of food value chains in storage, logistics, transportation, and wholesale and retail distribution. It also explores how policies can help smallholder farmers connect to this "hidden middle" in more gainful ways and help them climb out of poverty as well.

Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity.

Epidemiological and clinical reports indicate that SARS-CoV-2 virulence hinges upon the triggering of an aberrant host immune response, more so than on direct virus-induced cellular damage. To elucidate the immunopathology underlying COVID-19 severity, we perform cytokine and multiplex immune profiling in COVID-19 patients. We show that hypercytokinemia in COVID-19 differs from the interferon-gamma-driven cytokine storm in macrophage activation syndrome, and is more pronounced in critical versus mild-moderate COVID-19. Systems modelling of cytokine levels paired with deep-immune profiling shows that classical monocytes drive this hyper-inflammatory phenotype and that a reduction in T-lymphocytes correlates with disease severity, with CD8+ cells being disproportionately affected. Antigen presenting machinery expression is also reduced in critical disease. Furthermore, we report that neutrophils contribute to disease severity and local tissue damage by amplification of hypercytokinemia and the formation of neutrophil extracellular traps. Together our findings suggest a myeloid-driven immunopathology, in which hyperactivated neutrophils and an ineffective adaptive immune system act as mediators of COVID-19 disease severity.

Accelerated menopausal changes as disease model for development of osteoarthritis, focum

Purpose: After the age of fifty years, the percentage of females with degenerative disorders, including osteoarthritis (OA), increases rapidly. It has been suggested that menopause, and the change in hormones during menopausal transition, influences the development of these disorders. During menopausal transition, not only the hormone levels change, but also metabolism and inflammatory responses. Investigating the influence of menopausal changes, including protein change, on the development of degenerative disorders is difficult, because these changes occur slowly. However, identifying these changes is crucial to develop novel female-specific prevention strategies and therapies for these disorders. Therefore, we propose the use of an unique and novel human model to investigate the influence of menopause on the development of degenerative disorders by modelling a “sudden menopause”, in which we expect that menopausal-related changes will occur faster: the Females discontinuing Oral Contraceptives Use at Menopausal age (FOCUM) model. This model does not have the limitations in generalizability of animal models. Nor does it have the limitations of subsequent hormonal support, malignancy and its associated treatments that are pertinent to human models with a sudden menopause caused by ovariectomy.The aim of our study is to develop the FOCUM model as a disease model for the development of OA. We want to identify when changes, especially in proteins, occur after a “sudden menopause” and which of these changes are associated with the development of OA after two years. Furthermore, we want to explore if the model can also be used to learn more about the development of cardiovascular diseases, diabetes, osteoporosis and tendinopathies. In this abstract we will report on the feasibility of our inclusion. Our aim is to include 50 female participants from the general population in and nearby Rotterdam within one year. Methods: Our study design is a pilot observational prospective cohort study with two years of follow-up. Our main questions for this pilot study are: will the inclusion of participants be feasible and what are the important time points to find changes in proteins? Females between 50 and 60 years of age, who are currently using a combined oral contraceptive and started oral contraceptive use before the age of 45, are recruited from pharmacies and (if necessary) general practices. In general, females are advised to stop oral contraceptive use at the age of 52. Females who are willing to stop oral contraceptive use at short term are invited to participate. Different measurements are performed before (T0 = 0 to 30 days) and after (T1 = 6 weeks;T2 = 6 months;T3 = 1 year;T4 = 2 years) stopping oral contraceptive use. At every time point of measurements a questionnaire is filled in, a normal photograph of both hands is taken and a sample of blood is drawn to measure hormones, proteins, glucose, cholesterol, DNA-methylation and immunological aspects of cells. At the first and final time point of measurements, also a physical examination, an radiograph of both hands, an MRI scan of one knee, a DXA-scan, and an ultrasound tissue characterization of one Achilles tendon are performed. To establish which time points of measurements are most relevant to find changes in proteins after hormone change, we will examine changes in serum levels of approximately 150 different inflammation and cardiometabolic related proteins by using the Olink-technology at different time points of measurements. At the first stage of this study, we will use the Principal Component Analysis on the change in protein levels over time. Thereafter, we will test for the association between principal components and hormone change. At the second stage of this study, we will relate these principal components to various OA outcomes. Results: In January 2020, we sent invitations to 108 local pharmacies to participate in this study. At that time, a total of 55 pharmacies were willing to participate. The participating pharmacies were asked to search in their own information system to identify all possible eligible subjects, based on age and oral contraceptive use, and to send an invitation letter in their name to these subjects. Unfortunately, due to COVID restrictions we started sending these invitation letters by the end of June 2020, four months later than planned. Until now, we have sent 534 invitations from 26 pharmacies to possible eligible subjects. A total of 107 females replied positively and gave permission to provide them more information about the study. After giving information and screening for in- and exclusion criteria, we now have 25 eligible participants who gave informed consent. Of them, 16 participants have had their first (baseline) measurements of 2,5 hours at the Erasmus MC. With the 29 participating pharmacies left, we expect to reach the targeted number of 50 inclusions by February 2021 and to report about the first stage of this study. Conclusions: At this time, we have included half of our study population. So the inclusion of 50 female participants for this study within one year seems to be feasible. By performing different measurements before and after stopping oral contraceptive use, we will be able to investigate when and which menopausal changes occur and which of these changes can be related to OA. With this model we hope to learn more about the influence of menopause on the development of OA, but also of cardiovascular diseases, diabetes, osteoporosis and tendinopathies, in order to develop new prevention strategies and therapies for these diseases.

Lung Transplantation for Acute Respiratory Distress Syndrome: A Multicenter Experience

Purpose Acute respiratory distress syndrome (ARDS) is a rapidly progressive lung disease with a high mortality rate. Although lung transplantation (LTx) is a well-established treatment for a variety of chronic pulmonary diseases, LTx for acute lung failure (due to ARDS) remains controversial. We retrospectively reviewed the post-transplant outcome of ARDS patients from three high-volume European transplant centers. Methods From August 1998 to May 2020, a total of 13 patients (mean age, 29.2 ±3.6 years) transplanted for ARDS, were identified. Demographics and clinical data of these patients were collected and analyzed. Results Viral infection (H1N1, cytomegalovirus, H3N1 and SARS-CoV-2) was the main reason (n=7/13, 53.8%) for ARDS. All patients were admitted to ICU, mechanical ventilated and 11/13 were supported with ECMO during listing, with a median LTx listing time of 3 days (IQR 1.5-14). Postoperatively, median length of mechanical ventilation after LTx was 33 days (IQR 17-52.5), ICU and hospital stay were respectively 39 days (IQR 19.5-58.5) and 54 days (IQR 43.5-127). Prolongation of peripheral postoperative ECMO was required in 7/13 (53.8%) patients with median duration of 2 days (IQR 2-7). The 30-day mortality was 7.7%, median survival 590 days, 1-year and 5-year survival rates were calculated as 71.6% and 54.2%, respectively. Median follow-up time was 536 (IQR 142-1524) days. Conclusion Given the lack of alternative treatment options the herein presented results support the concept of offering LTx to carefully selected ARDS patients.

Late Breaking Abstract - Physical activity in lung transplant recipients during Belgian COVID-19 lockdown

Introduction: SARS-CoV-2 caused a pandemic in 2020 with a 'lockdown' resulting in reduced mobility. Activity tracker companies noticed reduced physical activity (PA) in the general population. If observed in patients, this may add to the devastating consequences of physical inactivity. Aim: To investigate PA levels of lung transplant (LTX) recipients before and during the Belgian soft lockdown measures of COVID-19. A decline in daily step count during lockdown measures was hypothesized. Methods: 16 LTX recipients (56% male, mean±SD age 61±6.7 years, 30.2±12.7 months post LTX) involved in an RCT (NCT04122768) were included in the present sub-analysis. Daily step counts were collected by activity trackers, >4 weeks prior to (phase 1) and 4 weeks during the Belgian lockdown (phase 2). The differences in PA between both phases were compared with paired t-tests. Results: Daily number of steps was low in phase 1 (mean±SD 6910±4225 steps/day) but did not change during phase 2 (7016±5665 steps/day), p=0.89, see figure 1. Conclusions: The Belgian COVID-19 lockdown measures did not significantly affect the PA levels of LTX recipients compared to the preceding period.

Impact of the COVID-19 outbreak on acute stroke care.

BACKGROUND AND PURPOSE: There are concerns that the coronavirus disease 2019 (COVID-19) outbreak negatively affects the quality of care for acute cardiovascular conditions. We assessed the impact of the COVID-19 outbreak on trends in hospital admissions and workflow parameters of acute stroke care in Amsterdam, The Netherlands. METHODS: We used data from the three hospitals that provide acute stroke care for the Amsterdam region. We compared two 7-week periods: one during the peak of the COVID-19 outbreak (March 16th-May 3th 2020) and one prior to the outbreak (October 21st-December 8th 2019). We included consecutive patients who presented to the emergency departments with a suspected stroke and assessed the change in number of patients as an incidence-rate ratio (IRR) using a Poisson regression analysis. Other outcomes were the IRR for stroke subtypes, change in use of reperfusion therapy, treatment times, and in-hospital complications. RESULTS: During the COVID-19 period, 309 patients presented with a suspected stroke compared to 407 patients in the pre-COVID-19 period (IRR 0.76 95%CI 0.65-0.88). The proportion of men was higher during the COVID-19 period (59% vs. 47%, p < 0.001). There was no change in the proportion of stroke patients treated with intravenous thrombolysis (28% vs. 30%, p = 0.58) or endovascular thrombectomy (11% vs 12%, p = 0.82) or associated treatment times. Seven patients (all ischemic strokes) were diagnosed with COVID-19. CONCLUSION: We observed a 24% decrease in suspected stroke presentations during the COVID-19 outbreak, but no evidence for a decrease in quality of acute stroke care.