ABSTRACT
BackgroundJanus kinase inhibitors drugs (JAKi) are novel small molecule medications known to cause abnormalities such as elevations in hepatic transaminases, decreases in neutrophil and lymphocyte counts and elevations in cholesterol and creatinine kinase. Blood monitoring is recommended and dose adjustments are advised if abnormalities arise. Recent warnings by the EMA and MHRA have highlighted the importance of monitoring these medications.Timely review and management of patients on JAKi drugs is difficult to maintain with increasing workload amongst the rheumatology team. A baseline audit (2020) demonstrated that hospital blood monitoring guidelines for JAKi drugs were not being followed. The rheumatology multidisciplinary team met and utilised Quality Improvement methodology including fish and driver diagrams to address this. This led to the creation of a pharmacist-led JAKi blood monitoring clinic.ObjectivesTo establish a pharmacist-led rheumatology blood monitoring clinic for the JAKi drug class in order to: increase patient safety with increased compliance to blood monitoring, save consultant/nurse time, improve communication with primary care on the frequency of blood testing required, increase patient understanding of the importance of blood monitoring with JAKi drugs, reinforce counselling advice such as risk of infections, shingles and thrombosis and promote medication adherence.MethodsThe clinic was established in March 2021. Patients commencing JAKi drugs are referred to the pharmacist-led clinic by the medical team. The pharmacist contacts the patient by phone following delivery of their medication. The patient is counselled on their new medication and dates for blood checks are agreed. A letter is sent to the patient and their GP providing this information. The patient is booked into virtual telephone appointments and bloods are monitored every month for the first 3 months and every 3 months thereafter. Any change or abnormality in blood results are flagged early in the patient's treatment and if necessary, discussed with the consultant. Adjustments are made to the patient's dose if appropriate.ResultsIn order to evaluate the benefit of the pharmacist clinic a re-audit of compliance with blood monitoring (March 2021- September 2022) was carried out alongside a patient satisfaction postal survey (August 2022).A total of 58 patients were sampled in the re-audit. The re-audit found an increase in compliance in blood monitoring since the introduction of the pharmacist clinic. 98% of patients had their full blood count performed at 3 months compared to 56% in audit 1 and 95% of patients had their lipid profile completed at 3 months compared to 15% in audit 1 (Table 1).A patient satisfaction survey (N=62, response rate 48%) found that 28 (93%) patients either agreed or strongly agreed that they were more aware of the importance of attending for regular blood monitoring when prescribed JAKi therapy as a result of the clinic.The pharmacy team made several significant interventions (self-graded Eadon grade 4 and 5). For example by improving medication adherence, detecting haematological abnormalities that required JAKi dose reduction, identifying patients suffering from infection requiring intervention including shingles and Covid-19.Table 1.Comparison of audit results pre (Audit 1) and post (Audit 2) clinic establishmentAudit 1 (N=48)Audit 2 (N=58)Number of patients with full blood count completed at weeks 4, 8 & 1227 (56%)57 (98%)Number of patients with lipid profile completed at week 127 (15%)55 (95%)Number of patients LFTs completed at weeks 4, 8 & 1226 (54%)54 (93%)ConclusionIntroduction of the pharmacist-led clinic has increased patient safety by ensuring compliance with blood monitoring as per hospital guidelines. The clinic has paved the way for improved communication with primary care teams and has provided patients with extra support during their first months on treatment with their JAKi. It has also expanded the role of the rheumatology pharmacy team and saved nursing and medical time.Acknowled ementsI wish to thank the SHSCT Rheumatology team for all their help, support and guidance with this project.Disclosure of InterestsNone Declared.
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Older adults (OAs) are particularly vulnerable to negative mental health effects from isolation and loneliness. During the COVID-19 pandemic many older adults are experiencing greater isolation, and many mental health services have moved to remote access. Knowledge and experience of technology are likely barriers for OAs in accessing these supports. Our research aims to understand OAs' experience of, and attitudes towards, using technology;both quantitative and qualitative methods were employed. It was hypothesised that the older cohort (75+) would be less experienced and comfortable with technology and that greater exposure to technology would be associated with greater comfort with its use. Participants (n = 22) were service users (SUs) of an older adult mental health service in Ireland. Results indicated no differences in exposure to technology or comfort with technology based on age. Increased exposure to technology was associated with greater comfort with use, including for engagement with mental health services (MHS). This research has implications for how remote services are offered to and conducted with older people. © 2022, University of Galway. All rights reserved.
ABSTRACT
Introduction: Diabetic peripheral neuropathy (DPN) is the most common neuropathic syndrome seen in patients with diabetes. Roughly 30% of the diabetes patient population1 experience painful DPN symptoms including bilateral stabbing or burning pain in addition to numbness in the feet and lower legs. Traditionally painful DPN symptoms have been treated with conventional medical management (CMM) including glycemic control, general risk factor management, as well as pharmaceutical agents. These treatment approaches are often unsuccessful in the long-term1. Spinal cord stimulation (SCS) has been demonstrated as an effective treatment for painful DPN of the lower extremities with multiple publications dating back to 1996 showing benefits of SCS for pain relief and improved Quality of Life (QoL) in DPN patients (Figure 1)2-18. Method(s): A systematic literature review of the robust body of evidence for SCS in the treatment of painful DPN was conducted. Publications were selected for inclusion by two independent reviewers using defined selection criteria. Additional relevant publications from outside the search dates were included. Result(s): SCS was first documented as an effective treatment for DPN in three single-arm studies published between 1996 and 20122,4,5, one of which was followed-up to thirty-six months18, and another to seven-years3. These studies paved the way for two RCTs published in 20146,7, one of which was followed-up to five-years in two publications8,10, and another7 was followed-up with analyses on QoL9 and an evaluation of the effects of burst SCS17. Two meta-analyses were published in 2020 and 202111,12. A post-hoc analysis of a multi-center single-arm study on high frequency (10kHz) SCS to treat DPN was published in 202013 and followed by an RCT published in 202114 with additional 1-year follow-up15,16. Collectively these studies demonstrate that SCS is an effective therapy for patients with painful DPN by reducing pain and increasing QoL for DPN patients (Figure 1). Conclusion(s): This review of a large body of evidence shows a decades-long history of the effectiveness of SCS for symptom relief in patients suffering from painful DPN. Future research on the effectiveness of new waveforms and novel methods of energy delivery to the spinal cord are needed. The study of outcomes in addition to pain relief is also needed, which may better illustrate the breadth of effects of SCS therapy on the underlying disease factors. Increasing awareness of the current evidence is essential to increasing therapy adoption by expanding payer support and influencing referring health care provider behavior. Disclosure: Eric Grigsby, MD: AE Mann Foundation: Consulting Fee: Self, Bioness Inc.: Consulting Fee: Self, Medallion Therapeutics: Consulting Fee: Self, Medtronic: Consulting Fee: Self, SPR Therapeutics: Consultant: Self, Tenex Health: Consultant: Self, Voyager Therapeutics: Consultant: Self, Xalud: Consulting Fee: Self, AE Mann Foundation: Consulting Fee: Self, Medallion Therapeutics: Consulting Fee: Self, Bioness Inc.: N/A: Self, Medallion Therapeutics: N/A: Self, SPR Therapeutics: N/A: Self, Abbott / St. Jude Medical: N/A: Self, Tenex: N/A: Self, Vertos: N/A: Self, Xalud: N/A: Self, AE Mann Foundation: Consulting Fee: Self, Bioness Inc.: Consulting Fee: Self, Medtronic, Inc.: N/A: Self, Collegium Pharmaceutical, Inc.: Trustee: Self, Flowonix Medical: Served on speakers' bureau: Self, Jazz Pharmaceuticals: Served on speakers' bureau: Self, Jazz Pharmaceuticals: Trustee: Self, Spinal Restoration, Inc.: Trustee: Self, Jazz Pharmaceuticals: N/A: Self, Alfred Mann Foundation: N/A: Self, Boston Scientific: N/A: Self, CNS Therapeutics: N/A: Self, Collegium Pharmaceutical, Inc.: N/A: Self, Flowonix Medical: N/A: Self, Jazz Pharmaceuticals: N/A: Self, Medtronic, Inc.: N/A: Self, Myoscience: N/A: Self, NeurAxon Inc.: N/A: Self, Spinal Restoration, Inc.: N/A: Self, St. Jude Medical, Inc.: N/A: Self, Abbott Laboratories: Consultant: Self, Alfred Mann Foundation: Consulting Fee: Self, Cervel Neurotech, Inc.: Consultant: Self, CNS Therapeutics: Consultant: Self, Covidien: Consultant: Self, Cumberland Pharmaceuticals, Inc.: Consultant: Self, Flowonix Medical: Consultant: Self, Jazz Pharmaceuticals: Consultant: Self, Mainstay Medical: Consultant: Self, Medtronic, Inc.: Consultant: Self, Myoscience: Consultant: Self, NeuroPhage Pharmaceuticals: Consultant: Self, Nevro Corp: Consultant: Self, Palyon: Consultant: Self, Spinal Modulation: Consultant: Self, SPR Therapeutics: Consultant: Self, St. Jude Medical, Inc.: Consultant: Self, Tenex Health, Inc.: Consultant: Self, VertiFlex Inc.: Consultant: Self, Vertos Medical, Inc.: Consultant: Self, Xalud Therapeutics, Inc.: Contracted Research: Self, Medtronic, Inc.: Served on speakers' bureau: Self, Flowonix Medical: Served on advisory board: Self, Medtronic, Inc.: N/A: Self, Jazz Pharmaceuticals: N/A: Self, Medtronic, Inc.: Ownership Interest: Own Stock, Stock Options, Future Stock Options: Self, Nevro Corp: Ownership Interest: Own Stock, Stock Options, Future Stock Options: Self, Rachel Slangen, PhD: None, Lisa Johanek, PhD: Medtronic: Salary/Employee: Self, Maddie LaRue, PHD: Medtronic: Employee:, Cecile de Vos, PhD: None, Melissa Murphy: Medtronic: Consulting Fee:, Relievant: Consulting Fee:Copyright © 2023
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Introduction: The war in Ukraine is causing significant disruption to global agri-food systems, which are still recovering from the effects of the COVID-19 pandemic. In Australia, these global shocks followed a series of localized climate-induced crises from forest fires, floods and drought. There is a pressing need to increase our understanding of ways to strengthen the resilience of agri-food systems to multiple shocks and stresses that co-occur or follow on each other. The aims of this study in Melbourne, Australia, were to investigate how forest fire and pandemic shocks affected the agri-food system, to identify vulnerabilities in the system, and to explore opportunities to build resilience to future shocks and stresses. Methods: Semi-structured interviews were conducted during 2020-21 with 41 key stakeholders from government, industry and civil society organizations. Results and discussion: Vulnerabilities identified in agri-food supply chains included geographic and corporate concentration, complex "just in time” supply chains, critical infrastructure and logistics, and workforce availability. Strategies identified to build the resilience of agri-food systems include increasing the diversity of supply chains, decentralization, collaboration throughout agri-food supply chains, and ensuring sustainable livelihoods. Conclusion: Our study highlights the cascading effects of multiple shocks and stresses on agri-food systems, and the need for greater policy focus on transformative actions that build the resilience of agri-food systems to any future shock, and that counter the cumulative effects of underlying environmental stresses. Copyright © 2023 Murphy, Carey and Alexandra.
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The incidence of melanoma and nonmelanoma skin cancer continues to rise in Ireland. This study aimed to explore the tanning and sun-protection behaviour and attitudes, as well as awareness of signs of melanoma, of the Irish population. A cross-sectional study was performed in December 2020 via an online questionnaire. Respondents were recruited according to gender, age and geographical region. In total, 1043 respondents (49% female) completed the questionnaire (mean age 41 years;range 20-72). In total, 443 sunbathe when there is sunny weather in Ireland, with 245 wearing suncream less than half of the time. Thirty-eight per cent (n = 399) have used sunbeds in the last 12 months, despite the global COVID-19 pandemic. Almost half (49%) did not believe getting a sunburn was serious. Most (87%) were aware melanoma would have serious consequences for them and 91% believed it was important to protect themselves from getting melanoma. In total, 839 know that wearing sunscreen can prevent sunburn. However, the main reasons they do not apply it include just forgetting (n = 207), to get a tan (n = 177) and they just don't like putting it on (n = 359). The main reason for limiting sunbathing was to avoid wrinkles/ skin pigmentation (n = 356), followed by a fear of getting skin cancer (n = 334). The primary reason people sunbathed was to top up their supply of vitamin D (n = 336), which was closely followed by getting a tan. Eighty-five per cent reported feeling and looking better with a tan. Despite knowledge of the risks of sunburn, 208 respondents felt it was worth getting slightly sunburnt to get a tan. Most respondents were aware of sun-protection measures (n = 729), but 484 people were not confident about what to look for when performing a self-skin examination and only 410 know the signs of a melanoma. This study found that although the majority of people are aware of the risks of sunbathing, many are happy to take these risks in order to get a tan. Tans are still considered to be attractive by the majority of respondents. Although there are high levels of awareness regarding sun protection, knowledge regarding skin self-examination and the signs of melanoma is lacking. Our results indicate that health promotion interventions for skin cancer may need to focus on education regarding the signs of melanoma and consider strategies to alter the perceptions of the beneficial factors of tanning.
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Background: This study was designed to investigate patterns and risk factors for substance use among obstetrical patients who gave birth during the early period of the pandemic, and their partners. Method(s): Cross-sectional survey of obstetrical patients between March 17th and June 16th, 2020, at The Ottawa Hospital, Ottawa, Canada. Substance use was a composite measure of any alcohol, tobacco, or cannabis use since COVID-19 began. Four outcomes included: any participant substance use or increase in substance use, any partner substance use or increase in substance use. Adjusted risk ratios (ARR) and 95% confidence intervals (CI) are presented. Finding(s): Of 216 participants, 113 (52.3%) and 15 (6.9%) obstetrical patients reported substance use and increased use, respectively. Those born in Canada (ARR: 2.03;95% CI: 1.27-3.23) and those with lower household income (ARR: 1.38;95% CI: 1.04-1.85) had higher risk of substance use. Those with postpartum depression (ARR: 5.78;95%CI: 2.22-15.05) had the highest risk of increased substance use. Families affected by school/daycare closure reported a higher risk of increased partner substance use (ARR: 2.46;95% CI:1.38-4.39). Conclusion(s): This study found that risk factors for substance use included demographics (i.e., being born in Canada, income), mental health (postpartum depression), and school/childcare closures.Copyright © 2023 Taylor & Francis Group, LLC.
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Contemporary models of welfare capitalism have frequently been critiqued about their fit-for-purpose in provisioning for people's basic needs including care, and longer-term ecological sustainability. The Covid-19 pandemic has also exposed the need for better institutions and a new welfare architecture. We argue a post-productivist eco-social state can deliver sustainable well-being and meet basic needs. Arguing Universal Basic Services are an essential building block and prerequisite for a de-commodified welfare state, we focus on examining the form of income support that might best complement UBS. The article develops, from the perspective of feminist arguments and the capabilities approach, a case for Participation Income. This, we argue, can be aligned with targeted policy goals, particularly reward for and redistribution of human and ecological care or reproduction and other forms of socially valued participation. It may also, in the short term, be more administratively practical and politically feasible than universal basic income. © 2023 Cambridge University Press. All rights reserved.
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Objective: The COVID-19 pandemic has caused significant disruption to medical education and clinical training. This not only affected delivery of the clinical curriculum but also resulted in stressors which may impede learning. This study aimed to assess the impact of a modified on-line curriculum in selected clinical clerkships in the Faculty of Medical Sciences, UWI, Cave Hill Campus, during the COVID-19 pandemic. Design and Methods: Fourth and Fifth year medical students completed an online survey in January 2021 covering the following areas: student satisfaction, self-efficacy (Online Learning Self-Efficacy Scale) and perceived effectiveness of online versus face-to-face learning. Students who agreed/strongly agreed to the statement "Overall, I was highly satisfied with the clerkship placement" were classified as satisfied. Result(s): 88 of 131 students completed the survey (response rate = 67 %). More than half of students (51%) were satisfied with online clerkship delivery. Fewer than half of students (46%) believed online learning effectively increased their knowledge, compared to 56% for face-to-face learning. Perception of effectiveness of online learning and face-to-face teaching of clinical skills was 18% and 89%, respectively (p < 0.0001). Fewer students perceived online teaching to be effective for developing social competencies (27%) compared to face-to-face instruction (67%) (p < 0.001). Students satisfied with online learning were more likely to be female (OR = 2.6) and older respondents. Mean self-efficacy scores were higher for persons who perceived online teaching to be effective for increasing knowledge, improving clinical skills, and social competencies. Students' perception of online learning was strongly associated with online selfefficacy. Conclusion(s): Students perceived online learning to be least effective for enhancing clinical skills. Students' perception of effectiveness of online learning was strongly associated with online self-efficacy. Further research to examine how the perception of online delivery impacts student performance in online learning is recommended. Educators have been challenged to design online programmes that facilitate development of clinical and social skills. Understanding medical students' experiences and identifying unmet needs will help improve clerkship curriculum and support medical students during and after the COVID-19 pandemic.
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Objective: To provide an overview of the 'Improving Household Nutrition Security and Public Health in the CARICOM' (Food and Nutrition: FaN) project's objectives, design and methods, and summarize some of its core activities and achievements. Method(s): The three project countries were Jamaica, St. Kitts and Nevis, and St. Vincent and the Grenadines. To answer the research question, "What are the most effective, gendersensitive ways to improve food sovereignty, household food security, and nutrition in CARICOM states?", there were four objectives - two research objectives including scoping reviews and stakeholder engagement;and two objectives to design and assess interventions. The project was originally planned for execution January 2018 to January 2022. However, a 6-month no-cost extension was granted due to coronavirus disease 2019 (COVID-19)-related project delays. Result(s): Thirteen COVID-modified interventions were pursued under the categories schools, communities, and CARICOM supports and included revision of Primary and Secondary school curricula and development of school nutrition standards. Regional capacity was strengthened through community interventions, two Master of Public Health scholarships, and upgrading of lab equipment to test foods for fats, sodium, and sugar in Jamaica, among others. Dissemination was undertaken under the re-branded slogan and logo, "Food 4 Change Caribbean". The project website (www.food4changecaribbean.org) hosts reports and videos to ensure that resources can be accessed beyond the project time frame. Conclusion(s): Despite challenges precipitated by the COVID- 19 pandemic, including tabling of planned in-person activities, the project team was able to re-group and re-design interventions to accommodate the new reality.
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Purpose: This article explores the value of engaging a hybrid learning strategy in a micro-enterprise setting when responding to a global pandemic. The research question asks: “Does a hybrid learning strategy enhance a micro-enterprise's response to extreme events?”. Design/methodology/approach: A micro-enterprise owner–manager (OM) reflects on their experience running a business during the coronavirus disease 2019 (COVID-19) pandemic, which resulted in the complete decimation of the organization’s revenue stream in early 2020. Captured in conversation with an academic peer, these practitioner insights provide valuable case evidence relating to micro-enterprise response to extreme commercial events, such as a global pandemic. Findings: The journey from initial survival-mode to emergent market opportunity recognition and subsequent growth is recorded. The paper contributes to the limited research on the impact of learning strategy plans on micro-enterprise crisis response strategies and provides insights into the value of engaging a hybrid learning strategy when responding to a significant external business shock. Originality/value: Drawing from these insights, the authors offer a literature-informed framework from which to consider the dynamics of an adaptive strategic response in a micro-enterprise setting, offering a means through which micro-enterprises can plan for and respond to extreme events in the future. © 2022, Monica Murphy and Felicity Kelliher.
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Objectives: Universal testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) within birthing units is an effective strategy to contain infection and estimate community prevalence. Given the high-prevalence of COVID-19 cases in Ontario, the objective of this study was to determine the prevalence of active and recovered SARS-CoV-2 infection among pregnant individuals in Ottawa through universal SARS-CoV-2 and serology testing. Methods: From October 19th to November 27th, 2020, pregnant individuals admitted to triage assessment units at The Ottawa Hospital (TOH) were consented for SARS-CoV-2 testing. Swab and serology samples were analyzed using digital droplet polymerase chain reaction (ddPCR) and enzyme-linked immunosorbent assays, respectively. SARS-CoV-2 seropositivity was defined as a positive result for immunoglobulin (Ig) G, either alone or in combination with IgM and/or IgA. Results: From the 395 enrolled participants, 284 swab and 353 serology samples were collected. We found that 18 of 395 (4.6%) participants had evidence of SARS-CoV-2 exposure: 2/284 (0.70%) were positive for SARS-CoV-2 and 16/353 (4.5%) were positive for anti–SARS-CoV-2 IgG. Seropositive participants were similar to seronegative participants in terms of demographics, clinical characteristics, and pregnancy outcomes. Conclusions: The prevalence of SARS-CoV-2 ddPCR positivity and seropositivity in the obstetrical population at TOH was 0.70% and 4.5%, respectively in the fall of 2020. According to local public health data, the infection rate peaked at 0.6% during the study time period. Universal SARS-CoV-2 testing programs may help approximate community prevalence, however, justification of this strategy depends on testing capabilities and the local context of COVID-19 infection. Keywords: pregnancy;COVID-19;SARS-CoV-2;universal testing;seroprevalence
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BACKGROUND: Teaching methods can impact achievement emotions and cognitive load in learners. Due to COVID19, the University of Central Florida College of Medicine (UCF) adopted some online clinical-skills training for their first-year medical students (M1s) while the University of Florida College of Medicine (UF) was able to continue with limited in-person instruction. We hypothesized online learning could increase cognitive load, negatively impact self efficacy, and lead to increased levels of imposter syndrome associated with learning clinical skills. METHODS: M1s from UCF and UF from the 20-21 academic year were given an online survey during the Summer of 2021measuring Medical Student Wellbeing Index (WBI), Clance Imposter Phenomenon Scale (CIPS). Cognitive load and achievement emotions were measured using previously validated instruments on a 5-point Likert scale. Demographic data was collected, and IRB approval obtained. Descriptive statistics were obtained with SPSS 27 and reported as frequencies and percent response. Spearman correlation analysis was performed on all variables. T-tests were conducted to compare variables between UF and UCF. Overall response rate was 54% (44% and 61% for UCF and UF, respectively). RESULTS: Analyzing combined data from both schools for history and physical exam components, several statistically significant correlations were found (see Table 1). For both history and physical exam components UF learners had higher task value (4.66, 4.26 p<.001;4.70, 4.52 p=.042), enjoyment (4.34, 3.70 p<.001;4.28, 3.86 p=.001) and self-efficacy (4.43, 4.10 p=.004;4.36, 4.02 p=.007) and lower anxiety (2.32, 2.84, p=.003;2.32, 3.03 p<.001) and extrinsic load (1.88, 3.14 p<.001;2.07, 3.35 p=.001) compared to UCF learners, respectively. UF learners had lower WBI scores than UCF learners (250.74, 279.90 p=.024), but no differences in CIPS scores were found. Higher scores on CIPS and WBI scores indicate greater severity of imposter syndrome and reduced well-being, respectively. CONCLUSIONS: Teaching methods appear to have an impact on learners' achievement emotions, cognitive load, and well-being. Increased task value may mitigate a learners' extrinsic load with implications on how educators apply teaching methods. Further studies are needed to identify long-term impacts of online teaching methods.
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Introduction A global trial is currently investigating the impact of high-intensity interval training (HIIT) on survival in advanced prostate cancer (the INTERVAL trial). To ensure greater accessibility, we designed a parallel trial (EXACT), to determine the feasibility of exercise in those contraindicated to HIIT. Methods Men with metastatic castrate-resistant prostate cancer being actively treated with androgen deprivation therapy and a novel hormone therapy (abiraterone acetate or enzalutamide) are eligible to participate in 12- weeks of home-based walking and strengthening. Participants complete physical (e.g. 6-min walk test and timed sit-to-stand) and quality of life (e.g. BPI-SF;EQ-5D-5L;FACIT-fatigue;FACT-P) outcomes at baseline (T1), 12 (T2) and 24 weeks (T3). This trial was adapted to enable remote recruitment and delivery during the COVID-19 pandemic. Results To date, 118 patients have been screened, with 33 approached by their clinician to participate. 25 patients have consented, with 12 completing the trial without any intervention-related adverse events and 6 withdrawn. Recruitment and trial delivery was operational throughout the COVID-19 pandemic. Currently positive trends are evident for physical and quality of life outcomes at T2 and T3. Conclusions Although this trial is ongoing, early trends suggest this intervention is safe and feasible for men with advanced castration resistant prostate cancer and could improve physical capacity and quality of life.
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Rationale Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is characterised by an IL-6 driven cytokinemia, associated with a rapidly developing acute respiratory distress syndrome (ARDS). A blunted AAT response to IL-6 in SARS-CoV-2 has been associated with increased morbidity and mortality. One of the main functions of IL-6 is regulation of acute-phase proteins such as alpha-1 antitrypsin (AAT), a key lung anti-protease. We investigated the proteaseanti- protease balance in the circulation and pulmonary compartments in SARS-CoV-2 acute respiratory distress syndrome (ARDS). In addition, we investigated the effect of anti-IL-6 therapy on anti-protease defence. Methods Levels and activity of AAT and neutrophil elastase (NE) were measured in plasma (n=20), airway tissue (n=8) and tracheal secretions (n=13) of people with severe SARS-CoV-2 infection. AAT and IL-6 levels were also evaluated over time in people with moderate SARS-CoV-2 infection who received standard of care +/- tocilizumab (n=30). Results AAT plasma levels doubled in severe SARS-CoV-2 ARDS patients (329g/L +/- 08 g/L as compared to baseline levels 174g/L +/- 011 g/L, P<0001). In lung parenchyma AAT levels were increased. Despite no increase in neutrophils, an increased percentage of neutrophils involved in NET formation were observed in the alveoli. A protease-anti-protease imbalance was detected in tracheal aspirates (TA). NE was active and AAT inactivated, reflecting cleavage and complexation with NE. The major airway anti-protease, secretory leukoprotease inhibitor (SLPI) was decreased in SARS-CoV-2-infected lungs and cleaved in TAs. Induction of AAT in SARS-CoV-2 infection occurred mainly through IL-6 signalling. Tocilizumab (IL-6 receptor antagonist) down-regulated AAT during infection (13g/L+/-0225 from 2469 g/L+/-0197, P<00001) while IL-6 remained elevated (NS=0.0998) as reflected by the IL-6/AAT ratio (P=0046). Conclusion This study shows that the AAT response to SARS-CoV-2 infection is compartmentalized with an appropriate increase in plasma and alveoli but an inadequate response in airways. This underlines a significant, but potentially treatable, protease-antiprotease imbalance in SARS-CoV-2 ARDS as well as highlighting IL-6's importance in SARS-CoV-2 pathology not only as a pro-inflammatory cytokine but as an anti-inflammatory regulator. In conclusion there is unopposed NE activity in the airways of people with SARS-CoV-2 ARDS which could be amenable to AAT therapy. Our data suggest caution in the use of IL-6 blocking therapies in SARS-CoV-2-infected individuals.
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Rationale: It has been suggested that individuals with ZZ alpha-1 antitrypsin deficiency (AATD) might suffer from more severe and prolonged pulmonary exacerbations compared to their MM counterparts due to the loss of immunomodulatory AAT protein. During the COVID-19 pandemic it was advised that individuals with ZZ AATD should, where practicable, cocoon to avoid contracting COVID-19. Methods: A survey of ZZ AATD individuals attending the Irish National Centre for Expertise for AATD was conducted 1 year into the COVID-19 pandemic. It evaluated the effects of cocooning on patient-reported exacerbation frequency during the 1-year COVID-19 period versus the 2 years prior to COVID-19. 184 individuals were contacted by phone, mail, or email. Results: 114 (62%) individuals successfully completed the survey. 73 (64%) cocooned during the pandemic, with men (39) and women (34) almost equally likely to cocoon. Those who cocooned tended to have a lower baseline FEV1 (% predicted). Women who cocooned had a mean FEV1 of 73.5% compared to a mean of 97.5% for women who did not cocoon. Men who cocooned had a mean FEV1 of 52.8% compared to a mean of 78.9% for men who did not cocoon. Men benefited from lower rates of exacerbation due to cocooning. They suffered an average of 0.92 exacerbations during the cocooning period versus 1.56 exacerbations per year prior to the pandemic (P = 0.0298). Women, regardless of cocooning status and non-cocooning men also demonstrated a trend towards fewer exacerbations but these were not statistically significant. In terms of hospitalisations, there were no differences observed between men or women based on cocooning status. This was likely due to the low rate of hospital admissions during the 3-year period. 14 (12%) of 114 respondents contracted COVID-19, 7 (50%) of whom were hospitalised. There was a single fatality from COVID-19. Conclusion: Further work needs to be done to establish the effects of risk reduction behaviours such as cocooning on exacerbation frequency and which groups may benefit most from this strategy. Our survey suggests that men with more advanced respiratory disease were most likely to benefit from a cocooning strategy and this may be applicable to non-COVID threats in the future.