Human hypoxic pulmonary vasoconstriction is unaltered by 8 h of preceding isocapnic hyperoxia

Exposure to sustained hypoxia of 8 h duration increases the sensitivity of the pulmonary vasculature to acute hypoxia, but it is not known whether exposure to sustained hyperoxia affects human pulmonary vascular control. We hypothesized that exposure to 8 h of hyperoxia would diminish the hypoxic pulmonary vasoconstriction (HPV) that occurs in response to a brief exposure to hypoxia. Eleven healthy volunteers were studied in a crossover protocol with randomization of order. Each volunteer was exposed to acute isocapnic hypoxia (end-tidal PO2 = 50 mmHg for 10 min) before and after 8 h of hyperoxia (end-tidal PO2 = 420 mmHg) or euoxia (end-tidal PO2 = 100 mmHg). After at least three days, each volunteer returned and was exposed to the other condition. Systolic pulmonary artery pressure (an index of HPV) and cardiac output were measured using Doppler echocardiography. Eight hours of hyperoxia had no effect on HPV or the response of cardiac output to acute hypoxia

Elevation of iron storage in humans attenuates the pulmonary vascular response to hypoxia

Sustained hypoxia over several hours induces a progressive rise in pulmonary artery systolic pressure (PASP). Administration of intravenous iron immediately prior to the hypoxia exposure abrogates this effect, suggesting that manipulation of iron stores may modify hypoxia-induced pulmonary hypertension. Iron (ferric carboxymaltose) administered intravenously has a plasma half-life of 7-12 hours. Thus, any therapeutic use of intravenous iron would require its effect on PASP to persist long after the iron-sugar complex has been cleared from the blood. To examine this, we studied PASP during sustained (6-h) hypoxia on four separate days (days 0, 1, 8 and 43) in 22 participants. On day 0, the rise in PASP with hypoxia was well matched between the iron and saline groups. On day 1, each participant received either 1 g of ferric carboxymaltose or saline in a double-blind manner. After administration of intravenous iron, the rise in PASP with hypoxia was attenuated by ~50%, and this response remained suppressed on both days 8 and 43 (p<0.001). Following administration of intravenous iron, values for ferritin concentration, transferrin saturation and hepcidin concentration rose significantly (p<0.001, p <0.005 and p<0.001, respectively) and values for transferrin concentration fell significantly (p<0.001). These changes remained significant at day 43. We conclude that the attenuation of the pulmonary vascular response to hypoxia by elevation of iron stores persists long after the artificial iron-sugar complex has been eliminated from the blood. The persistence of this effect suggests that intravenous iron may be of benefit in some forms of pulmonary hypertension

Medium-term effects of SARS-CoV-2 infection on multiple vital organs, exercise capacity, cognition, quality of life and mental health, post-hospital discharge.

BACKGROUND: The medium-term effects of Coronavirus disease (COVID-19) on organ health, exercise capacity, cognition, quality of life and mental health are poorly understood. METHODS: Fifty-eight COVID-19 patients post-hospital discharge and 30 age, sex, body mass index comorbidity-matched controls were enrolled for multiorgan (brain, lungs, heart, liver and kidneys) magnetic resonance imaging (MRI), spirometry, six-minute walk test, cardiopulmonary exercise test (CPET), quality of life, cognitive and mental health assessments. FINDINGS: At 2-3 months from disease-onset, 64% of patients experienced breathlessness and 55% reported fatigue. On MRI, abnormalities were seen in lungs (60%), heart (26%), liver (10%) and kidneys (29%). Patients exhibited changes in the thalamus, posterior thalamic radiations and sagittal stratum on brain MRI and demonstrated impaired cognitive performance, specifically in the executive and visuospatial domains. Exercise tolerance (maximal oxygen consumption and ventilatory efficiency on CPET) and six-minute walk distance were significantly reduced. The extent of extra-pulmonary MRI abnormalities and exercise intolerance correlated with serum markers of inflammation and acute illness severity. Patients had a higher burden of self-reported symptoms of depression and experienced significant impairment in all domains of quality of life compared to controls (p<0.0001 to 0.044). INTERPRETATION: A significant proportion of patients discharged from hospital reported symptoms of breathlessness, fatigue, depression and had limited exercise capacity. Persistent lung and extra-pulmonary organ MRI findings are common in patients and linked to inflammation and severity of acute illness. FUNDING: NIHR Oxford and Oxford Health Biomedical Research Centres, British Heart Foundation Centre for Research Excellence, UKRI, Wellcome Trust, British Heart Foundation

Two doses of SARS-CoV-2 vaccination induce robust immune responses to emerging SARS-CoV-2 variants of concern

The extent to which immune responses to natural infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and immunization with vaccines protect against variants of concern (VOC) is of increasing importance. Accordingly, here we analyse antibodies and T cells of a recently vaccinated, UK cohort, alongside those recovering from natural infection in early 2020. We show that neutralization of the VOC compared to a reference isolate of the original circulating lineage, B, is reduced: more profoundly against B.1.351 than for B.1.1.7, and in responses to infection or a single dose of vaccine than to a second dose of vaccine. Importantly, high magnitude T cell responses are generated after two vaccine doses, with the majority of the T cell response directed against epitopes that are conserved between the prototype isolate B and the VOC. Vaccination is required to generate high potency immune responses to protect against these and other emergent variants

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Functional variation in the hypoxia-inducible factor (HIF) pathway in humans

By undertaking a number of different experimental approaches at the genetic, cellular/ molecular and integrative physiology levels, I investigated functional variation in the Hypoxia-Inducible Factor (HIF) transcription pathway in humans. My studies focused on Tibetan natives. Tibetan highlanders are adapted to life in a hypoxic environment and exhibit distinct physiological traits at high altitude. Recent studies identified positive selection at two genetic loci, EPAS1 (HIF2α) and EGLN1 (PHD2), in Tibetan highlanders and demonstrated an association of EGLN1/EPAS1 genotype with haemoglobin concentration. Both are genes of the HIF pathway, which coordinates an organism’s response to hypoxia. Patients living at sea level with genetic diseases of the HIF pathway have characteristic phenotypes at both the integrative physiology and cellular levels. I investigated whether Tibetans living at sea level also possess distinct phenotypic characteristics, and whether these may be related to underlying variation within the HIF pathway. I compared Tibetans living at sea level with Han Chinese, their most closely-related major ethnic group, and found that Tibetans possess a significantly different integrative physiology phenotype. Tibetans had a lower haemoglobin concentration and haematocrit, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 hours) hypoxia. Regarding genotype- phenotype relationships within the Tibetans, I found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by systemic hypoxia. At an intermediate cellular level, the relative expression and the hypoxic induction of HIF- regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. I also investigated whether the genetic variation in EPAS1 selected for in Tibetans may be functional at the molecular level by affecting transcription of EPAS1 in cells and whether certain coding variants in EGLN1 found in Tibetans affect protein (PHD2) activity in cells and in vitro. A small supplementary study was undertaken in patients with idiopathic erythrocytosis, who have elevated or inappropriately normal erythropoietin levels, to investigate if they have genetic alterations in the HIF system.</p

Interferon-β-induced pulmonary sarcoidosis in a 30-year-old woman treated for multiple sclerosis: a case report

Abstract Introduction With the increasing use of recombinant α and β interferon therapy for the treatment of various disorders, cases of interferon-associated sarcoidosis have been reported in the literature. The majority of these have been cases of interferon-α-induced sarcoidosis. We present the first case, to the best of our knowledge, of interferon-induced pulmonary sarcoidosis in a patient whose multiple sclerosis was treated with interferon-β. Case presentation We present the case of a 30-year-old Caucasian woman who presented with unusually persistent bilateral areas of lung consolidation on serial radiographs. Pulmonary sarcoidosis was diagnosed on transbronchial lung biopsy five months after the initiation of treatment with interferon-β for multiple sclerosis. Conclusions Sarcoidosis should be considered in the differential diagnosis of a patient who develops clinical or radiological pulmonary disease while undergoing interferon therapy. It is important to note that interferon-induced sarcoidosis, though usually seen in cases with interferon-α, can occur with interferon-β. Neurologists managing patients with multiple sclerosis should be aware of this association between interferon-β and sarcoidosis and promptly refer patients developing respiratory symptoms for further investigation.</p

Withdrawal of continuous positive airway pressure therapy for 2 weeks in obstructive sleep apnoea patients results in increased circulating platelet and leucocyte-derived microvesicles

In 2013 we reported that in patients with obstructive sleep apnoea (OSA), withdrawing their continuous positive airway pressure (CPAP) therapy for two weeks led to a significant increase in endothelial cell-derived microvesicles (MVs) [1]. Several other studies have found that the initiation of CPAP therapy in patients with OSA leads to a fall in endothelial [2, 3] and platelet [4, 5] MVs, but there have been no further studies investigating the impact of CPAP withdrawal in patients established on therapy, which provides a more robust experimental protocol. Therefore in this further exploratory study we have examined the impact of CPAP withdrawal on other subtypes of MVs