Ling Pei Ho

To date, there have been> 750 million reported cases of COVID-19 globally since the pandemic began in early 2020. 1 In the UK, there have been> 1 million patients hospitalized and 180000 deaths due to COVID-19. 2 Previous viral epidemics and conditions causing acute respiratory distress syndrome caused long-lasting health impacts on the affected survivors. 3, 4 At the time of conception of the Post-Hospitalisation COVID-19 (PHOSP-COVID) cohort in March 2020, the longer-term pulmonary and multisystem effects of COVID-19 and impact on health status were unknown. 5 We identified a need to establish a cohort of hospitalized COVID-19 survivors to collect detailed information about the medium-and long-term effects of COVID-19 on physical and mental health, lifestyle and occupation status.Although the majority of individuals with COVID-19 were not hospitalized, we expected that the consequences of …

Objective Endocrine systems are disrupted in acute illness, and symptoms reported following coronavirus disease 2019 (COVID‐19) are similar to those found with clinical hormone deficiencies. We hypothesised that people with severe acute COVID‐19 and with post‐COVID symptoms have glucocorticoid and sex hormone deficiencies. Design/Patients Samples were obtained for analysis from two UK multicentre cohorts during hospitalisation with COVID‐19 (International Severe Acute Respiratory Infection Consortium/World Health Organisation [WHO] Clinical Characterization Protocol for Severe Emerging Infections in the UK study), and at follow‐up 5 months after hospitalisation (Post‐hospitalisation COVID‐19 study). Measurements Plasma steroids were quantified by liquid chromatography–mass spectrometry. Steroid concentrations were compared against disease severity (WHO ordinal scale) and …

Sarcoidosis is a complex immune-mediated disease characterized by clusters of immune cells called granulomas. Despite major steps in understanding the cause of this disease, many questions remain. In this Review, we perform a mechanistic interrogation of the immune activities that contribute to granuloma formation in sarcoidosis and compare these processes with its closest mimic, tuberculosis, highlighting shared and divergent immune activities. We examine how Mycobacterium tuberculosis is sensed by the immune system; how the granuloma is initiated, formed, and perpetuated in tuberculosis compared with sarcoidosis; and the role of major innate and adaptive immune cells in shaping these processes. Finally, we draw these findings together around several recent high-resolution studies of the granuloma in situ that utilized the latest advances in single-cell technology combined with spatial methods to …

Healthy repair of the alveoli requires alveolar stem cells to differentiate into cells designed for gas exchange. In chronic lung fibrotic disease like idiopathic pulmonary fibrosis (IPF), alveolar epithelial cells regenerate abnormally. The cause of this is unknown but its highly cellular, inflamed and structurally altered regenerating niche is likely to be relevant. Here, in unique sets of human lung tissues capturing advancing fibrosis, and with a 33-plex single cell imaging mass cytometry (IMC), we provide a high resolution and comprehensive temporo-spatial cell atlas of the regenerating alveolar niches. Using a suite of mathematical tools, we expose an organized immune network and identify CD206hi alveolar macrophages as a central immune cell in the immune-alveolar epithelial interactome. A spatially-directed receptor-ligand analysis offers an in-silico mechanism by which these macrophages influenced alveolar regeneration. Our study unravels a complex cellular environment and identifies key interactions that influence alveolar regeneration in a fibrotic lung.

Background The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airways diseases are unknown.Methods Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at five-months and one-year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health related quality of life (HRQoL) of individuals with pre-existing airways disease (i.e., asthma, chronic obstructive pulmonary disease (COPD) or bronchiectasis) were compared to the non-airways group.Results A total of 615/2697 (22.8%) participants had a history of pre-existing airways diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At one-year, the airways group participants …

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in …

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute …

ObjectiveIdentify prevalence of self-reported swallow, communication, voice and cognitive compromise following hospitalisation for COVID-19.DesignMulticentre prospective observational cohort study using questionnaire data at visit 1 (2–7 months post discharge) and visit 2 (10–14 months post discharge) from hospitalised patients in the UK. Lasso logistic regression analysis was undertaken to identify associations.Setting64 UK acute hospital Trusts.ParticipantsAdults aged >18 years, discharged from an admissions unit or ward at a UK hospital with COVID-19.Main outcome measuresSelf-reported swallow, communication, voice and cognitive compromise.ResultsCompromised swallowing post intensive care unit (post-ICU) admission was reported in 20% (188/955); 60% with swallow problems received invasive mechanical ventilation and were more likely to have undergone proning (p=0.039). Voice problems …

BackgroundPersistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation.MethodsPHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0–10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness.ResultsWe included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median …

Introduction: Home spirometry can deliver objective measures of progression and treatment response in interstitial lung disease (ILD). A structured home spirometry programme can be established involving clinician feedback; how patient experience evolves over time is unclear.Aim: To examine how home spirometry use and understanding evolves in a real-world cohort within a UK ILD centre. To develop tools for patient-led home spirometry.Methodology: Home spirometry was offered based on clinical need; training and standardised e-mail result feedback were provided. 35 users completed an online questionnaire, with an experience range of 32% (<1 year), 34% (1-2 years) and 34% (>2 years).Results: Positive perception of spirometry increased with experience despite the majority considering it a reminder of their lung health. 71% of users undertook spirometry only when specified by clinician; 83% valued …

IntroductionMany adults hospitalised with COVID-19 have persistent symptoms such as fatigue, breathlessness and brain fog that limit day-to-day activities. These symptoms can last over 2 years. Whilst there is limited controlled studies on interventions that can support those with ongoing symptoms, there has been some promise in rehabilitation interventions in improving function and symptoms either using face-to-face or digital methods, but evidence remains limited and these studies often lack a control group.Methods and analysisThis is a nested single-blind, parallel group, randomised control trial with embedded qualitative evaluation comparing rehabilitation (face-to-face or digital) to usual care and conducted within the PHOSP-COVID study. The aim of this study is to determine the effectiveness of rehabilitation interventions on exercise capacity, quality of life and symptoms such as breathlessness and fatigue …

Background and Objective: Patients with IPF show variable survival duration. We assessed the use of various combinations of blood, lung function and imaging measures to predict mortality in IPF.Methods: In an Oxford IPF cohort (n=75) with CALIPER-compatible CTs we determined annualised change (∆) in forced vital capacity (FVC), total CT fibrosis score (TLF%), and CALIPER-measured lung volume (CTvol) over a 3-year period. Different combinations of these metrics were compared against mortality using Cox regression. We compared concordance indexes (c-statistic) of different Cox models to determine the most predictive and discriminative combination for mortality. Multivariate models were adjusted for age, gender, baseline TLF%, antifibrotic use and either included* or excluded† leukocytes.Results: Combined measurements of ∆CTvol, ∆FVC and ∆TLF% were more predictive of mortality than single …

One in ten SARS-CoV-2 infections result in prolonged symptoms termed long COVID, yet disease phenotypes and mechanisms are poorly understood. We studied the blood proteome of 719 previously hospitalised adults with long COVID grouped by symptoms. Elevated markers of myeloid inflammation and complement activation were associated with long COVID; elevated IL1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue, and anxiety/depression, while MATN2 and DPP10 were elevated in gastrointestinal (GI) symptoms, and C1QA in cognitive impairment. Proteins suggestive of neurodegeneration were elevated in cognitive impairment, whilst SCG3 (indicative of brain-gut axis disturbance) was specific to GI symptoms. Nasal inflammation was apparent after COVID-19 but did not associate with symptoms. Although SARS-CoV-2 specific IgG was elevated with some long COVID symptoms, virus was not detected from sputum. Thus, systemic inflammation is evident in long COVID and could be targeted in therapeutic trials tailored to pathophysiological differences between symptom groups.

IntroductionThe 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.MethodsIn 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 …

BackgroundMost studies of immunity to SARS-CoV-2 focus on circulating antibody, giving limited insights into mucosal defences that prevent viral replication and onward transmission. We studied nasal and plasma antibody responses one year after hospitalisation for COVID-19, including a period when SARS-CoV-2 vaccination was introduced.MethodsIn this follow up study, plasma and nasosorption samples were prospectively collected from 446 adults hospitalised for COVID-19 between February 2020 and March 2021 via the ISARIC4C and PHOSP-COVID consortia. IgA and IgG responses to NP and S of ancestral SARS-CoV-2, Delta and Omicron (BA.1) variants were measured by electrochemiluminescence and compared with plasma neutralisation data.FindingsStrong and consistent nasal anti-NP and anti-S IgA responses were demonstrated, which remained elevated for nine months (p < 0.0001). Nasal …

BackgroundIn patients with COVID-19 requiring supplemental oxygen, dexamethasone reduces acute severity and improves survival, but longer-term effects are unknown. We hypothesised that systemic corticosteroid administration during acute COVID-19 would be associated with improved health-related quality of life (HRQoL) one year after discharge. MethodsAdults admitted to hospital between February 2020 and March 2021 for COVID-19 and meeting current guideline recommendations for dexamethasone treatment were included using two prospective UK cohort studies. HRQoL, assessed by EQ-5D-5L utility index, pre-hospital and one year after discharge were compared between those receiving corticosteroids or not after propensity weighting for treatment. Secondary outcomes included patient reported recovery, physical and mental health status, and measures of organ impairment. Sensitivity analyses were undertaken to account for survival and selection bias. FindingsIn 1,888 participants included in the primary analysis, 1,149 received corticosteroids. There was no between-group difference in EQ-5D-5L utility index at one year (mean difference 0.004, 95% CI-0.026 to 0.034, p= 0.77). A similar reduction in EQ-5D-5L was seen at one year between corticosteroid exposed and non-exposed groups (mean (SD) change-0.12 (0.22) vs-0.11 (0.22), p= 0.32). Overall, there were no differences in secondary outcome measures. After sensitivity analyses modelled using a larger cohort of 109,318 patients admitted to hospital with COVID-19, EQ-5D-5L utility index at one year remained similar between the two groups. InterpretationSystemic …

Introduction: Immune checkpoint inhibitors (ICIs) have transformed outcomes in several cancers including melanoma. Patients on ICIs are at risk of immune related adverse events (ir-AEs). Checkpoint inhibitor Pneumonitis (CIP) is an uncommon but potentially life-threatening ir-AE. Little evidence exists to guide management. We present our experience managing CIP in a tertiary interstitial lung disease (ILD) service.  Methods: We retrospectively reviewed electronic case notes and imaging of consecutive patients diagnosed with CIP between July 2020 to December 2022.Results:The most common CT appearances were diffuse ground glass opacification followed by organising pneumonia. 7 patients (27%) had new radiological changes consistent with CIP but were asymptomatic. Pre-existing ILD was present in 8 patients (31%) and 14 patients (53%) had a history of previous irAEs. Combination ICIs were used in …

BackgroundThe risk factors for recovery from COVID-19 dyspnoea are poorly understood. We investigated determinants of recovery from dyspnoea in adults with COVID-19 and compared these to determinants of recovery from non-COVID-19 dyspnoea.MethodsWe used data from two prospective cohort studies: PHOSP-COVID (patients hospitalised between March 2020 and April 2021 with COVID-19) and COVIDENCE UK (community cohort studied over the same time period). PHOSP-COVID data were collected during hospitalisation and at 5-month and 1-year follow-up visits. COVIDENCE UK data were obtained through baseline and monthly online questionnaires. Dyspnoea was measured in both cohorts with the Medical Research Council Dyspnoea Scale. We used multivariable logistic regression to identify determinants associated with a reduction in dyspnoea between 5-month and 1-year follow-up …

Background: Long-COVID has emerged as a global health concern in the aftermath of the pandemic with persistent symptoms up to two years after initial illness.Aim: To evaluate the medium and long-term effects of hospitalisation due to COVID-19.Methods: PHOSP-COVID is a prospective, multi-centre study across 83 UK sites of hospitalised COVID-19 survivors. Tier 1 cohort mainly included hospital data collection where Tier 2 involved attending 2 research visits to obtain a wide range of physical measures, biological samples, patient reported outcomes and evaluation of ongoing symptoms and perceived recovery.Results: Between August 2020 and March 2022, 7935 participants were recruited: 5238 to Tier 1 and 2697 to Tier 2. Overall, the cohort has a mean age of 59 years, 40% were female, 82% White and 55% had 2 or more pre-existing comorbidities. About 38% of the cohort required non-invasive or …

Single cell spatial interrogation of the immune-structural interactions in COVID −19 lungs is challenging, mainly because of the marked cellular infiltrate and architecturally distorted microstructure. To address this, we develop a suite of mathematical tools to search for statistically significant co-locations amongst immune and structural cells identified using 37-plex imaging mass cytometry. This unbiased method reveals a cellular map interleaved with an inflammatory network of immature neutrophils, cytotoxic CD8 T cells, megakaryocytes and monocytes co-located with regenerating alveolar progenitors and endothelium. Of note, a highly active cluster of immature neutrophils and CD8 T cells, is found spatially linked with alveolar progenitor cells, and temporally with the diffuse alveolar damage stage. These findings offer further insights into how immune cells interact in the lungs of severe COVID-19 disease. We …