Publications by authors named "Peter M George"

179 Publications

A Mycobacterium species for Crohn's disease?

Pathology 2021 Jun 19. Epub 2021 Jun 19.

Southern Community Laboratories, Wellington Hospital, Wellington, New Zealand.

In ruminants Mycobacterium avium subspecies paratuberculosis (MAP) is the causative organism of a chronic granulomatous inflammatory bowel disease called Johne's disease (JD). Some researchers have hypothesised that MAP is also associated with Crohn's disease (CD), an inflammatory bowel disease in humans that shares some histological features of JD. Despite numerous attempts to demonstrate causality by researchers, direct microbiological evidence of MAP involvement in CD remains elusive. Importantly, it has not been possible to reliably and reproducibly demonstrate mycobacteria in the tissue of CD patients. Past attempts to visualise mycobacteria in tissue may have been hampered by the use of stains optimised for Mycobacterium tuberculosis complex (MTB) and the lack of reliable bacteriological culture media for both non-tuberculous mycobacteria (NTM) and cell-wall-deficient mycobacteria (CWDM). Here we describe a Ziehl-Neelsen (ZN) staining method for the demonstration of CWDM in resected tissue from patients with Crohn's disease, revealing the association of CWDM in situ with host tissue reactions, and posit this as a cause of the tissue inflammation. Using the ZN stain described we demonstrated the presence of CWDM in 18 out of 18 excised tissue samples from patients diagnosed as having Crohn's disease, and in zero samples out of 15 non-inflammatory bowel disease controls.
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http://dx.doi.org/10.1016/j.pathol.2021.03.003DOI Listing
June 2021

Muscle stimulation in advanced idiopathic pulmonary fibrosis: a randomised placebo-controlled feasibility study.

BMJ Open 2021 06 2;11(6):e048808. Epub 2021 Jun 2.

Harefield Respiratory Research Group, Royal Brompton and Harefield Clinical Group, Guy's and St Thomas' Hospitals NHS Trust, London, UK.

Objectives: To assess the acceptability of neuromuscular electrical stimulation (NMES) of the quadriceps muscles in people with idiopathic pulmonary fibrosis (IPF) and to identify whether a future definitive trial is feasible.

Design: A randomised, parallel, two-group, participant and assessor-blinded, placebo-controlled feasibility trial with embedded qualitative interviews.

Setting: Outpatient department, Royal Brompton and Harefield Hospitals.

Participants: Twenty-two people with IPF: median (25th, 75th centiles) age 76 (74, 82) years, forced vital capacity 62 (50, 75) % predicted, 6 min walk test distance 289 (149, 360) m.

Interventions: Usual care (home-based exercise, weekly telephone support, breathlessness management leaflet) with either placebo or active NMES for 6 weeks, with follow-up at 6 and 12 weeks.

Primary Outcome Measures: Feasibility of recruitment and retention, treatment uptake and adherence, outcome assessments, participant and outcome assessor blinding and adverse events related to interventions.

Secondary Outcome Measures: Outcome measures with potential to be primary or secondary outcomes in a definitive clinical trial. In addition, purposively sampled participants were interviewed to capture their experiences and acceptability of the trial.

Results: Out of 364 people screened, 23 were recruited: 11 were allocated to each group and one was withdrawn prior to randomisation. Compared with the control group, a greater proportion of the intervention group completed the intervention, remained in the trial blinded to group allocation and experienced intervention-related adverse events. Assessor blinding was maintained. The secondary outcome measures were feasible with most missing data associated with the accelerometer. Small participant numbers precluded identification of an outcome measure suitable for a definitive trial. Qualitative findings demonstrated that trial process and active NMES were acceptable but there were concerns about the credibility of placebo NMES.

Conclusions: Primarily owing to recruitment difficulties, a definitive trial using the current protocol to evaluate NMES in people with IPF is not feasible.

Trial Registration Number: NCT03499275.
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http://dx.doi.org/10.1136/bmjopen-2021-048808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8174518PMC
June 2021

COVID-19 pneumonia and the pulmonary vasculature - a marriage made in hell.

Eur Respir J 2021 Apr 16. Epub 2021 Apr 16.

National Heart and Lung Institute, Imperial College London, London, UK.

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http://dx.doi.org/10.1183/13993003.00811-2021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051183PMC
April 2021

Serum markers of pulmonary epithelial damage in systemic sclerosis-associated interstitial lung disease and disease progression.

Respirology 2021 May 17;26(5):461-468. Epub 2020 Dec 17.

Interstitial Lung Disease Unit, Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.

Background And Objective: The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury.

Methods: Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis.

Results: In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DL decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DL in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage.

Conclusion: Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.
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http://dx.doi.org/10.1111/resp.13988DOI Listing
May 2021

Cardiorenal Tissues Express SARS-CoV-2 Entry Genes and Basigin (BSG/CD147) Increases With Age in Endothelial Cells.

JACC Basic Transl Sci 2020 Nov 9;5(11):1111-1123. Epub 2020 Oct 9.

Cardiorespiratory Interface, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Vascular and cardiovascular inflammation and thrombosis occur in patients with severe coronavirus disease-2019 (COVID-19). Advancing age is the most significant risk factor for severe COVID-19. Using transcriptomic databases, the authors found that: 1) cardiovascular tissues and endothelial cells express putative genes for severe acute respiratory syndrome coronavirus-2 infection, including angiotensin-converting enzyme 2 () and basigin (); 2) severe acute respiratory syndrome coronavirus-2 receptor pathways /transmembrane serine protease 2 and /peptidylprolyl isomerase B(A) polarize to lung/epithelium and vessel/endothelium, respectively; 3) expression of host genes is relatively stable with age; and 4) notable exceptions are , which decreases with age in some tissues, and , which increases with age in endothelial cells, suggesting that expression in the vasculature may explain the heightened risk for severe disease with age.
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http://dx.doi.org/10.1016/j.jacbts.2020.09.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546186PMC
November 2020

Outcome of Hospitalization for COVID-19 in Patients with Interstitial Lung Disease. An International Multicenter Study.

Am J Respir Crit Care Med 2020 12;202(12):1656-1665

Oxford Interstitial Lung Disease Service, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.

The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non-idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17-2.18;  = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of <80% had an increased risk of death versus patients with FVC ≥80% (HR, 1.72; 1.05-2.83). Furthermore, obese patients with ILD had an elevated risk of death (HR, 2.27; 1.39-3.71). Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.
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http://dx.doi.org/10.1164/rccm.202007-2794OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737581PMC
December 2020

Progressive fibrosing interstitial lung disease: clinical uncertainties, consensus recommendations, and research priorities.

Lancet Respir Med 2020 09;8(9):925-934

Department of Pneumology, Ruhrlandklinik, University Hospital, University of Duisburg-Essen, Essen, Germany.

Within the spectrum of fibrosing interstitial lung diseases (ILDs) is a subset of patients who have inexorable progression of pulmonary fibrosis despite treatment, which is known as the progressive fibrotic phenotype. Although the concept of progressive fibrosing ILD has been applied largely to patients with idiopathic pulmonary fibrosis (IPF), there is now an increasing focus on irreversible progressive fibrosis in a proportion of patients with a range of underlying ILD diagnoses. Evidence has emerged to support a possible role for antifibrotic therapy in these patients. In this Position Paper, we discuss the importance of retaining diagnostic scrutiny within the multidisciplinary team and suggest a multidomain definition for progressive fibrosis. We consider the potential role of antifibrotic drugs as second-line therapy in the treatment algorithm for patients with progressive non-IPF ILD. We highlight risk factors that might predispose individuals to developing progressive fibrosis. Finally, we discuss key uncertainties and future directions for research and clinical practice.
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http://dx.doi.org/10.1016/S2213-2600(20)30355-6DOI Listing
September 2020

Respiratory follow-up of patients with COVID-19 pneumonia.

Thorax 2020 11 24;75(11):1009-1016. Epub 2020 Aug 24.

Aintree University Hospitals NHS Foundation Trust, Liverpool, UK

The COVID-19 pandemic has led to an unprecedented surge in hospitalised patients with viral pneumonia. The most severely affected patients are older men, individuals of black and Asian minority ethnicity and those with comorbidities. COVID-19 is also associated with an increased risk of hypercoagulability and venous thromboembolism. The overwhelming majority of patients admitted to hospital have respiratory failure and while most are managed on general wards, a sizeable proportion require intensive care support. The long-term complications of COVID-19 pneumonia are starting to emerge but data from previous coronavirus outbreaks such as severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) suggest that some patients will experience long-term respiratory complications of the infection. With the pattern of thoracic imaging abnormalities and growing clinical experience, it is envisaged that interstitial lung disease and pulmonary vascular disease are likely to be the most important respiratory complications. There is a need for a unified pathway for the respiratory follow-up of patients with COVID-19 balancing the delivery of high-quality clinical care with stretched National Health Service (NHS) resources. In this guidance document, we provide a suggested structure for the respiratory follow-up of patients with clinicoradiological confirmation of COVID-19 pneumonia. We define two separate algorithms integrating disease severity, likelihood of long-term respiratory complications and functional capacity on discharge. To mitigate NHS pressures, virtual solutions have been embedded within the pathway as has safety netting of patients whose clinical trajectory deviates from the pathway. For all patients, we suggest a holistic package of care to address breathlessness, anxiety, oxygen requirement, palliative care and rehabilitation.
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http://dx.doi.org/10.1136/thoraxjnl-2020-215314DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447111PMC
November 2020

The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis.

Am J Respir Crit Care Med 2021 02;203(3):339-347

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP. To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects. We prospectively recruited individuals with a CHP diagnosis ( = 110), individuals with an IPF diagnosis ( = 45), and control subjects ( = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways. Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included , , , and . However, in IPF, dominated, whereas the percentage of reads assigned to in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the burden was increased in CHP, and and burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP. The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
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http://dx.doi.org/10.1164/rccm.202002-0460OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874329PMC
February 2021

Interaction between the promoter polymorphism and mucin expression: is there a difference according to ILD subtype?

Thorax 2020 10 24;75(10):901-903. Epub 2020 Jun 24.

Interstitial Lung Disease Unit, Royal Brompton and Harefield NHS Foundation Trust/ National Heart and Lung Institute, Imperial College, London, UK.

The promoter variant rs35705950 is associated with idiopathic pulmonary fibrosis (IPF). MUC5B glycoprotein is overexpressed in IPF lungs. We examined immunohistochemical expression of MUC5B in different interstitial lung disease patterns according to rs35705950 T-allele carriage. We observed increased expression of MUC5B in T-allele carriers in both distal airways and honeycomb cysts in patients with IPF (n=23), but no difference in MUC5B expression according to T-carrier status in the distal airways of patients with idiopathic non-specific interstitial pneumonitis (n=17), in scleroderma-associated non-specific interstitial pneumonitis (n=15) or in control lungs (n=20), suggesting that tissue overexpression in rs35705950 T-carriers is specific to IPF.
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http://dx.doi.org/10.1136/thoraxjnl-2020-214579DOI Listing
October 2020

Pulmonary fibrosis and COVID-19: the potential role for antifibrotic therapy.

Lancet Respir Med 2020 08 15;8(8):807-815. Epub 2020 May 15.

National Institute for Health Research Biomedical Research Centre, University of Nottingham, Nottingham, UK. Electronic address:

In December, 2019, reports emerged from Wuhan, China, of a severe acute respiratory disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). By the end of April, 2020, over 3 million people had been confirmed infected, with over 1 million in the USA alone, and over 215 000 deaths. The symptoms associated with COVID-19 are diverse, ranging from mild upper respiratory tract symptoms to severe acute respiratory distress syndrome. The major risk factors for severe COVID-19 are shared with idiopathic pulmonary fibrosis (IPF), namely increasing age, male sex, and comorbidities such as hypertension and diabetes. However, the role of antifibrotic therapy in patients with IPF who contract SARS-CoV-2 infection, and the scientific rationale for their continuation or cessation, is poorly defined. Furthermore, several licensed and potential antifibrotic compounds have been assessed in models of acute lung injury and viral pneumonia. Data from previous coronavirus infections such as severe acute respiratory syndrome and Middle East respiratory syndrome, as well as emerging data from the COVID-19 pandemic, suggest there could be substantial fibrotic consequences following SARS-CoV-2 infection. Antifibrotic therapies that are available or in development could have value in preventing severe COVID-19 in patients with IPF, have the potential to treat severe COVID-19 in patients without IPF, and might have a role in preventing fibrosis after SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/S2213-2600(20)30225-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228727PMC
August 2020

Contemporary Concise Review 2019: Interstitial lung disease.

Respirology 2020 Jul 18;25(7):756-763. Epub 2020 Mar 18.

Interstitial Lung Disease Unit, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

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http://dx.doi.org/10.1111/resp.13803DOI Listing
July 2020

Early kinetic profiles of troponin I and T measured by high-sensitivity assays in patients with myocardial infarction.

Clin Chim Acta 2020 Jun 20;505:15-25. Epub 2020 Feb 20.

Christchurch Hospital, Christchurch, New Zealand.

The early concentration kinetic profiles of cardiac troponin in patients with non-ST-elevated myocardial infarction (NSTEMI) measured by high-sensitivity cardiac troponin I (hs-cTnI) and T (hs-cTnT) assays have not been described. In intermediate-to-high-risk of NSTEMI patients we measured serial cTn concentrations on ED arrival, at 1, 2, 3, 6-12, 24 and 48-hours with hs-cTnI and hs-cTnT assays. Log-normal curves were fitted to concentrations from time from symptom onset, and the time to rule-out decision thresholds estimated (hs-cTnI: 2 ng/L and 5 ng/L; hs-cTnT: 5 ng/L). Among 164 patients there were 58 NSTEMI. The hs-cTnI to hs-cTnT ratio increased linearly over the first 6-12 h following symptom onset. The estimated times from symptom onset to the 2 ng/L and 5 ng/L thresholds for hs-cTnI were 1.8 (0.1-3.1) and 1.9 (1.1-3.5) hours, and to the 5 ng/L threshold for hs-cTnT 1.9 (1.1-3.8) hours. The estimated time to exceed 5 ng/L was ≥3 hours in 32.6% (95%CI: 20.0% to 48.1%) cases for hs-cTnI and 33.3% (19.6% to 50.0%) for hs-cTnT. cTnI concentrations increased at a much more rapid rate than cTnT concentrations in patients with NSTEMI. Concentrations of a high proportion of patients took longer than 3 hours from symptom onset to exceed the 5 ng/L rule-out decision threshold.
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http://dx.doi.org/10.1016/j.cca.2020.02.009DOI Listing
June 2020

Dissecting the role of the small airways in idiopathic pulmonary fibrosis.

Authors:
Peter M George

Lancet Respir Med 2020 06 13;8(6):529-531. Epub 2020 Feb 13.

Royal Brompton and Harefield NHS Foundation Trust, London, UK; National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S2213-2600(20)30057-6DOI Listing
June 2020

Defining genetic risk factors for scleroderma-associated interstitial lung disease : IRF5 and STAT4 gene variants are associated with scleroderma while STAT4 is protective against scleroderma-associated interstitial lung disease.

Clin Rheumatol 2020 Apr 8;39(4):1173-1179. Epub 2020 Jan 8.

Interstitial Lung Disease Unit, National Heart and Lung Institute, Imperial College London, Royal Brompton and Harefield NHS Foundation Trust, Sydney Street, London, SW3 6NP, UK.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10-1.54), p = 0.015) and rs10488631 (OR 1.48 (1.14-1.92), p = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18-1.73), p = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24-2.39), p = 0.0098), and rs2004640 (OR 1.39 (1.11-1.75), p = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45-2.38), p = 6.6 × 10). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51-0.85), p = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.
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http://dx.doi.org/10.1007/s10067-019-04922-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142048PMC
April 2020

Defining a pathological role for the vasculature in the development of fibrosis and pulmonary hypertension in interstitial lung disease.

Am J Physiol Lung Cell Mol Physiol 2019 10 21;317(4):L431-L433. Epub 2019 Aug 21.

Department of Cardiothoracic Pharmacology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

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http://dx.doi.org/10.1152/ajplung.00330.2019DOI Listing
October 2019

King's Brief Interstitial Lung Disease questionnaire: responsiveness and minimum clinically important difference.

Eur Respir J 2019 09 5;54(3). Epub 2019 Sep 5.

Harefield Pulmonary Rehabilitation and Muscle Research Laboratory, Royal Brompton and Harefield NHS Foundation Trust, Harefield, UK.

Health status is increasingly used in clinical practice to quantify symptom burden and as a clinical trial end-point in patients with interstitial lung disease (ILD). The King's Brief Interstitial Lung Disease (KBILD) questionnaire is a brief, validated 15-item, disease-specific, health-related quality of life questionnaire that is increasingly used in clinical trials, but little data exist regarding the minimum clinically important difference (MCID). Using pulmonary rehabilitation as a model, we aimed to determine the responsiveness of KBILD and provide estimates of the MCID.KBILD scores, Chronic Respiratory Questionnaire (CRQ) scores, Medical Research Council (MRC) Dyspnoea score and incremental shuttle walk test (ISWT) distance were measured in 209 patients with ILD (105 with idiopathic pulmonary fibrosis (IPF)) before and after an outpatient pulmonary rehabilitation programme. Changes with intervention and Cohen's effect size were calculated. Anchor-based (linear regression and receiver operating characteristic plots) or distribution-based approaches (0.5 sd and standard error of measurement) were used to estimate the MCID of KBILD domain and total scores.KBILD, CRQ, MRC Dyspnoea and ISWT improved with intervention, and the effect sizes of KBILD domain and total scores ranged from 0.28 to 0.38. Using anchor-based estimates, the MCID estimates for KBILD-Psychological, KBILD-Breathlessness and activities, and KBILD-Total were 5.4, 4.4 and 3.9 points, respectively. Using distribution-based methods, the MCID estimate for KBILD-Chest symptoms was 9.8 points. The MCID estimates for KBILD in IPF patients were similar.In patients with ILD and IPF, KBILD is responsive to intervention with an estimated MCID of 3.9 points for the total score.
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http://dx.doi.org/10.1183/13993003.00281-2019DOI Listing
September 2019

Comparative aspects of the care of familial hypercholesterolemia in the "Ten Countries Study".

J Clin Lipidol 2019 Mar - Apr;13(2):287-300. Epub 2019 Jan 25.

School of Medicine, Faculty of Health and Medical Sciences, University of Western Australia, Perth, Western Australia, Australia; Department of Cardiology, Lipid Disorders Clinic, Cardiometabolic Services, Royal Perth Hospital, Perth, Western Australia, Australia. Electronic address:

Background: There is a lack of information on the health care of familial hypercholesterolemia (FH).

Objective: The objective of this study was to compare the health care of FH in countries of the Asia-Pacific region and Southern Hemisphere.

Methods: A series of questionnaires were completed by key opinion leaders from selected specialist centers in 12 countries concerning aspects of the care of FH, including screening, diagnosis, risk assessment, treatment, teaching/training, and research; the United Kingdom (UK) was used as the international benchmark.

Results: The estimated percentage of patients diagnosed with the condition was low (overall <3%) in all countries, compared with ∼15% in the UK. Underdetection of FH was associated with government expenditure on health care (ϰ = 0.667, P < .05). Opportunistic and systematic screening methods, and the Dutch Lipid Clinic Network criteria were most commonly used to detect FH; genetic testing was infrequently used. Noninvasive imaging of coronary calcium and/or carotid plaques was underutilized in risk assessment. Patients with FH were generally not adequately treated, with <30% of patients achieving guideline recommended low-density lipoprotein cholesterol targets on conventional therapies. Treatment gaps included suboptimal availability and use of lipoprotein apheresis and proprotein convertase subtilsin-kexin type 9 inhibitors. A deficit of FH registries, training programs, and publications were identified in less economically developed countries. The demonstration of cost-effectiveness for cascade screening, genetic testing, and specialized treatments were significantly associated with the availability of subsidies from the health care system (ϰ = 0.571-0.800, P < .05).

Conclusion: We identified important gaps across the continuum of care for FH, particularly in less economically developed countries. Wider implementation of primary and pediatric care, telehealth services, patient support groups, education/training programs, research activities, and health technology assessments are needed to improve the care of patients with FH in these countries.
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http://dx.doi.org/10.1016/j.jacl.2019.01.009DOI Listing
April 2020

Lung transplantation for idiopathic pulmonary fibrosis.

Lancet Respir Med 2019 03 6;7(3):271-282. Epub 2019 Feb 6.

Department of Interstitial Lung Disease, Royal Papworth Hospital NHS Foundation Trust, Cambridge, UK; Department of Medicine, University of Cambridge, Cambridge, UK.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with a poor prognosis. Lung transplantation is the only intervention shown to increase life expectancy for patients with IPF, but it is associated with disease-specific challenges. In this Review, we discuss the importance of a proactive approach to the management of IPF comorbidities, including gastro-oesophageal reflux, pulmonary hypertension, coronary artery disease, and malignancy. With a donor pool too small to meet demand and unacceptably high mortality on transplant waiting lists, we discuss different systems used internationally to facilitate organ allocation. We explore the rapidly evolving landscape of transplantation for patients with IPF with regards to antifibrotic therapy, technological advances in extracorporeal life support, advances in understanding of the genetics of the disease, and the importance of a holistic multidisciplinary approach to care. Finally, we consider potential advances over the next decade that are envisaged to improve transplantation outcomes in patients with advanced IPF.
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http://dx.doi.org/10.1016/S2213-2600(18)30502-2DOI Listing
March 2019

Gait speed and prognosis in patients with idiopathic pulmonary fibrosis: a prospective cohort study.

Eur Respir J 2019 02 7;53(2). Epub 2019 Feb 7.

Harefield Pulmonary Rehabilitation and Muscle Research Laboratory, Royal Brompton and Harefield NHS Foundation Trust, London, UK.

The 4-m gait speed (4MGS), a simple physical performance measure and surrogate marker of frailty, consistently predicts adverse prognosis in older adults. We hypothesised that 4MGS could predict all-cause mortality and nonelective hospitalisation in patients with idiopathic pulmonary fibrosis (IPF).4MGS and lung function were measured at baseline in 130 outpatients newly diagnosed with IPF. Survival status and nonelective hospital admissions were recorded over 1 year. We assessed the predictive value of 4MGS (as a continuous variable and as a binary variable: slow preserved 4MGS) by calculating hazard ratios using Cox proportional regression, adjusting for potential confounding variables. Receiver operating characteristic curves assessed discrimination between the multivariable regression models and established prognostic indices.Continuous 4MGS and slow 4MGS were independent predictors of all-cause mortality (4MGS: HR 0.03, 95% CI 0.01-0.31; p=0.004; slow 4MGS: 2.63, 95% CI 1.01-6.87; p=0.049) and hospitalisation (4MGS: HR 0.02, 95% CI 0.01-0.14; p<0.001; slow 4MGS: 2.76, 95% CI 1.16-6.58; p=0.02). Multivariable models incorporating 4MGS or slow 4MGS had better discrimination for predicting mortality than either the gender, age and lung physiology index or Composite Physiologic Index.In patients with IPF, 4MGS is an independent predictor of all-cause mortality and nonelective hospitalisation.
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http://dx.doi.org/10.1183/13993003.01186-2018DOI Listing
February 2019

Validity of a Novel Point-of-Care Troponin Assay for Single-Test Rule-Out of Acute Myocardial Infarction.

JAMA Cardiol 2018 11;3(11):1108-1112

Christchurch Hospital, Christchurch, New Zealand.

Importance: Emergency department (ED) investigations of patients with suspected acute myocardial infarction (AMI) are time consuming, partly because of the turnaround time of laboratory tests. Current point-of-care troponin assays shorten test turnaround times but lack precision at lower concentrations. Development of point-of-care troponin assays with greater analytical precision could reduce the decision-making time in EDs for ruling out AMI.

Objective: To determine the clinical accuracy for AMI of a single troponin concentration measured on arrival to ED with a new-generation, higher precision point-of-care assay with a 15-minute turnaround time.

Design, Setting, And Participants: This observational study occurred at a single urban regional ED. Adults presenting acutely from the community to the ED with symptoms suggestive of AMI were included. Troponin concentrations were measured on ED arrival with both a novel point-of-care assay (i-STAT TnI-Nx; Abbott Point of Care) and a high-sensitivity troponin I assay (Architect hs-cTnI; Abbott Diagnostics).

Main Outcomes And Measures: The primary outcome was type 1 AMI during index presentation. We compared the discrimination ability of the TnI-Nx assay with the hs-cTnI assay using the area under receiver operator characteristic curve (AUC) and sensitivity, negative predictive value, and the proportion of negative test results at thresholds with 100% sensitivity.

Results: Of 354 patients (255 [72.0%] men; mean [SD] age, 62 [12] years), 57 (16.1%) experienced an AMI. Eighty-five patients (24.0%) presented to the ED less than 3 hours after symptom onset. No difference was found between the AUC of the TnI-Nx assay (0.975 [95% CI, 0.958-0.993]) and the hs-cTnI assay (0.970 [95% CI, 0.949 to 0.990]; P = .46). A TnI-Nx assay result of less than 11 ng/L identified 201 patients (56.7%) as low risk, with a sensitivity of 100% (95% CI, 93.7%-100%) and a negative predictive value of 100% (95% CI, 98.2%-100%). In comparison, an hs-cTnI assay result of less than 3 ng/L identified 154 patients (43.5%) as low risk, with a sensitivity of 100% (95% CI, 93.7%-100%) and a negative predictive value of 100% (95% CI, 97.6%-100%).

Conclusions And Relevance: A novel point-of-care troponin assay that can produce a result 15 minutes after blood sampling had comparable discrimination ability to an hs-cTnI assay for ruling out AMI after a single blood test. Use in the ED may facilitate earlier decision making and could expedite the safe discharge of a large proportion of low-risk patients.
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http://dx.doi.org/10.1001/jamacardio.2018.3368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6583693PMC
November 2018

Effect of ambulatory oxygen on quality of life for patients with fibrotic lung disease (AmbOx): a prospective, open-label, mixed-method, crossover randomised controlled trial.

Lancet Respir Med 2018 10 28;6(10):759-770. Epub 2018 Aug 28.

National Heart and Lung Institute, Imperial College, London, UK.

Background: In fibrotic interstitial lung diseases, exertional breathlessness is strongly linked to health-related quality of life (HRQOL). Breathlessness is often associated with oxygen desaturation, but few data about the use of ambulatory oxygen in patients with fibrotic interstitial lung disease are available. We aimed to assess the effects of ambulatory oxygen on HRQOL in patients with interstitial lung disease with isolated exertional hypoxia.

Methods: AmbOx was a prospective, open-label, mixed-method, crossover randomised controlled clinical trial done at three centres for interstitial lung disease in the UK. Eligible patients were aged 18 years or older, had fibrotic interstitial lung disease, were not hypoxic at rest but had a fall in transcutaneous arterial oxygen saturation to 88% or less on a screening visit 6-min walk test (6MWT), and had self-reported stable respiratory symptoms in the previous 2 weeks. Participants were randomly assigned (1:1) to either oxygen treatment or no oxygen treatment for 2 weeks, followed by crossover for another 2 weeks. Randomisation was by a computer-generated sequence of treatments randomly permuted in blocks of constant size (fixed size of ten). The primary outcome, which was assessed by intention to treat, was the change in total score on the King's Brief Interstitial Lung Disease questionnaire (K-BILD) after 2 weeks on oxygen compared with 2 weeks of no treatment. General linear models with treatment sequence as a fixed effect were used for analysis. Patient views were explored through semi-structured topic-guided interviews in a subgroup of participants. This study was registered with ClinicalTrials.gov, number NCT02286063, and is closed to new participants with all follow-up completed.

Findings: Between Sept 10, 2014, and Oct 5, 2016, 84 patients were randomly assigned, 41 randomised to ambulatory oxygen first and 43 to no oxygen. 76 participants completed the trial. Compared with no oxygen, ambulatory oxygen was associated with significant improvements in total K-BILD scores (mean 55·5 [SD 13·8] on oxygen vs 51·8 [13·6] on no oxygen, mean difference adjusted for order of treatment 3·7 [95% CI 1·8 to 5·6]; p<0·0001), and scores in breathlessness and activity (mean difference 8·6 [95% CI 4·7 to 12·5]; p<0·0001) and chest symptoms (7·6 [1·9 to 13·2]; p=0·009) subdomains. However, the effect on the psychological subdomain was not significant (2·4 [-0·6 to 5·5]; p=0·12). The most common adverse events were upper respiratory tract infections (three in the oxygen group and one in the no-treatment group). Five serious adverse events, including two deaths (one in each group) occurred, but none were considered to be related to treatment.

Interpretation: Ambulatory oxygen seemed to be associated with improved HRQOL in patients with interstitial lung disease with isolated exertional hypoxia and could be an effective intervention in this patient group, who have few therapeutic options. However, further studies are needed to confirm this finding.

Funding: UK National Institute for Health Research.
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http://dx.doi.org/10.1016/S2213-2600(18)30289-3DOI Listing
October 2018

Restrictive lung defects: parenchymal, chest wall and neuromuscular.

Thorax 2018 10 7;73(10):989-991. Epub 2018 Jun 7.

Interstitial Lung Disease Unit, Royal Brompton Hospital, London, UK.

Sarcoidosis is a multisystem condition which may affect a number of organs and, within the cardiopulmonary system, most commonly manifests as parenchymal, airway-centred, nodal, vascular or cardiac disease. Pleural involvement is rare, but well described, and often presents as pleural effusions or pleural thickening. Here, we present the first case of active sarcoidosis manifesting as bilateral pleural calcification. We highlight the importance of a nuanced understanding of pulmonary physiology when dissecting coexistent extrathoracic and intrathoracic pulmonary restriction. We demonstrate the value of positron emission tomography scanning for identification of sites of sarcoid activity, in this case the pleura, to ensure tissue confirmation of this rare but functionally important manifestation of disease. Sarcoidosis should be considered within the differential diagnosis for patients with pleural calcification, not explained by more common causes.
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http://dx.doi.org/10.1136/thoraxjnl-2018-211895DOI Listing
October 2018