Publications by authors named "Onn Min Kon"

111 Publications

Pulmonary Innate Lymphoid Cell Responses during Rhinovirus-induced Asthma Exacerbations : A Clinical Trial.

Am J Respir Crit Care Med 2021 Sep 1. Epub 2021 Sep 1.

National Heart & Lung and Wright Felming Institute of Infection & Immunity, Respiratory Medicine, London, United Kingdom of Great Britain and Northern Ireland.

Rationale Type 2 innate lymphoid cells (ILC2s) are significant sources of type 2 cytokines, which are implicated in the pathogenesis of asthma and asthma exacerbations. The role of ILC2s in virus-induced asthma exacerbations is not well-characterized. Objectives To characterize pulmonary ILC responses following experimental rhinovirus challenge in patients with moderate asthma and healthy subjects. Methods Patients with moderate asthma and healthy subjects were inoculated with rhinovirus-16, and underwent bronchoscopy at baseline, day 3 and day 8 post-inoculation. Pulmonary ILC1s and ILC2s were quantified in bronchoalveolar lavage (BAL) using flow cytometry. The ratio of BAL ILC2:ILC1 was assessed to determine their relative contributions to the clinical and immune response to rhinovirus challenge. Measurements and Main Results At baseline, ILC2s were significantly higher in patients with asthma than healthy subjects. At day 8, ILC2s significantly increased from baseline in both groups, which was significantly higher in asthma than in healthy subjects (all comparisons P<0.05). In healthy subjects, ILC1s increased from baseline at day 3 (P=0.001), while in patients with asthma, ILC1s increased from baseline at day 8 (P=0.042). Patients with asthma had significantly higher ILC2:ILC1 ratios at baseline (P=0.024) and day 8 (P=0.005). Increased ILC2:ILC1 ratio in asthma correlated with clinical exacerbation severity and type 2 cytokines in nasal mucosal lining fluid. Conclusions An ILC2-predominant inflammatory profile in asthma was associated with increased severity and duration of rhinovirus infection compared with healthy subjects, supporting the potential role of ILC2s in the pathogenesis of virus-induced asthma exacerbations. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01773590.
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http://dx.doi.org/10.1164/rccm.202010-3754OCDOI Listing
September 2021

Defining the Role of Cellular Immune Signatures in Diagnostic Evaluation of Suspected Tuberculosis.

J Infect Dis 2021 Jul 31. Epub 2021 Jul 31.

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

Background: Diagnosis of paucibacillary tuberculosis (TB) including extrapulmonary TB is a significant challenge, particularly in high-income, low-incidence settings. Measurement of Mycobacterium tuberculosis (Mtb)-specific cellular immune signatures by flow cytometry discriminates active TB from latent TB infection (LTBI) in case-control studies; however, their diagnostic accuracy and clinical utility in routine clinical practice is unknown.

Methods: Using a nested case-control study design within a prospective multicenter cohort of patients presenting with suspected TB in England, we assessed diagnostic accuracy of signatures in 134 patients who tested interferon-gamma release assay (IGRA)-positive and had final diagnoses of TB or non-TB diseases with coincident LTBI. Cellular signatures were measured using flow cytometry.

Results: All signatures performed less well than previously reported. Only signatures incorporating measurement of phenotypic markers on functional Mtb-specific CD4 T cells discriminated active TB from non-TB diseases with LTBI. The signatures measuring HLA-DR+IFNγ + CD4 T cells and CD45RA-CCR7-CD127- IFNγ -IL-2-TNFα + CD4 T cells performed best with 95% positive predictive value (95% confidence interval, 90-97) in the clinically challenging subpopulation of IGRA-positive but acid-fast bacillus (AFB) smear-negative TB suspects.

Conclusions: Two cellular immune signatures could improve and accelerate diagnosis in the challenging group of patients who are IGRA-positive, AFB smear-negative, and have paucibacillary TB.
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http://dx.doi.org/10.1093/infdis/jiab311DOI Listing
July 2021

Innate-like Gene Expression of Lung-resident Memory CD8+ T-cells During Experimental Human Influenza: A Clinical Study.

Am J Respir Crit Care Med 2021 Jul 13. Epub 2021 Jul 13.

Imperial College London, 4615, Department of Infectious Disease, London, United Kingdom of Great Britain and Northern Ireland;

Rationale: Suboptimal vaccine immunogenicity and antigenic mismatch, compounded by poor uptake, means that influenza remains a major global disease. T-cells recognising peptides derived from conserved viral proteins could enhance vaccine-induced cross-strain protection.

Objectives: To investigate the kinetics, phenotypes and function of influenza virus-specific CD8+ resident-memory T-cells (Trm) in the lower airway and infer the molecular pathways associated with their response to infection in vivo.

Methods: Healthy volunteers, aged 18-55, were inoculated intranasally with influenza A(H1N1)2009. Blood, upper and (in a subgroup) lower airway samples were obtained throughout infection. Symptoms were assessed using self-reported diaries and nasal viral load by qPCR. T-cell responses were analysed by three-colour FluoroSpot, flow cytometry with MHC I-peptide tetramers and RNAseq, with candidate markers confirmed using immunohistochemistry of endobronchial biopsies.

Measurements And Main Results: Following challenge, 57% of participants became infected. Pre-existing influenza-specific CD8+ T-cells in blood correlated strongly with reduced viral load, which peaked at day 3. Influenza-specific CD8+ T-cells in BAL were highly enriched and predominantly expressed the Trm markers CD69 and CD103. Comparison between pre-infection CD8+ T-cells in BAL and blood by RNAseq revealed 3928 differentially expressed genes, including all major Trm cell markers. However, gene-set enrichment analysis of BAL CD8+ T-cells showed primarily innate cell-related pathways and, during infection, included upregulation of innate chemokines (Cxcl1, Cxcl10 and Cxcl16) that were also expressed by CD8+ cells in bronchial tissues.

Conclusions: CD8+ Trm cells in the human lung display innate-like gene and protein expression that demonstrates blurred divisions between innate and adaptive immunity. Clinical trial registration available at www.clinicaltrials.gov, ID: NCT02755948.
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http://dx.doi.org/10.1164/rccm.202103-0620OCDOI Listing
July 2021

Respiratory samples to diagnose tuberculosis in the absence of chest x-ray abnormalities.

Respir Med 2021 Aug-Sep;185:106488. Epub 2021 May 29.

Imperial College London, London, UK, Tuberculosis Service.

Background: The World Health Organisation states that the chest x-ray (CXR) has a 'high sensitivity for pulmonary tuberculosis (TB)' [1] and as such, is relied on worldwide as the cornerstone of screening for active pulmonary TB (pTB).

Method: This is a retrospective analysis of plain chest radiographs and microbiological yield in all patients who were diagnosed with pTB or intra-thoracic nodal tuberculosis (ITLN) in two London NHS Trusts.

Results: Between 2011 and 2017 8% of those diagnosed with pTB and 32% with ITLN TB had normal CXR appearances in the 6 weeks preceding diagnosis.

Discussion: Pulmomary TB was diagnosed in an additional 51 people based on CT scan and 43 people based on respiratory samples. ITLN TB was also diagnosed in a further 20 people using CT but only an extra 3 people from standard respiratory sampling. Our data suggests that CT imaging and respiratory samples should be sent on all suspected cases of pTB and ITLN TB even if the CXR is normal.
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http://dx.doi.org/10.1016/j.rmed.2021.106488DOI Listing
May 2021

A conceptual framework to accelerate the clinical impact of evolving research into long COVID.

Lancet Infect Dis 2021 06 22;21(6):756-757. Epub 2021 Apr 22.

NIHR Health Protection Research Unit in Respiratory Infections, National Heart and Lung Institute, Imperial College, London W2 1NY, UK. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(21)00136-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8062085PMC
June 2021

Multi-arm Trial of Inflammatory Signal Inhibitors (MATIS) for hospitalised patients with mild or moderate COVID-19 pneumonia: a structured summary of a study protocol for a randomised controlled trial.

Trials 2021 Apr 12;22(1):270. Epub 2021 Apr 12.

Imperial College, London and Imperial NHS Trust, London, UK.

Objectives: The primary objective of MATIS is to determine the efficacy of ruxolitinib (RUX) or fostamatinib (FOS) compared to standard of care (SOC) with respect to reducing the proportion of hospitalised patients progressing from mild or moderate to severe COVID-19 pneumonia. Secondary objectives, at 14 and 28 days, are to: Determine the efficacy of RUX or FOS to reduce mortality Determine the efficacy of RUX or FOS to reduce the need for invasive ventilation or ECMO Determine the efficacy of RUX or FOS to reduce the need for non-invasive ventilation Determine the efficacy of RUX or FOS to reduce the proportion of participants suffering significant oxygen desaturation Determine the efficacy of RUX or FOS to reduce the need for renal replacement therapy Determine the efficacy of RUX and FOS to reduce the incidence of venous thromboembolism Determine the efficacy of RUX and FOS to reduce the severity of COVID-19 pneumonia [graded by a 9-point modified WHO Ordinal Scale* Determine the efficacy of RUX or FOS to reduce systemic inflammation Determine the efficacy of RUX or FOS to the incidence of renal impairment Determine the efficacy of RUX or FOS to reduce duration of hospital stay Evaluate the safety of RUX and FOS for treatment of COVID-19 pneumonia.

Trial Design: A multi-arm, multi-stage (3-arm parallel-group, 2-stage) randomised controlled trial that allocates participants 1:1:1 and tests for superiority in experimental arms versus standard of care.

Participants: Patients will be recruited while inpatients during hospitalisation for COVID-19 in multiple centres throughout the UK including Imperial College Healthcare NHS Trust.

Inclusion: Patients age ≥ 18 years at screening Patients with mild or moderate COVID-19 pneumonia, defined as Grade 3 or 4 severity by the WHO COVID-19 Ordinal Scale Patients meeting criteria: Hospitalization AND SARS-CoV2 infection (clinically suspected or laboratory confirmed) AND Radiological change consistent with COVID-19 disease CRP ≥ 30mg/L at any time point Informed consent from patient or personal or professional representative Agreement to abstain from sexual intercourse or use contraception that is >99% effective for all participants of childbearing potential for 42 days after the last dose of study drug. For male participants, agreement to abstain from sperm donation for 42 days after the last dose of study drug.

Exclusion: Requiring either invasive or non-invasive ventilation including CPAP or high flow nasal oxygen at any point after hospital admission but before baseline, not related to a pre-existing condition (e.g., obstructive sleep apnoea) Grade ≥ 5 severity on the modified WHO COVID-19 Ordinal Scale, i.e. SpO < 90% on ≥ 60% inspired oxygen by facemask at baseline; non-invasive ventilation; or invasive mechanical ventilation In the opinion of the investigator, progression to death is inevitable within the next 24 hours, irrespective of the provision of therapy Known severe allergic reactions to the investigational agents Child-Pugh B or C grade hepatic dysfunction Use of drugs within the preceding 14 days that are known to interact with any study treatment (FOS or RUX), as listed in the Summary of Product Characteristics Pregnant or breastfeeding Any medical condition or concomitant medication that in the opinion of the investigator would compromise subjects' safety or compliance with study procedures. Any medical condition which in the opinion of the principal investigator would compromise the scientific integrity of the study Non-English speakers will be able to join the study. If participants are unable to understand verbal or written information in English, then hospital translation services will be requested at the participating site for the participant where possible.

Intervention And Comparator: RUXOLITINIB (RUX) (14 days): An oral selective and potent inhibitor of Janus Associated Kinases (JAK1 and JAK2) and cell proliferation (Verstovek, 2010). It is approved for the treatment of disease-related splenomegaly or constitutional symptoms in myelofibrosis, polycythaemia vera and graft-versus-host-disease. RUX will be administered orally 10mg bd Day 1-7 and 5mg bd Day 8-14. FOSTAMATINIB (FOS) (14 days): An oral spleen tyrosine kinase inhibitor approved for the treatment of thrombocytopenia in adult participants with chronic immune thrombocytopenia. FOS will be administered orally 150mg bd Day 1-7 and 100mg bd Day 8-14. Please see protocol for recommended dose modifications where required. COMPARATOR (Standard of Care, SOC): experimental arms will be compared to participants receiving standard of care. It is accepted that SOC may change during a rapidly evolving pandemic. Co-enrolment to other trials and rescue therapy, either pre- or post-randomisation, is permitted and will be accounted for in the statistical analysis.

Main Outcomes: Pairwise comparison (RUX vs SOC and FOS vs SOC) of the proportion of participants diagnosed with severe COVID-19 pneumonia within 14 days. Severe COVID-19 pneumonia is defined by a score ≥ 5 on a modified WHO COVID-19 Ordinal Scale, comprising the following indicators of disease severity: Death OR Requirement for invasive ventilation OR Requirement for non-invasive ventilation including CPAP or high flow oxygen OR O saturation < 90% on ≥60% inspired oxygen RANDOMISATION: Participants will be allocated to interventions using a central web-based randomisation service that generates random sequences using random permuted blocks (1:1:1), with stratification by age (<65 and ≥65 years) and site.

Blinding (masking): No participants or caregivers are blinded to group assignment. Clinical outcomes will be compared blind to group assignment.

Numbers To Be Randomised (sample Size): For an early informal dose examination by the Data Monitoring Committee a minimum of 30 participants will be recruited. For Stage 1 of this multi-arm multi-stage study, 171 participants will be randomised, with 57 participants in each arm. If at least one experimental intervention shows promise, then Stage 2 will recruit a further 95 participants per arm. Sample size calculations are given in the protocol.

Trial Status: Recruitment is ongoing and started 2 October 2020. We anticipate completion of Stage 1 by July 2021 and Stage 2 by April 2022. The current protocol version 2.0 of 11 February 2021 is appended.

Trial Registration: EudraCT: 2020-001750-22 , 9 July 2020 ClinicalTrials.gov: NCT04581954 , 9 October 2020 FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.
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http://dx.doi.org/10.1186/s13063-021-05190-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8039797PMC
April 2021

Symptomatic, biochemical and radiographic recovery in patients with COVID-19.

BMJ Open Respir Res 2021 04;8(1)

Imperial College Healthcare NHS Trust, London, UK.

Background: The symptoms, radiography, biochemistry and healthcare utilisation of patients with COVID-19 following discharge from hospital have not been well described.

Methods: Retrospective analysis of 401 adult patients attending a clinic following an index hospital admission or emergency department attendance with COVID-19. Regression models were used to assess the association between characteristics and persistent abnormal chest radiographs or breathlessness.

Results: 75.1% of patients were symptomatic at a median of 53 days post discharge and 72 days after symptom onset and chest radiographs were abnormal in 47.4%. Symptoms and radiographic abnormalities were similar in PCR-positive and PCR-negative patients. Severity of COVID-19 was significantly associated with persistent radiographic abnormalities and breathlessness. 18.5% of patients had unscheduled healthcare visits in the 30 days post discharge.

Conclusions: Patients with COVID-19 experience persistent symptoms and abnormal blood biomarkers with a gradual resolution of radiological abnormalities over time. These findings can inform patients and clinicians about expected recovery times and plan services for follow-up of patients with COVID-19.
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http://dx.doi.org/10.1136/bmjresp-2021-000908DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029037PMC
April 2021

When to consider tuberculosis: bronchiectasis in the elderly population.

BMJ Case Rep 2021 Mar 4;14(3). Epub 2021 Mar 4.

Respiratory Medicine, Imperial College Healthcare NHS Trust, London, UK.

In England patients aged 65 years and over experience a delay of more than 4 months between onset of symptoms and diagnosis of pulmonary TB. This report examines three cases of patients experiencing significant delays in both diagnosis and treatment. Each case had a background of bronchiectasis. Symptoms were initially believed to be secondary to their pre-existing lung disease. Immunosenescence, atypical presentation and pre-existing lung disease mean there is often a significant delay in diagnosis in this population at both a primary care and specialist level.
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http://dx.doi.org/10.1136/bcr-2020-239735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934723PMC
March 2021

Patterns of myocardial injury in recovered troponin-positive COVID-19 patients assessed by cardiovascular magnetic resonance.

Eur Heart J 2021 05;42(19):1866-1878

Royal Free London NHS Foundation Trust, Pond Street, London NW3 2QG, UK.

Background: Troponin elevation is common in hospitalized COVID-19 patients, but underlying aetiologies are ill-defined. We used multi-parametric cardiovascular magnetic resonance (CMR) to assess myocardial injury in recovered COVID-19 patients.

Methods And Results: One hundred and forty-eight patients (64 ± 12 years, 70% male) with severe COVID-19 infection [all requiring hospital admission, 48 (32%) requiring ventilatory support] and troponin elevation discharged from six hospitals underwent convalescent CMR (including adenosine stress perfusion if indicated) at median 68 days. Left ventricular (LV) function was normal in 89% (ejection fraction 67% ± 11%). Late gadolinium enhancement and/or ischaemia was found in 54% (80/148). This comprised myocarditis-like scar in 26% (39/148), infarction and/or ischaemia in 22% (32/148) and dual pathology in 6% (9/148). Myocarditis-like injury was limited to three or less myocardial segments in 88% (35/40) of cases with no associated LV dysfunction; of these, 30% had active myocarditis. Myocardial infarction was found in 19% (28/148) and inducible ischaemia in 26% (20/76) of those undergoing stress perfusion (including 7 with both infarction and ischaemia). Of patients with ischaemic injury pattern, 66% (27/41) had no past history of coronary disease. There was no evidence of diffuse fibrosis or oedema in the remote myocardium (T1: COVID-19 patients 1033 ± 41 ms vs. matched controls 1028 ± 35 ms; T2: COVID-19 46 ± 3 ms vs. matched controls 47 ± 3 ms).

Conclusions: During convalescence after severe COVID-19 infection with troponin elevation, myocarditis-like injury can be encountered, with limited extent and minimal functional consequence. In a proportion of patients, there is evidence of possible ongoing localized inflammation. A quarter of patients had ischaemic heart disease, of which two-thirds had no previous history. Whether these observed findings represent pre-existing clinically silent disease or de novo COVID-19-related changes remain undetermined. Diffuse oedema or fibrosis was not detected.
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http://dx.doi.org/10.1093/eurheartj/ehab075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7928984PMC
May 2021

Transcriptomic signatures for diagnosing tuberculosis in clinical practice: a prospective, multicentre cohort study.

Lancet Infect Dis 2021 03 25;21(3):366-375. Epub 2021 Jan 25.

Tuberculosis Research Centre, National Heart and Lung Institute, Imperial College London, London, UK. Electronic address:

Background: Blood transcriptomic signatures for diagnosis of tuberculosis have shown promise in case-control studies, but none have been prospectively designed or validated in adults presenting with the full clinical spectrum of suspected tuberculosis, including extrapulmonary tuberculosis and common differential diagnoses that clinically resemble tuberculosis. We aimed to evaluate the diagnostic accuracy of transcriptomic signatures in patients presenting with clinically suspected tuberculosis in routine practice.

Methods: The Validation of New Technologies for Diagnostic Evaluation of Tuberculosis (VANTDET) study was nested within a prospective, multicentre cohort study in secondary care in England (IDEA 11/H0722/8). Patients (aged ≥16 years) suspected of having tuberculosis in the routine clinical inpatient and outpatient setting were recruited at ten National Health Service hospitals in England for IDEA and were included in VANTDET if they provided consent for genomic analysis. Patients had whole blood taken for microarray analysis to measure abundance of transcripts and were followed up for 6-12 months to determine final diagnoses on the basis of predefined diagnostic criteria. The diagnostic accuracy of six signatures derived from the cohort and three previously published transcriptomic signatures with potentially high diagnostic performance were assessed by calculating area under the receiver-operating characteristic curves (AUC-ROCs), sensitivities, and specificities.

Findings: Between Nov 25, 2011, and Dec 31, 2013, 1162 participants were enrolled. 628 participants (aged ≥16 years) were included in the analysis, of whom 212 (34%) had culture-confirmed tuberculosis, 89 (14%) had highly probable tuberculosis, and 327 (52%) had tuberculosis excluded. The novel signature with highest performance for identifying all active tuberculosis gave an AUC-ROC of 0·87 (95% CI 0·81-0·92), sensitivity of 77% (66-87), and specificity of 84% (74-91). The best-performing published signature gave an AUC-ROC of 0·83 (0·80-0·86), sensitivity of 78% (73-83), and specificity of 76% (70-80). For detecting highly probable tuberculosis, the best novel signature yielded results of 0·86 (0·71-0·95), 77% (56-94%), and 77% (57-95%). None of the relevant cohort-derived or previously published signatures achieved the WHO-defined targets of paired sensitivity and specificity for a non-sputum-based diagnostic test.

Interpretation: In a clinically representative cohort in routine practice in a low-incidence setting, transcriptomic signatures did not have adequate accuracy for diagnosis of tuberculosis, including in patients with highly probable tuberculosis where the unmet need is greatest. These findings suggest that transcriptomic signatures have little clinical utility for diagnostic assessment of suspected tuberculosis.

Funding: National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(20)30928-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907671PMC
March 2021

CA 125 and TB.

BMJ Case Rep 2021 Jan 18;14(1). Epub 2021 Jan 18.

Faculty of Medicine, National Heart and Lung Institute, London, UK.

We present two unusual presentations of extrapulmonary tuberculosis (EPTB) and more specifically intra-abdominal tuberculosis (TB). These cases were initially suspicious for ovarian cancer, presenting with non-specific symptoms, ultrasound-confirmed ascites and elevated cancer antigen 125 tumour marker (CA 125). However, in both cases chest imaging demonstrated enlarged mediastinal nodes amenable to endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), which confirmed the diagnosis of TB. Both cases were successfully treated with quadruple TB therapy.
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http://dx.doi.org/10.1136/bcr-2020-238199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7816933PMC
January 2021

Predicting drug-induced liver injury from anti-tuberculous medications by early monitoring of liver tests.

J Infect 2021 02 1;82(2):240-244. Epub 2020 Dec 1.

Department of Infection, Northwick Park Hospital, London North West University Healthcare NHS Trust, London, United Kingdom.

Objective: Tuberculosis Drug Induced Liver Injury (TB-DILI) is a common and potentially severe complication associated with anti-tuberculous treatment (ATT). Optimal liver test monitoring for standard TB medication has not been established. We describe the predictive value of pre-treatment liver tests (LTs) and at 2-weeks after initiation of ATT for the detection of TB-DILI.

Methods: Patients initiating ATT were monitored with routine LTs pre-treatment and after 2-weeks. Logistic regression models were constructed to retrospectively identify pre-treatment variables associated with 'late' TB-DILI (>2 weeks after treatment initiation) and whether pre-treatment and 2-week alanine aminotransferase (ALT) levels could predict late TB-DILI.

Results: 1247 patients with active tuberculosis managed at 5 sites across north west London between January 2015 and December 2018 were monitored with routine LTs. 103 cases (8.3%) of ATT-associated DILI were diagnosed. 60 cases (58.3%) of TB-DILI occurred later than 2-weeks. The risk of late TB-DILI was 2.2-fold greater for every 30 U/L increment in ALT pre-treatment (OR 2.16, 95% CI 1.38-3.29 p<0.001) and 2.1-fold greater for every 30 U/L increment in ALT gradient at 2-weeks (OR 2.06, 95% CI 1.52-2.76 p<0.001).

Conclusion: Routine 2-week LTs capture early TB-DILI and may be valuable in predicting late TB-DILI in patients on ATT.
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http://dx.doi.org/10.1016/j.jinf.2020.09.038DOI Listing
February 2021

Insights into the molecular pathogenesis of ocular tuberculosis.

Tuberculosis (Edinb) 2021 01 12;126:102018. Epub 2020 Nov 12.

Moorfields Eye Hospital, NHS Foundation Trust, London, UK. Electronic address:

Unclear pathogenic mechanisms underlying the ocular tuberculosis (OTB) has resulted in perplexity related to the diagnosis and management of the disease. Developments in experimental research and innovations in molecular diagnostics have recently provided a new understanding of disease pathogenesis and natural history. The current review focuses on the new insights into OTB pathogenesis, derived from in vivo and in vitro studies on Mycobacterium tuberculosis dissemination and localization into the eye, in combination with histopathological studies on chorioretinal tissue and vascular network. Advances in the knowledge of OTB have influenced disease management in the clinical setting and lead to reconsideration of the role of existing treatments and suggesting potential new therapeutic approaches.
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http://dx.doi.org/10.1016/j.tube.2020.102018DOI Listing
January 2021

The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Review of 447 Patients with Tubercular Intermediate Uveitis and Panuveitis.

Ocul Immunol Inflamm 2020 Nov 17:1-11. Epub 2020 Nov 17.

Northwestern University, Feinberg School of Medicine, Department of Ophthalmology, Chicago, Illinois, USA.

Tubercular intermediate uveitis (TIU) and panuveitis (TBP) are difficult to manage because of limitations in diagnostic tools and lack of evidence-based treatment guidelines. The Collaborative Ocular Tuberculosis Study (COTS) analyzed treatment regimens and therapeutic outcomes in patients with TIU and TBP. Multicentre retrospective analysis. A total of 138 TIU and 309 TBP patients were included. A total of 382 subjects received antitubercular therapy (ATT) (n = 382/447; 85.4%) and 382 received corticosteroids (n = 382/447; 85.4%). Treatment failure was observed in 78 individuals (n = 78/447; 17.4%), occurring less frequently in patients receiving ATT (n = 66/382; 17.2%) compared to those who did not (n = 12/65; 18.5%). The study did not show any statistically significant therapeutic effect of ATT in patients with TIU and TBP. Taking into account the limitations of the retrospective, non-randomized study design, resultant reliance on reported data records, and unequal size of the samples, the current study cannot provide conclusive evidence on the therapeutic benefit of ATT in TIU and TBP.
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http://dx.doi.org/10.1080/09273948.2020.1808226DOI Listing
November 2020

Pediatric Endobronchial Ultrasound-Transbronchial Needle Aspiration Under Conscious Sedation for Suspected Tuberculosis in London.

Pediatr Infect Dis J 2020 10;39(10):e329-e331

From the Department of Respiratory, St Mary's Hospital, Imperial College Healthcare NHS Trust.

Tuberculosis (TB) is an important cause of childhood death and morbidity worldwide. The diagnosis in the pediatric population remains challenging due to the paucibacillary nature of the disease. Intrathoracic lymphadenopathy is one of the most common manifestations of primary disease but is often difficult to sample. A retrospective case review was performed of children (younger than 16 years) suspected with intrathoracic TB lymphadenopathy who underwent an endobronchial ultrasound (EBUS)-transbronchial needle aspiration (TBNA) between January 2010 and 2020 in a London TB center. Ten children between 11 years 4 months and 15 years 9 months, with weights ranging from 48 to 95 kg, underwent EBUS-TBNA. All procedures were performed under conscious sedation with no reported complications. Six of 10 cases showed granulomas on rapid onsite histologic evaluation. Nine of 10 cases were confirmed to have Mycobacterium tuberculosis. Seven of 10 cases were culture positive with a mean turn-around time of 13.7 days; of these, 4 of 7 were smear positive. Six of 7 culture positive cases were also TB polymerase chain reaction (PCR) positive. TB PCR identified 2 further cases where microscopy and culture remained negative. One case had multidrug-resistant TB identified on TB PCR allowing early initiation of correct drug therapy. In our cohort, we show EBUS-TBNA is a safe and effective way of investigating intrathoracic TB lymphadenitis in children and a high diagnostic rate can be achieved. In high-resource settings, we should approach childhood TB with a standardized diagnostic approach and utilize EBUS-TBNA as a diagnostic modality. Samples should be sent for culture but also for molecular assays to timely identify TB and drug-resistant disease.
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http://dx.doi.org/10.1097/INF.0000000000002819DOI Listing
October 2020

Use of Xpert MTB/RIF and Xpert Ultra in extrapulmonary tuberculosis.

Expert Rev Anti Infect Ther 2021 01 24;19(1):65-77. Epub 2020 Sep 24.

Imperial College Healthcare NHS Trust, St Mary's Hospital , London, UK.

Introduction: Tuberculosis (TB) remains a major global health burden. There still remains a large gap between the notified and estimated incident cases. Extrapulmonary (EP) TB represents 15% of all TB cases and the diagnosis is more challenging due to the paucity of the organism. Smear microscopy is often insensitive and culture methods are prolonged. With the introduction of Xpert MTB/RIF and more recently Xpert Ultra, this has changed TB diagnostics by providing a rapid accessible platform to diagnose TB and identify rifampicin resistance within 2 h.

Areas Covered: The diagnostic accuracy and the clinical role of Xpert MTB/RIF and Xpert Ultra in the different forms of EPTB.

Expert Opinion: Whilst significant advances have been made in TB diagnostics, there is still a need to optimize the diagnostic yield of Xpert MTB/RIF and Xpert Ultra in EPTB samples. Research is needed to facilitate standardization and optimal preparation of samples as well as understanding the role of Xpert MTB/RIF and Xpert Ultra in different burden settings. Alongside the current GeneXpert platform, the launch of rapid second-line drug resistance polymerase chain reactions and whole genome sequencing may help tackle the global health burden with a more comprehensive diagnostic approach and appropriate treatment.
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http://dx.doi.org/10.1080/14787210.2020.1810565DOI Listing
January 2021

The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Descriptive Review of Tubercular Uveitis in Paediatric Population.

Ocul Immunol Inflamm 2020 Aug 17:1-7. Epub 2020 Aug 17.

Centre for Ophthalmic Specialised Care, University of Lausanne, Lausanne, Switzerland.

Purpose: To examine disease profile of tubercular uveitis (TBU) in Paediatric population.

Methods: Among 945 patients of the retrospective multinational study by the Collaborative Ocular Tuberculosis Study (COTS)-1, 29 Paediatric patients diagnosed with TBU were analyzed.

Results: Mean age of disease presentation was 12.8 (range 4-18 years), with predominance of males (n = 14/20; 70.0%) and Asian ethnicity (n = 25/29; 86.2%). Posterior uveitis (n = 14/28; 50%) was the most frequent uveitis phenotype, with choroidal involvement occurring in 64.7% (n = 11/17). Incidence of optic disc edema and macular edema was higher in children (n = 8/18; 44.4% and n = 5/18; 27.8%, respectively) than in adults (n = 160/942; 16.9% and n = 135/942; 14.3%, respectively). Comparison of optic disc edema between subgroups showed a significant difference (). All patients received oral corticosteroids, most of them with antitubercular therapy. Treatment failure developed in 4.8% (n = 1/21).

Conclusions: Children have a more severe inflammatory response to the disease, and an intensive anti-inflammatory therapeutic regimen is required to achieve a positive treatment outcome.
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http://dx.doi.org/10.1080/09273948.2020.1781197DOI Listing
August 2020

Increased nasal mucosal interferon and CCL13 response to a TLR7/8 agonist in asthma and allergic rhinitis.

J Allergy Clin Immunol 2021 02 24;147(2):694-703.e12. Epub 2020 Jul 24.

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

Background: Acute respiratory viral infections are a major cause of respiratory morbidity and mortality, especially in patients with preexisting lung diseases such as asthma. Toll-like receptors are critical in the early detection of viruses and in activating innate immunity in the respiratory mucosa, but there is no reliable and convenient method by which respiratory mucosal innate immune responses can be measured.

Objective: We sought to assess in vivo immune responses to an innate stimulus and compare responsiveness between healthy volunteers and volunteers with allergy.

Methods: We administered the Toll-like receptor 7/8 agonist resiquimod (R848; a synthetic analogue of single-stranded RNA) or saline by nasal spray to healthy participants without allergy (n = 12), those with allergic rhinitis (n = 12), or those with allergic rhinitis with asthma (n = 11). Immune mediators in blood and nasal fluid and mucosal gene expression were monitored over time.

Results: R848 was well tolerated and significantly induced IFN-α2a, IFN-γ, proinflammatory cytokines (TNF-α, IL-2, IL-12p70), and chemokines (CXCL10, C-C motif chemokine ligand [CCL]2, CCL3, CCL4, and CCL13) in nasal mucosal fluid, without causing systemic immune activation. Participants with allergic rhinitis or allergic rhinitis with asthma had increased IFN-α2a, CCL3, and CCL13 responses relative to healthy participants; those with asthma had increased induction of IFN-stimulated genes DExD/H-box helicase 58, MX dynamin-like GTPase 1, and IFN-induced protein with tetratricopeptide repeats 3.

Conclusions: Responses to nasal delivery of R848 enables simple assessment of mucosal innate responsiveness, revealing that patients with allergic disorders have an increased nasal mucosal IFN and chemokine response to the viral RNA analogue R848. This highlights that dysregulated innate immune responses of the nasal mucosa in allergic individuals may be important in determining the outcome of viral exposure.
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http://dx.doi.org/10.1016/j.jaci.2020.07.012DOI Listing
February 2021

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 2: Guidelines for Initiating Antitubercular Therapy in Anterior Uveitis, Intermediate Uveitis, Panuveitis, and Retinal Vasculitis.

Ophthalmology 2021 02 27;128(2):277-287. Epub 2020 Jun 27.

Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

Topic: The Collaborative Ocular Tuberculosis Study (COTS), supported by the International Ocular Inflammation Society, International Uveitis Study Group, and Foster Ocular Immunological Society, set up an international, expert-led consensus project to develop evidence- and experience-based guidelines for the management of tubercular uveitis (TBU).

Clinical Relevance: The absence of international agreement on the use of antitubercular therapy (ATT) in patients with TBU contributes to a significant heterogeneity in the approach to the management of this condition.

Methods: Consensus statements for the initiation of ATT in TBU were generated using a 2-step modified Delphi technique. In Delphi step 1, a smart web-based survey based on background evidence from published literature was prepared to collect the opinion of 81 international experts on the use of ATT in different clinical scenarios. The survey included 324 questions related to tubercular anterior uveitis (TAU), tubercular intermediate uveitis (TIU), tubercular panuveitis (TPU), and tubercular retinal vasculitis (TRV) administered by the experts, after which the COTS group met in November 2019 for a systematic and critical discussion of the statements in accordance with the second round of the modified Delphi process.

Results: Forty-four consensus statements on the initiation of ATT in TAU, TIU, TPU, and TRV were obtained, based on ocular phenotypes suggestive of TBU and corroborative evidence of tuberculosis, provided by several combinations of immunologic and radiologic test results. Experts agreed on initiating ATT in recurrent TAU, TIU, TPU, and active TRV depending on the TB endemicity. In the presence of positive results for any 1 of the immunologic tests along with radiologic features suggestive of past evidence of tuberculosis infection. In patients with a first episode of TAU, consensus to initiate ATT was reached only if both immunologic and radiologic test results were positive.

Discussion: The COTS consensus guidelines were generated based on the evidence from published literature, specialists' opinions, and logic construction to address the initiation of ATT in TBU. The guidelines also should inform public policy by adding specific types of TBU to the list of conditions that should be treated as tuberculosis.
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http://dx.doi.org/10.1016/j.ophtha.2020.06.052DOI Listing
February 2021

Visual Morbidity in Ocular Tuberculosis - Collaborative Ocular Tuberculosis Study (COTS)-1: Report #6.

Ocul Immunol Inflamm 2020 Jun 30:1-9. Epub 2020 Jun 30.

Centre for Ophthalmic Specialised Care & University of Lausanne, Lausanne, Switzerland.

Objective: Aim of the study was to examine extent, natural history, and clinical features associated with visual impairment (VI) in patients diagnosed with ocular tuberculosis (OTB) by the Collaborative Ocular Tuberculosis Study (COTS)-1.

Methods: Multi-center retrospective cohort study. Main outcomes were VI.

Results: A total of 302 patients were included in the study, including 175 patients whose data related to BCVA were available throughout the 2 years of follow up. Mean BCVA grossly improved at 12, 18, and 24 months of follow-up ( < .001). Mean BCVA was worse at 12-18th month follow-up for patients treated with ATT versus patients who were not treated with ATT, but patients treated with ATT had a statistically significant improvement in BCVA at the 24-month endpoint.

Conclusions: OTB is associated with significant visual morbidity, future well-designed prospective studies are warranted to establish the causal association between OTB and visual loss.
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http://dx.doi.org/10.1080/09273948.2020.1774905DOI Listing
June 2020

The Collaborative Ocular Tuberculosis Study (COTS)-1: A Multinational Review of 165 Patients with Tubercular Anterior Uveitis.

Ocul Immunol Inflamm 2020 Jun 30:1-10. Epub 2020 Jun 30.

Feinberg School of Medicine, Department of Ophthalmology, Northwestern University, Chicago, Illinois, USA.

Purpose: The Collaborative Ocular Tuberculosis Study (COTS) Group sought to address the diagnostic uncertainty through retrospective cohort analysis of treatment regimens and therapeutic outcomes for patients with tubercular Anterior Uveitis (TAU) across international centers.

Methods: Multicentre retrospective analysis of patients diagnosed with TAU between January 2004 to December 2014 that had a minimum follow-up of 1 year.

Results: One hundred and sixty-five patients were included. One hundred and seven subjects received antitubercular therapy (ATT) (n = 107/165; 64.9%) with all the patients receiving topical steroid therapy. Treatment failure was noted in 17 patients (n = 17/165; 10.3%), more frequently described in patients that received ATT (n = 13/107, 12.2%), than those that did not receive ATT (n = 4/58, 6.9%).

Conclusion: In this retrospective study, addition of ATT did not have any statistically significant impact on outcome in patients with TAU.
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http://dx.doi.org/10.1080/09273948.2020.1761400DOI Listing
June 2020

Twenty-four Month Outcomes in the Collaborative Ocular Tuberculosis Study (COTS)-1: Defining the "Cure" in Ocular Tuberculosis.

Ocul Immunol Inflamm 2020 Jun 26:1-9. Epub 2020 Jun 26.

Department of Ophthalmology, Centre for Ophthalmic Specialised Care & University of Lausanne, Lausanne, Switzerland.

Purpose: To report the clinical findings, anatomical features, and treatment outcomes in subjects with ocular tuberculosis (OTB) at 24 months in the Collaborative Ocular Tuberculosis Study (COTS)-1.

Methods: Of the 945 subjects included in COTS-1, those who completed a 24-month follow-up after completion of treatment were included. The main outcome measure was a number of patients with treatment failure (TF).

Results: 228 subjects (120 males; mean age of 42.82 ± 14.73 years) were included. Most common phenotype of uveitis was posterior ( = 81; 35.53%), and panuveitis ( = 76; 33.33%). Fifty-two patients (22.81%) had TF. On univariable analysis, odds of high TF was observed with bilaterality (OR: 3.46, = .003), vitreous haze (OR: 2.14, = .018), and use of immunosuppressive therapies (OR: 5.45, = .003). However, only bilaterality was significant in the multiple regression model (OR: 2.84; = .02).

Conclusions: Majority of subjects (>75%) achieved cure in the COTS-1 at 24-month follow-up. The concept of "cure" may be a valuable clinical endpoint in trials for OTB.
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http://dx.doi.org/10.1080/09273948.2020.1761401DOI Listing
June 2020

Republished: Rifampicin induced shock during re-exposure for treatment of latent tuberculosis.

Drug Ther Bull 2020 10 20;58(10):157-159. Epub 2020 Jun 20.

Department of Chest and Allergy, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.

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http://dx.doi.org/10.1136/dtb.2020.232117repDOI Listing
October 2020

The Collaborative Ocular Tuberculosis Study (COTS) Consensus (CON) Group Meeting Proceedings.

Ocul Immunol Inflamm 2020 Apr 6:1-11. Epub 2020 Apr 6.

Advanced Eye Centre, Postgraduate Institute of Medical Education and Research (PGIMER), Chandigarh, India.

An international, expert led consensus initiative was set up by the Collaborative Ocular Tuberculosis Study (COTS) group to develop systematic, evidence, and experience-based recommendations for the treatment of ocular TB using a modified Delphi technique process. In the first round of Delphi, the group identified clinical scenarios pertinent to ocular TB based on five clinical phenotypes (anterior uveitis, intermediate uveitis, choroiditis, retinal vasculitis, and panuveitis). Using an interactive online questionnaires, guided by background knowledge from published literature, 486 consensus statements for initiating ATT were generated and deliberated amongst 81 global uveitis experts. The median score of five was considered reaching consensus for initiating ATT. The median score of four was tabled for deliberation through Delphi round 2 in a face-to-face meeting. This report describes the methodology adopted and followed through the consensus process, which help elucidate the guidelines for initiating ATT in patients with choroidal TB.
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http://dx.doi.org/10.1080/09273948.2020.1716025DOI Listing
April 2020

Collaborative Ocular Tuberculosis Study Consensus Guidelines on the Management of Tubercular Uveitis-Report 1: Guidelines for Initiating Antitubercular Therapy in Tubercular Choroiditis.

Ophthalmology 2021 02 11;128(2):266-276. Epub 2020 Jan 11.

Advanced Eye Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Electronic address:

Topic: An international, expert-led consensus initiative organized by the Collaborative Ocular Tuberculosis Study (COTS), along with the International Ocular Inflammation Society and the International Uveitis Study Group, systematically developed evidence- and experience-based recommendations for the treatment of tubercular choroiditis.

Clinical Relevance: The diagnosis and management of tubercular uveitis (TBU) pose a significant challenge. Current guidelines and literature are insufficient to guide physicians regarding the initiation of antitubercular therapy (ATT) in patients with TBU.

Methods: An international expert steering subcommittee of the COTS group identified clinical questions and conducted a systematic review of the published literature on the use of ATT for tubercular choroiditis. Using an interactive online questionnaire, guided by background knowledge from published literature, 81 global experts (including ophthalmologists, pulmonologists, and infectious disease physicians) generated preliminary consensus statements for initiating ATT in tubercular choroiditis, using Oxford levels of medical evidence. In total, 162 statements were identified regarding when to initiate ATT in patients with tubercular serpiginous-like choroiditis, tuberculoma, and tubercular focal or multifocal choroiditis. The COTS group members met in November 2018 to refine these statements by a 2-step modified Delphi process.

Results: Seventy consensus statements addressed the initiation of ATT in the 3 subtypes of tubercular choroiditis, and in addition, 10 consensus statements were developed regarding the use of adjunctive therapy in tubercular choroiditis. Experts agreed on initiating ATT in tubercular choroiditis in the presence of positive results for any 1 of the positive immunologic tests along with radiologic features suggestive of tuberculosis. For tubercular serpiginous-like choroiditis and tuberculoma, positive results from even 1 positive immunologic test were considered sufficient to recommend ATT, even if there were no radiologic features suggestive of tuberculosis.

Discussion: Consensus guidelines were developed to guide the initiation of ATT in patients with tubercular choroiditis, based on the published literature, expert opinion, and practical experience, to bridge the gap between clinical need and available medical evidence.
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http://dx.doi.org/10.1016/j.ophtha.2020.01.008DOI Listing
February 2021

A postgraduate qualification in tuberculosis-Message in a bottle.

Int J Infect Dis 2020 Mar 27;92S:S100-S102. Epub 2020 Feb 27.

Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy. Electronic address:

The TBCert is a distance-learning course, launched in 2019 and hosted by QMUL. The course is open to doctors, nurses, and public health workers who wish to subspecialize in TB. The course was established to elevate TB medicine to a subspecialty. We feel it is imperative to educate health practitioners from different sectors to deliver the most advanced level of care and control activities, standardisze training, reduce clinical variability, and instil best practice. The courses main objectives are to provide a relevant syllabus delivered through high quality teaching from world-class experts using an innovative interactive online platform. The curriculum is based on current internationally accepted (including WHO) guidelines and recommendations. Students are taught with pre-recorded lectures and regular live online webinar discussions delivered by experts in the field. Online discussion groups, one to one teaching-to-one teaching, and mentorship are organiszed to promote a shared as well as a tailored experience that helps students attain the learning outcomes and achieve their expectations.
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http://dx.doi.org/10.1016/j.ijid.2020.02.023DOI Listing
March 2020

Rifampicin induced shock during re-exposure for treatment of latent tuberculosis.

BMJ Case Rep 2020 Feb 2;13(1). Epub 2020 Feb 2.

Department of Chest and Allergy, St Mary's Hospital, Imperial College Healthcare NHS Trust, London, UK.

We present a case of a young Asian female with rheumatoid arthritis who received latent tuberculosis infection (LTBI) treatment prior to treatment with a biologic agent, and developed shock with resistant hypotension on re-exposure to rifampicin. We discuss the epidemiology, pathophysiology and management of rifampicin induced shock, concluding that clinicians should be aware of this rare, but potential adverse effect, and be aware that adverse reactions to rifampicin are more frequent during re-exposure or longer dosing interval regimes. The evidence for desensitisation following such a reaction is lacking and this approach is not currently recommended. We would suggest close collaboration between specialties prescribing immunosuppression and the tuberculosis team when LTBI treatment is required after a reaction, with patient involvement to discuss the risks and benefits of treatment options.
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http://dx.doi.org/10.1136/bcr-2019-232117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7021163PMC
February 2020

Epitope-specific airway-resident CD4+ T cell dynamics during experimental human RSV infection.

J Clin Invest 2020 01;130(1):523-538

Department of Infectious Disease, Imperial College London, London, United Kingdom.

BACKGROUNDRespiratory syncytial virus (RSV) is an important cause of acute pulmonary disease and one of the last remaining major infections of childhood for which there is no vaccine. CD4+ T cells play a key role in antiviral immunity, but they have been little studied in the human lung.METHODSHealthy adult volunteers were inoculated i.n. with RSV A Memphis 37. CD4+ T cells in blood and the lower airway were analyzed by flow cytometry and immunohistochemistry. Bronchial soluble mediators were measured using quantitative PCR and MesoScale Discovery. Epitope mapping was performed by IFN-γ ELISpot screening, confirmed by in vitro MHC binding.RESULTSActivated CD4+ T cell frequencies in bronchoalveolar lavage correlated strongly with local C-X-C motif chemokine 10 levels. Thirty-nine epitopes were identified, predominantly toward the 3' end of the viral genome. Five novel MHC II tetramers were made using an immunodominant EFYQSTCSAVSKGYL (F-EFY) epitope restricted to HLA-DR4, -DR9, and -DR11 (combined allelic frequency: 15% in Europeans) and G-DDF restricted to HLA-DPA1*01:03/DPB1*02:01 and -DPA1*01:03/DPB1*04:01 (allelic frequency: 55%). Tetramer labeling revealed enrichment of resident memory CD4+ T (Trm) cells in the lower airway; these Trm cells displayed progressive differentiation, downregulation of costimulatory molecules, and elevated CXCR3 expression as infection evolved.CONCLUSIONSHuman infection challenge provides a unique opportunity to study the breadth of specificity and dynamics of RSV-specific T-cell responses in the target organ, allowing the precise investigation of Trm recognizing novel viral antigens over time. The new tools that we describe enable precise tracking of RSV-specific CD4+ cells, potentially accelerating the development of effective vaccines.TRIAL REGISTRATIONClinicalTrials.gov NCT02755948.FUNDINGMedical Research Council, Wellcome Trust, National Institute for Health Research.
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http://dx.doi.org/10.1172/JCI131696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934186PMC
January 2020
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