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1. Outcome of hospitalisation for COVID-19 in patients with interstitial lung disease: an international multicentre study

Author

Drake, TM, Docherty, AB, Harrison, EM, Quint, JK, Adamali, H, Agnew, S, Babu, S, Barber, CM, Barratt, S, Bendstrup, E, Bianchi, S, Villegas, DC, Chaudhuri, N, Chua, F, Coker, R, Chang, W, Crawshaw, A, Crowley, LE, Dosanjh, D, Fiddler, CA, Forrest, IA, George, P, Gibbons, MA, Groom, K, Haney, S, Hart, SP, Heiden, E, Henry, M, Ho, L-P, Hoyles, RK, Hutchinson, J, Hurley, K, Jones, M, Jones, S, Kokosi, M, Kreuter, M, MacKay, L, Mahendran, S, Margaritopoulos, G, Molina-Molina, M, Molyneaux, PL, O’Brien, A, O’Reilly, K, Packham, A, Parfrey, H, Poletti, V, Porter, J, Renzoni, E, Rivera-Ortega, P, Russell, A-M, Saini, G, Spencer, LG, Stella, GM, Stone, H, Sturney, S, Thickett, D, Thillai, M, Wallis, T, Ward, K, Wells, AU, West, A, Wickremasinghe, M, Woodhead, F, Hearson, G, Howard, L, Baillie, JK, Openshaw, PJM, Semple, MG, Stewart, I, ISARIC4C Investigators, and Jenkins, RG

Subjects
body regions, respiratory system, behavioral disciplines and activities, respiratory tract diseases
Abstract

Rationale: The impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established. Objectives: To assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population. Methods: An international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to 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 ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and co-morbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of

Published
2020

11. Reconciling Healthcare Professional and Patient Perspectives in the Development of Disease Activity and Response Criteria in Connective Tissue Disease Related Interstitial Lung Diseases

Author

Saketkoo, La, Mittoo, S, Frankel, S, Lesage, D, Sarver, C, Phillips, K, Strand, V, Matteson, El, OMERACT Baughman RP, Brown, Kk, Christmann, Rb, Dellaripa, P, Denton, Cp, Distler, O, Fischer, A, Flaherty, K, Huscher, D, Khanna, D, Kowal Bielecka, O, Merkel, Pa, Oddis, Cv, Pittrow, D, Sandorfi, N, Seibold, Jr, Swigris, J, Wells, A, Antoniou, K, Castelino, Fv, Christopher Stine, L, Collard, Hr, Cottin, V, Danoff, S, Hedlund, R, Highland, Kb, Hummers, L, Lynch, Da, Kim, Ds, Ryu, Jh, Miller, Fw, Nichols, K, Proudman, Sm, Richeldi, L, Shah, Aa, van den Assum, P, Aggarwal, R, Ainslie, G, Alkassab, F, Allanore, Y, Anderson, Me, Andonopoulos, Ap, Antin Ozerkis, D, Arrobas, A, Ascherman, Dp, Assassi, S, Baron, M, Bathon, Jm, Baughman, Rp, Behr, J, Beretta, L, Bingham, Co, Binnie, M, Birring, Ss, Boin, F, Bongartz, T, Bourdin, A, Bouros, D, Brasington, R, Bresser, P, Buch, Mh, Burge, Ps, Carmona, L, Carreira, Pe, Carvalho, Cr, Catoggio, Lj, Chan, Km, Chapman, J, Chatterjee, S, Chua, F, Chung, L, Conron, M, Corte, T, Cosgrove, G, Costabel, U, Cox, G, Crestani, B, Crofford, Lj, Csuka, Me, Curbelo, P, Czirják, L, Daniil, Z, D'Arsigny, Cl, Davis, Gs, de Andrade JA, Dellaripa, Pf, De Vuyst, P, Dempsey, Oj, Derk, Ct, Distler, J, Dixon, Wg, Downey, G, Doyle, Mk, Drent, M, Durairaj, L, Emery, P, Espinoza, Lr, Farge, D, Fathi, M, Fell, Cd, Fessler, Bj, Fitzgerald, Je, Flaherty, Kr, Foeldvari, I, Fox, Ga, Frech, Tm, Freitas, S, Furst, De, Gabrielli, A, García Vicuña, R, Georgiev, Ob, Gerbino, A, Gillisen, A, Gladman, Dd, Glassberg, M, Gochuico, Br, Gogali, A, Goh, Ns, Goldberg, A, Goldberg, Hj, Gourley, Mf, Griffing, L, Grutters, Jc, Gunnarsson, R, Hachulla, E, Hall, Fc, Harari, S, Herrick, Al, Herzog, El, Hesselstrand, R, Highland, K, Hirani, N, Hodgson, U, Hollingsworth, Hm, Homer, Rj, Hoyles, Rk, Hsu, Vm, Hubbard, Rb, Hunzelmann, N, Isasi, Me, Isasi, Es, Jacobsen, S, Jimenez, Sa, Johnson, Sr, Jones, Ch, Kahaleh, B, Kairalla, Ra, Kalluri, M, Kalra, S, Kaner, Rj, Kinder, Bw, Kiter, G, Klingsberg, Rc, Kokosi, M, Kolb, Mr, Kowal Bielecka OM, Kur Zalewska, J, Kuwana, M, Lake, Fr, Lally, Ev, Lasky, Ja, Laurindo, Im, Able, L, Lee, P, Leonard, Ct, Lien, Dc, Limper, Ah, Liossis, Sn, Lohr, Km, Loyd, Je, Lundberg, Ie, Mageto, Yn, Maher, Tm, Mahmud, Th, Manganas, H, Marie, I, Marras, Tk, Martinez, Ja, Martinez, Fj, Mathieu, A, Matucci Cerinic, M, Mayes, Md, Mckown, Km, Medsger, Ta, Meehan, Rt, Mendes, Ac, Meyer, Kc, Millar, Ab, Moğulkoc, N, Molitor, Ja, Morais, A, Mouthon, L, Müller, V, Müller Quernheim, J, Nadashkevich, O, Nador, R, Nash, P, Nathan, Sd, Navarro, C, Neves, S, Noth, I, Nunes, H, Olson, Al, Opitz, Cf, Padilla, M, Pappas, D, Parfrey, H, Pego Reigosa JM, Pereira, Ca, Perez, R, Pope, Je, Porter, Jc, Renzoni, Ea, Riemekasten, G, Riley, Dj, Rischmueller, M, Rodriguez Reyna TS, Rojas Serrano, J, Roman, J, Rosen, Gd, Rossman, M, Rothfield, N, Sahn, Sa, Sanduzzi, A, Scholand, Mb, Selman, M, Senécal, Jl, Seo, P, Shah, A, Silver, Rm, Solomon, Jj, Steen, V, Stevens, W, Strange, C, Sussman, R, Sutton, Ed, Sweiss, Nj, Tornling, G, Tzelepis, Ge, Undurraga, A, Vacca, A, Vancheri, Carlo, Varga, J, Veale, Dj, Volkov, S, Walker, Ua, Wells, Au, Wencel, M, Wesselius, Lj, Wickremasinghe, M, Wilcox, P, Wilsher, Ml, Wollheim, Fa, Wuyts, Wa, Yung, G, Zanon, P, Zappala, Cj, Groshong, Sd, Leslie, Ko, Myers, Jl, Padera, Rf, Desai, Sr, Goldin, J, Kazerooni, Ea, Klein, Js, and Keen, Kj

Subjects
Male, medicine.medical_specialty, Delphi Technique, Consensus Development Conferences as Topic, Health Personnel, Immunology, Context (language use), Disease, Severity of Illness Index, Article, Idiopathic pulmonary fibrosis, Rheumatology, medicine, Immunology and Allergy, Humans, Disease management (health), Intensive care medicine, Connective Tissue Diseases, Randomized Controlled Trials as Topic, business.industry, Interstitial lung disease, Disease Management, respiratory system, Focus Groups, medicine.disease, Comorbidity, Connective tissue disease, respiratory tract diseases, Clinical trial, Treatment Outcome, Patient Satisfaction, Physical therapy, Quality of Life, ÍNDICE DE GRAVIDADE DA DOENÇA, Interdisciplinary Communication, business, Lung Diseases, Interstitial
Abstract

Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF.

Published
2014

12. Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: Provisional core sets of domains and instruments for use in clinical trials

Author

Saketkoo, La, Mittoo, S, Huscher, D, Khanna, D, Dellaripa, Pf, Distler, O, Flaherty, Kr, Frankel, S, Oddis, Cv, Denton, Cp, Fischer, A, Kowal Bielecka OM, Lesage, D, Merkel, Pa, Phillips, K, Pittrow, D, Swigris, J, Antoniou, K, Baughman, Rp, Castelino, Fv, Christmann, Rb, Christopher Stine, L, Collard, Hr, Cottin, V, Danoff, S, Highland, Kb, Hummers, L, Shah, Aa, Kim, Ds, Lynch, Da, Miller, Fw, Proudman, Sm, Richeldi, L, Ryu, Jh, Sandorfi, N, Sarver, C, Wells, Au, Strand, V, Matteson, El, Brown, Kk, Seibold, Jr, Aggarwal, R, Ainslie, G, Alkassab, F, Allanore, Y, Descartes, P, Anderson, Me, Andonopoulos, Ap, Antin Ozerkis, D, Arrobas, A, Ascherman, Dp, Assassi, S, Baron, M, Bathon, Jm, Behr, J, Beretta, L, Bingham, Co, Binnie, M, Birring, Ss, Boin, F, Bongartz, T, Bourdin, A, Bouros, D, Brasington, R, Bresser, P, Buch, Mh, Burge, Ps, Carmona, L, Carreira, Pe, Carvalho, Cr, Catoggio, Lj, Chan, Km, Chapman, J, Chatterjee, S, Chua, F, Chung, L, Conron, M, Corte, T, Cosgrove, G, Costabel, U, Cox, G, Crestani, B, Crofford, Lj, Csuka, Me, Curbelo, P, László, C, Daniil, Z, D'Arsigny, Cl, Davis, Gs, de Andrade JA, De Vuyst, P, Dempsey, Oj, Derk, Ct, Distler, J, Dixon, Wg, Downey, G, Doyle, Mk, Drent, M, Durairaj, L, Emery, P, Espinoza, Lr, Farge, D, Fathi, M, Fell, Cd, Fessler, Bj, Fitzgerald, Je, Fox, Ga, Foeldvari, I, Frech, Tm, Freitas, S, Furst, De, Gabrielli, A, García Vicuña, R, Georgiev, Ob, Gerbino, A, Gillisen, A, Gladman, Dd, Glassberg, M, Gochuico, Br, Gogali, A, Goh, Ns, Goldberg, A, Goldberg, Hj, Gourley, Mf, Griffing, L, Grutters, Jc, Gunnarsson, R, Hachulla, E, Hall, Fc, Harari, S, Herrick, Al, Herzog, El, Hesselstrand, R, Hirani, N, Hodgson, U, Hollingsworth, Hm, Homer, Rj, Hoyles, Rk, Hsu, Vm, Hubbard, Rb, Hunzelmann, N, Isasi, Me, Isasi, Es, Jacobsen, S, Jimenez, Sa, Johnson, Sr, Jones, Ch, Kahaleh, B, Kairalla, Ra, Kalluri, M, Kalra, S, Kaner, Rj, Kinder, Bw, Klingsberg, Rc, Kokosi, M, Kolb, Mr, Kur Zalewska, J, Kuwana, M, Lake, Fr, Lally, Ev, Lasky, Ja, Laurindo, Im, Able, L, Lee, P, Leonard, Ct, Lien, Dc, Limper, Ah, Liossis, Sn, Lohr, Km, Loyd, Je, Lundberg, Ie, Mageto, Yn, Maher, Tm, Mahmud, Th, Manganas, H, Marie, I, Marras, Tk, Antônio Baddini Martinez, J, Martinez, Fj, Mathieu, A, Matucci Cerinic, M, Mayes, Md, Mckown, Km, Medsger, Ta, Meehan, Rt, Cristina, Ma, Meyer, Kc, Millar, Ab, Moğulkoc, N, Molitor, Ja, Morais, A, Luc Mouthon, P, Müller, V, Müller Quernheim, J, Nadashkevich, O, Nador, R, Nash, P, Nathan, Sd, Navarro, C, Neves, S, Noth, I, Nunes, H, Olson, Al, Opitz, Cf, Padilla, M, Pappas, D, Parfrey, H, Pego Reigosa JM, Pereira, Ca, Perez, R, Pope, Je, Porter, Jc, Renzoni, Ea, Riemekasten, G, Riley, Dj, Rischmueller, M, Rodriguez Reyna TS, Rojas, Serrano, Roman, J, Rosen, Gd, Rossman, M, Rothfield, N, Sahn, Sa, Sanduzzi, A, Scholand, Mb, Selman, M, Senécal, Jl, Seo, P, Silver, Rm, Solomon, Jj, Steen, V, Stevens, W, Strange, C, Sussman, R, Sutton, Ed, Sweiss, Nj, Tornling, G, Tzelepis, Ge, Undurraga, A, Vacca, A, Vancheri, Carlo, Varga, J, Veale, Dj, Volkov, S, Walker, Ua, Wencel, M, Wesselius, Lj, Wickremasinghe, M, Wilcox, P, Wilsher, Ml, Wollheim, Fa, Wuyts, Wa, Yung, G, Zanon, P, Zappala, Cj, Groshong, Sd, Leslie, Ko, Myers, Jl, Padera, Rf, Desai, Sr, Goldin, J, Kazerooni, Ea, Klein, Js, Cenac, Sl, Grewal, Hk, Christensen, Am, Ferguson, S, Tran, M, Keen, K. J., Costabel, Ulrich (Beitragende*r), Raynauds & Scleroderma Association, Arthritis Research UK, The Scleroderma Society, and British Lung Foundation

Subjects
Lung Diseases, Connective tissue disease associated lung disease, CTD-ILD Special Interest Group, International Cooperation, Respiratory System, Medizin, Rheumatoid lung disease, Idiopathic pulmonary fibrosis, Quality of life, QUALITY-OF-LIFE, CYCLOPHOSPHAMIDE, SCLERODERMA LUNG, Registries, Connective Tissue Diseases, Societies, Medical, Randomized Controlled Trials as Topic, Interstitial lung disease, respiratory system, Connective tissue disease, Interstitial Fibrosis, medicine.anatomical_structure, Life Sciences & Biomedicine, Pulmonary and Respiratory Medicine, medicine.medical_specialty, Consensus, Clinical Sciences, END-POINT, Interstitial Lung Disease, Systemic disease and lungs, Medical, medicine, Humans, ENSAIO CLÍNICO CONTROLADO RANDOMIZADO, VALIDITY, Intensive care medicine, Lung, Science & Technology, COUGH, business.industry, Clinical study design, MORTALITY, SYSTEMIC-SCLEROSIS, 1103 Clinical Sciences, Congresses as Topic, medicine.disease, GEORGES RESPIRATORY QUESTIONNAIRE, respiratory tract diseases, Clinical trial, IPF, Physical therapy, Interstitial, Societies, business, Lung Diseases, Interstitial
Abstract

Rationale: Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods: The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology-a non-profit international organisation dedicated to consensus methodology in identification of outcome measures-conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results: A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion: Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Published
2014
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13. Interferon-gamma release assay (IGRA) conversion, reversion and implications for the diagnosis of latent tuberculosis infection using a multimodality approach: a retrospective, observational study within a central London TB centre

Author

Almond, M. H., O'Donoghue, M., Drey, N., Seneviratne, S., Lalvani, A., Wickremasinghe, M., and Kon, O. M.

Subjects
bacterial infections and mycoses, RC
Abstract

Introduction and Objectives\ud Accurate diagnosis & management of latent tuberculosis infection (LTBI) among TB contacts is critical for both the health of infected individuals and prevention of disease transmission. Interferon gamma release assays (IGRAs) measure T cell release of interferon-gamma following stimulation by antigens not confounded by the BCG vaccination. The current NICE guidelines recommend their use following a positive TST. In addition some centres have moved to a single step IGRA test for LTBI. Our institution adopts a triple investigation approach comprising a chest radiograph (CXR), TST and IGRA on presentation followed by a rescreen if the TST & IGRA are discordant or if pulmonary contacts are screened prior to 6 weeks. The aim of our study was to evaluate the prevalence of IGRA conversion and reversion in rescreened asymptomatic TB contacts that attended our centre.\ud \ud Methods\ud This was a retrospective, observational study carried out at a central London teaching hospital. The study population comprised 593 consecutive, adult TB contacts screened between 1 January 2008 and 31 December 2010. Data were collected through retrospective review of chest radiographs, TST & IGRA tests.\ud \ud Results\ud Of 498 asymptomatic TB contacts screened, 460 had both an initial TST and IGRA performed (Abstract P13 figure 1). 81 (17.7%) contacts had discordant TST & IGRA results. 52 (64%) of these discordant cases had a positive TST & Negative IGRA; these patients would have been discharged under NICE guidelines however, our rescreen revealed 9 (17%) positive 2nd IGRAs that is, conversion. Three of these patients were under 35 and would therefore by eligible for chemoprophylaxis. Twenty-nine (36%) of the discordant cases had a negative TST and positive IGRA however, 8 (28%) of these IGRAs reverted to negative. It is important to note that if following a single-step IGRA screening protocol (ie, without a rescreen) these cases may have been commenced on chemoprophylaxis unnecessarily (four of these reversion cases were under the age of 35).\ud \ud Conclusions\ud Our results show that adoption of either a sequential TST + ve/IGRA approach or single IGRA approach can result in a significant number of false negative LTBI diagnoses due to IGRA conversion. Conversely, we have also shown that an IGRA rescreen because of discordant TST/IGRA tests can improve LTBI diagnostic specificity and therefore reduce unnecessary chemoprophylaxis due to the effect of reversion.

Published
2011

14. Authors' reply

Author

Wilson, R, Wickremasinghe, M, Ozerovitch, L J, Davies, G, Wodehouse, T, Chadwick, M V, Abdallah, S, and Shah, P

Subjects
Letters to the Editor
Published
2006

25. Authors' reply.

Author

Wilson, R., Wickremasinghe, M., Ozerovitch, L. J., Davies, G., Wodehouse, T., Chadwick, M. V., Abdallah, S., and Shah, P.

Subjects
*LETTERS to the editor, *MYCOBACTERIUM avium
Abstract

A response to a letter to the editor about the article on Mycobacterium avium complex infection is presented.

Published
2006

26. Commentary

Author

Wickremasinghe, M.

Published
1997

27. Proteomic Analysis of Kveim Reagent Identifies Targets of Cellular Immunity in Sarcoidosis.

Author

Eberhardt C, Thillai M, Parker R, Siddiqui N, Potiphar L, Goldin R, Timms JF, Wells AU, Kon OM, Wickremasinghe M, Mitchell D, Weeks ME, and Lalvani A

Subjects
Adult, Electrophoresis, Polyacrylamide Gel, Female, Humans, Male, Middle Aged, Tandem Mass Spectrometry, Immunity, Cellular, Indicators and Reagents chemistry, Proteomics, Sarcoidosis immunology
Abstract

Background: Kveim-reagent (Kv) skin testing was a historical method of diagnosing sarcoidosis. Intradermal injection of treated sarcoidosis spleen tissue resulted in a granuloma response at injection site by 4-6 weeks. Previous work indicates proteins as the possible trigger of this reaction. We aimed to identify Kv-specific proteins and characterise the ex vivo response of Peripheral Blood Mononuclear Cells (PBMCs) from sarcoidosis, tuberculosis and healthy control patients when stimulated with both Kv and selected Kv-specific proteins., Methods: Kv extracts were separated by 1D-SDS-PAGE and 2D-DIGE and then underwent mass spectrometric analysis for protein identification. Sarcoidosis and control PBMCs were first stimulated with Kv and then with three selected recombinant protein candidates which were identified from the proteomic analysis. PBMC secreted cytokines were subsequently measured by Multiplex Cytokine Assay., Results: We observed significantly increased IFN-γ and TNF-α secretion from Kv-stimulated PBMCs of sarcoidosis patients vs. PBMCs from healthy volunteers (IFN-γ: 207.2 pg/mL vs. 3.86 pg/mL, p = 0.0018; TNF-α: 2375 pg/mL vs. 42.82 pg/mL, p = 0.0003). Through proteomic approaches we then identified 74 sarcoidosis tissue-specific proteins. Of these, 3 proteins (vimentin, tubulin and alpha-actinin-4) were identified using both 1D-SDS-PAGE and 2D-DIGE. Data are available via ProteomeXchange with identifier PXD005150. Increased cytokine secretion was subsequently observed with vimentin stimulation of sarcoidosis PBMCs vs. tuberculosis PBMCs (IFN-γ: 396.6 pg/mL vs 0.1 pg/mL, p = 0.0009; TNF-α: 1139 pg/mL vs 0.1 pg/mL, p<0.0001). This finding was also observed in vimentin stimulation of sarcoidosis PBMCs compared to PBMCs from healthy controls (IFN-γ: 396.6 pg/mL vs. 0.1 pg/mL, p = 0.014; TNF-α: 1139 pg/mL vs 42.29 pg/mL, p = 0.027). No difference was found in cytokine secretion between sarcoidosis and control PBMCs when stimulated with either tubulin or alpha-actinin-4., Conclusions: Stimulation with both Kveim reagent and vimentin induces a specific pro-inflammatory cytokine secretion from sarcoidosis PBMCs. Further investigation of cellular immune responses to Kveim-specific proteins may identify novel biomarkers to assist the diagnosis of sarcoidosis., Competing Interests: The authors have declared that no competing interests exist.

Published
2017
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28. Transcriptional blood signatures distinguish pulmonary tuberculosis, pulmonary sarcoidosis, pneumonias and lung cancers.

Author

Bloom CI, Graham CM, Berry MP, Rozakeas F, Redford PS, Wang Y, Xu Z, Wilkinson KA, Wilkinson RJ, Kendrick Y, Devouassoux G, Ferry T, Miyara M, Bouvry D, Valeyre D, Gorochov G, Blankenship D, Saadatian M, Vanhems P, Beynon H, Vancheeswaran R, Wickremasinghe M, Chaussabel D, Banchereau J, Pascual V, Ho LP, Lipman M, and O'Garra A

Subjects
Antitubercular Agents therapeutic use, Biomarkers blood, Case-Control Studies, Glucocorticoids therapeutic use, Humans, Inflammation Mediators blood, Interferons physiology, Lung Neoplasms diagnosis, Neutrophils metabolism, Pneumonia diagnosis, Pneumonia drug therapy, Receptors, Pattern Recognition genetics, Receptors, Pattern Recognition metabolism, Sarcoidosis, Pulmonary diagnosis, Sarcoidosis, Pulmonary drug therapy, Transcription, Genetic, Tuberculosis, Pulmonary diagnosis, Tuberculosis, Pulmonary drug therapy, Lung Neoplasms blood, Pneumonia blood, Sarcoidosis, Pulmonary blood, Transcriptome, Tuberculosis, Pulmonary blood
Abstract

Rationale: New approaches to define factors underlying the immunopathogenesis of pulmonary diseases including sarcoidosis and tuberculosis are needed to develop new treatments and biomarkers. Comparing the blood transcriptional response of tuberculosis to other similar pulmonary diseases will advance knowledge of disease pathways and help distinguish diseases with similar clinical presentations., Objectives: To determine the factors underlying the immunopathogenesis of the granulomatous diseases, sarcoidosis and tuberculosis, by comparing the blood transcriptional responses in these and other pulmonary diseases., Methods: We compared whole blood genome-wide transcriptional profiles in pulmonary sarcoidosis, pulmonary tuberculosis, to community acquired pneumonia and primary lung cancer and healthy controls, before and after treatment, and in purified leucocyte populations., Measurements and Main Results: An Interferon-inducible neutrophil-driven blood transcriptional signature was present in both sarcoidosis and tuberculosis, with a higher abundance and expression in tuberculosis. Heterogeneity of the sarcoidosis signature correlated significantly with disease activity. Transcriptional profiles in pneumonia and lung cancer revealed an over-abundance of inflammatory transcripts. After successful treatment the transcriptional activity in tuberculosis and pneumonia patients was significantly reduced. However the glucocorticoid-responsive sarcoidosis patients showed a significant increase in transcriptional activity. 144-blood transcripts were able to distinguish tuberculosis from other lung diseases and controls., Conclusions: Tuberculosis and sarcoidosis revealed similar blood transcriptional profiles, dominated by interferon-inducible transcripts, while pneumonia and lung cancer showed distinct signatures, dominated by inflammatory genes. There were also significant differences between tuberculosis and sarcoidosis in the degree of their transcriptional activity, the heterogeneity of their profiles and their transcriptional response to treatment.

Published
2013
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29. Sarcoidosis and tuberculosis cytokine profiles: indistinguishable in bronchoalveolar lavage but different in blood.

Author

Thillai M, Eberhardt C, Lewin AM, Potiphar L, Hingley-Wilson S, Sridhar S, Macintyre J, Kon OM, Wickremasinghe M, Wells A, Weeks ME, Mitchell D, and Lalvani A

Subjects
Adolescent, Adult, Aged, Biomarkers blood, Bronchoalveolar Lavage Fluid immunology, Diagnosis, Differential, Female, Humans, Male, Middle Aged, Sarcoidosis, Pulmonary immunology, Tuberculosis, Pulmonary immunology, Young Adult, Bronchoalveolar Lavage Fluid chemistry, Cytokines blood, Sarcoidosis, Pulmonary blood, Sarcoidosis, Pulmonary diagnosis, Tuberculosis, Pulmonary blood, Tuberculosis, Pulmonary diagnosis
Abstract

Background: The clinical, radiological and pathological similarities between sarcoidosis and tuberculosis can make disease differentiation challenging. A complicating factor is that some cases of sarcoidosis may be initiated by mycobacteria. We hypothesised that immunological profiling might provide insight into a possible relationship between the diseases or allow us to distinguish between them., Methods: We analysed bronchoalveolar lavage (BAL) fluid in sarcoidosis (n = 18), tuberculosis (n = 12) and healthy volunteers (n = 16). We further investigated serum samples in the same groups; sarcoidosis (n = 40), tuberculosis (n = 15) and healthy volunteers (n = 40). A cross-sectional analysis of multiple cytokine profiles was performed and data used to discriminate between samples., Results: We found that BAL profiles were indistinguishable between both diseases and significantly different from healthy volunteers. In sera, tuberculosis patients had significantly lower levels of the Th2 cytokine interleukin-4 (IL-4) than those with sarcoidosis (p = 0.004). Additional serum differences allowed us to create a linear regression model for disease differentiation (within-sample accuracy 91%, cross-validation accuracy 73%)., Conclusions: These data warrant replication in independent cohorts to further develop and validate a serum cytokine signature that may be able to distinguish sarcoidosis from tuberculosis. Systemic Th2 cytokine differences between sarcoidosis and tuberculosis may also underly different disease outcomes to similar respiratory stimuli.

Published
2012
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30. Enumeration of functional T-cell subsets by fluorescence-immunospot defines signatures of pathogen burden in tuberculosis.

Author

Casey R, Blumenkrantz D, Millington K, Montamat-Sicotte D, Kon OM, Wickremasinghe M, Bremang S, Magtoto M, Sridhar S, Connell D, and Lalvani A

Subjects
Adolescent, Adult, Aged, Case-Control Studies, Cell Count, Cross-Sectional Studies, Female, Flow Cytometry methods, Humans, Interferon-gamma metabolism, Interleukin-2 metabolism, Male, Middle Aged, Mycobacterium tuberculosis metabolism, Risk Factors, Tuberculosis blood, Microscopy, Fluorescence methods, T-Lymphocytes cytology, Tuberculosis microbiology
Abstract

Background: IFN-γ and IL-2 cytokine-profiles define three functional T-cell subsets which may correlate with pathogen load in chronic intracellular infections. We therefore investigated the feasibility of the immunospot platform to rapidly enumerate T-cell subsets by single-cell IFN-γ/IL-2 cytokine-profiling and establish whether immunospot-based T-cell signatures distinguish different clinical stages of human tuberculosis infection., Methods: We used fluorophore-labelled anti-IFN-γ and anti-IL-2 antibodies with digital overlay of spatially-mapped colour-filtered images to enumerate dual and single cytokine-secreting M. tuberculosis antigen-specific T-cells in tuberculosis patients and in latent tuberculosis infection (LTBI). We validated results against established measures of cytokine-secreting T-cells., Results: Fluorescence-immunospot correlated closely with single-cytokine enzyme-linked-immunospot for IFN-γ-secreting T-cells and IL-2-secreting T-cells and flow-cytometry-based detection of dual IFN-γ/IL-2-secreting T-cells. The untreated tuberculosis signature was dominated by IFN-γ-only-secreting T-cells which shifted consistently in longitudinally-followed patients during treatment to a signature dominated by dual IFN-γ/IL-2-secreting T-cells in treated patients. The LTBI signature differed from active tuberculosis, with higher proportions of IL-2-only and IFN-γ/IL-2-secreting T-cells and lower proportions of IFN-γ-only-secreting T-cells., Conclusions: Fluorescence-immunospot is a quantitative, accurate measure of functional T-cell subsets; identification of cytokine-signatures of pathogen burden, distinct clinical stages of M. tuberculosis infection and long-term immune containment suggests application for treatment monitoring and vaccine evaluation.

Published
2010
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