Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases
- Marina Tadolini1,44,
- Luigi Ruffo Codecasa2,44,
- José-María García-García3,
- François-Xavier Blanc4,
- Sergey Borisov5,
- Jan-Willem Alffenaar6,7,8,
- Claire Andréjak9,
- Pierre Bachez10,
- Pierre-Alexandre Bart11,
- Evgeny Belilovski5,
- José Cardoso-Landivar12,
- Rosella Centis13,
- Lia D'Ambrosio14,
- María-Luiza De Souza-Galvão12,
- Angel Dominguez-Castellano15,
- Samir Dourmane16,
- Mathilde Fréchet Jachym17,
- Antoine Froissart18,
- Vania Giacomet19,
- Delia Goletti20,
- Soazic Grard21,
- Gina Gualano22,
- Armine Izadifar23,
- Damien Le Du17,
- Margarita Marín Royo24,
- Jesica Mazza-Stalder25,
- Ilaria Motta26,
- Catherine Wei Min Ong27,28,
- Fabrizio Palmieri22,
- Frédéric Rivière29,
- Teresa Rodrigo3,
- Denise Rossato Silva30,
- Adrián Sánchez-Montalvá31,32,33,
- Matteo Saporiti2,
- Paolo Scarpellini34,
- Frédéric Schlemmer35,
- Antonio Spanevello36,37,
- Elena Sumarokova5,
- Eva Tabernero38,
- Paul Anantharajah Tambyah27,28,
- Simon Tiberi39,40,
- Alessandro Torre41,
- Dina Visca36,37,
- Miguel Zabaleta Murguiondo42,
- Giovanni Sotgiu43 and
- Giovanni Battista Migliori13
- 1Unit of Infectious Diseases, Department of Medical and Surgical Sciences, Alma Mater Studiorum University of Bologna, Bologna, Italy
- 2TB Reference Centre, Villa Marelli Institute, Niguarda Hospital, Milan, Italy
- 3Tuberculosis Research Programme (PII-TB), SEPAR, Barcelona, Spain
- 4Centre Hospitalier Universitaire, Nantes, France
- 5Moscow Research and Clinical Center for TB Control, Moscow, Russian Federation
- 6The University of Sydney, Sydney Pharmacy School, Sydney, New South Wales, Australia
- 7Westmead Hospital, Sydney, Australia
- 8Marie Bashir Institute of Infectious Diseases and Biosecurity, University of Sydney, Sydney, Australia
- 9Service de Pneumologie CHU AMIENS PICARDIE, France AND UR Université de Picardie Jules Verne, Amiens, France
- 10Service de Pneumologie, Clinique Saint Luc, Bouge, Belgium
- 11Department of Internal Medicine, Lausanne University, Lausanne, Switzerland
- 12Servicio Neumología, Vall D'Hebron University Hospital, Barcelona, Spain
- 13Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Tradate, Italy
- 14Public Health Consulting Group, Lugano, Switzerland
- 15Servicio de Enfermedades Infecciosas y Microbiología, Hospital Virgen Macarena, Sevilla, Spain
- 16Service de Pneumologie, Groupe hospitalier sud île de France (GHSIF), Melun, France
- 17Centre Hospitalier de Bligny, Briis Sous Forges, France
- 18Service de Médecine interne, CHI de Créteil, France
- 19Pediatric Infectious Diseases Unit, Department of Biomedical and Clinical Sciences, L. Sacco Hospital, University of Milan, Italy
- 20Translational Research Unit, National Institute for Infectious Diseases ‘L. Spallanzani’, IRCCS, Rome, Italy
- 21Centre de Lutte Antituberculeuse (CLAT 38), Grenoble, France
- 22Respiratory Infectious Diseases Unit, National Institute for Infectious Diseases ‘L. Spallanzani’, IRCCS, Rome, Italy
- 23Hôpital Européen de Paris La Roseraie, Aubervilliers, France
- 24Servicio Neumología, Hospital General Universitario de Castellón, Spain
- 25Pulmonary Division, Lausanne University Hospital CHUV, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
- 26Dipartimento di Scienze Mediche, Clinica Universitaria Malattie Infettive, Ospedale Amedeo di Savoia, Torino, Italia
- 27Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- 28Institute for Health Innovation & Technology (iHealthtech), National University of Singapore, Singapore
- 29Hôpital d'Instruction des Armées (HIA) Percy, Clamart, France
- 30Faculdade de Medicina, Universidade Federal do Rio Grande do Sul - UFRGS - Porto Alegre (RS) Brasil
- 31Infectious Diseases Department, International Health and Tuberculosis Unit, Vall d'Hebron University Hospital, Spain
- 32Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
- 33Grupo de Estudio de Infecciones por Micobacterias (GEIM), Spanish Society of Infectious Diseases (SEIMC), Spain
- 34Unit of Infectious Diseases, Università Vita e Salute, San Raffaele Hospital, Milan, Italy
- 35Hôpitaux Universitaires Henri Mondor, AP-HP, Créteil, France
- 36Division of Pulmonary Rehabilitation, Istituti Clinici Scientifici Maugeri, IRCCS, Tradate, Italy
- 37Department of Medicine and Surgery, Respiratory Diseases, University of Insubria, Tradate, Varese-Como, Italy
- 38Servicio Neumología, Hospital de Cruces, Bilbao, Spain
- 39Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- 40Division of Infection, Royal London Hospital, Barts Health NHS Trust, London, UK
- 41Department of Infectious Diseases, University of Milan, L. Sacco Hospital, Milan, Italy
- 42Servicio Neumología Hospital Universitario Marqués de Valdecilla, Santander, Spain
- 43Clinical Epidemiology and Medical Statistics Unit, Department of Medical, Surgical and Experimental Sciences, University of Sassari, Sassari, Italy
- 44Co-first authors
- Giovanni Battista Migliori, Servizio di Epidemiologia Clinica delle Malattie Respiratorie, Istituti Clinici Scientifici Maugeri IRCCS, Via Roncaccio 16, Tradate, Varese, 21049, Italy. E-mail: giovannibattista.migliori{at}icsmaugeri.it
Dear Editor,
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) pandemic has attracted interest because of its global rapid spread, clinical severity, high mortality rate, and capacity to overwhelm healthcare systems [1, 2]. SARS-CoV-2 transmission occurs mainly through droplets, although surface contamination contributes and debate continues on aerosol transmission [3–5].
The disease is usually characterised by initial signs and symptoms [4–9] similar to those of related viral infections (e.g., influenza, SARS, Middle East Respiratory Syndrome [MERS]) and tuberculosis (TB), although prognosis and complications sometimes differ. Experience with concomitant TB and COVID-19 is extremely limited.
One case-control study of COVID-19 patients with IGRA-confirmed TB infection [10] and a single case of TB with COVID-19 were submitted but not yet published in peer-reviewed journals [11]. In a recent analysis of 1217 consecutive respiratory specimens collected from COVID-19 patients Mycobacterium tuberculosis was not detected [12].
The present study describes the first-ever global cohort of current or former TB patients (post-TB treatment sequelae) with COVID-19, recruited by the Global Tuberculosis Network (GTN) in 8 countries and 3 continents. No analysis for determinants of outcome was attempted.
The study is nested within the GTN project monitoring adverse drug reactions [13, 14] for which the coordinating centre has an ethics committee approval, alongside ethics clearance from participating centres according to the respective national regulation [13, 14]. A specific nested database was created in collaboration with the 8 countries reporting patients with TB and COVID; the remaining countries did not observe COVID-19 yet in their patients at the moment this manuscript was written.
Continuous variables, if not otherwise specified, are presented as medians (IQR-Interquartile ranges).
Overall, 49 consecutive patients with current or former TB and COVID-19 from 26 centres in Belgium (1), Brazil (Porto Alegre, Rio Grande do Sul State; 1), France (12), Italy (17), Russia (Moscow Region; 6), Singapore (1), Spain (10) and Switzerland (Vaud Canton; 1) were recruited (dataset updated as of April 25th, 2020, table 1).
Demographic, epidemiological and clinical characteristics of a cohort of 49^ tuberculosis patients with COVID-19 disease
The first onset of COVID-19 in the cohort was observed in an Italian patient with TB sequelae on March 12th, 2020 (symptoms from March 6th).
Of 49 patients, 26 (53.0%) had TB before COVID-19, 14 (28.5%) had COVID-19 first and 9 (18.3%) had both diseases diagnosed within the same week (4 on the same day).
Forty-two (85.7%) patients had active TB [median age 45.5 (28.0–63.0) years] and 7 (14.3%) had post-TB treatment sequelae [median age: 69.0 (66.0–70.0) years; p-value=0.01]; the patients with TB sequelae (from 5 centres in Italy, Singapore, Spain and Switzerland) were cured 8.2 (2.7–44.3) years earlier.
Overall, 26/49 (53.1%) patients were migrants, 15/48 (31.3%) unemployed, and 2/48 (4.1%) health care workers (medical doctor and radiology technician).
Forty-six (93.9%) patients had confirmed SARS-CoV-2 infection and 3 other patients (6.1%) had chest High Resolution Computerized Tomography (HRCT) highly suggestive of COVID-19 related pneumonia (bilateral ground glass opacities) [15].
Forty-eight patients had pulmonary TB (one caused by Mycobacterium bovis).
Thirty-seven patients had drug-susceptible (or were treated with the standard first-line regimen for new cases) and eight had drug-resistant TB (and were treated with second-line drugs).
Of the 14 non-clustered patients with COVID-19 diagnosis preceding TB, a child of Gambian origin (3 months old) had SARS-CoV-2 identified 3 days before TB diagnosis although TB was probably pre-existing (pulmonary and extra-pulmonary TB, meningitis). The child is continuing anti-TB treatment and has now recovered from COVID-19. Altogether the diagnosis of COVID-19 preceded that of TB by a median (range) time of 4 (2–10) days.
Those 14 patients, managed in 9 centres (in France, Italy, Russia, Spain) were young [median age 33 (26.0–46.0) years]; 11/14 (78.5%) were migrants.
Of the 19 patients undergoing anti-TB treatment, the diagnosis of COVID-19 was made during month 1–2 for 10 (52.6%), month 3–4 for 3 (15.7%), month 4–6 for 3 (15.7%) and after 6 months for 3 (15.7%) patients.
Signs and symptoms attributed to COVID-19 included (in different combinations) fever (32/48, 81.2%), dry cough (27/48, 56.2%) and dyspnoea (17/48, 35.4%).
Radiological information was available for 48/49 (98.0%) patients: 23 (47.9%) presented cavities (table 1).
Twenty-one patients manifested a typical HRCT COVID-19 pattern (bilateral ground glass opacities), whereas 23 had different patterns at HRCT or chest radiography essentially reporting TB-related lesions (e.g., infiltrates, consolidations, cavities, etc.) and 5 were not studied during the course of COVID-19 disease.
Forty- three (87.8%) patients were hospitalised and, provisionally, the overall median (IQR) number of hospital admission days was 15 (8–27). Six patients needed non-invasive ventilation and 14 oxygen supply.
Medication for COVID-19 was reported for 28 patients in all countries except Belgium and Brazil (which had a single case each): 22 (78.6%) received, in different combinations, hydroxychloroquine, 12 (42.9%) received an anti-HIV protease inhibitor (i.e. lopinavir/ritonavir, darunavir/cobicistat), 7 (25.0%) patients received azithromycin, and 1 (3.6%) patient received other drugs (i.e. enoxaparin and N-acetyl-cysteine, NAC). Seventeen (60.8%) patients received a monotherapy (i.e. 11 hydroxychloroquine, 5 lopinavir/ritonavir, and 1 azithromycin), 9 (32.1%) received a combination of two drugs (i.e. 5 hydroxychloroquine and protease inhibitor; 4 hydroxychloroquine plus azithromycin), 2 (7.1%) received ≥3 drugs (i.e. 1 hydroxychloroquine, lopinavir/ritonavir and azithromycin; 1 hydroxychloroquine, lopinavir/ritonavir and azithromycin, enoxaparine and NAC).
The case fatality rate was high (6/49, 12.3%); 5/6 were >60 years old and all of them had ≥1 co-morbidities. Given the small number of deaths, larger studies are necessary.
This preliminary analysis suggests that:
1) In 19/49 (38.8%) patients COVID-19 appeared during anti-TB treatment and limited or no protection against COVID-19 might have favoured SARS-CoV-2 infection (which affected two healthcare workers).
2) The diagnosis of TB and COVID-19 was done simultaneously or within 7 days in 9 patients, posing differential diagnosis challenges, suggesting that clinical assessments to investigate COVID-19 (e.g. clinical picture, HRCT) facilitated the identification of (a probably pre-existing) TB. Any contribution of COVID-19 to TB pathogenesis cannot be excluded or confirmed.
3) Although the diagnosis of COVID-19 preceded that of TB in 14 patients, larger studies are needed to understand any role played by SARS-CoV-2 in the progression of TB infection to disease. Given that up to a quarter of the population in some regions of the work are latently infected, SARS-CoV-2 infection might boost the development of active TB in the coming months [10]. As we do not include individuals with latent TB infection followed-up over time, we cannot report on the potential contribution of COVID-19 towards development of active disease. Probably, an overlap of signs/symptoms of COVID-19 and TB occurred and COVID-19 was diagnosed earlier because of a higher index of suspicion while TB may have been there since before. Or, differently, COVID brought to clinical evaluation/diagnostic assessment TB patients at an earlier stage of disease before the occurrence of TB-related symptoms.
4) In 7 cases COVID-19 occurred in patients with TB sequelae. They were older than patients under anti-TB treatment and presented higher (although not statistically significant) mortality. All but one had co-morbidities (4 Chronic Obstructive Pulmonary Disease; 1 HIV co-infection plus liver and kidney diseases, hypertension and cancer present in different combinations). They presented unilateral or bilateral radiological sequelae of previous infiltrates (4 patients) or cavities (3 patients). Larger numbers are necessary to further understand the role played by TB sequelae.
5) The impact on the healthcare system (e.g., days of admission, intensive care unit beds, etc.) was relevant, and will deserve further evaluation.
6) The information on BCG (Bacillus Calmette-Guérin) vaccination is modest (30 patients with information, 19 previously vaccinated in all 8 countries) and no significant elements can be provided to the ongoing debate on its protective role.
7) We presently have no data on drug-drug interactions.
This is, to our knowledge, the first published cohort of patients with active TB and COVID-19. Our study represents a “snapshot” of a cohort of patients at different stages of disease. No attempt was made to obtain representation of the larger universe of patients with both diseases and the small sample size precludes an analysis of risk factors. We cannot exclude that some findings have a casual origin.
The information available on the patients recently admitted was accurate, but some details on previous TB were incomplete, and some examinations were not performed either because the patients refused or the patients’ condition was too severe. Although case reporting is comprehensive in the countries/regions covered by GTN, the study reflects the initial stages of the COVID-19 epidemic only, and representative longitudinal observations will be necessary to evaluate the interactions between COVID-19 and TB.
We believe that this descriptive research can motivate larger studies to enable analyses of interactions and determinants of outcomes in patients with both diseases. The study will continue to follow-up the patients and accrue more records. We therefore invite interested clinicians and programmes to contact the corresponding author and help improve the understanding of how to optimise care for these patients.
Acknowledgements
The article is part of the scientific activities of the Global Tuberculosis Network (GTN); GREPI (Groupe de Recherche et d'Enseignement en Pneumo-Infectiologie), a working group from SPLF (Société de Pneumologie de Langue Française); SEPAR (Sociedad Española de Neumología and Cirugía Torácica); Moscow Society of Phtisiology and of the WHO Collaborating Centre for Tuberculosis and Lung Diseases, Tradate, ITA-80, 2017-2020- GBM/RC/LDA).
The Authors wish to thank Dr. Enrico Girardi (National Institute for Infectious Diseases, L. Spallanzani, IRCCS, Rome, Italy) for the useful comments on the manuscript.
Footnotes
Conflict of interest: Dr. Tadolini has nothing to disclose.
Conflict of interest: Dr. García-García has nothing to disclose.
Conflict of interest: Dr. Andréjak has nothing to disclose.
Conflict of interest: Dr. Centis has nothing to disclose.
Conflict of interest: Dr. De Souza-Galvão has nothing to disclose.
Conflict of interest: Dr. Fréchet Jachym has nothing to disclose.
Conflict of interest: Dr. Marín Royo has nothing to disclose.
Conflict of interest: Dr. Mazza-Stalder has nothing to disclose.
Conflict of interest: Dr. Rivière has nothing to disclose.
Conflict of interest: Dr. Sánchez-Montalvá has nothing to disclose.
Conflict of interest: Dr. Spanevello has nothing to disclose.
Conflict of interest: Dr. Tambyah has nothing to disclose.
Conflict of interest: Dr. Visca has nothing to disclose.
Conflict of interest: Dr. Sotgiu has nothing to disclose.
Conflict of interest: Dr. Migliori has nothing to disclose.
Conflict of interest: Dr. Alffenaar has nothing to disclose.
Conflict of interest: Dr. Bachez has nothing to disclose.
Conflict of interest: Dr. Bart has nothing to disclose.
Conflict of interest: Dr. Belilovski has nothing to disclose.
Conflict of interest: Dr. Blanc has nothing to disclose.
Conflict of interest: Dr. Borisov has nothing to disclose.
Conflict of interest: Dr. Cardoso Landivar has nothing to disclose.
Conflict of interest: Dr. Codecasa has nothing to disclose.
Conflict of interest: Dr. D'Ambrosio has nothing to disclose.
Conflict of interest: Dr. Dominguez-Castellano has nothing to disclose.
Conflict of interest: Dr. Dourmane has nothing to disclose.
Conflict of interest: Dr. Froissart has nothing to disclose.
Conflict of interest: Dr. Giacomet has nothing to disclose.
Conflict of interest: Dr. Goletti has nothing to disclose.
Conflict of interest: Dr. Grard has nothing to disclose.
Conflict of interest: Dr. Gualano has nothing to disclose.
Conflict of interest: Dr. Izadifar has nothing to disclose.
Conflict of interest: Dr. Le Du has nothing to disclose.
Conflict of interest: Dr. Motta has nothing to disclose.
Conflict of interest: Dr. Ong has nothing to disclose.
Conflict of interest: Dr. Palmieri has nothing to disclose.
Conflict of interest: Dr. Rodrigo has nothing to disclose.
Conflict of interest: Dr. Rossato Silva has nothing to disclose.
Conflict of interest: Dr. Saporiti has nothing to disclose.
Conflict of interest: Dr. Scarpellini has nothing to disclose.
Conflict of interest: Dr. Schlemmer has nothing to disclose.
Conflict of interest: Dr. Sumarokova has nothing to disclose.
Conflict of interest: Dr. Tabernero has nothing to disclose.
Conflict of interest: Dr. Tiberi has nothing to disclose.
Conflict of interest: Dr. Torre has nothing to disclose.
Conflict of interest: Dr. Zabaleta Murguiondo has nothing to disclose.
- Received April 25, 2020.
- Accepted May 10, 2020.
- Copyright ©ERS 2020
This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.