key: cord-0972331-i91t0r8j
authors: Migliori, Giovanni Battista; Visca, Dina; Boom, Martin van den; Tiberi, Simon; Silva, Denise Rossato; Centis, Rosella; D’Ambrosio, Lia; Thomas, Tania; Pontali, Emanuele; Saderi, Laura; Simon Schaaf, H.; Sotgium, Giovanni
title: Tuberculosis, COVID-19 and hospital admission: consensus on pros and cons based on a review of the evidence
date: 2021-01-28
journal: Pulmonology
DOI: 10.1016/j.pulmoe.2020.12.016
sha: 1cf7f6c23c3a41ab7455ece2cbb4f1b618af11e2
doc_id: 972331
cord_uid: i91t0r8j

The scientific debate on the criteria guiding hospitalization of tuberculosis (TB) and COVID-19 patients is ongoing. The aim of this review is to present the available evidence on admission for TB and TB/COVID-19 patients and discuss the criteria guiding hospitalization. Furthermore, recommendations are made as derived from recently published World Health Organization documents, based on Global Tuberculosis Network (GTN) expert opinion. The core published documents and guidelines on the topic have been reviewed. The proportion of new TB cases admitted to hospital ranges between 50% and 100% while for multidrug-resistant (MDR) TB patients it ranges between 85 and 100% globally. For TB patients with COVID-19 the proportion of cases admitted is 58%, probably reflecting different scenarios related to the diagnosis of COVID-19 before, after or at the same time of the active TB episode. The hospital length of stay for drug-susceptible TB ranges from 20 to 60 days in most of countries, ranging from a mean of 10 days (USA) to around 90 days in the Russian Federation. Hospitalization is longer for MDR-TB (50-180 days). The most frequently stated reasons for recommending hospital admission include: severe TB, infection control concerns, co-morbidities and drug adverse events which cannot be managed at out-patient level. The review also provides suggestions on hospital requirements for safe admissions as well as patient discharge criteria, while underlining the relevance of patient-centred care through community/home-based care.

Tuberculosis (TB) and COVID- 19 show similarities and differences, as recently discussed in the scientific literature [1] [2] [3] [4] [5] [6] [7] .

Both diseases have similar signs and symptoms 6-10 , rendering their differential diagnosis difficult as they may also present concomitantly. They might require hospital admission, although justified by different reasons.

Indications of hospital admission for COVID-19 patients have been changing during the evolution of the ongoing pandemic. The occurrence of clinical deterioration 11, 12 with progressive dyspnoea and desaturation requiring medical therapy (e.g., dexamethasone) and non-invasive or invasive ventilatory support represents the most important recommendation for an immediate hospitalization as in other respiratory conditions [12] [13] [14] . Nevertheless, no previously used criteria or scores have been validated for COVID-19 patients to decide in favour of hospitalization or not 15 and new specific criteria are being explored 16 .

Indications of hospital admission for TB patients are more complex, and in different countries can go far beyond the occurrence of a life-threatening condition. Moreover, they evolved over time. At the time of sanatoria and during the pre-antibiotic era 17, 18 admission was used as an 'isolation' intervention to reduce Mycobacterium tuberculosis transmission within the community and as support measure to ensure rest, optimal nutrition and eventually to perform pneumothorax after Carlo Forlanini's discovery in 1907 19 . In addition, in children severe extra-pulmonary TB and social circumstances likely contributed to hospitalization 20 .

Over time, hospital admission was considered ideal to better monitor the initial phase of anti-TB treatment and eventually drug adverse events, and, in some countries, to ensure adequate adherence to the prescribed regimen 21, 22 . Furthermore, in several countries hospital admission is still considered an administrative measure of infection control, as patients cannot be discharged until J o u r n a l P r e -p r o o f they achieve sputum smear and/or culture conversion 21, 22 Although the World Health Organization (WHO) recommends limiting unnecessary hospitalization, this is often complicated by a 'per occupied bed' refund mechanism prevailing in some countries [22] [23] [24] and a sub-optimal Directly Observed Treatment (DOT)/patient's support practices at outpatient settings.

The present review evaluates the available evidence on hospital admission for TB and TB/COVID-19 and discusses the criteria guiding hospitalization.

Finally, recommendations are made following a recently published WHO (Regional Office for Europe) document on how to reduce Mycobacterium tuberculosis transmission in Europe 21, 22 .

A non-systematic search of the scientific literature in English was carried out on PubMed without time restrictions using the following key-words: 'hospital admission' 'COVID-19', 'tuberculosis', 'length of stay', 'ambulatory care', 'prevention', 'infection control', and 'workplace'.

As hospital admission implies programmatic costs, we report available information on this obtained from the literature review.

Data on TB admissions were retrieved from countries of the WHO European Region (WHO workshop: Lessons learned from finance reforms on TB control, Copenhagen, Denmark, April 26 th 2016; unpublished data reporting 2014 data) and from relevant existing cohorts allowing analysis of hospital admission-related information.

They include a secondary analysis of a large GTN cohort (global bedaquiline study) 25 and, for the duration of the hospital stay for TB in patients with COVID-19, from the ongoing global study on TB/COVID-19 26 (interim analysis, November 27 th , 2020, see references for details on the two studies).

WHO definitions of multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB were adopted 27 . Although not approved by WHO (but largely used by clinicians), pre-XDR TB was defined as a form of TB caused by an MDR-TB strain with additional resistance to either a fluoroquinolone or a second line-injectable agent (amikacin, capreomycin or kanamycin) 25, 28 . In 2018 the Netherlands and Portugal reported the lowest proportion of admitted drug-susceptible TB cases (30%), Ireland and Sweden ~50%, Estonia and Hungary 60%, and the remaining countries a proportion higher than 80% (Figure 3 

Although the bedaquiline study was not specifically designed to describe hospital admission (its main focus was the programmatic evaluation of safety and effectiveness of bedaquiline-containing regimens), it included detailed information on this, which is useful to report and discuss. In this study, countries from different settings had different rules/practices on TB patients' admission and discharge. Furthermore, as the study described the early phase of bedaquilne use, a possible bias related to increased hospital admissions due to uncomplete understanding on adverse events severity cannot be excluded. 26 At an interim analysis (preliminary data, unpublished) on the first 381 patients, 222 (58%) were hospitalized for TB (46/222 with final anti-TB treatment outcome and 176/222 still on treatment), 118 (31%) were not hospitalized, and 41 (11%) with unavailable data.

Importantly, 141 (37%) patients were admitted for concomitant TB and COVID-19. More information on hospital admissions will be possible when the global dataset, in its final format, will be analyzed.

The median (IQR) LOS for TB patients with a final treatment outcome was 29 (10.8-36.5) days, lower than that for patients still on treatment (47, 13.5-106.5 days).

Africa A cost analysis performed in South Africa 31 clearly demonstrated that significant savings can be obtained by reducing the LOS of MDR-TB cases. A decentralised model of TB care improves case detection and treatment initiation rates, ensuring treatment outcomes comparable to those seen in centralised specialist centre 32 . Adoption of decentralised treatment in South Africa may reduce the overall costs for the national TB programme by 15-18% 31, 33 .

Hospital admission could be limited to patients facing treatment-related issues (such as lifethreatening conditions, drug adverse events, failure, need to use injectable medicines or other treatment measures not manageable outside the hospital), which might more frequently occur in patients with XDR-than with MDR-TB (although XDR-TB does not per se contraindicate the possibility of home management) 31 . Adequate referral system from primary healthcare to specialised services is needed to maintain a continuum of care.

Children are often admitted to hospital for diagnostic reasons, but long-term admission is mainly because of disease severity, including TB meningitis, TB/HIV co-infection and drug-resistant TB, social circumstances or a combination of disease severity and social circumstances 34 . days for extra-pulmonary TB cases. Sputum smear conversion to negative was considered the key criterion for discharge in 61% of the centres 40 . A switch from hospital-to home-based treatment (limiting hospital admission to severe cases) was recommended based on cost-effectiveness 41 . In the study no information of the patients' drug resistance profile was available.

In a Portuguese sample of 15,296 TB cases (4,415, 28.9% admitted) enrolled between 2008 and 2013, hospital admission did not influence treatment outcomes, with 13.8% unfavourable outcomes among hospitalized patients compared with 7.6% among non-hospitalized ones 42, 43 .

In the Russian Federation, as published in 2007, the LOS was rather longer both before (86 days) and after (90 days) the implementation of the WHO Directly observed treatment, short-course (DOTS) Strategy 44 . This LOS refers to patients with drug-susceptible TB.

In Spain 41% of cases were managed in 2014-2015 as outpatients 45 2) alcoholic liver disease and hepatitis (median, IQR: 23, 14-37.5, days) and 3) adverse drug events (median, IQR: 20, 13-30, days).

1) The proportion of newly diagnosed admitted TB cases ranges between 50% and 100% (47% in Brazil, 57% in USA, 65% in Canada, >80% in the WHO European Region where the proportion of patients hospitalized is higher than in the other settings evaluated;

2) The proportion of MDR-TB admitted patients is ~100% in Europe and 85% in the bedaquiline study;

3) The proportion of TB and COVID-19 admitted patients is around 58% according to the limited evidence available, which included about 80% of drug-susceptible TB patients 26 . Specific recommendations on hospitalization of TB/COVID-19 patients are not yet available. As of today, we need to consider the existing criteria for the most severe prevalent condition. If TB is the most relevant condition, the criteria defined above can be used to guide decisions. COVID-19 hospitalization will be needed when the disease is clinically severe, i.e. in presence of respiratory failure (desaturations, and need for oxygen supplementation or mechanical ventilation) or, in the future, when the patient will meet specific clinical-radiological scores that are under study 12 . Bacteriological conversion per se is not a mandatory criterion for hospital discharge, given that precautions are recommended to educate family members on basic infection control and prevention requirements and to monitor the continuation of treatment at home. Adequate treatment can render patients rapidly non-infectious, although sputum smear positivity can be present for a longer period (dead bacilli) 21, 22 . Nevertheless, transmission can occur if an ineffective regimen is prescribedfor example, when a first-line or sub-optimal regimen is used in MDR-TB patients. Thus, MDR-and XDR-TB regimens need to be guided by rapid drug susceptibility testing 21, 22, 29, 51, 52 .

Typically, patients have already infected their household members prior to diagnosis 21, 22 .

Therefore, contact-tracing of household members and other close contacts is essential to rapidly diagnose and treat them and reduce transmission of Mycobacterium tuberculosis within the community.

In summary, ambulatory treatment of TB (regardless of smear and drug-susceptibility patterns) is possible from the beginning to reduce the risk of hospital transmission and improve treatment adherence. Importantly, outpatient care should be organised following strict infection control and prevention measures.

Existing evidence from WHO guidance and the literature review indicate that a high proportion of TB cases continue to be admitted in hospitals, and for relatively long length of stay. This is particularly evident in Europe.

Among the different reasons behind this finding, existing legislation on infection control (e.g. patients cannot be discharged until bacteriological conversion has been achieved) and funding mechanisms (focus on per bed occupancy) play a role, slowing down the 'reduction of unnecessary hospital admission' recommended by WHO.

A collaboration of all stakeholders involved in TB prevention, diagnosis and treatment is necessary to support the WHO recommendations in order to reduce patient suffering, TB transmission and lower costs within a patient-centred vision. The Authors wish to thank Szabolcs Szigeti and Alexandre Lourenco for providing data on hospital admission in Europe as well as Alberto L. Garcia-Basteiro (Barcelona Institute for Global Health, Barcelona, Spain) and Askar Yedilbayev (WHO Regional Office for Europe, Copenhagen, Denmark) for their useful comments on the manuscript.

None.

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

Celebrating World Tuberculosis Day at the time of COVID-19

New diseases and old threats: lessons from tuberculosis for the COVID-19 response

COVID-19 and tuberculosis-threats and opportunities

Let us not forget the mask in our attempts to stall the spread of COVID-19

Tuberculosis in the time of COVID-19: quality of life and digital innovation

Tuberculosis, COVID-19 and migrants: Preliminary analysis of deaths occurring

World Health Organization. WHO Information Note on Tuberculosis and COVID-19

Tuberculosis and COVID-19 interaction: a review of biological, clinical and public health effects

Active tuberculosis, sequelae and COVID-19 co-infection: first cohort of 49 cases

Clinical characteristics of COVID-19 and active tuberculosis co-infection in an Italian reference hospital

Epidemic and pandemic viral infections: impact on tuberculosis and the lung. A consensus by the World Association for Infectious Diseases and Immunological Disorders (WAidid), Global Tuberculosis Network (GTN) and members of ESCMID Study Group for Mycobacterial Infections (ESGMYC)

Coronavirus Disease-19: An Interim Evidence Synthesis of the World Association for Infectious Diseases and Immunological Disorders (Waidid)

COVID-19 pandemic and non invasive respiratory management: Every Goliath needs a David. An evidence based evaluation of problems

Non-invasive mechanical ventilation in patients with diffuse interstitial lung diseases

Utility of established prognostic scores in COVID-19 hospital admissions: multicentre prospective evaluation of CURB-65, NEWS2 and qSOFA

The challenge of deciding between home-discharge versus hospitalization in COVID-19 patients: The role of initial imaging and clinicolaboratory data

Tuberculosis sanatorium treatment at the advent of the chemotherapy era

Extensively drug-resistant tuberculosis: back to the future

A Physical Cure for Tuberculosis: Carlo Forlanini and the Invention of Therapeutic Pneumothorax

Tuberculosis: A biosocial study of admissions to a children's sanatorium (1936-1954

Guiding principles to reduce tuberculosis transmission in the WHO European region. Copenhagen, World Health Organization Regional Office For Europe

Reducing tuberculosis transmission: a consensus document from the World Health Organization Regional Office for Europe

Key role of tuberculosis services funding mechanisms in tuberculosis control and elimination

Factors associated with length of hospital stay among HIV positive and HIV negative patients with tuberculosis in Brazil

Effectiveness and safety of bedaquiline-containing regimens in the treatment of MDR-and XDR-TB: a multicentre study

The TB/COVID-19 Global Study Group. TB and COVID-19 co-infection: rationale and aims of a global Study

Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO

Surveillance of adverse events in the treatment of drug-resistant tuberculosis: first global report

Wejse C and members of the Global Tuberculosis Network. MDR/XDR-TB management of patients and contacts: Challenges facing the . The 2020 clinical update by the Global Tuberculosis Network

92S: S15-S25

European Centre for Disease Prevention and Control/WHO Regional Office for Europe. Tuberculosis surveillance and monitoring in Europe 2020 -2018 data

Impact of reduced hospitalisation on the cost of treatment for drug-resistant tuberculosis in South Africa

Community-based treatment of drug-resistant tuberculosis in Khayelitsha, South Africa

What is the cost of diagnosis and management of drug resistant tuberculosis in South Africa?

Clinical features and outcome in children admitted to a tuberculosis hospital in the Western Cape Province: the influence of HIV infection and drug resistance

Costeffectiveness of home-based versus in-hospital treatment of paediatric tuberculous meningitis

Trends in Duration of Hospitalization for Patients with Tuberculosis in Montreal, Canada from 1993 to

Predictors of hospitalization of tuberculosis patients in Montreal, Canada: a retrospective cohort study

Burden of Active Tuberculosis in an Integrated Health Care System, 1997-2016: Incidence, Mortality, and Excess Health Care Utilization

Hospitalization rates, length of stay and in-hospital mortality in a cohort of HIV infected patients from Rio de Janeiro, Brazil

Hospital admission policy for tuberculosis in pulmonary centres in Italy: a national survey. AIPO Tuberculosis Study Group. Italian Association of Hospital Pulmonologists

Cost-comparison of different management policies for tuberculosis patients in Italy

Does hospitalization influence tuberculosis' treatment outcome? -A Portuguese nationwide study

To be or not to be hospitalised with tuberculosis in Portugal

Reform of tuberculosis control and DOTS within Russian public health systems: an ecological study

Grupo de Trabajo del Programa Integrado de Investigación en Tuberculosis (PII TB)

Length of hospital stay for TB varies with comorbidity and hospital location

COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study

World Health Organization Regional Office for Europe. A people-centred model of TB care. Blueprint for EECA countries, first edition. Copenhagen, World Health Organization Regional Office for Europe

Risk factors for early mortality in patients with pulmonary tuberculosis admitted to the emergency room

Medical masks and Respirators for the Protection of Healthcare Workers from SARS-CoV-2 and other viruses

Module 4: treatment -drug-resistant tuberculosis treatment. Geneva: World Health Organization; 2020. Licence: CC BY-NC-SA 3.0 IGO

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline

Out of 39 GTN members responding, a single member, although agreeing with the paper, was