
==== Front
Indian J Crit Care Med
Indian J Crit Care Med
IJCCM
Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine
0972-5229
1998-359X
Jaypee Brothers Medical Publishers

39234233
10.5005/jp-journals-10071-24783
Guidelines
ISCCM Position Statement on the Approach to and Management of Critically Ill Patients with Tuberculosis
Chacko Binila 1https://orcid.org/0000-0002-1609-2208

Chaudhry Dhruva 2https://orcid.org/0000-0001-5138-2908

Peter John V 3https://orcid.org/0000-0002-3423-1830

Khilnani Gopi C 4https://orcid.org/0000-0003-0820-0624

Saxena Prashant 5https://orcid.org/0009-0000-6735-9833

Sehgal Inderpaul S 6https://orcid.org/0000-0003-0516-9350

Ahuja Kunal 7https://orcid.org/0009-0006-6666-088X

Rodrigues Camilla 8https://orcid.org/0000-0002-6105-6660

Modi Manish 9https://orcid.org/0000-0002-5494-3704

Jaiswal Anand 10https://orcid.org/0009-0004-3523-8083

Jasiel G Joel 11https://orcid.org/0009-0004-7565-4129

Sahasrabudhe Shrikant 12https://orcid.org/0000-0002-6074-8569

Bose Prithviraj 13https://orcid.org/0000-0003-4522-0261

Ahuja Aman 14https://orcid.org/0000-0003-0307-3427

Suprapaneni Vineela 15https://orcid.org/0000-0003-0726-4474

Prajapat Brijesh 16https://orcid.org/0000-0002-1854-8408

Manesh Abi 17https://orcid.org/0000-0001-9970-9674

Chawla Rajesh 18https://orcid.org/0000-0003-2659-2430

Guleria Randeep 19https://orcid.org/0000-0002-6258-2160

1,3,11,13 Medical Intensive Care Unit, Christian Medical College, Vellore, Tamil Nadu, India
2 Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India
4,7 Department of Pulmonary, Critical Care and Sleep Medicine, PSRI Hospital, New Delhi, India
5 Department of Pulmonary, Critical Care and Sleep Medicine, Fortis Hospital, Vasant Kung, New Delhi, India
6 Department of Pulmonary Medicine, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab, India
8 Department of Lab Medicine, Hinduja Hospital, Mumbai, Maharashtra, India
9 Department of Neurology, Postgraduate Institute of Medical Education and Research, Chandigarh, Punjab, India
10 Deparment of Respiratory Diseases, Medanta Medicity, Gurugram, Haryana, India
12 Department of Critical Care Medicine and Pulmonology, KIMS Manavata Hospital, Nashik, Maharashtra, India
14,15 Department of Pulmonary and Critical Care Medicine, PGIMS, Rohtak, Haryana, India
16 Department of Pulmonary and Critical Care Medicine, Yashoda Group of Hospitals, Ghaziabad, Uttar Pradesh, India
17 Department of Infectious Diseases, Christian Medical College, Vellore, Tamil Nadu, India
18 Department of Respiratory Medicine, Critical Care and Sleep Medicine, Indraprastha Apollo Hospitals, New Delhi, India
19 Institute of Internal Medicine and Respiratory and Sleep Medicine, Medanta Medical School, Gurugram, Haryana, India
Binila Chacko, Medical Intensive Care Unit, Christian Medical College, Vellore, Tamil Nadu, India, Phone: +91 9600272412, e-mail: binilachacko@gmail.com; Dhruva Chaudhry, Department of Pulmonary and Critical Care Medicine, Pt BDS Post Graduate Institute of Medical Sciences, Rohtak, Haryana, India, Phone: +91 9991101616, e-mail: dhruvachaudhry@yahoo.co.in
8 2024
10 8 2024
28 Suppl 2 S67S91
02 7 2024
24 7 2024
Copyright © 2024; The Author(s).
2024
https://creativecommons.org/licenses/by-nc/4.0/ © The Author(s). 2024 Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Abstract

Tuberculosis (TB) is an important cause of morbidity and mortality globally. About 3–4% of hospitalized TB patients require admission to the intensive care unit (ICU); the mortality in these patients is around 50–60%. There is limited literature on the evaluation and management of patients with TB who required ICU admission. The Indian Society of Critical Care Medicine (ISCCM) constituted a working group to develop a position paper that provides recommendations on the various aspects of TB in the ICU setting based on available evidence. Seven domains were identified including the categorization of TB in the critically ill, diagnostic workup, drug therapy, TB in the immunocompromised host, organ support, infection control, and post-TB sequelae. Forty-one questions pertaining to these domains were identified and evidence-based position statements were generated, where available, keeping in focus the critical care aspects. Where evidence was not available, the recommendations were based on consensus. This position paper guides the approach to and management of critically ill patients with TB.

How to cite this article

Chacko B, Chaudhry D, Peter JV, Khilnani G, Saxena P, Sehgal IS, et al. isccm Position Statement on the Approach to and Management of Critically Ill Patients with Tuberculosis. Indian J Crit Care Med 2024;28(S2):S67–S91.

Keywords

Antituberculous treatment
Critically ill
Immunocompromised host
Infection prevention and control
Organ support
Tuberculosis
==== Body
pmcIntroduction

Tuberculosis (TB) is an important cause of morbidity and mortality globally. In 2021, around 10.6 million people were estimated to be infected with TB and 1.6 million died.1 This important communicable disease is more prevalent among marginalized socio-economic status communities with limited access to healthcare.2 In India, 2.77 million people were estimated to be affected with TB in 2022 with a mortality of 0.32 million and an incidence of 196 per 100,000 population.3 About 3–4% of hospitalized TB patients require admission to the intensive care unit (ICU); the mortality in this subset of patients is around 50–60%.4,5 Despite the burden of TB and the likelihood of such patients needing ICU care, there is limited literature on the management of patients with TB who require ICU admission. The Indian Society of Critical Care Medicine (ISCCM) position paper aims to bridge this gap by providing recommendations on the various aspects of TB in the ICU setting.

Methods

The ISCCM convened a conclave meeting on 16th July 2023 to identify the writing group for TB and to set out the objectives for the position statement. The working group comprised 19 members including a chair and co-chair and 4 women with considerable experience in TB, who are working in academic and private institutions across India in critical care, respiratory medicine, infectious disease, neurology, and microbiology. The domains were deliberated and outlined at the conclave and broad questions were constructed. Seven subgroups were created, each with a coordinator, to refine and finalize the questions and work on the domains. The domains were as follows:

Categorization of TB in critically ill.

Diagnostic workup.

Drug therapy.

TB in the immunocompromised host.

Organ support.

Infection control, and

Post-TB sequelae.

Relevant articles on the subject were identified by a literature search undertaken by each of the subgroups, using search terms pertaining to the domains allocated to them. A tutorial on how to perform a PubMed® search was done at the conclave to ensure that authors had a clear understanding on how to perform a thorough literature search using the appropriate search terms. The recommendations of the subgroups were made based on available evidence. Grading of recommendations was not done as there was limited research on this topic in terms of randomized clinical trials, and hence it was decided at the conclave that this would be a position paper and not a guideline. Where evidence was not available, the recommendations were based on consensus. Although a Delphi process would have been ideal to make the recommendations where evidence was not available, this was not undertaken. The recommendations of each of the subgroups were reviewed by a three-member core group (DC, BC, JVP), and position statements and the commentary were refined, ensuring that they were accurate and reflected current evidence. Care was taken to ensure that the recommendations focused on the approach to, the evaluation and management of a critically ill patient with TB. The executive summary provides a quick reference guide on the approach to and management of critically ill patients with TB.

Executive summary

No.	Question	Position statement	
Categorization of TB	
1	How should TB be categorized in the critically ill?	In the critically ill patient, TB should be categorized as pulmonary and extrapulmonary TB.	
2	When should TB be suspected in critically ill patients?	TB should be considered in ICU patients with risk factors for developing TB, particularly in high endemic areas, in the setting of nonresolving community-acquired pneumonia (CAP), acute respiratory distress syndrome (ARDS), meningitis, intracranial or bony lesions, pleural or pericardial effusion, psoas abscess, and multiorgan failure.	
3	What are the reasons for ICU admission in patients with TB?	Patients with TB are usually admitted to the ICU with a process that is directly related to TB or due to secondary processes.	
4	What should the diagnostic approach be in patients with suspected pulmonary TB?	Patients with a high risk of TB, with compatible clinical features and radiological abnormalities, should undergo tests for microbiological confirmation of TB.	
5	What should the diagnostic approach be in patients with suspected CNS TB?	The diagnostic approach of a critically ill patient with suspected CNS TB is based on clinical features, imaging, and cerebrospinal (CSF) analysis.	
6	When would you suspect drug-resistant TB in ICU patients with suspected TB?	Given the high level of drug resistance to TB, drug resistance must be ruled out in all patients who are admitted to the ICU with suspected TB. Multidrug resistance must be particularly considered in patients >40 years, those with prior history of TB, poor compliance, or failure to TB treatment, and in HIV co-infection.	
Diagnostic workup	
7	Is there a role of microscopy in the diagnosis of TB?	Microscopy remains the primary method for diagnosing M. tuberculosis infection and is important in detecting patients with high bacterial load.	
8	What is the role of molecular testing in the diagnosis of TB in critically ill?	Molecular testing (Xpert MTB/Rif or Xpert Ultra) should be performed initially on ALL samples obtained from pulmonary or extrapulmonary sites to arrive at a rapid diagnosis of TB and for detecting rifampicin-resistance. LPA, recommended by the guidelines for the PMDT in India, must be performed to further evaluate for drug resistance. The current reference for drug resistance is phenotypic DST using solid (LJ) medium and liquid (MGIT) medium cultures.	
9	What is the role of cultures in the diagnosis of TB?	Culture remains the gold standard for TB diagnosis for pulmonary and extrapulmonary TB as it enables accurate identification and subsequent susceptibility testing. However, the turnaround time is high.	
10	Is there a role for ADA in the diagnosis of extrapulmonary TB?	ADA is a useful adjunct test in the diagnosis of extrapulmonary TB. It must be used in conjunction with other tests to diagnose TB.	
11	What is the role of invasive diagnostic tests for TB?	Invasive tests such as bronchoscopic procedures, biopsy techniques, and conventional surgery may be required to diagnose pulmonary and extrapulmonary TB when noninvasive and less invasive tests fail to give a diagnosis	
12	What is the role of imaging in the diagnosis of TB?	Chest radiography is the mainstay imaging for pulmonary parenchymal TB. CT and MRI are used for the evaluation of pulmonary and extrapulmonary TB.	
Drug therapy	
13	When should anti-TB be initiated in a critically ill patient?	Timely initiation of anti-TB drugs is essential for treatment success, particularly in those with high disease severity.	
14	Which anti-TB regimen should be initiated in a critically ill patient?	As per the National TB Eradication Program (NTEP), a weight based, standard anti-TB regimen with four drugs should be initiated unless drug resistance is suspected or demonstrated. Higher doses of anti-TB drugs may be considered in severe disease.	
15	Do enterally administered anti-TB drugs achieve therapeutic levels in critically ill patients?	Absorption of enterally administered anti-TB drugs is reduced in the critically ill patient and if administered when continuous enteral feeds are given. Therapeutic levels may be achieved with enteral pyrazinamide but not with INH, rifampicin, and ethambutol.	
16	Is there a role for higher doses of anti-TB drugs or IV anti-TB drugs in TB meningitis and severe illness?	Higher doses of anti-TB drugs or intravenous preparations where available, may be considered in TB meningitis and severe illness.	
17	What is the role of other intravenous antibiotics in TB?	Although several IV antibiotics such as aminoglycosides, quinolones, linezolid, and carbapenems are effective against TB, these second-line drugs should be used only in the setting of DR-TB, life-threatening TB, and in those who do not tolerate first-line anti-TB drugs.	
18	How should DR-TB be treated in the ICU?	Patients with DR-TB should be enrolled in the NTEP if not already enrolled. The NTEP has adopted bedaquiline-based DR-TB regimen in India based on WHO guidelines. Treatment should be started in consultation with respiratory physicians and NTEP. The recommended drugs and duration of treatment in such patients are guided by program management of DR-TB in India.	
19	Is there a risk of drug-drug interaction with commonly used anti-TB drugs?	There are significant drug-drug interactions with the commonly used anti-TB drugs. Clinicians need to be familiar with the common interactions in the ICU setting.	
20	What is the role of steroids in TB?	Corticosteroids may be effective in reducing clinically relevant adverse outcomes in some forms of TB.	
21	Is there a role for TDM in DR-TB?	There is insufficient evidence to recommend routine TDM during treatment of DR-TB.	
22	How do risk prediction scores perform in TB?	Risk prediction scores should not be relied on for mortality prediction in TB.	
TB in the immunocompromised host	
23	Does the immunocompromised state predispose an individual to reactivation of latent TB or the acquisition of TB?	Since immunocompromised patients are at risk for TB, the clinical suspicion should be high in patients admitted to the ICU. The interpretation of tests for latent TB infection (such as TST and IGRA are likely to be influenced by immunosuppression and the severity of critical illness.	
24	Is the clinical presentation of TB in the immunocompromised individual similar to that of the immunocompetent host?	In an immunocompromised host, the clinical presentation of TB may be more insidious and likely to be disseminated. TB should be suspected when there is unexplained worsening of clinical status. The surveillance for atypical presentations of TB should be robust in order to pick them up early.	
25	What should the diagnostic work be in the immunocompromised host who is suspected to have TB infection?	Taking into consideration the indolent nature of TB in the immunocompromised patient, cross sectional imaging should be considered early to direct diagnostic sampling. Early invasive sampling including bronchial lavage and/or biopsy is advocated in these patients.	
26	What would the approach be to the management of TB in the setting of intestinal malabsorption?	In patients with anticipated poor enteral uptake of ATT (short bowel, gut GVHD, severe multiorgan dysfunction with high-dose vasoactive medications), parenteral ATT may be considered along with TDM.	
27	What would the approach be to IRIS in TB?	IRIS should be suspected when there is paradoxical worsening of symptoms, typically seen when immunosuppression is reduced or reversed. IRIS can also occur in the immunocompetent host. A course of steroids should be considered.	
Organ support	
28	Is the ventilatory management of respiratory failure due to TB different from the ventilatory management of respiratory failure due to other infective etiologies?	There is limited data on the management of respiratory failure in patients with TB. The management of respiratory failure in patients with TB should be along the same lines of management as with other infective etiologies of hypoxemic and hypercapnic respiratory failure.	
29	Should noninvasive respiratory support be considered in the management of acute respiratory failure due to TB?	The use of noninvasive respiratory support including HFNC is challenging given their tendency to cause aerosol dispersion and spread of infection to HCWs. It is preferable to use them in isolation facilities with adequate precautions by staff.	
30	Is there a role for ECMO support in TB?	There is limited evidence for the use of ECMO in TB. It may be considered in TB in the setting of refractory respiratory or cardiac failure.	
31	How should massive hemoptysis be managed?	Patients with massive or life-threatening hemoptysis should be managed in an ICU with focus on airway and hemodynamic stabilization, evaluation of the source of bleed by CT angiogram or bronchoscopy and consideration of bronchial artery embolization as an early treatment option. Nebulized and/or intravenous tranexamic acid may reduce the volume of hemoptysis.	
32	When should tracheostomy be considered in patients ventilated for TB?	The indications and timing of tracheostomy in patients admitted to the ICU with TB is similar to that of other patients admitted to critical care. There is inconclusive evidence to recommend early tracheostomy in patients with TB.	
33	What is the optimal management of hypotension due to adrenal insufficiency and septic shock with mycobacteremia (Landouzy sepsis)?	In TB, shock may be due to adrenal insufficiency, secondary bacterial sepsis, or mycobacteremia. Shock should be managed along the same lines as the management of septic shock. Early initiation of anti-TB treatment is important. Steroids are indicated for refractory septic shock, adrenal insufficiency, and shock due to mycobacteremia.	
34	What is the optimal management of renal failure in patients with TB?	Renal failure in TB should be managed along the same lines as the approach to the management of acute kidney injury in the setting of other infectious diseases. Drug dosing should be optimized for renal function, and nephrotoxic agents should be avoided.	
35	Is there a role for first line anti-TB drugs in patients with liver involvement in TB?	Patients with liver involvement due to TB should be started on standard four-drug regimen, irrespective of baseline liver function tests.	
36	Is there a role for low-volume PLEX in patients with liver dysfunction due to TB or DILI?	In patients with ALF or ACLF due to anti-TB drugs-induced DILI, low-volume plasma exchange may be considered especially in those who fulfill the King's College criteria for liver transplantation but do not have access to the same.	
Infection control	
37	What are the recommended isolation systems for patients with presumed or documented infectious TB in the ICU?	Respiratory isolation of individuals with confirmed or suspected infectious TB is advised, ideally in an AIIR equipped with a HEPA filter and negative pressure. Closed suctioning is recommended for intubated patients. The application of a bacterial filter to the ventilator tubing's expiratory limb may reduce the transmission of infection.	
38	What are the key IPC measures for HCWs taking care of patients with suspected or confirmed tuberculosis in the ICU?	Healthcare professionals entering rooms of patients with suspected or confirmed contagious TB disease must wear a properly sized N95 disposable respirator.	
39	When can respiratory isolation precautions be discontinued for critically ill patients with pulmonary TB?	For sputum-positive rifampicin susceptible TB patients, a minimum of 2 weeks of isolation is suggested, while on effective anti-TB treatment.	
40	Is there a role for routine testing and surveillance of HCWs managing infectious TB patients?	The role and benefit of regular testing and surveillance for TB infection among HCWs in the ICU, using TST or IGRA, in endemic countries like India is unclear.	
41	Post TB sequelae: What are the reasons for ICU admission?	Post-TB sequelae patients may present to the ICU with respiratory failure due to exacerbation of obstructive airway disease or restrictive fibrotic lung disease, pulmonary hypertension, hemoptysis due to bronchiectasis, aspergillosis or vascular causes or with secondary infections. There are currently no evidence-based recommendations for the investigation and management of PTLA.	
ACLF, acute on chronic liver failure; ADA, adenosine deaminase; AIIR, airborne infection isolation room; ALF, acute liver failure; ARDS, acute respiratory distress syndrome; ATT, antituberculous treatment; CAP, community-acquired pneumonia; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; DILI, drug-induced liver disease; DR-TB, drug resistant TB; DST, drug sensitivity testing; ECMO, extracorporeal membrane oxygenation; GVHD, graft vs host disease; HCW, healthcare worker; HEPA, high efficiency particulate air; HFNO, high frequency nasal oxygen; HIV, human immunodeficiency virus; IGRA, interferon gamma release assay; IRIS, immune reconstitution inflammatory syndrome; ICU, intensive care unit; ICP, intracranial pressure; IV, intravenous; LJ, Lowenstein-Jensen medium; LPA, line probe assay; MGIT, Mycobacteria growth indicator tube; MRI, magnetic resonance imaging, NTEP, National Tuberculosis Eradication Program; TB, tuberculosis, TDM, therapeutic drug monitoring; TST, tuberculin skin test; PMDT, programmatic management of drug-resistant tuberculosis; PTLA, post-TB lung abnormality; PLEX, plasma exchange; WHO, World health organization

Categorization of TB in Critically Ill

Q1: How should TB be Categorized in the Critically ill?

Position statement: In critically ill patients, TB should be categorized as either pulmonary or extrapulmonary TB.

Commentary: TB is generally categorized as pulmonary and extrapulmonary TB.6,7 The same classification is applicable to the critically ill.8

Q2: When should TB be Suspected in Critically Ill Patients?

Position statement: TB should be considered in ICU patients with risk factors for developing TB, particularly in high endemic areas, in the setting of nonresolving community-acquired pneumonia (CAP), acute respiratory distress syndrome (ARDS), meningitis, intracranial or bony lesions, pleural or pericardial effusion, psoas abscess, and multiorgan failure.

Commentary: Patients with pulmonary TB can present acutely or sub-acutely. Tuberculosis should be suspected in a patient who presents with fever and cough of ≥14 days with hemoptysis, weight loss, or features of organ dysfunction, particularly in high endemic areas and in those with risk factors for developing TB (Fig. 1). Tuberculosis can present as CAP9 or ARDS10–12 or life-threatening hemoptysis. The presence of miliary or centrilobular nodules, consolidation with or without cavitation, and pleural effusion should raise the clinical suspicion of TB as a cause of respiratory failure.13 Patients with extrapulmonary TB may present with acute respiratory failure, septic shock, and multiorgan failure.14 Those with central nervous system (CNS) TB (meningitis, meningoencephalitis, space-occupying lesion, epidural abscess causing cord compression, or a combination of these) and pericardial TB may require ICU admission.8,9 Although isolated involvement of other organs such as the liver,15 gastrointestinal,16 or urogenital17 is uncommon in TB patients admitted to the ICU, such patients may require ICU care postoperatively if surgical intervention is required or if they develop organ dysfunction. Disseminated TB should be suspected when there is concurrent involvement of two or more noncontiguous sites; miliary pattern on chest X-ray is a common finding.18

Fig. 1 When to suspect TB in the critically ill. The figure demonstrates an algorithmic approach to the diagnosis of tuberculosis (TB) in the critically ill. Several risk factors (host factors) predispose to the development of TB. The symptoms in pulmonary, central nervous system (CNS), and disseminated/miliary TB as well as the radiological features in these forms of TB are listed

Q3: What are the Reasons for ICU Admission in Patients with TB?

Position statement: Patients with TB are usually admitted to the ICU with a process that is directly related to TB or due to secondary processes.

Commentary: Patients with TB may require admission to the ICU for a process that is directly related to TB (pulmonary or extrapulmonary manifestations) or due to secondary processes (Table 1). In pulmonary TB, patients may present with massive hemoptysis that requires airway protection and intubation, severe hypoxia due to superimposed pneumonia or ARDS, or pneumothorax. Patients with pulmonary or extrapulmonary TB can also present with respiratory failure due to pulmonary embolism.19 Isolated massive pleural effusion as a cause of hypoxia is uncommon in TB. Patients with extrapulmonary TB may present with seizures, electrolyte abnormalities, features of hydrocephalus, pericardial tamponade, sepsis, multiorgan dysfunction, or complications related to drug therapy.20,21 In a series of 48 patients admitted to the ICU with TB meningitis, 47 patients were referred because of neurological deterioration; 22 were comatose at admission; 36 patients (75%) required ventilatory support, and 16 needed neurosurgery.22

Table 1 Indications for ICU admission in tuberculosis8

Site	Primary process	Secondary process*	
Parenchymal lung disease	Nonresolving community-acquired pneumonia (CAP)
TB acute respiratory distress syndrome (ARDS)
Fibro-cavitary disease
Miliary TB
TB bronchopneumonia	Superimposed bacterial infection
Fungal infection (e.g., Aspergillosis)
TB sequelae (fibrosis, cavitation)
IRIS
Hemoptysis (Rasmussen's aneurysm)	
Pleural disease	Massive pleural effusion
TB empyema	Pneumothorax	
CNS disease	Subacute or chronic TB meningitis
Basal arachnoiditis due to TB
Tuberculoma
TB brain abscess
Spinal arachnoiditis	Coma or altered conscious state (multi-factorial causes)
Noncommunicating hydrocephalus
Focal neurologic signs (cranial nerve palsy, hemiparesis)
Seizures
Electrolyte abnormalities	
Pericardial disease	Pericardial tamponade
Constrictive pericarditis	Heart failure
Organ dysfunction due to heart failure	
Abdominal TB	Massive ascites
Intestinal obstruction or perforation (ileocecal TB)	Secondary bacterial peritonitis
Sepsis	
Disseminated TB	Respiratory failure due to miliary TB
Multiorgan dysfunction
Hypotension due to adrenal involvement	Secondary sepsis	
Musculoskeletal TB	Psoas abscess	Paraplegia
Superimposed bacterial infection	
ARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia; CNS, central nervous system; ICU, intensive care admission; IRIS, immune reconstitution inflammatory syndrome; TB, tuberculosis. *In addition patients on treatment for tuberculosis (TB) may present with drug toxicity due to antitubercular drugs, intercurrent infections, pulmonary embolism, cardiac or neurological events unrelated to the primary TB process

Q4: What should the Diagnostic Approach be in Patients with Suspected Pulmonary TB?

Position statement: Patients with a high risk of TB, with compatible clinical features and radiological abnormalities, should undergo tests for microbiological confirmation of TB.

Commentary: The guidelines followed in the radiological and microbiological evaluation and confirmation of TB are similar to those of nonICU patients.23 Patients with a high risk of TB with compatible clinical and radiological abnormalities should be investigated further to confirm the diagnosis of TB. For microbiological confirmation, sputum, endotracheal aspirate, bronchial washing, or bronchoalveolar lavage should be sent for microscopy, molecular tests, and cultures (Figs 1 and 2). Biopsy may be required in some situations to confirm the diagnosis. In an intubated patient, microbiological sampling of the lower respiratory tract, by means of bronchoalveolar lavage, is likely to improve the yield and facilitate the diagnosis of pulmonary TB.24,25

Fig. 2 Diagnostic approach to TB in the critically ill. The figure outlines a diagnostic approach to tuberculosis (TB) in the intensive care unit (ICU). Several clinical features would raise the suspicion of TB. TB may be confirmed with a combination of tests that include radiology, microbiology, and histopathology. ARDS acute respiratory distress syndrome, HRCT high resolution computed tomography, MRI magnetic resonance imaging, ETA endotracheal aspirate, BAL bronchoalveolar lavage, AFB acid fast bacilli. * Pleural, pericardial, or ascitic fluid can be sent for microbiology and histopathology

The role of tuberculin skin test (TST) and interferon-gamma release assay (IGRA) in the diagnosis of TB merit mention. These tests are used for diagnosing latent TB infection (LTBI).26 Neither of the tests predicted the subsequent development of active TB among household contacts of pulmonary TB during follow-up.26 Its role in the diagnosis of LTBI in high-prevalence areas and its relevance in the ICU are questionable.

Q5: What should the Diagnostic Approach be in Patients with Suspected CNS TB?

Position statement: The diagnostic approach of a critically ill patient with suspected CNS TB is based on clinical features, imaging, and cerebrospinal (CSF) analysis.

Commentary: The evaluation of a patient with suspected CNS TB is the same as a nonICU patient. Any patient presenting with fever, headache, altered sensorium, seizures, focal neurological deficits, or a combination of these symptoms for more than 1 week should be investigated for CNS TB. Clinical examination may reveal neck rigidity, cranial nerve palsy, focal neurological deficits, and signs of raised intracranial pressure (ICP), including papilledema. Patients presenting with features of meningitis could also have abnormalities on chest imaging. The diagnostic approach would involve imaging (computed tomography [CT] and/or magnetic resonance imaging [MRI] with contrast), CSF analysis, and microbiological confirmation (Figs 1 and 2).27–29

Although molecular diagnostic tests such as the Xpert/Rif can enable rapid diagnosis of CNS TB, CSF culture is likely to increase the sensitivity of TB meningitis diagnosis.30 Since cultures take 6–8 weeks, anti-TB treatment should be initiated immediately if there is a high probability of TB even when molecular tests are negative as it does not rule out CNS TB given their modest sensitivity. When the index of suspicion is high, it is important to also look for evidence of active TB elsewhere. In immune-deficiency states, it is important to evaluate for a concomitant cryptococcal meningitis.31

Q6: When would you Suspect Drug-resistant (DR)-TB in Patients Admitted to ICU with Suspected TB?

Position statement: Given the high prevalence of DR-TB, drug resistance must be ruled out in all patients who are admitted to the ICU with suspected TB. Multidrug resistance must be particularly considered in patients >40 years, those with prior history of TB, poor compliance, or failure to TB treatment, and in human immunodeficiency virus (HIV) co-infection.

Commentary: In 2022 TB was reported as the biggest DR airborne epidemic.32 The term DR-TB33,34 encompasses (a) mono resistance to a first-line anti-TB drug, (b) multidrug-resistant TB (MDR-TB) that are resistant to isoniazid and rifampicin, (c) pre-extensively drug-resistant TB (pre-XDR-TB MDR/RR-TB) that are also resistant to a fluoroquinolone, and (d) extensively drug-resistant TB (XDR-TB) where the isolates are resistant to other important medications including bedaquiline and/or linezolid.

In India, DR-TB was found to be prevalent in 24.9% of newly diagnosed patients and in 58.4% of patients who had received prior treatment; 18.8% of patients with HIV and TB co-infection had drug resistance.35 Multidrug-resistant ranged from 3.5 to 26.7% in treatment naïve and in patients who had received prior treatment respectively.35 A significant increase in MDR (p < 0.001) of 12% over time was reported from a tertiary care hospital in New Delhi (4.7% in 2000 to 19.8% in 2012).36 The global pooled prevalence of MDR-TB was 11.6% (95% CI, 9.1–14.5) in a review of 148 studies37 with substantial heterogeneity (I2 99.6) and a sample size of 3,18,430 individuals.

The risk factors for MDR-TB vary depending on the area. An increased risk of MDR-TB was found in a meta-analysis among patients ≥ 40 years of age who were unemployed, did not have health insurance, had a positive smear, had not completed or failed their TB treatment, had an adverse drug reaction, were nonadherent, had HIV, COPD, or had an infection with M. tuberculosis Beijing.38 Male gender and a history of prior TB therapy are risk factors for drug resistance in extrapulmonary TB.39

Diagnostic Workup

Q7: Is there a Role of Microscopy in the Diagnosis of TB?

Position statement: Microscopy remains the primary method for diagnosing M. tuberculosis infection and is important in detecting patients with high bacterial load.

Commentary: The sensitivity of smear and microscopy for diagnosing M. tuberculosis ranges from 20 to 80% and is low in pediatric TB, extra-pulmonary TB, or TB with HIV infection.40 Ziehl-Neelsen stain involving carbol fuchsin for acid-fast staining is rapid, cheap, and affordable in resource-limited settings. Microscopy is important in detecting patients with pulmonary TB with high bacterial load and high risk of transmission. Fluorescent microscopy enhances the sensitivity of smear microscopy as it increases productivity with light-emitting diodes.41,42 Microscopy cannot distinguish between viable and dead bacilli and is not useful for early detection of treatment failure or drug resistance.

Q8: What is the Role of Molecular Testing in the Diagnosis of TB in the Critically Ill?

Position statement: Molecular testing (Xpert MTB/Rif or Xpert Ultra) should be performed initially on all samples obtained from pulmonary or extrapulmonary sites to arrive at a rapid diagnosis of TB and to detect rifampicin-resistance. Line probe assays (LPAs), recommended by the guidelines for the Programmatic Management of Drug-Resistant Tuberculosis (PMDT) in India, must be performed to further evaluate for drug resistance. The current reference for drug resistance is phenotypic drug susceptibility testing (pDST) using solid Lowenstein-Jensen (LJ) medium and the liquid mycobacteria growth indicator tube (MGIT) medium cultures.

Commentary: In a critically ill patient, time is highly crucial so early diagnosis and initiation of treatment is important. In adults with suspected pulmonary TB, Xpert MTB/RIF or Xpert MTB/RIF Ultra or TrueNAT should be used as the initial diagnostic test for TB and for detecting rifampicin resistance in sputum.43,44 Xpert Ultra performs slightly better than Xpert MTB/Rif (Table 2).45

Table 2 Performance of the Xpert test in various forms of TB

Type of TB	Number of studies/specimens	Comparator	Sensitivity (95% CI)	Specificity (95% CI)	
Pulmonary TB (Xpert)45	7	Culture	84.7% (78.6–89.9)	98.4% (97.0–99.3)	
Pulmonary TB (Xpert Ultra)45	7	Culture	90.9% (86.2–94.7)	95.6% (93.0–97.4)	
TB meningitis (Xpert)45	5	CRS	37% (25–50)	100%	
TB meningitis (Xpert Ultra)46	6	CRS	64% (45–80)	100%	
Cochrane review					
Pleural (Xpert)48	27	Culture	50.9% (39.7–62.8)	99.2% (98.2–99.7)	
Pleural tissue (Xpert)	3	Culture	30.5% (3.5–77.8)	97.4% (92.1–99.3)	
CSF (Xpert)48	29	Culture	71.1% (60.9–80.4)	98.0% (97.0 to 98.8)	
Lymph node aspirate (Xpert)	17	Culture	87.6% (81.7–to 92.0)	86.0% (78.4–91.5)	
Urine (Xpert)48	13	Culture	82.7% (69.6–91.1)	98.7% (94.8–99.7)	
Peritoneal (Xpert)	16	Culture	59.2% (45.2–73.5)	97.9% (96.2–99.1)	
Pericardial (Xpert)48	7	Culture	65.7% (46.3–81.4)	96.0% (85.8–99.3)	
Genitourinary–urine (Xpert)	13	Culture	82.7% (69.6 to 91.1)	98.7% (94.8–99.7)	
Adults					
Extrapulmonary TB (Xpert)47	572*	CRS	75% (70–80)	98% (97–100)	
Lymph node (Xpert)47	279	CRS	90% (86–94)	71.5 (60–83)	
CSF (Xpert)	45	CRS	53% (28 to 79)	100%	
Pleural (Xpert)	159	CRS	30% (17–44)	100%	
Peritoneal (Xpert)47	80	CRS	32% (12–51)	100%	
Children					
Extrapulmonary TB (Xpert)47	8 (652*)	CRS	71% (63–79)	97% (95–99)	
Lymph node (Xpert)47	6	CRS	80% (70–88)	94% (89–97)	
CSF (Xpert)47	5	CRS	42% (22–63)	99% (95–100)	
CI, confidence interval/credible interval; CRS, composite reference standard. *number of specimens

The performance of Xpert for samples obtained from pulmonary and extrapulmonary sites, when compared with culture or composite reference standard (CRS), is summarized in Table 2.45–48 In adults and children with signs and symptoms of TB meningitis, the World Health Organization (WHO) strongly recommends that Xpert MTB/RIF or Xpert Ultra should be used in CSF as an initial diagnostic test for TB meningitis rather than smear microscopy and culture.49 In a meta-analysis of six studies that used a CRS, Xpert Ultra had a pooled sensitivity of 64% and specificity of 100% for TB meningitis.46 Although Xpert Ultra seems to represent a step forward in TB meningitis diagnosis, it cannot fully exclude TB meningitis.49 The sensitivity of Xpert was high for lymph node samples (>80%) and low for pleural (30–50.9%) and peritoneal fluid (32–59.2%), while the specificity was generally above 85% for all extrapulmonary sites (Table 2).47,48

Testing for resistance to isoniazid (INH) and fluoroquinolone is important in settings where the prevalence of resistance is >5%.50 Both Xpert MTB/RIF and Xpert Ultra perform similarly in detecting rifampicin resistance.45 With regards to picking up multidrug resistance, the Xpert MTB/XDR assay51 has high diagnostic accuracy and meets the WHO's minimum target product profile criteria for a next-generation DST. The performance of the various tests to detect drug resistance is summarized in Table 3. It is necessary to consider the reference sample under examination and the diagnostic accuracy of the test when interpreting the results of the quick diagnostic genomic DST.

Table 3 Performance of molecular tests against culture-based DST to detect drug-resistant TB

Test	Number of studies/specimens	Sensitivity	Specificity	
Near patient technology-automated or semi-automated NAAT assay	
Xpert MTB/RIF54	48 studies, 8020 participants	Rifampicin resistance:
96% (94–97%)	Rifampicin resistance:
98% (98–99%)	
Truenat MTB55	1 study, 250 participants	89.3% (66.0–87.4)	92.2% (87.2–95.6)	
Truenat MTB55	1 study, 250 participants	81.7% (70.7–89.8)	94.9% (89.8–97.9)	
Xpert MTB/XDR
Cochrane review56	Isoniazid resistance
6 cohorts, 1083 participants	94.2% (87.5–97.4)	98.5% (92.6–99.7)	
	Fluoroquinolone resistance
6 cohorts, 1021 participants	93.2% (88.1–96.2)	98.0% (90.8–99.6)	
	Ethionamide resistance:
4 cohorts, 434 participants	98.0% (74.2–99.9)	99.7% (83.5–100.0)	
	Amikacin resistance 4 cohorts, 490 participants	86.1% (75.0–92.7)	98.9% (93.0–99.8)	
Xpert MTB/XDR57	1 study
497 participants	Isoniazid 96.8%
Fluoroquinolones 90.0%
Kanamycin, 70.0%
Amikacin 83.3%
Capreomycin 70.0%
Ethionamide 61.8%	Isoniazid 95.8%
Fluoroquinolones 98.3%
Kanamycin 99.6%
Amikacin 99.6%
Capreomycin 99.6%
Ethionamide 99.6%	
Line probe assays				
GenoType® MTBDR assay58INH and Rifampicin resistance	10 studies, 3,349 specimens	INH 84.3% (76.6–89.8)
Rifampicin 98.1%, (95.9–99.1)	INH Resistance
99.5%
Rifampicin resistance 98.7%	
GenoType® MTBDR assay59
Fluoroquinolone resistance	9 studies, 1,771 participants	86.2% (74.6–93.0%)		
GenoType® MTBDR assay59
Second line injectable drugs	8 studies, 1,639 participants	87.0% (38.1–98.6%)	99.5 (93.6–100.0%)	
GenoType® MTBDR assay59
XDR TB	6 studies, 1,420 participants	69.4 (38.8–89.0%)	99.4 (95.0–99.3%)	
Values in parentheses indicate confidence intervals (CI) unless specified.

Line probe assays are recommended to confirm and further evaluate drug resistance. The LPA test offers an advantage as it is directly performed on clinical samples, has a short turnaround time of 24–48 hours, and detects DR not only to first-line but also to second-line anti-TB drugs.52,53 It has the advantage of rapid screening for MDR-TB in areas where the prevalence of DR-TB is high and enables timely initiation of appropriate anti-TB drugs. The performance of LPAs against the gold standard is provided in Table 3.54–59

The current reference method for assessing DR is pDST,60 which is a sensitive diagnostic technique that uses cultured isolates exposed to bacterial growth in the presence of antibiotics. Phenotypic drug susceptibility test is available using both solid (LJ) medium and liquid (MGIT) medium but critical concentrations are limited and available only for rifampicin, isoniazid, levofloxacin, moxifloxacin, bedaquiline, linezolid, clofazimine, amikacin, and streptomycin.61 In general, a liquid culture medium is preferred. However, the disadvantages of cultures include a long turnaround time, an extremely labor-intensive and complex procedure, and the need for specialized infrastructure, which restricts its impact and accessibility.

Whole genome sequencing is a promising tool that is currently being evaluated to guide individualized clinical decisions for the most complicated TB-resistant cases, predict resistance to first- and second-line anti-TB, characterize hetero-resistance and mixed infections, study taxonomy and transmission dynamics, and discover targets involved in phenotypic resistance and resistance-conferring mutations.62 Its role in the ICU setting is currently limited.

Q9: What is the Role of Cultures in the Diagnosis of TB?

Position statement: Culture remains the gold standard for TB diagnosis for pulmonary and extrapulmonary TB as it enables accurate identification and subsequent susceptibility testing. However, the turnaround time is long.

Commentary: Cultures should be done on all samples even if a rapid diagnosis of TB is made on microscopy or molecular tests, since it enables accurate identification and subsequent susceptibility testing. The traditional LJ medium, the prototype of the traditional solid medium, is cost-effective and less likely to get contaminated. Liquid culture is faster and offers improved sensitivity.63 The MGIT 960 technique is an advanced and semi-automated method for the cultivation of M. tuberculosis in a controlled and monitored system. In a study involving 14,597 isolates, 41% were positive by the MGIT 960 TB system while 24% grew on the conventional LJ medium within 6 weeks.64 Typically, all positive MGIT cultures grow both M. tuberculosis complex (MTBC) and most nontuberculous mycobacteria (NTM). These need to be further characterized. Cultures increase the sensitivity in the diagnosis of extrapulmonary TB.27,48

Q10: Is there a Role for Adenosine Deaminase (ADA) in the Diagnosis of Extrapulmonary TB?

Position statement: Adenosine deaminase is a useful adjunct test in the diagnosis of extrapulmonary TB. It must be used in conjunction with other tests to diagnose TB.

Commentary: Pleural fluid ADA is a useful diagnostic test for tuberculous pleural effusion. In a systematic review of 174 publications, the sensitivity, specificity, and diagnostic odds ratio were 92, 90, and 0.97%, respectively. The threshold used for ADA in the studies ranged from 40 to >65 IU/l. All studies however showed a high risk of bias.65 In CNS TB, ADA has low to moderate diagnostic utility.66,67 In one study, the widely used cut-off value of 10 U/l had a specificity of 82% and a sensitivity of 50%.67 In abdominal TB, a meta-analysis of 24 articles demonstrated a pooled sensitivity and specificity of 93% and 95%, respectively.68 In a study involving 105 patients with TB pericarditis, the sensitivity and specificity for ADA were 82.1 and 92.4%, respectively when a threshold of 40 U/l was used.69

Q11: What is the Role of Invasive Diagnostic Tests for TB?

Position statement: Invasive tests such as bronchoscopic procedures, biopsy techniques, and conventional surgery may be required to diagnose pulmonary and extrapulmonary TB when noninvasive and less invasive tests fail to give a diagnosis.

Commentary: In the diagnosis of pulmonary TB, if a diagnosis cannot be made based on sampling of the respiratory tract, bronchoscopic procedures such as (BAL) may be required, targeting areas of radiographic abnormality.70 Bronchoalveolar lavage is likely to improve the yield and facilitate the diagnosis of pulmonary TB.24,25 If endobronchial lesions are observed, biopsies may be taken.70 Transbronchial lung biopsies have now been largely replaced with endobronchial ultrasound (EBUS)-guided needle aspiration of lung lesions as well as paratracheal, subcarinal, and hilar lymphadenopathy.70 Image-guided or surgical biopsy may be required for peripheral lung lesions.70

In extrapulmonary TB involving the pleura, pericardium, lymph nodes, bones and joints, bowel, peritoneum, kidney, fallopian tubes, and epididymis, noninvasive techniques may not be feasible and other methods may not be diagnostic. Many of these sites may be amenable to percutaneous aspiration and/or biopsy.71 In disseminated TB, a diagnosis may also be obtained through bone marrow, lung, or liver biopsy.71 Samples must be subject to histopathological examination and cultures.

Q12: What is the Role of Imaging in the Diagnosis of TB?

Position statement: Chest radiography is the mainstay imaging for pulmonary parenchymal TB. Computed tomography and MRI are used for the evaluation of pulmonary and extrapulmonary TB.

Commentary: In parenchymal disease of the lung due to TB, chest radiography remains the main process for the evaluation of TB. Computed tomography is more sensitive than radiography for the detection of lymphadenopathy.72 Magnetic resonance imaging is superior to CT in the detection and assessment of CNS TB.72 Contrast MRI is superior to CT for the evaluation of meningitis and its complications, including hydrocephalus as well as characterizing homogeneous or ring-enhancing tuberculoma, and miliary TB involving the brain.72 Abdominal lymph nodes are best evaluated on CT.72 F-FDG18 PET may help differentiate active and inactive pulmonary TB and assess treatment response.73 Since tubercular lesions demonstrate high F-FDG18 uptake, it has the potential to be used for the diagnosis of spinal infections and monitoring treatment response in select cases of extrapulmonary TB.72

Drug Therapy for TB

Q13: When should Anti-TB be Initiated in a Critically ill Patient?

Position statement: Timely initiation of anti-TB drugs is essential for treatment success, particularly in those with high disease severity.

Commentary: Early diagnosis and treatment are likely to improve outcomes in all forms of TB. In one study of TB patients with septic shock, early and appropriate anti-TB treatment appeared to improve mortality.74

Q14: Which Anti-TB Regimen should be Initiated in a Critically Ill Patient?

Position statement: As per the National TB Eradication Program (NTEP), a weight based, standard anti-TB regimen with four drugs should be initiated unless drug resistance is suspected or demonstrated. Higher doses of anti-TB drugs may be considered in severe disease.

Commentary: As per the NTEP guidelines, a weight-based, standard anti-TB regimen with four drugs (rifampicin, isoniazid, pyrazinamide, and ethambutol) should be initiated unless drug resistance is suspected or demonstrated (Table 4). Higher doses of anti-TB drugs may be considered in severe disease.14,75,76 For both adults and children, the WHO recommends an intensive treatment regimen with four drugs for 2 months, followed by a continuation regimen (rifampicin, isoniazid) for 4 months except for CNS TB and bone or joint TB.77 However, the current RNTCP guideline advocates a three-drug regimen in the continuation phase (rifampicin, isoniazid, ethambutol) because of the risk of isoniazid mono-resistance.78 Streptomycin is recommended instead of ethambutol in the intensive phase if vision is impaired or cannot be assessed.78

Table 4 Overview of anti-tubercular drugs and their relevance to critical care14

Drug	Dosing	IV	Comments	CSF	
Isoniazid	Adults: 5 mg/kg/d
Children: 10 mg/kg/d (max. 300 mg/d)	Available*	Enteral absorption is reduced in the setting of sepsis, respiratory failure75,83	100%	
Rifampicin	Adults: 10 mg/kg/d (max. 600 mg/d)
Children: 15–20 mg/kg/d (max. 600 mg/d)	Available*	In critically ill patients with TB and respiratory failure, Cmax below recommended level (>8 mg/L) when given orally.83 Higher oral dose (35 mg/kg) or 20 mg/kg IV achieves CSF MIC in >93% of patients87	10–20%	
Ethambutol	Adults: 15 mg/kg/d
Children: 20–30 mg/kg/d (max. 1200 mg/d)	Available*	In TB meningoencephalitis and HIV infection IV INH and ethambutol resulted in better clinical outcomes as compared with oral treatment.89	25–50%	
Pyrazinamide	Adults: 25 mg/kg/d
Children: 35 mg/kg/d (max. 2000 mg)	Not available	Absorption rapid after oral administration, peak concentration in 1–2 hours. Minor changes in bioavailability when taken with meal. Serious adverse events are frequent, particularly in elderly.91	100%	
Moxifloxacin	Adults: < 30 kg, 400 mg once daily
30–50 kg 600 mg once daily
> 60 kg, 800 mg once daily
Children: 10–15 mg/kg once daily	Available	Second-line drug; majority of trials, treatment success not in favor of quinolones over standard regimens.93 Survival benefit for TB meningitis in one trial.93	AUC for CSF to plasma 0.82 at 400 mg once day94	
Amikacin	Adults: 15 mg/kg/day	Available	Effective for MDR-TB; Among 437 MDR-TB of whom 288 were HIV co-infected, 270 (62%) developed hearing loss.92	Mean (SD) 1.65 (1.6) mg/L children92	
Carbapenems	Imipenem, ertapenem and meropenem used in studies.	Available	Bactericidal activity greater with meropenem at 6 gm daily than with 3 gm daily.96 In vitro studies suggested that activity of carbapenems increases when used with clavulanate.97	Low; 79% undetectable98	
Linezolid	Adults: 600 mg/day	Available	Risk-benefit ratio favors 600 mg/day.98 Adverse events less and longer tolerance to drug when switched from 600 to 300 mg per day of linezolid.100	~ 30%102	
*Not available in India; AUC, area under the curve; CSF, cerebrospinal fluid; IV, intravenous; MDR, multi-drug resistant; MIC, minimum inhibitory concentration

In critically ill patients, first-line enterally administered drugs appear to be superior to second-line parenteral drugs plus ethambutol. In a study of 178 critically ill patients, an alternative regimen that included IV levofloxacin plus oral ethambutol plus IM streptomycin or IV amikacin, without rifampicin and isoniazid was associated with a significantly (p = 0.011) higher (63.5%) mortality when compared with the mortality of 51.4% among 284 critically ill patients who were administered of rifampicin, INH, pyrazinamide, and ethambutol enterally.79 There is some evidence that higher doses of the usual anti-TB drugs (e.g., rifampicin up to 35 mg/kg/d) are safe and may reduce the time to culture conversion and may be associated with better survival in severe disease.80,81

Q15: Do Enterally Administered Anti-TB Drugs Achieve Therapeutic Levels in Critically Ill Patients?

Position statement: Absorption of enterally administered anti-TB drugs is reduced in critically ill patients and if administered when continuous enteral feeds are given. Therapeutic levels may be achieved with enteral pyrazinamide but not with INH, rifampicin, and ethambutol.

Commentary: Multiple factors alter drug pharmacokinetics in critical illness and include reduced absorption, increased volume of distribution, augmented renal clearance, genetic variations in drug metabolization, and poor penetration into infected compartments.76 Pharmacokinetic studies in 10 critically ill patients showed that a fixed-dose combination of rifampicin, INH, pyrazinamide, and ethambutol, given according to weight via a nasogastric tube resulted in sub-therapeutic rifampicin plasma concentrations in a majority of patients, while other drugs had a more favorable pharmacokinetic profile.82 In a study of eight critically ill patients with TB and acute respiratory failure, blood samples were obtained at steady state.83 The Cmax of pyrazinamide was above the recommended concentration of >20 mg/L; for rifampicin, the Cmax was below the recommended level of >8 mg/L and the Cmax of INH was below the recommended levels of >3 mg/L.83 In another study involving 20 critically ill patients, rifampicin concentrations were low in all patients receiving continuous enteral feeding.84 In another study of 81 HIV patients hospitalized for sepsis, with or without meningitis, who were initiated on first-line anti-TB drugs, 49 completed pharmacokinetic studies.75 Serum Cmax targets were achieved in 8.2% with 450 mg of rifampicin, 0% with 300 mg of INH, 89.8% with 1500 mg of pyrazinamide, and 63.2% with 1200 mg of ethambutol.75 Enteral administration of pyrazinamide results in rapid absorption with peak concentration achieved within 1–2 hours.85 Only minor changes in bioavailability occur when it is taken with a meal.

Q16: Is there a Role for Higher Doses of Anti-TB Drugs or Intravenous Anti-TB Drugs in TB Meningitis and Severe Illness?

Position statement: Higher doses of anti-TB drugs or intravenous (IV) preparations, where available, may be considered in TB meningitis and severe illness.

Commentary: Given the reduced bioavailability of enterally administered anti-TB drugs INH, ethambutol, and rifampicin, it may be preferable to administer these drugs at higher doses, or intravenously when they are available, along with enteral pyrazinamide in critically ill patients.76 In one of the earliest phase II trials of patients with TB meningitis, a higher oral dose of rifampicin (13 mg/kg) was found to be safe and possibly associated with survival benefits in severe disease.81 In another study, a higher dose of oral rifampicin (17 mg/kg and 20 mg/kg) resulted in approximately similar AUC0–24, but lower plasma Cmax values compared with 600 mg IV over 1.5 hours.86 In a phase II study, which was predominantly done on HIV individuals, standard dosing of rifampicin (10 mg/kg) was able to achieve CSF concentrations above minimal inhibitory concentration (MIC) in only 11% (2/18) of patients when compared with 93% (14/15) in those receiving 20 mg/kg IV of rifampicin and 95% (18/19) in those receiving 35 mg/kg of rifampicin.87 In another study of 46 HIV individuals, the AUC0-24 for rifampicin was 42.9 µg.h/mL for the standard (10 mg/kg) oral dose, 295.2 µg. h/mL for high (35 mg/kg) oral dose and 206.5 µg.h/mL for IV administration.88 In one study of patients with TB meningoencephalitis and HIV infection, IV INH and ethambutol resulted in higher sputum conversion, clinical improvement, and improved mortality when compared with oral treatment.89 In another study of 152 patients with pulmonary TB, 65 patients received parenteral INH, ethambutol, and rifamycin.90 After the intensive phase, sputum conversion was significantly higher (p < 0.05) in patients treated parenterally (100%) when compared with 71% among controls.90 Given these observations, IV formulations of INH, rifampicin, and ethambutol should be administered where available14 or a higher dose of enterally administered rifampicin may be justified in the critically ill patient with TB, when IV formulations are not available. Since pyrazinamide is not available as an IV preparation and has a favorable pharmacokinetic profile, a standard dose of pyrazinamide can be administered enterally in the critically ill patient. Serious adverse events are however frequent, particularly in the elderly.91 The first- and second-line anti-TB drugs and dosing are given in Table 4. Intravenous preparations of rifampicin, INH, and ethambutol are not available in India. Further studies are required to evaluate the safety and efficacy of higher doses of enterally administered anti-TB drugs in the critically ill.

Q17: What is the Role of Other Intravenous Antibiotics in TB?

Position statement: Although several IV antibiotics such as aminoglycosides, quinolones, linezolid, and carbapenems are effective against TB, these second-line drugs should be used only in the setting of DR-TB, life-threatening TB and in those who do not tolerate first-line anti-TB drugs.

Commentary: Several IV antibiotics commonly used in the treatment of gram-positive and gram-negative organisms are effective against TB (Table 4). However, they are considered only in the setting of drug-resistant TB, intolerance to first-line drugs, or in patients with life-threatening TB. These include aminoglycosides (such as streptomycin, amikacin, and kanamycin), quinolones (such as moxifloxacin, levofloxacin, and gatifloxacin) linezolid and carbapenems (such as ertapenem, imipenem, and meropenem).

IV amikacin is effective in the treatment of MDR-TB. Among 437 MDR-TB of whom 288 were HIV co-infected, 228 (73%) had a good outcome in terms of cure or treatment completion; 270 (62%) developed hearing loss.92 Quinolones are available as IV formulations and used as second-line drugs in TB. In most trials, treatment success was not in favor of quinolones over standard regimens.93 Survival benefit for TB meningitis was observed in only one of three published trials.93,94

In a systematic review of the use of carbapenems in TB that included two studies on ertapenem, one on imipenem and four on meropenem, that included patients with XDR-TB, the authors concluded that culture conversion rates ranged between 60 and 94.8% with the proportion of adverse events attributable to carbapenems below 15%.95 The bactericidal activity of meropenem was greater with 6 gm daily than with 3 gm daily.96 Although β-lactam antibiotics have achieved overall success, their usage for treating TB is limited due to inherent resistance induced by the existence of a chromosomally-encoded gene (BLaC) in M. tuberculosis, which encodes for a Class A Ambler β-lactamase (BlaC). In vitro studies suggested that the activity of carbapenems against M. tuberculosis was increased when used in combination with clavulanate, a BLaC inhibitor.97 In TB meningitis, CSF levels were undetectable in 79% of samples.98

Linezolid may be effective in treating XDR or pre-XDR-TB. In a recently published study, of the 181 participants enrolled, 88% had XDR or pre-XDR-TB.99 A favorable outcome was observed in 84–93% of participants who were administered bedaquiline-pretomanid-linezolid (BPaL) combination. The overall risk-benefit ratio favored the group that received a lower dose of linezolid (600 mg/d) for 26 weeks compared with the higher dose (1200 mg/d) for 26 weeks or 600 mg for 9 weeks.99 In another study involving 69 patients, better treatment outcomes, fever recurring adverse events, and tolerance to longer duration of linezolid were observed when patients were switched from 600 to 300 mg per day of linezolid.100 There was pharmacokinetic evidence of the potential usefulness of linezolid in TB meningitis,101 with the extent of CSF penetration around 30% of plasma exposure and correlating with CSF protein concentrations.102

It must be kept in mind that the indiscriminate use of these antibiotics as empiric treatment for fever of unknown origin could potentially mask an underlying tubercular infection and may delay its diagnosis.

Q18: How Should Drug-resistant TB (DR-TB) be Treated in the ICU?

Position statement: Patients with DR-TB should be enrolled in The National TB Elimination Programme (NTEP) if not already enrolled. The NTEP has adopted a bedaquiline-based DR-TB regimen in India based on WHO guidelines. Treatment should be started in consultation with respiratory physicians and NTEP. The recommended drugs and duration of treatment in such patients are guided by the program management of DR-TB in India.

Commentary: Patients with MDR-TB need a multi-disciplinary approach. The recommended anti-TB drug regimen is based on the findings from the NiX-TB,103 ZeNiX-TB99 and TB-PRACTECAL trials.104 In the NiX-TB trial, the safety and efficacy of an all-oral three-drug BPaL regimen administered over 6 months in patients with treatment-intolerant or nonresponsive MDR-TB or XDR-TB was assessed. With this regimen, 90% (95% CI, 83–95%) of patients had satisfactory outcomes; nevertheless, the daily high dose of linezolid was associated with a significant incidence of side effects, with 48% developing anemia and/or thrombocytopenia and 81% developing peripheral neuropathy.

Linezolid at lower daily doses was better tolerated with fewer adverse events.99,100,104 Three 24-week BPaL-based therapy regimens with linezolid (BPaL, BPaLC (with clofazimine), and BPaLM (with moxifloxacin) were compared to standard-of-care treatment in the TB-PRACTECAL trial to assess their efficacy and safety. At 72 weeks, 89% of patients in the BPaLM arm reported treatment success, compared to 52% of patients in the standard-of-care arm.

The WHO updated its DR-TB guidelines in 2022,33 recommending the BPaLM regimen as the preferred regimen for patients with MDR/RR-TB when fluoroquinolone susceptibility is presumed or documented, and BPaL alone for patients with additional fluoroquinolone resistance (pre-XDR-TB).

Q19: Is there a Risk of Drug-drug Interaction with Commonly Used Anti-TB Drugs?

Position statement: There are significant drug-drug interactions with the commonly used anti-TB drugs. Clinicians need to be familiar with the common interactions in the ICU setting.

Commentary: The commonly used anti-TB drugs have significant drug interactions by virtue of inhibition or activation of enzymes. The mechanism of action of the anti-TB drugs, the mechanism of drug-drug interaction, and the important drug interactions are summarized in Table 5. Clinicians must be familiar with the common interactions in the ICU setting, particularly with rifampicin (Table 6). Therapeutic drug monitoring (TDM) may be considered, where available, when significant drug interactions are likely to lead to toxicity or sub-therapeutic effect. For more information, the readers may refer to the exhaustive review of the drug interactions published in 2020.105

Table 5 Important drug-drug interactions and mechanisms105

Drug	Mechanism of action/mechanism of drug interaction	Important drugs interactions	
Isoniazid	Destruction of cell wall, generating RO
Drug interaction:
Inhibits cytochrome P450 system and acts as a mild monoamine oxidase inhibitor	Disulfiram, acetaminophen, antacids, rifampicin, oral hypoglycemic agents, anticonvulsants, theophylline	
Rifampicin	Inhibits DNA-dependent RNA polymerase; decreases affinity of RNA polymerase for short RNA transcripts.
Drug interaction:
Induces P450 cyto-chrome oxidases (CYP3A4, CYP2A, CYP2B, CYP2C, CYP3A), and human P glycoprotein ABC transporter	Morphine, antacids, antiarrhythmics, several antibiotics, anticoagulants, anticonvulsants, antidepressants, INH, pyrazinamide, bronchodilators, steroids, tacrolimus, cyclosporin, retrovirals, thyroid hormones	
Ethambutol	Inhibits arabinosyl transferases involved in synthesis of mycobacterial cell wall	Coadministration with aluminum salts delays and reduces the absorption of ethambutol. Other drugs potentially causing optic neuritis should be avoided	
Pyrazinamide	Nicotinamide analog; inhibits the coenzyme A biosynthesis	Concomitant administration of pyrazinamide with isoniazid and/or rifampin is associated with an increased risk of hepatotoxicity	
Fluroquinolones	Inhibits DNA gyrase	Antacids, antiarrhythmics, rifampicin, warfarin, insulin, bronchodilators, cyclosporin, tacrolimus	
Amikacin	Blocks 30S ribosomal subunit	Diuretics, cephalosporins, cyclosporin, colistimethate sodium, tacrolimus	
Carbapenems	Inhibiting BlaC beta-lactams	Caution in patients with TB meningitis and when coadministered with ganciclovir and valproic acid	
Linezolid	Binds 50S subunit of prokaryotic ribosome, prevents formation of initiation complex, inhibits protein synthesis
Drug interaction:
Reversible inhibitor of monoamine oxidases A and B and serotonin agonists	Rifampicin, warfarin, antidepressants (SSRI like fluoxetine, sertraline), fentanyl, morphine derivatives	
ROS, reactive oxygen species; SSRI, selective serotonin reuptake Inhibitor

Table 6 Drugs frequently prescribed in the ICU and their interaction with rifampicin

Drugs	Comment	
Oral anticoagulants	Avoid newer oral anticoagulants (dabigatran, rivaroxaban, apixaban), warfarin may be used with international normalized ratio monitoring (dose escalation likely required)	
Glucocorticoids	Increase dose of glucocorticoid 2–3-fold	
Azoles	If possible, avoid (voriconazole, itraconazole, posaconazole). Fluconazole has less reduction in serum concentration compared to other azoles. Monitor for response	
Atorvastatin	Monitor lipid panel; increased dose will likely be needed	
Phenytoin	Monitor serum phenytoin concentrations and seizure activity, dose escalation likely required	
Midazolam	Preferably avoid with rifampin, use alternatives	
Tacrolimus	Monitor serum tacrolimus concentrations and clinical response, increased dose may be required, use alternatives if possible	
Cyclosporine	Monitor serum cyclosporine concentrations, dose escalation likely required	
Anti-retroviral drugs	Use dolutegravir-based regimen, double the dose of dolutegravir	

Multiple drug interactions, particularly with calcineurin inhibitors (CNI), mTOR (mammalian target of rapamycin) inhibitors, and glucocorticoids106 can occur in post-transplant patients on immunosuppression. These can lead to an increased risk of graft rejection, up to 25%.107 Based on these, modifications of immunosuppressant medication doses have been suggested to the tune of a three to five-fold increase in CNI or mTOR inhibitors, with doubling of steroid dose.108 Though some investigators have demonstrated adequate serum levels,109 other investigators have reported the relative impossibility of such attempts.110,111

Q20: What is the Role of Corticosteroids in TB?

Position statement: Corticosteroids may be effective in reducing clinically relevant adeverse outcomes in some forms of TB.

Commentary: Corticosteroids may be effective in reducing clinically relevant outcomes in some forms of TB (Table 7).112–116 In patients with pulmonary TB admitted to ICU with acute respiratory failure (ARF) (n = 124), steroids were associated with reduced 90-day mortality (OR 0.47; 95% CI, 0.22–0.98; p = 0.049) using inverse probability treatment weighting (IPTW) method.117 Steroids were prescribed in this study for ARDS, shock, wheeze, or disseminated TB. On TB pleural effusions, six trials (n = 590) were summarized in a Cochrane review.112 The risk of residual pleural effusion on chest X‐ray reduced by 45% at 8 weeks and 65% at 24 weeks.112 In TB meningitis, a systematic review of nine RCTs (n = 1337), showed a reduction in death (RR 0.75, 95% CI, 0.65–0.87); however, there was no effect on disabling neurological deficits.113 In HIV-negative individuals, steroids may reduce the risk of death (4 trials, n = 660, RR 0.80, 95% CI, 0.59–1.09), and the need for pericardiocentesis (RR 0.85, 95% CI, 0.70–1.04) in patients with TB pericardial effusions; there is uncertainty on the effect of steroids on constriction and in HIV individuals.118 In a small study of 13 patients, high dose methylprednisolone (500–1000 mg/d for 3 days) was associated with higher 3-month survival in miliary TB complicated by ARDS.114 Steroids may also be indicated in immune reconstitution inflammatory syndrome (IRIS) and adrenal insufficiency. The role of steroids in the various forms of TB is summarized in Table 7.

Table 7 Steroids for tuberculosis

Type of TB	Steroid type and dose	Comments and supporting evidence	
Pulmonarya	Adults: Prednisolone 50 mg or equivalent; duration unclear	Pulmonary TB admitted to ICU with ARF (n = 124), steroids reduced 90-day mortality (OR 0.47; 95% CI, 0.22–0.98; p = 0.049) using IPTW method.117 Steroids prescribed for ARDS, shock, wheeze or disseminated TB. Meta-analysis suggested that steroids could be effective in reducing mortality for all forms, including pulmonary TB.115	
TB pleural effusion	Prednisolone 1 mg/kg reduced after 1–2 weeks, total duration max up to 3 months	Six trials (n = 590) summarized in a Cochrane review. Risk of residual pleural effusion on chest X‐ray reduced by 45% at 8 weeks and by 65% at 24 weeks.112	
TB meningitis	Dexamethasone 0.6 mg/kg children, 0.4 mg/kg adults intravenously to be tapered on a weekly basis by 0.1 mg/kg—then oral therapy starting at 4 mg per day decreasing by 1 mg every 7 days;119
Prednisolone 2–4 mg/kg children, adults 2.5 mg/kg for 6–8 weeks and then taper116	Systematic review of nine RCTs (n = 1337), reduction in death (RR 0.75, 95% CI, 0.65–0.87); no effect on disabling neurological deficits.113	
Pericardial	Adults: prednisone 60 mg/day (or equivalent) for 4 weeks, followed by 30 mg/day for 4 weeks, 15 mg/day for 2 weeks, and 5 mg/day for 1 week	In HIV-negative individuals, may reduce risk of death (4 trials, n = 660, RR 0.80, 95% CI, 0.59–1.09), need for pericardiocentesis (RR 0.85, 95% CI, 0.70–1.04); uncertainty on effect on constriction and in HIV individuals.118	
TB-associated IRIS	Prednisone 40 mg per day for 14 days, followed by 20 mg per day for 14 days	RCT on prophylactic prednisolone to reduce IRIS in patients with TB and HIV infection who were ART naïve was associated with lower incidence of TB-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers.143	
Adrenal insufficiency	Hydrocortisone 50–100 mg 6–8 hourly acute phase; maintenance prednisolone	Adrenal insufficiency can be confirmed by diminished response to synthetic adrenocorticotropin. Should be suspected when there is hypotension needing high-dose vasoactive agents	
aincludes pulmonary and tuberculosis (TB) acute respiratory distress syndrome (ARDS); ART, anti-retroviral therapy; HIV, human immunodeficiency virus; ICU, intensive care unit; IPTW, inverse probability of treatment weighted; RCTs, randomized controlled trials; RR, risk ratio; IRIS, immune reconstitution inflammation syndrome;

Q21: Is there a Role for TDM in DR-TB?

Position statement: There is insufficient evidence to recommend routine TDM during the treatment of DR-TB.

Commentary: There is currently little evidence to support TDM for medications used to treat MDR/RR-TB. Even though there is good reason to use TDM, it is unclear if this enhances treatment outcomes and lowers resistance risk. However, given that rifampicin exhibits a significant amount of pharmacokinetic variability and that the exposures resulting from the recommended doses lie on the steep side of the dose-response curve, ensuring adequate drug concentrations, either through TDM or higher dosing, may play a significant role in DR-TB prevention strategies.119 TDM may be considered in patients who are slow to respond to treatment, have drug-resistant TB, are at risk of drug-drug interactions, or have concurrent disease states that significantly complicate the clinical situation.120

Q22: How do Risk Prediction Scores Perform in TB in the Critically Ill?

Position statement: Risk prediction scores should not be relied on for mortality prediction in TB.

Commentary: Tuberculosis requiring ICU admission has high mortality. In a systematic review of 17 studies, APACHE II, SOFA, and SPAS II scores underestimated mortality in pulmonary TB.121 Factors associated with negative outcomes included hospital-acquired infections, need of mechanical ventilation and vasopressors, delay in initiation of anti-TB treatment, more than one organ involvement, and higher severity score.

Tuberculosis in the Immunocompromised Host

Among patients admitted to the ICU with TB, immunocompromised patients comprise 6.9–68.7% of the cases.122,123 The umbrella term of “immunocompromised individual” includes patients with acquired or primary immune deficiency, patients on glucocorticoids, other immunosuppressant drugs for the treatment of connective tissue disorders, post solid organ transplant, and hematological malignancies in the pre- and post-transplant periods.124 The increasing efficacy of treatment for these diseases has resulted in a change in the scenario from uniformly fatal diagnoses to treatable or manageable chronic comorbid conditions. At the same time, the presence of immune deficiency of a chronic nature and the ubiquitous presence of TB bacilli (especially in countries with high prevalence of TB) makes the risk of infection with TB several-fold higher.122 Understanding the risks of infection and clinical syndromes that tuberculosis manifests with, in the immunocompromised critically ill individual is essential to diagnose TB and to provide optimal care.

Q23: Does the Immunocompromised State Predispose an Individual to Reactivation of Latent TB or the Acquisition of TB?

Position statement: Since immunocompromised patients are at risk for TB, the clinical suspicion should be high in patients admitted to the ICU. The interpretation of tests for latent TB infection (such as the TST and IGRA) are likely to be influenced by immunosuppression and the severity of critical illness.

Commentary: Immunocompromised hosts have a 10–110-fold higher risk of latent TB reactivation in HIV infection and 20 times higher risk in solid organ transplants than the general population.125,126 While latent TB screening by TST or IGRA is advised before the use of immunosuppressive drugs such as anti-TNF alpha, and prior to solid organ and hematological transplants,125,126 in severely ill patients with coexisting immunological insufficiency (acquired or primary), these tests may yield more ambiguous results.127,128 After recovery from critical illness, 48% of results remain ambiguous.127 These results were related with higher severity of critical illness and lower blood albumin levels.

Solid organ transplant recipients have the highest TB risk compared to allogenic hematopoietic stem cell transplant (HSCT) recipients and the general population.129 Lung transplant recipients have a 5.6-fold higher risk of TB than other stem cell recipients.130 Allogenic transplant with unrelated donor (RR 23.9), prior total body irradiation (RR 4.9), and persistent GVHD (RR 3.6) should raise clinical suspicion for TB in post-HSCT patients.131

Tuberculosis symptoms typically appear in the first year after solid organ transplantation, albeit the timing varies.130 Up to 30% of patients may acquire TB later in the post-transplant phase, with renal transplants causing symptoms later than lung and liver transplants.130 Pulmonary was the most common site in renal transplant recipients, with a median presentation period of 46–196 days. Post-allogenic HSCT recipients average 150 days of symptoms,129 with a median gap of 6–7 weeks between symptoms and diagnosis.132

Q24: Is the Clinical Presentation of TB in the Immunocompromised Individual Similar to that of the Immunocompetent Host?

Position statement: In an immunocompromised host, the clinical presentation of TB may be more insidious and likely to be disseminated. TB should be suspected when there is unexplained worsening of clinical status. The surveillance for atypical presentations of TB should be robust in order to pick them up early.

Commentary: In the immunocompetent host, the most common reason for admission due to TB is acute respiratory failure, followed by septic shock with multiorgan dysfunction.4 In contrast, the clinical presentation of TB infection in the immunocompromised patient is more insidious. The symptoms are limited in intensity even though TB may be of a disseminated nature.122 In patients with HIV co-infection, lower CD4 counts are associated with a higher prevalence of extrapulmonary infections and miliary TB, which signifies hematogenous dissemination.133

In the immunocompromised post-solid organ transplant recipient, about one-third to one-half of all cases of active TB are disseminated or occur at extrapulmonary sites. Atypical presentation of TB such as pyomyositis, cutaneous ulcers or abscess, and tenosynovitis also occurs.108,134 Clinical suspicion for TB should be high in patients with respiratory failure after treatment for acute rejection.124,135

The absence of fever in about 20–31% of patients could confound the diagnostic paradigm.124,135 As in other groups of immunocompromised patients, clinical presentation is indolent. Atypical presentations including diffuse alveolar hemorrhage have been reported.131

Q25: What should the Diagnostic Work be in the Immunocompromised Host Who is Suspected to have TB Infection?

Position statement: Taking into consideration the indolent nature of TB in the immunocompromised patient, cross-sectional imaging should be considered early to guide diagnostic sampling. Early invasive sampling including bronchial lavage and/or biopsy is advocated in these patients.

Commentary: In post-renal transplant patients, the pattern of pulmonary involvement was found to be miliary nodules (40%), cavitation and centrilobular tree-in-bud nodules (22.5%), ground-glass attenuation and consolidation (15%), mediastinal lymph node enlargement (12.5%) and pleural effusion (10%) constituted the major HRCT patterns.136

In post-HSCT patients, most common pattern of pulmonary involvement of the chest X-ray was that of consolidation (100%) and nodules (80%).82 On cross-sectional imaging, the most common imaging findings were consolidation (100%), nodules (71%), tree-in-bud appearance (43%), and ground-glass opacity (43%).136 In contrast, cavitations were only found in 14% of patients and lymphadenopathies in 71% of patients.136

In post-renal transplant recipients, respiratory samples yielded microbiological evidence of TB, but the culture of at least one sample from other areas was positive in 53% of patients.124 In a study of patients with HIV co-infection, invasive sampling in the form of BAL and organ biopsy were needed in 11% and 25% of the patients respectively.137

Q26: What would the Approach be in the Management of TB in the Setting of Intestinal Malabsorption?

Position statement: In patients with anticipated poor enteral uptake of antituberculous treatment (ATT) [short bowel, gut graft vs host disease (GVHD), severe multiorgan dysfunction with high-dose vasoactive medications], parenteral ATT may be considered along with TDM.

Commentary: Data is lacking on ATT in patients with anticipated poor enteral uptake of ATT. This includes critically ill patients on organ support, short bowel syndrome, and gut GVHD. Case reports and expert opinions are the sources of information for these patients.138,139 Expert opinion has advocated pragmatically to initially use an IV regimen in critically ill patients.76 The suggested regimens include rifampicin along with moxifloxacin and amikacin,76 IV fluoroquinolones with oral anti-TB drugs,140 or higher doses of rifampicin (15 mg/kg/day) along with fluoroquinolone (levofloxacin 20 mg/kg/day).81

Q27: What would the Approach be to IRIS in TB?

Position statement: IRIS should be suspected when there is paradoxical worsening of symptoms, typically seen when immunosuppression is reduced or reversed. IRIS can also occur in the immunocompetent host. A course of steroids should be considered.

Commentary: IRIS describes the paradoxical worsening of a pre-existing infectious process, typically seen when immunosuppression is reduced/reversed. Although it is seen in patients with HIV-TB co-infection, it can also be seen in immunocompetent patients diagnosed with TB, solid organ transplant, and post-HSCT. In one study, the prophylactic use of prednisolone in patients with TB and HIV infection who were ART naïve was associated with a lower incidence of TB-associated IRIS than placebo, without evidence of an increased risk of severe infections or cancers.141 However, evidence or treatment protocols for solid organ transplants are nonexistent, with case reports suggesting the continuation of ATT142 and high-dose corticosteroids,143 with some advocating the use of NSAIDS and tocilizumab.144

Organ Support

Q28: Is the Ventilatory Management of Respiratory Failure due to TB Different from the Ventilatory Management of Respiratory Failure due to Other Infective Etiologies?

Position statement: There is limited data on the management of respiratory failure in patients with TB. The management of respiratory failure in patients with TB should be along the same lines of management as with other infective etiologies of hypoxemic and hypercapnic respiratory failure.

Commentary: In a case series published in 1987, of the 15 patients admitted with respiratory failure due to TB, 11 required mechanical ventilation and 4 patients had evidence of hypercapnic respiratory failure.145 The radiological features ranged from lobar pneumonia, pleural effusion, bronchopneumonia, and miliary involvement to the destruction of lungs; 33% died in ICU.145,146 In a study from North India21 involving 63 patients, 90.5% were ventilated and the mortality was 44.4%. In a larger study of 212 patients, 87.7% were ventilated and the mortality was 50%.8

In the absence of studies that have focused on invasive mechanical ventilation for respiratory failure due to TB, the current guidelines for safe ventilatory strategies that were summarized in the recent 2023 European Society of Intensive Care Medicine (ESICM) should be followed.147 This includes low tidal volume (LTV: 4–8 mL/kg predicted body weight), titration of positive end-expiratory pressure (PEEP), maintenance of a plateau pressure of <30 cm H20, avoidance of prolonged high-pressure recruitment maneuvers (airway pressures maintained ≥35 cm H20 for at least 1 minute), judicious use of continuous infusion of neuromuscular blocking agents and the use of prone positioning in patients with moderate-severe ARDS (defined as PaO2/FiO2 < 150 and PEEP ≥ 5 cm H20), despite optimization of ventilation settings.147

Q29: Should Noninvasive Respiratory Support be Considered in the Management of Acute Respiratory Failure Due to TB?

Position statement: The use of noninvasive respiratory support including HFNC is challenging given their tendency to cause aerosol dispersion and spread of infection to HCWs. It is preferable to use this in isolation facilities with adequate precautions by staff.

Commentary: A recent study examined the extent of exhaled air dispersion with the use of noninvasive ventilation (NIV) devices.148 They observed that continuous positive airway pressure (CPAP) dispersed air up to 366 mm in the sagittal plane, with the use of positive end-expiratory pressure (PEEP) up to 20 cm H2O via nasal pillows, whereas HFNO dispersed up to 205 mm with flow up to 60 L/min. The dispersion on HFNO increased to 620 mm when the interface became loose. A meta-analysis showed that NIV was a significant risk factor for transmission of acute respiratory infections, with an odds ratio of 3.1 (1.4–6.8), while HFNO was not.149 However, these studies were done in the non-TB setting.

In a small case series of 3 patients, published in 2005, NIV was used to successfully treat patients with moderate-severe ARDS due to TB with PF ratios in the range of 110–120.150 In another study of 58 patients with acute exacerbation of pulmonary TB sequelae, 86.2% were successfully weaned off supports.151 In a more recent study of 44 patients with TB and respiratory failure who required mechanical ventilation, the use of NIV post-extubation was associated with a significant (p < 0.001) reduction in the duration of ventilation (–36.2 hours, 95% CI, –53.6 to –18.8 hours) and a significant reduction in the risk (RR 0.44, 95% CI, 0.24–0.83) of ventilatory associated pneumonia.152

Q30: Is there a Role for Extracorporeal Membrane Oxygenation (ECMO) Support in TB?

Position statement: There is limited evidence for the use of ECMO in TB. It may be considered in TB in the setting of refractory respiratory or cardiac failure.

Commentary: A systematic review of case reports on the use of ECMO in 43 cases of TB over 47 years, was published in 2024.153 The indications for ECMO were ARDS in 83.4% (n = 30) and cardiac failure in 9 patients. Twenty-seven patients were exclusively on veno-venous ECMO (VV ECMO), while 5 patients were exclusively on veno-arterial ECMO (VA ECMO). In 4 patients, VA ECMO was commenced for respiratory failure coupled with hemodynamic instability. At the end of the observation period, 81.4% survived. The authors concluded that ECMO could have a positive effect on overcoming ARDS or bridging the time until response to anti-TB drugs.153

Q31: How Should Massive Hemoptysis be Managed?

Position statement: Patients with massive or life-threatening hemoptysis should be managed in an ICU with a focus on airway and hemodynamic stabilization, evaluation of source of bleed by CT angiogram or bronchoscopy, and consideration of bronchial artery embolization as an early treatment option. Nebulized and/or intravenous tranexamic acid may reduce the volume of hemoptysis.

Commentary: Patients presenting with massive hemoptysis should be initially stabilized with a focus on airway, breathing and circulation and correction of coagulopathy. The evaluation of the source of bleeding should be done by bronchoscopy or CT angiogram. In one study of 28 patients with massive hemoptysis of diverse etiology, bronchoscopy was essential in making the diagnosis in only 10.7% of cases and it was comparable with radiographs in 82% of the patients.154 Although bronchoscopy and CT were comparable in identifying the site of bleeding (73 vs 70%), CT was more efficient in identifying the cause of bleeding.155 If the airway is compromised, intubation will be required; selective intubation of one bronchus and single lung ventilation using double lumen endotracheal tube may be required to prevent aspiration of blood into the normal lung.156

Nebulized and/or intravenous tranexamic acid at the dose of 500 mg thrice daily may be associated with a reduction in the volume of hemoptysis. Inhaled tranexamic acid is safe157 and may be associated with a reduction in the volume of hemoptysis in nonmassive hemoptysis.158 Its role in massive hemoptysis is unclear.

The definitive management for life-threatening hemoptysis is bronchial artery embolization. In a systematic review of the role of bronchial arterial embolization for hemoptysis, 22 studies were included.159 The common indications included TB, post-TB sequelae, and aspergillomas. The overall success of embolization, defined as complete cessation of bleeding, ranged from 70 to 99%; recurrence rates were high at 10–57% and attributed to incomplete initial embolization, recanalization of previously embolized arterial, and the development of new collaterals.159

Q32: When Should Tracheostomy Considered in Patients Ventilated for TB?

Position statement: The indications and timing of tracheostomy in patients admitted to the ICU with TB are similar to those of other patients admitted to critical care. There is inconclusive evidence to recommend early tracheostomy in patients with TB.

Commentary: A proportion of patients admitted to the ICU for the management of TB may require tracheostomy. In one study published in 2018, of the 63 patients admitted to the ICU, 9 patients (14.3%) required tracheostomy.21 In another study of patients with TB-ARDS, 5 out of 47 (10.4%) required tracheostomy.10 There are no studies that have addressed the question of timing of tracheostomy in TB patients admitted to the ICU. However, two recent systematic reviews on tracheostomy in critically ill patients, which have included 15 studies with 3,003 patients160and 17 studies enrolling 3,145 patients,161 respectively, showed that early tracheostomy (≤7 days) was associated with a reduced in ventilator-associated pneumonia (VAP); however, there was significant heterogeneity of treatment effects (I2 > 60%). The duration of ventilation was reduced by about 1 day with early tracheostomy. There was no effect of early tracheostomy on mortality. In the Indian setting, where there may be financial constraints on prolonged hospitalization and the challenges of managing a tracheostomy at home, the decision on tracheostomy should be made with much deliberation.

Q33: What is the Optimal Management of Hypotension due to Adrenal Insufficiency and Septic Shock with Mycobacteremia (Landouzy Sepsis)?

Position statement: In TB, shock may be due to adrenal insufficiency, secondary bacterial sepsis, or mycobacteremia. Shock should be managed along the same lines as the management of septic shock. Early initiation of anti-TB treatment is important. Steroids are indicated for refractory septic shock, adrenal insufficiency, and shock due to mycobacteremia.

Commentary: Adrenal insufficiency can occur in the setting of TB due to involvement of the adrenal gland due to TB or due to relative adrenal insufficiency during critical illness. It can be confirmed by diminished response to synthetic adrenocorticotropin. Adrenal insufficiency should be suspected when there is hypotension requiring high-dose vasoactive agents. In the acute setting, replacement should be done with IV hydrocortisone. Subsequently, replacement doses of oral steroids (prednisolone) may be required.

Very few case reports of mycobacterial septicemia exist, and most are documented in those with HIV.162 Immunocompetent patients may also present with fulminant multiorgan failure and vasoplegic shock, indistinguishable from bacterial sepsis. The overall management of this condition is the same as that of septic shock, in general. Anecdotal reports on the use of pulse steroids exist.163 However, the disease is almost always fatal.162–164

Q34: What is the Optimal Management of Renal Failure in Patients with TB?

Position statement: Renal failure in TB should be managed along the same lines as the approach to managing acute kidney injury in the setting of other infectious diseases. Drug dosing should be optimized for renal function, and nephrotoxic agents should be avoided.

Commentary: Renal failure may occur as part of the multiorgan dysfunction syndrome in TB or as a result of secondary infections. It should be managed along standard guidelines for the management of renal failure. Drug dosing would need to be adjusted in the setting of renal failure. Isoniazid and rifampicin do not require any dose adjustment in renal failure.165 Although pyrazinamide is largely cleared by the liver, due to possible delayed elimination of the drug and its metabolite, a dose of 25–30 mg/kg thrice weekly is recommended in stage IV and V chronic kidney disease (CKD) and in patients on hemodialysis.165 The dose of ethambutol needs to be reduced to 15–25 mg/kg thrice weekly in CKD stages IV and V.165

Q35: Is there a Role for First-line Anti-TB Drugs in Patients with Liver Involvement in TB?

Position statement: Patients with liver involvement due to TB should be started on standard four-drug regimen, irrespective of baseline liver function tests.

Commentary: Patients with liver involvement due to TB (based on imaging or biopsy) should be started on standard four-drug regimen, irrespective of baseline liver function tests. In case of subsequent clinical or biochemical worsening, close monitoring, and possible biopsy is warranted to differentiate between hepatic TB and drug-induced liver injury (DILI) and TB-related IRIS. If DILI is suspected, hepatotoxic anti-TB drugs should be discontinued and rechallenged. If the diagnosis is TB-related IRIS, the drugs may be continued with close monitoring and steroid cover. A meta-analysis published in 2015 showed inferior outcomes in patients with hepatic TB treated with monotherapy or nonhepatoxic regimens compared to those with full-dose multi-drug therapy with INH, rifampicin, pyrazinamide, and ethambutol.166

Q36: Is there a Role for Low-volume Plasma Exchange (PLEX) in Patients with Liver Dysfunction due to TB or DILI?

Position statement: In patients with acute liver failure (ALF) or acute on chronic liver failure (ACLF) due to anti-TB drugs induced DILI, low-volume plasma exchange may be considered especially in those who fulfill the King's College criteria for liver transplantation but do not have access to the same.

Commentary: There is emerging evidence that shows that low-volume PLEX in specific sub-populations of liver failure may provide a mortality benefit over standard medical therapy, especially in patients with limited access to liver transplantation. A recent meta-analysis has shown promising results in ALF and ACLF, not specific to TB or TB-DILI. Preliminary data from a prospective trial conducted to assess the role of PLEX in DILI (which had 14% of patients with TB-DILI) showed survival benefit over standard medical care and improvement in hepatic encephalopathy. Based on this, it may be reasonable to consider PLEX as an option in ALF and ACLF, especially in areas without access to liver transplantation.167–170

Infection Control

There is evidence that primary transmission of drug-resistant bacteria is the main mechanism for the global spread of drug resistant TB, rather than acquired resistance. So, identifying the source of infection quickly and halting its spread by effective infection prevention and control (IPC) measures are therefore imperative. Infection prevention and control strategies focus on lowering the concentration in airborne particles and the duration of exposure among healthcare providers.

Healthcare workers (HCWs) have an increased risk of contracting M. tuberculosis infection when compared with the general population.171 It is therefore critical to implement and maintain effective strategies for controlling TB infections.172 Administrative control implementation,173,174 utilizing triage, and patient isolation, are the fundamental and essential components of any IPC strategy. Furthermore, the strategies prioritize the implementation of respiratory hygiene and the timely initiation of effective treatment. Additional methods encompass engineering and environmental controls. While the evidence for the effectiveness of IPC measures is limited, the deployment of numerous measures has shown a definite decrease in the risk of TB occurrence among HCWs and those visiting healthcare facilities.174

Q37: What are the Recommended Isolation Systems for Patients with Presumed or Documented Infectious TBs in the ICU?

Position statement: Respiratory isolation of individuals with confirmed or suspected infectious TB is advised, ideally in an airborne infection isolation room (AIIR) equipped with a high-efficiency particulate air (HEPA) filter and negative pressure. Closed suctioning is recommended for intubated patients. The application of a bacterial filter to the ventilator tubing's expiratory limb may reduce the transmission of infection.

Commentary: Patients diagnosed or suspected to have pulmonary TB should be isolated in an AIIR to mitigate the potential transmission of TB particles. It was found that respiratory isolation of patients with putative or confirmed infectious TB reduced the risk of active TB infection among HCWs by 2% and latent TB infection by 45%,172 respectively. It is recommended that AIIR implement negative pressure ventilation, with a minimum of 6 air changes per hour (ACH) and a maximum of 12 per day.175 High-efficiency particulate air filters are recommended to handle the exhaust from the room. Therapeutic interventions and diagnostic assessments that necessitate patients to be transferred from the isolation facility must be limited and preferably performed within the AIIR as far as possible.

Although animal models have demonstrated a reduction in latent TB infection in rooms treated with upper room ultraviolet germicidal irradiation (UVGI) with ultraviolet-C light to kill or inactivate airborne M. tuberculosis,176 the evidence is scant, and its efficacy may be compromised when the relative humidity in the room exceeds 50–60%.177

Nonventilated patients diagnosed or suspected of having TB who are coughing should be provided with surgical masks.175 Although studies have demonstrated a decline in latent TB infection among HCWs,178 there is no evidence indicating a reduction in active TB infection. Drawing a parallel from the patients wearing masks to decrease transmission, we recommend that closed suctioning is used for intubated patients to reduce the dispersal of respiratory secretions that contain infectious M. tuberculosis. Furthermore, to prevent the spread of pathogens, endotracheal tubes or the expiratory side of the ventilator may be equipped with a bacterial filter capable of capturing particles as small as 0.3 µm with an efficacy of at least 95%. Standard environmental cleaning of the ICU room should be sufficient to disinfect the room given that M. tuberculosis is transmitted exclusively through airborne transmission and not through surface contact.179

Q38: What are the Key IPC Measures for HCWs Taking Care of Patients with Suspected or Confirmed Tuberculosis in the ICU?

Position statement: Healthcare professionals entering rooms of patients with suspected or confirmed contagious TB disease should wear a properly sized N95 disposable respirator.

Commentary: Although surgical masks can reduce the number of infectious particulates in the air, their filtration efficiency is only 50% and they fail to form a secure seal on the face; therefore, they are unsuitable for HCWs. Specific respiratory protection, including properly fitted N95 masks, filters at least 95% of particulate 1 µm in diameter when utilized appropriately and with a snug facial seal. In order to achieve this, medical facilities that treat TB patients should establish protocols for periodic respirator fit testing, initial respirator fit testing, and annual respirator training.175

Sputum induction and nebulization therapy provoke coughing, heightening the risk of transmission of M. tuberculosis.180,181 While doing procedures that generate aerosols, such as intubation, bronchoscopy, or sputum induction, HCWs should wear at the barest minimum, N95 respirators.182 However, for these procedures, it is advisable to use a higher level of respiratory protection, such as an elastomeric full-facepiece respirator or a powered air-purifying respirator (PAPR), instead of a N95 disposable respirator.175,182

Q39: When can Respiratory Isolation Precautions be Discontinued for Critically Ill Patients with Pulmonary TB?

Position statement: For sputum-positive rifampicin susceptible TB patients, a minimum of 2 weeks of isolation is suggested, while on effective anti-TB treatment.

Commentary: There is a lack of distinct, unequivocal guidelines and insufficient evidence regarding the de-isolation of patients with sputum-positive pulmonary tuberculosis.183 The 2 weeks of isolation is based on a review article by Rouillon et al. in the 1970s, which suggested that with effective treatment, patients may lose infectivity in probably less than 2 weeks.184 Dharmadhikari et al. found that patients on successful treatment lose infectivity, even if they are AFB microscopy and culture positive.185 There is evidence to suggest that isolation may be needed for patients with negative smears, as they too possess the capacity to transmit the infection; research has shown that smear-negative culture-positive tuberculosis is responsible for approximately 17% of TB transmission.186

Q40: Is there a Role for Routine Testing and Surveillance of HCWs Managing Infectious TB Patients?

Position statement: The role and benefit of regular testing and surveillance for TB infection among HCWs in the ICU, using TST or IGRA, in endemic countries like India is unclear.

Commentary: At present, there is no gold standard test for establishing the diagnosis of LTBI. Two screening tests, TST and IGRAs, are recommended for diagnosing LTBI. Although IGRA may aid in the early detection and mitigation of potential exposures in high-income countries with low TB prevalence, their application in low- and middle-income countries with high endemicity lacks definitive guidelines. Data from high endemic countries have yielded mixed conclusions with regards to active screening. While a study from South India suggested a potential role for screening of HCWs based on a higher annual risk of TB infection,187 a recent individual patient meta-analysis of individual patients found that the efficacy of both IGRA and TST was inferior in countries with a high incidence of TB.188,189

Post-tuberculosis Sequelae

The term post-tuberculosis describes the range of pathological conditions experienced by TB survivors involving various organ systems.190 These post-TB sequelae mainly arise from the disease process or the side effects related to TB treatment.

Q41: Post-TB Sequelae: What are the Reasons for ICU Admission?

Position statement: Post-TB sequelae patients may present to the ICU with respiratory failure due to exacerbation of obstructive airway disease or restrictive fibrotic lung disease, pulmonary hypertension, hemoptysis due to bronchiectasis, aspergillosis or vascular causes or with secondary infections. There are currently no evidence-based recommendations for the investigation and management of post TB lung abnormality (PTLA).

Commentary: One of the most common post-TB sequelae is post-TB lung illness, which can result in respiratory failure and the need for ICU admission. This can happen because of post-TB issues linked to the vascular system, parenchyma, pleura, mediastinum, or airway. Airflow limitation, restrictive diseases, or a combination of both, occasionally linked to respiratory failure, are functional conditions affecting patients.

Studies have shown that up to 50% of patients experience health issues due to PTLA.191,192 Fibrosis accounts for 25.0–70.4%, cavitation for 8.3–83.7%, and bronchiectasis for 4.3–11.2% of the imaging-defined PTLA.193 Younger individuals, patients without HIV and people from high endemic areas are at risk of developing PTLA. In a review of 17 studies among HIV-infected and uninfected individuals, HIV individuals with low CD4 counts and TB were four times more likely to have normal chest radiographs and less cavitation than individuals with higher CD4 counts.194 The extent of impairment in lung functions is more in DR-TB when compared with drug-sensitive TB.195

Exacerbations of chronic obstructive pulmonary disease (COPD), bronchiectasis, and pneumonia are also more frequent after pulmonary TB.196,197 Population-based studies PLATINO and BOLD suggest that prior TB doubles the risk of developing COPD.196,198 According to a recent review, persons over 40 years of age who had a history of TB were significantly more likely to get COPD (odds ratio (OR) 3.05, 95% CI, 2.42–3.85).197 Lung involvement in post-TB COPD is heterogeneous199,200 and may not respond as well to bronchodilators as a regular COPD patient; the use of inhaled corticosteroids in post-TB COPD may increase the risk of reactivation of TB.201

A cross-sectional study of 100 patients indicated a 2.13-fold increase in the chances of pulmonary hypertension post-TB with each further TB episode (CI: 1.17–3.88; p = 0.013).202 Post-TB studies have shown that the prevalence of pulmonary hypertension ranges from 6.3% in outpatients to 42.4% in hospitalized patients and 67% in patients with chronic respiratory failure.203

Patients with a history of TB may present with hemoptysis either from airway-related broncholiths, bronchiectasis, pulmonary aspergillosis, and vascular causes from rupture of Rasmussen's aneurysm or from dilated bronchial arteries. Chronic pulmonary aspergillosis commonly complicates treated pulmonary TB with residual cavitation. Other presentations of aspergillosis that may complicate PTLA include aspergilloma, allergic bronchopulmonary aspergillosis, invasive and chronic pulmonary aspergillosis or asymptomatic colonization. Based on symptoms of cough, weight loss, hemoptysis, CT chest features of cavitation, a fungus ball, pleural thickening, and pulmonary fibrosis, and positive IgG to A. fumigatus, a cross-sectional prospective study from Uganda found that 4.9% of patients who had finished TB treatment 2 years prior had “definite” and another 2.3% had “probable” chronic pulmonary aspergillosis. This increased to 26% among patients with a cavity on CXR.204

Future Directions

There is paucity of good trials on TB in the critically ill. Given that an increasing number of patients are admitted to ICUs with TB and its complications in our country, it is incumbent on ICU practitioners to not only be aware of the problem but also channel efforts to reduce mortality. It is important to focus on studies that will explore rapid diagnostic tests in the ICU setting, particularly for extrapulmonary TB where delays in diagnosis and treatment may result in worse outcomes. Studies on the use of IV anti-TB drugs and/or the use of higher doses of anti-TB drugs in ICU patients is important to address the problems of subtherapeutic concentrations of drugs which are common due to a multiplicity of factors. Therapeutic drug monitoring would be another vital area that would need to become integral to the management of TB in the critically ill. Awareness and knowledge on the key aspects of TB and its management will go a long way in improving outcomes of TB in the critically ill.

Conclusion

Tuberculosis continues to be a major problem in developing countries including India. The more recent increase has been attributed to the COVID-19 pandemic, due to the disruption of services because of the lockdown and diversion of healthcare resources to tackling the pandemic. Newer therapies for the management of cancers and immune disorders, particularly the use of highly potent immunosuppressive agents, have contributed to re-activation of TB in these patient cohorts. These factors have resulted in an increase in the number of patients with TB in the ICU setting. Mortality continues to be unacceptably high among patients with TB admitted to the ICU at 50–60%. Newer diagnostic tests with faster turnaround are likely to help with the early diagnosis of TB including drug-resistant TB. The possibility of use of higher doses of anti-TB drugs in critically ill patients, the availability of IV preparations and the options of TDM of anti-TB drugs is likely to improve diagnostics and management in the ICU patients. More studies are required in the ICU setting to inform decision making in critically ill patients.

Orcid

Binila Chacko https://orcid.org/0000-0002-1609-2208

Dhruva Chaudhry https://orcid.org/0000-0001-5138-2908

John V Peter https://orcid.org/0000-0002-3423-1830

Gopi C Khilnani https://orcid.org/0000-0003-0820-0624

Prashant Saxena https://orcid.org/0009-0000-6735-9833

Inderpaul S Sehgal https://orcid.org/0000-0003-0516-9350

Kunal Ahuja https://orcid.org/0009-0006-6666-088X

Camilla Rodrigues https://orcid.org/0000-0002-6105-6660

Manish Modi https://orcid.org/0000-0002-5494-3704

Anand Jaiswal https://orcid.org/0009-0004-3523-8083

Joel Jasiel G https://orcid.org/0009-0004-7565-4129

Shrikant Sahasrabudhe https://orcid.org/0000-0002-6074-8569

Prithviraj Bose https://orcid.org/0000-0003-4522-0261

Aman Ahuja https://orcid.org/0000-0003-0307-3427

Vineela Suprapaneni https://orcid.org/0000-0003-0726-4474

Brijesh Prajapat https://orcid.org/0000-0002-1854-8408

Abi Manesh https://orcid.org/0000-0001-9970-9674

Rajesh Chawla https://orcid.org/0000-0003-2659-2430

Randeep Guleria https://orcid.org/0000-0002-6258-2160

Source of support: Nil

Conflict of interest: None
==== Refs
References

1. Bagcchi S WHO's Global Tuberculosis Report 2022 Lancet Microbe 2023 4 e20 10.1016/S2666-5247(22)00359-7 36521512
2. Litvinjenko S Magwood O Wu S Wei X Burden of tuberculosis among vulnerable populations worldwide: an overview of systematic reviews Lancet Infect Dis 2023 23 1395 1407 10.1016/S1473-3099(23)00372-9 37696278
3. Mandal S Rao R Joshi R Estimating the Burden of Tuberculosis in India: A Modelling Study Indian J Community Med Off Publ Indian Assoc Prev Soc Med 2023 48 436 442 10.4103/ijcm.ijcm_160_23
4. Chaudhry D Tyagi D Tuberculosis in Intensive Care Unit Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2021 25 S150 S154 10.5005/jp-journals-10071-23872
5. Erbes R Oettel K Raffenberg M Mauch H Schmidt-Ioanas M Lode H Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care Eur Respir J 2006 27 1223 1228 10.1183/09031936.06.00088105 16481385
6. Barss L Connors WJA Fisher D Chapter 7: Extra-pulmonary tuberculosis Can J Respir Crit Care Sleep Med 2022 6 87 108 10.1080/24745332.2022.2036073
7. Diagnostic Standards and Classification of Tuberculosis in Adults and Children This official statement of the American Thoracic Society and the Centers for Disease Control and Prevention was adopted by the ATS Board of Directors, July 1999. This statement was endorsed by the Council of the Infectious Disease Society of America, September 1999 Am J Respir Crit Care Med 2000 161 1376 1395 10.1164/ajrccm.161.4.16141 10764337
8. Thomas L Chacko B Jupudi S Mathuram A George T Gunasekaran K et al. Clinical Profile and Outcome of Critically Ill Patients with Tuberculosis Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2021 25 21 28 10.5005/jp-journals-10071-23503
9. Dheda K Makambwa E Esmail A The Great Masquerader: Tuberculosis Presenting as Community-Acquired Pneumonia Semin Respir Crit Care Med 2020 41 592 604 10.1055/s-0040-1710583 32564347
10. Sudarsan TI Thomas L Samprathi A Chacko B Mathuram A George T et al. Tuberculous ARDS is associated with worse outcome when compared with non-tuberculous infectious ARDS J Crit Care 2021 61 138 143 10.1016/j.jcrc.2020.10.015 33161242
11. Muthu V Dhooria S Aggarwal AN Behera D Sehgal IS Agarwal R Acute respiratory distress syndrome due to tuberculosis in a respiratory ICU over a 16-year period Crit Care Med 2017 45 e1087 e1090 10.1097/CCM.0000000000002479 28441233
12. Agarwal R Gupta D Aggarwal AN Behera D Jindal SK Experience with ARDS caused by tuberculosis in a respiratory intensive care unit Intensive Care Med 2005 31 1284 1287 10.1007/s00134-005-2721-2 16007416
13. Sharma SK Mohan A Miliary Tuberculosis Microbiol Spectr 2017 5 10.1128/microbiolspec.TNMI7-0013-2016
14. Otu A Hashmi M Mukhtar AM Kwizera A Tiberi S Macrae B et al. The critically ill patient with tuberculosis in intensive care: Clinical presentations, management and infection control J Crit Care 2018 45 184 196 10.1016/j.jcrc.2018.03.015 29571116
15. Alvarez SZ Hepatobiliary tuberculosis J Gastroenterol Hepatol 1998 13 833 839 10.1111/j.1440-1746.1998.tb00743.x 9736180
16. Malikowski T Mahmood M Smyrk T Raffals L Nehra V Tuberculosis of the gastrointestinal tract and associated viscera J Clin Tuberc Mycobact Dis 2018 12 1 8 10.1016/j.jctube.2018.04.003
17. Muneer A Macrae B Krishnamoorthy S Zumla A Urogenital tuberculosis - epidemiology, pathogenesis and clinical features Nat Rev Urol 2019 16 573 598 10.1038/s41585-019-0228-9 31548730
18. Khan FY Review of literature on disseminated tuberculosis with emphasis on the focused diagnostic workup J Fam Community Med 2019 26 83 91 10.4103/jfcm.JFCM_106_18
19. Gupta A Mrigpuri P Faye A Bandyopadhyay D Singla R Pulmonary tuberculosis - An emerging risk factor for venous thromboembolism: A case series and review of literature Lung India Off Organ Indian Chest Soc 2017 34 65 69 10.4103/0970-2113.197110
20. Muthu V Agarwal R Dhooria S Aggarwal AN Behera D Sehgal IS Outcome of critically ill subjects with tuberculosis: Systematic review and meta-analysis Respir Care 2018 63 1541 1554 10.4187/respcare.06190 30206126
21. Behera D Prasad K Aggarwal AN Profile of atients with active tuberculosis admitted to a respiratory Intensive Care Unit in a Tertiary Care Center of North India Indian J Crit Care Med 2018 22 63 66 10.4103/ijccm.IJCCM_491_17 29531444
22. Verdon R Chevret S Laissy JP Wolff M Tuberculous meningitis in adults: review of 48 cases Clin Infect Dis Off Publ Infect Dis Soc Am 1996 22 982 988 10.1093/clinids/22.6.982
23. Behr MA Lapierre SG Kunimoto DY Lee RS Long R Sekirov I et al. Chapter 3: Diagnosis of tuberculosis disease and drug-resistant tuberculosis Can J Respir Crit Care Sleep Med 2022 10.1080/24745332.2022.2035638
24. Bai W Liu L Wu L Chen S Wu S Wang Z et al. Assessing the utility of the Xpert Mycobacterium tuberculosis/rifampin assay for analysis of bronchoalveolar lavage fluid in patients with suspected pulmonary tuberculosis J Clin Lab Anal 2022 36 e24154 10.1002/jcla.24154 34850984
25. Neves CP Costa AG Safe IP de Souza Brito A Jesus JS Kritski AL et al. The role of mini-bronchoalveolar lavage fluid in the diagnosis of pulmonary tuberculosis in critically ill patients BMC Infect Dis 2020 20 229 10.1186/s12879-020-04954-3 32188399
26. Sharma SK Vashishtha R Chauhan LS Sreenivas V Seth D Comparison of TST and IGRA in diagnosis of latent tuberculosis infection in a high TB-burden setting PLOS ONE 2017 12 e0169539 10.1371/journal.pone.0169539 28060926
27. Dian S Ganiem AR van Laarhoven A Central nervous system tuberculosis Curr Opin Neurol 2021 34 396 402 10.1097/WCO.0000000000000920 33661159
28. Leonard JM Central nervous system tuberculosis Microbiol Spectr 2017 5 10.1128/microbiolspec.TNMI7-0044-2017
29. Marais S Thwaites G Schoeman JF Török ME Misra UK Prasad K et al. Tuberculous meningitis: A uniform case definition for use in clinical research Lancet Infect Dis 2010 10 803 812 10.1016/S1473-3099(10)70138-9 20822958
30. Nhu NTQ Heemskerk D Thu DDA Chau TTH Mai NTH Nghia HDT et al. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous meningitis J Clin Microbiol 2014 52 226 233 10.1128/JCM.01834-13 24197880
31. Ellis J Cresswell FV Rhein J Ssebambulidde K Boulware DR Cryptococcal meningitis and tuberculous meningitis co-infection in HIV-infected Ugandan Adults Open Forum Infect Dis 2018 5 ofy193 10.1093/ofid/ofy193 30182032
32. Paulson T Epidemiology: A mortal foe Nature 2013 502 S2 S3 10.1038/502S2a 24108078
33. WHO consolidated guidelines on drug-resistant tuberculosis treatment n.d Available from: https://www.who.int/publications-detail-redirect/9789241550529 (Accessed May 21, 2024)
34. Meeting report of the WHO expert consultation on drug-resistant tuberculosis treatment outcome definitions n.d Available from: https://www.who.int/publications-detail-redirect/9789240022195 (Accessed May 21, 2024)
35. Lohiya A Abdulkader RS Rath RS Jacob O Chinnakali P Goel AD et al. Prevalence and patterns of drug resistant pulmonary tuberculosis in India-A systematic review and meta-analysis J Glob Antimicrob Resist 2020 22 308 316 10.1016/j.jgar.2020.03.008 32247079
36. Raveendran R Oberoi JK Wattal C Multidrug-resistant pulmonary & extrapulmonary tuberculosis: A 13 years retrospective hospital-based analysis Indian J Med Res 2015 142 575 582 10.4103/0971-5916.171285 26658593
37. Salari N Kanjoori AH Hosseinian-Far A Hasheminezhad R Mansouri K Mohammadi M Global prevalence of drug-resistant tuberculosis: a systematic review and meta-analysis Infect Dis Poverty 2023 12 57 10.1186/s40249-023-01107-x 37231463
38. Pradipta IS Forsman LD Bruchfeld J Hak E Alffenaar JW Risk factors of multidrug-resistant tuberculosis: A global systematic review and meta-analysis J Infect 2018 77 469 478 10.1016/j.jinf.2018.10.004 30339803
39. Diriba G Tola HH Alemu A Yenew B Gamtesa DF Kebede A Drug resistance and its risk factors among extrapulmonary tuberculosis in Ethiopia: A systematic review and meta-analysis PLoS ONE 2021 16 e0258295 10.1371/journal.pone.0258295 34624050
40. Huang Y Ai L Wang X Sun Z Wang F Review and updates on the diagnosis of tuberculosis J Clin Med 2022 11 5826 10.3390/jcm11195826 36233689
41. Fluorescent light-emitting diode (LED) microscopy for diagnosis of tuberculosis: Policy Statement Geneva World Health Organization 2011 ISBN-13: 978-92-4-150161-3
42. Pai M Kalantri S Dheda K New tools and emerging technologies for the diagnosis of tuberculosis: Part II. Active tuberculosis and drug resistance Expert Rev Mol Diagn 2006 6 423 432 10.1586/14737159.6.3.423 16706744
43. Rapid Communication: Molecular assays as initial tests for the diagnosis of tuberculosis and rifampicin resistance n.d Available from: https://www.who.int/publications-detail-redirect/9789240000339 (Accessed May 21, 2024)
44. Shapiro AE Ross JM Yao M Schiller I Kohli M Dendukuri N et al. Xpert MTB/RIF and Xpert Ultra assays for screening for pulmonary tuberculosis and rifampicin resistance in adults, irrespective of signs or symptoms Cochrane Database Syst Rev 2021 3 CD013694 10.1002/14651858.CD013694.pub2 33755189
45. Zifodya JS Kreniske JS Schiller I Kohli M Dendukuri N Schumacher SG et al. Xpert Ultra versus Xpert MTB/RIF for pulmonary tuberculosis and rifampicin resistance in adults with presumptive pulmonary tuberculosis Cochrane Database Syst Rev 2021 2 CD009593 10.1002/14651858.CD009593.pub5 33616229
46. Shen Y Yu G Zhao W Lang Y Efficacy of Xpert MTB/RIF Ultra in diagnosing tuberculosis meningitis Medicine (Baltimore) 2021 100 e26778 10.1097/MD.0000000000026778 34398057
47. Tadesse M Abebe G Bekele A Bezabih M Yilma D Apers L et al. Xpert MTB/RIF assay for the diagnosis of extrapulmonary tuberculosis: a diagnostic evaluation study Clin Microbiol Infect Off Publ Eur Soc Clin Microbiol Infect Dis 2019 25 1000 1005 10.1016/j.cmi.2018.12.018
48. Kohli M Schiller I Dendukuri N Dheda K Denkinger CM Schumacher SG et al. Xpert® MTB/RIF assay for extrapulmonary tuberculosis and rifampicin resistance Cochrane Database Syst Rev 2018 8 CD012768 10.1002/14651858.CD012768.pub2 30148542
49. Donovan J Cresswell FV Thuong NTT Boulware DR Thwaites GE Bahr NC et al. Xpert MTB/RIF Ultra for the diagnosis of tuberculous meningitis: A small step Forward Clin Infect Dis Off Publ Infect Dis Soc Am 2020 71 2002 2005 10.1093/cid/ciaa473
50. WHO standard: universal access to rapid tuberculosis diagnostics n.d Available from: https://www.who.int/publications-detail-redirect/9789240071315 (Accessed May 21, 2024)
51. Penn-Nicholson A Georghiou SB Ciobanu N Kazi M Bhalla M David A et al. Detection of isoniazid, fluoroquinolone, ethionamide, amikacin, kanamycin, and capreomycin resistance by the Xpert MTB/XDR assay: a cross-sectional multicentre diagnostic accuracy study Lancet Infect Dis 2022 22 242 9 10.1016/S1473-3099(21)00452-7 34627496
52. Madhuri K Deshpande S Dharmashale S Bharadwaj R Utility of Line Probe Assay for the Early Detection of Multidrug-Resistant Pulmonary Tuberculosis J Glob Infect Dis 2015 7 60 65 10.4103/0974-777X.157237 26069424
53. Pillay S de Vos M Derendinger B Streicher EM Dolby T Scott LA et al. Non-actionable results, accuracy, and effect of first- and second-line line probe assays for diagnosing drug-resistant tuberculosis, including on smear-negative specimens, in a high-volume laboratory Clin Infect Dis 2023 76 e920 e929 10.1093/cid/ciac556 35788278
54. Horne DJ Kohli M Zifodya JS Schiller I Dendukuri N Tollefson D et al. Xpert MTB/RIF and Xpert MTB/RIF Ultra for pulmonary tuberculosis and rifampicin resistance in adults Cochrane Database Syst Rev 2019 2019 CD009593 10.1002/14651858.CD009593.pub4
55. Ssengooba W Katamba A Sserubiri J Semugenze D Nyombi A Byaruhanga R et al. Performance evaluation of Truenat MTB and Truenat MTB-RIF DX assays in comparison to gene XPERT MTB/RIF ultra for the diagnosis of pulmonary tuberculosis in Uganda BMC Infect Dis 2024 24 190 10.1186/s12879-024-09063-z 38350885
56. Pillay S Steingart KR Davies GR Chaplin M De Vos M Schumacher SG et al. Xpert MTB/XDR for detection of pulmonary tuberculosis and resistance to isoniazid, fluoroquinolones, ethionamide, and amikacin Cochrane Database Syst Rev 2022 5 CD014841 10.1002/14651858.CD014841.pub2 35583175
57. Chen X Li R Ge S Li Y Cai C Weng T et al. Rapid detection of extensive drug resistance by Xpert MTB/XDR optimizes therapeutic decision-making in rifampin-resistant tuberculosis patients J Clin Microbiol 2023 61 e0183222 10.1128/jcm.01832-22 37249422
58. Ling DI Zwerling AA Pai M GenoType MTBDR assays for the diagnosis of multidrug-resistant tuberculosis: Ameta-analysis Eur Respir J 2008 32 1165 1174 10.1183/09031936.00061808 18614561
59. Bai Y Wang Y Shao C Hao Y Jin Y GenoType MTBDRplus assay for rapid detection of multidrug resistance in mycobacterium tuberculosis: A meta-analysis PLOS ONE 2016 11 e0150321 10.1371/journal.pone.0150321 26934724
60. Gilpin C Korobitsyn A Weyer K Current tools available for the diagnosis of drug-resistant tuberculosis Ther Adv Infect Dis 2016 3 145 151 10.1177/2049936116673553 28386407
61. Technical manual for drug susceptibility testing of medicines used in the treatment of tuberculosis n.d Available from: https://www.who.int/publications-detail-redirect/9789241514842 (Accessed May 21, 2024)
62. Cabibbe AM Walker TM Niemann S Cirillo DM Whole genome sequencing of mycobacterium tuberculosis Eur Respir J 2018 52 1801163 10.1183/13993003.01163-2018 30209198
63. Rageade F Picot N Blanc-Michaud A Chatellier S Mirande C Fortin E et al. Performance of solid and liquid culture media for the detection of mycobacterium tuberculosis in clinical materials: meta-analysis of recent studies Eur J Clin Microbiol Infect Dis Off Publ Eur Soc Clin Microbiol 2014 33 867 870 10.1007/s10096-014-2105-z
64. Rodrigues C Shenai S Sadani M Sukhadia N Jani M Ajbani K et al. Evaluation of the bactec MGIT 960 TB system for recovery and identification of Mycobacterium tuberculosis complex in a high through put tertiary care centre Indian J Med Microbiol 2009 27 217 221 10.4103/0255-0857.53203 19584501
65. Aggarwal AN Agarwal R Sehgal IS Dhooria S Adenosine deaminase for diagnosis of tuberculous pleural effusion: A systematic review and meta-analysis PloS One 2019 14 e0213728 10.1371/journal.pone.0213728 30913213
66. Ekermans P Dusé A George J The dubious value of cerebrospinal fluid adenosine deaminase measurement for the diagnosis of tuberculous meningitis BMC Infect Dis 2017 17 104 10.1186/s12879-017-2221-3 28143441
67. Pannu AK Selvam S Rahman N Kumar D Saroch A Sharma AK et al. Cerebrospinal fluid adenosine deaminase for the diagnosis of tuberculous meningitis Biomark Med 2023 17 209 218 10.2217/bmm-2022-0838 37102870
68. Zhou R Qiu X Ying J Yue Y Ruan T Yu L et al. Diagnostic performance of adenosine deaminase for abdominal tuberculosis: A systematic review and meta-analysis Front Public Health 2022 10 938544 10.3389/fpubh.2022.938544 36211645
69. Hu X Xing B Wang W Yang P Sun Y Zheng X et al. Diagnostic values of Xpert MTB/RIF, T-SPOT.TB and adenosine deaminase for HIV-negative tuberculous pericarditis in a high burden setting: A prospective observational study Sci Rep 2020 10 16325 10.1038/s41598-020-73220-y 33004934
70. Bhowmik A Herth FJF Bronchoscopy and other invasive procedures for tuberculosis diagnosis. In: Migliori GB Bothamley G Duarte R Rendon A Tuberculosis, Sheffield, United Kingdom European Respiratory Society 2018 137 151 10.1183/2312508X.10020518
71. JoR Free full-text Extrapulmonary tuberculosis—An update on the diagnosis, treatment and drug resistance n.d Available from: https://www.mdpi.com/2673-527X/1/2/15 (Accessed May 21, 2024)
72. Skoura E Zumla A Bomanji J Imaging in tuberculosis Int J Infect Dis IJID Off Publ Int Soc Infect Dis 2015 32 87 93 10.1016/j.ijid.2014.12.007
73. Malherbe ST Chen RY Dupont P Kant I Kriel M Loxton AG et al. Quantitative 18F-FDG PET-CT scan characteristics correlate with tuberculosis treatment response EJNMMI Res 2020 10 8 10.1186/s13550-020-0591-9 32040770
74. Kethireddy S Light RB Mirzanejad Y Maki D Arabi Y Lapinsky S et al. Mycobacterium tuberculosis septic shock Chest 2013 144 474 482 10.1378/chest.12-1286 23429859
75. Rao PS Moore CC Mbonde AA Nuwagira E Orikiriza P Nyehangane D et al. Population Pharmacokinetics and Significant Under-Dosing of Anti-Tuberculosis Medications in People with HIV and Critical Illness Antibiotics 2021 10 739 10.3390/antibiotics10060739 34207312
76. Mer M Zumla A Dünser MW Limiting consumption in tuberculosis: current concepts in anti-tuberculosis treatment in the critically ill patient Intensive Care Med 2018 44 2229 31 10.1007/s00134-018-5161-5 29752523
77. WHO consolidated guidelines on tuberculosis: module 4: treatment: drug-susceptible tuberculosis treatment n.d Available from: https://www.who.int/publications-detail-redirect/9789240048126 (Accessed May 21, 2024)
78. Index-TB guidelines: guidelines on extra-pulmonary tuberculosis in India n.d Available from: https://iris.who.int/handle/10665/278953 (Accessed July 18, 2024)
79. Anton C Lemos CX Machado FD Bernardi RM Freitas AA Silva DR Tuberculosis in the intensive care unit: alternative treatment regimens and association with mortality Trop Med Int Health TM IH 2021 26 111 114 10.1111/tmi.13511 33159399
80. Boeree MJ Heinrich N Aarnoutse R Diacon AH Dawson R Rehal S et al. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: A multi-arm, multi-stage randomised controlled trial Lancet Infect Dis 2017 17 39 49 10.1016/S1473-3099(16)30274-2 28100438
81. Ruslami R Ganiem AR Dian S Apriani L Achmad TH van der Ven AJ et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial Lancet Infect Dis 2013 13 27 35 10.1016/S1473-3099(12)70264-5 23103177
82. Koegelenberg CFN Nortje A Lalla U Enslin A Irusen EM Rosenkranz B et al. The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care South Afr Med J Suid-Afr Tydskr Vir Geneeskd 2013 103 394 398 10.7196/samj.6344
83. Hernandez-Cardenas C Lugo-Goytia G Pharmacokinetics of antituberculosis drugs in critically ill patients with tuberculosis and acute respiratory failure Crit Care 2014 18 p 354 10.1186/cc13544
84. Perumal R Naidoo K Naidoo A Letsoalo MP Esmail A Joubert I et al. The impact of enteral feeding and therapeutic monitoring of rifampicin with dose escalation in critically ill patients with tuberculosis Int J Infect Dis IJID Off Publ Int Soc Infect Dis 2023 126 174 180 10.1016/j.ijid.2022.11.033
85. Peloquin CA Bulpitt AE Jaresko GS Jelliffe RW James GT Nix DE Pharmacokinetics of pyrazinamide under fasting conditions, with food, and with antacids Pharmacotherapy 1998 18 1205 1211 9855317 9855317
86. Yunivita V Dian S Ganiem AR Hayati E Achmad TH Dewi AP et al. Pharmacokinetics and safety/tolerability of higher oral and intravenous doses of rifampicin in adult tuberculous meningitis patients Int J Antimicrob Agents 2016 48 415 421 10.1016/j.ijantimicag.2016.06.016 27526979
87. Cresswell FV Meya DB Kagimu E Grint D Te Brake L Kasibante J et al. High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly Human immunodeficiency virus (HIV)-positive Ugandan adults: A phase II open-label randomized controlled trial Clin Infect Dis 2021 73 876 884 10.1093/cid/ciab162 33693537
88. Wasserman S Davis A Stek C Chirehwa M Botha S Daroowala R et al. Plasma pharmacokinetics of high-dose oral versus intravenous Rrifampicin in patients with tuberculous meningitis: A randomized controlled trial Antimicrob Agents Chemother n.d.; 65 e00140 21 10.1128/AAC.00140-21
89. Butov D Feshchenko Y Kuzhko M Gumenuik M Yurko K Grygorova A et al. Effectiveness of intravenous isoniazid and ethambutol administration in patients with tuberculosis meningoencephalitis and HIV infection Tuberc Respir Dis 2020 83 96 103 10.4046/trd.2019.0021
90. Kuzhko M Gumeniuk M Butov D Tlustova T Denysov O Sprynsian T Features of intravenous anti TB therapy in patients with first diagnosed pulmonary TB in the intensive phase of treatment Eur Respir J 2017 50 10.1183/1393003.congress-2017.PA3496
91. Kwon BS Kim Y Lee SH Lim SY Lee YJ Park JS et al. The high incidence of severe adverse events due to pyrazinamide in elderly patients with tuberculosis PloS One 2020 15 e0236109 10.1371/journal.pone.0236109 32692774
92. Modongo C Sobota RS Kesenogile B Ncube R Sirugo G Williams SM et al. Successful MDR-TB treatment regimens including amikacin are associated with high rates of hearing loss BMC Infect Dis 2014 14 542 10.1186/1471-2334-14-542 25300708
93. Pranger AD van der Werf TS Kosterink JGW Alffenaar JWC The Role of fluoroquinolones in the treatment of tuberculosis in 2019 Drugs 2019 79 161 171 10.1007/s40265-018-1043-y 30617959
94. Alffenaar JWC van Altena R Bökkerink HJ Luijckx GJ van Soolingen D Aarnoutse RE et al. Pharmacokinetics of moxifloxacin in cerebrospinal fluid and plasma in patients with tuberculous meningitis Clin Infect Dis Off Publ Infect Dis Soc Am 2009 49 1080 1082 10.1086/605576
95. Sotgiu G D'Ambrosio L Centis R Tiberi S Esposito S Dore S et al. Carbapenems to treat multidrug and extensively drug-resistant tuberculosis: A systematic review Int J Mol Sci 2016 17 373 10.3390/ijms17030373 26985890
96. De Jager V Gupte N Nunes S Barnes GL van Wijk RC Mostert J et al. Early bactericidal activity of meropenem plus clavulanate (with or without ifampin) for tuberculosis: The COMRADE randomized, phase 2A clinical trial Am J Respir Crit Care Med 2022 205 1228 1235 10.1164/rccm.202108-1976oc 35258443
97. van Rijn SP Zuur MA Anthony R Wilffert B van Altena R Akkerman OW et al. Evaluation of Carbapenems for treatment of multi- and extensively drug-resistant mycobacterium tuberculosis Antimicrob Agents Chemother 2019 63 e01489 14918 10.1128/AAC.01489-18 30455232
98. Maranchick NF Alshaer MH Smith AGC Avaliani T Gujabidze M Bakuradze T et al. Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis Front Pharmacol 2022 13 1048653 10.3389/fphar.2022.1048653 36578553
99. Conradie F Bagdasaryan TR Borisov S Howell P Mikiashvili L Ngubane N et al. Bedaquiline-pretomanid-linezolid regimens for drug-resistant tuberculosis N Engl J Med 2022 387 810 823 10.1056/NEJMoa2119430 36053506
100. Mase A Lowenthal P True L Henry L Barry P Flood J Low-dose linezolid for treatment of patients with multidrug-resistant tuberculosis Open Forum Infect Dis 2022 9 ofac500 10.1093/ofid/ofac500 36601556
101. Kempker RR Smith AGC Avaliani T Gujabidze M Bakuradze T Sabanadze S et al. Cycloserine and linezolid for tuberculosis meningitis: Ppharmacokinetic evidence of potential Uusefulness Clin Infect Dis Off Publ Infect Dis Soc Am 2022 75 682 629 10.1093/cid/ciab992
102. Abdelgawad N Wasserman S Abdelwahab MT Davis A Stek C Wiesner L et al. Linezolid population pharmacokinetic model in plasma and cerebrospinal fluid among patients with tuberculosis Meningitis J Infect Dis 2024 229 1200 8 10.1093/infdis/jiad413 37740554
103. Francesca C Andreas HD Nosipho N PaulineDaniel F Angela MC et al. Treatment of highly drug-resistant pulmonary tuberculosis N Engl J Med 2020 382 893 902 10.1056/NEJMoa1901814 32130813
104. Bern-Thomas N Catherine B Emil K Ilaria M Nargiza P Zinaida T et al. A 24-week, all-oral regimen for rifampin-resistant tuberculosis N Engl J Med 2022 387 2331 2343 10.1056/NEJMoa2117166 36546625
105. Riccardi N Canetti D Rodari P Besozzi G Saderi L Dettori M et al. Tuberculosis and pharmacological interactions: A narrative review Curr Res Pharmacol Drug Discov 2021 2 100007 10.1016/j.crphar.2020.100007 34909643
106. Bumbacea D Arend SM Eyuboglu F Fishman JA Goletti D Ison MG et al. The risk of tuberculosis in transplant candidates and recipients: A TBNET consensus statement Eur Respir J 2012 40 990 1013 10.1183/09031936.00000712 22496318
107. Clinical presentation and outcome of tuberculosis in kidney, liver, and heart transplant recipients in Spain Spanish Transplantation Infection Study Group, GESITRA - PubMed n.d. Available from: https://pubmed.ncbi.nlm.nih.gov/9158022/ (Accessed April 20, 2024)
108. Singh N Paterson DL Mycobacterium tuberculosis infection in solid-organ transplant recipients: impact and implications for management Clin Infect Dis Off Publ Infect Dis Soc Am 1998 27 1266 1277 10.1086/514993
109. al-Sulaiman MH Dhar JM al-Khader AA Successful use of rifampicin in the treatment of tuberculosis in renal transplant patients immunosuppressed with cyclosporine Transplantation 1990 50 597 598 10.1097/00007890-199010000-00014 2219282
110. Körner MM Hirata N Tenderich G Minami K Mannebach H Kleesiek K et al. Tuberculosis in heart transplant recipients Chest 1997 111 365 369 10.1378/chest.111.2.365 9041983
111. Muñoz P Palomo J Muñoz R Rodríguez-Creixéms M Pelaez T Bouza E Tuberculosis in heart transplant recipients Clin Infect Dis Off Publ Infect Dis Soc Am 1995 21 398 402 10.1093/clinids/21.2.398
112. Ryan H Yoo J Darsini P Corticosteroids for tuberculous pleurisy Cochrane Database Syst Rev 2017 3 CD001876 10.1002/14651858.CD001876.pub3 28290161
113. Prasad K Singh MB Ryan H Corticosteroids for managing tuberculous meningitis Cochrane Database Syst Rev 2016 2016 CD002244 10.1002/14651858.CD002244.pub4
114. Wakamatsu K Nagata N Kumazoe H Honjo S Hamada M Katsuki K et al. Efficacy of steroid pulse therapy for miliary tuberculosis complicated by acute respiratory distress syndrome J Clin Tuberc Mycobact Dis 2022 29 100341 10.1016/j.jctube.2022.100341
115. Critchley JA Young F Orton L Garner P Corticosteroids for prevention of mortality in people with tuberculosis: A systematic review and meta-analysis Lancet Infect Dis 2013 13 223 237 10.1016/S1473-3099(12)70321-3 23369413
116. Donald PR Van Toorn R Use of corticosteroids in tuberculous meningitis Lancet Lond Engl 2016 387 2585 2587 10.1016/S0140-6736(16)30770-X
117. Yang JY Han M Koh Y Kim WS Song JW Oh YM et al. Effects of corticosteroids on cCritically ill pPulmonary tuberculosis patients with acute rRespiratory failure: A propensity analysis of mortality Clin Infect Dis 2016 63 1449 1455 10.1093/cid/ciw616 27609755
118. Wiysonge CS Ntsekhe M Thabane L Volmink J Majombozi D Gumedze F et al. Interventions for treating tuberculous pericarditis Cochrane Database Syst Rev 2017 9 CD000526 10.1002/14651858.CD000526.pub2 28902412
119. Boeree MJ Diacon AH Dawson R Narunsky K du Bois J Venter A et al. A dose-ranging trial to optimize the dose of rifampin in the treatment of tuberculosis Am J Respir Crit Care Med 2015 191 1058 1065 10.1164/rccm.201407-1264OC 25654354
120. Peloquin CA Therapeutic drug monitoring in the treatment of tuberculosis Drugs 2002 62 2169 2183 10.2165/00003495-200262150-00001 12381217
121. Galvin J Tiberi S Akkerman O Kerstjens HAM Kunst H Kurhasani X et al. Pulmonary tuberculosis in intensive care setting, with a focus on the use of severity scores, a multinational collaborative systematic review Pulmonology 2022 28 297 309 10.1016/j.pulmoe.2022.01.016 35227650
122. Azoulay E Russell L Van de Louw A Metaxa V Bauer P Povoa P et al. Diagnosis of severe respiratory infections in immunocompromised patients Intensive Care Med 2020 46 298 314 10.1007/s00134-019-05906-5 32034433
123. Loh WJ Yu Y Loo CM Low SY Factors associated with mortality among patients with active pulmonary tuberculosis requiring intensive care Singapore Med J 2017 58 656 659 10.11622/smedj.2016160 27653545
124. Gras J De Castro N Montlahuc C Champion L Scemla A Matignon M et al. Clinical characteristics, risk factors, and outcome of tuberculosis in kidney transplant recipients: A multicentric case-control study in a low-endemic area Transpl Infect Dis 2018 20 e12943 10.1111/tid.12943 29890021
125. Lewinsohn DM Leonard MK LoBue PA Cohn DL Daley CL Desmond E et al. Official American Thoracic Society/Infectious Diseases Society of America/Centers for Disease Control and Prevention Clinical Practice Guidelines: Diagnosis of tuberculosis in adults and cChildren Clin Infect Dis Off Publ Infect Dis Soc Am 2017 64 111 115 10.1093/cid/ciw778
126. Ai JW Ruan QL Liu QH Zhang WH Updates on the risk factors for latent tuberculosis reactivation and their managements Emerg Microbes Infect 2016 5 e10 10.1038/emi.2016.10 26839146
127. Huang CT Ruan SY Tsai YJ Kuo PH Ku SC Lee PL et al. Effects of acute critical illnesses on the performance of interferon-gamma release assay Sci Rep 2016 6 19972 10.1038/srep19972 26804487
128. Ward JD Cornaby C Schmitz JL Indeterminate QuantiFERON Gold Plus results reveal deficient Interferon Gamma responses in severely ill COVID-19 patients J Clin Microbiol 2021 59 e0081121 10.1128/JCM.00811-21 34232708
129. de la Cámara R Martino R Granados E Rodriguez-Salvanés FJ Rovira M Cabrera R et al. Tuberculosis after hematopoietic stem cell transplantation: Incidence, clinical characteristics and outcome. Spanish Group on Infectious Complications in Hematopoietic Transplantation Bone Marrow Transplant 2000 26 291 298 10.1038/sj.bmt.1702506 10967568
130. Torre-Cisneros J Doblas A Aguado JM San Juan R Blanes M Montejo M et al. Tuberculosis after solid-organ transplant: incidence, risk factors, and clinical characteristics in the RESITRA (Spanish Network of Infection in Transplantation) cohort Clin Infect Dis Off Publ Infect Dis Soc Am 2009 48 1657 1665 10.1086/599035
131. Ramos JF Batista MV Costa SF Tuberculosis in hematopoietic stem cell transplant recipients Mediterr J Hematol Infect Dis 2013 5 e2013061 10.4084/MJHID.2013.061 24363876
132. Ip MS Yuen KY Woo PC Luk WK Tsang KW Lam WK et al. Risk factors for pulmonary tuberculosis in bone marrow transplant recipients Am J Respir Crit Care Med 1998 158 1173 1177 10.1164/ajrccm.158.4.9712072 9769278
133. Jones BE Young SM Antoniskis D Davidson PT Kramer F Barnes PF Relationship of the manifestations of tuberculosis to CD4 cell counts in patients with human immunodeficiency virus infection Am Rev Respir Dis 1993 148 1292 1297 10.1164/ajrccm/148.5.1292 7902049
134. Fiske CT Griffin MR Erin H Warkentin J Lisa K Arbogast PG et al. Black race, sex, and extrapulmonary tuberculosis risk: an observational study BMC Infect Dis 2010 10 16 10.1186/1471-2334-10-16 20096113
135. Marques IDB Azevedo LS Pierrotti LC Caires RA Sato VAH Carmo LPF et al. Clinical features and outcomes of tuberculosis in kidney transplant recipients in Brazil: A report of the last decade Clin Transplant 2013 27 E169 E176 10.1111/ctr.12077 23351041
136. Pereira M Gazzoni FF Marchiori E Irion K Moreira J Giacomelli IL et al. High-resolution CT findings of pulmonary Mycobacterium tuberculosis infection in renal transplant recipients Br J Radiol 2016 89 20150686 10.1259/bjr.20150686 26607644
137. Pecego AC Amancio RT Ribeiro C Mesquita EC Medeiros DM Cerbino J et al. Six-month survival of critically ill patients with HIV-related disease and tuberculosis: A retrospective study BMC Infect Dis 2016 16 270 10.1186/s12879-016-1644-6 27286652
138. Mittal S Madan K Aggarwal N Dhar A Tuberculosis and short bowel: A tTherapeutic challenge Indian J Crit Care Med Peer-Rev Off Publ Indian Soc Crit Care Med 2019 23 199 10.5005/jp-journals-10071-23157
139. Erdstein AA Daas P Bradstock KF Robinson T Hertzberg MS Tuberculosis in allogeneic stem cell transplant recipients: still a problem in the 21st century Transpl Infect Dis Off J Transplant Soc 2004 6 142 146 10.1111/j.1399-3062.2004.00068.x
140. Tseng YT Chuang YC Shu CC Hung CC Hsu CF Wang JY Empirical use of fluoroquinolones improves the survival of critically ill patients with tuberculosis mimicking severe pneumonia Crit Care 2012 16 R207 10.1186/cc11839 23098258
141. Meintjes G Stek C Blumenthal L Thienemann F Schutz C Buyze J et al. Prednisone for the prevention of paradoxical tuberculosis-associated IRIS N Engl J Med 2018 379 1915 1925 10.1056/NEJMoa1800762 30428290
142. Iglesias J Ledesma KJ Couto PJ Liu J Immune Reconstitution Inflammatory Syndrome occurring in a kidney transplant pPatient with extrapulmonary tTuberculosis Case Rep Transplant 2017 2017 6290987 10.1155/2017/6290987 28367350
143. Lee S Yi NJ Kwak N Kim H Young HS Lee JM et al. Immune Reconstitution Inflammatory Syndrome and drug-induced liver injury during treatment of disseminated tTuberculosis in a liver transplant recipient: A case report Transplant Proc 2023 55 1972 1974 10.1016/j.transproceed.2023.06.007 37468353
144. Liu S Huo F Dai G Wu J Qin M Mao H et al. Case report: Immune reconstitution inflammatory syndrome after hematopoietic stem cell transplantation for severe combined immunodeficiency Front Immunol 2022 13 960749 10.3389/fimmu.2022.960749 36225916
145. Levy H Kallenbach JM Feldman C Thorburn JR Abramowitz JA Acute respiratory failure in active tuberculosis Crit Care Med 1987 15 221 225 10.1097/00003246-198703000-00008 3469061
146. Bhurayanontachai R Maneenil K Factors influencing development and mortality of acute respiratory failure in hospitalized patient with active pulmonary tuberculosis: A 10-year retrospective review J Thorac Dis 2016 8 1721 30 10.21037/jtd.2016.06.22 27499962
147. Grasselli G Calfee CS Camporota L Poole D Amato MBP Antonelli M et al. ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies Intensive Care Med 2023 49 727 759 10.1007/s00134-023-07050-7 37326646
148. Hui DS Chow BK Lo T Tsang OTY Ko FW Ng SS et al. Exhaled air dispersion during high-flow nasal cannula therapy versus CPAP via different masks Eur Respir J 2019 53 1802339 10.1183/13993003.02339-2018 30705129
149. Tran K Cimon K Severn M Pessoa-Silva CL Conly J Aerosol generating procedures and risk of transmission of acute respiratory infections to healthcare workers: A systematic review PloS One 2012 7 e35797 10.1371/journal.pone.0035797 22563403
150. Agarwal R Gupta D Handa A Aggarwal AN Noninvasive ventilation in ARDS caused by Mycobacterium tuberculosis: report of three cases and review of literature Intensive Care Med 2005 31 1723 1724 10.1007/s00134-005-2823-x 16195903
151. Aso H Kondoh Y Taniguchi H Kimura T Nishiyama O Kato K et al. Noninvasive ventilation in patients with acute exacerbation of pulmonary tuberculosis sequelae Intern Med Tokyo Jpn 2010 49 2077 2083 10.2169/internalmedicine.49.3749
152. Kang NM Zhang N Luo BJ Wu ED Shi JQ Li L et al. Sequential non-invasive following short-term invasive mechanical ventilation in the treatment of tuberculosis with respiratory failure: A randomized controlled study BMC Pulm Med 2021 21 203 10.1186/s12890-021-01563-x 34162374
153. Idris R Zielbauer AS Koepsell J Kloka J Wetzstein N Extracorporeal membrane oxygenation (ECMO) in patients with tuberculosis: systematic review and meta-analysis of 43 cases BMC Pulm Med 2024 24 47 10.1186/s12890-023-02715-x 38254072
154. Hsiao EI Kirsch CM Kagawa FT Wehner JH Jensen WA Baxter RB Utility of fiberoptic bronchoscopy before bronchial artery embolization for massive hemoptysis AJR Am J Roentgenol 2001 177 861 867 10.2214/ajr.177.4.1770861 11566690
155. Revel MP Fournier LS Hennebicque AS Cuenod CA Meyer G Reynaud P et al. Can CT replace bronchoscopy in the detection of the site and cause of bleeding in patients with large or massive hemoptysis? AJR Am J Roentgenol 2002 179 1217 1224 10.2214/ajr.179.5.1791217 12388502
156. Radchenko C Alraiyes AH Shojaee S A systematic approach to the management of massive hemoptysis J Thorac Dis 2017 9 S1069 1086 10.21037/jtd.2017.06.41 29214066
157. Wand O Guber E Guber A Shochet GE Israeli-Shani L Shitrit D Inhaled tranexamic acid for hHemoptysis treatment: A rRandomized controlled trial Chest 2018 154 1379 1384 10.1016/j.chest.2018.09.026 30321510
158. Gopinath B Mishra PR Aggarwal P Nayaka R Naik SR Kappagantu V et al. Nebulized vs IV Tranexamic acid for hemoptysis: A pilot randomized controlled trial Chest 2023 163 1176 1184 10.1016/j.chest.2022.11.021 36410494
159. Panda A Bhalla AS Goyal A Bronchial artery embolization in hemoptysis: A systematic review Diagn Interv Radiol Ank Turk 2017 23 307 317 10.5152/dir.2017.16454
160. Deng H Fang Q Chen K Zhang X Early versus late tracheotomy in ICU patients: A meta-analysis of randomized controlled trials Medicine (Baltimore) 2021 100 e24329 10.1097/MD.0000000000024329 33546065
161. Chorath K Hoang A Rajasekaran K Moreira A Association of early vs late tracheostomy placement with pneumonia and ventilator days in critically ill patients: A meta-analysis JAMA Otolaryngol Head Neck Surg 2021 147 450 459 10.1001/jamaoto.2021.0025 33704354
162. Angoulvant D Mohammedi I Duperret S Bouletreau P Septic shock caused by Mycobacterium tuberculosis in a non-HIV patient Intensive Care Med 1999 25 238 10.1007/s001340050825 10193559
163. Dasarathan LV Gaikwad P Telugu RB Disseminated mycobacterial septicemia presented as acute abdomen: a surgeon's perspective on Landouzy's sepsis BMJ Case Rep CP 2020 13 e237574 10.1136/bcr-2020-237574
164. Michel P Barbier C Loubière Y Hayon JH Ricôme JL Three cases of septic shock due to tuberculosis without HIV pathology Intensive Care Med 2002 28 1827 1828 10.1007/s00134-002-1526-9 12447531
165. British Thoracic Society Standards of Care Committee and Joint Tuberculosis CommitteeMilburn H Ashman N Davies P Doffman S Drobniewski F et al. Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease Thorax 2010 65 557 570 10.1136/thx.2009.133173 20522863
166. Hickey AJ Gounder L Moosa MYS Drain PK A systematic review of hepatic tuberculosis with considerations in human immunodeficiency virus co-infection BMC Infect Dis 2015 15 209 10.1186/s12879-015-0944-6 25943103
167. Mohamed MMG Osman A El-Halawany H Plasma exchange for patients with acute or acute on chronic liver failure; meta-analysis of randomized controlled trials Clin Res Hepatol Gastroenterol 2022 46 102014 10.1016/j.clinre.2022.102014 36031099
168. Goel A Zachariah U Daniel D Eapen CE Growing evidence for survival benefit with plasma exchange to treat liver failure J Clin Exp Hepatol 2023 13 1061 1073 10.1016/j.jceh.2023.06.002 37975044
169. Singh KA Kumar SE Zachariah UG Daniel D David V Subramani K et al. Single-centre eExperience with low-volume plasma exchange and low-dDose steroid to treat patients with idiosyncratic drug-induced acute liver failure J Clin Exp Hepatol 2024 14 101303 10.1016/j.jceh.2023.11.003 38076447
170. Jothimani D Sachan D Saha S Kalyamoorthy I Rela M 4. Role of therapeutic plasma exchange (TPE) in patients with drug induced liver injury J Clin Exp Hepatol 2018 8 S83 10.1016/j.jceh.2018.06.425
171. Baussano I Nunn P Williams B Pivetta E Bugiani M Scano F Tuberculosis among Health Care Workers Emerg Infect Dis 2011 17 488 494 10.3201/eid1703.100947 21392441
172. WHO consolidated guidelines on tuberculosis: Module 1: Prevention – infection prevention and control n.d Available from: https://www.who.int/publications-detail-redirect/9789240055889 (Accessed May 21, 2024)
173. Karat AS Gregg M Barton HE Calderon M Ellis J Falconer J et al. Evidence for the use of triage, Rrespiratory isolation, and effective Ttreatment to reduce the transmission of Mycobacterium Tuberculosis in healthcare settings: A systematic review Clin Infect Dis Off Publ Infect Dis Soc Am 2020 72 155 1572 10.1093/cid/ciaa720
174. Azeredo ACV Holler SR de Almeida EGC Cionek OAGD Loureiro MM Freitas AA et al. Tuberculosis in health care workers and the impact of implementation of hospital infection-control measures Workplace Health Saf 2020 68 519 525 10.1177/2165079920919133 32502371
175. Guidelines for Preventing the Transmission of Mycobacterium tuberculosis in Health-Care Settings, 2005 n.d Available from: https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5417a1.htm (Accessed May 21, 2024)
176. Mphaphlele M Dharmadhikari AS Jensen PA Rudnick SN van Reenen TH Pagano MA et al. Institutional Tuberculosis Transmission. Controlled trial of upper room ultraviolet air disinfection: A basis for new dosing guidelines Am J Respir Crit Care Med 2015 192 477 484 10.1164/rccm.201501-0060OC 25928547
177. Xu P Kujundzic E Peccia J Schafer MP Moss G Hernandez M et al. Impact of environmental factors on efficacy of upper-room air ultraviolet germicidal irradiation for inactivating airborne mycobacteria Environ Sci Technol 2005 39 9656 9664 10.1021/es0504892 16475348
178. Menzies D Joshi R Pai M Risk of tuberculosis infection and disease associated with work in health care settings Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2007 11 593 605
179. Australian Guidelines for the Prevention and Control of Infection in Healthcare (2019) NHMRC n.d Available from: https://www.nhmrc.gov.au/about-us/publications/australian-guidelines-prevention-and-control-infection-healthcare-2019 (Accessed May 21, 2024)
180. Beck-Sagué C Dooley SW Hutton MD Otten J Breeden A Crawford JT et al. Hospital outbreak of multidrug-resistant Mycobacterium tuberculosis infections. Factors in transmission to staff and HIV-infected patients JAMA 1992 268 1280 1286 10.1001/jama.1992.03490100078031 1507374
181. Pizzichini E Pizzichini MMM Leigh R Djukanović R Sterk PJ Safety of sputum induction Eur Respir J Suppl 2002 37 9s 18s 10.1183/09031936.02.00000902 12361366
182. Culver DA Gordon SM Mehta AC Infection control in the bronchoscopy suite: A review of outbreaks and guidelines for prevention Am J Respir Crit Care Med 2003 167 1050 1056 10.1164/rccm.200208-797CC 12684244
183. Petersen E Khamis F Migliori GB Bay JG Marais B Wejse C et al. De-isolation of patients with pulmonary tuberculosis after start of treatment — clear, unequivocal guidelines are missing Int J Infect Dis 2017 56 34 38 10.1016/j.ijid.2017.01.029 28163167
184. Rouillon A Perdrizet S Parrot R Transmission of tubercle bacilli: The effects of chemotherapy Tubercle 1976 57 275 299 10.1016/s0041-3879(76)80006-2 827837
185. Dharmadhikari AS Mphahlele M Venter K Stoltz A Mathebula R Masotla T et al. Rapid impact of effective treatment on transmission of multidrug-resistant tuberculosis Int J Tuberc Lung Dis 2014 18 1019 1025 10.5588/ijtld.13.0834 25189547
186. Behr MA Warren SA Salamon H Hopewell PC Ponce de Leon A Daley CL et al. Transmission of Mycobacterium tuberculosis from patients smear-negative for acid-fast bacilli Lancet Lond Engl 1999 353 444 449 10.1016/s0140-6736(98)03406-0
187. Christopher DJ James P Daley P Armstrong L Isaac BTJ Thangakunam B et al. High annual risk of tuberculosis infection among nursing students in South India: A Cohort Study PLOS ONE 2011 6 e26199 10.1371/journal.pone.0026199 22022565
188. Hamada Y Gupta RK Quartagno M Izzard A Acuna-Villaorduna C Altet N et al. Predictive performance of interferon-gamma release assays and the tuberculin skin test for incident tuberculosis: an individual participant data meta-analysis eClinicalMedicine 2023 56 101815 10.1016/j.eclinm.2022.101815 36636295
189. Islam MS Gurley ES Banu S Hossain K Heffelfinger JD Chowdhury KIA et al. Prevalence and incidence of tuberculosis infection among healthcare workers in chest diseases hospitals, Bangladesh: Putting infection control into context PLOS ONE 2023 18 e0291484 10.1371/journal.pone.0291484 37756289
190. Nightingale R Carlin F Meghji J McMullen K Evans D van der Zalm MM et al. Post-TB health and wellbeing Int J Tuberc Lung Dis 2023 27 248 283 10.5588/ijtld.22.0514 37035971
191. Allwood BW van der Zalm MM Amaral AFS Byrne A Datta S Egere U et al. Post-tuberculosis lung health: Perspectives from the First International Symposium Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2020 24 820 828 10.5588/ijtld.20.0067
192. Visca D Centis R Munoz-Torrico M Pontali E Post-tuberculosis sequelae: The need to look beyond treatment outcome Int J Tuberc Lung Dis Off J Int Union Tuberc Lung Dis 2020 24 761 762 10.5588/ijtld.20.0488
193. Meghji J Simpson H Squire SB Mortimer K A Systematic review of the prevalence and pattern of imaging defined post-TB lung disease PLOS ONE 2016 11 e0161176 10.1371/journal.pone.0161176 27518438
194. Kwan CK Ernst JD HIV and tuberculosis: A deadly human syndemic Clin Microbiol Rev 2011 24 351 376 10.1128/CMR.00042-10 21482729
195. Ivanova O Hoffmann VS Lange C Hoelscher M Rachow A Post-tuberculosis lung impairment: systematic review and meta-analysis of spirometry data from 14,621 people Eur Respir Rev 2023 32 220221 10.1183/16000617.0221-2022 37076175
196. Amaral AFS Coton S Kato B Tan WC Studnicka M Janson C et al. Tuberculosis associates with both airflow obstruction and low lung function: BOLD results Eur Respir J 2015 46 1104 1112 10.1183/13993003.02325-2014 26113680
197. Byrne AL Marais BJ Mitnick CD Lecca L Marks GB Tuberculosis and chronic respiratory disease: a systematic review Int J Infect Dis 2015 32 138 146 10.1016/j.ijid.2014.12.016 25809770
198. Menezes AMB Hallal PC Perez-Padilla R Jardim JRB Muiño A Lopez MV et al. Tuberculosis and airflow obstruction: evidence from the PLATINO study in Latin America Eur Respir J 2007 30 1180 1185 10.1183/09031936.00083507 17804445
199. Gupte AN Paradkar M Selvaraju S Thiruvengadam K Shivakumar SVBY Sekar K et al. Assessment of lung function in successfully treated tuberculosis reveals high burden of ventilatory defects and COPD PLoS ONE 2019 14 e0217289 10.1371/journal.pone.0217289 31120971
200. Lee JH Chang JH Lung function in patients with chronic airflow obstruction due to tuberculous destroyed lung Respir Med 2003 97 1237 1242 10.1016/s0954-6111(03)00255-5 14635980
201. Gai X Allwood B Sun Y Post-tuberculosis lung disease and chronic obstructive pulmonary disease Chin Med J (Engl) 2023 136 1923 1928 10.1097/CM9.0000000000002771 37455331
202. Louw E Baines N Maarman G Osman M Sigwadhi L Irusen E et al. The prevalence of pulmonary hypertension after successful tuberculosis treatment in a community sample of adult patients Pulm Circ 2023 13 e12184 10.1002/pul2.12184 36699148
203. van Heerden JK Louw EH Thienemann F Engel ME Allwood BW The prevalence of pulmonary hypertension in post-tuberculosis and active tuberculosis populations: a systematic review and meta-analysis Eur Respir Rev 2024 33 230154 10.1183/16000617.0154-2023 38232991
204. Page ID Byanyima R Hosmane S Onyachi N Opira C Richardson M et al. Chronic pulmonary aspergillosis commonly complicates treated pulmonary tuberculosis with residual cavitation Eur Respir J 2019 53 1801184 10.1183/13993003.01184-2018 30705126
