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Copyright ©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Crit Care Med. Jun 9, 2024; 13(2): 91435
Published online Jun 9, 2024. doi: 10.5492/wjccm.v13.i2.91435
Diagnosis and management of severe pulmonary and extrapulmonary tuberculosis in critically ill patients: A mini review for clinicians
Dominic Ti Ming Tan, Kay Choong See, Department of Medicine, National University Hospital, Singapore 119228, Singapore
ORCID number: Dominic Ti Ming Tan (0000-0002-3439-2597); Kay Choong See (0000-0003-2528-7282).
Author contributions: Tan DTM performed the literature review and wrote the paper; See KC oversaw the write up and contributed to the final edit.
Conflict-of-interest statement: The authors declare that there are no conflict-of-interests.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Dominic Ti Ming Tan, MBChB, Doctor, Department of Medicine, National University Hospital, 1E Kent Ridge Road, Singapore 119228, Singapore. dominic.tan.ti.ming@gmail.com
Received: December 30, 2023
Revised: February 4, 2024
Accepted: March 25, 2024
Published online: June 9, 2024

Abstract

Among critically ill patients, severe pulmonary and extrapulmonary tuberculosis has high morbidity and mortality. Yet, it is a diagnostic challenge given its nonspecific clinical symptoms and signs in early stages of the disease. In addition, management of severe pulmonary and extrapulmonary tuberculosis is complicated given the high risk of drug-drug interactions, drug-disease interactions, and adverse drug reactions. To help clinicians acquire an up-to-date approach to severe tuberculosis, this paper will provide a narrative review of contemporary diagnosis and management of severe pulmonary and extrapulmonary tuberculosis in critically ill patients.

Key Words: Tuberculosis, Severe tuberculosis, Mycobaterium tuberculosis, Critical care, Intensive care, Diagnosis of tuberculosis, Management of tuberculosis

Core Tip: Tuberculosis requiring high dependency or intensive care support is rare yet carries a high morbidity and mortality rate. Whilst pulmonary disease remains the most common manifestation, the management of other lesser known extrapulmonary disease also pose their own set of challenges. Modern advances in diagnosis and treatment options aim to tackle the challenges of delayed recognition and reduce complication rates. We discuss the myriad of ways tuberculosis can manifest in the intensive care unit, the challenges in its management, and the diagnostic tools available for early diagnosis and treatment.



INTRODUCTION

Tuberculosis (TB), a pandemic disease caused by the bacillus Mycobacterium tuberculosis, remains a significant public health problem worldwide with an estimated 7.2 million newly diagnosed TB cases in 2022. In the same year, TB ranked as the single leading cause of death from a single infectious agent, trailing only behind COVID-19, with its numbers nearly double that of deaths caused by human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The World Health Organization (WHO) defines death from TB as all-cause mortality during the cause of TB treatment, accounting for 1.0 million deaths in 2022[1]. The aim of treatment is to reduce the incidence of resistance and achieve full bacterial clearance to limit the risk of transmission[2]. If the diagnosis and initiation of therapy of TB are achieved early, most cases can be managed in an outpatient setting. Hospitalisation is usually only required in patients presenting with other comorbidities, complications of TB or from the treatment itself. Around 3.4% of hospitalised TB cases require HD/ICU admission, especially those with extensive and rapidly progressive disease[3], a considerably high number given the availability of curative treatment[4].

Most patients requiring HD/ICU admissions are a result of respiratory failure or central nervous system (CNS) involvement with the need for mechanical ventilation, close neurological monitoring, and haemodynamic support. Mortality rates amongst these patients remain high, estimated to be between 33% and 67%[5]. Complications arising from severe TB disease or from prolonged ICU stay contribute to admission and mortality rates. Many of these patients go on to develop multiorgan failure, which poses its own set of challenges due to the risk of drug-drug interactions, drug-disease interactions, and adverse drug reactions.

Early recognition and accurate intervention to prevent of progression to severe TB and reduce complication rates is therefore paramount in the management of these patients. TB remains a diagnostic challenge due to its nonspecific clinical symptoms and signs especially in the early stage of disease coupled by the limitations of confirmatory tests. We review the contemporary diagnosis and management of severe pulmonary and extrapulmonary tuberculosis in critically ill patients.

ADMISSION TO THE CRITICAL CARE UNIT
Lung-related disease and complications

The lungs are the most common site of involvement in TB. Pulmonary TB may present in the form of parenchymal or extraparenchymal lung disease. Initial radiological screening is helpful in detecting evidence of pulmonary TB involvement, whether it be through plain chest radiographs or computed tomographic scans. Parenchymal radiological findings can vary significantly, ranging from opacities of various kinds (focal or diffuse, reticular or nodular, with and/or without internal cavitation). Extraparenchymal radiological findings include evidence of miliary TB, intrathoracic lymphadenopathy, pleural effusions and endobronchial disease[6].

Acute respiratory failure is common in pulmonary TB infections. TB infection damages the lung alveoli capillary membranes starting a pro-inflammatory reaction. This leads to an increase in extravascular lung water which thereafter creates a V/Q mismatch and increases the alveolar-arterial gradient. Interstitial granulomatous infections, obliterative endarteritis, and the destruction of air spaces by caseating granulomas and cavitating lesions also contribute to the pathophysiology of acute respiratory failure in pulmonary TB[7].

The most common indication for ICU admission in these patients is the development of respiratory failure and acute respiratory distress syndrome (ARDS), accounting for approximately 36.3% of ICU admissions[8-10]. A recent systematic review demonstrated an average mortality rate of 52.9%, much higher than that of any other cause of respiratory failure including the standard non-tuberculous pneumonia of 25%[8].

Management strategies are similar to those of other patients with non-tuberculous ARDS. Initial trials of noninvasive ventilatory (NIV) management may be given to patients with mild-moderate ARDS. Whilst NIV management has been shown to improve respiratory failure and serves as a protective factor for mortality in these patients, the progression to moderate-severe ARDS and the failure rate to mechanical ventilation is high[10,11]. Management of these patients should follow the same principles of severe non-tuberculous ARDS. The use of lung-protective ventilation, neuromuscular paralysis, restriction of recruitment manoeuvres, and prone positioning in refractory hypoxaemia should be considered. Where there is a sudden increase in airway pressures, patients should be evaluated for the development of pneumothoraces as this is a common complication in patients with pulmonary TB requiring mechanical ventilation, with an incidence of between 4% and 17% in mechanically ventilated patients[3,12]. In these patients, decompressive thoracocentesis should be considered.

Ventilator-associated pneumonia is a complication (10.8%)[8]. Underlying immunosuppression and prolonged ventilation give rise to increased risks of sepsis and nosocomial infections. Sepsis was present in 9.5% of cases and multiorgan dysfunction in 10.5% cases, both also being included as predictors of mortality[8]. Major haemoptysis (defined as > 50 mL in a single episode or > 200 mL over the course of 24 h) is also commonly seen (3.8%), requiring mechanical ventilation for airway control and gas exchange[8,13]. The principles of management of major haemoptysis adopts a similar approach to non-tuberculous patients with pulmonary haemorrhage.

In more severe disseminated cases of TB such as in miliary TB, there is a haematological seeding of TB from a localised source (usually from pulmonary TB) into the bloodstream resulting in a disseminated infection. This can cause disseminated intravascular coagulation and these patients are also much more likely to develop acute respiratory failure and ARDS[5,8,13].

TB in the CNS

TB infections of the CNS can occur either as the sole manifestation of TB or as concurrent infections with either pulmonary or other extrapulmonary sites of infection. These are usually considered the most severe form of TB, accounting for 1% of active TB cases and 5%-10% of extrapulmonary TB cases[14]. Manifestations include TB meningitis and cerebral tuberculomas, of which the former is its most common manifestation. Radiological imaging in approximately 50% of cases will carry evidence of active or previous pulmonary TB[13]. The pathophysiology usually involves disseminated infection involving the haematogenous spread (commonly a complication of miliary TB) of the Mycobacterium to the brain meninges and tissue. Recognising TB in the CNS can be challenging due to the overlap with other neurological disease. In TB meningitis, patients typically present with symptoms of subacute or chronic meningitis (malaise, fatigue, anorexia, vomiting, headache, and fever)[15]. With cerebral tuberculomas, the lesions may be large enough for patients to present with signs and symptoms typical of a space-occupying lesion (cranial nerve palsies most commonly involving CN III, VI and VII seizures, pyramidal or cerebellar signs)[16]. The duration of symptoms before presentation is wide and ranges from several days to months[17].

Most patients requiring ICU admissions show more severe manifestations of disease. Altered mental status due to extrapulmonary involvement of the CNS can account for up to 40% of ICU admissions in some centres[18]. Severe altered mental status or comatose states often necessitate mechanical intubation and ventilation. In a systemic review and meta-analysis by Wang et al[17], the mortality rate for these patients was 64.8%, with other studies predominantly involving adults showing a 40%-53% mortality with significant neurological disability in survivors[19]. In these patients, the requirement of mechanical ventilation was associated with a poorer prognosis[20].

Comatose states are associated with raised intracranial pressures (ICP)[21]. Hydrocephalus is the most common attributing cause and results from CSF blockage either at the basal cistern or absorptive arachnoid granulations (a communicating hydrocephalus in 70%-80%), or at the cerebral aqueduct or fourth ventricle outlet (a noncommunicating hydrocephalus in 20%-30%)[19,22]. Other reasons for a raised ICP include cerebral oedema, tuberculoma formation, hyperthermia, impaired ventilation (hyper- or hypocapnia) and hyponatraemia[21]. It is thus no surprise that raised ICP, cerebral ischaemia, hyponatraemia and seizures are all associated with a poorer outcome[21]. The main challenges in the ICU come from having to optimise ICP and cerebral perfusion and manage the intricacies of hyponatraemia[19]. In these patients, management aims at general neuro-intensive supportive care to optimise parameters such as temperature, strict fluid and electrolyte management, blood sugar control, patient positioning, the monitoring of ICP, and the monitoring of gaseous exchange and tissue perfusion[23].

Donovan et al[19] described noninvasive and invasive forms of intracranial pressure monitoring. Transcranial doppler ultrasound can be used to evaluate the cerebral blood flow velocities in the basal arteries of the brain and thus inferring ICP, and optic nerve sheath diameter ultrasound can also be used for early ICP detection. Limited data are available detailing their efficacy in their use in guiding management or improving outcomes but can be a consideration where resources are limited. The gold standard would be through an intracranial (intraventricular/intraparenchymal) device insertion through neurosurgical intervention but carry its inherent risks of bleed and infection due to its invasive nature.

Some studies suggest that a communicating hydrocephalus can be treated conservatively with medical therapy alone. Acetazolamide aims at reducing CSF production, however a third of these patients also have been found to require concomitant repeated large volume lumbar punctures[19,24]. Where conservative measures fail, or in the case of a noncommunicating hydrocephalus, treatment usually involves the insertion of a ventriculo-peritoneal shunt or performing an endoscopic third ventriculostomy[25]. Other neurosurgical interventions may be indicated in the removal of a large tuberculoma.

Hyponatraemia accompanies critical illness and occurs in around 40%-50% patients with TB CNS infections and is associated with worse outcomes[26]. The cause of this is usually due to either syndrome of inappropriate antidiuretic hormone secretion (SIADH) or cerebral salt wasting due to atrial natriuretic peptide secretion. The treatment difficulties arise from being able to distinguishing the two, as the management for each differs. There is still no guideline for treatment of hyponatraemia specifically in patients with TB CNS infections. Fluid restriction is generally recommended as first-line treatment for SIADH but may be potentially harmful in hypovolemic patients with cerebral salt wasting[27]. Fludrocortisone has been used in previous studies to achieve faster correction of plasma sodium than IV/PO salt supplementation alone but was associated with severe hypertension and hypokalaemia and did not show to influence mortality or disability at 6 mo[19]. Some studies also show that the use of hypertonic saline may be useful in treating hyponatraemia in both SIADH and cerebral salt wasting, with the added benefits in reducing ICP levels[28]. The use of mannitol is still largely debated.

Disseminated TB and extrapulmonary manifestations

In truth, disseminated disease and haematogenous spread (as discussed in the case of miliary TB) can effectively affect any organ. About a third of patients with pulmonary TB present with gastrointestinal TB and tuberculous peritonitis[29]. Clinical symptoms and signs vary depend on the organ affected and range from abdominal pain, ascites (especially in peritoneal disease), weight loss, and few with an acute abdomen secondary to strictures and obstruction[30]. Diagnosis is usually made by a combination of clinical judgment, imaging, and occasionally ascitic taps and peritoneal biopsies. Gastrointestinal TB may not be particularly relevant in the ICU unless significant complications arise such as significant ascites causing diaphragmatic splinting or intestinal obstruction necessitating the need for surgery.

Spread to the pericardium can also result in TB pericarditis and resultant pericardial effusion. The diagnosis is usually based on electrocardiography and echocardiography. Treatment is mainly through anti-TB medications and glucocorticoid treatment. 10% of these patients eventually go on to develop large effusions resulting a tamponade physiology and eventually require pericardiocentesis and drainage[30].

Manifestations of adrenal insufficiency has also been reported, either through direct involvement of the adrenal glands or from disseminated seeding[31]. TB is the second most common cause of chronic adrenal insufficiency after autoimmune disease, present in 6%-10% of patients with active TB[31,32]. A high degree of suspicion is required in patients with vasopressor-dependent shock. Shock associated with hyponatraemia, hyperkalaemia, anaemia, and skin hyperpigmentation are key findings. Treatment usually involves high-dose steroids and fluid resuscitation.

Septic shock and multiorgan failure

A recent systematic review by Galvin et al[8] showed that sepsis was present in 10.5%and multiorgan failure in 9.5% of TB patients admitted to the ICU, with most cases related to a secondary bacterial infection. Isolated TB-related septic shock is extremely rare in immunocompetent individuals; Kethireddy et al[33] described only 1% of TB-related septic shock in a large cohort study but a high mortality rate (80% vs 49% in patients with shock due to other causes). Of these patients, approximately 31.6% required vasopressor support and 92.5% had warm shock[34]. Delay in treatment was found to be the main reason for high mortality, attributable to septicaemia and subsequent multiorgan failure[5]. Treatment involves giving the appropriate antimicrobial early (antituberculosis therapy in the setting of TB without other causes), fluid resuscitation, vasopressor support and where needed, stress-dose glucocorticoid therapy and renal replacement therapy. Hagan and Nathani[5] helpfully describe the pathophysiology for other potential reasons necessitating the need for ICU admission (Table 1).

Table 1 Other causes for intensive care unit admissions[5].
Presentation
Potential cause
Massive haemoptysisRasmussen aneurysm
Cardiogenic shockMassive pericardial effusion from TB pericarditis
Liver failureDrug reaction
Renal failureDrug reaction (usually rifampicin)
Disseminated intravascular coagulationMiliary TB
Pituitary apoplexy/stroke mimicsCerebral tuberculoma
Airway obstructionLaryngeal/retropharyngeal TB
Known TB patient electively admittedPost-thoracic surgery
ASSOCIATED RISK FACTORS AND SCORING SYSTEMS

Independent risk factors owing to increased mortality include diabetes, chronic smoking and alcohol abuse, active immunosuppression, chronic pancreatitis, as well and concomitant infections with HIV/AIDS[12]. It is reported that people with concomitant HIV are 30 times more likely to develop active TB and carry an earlier age of hospitalisation and rate of respiratory failure[35]. Risk factors of inpatient mortality include the presence of ARDS and the need for mechanical ventilation, the presence of septic shock requiring vasopressor support, multiorgan failure, the presence of other nosocomial and/or ventilator-associated pneumonia, and delayed treatment[5,12,36]. Miliary TB is also a negative predictor for survival, with individuals more likely to develop ARDS than those with isolated pulmonary TB[5]. Many studies have used scoring systems for estimating ICU mortality and to guide clinical decision making. The use of the APACHE II, SAPS, and SOFA scores has been described to be helpful in predicting short-term and long-term outcomes in patients in the ICU[3,37]. High APACHE, SAPS and SOFA scores have been associated with higher mortality rates[37].

DIAGNOSIS OF TB IN THE ICU

The diagnosis of TB requires microbiological confirmation. Global efforts have been made to accelerate the development and expand on new diagnostic technologies. At present, most TB case detection remains dependent on clinical symptoms, microbiology, molecular methods, and radiological findings. This poses a challenge in critically ill patients as appropriate sample collection can be challenging due to poor general conditions. The WHO recommends sending off at least two sputum specimens for culture in all patients suspected to have pulmonary TB[38]. The importance of good quality sputum and smear examination is widely recognised[39]. Samples should be, where available, sent for acid-fast bacilli staining (Ziehl-Neelsen staining).

It has been shown that the diagnostic yield in a patient who is able to spontaneously expectorate a good quality sputum sample is similar to that of a bronchoscopy sample[40]. In patients who are unable to spontaneously expectorate, induced sputum collection should be attempted. For critically ill patients who are mechanically ventilated, more invasive techniques to obtain sputum samples such as deep suctioning to obtain endotracheal aspirates or a bronchoalveolar lavage can be attempted. Culture examinations have seen much progress over the years and newer liquid culture methods have a mean time to detection of between 12.9 d and 15.0 d[41]. This however can still lead to diagnostic delays and as such, molecular testing should be done in all critically ill patients (see below). Lange and Mori describe the methods of collection and processing for the diagnosis of TB in Tables 2 and 3[42]. To diagnose extrapulmonary TB, samples from suspected sites of infection should be cultured. The diagnosis remains challenging because clinical specimens may be potentially inaccessible for appropriate sampling, and may require more invasive diagnostic procedures[43].

Table 2 Methods of collection and processing sputum samples for diagnosis of tuberculosis[42].
Specimen
Amount
Preservation
Comment
Sputum2-5 mLUnprocessedAt least 2x, recommended to be in the morning on an empty stomach
Induced sputum2-5 mLUnprocessedExpectoration following inhalation of 3% NaCl solution
Bronchial secretions or bronchoalveolar lavage samples2-5 mLUnprocessedBAL-ELISPOT should be performed on the same day of sample collection
Gastric aspirates > 2 mLIn 1-2 mL phosphate buffer (trinatrium phosphate) Early morning gastric aspirates, only when sputum cannot be aspirated and when bronchoscopy and lavage is not indicated
Table 3 Methods of collection and processing of non-sputum samples for diagnosis of tuberculosis[42].
Specimen
Amount
Preservation
Comment
Biopsy of specimen (e.g., lymph nodes, peritoneal biopsies)2 separate portionsIn 0.9% NaCl for microbiological examination N/A
In formalin for histopathological examination
Pleural effusion/ascitesAt least 20 mLUnprocessedELISPOT should be performed on the same day of sample collection
CSF2-3 mLUnprocessedELISPOT should be performed on the same day of sample collection
Urine30 mLUnprocessed3x specimen. First specimen of urine in the morning with fluid restriction the evening/night before
Stool5-10 mLUnprocessed3x specimen
Blood5-10 mLHeparin- or lithium-citrated tubesOnly in immunosuppressed patients
Not in EDTA blood
Bone marrow2 separate portionsIn heparin- or lithium-citrated tubesOnly in immunosuppressed patients
Air-dried smears and/or formalin preserved biopsies
Not in EDTA blood

Modern nucleic acid amplification test (NAAT) results can be rapidly made available within 1 d after obtaining a sample with high specificity rates. A meta-analysis for the GeneXpert MTB/RIF showed that it displayed high specificity regardless of the specimen type (85.3% in bone/joint tissue, 86% in lymph node aspirates, 98% in CSF), but had varied sensitivities among the specimen types (94.6% in bone/joint tissue, 83.1% in lymph node aspirates, 71.1% in CSF)[44]. A negative NAAT result in the presence of a positive AFB smear strongly indicates the presence of a non-tuberculous mycobacteria species in the specimen[39]. Line probe assays in modern NAATs are also able to detect common genomic mutations to test for antibiotic resistance and has enabled the rapid diagnosis of multidrug-resistant tuberculosis in more than 85% of all cases[45].

In addition to the above, radiological imaging can help in supporting the diagnosis. Where there are inconclusive reports with a high clinical suspicion of TB based on the clinical history, examination, and radiological findings, empirical antituberculosis therapy should be considered to reduce the delay to treatment and risk of disease progression. Survival of individuals with TB is shown to be improved significantly if started within 14 d of hospitalisation[12,36].

TREATMENT OF TB
First-line treatment and barriers in the critically ill

Anti-TB medications (ATTs) are the mainstay of TB treatment. In patients with drug-sensitive TB, WHO guidelines recommend a standard treatment of rifampicin, isoniazid, pyrazinamide, and ethambutol[46], in a regimen comprising of 2 mo of all four drugs, followed by 4 mo of rifampicin and isoniazid. This regimen can be extended in the setting of extrapulmonary TB (i.e. TB meningitis, joint, bone) and those with extensive disease. Rifampicin resistance is becoming an increasing threat and resistant strains carry a higher mortality[47]. Where there is intolerance or development of complications from first-line ATTs, or in the setting of drug-resistant or multidrug-resistant TB, other second-line ATTs can be used. These range from injectable agents (amikacin, streptomycin), fluoroquinolones (levofloxacin, moxifloxacin), and other bacteriostatic second-line agents like cycloserine or para-aminosalicylic acid[48]. These unfortunately often come with the administration of a greater number of medications with the increased risk of drug interactions and adverse effects. Treatment of TB in patients who are critically ill is complicated by organ dysfunction, issues with the route of administration affecting drug absorption and bioavailability, hepatic and renal impairment requiring dose modification, and drug-drug interactions. Treatment of TB in the ICU therefore typically revolves around ATT medications, management of complications, organ support, adjuvant therapies, and prevention.

Impaired absorption and pharmacodynamics

The success of treatment heavily depends on having achieved an adequate serum concentration of ATTs in the body. Most available ATTs are available in peroral formulations, making administration difficult in critically ill patients who often require endotracheal intubation and with multiorgan failure. Hypoalbuminaemia is one of the most common laboratory findings in TB patients in the intensive care unit and is an associated risk factor for a higher mortality[49]. Hypoalbuminaemia can contribute to gut oedema, impairing enteral absorption leading to low serum concentrations of ATTs, as well as impair the volume of distribution of ATTs by altering the drug binding of albumin-bound rifampicin and ethambutol[30,50]. Other factors impairing enteral absorption of ATTs in critically ill patients would include gastroparesis and intestinal ileus, ulcer prophylaxis, and gut microbiome changes (especially in the setting of concurrent broad-spectrum antibiotic administration). Parenteral administration of higher doses or the use of intravenous formularies may be required. Administering ATTs intravenously may help to bypass the first-pass metabolism in the gut but may necessitate the use of alternative regimes which are also associated with poorer efficacy and outcomes[45]. Liver and renal impairment, effectively altering drug elimination, also play a key role.

Nephrotoxicity

Alterations of renal clearance inadvertently affect ATT drug elimination. Dose adjustments are required in certain ATTs for patients with a CrCl of < 30 mL/min/1.73 m2 (see Table 4). This is crucial to avoid adverse side effects that come from supratherapeutic levels of drug toxicity. Close monitoring of serum drug levels and the involvement of a multidisciplinary team involving nephrology physicians, pharmacists, and the primary treatment team is crucial.

Table 4 Dose adjustment in antituberculosis therapies in patients with renal dysfunction.
Antimycobacterial agent
Normal daily dose in adults
CrCl 30-60
CrCl 10-29
CrCl < 10
Haemodialysis
Peritoneal dialysis
Isoniazid 5 mg/kg (typically 300 mg)No dose adjustment No dose adjustmentNo dose adjustment No dose adjustmentNo dose adjustment
Rifampicin10 mg/kg (typically 600 mg)No dose adjustmentNo dose adjustment No dose adjustmentNo dose adjustmentNo dose adjustment
Ethambutol15 mg/kg15 mg/kg/d15 mg/kg q48h15 mg/kg q48h15 mg/kg three times weekly post-HD15 mg/kg q48h
Pyrazinamide15-30mg/kgNo dose adjustment15-30 mg/kg q48h15-30 mg/kg three times weekly15-30 mg/kg three times weekly post-HDNo dose adjustment
Hepatoxicity

It is important to get a baseline liver function test prior to initiation of any therapy as drug-induced hepatitis is reported to occur in 3%-13% of patients[51]. Liver function should be closely monitored as soon as ATTs are initiated as the first sign of drug-induced hepatotoxicity is usually an increase in liver enzymes more than three times the upper limit of normal. Should there be the presence of liver enzyme derangement prior to the initiation of therapy, it should be established that the deranged liver enzymes is not due to TB itself, especially in the setting of disseminated TB. Initiation of appropriate ATT treatment in this setting would thereby be the solution to treat and improve overall liver function. Patients at higher risk of hepatotoxicity include those with co-infection with hepatitis viruses, chronic alcohol misuse, and concomitant administration of other hepatotoxic drugs[46]. Patients with deranged liver enzymes or high-risk individuals should be screened for viral hepatitis prior to initiation of therapy.

Common offending agents for hepatoxicity are pyrazinamide, isoniazid, and/or rifampicin in order of highest to lowest risk. If transaminitis occurs with values more than three to five times the upper limit of normal, or if there is significant hyperbilirubinaemia, termination of ATTs or the use of less hepatotoxic alternatives should be considered[5]. A prolonged regimen of streptomycin and levofloxacin with ethambutol can be considered in such cases. Rifampicin and Isoniazid can be slowly reintroduced with close monitoring once liver function improves, and an extended duration of treatment can be considered ranging from 9 mo to 24 mo depending on the liver profile[52].

Other adverse effects

Ethambutol and isoniazid are known for their neurotoxic effects. In critically ill patients, who are often sedated for mechanical ventilation, neurological adverse effects may be difficult to monitor. One should be aware of potential effects and closely monitor for symptoms where possible. Rifampicin is a known potent inducer of the cytochrome P450 enzyme system, and dose adjustments should be taken in the concomitant administration of drugs that are metabolised in the liver. Rifampicin is also known to be able to induce thrombocytopaenia, so platelet counts should be closely monitored whilst on treatment[53].

Immune reconstitution inflammatory syndrome/paradoxical drug reactions

The paradoxical drug reaction is defined as the rapid clinical deterioration after initiation of ATT or radiological worsening of pre-existing lesions or the development of new lesions. This owes to the immune response to dead bacilli and immune reconstitution. Immune reconstitution inflammatory syndrome (IRIS) can present as a new TB diagnosis in HIV patients recently started on ART (with lower CD4 counts at the time of ART initiation being associated with an increased risk)[54]. The mainstay treatment for this is the administration of glucocorticoids. Where glucocorticoids fail, thalidomide and montelukast may have a role in the treatment of IRIS/paradoxical drug reactions[5].

ADJUVANT THERAPIES
Role of steroids

The role of steroids in the management of pulmonary TB remain unclear. A meta-analysis suggested the possibility of some benefit in improving prognosis in patients with TB-related septic shock and multiorgan failure, but further evaluation is required[55]. Most of the current evidence suggest that adjuvant steroid therapy is only clinically indicated in the management of TB meningitis and pericardial TB[56].

Role of antiplatelet therapy

With complications of vasculitis and stroke in TB meningitis, the role of antiplatelet therapy in reducing the rates of such complications remain in question. Several trials examining the role of Aspirin in the management of TB meningitis are non-conclusive[57].

PREVENTION

The role of BCG vaccinations in reducing the incidence of TB is widely accepted. Active contact tracing and screening of household members should be performed in suspected or confirmed cases of TB so that early disease can be detected and treated timely. Given their associated risks in increased mortality, the control of risk factors likely diabetes and smoking cessation can help reduce the severity of TB infections. Antiretroviral therapy to increase CD4 T-cell count in patients with HIV is also the most effective preventive strategy against TB in these subset of patients[58]. In the setting of the intensive care unit, precautions to prevent the spread of disease should be optimised. Patients should be isolated in a negative pressure room, aerosol-generating or high-risk procedures like endotracheal intubation, bronchoscopy, and nebulisation should be avoided as much as possible. Closed suctioned systems should be used in mechanically ventilated patients. Strict infection control, hand washing, and the use N95 masks and proper PAPR should be adhered to whenever contact with these patients are required.

CONCLUSION

TB is a global problem but remains an elusive disease due to its nonspecific clinical presentation in early disease. Although uncommon, delays in diagnosis and treatment initiation can lead to severe disease requiring ICU care, where mortality rates remain high. An awareness of patient populations with increased risk factors such as those with concurrent HIV infection and other comorbidities should prompt clinicians to pay extra attention to these patients. Administration of the recommended treatment regimens can be difficult in critically ill patients due to altered drug absorption, pharmacodynamics, pharmacokinetics, as well drug-drug interactions. Clinicians should be aware of the diagnostic tools available to them, have a high index of suspicion to diagnose and treat these patients, involve other members in a multidisciplinary team, and take optimal steps to ensure that the transmission of TB is prevented.

Footnotes

Provenance and peer review: Invited article; Externally peer reviewed.

Peer-review model: Single blind

Specialty type: Critical care medicine

Country/Territory of origin: Singapore

Peer-review report’s scientific quality classification

Grade A (Excellent): 0

Grade B (Very good): 0

Grade C (Good): C

Grade D (Fair): D

Grade E (Poor): 0

P-Reviewer: Herawati F, Indonesia; Surani S, United States S-Editor: Gong ZM L-Editor: Filipodia P-Editor: Che XX

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