The Role of Steroids in the Treatment of Tuberculosis

1.1 Historical context

The history of corticosteroid use in tuberculosis (TB) treatment represents a fascinating journey of medical discovery that spans over seven decades. The initial observations of corticosteroid effects in TB patients emerged during the early antibiotic era, when clinicians began noticing the complex interplay between host inflammatory responses and mycobacterial infection [1]. The introduction of cortisone in the late 1940s and early 1950s created both excitement and controversy in the medical community, as physicians observed dramatic symptomatic improvements in TB patients, albeit with concerns about potential disease progression [2].

Early clinical observations documented that corticosteroids could rapidly reduce fever, improve appetite, and enhance general well-being in TB patients, particularly those with severe systemic symptoms [3, 4]. However, these benefits were tempered by reports of disease exacerbation when steroids were used without concurrent antituberculosis therapy (ATBT), leading to the fundamental understanding that corticosteroids should never be administered alone in active TB [5]. This dichotomy between symptom relief and potential harm established the foundation for decades of careful investigation into the appropriate role of corticosteroids in TB management.

1.2 Evolution of corticosteroid use as adjunctive therapy in TB

The evolution of corticosteroid use as adjunctive therapy in TB has been marked by progressive refinement of indications, dosing strategies, and patient selection criteria. Research conducted since the 1960s has systematically evaluated corticosteroid efficacy across various forms of TB, leading to evidence-based recommendations for specific clinical scenarios [6].

The development of standardized treatment protocols incorporating corticosteroids emerged gradually through international collaborative efforts. The World Health Organization and professional societies began incorporating corticosteroid recommendations into TB treatment guidelines during the 1980s and 1990s, initially focusing on severe extrapulmonary forms of the disease [7]. The evidence base expanded significantly with large randomized controlled trials conducted in various geographical settings, particularly for tuberculous meningitis (TBM) and pericarditis, where corticosteroids demonstrated clear mortality benefits [8–15].

1.3 Current global perspectives on adjunctive steroid therapy

Contemporary global perspectives on adjunctive steroid therapy in TB reflect both consensus on established indications and ongoing debates about expanding applications. International guidelines consistently recommend corticosteroids for TBM and pericarditis, where high-quality evidence supports mortality reduction [16].

While the distinction between high-burden and low-burden settings provides a useful epidemiological framework, the observed regional variations in corticosteroid use are driven by a complex interplay of additional factors. These include significant disparities in healthcare infrastructure, which impact both the diagnosis of steroid-responsive conditions (like TBM) and the ability to safely monitor for steroid-related adverse effects (such as hyperglycemia). Furthermore, differences in access to a consistent supply of first-line and second-line TB antibiotics, as well as the capacity to rapidly diagnose drug resistance, fundamentally alter the risk-benefit calculation for adjuvant immunotherapy [7, 8]. The prevalence of HIV co-infection and the consequent need to manage immune reconstitution inflammatory syndrome (IRIS) also serve as major determinants of corticosteroid utilization patterns [9]. Therefore, clinical practice is shaped not merely by TB incidence but by the specific resources and challenges inherent to each healthcare ecosystem [17].

2.1 Host immune response to Mycobacterium tuberculosis

The mechanisms governing the host immune response when Mycobacterium tuberculosis (MTB) first interacts with human lung cells remain poorly understood. The response involves multiple components, including innate immunity, granuloma formation, and adaptive immunity. Increasingly, researchers recognize the importance of immune elements that connect the innate and adaptive systems [18].

Innate immunity represents the critical first line of defense against TB, yet paradoxically, these same protective mechanisms often contribute to the immunopathological processes that characterize TB disease. This dual nature of innate immunity in TB creates a complex landscape where the balance between protection and pathology determines clinical outcomes [18] (Table A1).

Key innate immune cells, including epithelial cells, neutrophils, NK cells, macrophages, and dendritic cells, shape the immunopathology of TB. Their response to MTB highlights a balance between host defense and tissue damage. While these mechanisms evolved for protection, MTB has adapted to exploit them [18].

TB treatment will increasingly depend on modulating the immune response alongside antibiotics, optimizing defense while minimizing harm. This calls for a context-sensitive understanding of innate immunity and precision medicine approaches that customize therapy to individual patients [18].

Adaptive immunity is a critical component of the host immune response against MTB. Macrophages and phagocytic cells carry phagocytized organisms from the lung to draining lymph nodes, where they present MTB antigens to T cells, inducing an adaptive immune response; this occurs two to six weeks after infection [18] (Table B1).

2.2 Balance between protective immunity and tissue damage

The formation of granulomas represents the hallmark of TB pathology, serving both protective and pathological roles. It helps in containing the infection but also causes local tissue damage. The extent of this pathology depends on bacterial load, host genetics, and especially the strength of the inflammatory response. Excessive inflammation, not just bacterial presence, is a primary driver of tissue destruction, particularly through mediators like TNF-α, IL-1β, and IL-6, as well as increased levels of MMP-1 and MMP-9. These factors contribute to cavity formation and bacterial spread, highlighting the value of therapies that modify the immune response [19].

2.3 Role of inflammatory cascades in TB pathogenesis

Inflammatory cascades play a complex role in the pathogenesis of TB, mediating both protective immunity and disease progression. Cytokines, immune cells, and signaling pathways all contribute to the host-pathogen interactions in MTB infection. These mechanisms are essential for infection control, granuloma development, and the resulting tissue pathology.

Innate immune recognition and inflammatory signaling: innate immune cells serve as the primary defense against MTB by recognizing pathogen-associated molecular patterns (PAMPs) via pattern recognition receptors (PRRs) like TLRs, CLRs, and NLRs. The activation of these receptors initiates inflammatory cascades, notably the NF-κB and MAPK pathways, which stimulate the release of proinflammatory cytokines – IL-1, IL-6, TNF-α, and IFN-γ – crucial for restricting bacterial growth [19]. To ensure its survival, MTB employs virulence factors such as RipA, ESAT-6, PE/PPE proteins, ManLAM, Zmp1, Hip1, PknG, and SapM to modulate host inflammatory signaling, disrupting autophagy, apoptosis, and metabolic functions in macrophages [20].

Inflammasome activation and cytokine secretion: NLRP3 inflammasome activation by MTB triggers caspase-1 and the release of IL-1β and IL-18. Aberrant activation can worsen inflammation and tissue injury without improving bacterial clearance [21, 22]. Modulating inflammasome signaling may, therefore, offer a host-directed approach to balancing infection control with inflammation [23].

Macrophage polarization and dysfunction: macrophages, primary host cells for MTB, polarize into either M1 (proinflammatory, bactericidal) or M2 (antiinflammatory, may aid bacterial survival) phenotypes. MTB skews polarization toward an M2-like state to dampen host inflammatory responses [24, 25]. Extracellular vesicles further influence macrophage signaling via miRNAs, affecting MAPK and PI3K/AKT pathways and impacting bacterial growth control [26].

Cytokine network and immune regulation: disease outcomes depend on the balance of pro-(TNF-α, IL-6, IL-12, IFN-γ) and antiinflammatory (IL-10, TGF-β) cytokines. In TB, elevated IL-6 and IL-10 impair immune function and T-cell responses, while IL-1 drives inflammation that may worsen the disease [27, 28]. Regulatory T cells help control pathology but can also promote bacterial persistence [29].

Granuloma formation and progression: the granuloma serves as a host-protective factor as well as a shelter for the long-term survival of the tubercle bacterium within the host. Inflammatory cascades, particularly cytokines like TNF-α, maintain granuloma integrity. Dysregulation can cause necrosis and cavitation, increasing bacterial spread [30]. Vascular and lymphatic remodeling in granulomas also affect immune cell movement and inflammation [31].

Role of inflammatory genes and signaling pathways: gene expression analysis in active TB reveals upregulation of inflammatory genes and links immune checkpoints, such as PD–L1, to disease progression. Machine learning identifies crucial genes and miRNAs as potential biomarkers or therapeutic targets [32].

Influence of comorbidities and microbiome: comorbidities such as malnutrition and diabetes amplify inflammation, raising the risk of active TB [33, 34]. The microbiome also affects lung immunity, as gut microbial short-chain fatty acids help regulate inflammation [35, 36].

3.1 Mechanisms of action

3.2 Immunomodulatory balance

Reduction of excessive inflammatory response: corticosteroids benefit TB patients by suppressing harmful inflammation responsible for complications. Studies show adjunctive corticosteroids reduce markers like C-reactive protein (CRP) and proinflammatory cytokines [44], which are vital in severe forms such as meningitis and pericarditis, where inflammation threatens organ function [45].

Early initiation and proper dosing are crucial; corticosteroids given with ATBT prevent damaging inflammation [6]. Moderate doses (0.5–1 mg/kg/day prednisolone equivalent) reduce inflammation without impairing bacterial clearance [46].

Prevention of tissue damage and scarring: corticosteroids prevent tissue damage and fibrosis in TB by suppressing matrix metalloproteinases (MMPs) and increasing TIMPs, thereby maintaining tissue structure [47]. In TBM, they reduce risks such as hydrocephalus and infarction [45], while in pericarditis, they lower the risk of constrictive pericarditis by curbing fibroblast activity [48].

Their antifibrotic benefits include regulating fibroblasts, decreasing matrix production, and supporting matrix degradation [49]. This leads to less pleural thickening and better lung function in pulmonary TB (PTB) [49]. Adjunctive corticosteroids also result in improved long-term outcomes, likely by preventing tissue remodeling [50].

Improved drug penetration to infection sites: corticosteroids can improve ATBT penetration by reducing inflammation-induced barriers like vasculitis, edema, and fibrosis [51]. By decreasing granuloma size and inflammation, corticosteroids facilitate better drug distribution to sites where bacteria may persist despite treatment [52], thereby enhancing treatment outcomes and reducing relapse risk [6]. Similar benefits have been observed in extrapulmonary TB (EPTB), such as TB meningitis, lymph node disease, and pericardial disease [6].

Enhanced clinical recovery and functional outcomes: adjunctive corticosteroid therapy in TB provides benefits beyond survival, including faster symptom relief and improved quality of life, with an earlier return to daily activities [6]. In TBM, especially when started early, corticosteroids decrease neurological complications and enhance cognitive function [45].

In critical organ involvement, such as pericardial or spinal TB, corticosteroids reduce surgery rates, enhance cardiac and mobility outcomes, and help lower healthcare costs [53]. These advantages support the selective use of corticosteroids in TB.

3.3 Potential risks and concerns

Immunosuppression and infection susceptibility: corticosteroids suppress both innate and adaptive immunity, increasing the risk of opportunistic and latent infections, especially in TB patients with HIV [54]. Infection risk rises with higher doses and longer treatments [54], though short-term, moderate-dose regimens (6–8 weeks) commonly used in TB trials are generally safe [6]. Assessing individual factors such as nutritional status, comorbidities, and concurrent medications is important. Careful infection monitoring and prophylaxis for high-risk patients are crucial for safe corticosteroid therapy in TB [55].

Impact on mycobacterial clearance: corticosteroid use in TB may impair mycobacterial clearance, raising concerns about treatment failure or relapse. Concurrent initiation of corticosteroids with ATBT is more effective than delayed use [6]. Clinical studies and meta-analyses show no increased risk of treatment failure or relapse with corticosteroids when effective ATBT are given [24, 28]. However, these findings are mostly in HIV-negative, drug-susceptible patients. The effects in drug-resistant or severely immunocompromised cases remain uncertain [56].

Risk of treatment failure or relapse: most studies show that appropriate corticosteroid use does not increase treatment failure or relapse rates, though risks rise if drug-resistant TB is missed and untreated [57]. Corticosteroids may also mask symptoms, delaying recognition of treatment failure [58]. While long-term follow-up data are limited, relapse rates remain low if corticosteroids are properly used. A systematic review found no increase in relapse up to five years in such patients [45]. However, varying study quality complicates firm conclusions. Relapse risk increases with inadequate therapy, poor adherence, and severe immunosuppression [56]. Regular monitoring during and after treatment is essential.

Masking of symptoms and delayed diagnosis: corticosteroids can mask symptoms and imaging findings of TB and other infections, delaying diagnosis and complicating treatment monitoring. Their antiinflammatory effects may suppress fever, lower inflammatory markers, and improve symptoms, giving a false sense of recovery even as infection persists – especially with undiagnosed drug resistance or co-infections [59]. Corticosteroids may also reduce visible inflammation on imaging, so radiological improvement doesn’t always mean the infection is cleared [58]. They can further obscure paradoxical reactions (PRs) or IRIS, making these issues harder to identify [17]. Vigilance is essential for the early detection of complications or treatment failure in patients receiving corticosteroids.

4.1 Rationale for corticosteroid use in TB

Controlling MTB largely depends on the host’s immune response, but overstimulation can cause severe tissue damage and worse clinical outcomes, especially in EPTB. Because of their antiinflammatory and immunomodulatory effects, adjunctive corticosteroids have been extensively studied to reduce the morbidity and mortality of severe TB, primarily in meningeal, pericardial, and pleural forms.

Corticosteroids have long been studied as adjunctive therapy in TB, with accumulating evidence supporting their use in specific clinical contexts. Over the past two decades, a series of systematic reviews, meta-analyses, and expert assessments have clarified the role of corticosteroids across various TB manifestations, particularly in extrapulmonary and high-risk patient populations.

A broader conceptual framework emphasizes corticosteroids as part of host-directed therapy. Antiinflammatory adjuncts, including steroids, underscore how dampening excessive host inflammation improves outcomes in TB without impairing bacteriological clearance [2, 5, 6, 14]. These findings align with narrative reviews and expert syntheses, which support selective and evidence-guided use of corticosteroids in TB, stressing individualized decision-making based on disease site, comorbidities, and patient frailty.

In conclusion, corticosteroids are strongly recommended for TBM, pericardial TB, and pleural TB, where mortality and morbidity benefits are robustly demonstrated. Their role is also supported in other extrapulmonary forms such as abdominal and endobronchial TB, though the evidence base is somewhat narrower. In PTB, however, the benefit remains unproven for routine use, warranting further investigation. In TB-HIV co-infection, emerging high-quality data now affirm a mortality benefit, strengthening the case for their inclusion in management protocols. This body of literature positions corticosteroids as a key adjunctive therapy, but one best applied selectively and in accordance with disease-specific evidence (Table C1).

4.2 Pulmonary tuberculosis

The value of corticosteroids in PTB remains less definitive. A report highlighted variable effects on sputum culture conversion [60], and the Cochrane review by Critchley et al. (2014) concluded that routine corticosteroid use in PTB lacks robust evidence. There is clearer alignment that corticosteroids should not be universally applied in drug-sensitive pulmonary disease. Instead, their use may be more justified in severe or complicated cases [1].

Adjunctive corticosteroid therapy has been explored for severe PTB, especially in cases complicated by acute respiratory failure, massive pulmonary involvement, and related complications. Evidence remains mixed, and the benefit is generally more pronounced in EPTB, though some studies point to potential advantages in select subsets of PTB.

In severe pulmonary disease, corticosteroids have been used as adjuncts in cases presenting with acute respiratory distress syndrome (ARDS) and respiratory failure. In critically ill patients, studies excluding HIV-positive individuals have found that steroids can significantly reduce mortality, potentially by dampening the intense cytokine response following anti-TB treatment, especially among those with high mycobacterial loads [61]. For massive pulmonary involvement, systematic reviews report that adjunct corticosteroids offer earlier and more sustained clinical and radiographic improvement, such as faster resolution of infiltrates and cavity closure, though not sputum conversion [62].

Randomized controlled trials and meta-analyses indicate that steroids can speed up clinical progress (weight gain, fever resolution, improved serum albumin, rapid radiographic improvement) without increasing relapse or severe side effects [6]. However, recent cohort studies are inconsistent regarding the mortality benefits – steroids have not been shown to lower ICU or hospital mortality in all patients needing mechanical ventilation [63]. Functionally, steroids are associated with quicker recovery and radiologic improvements, but not always a reduction in mortality, especially in those on ventilation. The long-term impact on lung function or quality of life remains uncertain [6, 62]. While corticosteroids may lessen acute inflammation and hypoxemia in ARDS and severe TB, their direct impact on TB-related hypoxemia is unclear and varies by comorbidities and severity [61]. In the ICU, steroid outcomes are mixed – some data link them with higher in-hospital mortality, possibly due to sicker patients receiving steroids. No clear evidence supports shorter ICU stays or less time on ventilation [63].

For TB complications, corticosteroids are proven adjuncts in pleural TB, speeding effusion resolution and limiting residual thickening [11, 49]. For empyema, the evidence is weaker but suggests some antiinflammatory benefit [44]. In endobronchial TB, steroids may decrease bronchial stenosis and airway damage, but the evidence relies mostly on expert consensus [2]. Limited data suggest steroids could reduce posttuberculous bronchiectasis by reducing early airway inflammation, but robust long-term data are missing [2].

4.3 Extrapulmonary TB

Adjunctive corticosteroid therapy has a well-established but variable role in the management of EPTB, with robust evidence supporting its benefit in some anatomical sites and limited or mixed data for others [2, 6, 64].

Central nervous system (CNS) TB: corticosteroids are strongly recommended as adjunctive therapy for TBM. They reduce mortality and improve neurological outcomes, especially in moderate to severe disease. Duration and regimen may vary: TBM typically warrants several weeks, while CNS tuberculomas may require prolonged steroid use depending on clinical response [65, 66].

Cardiovascular TB (pericardial TB): adjunctive corticosteroids are beneficial in tuberculous pericarditis, including both effusive and constrictive types. Studies demonstrate reduced mortality, fewer procedures (e.g., pericardiocentesis), and improved symptomatic and hemodynamic recovery. However, steroids do not reduce the incidence of long-term constriction in pericardial TB [2, 6, 64].

Gastrointestinal (GI) TB: there is insufficient evidence to routinely recommend corticosteroids for GI TB (intestinal, peritoneal). Some observational data suggest potential benefit in severe disease, but no high-quality trials support their routine use in GI forms of EPTB [6, 64].

Genitourinary TB: evidence for corticosteroid benefit in genitourinary TB is sparse. No robust clinical trial data are available, and routine use is not recommended outside of specific cases with severe inflammatory complications [2].

Skeletal TB: the use of corticosteroids in skeletal (bone and joint) TB lacks strong evidence and is not routinely recommended. They may be considered in cases with significant inflammatory symptoms or spinal cord compression, but this is largely extrapolated from neuro-TB guidelines and clinical judgment [2].

Lymph node TB: RCTs in adults and children demonstrate some benefits of adjunctive corticosteroids in tuberculous lymphadenitis, namely faster symptom relief, prevention of complications, and higher rates of resolution at six months [6].

Evidence-based recommendations: adherence to local and international guidelines, as well as the involvement of specialist care, are essential for the optimal management of EPTB with steroids (Table 1).

4.4 Recommended doses

TBM: adjuvant corticosteroid therapy with dexamethasone or prednisolone is strongly recommended for patients with TBM, with tapering over six to eight weeks based on severity [64].

• Stage 1 TBM (GCS 15, no neurological deficits) should receive dexamethasone for six weeks: start IV at 0.3 mg/kg for one week, 0.2 mg/kg for the second week, and 0.1 mg/kg for the third week. Switch to oral dexamethasone: 3 mg/day (week four), 2 mg/day (week five), and 1 mg/day (week six).

• Stages 2 and 3 TBM (GCS 11–14 or focal deficits; GCS ≤ 10): use an eight-week dexamethasone course. Begin IV at 0.4 mg/kg for one week, then 0.3 mg/kg (week two), 0.2 mg/kg (week three), and 0.1 mg/kg (week four). Taper orally with 4 mg/day (week five), 3 mg/day (week six), 2 mg/day (week seven), and 1 mg/day (week eight).

Tuberculous pericardial effusion: an initial adjuvant corticosteroid therapy may be considered (conditional recommendation, very low certainty of evidence). The proposed oral prednisolone regimen lasts 11 weeks, starting at 60 mg/day for four weeks, then reducing to 30 mg/day for the next four weeks, 15 mg/day for two weeks, and concluding with 5 mg/day for one week [67].

4.5 Special conditions

The role of corticosteroids as adjunct therapy in TB varies depending on special clinical situations, including HIV-TB co-infection, pregnancy and lactation, the elderly, pediatrics, and drug-resistant TB. Evidence-based recommendations from guidelines and recent literature support the selective use of this approach in specific scenarios.

HIV-TB co-infection: corticosteroids are mainly indicated for managing TB-associated immune reconstitution inflammatory syndrome (TB-IRIS) in HIV-TB co-infected patients, particularly during antiretroviral therapy (ART) initiation. A randomized placebo-controlled trial showed that prednisone reduced TB-IRIS risk and symptoms without increasing the risk of infection. Corticosteroids show mortality and morbidity benefits in TBM and pericarditis in HIV-uninfected patients, but there is less clear benefit in HIV co-infection; risks include opportunistic infections if ART is not administered. ART should be started early in co-infected patients, with corticosteroids used in select inflammatory complications [2, 6, 44, 68]

Pregnancy and lactation: first-line anti-TB drugs (except streptomycin) are generally considered safe during pregnancy. Corticosteroids may be used when indicated, for example, in TB meningitis or pericarditis [2].

Elderly patients: there is limited direct evidence on corticosteroid use specifically in elderly TB patients. Considerations include comorbidities, an increased risk of adverse corticosteroid effects, and drug-drug interactions. Use should be individualized with careful monitoring, especially in cases of TB meningitis or pericarditis, where corticosteroids have an established benefit [6].

Pediatrics: corticosteroids are recommended adjunctively in pediatric TBM and complicated pericarditis [6].

Drug-resistant TB: evidence for the benefit of corticosteroids in multidrug-resistant TB (MDR-TB) is insufficient. Corticosteroids may be used selectively for specific complications, like TB meningitis or pericarditis, in MDR-TB cases. Management must be cautious due to complex drug regimens and potential adverse effects; guidelines recommend expert consultation.

Paradoxical deterioration: PR refers to clinical or radiological worsening of TB despite effective anti-TB treatment and reduced bacterial load. PR typically develops two weeks to several months after the onset of therapy and is diagnosed after excluding treatment failure, drug resistance, or other infections. It results from an excessive immune response to mycobacterial antigens released during therapy. Manifestations include worsening pulmonary infiltrates, new or enlarged lymph nodes, pleural or pericardial effusions, or CNS involvement [69, 70].

Corticosteroids mitigate inflammation and immune-mediated tissue injury during PR. The strongest evidence supports their use in EPTB (TB meningitis, pericarditis, severe pleural TB) with paradoxical worsening. Their role in PTB PR is less defined but may be considered in severe cases. Corticosteroids can provide relief from fever, respiratory distress, and organ dysfunction due to inflammation [69].

5.1 Selection

Prednisolone and dexamethasone are both used to manage TB, particularly in severe forms such as TBM and pericardial TB. Despite similar molecular structures, these corticosteroids differ in their GR binding affinities and half-lives, potentially affecting their pharmacodynamics and therapeutic effects in TB. No direct head-to-head clinical trials have established the superiority of one over the other as adjunct therapy. Dexamethasone is usually started intravenously, with a tapered switch to oral dosing, while prednisolone typically involves oral administration with tapering doses [2, 6, 64, 68].

5.2 Bioavailability considerations

Differences in corticosteroid bioavailability impact effectiveness. Prednisolone is well absorbed orally for outpatient use. Dexamethasone has high bioavailability both orally and intravenously, with greater potency and a longer duration, which influence dosing and tapering in TB treatment [6, 64].

5.3 Route of administration

Overall, the route of administration is guided by disease severity, the need for rapid onset of action, and patient status, with intravenous methods preferred in critical cases like TBM [2, 6, 64].

• Oral: prednisolone is typically administered orally, particularly in TB forms where long-term outpatient therapy is feasible.

• Intravenous (IV): dexamethasone is often given intravenously initially in serious TB presentations, such as TBM, for rapid antiinflammatory effects, followed by oral tapering.

• Intrathecal: intrathecal corticosteroid administration is not generally recommended or supported for TBM due to a lack of robust evidence and potential risks.

5.4 Pharmacokinetic properties

The pharmacokinetics of corticosteroids (absorption, distribution, metabolism, and excretion) vary significantly between different agents and are crucial for selecting the right drug for a specific clinical situation (e.g., acute inflammation vs. chronic replacement therapy) [71, 72]. These properties are described as follows [71, 72]:

Absorption:

• Oral bioavailability: generally high (>80%) for most corticosteroids

• Peak plasma concentrations: one to three hours after oral administration

• Food effects: may delay absorption but do not significantly affect bioavailability

Distribution:

• Protein binding: high (>90%) to corticosteroid-binding globulin (high affinity but low capacity) and albumin (low affinity but high capacity).

• The free, unbound fraction is the pharmacologically active form.

• During inflammation, the binding affinity of cortisol declines, resulting in a higher free cortisol concentration at the site of interest to alleviate the active inflammatory process.

• Volume of distribution: varies depending on the drug’s lipophilicity and protein binding.

• Crossing barriers: corticosteroids readily cross the placenta. Their ability to cross the blood-brain barrier varies.

Metabolism:

• Primary site: hepatic, via CYP3A4 and other enzymes.

• Prednisone is an inactive prodrug that must be converted in the liver to its active form, prednisolone.

• The addition of a fluorine atom (e.g., dexamethasone, triamcinolone, betamethasone) increases glucocorticoid potency and extends the half-life by slowing metabolism.

Elimination:

• Primary route: renal excretion of metabolites

• Dosage adjustment: may be required in severe hepatic impairment.

5.5 Clinical considerations

Dosing frequency based on half-life:

• Short-acting (8–12 hours): two to three times daily

• Intermediate-acting (12–36 hours): one to two times daily

• Long-acting (36–72 hours): Once daily

Special clinical notes:

• Hydrocortisone: preferred for physiological replacement therapy due to its similar structure to endogenous cortisol.

• Prednisolone versus prednisone: prednisolone is the active form; prednisone requires hepatic conversion.

• Dexamethasone: minimal mineralocorticoid activity makes it preferred for cerebral edema and inflammatory conditions.

• Methylprednisolone: often preferred for pulse therapy due to its high antiinflammatory potency with minimal mineralocorticoid effects (Table 2).

5.6 Relationship to antimicrobial therapy initiation

Adjunct corticosteroids are administered concomitantly with ATBT. Early initiation alongside ATBT is standard, especially in TBM and severe extrapulmonary forms, to reduce inflammation-mediated tissue damage. In TBM, corticosteroids reduce mortality and neurological complications when given early with ATT [2, 6, 64].

Basic conversion formula: equivalent dose = (dose of current drug × potency of current drug) ÷ target drug potency [73].

Example conversions:

• Prednisolone 20 mg to Dexamethasone: (20 × 4) ÷ 25 = 3.2 mg Dexamethasone

• Hydrocortisone 100 mg to Methylprednisolone: (100 × 1) ÷ 5 = 20 mg Methylprednisolone

• Dexamethasone 6 mg to Prednisolone: (6 × 25) ÷ 4 = 37.5 mg Prednisolone

6.1 Common adverse effects

Corticosteroids, when used as adjunct therapy in TB treatment, are associated with a spectrum of common adverse effects that are generally dose-dependent and duration-related. These effects are consistent with the well-established adverse effect profile of systemic corticosteroids.

Metabolic effects: the most frequently reported adverse effects include hyperglycemia, with a global prevalence of 18–30% [74]. This is particularly concerning for patients with diabetes mellitus or those at risk of developing diabetes.

Cardiovascular effects: the reported prevalence of hypertension among long-term users of glucocorticoids is more than 30%. This effect is mediated through mineralocorticoid activity and sodium retention [75].

GI effects: peptic ulcer disease and gastric irritation represent significant concerns, with an increased risk of bleeding by 40% in patients receiving corticosteroids [76].

Psychiatric effects: mood alterations, including euphoria, depression, and anxiety, which are dose-dependent and may manifest within days of treatment initiation [77]. Sleep disturbances and increased irritability are also frequently reported [78].

Dermatological effects: skin thinning, easy bruising, and delayed wound healing are common long-term effects; striae and acneiform eruptions may also develop [79].

6.2 Serious complications

While less common, serious adverse effects of corticosteroids in TB treatment can be life-threatening and require immediate medical attention.

Immunosuppression and opportunistic infections: the most significant concern with corticosteroid use in TB is the potentially increased risk of susceptibility to opportunistic infections, which rises with higher doses and longer therapy duration. Risks are further increased in patients with HIV or advanced age. Glucocorticoids can also mask symptoms of infection by suppressing inflammatory and fever responses, leading to delayed detection [79].

Adrenal suppression: suppression of the hypothalamic-pituitary-adrenal axis is a serious complication that can occur with corticosteroid therapy lasting more than two to three weeks [79]. This can lead to an adrenal crisis upon abrupt discontinuation, characterized by hypotension, electrolyte abnormalities, and cardiovascular collapse.

Avascular necrosis: osteonecrosis, particularly of the femoral head, is a rare but serious complication in patients receiving corticosteroids. The risk increases with higher cumulative doses and longer durations of therapy [80].

6.3 Drug interactions

The interaction between corticosteroids and anti-TB medications is complex and clinically significant, primarily involving effects on drug metabolism through the cytochrome P450 system. The most clinically relevant interactions occur between corticosteroids and first-line anti-TB drugs. These interactions can affect both the efficacy of TB treatment and corticosteroid metabolism, potentially leading to treatment failure or increased toxicity.

Rifampin-corticosteroid interactions: rifampin activates the pregnane X receptor, thereby increasing the activity of cytochrome P450 (notably CYP3A4), glucuronosyltransferase, and p-glycoprotein [81, 82]. This substantially raises corticosteroid metabolism and lowers their bioavailability, especially via enhanced CYP3A4 expression in the liver and intestine [83].

Key considerations include:

• CYP3A4 induction leads to increased corticosteroid clearance

• Time-dependent induction, with maximum effects occurring after 7–14 days of rifampin therapy

• Individual variability in enzyme induction responses

• Potential for significant drug interactions with other CYP3A4 substrates

The clinical implications include:

• Reduced corticosteroid half-life

• Decreased bioavailability of oral corticosteroids

• Need for dose adjustment in patients receiving rifampin

Isoniazid interactions: isoniazid can inhibit certain metabolic pathways, potentially leading to increased corticosteroid levels in some patients. However, this interaction is generally less clinically significant than the rifampin interaction [82].

6.4 Monitoring requirements

Comprehensive monitoring is essential to ensure the safe and effective use of corticosteroids as adjunct therapy in TB treatment [84].

7.1 Novel antiinflammatory approaches

The development of targeted antiinflammatory therapies represents a paradigm shift from the traditional approach to TB treatment. These emerging strategies aim to modulate specific inflammatory pathways while minimizing systemic adverse effects.

7.2 TNF-α inhibitors and other biologics

Tumor necrosis factor-alpha (TNF-α) plays a dual role in TB pathogenesis, serving both protective and pathological functions. Following TNF antagonist therapy, the relative risk for TB increases up to 25 times, depending on the clinical setting and the TNF antagonist used [85]. However, recent evidence suggests potential therapeutic applications in specific clinical scenarios. Current research focuses on [86]:

• Selective TNF-α inhibition with reduced systemic immunosuppression

• Combination strategies with enhanced anti-TB therapy

• Risk stratification protocols for safe TNF-α inhibitor use

• Novel biologics targeting other inflammatory mediators (IL-1β, IL-6, IL-17)

7.3 Selective glucocorticoid receptor modulators (SGRMs)

Selective glucocorticoid receptor modulators (SGRMs) represent a significant advancement in antiinflammatory therapy, aiming to retain the antiinflammatory benefits of corticosteroids while minimizing unwanted metabolic and immunosuppressive effects. These ligands alter the GR’s shape, activating only select signaling pathways, and thus act as both agonists and antagonists.

Recent developments include:

Vamorolone: a novel GRM, the dissociated steroid vamorolone, received marketing approval in 2024, confirming that altering the transrepression-transactivation profile is a valid strategy [87].

Targeted delivery systems: targeted delivery of a GRM payload via an immunology antibody–drug conjugate (iADC) may deliver significant efficacy at doses that do not lead to unwanted side effects. This approach could revolutionize TB treatment by providing localized antiinflammatory effects [88].

Key advantages of SGRMs in TB treatment:

• Preserved antiinflammatory efficacy with reduced metabolic side effects

• Maintained antimicrobial immunity through selective pathway modulation

• Reduced risk of opportunistic infections

• Potential for prolonged treatment courses with improved safety profiles

Host-directed therapies represent a complementary approach to conventional antimicrobial treatment, targeting host pathways that influence TB pathogenesis and treatment outcomes.

Autophagy modulators: autophagy is vital in clearing mycobacteria and supporting immune responses. Glucocorticoids suppress TBK1 kinase, hindering autophagosome maturation, prompting interest in autophagy boosters as adjunct therapy. Understanding the mechanisms and key players involved in modulating antibacterial autophagy will provide innovative improvements in anti-TB therapy via an autophagy-targeting approach [89].

MMP Inhibitors: MMPs drive tissue destruction in TB, particularly in pulmonary cavitation and CNS involvement. Research is focused on using selective MMP inhibitors, combining them with antiinflammatories for extra protection, and monitoring therapy through MMP biomarker levels [90].

Reduced systemic toxicity approaches: novel delivery systems and formulation strategies aim to maximize therapeutic benefits while minimizing systemic exposure [91, 92]:

• Inhaled corticosteroids for PTB

• Targeted nanoparticle delivery to infection sites

• Controlled-release formulations for sustained local effects

7.4 Biomarkers and personalized medicine

The integration of biomarkers and personalized medicine approaches represents a critical advancement in optimizing corticosteroid adjunct therapy for TB patients.