The Use of Corticosteroids in Patients With Pleural and Pericardial Tuberculosis

Abstract

Tuberculous (TB) pleural effusions and pericarditis are relatively common extrapulmonary complications associated with this infection. Corticosteroids have been studied with standard antituberculous medications in the management of tuberculous pleural effusion and pericarditis due to their anti-inflammatory effect and their potential to modulate host inflammatory responses. However, current studies have reported conflicting results and inconsistent benefits of adjunctive corticosteroids with TB drug treatment. In TB pleural effusion, corticosteroids have reduced the duration of symptoms and accelerated the reabsorption of pleural fluid, but their long-term benefits, such as less residual pleural thickening and improved lung function, remain inconsistent across studies. Similarly, studies on TB pericarditis have shown mixed results, with some indicating faster resolution of symptoms and reduced incidence of constrictive pericarditis, while others found no difference in mortality and other complications. Although corticosteroids may offer some benefits in managing pleural or pericardial tuberculosis, the current evidence is not sufficient to support their routine use. Key questions include the optimal corticosteroid dosage, the timing of corticosteroid initiation during the infection, and the duration of corticosteroid treatment. More research is needed to determine which cases benefit from corticosteroids as adjunctive therapy in patients with pleural and pericardial tuberculosis.

1. Introduction

Tuberculous pleural effusions are frequent complications of tuberculosis (TB) and can occur during either primary infections or reactivation of latent infections.1,2 The pathogenesis involves both pleural space infection and delayed hypersensitivity reactions to mycobacterial bacilli in this space.2 The treatment approach is the same as for active pulmonary TB, with therapeutic thoracentesis if the effusion causes dyspnea.3 Tuberculous pericarditis is another extrapulmonary TB complication, found in 1 %–2 % cases with pulmonary TB.4,5 Pericardial infection usually develops by hematogenous spread during primary infections or by retrograde lymphatic spread from thoracic lymph nodes.6 This diagnosis may require pericardiocentesis and is often delayed, especially if the diagnosis depends on mycobacterial culture results, and this delay can lead to pericardial fibrosis and increased mortality.7

Corticosteroids have been proposed as adjunctive therapy during TB treatment in the management of tuberculous pleural effusions and pericarditis due to their anti-inflammatory effects7 and potential to modulate host immune responses.8 Corticosteroids have potent anti-inflammatory actions by inhibiting pro-inflammatory cytokines and reduce the exaggerated immune responses and tissue inflammation characteristic of tuberculosis.9 In tuberculous pleural and pericardial effusions, corticosteroids may also modulate the fibrotic response by suppressing collagen deposition and reducing scar formation. 10–12 This can promote faster resolution of effusions and reduce the development of constrictive, fibrotic complications.

However, the use of corticosteroids in TB remains controversial, primarily due to concerns about their potential to exacerbate TB infection and delay microbiological clearance.13 Because corticosteroids have immunosuppressive effects, their routine use might decrease host defense responses against the infection and slow its resolution. In addition, in patients with HIV, corticosteroids could increase the frequency of opportunistic infections and tumors. 8 Finally, there is also a possibility that corticosteroids’ anti-inflammatory effects will reduce the efficacy of TB drugs, due to reduced drug accumulation at sites of infection.14

This review summarizes studies using corticosteroids as adjunctive treatment in patients with tuberculous pleural and pericardial effusions.

2. Corticosteroids in tuberculous pleural effusions

Pleural effusions occur in approximately one third of patients with tuberculosis, usually during primary infections.15 Laboratory studies have shown that these effusions have high concentrations of proinflammatory cytokines.16 This inflammatory response helps control the infection, but excessive inflammation can cause pleural fibrosis.8

Radiographic studies, especially computed tomography, in patients with pleural TB frequently show peripheral micronodules and subpleural thickening, which are distinctive features of pleural effusions associated with TB.17,18 Tuberculous empyema causes thickened visceral and parietal pleura separated by dense fluid with septations.19 Residual pleural thickening and pleural calcification can develop even with treatment.18–20 Pleural TB images on ultrasonography range from mobile clear fluid to complex effusions with septations and loculations.20,21 Pleural thickening with nodularity is seen frequently on ultrasound images; Koengelenberg et al. studied 20 patients with tuberculous effusions and found pleural thickening in 18 cases and pleural nodules in 4 cases.21 Loculated pleural fluid suggests active infection in the pleural space.22

The diagnosis of pleural TB diagnosis requires positive cultures from either the pleural fluid or pleural tissue.19 Due to the small number of bacilli in pleural infections, establishing a definitive diagnosis is challenging.23 A retrospective study published in 2019 found that in 103 cases with pleural TB cases, a confirmatory microbiological diagnosis was established in only 16 patients (15.5 %), 14 by cultures and or stains of fluid and 6 by cultures of pleural tissue. Four of the latter patients had negative pleural fluid microbiological studies.24

Tuberculous pleural effusions and associated lung infection can cause restrictive ventilatory defects and small airway obstruction.25,26 Thoracentesis and early institution of TB drugs can reduce the development of restriction. In a study published in 2003, small airway obstructive patterns improved after 6 months of treatment, but residual restriction persisted, and this was proportional to the size and complexity of fluid collection prior to the start of treatment.25 However, a more recent study in 2019 found that there was no correlation between the restrictive abnormality i.e., a reduction in FVC, and small airway obstruction and the initial volume of fluid or the residual pleural thickening.26

The cornerstone for TB pleural effusion/pleuritis treatment is standard TB drug regimens with therapeutic thoracentesis if the effusion causes dyspnea.3 Complete drainage of pleural fluid by catheter drainage may not reduce residual pleural thickening or increase the vital capacity at the end of treatment.27 Theoretically, suppressing this inflammatory response with corticosteroids could help resolve pleural effusions and improve outcomes. It has also been suggested that administering corticosteroids directly into the pleural cavity may have a more potent anti-inflammatory effect.28 This approach allows for corticosteroids to be delivered directly to the site of inflammation, resulting in greater efficacy than systemic administration. By achieving higher local concentrations, intrapleural corticosteroids can enhance their therapeutic benefits and minimize systemic side effects.

This review identified 6 studies that reported information on patients with tuberculosis and pleural effusion who were treated with intrapleural corticosteroids (Table 1).29–46 The total number of patients in these studies was 377, and 5 studies were published before 1970, i.e., before the introduction of rifampin into TB treatment. In addition, twelve studies reported results in patients who received oral corticosteroids during the treatment for tuberculosis complicated by pleural effusion. These studies included 987 patients; two studies were published before 1970. In general, these studies have reported conflicting results and inconsistent benefits of adjunctive corticosteroids.

Table 1.

Corticosteroid as an adjunct to anti-TB treatment in TB pleural effusion studies.

Authors (year)	Study Population	Anti-TB treatment (ATT)	Intervention	Control	Main Findings
Mathur (1960)29	50 patients	All patients received streptomycin injection daily and oral isoniazid (INH) daily.	2 groups: ATT with intrapleural hydrocortisone 250 mg in 10 patients, and 125 mg in 15 patients (1–4 instillations) ATT alone	ATT	Faster resolution of pleural effusion and less residual pleural thickening in the steroid-treated group.
Menon (1964)30	49 patients	All patients received intramuscular (IM) streptomycin 1 g daily and oral INH 100 mg twice daily × 6 weeks, followed by sodium 4-aminosalicylic acid (PAS) 5 g and isoniazid 100 mg twice daily.	3 groups: ATT with complete fluid aspiration and intrapleural streptomycin 3 g q 4 days (no intramuscular streptomycin on the days of the intrapleural injections) ATT with complete aspiration and intrapleural 25 mg hydrocortisone q 4 days ATT with oral prednisolone 5 mg orally three times daily for 2–4 weeks and gradually tapered off and given up during the following 2–3 weeks without aspiration of fluid.	None	Both the intrapleural and oral steroid groups had a more rapid absorption of pleural fluid compared to the intrapleural streptomycin group. The oral steroid group showed less residual pleural change compared to the other two groups.
Mathur (1965)31	102 patients	All patients received streptomycin 1 g IM daily and INH 300 mg daily orally in three equal divided doses.	2 groups: ATT with intrapleural hydrocortisone 250 mg in 10 patients and 125 mg in 67 patients (1–4 instillations) ATT alone	ATT	Faster absorption of pleural fluid on chest x-ray in the intrapleural steroid group. There was no complication and minimal residual pleural thickening was observed in only ten cases in the steroid group.
Singh (1965)32	50 patients	All patients received standard anti-TB treatment.	3 groups: ATT with multiple aspirations, and intrapleural dexamethasone ATT with multiple aspirations ATT alone	ATT	Symptoms of cough, dyspnea, and chest pain relieved faster in the intrapleural steroid group. Lower incidence of pleural thickening, shorter time taken for complete absorption of fluid, reduction in protein content, specific gravity, and cell count were observed in the steroid group.
Grewal (1969)33	102 patients	All patients received 1 g streptomycin daily + INH 300 mg daily × 3 months then switch to INH 300 mg daily + PAS daily or INH 300 mg daily + 150 mg thioacetazone daily.	4 groups: ATT with oral prednisolone (20 mg daily × 2 weeks, 15 mg daily × 2 weeks, 10 mg daily × 2 weeks, then 5 mg daily × 2 weeks) ATT with repeated aspirations twice a week and intrapleural hydrocortisone 100 mg at each aspiration ATT with repeated aspirations ATT alone	ATT	Oral steroids with ATT showed superior outcomes in resolution of fever, improvements in X-ray, reduction in ESR, and prevention of subsequent pleural thickening. Intrapleural steroids still showed improved outcomes compared to the non-steroid groups.
Suresh (2021)34	24 patients	All patients received anti-TB treatment per Revised National Tuberculosis Control Program in India (RNTCP) guideline	4 groups: ATT with therapeutic aspirations ATT with oral prednisolone 1 mg/kg/day for first 2 weeks and slowly tapered to 0.5 mg/kg/day for next 2 weeks followed by 0.25 mg/kg/day for next 2 weeks followed by 0.1 mg/kg/day for last 2 weeks. ATT with intrapleural dexamethasone 5 mg during every therapeutic aspiration ATT with oral corticosteroids in the form of prednisolone 1 mg/kg/day for first 2 weeks and slowly tapered to 0.5 mg/kg/day for next 2 days followed by 0.25 mg/kg/day for next 2 weeks followed by 0.1 mg/kg/day for last 2 weeks with intrapleural dexamethasone 5 mg during every therapeutic aspiration	ATT with therapeutic aspirations	After 6 months, the oral steroid group showed better resolution of the effusion compared to other groups. There was less residual pleural thickening in all treatment groups. Oral steroid administration in adjunct to ATT demonstrated better results over intrapleural as well as oral and intrapleural steroid combined.
Aspin (1958)35	30 patients	All patients received streptomycin 1 g and INH 300 mg daily for at least 6 months.	2 groups: ATT with ACTH 40 units daily ATT with oral prednisone 20 mg daily	None	Patients treated with ACTH (40 units daily) or prednisone (20 mg daily) in addition to streptomycin and isoniazid; the pleural fluid absorbed dramatically without the need for other than diagnostic aspiration.
Smith (1958)36	6 pediatric patients	All patients received standard INH and PAS.	5 patients received oral prednisone for 5–9 weeks, and one patient received hydrocortisone for 7 days.	None	Corticosteroids (oral and intravenous) given simultaneously with ATT frequently hasten clinical and radiographic improvement without significant adverse effects on the underlying TB infection.
Lee (1988)37	40 patients	All patients received INH 300 mg/day, rifampin 450 mg/day; and ethambutol, 20 mg/kg/day for the initial 3 months, and INH and rifampin for the subsequent 6–9 months.	2 groups: ATT with oral prednisone 0.75 mg/kg/day, then was diminished by two-thirds if there was clinically improvement, then the dose was diminished by 5 mg/week until discontinued. ATT with placebo	ATT with placebo	Adrenal corticosteroids administration with standard ATT resulted in the more rapid relief of clinical symptoms and absorption of pleural effusion. Pleural adhesion was not observed in the steroid group.
Galarza (1995)38	117 patients	All patients received INH 5 mg/kg/day or a total daily dose of 300 mg, and rifampicin 10 mg/kg/day or a total daily dose of 600 mg/day, once a day for 6 months as a combination tablet.	2 groups: ATT with prednisone, which was administered in a single oral dose of 1 mg/kg/day during the first 15 days, and then gradually tapered off as follows: To 0 5 mg/kg/day from day 16–20 of treatment, then to 0–25 mg/kg/day from day 21–26, and finally to 0–10 mg/kg/day for the remaining days of the month. The total period of corticosteroid (or placebo) treatment was 30 days. ATT with placebo	ATT with placebo	The duration of fever was similar in both groups during the treatment. FVC was also similar at the end of the treatment in both groups. There was significantly faster reabsorption of pleural effusion in steroid group, but this benefit disappeared after one month. There was no difference in pleural thickening and there was no side effect from steroids. The advantage of adding corticosteroids to ATT is not clinically relevant, and its routine use in the treatment of tuberculous pleuritis is not recommended.
Wyser (1996)39	74 patients	All patients received standard 3-drug anti-TB regimen for 6 months.	2 groups: ATT with oral prednisone at a dose of 0.75 mg/kg/d for up to 4 weeks with gradual reduction over an additional 2 weeks ATT with placebo	ATT with placebo	Standard ATT and early complete drainage are adequate for the treatment of TB pleurisy. The addition of short-term oral prednisone therapy does not result in clinically relevant earlier symptom relief or reduce residual pleural thickening.
Bang (1997)40	83 patients	All patients received INH, rifampicin, pyrazinamide, and ethambutol for the initial 2 months, and INH and rifampin for the subsequent 7 months.	2 groups: ATT with oral prednisolone 1 mg/kg BID and tapered 10 mg per week until discontinuation ATT alone	ATT	Corticosteroids with ATT produces more rapid relief of clinical symptoms in patients with tuberculous pleurisy, but resolution of pleural effusion and occurrence of pleural adhesions were not changed.
Lee (1999)41	82 patients	All patients received INH, rifampicin, pyrazinamide, and ethambutol for 6 months or received INH, rifampicin, pyrazinamide, and ethambutol for the initial 2 months, then INH, rifampin, and pyrazinamide for the subsequent 4 months.	2 groups: ATT with oral prednisone 30 mg/day × 1 month, then taper off × 1 month ATT alone	ATT	Administration of oral prednisolone in conjunction with ATT improved the absorption of pleural effusion and decreased the residual pleural thickening without serious side effects during the treatment.
Elliott (2004)42	197 HIV patients	All patient received INH, rifampicin, pyrazinamide, and ethambutol for the initial 2 months, then INH and rifampin for the subsequent 4 months.	2 groups: ATT with oral prednisolone 50 mf daily × 2 weeks, 40 mg daily × 2 weeks, 25 my daily × 2 weeks, then 15 mg daily × 2 weeks (8 weeks in total) ATT alone	ATT	The use of oral prednisolone in addition to ATT was associated with statistically significant more rapid improvement in all the principal symptoms and signs of pleural tuberculosis, particularly during the first few weeks of treatment; however, it had no effect on survival. The use of oral prednisolone had little effect on HIV-associated opportunistic infections; the exception was Kaposi sarcoma, which occurred only in the prednisolone group. Oral prednisolone should not be used in the treatment of pleural tuberculosis, regardless of HIV status, due to the lack of survival benefit and the significant increase in incidence of Kaposi sarcoma.
Mansour (2006)43	190 patients	All patients received 2 months with 3 anti-tuberculosis (TB) drugs followed by 4 months with 2 anti-TB drugs.	3 groups: ATT with oral prednisolone, 30 mg/day for 10 days ATT with aspirations ATT alone	ATT	Fever and constitutional symptoms resolved faster and there was a significantly greater reduction in the size of pleural effusion after 10 days in the steroid group. However, after 6 months the difference in reduction in the size of pleural effusion was not statistically significant. Corticosteroids and therapeutic thoracentesis are not necessary in the management of TB pleural effusion.
Dubba (2022)44	80 patients	All patients received standard anti-TB treatment (alternate day regimen) under Directly Observed Treatment Short-course (DOTS) therapy based on Revised National TB Control Program (RNTCP).	2 groups: ATT with oral prednisolone 0.75 mg/kg body weight per day for 2 weeks there after tapering of the dose done every second weekly in next 4 weeks. ATT alone	ATT	Addition of the corticosteroids to the standard ATT results in more rapid relief of clinical symptoms. The rapidity in pleural fluid absorption and incidence of pleural thickening are not influenced by adding corticosteroids to the ATT. There was no recurrence of pleural effusion after addition of corticosteroids to ATT.
Bhingardeve (2022) (Abstract)45	40 patients	All patients received standard anti-TB treatment.	2 groups: ATT with oral prednisolone 0.75 mg/kg in addition to anti-TB treatment for 4 weeks. Steroids were tapered gradually over 2 weeks. ATT alone	ATT	Adjunctive oral prednisolone therapy was associated with decreased incidence of radiographic and functional sequelae in free-flowing type tuberculous pleural effusion patients. Resolution of clinical symptoms and effusion were significantly higher in the steroid group.
Zhang (2022) (Abstract)46	48 patients	All patients received standard anti-TB treatment.	2 groups: ATT with oral prednisolone ATT alone	ATT	Oral prednisolone led to statistically significant reductions in pleural opacification; end of treatment opacification was similar in both groups. Median prednisolone dose was 20 mg and median duration was 9 weeks. Given the incidence of steroid related side effects, correlation with disability and lung function is required to guide its use.

Most of the studies have reported that corticosteroids reduce the duration of symptoms 32,33,36,37,40,41,44,45 and time required for pleural fluid clearance.29–37,41,43,44 Some studies suggest that corticosteroids can also reduce residual pleural thickening.30–35,41 Recent studies in 2022 showed that adjunctive oral prednisolone significantly increased the initial clearance of the pleural fluid,37,38 but at the end of treatment, residual fluid volumes and pleural thickening were similar in corticosteroid-treated and the non-corticosteroid-treated patients in one of these studies.46 Some studies showed faster clearance of pleural effusion in the corticosteroid group at the start of treatment, but this benefit disappeared over time and there was no difference in outcome at the end of treatment. 38,43,44 However, some studies have not reported any benefit or difference in outcomes in corticosteroid-treated patients.38,39

A randomized trial with 197 HIV patients with TB pleural effusion treated with or without a prednisolone taper with standard TB drug treatment did not document any difference in mortality rates.42 This study also reported that treatment with oral prednisolone was associated with a significant increase in the incidence of Kaposi sarcoma.42 Due to lack of survival benefit and the increase in incidence of Kaposi sarcoma, these authors concluded that oral corticosteroids should not be used in TB-associated pleural effusions in patients with HIV.42 A recent systematic review and meta-analysis in 2017 included six trials with 633 participants treated at large tertiary care hospitals in Taiwan, Spain, South Africa, Korea, and Uganda.37–42 This study suggests that the long-term effect of the addition of corticosteroids in patients with tuberculous pleural effusion is uncertain.8

In future studies, respiratory function (spirometry) and mortality are probably the most important outcomes to evaluate the effects of corticosteroid treatment as an adjunct to standard TB treatment in patients with pleural effusions. However, early improvement in symptoms is also an important patient benefit.

3. Corticosteroids in tuberculous pericarditis

The management of TB pericarditis requires prompt treatment with anti-tuberculous drugs and pericardiectomy/pericardiocentesis in patients who are not responding to medical therapy or who are hemodynamically unstable. Tuberculous pericarditis can cause pericardial constriction which develops in 30–60 % of cases and is associated with increased mortality.47 Despite improvement in outcomes with anti-tuberculous drugs, the best treatment to prevent progression to constriction remains uncertain.

This review identified 9 studies that reported results with corticosteroids in patients with tuberculosis pericarditis (Table 2).48,49,52–57 These studies included 2008 patients; one study was published before 1970. Corticosteroids had mixed results in these studies. One early study evaluated 28 patients with pericardial effusions who were allocated to corticosteroids or no corticosteroids for an undisclosed period.48 The primary outcome was the development of constriction requiring pericardiectomy. Although there were limitations in the study design, the results indicated that corticosteroid treatment was not effective. A retrospective cohort study by Rooney49 followed 28 patients with pericardial effusion who were treated with standard TB drugs. Eighteen patients also received prednisolone 60 mg daily for 6–8 weeks, and these patients had more rapid resolution of effusions. No patients on corticosteroids died, but four patients on placebo died. Two randomized-controlled trials published by Strang et al. reported lower mortality rates and fewer surgical interventions with prednisolone adjunctive therapy in patients with tuberculous pericarditis.50,51 The patients in these two studies were monitored for ten years with a follow-up rate of 96 %,52 and a multivariable analysis demonstrated that prednisolone significantly reduced the overall death rate and the death rate associated with pericarditis (p = 0.004). The authors concluded that, unless contraindicated, corticosteroid should be added to the treatment regimens in patients with TB pericarditis.

Table 2.

Corticosteroid as an adjunct to anti-TB treatment in TB pericarditis studies.

Author (year)	Type of Study	Number of Patients	Intervention	Primary Outcomes	Findings
Schrire (1959)48	Non-randomized controlled trial	28 patients with pericardial effusion	Cortisone, 300 mg loading dose, 100 mg/day maintenance dose for several weeks in 14 participants. At a later date, prednisolone 60 mg/day with a maintenance dose of 30 mg/day was substituted.	Development of constriction requiring pericardiectomy	Steroid therapy was ineffective at preventing the development of constriction.
Rooney (1970)49	Retrospective cohort study	28 patients with effusive pericarditis	Prednisolone 60 mg daily, tapered over 6–8 weeks	All-cause deaths; pericardiectomy	More rapid resolution of pericardial effusions. Fewer deaths compared to placebo.
Hakim (2000)53	Randomized controlled trial	58 HIV seropositive patients with tuberculous pericarditis	Prednisolone for 6 weeks at 60 mg/day for the first week, and tapering by 10 mg/day every week	All-cause deaths; clinical improvement; echocardiographic and radiologic fluid resolution	After 18 months of follow up, mortality was significantly lower in the prednisolone group. More rapid resolution of raised JVP, hepatomegaly, and ascites. No difference in the rate of radiologic and echocardiographic resolution of pericardial effusions.
Strang (1988)51 (2004)52	Randomized controlled trial	143 patients with constrictive pericarditis and 240 patients with pericardial effusion	Prednisolone for the first 11 weeks	All-cause deaths; deaths from pericarditis; pericardiectomy	In patients with constrictive pericarditis, significantly improved clinical parameters (heart rate, JVP, physical activity). Reduced mortality during follow-up (4 % prednisolone vs. 11 % placebo). Fewer patients treated with steroids required pericardiectomy (21 % vs. 30 %). In patients with effusion, significant reduction in mortality (3 % vs. 14 %) and repeat pericardiocentesis. In 10-year follow-up, prednisolone reduced the overall death rate and significantly reduced the risk of death from pericarditis (p = 0.004).
Reuter (2006)54	Randomized controlled trial	57 patients with tuberculous pericarditis	3 treatment groups: 200 mg intrapericardial triamcinolone hexacetonide; oral prednisone plus intrapericardial placebo; or 5 ml intra-pericardial 0.9 % saline (placebo).	All-cause deaths; death from pericarditis; constrictive pericarditis requiring pericardiectomy	Intrapericardial and systemic corticosteroids were well tolerated but did not improve clinical outcomes.
Mayosi (2014)55	Randomized double-blind multicenter trial	1400 adults with tuberculous pericarditis. 2/3 were HIV positive	Prednisolone tapered over 6 weeks	All-cause deaths; cardiac tamponade requiring peri cardiocentesis; constrictive pericarditis	Prednisolone did not significantly affect mortality, cardiac tamponade necessitating pericardiocentesis, or constrictive pericarditis in patients with tuberculous pericarditis.
Shenje (2017)57	Pilot study	14 patients with tuberculous pericarditis	Prednisolone 120 mg/day for one week	Inflammatory markers	Prednisolone significantly reduced IL-6 concentrations in plasma after 8 h of treatment, IL-1beta concentrations in saliva, and IL-8 concentrations in both pericardial fluid and saliva by 24 h.
Ferri (2021)56	Retrospective cohort study	40 patients with pericardial effusion	Prednisolone initiated at 1 mg/kg daily and reduced weekly	Progression to constrictive pericarditis	Reduction in progression to constrictive pericarditis (13.6 % vs 38.8 %).

More recent studies include a retrospective cohort study conducted in 2021 with 40 patients with pericardial effusion.56 This study found that prednisone in HIV-negative patients with severe TB pericardial effusion potentially reduces the progression to constrictive pericarditis (13.6 % in the prednisone group vs. 38.8 % in the non-prednisone group). Finally, a pilot study reported by Shenje et al. in 201757 evaluated the effect of prednisolone on the levels of inflammatory markers in patients with pericardial tuberculosis. Samples from 14 patients demonstrated compartmentalized immune responses in the pericardium, and prednisolone significantly reduced IL-6 concentrations in plasma after 8 h of treatment and IL-8 concentrations in both pericardial fluid and saliva at 24 h.

Evidence in HIV-positive patients is limited. Hakim et al.53 found a promising but nonsignificant decrease in mortality in HIV-positive patients receiving prednisolone and slight improvements in their physical activity levels, However, the study found no significant difference in the rate of pericardial effusion resolution based on echocardiography. Reuter et al. compared intrapericardial and systemic corticosteroids in both HIV-positive and HIV-negative patients with TB, and found that while both approaches were well tolerated, neither significantly improved clinical outcomes in patients with tuberculous pericarditis.54

The Investigation of the Management of Pericarditis (IMPI) trial is the largest study conducted comparing the effectiveness of adjunctive anti-inflammatory drugs for the treatment TB pericarditis.55 The study was multicenter, randomized, double-blind, placebo-controlled trial with 1400 adults with tuberculous pericarditis assigned to receive oral prednisolone or placebo for six weeks. Two-thirds of the participants also had HIV infection. Prednisolone significantly reduced the incidence of constrictive pericarditis (4.4 % vs. 7.8 %; hazard ratio: 0.56; 95 % CI: 0.36–0.87) and hospitalization (20.7 % vs. 25.2 %; hazard ratio: 0.79; 95 % CI: 0.63–0.99) when compared to a placebo. However, the study found that prednisolone did not significantly reduce the overall mortality in patients with tuberculous pericarditis.

In summary, adjunctive corticosteroids appear to reduce mortality and morbidity in tuberculous pericardial effusion in both HIV-negative and positive patients. Adverse events are infrequent in corticosteroid-treated patients, especially when a treated group could be compared to a control group in a study. In one study, Kaposi’s sarcoma only developed in control patients and did not develop in patients treated with corticosteroids.53 Therefore, adjunctive corticosteroids should be considered in most patients, even if the effusion is not hemodynamically significant given the potential for the development of pericardial constriction.

4. Discussion

Current studies have reported conflicting results and inconsistent benefits of adjunctive corticosteroids with TB drug treatment, and therefore the studies do not support the routine use of corticosteroids in the management of either pleural or pericardial tuberculosis. In TB pleural effusions, corticosteroids have shown some benefit in accelerating symptom resolution and reducing the time needed for pleural fluid clearance, but the benefits regarding long-term outcomes, such as residual pleural thickening and lung function, remain inconsistent across studies. Notably, corticosteroids do not appear to significantly reduce overall mortality or alter the course of the disease in immunocompromised patients, including those with HIV, in whom their use may even pose additional risks.

A critical concern with the use of corticosteroids in managing tuberculous pleural effusion is the suppression of host defense responses necessary for controlling the infection. The pleural fluid in TB pleural effusion is rich in biomarkers, such as ADA, IFN-γ, and IL-27,58,59 which are essential for the host defense against Mycobacterium tuberculosis. While corticosteroids can reduce inflammation and alleviate symptoms, these drugs may impair the host’s ability to effectively control the infection, potentially leading to delayed bacterial clearance. This suggests that while corticosteroids may expedite the resolution of effusions and reduce fibrotic complications, they may also inadvertently create a more favorable environment for TB persistence or reactivation. The immunosuppressive effect is particularly concerning in immunocompromised patients, in whom the risk of opportunistic infections and malignancies is increased. Future studies should investigate biomarker patterns in pleural fluid with and without corticosteroid treatment to determine the appropriate balance of inflammation necessary for optimal outcomes.

In TB pericarditis, adjunctive corticosteroids may improve clinical outcomes and reduce the incidence of constrictive pericarditis, but published trial outcomes are not uniformly consistent. The IMPI trial, the largest available trial, reported a significant reduction in constriction and hospitalization rates but did not show a mortality benefit. Other studies have mixed results, with some indicating more rapid resolution of symptoms and fewer surgical interventions, and others found no significant differences in long-term clinical outcomes.

Clinicians face significant problems when evaluating and treating patients with new onset pleural effusions and or pericardial effusions. The likelihood that the patient has tuberculosis depends on the region of the world in which he or she lives. Routine studies of pleural effusions or pericardial effusions may not provide a definitive microbiological diagnosis. In addition, biopsy of the pleura and pericardium is relatively uncommon, especially in patients managed in outpatient clinics. Finally, the patient may not have evidence of tuberculous infection in other regions of the body. Consequently, the clinician will need to decide about starting empiric treatment; in addition, some patients will require intermittent drainage of pleural fluid or pericardial fluid with indwelling catheters. The decision to add anti-inflammatory drugs is not straightforward. Important questions include the dose, the tapering schedule, and the timing in relationship to starting antituberculous drugs. In addition, there may be drug interactions which reduce the efficacy of either treatment arm. Patients benefit from prompt treatment if the diagnosis is tuberculosis. The outcomes associated with an incorrect diagnosis clearly will depend on the eventual pathologic process causing the fluid accumulation. Frequent follow-up with chest imaging and expert consultation are essential in these cases. Ultrasound studies of the pleura and pericardium, if the expertise is available, can facilitate treatment decisions in these patients.

For HIV-positive patients with pleural and pericardial TB, corticosteroid therapy presents some unique risks that require careful consideration. The potential benefits regarding hospitalization duration and clinical outcomes appear to be similar in HIV-positive and HIV-negative patients.44,45 However, one important concern is the temporary increase in HIV RNA levels observed with corticosteroid use.60 Although this spike typically resolves after discontinuation of treatment, it still represents a period of increased viral activity that could potentially affect disease progression in patients not receiving antiretroviral therapy. In addition, two studies in this review found a significantly increased incidence of HIV-associated malignancies in patients who received prednisolone compared to those who did not.42,55 Therefore, the use of corticosteroids in immunocompromised patients with TB must be carefully balanced, considering both the potential for immune suppression and the benefits for specific TB-related complications. Patients on corticosteroids for more than 4 weeks probably should receive prophylaxis for Pneumocystis jirovecii. This is particularly true in patients with HIV infection with low CD4 counts.61

5. Conclusions

Current evidence supports the routine use of corticosteroids in patients with pericardial effusions but not pleural effusions. The potential suppression of inflammation raises concerns about their effect on immune responses and infection control. Important questions include the optimal dose of a corticosteroid in pleural or pericardial tuberculosis, the timeframe during the infection for starting the corticosteroid, and the duration of corticosteroid treatment. In patients with pleural tuberculosis, the use of intrapleural administration provides another option in this management. The use of ultrasound may help identify patients with complicated effusions that are more likely to organize and cause mechanical effects. More research is needed to answer these questions to maximize therapeutic benefits while minimizing risks. Future studies should focus on long-term respiratory function and mortality outcomes to guide treatment approaches. However, symptomatic improvement is a relevant outcome in these patients, and study size will likely limit the possibility of determining hard outcomes such as mortality.