|Year : 2017 | Volume
| Issue : 2 | Page : 70-75
Use of corticosteroids in tuberculosis
Saurabh K Singh, Kamlesh K Tiwari
Department of Pulmonary Medicine, Gajra Raja Medical College and Jayarogya Group of Hospitals, Gwalior, Madhya Pradesh, India
|Date of Web Publication||4-Jul-2017|
Saurabh K Singh
Department of Pulmonary Medicine, Gajra Raja Medical College and Jayarogya Group of Hospitals, Gwalior - 474 009, Madhya Pradesh
Source of Support: None, Conflict of Interest: None
Tuberculosis (TB) is considered as a lethal disease in the present era. Effective antituberculous therapy is available, which has reduced significantly the morbidity and mortality due to TB. Literature advocates the use of corticosteroids in TB. Use of corticosteroids in conjunction with antituberculous therapy showed a reduction in mortality and morbidity in pericardial and central nervous system TB. Signs and symptoms in pleural and severe pulmonary TB improve rapidly with the addition of corticosteroids. Corticosteroid should be used cautiously with antituberculous therapy in view of drug interaction seen between them.
Keywords: Central nervous system, corticosteroids, pericardial, tuberculosis
|How to cite this article:|
Singh SK, Tiwari KK. Use of corticosteroids in tuberculosis. J Assoc Chest Physicians 2017;5:70-5
| Introduction|| |
Worldwide, about 1.5 million peoples are dieing annually due to tuberculosis (TB); hence, it is considered as a lethal infectious disease in the present era. However, around 43 million lives were saved through TB diagnosis and treatment between 2000 and 2014, and the TB death rate dropped 47% between 1990 and 2015.
Tissue damage caused by inflammatory reaction to Mycobacterium may cause edema leading to organ dysfunction. This may result in atelectasis or fluid blockage. Treatment of TB due to drug-susceptible disease requires at least 6 months of therapy, whereas the multidrug resistance TB requires treatment of 24 months. To counter these inflammatory reactions, we require add-on corticosteroids treatment. On the contrary, steroids can make people vulnerable to other infections. Earlier, animal models showed that corticosteroids can markedly increase the virulence of TB if used with and without antituberculous therapy., However, in humans, it was shown that at-risk patients who were receiving low-dose corticosteroid for rheumatic diseases do not develop reactivation of TB. This study also showed that chemoprophylaxis with isoniazid (INH) is unnecessary in those receiving corticosteroids.
In another study, the prevalence of active TB and positive tuberculin skin tests (TST) was assessed in 132 corticosteroid-treated patients having asthma for an evaluation period that represented the 620 corticosteroid-years of therapy. There was no evidence of active TB in any of these patients. This study also concluded that INH is not indicated for corticosteroid-treated patients having asthma regardless of their tuberculin status. It may worsen the clinical course of TB itself if corticosteroids are used alone without antituberculous therapy. However, the American Thoracic Society recommends the use of INH prophylaxis in steroid-treated patients with TST positive. Pharmacokinetic interactions have been shown between rifampicin and steroids to cause a decrease in efficacy of both the drugs.
The use of corticosteroid in patients with TB is quite a controversial topic. It has been used for all forms of TB since a very long time. However, its effect and benefit in various forms of TB are quite different. Its effect and benefit in TB are entirely organ specific. With this, we try to review the use of corticosteroids in various forms of TB.
| Meningitis|| |
Without treatment, tuberculous meningitis (TBM) is uniformly a fatal disease, and, at times, it leads to a neurological deficit. Corticosteroids are being in use along with antitubercular treatment for the management of tuberculous meningitis for the last 60 years. In a review of five studies by Prasad et al., steroids were associated with fewer deaths (relative risk [RR] 0.79; 95% confidence interval [CI] 0.65–0.97) and a reduced incidence of death and severe residual disability (RR 0.58, 95% CI 0.38–0.88). Prasad et al. again reviewed the effect of steroid in tubercular meningitis by including two more studies and found that corticosteroids reduced the risk of death (RR 0.78, 95% CI 0.67–0.91). Disabling neurological deficit was also reduced in the corticosteroid-treated group (RR 0.82, 95% CI 0.70–0.97; 720 participants, three trials). Further extending the research, Prasad et al. in 2016 concluded that corticosteroid could reduce mortality caused by tuberculous meningitis in the short term in human immunodeficiency virus (HIV)-negative children and adults, but its effect in an HIV-positive person was uncertain. They further added that corticosteroid had no effect on the number of people who survived tuberculous meningitis with disabling neurological deficit.
In a randomized, double-blind, placebo-controlled trial in Vietnam, the inpatients over 14 years of age who had tuberculous meningitis, with or without HIV infection, were assigned to receive dexamethasone and placebo. Dexamethasone was given in a tapering dose for 8 weeks. A reduced risk of death (RR 0.69; 95% CI 0.52–0.92; P = 0.01) was seen in the dexamethasone-treated group. It was not associated with a significant reduction in the proportion of patients with severely disabled condition among survivors in the dexamethasone group versus in the placebo group or in the proportion of patients who had either died or were severely disabled after 9 months (odds ratio, 0.81; 95% CI 0.58–1.13; P = 0.22). Usage of adjunctive dexamethasone for up to 2 years of follow-up also showed improvement in the probability of survival in patients with TBM.
No trial has been performed to compare the efficacy of different corticosteroid regimen. Therefore, the choice of corticosteroid depends upon the regimen used in different trials. Dexamethasone in the doses of 0.4 mg/kg/day is recommended in adults (>14 years) in conjugation with antitubercular drugs. The dose should be reduced over 6–8 weeks, while in children (<14 years), prednisolone 4 mg/kg/24 h (or equivalent dexamethasone 0.6 mg/kg/24 h) is given for 4 weeks followed by a reducing dose over 4 weeks. In adults, it has been recommended that the effect of corticosteroid should be assessed within a month of starting the treatment. Tapering of the dose should be initiated, once it seems to be safe.
| Pleural Effusion|| |
Studies have shown that the use of corticosteroid in TB is conflicting. In the study, performed by Mathur et al., an intra-pleural instillation of hydrocortisone in the cases of tubercular pleural effusion showed dramatic response in the general condition of the patients in comparison to the control group. Disappearance of the pleural fluid was also faster in the hydrocortisone group as compared to the control group. Similarly, favorable outcomes were shown by other studies that used intrapleural corticosteroids, for tuberculous pleural effusion.
In another study by Grewal et al., 102 patients with pleural TB were treated with either chemotherapy (INH and streptomycin), chemotherapy plus systemic corticosteroids, chemotherapy plus repeated thoracocentesis, or chemotherapy plus repeated thoracocentesis and intrapleural corticosteroids. In this study, a treatment with prednisolone, in a dose of 20 mg/day followed by a tapering off along with an antituberculous drug, was significantly better than the treatment with intrapleural instillation of steroid.
Lee et al. demonstrated that administration of corticosteroid in parallel with antituberculous drug would resolve the clinical symptoms more quickly and would hasten the absorption of tuberculous pleural effusion. However, no influence was seen on pleural adhesion by the addition of corticosteroid in a small cohort. Galarza et al. used oral corticosteroid along with antituberculous treatment and found that addition of steroid had no effect on the clinical outcome or the development of long-term pleural sequelae in tuberculous effusion.
Wyser et al. conducted the first double-blind, placebo-controlled, randomized study by using corticosteroid in tuberculous pleural effusion. They used three-drug chemotherapy and performed thoracocentesis in all cases. At the end of the study, they found a significant improvement in symptoms in the prednisolone group as compared to the placebo group. Residual thickening was seen in 53.3% of the patients on prednisolone as compared to 605 patients in the placebo group, and this difference was not significant. Lung function test was also comparable at the end of the study in both the groups. These studies concluded that standard antituberculous therapy and early complete drainage could be considered adequate for the treatment of tuberculous effusion. Similarly, Bang et al. showed a more rapid improvement in clinical features in the corticosteroid group, but absorption of pleural effusion and occurrence of pleural adhesion was not significant.
Elliott et al. conducted a randomized, double-blind, placebo-controlled trial of prednisolone as an adjunct to TB treatment in adults with HIV-1-associated tuberculous pleural effusion. They showed use of prednisolone was associated with more rapid improvement in all the principal signs and symptoms of pleural effusion. There was a more rapid improvement in the prednisolone group. However, prednisolone was associated with a significantly higher incidence of Kaposi sarcoma. This study did not recommend the use of prednisolone in HIV-associated tuberculous pleurisy due to lack of survival benefit and the increased risk of Kaposi sarcoma.
Cochrane review performed by Engel et al. found that there were insufficient data to support evidence-based recommendations regarding the use of adjunctive corticosteroids in people with pleural effusion due to TB. However, the addition of corticosteroid hastens the absorption of pleural fluid, and there occurs a faster recovery from sign and symptoms of tuberculous pleural effusion.
Corticosteroids can be in conjunction with antituberculous chemotherapy in the severely ill patients with pleural TB. This could be administered as prednisolone 0.75 mg/kg/day initially and then tapered off, when improvement of the chest X-ray is seen.
| Pulmonary Tuberculosis|| |
Eighteen trials, including 3816 participants, were reviewed to know the role of adjunctive steroid therapy for managing pulmonary TB. When compared to taking placebo or no steroid, corticosteroid use was not shown to reduce the all-cause mortality, or result in higher sputum conversion at 2 months or at 6 months. However, corticosteroid use was found to increase weight gain, decrease length of hospital stay (data not pooled, three trials, 379 participants, and very low quality of evidence), and increase clinical improvement within 1 month.
The study using meta-regression analysis to examine the relationship between corticosteroid dose and sputum culture conversion, using published data from controlled clinical trials including 1806 corticosteroid-treated TB patients, found that adjunctive corticosteroids accelerate sputum culture conversion in pulmonary TB. The study raised concerns that the doses required are unlikely to support a favorable benefit risk balance for individual patients with TB.
In one of the earlier systematic reviews, it has been concluded that a systemic corticosteroid therapy in conjunction with antitubercular drug can safely provide significant early and prolonged clinical and radiographic benefits in selected patients with advanced pulmonary TB.
Role of steroid in miliary TB is still controversial. Very few studies had been performed to know the role of corticosteroids in military TB. In a study, performed by Sun et al. on 55 patients with miliary TB, the effect of corticosteroid was evaluated. They found that an addition of corticosteroid to the chemotherapy helped in the control of infection and lessened toxic symptoms.
| Endobronchial Tuberculosis|| |
It is a type of pulmonary TB. The role of steroid in endobronchial TB is quite controversial. Nemir et al. conducted a double-blind study to know the effectiveness of corticosteroid. They found that patients receiving adjunct steroid therapy before the fourth month of tuberculous infection had a 76% chance of improvement as compared to a 36% chance of improvement in a placebo group suggesting the value of prednisone in an early stage. Because of the anti-inflammatory properties, the use of corticosteroids reduces inflammation and, thus, reduces the local pressure. Another study, performed in childhood endobronchial TB, concludes that whenever severe bronchial compression had been demonstrated, steroids remained beneficial and should be added.
In a study, performed by Park et al. in adults, they showed that after treatment, the healing rate of bronchoscopic findings and the changes in pulmonary function were equal in both the non-corticosteroid and the corticosteroid groups and concluded that prompt treatment with early diagnosis, before the formation of fibrosis would be necessary to prevent the complications of endobronchial TB. Prednisolone at the dose of 1 mg/kg was prescribed for 4–6 weeks followed by slow taper for the same for the edematous-hyperemic, actively caseating and tumorous types, as these tend to progress to tracheobronchial stenosis. Um et al. found that oral corticosteroids (prednisolone equivalent ≥30 mg/day) did not reduce the frequency of persistent airway stenosis in adults.
| Pericardial Effusion|| |
In a study, performed by Strang et al., they conducted a placebo-controlled, double-blind trial in the patients of tuberculous pericarditis. Their patients were randomly allocated to receive, in addition to chemotherapy, either prednisolone or placebo for the first 11 weeks. They found a more rapid improvement in the signs and symptoms in the prednisolone group. Mortality in the prednisolone group was 4% as compared to 11% in the placebo group. The need for pericardiectomy was also more in the placebo group. This trial concluded that unless contraindicated, antituberculous drug should be supplemented with steroids in pericarditis.
In another study, performed by Strang et al., the 240 cases of active tuberculous effusion were randomly allocated to prednisolone or matching placebo for the first 11 weeks, on a double-blind basis. In the comparison between the prednisolone and placebo groups, prednisolone reduced the risk of death and the need for repeat pericardiocentesis during the 24 months of follow-up. It also reduced the need for open surgical drainage because of the rapid re-accumulation of pericardial fluid despite repeated pericardiocentesis (4% vs. 9% for placebo). There was a low incidence of pericarditis in the prednisolone group during 2 years of follow-up.
Later on, these patients with pericardial effusion and pericarditis were followed up for 10 years by Strang et al. In a multivariate survival analysis (stratified by type of pericarditis), prednisolone reduced the overall death rate after adjusting for age and sex, and substantially reduced the risk of death from pericarditis.
In another study by Hakim et al., performed to know the effect of adjunctive prednisolone on morbidity, pericardial fluid resolution, and mortality in patients with HIV seropositive with effusive tuberculous pericarditis, they found that adjunctive prednisolone produced a marked reduction in mortality in the patient of effusion. In the prednisolone-treated group, there was a significantly rapid resolution of raised jugular venous pressure, hepatomegaly, and ascitis. Improvement in physical activity was also more in the prednisolone group. However, Reuter et al. found that intrapericardial and systemic corticosteroids were well tolerated but did not improve the clinical outcome in the patients with tuberculous pericarditis.
The result of the Investigation of the Management of Pericarditis (IMPI) trial is still awaited. The IMPI trial is a multicenter, international, randomized, double-blind placebo-controlled, 2 × 2 factorial study. In this study, eligible patients were randomly assigned to receive oral prednisolone or placebo for 6 weeks and Mycobacterium w immunotherapy or placebo for 3 months. The patients were followed up at weeks 2, 4, and 6 and months 3 and 6 during the intervention period and 6-monthly, thereafter, for up to 4 years. IMPI is the largest trial conducted so far comparing an adjunctive immunotherapy in pericarditis. Its results will define the role of adjunctive corticosteroids and M. w immunotherapy in patients with TB pericardial effusion.
The recommended prednisolone dose for tuberculous pericarditis is 1 mg/kg/day in the acute phase tapered off during the next 3 months.
| Adrenal Insufficiency|| |
Adrenal gland involvement due to TB causes the adrenal gland destruction leading to adrenal insufficiency. Rifampicin is the well-known hepatic enzyme inducer and, thus, may unmask subclinical adrenal insufficiency, which may lead to addisonian crisis. Brooke and Monson suggested that glucocorticoid replacement should be given three times daily, with the largest dose (10–20 mg) before getting out of bed to mimic the physiological peak just before waking, followed by 5 mg at midday and 5 mg at 6 PM. They also suggested that a treatment with fludrocortisone was to achieve normal sodium homeostasis in a dose of 50–100 mg twice daily.
| Abdominal Tuberculosis|| |
The role of steroid in the management of abdominal TB is not well established, and, thus, the corticosteroids have not been used routinely in abdominal TB. Suggestion had been made to use the steroid to reduce the late adhesive complications. In a small group of patients, the use of corticosteroid in combination of antituberculous drugs found to reduce the frequency of morbidity and complications in patients with peritoneal TB. However, to implement the use of corticosteroids for abdominal TB, a double-blind study in a larger cohort is needed.
| Upper Respiratory Tract Tuberculosis|| |
The use of antituberculous drugs is considered sufficient for the treatment of upper respiratory tract TB. Patients having difficulty in eating and swallowing the antituberculous medication due to laryngeal ulcers, pharyngitis, and oral ulcers may get relief by using a short course of prednisolone 40–60 mg with a rapid tapering within 2–3 weeks. This should be used in adjunct with antituberculous medication.
| Hypersensitivity to Antituberculous Drugs|| |
Any offending drug is supposed to be stopped in the cases of hypersensitivity reactions occurring due to antituberculous drug. In the case of multidrug resistance or the drug cannot be replaced, desensitization therapy for the antituberculous drug has shown effective results. The cases of severe or generalized erythematous rash or rashes with angioedema should be treated with systemic steroids.
| Ocular Tuberculosis|| |
Topical and/or systemic steroid is used in ocular TB along with antituberculous drugs. Prednisolone acetate eyedrops are used in the treatment of phlyctenular keratoconjunctivitis, episcleritis, scleritis, interstitial keratitis, and uveitis. Systemic steroids are used for the first few weeks with an antituberculous treatment to decrease damage caused to the ocular tissues. A systemic corticosteroid use without the addition of antituberculous drug may worsen the clinical process of tuberculous choroiditis. Periocular steroids are also advocated in moderate-to-severe chronic uveitis, posterior scleritis, or recalcitrant anterior uveitis.
| Tuberculosis Immune Reconstitution Inflammatory Syndrome|| |
Most of the cases of HIV-associated tuberculosis immune reconstitution inflammatory syndrome (TB-IRIS) are transient and do not require any treatment. Occasionally, the inflammation may be worst and may lead to death of the patient. In such life-threatening manifestations, a temporary stoppage of antiretroviral therapy is recommended followed by the use of short course of corticosteroids with 1 mg/kg/day of prednisolone for 1–2 weeks with a gradual reduction, thereafter. In a double-blind, placebo-controlled trial, it was found that in the patients with TB-IRIS, prednisone reduced the need for hospitalization and therapeutic procedures, and hastened improvements in symptoms, performance, and quality of life. Proposed mechanism of prednisolone is the suppression of predominantly proinflammatory cytokine responses of innate immune origin. At times, TB-IRIS can develop in a non-HIV infected person. Such paradoxical reactions can be managed by a continuation of antituberculous therapy. Corticosteroids are needed for severe pleural and central nervous system edema in the doses that are described in the previous sections.
| Conclusion|| |
The use of corticosteroid is recommended in treating tuberculous meningitis and pericarditis. In tuberculous pleural effusion, it causes the faster recovery of clinical symptoms, but final outcomes remain the same. Similarly, in pulmonary TB, corticosteroids relieve the morbidity in a severe disease, but the final outcome remains the same with and without corticosteroids. In abdominal TB, corticosteroids lead to a rapid improvement in the condition of patients in a small trial, but its use in peritoneal TB needs more studies. Upper respiratory tract TB showed a rapid relief in difficulty in swallowing, when corticosteroids were used along with antituberculous therapy. For ocular TB, topical and systemic corticosteroids can be used. Severe hypersensitivity reactions due to antituberculous drug required corticosteroids therapy. In cases of adrenal crisis, a corticosteroid replacement becomes mandatory.
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