Adjunctive Steroids for Tuberculous Meningitis — More Evidence, More Questions
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《新英格兰医药杂志》
Tuberculosis continues to plague global health. The World Health Organization (WHO) has estimated an annual incidence of 8.8 million cases of tuberculosis worldwide, with 1.8 million deaths. Most of the disease burden is in Africa and Southeast Asia, where the annual incidence rates are 350 and 182 cases per 100,000 population, respectively.1
Of the 22 "high-burden" countries that account for 80 percent of the world's estimated incidence, only Vietnam has met the WHO targets for both case detection (70 percent) and treatment success (85 percent). Despite nationwide use of directly observed therapy, a low prevalence of coinfection with the human immunodeficiency virus (HIV) (1.8 percent), and a low incidence of multidrug resistance (2.3 percent), the mortality from tuberculosis remains at 25 per 100,000 population in Vietnam, which is unacceptably high.2
Meningitis is a particularly severe form of tuberculosis, and it occurs most frequently in countries such as Vietnam, where the incidence of tuberculosis is very high. Pathological observations have suggested that the rupture of a subependymal or parameningeal tubercle into the subarachnoid space initiates meningeal infection, and the resultant basilar inflammatory response leads to cranial-nerve injury, intracranial vasculitis with stroke, and communicating hydrocephalus.3 Death or severe neurologic impairment is the outcome in most patients, despite antituberculous therapy.4
Adjunctive interventions to improve the clinical outcome of tuberculous meningitis have been attempted for decades; these have included the intrathecal injection of tuberculin, heparin, or fibrinolytic agents.5,6,7 However, the antiinflammatory effect of corticosteroids is the most biologically plausible way to abort the pathologic sequelae, and a potential benefit of steroids as an adjunct to antituberculous therapy has been observed in case series and small clinical trials for more than 50 years.8,9,10 Most of these clinical trials, with enrollments ranging from 12 to 160 patients each, showed a reduction in the incidence of neurologic sequelae, mortality, or both in the patients randomly assigned to receive adjunctive steroids for tuberculous meningitis. However, it has been difficult to draw firm conclusions from these studies because of methodologic limitations in study design such as small samples, improper concealment of treatment-group assignments, and lack of assessment of coinfection with HIV.
In this issue of the Journal, Thwaites et al. report the results of a prospective, randomized, placebo-controlled trial of adjunctive dexamethasone in 545 patients over 14 years of age with tuberculous meningitis in two hospitals in Vietnam.11 The investigators enrolled patients with definite, probable, or possible tuberculous meningitis, participants were stratified on study entry according to clinical severity (with the use of British Medical Research Council criteria for severity grade), and the results were analyzed after adjustment for the effect of the disease-severity grade and HIV status. The primary outcome was death or severe disability nine months after randomization, although the study was powered statistically by the end point of mortality. The degree of disability was determined with the use of two questionnaires about symptoms, with the worst of the two scores recorded as the outcome.
The results of the trial showed that adjunctive treatment with dexamethasone reduced mortality among patients over 14 years of age with tuberculous meningitis, but there was no demonstrable improvement in the combined end point of death or severe disability after nine months. A survival benefit from adjunctive steroids can be explained by a reduction in inflammation both systemically and within the central nervous system. Reduction in inflammatory cytokine generation within the cerebrospinal fluid may impair the diapedesis of neutrophils and mononuclear cells and prevent death from vasculitis-induced stroke and obstructive hydrocephalus. An additional explanation for the survival benefit, supported by the study, is the reduction in the dexamethasone group of severe adverse events, including potentially fatal clinical hepatitis. Furthermore, reducing adverse events results in fewer alterations in the dose and regimen of antituberculous agents and may be an additional reason for improved overall survival, since such alterations may compromise clinical efficacy.
The results of the effect of dexamethasone among subgroups stratified according to disease-severity grade and HIV status require cautious interpretation. Although the authors show no evidence for heterogeneity among subgroups regarding the effect of treatment, the study was powered by the overall mortality end point. Therefore, the "homogeneous" effect observed may easily be explained by an inadequate number of patients within subgroups to permit detection of an actual difference.
The explanation for the lack of an identified improvement in morbidity can also be explained, but it may result more from the study design than from the lack of a therapeutic effect. First, only 82 percent of enrolled patients had probable or definite tuberculous meningitis; the inclusion of patients with possible tuberculous meningitis may have reduced the likelihood of an observed effect in the morbidity end point. Second, the morbidity end point was identified from the results of relatively crude questionnaires that were designed by previous investigators for measuring morbidity from stroke. The ability of these questionnaires to measure sequelae of a complex inflammatory disease of the central nervous system in which stroke is an important, but not exclusive, consequence is debatable. Although the authors tried to reduce variability among observers in the assessment of morbidity by training the data collectors, they report no data showing the degree of reliability over chance agreement, and the crude nature of the subjective reporting of the participants remains a potential explanation for the lack of an identified benefit from dexamethasone.
Overall, this large study provides the strongest evidence to date that adjunctive treatment with dexamethasone improves survival among patients over 14 years of age with tuberculous meningitis. Differential effects among subgroups of patients with different degrees of disease severity and among those coinfected with HIV remain possible and require additional investigation. Dexamethasone had no demonstrable benefit on morbidity; therefore, future investigations with more refined clinical instruments to measure morbidity will be needed. Nonetheless, the authors should be applauded for their diligent effort with such a large group of patients with tuberculous meningitis in a resource-poor environment where the disease burden is high.
Despite current efforts at public health control and the increasing use of directly observed therapy worldwide, a new case of tuberculosis is identified every four seconds. The burden of disease remains a mountainous challenge, and the mountain can be conquered only one step at a time. The study by Thwaites et al. is a stride in the right direction.
Source Information
From Yale University School of Medicine, New Haven, Conn.
References
World Health Organization. Fact Sheet N104. Tuberculosis. March 2004. (Accessed October 1, 2004, at http://www.who.int/mediacentre/factsheets/fs104/en.)
Global tuberculosis control: Vietnam. WHO report 2004. (Accessed October 1, 2004, at http://www.who.int/tb/publications/global_report/2004/en/VietNam.pdf.)
Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933;52:5-37.
Hosoglu S, Geyik MF, Balik I, et al. Predictors of outcome in patients with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:64-70.
St Hill CA, Riley C, Gifford JH. Use of intrathecal heparin in conjunction with streptomycin in treatment of tuberculous meningitis: preliminary report. J Clin Pathol 1948;1:157-161.
Smith HV, Vollum RL. Effects of intrathecal tuberculin and streptomycin in tuberculous meningitis: interim report. Lancet 1950;2:275-286.
Cathie IA. Bacterial fibrinolysin, its possible therapeutic application in tuberculous meningitis. J Clin Pathol 1949;2:73-76.
Shane SJ, Riley C. Tuberculous meningitis: combined therapy with cortisone and antimicrobial agents. N Engl J Med 1953;249:829-834.
O'Toole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis: relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969;70:39-48.
Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872-887.
Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-1751.
Related Letters:
Dexamethasone for Tuberculous Meningitis
Seligman S. J., Vagenakis A. G., Kyriazopoulou V., Marras T. K., Thwaites G. E., Quy H. T., Farrar J. J., Quagliarello V.(Vincent Quagliarello, M.D)
Of the 22 "high-burden" countries that account for 80 percent of the world's estimated incidence, only Vietnam has met the WHO targets for both case detection (70 percent) and treatment success (85 percent). Despite nationwide use of directly observed therapy, a low prevalence of coinfection with the human immunodeficiency virus (HIV) (1.8 percent), and a low incidence of multidrug resistance (2.3 percent), the mortality from tuberculosis remains at 25 per 100,000 population in Vietnam, which is unacceptably high.2
Meningitis is a particularly severe form of tuberculosis, and it occurs most frequently in countries such as Vietnam, where the incidence of tuberculosis is very high. Pathological observations have suggested that the rupture of a subependymal or parameningeal tubercle into the subarachnoid space initiates meningeal infection, and the resultant basilar inflammatory response leads to cranial-nerve injury, intracranial vasculitis with stroke, and communicating hydrocephalus.3 Death or severe neurologic impairment is the outcome in most patients, despite antituberculous therapy.4
Adjunctive interventions to improve the clinical outcome of tuberculous meningitis have been attempted for decades; these have included the intrathecal injection of tuberculin, heparin, or fibrinolytic agents.5,6,7 However, the antiinflammatory effect of corticosteroids is the most biologically plausible way to abort the pathologic sequelae, and a potential benefit of steroids as an adjunct to antituberculous therapy has been observed in case series and small clinical trials for more than 50 years.8,9,10 Most of these clinical trials, with enrollments ranging from 12 to 160 patients each, showed a reduction in the incidence of neurologic sequelae, mortality, or both in the patients randomly assigned to receive adjunctive steroids for tuberculous meningitis. However, it has been difficult to draw firm conclusions from these studies because of methodologic limitations in study design such as small samples, improper concealment of treatment-group assignments, and lack of assessment of coinfection with HIV.
In this issue of the Journal, Thwaites et al. report the results of a prospective, randomized, placebo-controlled trial of adjunctive dexamethasone in 545 patients over 14 years of age with tuberculous meningitis in two hospitals in Vietnam.11 The investigators enrolled patients with definite, probable, or possible tuberculous meningitis, participants were stratified on study entry according to clinical severity (with the use of British Medical Research Council criteria for severity grade), and the results were analyzed after adjustment for the effect of the disease-severity grade and HIV status. The primary outcome was death or severe disability nine months after randomization, although the study was powered statistically by the end point of mortality. The degree of disability was determined with the use of two questionnaires about symptoms, with the worst of the two scores recorded as the outcome.
The results of the trial showed that adjunctive treatment with dexamethasone reduced mortality among patients over 14 years of age with tuberculous meningitis, but there was no demonstrable improvement in the combined end point of death or severe disability after nine months. A survival benefit from adjunctive steroids can be explained by a reduction in inflammation both systemically and within the central nervous system. Reduction in inflammatory cytokine generation within the cerebrospinal fluid may impair the diapedesis of neutrophils and mononuclear cells and prevent death from vasculitis-induced stroke and obstructive hydrocephalus. An additional explanation for the survival benefit, supported by the study, is the reduction in the dexamethasone group of severe adverse events, including potentially fatal clinical hepatitis. Furthermore, reducing adverse events results in fewer alterations in the dose and regimen of antituberculous agents and may be an additional reason for improved overall survival, since such alterations may compromise clinical efficacy.
The results of the effect of dexamethasone among subgroups stratified according to disease-severity grade and HIV status require cautious interpretation. Although the authors show no evidence for heterogeneity among subgroups regarding the effect of treatment, the study was powered by the overall mortality end point. Therefore, the "homogeneous" effect observed may easily be explained by an inadequate number of patients within subgroups to permit detection of an actual difference.
The explanation for the lack of an identified improvement in morbidity can also be explained, but it may result more from the study design than from the lack of a therapeutic effect. First, only 82 percent of enrolled patients had probable or definite tuberculous meningitis; the inclusion of patients with possible tuberculous meningitis may have reduced the likelihood of an observed effect in the morbidity end point. Second, the morbidity end point was identified from the results of relatively crude questionnaires that were designed by previous investigators for measuring morbidity from stroke. The ability of these questionnaires to measure sequelae of a complex inflammatory disease of the central nervous system in which stroke is an important, but not exclusive, consequence is debatable. Although the authors tried to reduce variability among observers in the assessment of morbidity by training the data collectors, they report no data showing the degree of reliability over chance agreement, and the crude nature of the subjective reporting of the participants remains a potential explanation for the lack of an identified benefit from dexamethasone.
Overall, this large study provides the strongest evidence to date that adjunctive treatment with dexamethasone improves survival among patients over 14 years of age with tuberculous meningitis. Differential effects among subgroups of patients with different degrees of disease severity and among those coinfected with HIV remain possible and require additional investigation. Dexamethasone had no demonstrable benefit on morbidity; therefore, future investigations with more refined clinical instruments to measure morbidity will be needed. Nonetheless, the authors should be applauded for their diligent effort with such a large group of patients with tuberculous meningitis in a resource-poor environment where the disease burden is high.
Despite current efforts at public health control and the increasing use of directly observed therapy worldwide, a new case of tuberculosis is identified every four seconds. The burden of disease remains a mountainous challenge, and the mountain can be conquered only one step at a time. The study by Thwaites et al. is a stride in the right direction.
Source Information
From Yale University School of Medicine, New Haven, Conn.
References
World Health Organization. Fact Sheet N104. Tuberculosis. March 2004. (Accessed October 1, 2004, at http://www.who.int/mediacentre/factsheets/fs104/en.)
Global tuberculosis control: Vietnam. WHO report 2004. (Accessed October 1, 2004, at http://www.who.int/tb/publications/global_report/2004/en/VietNam.pdf.)
Rich AR, McCordock HA. The pathogenesis of tuberculous meningitis. Bull Johns Hopkins Hosp 1933;52:5-37.
Hosoglu S, Geyik MF, Balik I, et al. Predictors of outcome in patients with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:64-70.
St Hill CA, Riley C, Gifford JH. Use of intrathecal heparin in conjunction with streptomycin in treatment of tuberculous meningitis: preliminary report. J Clin Pathol 1948;1:157-161.
Smith HV, Vollum RL. Effects of intrathecal tuberculin and streptomycin in tuberculous meningitis: interim report. Lancet 1950;2:275-286.
Cathie IA. Bacterial fibrinolysin, its possible therapeutic application in tuberculous meningitis. J Clin Pathol 1949;2:73-76.
Shane SJ, Riley C. Tuberculous meningitis: combined therapy with cortisone and antimicrobial agents. N Engl J Med 1953;249:829-834.
O'Toole RD, Thornton GF, Mukherjee MK, Nath RL. Dexamethasone in tuberculous meningitis: relationship of cerebrospinal fluid effects to therapeutic efficacy. Ann Intern Med 1969;70:39-48.
Dooley DP, Carpenter JL, Rademacher S. Adjunctive corticosteroid therapy for tuberculosis: a critical reappraisal of the literature. Clin Infect Dis 1997;25:872-887.
Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-1751.
Related Letters:
Dexamethasone for Tuberculous Meningitis
Seligman S. J., Vagenakis A. G., Kyriazopoulou V., Marras T. K., Thwaites G. E., Quy H. T., Farrar J. J., Quagliarello V.(Vincent Quagliarello, M.D)