To the Editor: Mai et al. (Dec. 13 issue) report that dexamethasoneimproved survival among patients with definite bacterial meningitis.1However, dexamethasone was associated with decreased survivalin the group of patients with probable meningitis, which washypothesized to be due to delayed antituberculosis treatmentin patients with presumed tuberculous meningitis. Since it isrecommended that corticosteroids be given before or at the timeof the initial dose of antibiotics,2 do the authors recommendthat only patients with positive Gram's staining of cerebrospinalfluid receive corticosteroids? Should this restriction be appliedonly to countries with a high incidence of tuberculous meningitis?
How long was the delay in antituberculosis therapy after dexamethasonetreatment for the eight patients with presumed tuberculous meningitisin the group of patients with probable meningitis? In the ninepatients with confirmed tuberculous meningitis in the alternative-diagnosisgroup, four patients received dexamethasone and five patientsreceived placebo, and yet there was a trend toward increasedmortality among those who received dexamethasone. In light ofthe authors' previous findings on the benefits of dexamethasonein patients with tuberculous meningitis,3 was there a delayin the receipt of antituberculosis drugs in the four patientswith confirmed tuberculous meningitis who received dexamethasone?If so, what was the difference in the delay in administeringantituberculosis drugs between the eight patients with presumedtuberculous meningitis and the four patients with confirmedtuberculous meningitis who received dexamethasone?
Edward D. Chan, M.D. National Jewish Medical and Research Center Denver, CO 80206 chane{at}njc.org
References
Mai NTH, Chau TTH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007;357:2431-2440. [Free Full Text]
de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556. [Free Full Text]
Thwaites GE, Bang ND, Dung NH, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-1751. [Free Full Text]
To the Editor: Scarborough and coworkers (Dec. 13 issue)1 concludethat there is no role for adjunctive corticosteroids for bacterialmeningitis in developing countries like Malawi, where the mainpathogen is pneumococcus and where there is a high prevalenceof infection with the human immunodeficiency virus (HIV). Thismight unnecessarily deprive a subgroup of patients — thosewho are HIV-negative, present early, and have had no previousexposure to antibiotic therapy — from the potential benefitsof adjunctive corticosteroids. In another developing countrywhere the HIV prevalence is lower, corticosteroids given beforeor with antibiotics have improved the rate of survival amongpatients with proven bacterial meningitis.2 A recent meta-analysisalso concluded that corticosteroid therapy reduced the rateof mortality among adults, especially in the subgroup of patientswith pneumococcal meningitis.3 An appropriate risk stratificationof patients with meningitis and a judicious use of corticosteroidsmight prove beneficial even in resource-poor, HIV-prevalentareas.
Catherine W. Ong, M.D. Li Yang Hsu, M.P.H. Paul A. Tambyah,M.D. National University Hospital Singapore 119074, Singapore hsuliyang{at}gmail.com
References
Scarborough M, Gordon SB, Whitty CJM, et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007;357:2441-2450. [Free Full Text]
Mai NTH, Chau TTH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007;357:2431-2440. [Free Full Text]
van de Beek D, de Gans J, McIntyre P, Prasad K. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2007;1:CD004405-CD004405. [Medline]
To the Editor: Local epidemiologic characteristics of bacterialmeningitis may affect the therapeutic role of corticosteroids.1,2Induction of the inflammatory response is probably the crucialelement in the damage from the infection. However, differencesare observed among genetic lineages within the same etiologicagent of meningitis. Such conclusions were recently reportedregarding Streptococcus pneumoniae, for which both genotypeand capsular types determine the pathogenic behavior of pneumococci.3An association of fatal meningococcal disease with meningococcalisolates of the clonal complex ST-11 was observed in patientswith Neisseria meningitidis.4 These isolates induce strongerinflammation and apoptosis during meningococcal sepsis.5 Hostfactors may also influence the induction inflammatory response.Future studies and trials should consider bacterial and hostfactors that are usually overlooked in addressing the issueof corticosteroids.
Scarborough M, Gordon SB, Whitty CJM, et al. Corticosteroids for bacterial meningitis in adults in sub-Saharan Africa. N Engl J Med 2007;357:2441-2450. [Free Full Text]
Mai NTH, Chau TTH, Thwaites G, et al. Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis. N Engl J Med 2007;357:2431-2440. [Free Full Text]
Sjostrom K, Spindler C, Ortqvist A, et al. Clonal and capsular types decide whether pneumococci will act as a primary or opportunistic pathogen. Clin Infect Dis 2006;42:451-459. [CrossRef][ISI][Medline]
Trotter CL, Fox AJ, Ramsay ME, et al. Fatal outcome from meningococcal disease -- an association with meningococcal phenotype but not with reduced susceptibility to benzylpenicillin. J Med Microbiol 2002;51:855-860. [Free Full Text]
Zarantonelli ML, Lancellotti M, Deghmane AE, et al. Hyperinvasive genotypes of Neisseria meningitidis in France. Clin Microbiol Infect (in press).
To the Editor: In his editorial (Dec. 13 issue), Greenwood assertsthat "the administration of dexamethasone is now widely acceptedas standard practice in the management of acute bacterial meningitisin children in the industrialized world."1 We agree that itis a common practice but do not believe that it is widely acceptedas standard practice in the United States.
The American Academy of Pediatrics (AAP)2 acknowledges thatdexamethasone may be beneficial for the treatment of Haemophilusinfluenzae meningitis, but it also advises that "adjunctivetherapy with dexamethasone may be considered [for pneumococcalmeningitis] after weighing the potential benefits and possiblerisks. Experts do not agree on a recommendation to use corticosteroidsin pneumococcal meningitis; data are not sufficient to demonstratea clear benefit in children." Similarly, the 2004 Practice Guidelinesfor the Management of Bacterial Meningitis3 of the InfectiousDiseases Society of America acknowledge the lack of consensusand refer to the AAP statement.
We agree with Greenwood that "the debate about the value ofcorticosteroids in acute bacterial meningitis will continue,"but we believe the debate will continue for children in theUnited States as well.
George K. Siberry, M.D., M.P.H. Julia A. McMillan, M.D. Johns Hopkins Medical Institutions Baltimore, MD 21287 gsiberr1{at}jhmi.edu
References
Greenwood BM. Corticosteroids for acute bacterial meningitis. N Engl J Med 2007;357:2507-2509. [Free Full Text]
Pickering LK, Baker CJ, Long SS, McMillan JA, eds. 2006 Red book: report of the Committee on Infectious Diseases. 27th ed. Elk Grove Village, IL: American Academy of Pediatrics, 2006.
Tunkel AR, Hartman BJ, Kaplan SL, et al. Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 2004;39:1267-1284. [CrossRef][ISI][Medline]
Dr. Mai and colleagues reply: Chan is right to highlight theproblem of how to select patients with bacterial meningitiswho are most likely to benefit from adjunctive corticosteroids,when diagnostic confirmation of the disease may take hours (withGram's stain of cerebrospinal fluid) or days (with cerebrospinalfluid culture), or may not be possible (as is true throughoutmost of the developing world). However, we do not recommendrestricting dexamethasone to patients with a positive Gram'sstain, because the modest sensitivity of this test would meana significant proportion of patients with disease subsequentlyconfirmed by culture would miss the potential benefits of dexamethasonetreatment. Instead, we suggest that physicians — especiallythose working in settings with a high prevalence of tuberculosis— not administer adjunctive corticosteroids if there areclinical features suggestive of tuberculous meningitis. We recommendidentifying these features with the aid of a simple, clinicaldiagnostic algorithm.1 Unfortunately, the time delay betweenentry into our study and the start of treatment with antituberculosisdrugs was not recorded, but in most patients it was between2 and 5 days. The delay was unlikely to have been influencedby the findings of our previous study of tuberculous meningitis,which showed that dexamethasone improved the outcome among patientstreated with antituberculosis drugs.2
Determining which patients with bacterial meningitis receivethe most benefit from adjunctive dexamethasone is an ongoingchallenge. It remains uncertain how the treatment effect variesacross subgroups defined by age, sex, bacterial pathogen, andHIV status. Taha and Alonso suggest that host and bacterialfactors may also influence disease severity and response tocorticosteroids. There are plausible biologic reasons for asignificant effect of all these variables on treatment outcome,but proving their importance will require further very large,controlled trials.
Nguyen Thi Hoang Mai, M.D. Guy Thwaites, M.D. Jeremy J. Farrar,F.R.C.P. Hospital for Tropical Diseases Ho Chi Minh City, Vietnam jfarrar{at}oucru.org
References
Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:1287-1292. [CrossRef][ISI][Medline]
Thwaites GE, Bang ND, Dung NH, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741-1751. [Free Full Text]
Dr. Scarborough and colleagues reply: Two letters suggest thatit might be possible to identify subgroups of patients in whomadjuvant corticosteroid therapy is likely to be beneficial.Ong et al. propose stratification according to clinical criteria.To be of use in directing therapy, such criteria must be availableat the time of admission; this is unlikely in the case of thecausative organism and, in our experience, in the case of HIVserostatus. Given that caveat, our study failed to show thatthe length of history, organism, previous exposure to antibiotictherapy, or HIV status influenced the effect of adjuvant corticosteroidtherapy. Of the 45 HIV-negative patients, 8 of 22 corticosteroid-treatedpatients, as compared with 10 of 23 patients who received placebo,died by day 40. A pediatric study in Malawi, in which 302 of459 patients were HIV-negative, also showed no benefit fromadjunctive corticosteroids in this subgroup.1
Taha and Alonso suggest that patient selection on the basisof host and pathogen genotype may improve the outcome. Thisis an attractive proposition, and we acknowledge the need formore detailed data collection. However, we question the feasibilityof determining host and pathogen genotype in a manner sufficientlytimely to direct therapy for individual patients, and we thinkit unlikely that the technology will become available in resource-poorsettings in the foreseeable future, especially given that theannual health care spending in such settings is frequently lessthan $10 per person.2 A dramatic improvement in outcome couldperhaps be achieved by promoting public awareness of the symptomsand signs of meningitis, by improving access to health care,and by ensuring the availability of effective antibiotics. Certainpatient subgroups may indeed benefit from adjuvant corticosteroidtherapy, and we share the concerns of others that we have beenunable to determine satisfactorily the factors that predicta benefit.
Matthew Scarborough, M.R.C.P. University of Oxford Oxford OX3 9DU, United Kingdom matthew.scarborough{at}ndcls.ox.ac.uk
Stephen Gordon, M.D. Liverpool School of Tropical Medicine Liverpool L3 5QA, United Kingdom
Timothy Peto, Ph.D. University of Oxford Oxford OX3 9DU, United Kingdom
References
Molyneux EM, Walsh AL, Forsyth H, et al. Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Lancet 2002;360:211-218. [CrossRef][ISI][Medline]
Kirigia JM, Preker A, Carrin G, Mwikisa C, Diarra-Nama AJ. An overview of health financing patterns and the way forward in the WHO African Region. East Afr Med J 2006;83:Suppl:S1-S28. [Medline]
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