USA Today 3/27, 1A, Sternberg) reports that “independent analyses performed at the request of USA Today suggest the meteoric rise of angioplasty during the past three decades has ended.”

One of these analyses, based on information from 337 hospitals, indicated that  “[t]he number of angioplasty procedures performed each year appears to have declined by 10 percent to 15 percent over the past two years.” The other analysis, which was performed by the Santa Fe-based market analysis firm Qforma, using data from IMS Health, a healthcare information company, indicated that “[t]he use of angioplasty and stents…began dropping in June 2006, when results of two landmark studies that cast doubt on the procedure began filtering into the medical community.” Some recent “research suggests angioplasty is used too often, and in many cases, the modest benefits don’t justify the procedure’s cost.” This “topic will be debated at the annual scientific session of the American College of Cardiology starting this weekend in Chicago.”

http://www.usatoday.com/news/health/2008-03-26-angioplasty-decline_N.htm

FDA commissioner von Eschenbach said that the agency’s “regulatory role has expanded and its workforce has been overextended.”

Currently, the FDA’s “budget is more than $2 billion annually,” and “Democratic lawmakers have criticized von Eschenbach for failing to press publicly for more funding.” An independent advisory panel “to the FDA said the agency’s budget will need to increase to $3.7 billion by 2013, excluding rent for offices and revenue from the fees drugmakers pay for the FDA to review new product applications.”

Wall Street Journal (3/27, D1, Winstein) reports that a Harvard University study published in the New England Journal of Medicine suggests that “last-minute approvals by the Food and Drug Administration (FDA)” tend to be “unsafe.” Investigators discovered “that [o]f the 313 drugs approved from 1993 to 2004, 97 were approved within two months of deadline.” And, “of 21 withdrawals and black-box warnings for drugs approved since 1993, the 97 drugs approved near the FDA’s deadline had a 14 percent rate of severe safety problems down the road, compared with three percent for 216 other drugs.”

http://online.wsj.com/article/SB120656190873766273.html.html

The Wall Street Journal (3/26, B4, Whalen, et al.) reports, “Three European countries — France, Italy, and Denmark — recalled the blood-thinning drug heparin or its ingredients.” This latest recall comes on the heels of an announcement by Italian company, Opocrin SpA, that “it bought some ingredients from Shenzhen,” China, which “turned out to be contaminated.”phone alltel ringtone free musicharrington amanda picsfree ringtone 5300 sanyoadam g polyphonic ringtoneairtel ringtones liveamp ringtone hollywood free bollywood nokiatamil 1100 ringtonessanyo ringtone 7300 Map

UPI, 2/27/08:  One-in-four U.S. adults suffers from non-alcoholic fatty liver disease — liver disease characterized by excessive fat in the liver, U.S. researchers said.

Non-alcoholic fatty liver disease, the most common cause of abnormal liver enzymes, is considered by many to be a manifestation of the metabolic syndrome — belly fat, elevated blood pressure, insulin resistance, high cholesterol — which result in an increased risk of coronary heart disease.

Study leader Joanne Krasnoff of the University of California San Francisco recruited 37 adult patients with a spectrum of non-alcoholic fatty liver disease severity measured by liver biopsy.

Patients had suboptimal cardiorespiratory fitness, muscle strength, body composition and physical activity participation. More than 97 percent had a body fat percentage that put them at increased risk for morbidity and mortality and less than 20 percent met recommended guidelines for physical activity.

The study, published in the April issue of Hepatology, demonstrated lower cardiorespiratory fitness in subjects with increasing non-alcoholic fatty liver disease severity.

However, the finding raised the question of a cause-or-effect phenomenon — does cardiorespiratory fitness attenuate non-alcoholic fatty liver disease, or does increasing non-alcoholic fatty liver disease severity result in a decline in cardiorespiratory fitness? the authors asked.

MEDSCAPE:  A 55-year-old woman with a past medical history of congestive heart failure, hypertension, hyperlipidemia, asthma, gastroesophageal reflux disease, and lupus anticoagulant syndrome presents to the emergency department (ED) with severe, progressive shortness of breath that has lasted for the past 12 hours, with associated chest pressure and wheezing. She denies having any leg swelling, chills, sore throat, coughing, or heartburn. Before reaching the ED, she used her albuterol inhaler without relief of symptoms and contacted emergency medical services (EMS). She has a 40-pack-year history of tobacco use, as well as a history of alcoholism (with her last consumption being 4 years before presentation) and remote marijuana use. Her medication regimen includes furosemide, fosinopril, isosorbide nitrate, pantoprazole, spironolactone, and enteric-coated aspirin, but she has a well-documented history of noncompliance.

On physical examination, the patient is afebrile, with a heart rate of 150 bpm, a blood pressure of 202/126 mm Hg, a respiratory rate of 26 breaths/min, and an oxygen saturation of 81% while breathing room air (which improved to 92% when she was given a non-rebreather face mask). In general, she has labored respirations and is unable to speak in full sentences. She has no jugular venous distention of the neck; however, her lung fields are remarkable for bilateral crackles. Her heart sounds include S1 and S2, but no murmurs, rubs, or gallops are noted. The patient has 1+ pitting edema of the lower extremities bilaterally. Incidentally, an atopic dyshidrotic eczematous rash of the skin is noted on the palmar and plantar surfaces of the patient’s hands and feet.

An arterial blood gas drawn while the patient is breathing room air reveals a pH of 7.27, with a partial oxygen pressure of 54 mm Hg and a partial carbon dioxide pressure of 63 mm Hg. The complete blood count (CBC), coagulation profile, serum electrolyte panel, and renal function test are unremarkable. An electrocardiogram (ECG) is performed (see Figure 1), and it shows a tachycardic rhythm of 152 bpm, with a left bundle branch block (which is noted to be pre-existing when compared with a previous ECG). A chest radiograph is performed, which reveals evidence of pulmonary edema.

 

DISCUSSION:  The initial ECG (see below) reveals a tachycardic rhythm that is regular and consistent with clockwise typical atrial flutter with a 2:1 atrioventricular conduction block^[1]; this is consistent with congestive heart failure. Atrial flutter is a relatively common atrial tachyarrhythmia and is the most significant of the atrial tachyarrhythmias, after sinus tachycardia and atrial fibrillation. Atrial flutter is defined by the presence of stable, uniform atrial activation, which is seen on ECG as flutter waves (most evident in lead II; see Figure 1), and has traditionally been characterized as a macroreentrant arrhythmia, with atrial rates ranging from 240 to 400 bpm^[1] (though the rate is most commonly around 300 bpm). Depending on the ventricular rate, the rhythm can interfere with cardiac output, leading to heart failure or atrial thrombus formation. Thrombus places the patient at risk for possible systemic embolization and stroke. Atrial flutter usually includes an atrioventricular (AV) block, with the rhythm commonly conducted at a 2:1 or 4:1 ratio; less commonly, a ratio of 3:1 or 5:1 is seen.^[1]

The pathophysiology of atrial flutter includes multiple reentrant or ectopic atrial waveforms reaching the AV node. There are 2 forms of atrial flutter, referred to as type I and type II. Type I, also called typical, common, or isthmus-dependent atrial flutter, involves a reentrant circuit that encircles the tricuspid annulus of the right atrium, with rates that average 240-340 bpm. The depolarizing impulse can travel in a “counterclockwise” fashion around the tricuspid annulus, resulting in negative flutter waves in the inferior leads, or it can travel in a “clockwise” fashion, resulting in positive flutter waves in the inferior leads. Type II atrial flutter, also known as atypical aflutter, is less common and remains uncharacterized except for unusually high rates of
340-440 beats/min.^[1,2] The exact etiology of atrial flutter is unknown, but it has been found to occur in patients with a variety of conditions, such as heart failure, pericarditis, valvular disease, pulmonary embolism, chronic obstructive pulmonary disease, and hyperthyroidism, as well as following most types of cardiac surgery. It is estimated that 200,000 new cases of atrial flutter are diagnosed each year in the United States. The condition tends to be more common in elderly men and in patients with the above mentioned comorbidities; however, it can also occur in patients without identifiable risk factors.^[1]

After addressing the need for immediate cardioversion in patients with atrial flutter who may be hemodynamically unstable,^[1] the general goals for pharmacotherapy include ventricular rate control, conversion to a normal sinus rhythm (NSR), prevention of recurrent episodes, minimization of the risk of thromboembolic complications, and minimization of any adverse effects from pharmacologic therapy.^[2] Ventricular rate control can alleviate the symptoms associated with a rapid ventricular response. Two classes of medications are routinely used: calcium channel blockers (eg. diltiazem) and beta-blockers (eg. metoprolol). Both classes of medications work by blocking conduction of the atrial tachydysrhythmia through the AV node. The potential for hypotension associated with the negative inotropic effects of these drugs should be considered when they are used to treat atrial flutter.

After controlling the ventricular rate, the safety of attempting restoration of an NSR must be established; addressing the need for anticoagulation therapy for the prevention of thromboembolic phenomenon should be the first consideration. The success rate of direct current (DC) synchronized cardioversion is >95% for returning the heart to an NSR; however, as with atrial fibrillation, the success rate of sinus rhythm maintenance after 1 year of DC cardioversion without the aid of antiarrhythmic pharmacotherapy varies from 20 to 50%. Atrial flutter generally requires less energy for conversion than atrial fibrillation; in many cases, conversion is achieved with as little as 50 joules. Pharmacologic cardioversion is an alternative to electrical cardioversion, and it offers several choices with regard to specific medications. Procainamide is effective in 0-13% of patients; flecainide, in approximately 10% of patients; and dofetilide, in approximately 70-80% of patients. Ibutilide can convert recent-onset atrial flutter to an NSR in 63% of patients with a single infusion. Large, single oral doses of type IC antiarrhythmic agents, such as propafenone
(450-600 mg) or flecainide (200-300 mg), have been shown to be effective in converting recent-onset atrial fibrillation to an NSR as well.^[2] Oral amiodarone during the loading period (>1 mo) has been shown to convert 18% of cases of atrial fibrillation or flutter to an NSR. Intravenous amiodarone is also effective in converting an atrial flutter to an NSR, and it slows the ventricular rate in patients with a rapid ventricular response. A final option is atrial overdrive pacing, which can be performed invasively or through the use of a transesophageal electrode to pace the left atrium; this therapy has a success rate of approximately 50%.^[2] A combination of DC cardioversion and antiarrhythmic therapy is most commonly used to effectively restore an NSR and maintain sinus rhythm.^[1,2]

After the initial episode of atrial flutter has terminated and any underlying precipitating factors have been treated, some patients may not need any further intervention, except for avoidance of the precipitating factor (eg, alcohol, caffeine); however, as mentioned above, approximately 30% of patients remain in sinus rhythm at 1 year without antiarrhythmic therapy, requiring some sort of maintenance therapy. The guidelines regarding the use of antiarrhythmic agents in atrial flutter are similar to those for using antiarrhythmic agents in atrial fibrillation. In addition, radiofrequency ablation has a high success rate and low complication rate for treating atrial flutter, and in some cases, it may be a more favorable option when compared with lifelong antiarrhythmic drug therapy because of adverse reactions that can include fatal proarrhythmic events and organ toxicity. Antiarrhythmics used to treat atrial fibrillation have been shown to be effective in treating fibrillation or flutter during a 6- to 12-month follow-up; the specific characteristics and the adverse effects of each antiarrhythmic agent should be considered when selecting which pharmacologic agent to use. Generally speaking, class IC agents may be used in patients without structural
heart disease^[3]; however, for patients with left ventricular hypertrophy with or without ischemia or conduction delay, class III agents (specifically, sotalol or amiodarone) are the drugs of choice. For patients with significant systolic dysfunction, dofetilide can be an effective option provided that there is no evidence of renal dysfunction.^[1,2]

There is an increased risk of thromboembolic complications for patients who have been in atrial flutter for more than 48 hours, which may result from episodic atrial fibrillation leading to impaired left atrial appendage function and subsequent thrombus formation. The same anticoagulation strategy used in patients with atrial fibrillation may be applied to patients with atrial flutter.^[2] Some reports have demonstrated thrombus in the left atrium appendage in as many as 43% of patients with atrial flutter, with postcardioversion thromboembolic events occurring in up to 7% of patients who were not anticoagulated. These events, if not occurring immediately after cardioversion, typically occur at about 3 days following cardioversion, with almost all cases occurring within 10 days after restoration of an NSR. Stunning of the left atrial appendage is thought to contribute to thrombogenicity and may play a role for as long as 4 weeks following cardioversion. This is believed to be the source of emboli in patients who have had a thromboembolic event after cardioversion despite no evidence of thrombus found on transesophageal electrocardiography (TEE). Anticoagulation is also recommended for at least 1 week after any ablation of an atrial flutter that persists for more than 48 hours. Adequate anticoagulation, as recommended by the American College of Chest Physicians, has been shown to decrease thromboembolic complications in patients with chronic atrial flutter and in patients undergoing cardioversion.^[2]

The patient in this case was placed on noninvasive positive pressure ventilation for her pulmonary edema and treated with intravenous diltiazem for the rapid ventricular response to the underlying 2:1 atrial flutter rhythm. Administration of diltiazem resulted in conversion to a variable block that was mainly 4:1, resulting in a heart rate of around 80 bpm. Additional intravenous pharmacologic therapy with furosemide, nitroglycerin, and morphine sulfate was administered for her congestive heart failure. Heparin was administered as an anticoagulant for the atrial flutter. After several hours, the patient improved notably and was in no evident respiratory distress. The initial examination of cardiac enzymes was unremarkable, and she was admitted to a cardiac unit on a monitored floor for further management of her congestive heart failure, evaluation for possible myocardial ischemia, and workup for her atrial flutter. She continued to improve with intravenous diuretic therapy; on hospital day 2, she underwent a TEE that did not reveal structural heart disease or thrombus in the left atrium. She was DC cardioverted successfully (see ECG in Figure 2) and discharged on warfarin therapy with follow-up.

Title:  Dexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis

NEJM:  Volume 357:2431-2440	,	December 13, 2007	,	Number 24

 

ABSTRACT

Background It is uncertain whether all adults with bacterial meningitis benefit from treatment with adjunctive dexamethasone. Methods We conducted a randomized, double-blind, placebo-controlled trial of dexamethasone in 435 patients over the age of 14 years who had suspected bacterial meningitis. The goal was to determine whether dexamethasone reduced the risk of death at 1 month and the risk of death or disability at 6 months.

Results A total of 217 patients were assigned to the dexamethasone group, and 218 to the placebo group. Bacterial meningitis was confirmed in 300 patients (69.0%), probable meningitis was diagnosed in 123 patients (28.3%), and an alternative diagnosis was made in 12 patients (2.8%). An intention-to-treat analysis of all the patients showed that dexamethasone was not associated with a significant reduction in the risk of death at 1 month (relative risk, 0.79; 95% confidence interval [CI], 0.45 to 1.39) or the risk of death or disability at 6 months (odds ratio, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (relative risk, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (odds ratio, 0.56; 95% CI, 0.32 to 0.98). These effects were not found in patients with probable bacterial meningitis. Results of multivariate analysis indicated that dexamethasone treatment for patients with probable bacterial meningitis was significantly associated with an increased risk of death at 1 month, an observation that may be explained by cases of tuberculous meningitis in the treatment group.

Conclusions Dexamethasone does not improve the outcome in all adolescents and adults with suspected bacterial meningitis; a beneficial effect appears to be confined to patients with microbiologically proven disease, including those who have received prior treatment with antibiotics.

NEJM�� Volume 358:1399-1401 ,�� March 27, 2008,�� �� Number 13

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Corticosteroids for Bacterial Meningitis
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To the Editor: Mai et al. (Dec. 13 issue) report that dexamethasone improved survival among patients with definite bacterial meningitis.¹ However, dexamethasone was associated with decreased survival in the group of patients with probable meningitis, which was hypothesized to be due to delayed antituberculosis treatment in patients with presumed tuberculous meningitis. Since it is recommended that corticosteroids be given before or at the time of the initial dose of antibiotics,² do the authors recommend that only patients with positive Gram’s staining of cerebrospinal fluid receive corticosteroids? Should this restriction be applied only to countries with a high incidence of tuberculous meningitis?

How long was the delay in antituberculosis therapy after dexamethasone treatment for the eight patients with presumed tuberculous meningitis in the group of patients with probable meningitis? In the nine patients with confirmed tuberculous meningitis in the alternative-diagnosis group, four patients received dexamethasone and five patients received placebo, and yet there was a trend toward increased mortality among those who received dexamethasone. In light of the authors’ previous findings on the benefits of dexamethasone in patients with tuberculous meningitis,³ was there a delay in the receipt of antituberculosis drugs in the four patients with confirmed tuberculous meningitis who received dexamethasone? If so, what was the difference in the delay in administering antituberculosis drugs between the eight patients with presumed tuberculous meningitis and the four patients with confirmed tuberculous meningitis who received dexamethasone?

^{Edward D. Chan, M.D.
National Jewish Medical and Research Center
Denver, CO 80206
chane@njc.org}

References

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1. 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]
2. de Gans J, van de Beek D. Dexamethasone in adults with bacterial meningitis. N Engl J Med 2002;347:1549-1556.��[Free��Full��Text]
3. 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]

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To the Editor: Scarborough and coworkers (Dec. 13 issue)¹ conclude that there is no role for adjunctive corticosteroids for bacterial meningitis in developing countries like Malawi, where the main pathogen is pneumococcus and where there is a high prevalence of infection with the human immunodeficiency virus (HIV). This might unnecessarily deprive a subgroup of patients �?’ those who are HIV-negative, present early, and have had no previous exposure to antibiotic therapy �?’ from the potential benefits of adjunctive corticosteroids. In another developing country where the HIV prevalence is lower, corticosteroids given before or with antibiotics have improved the rate of survival among patients with proven bacterial meningitis.² A recent meta-analysis also concluded that corticosteroid therapy reduced the rate of mortality among adults, especially in the subgroup of patients with pneumococcal meningitis.³ An appropriate risk stratification of patients with meningitis and a judicious use of corticosteroids might prove beneficial even in resource-poor, HIV-prevalent areas.
Catherine W. Ong, M.D.
Li Yang Hsu, M.P.H.
Paul A. Tambyah, M.D.
National University Hospital
Singapore 119074, Singapore
hsuliyang@gmail.com

References

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1. 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]
2. 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]
3. 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]

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To the Editor: Local epidemiologic characteristics of bacterial meningitis may affect the therapeutic role of corticosteroids.^1,2 Induction of the inflammatory response is probably the crucial element in the damage from the infection. However, differences are observed among genetic lineages within the same etiologic agent of meningitis. Such conclusions were recently reported regarding Streptococcus pneumoniae, for which both genotype and capsular types determine the pathogenic behavior of pneumococci.³ An association of fatal meningococcal disease with meningococcal isolates of the clonal complex ST-11 was observed in patients with Neisseria meningitidis.⁴ These isolates induce stronger inflammation and apoptosis during meningococcal sepsis.⁵ Host factors may also influence the induction inflammatory response. Future studies and trials should consider bacterial and host factors that are usually overlooked in addressing the issue of corticosteroids.
Muhamed-Kheir Taha, M.D., Ph.D.
Jean-Michel Alonso, M.D., Ph.D.
Institut Pasteur
75015 Paris, France
mktaha@pasteur.fr

References

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1. 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]
2. 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]
3. 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]
4. 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]
5. Zarantonelli ML, Lancellotti M, Deghmane AE, et al. Hyperinvasive genotypes of Neisseria meningitidis in France. Clin Microbiol Infect (in press).

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To the Editor: In his editorial (Dec. 13 issue), Greenwood asserts that “the administration of dexamethasone is now widely accepted as standard practice in the management of acute bacterial meningitis in children in the industrialized world.”¹ We agree that it is a common practice but do not believe that it is widely accepted as standard practice in the United States. The American Academy of Pediatrics (AAP)² acknowledges that dexamethasone may be beneficial for the treatment of Haemophilus influenzae meningitis, but it also advises that “adjunctive therapy with dexamethasone may be considered [for pneumococcal meningitis] after weighing the potential benefits and possible risks. Experts do not agree on a recommendation to use corticosteroids in pneumococcal meningitis; data are not sufficient to demonstrate a clear benefit in children.” Similarly, the 2004 Practice Guidelines for the Management of Bacterial Meningitis³ of the Infectious Diseases Society of America acknowledge the lack of consensus and refer to the AAP statement.

We agree with Greenwood that “the debate about the value of corticosteroids in acute bacterial meningitis will continue,” but we believe the debate will continue for children in the United States as well.

^{George K. Siberry, M.D., M.P.H.
Julia A. McMillan, M.D.
Johns Hopkins Medical Institutions
Baltimore, MD 21287
gsiberr1@jhmi.edu}

References

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1. Greenwood BM. Corticosteroids for acute bacterial meningitis. N Engl J Med 2007;357:2507-2509.��[Free��Full��Text]
2. 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.
3. 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]

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Dr. Mai and colleagues reply: Chan is right to highlight the problem of how to select patients with bacterial meningitis who are most likely to benefit from adjunctive corticosteroids, when diagnostic confirmation of the disease may take hours (with Gram’s stain of cerebrospinal fluid) or days (with cerebrospinal fluid culture), or may not be possible (as is true throughout most of the developing world). However, we do not recommend restricting dexamethasone to patients with a positive Gram’s stain, because the modest sensitivity of this test would mean a significant proportion of patients with disease subsequently confirmed by culture would miss the potential benefits of dexamethasone treatment. Instead, we suggest that physicians �?’ especially those working in settings with a high prevalence of tuberculosis �?’ not administer adjunctive corticosteroids if there are clinical features suggestive of tuberculous meningitis. We recommend identifying these features with the aid of a simple, clinical diagnostic algorithm.¹ Unfortunately, the time delay between entry into our study and the start of treatment with antituberculosis drugs was not recorded, but in most patients it was between 2 and 5 days. The delay was unlikely to have been influenced by the findings of our previous study of tuberculous meningitis, which showed that dexamethasone improved the outcome among patients treated with antituberculosis drugs.² Determining which patients with bacterial meningitis receive the most benefit from adjunctive dexamethasone is an ongoing challenge. It remains uncertain how the treatment effect varies across subgroups defined by age, sex, bacterial pathogen, and HIV status. Taha and Alonso suggest that host and bacterial factors may also influence disease severity and response to corticosteroids. There are plausible biologic reasons for a significant 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@oucru.org}

References

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1. 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]
2. 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]

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Dr. Scarborough and colleagues reply: Two letters suggest that it might be possible to identify subgroups of patients in whom adjuvant 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 available at the time of admission; this is unlikely in the case of the causative organism and, in our experience, in the case of HIV serostatus. Given that caveat, our study failed to show that the length of history, organism, previous exposure to antibiotic therapy, or HIV status influenced the effect of adjuvant corticosteroid therapy. Of the 45 HIV-negative patients, 8 of 22 corticosteroid-treated patients, as compared with 10 of 23 patients who received placebo, died by day 40. A pediatric study in Malawi, in which 302 of 459 patients were HIV-negative, also showed no benefit from adjunctive corticosteroids in this subgroup.¹ Taha and Alonso suggest that patient selection on the basis of host and pathogen genotype may improve the outcome. This is an attractive proposition, and we acknowledge the need for more detailed data collection. However, we question the feasibility of determining host and pathogen genotype in a manner sufficiently timely to direct therapy for individual patients, and we think it unlikely that the technology will become available in resource-poor settings in the foreseeable future, especially given that the annual health care spending in such settings is frequently less than $10 per person.² A dramatic improvement in outcome could perhaps be achieved by promoting public awareness of the symptoms and signs of meningitis, by improving access to health care, and by ensuring the availability of effective antibiotics. Certain patient subgroups may indeed benefit from adjuvant corticosteroid therapy, and we share the concerns of others that we have been unable to determine satisfactorily the factors that predict a benefit.

^{Matthew Scarborough, M.R.C.P.
University of Oxford
Oxford OX3 9DU, United Kingdom
matthew.scarborough@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

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1. 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]
2. 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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