JECH Online First, published on November 13, 2013 as 10.1136/jech-2013-202525 Editorial

Tuberculous meningitis treatment regimens and impact of vaccination require further research if the unacceptably high mortality and morbidity is to be reduced.

characteristic features of pulmonary TB are present. Brain imaging, with CT or MRI, may help in suggesting a diagnosis of TBM with hydrocephalus, tuberculoma, basilar meningeal enhancement and basal ganglial infarction, all suggestive but not specific for TBM. A prior history of TB or known close contacts with patients with TB should be ascertained in the history in all patients.

CLINICAL PICTURE

IMPACT ON THE PATIENTS

TBM has been traditionally characterised as a subacute or chronic infection. However, it can develop and progress in less than a week from onset of the first symptoms. In countries with a high burden of TB, the diagnosis of TBM should be considered in all patients presenting with meningitis. Early diagnosis and initiation of effective drugs saves lives and reduces long-term disability. The clinical symptoms of TBM are broad and can be analogous to other forms of meningoencephalitis. This leads to delays in establishing a diagnosis. Coinfection with HIV does not change the neurological presentation of TBM5 even though in individuals coinfected with HIV there is a greater range of other potential diagnoses from opportunistic diseases than in patients who are not coinfected with HIV. Moreover, in many countries access to healthcare for HIV-positive individuals remains less good than HIV-negative individuals and this can lead to delays in health-seeking behaviour. Patients with and without HIV present with fever, altered mental status, meningism and focal neurological signs, particularly cranial nerve lesions and hemiparesis are common. The characteristic cerebrospinal fluid (CSF) features in TBM are straw coloured CSF, leucocytosis with a predominant lymphocytosis, low CSF:blood glucose ratio, moderately raised lactate and increased protein level. However, particularly in those who present early, within 7 days, and in those who are HIV-positive with low CD4 counts, the CSF may show a polymorphonuclear leucocytosis and the CSF glucose can be normal or only very slightly reduced on admission. In these patients, the diagnosis can be extremely difficult and consideration should be given to treating with broad-spectrum antibiotics and to repeating the CSF investigation if the patient does not improve within 48–72 h. The insensitive ZN test for acid-fast bacilli in the CSF and the time for mycobacterial culture add to the difficultly in establishing a diagnosis. A chest X-ray can help in the diagnosis if miliary TB is seen or the

Early diagnosis of TBM plays a crucial role in saving lives and reducing disability because the prognosis is dependent on the patient’s severity at the time that effective antibiotics and steroids are started. Sadly in practice, many patients are initially treated for pyogenic meningitis and when not improving, the diagnosis of TBM is considered, often after many days. This then may involve a transfer to a tertiary medical centre, which further adds to the delays in diagnosis and treatment. TBM must be considered a medical emergency as with all forms of brain infections, and clinicians need to appreciate the importance of early treatment.

Thinh Tran Thi Van,1 Jeremy Farrar1,2,3 BURDEN OF DISEASE Tuberculosis (TB) is one of the most important infectious diseases and one of ten most common causes of death globally,1 with almost 10 million new cases per year and 1.5 million deaths (WHO report 2011).2 It is estimated that a third of the world’s population is infected with TB of whom approximately 10% will develop clinically apparent disease. TB is also in the top 15 of causes of disease burden worldwide in the rank of disability-adjusted life years.3 The WHO estimates that five countries India, China, South Africa, Indonesia and Pakistan account for over 70% of the global burden of disease.2 Southern and eastern sub-Saharan Africa is the most affected region by the HIV/AIDS-TB combination.3 But the reality is that in all lowincome and middle-income countries and increasingly in high-income countries, TB remains a major public health problem. Tuberculous meningitis (TBM) is the most severe form of TB with a high mortality and many of the survivors are left with chronic neurological sequelae, which affect their daily lives and those of their family and community. The impact of this disease is even more severe in those coinfected with HIV. Patients coinfected with HIV are at more than 20 times higher risk of developing TB, compared with noninfected individuals.2 In a recent studies from Vietnam, the mortality rate in the 1st year following diagnosis of TBM in HIV and non-HIV infected adult patients was approximately 65% and 30%, respectively, and over 50% of survivors suffer from long-term disability.4 In countries with the greatest burden of TB, TBM is most commonly seen in children while in lower TB transmission settings, most cases of TBM occur in adults. It is now the third most common cause of bacterial meningitis in the UK. Several aspects of TBM including the underlying immunopathogenesis, the availability of sensitive and specific diagnostic tests, optimal 1

Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam; 2Centre for Tropical Medicine, University of Oxford, Churchill Hospital, Oxford, UK; 3Singapore Infectious Disease Initiative, Singapore Correspondence to Professor Jeremy Farrar, Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City Quan 5, Vietnam; [email protected]

VanCopyright TTT, et al. J Epidemiol Community Health 2013 Vol 0 No 0 Article author (orMonth their employer)

CURRENT TREATMENT Anti-TB chemotherapy should be started as soon as possible in all patients with suspected TBM without waiting for the microbiological confirmation. The optimal treatment for TBM has not been definitely established. It is recommended by WHO that patients with drug sensitive TBM should receive anti-TB treatment for 9–12 months with the combination of four drugs (rifampicin, isoniazid, pyrazinamide and streptomycin) for the intensive phase, and two drugs (rifampicin, isoniazid) for the continuation phase.6 The British Infection Society guideline recommends 12 months of anti-TB drugs for TBM.7 A recent study assessed the use of high dose intravenous rifampicin (600 mg, approximately 13 mg/ kg), and either oral moxifloxacin 400 mg, moxifloxacin 800 mg or ethambutol 750 mg for 2 weeks compared with standard therapy. Sixty patients were randomised and the investigators reported a reduction in mortality from 65% to 35% in the intensive treatment group.8 The results from this combined clinical and pharmacological study could be of huge importance in reducing the mortality in TBM. The results of an ongoing large randomised clinical trial of high dose rifampicin 15 mg/kg/day and levofloxacin 20 mg/kg/day in 750 patients is eagerly awaited (ISRCTN61649292).9 Adjunctive corticosteroids (dexamethasone) are recommended for all patients with TBM regardless of the severity of

2013. Produced by BMJ Publishing Group Ltd under licence.

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Editorial disease. Corticosteroids are believed to reduce the intracranial inflammatory response leading to improved outcome, and two pivotal trials in Vietnamese adults and in South African children showed that it saves lives.4 10 In HIV-infected adults with TBM, dexamethasone has not been demonstrated to reduce the risk of death. However, it is recommended that they are used as there is a non-significant trend for a reduction in mortality rates and no evidence of an increase in adverse events with corticosteroid. In HIV-positive ARV naïve patients, concurrent management of the HIV infection and TB is a huge challenge due to pharmacological interactions between the HIV and the TB drugs and the potential for worsening of the clinical status caused by an Immune Reconstitution Syndrome. There is no evidence supporting the immediate initiation of ARV in patients presenting with TBM. A trial in HIV co-infected patients with pulmonary TB demonstrates that starting ART 2 weeks after starting TB treatment improves survival, comparing with starting after 8 weeks.11 However, the evidence in TBM found that immediate ARV treatment did not improve the outcome but was associated with increase in severe adverse events,12 and starting ARV tends to be deferred until the TB treatment has been initiated and the patients are stable on their TB drugs. The optimal time for initiation of ARV has not been defined, and there are different recommendations between international guidelines on when to start ARV in patients with TBM.

FUTURE RESEARCH+CHALLENGES There is an urgent need to develop and implement sensitive and specific diagnostic tests that can improve the early diagnosis of TBM. The GenXpert MTB/RIF (Cepheid, Sunnyvale, USA) has recently been assessed and introduced in many parts of the world. It is a rapid test for detecting Mycobacterium tuberculosis and rifampicin resistance, and is the first diagnostic test to have been endorsed by the WHO. This is a very promising test for early TB diagnosis and can produce results in approximately 2 h, compared with approximately 2 months for culture by traditional methods. However, this method is currently recommended by WHO for sputum samples, and not yet for extrapulmonary specimens. If this test can be proven to work in TBM it could revolutionise the management of TBM. This is an absolute priority. The other priorities for the future are continued education of clinicians to encourage earlier consideration of a diagnosis of TBM, improving near bedside diagnostics and faster laboratory 2

confirmation of resistance patterns, and the clinical trials involving the reassessing of existing treatment regimens and development of new anti-TB drugs with improved penetration into CSF. The BCG vaccine was demonstrated to protect against TBM, particularly in children, and has been used widely for more than 50 years.13 BCG is the only licensed vaccine for TB and remains in use globally although it is an imperfect vaccine. There is an urgent need for an effective and affordable vaccine, which can be used in all patients including children and adults and in those individuals who are immunocompromised. In the last decade, there has been development of many new vaccine candidates aimed at preventing active TB or even to one day eradicating M tuberculosis infection. In 2012, 12 potential TB vaccines were in clinical trials. This is a potentially wonderful pipeline however the great challenges faced by vaccine developers was highlighted with the recent results from a Phase II trial in South Africa.14 Even in the most optimistic scenario, a new vaccine is unlikely to be available and implemented before 2020.15 In the meantime, enhanced case detection through enhanced screening, improved diagnostics and better treatment remain our most potent weapons against TB, including TBM.

Provenance and peer review Commissioned; externally peer reviewed. To cite Van TTT, Farrar J. J Epidemiol Community Health Published Online First: [ please include Day Month Year] doi:10.1136/jech-2013-202525 Received 18 February 2013 Revised 9 October 2013 Accepted 9 October 2013 J Epidemiol Community Health 2013;0:1–2. doi:10.1136/jech-2013-202525

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CONCLUSION TB meningitis is an ancient scourge, which remains a major public health challenge in the 21st century. Diagnostics has remained largely unchanged for 100 years and treatment is based on extrapolations from pulmonary TB drugs assessed in studies almost 50 years ago. Saving lives and reducing disability in patients with TBM requires continued education of clinicians to consider the diagnosis earlier, enhancing diagnostics and improving treatment. We can make a real difference today by implementing what we already know. Further improvements will depend on challenging existing dogma on treatment and development of new drugs with greater activity against MTB and better penetration into the CSF. We are in an extraordinary scientific age with new technologies opening up exciting possibilities for saving lives. TB remains of the great global challenges. We need to ensure we move these advances into the clinic as quickly as possible, establish an evidence base for their utility and do not allow unnecessary regulations to delay their assessment and implementation. Contributors JF had the idea, TTTV wrote the first draft, both authors contributed to the editing. Competing interests None.

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Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013;380:2095–128. WHO. Global tuberculosis control: WHO report 2011. 2011. Murray CJ, Vos T, Lozano R, et al. Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet 2013;380:2197–223. Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med 2004;351:1741–51. Thwaites GE, Duc Bang N, Huy et al. The influence of HIV infection on clinical presentation, response to treatment, and outcome in adults with Tuberculous meningitis. J Infect Dis 2005;192:2134–41. WHO. Treatment of tuberculosis guidelines. 4th edn. World Health Organization, 2010. Thwaites G, Fisher M, Hemingway C, et al. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children. J Infect 2009;59:167–87. Ruslami R, Ganiem AR, Dian S, et al. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013;13:27–35. Heemskerk D, Day J, Chau TT, et al. Intensified treatment with high dose rifampicin and levofloxacin compared to standard treatment for adult patients with tuberculous meningitis (TBM-IT): protocol for a randomized controlled trial. Trials 2011;12:25. Schoeman JF, Van Zyl LE, Laubscher JA, et al. Effect of corticosteroids on intracranial pressure, computed tomographic findings, and clinical outcome in young children with tuberculous meningitis. Pediatrics 1997;99:226–31. Blanc FX, Sok T, Laureillard D, et al. Earlier versus later start of antiretroviral therapy in HIV-infected adults with tuberculosis. N Engl J Med 2011;365:1471–81. Torok ME, Yen NT, Chau TT, et al. Timing of initiation of antiretroviral therapy in human immunodeficiency virus (HIV)—associated tuberculous meningitis. Clin Infect Dis 2011;52:1374–83. Hart PD, Sutherland I. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Br Med J 1977;2:293–5. Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet 2013;381:1021–8. Kaufmann SH. Fact and fiction in tuberculosis vaccine research: 10 years later. Lancet Infect Dis 2011;11:633–40.

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Tuberculous meningitis.

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