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- ItemKnowledge gaps and research priorities in tuberculous meningitis(Wellcome Open Research, 2019-11-28) Seddon, James A.; Wilkinson, Robert; Van Crevel, Reinout; Figaji, Anthony; Thwaites, Guy E.; Tuberculous Meningitis International Research ConsortiumENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most severe and disabling form of tuberculosis (TB), accounting for around 1-5% of the global TB caseload, with mortality of approximately 20% in children and up to 60% in persons co-infected with human immunodeficiency virus even in those treated. Relatively few centres of excellence in TBM research exist and the field would therefore benefit from greater co-ordination, advocacy, collaboration and early data sharing. To this end, in 2009, 2015 and 2019 we convened the TBM International Research Consortium, bringing together approximately 50 researchers from five continents. The most recent meeting took place on 1 st and 2 nd March 2019 in Lucknow, India. During the meeting, researchers and clinicians presented updates in their areas of expertise, and additionally presented on the knowledge gaps and research priorities in that field. Discussion during the meeting was followed by the development, by a core writing group, of a synthesis of knowledge gaps and research priorities within seven domains, namely epidemiology, pathogenesis, diagnosis, antimicrobial therapy, host-directed therapy, critical care and implementation science. These were circulated to the whole consortium for written input and feedback. Further cycles of discussion between the writing group took place to arrive at a consensus series of priorities. This article summarises the consensus reached by the consortium concerning the unmet needs and priorities for future research for this neglected and often fatal disease.
- ItemDecision-making in the diagnosis of tuberculous meningitis(Wellcome Open Research, 2020-01-23) Boyles, Tom H.; Lynen, Lutgarde; Seddon, James A.; Tuberculous Meningitis International Research ConsortiumENGLISH ABSTRACT: Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) but diagnosis is difficult and delays in initiating therapy increase mortality. All currently available tests are imperfect; culture of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) is considered the most accurate test but is often negative, even when disease is present, and takes too long to be useful for immediate decision making. Rapid tests that are frequently used are conventional Ziehl-Neelsen staining and nucleic acid amplification tests such as Xpert MTB/RIF and Xpert MTB/RIF Ultra. While positive results will often confirm the diagnosis, negative tests frequently provide insufficient evidence to withhold therapy. The conventional diagnostic approach is to determine the probability of TBM using experience and intuition, based on prevalence of TB, history, examination, analysis of basic blood and CSF parameters, imaging, and rapid test results. Treatment decisions may therefore be both variable and inaccurate, depend on the experience of the clinician, and requests for tests may be inappropriate. In this article we discuss the use of Bayes' theorem and the threshold model of decision making as ways to improve testing and treatment decisions in TBM. Bayes' theorem describes the process of converting the pre-test probability of disease to the post-test probability based on test results and the threshold model guides clinicians to make rational test and treatment decisions. We discuss the advantages and limitations of using these methods and suggest that new diagnostic strategies should ultimately be tested in randomised trials.
- ItemTuberculous meningitis : new tools and new approaches required [version 1; peer review: not peer reviewed](F1000Research, 2019) Seddon, James A.; Thwaites, Guy E.; Tuberculous Meningitis International Research ConsortiumENGLISH ABSTRACT: Tuberculous meningitis is the most severe form of tuberculosis and causes widespread mortality and morbidity. Understanding of the epidemiology and pathogenesis is incomplete, and the optimal diagnosis and treatment are poorly defined. To generate research collaboration and coordination, as well as to promote sharing of ideas and advocacy efforts, the International Tuberculous Meningitis Research Consortium was formed in 2009. During the most recent meeting of this group in Lucknow, India, in March 2019, the Consortium decided to bring together key articles on tuberculous meningitis in one supplement. The supplement covers recent scientific updates, expert perspectives on specific clinical challenges, consensus statements on how to conduct research, and a set of priorities for future investigation.
- ItemThe current global situation for tuberculous meningitis : epidemiology, diagnostics, treatment and outcomes [version 1; peer review: 2 approved](F1000Research, 2019) Seddon, James A.; Tugume, Lillian; Solomons, Regan; Prasad, Kameshwar; Bahr, Nathan C.ENGLISH ABSTRACT: Tuberculous meningitis (TBM) results from dissemination of M. tuberculosis to the cerebrospinal fluid (CSF) and meninges. Ischaemia, hydrocephalus and raised intracranial pressure frequently result, leading to extensive brain injury and neurodisability. The global burden of TBM is unclear and it is likely that many cases are undiagnosed, with many treated cases unreported. Untreated, TBM is uniformly fatal, and even if treated, mortality and morbidity are high. Young age and human immunodeficiency virus (HIV) infection are potent risk factors for TBM, while Bacillus Calmette–Guérin (BCG) vaccination is protective, particularly in young children. Diagnosis of TBM usually relies on characteristic clinical symptoms and signs, together with consistent neuroimaging and CSF parameters. The ability to confirm the TBM diagnosis via CSF isolation of M. tuberculosis depends on the type of diagnostic tests available. In most cases, the diagnosis remains unconfirmed. GeneXpert MTB/RIF and the next generation Xpert Ultra offer improved sensitivity and rapid turnaround times, and while roll-out has scaled up, availability remains limited. Many locations rely only on acid fast bacilli smear, which is insensitive. Treatment regimens for TBM are based on evidence for pulmonary tuberculosis treatment, with little consideration to CSF penetration or mode of drug action required. The World Health Organization recommends a 12-month treatment course, although data on which to base this duration is lacking. New treatment regimens and drug dosages are under evaluation, with much higher dosages of rifampicin and the inclusion of fluoroquinolones and linezolid identified as promising innovations. The inclusion of corticosteroids at the start of treatment has been demonstrated to reduce mortality in HIV-negative individuals but whether they are universally beneficial is unclear. Other host-directed therapies show promise but evidence for widespread use is lacking. Finally, the management of TBM within health systems is sub-optimal, with drop-offs at every stage in the care cascade.
- ItemRenal dysfunction by baseline CD4 cell count in a cohort of adults starting antiretroviral treatment regardless of CD4 count in the HIV Prevention Trials Network 071 [HPTN 071; Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART)] study in South Africa(Wiley, 2019) Bock, P.; Nel, K.; Fatti, G.; Sloot, R.; Ford, N.; Voget, J.; Gunst, C.; Grobbelaar, N.; Louis, F.; Floyd, S.; Hayes, R.; Ayles, H.; Beyers, N.; Fidler, S.Objectives: Renal dysfunction is a significant cause of morbidity and mortality among HIV-positive individuals. This study evaluated renal dysfunction in a cohort of adults who started antiretroviral treatment (ART) regardless of CD4 count at three Department of Health (DOH) clinics included in the HIV Prevention Trials Network 071 (HPTN 071) Population Effect of Antiretroviral Therapy to Reduce HIV Transmission (PopART) trial. Methods: A retrospective cohort analysis of routine data for HIV-positive individuals starting ART between January 2014 and November 2015 was completed. Incident renal dysfunction was defined as an estimated glomerular filtration rate (eEGFR) < 60 mL/min after ART initiation among individuals with a baseline (pre-ART) eGFR ≥ 60 mL/min. Results: Overall, 2423 individuals, with a median baseline CD4 count of 328 cells/μL [interquartile range (IQR) 195–468 cells/μL], were included in the analysis. Forty-seven individuals had a baseline eGFR < 60 mL/min. Among 1634 nonpregnant individuals started on a tenofovir-containing ART regimen and with a baseline eGFR ≥ 60 mL/min, 27 developed an eGFR < 60 mL/min on ART. Regression analysis showed lower odds of baseline eGFR < 60 mL/min at baseline CD4 counts of > 500 cells/μL [adjusted odds ratio (aOR) 0.29; 95% confidence interval (CI) 0.11–0.80], 351–500 cells/μL (aOR 0.22; 95% CI 0.08–0.59) and 201–350 (aOR 0.48; 95% CI: 0.24–0.97) compared with baseline CD4 counts < 200 cells/μL. Conclusions: This study showed low rates of renal dysfunction at baseline and on ART, with lower rates of baseline renal dysfunction among individuals with baseline CD4 counts > 200 cells/μL. Strategies that use baseline characteristics, such as age, to identify individuals at high risk of renal dysfunction on ART for enhanced eGFR monitoring may be effective and should be the subject of future research.