Distinct phylogenetic lineages of Mycobacterium tuberculosis (MTB) cause disease in patients of particular genetic ancestry, and elicit different patterns of cytokine and chemokine secretion when ...cultured with human macrophages in vitro. Circulating and antigen-stimulated concentrations of these inflammatory mediators might therefore be expected to vary significantly between tuberculosis patients of different ethnic origin. Studies to characterise such variation, and to determine whether it relates to host or bacillary factors, have not been conducted. We therefore compared circulating and antigen-stimulated concentrations of 43 inflammatory mediators and 14 haematological parameters (inflammatory profile) in 45 pulmonary tuberculosis patients of African ancestry vs. 83 patients of Eurasian ancestry in London, UK, and investigated the influence of bacillary and host genotype on these profiles. Despite having similar demographic and clinical characteristics, patients of differing ancestry exhibited distinct inflammatory profiles at presentation: those of African ancestry had lower neutrophil counts, lower serum concentrations of CCL2, CCL11 and vitamin D binding protein (DBP) but higher serum CCL5 concentrations and higher antigen-stimulated IL-1 receptor antagonist and IL-12 secretion. These differences associated with ethnic variation in host DBP genotype, but not with ethnic variation in MTB strain. Ethnic differences in inflammatory profile became more marked following initiation of antimicrobial therapy, and immunological correlates of speed of elimination of MTB from the sputum differed between patients of African vs. Eurasian ancestry. Our study demonstrates a hitherto unappreciated degree of ethnic heterogeneity in inflammatory profile in tuberculosis patients that associates primarily with ethnic variation in host, rather than bacillary, genotype. Candidate immunodiagnostics and immunological biomarkers of response to antimicrobial therapy should be derived and validated in tuberculosis patients of different ethnic origin.
Abstract
Background
An effective tuberculosis (TB) vaccine is urgently needed to support the End TB Strategy to reduce the number of new TB cases by 80% by 2030. M72/AS01E candidate vaccine is an ...adjuvanted recombinant fusion protein derived from Mycobacterium tuberculosis Mtb32A and Mtb39A proteins.
Methods
We conducted a randomized, double-blind, placebo-controlled phase 2b trial (NCT01755598) in Southern and Eastern Africa to assess M72/AS01E’s efficacy against bacteriologically confirmed pulmonary TB disease in HIV-seronegative (HIV–) adults aged 18–50 years infected with Mtb (defined by a positive IFN-γ release assay). Participants were randomized 1:1 to receive M72/AS01E or placebo at day D0 and D30. Reactogenicity, safety, immunogenicity were assessed, and incident TB disease measured from D30 postdose 2 up to ≥24 months for this analysis (follow-up ongoing up to 37 months). Efficacy against various TB disease case definitions (Figure 1) was estimated. Primary objective: efficacy against culture- or PCR-confirmed pulmonary TB disease in HIV– adults (case definition 1; success criterion: lower limit of 90% 2-sided CI >0%, power: 80%).
Results
Demographic characteristics were similar between M72/AS01E (1786) and placebo (1787) recipients. Efficacy against pulmonary TB disease case definition 1 was 54.0% (90% CI: 13.9, 75.4; P = 0.042); efficacy against other case definitions and a sensitivity analysis are shown in Figure 1. Leading solicited symptoms were pain, fatigue, and headache (Figure 2). In all recipients, unsolicited symptoms (D0–29) were more frequent after M72/AS01E (67.4%) than placebo (45.4%), mainly attributable to increased injection site reactions and flu-like symptoms. Serious adverse events (D0–month 7) incidences were similar between groups (M72/AS01E: 1.6%; placebo: 1.8%). During the study, 24 adults died (14 due to traumatic events); all deaths were unrelated to the trial.
Conclusion
M72/AS01E presents a clinically acceptable safety profile and significantly reduces bacteriologically confirmed pulmonary TB disease incidence in HIV– adults with latent Mtb infection.
Funding. BMGF; Aeras; DFID UK; DGIS; AusAID; GlaxoSmithKline Biologicals SA.
Disclosures
O. Van Der Meeren, GSK: Employee and Shareholder, Salary. M. Hatherill, Aeras: Investigator, Research grant. R. J. Wilkinson, GSK: Grant Investigator, indirect funding. H. M. Ayles, GSK: Grant Investigator, Research grant. G. Henostroza, Aeras: Investigator, Grant recipient. M. A. Demoitié, GSK: owns stocks and is named inventor on patent applications relating to certain uses of M72/AS01E, Salary. T. Singh, GSK: Employee and Shareholder, Salary. E. J. Akite, GSK: Employee, Salary. A. K. Azam, GSK: Employee, Salary. A. Bollaerts, GSK: Employee, Salary. A. M. Ginsberg, GSK: Collaborator, Research support. BMGF: Grant Investigator, Grant recipient. UK DFID: Grant Investigator, Grant recipient. P. Gillard, GSK: Employee and Shareholder, Salary and stock. D. R. Tait, Aeras: Employee, Salary. GSK: Shareholder, Salary.
The assessment and management of tuberculous meningitis (TBM) is often complex, yet no standardised approach exists, and evidence for the clinical care of patients, including those with critical ...illness, is limited. The roles of proformas and checklists are increasing in medicine; proformas provide a framework for a thorough approach to patient care, whereas checklists offer a priority-based approach that may be applied to deteriorating patients in time-critical situations.
We aimed to develop a comprehensive assessment proforma and an accompanying ‘priorities’ checklist for patients with TBM, with the overriding goal being to improve patient outcomes. The proforma outlines what should be asked, checked, or tested at initial evaluation and daily inpatient review to assist supportive clinical care for patients, with an adapted list for patients in critical care. It is accompanied by a supporting document describing why these points are relevant to TBM. Our priorities checklist offers a useful and easy reminder of important issues to review during a time-critical period of acute patient deterioration. The benefit of these documents to patient outcomes would require investigation; however, we hope they will promote standardisation of patient assessment and care, particularly of critically unwell individuals, in whom morbidity and mortality remains unacceptably high.
Tuberculous intracranial mass lesions are common in settings with high tuberculosis (TB) incidence and HIV prevalence. The diagnosis of such lesions, which include tuberculoma and tuberculous ...abscesses, is often presumptive and based on radiological features, supportive evidence of TB elsewhere and response to TB treatment. However, the treatment response is unpredictable, with lesions frequently enlarging paradoxically or persisting for many years despite appropriate TB treatment and corticosteroid therapy. Most international guidelines recommend a 9-12 month course of TB treatment for central nervous system TB when the infecting
Mycobacterium tuberculosis
(
M.tb
) strain is sensitive to first-line drugs. However, there is variation in opinion and practice with respect to the duration of TB treatment in patients with tuberculomas or tuberculous abscesses. A major reason for this is the lack of prospective clinical trial evidence. Some experts suggest continuing treatment until radiological resolution of enhancing lesions has been achieved, but this may unnecessarily expose patients to prolonged periods of potentially toxic drugs. It is currently unknown whether persistent radiological enhancement of intracranial tuberculomas after 9-12 months of treatment represents active disease, inflammatory response in a sterilized lesion or merely revascularization. The consequences of stopping TB treatment prior to resolution of lesional enhancement have rarely been explored. These important issues were discussed at the 3
rd
International Tuberculous Meningitis Consortium meeting. Most clinicians were of the opinion that continued enhancement does not necessarily represent treatment failure and that prolonged TB therapy was not warranted in patients presumably infected with
M.tb
strains susceptible to first-line drugs. In this manuscript we highlight current medical treatment practices, benefits and disadvantages of different TB treatment durations and the need for evidence-based guidelines regarding the treatment duration of patients with intracranial tuberculous mass lesions.
Hyponatremia is the commonest electrolyte abnormality in hospitalized patients and is associated with poor outcome. Hyponatremia is categorized on the basis of serum sodium into severe (< 120 mEq/L), ...moderate (120-129 mEq/L) and mild (130-134mEq/L) groups. Serum sodium has an important role in maintaining serum osmolality, which is maintained by the action of antidiuretic hormone (ADH) secreted from the posterior pituitary, and natriuretic peptides such as atrial natriuretic peptide and brain natriuretic peptide. These peptides act on kidney tubules via the renin angiotensin aldosterone system. Hyponatremia <120mEq/L or a rapid decline in serum sodium can result in neurological manifestations, ranging from confusion to coma and seizure. Cerebral salt wasting (CSW) and syndrome of inappropriate secretion of ADH (SIADH) are important causes of hyponatremia in tuberculosis meningitis (TBM). CSW is more common than SIADH. The differentiation between CSW and SIADH is important because treatment of one may be detrimental for the other; evidence of hypovolemia in CSW and euvolemia or hypervolemia in SIADH is used for differentiation. In addition, evidence of dehydration, polyuria, negative fluid balance as assessed by intake output chart, weight loss, laboratory evidence and sometimes central venous pressure are helpful in the diagnosis of these disorders. Volume contraction in CSW may be more protracted than hyponatremia and may contribute to border zone infarctions in TBM. Hyponatremia should be promptly and carefully treated by saline and oral salt, while 3% saline should be used in severe hyponatremia with coma and seizure. In refractory patients with hyponatremia, fludrocortisone helps in early normalization of serum sodium without affecting polyuria or functional outcome. In SIADH, V2 receptor antagonist conivaptan or tolvaptan may be used if the patient is not responding to fluid restriction. Fluid restriction in SIADH has not been found to be beneficial in TBM and should be avoided.
There is a growing interest in the use of
F-FDG PET-CT to monitor tuberculosis (TB) treatment response. However, TB causes complex and widespread pathology, which is challenging to segment and ...quantify in a reproducible manner. To address this, we developed a technique to standardise uptake (Z-score), segment and quantify tuberculous lung lesions on PET and CT concurrently, in order to track changes over time. We used open source tools and created a MATLAB script. The technique was optimised on a training set of five pulmonary tuberculosis (PTB) cases after standard TB therapy and 15 control patients with lesion-free lungs.
We compared the proposed method to a fixed threshold (SUV > 1) and manual segmentation by two readers and piloted the technique successfully on scans of five control patients and five PTB cases (four cured and one failed treatment case), at diagnosis and after 1 and 6 months of treatment. There was a better correlation between the Z-score-based segmentation and manual segmentation than SUV > 1 and manual segmentation in terms of overall spatial overlap (measured in Dice similarity coefficient) and specificity (1 minus false positive volume fraction). However, SUV > 1 segmentation appeared more sensitive. Both the Z-score and SUV > 1 showed very low variability when measuring change over time. In addition, total glycolytic activity, calculated using segmentation by Z-score and lesion-to-background ratio, correlated well with traditional total glycolytic activity calculations. The technique quantified various PET and CT parameters, including the total glycolytic activity index, metabolic lesion volume, lesion volumes at different CT densities and combined PET and CT parameters. The quantified metrics showed a marked decrease in the cured cases, with changes already apparent at month one, but remained largely unchanged in the failed treatment case.
Our technique is promising to segment and quantify the lung scans of pulmonary tuberculosis patients in a semi-automatic manner, appropriate for measuring treatment response. Further validation is required in larger cohorts.
One third of the world's population is estimated to be infected with Mycobacterium tuberculosis, representing a huge reservoir of potential tuberculosis (TB) disease. Risk of progression to active TB ...is highest in those with HIV coinfection. However, the nature of the host-pathogen relationship in those with "latent TB infection" and how this is affected by HIV coinfection are poorly understood. The traditional paradigm that distinguishes latent infection from active TB as distinct compartmentalised states is overly simplistic. Instead the host-pathogen relationship in "latent TB infection" is likely to represent a spectrum of immune responses, mycobacterial metabolic activity, and bacillary numbers. We propose that the impact of HIV infection might better be conceptualised as a shift of the spectrum towards poor immune control, higher mycobacterial metabolic activity, and greater organism load, with subsequent increased risk of progression to active disease. Here we discuss the evidence for such a model and the implications for interventions to control the HIV-associated TB epidemic.
PDF
