Determinants of treatment-related paradoxical reactions during anti-tuberculosis therapy: a case control study

BACKGROUND: Inflammatory response following initial improvement with anti-tuberculosis (TB) treatment has been termed a paradoxical reaction (PR). HIV co-infection is a recognised risk, yet little is known about other predictors of PR, although some biochemical markers have appeared predictive. We report our findings in an ethnically diverse population of HIV-infected and uninfected adults. METHODS: Prospective and retrospective clinical and laboratory data were collected on TB patients seen between January 1999-December 2008 at four UK centres selected to represent a wide ethnic and socio-economic mix of TB patients. Data on ethnicity and HIV status were obtained for all individuals. The associations between other potential risk factors and PR were assessed in a nested case-control study. All PR cases were matched two-to-one to controls by calendar time and centre. RESULTS: Of 1817 TB patients, 82 (4.5 %, 95 % CI 3.6-5.5 %) were identified as having a PR event. The frequency of PR was 14.4 % (18/125; 95 % CI 8.2-20.6 %) and 3.8 % (64/1692; 2.9-4.7) for HIV-positive and HIV-negative individuals respectively. There were no differences observed in PR frequency according to ethnicity, although the site was more likely to be pulmonary in those of black and white ethnicity, and lymph node disease in those of Asian ethnicity. In multivariate analysis of the case-control cohort, HIV-positive patients had five times the odds of developing PR (aOR = 5.05; 95 % CI 1.28-19.85, p = 0.028), whilst other immunosuppression e.g. diabetes, significantly reduced the odds of PR (aOR = 0.01; 0.00-0.27, p = 0.002). Patients with positive TB culture had higher odds of developing PR (aOR = 6.87; 1.31-36.04, p = 0.045) compared to those with a negative culture or those in whom no material was sent for culture. Peripheral lymph node disease increased the odds of a PR over 60-fold 4(9.60-431.25, p < 0.001). CONCLUSION: HIV was strongly associated with PR. The increased potential for PR in people with culture positive TB suggests that host mycobacterial burden might be relevant. The increased risk with TB lymphadenitis may in part arise from the visibility of clinical signs at this site. Non-HIV immunosuppression may have a protective effect. This study highlights the difficulties in predicting PR using routinely available demographic details, clinical symptoms or biochemical markers

Coupling of CFD and semiempirical methods for designing three-phase condensate separator: case study and experimental validation

This study presents an approach to determine the dimensions of three-phase separators. First, we designed different vessel configurations based on the fluid properties of an Iranian gas condensate field. We then used a comprehensive computational fluid dynamic (CFD) method for analyzing the three-phase separation phenomena. For simulation purposes, the combined volume of fluid–discrete particle method (DPM) approach was used. The discrete random walk (DRW) model was used to include the effect of arbitrary particle movement due to variations caused by turbulence. In addition, the comparison of experimental and simulated results was generated using different turbulence models, i.e., standard k–ε, standard k–ω, and Reynolds stress model. The results of numerical calculations in terms of fluid profiles, separation performance and DPM particle behavior were used to choose the optimum vessel configuration. No difference between the dimensions of the optimum vessel and the existing separator was found. Also, simulation data were compared with experimental data pertaining to a similar existing separator. A reasonable agreement between the results of numerical calculation and experimental data was observed. These results showed that the used CFD model is well capable of investigating the performance of a three-phase separator

Fluoroquinolones and isoniazid-resistant tuberculosis: implications for the 2018 WHO guidance.

INTRODUCTION: 2018 World Health Organization (WHO) guidelines for the treatment of isoniazid (H)-resistant (Hr) tuberculosis recommend a four-drug regimen: rifampicin (R), ethambutol (E), pyrazinamide (Z) and levofloxacin (Lfx), with or without H ([H]RZE-Lfx). This is used once Hr is known, such that patients complete 6 months of Lfx (≥6[H]RZE-6Lfx). This cohort study assessed the impact of fluoroquinolones (Fq) on treatment effectiveness, accounting for Hr mutations and degree of phenotypic resistance. METHODS: This was a retrospective cohort study of 626 Hr tuberculosis patients notified in London, 2009-2013. Regimens were described and logistic regression undertaken of the association between regimen and negative regimen-specific outcomes (broadly, death due to tuberculosis, treatment failure or disease recurrence). RESULTS: Of 594 individuals with regimen information, 330 (55.6%) were treated with (H)RfZE (Rf=rifamycins) and 211 (35.5%) with (H)RfZE-Fq. The median overall treatment period was 11.9 months and median Z duration 2.1 months. In a univariable logistic regression model comparing (H)RfZE with and without Fqs, there was no difference in the odds of a negative regimen-specific outcome (baseline (H)RfZE, cluster-specific odds ratio 1.05 (95% CI 0.60-1.82), p=0.87; cluster NHS trust). Results varied minimally in a multivariable model. This odds ratio dropped (0.57, 95% CI 0.14-2.28) when Hr genotype was included, but this analysis lacked power (p=0.42). CONCLUSIONS: In a high-income setting, we found a 12-month (H)RfZE regimen with a short Z duration to be similarly effective for Hr tuberculosis with or without a Fq. This regimen may result in fewer adverse events than the WHO recommendations

Current use and acceptability of novel diagnostic tests for active tuberculosis: a worldwide survey

Objective: To determine the current use and potential acceptance (by tuberculosis experts worldwide) of novel rapid tests for the diagnosis of tuberculosis that are in line with World Health Organization target product profiles. Methods: A multilingual survey was disseminated online between July and November of 2016. Results: A total of 723 individuals from 114 countries responded to the survey. Smear microscopy was the most commonly used rapid tuberculosis test (available to 90.9% of the respondents), followed by molecular assays (available to 70.7%). Only a small proportion of the respondents in middle-and low-income countries had access to interferon-gamma-release assays. Serological and lateral flow immunoassays were used by more than a quarter (25.4%) of the respondents. Among the respondents who had access to molecular tests, 46.7% were using the Xpert assay overall, that proportion being higher in lower middle-income countries (55.6%) and low-income countries (76.6%). The data also suggest that there was some alignment of pricing for molecular assays. Respondents stated they would accept novel rapid tuberculosis tests if available, including molecular assays (acceptable to 86.0%) or biomarker-based serological assays (acceptable to 81.7%). Simple biomarker-based assays were more commonly deemed acceptable in middle-and lowincome countries. Conclusions: Second-generation molecular assays have become more widely available in high-and low-resource settings. However, the development of novel rapid tuberculosis tests continues to be considered important by tuberculosis experts. Our data also underscore the need for additional training and education of end users

Screening for latent TB, HIV, and hepatitis B/C in new migrants in a high prevalence area of London, UK: a cross-sectional study.

BACKGROUND: Rising rates of infectious diseases in international migrants has reignited the debate around screening. There have been calls to strengthen primary-care-based programmes, focusing on latent TB. We did a cross-sectional study of new migrants to test an innovative one-stop blood test approach to detect multiple infections at one appointment (HIV, latent tuberculosis, and hepatitis B/C) on registration with a General Practitioner (GP) in primary care. METHODS: The study was done across two GP practices attached to hospital Accident and Emergency Departments (A&E) in a high migrant area of London for 6 months. Inclusion criteria were foreign-born individuals from a high TB prevalence country (>40 cases per 100,000) who have lived in the UK ≤ 10 years, and were over 18 years of age. All new migrants who attended a New Patient Health Check were screened for eligibility and offered the blood test. We followed routine care pathways for follow-up. RESULTS: There were 1235 new registrations in 6 months. 453 attended their New Patient Health Check, of which 47 (10.4%) were identified as new migrants (age 32.11 years [range 18-72]; 22 different nationalities; time in UK 2.28 years [0-10]). 36 (76.6%) participated in the study. The intervention only increased the prevalence of diagnosed latent TB (18.18% [95% CI 6.98-35.46]; 181.8 cases per 1000). Ultimately 0 (0%) of 6 patients with latent TB went on to complete treatment (3 did not attend referral). No cases of HIV or hepatitis B/C were found. Foreign-born patients were under-represented at these practices in relation to 2011 Census data (Chi-square test -0.111 [95% CI -0.125 to -0.097]; p < 0.001). CONCLUSION: The one-stop approach was feasible in this context and acceptability was high. However, the number of presenting migrants was surprisingly low, reflecting the barriers to care that this group face on arrival, and none ultimately received treatment. The ongoing UK debate around immigration checks and charging in primary care for new migrants can only have negative implications for the promotion of screening in this group. Until GP registration is more actively promoted in new migrants, a better place to test this one-stop approach could be in A&E departments where migrants may present in larger numbers

Ethnic Variation in Inflammatory Profile in Tuberculosis

PMCID: PMC3701709This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

Control of tuberculosis in large cities in developed countries: an organizational problem

Tuberculosis (TB) is still a serious public health issue, even in large cities in developed countries. Control of this old disease is based on complicated programs that require completion of long treatments and contact tracing. In an accompanying research article published in BMC Public Health, Bothamley and colleagues found that areas with a ratio lower than one nurse per forty notifications had increased rates with respect to TB notifications, smear-positive cases, loss to follow-up and treatment abandonment across the UK. Furthermore, in these areas there was less opportunity for directly observed therapy, assistance with complex needs, educational outreach and new-entrant screening. In this commentary, we discuss the importance of improving organizational aspects and evaluating TB control programs. According to Bothamley and colleagues, a ratio of one nurse per forty notifications is an effective method of reducing the high TB incidences observed in London and in other cities in developed countries, or to maintain the decline in incidence in cities with lower incidences. It is crucial to evaluate TB programs every year to detect gaps early

Vitamin D accelerates resolution of inflammatory responses during tuberculosis treatment

Calcidiol, the major circulating metabolite of vitamin D, supports induction of pleiotropic antimicrobial responses in vitro. Vitamin D supplementation elevates circulating calcidiol concentrations, and thus has a potential role in the prevention and treatment of infection. The immunomodulatory effects of administering vitamin D to humans with an infectious disease have not previously been reported. To characterize these effects, we conducted a detailed longitudinal study of circulating and antigen-stimulated immune responses in ninety-five patients receiving antimicrobial therapy for pulmonary tuberculosis who were randomized to receive adjunctive high-dose vitamin D or placebo in a clinical trial, and who fulfilled criteria for per-protocol analysis. Vitamin D supplementation accelerated sputum smear conversion and enhanced treatment-induced resolution of lymphopaenia, monocytosis, hypercytokinaemia, and hyperchemokinaemia. Administration of vitamin D also suppressed antigen-stimulated proinflammatory cytokine responses, but attenuated the suppressive effect of antimicrobial therapy on antigen-stimulated secretion of IL-4, CC chemokine ligand 5, and IFN-α. We demonstrate a previously unappreciated role for vitamin D supplementation in accelerating resolution of inflammatory responses during tuberculosis treatment. Our findings suggest a potential role for adjunctive vitamin D supplementation in the treatment of pulmonary infections to accelerate resolution of inflammatory responses associated with increased risk of mortality

Two interferon gamma release assays for predicting active tuberculosis: the UK PREDICT TB prognostic test study

National Institute for Health Research (NIHR