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BackgroundDrug resistant TB is a growing concern with 11.6% of laboratory confirmed cases being resistant to at least one first-line drug in England. Currently whole genome sequencing (WGS) still requires a positive culture before providing drug susceptibilities hence potentially introducing a delay of weeks. Xpert MTB/XDR (Cepheid, USA) is a rapid PCR test for identification of drug resistant TB including resistance to INH, fluoroquinolones, ethionamide and 2nd line injectables. This may provide an initial rapid result pending WGS to allow initiation of DR or MDR regimes.AimsTo establish the limit of detection (LoD) of Xpert MTB/XDR using frozen MTB cultures with known resistance patterns.MethodsThis retrospective study in London used resistant clinical MTB cultures which were sub-cultured in 7H9 media and incubated for 7 days. 500µl of the culture positive broth for each strain was tested using Xpert MTB/XDR following the Cepheid GeneXpert SOP. Resistance patterns for each stain were compared to the genotypic susceptibilities using PhyRes SE, an online software for WGS analysis.Five strains were used to establish the LoD on Xpert MTB/XDR by performing seven ten-fold serial dilutions from 0.5 McFarland measured on a densitometer to a dilution of 107.ResultsFourteen clinical strains were verified on Xpert MTB/XDR and the same resistance patterns were correctly identified in 13 stains (93%) when compared to WGS. A discrepant result was found with fluoroquinolone resistance where low detection was identified on Xpert MTB/XDR but not on WGS. All INH resistance were correctly identified. The LoD across 5 strains using Xpert MTB/XDR varied between a four-fold (104) to six-fold (106) dilutions. Fluoroquinolone sensitivity patterns were an issue from a dilution of 104 onwards with results reading ‘indeterminate’ or ‘low detected’ (figure 1).Abstract S84 Figure 1Xpert MTB/XDR results for MTB detection and drug resistance patterns for 5 drug resistant strains with seven serial ten-fold dilutionsConclusionsXpert MTB/XDR could be used as a tool to rapidly identify TB and drug susceptibilities. It identified all INH resistant cases and may be useful in PCR positive samples awaiting culture and WGS, allowing for the appropriate WHO regimens being started earlier for INH/MDR TB. Care must be taken with regards to indeterminate fluoroquinolone results as this may provide a false positive reading.

IntroductionRifampicin plays a key role in tuberculosis (TB) treatment, due to its bactericidal and sterilizing capacity. The dose currently recommended by WHO is 10 mg/kg but achieving this dose can be limited by fixed dose preparations and risks under dosing. Low plasma levels of rifampicin may potentially contribute to poor treatment response. Therapeutic drug monitoring (TDM) has been proposed as a method to support early optimisation of dosing particularly in high-risk groups e.g. CNS TB or slow treatment response. The main aim of this study was to investigate whether standard dosing of rifampicin is likely to lead to therapeutic drug levels and to describe the impact of dose escalation.MethodWe performed a retrospective review of all adult patients who had rifampicin levels (2 hours post dose or 6 hours where delayed absorption was suspected) taken between August 2018 and August 2021, identifying 58 patients. Patient demographics, clinical characteristics including weight at time of level, dose adjustments and rationale for taking level were collected from patient records. Levels below 8 mg/L were considered subtherapeutic.ResultsThe most frequent reason for conducting a rifampicin level was due to slow/poor response (34%) followed by high burden of disease (24%). Just under half of patients (48%) were being treated for pulmonary TB, followed by extrapulmonary TB (24%). Of the 58 patients who had levels measured, 40 (69%) patients had levels that were considered to be subtherapeutic. Figure 1 displays if therapeutic levels were achieved with standard rifampicin dosing (10 mg/kg). In the subtherapeutic group, 31 (78%) had their dosage increased of which 19 (61%) patients had a level taken post dose escalation. Eleven 11 (58%) patients from this group had levels within therapeutic range.Abstract P142 Figure 1Percentage of patients attaining therapeutic levels based on initial rifampicin dose (mg/kg)ConclusionBased on our finding’s a significant proportion of patients show subtherapeutic levels on standard dosing particularly in those with apparent severe or poorly responding disease. TDM is a useful tool to individualise rifampicin dosing and early optimisation increases the likelihood of attaining a therapeutic level. This may be particularly beneficial in patients who may be at risk of low plasma levels e.g. malnourished/disseminated/CNS TB.

BackgroundLatent TB infection (LTBI) remains an important reservoir of TB even in low incidence countries. The prevalence of latent infection is higher in patients with chronic kidney disease and those receiving dialysis.1 Those with LTBI on renal replacement therapy (RRT) are known to have higher risks of reactivation to active disease.2 Our centre data has shown risk is highest within the first 24 months of initiating RRT. At present there is no uniform TB screening and with ad hoc testing by clinicians.AimFeasibility and yield of screening new dialysis starters for LTBI with a QuantiFERON blood test.MethodsThis analysis is between the period 1st May 2021 and 30th April 2022 at our group of West London based dialysis centres as we started to implement this new pathway. Within the first three months of dialysis initiation a QuantiFERON blood test is included as part of routine initiation or monthly infection screening. Positive and recurrent indeterminate results are referred to the TB service. Comorbidities and individual risk factors are collected through electronic patient records.Results464 patients have started dialysis during this time. 371 haemodialysis patients, 93 peritoneal dialysis. There has been a gradual increase in monthly QuantiFERON testing as awareness of the pilot has increased (6–17 tests performed per month). 107/464 (23%) patients have now had a QuantiFERON test. A schematic of the results are shown in the figure below.Abstract P156 Figure 1ConclusionsOur pilot has shown routine testing for LTBI can be implemented in this high risk group and has allowed a significant proportion (14%) of high risk individuals to be assessed by a TB clinician and the multi-disciplinary team. Suitable patients are offered latent TB treatment or may be investigated for active infection.ReferencesGetahun, H., Matteelli, A., Chaisson, R.E., Raviglione, M., 2015. Latent Mycobacterium tuberculosis Infection. New England Journal of Medicine 372, 2127–2135. doi:10.1056/nejmra1405427Horsburgh CR Jr, Rubin EJ. Clinical practice. Latent tuberculosis infection in the United States. N Engl J Med. 2011 Apr 14;364(15):1441–8. doi: 10.1056/NEJMcp1005750. PMID: 21488766.

Abstract Rationale Respiratory virus infections are associated with chronic obstructive pulmonary disease (COPD) exacerbations, but a causative relationship has not been proven. Studies of naturally occurring exacerbations are difficult and the mechanisms linking virus infection to exacerbations are poorly understood. We hypothesized that experimental rhinovirus infection in subjects with COPD would reproduce the features of naturally occurring COPD exacerbations and is a valid model of COPD exacerbations. Objectives To evaluate experimental rhinovirus infection as a model of COPD exacerbation and to investigate the mechanisms of virus-induced exacerbations. Methods We used experimental rhinovirus infection in 13 subjects with COPD and 13 nonobstructed control subjects to investigate clinical, physiologic, pathologic, and antiviral responses and relationships between virus load and these outcomes. Measurements and Main Results Clinical data; inflammatory mediators in blood, sputum, and bronchoalveolar lavage; and viral load in nasal lavage, sputum, and bronchoalveolar lavage were measured at baseline and after infection with rhinovirus 16. After rhinovirus infection subjects with COPD developed lower respiratory symptoms, airflow obstruction, and systemic and airway inflammation that were greater and more prolonged compared with the control group. Neutrophil markers in sputum related to clinical outcomes and virus load correlated with inflammatory markers. Virus load was higher and IFN production by bronchoalveolar lavage cells was impaired in the subjects with COPD. Conclusions We have developed a new model of COPD exacerbation that strongly supports a causal relationship between rhinovirus infection and COPD exacerbations. Impaired IFN production and neutrophilic inflammation may be important mechanisms in virus-induced COPD exacerbations.

Tuberculosis (TB) and multi-drug resistant TB (MDR-TB) are some of the most deadly infectious lung diseases worldwide. Medications such as ethambutol and fluoroquinolones, used in treatment, have potentially severely debilitating side effects, namely ocular toxicity. Current monitoring is infrequent and can lead to unnecessary progression of side effects until irreversible or fatal. Mobile health (m-health) may be able to provide suitable solutions.Methods196 eyes from 96 participants sourced from St Mary’s TB clinics, Western Eye Hospital outpatient clinics, Charing Cross Hospital MS clinics and student volunteers were examined using a digital colour vision test (EnChroma). The results were compared to currently used analogue tests during two phases. Phase one involved comparison to the Farnsworth D15 test (FD15) and phase two to the Ishihara plate test. Participant self-assessment and opinions on the usability of the m-health solution were recorded.ResultsThere was good correlation between the EnChroma and Ishihara tests (r=0.81, p<2.3X10-10), correlation between EnChroma and the FD15 was poor (r=0.49, p<2.3X10-10). The qualitative analysis showed high trust and ease of use when scored by patients and clinicians.Abstract P30 Figure 1Correlation of EnChroma comparison to Ishihara test, (n=40). Axis numbers correspond to results with EnChroma result on the x-axis and the Ishihara test result on the y-axis. Normal=1, protan=2, deutan=3, tritan=4, unknown=5. Bubble size denotes number of participants.DiscussionThe low correlation between the EnChroma and FD15 tests could be due to oversensitivity of the EnChroma test, however previous studies comparing the FD15 to other colour vision tests showed a low sensitivity for the FD15, (0.59)1 suggesting that EnChroma results may be true abnormalities rather than false positives.Apps like EnChroma have the potential to revolutionise, modernise and personalise colour vision testing in medicine, however the study lacks power (shown by the large confidence intervals) and will have to be repeated on a larger scale. Patients are keen to engage with m-health and more, suitable solutions should be explored. M-health has the potential to enable rapid point of care testing and fully remote management of side effects in TB and MDR-TB with further potential in other conditions.ReferenceMarechal M, Delbarre M, Tesson J, Lacambre C, Lefebvre H, Froussart-Maille F. Color Vision Tests in Pilots’ Medical Assessments. Aerospace Medicine and Human Performance. 2018;89(8):737–743. Available from doi:10.3357/AMHP.5009.2018 [Accessed May 4, 2021].

There is substantial circumstantial evidence that CD4 lymphocytes have a role in the pathogenesis of chronic asthma. We investigated the efficacy and safety in severe corticosteroid-dependent asthma of a single intravenous infusion of keliximab (IDEC CE9·1), a chimeric monoclonal antibody to CD4. 22 patients were recruited from two asthma clinics. In an ascending-dose design, the first eight patients were assigned 0·5 mg/kg keliximab (six) or placebo (two); the next seven were assigned 1·5 mg/kg (five) or placebo (two); and the last seven were assigned 3·0 mg/kg (five) or placebo (two). Masked data on safety for each dose group were assessed before progression to the next dose. Patients kept a daily symptom diary and measured morning and evening peak expiratory flow (PEF) at home. PEF and forced expiratory volume in 1 s (FEV 1) were measured at follow-up clinic visits. Patients given 0·5 mg/kg or 1·5 mg/kg keliximab and placebo recipients did not differ in change from baseline of PEF, FEV 1, or symptom score. Those given 3·0 mg/kg keliximab differed significantly from placebo recipients in change in morning PEF (median area under curve [AUC] 445 vs −82·5, p=0·005) and evening PEF (median AUC 548 vs −85, p=0·014). Symptom score showed the same pattern (though differences did not achieve significance), but there was no difference in clinic FEV 1. There were no serious adverse effects related to treatment. Two patients had mild exacerbations of eczema and one developed a transient maculopapular rash. All doses of keliximab were associated with a reduction from baseline in CD4 count. Our findings raise the possibility that T-cell-directed treatment may be an alternative approach to the treatment of severe asthma.

BackgroundAn estimated 44 million artisanal and small-scale miners (ASM), largely based in developing economies, face significant occupational respiratory diseases risks. We aimed to review studies describing silicosis and tuberculosis (TB) prevalence and respirable crystalline silica (RCS) exposures among ASM and use previous evidence to model the relationship between silica exposure and silicosis and TB outcomes.MethodsWe searched PubMed, Web of Science, Scopus and Embase for studies published before the 24th March 2023. Our primary outcomes were silicosis or TB among ASM. Secondary outcomes were respirable dust or silica measurements, spirometry values and respiratory symptom prevalence. A systematic review and meta-analysis were performed and risk of bias assessed using the Joanna Briggs Prevalence Critical Appraisal Tool. Logistic and Poisson regression models with predefined parameters were used to estimate silicosis prevalence and TB incidence at increasing distributions of cumulative silica exposure.ResultsWe identified 18 eligible studies that included 29,562 miners from 13 distinct populations in 10 countries. Silicosis prevalence ranged from 11 to 37%, despite four of five studies reporting an average median duration of mining of <6 years. Tuberculosis prevalence was high; microbiologically confirmed disease ranged from 1.8 to 12% in six studies and clinical disease 3.0 to 17% in four studies. Meta-analysis results demonstrated very high heterogeneity (I 2 Silicosis 97% and microbiological TB 98%). Average RCS intensity was very high (range 0.19–89.5 mg/m3) in five studies. Respiratory symptoms across three studies were common while spirometry findings in three studies were mixed. Our modelling demonstrated greater reductions in silicosis prevalence and TB incidence at high RCS exposure distributions, which were robust across multiple scenarios (figure 1). These models may be viewed interactively at: https://phowlett.shinyapps.io/sil_tb_app/. Study quality was mixed; recurrent issues included selection and measurement bias.Abstract S59 Figure 1Modelled estimates of number of silicosis cases and annual tuberculosis (TB) cases at cumulative RCS distributions of increasing mean values. In plot A, the silicosis prevalence (%) by distributions of increasing mean cumulative RCS (mg/m3-year) is estimated at three different strengths of association between RCS exposure and silicosis OR 1.2, 1.3 and 1.5. In plot B, annual TB cases are estimated at the same three different strengths of association between mean cumulative RCS (mg/m3-year) and silicosisDiscussionDespite limitations of included studies, the prevalence of silicosis and TB appears high which is likely due to RCS exposures between 4–1790 times above the US permissible exposure limit. Our modelling demonstrated the greatest respiratory health benefits of reducing RCS are in those with the highest exposures. Effective low-cost interventions are available and should be studied and implemented.

Background and aimsThe chemoattractant receptor-homologous molecule expressed on T helper type 2 cells (CRTH2) antagonist timapiprant improved lung function and asthma control in a phase 2 study, with evidence suggesting reduced exacerbations. We aimed to assess whether timapiprant attenuated or prevented asthma exacerbations induced by experimental rhinovirus (RV) infection. We furthermore hypothesised that timapiprant would dampen RV-induced type 2 inflammation and consequently improve antiviral immune responses.MethodsAtopic patients with partially controlled asthma on maintenance inhaled corticosteroids were randomised to timapiprant (n=22) or placebo (n=22) and challenged with RV-A16 3 weeks later. The primary endpoint was the cumulative lower respiratory symptom score over the 14 days post infection. Upper respiratory symptoms, spirometry, airway hyperresponsiveness, exhaled nitric oxide, RV-A16 virus load and soluble mediators in upper and lower airways samples, and CRTH2 staining in bronchial biopsies were additionally assessed before and during RV-A16 infection.ResultsSix subjects discontinued the study and eight were not infected; outcomes were assessed in 16 timapiprant-treated and 14 placebo-treated, successfully infected subjects. There were no differences between treatment groups in clinical exacerbation severity including cumulative lower respiratory symptom score day 0–14 (difference 3.0 (95% CI −29.0 to 17.0), p=0.78), virus load, antiviral immune responses, or RV-A16-induced airway inflammation other than in the bronchial biopsies, where CRTH2 staining was increased during RV-A16 infection in the placebo-treated but not the timapiprant-treated group. Timapiprant had a favourable safety profile, with no deaths, serious adverse events or drug-related withdrawals.ConclusionTimapiprant treatment had little impact on the clinicopathological changes induced by RV-A16 infection in partially controlled asthma.

The balance between histone deacetylase activity and histone acetyltransferase activity is one of the mechanisms controlling and limiting inflammatory cell activity. These investigators show that patients with chronic obstructive pulmonary disease (COPD), as compared with normal subjects and patients with asthma, cystic fibrosis, or pneumonia, had reductions in histone deacetylase activity. Greater reductions were observed in patients with more severe disease. Patients with chronic obstructive pulmonary disease (COPD), as compared with normal subjects and patients with asthma, cystic fibrosis, or pneumonia, had reductions in histone deacetylase activity. The global burden of chronic obstructive pulmonary disease (COPD) — a common and debilitating chronic inflammatory disease that is characterized by the progressive development of airflow limitation and is poorly reversible — is increasing. 1 Cigarette smoking is strongly linked with the ongoing inflammation in the airways and lung parenchyma, and the severity of airflow limitation is correlated with the degree of pulmonary inflammation. 2 , 3 The inflammatory processes in COPD are complex. 4 Neutrophil chemotactic mediators, such as interleukin-8 and leukotriene B 4 , and proinflammatory cytokines, such as tumor necrosis factor α, are increased in the sputum of patients with COPD, . . .

Introduction and ObjectivesThe BTS Multidrug Resistant (MDR) Tuberculosis (TB) Clinical Advice Service (CAS) provides an electronic forum to review, discuss and record formal feedback through an MDT delivered by national experts for cases of MDR and complex TB, submitted by local managing clinicians. This process provides specialist peer-review to support clinical requests for the use of new or high-cost drugs. The service also receives requests for advice on Non-Tuberculous Mycobacteria (NTM). Here we report CAS activity for referred NTM cases posted January 2018-June 2022.MethodsNTM cases submitted to the service during this period were extracted from the CAS data platform using a reporting template developed to capture data on TB patients and their illness – with the first records representing the start of the current CAS.Results85 patients with NTM were referred to the CAS (49% pulmonary disease). This comprised 18% of all CAS cases – making it the largest group discussed that were not known or suspected MDR/XDR TB. The percentage increased from 8.7% in 2018 to 31% in 2022 (p=0.001, test for trend). The median age was 52.7 years (IQR 34.5), 60% were male and 80% were UK-born, with a similar proportion of white ethnicity. Underlying clinical risk factors for NTM were noted in >95% and ranged from COPD or bronchiectasis to immunosuppression in 1/3rd. No cases with underlying Cystic fibrosis were reported. The commonest organisms were M. avium complex and M. abscessus. Referrals were generally for advice on treatment. 85% were discussed at the MDT, with 73% discussed once. 24 cases requested support for bedaquiline use – and 13 (54%) were approved. Additionally, there were 5 cases where the panel recommended bedaquiline, though the managing clinician had not requested it.ConclusionsThe data indicate there is considerable and increasing demand for expert advice to manage patients with NTM. This appears to be in non-CF NTM, implying other networks may provide similar support for CF patients. The case-mix argues for regional NTM networks that could manage most current referrals – enabling a national group to focus on highly complex patients being considered for new and/or high-cost therapies.The authors have produced this abstract on behalf of the BTS MDR TB CAS, London, UK.