Browsing by Department "Division of Pulmonology"
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- ItemOpen AccessAclidinium bromide and formoterol fumarate as a fixed-dose combination in COPD: pooled analysis of symptoms and exacerbations from two six-month, multicentre, randomised studies (ACLIFORM and AUGMENT)(2015-08-02) Bateman, Eric D; Chapman, Kenneth R; Singh, Dave; D’Urzo, Anthony D; Molins, Eduard; Leselbaum, Anne; Gil, Esther GAbstract Background The combination of aclidinium bromide, a long-acting anticholinergic, and formoterol fumarate, a long-acting beta2-agonist (400/12 μg twice daily) achieves improvements in lung function greater than either monotherapy in patients with chronic obstructive pulmonary disease (COPD), and is approved in the European Union as a maintenance treatment. The effect of this combination on symptoms of COPD and exacerbations is less well established. We examined these outcomes in a pre-specified analysis of pooled data from two 24-week, double-blind, parallel-group, active- and placebo-controlled, multicentre, randomised Phase III studies (ACLIFORM and AUGMENT). Methods Patients ≥40 years with moderate to severe COPD (post-bronchodilator forced expiratory volume in 1 s [FEV1]/forced vital capacity <70 % and FEV1 ≥30 % but <80 % predicted normal) were randomised (ACLIFORM: 2:2:2:2:1; AUGMENT: 1:1:1:1:1) to twice-daily aclidinium/formoterol 400/12 μg or 400/6 μg, aclidinium 400 μg, formoterol 12 μg or placebo via Genuair™/Pressair®. Dyspnoea (Transition Dyspnoea Index; TDI), daily symptoms (EXAcerbations of Chronic pulmonary disease Tool [EXACT]-Respiratory Symptoms [E-RS] questionnaire), night-time and early-morning symptoms, exacerbations (Healthcare Resource Utilisation [HCRU] and EXACT definitions) and relief-medication use were assessed. Results The pooled intent-to-treat population included 3394 patients. Aclidinium/formoterol 400/12 μg significantly improved TDI focal score versus placebo and both monotherapies at Week 24 (all p < 0.05). Over 24 weeks, significant improvements in E-RS total score, overall night-time and early-morning symptom severity and limitation of early-morning activities were observed with aclidinium/formoterol 400/12 μg versus placebo and both monotherapies (all p < 0.05). The rate of moderate or severe HCRU exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg compared with placebo (p < 0.05) but not monotherapies; the rate of EXACT-defined exacerbations was significantly reduced with aclidinium/formoterol 400/12 μg versus placebo (p < 0.01) and aclidinium (p < 0.05). Time to first HCRU or EXACT exacerbation was longer with aclidinium/formoterol 400/12 μg compared with placebo (all p < 0.05) but not the monotherapies. Relief-medication use was reduced with aclidinium/formoterol 400/12 μg versus placebo and aclidinium (p < 0.01). Conclusions Aclidinium/formoterol 400/12 μg significantly improves 24-hour symptom control compared with placebo, aclidinium and formoterol in patients with moderate to severe COPD. Furthermore, aclidinium/formoterol 400/12 μg reduces the frequency of exacerbations compared with placebo. Trial registration NCT01462942 and NCT01437397 (ClinicalTrials.gov)
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- ItemOpen AccessBetter antiretroviral therapy outcomes at primary healthcare facilities: an evaluation of three tiers of ART services in four South African provinces(Public Library of Science, 2010) Fatti, Geoffrey; Grimwood, Ashraf; Bock, PeterBACKGROUND: There are conflicting reports of antiretroviral therapy (ART) effectiveness comparisons between primary healthcare (PHC) facilities and hospitals in low-income settings. This comparison has not been evaluated on a broad scale in South Africa. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort study was conducted including ART-naïve adults from 59 facilities in four provinces in South Africa, enrolled between 2004 and 2007. Kaplan-Meier estimates, competing-risks Cox regression, generalised estimating equation population-averaged models and logistic regression were used to compare death, loss to follow-up (LTFU) and virological suppression (VS) between PHC, district and regional hospitals. 29 203 adults from 47 PHC facilities, nine district hospitals and three regional hospitals were included. Patients at PHC facilities had more advanced WHO stage disease when starting ART. Retention in care was 80.1% (95% CI: 79.3%-80.8%), 71.5% (95% CI: 69.1%-73.8%) and 68.7% (95% CI: 67.0%-69.7%) at PHC, district and regional hospitals respectively, after 24 months of treatment ( P <0.0001). In adjusted regression analyses, LTFU was independently increased at regional hospitals (aHR 2.19; 95% CI: 1.94−2.47) and mortality was independently elevated at district hospitals (aHR 1.60; 95% CI: 1.30−1.99) compared to PHC facilities after 12 months of ART. District and regional hospital patients had independently reduced probabilities of VS, aOR 0.76 (95% CI: 0.59−0.97) and 0.64 (95% CI: 0.56−0.75) respectively compared to PHC facilities over 24 months of treatment. Conclusions/Significance: ART outcomes were superior at PHC facilities, despite PHC patients having more advanced clinical stage disease when starting ART, suggesting that ART can be adequately provided at this level and supporting the South African government's call for rapid up-scaling of ART at the primary level of care. Further prospective research is required to determine the degree to which outcome differences are attributable to either facility level characteristics or patient co-morbidity at hospital level.
- ItemOpen AccessBudesonide/formoterol and formoterol provide similar rapid relief in patients with acute asthma showing refractoriness to salbutamol(BioMed Central Ltd, 2006) Bateman, ED; Fairall, L; Lombardi, DM; English, RBACKGROUND:To compare the efficacy and safety of budesonide/formoterol (Symbicort(R)) with formoterol (Oxis(R)) in the treatment of patients with acute asthma who showed evidence of refractoriness to short-acting beta2-agonist therapy. METHODS: In a 3 hour, randomized, double-blind study, a total of 115 patients with acute asthma (mean FEV1 40% of predicted normal) and a refractory response to salbutamol (mean reversibility 2% of predicted normal after inhalation of 400 mug), were randomized to receive either budesonide/formoterol (320/9 mug, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 1280/36 mug]) or formoterol (9 mug, 2 inhalations at t = -5 minutes and 2 inhalations at 0 minutes [total dose 36 mug]). The primary efficacy variable was the average FEV1 from the first intake of study medication to the measurement at 90 minutes. Secondary endpoints included changes in FEV1 at other timepoints and change in respiratory rate at 180 minutes. Treatment success, treatment failure and patient assessment of the effectiveness of the study medication were also measured. RESULTS: FEV1 increased after administration of the study medication in both treatment groups. No statistically significant difference between the treatment groups was apparent for the primary outcome variable, or for any of the other efficacy endpoints. There were no statistically significant between-group differences for treatment success, treatment failure or patient assessment of medication effectiveness. Both treatments were well tolerated. CONCLUSION: Budesonide/formoterol and formoterol provided similarly rapid relief of acute bronchoconstriction in patients with asthma who showed evidence of refractoriness to a short-acting beta2-agonist.
- ItemOpen AccessBuilding capacity for antiretroviral delivery in South Africa: A qualitative evaluation of the PALSA PLUS nurse training programme(BioMed Central Ltd, 2008) Stein, J; Lewin, S; Fairall, L; Mayers, P; English, R; Bheekie, A; Bateman, E; Zwarenstein, MBACKGROUND: South Africa recently launched a national antiretroviral treatment programme. This has created an urgent need for nurse-training in antiretroviral treatment (ART) delivery. The PALSA PLUS programme provides guidelines and training for primary health care (PHC) nurses in the management of adult lung diseases and HIV/AIDS, including ART. A process evaluation was undertaken to document the training, explore perceptions regarding the value of the training, and compare the PALSA PLUS training approach (used at intervention sites) with the provincial training model. The evaluation was conducted alongside a randomized controlled trial measuring the effects of the PALSA PLUS nurse-training (Trial reference number ISRCTN24820584). METHODS: Qualitative methods were utilized, including participant observation of training sessions, focus group discussions and interviews. Data were analyzed thematically. RESULTS: Nurse uptake of PALSA PLUS training, with regard not only to ART specific components but also lung health, was high. The ongoing on-site training of all PHC nurses, as opposed to the once-off centralized training provided for ART nurses only at non-intervention clinics, enhanced nurses' experience of support for their work by allowing, not only for ongoing experiential learning, supervision and emotional support, but also for the ongoing managerial review of all those infrastructural and system-level changes required to facilitate health provider behaviour change and guideline implementation. The training of all PHC nurses in PALSA PLUS guideline use, as opposed to ART nurses only, was also perceived to better facilitate the integration of AIDS care within the clinic context. CONCLUSION: PALSA PLUS training successfully engaged all PHC nurses in a comprehensive approach to a range of illnesses affecting both HIV positive and negative patients. PHC nurse-training for integrated systems-based interventions should be prioritized on the ART funding agenda. Training for individual provider behaviour change is nonetheless only one aspect of the ongoing system-wide interventions required to effect lasting improvements in patient care in the context of an over-burdened and under-resourced PHC system.
- ItemOpen AccessCan point-of-care urine LAM strip testing for tuberculosis add value to clinical decision making in hospitalised HIV-infected persons(Public Library of Science, 2013) Peter, Jonathan G; Theron, Grant; Dheda, KeertanBACKGROUND: The urine lipoarabinomannan (LAM) strip-test (Determine®-TB) can rapidly rule-in TB in HIV-infected persons with advanced immunosuppression. However, given high rates of empiric treatment amongst hospitalised patients in high-burden settings (∼50%) it is unclear whether LAM can add any value to clinical decision making, or identify a subset of patients with unfavourable outcomes that would otherwise have been missed by empiric treatment. METHODS: 281 HIV-infected hospitalised patients with suspected TB received urine LAM strip testing, and were categorised as definite (culture-positive), probable-, or non-TB. Both the proportion and morbidity of TB cases identified by LAM testing, early empiric treatment (initiated prior to test result availability) and a set of clinical predictors were compared across groups. RESULTS: 187/281 patients had either definite- (n = 116) or probable-TB (n = 71). As a rule-in test for definite and probable-TB, LAM identified a similar proportion of TB cases compared to early empiric treatment (85/187 vs. 93/187, p = 0.4), but a greater proportion than classified by a set of clinical predictors alone (19/187; p<0.001). Thirty-nine of the 187 (21%) LAM-positive patients who had either definite- or probable-TB were missed by early empiric treatment, and of these 25/39 (64%) would also have been missed by smear microscopy. Thus, 25/187 (8%) of definite- or probable-TB patients with otherwise delayed initiation of TB treatment could be detected by the LAM strip test. LAM-positive patients missed by early empiric treatment had a lower median CD4 count (p = 0.008), a higher median illness severity score (p = 0.001) and increased urea levels (p = 0.002) compared to LAM-negative patients given early empiric treatment. CONCLUSIONS: LAM strip testing outperformed TB diagnosis based on clinical criteria but in day-to-day practice identified a similar proportion of patients compared to early empiric treatment. However, compared to empiric treatment, LAM identified a different subset of patients with more advanced immunosuppression and greater disease severity.
- ItemOpen AccessClinical diagnostic utility of IP-10 and LAM antigen levels for the diagnosis of tuberculous pleural effusions in a high burden setting(Public Library of Science, 2009) Dheda, Keertan; Van-Zyl Smit, Richard N; Sechi, Leonardo A; Badri, Motasim; Meldau, Richard; Symons, Gregory; Khalfey, Hoosein; Carr, Igshaan; Maredza, Alice; Dawson, RodneyBACKGROUND: Current tools for the diagnosis of tuberculosis pleural effusions are sub-optimal. Data about the value of new diagnostic technologies are limited, particularly, in high burden settings. Preliminary case control studies have identified IFN-γ-inducible-10kDa protein (IP-10) as a promising diagnostic marker; however, its diagnostic utility in a day-to-day clinical setting is unclear. Detection of LAM antigen has not previously been evaluated in pleural fluid. METHODS: We investigated the comparative diagnostic utility of established (adenosine deaminase [ADA]), more recent (standardized nucleic-acid-amplification-test [NAAT]) and newer technologies (a standardized LAM mycobacterial antigen-detection assay and IP-10 levels) for the evaluation of pleural effusions in 78 consecutively recruited South African tuberculosis suspects. All consenting participants underwent pleural biopsy unless contra-indicated or refused. The reference standard comprised culture positivity for M. tuberculosis or histology suggestive of tuberculosis. Principal FINDINGS: Of 74 evaluable subjects 48, 7 and 19 had definite, probable and non-TB, respectively. IP-10 levels were significantly higher in TB vs non-TB participants (p<0.0001). The respective outcomes [sensitivity, specificity, PPV, NPV %] for the different diagnostic modalities were: ADA at the 30 IU/L cut-point [96; 69; 90; 85], NAAT [6; 93; 67; 28], IP-10 at the 28,170 pg/ml ROC-derived cut-point [80; 82; 91; 64], and IP-10 at the 4035 pg/ml cut-point [100; 53; 83; 100]. Thus IP-10, using the ROC-derived cut-point, missed ∼20% of TB cases and mis-diagnosed ∼20% of non-TB cases. By contrast, when a lower cut-point was used a negative test excluded TB. The NAAT had a poor sensitivity but high specificity. LAM antigen-detection was not diagnostically useful. CONCLUSION: Although IP-10, like ADA, has sub-optimal specificity, it may be a clinically useful rule-out test for tuberculous pleural effusions. Larger multi-centric studies are now required to confirm our findings.
- ItemOpen AccessClinical utility of a commercial LAM-ELISA assay for TB diagnosis in HIV-infected patients using urine and sputum samples(Public Library of Science, 2010) Dheda, Keertan; Davids, Virginia; Lenders, Laura; Roberts, Teri; Meldau, Richard; Ling, Daphne; Brunet, Laurence; Smit, Richard van Zyl; Peter, Jonathan; Green, Clare; Badri, Motasim; Sechi, Leonardo; Sharma, Surendra; Hoelscher, Michael; Dawson, RodneyBACKGROUND: The accurate diagnosis of TB in HIV-infected patients, particularly with advanced immunosuppression, is difficult. Recent studies indicate that a lipoarabinomannan (LAM) assay (Clearview-TB®-ELISA) may have some utility for the diagnosis of TB in HIV-infected patients; however, the precise subgroup that may benefit from this technology requires clarification. The utility of LAM in sputum samples has, hitherto, not been evaluated. METHODS: LAM was measured in sputum and urine samples obtained from 500 consecutively recruited ambulant patients, with suspected TB, from 2 primary care clinics in South Africa. Culture positivity for M. tuberculosis was used as the reference standard for TB diagnosis. RESULTS: Of 440 evaluable patients 120/387 (31%) were HIV-infected. Urine-LAM positivity was associated with HIV positivity (p = 0.007) and test sensitivity, although low, was significantly higher in HIV-infected compared to uninfected patients (21% versus 6%; p<0.001), and also in HIV-infected participants with a CD4 <200 versus >200 cells/mm 3 (37% versus 0%; p = 0.003). Urine-LAM remained highly specific in all 3 subgroups (95%-100%). 25% of smear-negative but culture-positive HIV-infected patients with a CD4 <200 cells/mm 3 were positive for urine-LAM. Sputum-LAM had good sensitivity (86%) but poor specificity (15%) likely due to test cross-reactivity with several mouth-residing organisms including actinomycetes and nocardia species. CONCLUSIONS: These preliminary data indicate that in a high burden primary care setting the diagnostic usefulness of urine-LAM is limited, as a rule-in test, to a specific patient subgroup i.e. smear-negative HIV-infected TB patients with a CD4 count <200 cells/mm 3 , who would otherwise have required further investigation. However, even in this group sensitivity was modest. Future and adequately powered studies in a primary care setting should now specifically target patients with suspected TB who have advanced HIV infection.
- ItemOpen AccessComparison of a clinical prediction rule and a LAM antigen-detection assay for the rapid diagnosis of TBM in a high HIV prevalence setting(Public Library of Science, 2010) Patel, Vinod B; Singh, Ravesh; Connolly, Cathy; Kasprowicz, Victoria; Zumla, Allimudin; Ndungu, Thumbi; Dheda, KeertanBackground/Objective: The diagnosis of tuberculous meningitis (TBM) in resource poor TB endemic environments is challenging. The accuracy of current tools for the rapid diagnosis of TBM is suboptimal. We sought to develop a clinical-prediction rule for the diagnosis of TBM in a high HIV prevalence setting, and to compare performance outcomes to conventional diagnostic modalities and a novel lipoarabinomannan (LAM) antigen detection test (Clearview-TB®) using cerebrospinal fluid (CSF). METHODS: Patients with suspected TBM were classified as definite-TBM (CSF culture or PCR positive), probable-TBM and non-TBM. RESULTS: Of the 150 patients, 84% were HIV-infected (median [IQR] CD4 count = 132 [54; 241] cells/µl). There were 39, 55 and 54 patients in the definite, probable and non-TBM groups, respectively. The LAM sensitivity and specificity (95%CI) was 31% (17;48) and 94% (85;99), respectively (cut-point ≥0.18). By contrast, smear-microscopy was 100% specific but detected none of the definite-TBM cases. LAM positivity was associated with HIV co-infection and low CD4 T cell count (CD4<200 vs. >200 cells/µl; p = 0.03). The sensitivity and specificity in those with a CD4<100 cells/µl was 50% (27;73) and 95% (74;99), respectively. A clinical-prediction rule ≥6 derived from multivariate analysis had a sensitivity and specificity (95%CI) of 47% (31;64) and 98% (90;100), respectively. When LAM was combined with the clinical-prediction-rule, the sensitivity increased significantly (p<0.001) to 63% (47;68) and specificity remained high at 93% (82;98). CONCLUSIONS: Despite its modest sensitivity the LAM ELISA is an accurate rapid rule-in test for TBM that has incremental value over smear-microscopy. The rule-in value of LAM can be further increased by combination with a clinical-prediction rule, thus enhancing the rapid diagnosis of TBM in HIV-infected persons with advanced immunosuppression.
- ItemOpen AccessComparison of quantitative techniques including Xpert MTB/RIF to evaluate mycobacterial burden(Public Library of Science, 2011) van Zyl-Smit, Richard N; Binder, Anke; Meldau, Richard; Mishra, Hridesh; Semple, Patricia L; Theron, Grant; Peter, Jonathan; Whitelaw, Andrew; Sharma, Suren K; Warren, Robin; Bateman, Eric D; Dheda, KeertanIntroduction: Accurate quantification of mycobacterial load is important for the evaluation of patient infectiousness, disease severity and monitoring treatment response in human and in-vitro laboratory models of disease. We hypothesized that newer techniques would perform as well as solid media culture to quantify mycobacterial burden in laboratory specimens. METHODS: We compared the turn-around-time, detection-threshold, dynamic range, reproducibility, relative discriminative ability, of 4 mycobacterial load determination techniques: automated liquid culture (BACTEC-MGIT-960), [ 3 H]-uracil incorporation assays, luciferase-reporter construct bioluminescence, and quantitative PCR(Xpert -MTB/RIF) using serial dilutions of Mycobacterium bovis and Mycobacterium tuberculosis H37RV. Mycobacterial colony-forming-units(CFU) using 7H10-Middlebrook solid media served as the reference standard. RESULTS: All 4 assays correlated well with the reference standard, however, bioluminescence and uracil assays had a detection threshold ≥1×10 3 organisms. By contrast, BACTEC-MGIT-960 liquid culture, although only providing results in days, was user-friendly, had the lowest detection threshold (<10 organisms), the greatest discriminative ability (1 vs. 10 organisms; p = 0.02), and the best reproducibility (coefficient of variance of 2% vs. 38% compared to uracil incorporation; p = 0.02). Xpert-MTB/RIF correlated well with mycobacterial load, had a rapid turn-around-time (<2 hours), was user friendly, but had a detection limit of ∼100 organisms. CONCLUSIONS: Choosing a technique to quantify mycobacterial burden for laboratory or clinical research depends on availability of resources and the question being addressed. Automated liquid culture has good discriminative ability and low detection threshold but results are only obtained in days. Xpert MTB/RIF provides rapid quantification of mycobacterial burden, but has a poorer discrimination and detection threshold.
- ItemOpen AccessComparison of same day diagnostic tools including Gene Xpert and unstimulated IFN-γ for the evaluation of pleural tuberculosis: a prospective cohort study(BioMed Central, 2014-04-08) Meldau, Richard; Peter, Jonny; Theron, Grant; Calligaro, Greg; Allwood, Brian; Symons, Greg; Khalfey, Hoosain; Ntombenhle, Gina; Govender, Ureshnie; Binder, Anke; van Zyl-Smit, Richard; Dheda, KeertanBackground: The accuracy of currently available same-day diagnostic tools (smear microscopy and conventional nucleic acid amplification tests) for pleural tuberculosis (TB) is sub-optimal. Newer technologies may offer improved detection. Methods: Smear-microscopy, adenosine deaminase (ADA), interferon gamma (IFN-γ), and Xpert MTB/RIF [using an unprocessed (1 ml) and centrifuged (~20 ml) sample] test accuracy was evaluated in pleural fluid from 103 consecutive patients with suspected pleural TB. Culture for M.tuberculosis and/or histopathology (pleural biopsy) served as the reference standard. Patients were followed prospectively to determine their diagnostic categorisation. Results: Of 93 evaluable participants, 40 had definite-TB (reference positive), 5 probable-TB (not definite but treated for TB) and 48 non-TB (culture and histology negative, and not treated for TB). Xpert MTB/RIF sensitivity and specificity (95% CI) was 22.5% (12.4 - 37.6) and 98% (89.2 - 99.7), respectively, and centrifugation did not improve sensitivity (23.7%). The Xpert MTB/RIF internal positive control showed no evidence of inhibition. Biomarker specific sensitivity, specificity, PPV, and NPVs were: ADA (48.85 IU/L; rule-in cut-point) 55.3% (39.8 - 69.9), 95.2% (83.9 - 98.7), 91.4 (73.4 - 95.4), 69.7% (56.7 - 80.1); ADA (30 IU/L; clinically used cut-point) 79% (63.7 - 89), 92.7% (80.6 - 97.5), 91.0 (73.4 - 95.4), 82.7% (69.3 - 90.1); and IFN-γ (107.7 pg/ml; rule-in cut-point) 92.5% (80.2 - 97.5), 95.9% (86.1 - 98.9), 94.9% (83.2 - 98.6), 93.9% (83.5 - 97.9), respectively (IFN-γ sensitivity and NPV better than Xpert [p < 0.05] and rule-in ADA [p < 0.05]). Conclusion: The usefulness of Xpert MTB/RIF to diagnose pleural TB is limited by its poor sensitivity. IFN-γ is an excellent rule-in test and, compared to ADA, has significantly better sensitivity and rule-out value in a TB-endemic setting.
- ItemOpen AccessComparison of the EQ-5D-Y-5L, EQ-5D-Y-3L and PedsQL in children and adolescents(2022-06-16) Verstraete, Janine; Scott, DesBackground There is an increased use of Patient-Reported Outcome Measures (PROMs) in children and adolescents. The aim of this study was to compare the feasibility, concurrent validity and known-group validity of the EQ-5D-Y-3L (Y-3L), EQ-5D-Y-5L (Y-5L) and PedsQL self-report PROMs. Methods Five hundred and fifty children and adolescents, aged 8–15-years, with acute and chronic health conditions and a general population sample were recruited from schools and hospitals in Cape Town South Africa. All respondents self-completed the Y-5L, PedsQL, Self-Rated Health Question and Y-3L. Feasibility of the measures was determined by comparing the number of missing responses. Convergent validity was assessed by Spearman’s and Intra-class correlations on the corresponding items and summary scores respectively. Known-groups validity across health conditions was assessed across the summary scores of the measures with analysis of variance (ANOVA). Results The Y-3L and Y-5L had a total of 1% and 3.5% missing responses compared to 19% on the PedsQL. Similar items on the PedsQL and Y-3L/Y-5L showed high correlations (> 0.5) and related items showed moderate correlations (0.3). PedsQL total score was moderately and significantly associated with Y-3L and Y-5L level sum and VAS scores. The Y-3L and Y-5L level sum and VAS scores showed significant differences between known health groups whereas the PedsQL only showed differences between those with acute and chronic illness. Conclusion The results of this study show that the Y-3L and Y-5L showed comparable psychometric validity to the PedsQL. When considering the choice between the PedsQL, Y-5L and Y-3L these study results indicate that the EQ-5D-Y instruments (Y-3L and Y-5L) are recommended for studies assessing known-group validity or where missing data should be minimised. The PedsQL generic measure may be preferable in future studies including the general population where a ceiling effect is anticipated. When considering the choice between the Y-5L and the Y-3L there was no systematic difference in the validity between these instruments or between the Y-3L or Y-5L and the PedsQL. Thus, the selection of EQ-5D-Y measures to include in future studies should be guided by the characteristics of the population to be tested.
- ItemOpen AccessCorrelation of mycobacterium tuberculosis specific and non-specific quantitative Th1 T-cell responses with bacillary load in a high burden setting(Public Library of Science, 2012) Theron, Grant; Peter, Jonny; Lenders, Laura; van Zyl-Smit, Richard; Meldau, Richard; Govender, Ureshnie; Dheda, KeertanBACKGROUND: Measures of bacillary load in patients with tuberculosis (TB) may be useful for predicting and monitoring response to treatment. The relationship between quantitative T-cell responses and mycobacterial load remains unclear. We hypothesised that, in a HIV-prevalent high burden setting, the magnitude of mycobacterial antigen-specific and non-specific T-cell IFN-γ responses would correlate with (a) bacterial load and (b) culture conversion in patients undergoing treatment. METHODS: We compared baseline (n = 147), 2 (n = 35) and 6 month (n = 13) purified-protein-derivative (PPD) and RD1-specific (TSPOT.TB and QFT-GIT) blood RD1-specific (TSPOT.TB; QFT-GIT) responses with associates of sputum bacillary load in patients with culture-confirmed TB in Cape Town, South Africa. RESULTS: IFN-γ responses were not associated with liquid culture time-to-positivity, smear-grade, Xpert MTB/RIF-generated cycle threshold values or the presence of cavities on the chest radiograph in patients with culture-confirmed TB and irrespective of HIV-status. 2-month IGRA conversion rates (positive-to-negative) were negligible [<11% for TSPOT.TB (3/28) and QFT-GIT (1/29)] and lower compared to culture [60% (21/35); p<0.01]. CONCLUSIONS: In a high burden HIV-prevalent setting T-cell IFN-γ responses to M. tuberculosis- specific and non-specific antigens do not correlate with bacillary load, including Xpert MTB/RIF-generated C T values, and are therefore poorly suited for monitoring treatment and prognostication.
- ItemOpen AccessA descriptive study of IgG subclasses and allotypes in children with pulmonary tuberculosis in the Western Cape(1997) Potgieter, Stephanus Theron; Beatty, David WilliamSTUDY OBJECTIVES: An analysis of IgG subclasses and allotypes in children with pulmonary Tuberculosis (PTB) in the Western Cape. DESIGN: Consecutive children under 15 years of age with microbiological proven PTB over an 8 month period- November 1993 to July 1994. SETTING: Teaching Hospitals in Cape Town. PATIENTS: Thirty-five cases were selected from 99 consecutive cases that were Mycobacterium tuberculosis positive, 15 of which were of Mixed and 20 were of Black Ancestry. CONTROL GROUP: Sera were selected from 224 Black Ancestry (59 children and 165 adults) and 211 Mixed Ancestry (67 children and 144 adults) that had no evidence for active tuberculosis or a history of previous TB diagnosis. MEASUREMENTS AND RESULTS: IgG subclasses, total IgG,and five allotypes: Glm(a), Glm(f), G2m(n), G3m(bl), G3m(gl) were determined by ELISA techniques. In the Mixed ancestry group the Glm(f) (p= 0.01), G2m(n) (p= 0.04) and G3m(gl) (p=0.001) allotypes were less frequently found in children with proven PTB. In the Black Ancestry subjects the G3m(g 1) allotype was significantly less common than in the control group (p < 0.001). CONCLUSIONS: Because allotypes are inherited in a Mendelian fashion, the observed association of childhood PTB and certain allotypes strengthens the hypothesis that a genetic susceptibility exists to acquiring TB.
- ItemOpen AccessThe development and validation of a respiratory guideline for nurses in primary care in South Africa(2006) English, René Glynnis; Bateman, Eric D; Bachmann, MaxThe Practical Aproach to Lung Health in South Africa (P ALSA) initiative aims to improve the diagnosis and management of patients with respiratory diseases in primary care. An algorithm-based syndromic guideline integrating common respiratory diseases for nurses was developed after review of a generic respiratory guideline, medical literature, local policies, and qualitative research.
- ItemOpen AccessDevelopment of a simple reliable radiographic scoring system to aid the diagnosis of pulmonary tuberculosis(Public Library of Science, 2013) Pinto, Lancelot M; Dheda, Keertan; Theron, Grant; Allwood, Brian; Calligaro, Gregory; van Zyl-Smit, Richard; Peter, Jonathan; Schwartzman, Kevin; Menzies, Dick; Bateman, Eric; Pai, Madhukar; Dawson, RodneyRationale: Chest radiography is sometimes the only method available for investigating patients with possible pulmonary tuberculosis (PTB) with negative sputum smears. However, interpretation of chest radiographs in this context lacks specificity for PTB, is subjective and is neither standardized nor reproducible. Efforts to improve the interpretation of chest radiography are warranted. Objectives To develop a scoring system to aid the diagnosis of PTB, using features recorded with the Chest Radiograph Reading and Recording System (CRRS). METHODS: Chest radiographs of outpatients with possible PTB, recruited over 3 years at clinics in South Africa were read by two independent readers using the CRRS method. Multivariate analysis was used to identify features significantly associated with culture-positive PTB. These were weighted and used to generate a score. RESULTS: 473 patients were included in the analysis. Large upper lobe opacities, cavities, unilateral pleural effusion and adenopathy were significantly associated with PTB, had high inter-reader reliability, and received 2, 2, 1 and 2 points, respectively in the final score. Using a cut-off of 2, scores below this threshold had a high negative predictive value (91.5%, 95%CI 87.1,94.7), but low positive predictive value (49.4%, 95%CI 42.9,55.9). Among the 382 TB suspects with negative sputum smears, 229 patients had scores <2; the score correctly ruled out active PTB in 214 of these patients (NPV 93.4%; 95%CI 89.4,96.3). The score had a suboptimal negative predictive value in HIV-infected patients (NPV 86.4, 95% CI 75,94). CONCLUSIONS: The proposed scoring system is simple, and reliably ruled out active PTB in smear-negative HIV-uninfected patients, thus potentially reducing the need for further tests in high burden settings. Validation studies are now required.
- ItemOpen AccessDiagnosis and treatment of urticaria and angioedema: a worldwide perspective(BioMed Central Ltd, 2012) Sánchez-Borges, Mario; Asero, Riccardo; Ansotegui, Ignacio; Baiardini, Ilaria; Bernstein, Jonathan; Canonica, G Walter; Gower, Richard; Kahn, David; Kaplan, Allen; Katelaris, Connie; Maurer, Marcus; Park, Hae; Potter, Paul; Saini, Sarbjit; TassinariUrticaria and angioedema are common clinical conditions representing a major concern for physicians and patients alike. The World Allergy Organization (WAO), recognizing the importance of these diseases, has contributed to previous guidelines for the diagnosis and management of urticaria. The Scientific and Clinical Issues Council of WAO proposed the development of this global Position Paper to further enhance the clinical management of these disorders through the participation of renowned experts from all WAO regions of the world. Sections on definition and classification, prevalence, etiology and pathogenesis, diagnosis, treatment, and prognosis are based on the best scientific evidence presently available. Additional sections devoted to urticaria and angioedema in children and pregnant women, quality of life and patient-reported outcomes, and physical urticarias have been incorporated into this document. It is expected that this article will supplement recent international guidelines with the contribution of an expert panel designated by the WAO, increasing awareness of the importance of urticaria and angioedema in medical practice and will become a useful source of information for optimum patient management worldwide.
- ItemOpen AccessDiagnostic accuracy of a liquid chromatography-tandem mass spectrometry assay in small hair samples for rifampin-resistant tuberculosis drug concentrations in a routine care setting(2021-01-22) Metcalfe, John; Bacchetti, Peter; Esmail, Ali; Reckers, Andrew; Aguilar, David; Wen, Anita; Huo, Shu; Muyindike, Winnie R; Hahn, Judith A; Dheda, Keertan; Gandhi, Monica; Gerona, RoyBackground Treatment monitoring of drug-resistant tuberculosis (DR-TB) in resource-limited settings is challenging. We developed a multi-analyte assay for eleven anti-TB drugs in small hair samples as an objective metric of drug exposure. Methods Small hair samples were collected from participants at various timepoints during directly observed RR-TB treatment at an inpatient tertiary referral facility in South Africa (DR-TB cohort). We assessed qualitative determination (i.e., detection above limit of detection) of bedaquiline, linezolid, clofazimine, pretomanid, levofloxacin, moxifloxacin, pyrazinamide, isoniazid, ethambutol, ethionamide, and prothionamide in an LC-MS/MS index panel assay against a reference standard of inpatient treatment records. Because treatment regimens prior to hospitalization were not available, we also analyzed specificity (for all drugs except isoniazid) using an external cohort of HIV-positive patients treated for latent TB infection with daily isoniazid (HIV/LTBI cohort) in Uganda. Results Among the 57 DR-TB patients (58% with pre-XDR/XDR-TB; 70% HIV-positive) contributing analyzable hair samples, the sensitivity of the investigational assay was 94% or higher for all drugs except ethionamide (58.5, 95% confidence interval [CI], 40.7–99.9). Assay specificity was low across all tested analytes within the DR-TB cohort; conversely, assay specificity was 100% for all drugs in the HIV/LTBI cohort. Conclusions Hair drug concentrations reflect long-term exposure, and multiple successive regimens commonly employed in DR-TB treatment may result in apparent false-positive qualitative and falsely elevated quantitative hair drug levels when prior treatment histories within the hair growth window are not known.
- ItemOpen AccessDiagnostic accuracy of an integrated respiratory guideline in identifying patients with respiratory symptoms requiring screening for pulmonary tuberculosis: a cross-sectional study(BioMed Central Ltd, 2006) English, Rene; Bachmann, Max; Bateman, Eric; Zwarenstein, Merrick; Fairall, Lara; Bheekie, Angeni; Majara, Bosielo; Lombard, Carl; Scherpbier, Robert; Ottomani, SalahBACKGROUND:To evaluate the diagnostic accuracy of the integrated Practical Approach to Lung Health in South Africa (PALSA) guideline in identifying patients requiring bacteriological screening for tuberculosis (TB), and to determine which clinical features best predict suspected and bacteriologically-confirmed tuberculosis among patients with respiratory symptoms. METHODS: A prospective, cross-sectional study in which 1392 adult patients with cough and/or difficult breathing, attending a primary care facility in Cape Town, South Africa, were evaluated by a nurse using the guideline. The accuracy of a nurse using the guideline to identify TB suspects was compared to that of primary care physicians' diagnoses of (1) suspected TB, and (2) proven TB supported by clinical information and chest radiographs. RESULTS: The nurse using the guideline identified 516 patients as TB suspects compared with 365 by the primary care physicians, representing a sensitivity of 76% (95% confidence interval (CI) 71%-79%), specificity of 77% (95% CI 74%-79%), positive predictive value of 53% (95% CI 49%-58%), negative predictive value of 90% (95% CI 88%-92%), and area under the receiver operating characteristic curve (ARUC) of 0.76 (95% CI 0.74-0.79). Sputum results were obtained in 320 of the 365 primary care physicians TB suspects (88%); 40 (13%) of these were positive for TB. Only 4 cases were not identified by the nurse using the guideline. The primary care physicians diagnostic accuracy in diagnosing bacteriologically-confirmed TB (n = 320) was as follows: sensitivity 90% (95% CI 76%-97%), specificity 65% (95% CI 63%-68%), negative predictive value 7% (95% CI 5%-10%), positive predictive value 99.5% (95% CI 98.8%-99.8%), and ARUC 0.78 (95% CI 0.73-0.82). Weight loss, pleuritic pain, and night sweats were independently associated with the diagnosis of bacteriologically-confirmed tuberculosis (positive likelihood ratio if all three present = 16.7, 95% CI 5.9-29.4). CONCLUSION: The PALSA guideline is an effective screening tool for identifying patients requiring bacteriological screening for pulmonary tuberculosis in this primary care setting. This supports the randomized trial finding that use of the guideline increased TB case detection.