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Climatic change will have an impact on production and release of pollen, with consequences for the duration and magnitude of aeroallergen seasonal exposure and allergic diseases. Evaluations of pollen aerobiology in the southern hemisphere have been limited by resourcing and the density of monitoring sites. This review emphasizes inconsistencies in pollen monitoring methods and metrics used globally. Research should consider unique southern hemisphere biodiversity, climate, plant distributions, standardization of pollen aerobiology, automation, and environmental integration. For both hemispheres, there is a clear need for better understanding of likely influences of climate change and comprehending their impact on pollen-related health outcomes.

Chronic urticaria (CU) affects about 1% of the world population of all ages, mostly young and middle-aged women. It usually lasts for several years (> 1 year in 25-75% of patients) and often takes > 1 year before effective management is implemented. It presents as chronic spontaneous urticaria (CSU), chronic inducible urticaria (CIndU) or both in the same person. More than 25% of cases are resistant to H1 -antihistamines, even at higher doses, and third- and fourth-line therapies (omalizumab and ciclosporin) control the disease only in two-thirds of H1 -antihistamine-resistant patients. Here we review the impact of CU on different aspects of patients' quality of life and the burden of this chronic disease for the patient and society. CU may have a strong impact on health-related quality of life (HRQoL), particularly when CSU is associated with angio-oedema and/or CIndU (Dermatology Life Quality Index > 10 in 30% of patients). Comorbidities, such as anxiety and depression, which are present in more than 30% of patients with CSU, compound HRQoL impairment. Severe pruritus and the unpredictable occurrence of weals and angio-oedema are responsible for sleep disorders; sexual dysfunction; limitations on daily life, work and sports activities; interfering with life within the family and in society; and patients' performance at school and work (6% absenteeism and 25% presenteeism). Apart from treatment costs, with annual values between 900 and 2400 purchasing power parity dollars (PPP$) in Europe and the USA, CU is associated with a high consumption of medical resources and other indirect costs, which may reach a total annual cost of PPP$ 15 550.

Background Timely identification of people who are at risk of dying is an important first component of end-of-life care. Clinicians often fail to identify such patients, thus trigger tools have been developed to assist in this process. We aimed to evaluate the performance of a identification tool (based on the Gold Standards Framework Prognostic Indicator Guidance) to predict death at 12 months in a population of hospitalised patients in South Africa. Methods Patients admitted to the acute medical services in two public hospitals in Cape Town, South Africa were enrolled in a prospective observational study. Demographic data were collected from patients and patient notes. Patients were assessed within two days of admission by two trained clinicians who were not the primary care givers, using the identification tool. Outcome mortality data were obtained from patient folders, the hospital electronic patient management system and the Western Cape Provincial death registry which links a unique patient identification number with national death certificate records and system wide electronic records. Results 822 patients (median age of 52 years), admitted with a variety of medical conditions were assessed during their admission. 22% of the cohort were HIV-infected. 218 patients were identified using the screening tool as being in the last year of their lives. Mortality in this group was 56% at 12 months, compared with 7% for those not meeting any criteria. The specific indicator component of the tool performed best in predicting death in both HIV-infected and HIV-uninfected patients, with a sensitivity of 74% (68–81%), specificity of 85% (83–88%), a positive predictive value of 56% (49–63%) and a negative predictive value of 93% (91–95%). The hazard ratio of 12-month mortality for those identified vs not was 11.52 (7.87–16.9, p Conclusions The identification tool is suitable for use in hospitals in low-middle income country setting that have both a high communicable and non-communicable disease burden amongst young patients, the majority under age 60.

Background: cold urticaria (ColdU), that is, the occurrence of wheals or angioedema in response to cold exposure, is classified into typical and atypical forms. The diagnosis of typical ColdU relies on whealing in response to local cold stimulation testing (CST). It can also manifest with cold-induced anaphylaxis (ColdA). We aimed to determine risk factors for ColdA in typical ColdU. Methods: an international, cross-sectional study COLD-CE was carried out at 32 urticaria centers of reference and excellence (UCAREs). Detailed history was taken and CST with an ice cube and/or TempTest(R) performed. ColdA was defined as an acute cold-induced involvement of the skin and/or visible mucosal tissue and at least one of: cardiovascular manifestations, difficulty breathing, or gastrointestinal symptoms. Results: of 551 ColdU patients, 75% (n = 412) had a positive CST and ColdA occurred in 37% (n = 151) of the latter. Cold-induced generalized wheals, angioedema, acral swelling, oropharyngeal/laryngeal symptoms, and itch of earlobes were identified as signs/symptoms of severe disease. ColdA was most commonly provoked by complete cold water immersion and ColdA caused by cold air was more common in countries with a warmer climate. Ten percent (n = 40) of typical ColdU patients had a concomitant chronic spontaneous urticaria (CSU). They had a lower frequency of ColdA than those without CSU (4% vs. 39%, p = .003). We identified the following risk factors for cardiovascular manifestations: previous systemic reaction to a Hymenoptera sting, angioedema, oropharyngeal/laryngeal symptoms, and itchy earlobes. Conclusion: coldA is common in typical ColdU. High-risk patients require education about their condition and how to use an adrenaline autoinjector., GA(2)LEN UCARE Network

Rare Thromboembolic Events among Vaccinated South Africans Among 288,368 South African health care workers who received the Ad26.COV2.S vaccine, no cases of vaccine-induced immune thrombotic thromb...

Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. Methods: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. Results: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11–540) and 307 (14–429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. Conclusions: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. Trial registration: The study is registered with ClinicalTrials.gov (NCT03472040).

PURPOSE OF REVIEW: Immune-mediated adverse drug reactions (IM-ADRs) are many times more common in HIV-infected patients. Usual offending drugs include antiretroviral and antiinfectives, but the burden of specific drug IM-ADRs is population-specific; changing as new and fixed dose combinations enter the market, and drug-resistance patterns demand. This review considers recent literature on epidemiology, mechanisms, clinical management and prevention of IM-ADRs amongst persons living with HIV/AIDS. RECENT FINDINGS: Epidemiological studies continue to describe high rates of delayed hypersensitivity to known offenders, as well as similar reactions in preexposure prophylaxis. IM-ADRs to oral and injectable integrase strand transfer inhibitors are reported with expanding use. The clinical spectrum and management of IM-ADRs occurring in HIV-infected populations is similar to uninfected; with exceptions such as a recently described severe delayed efavirenz DILI with high mortality. Furthermore, the context can be unique, such as the lower than expected mortality in a Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) cohort from a HIV/TB high burden setting. Programmatic data showing the near complete elimination of Abacavir drug hypersensitivity syndrome following implementation of HLA-B57:01 screening is a stellar example of how prevention is possible with mechanistic insight. SUMMARY: IM-ADRs remain a challenge in persons living with HIV. The complexities posed by polypharmacy, overlapping drug toxicities, drug interactions, overlap of IM-ADRs with other diseases, limited alternative drugs, and vulnerable patients with advanced immunosuppression with high mortality, necessitate increased use of drug provocation testing, treat-through and desensitization strategies. There is an urgent need for improved diagnostics and predictive biomarkers for prevention, or to guide treat-through, rechallenge and desensitization approaches.

Background. Delirium is associated with increased mortality and length of hospital stay. Limited data are available from HIV-infected acute hospital admissions in developing countries. We conducted a prospective study of delirium among acute medical admissions in South Africa (SA), a developing country with universal antiretroviral therapy (ART) access and high burdens of tuberculosis (TB) and non-communicable disease. Objectives. To identify the prevalence of, risk factors for and outcomes of delirium in HIV-infected individuals in acute general medical admissions. Methods. Three cohorts of adult acute medical admissions to Groote Schuur and Victoria Wynberg hospitals, Cape Town, SA, were evaluated for prevalent delirium within 24 hours of admission. Reference delirium testing was performed by either consultant physicians or neuropsychologists, using the Confusion Assessment Method. Results. The study included 1 182 acute medical admissions, with 318 (26.9%) HIV-infected. The median (interquartile range) age and CD4 count were 35 (30 - 43) years and 132 (61 - 256) cells/µL, respectively, with 140/318 (44.0%) using ART on admission. The prevalence of delirium was 17.6% (95% confidence interval (CI) 13.7 - 22.1) among HIV-infected patients, and delirium was associated with increased inpatient mortality. In multivariable logistic regression analysis, factors associated with delirium were age ≥55 years (adjusted odds ratio (aOR) 6.95 (95% CI 2.03 - 23.67); p =0.002), and urea ≥15 mmol/L (aOR 4.83 (95% CI 1.7 - 13.44); p =0.003), while ART use reduced risk ( p =0.014). A low CD4 count, an unsuppressed viral load and active TB were not predictors of delirium; nor were other previously reported risk factors such as non-opportunistic acute infections or polypharmacy. Conclusions. Delirium is common and is associated with increased mortality in HIV-infected acute medical admissions in endemic settings, despite increased ART use. Older HIV-infected patients with renal dysfunction are at increased risk for inpatient delirium, while those using ART on admission have a reduced risk.

BACKGROUND: Based on current WHO guidelines, hospitalized tuberculosis (TB) and HIV co-infected patients with CD4 count

International audience; Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

As South Africa continues to battle the second wave of SARS-CoV-2 infections, the imminent arrival of vaccines against COVID-19 offers hope. Vaccine roll-out has been accompanied by heightened media coverage that has created both excitement and anxiety, reporting on the shortened timeline of vaccine trials and approvals, as well as the recent series of anaphylaxis cases associated with the two approved mRNA COVID-19 vaccines. Patients with allergic and other immune-based diseases are subgroups especially concerned about vaccine safety and efficacy. This practice guideline offers broad recommendations for COVID-19 vaccination in various subgroups of allergic and immunebased disease, highlighting risk/benefit evaluation, and where and how routine vaccination should be altered.

Background Patients with previous tuberculosis may have residual DNA in sputum that confounds nucleic acid amplification tests such as Xpert MTB/RIF. Little is known about the frequency of Xpert-positive, culture-negative ("false positive") results in retreatment patients, whether these are distinguishable from true positives, and whether Xpert's automated filter-based wash step reduces false positivity by removing residual DNA associated with nonintact cells. Methods Pretreatment patients (n = 2889) with symptoms of tuberculosis from Cape Town, South Africa, underwent a sputum-based liquid culture and Xpert. We also compared Xpert results from dilutions of intact or heat-lysed and mechanically lysed bacilli. Results Retreatment cases were more likely to be Xpert false-positive (45/321 Xpert-positive retreatment cases were false-positive) than new cases (40/461) (14% [95% confidence interval {CI}, 10%-18%] vs 8% [95% CI, 6%-12%];P= .018). Fewer years since treatment completion (adjusted odds ratio [aOR], 0.85 [95% CI, .73-.99]), less mycobacterial DNA (aOR, 1.14 [95% CI, 1.03-1.27] per cycle threshold [CT]), and a chest radiograph not suggestive of active tuberculosis (aOR, 0.22 [95% CI, .06-.82]) were associated with false positivity. CThad suboptimal accuracy for false positivity: 46% of Xpert-positives with CT> 30 would be false positive, although 70% of false positives would be missed. CT's predictive ability (area under the curve, 0.83 [95% CI, .76-.90]) was not improved by additional variables. Xpert detected nonviable, nonintact bacilli without a change in CTvs controls. Conclusions One in 7 Xpert-positive retreatment patients were culture negative and potentially false positive. False positivity was associated with recent previous tuberculosis, high CT, and a chest radiograph not suggestive of active tuberculosis. Clinicians may consider awaiting confirmatory testing in retreatment patients with CT> 30; however, most false positives fall below this cut-point. Xpert can detect DNA from nonviable, nonintact bacilli.

Delayed immune-mediated adverse drug reactions (IM-ADRs) are defined as reactions occurring more than 6 hours after dosing. They include heterogeneous clinical phenotypes that are typically T-cell-mediated reactions with distinct mechanisms across a wide spectrum of severity from benign exanthems through to life-threatening cutaneous or organ-specific diseases. For mild reactions such as benign exanthem, considerations for delabeling are similar to immediate reactions and may include a graded or single-dose drug challenge with or without preceding skin or patch testing. Evaluation of challenging cases such as the patient who is on multiple drugs at the time a severe delayed IM-ADR occurs should prioritize clinical ascertainment of the most likely phenotype and implicated drug(s). Although not widely available and validated, procedures such as patch testing, delayed intradermal skin testing, and laboratory-based functional drug assays or genetic (human leukocyte antigen) testing may provide valuable information to further help risk stratify patients and identify the likely implicated and/or cross-reactive drug(s). The decision to use a drug challenge as a diagnostic or delabeling tool in a patient with a severe delayed IM-ADR should weigh the risk-benefit ratio, balancing the severity and priority for the treatment of the underlying, and the availability of alternative efficacious and safe treatments.

The potential role for serological tests in the current COVID-19 pandemic has generated very considerable recent interest across many sectors worldwide, inter alia pathologists seeking additional weapons for their armoury of diagnostic tests; epidemiologists seeking tools to gain seroprevalence data that will inform improved models of the spread of disease; research scientists seeking tools to study the natural history of COVID-19 disease; vaccine developers seeking tools to assess vaccine efficacy in clinical trials; and companies and governments seeking tools to aid return-to-work decision-making. However, much of the local debate to date has centred on questions surrounding whether regulatory approval processes are limiting access to serological tests, and has not paused to consider the intrinsically limiting impact of underlying fundamental biology and immunology on where and how different COVID-19 serological tests can usefully be deployed in the response to the current pandemic. We review, from an immunological perspective, recent experimental evidence on the time-dependency of adaptive immune responses following SARS-CoV-2 infection and the impact of this on the sensitivity and specificity of COVID-19 antibody tests made at different time points post infection. We interpret this scientific evidence in terms of mooted clinical applications for current COVID-19 antibody tests in identifying acute infections, in confirming recent or past infections at the individual and population level, and in detecting re-infection and protective immunity. We conclude with guidance on where current COVID-19 antibody tests can make a genuine impact in the pandemic.

Effective treatment for drug-sensitive TB remains a long, multidrug endeavor. Therapeutic complexity is increased by HIV coinfection (>60% of incident TB cases are co-infected in HIV/TB endemic settings) and the growing burden of multi- and extremely drug-resistant TB (MDR- and XDR-TB). CADRs are common adverse reactions in both drug-sensitive and resistant anti-TB regimens, and the majorities are delayed T-cell-mediated reactions. Individual anti-TB drugs cause different CADR phenotypes of varying severity, while SCAR phenotypes such as DRESS, SJS/TEN, and LDE have been associated with many chemically different anti-TB drugs. The key management challenges include (1) multiple possible offending drugs, with a lack of accurate diagnostic testing, (2) high TB-related mortality with prolonged treatment interruptions, and (3) not unnecessarily excluding effective non-culprit anti-TB drugs in CADR patients. We discuss the spectrum of anti-TB drug-associated CADRs and offending drugs, as well as the pragmatic utility of drug provocation testing to identify culprit drugs and minimize treatment interruptions.

Here we will review some breakthroughs in science and translational medicine that are shaping the field of adverse drug reactions (ADR), including cutaneous adverse drugs reactions (CADR) and the subcategory of severe cutaneous adverse reactions (SCAR). This includes the discovery of multiple new associations (genetic and beyond) yielding insight into mechanisms of disease pathogenesis. Further advances will come from personalized/precision medicine initiatives looking at how an individual’s unique combination of genome, epigenome, transcriptome, proteome, metabolome, phenome, and exposome predisposes them to CADR. Multiple disciplines of “omics” (i.e., genomics, epigenomics) stand to contribute to the field. The ultimate goals of CADR research are to improve diagnosis and treatment, but also prevention of disease by predicting reactions before medications are given and before new drugs are developed and used in man.

CADR is more common in HIV-infected persons, although the incidence is declining because of the new safer drugs and early initiation of antiretroviral therapy. The presentation and clinical course does not seem to differ from that in the general population. Antiretrovirals, antituberculosis drugs, and drugs for treating opportunistic infections are most commonly implicated. HIV-associated CADR poses major diagnostic and management challenges because of polypharmacy, overlapping drug toxicities, drug interactions, overlap of CADR with other diseases, and limited alternative drugs. We discuss pragmatic management strategies of HIV-associated CADR focusing on resource-limited settings, where HIV infection and associated CADR are most common.

Adverse drug reactions (ADRs) are associated with significant morbidity, mortality, and cost. The pharmacogenomics of ADRs may encompass "on-target" pharmacologically mediated reactions or "off-target" pharmacologic or immune-mediated ADRs. Immune-mediated ADRs may be associated with immunologic memory of varying duration or without immune memory yet exhibit an immunologic phenotype such as urticaria.On-target pharmacologic ADRs are those that typically develop in a concentration-dependent manner and therefore involve genes associated with drug disposition and/or a known pharmacodynamic target. Reactions with an off-target pharmacologic or immunologic component involve genes associated with diverse pharmacologic, innate, and adaptive immune system pathways. These reactions include non-IgE-mediated mast cell activation, aspirin-exacerbated respiratory disease, nonimmune drug-induced thrombocytopenia, and heparin-induced thrombocytopenia, and also those ADRs with known immunologic memory such as IgE-mediated reactions and T cell-mediated delayed drug reactions.The utility of pharmacogenomic screening is influenced by a variety of economic, genetic, and clinical factors, which determine the overall burden of a particular ADR. Regardless of whether genes associated with drug allergy syndromes translate directly into the clinic as preventive markers, they provide valuable insights into mechanisms and pathogenesis that may help identify future therapeutic targets and guide safer drug design and development.This chapter discusses specific examples of each ADR classification and the associated pharmacogenomic risk factors and will highlight examples where pharmacogenomic associations have been successfully implemented into personalized medicine programs, as well as opportunities for future translation.

Background Urine LAM testing has been approved by the WHO for use in hospitalised patients with advanced immunosuppression. However, sensitivity remains suboptimal. We therefore examined the incremental diagnostic sensitivity of early morning urine (EMU) versus random urine sampling using the Determine® lateral flow lipoarabinomannan assay (LF-LAM) in HIV-TB co-infected patients. Methods Consenting HIV-infected inpatients, screened as part of a larger prospective randomized controlled trial, that were treated for TB, and could donate matched random and EMU samples were included. Thus paired sample were collected from the same patient, LF-LAM was graded using the pre-January 2014, with grade 1 and 2 manufacturer-designated cut-points (the latter designated grade 1 after January 2014). Single sputum Xpert-MTB/RIF and/or TB culture positivity served as the reference standard (definite TB). Those treated for TB but not meeting this standard were designated probable TB. Results 123 HIV-infected patients commenced anti-TB treatment and provided matched random and EMU samples. 33% (41/123) and 67% (82/123) had definite and probable TB, respectively. Amongst those with definite TB LF-LAM sensitivity (95%CI), using the grade 2 cut-point, increased from 12% (5–24; 5/43) to 39% (26–54; 16/41) with random versus EMU, respectively (p = 0.005). Similarly, amongst probable TB, LF-LAM sensitivity increased from 10% (5–17; 8/83) to 24% (16–34; 20/82) (p = 0.001). LF-LAM specificity was not determined. Conclusion This proof of concept study indicates that EMU could improve the sensitivity of LF-LAM in hospitalised TB-HIV co-infected patients. These data have implications for clinical practice. Electronic supplementary material The online version of this article (doi:10.1186/s12879-017-2313-0) contains supplementary material, which is available to authorized users.

Summary Background The Xpert MTB/RIF test for tuberculosis is being rolled out in many countries, but evidence is lacking regarding its implementation outside laboratories, ability to inform same-day treatment decisions at the point of care, and clinical effect on tuberculosis-related morbidity. We aimed to assess the feasibility, accuracy, and clinical effect of point-of-care Xpert MTB/RIF testing at primary-care health-care facilities in southern Africa. Methods In this pragmatic, randomised, parallel-group, multicentre trial, we recruited adults with symptoms suggestive of active tuberculosis from five primary-care health-care facilities in South Africa, Zimbabwe, Zambia, and Tanzania. Eligible patients were randomly assigned using pregenerated tables to nurse-performed Xpert MTB/RIF at the clinic or sputum smear microscopy. Participants with a negative test result were empirically managed according to local WHO-compliant guidelines. Our primary outcome was tuberculosis-related morbidity (measured with the TBscore and Karnofsky performance score [KPS]) in culture-positive patients who had begun anti-tuberculosis treatment, measured at 2 months and 6 months after randomisation, analysed by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT01554384. Findings Between April 12, 2011, and March 30, 2012, we randomly assigned 758 patients to smear microscopy (182 culture positive) and 744 to Xpert MTB/RIF (185 culture positive). Median TBscore in culture-positive patients did not differ between groups at 2 months (2 [IQR 0–3] in the smear microscopy group vs 2 [0·25–3] in the MTB/RIF group; p=0·85) or 6 months (1 [0–3] vs 1 [0–3]; p=0·35), nor did median KPS at 2 months (80 [70–90] vs 90 [80–90]; p=0·23) or 6 months (100 [90–100] vs 100 [90–100]; p=0·85). Point-of-care MTB/RIF had higher sensitivity than microscopy (154 [83%] of 185 vs 91 [50%] of 182; p=0·0001) but similar specificity (517 [95%] 544 vs 540 [96%] of 560; p=0·25), and had similar sensitivity to laboratory-based MTB/RIF (292 [83%] of 351; p=0·99) but higher specificity (952 [92%] of 1037; p=0·0173). 34 (5%) of 744 tests with point-of-care MTB/RIF and 82 (6%) of 1411 with laboratory-based MTB/RIF failed (p=0·22). Compared with the microscopy group, more patients in the MTB/RIF group had a same-day diagnosis (178 [24%] of 744 vs 99 [13%] of 758; p vs 115 [15%] of 758; p=0·0002). Although, by end of the study, more culture-positive patients in the MTB/RIF group were on treatment due to reduced dropout (15 [8%] of 185 in the MTB/RIF group did not receive treatment vs 28 [15%] of 182 in the microscopy group; p=0·0302), the proportions of all patients on treatment in each group by day 56 were similar (320 [43%] of 744 in the MTB/RIF group vs 317 [42%] of 758 in the microscopy group; p=0·6408). Interpretation Xpert MTB/RIF can be accurately administered by a nurse in primary-care clinics, resulting in more patients starting same-day treatment, more culture-positive patients starting therapy, and a shorter time to treatment. However, the benefits did not translate into lower tuberculosis-related morbidity, partly because of high levels of empirical-evidence-based treatment in smear-negative patients. Funding European and Developing Countries Clinical Trials Partnership, National Research Foundation, and Claude Leon Foundation.

Background Genotype® MTBDRsl (MTBDRsl) is a rapid DNA-based test for detecting specific mutations associated with resistance to fluoroquinolones and second-line injectable drugs (SLIDs) in Mycobacterium tuberculosis complex. MTBDRsl version 2.0 (released in 2015) identifies the mutations detected by version 1.0, as well as additional mutations. The test may be performed on a culture isolate or a patient specimen, which eliminates delays associated with culture. Version 1.0 requires a smear-positive specimen, while version 2.0 may use a smear-positive or -negative specimen. We performed this updated review as part of a World Health Organization process to develop updated guidelines for using MTBDRsl. Objectives To assess and compare the diagnostic accuracy of MTBDRsl for: 1. fluoroquinolone resistance, 2. SLID resistance, and 3. extensively drug-resistant tuberculosis, indirectly on a M. tuberculosis isolate grown from culture or directly on a patient specimen. Participants were people with rifampicin-resistant or multidrug-resistant tuberculosis. The role of MTBDRsl would be as the initial test, replacing culture-based drug susceptibility testing (DST), for detecting second-line drug resistance. Search methods We searched the following databases without language restrictions up to 21 September 2015: the Cochrane Infectious Diseases Group Specialized Register; MEDLINE; Embase OVID; Science Citation Index Expanded, Conference Proceedings Citation Index-Science, and BIOSIS Previews (all three from Web of Science); LILACS; and SCOPUS; registers for ongoing trials; and ProQuest Dissertations & Theses A&I. We reviewed references from included studies and contacted specialists in the field. Selection criteria We included cross-sectional and case-control studies that determined MTBDRsl accuracy against a defined reference standard (culture-based DST, genetic sequencing, or both). Data collection and analysis Two review authors independently extracted data and assessed quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We synthesized data for versions 1.0 and 2.0 separately. We estimated MTBDRsl sensitivity and specificity for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis when the test was performed indirectly or directly (smear-positive specimen for version 1.0, smear-positive or -negative specimen for version 2.0). We explored the influence on accuracy estimates of individual drugs within a drug class and of different reference standards. We performed most analyses using a bivariate random-effects model with culture-based DST as reference standard. Main results We included 27 studies. Twenty-six studies evaluated version 1.0, and one study version 2.0. Of 26 studies stating specimen country origin, 15 studies (58%) evaluated patients from low- or middle-income countries. Overall, we considered the studies to be of high methodological quality. However, only three studies (11%) had low risk of bias for the reference standard; these studies used World Health Organization (WHO)-recommended critical concentrations for all drugs in the culture-based DST reference standard. MTBDRsl version 1.0 Fluoroquinolone resistance: indirect testing, MTBDRsl pooled sensitivity and specificity (95% confidence interval (CI)) were 85.6% (79.2% to 90.4%) and 98.5% (95.7% to 99.5%), (19 studies, 2223 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 86.2% (74.6% to 93.0%) and 98.6% (96.9% to 99.4%), (nine studies, 1771 participants, moderate quality evidence). SLID resistance: indirect testing, MTBDRsl pooled sensitivity and specificity were 76.5% (63.3% to 86.0%) and 99.1% (97.3% to 99.7%), (16 studies, 1921 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 87.0% (38.1% to 98.6%) and 99.5% (93.6% to 100.0%), (eight studies, 1639 participants, low quality evidence). Extensively drug-resistant tuberculosis: indirect testing, MTBDRsl pooled sensitivity and specificity were 70.9% (42.9% to 88.8%) and 98.8% (96.1% to 99.6%), (eight studies, 880 participants); direct testing (smear-positive specimen), pooled sensitivity and specificity were 69.4% (38.8% to 89.0%) and 99.4% (95.0% to 99.3%), (six studies, 1420 participants, low quality evidence). Similar to the original Cochrane review, we found no evidence of a significant difference in MTBDRsl version 1.0 accuracy between indirect and direct testing for fluoroquinolone resistance, SLID resistance, and extensively drug-resistant tuberculosis. MTBDRsl version 2.0 Fluoroquinolone resistance: direct testing, MTBDRsl sensitivity and specificity were 97% (83% to 100%) and 98% (93% to 100%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. SLID resistance: direct testing, MTBDRsl sensitivity and specificity were 89% (72% to 98%) and 90% (84% to 95%), smear-positive specimen; 80% (28% to 99%) and 100% (40% to 100%), smear-negative specimen. Extensively drug-resistant tuberculosis: direct testing, MTBDRsl sensitivity and specificity were 79% (49% to 95%) and 97% (93% to 99%), smear-positive specimen; 50% (1% to 99%) and 100% (59% to 100%), smear-negative specimen. We had insufficient data to estimate summary sensitivity and specificity of version 2.0 (smear-positive and -negative specimens) or to compare accuracy of the two versions. A limitation was that most included studies did not consistently use the World Health Organization (WHO)-recommended concentrations for drugs in the culture-based DST reference standard. Authors' conclusions In people with rifampicin-resistant or multidrug-resistant tuberculosis, MTBDRsl performed on a culture isolate or smear-positive specimen may be useful in detecting second-line drug resistance. MTBDRsl (smear-positive specimen) correctly classified around six in seven people as having fluoroquinolone or SLID resistance, although the sensitivity estimates for SLID resistance varied. The test rarely gave a positive result for people without drug resistance. However, when second-line drug resistance is not detected (MTBDRsl result is negative), conventional DST can still be used to evaluate patients for resistance to the fluoroquinolones or SLIDs. We recommend that future work evaluate MTBDRsl version 2.0, in particular on smear-negative specimens and in different settings to account for different resistance-causing mutations that may vary by strain. Researchers should also consider incorporating WHO-recommended critical concentrations into their culture-based reference standards.

Summary Background HIV-associated tuberculosis is difficult to diagnose and results in high mortality. Frequent extra-pulmonary presentation, inability to obtain sputum, and paucibacillary samples limits the usefulness of nucleic-acid amplification tests and smear microscopy. We therefore assessed a urine-based, lateral flow, point-of-care, lipoarabinomannan assay (LAM) and the effect of a LAM-guided anti-tuberculosis treatment initiation strategy on mortality. Methods We did a pragmatic, randomised, parallel-group, multicentre trial in ten hospitals in Africa—four in South Africa, two in Tanzania, two in Zambia, and two in Zimbabwe. Eligible patients were HIV-positive adults aged at least 18 years with at least one of the following symptoms of tuberculosis (fever, cough, night sweats, or self-reported weightloss) and illness severity necessitating admission to hospital. Exclusion criteria included receipt of any anti-tuberculosis medicine in the 60 days before enrolment. We randomly assigned patients (1:1) to either LAM plus routine diagnostic tests for tuberculosis (smear microscopy, Xpert-MTB/RIF, and culture; LAM group) or routine diagnostic tests alone (no LAM group) using computer-generated allocation lists in blocks of ten. All patients were asked to provide a urine sample of at least 30 mL at enrolment, and trained research nurses did the LAM test in patients allocated to this group using the Alere Determine tuberculosis LAM Ag lateral flow strip test (Alere, USA) at the bedside on enrolment. On the basis of a positive test result, the nurses made a recommendation for initiating anti-tuberculosis treatment. The attending physician made an independent decision about whether to start treatment or not. Neither patients nor health-care workers were masked to group allocation and test results. The primary endpoint was 8-week all-cause mortality assessed in the modified intention-to-treat population (those who received their allocated intervention). This trial is registered with ClinicalTrials.gov, number NCT01770730. Findings Between Jan 1, 2013, and Oct 2, 2014, we screened 8728 patients and randomly assigned 2659 to treatment (1336 to LAM, 1323 to no LAM). 108 patients did not receive their allocated treatment, mainly because they did not meet the inclusion criteria, and 23 were excluded from analysis, leaving 2528 in the final modified intention-to-treat analysis (1257 in the LAM group, 1271 in the no LAM group). Overall all-cause 8-week mortality occurred in 578 (23%) patients, 261 (21%) in LAM and 317 (25%) in no LAM, an absolute reduction of 4% (95% CI 1–7). The risk ratio adjusted for country was 0·83 (95% CI 0·73–0·96), p=0·012, with a relative risk reduction of 17% (95% CI 4–28). With the time-to-event analysis, there were 159 deaths per 100 person-years in LAM and 196 per 100 person-years in no LAM (hazard ratio adjusted for country 0·82 [95% CI 0·70–0·96], p=0·015). No adverse events were associated with LAM testing. Interpretation Bedside LAM-guided initiation of anti-tuberculosis treatment in HIV-positive hospital inpatients with suspected tuberculosis was associated with reduced 8-week mortality. The implementation of LAM testing is likely to offer the greatest benefit in hospitals where diagnostic resources are most scarce and where patients present with severe illness, advanced immunosuppression, and an inability to self-expectorate sputum. Funding The European & Developing Countries Clinical Trials Partnership, the South African Medical Research Council, and the South African National Research Foundation.

OBJECTIVE: To examine whether a lipoarabinomannan (LAM) enzyme-linked immunosorbent assay (ELISA) that offers diagnostic utility using urine in patients with tuberculosis (TB) and human immunodeficiency virus (HIV) co-infection can be used in induced sputum to diagnose sputum-scarce patients with suspected TB. DESIGN: LAM was measured in induced sputum samples obtained from 61 consecutively recruited sputum-scarce TB suspects in a tertiary hospital respiratory clinic in South Africa. Liquid culture positivity for Mycobacterium tuberculosis was used as the reference standard. Receiver operating characteristic analysis was used to assess alternative LAM concentration cut-offs. RESULTS: A total of 87% (53/61) of study patients had a valid M. tuberculosis culture result; 49% (23/53) were HIV-infected and 17% (9/53) were culture-positive for M. tuberculosis. Induced sputum smear microscopy and LAM ELISA had an overall sensitivity of 56% (95%CI 27-81); however the specificity of LAM ELISA was 48% (95%CI 34-62) while the positive and negative predictive values were respectively 18% (95%CI 8-36) and 84% (95%CI 65-94). An optimal rule-in cut-off selected by receiver operating characteristic (LAM concentration >5.73 ng/ml) increased test specificity to 98% and reduced sensitivity to 22%. Normalisation of the assay for sample total protein or cell count did not improve diagnostic accuracy. CONCLUSIONS: In this proof-of-concept study the ELISA was not clinically useful for TB diagnosis using induced sputum.

Information regarding the utility of adjunct diagnostic tests in combination with Xpert MTB/RIF (Cepheid, Sunnyvale, CA, USA) is limited. We hypothesised adjunct tests could enhance accuracy and/or reduce the cost of tuberculosis (TB) diagnosis prior to MTB/RIF testing, and rule-in or rule-out TB in MTB/RIF-negative individuals. We assessed the accuracy and/or laboratory-associated cost of diagnosis of smear microscopy, chest radiography (CXR) and interferon-γ release assays (IGRAs; T-SPOT-TB (Oxford Immunotec, Oxford, UK) and QuantiFERON-TB Gold In-Tube (Cellestis, Chadstone, Australia)) combined with MTB/RIF for TB in 480 patients in South Africa. When conducted prior to MTB/RIF: 1) smear microscopy followed by MTB/RIF (if smear negative) had the lowest cost of diagnosis of any strategy investigated; 2) a combination of smear microscopy, CXR (if smear negative) and MTB/RIF (if imaging compatible with active TB) did not further reduce the cost per TB case diagnosed; and 3) a normal CXR ruled out TB in 18% of patients (57 out of 324; negative predictive value (NPV) 100%). When downstream adjunct tests were applied to MTB/RIF-negative individuals, radiology ruled out TB in 24% (56 out of 234; NPV 100%), smear microscopy ruled in TB in 21% (seven out of 24) of culture-positive individuals and IGRAs were not useful in either context. In resource-poor settings, smear microscopy combined with MTB/RIF had the highest accuracy and lowest cost of diagnosis compared to either technique alone. In MTB/RIF-negative individuals, CXR has poor rule-in value but can reliably rule out TB in approximately one in four cases. These data inform upon the programmatic utility of MTB/RIF in high-burden settings.

Xpert MTB/RIF is a novel automated molecular diagnostic recently endorsed by the World Health Organization. However, performance-related data from high HIV prevalence settings are limited.The impact of sample-related factors on performance and the significance of Xpert MTB/RIF-positive culture-negative discordance remain unclear.Xpert MTB/RIF was evaluated using single archived spot-sputum samples from 496 South African patients with suspected TB. Mycobacterium tuberculosis culture positivity and phenotypic resistance to rifampicin served as reference standards.Overall, Xpert MTB/RIF detected 95% (95% confidence interval [CI], 88-98%; 89 of 94) of smear-positive culture-positive cases and the specificity was 94% (91-96%; 320 of 339). The sensitivity in smear-negative cases was 55% (35-73%; 12 of 22) when the analysis was restricted to 1 ml of unprocessed sputum and culture time-to-positivity of less than or equal to 28 days. Compared with smear microscopy (n=94), Xpert MTB/RIF detected an additional 17 cases (n=111) representing an 18% (11-27%; 111 vs. 94) relative increase in the rapid TB case detection rate. Moreover, compared with smear microscopy, the inclusion of Xpert MTB/RIF-positive culture-negative TB cases (ruled-in by an alternative diagnostic method) resulted in the detection of a further 16 cases (n=127), thus significantly increasing the rapid TB case detection rate to 35% (95% CI, 26-45%; 94 to 111 vs. 94 to 127; P0.01), the overall specificity to 99.1% (97-100%; 320 of 323; P0.001), and sensitivity in smear-negative TB to 60% (P=0.12). Performance strongly correlated with smear status and culture time-to-positivity. In patients infected with HIV compared with patients uninfected with HIV Xpert MTB/RIF showed a trend to reduced sensitivity (P=0.09) and significantly reduced negative predictive value (P=0.01). The negative predictive value for rifampicin resistance was 99.4%.XpertMTB/RIF outperformed smear microscopy, established a diagnosis in a significant proportion of patients with smear-negative TB, detected many highly likely TB cases missed by culture, and accurately ruled out rifampicin-resistant TB. Sample-specific factors had limited impact on performance. Performance in patients infected with HIV, especially those with advanced immunosuppression, warrants further study.

Polyvalent immunoglobin, derived from pooled human plasma, can be administered via the intravenous, subcutaneous or intramuscular route. Therapy is standard of care in the treatment of a number of immune-mediated pathologies across disciplines. By volume, the majority is used in neurology (~40%). In primary immunodeficiencies, therapy reconstitutes humoral immunity at replacement doses (0.4 - 0.6 g/kg/month), decreasing infections, and is usually lifelong. However, high doses, usually 2 g/kg total dose over five days, are required for immunomodulation in autoimmune and inflammatory indications. A high-quality evidence base supports use in primary antibody failure, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, acute idiopathic thrombocytopenia, Kawasaki disease and immunobullous diseases. Low-quality evidence shows benefit in many other uncommon autoimmune and immunodeficient conditions. In South Africa, use of immunoglobulin therapy is restricted and, given the cost involved, will likely remain so. Therefore, the incremental benefit over other forms of immunosuppression, particularly corticosteroids, must be assessed carefully on a case-by-case basis. In most cases, therapy will be second-line or 'rescue' and motivation will be required. This short review aims to provide clinicians with the necessary understanding of the therapy, general considerations for use, and evidence base and quality thereof for well-established indications.

BACKGROUND: There are limited data about the epidemiology and treatment-related outcomes associated with capreomycin resistance in patients with XDR-TB. Capreomycin achieves high serum concentrations relative to MIC but whether capreomycin has therapeutic benefit despite microbiological resistance remains unclear. METHODS: We reviewed the susceptibility profiles and outcomes associated with capreomycin usage in patients diagnosed with XDR-TB between August 2002 and October 2012 in two provinces of South Africa. Patients whose isolates were genotypically tested for capreomycin resistance were included in the analysis. RESULTS: Of 178 XDR-TB patients 41% were HIV-infected. 87% (154/178) isolates contained a capreomycin resistance-conferring mutation [80% (143/178) rrs A1401G and 6% (11/178) were heteroresistant (containing both the rrs A1401G mutation and wild-type sequences)]. Previous MDR-TB treatment, prior usage of kanamycin, or strain type was not associated with capreomycin resistance. 92% (163/178) of XDR-TB patients were empirically treated with capreomycin. Capreomycin resistance decreased the odds of sputum culture conversion. In capreomycin sensitive and resistant persons combined weight at diagnosis was the only independent predictor for survival (p=

Background Accurate and rapid tests for tuberculosis (TB) drug resistance are critical for improving patient care and decreasing the transmission of drug-resistant TB. Genotype®MTBDRsl (MTBDRsl) is the only commercially-available molecular test for detecting resistance in TB to the fluoroquinolones (FQs; ofloxacin, moxifloxacin and levofloxacin) and the second-line injectable drugs (SLIDs; amikacin, kanamycin and capreomycin), which are used to treat patients with multidrug-resistant (MDR-)TB. Objectives To obtain summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and extensively drug-resistant TB (XDR-TB; defined as MDR-TB plus resistance to a FQ and a SLID) when performed (1) indirectly (ie on culture isolates confirmed as TB positive) and (2) directly (ie on smear-positive sputum specimens). To compare summary estimates of the diagnostic accuracy of MTBDRsl for FQ resistance, SLID resistance and XDR-TB by type of testing (indirect versus direct testing). The populations of interest were adults with drug-susceptible TB or drug-resistant TB. The settings of interest were intermediate and central laboratories. Search methods We searched the following databases without any language restriction up to 30 January 2014: Cochrane Infectious Diseases Group Specialized Register; MEDLINE; EMBASE; ISI Web of Knowledge; MEDION; LILACS; BIOSIS; SCOPUS; the metaRegister of Controlled Trials; the search portal of the World Health Organization International Clinical Trials Registry Platform; and ProQuest Dissertations & Theses A&I. Selection criteria We included all studies that determined MTBDRsl accuracy against a defined reference standard (culture-based drug susceptibility testing (DST), genetic testing or both). We included cross-sectional and diagnostic case-control studies. We excluded unpublished data and conference proceedings. Data collection and analysis For each study, two review authors independently extracted data using a standardized form and assessed study quality using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. We performed meta-analyses to estimate the pooled sensitivity and specificity of MTBDRsl for FQ resistance, SLID resistance, and XDR-TB. We explored the influence of different reference standards. We performed the majority of analyses using a bivariate random-effects model against culture-based DST as the reference standard. Main results We included 21 unique studies: 14 studies reported the accuracy of MTBDRsl when done directly, five studies when done indirectly and two studies that did both. Of the 21 studies, 15 studies (71%) were cross-sectional and 11 studies (58%) were located in low-income or middle-income countries. All studies but two were written in English. Nine (43%) of the 21 included studies had a high risk of bias for patient selection. At least half of the studies had low risk of bias for the other QUADAS-2 domains. As a test for FQ resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 83.1% (95% confidence interval (CI) 78.7% to 86.7%) and the pooled specificity was 97.7% (95% CI 94.3% to 99.1%), respectively (16 studies, 1766 participants; 610 confirmed cases of FQ-resistant TB; moderate quality evidence). When performed directly, the pooled sensitivity was 85.1% (95% CI 71.9% to 92.7%) and the pooled specificity was 98.2% (95% CI 96.8% to 99.0%), respectively (seven studies, 1033 participants; 230 confirmed cases of FQ-resistant TB; moderate quality evidence). For indirect testing for FQ resistance, four (0.2%) of 1766 MTBDRsl results were indeterminate, whereas for direct testing 20 (1.9%) of 1033 were MTBDRsl indeterminate (P < 0.001). As a test for SLID resistance measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 76.9% (95% CI 61.1% to 87.6%) and the pooled specificity was 99.5% (95% CI 97.1% to 99.9%), respectively (14 studies, 1637 participants; 414 confirmed cases of SLID-resistant TB; moderate quality evidence). For amikacin resistance, the pooled sensitivity and specificity were 87.9% (95% CI 82.1% to 92.0%) and 99.5% (95% CI 97.5% to 99.9%), respectively. For kanamycin resistance, the pooled sensitivity and specificity were 66.9% (95% CI 44.1% to 83.8%) and 98.6% (95% CI 96.1% to 99.5%), respectively. For capreomycin resistance, the pooled sensitivity and specificity were 79.5% (95% CI 58.3% to 91.4%) and 95.8% (95% CI 93.4% to 97.3%), respectively. When performed directly, the pooled sensitivity for SLID resistance was 94.4% (95% CI 25.2% to 99.9%) and the pooled specificity was 98.2% (95% CI 88.9% to 99.7%), respectively (six studies, 947 participants; 207 confirmed cases of SLID-resistant TB, 740 SLID susceptible cases of TB; very low quality evidence). For indirect testing for SLID resistance, three (0.4%) of 774 MTBDRsl results were indeterminate, whereas for direct testing 53 (6.1%) of 873 were MTBDRsl indeterminate (P < 0.001). As a test for XDR-TB measured against culture-based DST, the pooled sensitivity of MTBDRsl when performed indirectly was 70.9% (95% CI 42.9% to 88.8%) and the pooled specificity was 98.8% (95% CI 96.1% to 99.6%), respectively (eight studies, 880 participants; 173 confirmed cases of XDR-TB; low quality evidence). Authors' conclusions In adults with TB, a positive MTBDRsl result for FQ resistance, SLID resistance, or XDR-TB can be treated with confidence. However, MTBDRsl does not detect approximately one in five cases of FQ-resistant TB, and does not detect approximately one in four cases of SLID-resistant TB. Of the three SLIDs, MTBDRsl has the poorest sensitivity for kanamycin resistance. MTBDRsl will miss between one in four and one in three cases of XDR-TB. The diagnostic accuracy of MTBDRsl is similar when done using either culture isolates or smear-positive sputum. As the location of the resistance causing mutations can vary on a strain-by-strain basis, further research is required on test accuracy in different settings and, if genetic sequencing is used as a reference standard, it should examine all resistance-determining regions. Given the confidence one can have in a positive result, and the ability of the test to provide results within a matter of days, MTBDRsl may be used as an initial test for second-line drug resistance. However, when the test reports a negative result, clinicians may still wish to carry out conventional testing.

The determinants of Xpert MTB/RIF sensitivity, a widely used PCR test for the diagnosis of tuberculosis (TB) are poorly understood. We compared culture time-to-positivity (TTP; a surrogate of bacterial load), MTB/RIF TB-specific and internal positive control (IPC)-specific CT values and clinical characteristics in patients with suspected TB who provided expectorated (n = 438) or induced sputum (n = 128), tracheal aspirates (n = 71), bronchoalveolar lavage fluid (n = 152), pleural fluid (n = 76), cerebral spinal fluid (CSF; n = 152), pericardial fluid (n = 131), or urine (n = 173) specimens. Median bacterial load (TTP in days) was the strongest associate of MTB/RIF positivity in each fluid. TTP correlated with CT values in pulmonary specimens but not extrapulmonary specimens (Spearman's coefficient 0.5043 versus 0.1437; p = 0.030). Inhibition affected a greater proportion of pulmonary specimens than extrapulmonary specimens (IPC CT > 34: 6% (47/731) versus 1% (4/381; p < 0.0001). Pulmonary specimens had greater load than extrapulmonary specimens [TTPs (interquartile range) of 11 (7–16) versus 22 (18–33.5) days; p < 0.0001]. HIV-infection was associated with a decreased likelihood of MTB/RIF-positivity in pulmonary specimens but an increased likelihood in extrapulmonary specimens. Mycobacterial load, which displays significant variation across different body compartments, is the main determinant of MTB/RIF-positivity rather than PCR inhibition. MTB/RIF CT is a poor surrogate of load in extrapulmonary specimens.

Background: 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

In tuberculosis-endemic settings, patients are often treated empirically, meaning that they are placed on treatment based on clinical symptoms or tests that do not provide a microbiological diagnosis (eg, chest radiography). New tests for tuberculosis, such as the Xpert MTB/RIF assay (Cepheid, Sunnyvale, CA, USA), are being implemented at substantial cost. To inform policy and rationally drive implementation, data are needed for how these tests affect morbidity, mortality, transmission, and population-level tuberculosis burden. If people diagnosed by use of new diagnostics would have received empirical treatment a few days later anyway, then the incremental benefit might be small. Will new diagnostics substantially improve outcomes and disease burden, or simply displace empirical treatment? Will the extent and accuracy of empirical treatment change with the introduction of a new test? In this Personal View, we review emerging data for how empirical treatment is frequently same-day, and might still be the predominant form of treatment in high-burden settings, even after Xpert implementation; and how Xpert might displace so-called true-positive, rather than false-positive, empirical treatment. We suggest types of studies needed to accurately assess the effect of new tuberculosis tests and the role of empirical treatment in real-world settings. Until such questions can be addressed, and empirical treatment is appropriately characterised, we postulate that the estimated population-level effect of new tests such as Xpert might be substantially overestimated.

The accuracy and impact of new tuberculosis (TB) tests, such as Xpert MTB/RIF, when performed on bronchoalveolar lavage fluid (BALF) obtained from patients with sputum-scarce or smear-negative TB is unclear.South African patients with suspected pulmonary TB (n=160) who were sputum-scarce or smear-negative underwent bronchoscopy. MTB/RIF was performed on uncentrifuged BALF (1 ml) and/or a resuspended pellet of centrifuged BALF (∼10 ml). Time to TB detection and anti-TB treatment initiation were compared between phase one, when MTB/RIF was performed as a research tool, and phase two, when it was used for patient management.27 of 154 patients with complete data had culture-confirmed TB. Of these, a significantly lower proportion were detected by smear microscopy compared with MTB/RIF (58%, 95% CI 39% to 75% versus 93%, 77% to 98%; p0.001). Of the 127 patients who were culture negative, 96% (91% to 98%) were MTB/RIF negative. When phase two was compared with phase one, MTB/RIF reduced the median days to TB detection (29 (18-41) to 0 (0-0); p0.001). However, more patients initiated empirical therapy (absence of a positive test in those commencing treatment) in phase one versus phase two (79% (11/14) versus 28% (10/25); p=0.026). Consequently, there was no detectable difference in the overall proportion of patients initiating treatment (26% (17/67; 17% to 37%) versus 36% (26/73; 26% to 47%); p=0.196) or the days to treatment initiation (10 (1-49) versus 7 (0-21); p=0.330). BALF centrifugation, HIV coinfection and a second MTB/RIF did not result in detectable changes in accuracy.MTB/RIF detected TB cases more accurately and more rapidly than smear microscopy and significantly reduced the rate of empirical treatment.

Objectives. Hospitalisation for medical illness has ongoing impact on individuals, healthcare services and society beyond discharge. This study’s objective was to determine the 12-month mortality and functional outcomes of patients admitted to the acute medical service at Groote Schuur Hospital (GSH). Methods. Follow-up, using the hospital records system and provincial death registry, together with telephonic interviews or home visits, was attempted for 465 medical inpatients admitted to GSH between 14 September and 16 November 2009. Functional outcomes were assessed using the Katz activities of daily living (ADL) score and Barthel index (BI). Outcome measures. The major study outcomes included: 12-month mortality (overall and unexpected), changes in functional status and pre- and post-admission employment rates. Results. Inpatient mortality was 11%. At 12-month follow-up, 35% (145/415) were deceased and 30% (125/415) could not be traced; 38% (55/145) of deaths were considered expected and unexpected mortality was associated with age >40 years (p=0.02) and an admission urea >7.0 mmol/l (p=0.004). Katz ADL deteriorated in 15% (21/143) of interviewed patients and was associated with age >50 years (p=0.005); 23% (33/143) had improved Katz ADL associated with admission human immunodeficiency virus (HIV) (p=0.01), tuberculosis (TB) infection (p=0.05) and sepsis (p=0.02). Employment rates declined from 41% (59/145) pre-admission to 18% (26/145) at 12 months (p

BACKGROUND: 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 [

Introduction Tuberculosis remains a significant global disease burden with an estimated 9 million new cases and 1.5 million deaths in 2013. BCG continues to be the only licensed TB vaccine, however it is poorly efficacious against adult pulmonary TB disease and there is a desperate need for a better vaccine to provide greater and more consistent protection. Development of such a vaccine has been hampered by the lack of reliable and validated correlates of protection. A human mycobacterial challenge model, using BCG as a surrogate for Mycobacterium tuberculosis challenge would facilitate improved vaccine selection for progression into future field efficacy testing. In this study we evaluate the effect of two BCG strains at two doses to optimise this model. Methods 40 healthy BCG-naive adults were assigned to one of four groups to receive intradermal BCG SSI or BCG Tice at standard or high dose. Two weeks following BCG challenge, skin biopsy from the BCG challenge site was performed. Volunteers were followed up for 28 days from challenge to assess reactogenicity and ensure no safety concerns. BCG mycobacterial load was quantified by solid culture and quantitative PCR. Results BCG, regardless of strain or dose, was tolerated well and reactogenicity was similar between groups. BCG strain did not significantly affect BCG recovery from skin biopsy, however there was significantly greater recovery from the high dose challenge groups compared with the standard dose. Consistent with previous findings there was an inverse correlation between ex-vivo IFN-γ ELISpot responses to PPD and amount of BCG recovered from the skin biopsies. Conclusions High dose BCG challenge regardless of strain used, significantly improves the sensitivity of this human mycobacterial challenge model. Practical reasons favour the use of BCG SSI over BCG Tice, as BCG SSI is licensed for intradermal administration in the UK and preparation is more straightforward with less product wastage or variability in dose between vials of BCG SSI. Looking ahead we plan to use this optimised BCG SSI challenge model to evaluate novel TB vaccine candidates in order to improve the selection of which vaccines then progress to expensive field efficacy trials.

We would like to congratulate Catharina Boehme and colleagues (April 30, p 1495) on their study, the results of which show the excellent performance of Xpert MTB/RIF in health facilities in high-burden, resource-poor settings. The sensitivity of Xpert MTB/RIF was not reduced in individuals infected with HIV compared with those who were uninfected and convincingly outperformed smear microscopy. Thus, Xpert MTB/RIF represents a fundamental advance in the diagnosis of tuberculosis. We have shown a diminished negative predictive value (NPV) and negative likelihood ratio (LR) of Xpert MTB/RIF for the detection of tuberculosis in individuals infected with HIV versus those who were uninfected, suggesting that substantial numbers of patients infected with HIV who are negative by Xpert MTB/RIF actually have active tuberculosis. The likelihood of this false-negativity occurring increased with advanced immunosuppression. The conclusiveness of our fi ndings was limited by our retrospective study design and small sample size. However, these data have now been prospectively confi rmed in 6648 patients by Boehme and colleagues. In their study, the NPV was 91·3% (389/426; 95% CI 88·3–93·6) in patients infected with HIV versus 96·0% (748/779; 94·4–97·2; p

Background The successful cure of tuberculosis (TB) is dependent on adherence to treatment. Various factors influence adherence, however, few are easily modifiable. There are limited data regarding correlates of psychological distress and their association with non-adherence to anti-TB treatment. Methods In a trial of a new TB test, we measured psychological distress (K-10 score), TB-related health literacy, and morbidity (TBscore), prior to diagnosis in 1502 patients with symptoms of pulmonary TB recruited from clinics in Cape Town (n = 419), Harare (n = 400), Lusaka (n = 400), Durban (n = 200), and Mbeya (n = 83). Socioeconomic, demographic, and alcohol usage-related data were captured. Patients initiated on treatment had their DOTS cards reviewed at two-and six-months. Results 22 %(95 % CI: 20 %, 25 %) of patients had severe psychological distress (K-10 ≥ 30). In a multivariable linear regression model, increased K-10 score was independently associated with previous TB [estimate (95 % CI) 0.98(0.09-1.87); p = 0.0304], increased TBscore [1(0.80, 1.20); p