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BackgroundThe WHO-recommended tuberculosis screening and diagnostic algorithm in ambulatory people living with HIV is a four-symptom screen (known as the WHO-recommended four symptom screen [W4SS]) followed by a WHO-recommended molecular rapid diagnostic test (eg Xpert MTB/RIF [hereafter referred to as Xpert]) if W4SS is positive. To inform updated WHO guidelines, we aimed to assess the diagnostic accuracy of alternative screening tests and strategies for tuberculosis in this population.MethodsIn this systematic review and individual participant data meta-analysis, we updated a search of PubMed (MEDLINE), Embase, the Cochrane Library, and conference abstracts for publications from Jan 1, 2011, to March 12, 2018, done in a previous systematic review to include the period up to Aug 2, 2019. We screened the reference lists of identified pieces and contacted experts in the field. We included prospective cross-sectional, observational studies and randomised trials among adult and adolescent (age ≥10 years) ambulatory people living with HIV, irrespective of signs and symptoms of tuberculosis. We extracted study-level data using a standardised data extraction form, and we requested individual participant data from study authors. We aimed to compare the W4SS with alternative screening tests and strategies and the WHO-recommended algorithm (ie, W4SS followed by Xpert) with Xpert for all in terms of diagnostic accuracy (sensitivity and specificity), overall and in key subgroups (eg, by antiretroviral therapy [ART] status). The reference standard was culture. This study is registered with PROSPERO, CRD42020155895.FindingsWe identified 25 studies, and obtained data from 22 studies (including 15 666 participants; 4347 [27·7%] of 15 663 participants with data were on ART). W4SS sensitivity was 82% (95% CI 72-89) and specificity was 42% (29-57). C-reactive protein (≥10 mg/L) had similar sensitivity to (77% [61-88]), but higher specificity (74% [61-83]; n=3571) than, W4SS. Cough (lasting ≥2 weeks), haemoglobin (

Background: QuantiFERON Gold Plus (Plus) assay has two approved methods for blood collection: direct in-tube (Plus direct) or the transfer of blood from a lithium heparin tube (Plus transfer). Currently, there is little data comparing the results of Plus and the QuantiFERON Gold In-Tube (Gold) based on blood collection. Methods: In 2017, high risk healthcare workers undergoing annual tuberculosis infection screening at Houston Methodist Hospital, a private hospital in the Texas Medical Center (Houston, TX, U.S.A.) were consented and enrolled in a study comparing the Gold-in-tube (Gold), Plus direct in-tube, and Plus transfer assays. Blood was drawn concurrently for all 3 assays. Results: Phlebotomy occurred on 300 consecutive, consented and enrolled participants in the study. The proportion of positive test results for the Gold, Plus direct and Plus transfer assays were 10% (29/300), 12% (35/299) and 17% (51/299), respectively. The agreement in the results of Gold versus Plus direct, Gold versus Plus transfer, and Plus direct versus Plus transfer was 91%, kappa (κ) = 0.56; 91%, κ = 0.59; and 85%, κ = 0.37, respectively. Conclusions: Among high risk healthcare workers in a low prevalence tuberculosis setting, the Gold Plus assay had a higher proportion of positive results than the Gold in-tube assay. The agreement between the Gold, Plus direct and Plus transfer assays was unexpectedly low for simultaneously obtained samples. Blood transfer using lithium heparin offers individual clinics and public health programs greater ability to customize protocols, but variability of results still exists. [ABSTRACT FROM AUTHOR]

Interferon-γ release assays (IGRAs) are the preferred diagnostic test for tuberculosis (TB) infection in at-risk populations in developed countries. However, IGRAs have high false-negative rates in patients with TB disease. Population-based studies assessing the factors associated with negative IGRA results in TB patients have not been performed. Using statewide TB surveillance data of culture-confirmed TB patients in Texas, USA, during 2013-2015, we describe the patient characteristics and treatment outcomes associated with false-negative IGRA results. Among 2,854 TB patients, 1,527 (53.5%) had an IGRA result; 97.4% (1,487/1,527) of those had a positive (87.7%) or negative (12.3%) result. Older age, HIV co-infection, non-Hispanic white race/ethnicity, and being tested with T-SPOT.TB were associated with negative IGRA results. TB patients with negative IGRA results had a higher mortality, potentially due to delayed treatment. Healthcare providers should consider these risk factors when making decisions for patients with suspected TB and negative IGRA results and potentially provide treatment. [ABSTRACT FROM AUTHOR]

Background: Tracking the dissemination of specific Mycobacterium tuberculosis (Mtb) strains using genotyped Mtb isolates from tuberculosis patients is a routine public health practice in the United States. The present study proposes a standardized cluster investigation method to identify epidemiologic-linked patients in Mtb genotype clusters. The study also attempts to determine the proportion of epidemiologic-linked patients the proposed method would identify beyond the outcome of the conventional contact investigation. Methods: The study population included Mtb culture positive patients from Georgia, Maryland, Massachusetts and Houston, Texas. Mtb isolates were genotyped by CDC's National TB Genotyping Service (NTGS) from January 2006 to October 2010. Mtb cluster investigations (CLIs) were conducted for patients whose isolates matched exactly by spoligotyping and 12-locus MIRU-VNTR. CLIs were carried out in four sequential steps: (1) Public Health Worker (PHW) Interview, (2) Contact Investigation (CI) Evaluation, (3) Public Health Records Review, and (4) CLI TB Patient Interviews. Comparison between patients whose links were identified through the study's CLI interviews (Step 4) and patients whose links were identified earlier in CLI (Steps 1-3) was conducted using logistic regression. Results: Forty-four clusters were randomly selected from the four study sites (401 patients in total). Epidemiologic links were identified for 189/401 (47%) study patients in a total of 201 linked patient-pairs. The numbers of linked patients identified in each CLI steps were: Step 1 - 105/401 (26.2%), Step 2 - 15/388 (3.9%), Step 3 - 41/281 (14.6%), and Step 4 - 28/119 (30%). Among the 189 linked patients, 28 (14.8%) were not identified in previous CI. No epidemiologic links were identified in 13/44 (30%) clusters. Conclusions: We validated a standardized and practical method to systematically identify epidemiologic links among patients in Mtb genotype clusters, which can be integrated into the TB control and prevention programs in public health settings. The CLI interview identified additional epidemiologic links that were not identified in previous CI. One-third of the clusters showed no epidemiologic links despite being extensively investigated, suggesting that some improvement in the interviewing methods is still needed. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) surveillance among the homeless is not supported by the political will necessary for TB elimination.We merged the first stakeholder-accepted enumeration of homeless persons with existing surveillance data to assess TB risk among the homeless in Houston, Texas. The average incidence per 100 000 was 411 among homeless and 9.5 among housed persons. The homeless were more likely than the housed to be US-born, clustered, and in a larger-sized cluster.Multivariate analysis revealed that TB rates among the homeless were driven not by comorbidities but by social determinants. Homeless patients were hospitalized more days than the housed and required more follow-up time. Reporting of TB rates for populations with known health disparities could help reframe TB prevention and better target limited funds. [ABSTRACT FROM AUTHOR]

Background: Tuberculosis (TB) of the central nervous system (CNSTB) is associated with higher mortality rates than other forms of TB. Epidemiologic associations with and prognostic indicators of CNSTB have not been assessed in a large US population-based study.Methods: Between 1995 and 2004 and using a population-based active surveillance study, we compared patients with CNSTB to patients with TB affecting sites other than CNS (non-CNSTB) with respect to sociodemographic, clinical and Mycobacterium tuberculosis genotype variables. Risk factors associated with mortality at 180 days were compared between the 2 groups.Results: We enrolled 92 patients with CNSTB and 3570 with non-CNSTB. HIV co-infection was present in 31 (33.7%) of the CNSTB cases. In a Cox proportion hazard model, we found that CNSTB patients who died within 180 days were more likely to be older (HR 1.06, 95% CI 1.02-1.10), have a positive MTB culture from a CNS source (HR 5.11, 95% CI 1.06-24.62) and have hydrocephalus (HR 10.62, 95% CI 3.28-34.36) than patients who survived CNSTB. HIV co-infection association with mortality was not statistically significant (HR 1.74, 95% CI 0.35-8.62).Conclusions: In our cohort, hydrocephalus was the most important predictor of mortality post-CNSTB diagnosis. [ABSTRACT FROM AUTHOR]

Background: Alcohol mediates detrimental alterations in the immune response to Mycobacterium tuberculosis. The association between quantity and frequency of alcohol use and the prevalence of cavitary disease in tuberculosis (TB) has not been analyzed. To investigate the relationship of alcohol use and the prevalence of cavitary disease in a 6-year population-based data set of individuals with TB. Methods: We assessed quantity and frequency of alcohol use (daily alcohol use, years of alcohol use, and lifetime alcohol use) with a standardized questionnaire. The study group consisted of 1,250 patients analyzed for cavitary disease (HIV sero-negative subjects that were 18 years or older). Significant covariates for cavitary disease were entered into multiple logistic regression models. Results: Although daily alcohol use, years of alcohol use, and alcohol use 30 days or 6 months before symptom onset were significant predictors of cavitary disease in univariate analysis, no independent associations were found between alcohol use and cavitary disease in the multivariate analysis. Only diabetes mellitus was independently associated with cavitary disease at any level or frequency of alcohol use. Conclusion: Alcohol use is not independently associated with increased prevalence of cavitary disease in adult patients with TB. [ABSTRACT FROM AUTHOR]

To examine trends in the incidence and epidemiology of cryptococcosis, active, population-based surveillance was conducted during 1992-2000 in 2 areas of the United States (the Atlanta, Georgia, and Houston, Texas, metropolitan areas; combined population, 7.4 million). A total of 1491 incident cases were detected, of which 1322 (89%) occurred in HIV-infected persons. The annual incidence of cryptococcosis per 1000 persons with AIDS decreased significantly during the study period, from 66 in 1992 to 7 in 2000 in the Atlanta area, and from 24 in 1993 to 2 in 2000 in the Houston area. Poisson regression analysis revealed that African American persons with AIDS were more likely than white persons with AIDS to develop disease. Less than one-third of all HIV-infected persons with cryptococcosis were receiving antiretroviral therapy before diagnosis. Our findings suggest that HIV-infected persons who continue to develop cryptococcosis in the era of highly active antiretroviral therapy (HAART) in the United States are those with limited access to health care. More efforts are needed to expand the availability of HAART and routine HIV care services to these persons. [ABSTRACT FROM AUTHOR]

Supplemental Digital Content is available in the text. Background: Cardiac magnetic resonance techniques permit quantification of the myocardial extracellular volume fraction (ECV), representing a surrogate marker of reactive interstitial fibrosis, and late gadolinium enhancement (LGE), representing replacement fibrosis or scar. ECV and LGE have been independently linked with heart failure (HF) events. In deriving ECV, coronary artery disease type LGE, but not non-coronary artery disease type LGE, has been consistently excluded. We examined the associations between LGE, global ECV derived from myocardial tissue segments free of any detectable scar, and subsequent HF events. Methods: Mid short-axis T1 maps were divided into 6 cardiac segments, each classified as LGE absent or present. Global ECV was derived from only segments without LGE. ECV was considered elevated if >30%, the upper 95% bounds of a reference group without known cardiac disease (n=28). Patients were divided into 4 groups by presence of elevated ECV and of any LGE. Subsequent HF hospitalization and any death were ascertained. Their relationship with ECV was examined separately and as a composite with Cox proportional hazard models. Results: Of 1604 serial patients with T1 maps, 1255 were eligible after exclusions and followed over a median 26.3 (interquartile range, 15.9–37.5) months. Patients with elevated ECV had increased risk for death (hazard ratio [HR] 2.45 [95% CI, 1.76–3.41]), HF hospitalization (HR, 2.45 [95% CI, 1.77–3.40]), and a combined end point of both outcomes (HR, 2.46 [95% CI, 1.94–3.14]). After adjustments for covariates including LGE, the relationship persisted for death (HR, 1.82 [95% CI, 1.28–2.59]), hospitalization (HR, 1.60 [95% CI, 1.12–2.27]), and combined end points (HR, 1.73 [95% CI, 1.34–2.24]). Conclusions: ECV measures of diffuse myocardial fibrosis were associated with HF outcomes, despite exclusion of replacement fibrosis segments from their derivation and even among patients without any scar. ECV may have a synergistic role with LGE in HF risk assessment. [ABSTRACT FROM AUTHOR]

Abstract: Tuberculosis genotypic clustering is used as a proxy for recent transmission. The association between clustering and recent transmission becomes problematic when the genotyping method lacks specificity in defining a cluster, as well as for clusters with extensive jurisdictional histories and/or common genotypes. We investigated the four largest spoligotype/12 loci MIRU-VNTR-defined clusters in Harris County, Texas from 2006–2012 to determine their historical contribution to tuberculosis morbidity, estimate the contributions from recent and remote transmission, and determine the impact of secondary genotyping on cluster definition. The clusters contained 189, 64, 51 and 38 cases. Each cluster was linked to cluster(s) previously identified by Houston Tuberculosis Initiative; 3 since 1995 and the fourth in 2002. Among cases for which timing of Mycobacterium tuberculosis transmission relative to tuberculosis disease could be ascertained, nearly equal proportions were associated with recent and remote transmission. The extent to which genotyping with an additional 12 MIRU-VNTR loci modified the cluster definition varied from little or no impact for the two smaller clusters to moderate impact for the larger clusters. Tuberculosis control measures to reduce morbidity associated with large clusters must involve strategies to identify and treat individuals who recently acquired infection, as well as persons infected for years. [Copyright &y& Elsevier]

Summary: Background: Multidrug-resistant (MDR) tuberculosis is a potential threat to tuberculosis elimination, but the extent of MDR tuberculosis disease in the USA that is attributable to transmission within the country is unknown. We assessed transmission of MDR tuberculosis and potential contributing factors in the USA. Methods: In a cross-sectional study, clinical, demographic, epidemiological, and Mycobacterium tuberculosis genotype data were obtained during routine surveillance of all verified cases of MDR tuberculosis reported from eight states in the USA (California from Jan 1, 2007, to Dec 31, 2009; Texas from Jan 1, 2007, to March 31, 2009; and the states of Colorado, Maryland, Massachusetts, New York, Tennessee, and Washington from Jan 1, 2007 to Dec 31, 2008). In-depth interviews and health-record abstraction were done for all who consented to ascertain potential interpersonal connections. Findings: 168 cases of MDR tuberculosis were reported in the eight states during our study period. 92 individuals (55%) consented to in-depth interview. 20 (22%) of these individuals developed MDR tuberculosis as a result of transmission in the USA; a source case was identified for eight of them (9%). 20 individuals (22%) had imported active tuberculosis (ie, culture-confirmed disease within 3 months of entry into the USA). 38 (41%) were deemed to have reactivation of disease, of whom 14 (15%) had a known previous episode of tuberculosis outside the USA. Five individuals (5%) had documented treatment of a previous episode in the USA, and so were deemed to have relapsed. For nine cases (10%), insufficient evidence was available to definitively classify reason for presentation. Interpretation: About a fifth of cases of MDR tuberculosis in the USA can be linked to transmission within the country. Many individuals acquire MDR tuberculosis before entry into the USA. MDR tuberculosis needs to be diagnosed rapidly to reduce potential infectious periods, and clinicians should consider latent tuberculosis infection treatment—tailored to the results of drug susceptibility testing of the putative source case—for exposed individuals. Funding: Centers for Disease Control and Prevention. [Copyright &y& Elsevier]

Objective. To investigate the transmission dynamics of pediatric tuberculosis (TB) by analyzing the clinical characteristics with the molecular profiles of Mycobacterium tuberculosis isolates during a 5-year period. Methods. A retrospective review of a prospective population-based active surveillance and molecular epidemiology project was conducted in private and public pediatric clinics within Houston and Harris County, Texas. The study population consisted of patients who had pediatric TB diagnosed from October 1, 1995, through September 30, 2000. Cases and potential source cases (PSC) were interviewed using a standardized questionnaire. Available Mycobacterium tuberculosis isolates from cases and PSCs were characterized and compared by IS6110 restriction fragment length polymorphism, spoligotyping, and genetic group assignment. Clinical characteristics were described, and molecular characterizations were compared. Data were analyzed by using EpiInfo 6.02b and SAS 8.2. Results. A total of 220 (92%) of 238 pediatric TB cases were included. Epidemiologic and clinical findings were consistent with previous studies. Molecular profiles from 3 cases did not match the profile of PSC. Four previously unknown PSCs were identified using molecular techniques. Fifty-one (71.8%) of 71 isolates matched at least 1 other Houston Tuberculosis Initiative TB database isolate and were grouped into 33 molecular clusters. Cases were more likely to be clustered when the patients were younger than 5 years, identified a source case, or were US born. Conclusions. Traditional contact tracing may not always be accurate, and molecular characterization can lead to identification of previously unrecognized source cases. Recent transmission plays a significant role in the transmission of TB to children as evident by the high degree of clustering found in our study population. [ABSTRACT FROM AUTHOR]