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SUMMARY Identification and treatment of latent tuberculosis infection (LTBI) can substantially reduce the risk of developing active disease. However, there is no diagnostic gold standard for LTBI. Two tests are available for identification of LTBI: the tuberculin skin test (TST) and the gamma interferon (IFN-γ) release assay (IGRA). Evidence suggests that both TST and IGRA are acceptable but imperfect tests. They represent indirect markers of Mycobacterium tuberculosis exposure and indicate a cellular immune response to M. tuberculosis . Neither test can accurately differentiate between LTBI and active TB, distinguish reactivation from reinfection, or resolve the various stages within the spectrum of M. tuberculosis infection. Both TST and IGRA have reduced sensitivity in immunocompromised patients and have low predictive value for progression to active TB. To maximize the positive predictive value of existing tests, LTBI screening should be reserved for those who are at sufficiently high risk of progressing to disease. Such high-risk individuals may be identifiable by using multivariable risk prediction models that incorporate test results with risk factors and using serial testing to resolve underlying phenotypes. In the longer term, basic research is necessary to identify highly predictive biomarkers.

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Objective Survivors of severe critical illness frequently develop substantial and persistent physical complications, including muscle weakness, impaired physical function, and decreased health-related quality of life (HRQOL). Our objective was to determine the longitudinal epidemiology of muscle weakness, physical function, and HRQOL, and their associations with critical illness and intensive care unit exposures. Design A multi-site prospective study with longitudinal follow-up at 3, 6, 12, and 24 months after acute lung injury. Setting 13 intensive care units from 4 academic teaching hospitals. Patients 222 survivors of acute lung injury. Measurements and Main Results At each time point, patients underwent standardized clinical evaluations of extremity, hand grip, and respiratory muscle strength; anthropometrics (height, weight, mid-arm circumference, and triceps skin fold thickness), 6-minute walk distance, and the Medical Outcomes Short-Form 36 (SF-36) HRQOL survey. During their hospitalization, survivors also had detailed daily evaluation of critical illness and related treatment variables. Over one-third of survivors had objective evidence of muscle weakness at hospital discharge, with most improving within 12 months. This weakness was associated with substantial impairments in physical function and HRQOL that persisted at 24 months. The duration of bed rest during critical illness was consistently associated with weakness throughout 24-month follow-up. The cumulative dose of systematic corticosteroids and use of neuromuscular blockers in the intensive care unit were not associated with weakness. Conclusions Muscle weakness is common after ALI, usually recovering within 12 months. This weakness is associated with substantial impairments in physical function and HRQOL that continue beyond 24 months. These results provide valuable prognostic information regarding physical recovery after ALI. Evidence-based methods to reduce the duration of bed rest during critical illness may be important for improving these long-term impairments.

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The risk of CINMA is nearly 50% in ICU patients with sepsis, multi-organ failure, or protracted mechanical ventilation. The association of CINMA with frequently cited CINMA risk factors (glucocorticoids, neuromuscular blockers) and with short-term survival is uncertain. Available data indicate glycemic control as a potential strategy to decrease CINMA risk.

Objective To determine adherence to and effectiveness of ART in adolescents versus adults in southern Africa Design Observational cohort study Setting Aid for AIDS, a private-sector disease-management program in southern Africa Subjects Adolescents (age 11–19 years; n=154) and adults (n=7,622) initiating ART between 1999 and 2006 and having a viral-load measurement within one year after ART initiation Main Outcome Measures Primary: virologic suppression (HIV viral load ≤400 copies/mL), viral rebound and CD4+ T-cell count at 6, 12, 18, 24 months after ART initiation. Secondary: adherence assessed by pharmacy refills at 6, 12 and 24 months. Multivariate analyses: log-linear regression and Cox proportional hazards. Results A significantly smaller proportion of adolescents achieved 100% adherence at each time point (adolescents: 20.7% at 6 months, 14.3% at 12 months, 6.6% at 24 months; adults: 40.5%, 27.9%, and 20.6% at each time point, respectively; p<0.01). Patients achieving 100% 12-month adherence were significantly more likely to exhibit virologic suppression at 12 months, regardless of age. However, adolescents achieving virologic suppression had significantly shorter time to viral rebound (adjusted hazard ratio 2.03; 95% CI 1.31–3.13; p<0.003). Adolescents were less likely to experience long-term immunologic recovery despite initial CD4+ T-cell counts comparable to adults. Conclusions Compared to adults, adolescents in southern Africa are less adherent to ART and have lower rates of virologic suppression and immunologic recovery and a higher rate of virologic rebound after initial suppression. Studies must determine specific barriers to adherence in this population and develop appropriate interventions.

SUMMARYTuberculosis (TB) is the leading infectious cause of mortality worldwide, due in part to a limited understanding of its clinical pathogenic spectrum of infection and disease. Historically, scientific research, diagnostic testing, and drug treatment have focused on addressing one of two disease states: latent TB infection or active TB disease. Recent research has clearly demonstrated that human TB infection, from latent infection to active disease, exists within a continuous spectrum of metabolic bacterial activity and antagonistic immunological responses. This revised understanding leads us to propose two additional clinical states: incipient and subclinical TB. The recognition of incipient and subclinical TB, which helps divide latent and active TB along the clinical disease spectrum, provides opportunities for the development of diagnostic and therapeutic interventions to prevent progression to active TB disease and transmission of TB bacilli. In this report, we review the current understanding of the pathogenesis, immunology, clinical epidemiology, diagnosis, treatment, and prevention of both incipient and subclinical TB, two emerging clinical states of an ancient bacterium.