Tuberculosis (TB), caused by infection with Mycobacterium tuberculosis (M. tuberculosis), is a major cause of morbidity and mortality worldwide and efforts to control TB are hampered by difficulties with diagnosis, prevention and treatment 1,2. Most people infected with M. tuberculosis remain asymptomatic, termed latent TB, with a 10% lifetime risk of developing active TB disease, but current tests cannot identify which individuals will develop disease 3. The immune response to M. tuberculosis is complex and incompletely characterized, hindering development of new diagnostics, therapies and vaccines 4,5. We identified a whole blood 393 transcript signature for active TB in intermediate and high burden settings, correlating with radiological extent of disease and reverting to that of healthy controls following treatment. A subset of latent TB patients had signatures similar to those in active TB patients. We also identified a specific 86-transcript signature that discriminated active TB from other inflammatory and infectious diseases. Modular and pathway analysis revealed that the TB signature was dominated by a neutrophil-driven interferon (IFN)-inducible gene profile, consisting of both IFN-γ and Type I IFNαβ signalling. Comparison with transcriptional signatures in purified cells and flow cytometric analysis, suggest that this TB signature reflects both changes in cellular composition and altered gene expression. Although an IFN signature was also observed in whole blood of patients with Systemic Lupus Erythematosus (SLE), their complete modular signature differed from TB with increased abundance of plasma cell transcripts. Our studies demonstrate a hitherto under-appreciated role of Type I IFNαβ signalling in TB pathogenesis, which has implications for vaccine and therapeutic development. Our study also provides a broad range of transcriptional biomarkers with potential as diagnostic and prognostic tools to combat the TB epidemic.
Summary The analysis of patient blood transcriptional profiles offers a means to investigate immunological mechanisms relevant to human diseases on a genome-wide scale. In addition, such studies provide a basis for the discovery of clinically-relevant biomarker signatures. We designed a strategy for microarray analysis that is based on the identification of transcriptional modules formed by genes coordinately expressed in multiple disease datasets. Mapping changes in gene expression at the module-level generated disease-specific transcriptional fingerprints which provide a stable framework for the visualization and functional interpretation of microarray data. These transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Thus, this work describes the implementation and application of a methodology designed to support systems-scale analysis of the human immune system in translational research settings.
The survival of young children with sickle cell disease (SCD) has improved, but less is known about older children and adolescents. We studied the Dallas Newborn Cohort (DNC) to estimate contemporary 18-year survival for newborns with SCD and document changes in the causes and ages of death over time. We also explored whether improvements in the quality of medical care were temporally associated
BACKGROUND Silent cerebral infarcts are the most common neurologic injury in children with sickle cell anemia and are associated with the recurrence of an infarct (stroke or silent cerebral infarct). We tested the hypothesis that the incidence of the recurrence of an infarct would be lower among children who underwent regular blood-transfusion therapy than among those who received standard care. METHODS In this randomized, single-blind clinical trial, we randomly assigned children with sickle cell anemia to receive regular blood transfusions (transfusion group) or standard care (observation group). Participants were between 5 and 15 years of age, with no history of stroke and with one or more silent cerebral infarcts on magnetic resonance imaging and a neurologic examination showing no abnormalities corresponding to these lesions. The primary end point was the recurrence of an infarct, defined as a stroke or a new or enlarged silent cerebral infarct. RESULTS A total of 196 children (mean age, 10 years) were randomly assigned to the observation or transfusion group and were followed for a median of 3 years. In the transfusion group, 6 of 99 children (6%) had an end-point event (1 had a stroke, and 5 had new or enlarged silent cerebral infarcts). In the observation group, 14 of 97 children (14%) had an end-point event (7 had strokes, and 7 had new or enlarged silent cerebral infarcts). The incidence of the primary end point in the transfusion and observation groups was 2.0 and 4.8 events, respectively, per 100 years at risk, corresponding to an incidence rate ratio of 0.41 (95% confidence interval, 0.12 to 0.99; P = 0.04). CONCLUSIONS Regular blood-transfusion therapy significantly reduced the incidence of the recurrence of cerebral infarct in children with sickle cell anemia. (Funded by the National Institute of Neurological Disorders and Stroke and others; Silent Cerebral Infarct Multi-Center Clinical Trial ClinicalTrials.gov number, NCT00072761, and Current Controlled Trials number, ISRCTN52713285.)
Contemporary survival data are not available for children with sickle cell disease (SCD). The few previous childhood SCD cohort studies do not reflect the benefits of modern therapy. We defined an inception cohort of newborns with sickle cell anemia (SS), sickle-°-thalassemia (S°), sickle-hemoglobin C disease (SC), or sickle- ؉ -thalassemia (S ؉ ) who were identified by newborn screening and followed for up to 18 years. The incidence of death and stroke were calculated. Overall survival, SCD-related survival (considering only SCD-related deaths), and strokefree survival were determined. The 711 subjects provided 5648 patient-years of observation. Twenty-five subjects died; mean age at death was 5.6 years. Five patients died from infection. Thirty had at least one stroke. Among SS and S°s ubjects (n ؍ 448), the overall rates of death and stroke were 0.59 and 0.85/100 patient-years. Survival analysis of SS and S°subjects predicted the cumulative overall, SCD-related, and stroke-free survival to be 85.6%, 93.6%, and 88.5% by 18 years of age. No SCD-related deaths or strokes occurred in SC or S ؉ subjects (n ؍ 263). Childhood mortality from SCD is decreasing, the mean age at death is increasing, and a smaller proportion of deaths are from infection.
The survival of children with sickle cell disease (SCD) has improved over the past several decades, especially for very young children. However, we know less about mortality during adolescence, and we do not accurately know the current proportion of children born with SCD who survive to adulthood. The first report from the Dallas Newborn Cohort (DNC), which included follow-up through June 2002, estimated overall survival at 18 years of age to be 85.6% (95% C.I.: 73.4 – 97.8) for individuals with sickle cell anemia (SS) or sickle-β0-thalassemia (Sβ0) (Blood2004;103:4023–7). The confidence interval of this estimate was wide because only 8 cohort subjects were 18 years old at the time. Here we update the survival analysis with 5 more years of accrual and follow-up to provide an accurate, contemporary estimate of mortality for patients with SCD through 18 years of age. The DNC includes all individuals with SS, Sβ0, sickle-hemoglobin C disease (SC), or sickle-β+-thalassemia (Sβ+) who were diagnosed by the newborn screening program of Texas (initiated November 1, 1983) and seen at least once in our center. Subjects were analyzed in two separate groups because of clinical similarity: SS/Sβ0 and SC/Sβ+. Overall survival was analyzed by the Kaplan-Meier method. Subjects were censored at the time of their last clinical encounter. Between July 2002 and July 2007 we identified 229 new members of the DNC and added 3,201 additional patient-years of follow-up. The cohort now includes 940 subjects (572 SS, 284 SC, 63 Sβ+, 21 Sβ0; 52.8% male), and it provides a total of 8,857 patient-years of follow-up (5,819 SS/Sβ0 patient-years, 3,039 SC/Sβ+ patient-years). Mean follow-up is 9.4 years (range 0.1– 20.6 years), and 97 subjects are now at least 18 years of age at last follow-up. To date, 92 subjects (9.8%) have been lost to follow-up (not seen for >5 years), and 33 subjects have died (30 SS/Sβ0, 3 SC/Sβ+). There were 7 new deaths in DNC patients since 2002, all of which occurred in patients who were 18 years of age or older. Of all deaths, 23 were SCD-related (5 acute chest syndrome, 5 sepsis, 4 multi-organ failure syndrome, 9 other), and 10 were apparently unrelated to SCD (4 trauma or accidental death, 6 unrelated medical conditions). All SC/Sβ+ deaths were apparently unrelated to SCD. Overall survival at 18 years was 93.9% (95% C.I. 90.3 – 96.2; 81 patients > 18 years of age) for SS/Sβ0 subjects and 98.4% (95% C.I. 94.4 – 99.5; 16 patients > 18 years) for SC/Sβ+ subjects. The overall incidence of death in the SS/Sβ0 and SC/Sβ+ subgroups was 0.52 and 0.10 per 100 patient-years, decreased from 0.59 and 0.24 in the original DNC analysis. Survival also appears to be improving across cohort eras (Figure). In conclusion, approximately 6% of children with SS or Sβ0 die during childhood, but almost all children with SC or Sβ+ live to become adults. Although early childhood mortality has greatly decreased, we show that many adolescents and young adults still die from SCD. Notably, acute chest syndrome and multi-organ failure have now surpassed sepsis as the leading causes of death. These data provide the accurate, contemporary foundation for the counseling of parents of newborns with SCD and for genetic counseling for prospective parents. Finally, given the marked decrease in early mortality we show here, new efforts to improve survival in SCD should focus on adolescents and young adults. Figure Figure
Children with sickle cell anemia have a high prevalence of silent cerebral infarcts (SCIs) that are associated with decreased full-scale intelligence quotient (FSIQ). While the educational attainment of parents is a known strong predictor of the cognitive development of children in general, the role of parental education in sickle cell anemia along with other factors that adversely affect cognitive function (anemia, cerebral infarcts) is not known. We tested the hypothesis that both the presence of SCI and parental education would impact FSIQ in children with sickle cell anemia. A multicenter, cross-sectional study was conducted in 19 US sites of the Silent Infarct Transfusion Trial among children with sickle cell anemia, age 5–15 years. All were screened for SCIs. Participants with and without SCI were administered the Wechsler Abbreviated Scale of Intelligence. A total of 150 participants (107 with and 43 without SCIs) were included in the analysis. In a multivariable linear regression model for FSIQ, the absence of college education for the head of household was associated with a decrease of 6.2 points (P=0.005); presence of SCI with a 5.2 point decrease (P=0.017); each $1000 of family income per capita with a 0.33 point increase (P=0.023); each increase of 1 year in age with a 0.96 point decrease (P=0.023); and each 1% (absolute) decrease in hemoglobin oxygen saturation with 0.75 point decrease (P=0.030). In conclusion, FSIQ in children with sickle cell anemia is best accounted for by a multivariate model that includes both biologic and socioenvironmental factors.
The most common form of neurologic injury in sickle cell anemia (SCA) is silent cerebral infarction (SCI). In the Silent Cerebral Infarct Multi-Center Clinical Trial, we sought to identify risk factors associated with SCI. In this cross-sectional study, we evaluated the clinical history and baseline laboratory values and performed magnetic resonance imaging of the brain in participants with SCA (HbSS or HbS°thalassemia) between the ages of 5 and 15 years with no history of overt stroke or seizures. Neuroradiology and neurology committees adjudicated the presence of SCI. SCIs were diagnosed in 30.8% (251 of 814) participants who completed all evaluations and had valid data on all prespecified demographic and clinical covariates. The mean age of the participants was 9.1 years, with 413 males (50.7%). In a multivariable logistic regression analysis, lower baseline hemoglobin concentration (P < .001), higher baseline systolic blood pressure (P ؍ .018), and male sex (P ؍ .030) were statistically significantly associated with an increased risk of an SCI. Hemoglobin concentration and systolic blood pressure are risk factors for SCI in children with SCA and may be therapeutic targets for decreasing the risk of SCI. This study is registered at www.clinicaltrials.gov as #NCT00072761. IntroductionSilent cerebral infarcts (SCIs) have been recognized by neuroimaging in neurologically normal older adult populations since 1981 1 and were documented in sickle cell anemia (SCA) soon afterward. 2 As with overt stroke, SCIs represent a clinical finding that is common in older adults without SCD, but they appear during early childhood in persons with SCA. SCIs are defined as an MRI signal abnormality visible on 2 views on the T2-weighted images (axial and coronal) that must measure at least 3 mm in one dimension; further, the person deemed to have an SCI must have an absence of focal neurologic deficit compatible with the anatomic location of the brain lesion. 3 SCI is the most common form of neurologic injury among children with SCA, occurring in at least 27% before 6 years of life 4 and 37% by 14 years of life. 5 SCIs in children with SCA are associated with increased risk of future overt strokes and new or progressive SCIs. 6,7 In addition, children with SCA and SCI have been found to have poorer cognitive function The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. 3684BLOOD, 19 APRIL 2012 ⅐ VOLUME 119, NUMBER 16For personal use only. on March 28, 2019. by guest www.bloodjournal.org From than children with SCA with normal MRI of the brain 8-10 or sibling controls. 10,11 Clinical and laboratory risk factors for SCI have been evaluated only sparingly. In the most rigorous study to date, the investigators from the Cooperative Study for Sickle Cell Disease (CSSCD) described risk factors associated with SCI in 42 participants, comparing them with 188 controls with ...
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