Barbara R. Neas

The incidence of immune thrombocytopenic purpura in children and adults: A critical review of published reports

Reports of the incidence of ITP are few and their methodology is variable. Accurate estimates of the incidence of immune thrombocytopenic purpura (ITP) are important to understand the medical and public health impact of the disease. To critically review all published reports on the incidence of ITP in children and adults, all articles identified on the Medline database (searched January 1, 1966‐August 7, 2009) that reported data on the incidence of ITP were retrieved. Articles which directly estimated the incidence of ITP were selected for review. Eight articles reported the incidence of acute ITP in children. After review, four were determined to have the strongest estimates, based on the method of patient identification and study design. The lowest incidence estimate in these four studies was 2.2 per 105 children/year (95% confidence interval 1.9, 2.4) and the highest incidence estimate was 5.3 per 105 children/year (95% confidence interval 4.3, 6.4). Three studies reported the incidence of ITP in adults. The estimate from the article with the strongest methodology reported an incidence estimate of 3.3 per 105 adults/year. The current strongest estimate of the incidence of acute ITP in children is between 1.9 and 6.4 per 105 children/year; for adults the current strongest estimate of the incidence of ITP is 3.3 per 105 adults/year. An important limitation of these studies is that they are primarily from Europe and may not be generalizable to all regions. Am. J. Hematol. 2010.

Deficiency of Type I IFN Receptor in Lupus-Prone New Zealand Mixed 2328 Mice Decreases Dendritic Cell Numbers and Activation and Protects from Disease

Type I IFNs are potent regulators of innate and adaptive immunity and are implicated in the pathogenesis of systemic lupus erythematosus. Here we report that clinical and pathological lupus nephritis and serum anti-nuclear Ab levels are greatly attenuated in New Zealand Mixed (NZM) 2328 mice deficient in type I IFN receptors (IFNAR). To determine whether the inflammatory environment in NZM 2328 mice leads to IFNAR-regulated changes in dendritic cells (DC), the number, activation, and function of DC subsets were compared in 2- and 5-mo-old (clinically healthy) female NZM and NZM-IFNAR−/− mice. Numbers of activated CD40high plasmacytoid DC (pDC) were significantly increased in renal lymph nodes of 2-mo-old NZM but not NZM-IFNAR−/− mice, suggesting an early IFNAR-dependent expansion and activation of pDC at disease sites. Relative to NZM spleens, NZM-IFNAR−/− spleens in 5-mo-old mice were significantly decreased in size and contained reduced numbers of conventional DC subsets, but not pDC. Splenic and renal lymph node NZM-IFNAR−/− DC analyzed directly ex vivo expressed significantly less CD40, CD86, and PDL1 than did NZM DC. Upon activation with synthetic TLR9 ligands in vitro, splenic NZM-IFNAR−/− DC produced less IL-12p40/70 and TNF-α than did NZM DC. The limited IFNAR−/− DC response to endogenous activating stimuli correlated with reduced numbers of splenic activated memory CD4+ T cells and CD19+ B cells in older mice. Thus, IFNAR signaling significantly increases DC numbers, acquisition of Ag presentation competence, and proinflammatory function before onset of clinically apparent lupus disease.

Confirmation of genetic linkage between human systemic lupus erythematosus and chromosome 1q41

OBJECTIVE Genetic susceptibility to systemic lupus erythematosus (SLE) is undoubtedly complex and, presumably, involves multiple loci. Linkage of SLE to D1S229 at chromosome 1q41 has been previously reported in a cohort of 52 affected sibpairs. The present study sought to confirm this reported linkage in an independent cohort of 127 extended multiplex SLE pedigrees containing 107 affected sibpairs. METHODS Genotype data were collected for D1S229 and 18 flanking microsatellite markers spanning chromosome 1q32-1q42. Analyses of genotype data included a model-based logarithm of odds (LOD) score approach, affected sibpair analyses, and transmission disequilibrium tests. RESULTS A maximum LOD score of 1.46 was found with D1S229 in a subgroup of 78 European American pedigrees, with additional support from multiple markers clustered around D1S229. Increased allele sharing in affected siblings was most significant at D1S2616, particularly in European Americans (P = 0.0005), followed by D1S229 (P = 0.002), D1S490 (P = 0.028), and D1S1605 (P = 0.037). Although linkage in a subgroup of 40 African American pedigrees was not suggested by the analyses of any marker tested in the chromosomal region surrounding D1S229, a maximum LOD score of 3.03 was found with D1S3462, mapped 15 centimorgans distal to D1S229. CONCLUSION Our linkage analysis results in European Americans at D1S229 are remarkably similar to those previously reported. That at least 1 genetic effect near this locus is important for susceptibility to lupus should now be generally accepted, and efforts to identify the gene are thereby justified.

Directness of transport of major trauma patients to a level I trauma center: a propensity-adjusted survival analysis of the impact on short-term mortality.

BACKGROUND Whether severely injured patients should be transported directly to tertiary trauma centers, bypassing closer nontertiary facilities, or be transported first to nearby, less-specialized facilities for immediate care and stabilization has been studied with mixed findings. Differences in study locale, case mix, and variation in the structure and level of maturation of the trauma system may explain some of the discrepancy in findings. In addition, risk adjustment strategies used in these studies did not take into account prehospital baseline characteristics as well as time since injury. METHODS This was a retrospective cohort study of 1,998 patients treated at a Level I trauma center between January 1, 2006, and December 31, 2007. Propensity-adjusted survival analyses were used to compare short-term mortality outcomes in transferred versus directly transported major trauma patients. RESULTS A total of 1,398 patients were transported directly to the Level I trauma center and 600 patients were transferred from lower level facilities. After adjusting for the propensity to be transported directly, age, injury severity score, severe head injury, emergency medical service or emergency department intubation, comorbid conditions, and time to definitive Level I trauma care, the 2-week mortality risk in transferred patients was almost three-fold that of patients transported directly to a Level I trauma center (hazard ratio, 2.7; 95% confidence interval, 1.31-5.6). CONCLUSION Transferred patients in a predominantly rural region are at an increased risk of short-term mortality. This suggests that severely injured patients should be transported directly to tertiary trauma centers. For patients requiring immediate stabilization at nontertiary facilities, this should be performed promptly without unnecessary delays.

Survival Benefit of Transfer to Tertiary Trauma Centers for Major Trauma Patients Initially Presenting to Nontertiary Trauma Centers

OBJECTIVES Recent evidence suggests a measurable reduction in mortality for patients transferred from a nontertiary trauma center (Level III or IV) to a Level I trauma center, but not for those transferred to a Level II trauma center. Whether this can be generalized to a predominantly rural region with fewer tertiary trauma care resources is uncertain. This study sought to evaluate mortality differences for patients initially presenting to nontertiary trauma centers in a predominantly rural region depending on transfer status. METHODS This was a retrospective cohort study of patients initially presenting to 104 nontertiary trauma centers in Oklahoma and meeting the states criteria for major trauma. Patients dying within 1 hour of emergency department (ED) arrival at the nontertiary trauma center were excluded. The exposure variable of interest was admission status, which was categorized as either transfer to a tertiary (Level I or II) trauma center within 24 hours or admission to a nontertiary trauma center. Propensity scores were used to minimize the selection bias inherent in the decision to admit or transfer a patient for higher-level care. Multiple logistic regression was used to generate three propensity score models: probability of transfer to either a Level I or II, Level I only, and Level II only. Propensity scores were then included as a covariate in multivariable Cox regression models assessing outcome differences between admitted and transferred patients. The outcome of interest was 30-day mortality, defined as death at either the nontertiary trauma center or the tertiary trauma center within 30 days of arrival at the initial Level III/IV centers ED. RESULTS A total of 6,229 patients met study criteria, of whom 2,669 (43%) were transferred to tertiary trauma centers. Of those transferred, 1,422 patients (53%) were transferred to a Level I trauma center. Crude mortality was lower for patients transferred to tertiary trauma centers compared to those remaining at nontertiary trauma facilities (hazard ratio [HR] = 0.59; 95% confidence interval [CI] = 0.48 to 0.72). After adjusting for the propensity to be transferred, Injury Severity Score (ISS), presence of severe head injury, and age, transfer to a tertiary trauma center was associated with a significantly lower 30-day mortality (HR = 0.38; 95% CI = 0.30 to 0.50) compared to admission and treatment at a nontertiary trauma center. The observed survival benefit was similar for patients transferred to a Level I trauma center (HR = 0.36; 95% CI = 0.20 to 0.4) and those transferred to a Level II center (HR = 0.45; 95% CI = 0.33 to 0.61). CONCLUSIONS This study suggests a survival benefit among patients initially presenting to nontertiary trauma centers who are subsequently transferred to tertiary trauma centers compared to those remaining in nontertiary trauma centers, even after adjusting for variables affecting the likelihood of transfer. Although this survival benefit was larger for patients treated at a Level I trauma center, Level II trauma centers in a region with few tertiary trauma resources demonstrated a measurable benefit as well.

The Prevalence of ADHD: Its Diagnosis and Treatment in Four School Districts Across Two States

Objective: To describe the epidemiology of ADHD in communities using a DSM-IVTR case definition. Method: This community-based study used multiple informants to develop and apply a DSM -IVTR-based case definition of ADHD to screening and diagnostic interview data collected for children 5-13 years of age. Teachers screened 10,427 children (66.4%) in four school districts across two states (SC and OK). ADHD ratings by teachers and parent reports of diagnosis and medication treatment were used to stratify children into high and low risk for ADHD. Parents (n = 855) of high risk and gender frequency-matched low risk children completed structured diagnostic interviews. The case definition was applied to generate community prevalence estimates, weighted to reflect the complex sampling design. Results: ADHD prevalence was 8.7% in SC and 10.6% in OK. The prevalence of ADHD medication use was 10.1% (SC) and 7.4% (OK). Of those medicated, 39.5% (SC) and 28.3% (OK) met the case definition. Comparison children taking medication had higher mean symptom counts than other comparison children. Conclusions: Our ADHD estimates are at the upper end of those from previous studies. The identification of a large proportion of comparison children taking ADHD medication suggests that our estimates may be conservative; these children were not included as cases in the case definition, although some might be effectively treated.

HLA-DQ gene complementation and other histocompatibility relationships in man with the anti-Ro/SSA autoantibody response of systemic lupus erythematosus.

A strong gene interaction between HLA-DQ1 and DQ2 alleles has been associated with anti-Ro/SSA autoantibodies (Harley, J.B., M. Reichlin, F. C. Arnett, E. L. Alexander, W. B. Bias, and T. T. Provost. 1986. Science [Wash. DC]. 232:1145-1147; Harley, J. B., A. S. Sestak, L. G. Willis, S. M. Fu, J. A. Hansen, and M. Reichlin. 1989. Arthritis Rheum. 32:826-836; Hamilton, R. G., J. B. Harley, W. B. Bias, M. Roebber, M. Reichlin, M. C. Hochberg, and F. C. Arnett. 1988. Arthritis Rheum. 31:496-505). To test a gene complementation mechanism for these results, restriction fragment length polymorphisms (RFLP) of the DQ alpha and DQ beta genes have been related to Ro/SSA precipitins in patients with systemic lupus erythematosus. In this study Ro/SSA precipitins are related to the simultaneous presence of a particular pair of RFLPs. A DQ alpha RFLP associated with HLA-DQ1 and a DQ beta RFLP associated with HLA-DQ2 predict that the alpha beta heterodimer in HLA-DQ1/DQ2 heteroxygotes is most closely related to anti-Ro/SSA autoantibodies, thereby supporting a gene complementation mechanism. Beyond this effect, an RFLP associated with HLA-DQ2 and/or DR7 is also related to Ro/SSA precipitins. Multiple molecular histocompatibility mechanisms are implicated, therefore, in the production of anti-Ro/SSA autoantibodies in autoimmune disease. For anti-Ro/SSA autoantibodies in SLE, and perhaps more generally, these data show that the histocompatibility antigens are among the elements that confer autoimmune response specificity and restrict the production of particular autoantibodies among patients with systemic lupus erythematosus.

The psychometric properties of the Vanderbilt attention-deficit hyperactivity disorder diagnostic teacher rating scale in a community population.

Objective: This study examined the psychometric properties of the Vanderbilt AD/HD Diagnostic Teacher Rating Scale (VADTRS). Methods: Information was collected from teachers and parents in 5 school districts (urban, suburban, and rural). All teachers in participating schools were asked to complete the VADTRS on all their students. Construct validity was evaluated through an exploratory factor analysis investigation of the 35 items that made up the 4 scales of inattention, hyperactivity, conduct/oppositional problems, and anxiety/depression problems. Convergent validity was assessed among a subsample of participants whose teachers completed the Strengths and Difficulties Questionnaire (SDQ). Finally, predictive validity was examined for another subsample of high- and low-risk children whose parents completed a structured psychiatric interview, the Diagnostic Interview Schedule for Children-IV. Results: For construct validity, a 4-factor model (inattention, hyperactivity, conduct/oppositional, and anxiety/depression problems) fits the data well. The estimates of the KR20 coefficient for a binary item version of the scale ranged from .85 to .94. Convergent validity with the SDQ was high (Pearson’s correlations > .72) for these 4 factors. For predictive validity, the VADTRS produced a sensitivity of .69, specificity of .84, positive predictive value of .32, and negative predictive value of .96 when predicting future case definitions among children whose parents completed a diagnostic interview. Conclusion: The confirmation of the construct and convergent validity and acceptable scale reliabilities found in this study further supports the utility of the VADTRS as a diagnostic rating scale for attention-deficit hyperactivity disorder. The low predictive validity further demonstrates the need for multiple observers in establishing the diagnosis.

Comparison of autoantibody specificities between traditional and bead-based assays in a large, diverse collection of patients with systemic lupus erythematosus and family members.

OBJECTIVE Replacement of standard immunofluorescence methods with bead-based assays for antinuclear antibody (ANA) testing is a new clinical option. The aim of this study was to evaluate a large, multiethnic cohort of patients with systemic lupus erythematosus (SLE), blood relatives, and unaffected control individuals for familial aggregation and subset clustering of autoantibodies by high-throughput serum screening technology and traditional methods. METHODS Serum samples (1,540 SLE patients, 1,154 unaffected relatives, and 906 healthy, population-based controls) were analyzed for SLE autoantibodies using a bead-based assay, indirect immunofluorescence (IIF), and immunodiffusion. Autoantibody prevalence, sensitivity for disease detection, clustering of autoantibodies, and associations between newer methods and standard immunodiffusion results were evaluated. RESULTS The frequencies of ANAs in the sera from African American, Hispanic, and European American patients with SLE were 89%, 73%, and 67%, respectively, by BioPlex 2200 bead-based assay and 94%, 84%, and 86%, respectively, by IIF. When comparing the serum prevalence of 60-kd Ro, La, Sm, nuclear RNP A, and ribosomal P autoantibodies across assays, the sensitivity of detection ranged from 0.92 to 0.83 and the specificity ranged from 0.90 to 0.79. Autoantibody cluster analysis showed associations of autoantibody specificities in 3 subsets: 1) 60 kd Ro, 52-kd Ro, and La, 2) spliceosomal proteins, and 3) double-stranded DNA (dsDNA), chromatin, and ribosomal P. Familial aggregation of Sm/RNP, ribosomal P, and 60-kd Ro in SLE patient sibling pairs was observed (P ≤ 0.004). Simplex-pedigree SLE patients had a greater prevalence of dsDNA (P = 0.0003) and chromatin (P = 0.005) autoantibodies compared to patients with a multiplex SLE pedigree. CONCLUSION The frequencies of ANAs detected by a bead-based assay are lower than those detected by IIF in European American patients with SLE. These assays have strong positive predictive values across ethnic groups, provide useful information for clinical care, and provide unique insights into familial aggregation and autoantibody clustering.

B lymphocyte stimulator levels in systemic lupus erythematosus: higher circulating levels in African American patients and increased production after influenza vaccination in patients with low baseline levels.

OBJECTIVE To examine the relationship between circulating B lymphocyte stimulator (BLyS) levels and humoral responses to influenza vaccination in systemic lupus erythematosus (SLE) patients, as well as the effect of vaccination on BLyS levels, and to investigate clinical and serologic features of SLE that are associated with elevated BLyS levels. METHODS Clinical history, disease activity measurements, and blood specimens were collected from 60 SLE patients at baseline and after influenza vaccination. Sera were tested for BLyS levels, lupus-associated autoantibodies, serum interferon-α (IFNα) activity, 25-hydroxyvitamin D (25[OH]D), and humoral responses to influenza vaccination. RESULTS Thirty percent of the SLE patients had elevated BLyS levels, with African American patients having higher BLyS levels than white patients (P = 0.006). Baseline BLyS levels in patients were not correlated with humoral responses to influenza vaccination (P = 0.863), and BLyS levels increased postvaccination only in the subset of patients with BLyS levels in the lowest quartile (P = 0.0003). Elevated BLyS levels were associated with increased disease activity, as measured by the SLE Disease Activity Index, physicians global assessment, and Systemic Lupus Activity Measure in white patients (P = 0.035, P = 0.016, and P = 0.018, respectively), but not in African Americans. Elevated BLyS levels were also associated with anti-nuclear RNP (P = 0.0003) and decreased 25(OH)D (P = 0.018). Serum IFNα activity was a significant predictor of elevated BLyS in a multivariate analysis (P = 0.002). CONCLUSION Our findings indicate that African American patients with SLE have higher BLyS levels regardless of disease activity. Humoral response to influenza vaccination is not correlated with baseline BLyS levels in SLE patients, and only those patients with low baseline BLyS levels demonstrate an increased BLyS response after vaccination.