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Background Asthma with neutrophil predominance is challenging to treat with corticosteroids. Novel treatment options for asthma include those that target innate immune activity. Recent literature has indicated a significant role for IL-1β in both acute and chronic neutrophilic asthma. Objective This study used inhaled endotoxin (LPS) challenge as a model of innate immune activation to (1) assess the safety of the IL-1 receptor antagonist anakinra in conjunction with inhaled LPS and (2) to test the hypothesis that IL-1 blockade will suppress the acute neutrophil response to challenge with inhaled LPS. Methods In a phase I clinical study 17 healthy volunteers completed a double-blind, placebo-controlled crossover study in which they received 2 daily subcutaneous doses of 1 mg/kg anakinra (maximum dose, 100 mg) or saline (placebo). One hour after the second treatment dose, subjects underwent an inhaled LPS challenge. Induced sputum was assessed for neutrophils 4 hours after inhaled LPS. The effect of anakinra compared with placebo on airway neutrophil counts and airway proinflammatory cytokine levels after LPS challenge was compared by using a linear mixed-model approach. Results Anakinra pretreatment significantly diminished airway neutrophilia compared with placebo. LPS-induced IL-1β, IL-6, and IL-8 levels were significantly reduced during the anakinra treatment period compared with those seen after placebo. Subjects tolerated the anakinra treatment well without an increased frequency of infections attributable to anakinra treatment. Conclusions Anakinra effectively reduced airway neutrophilic inflammation and resulted in no serious adverse events in a model of inhaled LPS challenge. Anakinra is a potential therapeutic candidate for treatment of asthma with neutrophil predominance in diseased populations.

African Americans disproportionally experience uncontrolled asthma1. Because asthma control is now the focus of asthma management,2 publicly available questionnaires like the Asthma Control Test™ (ACT)3 and childhood Asthma Control Test (ACTc)4 represent the most accessible, standardized, non-physician methods of assessing control and are typically considered cost-effective and easily implemented asthma care strategies for primary care offices. Both the ACT (≥12 years old) and ACTc (80% (kappa=0.34, p=0.0095). Additionally, a cutpoint of >19 only had a sensitivity of 50% and a specificity of 64% in these younger children. In this study, we demonstrate that the ACTc as currently used may not accurately predict asthma control in African American children < 12-years-old, showing limited functionality in this group with low sensitivity and specificity for mirroring the gold standard of physician assessment of asthma control. Surprisingly, this points to a clear discrepancy between caregiver and provider perception of asthma control in children < 12 years old. While the ACTc queries both child and caregiver, greater weight is given to those caregiver-answered questions. Hence, failure of a caregiver to recognize not well-controlled asthma has implications for impacting asthma treatment plans and may also contribute to the increased risks of morbidity and mortality associated with uncontrolled asthma in this population. Although the ACT had better performance in children ≥12-years-old (who do fill out their own questionnaires), we also found that sensitivity for determining asthma control could be increased by changing the ACT cutpoint to 18 rather than >19 (with a previously reported sensitivity of 71.3% and specificity of 70.8% in a primarily Caucasian population6). Limitations to our study include its retrospective nature, small sample size, unknown impact of socioeconomic status or the nature of the visit (scheduled versus urgent care), and possible investigator bias (non-blinding to ACT/c and spirometry results). Overall, our results suggest that current use of the ACT and ACTc may require adjustment to better correlate with physician assessment of asthma control in African American children. Additional prospective studies are required to further explore these findings and inform alternate clinical practice standards.

Primary immunodeficiencies (PID) comprise a diverse group of clinical disorders with varied genetic defects. Paradoxically, a substantial proportion of PID patients develop autoimmune phenomena in addition to having increased susceptibility to infections from their impaired immunity. Although much of our understanding comes from data gathered through experimental models, there are several well-characterized PID that have improved our knowledge of the pathways that drive autoimmunity. The goals of this review will be to discuss these immunodeficiencies and to review the literature with respect to the proposed mechanisms for autoimmunity within each put forth to date.

Background : Venous thromboembolism (VTE) prophylaxis is underutilized in hospitalized medical patients. Underutilization might occur as a result of resident practice variation incurred by using a complex risk assessment tool. Objective : To examine what impact repetitive exposure to an electronic point-based VTE risk assessment tool has on resident inter-rater reliability and protocol adherence. Design : Pre and post intervention cross-sectional cohort study. Setting : Single academic center. Patients : Convenience samples of Internal Medicine residents. Interventions : Residents completed clinical vignettes before and after any exposure to an electronic risk assessment tool and reminder alert. They were asked to make three determinations using a point-based VTE risk assessment tool: risk stratification, identify contraindications, and VTE prevention strategy. Measurements : Inter-rater reliability for risk assessment, contraindications, and VTE prophylaxis strategy and protocol adherence. Results : Kappa scores for VTE risk assessment did not change, but improved for VTE plan increasing from 0.28 to 0.37. Protocol adherence improved from 71% in 2008 to 79% (P = 0.06). There was a significant decrease in under-prophylaxis (22% to 6%, P 0.0001) but a significant increase in over-prophylaxis (7% to 16%, P = 0.001). Conclusions : Using clinical vignettes, we determined that daily exposure to an electronic risk assessment tool did not improve the inter-rater reliability of a point-based risk assessment tool when used by medical residents. This might be due to inexperienced providers using a complex point-based tool. Overall, adherence improved, and under-prophylaxis decreased, but over-prophylaxis increased. Clinical vignettes are a generalizable method to monitor resident prophylaxis practices and way to identify educational and process improvement opportunities. doi:10.4021/jocmr766w

Introduction: Hereditary Angioedema (HAE) is a potentially life-threatening condition consisting of recurrent episodes of limb, abdominal, genital, facial or laryngeal swelling. Unregulated bradykinin activity is known to be the main driving mechanism for the characteristic edema flares in HAE. Thus, a bradykinin receptor antagonist is a sensible treatment for acute attacks of HAE. Methods: A Pubmed literature search was conducted from 2005-present using the search terms icatibant, HOE 140, angioedema, and hereditary angioedema singly and in combination. Non-English articles were excluded. Results: Overall, there have been a total of 116 patients (314 attacks) treated with icatibant. Of these attacks, the majority reported the onset of symptom relief within two hours and the resolution of symptoms within 12–24 hours. Thirty patients (9.6%) had recurrent symptoms; five were treated with rescue Berinert, seven were treated with an additional dose of icatibant, and the remainder 18 were given either C1-INH concentrate, anti-emetics, or opiates. The most reported adverse effect from icatibant was a local reaction (swelling, burning, erythema, and itching). Icatibant use has also been reported with ACE-inhibitor induced, acquired, and HAE type III angioedema as well as in one case as prophylaxis. Conclusion: The numerable new treatments for HAE now gaining favor, including icatibant, provide an exciting opportunity for both patients and providers to take swift control of this disease process.

Immunoglobulin replacement can be life-saving for certain individuals with immunodeficiencies. Subcutaneous IgG (SCIG) is an increasingly used method of replacement over intravenous IgG (IVIG), with potential advantages including fewer systemic side effects, no need for IV access, patient-reported improved quality of life, and decreased cost. However, while patients with certain associated co-morbidities, such as protein-losing enteropathy, may demonstrate more stable IgG levels when on SCIG compared to IVIG, the clinical significance of these experiences is not well described. Using retrospective chart review, we examined three cases in which SCIG and IVIG was administered to patients with either common variable immunodeficiency (CVID) or secondary humoral immunodeficiency and protein-losing gastrointestinal co-morbid disease. Both outpatient and inpatient records were reviewed for data regarding treatment with IVIG versus SCIG, reported frequency and severity of infections, hospitalizations, and IgG levels. All three patients demonstrated improvement in infection rate, stability of IgG levels, and co-morbid disease when on SCIG as compared to IVIG. These findings suggest that the pharmacokinetics of SCIG may translate into more consistent serum IgG levels, contributing to clinical improvement in immunodeficient patients with protein-losing comorbidities when compared to IVIG. Limitations to this study are small patient numbers, retrospective design, and potential therapeutic bias. Further characterization of the effects of co-morbid conditions on immunoglobulin replacement is critical to providing improved and informed patient care.

Increasing BMI has been proposed to be associated with asthma development and with airway hyperresponsiveness that is harder to treat with conventional therapies1,2. Increased BMI has been associated with ozone-induced decrements in spirometry3 in humans as well as with increased pulmonary inflammation following ozone (O3) exposure in murine models of obese mice.4,5 Murine studies have recently demonstrated that the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, responsible for release of mature IL-1β from a cell, played an important role in obesity-induced airway hyperresponsiveness through the induction of IL-17a-producing innate lymphoid cells type 3 (ILC3)6. Furthermore, IL-1β blockade was able to mitigate obesity-induced airway hyperreactivity6. Addition of the saturated fatty acid palmitate to in vitro cultures (macrophage) after LPS-priming was sufficient to induce IL-1β release through NLRP3 activation.7 These two studies add to a growing body of evidence that the NLRP3 inflammasome may represent a central figure in BMI-driven pulmonary inflammation and enhanced susceptibility to environmental stimuli. Previous work has shown that increased BMI influences O3-induced decrements in spirometry in otherwise healthy human volunteers3. However, studies examining the relationship between pollutant-induced pulmonary inflammation in overweight and obese humans are still lacking. We hypothesized that increased BMI would be associated with increased airway inflammation after an environmental challenge with O3.

BACKGROUND: Venous thromboembolic events (VTE) are a significant cause of mortality in hospitalized medical and surgical patients. Despite recommendations and guidelines, current evidence demonstrates that VTE prophylaxis remains underutilized in at-risk patients. The process of providing VTE prophylaxis begins with assessing each patient's VTE risk. Using an individualized, point-based protocol in the assessment process is a complex task, and might contribute to variability in VTE prescribing behavior. There are no published data on how reliably residents can perform risk assessment and prophylaxis using a point-based VTE risk assessment tool. OBJECTIVE: Our aim was to determine inter-rater reliability of a point-based risk assessment tool by residents early in the academic year. DESIGN: The design was a cross-sectional-cohort observational study. SETTING: The site was an academic medical center. PATIENTS: Case-based clinical vignettes were used. INTERVENTIONS: Verbal instructions were given to medical residents about how to apply our hospital's point-based VTE risk assessment tool. MEASUREMENTS: Interobserver agreement was measured of: 1) risk score, 2) risk-stratification, 3) identification of contraindications, 4) VTE prophylaxis plan, and 5) resident adherence to the protocol. RESULTS: The intra-class correlation (ICC) for the total risk score was 0.66 and the kappa coefficient for risk stratification was 0.51. The kappa scores for absolute and relative contraindications were 0.29 and 0.23, respectively. The kappa score for the VTE plan was 0.28. CONCLUSIONS: We determined that, following brief instructions early in the academic year, a point-based VTE risk assessment tool has only fair to moderate inter-rater reliability, with suboptimal adherence to the protocol. Both might lead to underutilization of VTE prevention strategies. Journal of Hospital Medicine 2011. © 2011 Society of Hospital Medicine.