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We present the case of an apparently healthy 31-year-old man with malignant progression of coronary artery disease and recurrent angina resulting from suspected large vessel vasculitis. This case highlights the importance of considering vasculitis in patients without atherosclerotic risk factors, using a multidisciplinary team approach, and suppressing inflammation before coronary revascularization to improve outcomes. (Level of Difficulty: Beginner.), Central Illustration

PURPOSE: 1) To describe a case of autoimmune retinopathy mimicking heritable photoreceptor degeneration in a patient with common variable immune deficiency, and 2) to investigate the humoral and cell-mediated branches of the immune system in this patient to better understand the mechanism of immune-mediated photoreceptor damage in this disease. METHODS: Retrospective chart review with evaluation of multimodal imaging, genotype analysis, and investigation of circulating autoantibodies and T cell response to retinal antigens. RESULTS: A 40-year-old woman with bilateral, progressive vision loss was referred for evaluation of a possible inherited retinal degeneration. She was found to have asymmetric peripheral visual field constriction, cystoid macular edema, vitreous cells, and bone-spicule-like pigmentary changes in both eyes. An extensive workup for underlying infectious or inflammatory causes was unrevealing, and molecular analysis for heritable retinal degeneration failed to identify a plausible disease-causing genotype. Screening for anti-retinal antibodies showed the presence of multiple anti-retinal antibodies, consistent with a diagnosis of autoimmune retinopathy. Immunologic workup demonstrated markedly decreased levels of serum IgA and IgG, consistent with common variable immune deficiency. T-cells isolated from the patient showed increased proliferation when stimulated with human retinal proteins, supporting a role for both cell and humoral-mediated autoimmunity. Treatment with mycophenolate mofetil and intravenous immunoglobin therapy slowed the progression of disease and resulted in preservation of her central vision. CONCLUSIONS: Autoimmune retinopathy can be seen in common variable immune deficiency and have clinical findings similar to heritable photoreceptor degeneration. Both the humoral and cellular immune responses are involved in the pathophysiology. Immune modulatory therapy has stabilized the disease course in this patient and may play an important role in the management of autoimmune retinopathy.

Simple Summary Radiation therapy and immune checkpoint inhibitors (ICIs) have been demonstrated to cooperatively activate adaptive anti-tumor immunity with curative potential in preclinical models of melanoma. Receptor-targeted radionuclide therapy can be systemically injected to selectively deliver ionizing radiation to tumor sites throughout the body, potentially rendering all tumor sites more susceptible to anti-tumor immune response. In this study, we demonstrated the feasibility of delivering alpha-particle radiation to murine melanoma tumors using a 212Pb radiolabeled peptide [212Pb]VMT01 that targets the melanocortin 1 receptor (MC1R). Our data showed anti-tumor cooperation between [212Pb]VMT01 and ICIs in melanoma, mediated by induction of tumor-specific immunity. The immunogenicity of [212Pb]VMT01 in melanoma was also evidenced by enhanced tumor infiltrating lymphocytes and tumor vaccination assays. Abstract Radiotherapy can facilitate the immune recognition of immunologically “cold” tumors and enhance the efficacy of anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICIs) in melanoma. Systemic administration of receptor-targeted radionuclide therapy has the potential to selectively deliver radionuclides to multiple tumors throughout the body in metastatic settings. By triggering immunologic cell death and increasing the immune susceptibility of surviving tumor cells in these locations, targeted radionuclide therapies may overcome resistance to ICIs and render immunologically “cold” tumors throughout the body responsive to ICIs and immunologically “hot”. Here, we show the anti-tumor cooperation of targeted α-particle radionuclide therapy (α-TRT) and ICIs in preclinical models of melanoma. Melanocortin 1 receptor (MC1R)-targeted radiopeptide [212Pb]VMT01 was employed to deliver α-radiation to melanoma tumors in mice. A single injection of 4.1 MBq [212Pb]VMT01 significantly slowed the tumor growth of B16-F10 melanoma and the combination of [212Pb]VMT01 and ICIs induced a cooperative anti-tumor effect leading to 43% complete tumor response with no sign of malignancy on autopsy. Animals with complete response developed anti-tumor immunity to reject further tumor inoculations. This therapeutic cooperation was completely abolished in RAG1 KO mice, which are deficient in T-cell maturation. In addition, the anti-tumor cooperation was compromised when fractionated [212Pb]VMT01 was used in the combination. We also demonstrated that [212Pb]VMT01 induced immunogenic cell death in tumor vaccination assays and in vitro exposure to [212Pb]VMT01 sensitized immunotolerant melanoma to ICIs treatment in vivo. Enhanced tumor infiltrating CD3+, CD4+, CD8+ lymphocytes were observed following injection of 1.4 MBq [212Pb]VMT01. Overall, we demonstrated anti-tumor cooperation between α-TRT and ICIs in melanoma that is mediated by tumor specific immunity.

Aim Angioedema is a nonpitting edema that can lead to death secondary to airway obstruction. Previously, a staging system based on localization of the angioedema was proposed for risk stratification of likelihood of need for admission or airway intervention. This study aims to evaluate a staging system based on angioedema localization as a method of predicting need for admission or airway intervention. Methods This was a retrospective chart review of angioedema cases that presented to an academic emergency department (ED) from August 1, 2006, to January 31, 2018. Data were collected on location of swelling, treatment setting, and medical and procedural interventions. Cases were categorized by modified Ishoo criteria, defined as follows: 1, lips, face, periorbital, extremities, total body/diffuse swelling; 2, soft palate, posterior pharynx; 3, tongue; 4, larynx. Predictive probability of disposition by stage was then compared. Results A total of 320 patients were included in this study (median age, 44 years; 54.4% female). Stage 4 was more likely to require intensive care unit care without (probability 17%) and with (67%) airway intervention compared with stage 1 without (2.5%) and with (0.1%) airway intervention. Conversely, stage 1 was more likely to be treated in ED and discharged (85%) compared with stage 4 (0%). Stage 4 was also more likely to require airway intervention (67%) compared with other stages (1, 0.1%; 2, 8.6%; 3, 16%). Conclusion Higher‐stage patients were more likely to require higher levels of care and airway intervention. Thus, the staging system appears to be a valid method of predicting risk among ED angioedema patients., We have evaluated the Ishoo criteria for angioedema in the emergency department and reported that they are valid predictors of disposition and need for airway intervention. By this, higher‐stage patients were more likely to require higher levels of care and airway intervention, suggesting that these staging criteria could be of benefit to the triage and management of patients presenting with angioedema.

Background There are limited data regarding immunological correlates of protection for the modified vaccinia Ankara (MVA) smallpox vaccine. Methods A total of 523 vaccinia-naive subjects were randomized to receive 2 vaccine doses, as lyophilized MVA given subcutaneously, liquid MVA given subcutaneously (liquid-SC group), or liquid MVA given intradermally (liquid-ID group) 28 days apart. For a subset of subjects, antibody-dependent cellular cytotoxicity (ADCC), interferon-γ release enzyme-linked immunospot (ELISPOT), and protein microarray antibody-binding assays were conducted. Protein microarray responses were assessed for correlations with plaque reduction neutralization titer (PRNT), enzyme-linked immunosorbent assay, ADCC, and ELISPOT results. Results MVA elicited significant microarray antibody responses to 15 of 224 antigens, mostly virion membrane proteins, at day 28 or 42, particularly WR113/D8L and WR101H3L. In the liquid-SC group, responses to 9 antigens, including WR113/D8L and WR101/H3L, correlated with PRNT results. Three were correlated in the liquid-ID group. No significant correlations were observed with ELISPOT responses. In the liquid-ID group, WR052/F13L, a membrane glycoprotein, correlated with ADCC responses. Conclusions MVA elicited antibodies to 15 vaccinia strain antigens representing virion membrane. Antibody responses to 2 proteins strongly increased and significantly correlated with increases in PRNT. Responses to these proteins are potential correlates of protection and may serve as immunogens for future vaccine development. Clinical Trials Registration NCT00914732.

To examine the prevalence of hypogammaglobulinemia in chronic lymphocytic lymphoma (CLL) patients and to test the hypothesis that patients with hypogammaglobulinemia have a distinct clinical profile and outcome.Immunoglobulin levels (IgA, IgG, IgM, IgE) were measured in newly diagnosed, treatment naïve banked samples of 150 patients with CLL followed prospectively for outcomes. Cox regression models were used to assess the effects of clinical variables on overall survival (OS).The median age of the selected CLL cohort was 64 years with a male predominance; 96.2% of the patients were white. Fifty-nine deaths occurred during a median follow up of 6.8 years. Hypogammaglobulinemia in CLL was common in our cohort with 88 (58.7%, 95% CI: 50.4-66.6%) patients having a measurable isotype deficiency. The most common Ig deficiency was IgM (44.0%). IgA deficiency or low IgE was associated with higher Rai stages as well as with higher white blood cell counts at presentation. Any immunoglobulin deficiency was not associated with overall survival.A significant proportion of treatment-naïve CLL patients had underlying Ig deficiencies - both in isolation and in isotype combinations. Although a deficiency of IgA or IgE was associated with more severe disease at presentation, the impact of this association was mild.

Prediction models aim to use available data to predict a health state or outcome that has not yet been observed. Prediction is primarily relevant to clinical practice, but is also used in research, and administration. While prediction modeling involves estimating the relationship between patient factors and outcomes, it is distinct from casual inference. Prediction modeling thus requires unique considerations for development, validation, and updating. This document represents an effort from editors at 31 respiratory, sleep, and critical care medicine journals to consolidate contemporary best practices and recommendations related to prediction study design, conduct, and reporting. Herein, we address issues commonly encountered in submissions to our various journals. Key topics include considerations for selecting predictor variables, operationalizing variables, dealing with missing data, the importance of appropriate validation, model performance measures and their interpretation, and good reporting practices. Supplemental discussion covers emerging topics such as model fairness, competing risks, pitfalls of "modifiable risk factors", measurement error, and risk for bias. This guidance is not meant to be overly prescriptive; we acknowledge that every study is different, and no set of rules will fit all cases. Additional best practices can be found in the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines, to which we refer readers for further details., SCOPUS: ar.j, info:eu-repo/semantics/published

The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.

Moderate alcohol consumption has been associated with a lower risk of coronary artery disease (CAD) in the general population but has not been well studied in US veterans. We obtained self-reported alcohol consumption from Million Veteran Program participants. Using electronic health records, CAD events were defined as 1 inpatient or 2 outpatient diagnosis codes for CAD, or 1 code for a coronary procedure. We excluded participants with prevalent CAD (n = 69,995) or incomplete alcohol information (n = 8,449). We used a Cox proportional hazards model to estimate hazard ratios and 95% confidence intervals for CAD, adjusting for age, gender, body mass index, race, smoking, education, and exercise. Among 156,728 participants, the mean age was 65.3 years (standard deviation = 12.1) and 91% were men. There were 6,153 CAD events during a mean follow-up of 2.9 years. Adjusted hazard ratios (95% confidence intervals) for CAD were 1.00 (reference), 1.02 (0.92 to 1.13), 0.83 (0.74 to 0.93), 0.77 (0.67 to 0.87), 0.71 (0.62 to 0.81), 0.62 (0.51 to 0.76), 0.58 (0.46 to 0.74), and 0.95 (0.85 to 1.06) for categories of never drinker; former drinker; current drinkers of ≤0.5 drink/day, >0.5 to 1 drink/day, >1 to 2 drinks/day, >2 to 3 drinks/day, and >3 to 4 drinks/day; and heavy drinkers (>4 drinks/day) or alcohol use disorder, respectively. For a fixed amount of ethanol, intake at ≥3 days/week was associated with lower CAD risk compared with ≤1 day/week. Beverage preference (beer, wine, or liquor) did not influence the alcohol-CAD relation. Our data show a lower risk of CAD with light-to-moderate alcohol consumption among US veterans, and drinking frequency may provide a further reduction in risk.

BACKGROUND: We evaluated the overall and site-specific incidence of cancer in subjects with primary immunodeficiency diseases (PIDD) enrolled in the United States Immune Deficiency Network (USIDNET) registry compared with age-adjusted cancer incidence in the Surveillance, Epidemiology and End Results Program (SEER) database. We hypothesized that subjects with PIDD would have an increased incidence of cancer due to impaired immune function. METHODS: Overall and site-specific cancer incidence rates were evaluated in subjects with PIDD (n = 3,658) enrolled in the USIDNET registry from 2003–2015, and compared with age-adjusted incidence rates in the SEER database. RESULTS: We observed a 1.42-fold excess relative risk of cancer in subjects with PIDD compared to the age-adjusted SEER population (p

Background The burden of frequent respiratory exacerbations in COPD patients with mild-to-moderate spirometric impairment and smokers with preserved lung function is unknown. Methods We categorized COPD participants in COPDGene with post-bronchodilator FEV1%predicted≥50% by the annual exacerbation frequency into three groups: i)frequent exacerbators (top 5%; n = 109), ii)exacerbators (>0 but less than frequent exacerbators; n = 1,009), and iii)No exacerbation (n = 981). Exacerbations were defined as respiratory episodes requiring antibiotics and/or systemic steroids. We performed a Cox proportional hazards regression analysis to examine the association with mortality. We repeated the same process in current/former smokers with preserved spirometry (FEV1≥80%predicted and FEV1/FVC≥0.7). Results Among 2,099 COPD participants, frequent exacerbators had ≥1.8 exacerbations/year and were responsible for 34.3% of the total exacerbations. There were 102 (10.4%) deaths in the group with no exacerbations, 119 (11.8%) in the exacerbator group, and 24 (22%) in the frequent exacerbators. Adjusted mortality in frequent exacerbators was higher relative to individuals with no exacerbations (hazard ratio (HR) = 1.98; 95%CI = 1.25–3.13). An increase in frequency of exacerbations by one exacerbation/year was associated with increased mortality (HR = 1.40,95%CI = 1.21–1.62). Among 3,143 participants with preserved spirometry, frequent exacerbators had ≥0.8 exacerbations/year and were responsible for more than half of the exacerbations. There were 93 (4.2%) deaths in the group with no exacerbations, 28 (3.8%) in the exacerbator group, and 14 (7.6%) in the frequent exacerbators. The adjusted mortality was increased in frequent exacerbators with preserved spirometry relative to those with no exacerbations (HR = 2.25; 95%CI = 1.26–4.01). Conclusions In COPD participants with mild-to-moderate spirometric impairment and smokers with preserved spirometry, the frequent exacerbator phenotype is responsible for a large proportion of total exacerbations and associated with high mortality.

We assessed the clinical features and outcomes based on therapeutic options adopted during hospital stay for adult patients with macrophage activation syndrome and secondary hemophagocytic lymphohistiocytosis (MAS/sHLH). We conducted a retrospective chart review of all adult patients (age ≥ 18 years) diagnosed with MAS/sHLH at our center between 2010 and 2015. Inclusion criteria for patients were diagnosis of MAS/sHLH during admission and patients meeting at least 5 out of 8 of Henter’s criteria or at least 4 out of 6 of the criteria that were tested. Nineteen adult patients with MAS/sHLH met the inclusion criteria from January 2010 to October 2015 (median age 48 years; female 68.4%). Treatment had been personalized, depending on the clinical presentation and course of disease. Majority of the patients received anakinra, cyclosporine, intravenous immunoglobulins (IVIG), and steroids. Fourteen (74%) patients survived, with clinical improvement by the time of discharge. After excluding the three patients with underlying leukemia/lymphoma who opted for palliative care and subsequently died, the survival rate was 88%. A modified diagnostic and treatment protocol for adult patients with MAS/sHLH that incorporated graded introduction of medications based on clinical presentation and cytokine profile resulted in the best adult survival rate reported in literature.

Background Although high ferritin levels are associated with iron overload, it is known that ferritin is also an acute-phase reactant that may be elevated in conditions associated with acute and chronic inflammation. In addition, an elevated ferritin level is a criterion for the diagnosis of hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS). Therefore, the significance of elevated serum ferritin is often unclear. As HLH/MAS is a medical emergency, prompt diagnosis is important to guide appropriate treatment. Materials and Methods To study the spectrum of diagnoses associated with elevated serum ferritin, we did a retrospective review of adult patients admitted to our academic medical center from 2008-2012 with serum ferritin levels greater than 2,000ng/mL. The degree of hyperferritinemia was compared to different diagnoses and selected laboratory values. Results A total of 333 patients were identified with a serum ferritin level >2,000ng/mL. Hepatocellular injury was the most prevalent diagnosis with n = 126; infection was next with n = 96. Eleven patients were diagnosed with HLH/MAS. Conclusions Elevated ferritin, as an isolated finding, was not a specific marker for the diagnosis of HLH/MAS. However, as a group, HLH/MAS patients had the highest mean and median ferritin values.

The field of biologic immune modulators is currently mushrooming at a dizzying pace. Although most of these biologics are tested and approved for one or a few indications, their unanticipated side effects and off-label use have contributed significantly to our understanding of basic immune mechanisms, the involvement of cytokines in several apparently nonimmunologic diseases, and the importance of compartmentalized immune responses. In this review we attempt to give a bird's-eye view of the major biologics and to highlight insights and implications derived from their secondary effects and adverse reactions.

Soluble PD-1 and PD-L1 are detected in the serum and plasma of lung cancer patients. The significance of these soluble proteins as prognostic or predictive markers in lung cancer is uncertain. The testing methods used to detect soluble PD1/PD-L1 are variable with no agreement on a common definition of a positive test. The advantages of validating soluble PD1/PD-L1 relevance in lung cancer include easiness of obtaining blood samples for testing, serial measurements to assess response to treatments such as immunotherapy, and potentially early identification of cancer relapse in cases treated with curative intent. In this review, we present the available data published on soluble PD1 and PD-L1 in lung cancer.

The 21st century has brought with it a welcome call for increased rigor in observational research methods (1, 2). It is not that observational research methods are inherently flawed – they are not (3, 4). Observational studies can contribute valuable evidence supporting causal associations when designed and conducted using rigorous methods. The “flaws” are a result of reliance on outdated methodology, inadequate attention to threats to validity (such as confounding), opaque reporting of results, lack of replication, and a failure to interpret findings within the context of the limitations of observational research methodology. Aware of this situation and influenced by our experience as journal editors, we convened an ad hoc group of 47 editors of 35 respiratory, sleep, and critical care journals to offer guidance to authors, peer reviewers, and researchers on the design and reporting of observational causal inference studies. This guidance takes the form of a call for investigators to consider making major changes to their approach to such studies. This document represents our current best understanding of approaches to causal inference, an active area of research. We anticipate that best practice in this, as in any scientific endeavor, will continue to evolve, requiring this document to be updated every 5 to 10 years. We believe these changes will increase the rigor, validity, and value of the work we publish in our journals.

Rationale: Renal inflammation contributes to the pathophysiology of hypertension. CD161a + immune cells are dominant in the (SHR) spontaneously hypertensive rat and expand in response to nicotinic cholinergic activation. Objective: We aimed to phenotype CD161a + immune cells in prehypertensive SHR after cholinergic activation with nicotine and determine if these cells are involved in renal inflammation and the development of hypertension. Methods and Results: Studies used young SHR and WKY (Wistar–Kyoto) rats. Splenocytes and bone marrow cells were exposed to nicotine ex vivo, and nicotine was infused in vivo. Blood pressures, kidney, serum, and urine were obtained. Flow cytometry, Luminex/ELISA, immunohistochemistry, confocal microscopy, and Western blot were used. Nicotinic cholinergic activation induced proliferation of CD161a + /CD68 + macrophages in SHR-derived splenocytes, their renal infiltration, and premature hypertension in SHR. These changes were associated with increased renal expression of MCP-1 (monocyte chemoattractant protein-1) and VLA-4 (very-late antigen-4). LLT1 (lectin-like transcript 1), the ligand for CD161a, was overexpressed in SHR kidney, whereas vascular cellular and intracellular adhesion molecules were similar to those in WKY. Inflammatory cytokines were elevated in SHR kidney and urine after nicotine infusion. Nicotine-mediated renal macrophage infiltration/inflammation was enhanced in denervated kidneys, not explained by angiotensin II levels or expression of angiotensin type-1/2 receptors. Moreover, expression of the anti-inflammatory α7-nAChR (α7-nicotinic acetylcholine receptor) was similar in young SHR and WKY rats. Conclusions: A novel, inherited nicotinic cholinergic inflammatory effect exists in young SHR, measured by expansion of CD161a + /CD68 + macrophages. This leads to renal inflammation and premature hypertension, which may be partially explained by increased renal expression of LLT-1, MCP-1, and VLA-4.

Background Patients with primary antibody deficiencies have an increased frequency of sinonasal and pulmonary infections. Immunoglobulin (Ig) replacement is a standard therapy for common variable immunodeficiency (CVID) and other antibody deficiency diseases. Although there is convincing evidence that Ig replacement reduces pulmonary infections, there is little evidence that it reduces sinus infections or abates chronic rhinosinusitis (CRS). This study aims to identify the impact of Ig replacement on CRS in antibody deficiencies. Methods A single-center, retrospective chart review of adult patients from 1995 to 2015 was performed. Inclusion criteria were diagnosis of CVID or specific antibody deficiency (SAD), history of CRS requiring medical and/or surgical management within the year prior to presentation, treatment with Ig replacement therapy, and follow-up interval of at least 1 year after initiating Ig replacement. Patients with secondary immune deficiencies were excluded. Thirty-one patients met criteria. Data collected included pretreatment and posttreatment Lund-Mackay scores, and frequency of sinusitis and pulmonary infections requiring rescue antibiotics. Statistical analysis was performed using Wilcoxon signed-rank tests. Results A significant decline in the Lund-Mackay score was evidenced from pretreatment to posttreatment (p < 0.01). Treatment also resulted in significantly lower rates of sinusitis (p < 0.01) and pulmonary infections (p < 0.01). Additionally, 56% of patients who were on prophylactic antibiotics prior to Ig replacement were able to discontinue their use. Conclusion We present objective evidence showing that Ig replacement therapy has a positive impact on the frequency of sinusitis and confirm its positive impact on pulmonary infections in adult patients with CVID and SAD.

Aim To compare different variables among (S)CID patients diagnosed in the USA and Kuwait. Methods Review of patients registered in The US Immune Deficiency Network registry or Kuwait National PID Registry between 2004 and 2014. Results Totals of 98 and 69 (S)CID patients were registered during the study period in the USIDNET registry and the KNPIDR, respectively. The average annual incidence rate for the period 2004–2014 of (S)CID in children in Kuwait was 13.01/100,000 children, with an estimated occurrence of 1/7500 live births. There were differences between the two countries in the following variables: age at onset and diagnosis, family history of (S)CID, parental consanguinity, and outcome. More than 14% of (S)CID patients from USIDNET registry were diagnosed through newborn screening. Conclusions Patients' characteristics and molecular causes of S(CID) are different between USA and Kuwait. NBS for SCID should be started in countries where the incidence of (S)CID is high.

A 64-year-old white female presented with 4 years of episodic, productive cough, fevers, chills, night sweats, and weight loss. Over this period, she had documented recurrent Mycobacterium avium complex in the bronchiolar lavage and sputum despite taking antibiotics for 2 years. Result of ex

Background: While there is evidence in the literature of increased prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (CLL), there are no studies evaluating the prevalence of hypogammaglobulinemia in newly diagnosed diffuse large B cell lymphoma (DLBCL) or the relationship between hypogammaglobulinemia and presentation or outcomes. The objective of this study was to examine the prevalence of hypogammaglobulinemia in newly diagnosed DLBCL patients and to test the hypothesis that DLBCL patients with baseline hypogammaglobulinemia have a distinct clinical profile and outcome. Methods: We obtained banked frozen sera from 200 newly diagnosed, treatment-naïve, DLBCL patients from the Lymphoma SPORE Molecular Epidemiology Resource (MER), a prospective cohort study conducted at the Mayo Clinic and the University of Iowa. IgG/A/M levels were measured using immunoturbidimetric assay whereas IgE level was measured using electrochemiluminescence immunoassay; deficiency was defined using standard reference ranges. IgE levels were considered deficient if Results: The mean age (SD) of the cohort was 65.6 (13.4) years, 54% were males and 98% of the patients were white. Over a median follow-up of five years, there were 59 (29.5%) deaths. The prevalence of hypogammaglobulinemia, defined as any deficiency, in newly diagnosed, treatment-naïve DLBCL was 22.1% (44/199) in our cohort, and the most common Ig deficiency was for IgG ( Conclusions: To the best of our knowledge, this is the first study to report the prevalence of hypogammaglobulinemia in treatment naïve DLBCL. We found that any Ig deficiency was not uncommon in our cohort and it was associated with an inferior EFS and OS in DLBCL patients. The prevalence of hypogammaglobulinemia in DLBCL patients seems to be lower than has been described in CLL patients. While the underlying relationship between these two immunologic disorders deserves further study, our findings highlight the interaction between global immune dysfunction and emergence of a clonal B cell process. Disclosures Nowakowski: Genentech, Inc.: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Curis: Research Funding; Bayer: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Selvita: Membership on an entity's Board of Directors or advisory committees; NanoString: Research Funding; MorphoSys: Consultancy, Research Funding. Farooq:Celgene: Honoraria; Kite Pharma: Research Funding. Cerhan:NanoString: Research Funding; Celgene: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees.

Background While adherence to healthful dietary patterns has been associated with a lower risk of coronary artery disease (CAD) in the general population, limited data are available among US veterans. We tested the hypothesis that adherence to Dietary Approach to Stop Hypertension (DASH) food pattern is associated with a lower risk of developing CAD among veterans. Methods and Results We analyzed data on 153 802 participants of the Million Veteran Program enrolled between 2011 and 2016. Information on dietary habits was obtained using a food frequency questionnaire at enrollment. We used electronic health records to assess the development of CAD during follow‐up. Of the 153 802 veterans who provided information on diet and were free of CAD at baseline, the mean age was 64.0 (SD=11.8) years and 90.4% were men. During a mean follow‐up of 2.8 years, 5451 CAD cases occurred. The crude incidence rate of CAD was 14.0, 13.1, 12.6, 12.3, and 11.1 cases per 1000 person‐years across consecutive quintiles of Dietary Approach to Stop Hypertension score. Hazard ratios (95% confidence interval) for CAD were 1.0 (ref), 0.91 (0.84–0.99), 0.87 (0.80–0.95), 0.86 (0.79–0.94), and 0.80 (0.73–0.87) from the lowest to highest quintile of Dietary Approach to Stop Hypertension score controlling for age, sex, body mass index, race, smoking, exercise, alcohol intake, and statin use ( P linear trend, Conclusions Our data are consistent with an inverse association between Dietary Approach to Stop Hypertension diet score and incidence of CAD among US veterans.

Drug allergy pathways are standardized approaches for patients reporting prior drug allergies with the aim of quality improvement and promotion of antibiotic stewardship. At the International Drug Allergy Symposium during the 2018 American Academy of Allergy, Asthma and Immunology /World Allergy Organization Joint Congress in Orlando, Florida, drug allergy pathways were discussed from international perspectives with a focus on beta-lactam allergy pathways and pragmatic approaches for acute care hospitals. In this expert consensus document, we review current pathways, and detail important considerations in devising, implementing, and evaluating beta-lactam allergy pathways for hospitalized patients. We describe the key patient and institutional factors that must be considered in risk stratification, the central feature of pathway design. We detail shared obstacles to widespread beta-lactam allergy pathway implementation, and identify potential solutions to address these challenges.

Chronic Obstructive Pulmonary Disease is the third leading cause of death in the US, and is associated with periodic exacerbations, which account for the largest proportion of health care utilization, and lead to significant morbidity, mortality, and worsening lung function. A subset of patients with COPD have frequent exacerbations, occurring 2 or more times per year. Despite many interventions to reduce COPD exacerbations, there is a significant lack of knowledge in regards to their mechanisms and predisposing factors. We describe here an important observation that defines antibody deficiency as a potential risk factor for frequent COPD exacerbations. We report a case series of patients who have frequent COPD exacerbations, and who were found to have an underlying primary antibody deficiency syndrome. We also report on the outcome of COPD exacerbations following treatment in a subset with of these patients with antibody deficiency. We identified patients with COPD who had 2 or more moderate to severe exacerbations per year; immune evaluation including serum immunoglobulin levels and pneumococcal IgG titers was performed. Patients diagnosed with an antibody deficiency syndrome were treated with either immunoglobulin replacement therapy or prophylactic antibiotics, and their COPD exacerbations were monitored over time. A total of 42 patients were identified who had 2 or more moderate to severe COPD exacerbations per year. Twenty-nine patients had an underlying antibody deficiency syndrome: common variable immunodeficiency (8), specific antibody deficiency (20), and selective IgA deficiency (1). Twenty-two patients had a follow-up for at least 1 year after treatment of their antibody deficiency, which resulted in a significant reduction of COPD exacerbations, courses of oral corticosteroid use and cumulative annual dose of oral corticosteroid use, rescue antibiotic use, and hospitalizations for COPD exacerbations. This case series identifies antibody deficiency as a potentially treatable risk factor for frequent COPD exacerbations; testing for antibody deficiency should be considered in difficult to manage frequently exacerbating COPD patients. Further prospective studies are warranted to further test this hypothesis.

Background and Purpose— Inflammation may play an important role in the formation and rupture of cerebral aneurysms. Chemokines act as chemoattractants for leukocytes directing them toward sites of tissue inflammation. The purpose of this study was to determine whether chemokines and chemoattractant cytokines were increased in the lumen of human cerebral aneurysms. Methods— The concentrations of chemokines and other inflammatory molecules in blood samples drawn from the lumen of human cerebral aneurysms of 16 consecutive patients (harboring 18 aneurysms) were compared with blood samples from the femoral arteries of the same patients. Three aneurysms had ruptured. Results— The mean plasma concentration of regulated on activation, normal T cell expressed and secreted (RANTES), monokine-induced-by-γ-interferon (MIG), interferon-γ-induced protein-10 (IP-10), eotaxin, interleukin (IL) 8, and IL17 was significantly higher in samples taken from cerebral aneurysms compared with femoral arteries. In contrast, plasma concentrations of all remaining inflammatory molecules (except IL6) that were tested did not differ between cerebral aneurysms and femoral arteries. For unruptured aneurysms, there was a significantly higher mean plasma concentration of monocyte chemoattractant protein-1 as well as RANTES, MIG, IP-10, eotaxin, IL8, and IL17 in samples obtained from cerebral aneurysms. Conclusions— High plasma concentrations of chemokines (monocyte chemoattractant protein-1, RANTES, MIG, IP-10, and eotaxin) and chemoattractant cytokines (IL8 and IL17) were found in the lumen of human cerebral aneurysms. These findings suggest that there may be an active recruitment of inflammatory cells into the aneurysm wall that may be exploited therapeutically.

X-linked agammaglobulinemia is a primary humoral immunodeficiency characterized by hypogammaglobulinemia and increased susceptibility to infection. Although there is increased awareness of autoimmune and inflammatory complications in X-linked agammaglobulinemia (XLA), the spectrum of gastrointestinal manifestations has not previously been fully explored. We present a case report of a family with two affected patients with XLA. Given the gastrointestinal involvement of the grandfather in this family, we performed a retrospective descriptive analysis of XLA patients with reported diagnoses of GI manifestations and inflammatory bowel disease (IBD) or enteritis registered at the United States Immunodeficiency Network, a national registry of primary immunodeficiencies. In this cohort of patients with XLA, we found that up to 35% had concurrent gastrointestinal manifestations, and 10% had reported diagnoses of IBD or enteritis. The most commonly reported mutations were missense, which have been associated with a less severe XLA phenotype in the literature. The severity of symptoms were wide ranging, and management strategies were diverse and mainly experimental. Patients with XLA may require close monitoring with particular attention for GI manifestations including IBD and infectious enteritis. Further studies are needed to improve diagnosis and management of GI conditions in XLA patients.