Mark C. Glaum

Drug-induced rhinitis

Background Rhinitis is characterized by inflammation of the mucous membranes lining the nose and can be divided into two categories, allergic and non‐allergic. Drug‐induced is a type of non‐allergic rhinitis.

Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production.

BACKGROUND Toll-like receptors contribute to the establishment of adaptive immune responses. OBJECTIVE The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation. METHODS Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR. RESULTS Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts. CONCLUSION Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.

Systemic reactions to subcutaneous allergen immunotherapy and the response to epinephrine.

The use of epinephrine for anaphylaxis to subcutaneous allergen immunotherapy (SCIT) is the standard of care, but its use for mild systemic reactions (SRs) is somewhat controversial. The objective of this study is to determine the rate of SR to SCIT, the symptoms reported, and the response to intramuscular (i.m.) epinephrine over a 1 year period. This retrospective study was designed to evaluate SRs to SCIT to any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 773 subjects representing 14,707 visits, receiving approximately 28,000 injections over 1 year. Nurses were instructed to administer epinephrine (1:1000 v/v) 0.2 mL i.m. for signs or symptoms of a SR. SRs were graded using the universal grading system proposed by the World Allergy Organization (WAO) Joint Task Force for Grading SR to Immunotherapy. Thirty-one patients (4%) had 32 SRs, 22 (71%) female, average age 40 yr. Nineteen (61%) had a history of asthma; 7 (22.6%) had a history of a previous SR. SRs were reported on average 24 minutes after injection. Symptoms included: generalized pruritus, 34.4%; upper airway pruritus, 28.1%; cough, 25.0%; shortness of breath, 21.9%. Fourteen SRs were classified as Grade 1, thirteen Grade 2, two Grade 3, and three Grade 4. No Grade 5 or late phase reactions were reported. 29 (90.6%) reactions were treated with epinephrine, 27 (84.4%) glucocorticosteroid, and 30 (93.8%) H1 antihistamine. SRs occurred in 4% of patients receiving SCIT and all who received early intervention with epinephrine responded successfully. The WAO Grading system was useful.

Initial Observations of Cell-Mediated Drug Delivery to the Deep Lung

Using current methodologies, drug delivery to small airways, terminal bronchioles, and alveoli (deep lung) is inefficient, especially to the lower lungs. Urgent lung pathologies such as acute respiratory distress syndrome (ARDS) and post-lung transplantation complications are difficult to treat, in part due to the methodological limitations in targeting the deep lung with high efficiency drug distribution to the site of pathology. To overcome drug delivery limitations inhibiting the optimization of deep lung therapy, isolated rat Sertoli cells preloaded with chitosan nanoparticles were use to obtain a high-density distribution and concentration (92%) of the nanoparticles in the lungs of mice by way of the peripheral venous vasculature rather than the more commonly used pulmonary route. Additionally, Sertoli cells were preloaded with chitosan nanoparticles coupled with the anti-inflammatory compound curcumin and then injected intravenously into control or experimental mice with deep lung inflammation. By 24 h postinjection, most of the curcumin load (~90%) delivered in the injected Sertoli cells was present and distributed throughout the lungs, including the perialveloar sac area in the lower lungs. This was based on the high-density, positive quantification of both nanoparticles and curcumin in the lungs. There was a marked positive therapeutic effect achieved 24 h following curcumin treatment delivered by this Sertoli cell nanoparticle protocol (SNAP). Results identify a novel and efficient protocol for targeted delivery of drugs to the deep lung mediated by extratesticular Sertoli cells. Utilization of SNAP delivery may optimize drug therapy for conditions such as ARDS, status asthmaticus, pulmonary hypertension, lung cancer, and complications following lung transplantation where the use of high concentrations of anti-inflammatory drugs is desirable, but often limited by risks of systemic drug toxicity.

Osteoporosis in the at-risk asthmatic

The effect of inhaled glucocorticosteroids (ICS) on bone metabolism and subsequent osteoporosis is controversial. Explanations for this controversy include various study designs, duration of use, outcome measures, and population demographics of research studies with intranasal or inhalational ICS. Patients with poorly controlled asthma are at greatest risk of osteoporosis because they are commonly treated with intermittent or continuous systemic corticosteroids (SCS) or high‐dose ICS. A 45‐year‐old Caucasian woman presents with moderate‐to‐severe asthma with frequent albuterol use and nighttime awakenings at least once weekly. She is on fluticasone/salmeterol 500/50 μg one inhalation twice daily and montelukast 10 mg/day. She requires prednisone 15 mg three times per day for 5 days up to three times a year. Is this patient at greater risk of osteopenia, characterized by a T‐score between −1.0 and −2.5, and subsequent osteoporosis and an increased risk of fractures? If she has osteopenia, should she be treated with a bisphosphonate? The risk of osteoporosis and fracture increases significantly with frequent administration of SCS, and patients on such medications should undergo preventative measures and treatment. This study discuses factors that contribute to an increased risk of osteoporosis/osteopenia in patients with asthma and suggests recommendations based on the current literature.

Evaluation of combination long-acting β-2 agonists and inhaled glucocorticosteroids for treatment of asthma

Background: Treating asthma with a combination of inhaled corticosteroid and a long-acting β-2-agonist is often preferred when asthma is not controlled when using a low-medium dose of an inhaled corticosteroid. Objective: To review the pharmacology, efficacy and safety of inhalers containing combinations of long-acting bronchodilators and inhaled corticosteroids to treat moderate-to-severe, persistent asthma. Methods: Using a list of keywords, we conducted a PubMed search of the literature. Data provided by the manufacturer were also reviewed. Results: Fluticasone propionate with salmeterol and budesonide with formoterol are both well tolerated, have equal clinical efficacy and have recent data affirming their safe use in diverse patient populations. Conclusions: Combination inhalers improve asthma control in patients previously uncontrolled on inhaled corticosteroids.

Symptomatic Primary Selective Immunoglobulin M Deficiency with Nonprotective Pneumococcal Titers Responsive to Subcutaneous Immunoglobulin Treatment.

Selective immunoglobulin M deficiency (SIgMD) is a rare disorder with varying clinical features. The prevalence of SIgMD is 0.03-3%. Patients may be asymptomatic or else present with recurrent infection, autoimmunity, atopic disease and/or malignancy. About 50% of patients with symptomatic SIgMD also have impaired antibody responses to the pneumococcal polysaccharide vaccine. We report on an adult who presented with symptomatic SIgMD with impaired pneumococcal polysaccharide antibody responses and lymphopenia, who experienced a significant clinical improvement in the frequency of infections after subcutaneous immunoglobulin replacement therapy.

Biomarkers in Severe Asthma

Severe asthma is a heterogeneous disease with a variety of different phenotypes and endotypes. Biomarkers may facilitate the diagnosis and classification of severe asthma, predict efficacy of specific therapies, and assess medication response. Pulmonary function testing is an essential biomarker for the diagnosis and management of asthma. Recently, spirometric parameters reflecting small-airway obstruction have shown promise in the diagnosis and management of certain phenotypes of asthma. In addition, the presence of potential asthma biomarkers has been examined in a variety of biological samples including exhaled breath, blood, sputum, bronchoalveolar lavage fluid, bronchial brushings, bronchial biopsies, and urine. Biomarker candidates identified in these samples include fractional exhaled nitric oxide, eosinophils, neutrophils, IgE, cytokines, chemokines, and bioactive molecules. Despite the progress made in the identification of potential biomarkers for severe asthma, further studies are still needed to standardize collection methods, quantify measurement, and assess clinical significance of candidate biomarkers. Meanwhile, with the ongoing advancement in technologies related to proteomics, genomics, and metabolomics, the potential exists to discover more and more candidate biomarkers that will ultimately aid in the diagnosis and treatment of severe asthma.

35 Body Mass Index (BMI) and Immediate (“STAT”) Dose of Epinephrine im (EPI IM) Needed to Treat Subcutaneous Allergen Immunotherapy (SCIT) Systemic Reactions (SRS).

Background The purposes of this study are to document the number of SRs to SCIT, the relationship between BMI versus the severity of SRs [World Allergy Organization (WAO) Grade 1 to 5 reactions], and the possible relationship between BMI and the total amount of epi IM needed to treat the SRs. Methods This is a retrospective study of SRs to optimal dose SCIT with any combination of approximately 20 allergens (pollens, animal emanations, molds, and Hymenoptera) in 840 subjects representing 13,812 encounters over 12 months (June 2010–May 2011). Nurses administered stat epi IM (1:1000 v/v), 0.2 mg, immediately into the arm or thigh for any systemic signs or symptoms (SS) of a SR, including, but not limited to, itchy eyes, nose, pharynx, palms; rhinorrhea, nasal congestion, sneezing; and generalized erythema, pruritus, or urticaria. Repeat doses of epi IM were administered as necessary. Results 32 subjects (3.8%) each had one SR: 21 (66%) Grade 1, 10 (31%) Grade 2, 1 (3%) Grade 3, and Grades 4 or 5. BMIs were missing in 3 subjects. Fifteen of 29 were in the normal weight range (BMI 18.5–24.9), 9 Grade 1 (mean epi IM, 0.27 mg) and 6 Grade 2 (mean epi IM, 0.3 mg). Mean epi IM was 0.28 mg. Eight of 29 subjects were overweight (BMI 25–29.9), 7 Grade 1 (mean epi IM, 0.23 mg), and 1 Grade 3 (mean epi IM, 0.3 mg). Mean epi IM was 0.24 mg. Six of 29 were obese (BMI >30), 4 Grade 1 (mean epi IM, 0.3 mg) and 2 Grade 2 (mean epi IM, 0.2 mg). Mean epi IM was 0.27 mg. Conclusions SRs occurred in 3.8% of SCIT subjects. No significant association was found between BMI and the WAO Grade severity (P = 0.13 by Fishers exact test) and BMI and total epi IM dose given (P = 0.82 by Kruskal-Wallis test). BMI should not influence risk assessment of SCIT or IM epi administered for SR.

Asymptomatic long-standing panhypogammaglobulinemia with impaired antibody responses.

ASYMPTOMATIC LONG-STANDING PANHYPOGAMMAGLOBULINEMIA WITH IMPAIRED ANTIBODY RESPONSES Panhypogammaglobulinemia is the serologic hallmark of common variable immunodeficiency (CVID), a heterogeneous primary immunodeficiency syndrome.1 Although rare (incidence, 1:50,000–1:100,000), CVID represents one of the most common symptomatic humoral immunodeficiency syndromes.2 Panhypogammaglobulinemia in CVID is accompanied by impaired antibody responses to vaccines and recurrent sinopulmonary infections, particularly with encapsulated bacteria.3 Early descriptive reports noted that some patients with CVID remain free of infection despite profound hypogammaglobulinemia.3 A recent report4 from Spain describes a cohort of patients with hypogammaglobulinemia of unknown duration with autoimmune features but no history of recurrent sinopulmonary infections. We describe 3 patients with profound long-standing hypogammaglobulinemia who did not experience clinically significant bacterial sinopulmonary infections despite ineffective IgG boost responses after vaccination with bacterial vaccines. The first patient was a 51-year-old man, without a history of sinusitis, pneumonia, or other bacterial infections, who presented for a second opinion regarding a diagnosis of immunodeficiency. Medical records documented panhypogammaglobulinemia in 1997. At presentation, quantitative immunoglobulins revealed an IgG level of 169 mg/dL (reference range, 650–2,000 mg/dL), an IgM level of 25 mg/dL (reference range, 40–270 mg/dL), and an IgA level of less than 8 mg/dL (reference range, 50–100 mg/dL). The serum albumin level was normal, at 4.5 g/dL. Flow cytometry revealed normal numbers of CD3 CD8 T lymphocytes and CD19 B cells and a marginally low CD4 T-lymphocyte count of 461/ L (reference range, 560/ L-1,840/ L). The result of human immunodeficiency virus testing was negative. Prevaccination titers against tetanus toxoid were protective (1.2 IU/mL). Prevaccination titers against hemophilus influenza B (HIB) and Streptococcus pneumoniae were not protective, and 6 weeks after immunization with conjugated HIB and pneumococcal vaccine polyvalent (Pneumovax 23), titers failed to increase. The result of the computed tomographic (CT) scan of the chest was normal. The second patient was a 25-year-old woman who had markedly reduced serum globulin (1.6 g/dL; reference range, 2.5–3.0 g/dL) during routine evaluation at the age of 15 years. Ten years later, the patient was reevaluated and had profound panhypogammaglobulinemia. Her medical history was devoid of sinopulmonary infections. On referral, she had a serum IgG level of 81 mg/dL (reference range, 650-2,000 mg/dL), an IgM level of 10 mg/dL (reference range, 40–270 mg/dL), and an IgA level of less than 8 mg/dL (reference range, 50–100 mg/dL). Her serum albumin level was normal, at 4.5 g/dL. Flow cytometry revealed normal numbers of CD3 CD4 and CD3 CD8 T lymphocytes and CD19 B cells. Prevaccination antibody titers against HIB and tetanus toxoid were protective, whereas S pneumoniae titers were nonprotective. There was no increase in antibody titers after vaccination with pneumococcal vaccine polyvalent. The result of a CT scan of the chest was unremarkable. The third patient was a 46-year-old man with a history significant for idiopathic thrombocytopenia who was found to be hypogammaglobulinemic. Review of hospital records from 1989 revealed hypogammaglobulinemia; however, the patient denied any history of recurrent sinopulmonary infections. Serum immunoglobulin values in 1989 were as follows: IgG, 419 mg/dL (reference range, 650-2,000 mg/dL); IgM, 54 mg/dL (reference range, 40–270 mg/dL); and IgA, 49 mg/dL (reference range, 50–100 mg/dL). A subsequent evaluation in 2003 revealed an IgG level of 57 mg/dL (reference range, 650-2,000 mg/dL); an IgM level of 18 mg/dL (reference range, 40–270 mg/dL); and an IgA level of less than 8 mg/dL (reference range, 50–100 mg/dL). His serum albumin level was normal, at 4.1 g/dL, and flow cytometry revealed normal levels of CD3 CD4 and CD3 CD8 T lymphocytes and CD19 B cells. Antibody titers against tetanus toxoid (0.04 IU/mL), HIB (0.01 IU/mL), and 12 S pneumoniae serotypes were nonprotective. There was no increase in antibody titers against any vaccine component 6 weeks after vaccination. The result of a CT scan of the chest revealed innumerable centrilobular nodules throughout both lungs but no bronchiectasis. The 3 described patients presented with severe panhypogammaglobulinemia of long-standing duration with deficiency of at least 2 immunoglobulin classes (including IgG), decreasing 2 SDs below normal, and with absent polysaccharide antigen responses. Given the fact that these observations were unrelated to protein loss or other conditions associated with hypogammaglobulinemia, we have chosen to diagnose these patients as having CVID. Patients with CVID typically present with recurrent upper and lower respiratory tract infections;5 however, other presentations may include granulomatous disease,6 autoimmune processes, and lymphoproliferative disorders.7 Despite laboratory evidence of humoral immunodeficiency, these patients retained the ability to fight off bacterial sinopulmonary infections. One possible explanation is that these individuals possess an enhanced component of innate immunity (ie, alternative complement system, mannose-binding lectins, toll-like receptors, and defensins) that provides Disclosures: Authors have nothing to disclose.