Chapter 4: Stinging insect allergy and venom immunotherapy.

The Hymenoptera order is divided into three families: Apids, Vespidae, and Formicidae. Apids include the honeybee, bumblebee, and sweat bee, which are all docile and tend to sting mostly on provocation. The Africanized killer bee, a product of interbreeding between the domestic and African honeybee, is very aggressive and is found mostly in Mexico, Central America, Arizona, and California. The yellow jacket, yellow hornet, white (bald)-faced hornet, and paper wasp all belong to the Vespidae family. The Formicidae family includes the harvester ant and the fire ant. When a "bee" sting results in a large local reaction, defined as >5 in. and lasting >24 hours, the likelihood of anaphylaxis from a future sting is ∼5%. For comparison, when there is a history of anaphylaxis from a previous Hymenoptera sting and the patient has positive skin tests to venom, at least 60% of adults and 20-32% of children will develop anaphylaxis with a future sting. Both patient groups should be instructed about avoidance measures and carrying and knowing when to self-inject epinephrine, but immunotherapy (IT) with Hymenoptera venom is indicated for those patients with a history of anaphylaxis from the index sting and not for patients who have experienced a large local reaction. IT is highly effective in that by 4 years of injections, the incidence of subsequent sting-induced anaphylactic reactions is 3%. This incidence may increase modestly after discontinuation of injections but has not been reported >10% in follow-up.

Chapter 9: Asthma classification.

Asthma is a chronic inflammatory disorder of the airways resulting physiologically in hyperreactivity and clinically in recurrent episodes of wheezing, chest tightness, or coughing. Airway inflammation, smooth muscle contraction, epithelial sloughing, mucous hypersecretion, bronchial hyperresponsiveness, and mucosal edema contribute to the underlying pathophysiology of asthma. Diagnostic tests such as methacholine or mannitol challenges or spirometry (pre- and postbronchodilator responses) help to identify such underlying pathophysiology via assessments of bronchial hyperreactivity and lung mechanics but are imperfect and ultimately must be viewed in the context of a patient's clinical presentation including response to pharmacotherapy. The National Asthma Education and Prevention Program Expert Panel Report (2007) classifies asthma into either intermittent or persistent, and the latter is either mild, moderate, or severe. Some patients change in either direction from intermittent to persistent asthma. In addition, patients with asthma may be classified as allergic (IgE mediated), nonallergic (often triggered by viral upper respiratory tract infections or no apparent cause), occupational, aspirin-exacerbated respiratory disease, potentially (near) fatal, exercise induced, and cough variant asthma. In the latter, the patients have a nonproductive cough that responds to treatment for asthma but not with antibiotics, expectorants, mucolytics, antitussives, beta(2)-adrenergic agonists, treatment for acid reflux, or rhinosinusitis. Thus, cough variant asthma is in the differential diagnosis of chronic cough.

A novel mechanism of resistance to epidermal growth factor receptor antagonism in vivo.

Epidermal growth factor receptor (EGFR) is widely expressed in a number of solid tumors including colorectal cancers. Overexpression of this receptor is one means by which a cell can achieve positive signals for survival and proliferation; another effective means is by constitutive activation of EGFR. We have elucidated the role of constitutive EGFR signaling in malignant progression by stably transfecting colon cancer cells with a human transforming growth factor-alpha cDNA (a ligand for EGFR) under repressible control by tetracycline. We show that constitutive expression of transforming growth factor-alpha and its subsequent constitutive activation of EGFR allows for cancer cell survival in response to environmental stress in vitro and in vivo as well. The reversal of constitutive EGFR activation results in the loss of downstream mitogen-activated protein kinase and Akt activation, and a reduction in xenograft size that is associated with decreased proliferation and increased apoptosis. We used CI-1033, a small molecule antagonist of EGFR, to dissect an activation pathway that shows the ability of ERBb2 to activate Akt, but not Erk in the face of EGFR antagonism. This novel escape mechanism is a possible explanation of why anti-EGFR therapies have shown disappointing results in clinical trials.

Initiation of immunoglobulin therapy by subcutaneous administration in immunodeficiency patients naive to replacement therapy.

BACKGROUND: Patients with immunodeficiency diseases require lifelong treatment with immunoglobulin (Ig), yet few studies have vetted dosing strategies and effectiveness of Ig in older patient populations. Patients requiring subcutaneous (SC) Ig (SCIG) typically start with intravenous dosing before transitioning to SCIG weekly maintenance. In this retrospective review, we investigated an alternate strategy with higher initial SC doses among an older patient population with antibody deficiency syndromes. FINDINGS: Records of 13 patients (mean age, 70 years) with antibody deficiencies who were naive to treatment with Ig were assessed. SCIG (Vivaglobin® [Immune Globulin Subcutaneous (Human), 16% Liquid] or Hizentra® [Immune Globulin Subcutaneous (Human), 20% Liquid]) was given twice weekly (100 mg/kg) for 2 weeks, followed by weekly (100 mg/kg) administration The mean pretreatment IgG level was 460 mg/dL; at 1, 3, and 6 months after SCIG initiation, mean IgG serum levels were 852, 907, and 943 mg/dL, respectively. Maintenance doses were unchanged during 6 months of follow-up. All patients remain on SCIG (median, 44 months). One patient developed sepsis/cholangitis unrelated to treatment 3 months after starting SCIG; no other serious bacterial infections were reported. CONCLUSIONS: Initiation of SCIG by doubling the maintenance dose over 2 weeks may be a well-tolerated and effective option for patients with antibody deficiencies requiring Ig replacement, especially among older patients.

Characterization of specific antibody deficiency in adults with medically refractory chronic rhinosinusitis.

BACKGROUND: Specific antibody deficiency may predispose patients to recurrent respiratory tract infections. There is limited literature assessing specific antibody deficiency in chronic rhinosinusitis (CRS). This study evaluated the role of specific antibody deficiency in patients with CRS who have failed medical therapy. METHODS: We performed a retrospective chart review of patients with CRS who underwent functional endoscopic sinus surgery and had prior assessment for humoral immunodeficiency. Each patient's record was reviewed for serum quantitative immunoglobulin G (IgG) and IgA and anti-Streptococcus pneumoniae antibody titers measured at baseline and 6 weeks postvaccination with the 23-valent unconjugated pneumococcal vaccine. Clinical characteristics, including asthma, atopy, and nasal polyps, were recorded. RESULTS: Of the 129 CRS patients who met inclusion criteria, 93 (72%) had low baseline antipneumococcal titers. Fifteen (11.6%) patients were diagnosed with specific antibody deficiency based on an inadequate response to the pneumococcal polysaccharide vaccine. The group of patients with specific antibody deficiency had significantly lower serum IgA levels when compared with those patients with normal preimmunization titers (138 ± 67.3 versus 330 ± 356; p < 0.05). Patients with specific antibody deficiency had a significantly lower number of preimmunization protective antipneumococcal titers when compared with vaccine responders (1.41 versus 2.72; p < 0.0005). CONCLUSION: This retrospective study indicates that patients with medically refractory CRS may have a high prevalence of low preimmunization antipneumococcal titers and specific antibody deficiency. Furthermore, lower serum IgA levels identified in these specific antibody deficiency patients suggests that a prospective study to further characterize this relationship is warranted.