Subcutaneous Immunoglobulin 16.5% (Cutaquig®) in Primary Immunodeficiency Disease: Safety, Tolerability, Efficacy, and Patient Experience with Enhanced Infusion Regimens.

PURPOSE: To achieve reductions in infusion time, infusion sites, and frequency, a prospective, open-label, multicenter, Phase 3 study evaluated the safety, efficacy, and tolerability of subcutaneous immunoglobulin (SCIG) 16.5% (Cutaquig®, Octapharma) at enhanced infusion regimens. METHODS: Three separate cohorts received SCIG 16.5% evaluating volume, rate, and frequency: Cohort 1) volume assessment/site: up to a maximum 100 mL/site; Cohort 2) infusion flow rate/site: up to a maximum of 100 mL/hr/site or the maximum flow rate achievable by the tubing; Cohort 3) infusion frequency: every other week at twice the patient's weekly dose. RESULTS: For Cohort 1 (n = 15), the maximum realized volume per site was 108 mL/site, exceeding the currently labeled (US) maximum (up to 40 mL/site for adults). In Cohort 2 (n = 15), the maximum realized infusion flow rate was 67.5 mL/hr/site which is also higher than the labeled (US) maximum (up to 52 mL/hr/site). In Cohort 3 (n = 34), the mean total trough levels for every other week dosing demonstrated equivalency to weekly dosing (p value = 0.0017). All regimens were well tolerated. There were no serious bacterial infections (SBIs). Most patients had mild (23.4%) or moderate (56.3%) adverse events. The majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens and reported that switching to SCIG 16.5% was easy. CONCLUSIONS: SCIG 16.5% (Cutaquig®), infusions are efficacious, safe, and well tolerated with reduced infusion time, fewer infusion sites, and reduced frequency. Further, the majority of patients found the new infusion regimens to be better or somewhat better than their previous regimens.

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.

Safety and efficacy of home-based subcutaneous immunoglobulin G in elderly patients with primary immunodeficiency diseases.

BACKGROUND: Subcutaneous immunoglobulin (SCIG) is as effective as intravenous immunoglobulin (IVIG) in minimizing infections in patients with primary immunodeficiency diseases (PIDD) and is associated with fewer systemic adverse events (AEs). Self-infusion/home-based infusion of SCIG improves quality of life and may lower treatment costs compared with hospital or office-based IVIG therapy, but its suitability has not been assessed in elderly patients (≥ 65 years). METHODS: We conducted a retrospective chart review of 47 elderly patients with PIDD in a single clinical practice in the United States to evaluate the practicality, safety, and efficacy of home-based SCIG infusions in elderly patients with PIDD over a 13-month period. Measurements included baseline disease characteristics, previous and current immunoglobulin G (IgG) replacement regimens, self-administered versus assisted SCIG infusions, SCIG infusion parameters, serum IgG levels, infections, and AEs. RESULTS: Forty-seven of 111 elderly patients (42%) treated with IgG in this practice elected to receive SCIG. All 47 patients received SCIG infusions at home; 39 (83.0%) self-infused the medication. Most patients (n = 46; 98%) received weekly infusions, requiring a mean duration of 65.3 minutes. The mean SCIG dose of 103 mg/kg/week resulted in a mean steady-state serum IgG concentration of 1074 mg/dL. Two patients experienced serious infections on SCIG: an exacerbation of chronic obstructive pulmonary disease/bronchitis, and an abscess. There were no serious systemic AEs. Local injection site reactions, including swelling, redness, burning, or itching, were considered mild or moderate by the patients and resolved within 24 hours. No bruising, bleeding, or skin breakdown occurred, despite concomitant anticoagulant or platelet inhibitor treatment in 45% of patients. Two patients discontinued home-based SCIG, but did not continue any IgG treatment. No patient switched from SCIG to another route of IgG treatment. CONCLUSIONS: Home-based SCIG is safe and effective in elderly patients with PIDD, most of whom can self-infuse. Infection rates were low, and no AEs or difficulties in administering SCIG occurred that resulted in treatment discontinuation.

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.