Repeat treatment of acute hereditary angioedema attacks with open-label icatibant in the FAST-1 trial.

Hereditary angioedema (HAE) is characterized by potentially life-threatening recurrent episodes of oedema. The open-label extension (OLE) phase of the For Angioedema Subcutaneous Treatment (FAST)-1 trial (NCT00097695) evaluated the efficacy and safety of repeated icatibant exposure in adults with multiple HAE attacks. Following completion of the randomized, controlled phase, patients could receive open-label icatibant (30 mg subcutaneously) for subsequent attacks. The primary end-point was time to onset of primary symptom relief, as assessed by visual analogue scale (VAS). Descriptive statistics were reported for cutaneous/abdominal attacks 1-10 treated in the OLE phase and individual laryngeal attacks. Post-hoc analyses were conducted in patients with ≥ 5 attacks across the controlled and OLE phases. Safety was evaluated throughout. During the OLE phase, 72 patients received icatibant for 340 attacks. For cutaneous/abdominal attacks 1-10, the median time to onset of primary symptom relief was 1·0-2·0 h. For laryngeal attacks 1-12, patient-assessed median time to initial symptom improvement was 0·3-1·2 h. Post-hoc analyses showed the time to onset of symptom relief based on composite VAS was consistent across repeated treatments with icatibant. One injection of icatibant was sufficient to treat 88·2% of attacks; rescue medication was required in 5·3% of attacks. No icatibant-related serious adverse events were reported. Icatibant provided consistent efficacy and was well tolerated for repeated treatment of HAE attacks.

Chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis should be viewed as a spectrum of disorders in which the patients have persistent and/or recurrent candidiasis of the skin, nails and mucous membranes. Some of the conditions have genetic predispositions. A common immunologic abnormality is failure of the patient's T lymphocytes to produce cytokines that are essential for expression of cell-mediated immunity to Candida. Antifungal drugs are effective in clearing the infections, and treatments that restore cellular immunity have produced long term remissions.

Transfer factors: identification of conserved sequences in transfer factor molecules.

BACKGROUND: Transfer factors are small proteins that "transfer" the ability to express cell-mediated immunity from immune donors to non-immune recipients. We developed a process for purifying specific transfer factors to apparent homogeneity. This allowed us to separate individual transfer factors from mixtures containing several transfer factors and to demonstrate the antigen-specificity of transfer factors. Transfer factors have been shown to be an effective means for correction of deficient cellular immunity in patients with opportunistic infections, such as candidiasis or recurrent Herpes simplex and to provide prophylactic immunity against varicella-zoster in patients with acute leukemia. MATERIALS AND METHODS: Transfer factors of bovine and murine origin were purified by affinity chromatography and high performance liquid chromatography. Cyanogen bromide digests were sequenced. The properties of an apparently conserved sequence on expression of delayed-type hypersensitivity by transfer factor recipients were assessed. RESULTS: A novel amino acid sequence, LLYAQDL/VEDN, was identified in each of seven transfer factor preparations. These peptides would not transfer expression of delayed-type hypersensitivity to recipients, which indicates that they are not sufficient for expression of the specificity or immunological properties of native transfer factors. However, administration of the peptides to recipients of native transfer factors blocked expression of delayed-type hypersensitivity by the recipients. The peptides were not immunosuppressive. CONCLUSIONS: These findings suggest that the peptides may represent the portion of transfer factors that binds to the "target cells" for transfer factors. Identification of these cells will be helpful in defining the mechanisms of action of transfer factors.

Recognition of the immunocompromised patient.

The host defense systems in humans are highly specialized with respect to categories of infectious pathogens; yet, there is just enough overlap to protect one from minor defects. It is also important to appreciate that not all abnormalities reported from the laboratory are clinically significant. By appreciating the clinical syndromes that accompany various deficiencies, the surgeon can be aware of the at-risk patient.

Activities and characteristics of transfer factors.

This report summarizes three components of our transfer factor research program. Several clinical studies have used oral administration of transfer factor containing materials. Sceptics have rejected these findings by assuming that the acidic and enzymatic environment of the gastrointestinal tract would destroy the factors. To further examine this issue, we have conducted dose-response studies of the delayed-type hypersensitivity reaction in mice that were given transfer factor either by gavage or subcutaneously. There were no difference in the responses that were related to the route of administration. We conclude that oral route of administration is efficacious and should be used when possible. We have also studied the effects of transfer factors on immune responses by recipients. The details of this research are presented in the paper by Dr. Alvarez-Thull. Briefly, the study showed that recipients of a specific transfer factor responded to the antigen for which the factor was specific by secreting gamma-IFN, but no other cytokines. The structures of transfer factor molecules are unknown. We have developed a process for isolating transfer factors in pure form and we have obtained preliminary data concerning amino acid sequences. Our goal is to obtain the complete primary structure of several transfer factor molecules.

Profiles of cytokine production in recipients of transfer factors.

Transfer factors (TF) are proteins that transfer the ability to express cell-mediated immunity from immune donors to non-immune recipients. The mechanisms of these effects have not been defined. The experiments described in this report were undertaken to test the hypothesis that a mechanism through which the beneficial effects of TF are expressed in clinical situation is through "education" of the immune system to produce certain cytokines in response to antigenic stimulation. BALB/c mice were sensitized to Herpes simplexvirus (HSV) either by sublethal systemic or cutaneous infections by administration of a HSV-specific TF. One week later their spleen cells were collected and single cell suspensions were stimulated in vitro with irradiated HSV or concanavalin. A Culture supernatants were collected and assayed for content of IL-2, IL-4, IL-10 and IFN-g. Spleen cells from infected mice responded to concanavalin A and to HSV by secreting large amounts of IL-2 and IFN-g, modest amounts of IL-10, and no IL-4. Transfer factor recipients produced similar cytokine profiles in response to concavalin A. These mice, however, responded to HSV by secreting IFN-g, but no IL-2. Thus, TF treatment selectively affects cytokine production in response to antigenic stimulation.

Murine transfer factors: dose-response relationships and routes of administration.

Transfer factors are protein immunomodulators that transfer the ability to express cell-mediated immunity from immunized donors to nonimmune recipients. The effects are antigen-specific. The experiments described in this report are a comparison of the relationship of the route of administration of various transfer factors to the magnitude of the delayed hypersensitivity responses (footpad swelling) to the corresponding antigen in the recipients. Three doses of each of four affinity-purified transfer factor preparations were studied. There were no significant differences in the footpad responses by recipients of either oral or subcutaneous transfer factor. These results support proposals for oral administration of transfer factors in clinical trials.

Chronic mucocutaneous candidiasis.

Chronic mucocutaneous candidiasis is a complex disorder in which patients have chronic and recurrent Candida albicans infections of the skin, nails, and mucous membranes. There are several subgroups of patients with chronic mucocutaneous candidiasis, and these can be identified by associated disorders such as autoimmune diseases, endocrinopathies, thymoma, and interstitial keratitis, as well as the distribution and severity of the Candida infections. Several other disorders may coexist in patients with chronic mucocutaneous candidiasis. These include other infectious diseases, endocrinopathies, dental enamel dysplasia, vitiligo, and alopecia totalis. Successful treatment programs should include antifungal drugs and manipulations that correct the immunologic abnormalities that predispose the patient to Candida infections.

Radiologic findings of adult primary immunodeficiency disorders. Contribution of CT.

STUDY OBJECTIVE: We wished to review the chest radiographic and computed tomographic (CT) findings in adults with primary immunodeficiency disorders, and to evaluate the influence of CT on the treatment of these patients. DESIGN: Retrospective blinded review of radiographs, CT scans, and clinical data. SETTING: National referral center for immunodeficiency disorders. PATIENTS: Forty-six chest radiographs and 22 CT examinations of subjects with primary immunodeficiency disorders were independently scored. Nineteen of the subjects who had CT scans had B-cell deficiency, while 3 had T-cell deficiency. RESULTS: CT-detected bronchiectasis in 15 of 19 subjects with B-cell deficiency, compared with 7 cases detected on chest radiograph. Unsuspected upper lobe bronchiectasis was found on CT in 15 cases. Other CT findings in this group included small nodules in seven subjects, interstitial lines in four, air trapping in seven, ground glass or parenchymal consolidation in nine, evidence of small airways disease in nine, and mucus plugs in four. Two of the three subjects with T-cell disorders showed cavitation and two had unsuspected reactive mediastinal adenopathy. Clinical management appeared to be altered in five subjects with B-cell deficiency by CT findings of severe focal or diffuse bronchiectasis or small airways disease. Additionally, CT localized the bleeding site in three subjects with hemoptysis. CONCLUSIONS: CT is valuable for detection of bronchiectasis in subjects with B-cell immunodeficiency and may alter treatment of these patients.

Structural nature and functions of transfer factors.

Transfer factors are molecules that "educate" recipients to express cell-mediated immunity. This effect is antigen-specific. The most consistent effects of transfer factors on the immune system are expression of delayed-type hypersensitivity and production of lymphokines such as macrophage migration inhibitory factor (MIF), which is probably identical to gamma-interferon in response to exposure to antigen. Transfer factors bind to antigens in an immunologically specific manner. This discovery has enabled us to isolate individual transfer factors from mixtures that contain several transfer factors. This reactivity probably explains the specificity of individual transfer factors, and it has provided a method for purification of individual transfer factors to apparent homogeneity. The purified materials are immunologically active and antigen-specific. They have molecular weights of approximately 5,000 Da and appear to be composed entirely of amino acids. Transfer factors appear to offer a novel means of molecular immunotherapy for certain patients with defective cell-mediated immunity.

Purification of transfer factors.

Transfer factor activities have been studied in both clinical and basic science settings for several decades. Until now, highly purified transfer factors that are suitable for molecular analysis have not been available. This has impeded progress towards understanding the molecular and cellular basis of the activities of these important inducers of cell-mediated immune responses. Murine transfer factors with specificities for chicken egg albumin or horse spleen ferritin were purified to virtual homogeneity using a combination of affinity chromatography and reversed-phase and polytypic high performance liquid chromatography (hplc). Transfer factors prepared by this methodology were recovered in high yield and in biologically-active, antigen-specific forms. The purified materials were further analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis, chromatographic methods and an in vivo assay for immunological activity. For the first time definitions for unit transfer factor activity and specific activity are introduced. The results of these experiments indicate that transfer factors are a family of highly polar, hydrophilic molecules of low molecular weight (approximately 5,000) which are produced in small quantities by lymphoid cells and which have potent biological activity. The availability of purified transfer factors should facilitate definitive studies into the nature and mechanisms of production and action of these molecules.

Indomethacin-sensitive monocyte killing defect in a child with disseminated atypical mycobacterial disease.

A child with disseminated disease due to Mycobacterium avium had progressive disease in spite of 4.5 years of therapy with multiple antimicrobial agents selected on the basis of in vitro sensitivity testing of her organism. A defect in monocyte bactericidal activity was detected which was corrected in vitro by exposure of the patient's monocytes to indomethacin and normal serum. Indomethacin therapy resulted in normalization of monocyte bactericidal activity and striking, albeit temporary, clinical improvement.

Digoxin Immune Fab therapy in the management of digitalis intoxication: safety and efficacy results of an observational surveillance study.

An observational surveillance study was conducted to monitor the safety and effectiveness of treatment with Digoxin Immune Fab (Ovine) (Digibind) in patients with digitalis intoxication. Before April 1986, a relatively limited number of patients received treatment with digoxin-specific Fab fragments through a multicenter clinical trial. Beginning with commercial availability in July 1986, this study sought additional, voluntarily reported clinical data pertaining to treatment through a 3 week follow-up. The study included 717 adults who received Digoxin Immune Fab (Ovine). Most patients were greater than or equal to 70 years old and developed toxicity during maintenance dosing with digoxin. Fifty percent of patients were reported to have a complete response to treatment, 24% a partial response and 12% no response. The response for 14% of patients was not reported or reported as uncertain. Six patients (0.8%, 95% confidence interval 0.3% to 1.8%) had an allergic reaction to digoxin-specific antibody fragments. Three of the six had a history of allergy to antibiotic drugs. Twenty patients (2.8%, 95% confidence interval 1.7% to 4.3%) developed recrudescent toxicity. Risk of recrudescent toxicity increased sixfold when less than 50% of the estimated dose of antibody was administered. A total of 215 patients experienced posttreatment adverse events. The events for 163 patients (76%) were judged to result from manifestations of underlying disease and thus considered unrelated to Fab treatment. Digoxin-specific antibody fragments were generally well tolerated and clinically effective in patients judged by treating physicians to have potentially life-threatening digitalis intoxication.

Allergic histories and reactions of patients treated with digoxin immune Fab (ovine) antibody. The Digibind Study Advisory Panel.

Seven hundred seventeen adult patients with life-threatening digitalis intoxication were treated with Fab fragments of ovine antidigoxin immunoglobulin G (IgG). Results of the efficacy of treatment and adverse effects were collected with standard report forms. Eighty-two (11%) of the patients were recorded as having histories of allergy (71 patients) and/or asthma (11 patients). Of the "allergic" subjects, 35 described reactions to antibiotics, 19 to other medications, 3 to foods, and 2 to pollens; in 12 subjects the etiologic agent was not specified. Six subjects had adverse reactions that were probably or possibly due to allergy to components of the antibody preparation. Of these 4 (5%; 95% confidence interval (Cl) 1.8% to 12%) occurred in the 82 subjects with histories of allergy or asthma and 3 (9%; 95% Cl 1.8% to 23%) of these occurred in the 35 persons with histories of allergy to an antibiotic. In contrast, only 2 (0.3%; 95% Cl 0.04% to 1.1%) similar reactions occurred in the 635 subjects with no histories of allergy or asthma. All reactions responded to symptomatic treatment. The authors conclude that treatment of digitalis intoxication with ovine antidigoxin IgG-Fab (Digibind) is generally well tolerated and allergic reactions are rare. However, there is a significantly increased risk of reactions in patients with histories of allergy or asthma.