Successful replacement of allergen-specific immunotherapy by allergen-mixture therapy.

BACKGROUND: Some clinicians utilize allergen-specific immunotherapy (specific therapy), employing only the extracts of allergens that produce positive skin tests. Others use allergen-mixture immunotherapy (mixture therapy), employing premixed extracts containing both skin reactive and non-reactive (irrelevant) allergens. OBJECTIVE: The purpose of this study was to compare the efficacy of these two approaches and to identify sensitization to irrelevant allergens included in mixture therapy. METHOD: A total of 20 adults with allergic rhinitis/asthma who were switched from successful specific therapy (average duration of 6.1 years) to mixture therapy (2.0 years) were evaluated with symptom-medication scores, skin test results, and local/systemic reactions at three time points: before specific therapy, before, and 2 years after mixture therapy. RESULTS: Symptom-medication scores for all patients improved at the end of specific therapy and remained improved during mixture therapy (12.3 versus 12.0 with P = .75). The sums of positive skin tests at three points were not different (7.8 versus 8.3 versus 9.8 with P > .4 at all points). Reaction rates did not differ either. Skin sensitization to irrelevant allergens occurred in five patients during mixture therapy. These patients, however, also experienced spontaneous conversions from negative to positive reactions to the allergens not included in the therapy, indicating that sensitization may be partly due to a spontaneous increase in skin reactivity. CONCLUSION: These findings suggest that allergen-mixture immunotherapy is as efficacious as allergen-specific therapy and may be associated with skin sensitization in some patients. There was no evidence of increased adverse clinical reaction.

Prevalence of avocado allergy among atopic patients.

A 41-year-old woman with known food allergy to avocado was treated for anaphylaxis after eating a meal containing avocado. This prompted a study to determine the prevalence of avocado induced symptoms and skin reactivity in a group of atopic patients. One hundred consecutive atopic patients with allergic rhinitis undergoing skin testing before initiation of immunotherapy were also prick skin tested to avocado. Patients with symptoms upon avocado ingestion were also assessed for specific serum IgE antibodies to avocado. Of the 100 atopic patients not selected for avocado sensitivity, 21 had positive prick skin tests to avocado. Eight of the 21 avocado skin test positive patients reported that symptoms repeatedly followed the ingestion of avocado; two reported systemic reactions, but six noted oral symptoms only. Serum IgE antibodies to avocado were elevated in seven of the eight patients reporting symptoms after eating avocado. Seven of the eight patients also reported oral symptoms following cantaloupe ingestion. Four reported similar symptoms upon eating banana. Avocado-induced symptoms occurred in 8% of 100 consecutive atopic allergic rhinitis patients unselected for avocado reactivity. Oral, and less frequently systemic, allergy symptoms appear to be more common among the atopic population than previously appreciated.

Antibodies in patients with inflammatory bowel disease and the apparent influence of medications.

Patients with inflammatory bowel disease (IBD) are known to have increased antibodies to several food and bacterial antigens. To assess selected isotype contributions in greater detail, we examined the concentrations of IgA, IgG, IgE, and IgG4 antibodies to five selected antigens, two of bacterial and three of food origin. Thirty patients with IBD and thirty matched healthy controls were studied. Most antibodies were increased in IBD patients compared to controls. Statistically significant increases were more frequent in Crohn's disease (CD) than in ulcerative colitis (UC). An unexpected finding was that IBD patients treated with sulfasalazine had statistically higher levels of most IgA antibodies than healthy controls, while steroid treated patients had lower levels. These findings suggest differing effects on the immune systems of IBD patients by each of these commonly used drugs.

Hypersensitivity to therapeutic murine monoclonal antibodies.

OBJECTIVE: To determine the predictive value of pre-treatment skin tests and in vitro IgE/IgG4 anti-murine monoclonal antibodies in patients treated with murine monoclonal antibodies. DESIGN: Patients treated at two cancer institutions were evaluated by skin testing and solid phase immunoassays to detect IgE and IgG4 specific anti-murine monoclonal antibodies. Skin testing by scratch and intradermal skin testing was done on patients before treatment with murine monoclonal antibodies. IgE & IgG4 specific anti-murine monoclonal antibodies were determined before treatment in all patients and at 1, 7, 14 and 21 days post-treatment in 1 patient. SETTING: Cancer patients undergoing murine monoclonal antibody treatment in two university medical centers were recruited for the study. PARTICIPANTS: Twelve patients, aged 41-75 years with gastrointestinal cancers (colon, stomach, pancreas or liver) with metastatic disease, who had relapses or conventional therapy were enrolled. Some patients had previous exposure to rodents, either as laboratory personnel or had kept them as pets. INTERVENTION: One patient who experienced an anaphylactic reaction to murine monoclonal antibody infusion was desensitized so therapy could continue. MAIN OUTCOME MEASURES: Skin tests, immunoassays, and patient history were correlated with adverse reactions to infusions of murine monoclonal antibodies. MAIN RESULTS: Skin tests (scratch method) and/or in vitro immunoassays may predict allergic outcomes in patients receiving infusions of murine monoclonal antibodies. Intradermal skin testing with murine monoclonal antibodies may result in false positive reactions and have less predictive value. Specific IgE or IgG4 were elevated in the two patients who experienced severe adverse reactions to murine monoclonal antibodies but not in those patients with no reactions and therefore, may have some predictive value. A history of past exposure to mice may also increase the risk of adverse reactions. In one patient, intravenous desensitization enabled treatment to proceed. CONCLUSION: Scratch skin tests, in vitro IgE and/or IgG4 immunoassays together with a past history of previous exposure to murine antigen(s) may predict potential allergic reaction to therapy with murine monoclonal antibodies.

Food-induced anaphylaxis.

The Council on Scientific Affairs of the California Medical Association presents the following inventory of items of progress in allergy and immunology. Each item, in the judgment of a panel of knowledgeable physicians, has recently become reasonably firmly established, both as to scientific fact and important clinical significance. The items are presented in simple epitome, and an authoritative reference, both to the item itself and to the subject as a whole, is generally given for those who may be unfamiliar with a particular item. The purpose is to assist busy practitioners, students, researchers, and scholars to stay abreast of these items of progress in allergy and immunology that have recently achieved a substantial degree of authoritative acceptance, whether in their own field of special interest or another. The items of progress listed below were selected by the Advisory Panel to the Section on Allergy and Immunology of the California Medical Association, and the summaries were prepared under its direction.

IgG deficiency in adults with recurrent respiratory infections.

Total IgA, IgM, IgG, and IgG subclasses were measured in 136 consecutive adults with recurrent respiratory infections. Sinus and chest radiographs were also obtained. IgG antibodies to H. influenzae and tetanus toxoid were determined in 27 immunodeficient subjects. Fifty-eight of the 136 were deficient in some immunoglobulin isotype, three in IgA, three in IgM, and 52 in total IgG or one or more IgG subclasses. The most common IgG deficiencies were single IgG subclass deficiencies, particularly IgG3 or IgG4, and a mild decrease in total IgG (between 450 and 650 mg/dL). In 21/27 subjects with IgG deficiency, the response to booster immunization was blunted, even when IgG1 and IgG2 were normal. Thirty-eight patients were smokers, 37 being > 40 years of age at the onset of respiratory infections. Twenty patients were nonsmokers, 19 being < 40 years of age at the onset. In conclusion, adults with recurrent respiratory infections frequently have some variant of IgG deficiency, often associated with a functional impairment of specific antibody response. Smoking may represent a risk factor for IgG deficiency in adults.

IgG subclass deficiency associated with corticosteroids in obstructive lung disease.

IgG subclass levels were measured in three groups of adult patients with obstructive airways disease to discern the relationships among depressed IgG subclass levels, chronic corticosteroid use, and recurrent sinopulmonary infections. Group 1 consisted of patients with corticosteroid-dependent bronchial asthma, group 2 patients had corticosteroid-dependent chronic bronchitis/emphysema, and group 3 was comprised of asthma patients not requiring oral corticosteroids but associated with recurrent sinopulmonary infections. One or more IgG subclass deficiencies were noted in 66.7 percent of group 1, 46.7 percent of group 2, and 6.7 percent of group 3. Significant differences were noted between groups 1 and 3 (p = .0008) and between groups 2 and 3 (p = .018), but not between groups 1 and 2 (p = .5). IgG1 deficiency was the most common subclass deficiency found; 14 (77.8 percent) of 18 patients with detectable subclass deficiency demonstrated IgG1 deficiency. In this study population, IgG subclass level deficiencies appeared to be secondary to long-term low-dose corticosteroid therapy.

Immunoglobulin G subclasses in human colostrum, milk and saliva.

Previous studies have suggested local production of IgG4 in human colostrum and mature milk. We extended these observations to examine all IgG subclasses in mammary secretions and in saliva, a mucosal secretion. In human colostrum and milk, the geometric mean percentages of IgG contributed by IgG2 were 44% and 43%, respectively, and by IgG4, 6% in both. These percentages are significantly increased compared to the contributions in matched plasma, 29% for IgG2 and 2% for IgG4. The contribution of IgG1 (47%) and IgG3 (less than 4%) were decreased compared to plasma which contained 64% IgG1 and 6% IgG3. Similarly, in salivary secretions the percentages of IgG contributed by IgG2 and IgG4 were increased compared to serum while the percentage of IgG1 was decreased. IgG3 was not measurable in any saliva specimen by the technique used. These data demonstrate that IgG subclass distribution in two separate mucosal secretions is uniquely different from that in matching plasma or serum.

Immunoglobulin E and G4 antibodies in cysticercosis.

The importance of immunoglobulin G (IgG) subclass responses in different infections has been elucidated for a number of organisms, but few parasitic organisms have been examined in this regard. In the current study, quantitative radioimmunoassays were used to examine the IgE and IgG4 subclass responses to larval Taenia solium. Patients were divided into clinically infected (CI) and probably uninfected (PU) groups. Unexposed normal subjects were used as controls. The CI group had elevated geometric mean levels of total IgE in serum (28.6 IU/ml) and specific IgG4 antibodies (438.8 arbitrary units [AU]/ml) compared with controls (8.3 IU/ml and 50.1 AU/ml, respectively). The CI group also had significantly elevated levels in cerebrospinal fluid of total IgG4 (18.6 micrograms/ml) and specific IgG4 antibodies (86.0 AU/ml) compared with the PU group (2.5 micrograms/ml and 1.6 AU/ml, respectively). There was no specific IgE antibody response detected in either the CI or PU patient group. The marked IgG4 response of CI patients to T. solium merits further investigation.

A human IgG 3 is opsonic in vitro against type III group B streptococci.

Preparations of IgG 3 isolated by absorption of IgG 1, IgG 2, and IgG 4 from a human iv immunoglobulin with protein A-Sepharose were evaluated for their opsonic activities against type III group B streptococcal (GBS) strains. The resulting preparations were free of IgG 1 and IgG 2 and contained only trace amounts of IgG 4 (less than 2% of total IgG). These IgG 3 preparations exhibited excellent opsonic activities against type III GBS strains, similar to those of the unfractionated iv immunoglobulin (based on total IgG concentrations in the opsonic assays). In contrast, preparations of IgG 1, 2, and 4 eluted from protein A-Sepharose with 2 M acetic acid and 7 M urea were significantly less effective in enhancing phagocytosis and killing of type III GBS than IgG 3 preparations or iv immunoglobulin. The reasons for excellent opsonic activity of IgG 3 preparations as well as for decreased opsonic activity of IgG 1, 2, and 4 preparations are not clear. Perhaps alteration of IgG by lower pH and high concentrations of urea may have impaired the functional activity of IgG 1, 2, and 4 preparations. The significant finding of this study is the first demonstration of the excellent opsonic activity of IgG 3, emphasizing the importance of having intact IgG 3 in commercial immunoglobulin preparations used in prophylaxis or treatment of GBS infections.

Abnormal maxillary sinus radiographs in children: do they represent bacterial infection?

Thirty-three children with chronic tonsillitis and/or adenoid enlargement and without previous diagnosis of sinusitis were studied regarding the bacterial flora of their maxillary sinuses. Puncture of maxillary sinus was performed at surgery (adenoidectomy and/or tonsillectomy) and aspirates were cultured. Streptococcus pneumoniae was isolated from 8 of 12 (66.7%) patients whose x-rays showed completely opacified maxillary sinus. Streptococcus viridans, Streptococcus faecalis, and Staphylococcus epidermidis were recovered from 6 (28.6%) of the 21 patients with normal maxillary sinus radiographs. Bacterial titers were greater than 10(4) colonies/mL in all but one of the positive cultures. No anaerobic bacteria were isolated. History of bronchial asthma, presence of nasal purulent secretion, elevated blood eosinophils, and elevated serum IgE were found more frequently in children with complete opacification of maxillary sinus. Serum levels of IgG2 were low in 29% of the children, but no correlation was found between low IgG2 levels and positive cultures from maxillary sinus aspirates. We concluded that children with complete radiologic opacification of maxillary sinus had bacterial infection in almost 70% of the cases with symptoms that did not prompt their physicians to consider the diagnosis of sinusitis.

Quantitative immunoglobulins and IgG subclasses in patients with corticosteroid-dependent reversible airway obstruction.

Six of 12 patients with corticosteroid-dependent bronchial asthma and recurrent sinopulmonary infections were found to have significant abnormalities in quantitative immunoglobulins and/or IgG subclasses. Five patients had a combined quantitative immunoglobulin and IgG subclass deficiency and one patient had an isolated IgG deficiency. Combined IgG subclass deficiencies were observed in two patients, both with deficiencies of IgG2 and IgG3. The most common IgG subclass deficiencies were of IgG2 and IgG3, which were found in three patients each.

Familial IgE deficiency associated with sinopulmonary disease.

Three generations of relatives of 58-year-old nonidentical twins with chronic bronchitis and fibrotic lung disease were evaluated. Sera of 23 family members, 14 with a history of excessive sinopulmonary infections, were examined for deficiencies of immunoglobulin classes, IgG subclasses, and specific antibody to tetanus toxoid and Hemophilus influenzae type b. Of 14 symptomatic family members, 12 had serum IgE concentrations less than 5 IU/ml. Four had values less than 1 IU/ml. Serum IgE was greater than 10 IU/ml in all nine asymptomatic individuals. Inheritance of low IgE appeared to be autosomal dominant, with variable penetrance. IgA was low normal (70-90 mg/dl) in three individuals. Two of these were IgE deficient. One symptomatic child had unmeasurable IgG2 (less than 10 mg/dl) and IgE (less than 0.5 IU/ml). This kindred demonstrates that IgE deficiency can be familial, and associated with sinopulmonary disease.

IgG4 in human colostrum and human milk: continued local production or selective transport from serum.

Colostrum, mature milk, and paired plasma samples were obtained from 10 postpartum women who had not been previously studied. The geometric mean concentration of IgG4 in colostrum (3.3 micrograms/ml) was similar to the mean concentration in mature milk (3.0 micrograms/ml). The arithmetic mean for the percent of IgG = IgG4 was 10.3 +/- 3.3% for colostrum, 10.3 +/- 3.1% for mature milk, 2.6 +/- 0.3% for early plasma, and 1.7 +/- 0.3% for later plasma. Local mammary production of immunoglobulin was determined by subtracting the estimated serum contribution from the measured concentration in colostrum or milk. Evidence for local mammary production of IgG4 was found in 5 of 10 colostrum samples and 8 of 10 mature milk samples. These observations indicate that the previously observed selective enrichment of IgG4 in colostrum is also true for mature milk. These are the first studies suggesting continued local production of any immunoglobulin other than IgA in mature human breast milk.

IgG4 immunodeficiency.

IgG4 deficiency can be an isolated phenomenon, or it can occur in combination with deficiencies of IgG2, IgA, and/or IgG1 (in order of decreasing frequency). Isolated deficiency of IgG4 is associated with symptoms and signs which are similar to those associated with other IgG subclass deficiencies. The most common manifestation is an unusual frequency of pyogenic infections, most often of the respiratory tract. There is also an increased frequency of isolated serum IgG4 deficiency in subjects who have recurrent or chronic diarrhea, asthma, adverse reactions to foods, chronic candidiasis, pediatric AIDS, and autoimmune disorders. The mean and normal ranges of serum IgG4 in 400 subjects ages four months to 17 years are given. Diagnostic studies, unique features of IgG4, illustrative case reports and possible mechanisms are discussed.