N. Franklin Adkinson

Inflammatory Mediators in Late Antigen-Induced Rhinitis

To investigate the mechanisms responsible for the late-phase response in patients with allergies, we measured four biochemical mediators (histamine, tosyl-L-arginine methyl ester [TAME]-esterase, kinin, and prostaglandin D2) in nasal secretions after nasal challenge with pollen antigen in 12 patients with allergy. Nine patients had an immediate response and a recurrence of symptoms 3 to 11 hours after challenge. The clinical symptoms during recurrence were accompanied by a second increase in levels of histamine, TAME--esterase, and kinin over base-line values, although kinin levels were lower than during the immediate response. In contrast, although the levels of prostaglandin D2 were significantly increased during the immediate response, they did not increase above base line during the late response. Rechallenge with allergen 11 hours after the initial provocation, however, was associated with reappearance of all four biochemical mediators, including prostaglandin D2. We conclude that the late response to nasal challenge with allergen is accompanied by a second increase in the concentrations of histamine and TAME--esterase but differs from the immediate response in the lack of prostaglandin D2 production and in the amount of kinin generated. Since histamine is released only by mast cells and basophils and prostaglandin D2 is not produced by basophils, we suggest that these cells are partly responsible for the late-phase response.

Meta-analysis of genome-wide association studies of asthma in ethnically diverse North American populations

Asthma is a common disease with a complex risk architecture including both genetic and environmental factors. We performed a meta-analysis of North American genome-wide association studies of asthma in 5,416 individuals with asthma (cases) including individuals of European American, African American or African Caribbean, and Latino ancestry, with replication in an additional 12,649 individuals from the same ethnic groups. We identified five susceptibility loci. Four were at previously reported loci on 17q21, near IL1RL1, TSLP and IL33, but we report for the first time, to our knowledge, that these loci are associated with asthma risk in three ethnic groups. In addition, we identified a new asthma susceptibility locus at PYHIN1, with the association being specific to individuals of African descent (P = 3.9 × 10−9). These results suggest that some asthma susceptibility loci are robust to differences in ancestry when sufficiently large samples sizes are investigated, and that ancestry-specific associations also contribute to the complex genetic architecture of asthma.

The childhood asthma management program (CAMP): Design, rationale, and methods

The Childhood Asthma Management Program (CAMP) is a multicenter, randomized, double-masked clinical trial designed to determine the long-term effects of three inhaled treatments for mild to moderate childhood asthma: budesonide (a glucocorticoid used daily) and albuterol (a short-acting beta-agonist bronchodilator used as needed); nedocromil (a nonsteroid anti-inflammatory agent used daily) and albuterol; and placebo and albuterol. One thousand forty-one children (32% from ethnic minority groups), aged 5 to 12 years at screening, are currently participating. The primary outcome measure is lung growth as indicated by postbronchodilator forced expiratory volume in 1 second (FEV1) percent of predicted, observed over 5- to 6-year period. The trial also assesses differences between treatment groups with respect to airway responsiveness, morbidity, physical growth and development, and psychological growth and development. This report describes the design of the trial, the rationale for the design choices made, and the methods used to carry out the trial.

A Controlled Trial of Immunotherapy for Asthma in Allergic Children

BACKGROUND Injections of allergens are widely prescribed for patients with asthma, but little is known about the effectiveness of immunotherapy. METHODS We conducted a double-blind, placebo-controlled trial of multiple-allergen immunotherapy in 121 allergic children with moderate-to-severe, perennial asthma. The children, who required daily medication for their asthma, were randomly assigned to receive subcutaneous injections of either a mixture of up to seven aeroallergen extracts or a placebo. Maintenance injections were continued for 18 months or longer. Medications were adjusted every two to three weeks on the basis of peak flow rates and symptoms. The principal outcome was the daily medication score. Bronchial sensitivity to methacholine (the concentration provoking a 20 percent decrease in the forced expiratory volume in one second [PC20]) was measured twice yearly. RESULTS The median medication score declined from 5.4 to 4.9 in the immunotherapy group (P<0.001) and from 5.2 to 5.0 in the placebo group (P<0.001), but there was no significant difference between the groups (P>0.6). The number of days on which oral corticosteroids were used was similar in the two groups. Partial or complete remission of asthma occurred in 31 percent of the immunotherapy group and in 28 percent of the placebo group (P>0.5). There was no difference between the groups in the use of medical care, symptoms, or peak flow rates. The median PC20 increased significantly in both groups, but again with no difference between the two groups. CONCLUSIONS Immunotherapy with injections of allergens for over two years was of no discernible benefit in allergic children with perennial asthma who were receiving appropriate medical treatment.

Socioeconomic status and race as risk factors for cockroach allergen exposure and sensitization in children with asthma.

BACKGROUND The domestic cockroach has been identified as an important source of indoor aeroallergens worldwide in both temperate and tropical climates. Because cockroach populations are highest in crowded urban areas, some have suggested that the increased asthma morbidity and mortality rates in inner cities could be related in part to cockroach allergen exposure. We have examined cockroach allergen exposure in the homes of children with asthma in both urban and suburban locations and have related the rates of exposure and sensitization to socioeconomic, racial, and demographic factors. OBJECTIVE The study was designed to determine the independent contribution of race, socioeconomic status, and place of residence to the risk of cockroach allergen exposure and sensitization in children with asthma. METHODS Eighty-seven children with moderate to severe allergic asthma, aged 5 to 17 years, participating in a prospective trial of immunotherapy, were evaluated. Extracted dust samples from three home locations were analyzed by using two-site monoclonal immunoassays for major cockroach allergens (Bla g 1 and Bla g 2). A puncture skin test with a mixed cockroach allergen extract was performed in 81 of the 87 subjects. RESULTS In the 87 homes evaluated, 26% of the bedroom dust samples had detectable levels of cockroach allergen. In homes with detectable bedroom cockroach allergen levels, mean Bla g 1 and Bla g 2 concentrations in urban and suburban homes were similar. Over 80% of children with bedroom Bla g 1 or Bla g 2 of 1 U/gm or greater demonstrated skin sensitivity to cockroach allergen. The rate of cockroach sensitization was directly related to the level of bedroom exposure. African-American race was the only factor that was independently associated with cockroach allergen exposure (p = 0.05). Lower socioeconomic status, age greater than 11 years, cockroach exposure, and African-American race were all independently associated with cockroach allergen sensitization on the basis of stepwise multiple linear regression analysis. CONCLUSIONS African-American race and low socioeconomic status were both independent, significant risk factors for cockroach allergen sensitization in children with atopic asthma. Cockroach allergen is detectable throughout the house, including the critical bedroom environment.

The effect of cat removal on allergen content in household-dust samples

To evaluate the effect of cat removal on cat-allergen content in the home, serial house dust samples were collected from 15 homes during a 9- to 43-week period after cat removal. Samples were obtained with a hand-held vacuum cleaner, and allergen content was quantitated by a radioimmunoassay specific for the major cat allergen, Fe1 d I. Baseline Fe1 d I content ranged from 7.8 Food and Drug Administration units per gram of dust to 436.7 U/gm (median 61.2 U/gm), consistent with levels found in homes with a pet cat. Fe1 d I levels declined gradually in most homes, and by 20 to 24 weeks after cat removal, eight of 15 reached levels consistent with levels found in control homes without cats. In two of those homes, allergen levels fell much more rapidly after aggressive environmental control measures were undertaken. In the other seven homes, however, the decline occurred at a much slower rate, with three homes demonstrating persistent elevations in Fe1 d I content for 20 or more weeks. These data demonstrate that the task of allergen elimination from an indoor environment is extremely difficult, even when the source of a specific allergen can be identified and removed.

Ragweed Immunotherapy in Adult Asthma

BACKGROUND Although allergen immunotherapy is effective for allergic rhinitis, its role in treating asthma is unclear. METHODS We examined the efficacy of immunotherapy for asthma exacerbated by seasonal ragweed exposure. During an observation phase, adults with asthma who were sensitive to ragweed kept daily diaries and recorded peak expiratory flow rates between July and October. Those who reported seasonal asthma symptoms and medication use as well as decreased peak expiratory flow were randomly assigned to receive placebo or ragweed-extract immunotherapy in doses that increased weekly for an additional two years. RESULTS During the observation phase, the mean (+/- SE) peak expiratory flow rate measured in the morning during the three weeks representing the height of the pollination season was 454 +/- 20 liters per minute in the immunotherapy group and 444 +/- 16 liters per minute in the placebo group. Of the 77 patients who began the treatment phase, 64 completed one year of the study treatment and 53 completed two years. During the two treatment years, the mean peak expiratory flow rate was higher in the immunotherapy group (489 +/- 16 liters per minute, vs. 453 +/- 17 in the placebo group [P = 0.06] during the first year, and 480 +/- 12 liters per minute, vs. 461 +/- 13 in the placebo group [P = 0.03] during the second). Medication use was higher in the immunotherapy group than in the placebo group during observation and lower during the first treatment year (P = 0.01) but did not differ in the two groups during the second year (P = 0.7). Asthma-symptom scores were similar in the two groups (P = 0.08 in year 1 and P = 0.3 in year 2). The immunotherapy group had reduced hay-fever symptoms, skin-test sensitivity to ragweed, and sensitivity to bronchial challenges and increased IgG antibodies to ragweed as compared with the placebo group; there was no longer a seasonal increase in IgE antibodies to ragweed allergen in the immunotherapy group after two years of treatment. Reduced medication costs were counterbalanced by the costs of immunotherapy. CONCLUSIONS Although immunotherapy for adults with asthma exacerbated by seasonal ragweed exposure had positive effects on objective measures of asthma and allergy, the clinical effects were limited and many were not sustained for two years.

A Genome-Wide Association Study on African-Ancestry Populations For Asthma

BACKGROUND Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed. OBJECTIVES We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma. METHODS We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma. RESULTS A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated. CONCLUSIONS This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Dose response of IgE and IgG antibodies during ragweed immunotherapy

We studied the detailed dose-response relationship for ragweed (RW) antibody responses in 51 patients who received maximal-dose immunotherapy with crude RW extract. Serum RW-IgG and RW-IgE levels were determined by solid-phase radioimmunoassay at frequent intervals during initiation and maintenance of immunotherapy. Pretreatment RW-IgE ranged from 0.94 to 974 ng/ml (median 105); 45/51 patients had insignificant levels (less than 250 ng/ml) of RW-IgG. The maximal doses given ranged from 0.19 to 93.5 micrograms of RW antigen E per injection. All patients produced a significant IgG response (median peak 3462 ng/ml, range 689 to 24,395), and 46/51 had significant increases in IgE antibody (median peak 231 ng/ml, range 12 to 1528). A threshold dose was defined for each patients IgG and IgE response as that dose level which initiated a persistent increment in immunoglobulin to greater than or equal to 25% of pretreatment levels. The median threshold dose for IgE was 0.13 micrograms of antigen E, which was achieved in a median time of 42 days. The threshold dose for IgG was significantly higher (median 0.56 micrograms of antigen E; p = 0.001) and occurred significantly later (median 79 days; p = 0.003). Despite variability over 3 orders of magnitude, the thresholds for IgE and IgG responses were significantly correlated for individual patients (r = 0.487; p = 0.002). The maximum RW-IgE response occurred in a median of 107 days, after which IgE antibodies declined in 46 of 49 patients. The maximal IgG response occurred significantly later (median 245 days; p less than 0.001) and then plateaued or declined modestly. The doses required to achieve maximal IgE and IgG responses were significantly correlated (r = 0.638; p less than 0.001). The maximum IgG response was positively correlated with the maximal dose of RW antigen E received (r = 0592; p less than 0.001). In 28 of the 51 patients, the incremental rise in total serum IgE was more than twice that observed for RW-IgE at the time of the maximum response, suggesting a nonspecific effect of RW immunotherapy on total serum IgE levels. This discrepancy could not be accounted for by environmental stimulation from other known allergens, as assessed by skin testing, or by pretreatment levels of RW-IgE or total IgE. These observations indicate that the human IgE antibody response during high-dose RW immunotherapy is more sensitive to both stimulation and suppression by continuous allergen administration than is the IgG response.(ABSTRACT TRUNCATED AT 400 WORDS)

Immunotherapy for cat asthma

In 22 patients with cat asthma who were highly sensitive to cat, we compared, double-blind, the effects of immunotherapy with cat-hair and dander extract (11 patients) with effects of placebo (11 patients). Patients were matched by the dose of the cat extract expressed in Food and Drug Administration (FDA) units of Fel d I (previously called cat allergen 1) required for end point reaction in intradermal skin test end point titration (STEPT), for in vitro leukocyte histamine release (LHR), and for the dose of cat extract producing a 20% fall in FEV1 (cat-extract PD20) in bronchoprovocation test. Patients were matched also for bronchoprovocation dose of methacholine producing a 20% fall in FEV1 (methacholine PD20). Patients were randomly assigned to one of two treatment groups. During immunotherapy, doses were increased to maintenance dose of 4.56 FDA units of Fel d I, or, if this were less, to the highest tolerated dose. Systemic reactions to cat-extract immunotherapy were mild and infrequent. Before and during immunotherapy, we measured (in FDA units of Fel d I) cat-extract PD20, cat-extract intradermal STEPT, cat-extract in vitro LHR, serum levels of cat IgG and cat IgE, and methacholine PD20. After they had received 1 year of immunotherapy, patients receiving cat extract, in comparison to patients receiving placebo, had decreased cat-extract PD20 (p less than 0.01), diminished responses to cat-extract intradermal STEPT (p less than 0.025), increased IgE antibodies toward cat extract (p less than 0.01), increased IgG antibodies toward cat extract, Fel d I, and cat albumin (p less than 0.001), but no significant change in cat-extract in vitro LHR or in methacholine PD20. We conclude that cat-extract immunotherapy was well tolerated, significantly decreased skin and bronchial responses to cat extract, and significantly increased IgE antibodies to cat extract and IgG antibodies to cat extract, Fel d I, and cat albumin.