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Normal Pulmonary Function in Alpha-1-Antitrypsin Deficiency ZZ Phenotype
Abstracts S197
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Formoterol Induces Higher Levels of Total cAMP in TNFStimulated Human Monocytes than Salmeterol I. Nita1, A. Miller-Larsson2, S. Janciauskiene1; 1Clinical Sciences, Lund University, Malmö, SWEDEN, 2AstraZeneca R&D Lund, Lund, SWEDEN. RATIONALE: Formoterol and salmeterol are useful add-on drugs to inhaled corticosteroids in the treatment of asthmatic patients who are not satisfactorily controlled with ICS alone. Both are highly selective and potent 2-adrenoceptor agonists. However, formoterol is a full receptor agonist whereas salmeterol is a partial agonist, and differences in the efficacy of these drugs occur in vitro and in vivo following airway challenge. We aimed to compare the effects of formoterol and salmeterol on total cAMP levels in TNF-stimulated monocytes. METHODS: Human blood monocytes were isolated from buffy coats (n=6) by Ficoll-Paque procedure. Total cAMP was determined by the cAMP [125I] Direct Biotrak scintillation assay in monocytes (5x106 cells/ml) pre-treated for 1 h with 1 g/ml TNF with or without addition of 10-9, 10-8 or 10-7 M of formoterol or salmeterol for 3 min. RESULTS: Formoterol at 10-9 M maximally increased cAMP levels up to 280%, compared to TNF-treated controls, whereas salmeterol increased cAMP levels maximally to 167% and this effect was independent of the concentrations used. CONCLUSIONS: The observed difference in drug effects on total cAMP levels indicates a potential for greater inhibition of monocyte activity with formoterol versus salmeterol during a period of acute inflammation. The implications of this effect warrants further investigation. Funding: AstraZeneca
759
Normal Pulmonary Function in Alpha-1-Antitrypsin Deficiency ZZ Phenotype M. L. Fajt1, J. Gibbs2, L. H. Fisher3, T. J. Craig2; 1Department of Medicine, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA, 2Department of Allergy-Immunology and Pulmonary Medicine, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA, 3Department of Allergy-Immunology, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA. RATIONALE: Alpha-1-Antitrypsin ZZ deficiency patients with serum levels below 50mg/dL without significant lung disease are rare because these patients usually develop severe pulmonary disease early in life. METHODS: A Medline literature search of OVID and PubMed using Keywords: Alpha-1-Antitrypsin deficiency and Respiratory Function Testing Spirometry generated 88 articles from 1966 to present. Six articles addressed pulmonary function and symptoms in patients homozygous for the ZZ Alpha-1-Antitrypsin deficiency. RESULTS: We present a 41year old nonsmoking firefighter without past medical history who complained of episodic abdominal pain during a rou-
760
tine physical examination. He denied cough, wheezing, or dyspnea. Ultrasound revealed cholelithiasis within the gallbladder. ALT and AST were mildly elevated at 92u/L and 52u/L respectively. Liver biopsies showed Alpha-1-Antitrypsin deficiency. Laboratory studies demonstrated Alpha1-Antitrypsin serum level below 30mg/dL, which is the lowest detectable level in our laboratory, and ZZ phenotype. Pulmonary function testing was normal and the DLCO adjusted for alveolar ventilation was normal. Chest X-ray was without evidence of obstructive lung disease. CONCLUSIONS: Alpha-1-Antitrypsin deficiency predisposes patients to several diseases: most commonly emphysema, but also liver disease, and rarely panniculitis. Studies suggest that Alpha-1-Antitrypsin levels below 60-80 mg/dL provide insufficient lung protection, leading to a high risk of emphysematous transformation. Most patients with levels of alpha1antitrypsin below 50mg/dL have the protease inhibitor ZZ phenotype. These patients are rarely asymptomatic and seldom spared from lung disease especially at 41 years of age. This case and literature review emphasize the clinical need to consider atypical presentations of Alpha-1Antitrypsin deficiency. Funding: Pennsylvania State University- Milton S. Hershey Medical Center Asthma Hospitalizations in Children 2 Years Old or Less in New York State 1990-2004 T. J. Pitt1, R. Y. Lin2,3; 1St Vincent Hospital Manhattan-SVCMC, New York, NY, 2St Vincent Hospital Manhattan- SVCMC, New York, NY, 3New York Medical College, Valhalla, NY. RATIONALE: This study characterized hospital admissions in very young asthmatic children, a poorly understood group. METHODS: The New York State (NYS) acute hospitalization database was queried for patients admitted with asthma 2 years old between 1990-2004. RESULTS: There were >100,000 hospitalizations with the principal diagnosis of asthma. Male predominated. Admissions peaked in the last 4 months of the year but were less marked in recent years. In the latter third of the year, the mean age(in months) was consistently greater than the earlier months of the year regardless of the year of admission(20.4 ± 8.6 versus 18.6 ± 9.0, p<0.0001). Adjusting for other co-morbidities and demographic factors did not eliminate the association between time of year (latter third) and increased age. The age distribution during the latter third of the year showed a bimodal pattern that was not present in the earlier months, suggestive of a different population of older patients being admitted. Admissions with a concomitant diagnosis of respiratory tract infection, or otitis media peaked in November through January, whereas admissions without these co-morbidities peaked earlier in September through November. Only 1% of patients were readmitted within the same calendar year. CONCLUSIONS: Asthma hospitalizations in children 2 y.o are highly prevalent and have distinct temporal patterns with respect to age, and comorbid infections. The increased age of patients in the latter third of the year suggests that older children are preferentially affected by a factor that exacerbates asthma, possibly rhinoviruses.
761
MONDAY
CONCLUSIONS: Once-daily dosing with indacaterol demonstrated sustained 24-hour bronchodilatory efficacy, with similar efficacy on Days 1 and 7, and was generally well tolerated. Indacaterol 200g appears to be the optimal dose, with no significant differences in FEV1 AUC22-24h between doses 200g. Funding: Novartis Pharma AG
J ALLERGY CLIN IMMUNOL VOLUME 117, NUMBER 2
Formoterol Induces Higher Levels of Total cAMP in TNFStimulated Human Monocytes than Salmeterol I. Nita1, A. Miller-Larsson2, S. Janciauskiene1; 1Clinical Sciences, Lund University, Malmö, SWEDEN, 2AstraZeneca R&D Lund, Lund, SWEDEN. RATIONALE: Formoterol and salmeterol are useful add-on drugs to inhaled corticosteroids in the treatment of asthmatic patients who are not satisfactorily controlled with ICS alone. Both are highly selective and potent 2-adrenoceptor agonists. However, formoterol is a full receptor agonist whereas salmeterol is a partial agonist, and differences in the efficacy of these drugs occur in vitro and in vivo following airway challenge. We aimed to compare the effects of formoterol and salmeterol on total cAMP levels in TNF-stimulated monocytes. METHODS: Human blood monocytes were isolated from buffy coats (n=6) by Ficoll-Paque procedure. Total cAMP was determined by the cAMP [125I] Direct Biotrak scintillation assay in monocytes (5x106 cells/ml) pre-treated for 1 h with 1 g/ml TNF with or without addition of 10-9, 10-8 or 10-7 M of formoterol or salmeterol for 3 min. RESULTS: Formoterol at 10-9 M maximally increased cAMP levels up to 280%, compared to TNF-treated controls, whereas salmeterol increased cAMP levels maximally to 167% and this effect was independent of the concentrations used. CONCLUSIONS: The observed difference in drug effects on total cAMP levels indicates a potential for greater inhibition of monocyte activity with formoterol versus salmeterol during a period of acute inflammation. The implications of this effect warrants further investigation. Funding: AstraZeneca
759
Normal Pulmonary Function in Alpha-1-Antitrypsin Deficiency ZZ Phenotype M. L. Fajt1, J. Gibbs2, L. H. Fisher3, T. J. Craig2; 1Department of Medicine, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA, 2Department of Allergy-Immunology and Pulmonary Medicine, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA, 3Department of Allergy-Immunology, Pennsylvania State University-Milton S. Hershey Medical Center, Hershey, PA. RATIONALE: Alpha-1-Antitrypsin ZZ deficiency patients with serum levels below 50mg/dL without significant lung disease are rare because these patients usually develop severe pulmonary disease early in life. METHODS: A Medline literature search of OVID and PubMed using Keywords: Alpha-1-Antitrypsin deficiency and Respiratory Function Testing Spirometry generated 88 articles from 1966 to present. Six articles addressed pulmonary function and symptoms in patients homozygous for the ZZ Alpha-1-Antitrypsin deficiency. RESULTS: We present a 41year old nonsmoking firefighter without past medical history who complained of episodic abdominal pain during a rou-
760
tine physical examination. He denied cough, wheezing, or dyspnea. Ultrasound revealed cholelithiasis within the gallbladder. ALT and AST were mildly elevated at 92u/L and 52u/L respectively. Liver biopsies showed Alpha-1-Antitrypsin deficiency. Laboratory studies demonstrated Alpha1-Antitrypsin serum level below 30mg/dL, which is the lowest detectable level in our laboratory, and ZZ phenotype. Pulmonary function testing was normal and the DLCO adjusted for alveolar ventilation was normal. Chest X-ray was without evidence of obstructive lung disease. CONCLUSIONS: Alpha-1-Antitrypsin deficiency predisposes patients to several diseases: most commonly emphysema, but also liver disease, and rarely panniculitis. Studies suggest that Alpha-1-Antitrypsin levels below 60-80 mg/dL provide insufficient lung protection, leading to a high risk of emphysematous transformation. Most patients with levels of alpha1antitrypsin below 50mg/dL have the protease inhibitor ZZ phenotype. These patients are rarely asymptomatic and seldom spared from lung disease especially at 41 years of age. This case and literature review emphasize the clinical need to consider atypical presentations of Alpha-1Antitrypsin deficiency. Funding: Pennsylvania State University- Milton S. Hershey Medical Center Asthma Hospitalizations in Children 2 Years Old or Less in New York State 1990-2004 T. J. Pitt1, R. Y. Lin2,3; 1St Vincent Hospital Manhattan-SVCMC, New York, NY, 2St Vincent Hospital Manhattan- SVCMC, New York, NY, 3New York Medical College, Valhalla, NY. RATIONALE: This study characterized hospital admissions in very young asthmatic children, a poorly understood group. METHODS: The New York State (NYS) acute hospitalization database was queried for patients admitted with asthma 2 years old between 1990-2004. RESULTS: There were >100,000 hospitalizations with the principal diagnosis of asthma. Male predominated. Admissions peaked in the last 4 months of the year but were less marked in recent years. In the latter third of the year, the mean age(in months) was consistently greater than the earlier months of the year regardless of the year of admission(20.4 ± 8.6 versus 18.6 ± 9.0, p<0.0001). Adjusting for other co-morbidities and demographic factors did not eliminate the association between time of year (latter third) and increased age. The age distribution during the latter third of the year showed a bimodal pattern that was not present in the earlier months, suggestive of a different population of older patients being admitted. Admissions with a concomitant diagnosis of respiratory tract infection, or otitis media peaked in November through January, whereas admissions without these co-morbidities peaked earlier in September through November. Only 1% of patients were readmitted within the same calendar year. CONCLUSIONS: Asthma hospitalizations in children 2 y.o are highly prevalent and have distinct temporal patterns with respect to age, and comorbid infections. The increased age of patients in the latter third of the year suggests that older children are preferentially affected by a factor that exacerbates asthma, possibly rhinoviruses.
761
MONDAY
CONCLUSIONS: Once-daily dosing with indacaterol demonstrated sustained 24-hour bronchodilatory efficacy, with similar efficacy on Days 1 and 7, and was generally well tolerated. Indacaterol 200g appears to be the optimal dose, with no significant differences in FEV1 AUC22-24h between doses 200g. Funding: Novartis Pharma AG