- Email: [email protected]
Clinical Implication of Eosinophilic vs. Noneosinophilic Asthma in Children
Abstracts AB139
J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 2
Clinical Implication of Eosinophilic vs. Noneosinophilic Asthma in Children Y. Lee1, B. Choi1, J. Baek1, H. Lee2, K. Kim1, M. Sohn1, K. Kim1; 1Department of Pediatrics, Institute of Allergy, Yonsei University College of Medicine, Seoul, REPUBLIC OF KOREA, 2Department of Pediatrics, College of Medicine, Kwandong University, Goyang, REPUBLIC OF KOREA. RATIONALE: Eosinophil has a key role in asthmatic airway inflammation. However, there isn’t eosinophilic airway inflammation in some of asthmatic patients. The aim of this study was to compare clinical characteristics of eosinophilic and noneosinophilic asthma and to determine clinical significance of eosinophilic airway inflammation in asthmatic children. METHODS: Two hundreds thirty one asthmatic children were included. We defined asthmatic children who had symptoms of asthma for the last one year and showed that PC20 was below 16mg/dL in methacholine challenge test or dFEV1 was over 12% after b-agonist inhalation in pulmonary function test. According to sputum eosinophil counts (%), we divided the subjects into eosinophilic asthma group (3%) and noneosinophilic asthma group (3%). We compared the clinical characteristics between the two groups. RESULTS: Among 231 subjects, 128 subjects belonged to eosinophilic asthma group and 103 subjects belonged to noneosinophilic asthma group. Age and sex didn’t show significant differences between the two groups. PC20 was 6.19 8.88 mg/mL in eosinophilic asthma group, 7.59 9.95 mg/ mL in noneosinophilic asthma group, but didn’t show any significant difference. There were no significant differences in blood eosinophil counts (eosinophilic asthma vs. noneosinopilic asthma, 541 344 vs. 438 372/mL, P > 0.05), serum total IgE (592 650 vs. 554 592 kU/L, P > 0.05), serum ECP(43.3 40.3 vs. 32.7 38.2 mg/L, P > 0.05), respectively. FEV1 and FEV1/FVC didn’t show any significant differences between the two groups. CONCLUSIONS: There were no significant differences between eosinophilic and noneosinophilic asthmatic children identified by induced sputum in allergic inflammation, pulmonary function and airway hyperresponsiveness.
546
Can Subcutaneous IgG Therapy Provide Rapid and Sufficient Serum IgG Levels in Initiation and High Dose Maintenance Settings? J. S. Orange1, M. R. Stein1, H. L. Longhurst2, M. Borte3, B. Ritchie4, M. H. Sturzenegger5, S. Jolles6, M. Berger7; 1Children’s Hospital of Philadelphia, Philadelphia, PA, 2Barts and London NHS Trust London, London, UNITED KINGDOM, 3Municipal Hospital ‘‘St. Georg’’ Leipzig, Academic Teaching Hospital of the University of Leipzig, Leipzig, GERMANY, 4Division of Hematology, Faculty of Medicine, University of Alberta, Edmonton, AB, CANADA, 5Department of Neurology, University Hospital and University of Berne, Berne, SWITZERLAND, 6University Hospital of Wales, Cardiff, UNITED KINGDOM, 7CSL Behring LLC, King of Prussia, PA. RATIONALE: Subcutaneous IgG (SCIG) provides stable serum IgG levels, has fewer systemic adverse events than intravenous IgG (IVIG) and is convenient for home therapy. Currently, newly diagnosed patients with primary immunodeficiency (PID) are ‘‘loaded’’ with IVIG. For immunomodulation, in conditions such as multifocal motor neuropathy (MMN), IVIG is used, as high doses (2g/kg) are required. We report experience with SCIG in place of IVIG in these settings. METHODS: SCIG was initiated directly in 18 PID patients (0 to 70 years) using 100 mg/kg on 5 consecutive days in an outpatient setting. Patients with MMN (N 5 8), maintained on IVIG therapy, were switched to weekly SCIG infusions at a dose equivalent to previous IVIG dose. RESULTS: In PID, 94% of patients achieved serum IgG levels 5 g/L by Day 12. Daily treatment was tolerated well and provided additional opportunities for patient/parent training in self-infusion. In MMN, 7 of 8 patients tolerated SCIG well, maintained serum IgG levels of 14-22 g/L with a mean dose of 272 mg/kg/week, had stable or improved muscle strength and felt comfortable with home administration. CONCLUSIONS: Recent experience with SCIG shows that high IgG levels can be achieved within several days in previously untreated PID
patients. In addition, high serum levels required in immunomodulatory dosing can be maintained by SCIG. These findings suggest that initial SCIG loading in PID patients is reasonable, and that SCIG may be useful for maintenance therapy in some neuropathy patients because it offers sustained IgG levels, tolerability and convenience.
547
Effects of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Administration of 10% and 20% IgG in Yucatan Mini Pigs W. H. Bee1, T. Nekoroski1, L. Zhang1, D. Kang1, W. Teschner2, H. P. Schwarz2, E. M. Muchitsch2; 1Halozyme Inc., San Diego, CA, 2Baxter BioScience, Vienna, AUSTRIA. RATIONALE: rHuPH20 is a novel drug delivery enzyme that locally degrades hyaluronan and transiently increases bulk fluid flow, thereby facilitating improved subcutaneous (SC) absorption profiles of co-administered agents. Formulation with rHuPH20 permits delivery of volumes that substantially exceed typically tolerable SC limits, and achieves bioavailability of protein therapeutics that approximate that of IV administration. This study assessed the effects of increasing concentrations of rHuPH20 on SC infusion of IgG in mini pigs. METHODS: Volumes up to 110 mL of IgG +/- rHuPH20 were administered SC at 2.5-5 mL/min by syringe pump on the backs of pigs. Injection sites were assessed, as well as in-line pressure exerted at each dose. Blood was collected for IgG analysis. At necropsy, skin was collected for histopathology. RESULTS: In the absence of rHuPH20, a distinct firm ÔblebÕ occurred within 5 minutes (~ 25 mL) of initiating IgG administration. rHuPH20 increased the dispersion of the IgG, as assessed by an increased bleb area that was softer and had decreased erythema. With rHuPH20, fewer animals had in-line pressures >460 mmHg. Systemic IgG concentrations were increased in all animals, including controls, following IgG administration. No gross abnormalities were noted at necropsy, and histopathology revealed no meaningful differences between administrations with or without PH20. CONCLUSIONS: rHuPH20 decreased subcutaneous infusion site fluid pressure, erythema, and the number of animals with high in-line pressures during administration in mini pigs. The data indicate that rHuPH20 can facilitate SC administration of large volumes of IgG.
548
Evaluation of IgG Trough Level Ratios as an Aid to Dosing of Subcutaneous IgG M. Rojavin1, O. Zenker2, P. Kiessling2, M. Berger1; 1CSL Behring LLC, King of Prussia, PA, 2CSL Behring AG, Marburg, GERMANY. RATIONALE: Pharmacokinetics (PK) of subcutaneous (SC) IgG differ from intravenous (IV) IgG. In recent US studies, the SCIG dose was adjusted so the area under the curve (AUC) of serum IgG vs time would equal that with IVIG. Since SCIG gives near-constant IgG levels, we determined whether ratios of the trough levels on SCIG versus IVIG confirm equivalence of the AUCs. METHODS: PK substudies accompanied US trials of VivaglobinÒ (n 5 17, Ochs, et.al. J. Clin. Immunol 2006) and Ig-Pro20 (n 5 18, NTC00419341). The dose adjustment necessary to give AUC on SCIG non-inferior to AUC on IV was calculated for each subject. Trough IgG levels on the adjusted SC dose and previous IV dose were compared. RESULTS: The mean (6SD) of the individual dose adjustments for PK subjects on VivaglobinÒ and on IgPro20 were 1.37 6 0.21 and 1.53 6 0.16, respectively. Trough level ratios (TLRs) on the doses at which the mean SCIG AUC was non-inferior to the IVIG AUC were 1.2360.19 and 1.35 6 0.23, respectively. Regression analyses of TLR vs dose adjustment showed no significant correlation. CONCLUSIONS: Individual variability (SDs) in the SCIG dose adjustments necessary for equivalent AUCs, and the corresponding TLRs, exceed 15% of the means. TLRs do not correlate significantly with the required individual dose adjustments. When switching from IV to SC therapy, reliance on mean dose adjustment or mean TLR may result in significant under- or over-dosing. IgG doses on each route of therapy should be individually adjusted so the trough IgG meets or exceeds that patient’s ideal level.
MONDAY
545
J ALLERGY CLIN IMMUNOL VOLUME 125, NUMBER 2
Clinical Implication of Eosinophilic vs. Noneosinophilic Asthma in Children Y. Lee1, B. Choi1, J. Baek1, H. Lee2, K. Kim1, M. Sohn1, K. Kim1; 1Department of Pediatrics, Institute of Allergy, Yonsei University College of Medicine, Seoul, REPUBLIC OF KOREA, 2Department of Pediatrics, College of Medicine, Kwandong University, Goyang, REPUBLIC OF KOREA. RATIONALE: Eosinophil has a key role in asthmatic airway inflammation. However, there isn’t eosinophilic airway inflammation in some of asthmatic patients. The aim of this study was to compare clinical characteristics of eosinophilic and noneosinophilic asthma and to determine clinical significance of eosinophilic airway inflammation in asthmatic children. METHODS: Two hundreds thirty one asthmatic children were included. We defined asthmatic children who had symptoms of asthma for the last one year and showed that PC20 was below 16mg/dL in methacholine challenge test or dFEV1 was over 12% after b-agonist inhalation in pulmonary function test. According to sputum eosinophil counts (%), we divided the subjects into eosinophilic asthma group (3%) and noneosinophilic asthma group (3%). We compared the clinical characteristics between the two groups. RESULTS: Among 231 subjects, 128 subjects belonged to eosinophilic asthma group and 103 subjects belonged to noneosinophilic asthma group. Age and sex didn’t show significant differences between the two groups. PC20 was 6.19 8.88 mg/mL in eosinophilic asthma group, 7.59 9.95 mg/ mL in noneosinophilic asthma group, but didn’t show any significant difference. There were no significant differences in blood eosinophil counts (eosinophilic asthma vs. noneosinopilic asthma, 541 344 vs. 438 372/mL, P > 0.05), serum total IgE (592 650 vs. 554 592 kU/L, P > 0.05), serum ECP(43.3 40.3 vs. 32.7 38.2 mg/L, P > 0.05), respectively. FEV1 and FEV1/FVC didn’t show any significant differences between the two groups. CONCLUSIONS: There were no significant differences between eosinophilic and noneosinophilic asthmatic children identified by induced sputum in allergic inflammation, pulmonary function and airway hyperresponsiveness.
546
Can Subcutaneous IgG Therapy Provide Rapid and Sufficient Serum IgG Levels in Initiation and High Dose Maintenance Settings? J. S. Orange1, M. R. Stein1, H. L. Longhurst2, M. Borte3, B. Ritchie4, M. H. Sturzenegger5, S. Jolles6, M. Berger7; 1Children’s Hospital of Philadelphia, Philadelphia, PA, 2Barts and London NHS Trust London, London, UNITED KINGDOM, 3Municipal Hospital ‘‘St. Georg’’ Leipzig, Academic Teaching Hospital of the University of Leipzig, Leipzig, GERMANY, 4Division of Hematology, Faculty of Medicine, University of Alberta, Edmonton, AB, CANADA, 5Department of Neurology, University Hospital and University of Berne, Berne, SWITZERLAND, 6University Hospital of Wales, Cardiff, UNITED KINGDOM, 7CSL Behring LLC, King of Prussia, PA. RATIONALE: Subcutaneous IgG (SCIG) provides stable serum IgG levels, has fewer systemic adverse events than intravenous IgG (IVIG) and is convenient for home therapy. Currently, newly diagnosed patients with primary immunodeficiency (PID) are ‘‘loaded’’ with IVIG. For immunomodulation, in conditions such as multifocal motor neuropathy (MMN), IVIG is used, as high doses (2g/kg) are required. We report experience with SCIG in place of IVIG in these settings. METHODS: SCIG was initiated directly in 18 PID patients (0 to 70 years) using 100 mg/kg on 5 consecutive days in an outpatient setting. Patients with MMN (N 5 8), maintained on IVIG therapy, were switched to weekly SCIG infusions at a dose equivalent to previous IVIG dose. RESULTS: In PID, 94% of patients achieved serum IgG levels 5 g/L by Day 12. Daily treatment was tolerated well and provided additional opportunities for patient/parent training in self-infusion. In MMN, 7 of 8 patients tolerated SCIG well, maintained serum IgG levels of 14-22 g/L with a mean dose of 272 mg/kg/week, had stable or improved muscle strength and felt comfortable with home administration. CONCLUSIONS: Recent experience with SCIG shows that high IgG levels can be achieved within several days in previously untreated PID
patients. In addition, high serum levels required in immunomodulatory dosing can be maintained by SCIG. These findings suggest that initial SCIG loading in PID patients is reasonable, and that SCIG may be useful for maintenance therapy in some neuropathy patients because it offers sustained IgG levels, tolerability and convenience.
547
Effects of Recombinant Human Hyaluronidase (rHuPH20) on Subcutaneous Administration of 10% and 20% IgG in Yucatan Mini Pigs W. H. Bee1, T. Nekoroski1, L. Zhang1, D. Kang1, W. Teschner2, H. P. Schwarz2, E. M. Muchitsch2; 1Halozyme Inc., San Diego, CA, 2Baxter BioScience, Vienna, AUSTRIA. RATIONALE: rHuPH20 is a novel drug delivery enzyme that locally degrades hyaluronan and transiently increases bulk fluid flow, thereby facilitating improved subcutaneous (SC) absorption profiles of co-administered agents. Formulation with rHuPH20 permits delivery of volumes that substantially exceed typically tolerable SC limits, and achieves bioavailability of protein therapeutics that approximate that of IV administration. This study assessed the effects of increasing concentrations of rHuPH20 on SC infusion of IgG in mini pigs. METHODS: Volumes up to 110 mL of IgG +/- rHuPH20 were administered SC at 2.5-5 mL/min by syringe pump on the backs of pigs. Injection sites were assessed, as well as in-line pressure exerted at each dose. Blood was collected for IgG analysis. At necropsy, skin was collected for histopathology. RESULTS: In the absence of rHuPH20, a distinct firm ÔblebÕ occurred within 5 minutes (~ 25 mL) of initiating IgG administration. rHuPH20 increased the dispersion of the IgG, as assessed by an increased bleb area that was softer and had decreased erythema. With rHuPH20, fewer animals had in-line pressures >460 mmHg. Systemic IgG concentrations were increased in all animals, including controls, following IgG administration. No gross abnormalities were noted at necropsy, and histopathology revealed no meaningful differences between administrations with or without PH20. CONCLUSIONS: rHuPH20 decreased subcutaneous infusion site fluid pressure, erythema, and the number of animals with high in-line pressures during administration in mini pigs. The data indicate that rHuPH20 can facilitate SC administration of large volumes of IgG.
548
Evaluation of IgG Trough Level Ratios as an Aid to Dosing of Subcutaneous IgG M. Rojavin1, O. Zenker2, P. Kiessling2, M. Berger1; 1CSL Behring LLC, King of Prussia, PA, 2CSL Behring AG, Marburg, GERMANY. RATIONALE: Pharmacokinetics (PK) of subcutaneous (SC) IgG differ from intravenous (IV) IgG. In recent US studies, the SCIG dose was adjusted so the area under the curve (AUC) of serum IgG vs time would equal that with IVIG. Since SCIG gives near-constant IgG levels, we determined whether ratios of the trough levels on SCIG versus IVIG confirm equivalence of the AUCs. METHODS: PK substudies accompanied US trials of VivaglobinÒ (n 5 17, Ochs, et.al. J. Clin. Immunol 2006) and Ig-Pro20 (n 5 18, NTC00419341). The dose adjustment necessary to give AUC on SCIG non-inferior to AUC on IV was calculated for each subject. Trough IgG levels on the adjusted SC dose and previous IV dose were compared. RESULTS: The mean (6SD) of the individual dose adjustments for PK subjects on VivaglobinÒ and on IgPro20 were 1.37 6 0.21 and 1.53 6 0.16, respectively. Trough level ratios (TLRs) on the doses at which the mean SCIG AUC was non-inferior to the IVIG AUC were 1.2360.19 and 1.35 6 0.23, respectively. Regression analyses of TLR vs dose adjustment showed no significant correlation. CONCLUSIONS: Individual variability (SDs) in the SCIG dose adjustments necessary for equivalent AUCs, and the corresponding TLRs, exceed 15% of the means. TLRs do not correlate significantly with the required individual dose adjustments. When switching from IV to SC therapy, reliance on mean dose adjustment or mean TLR may result in significant under- or over-dosing. IgG doses on each route of therapy should be individually adjusted so the trough IgG meets or exceeds that patient’s ideal level.
MONDAY
545