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IgG Immunologic Monitoring To Identify Lung Recipients at Risk of Oportunistic Infections: Prospective Multicenter Study
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The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
extubation, significant reduction in respiratory complications, a trend toward lower transfusion requirement and improved overall survival. Graft survival was significantly improved with the use of ECMO. F1 Further longitudinal data is necessary. 444 Role of HLA-G Expression as a Predictive Marker of a Low Risk of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients: A 3-Year Prospective Study 1,2 G. Thabut,1 I. Krawice,2 E. Carosella,2 N. Rouas-Freiss.2 O. Brugiere, 1 ˆ Service de Pneumologie B et Transplantation Pulmonaire. Hopital CEA, Bichat, Paris, France; 2Laboratoire d’Hemato-Immunologie, ˆ Hopital Saint-Louis, Paris, France. Purpose: In lung Tx, the graft expression of the tolerogenic HLA-G molecule has been shown to be associated to a stable clinical condition observed at the date of tissue sampling. To evaluate the role of HLA-G as a predictive marker of graft tolerance, we planned a 3-year prospective study in a LTx recipients cohort to analyze if early expression HLA-G is associated to short and long-term functional stability of the graft, that is, a lower incidence of acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Methods and Materials: 41 LTx recipients were included and followed up 3 years post-LTx. Expression of HLA-G was analyzed by immunohistochemistry in the graft tissues from TBBx and dosage of soluble HLAG (sHLA-G) in plasma was performed by ELISA both at 3 and 12 months post-Tx in stable patients. Patients were classified first as those with or without histological detection of HLA-G in the graft at 3 and/or 12 months (hHLA-Gþ or - patients) and second as those with or without trough level sHLA-G 4 25 ng/ml at 3 and/or 12 months (sHLA-G þ or - patients). Freedom from BOS (by log-rank test) and an AR score were compared between both hHLA-G þ or - and sHLA-G þ or – patients. Results: Freedom from BOS at 3 year post-LTx was significantly higher for hHLA-G þ patients (n ¼ 21) compared to hHLA-G - patients (n ¼ 20) (p o 0.05, Figure 1) but did not differ for sHLA-G þ and sHLA-G – patients. No difference was observed for an ARS between hHLA-G þ or – patients and between sHLA-G þ and sHLA-G- patients (p ¼ ns). In addition, median through levels of sHLA-G was higher in hHLA-G þ patients compared to to hHLA-G – ones (p ¼ 0.02). Conclusions: Expression of HLA-G in the graft of stable LTx recipients seems predictive of a lower risk of BOS in long-term follow-up. An isolated dosage of sHLA-G seems of no clinical value as a predictive marker. 445 IgG Immunologic Monitoring To Identify Lung Recipients at Risk of Oportunistic Infections: Prospective Multicenter Study E. Sarmiento,1 J. Cifrian,2 R. Laporta,3 P. Ussetti,3 C. Bravo,4 S. Lopez,4 P. Morales,5 A. de Pablos,6 M. Jaramillo,1 J. Navarro,1 J. Rodriguez-Molina,1 J. Carbone.1 1Hospital General Universitario de Valdecilla, Gregorio Maran˜on, Madrid, Spain; 2Hospital Marques Santander, Spain; 3Hospital Universitario Puerta de Hierro, Madrid, Spain; 4Hospital Vall de Hebron, Barcelona, Spain; 5Hospital La Fe, Valencia, Spain; 6Hospital Universitario Doce de Octubre, Madrid, Spain. Purpose: Infection is a leading cause of morbidity and mortality in the first year following lung transplantation. However, reliable markers performed at fixed times before and after transplantation to detect patients at risk for developing these complications are lacking. The purpose of this study is to define the kinetics of humoral immunity parameters, and to evaluate the usefulness of assessment of these parameters in the identification of recipients at risk of developing severe infections after transplantation. Methods and Materials: We prospectively analyzed 97 adult lung recipients from May 2009 to May 2011 performed at 5 centers in Spain. Immunological studies were performed before transplantation and at 7 and 30 days after transplantation. The protocol included total immunoglobulin levels (IgG, IgM, IgA, nephelometry), complement factors (C3 and C4, nephelometry) and specific antibody titers to
pneumococcal polysaccharides (anti-PPS, ELISA, IgG: 23 serotypes), and to cytomegalovirus (ELISA, IgG). Clinical follow-up was performed over a 6-month period. Definition of outcomes: A. Opportunistic infections (including fungal and CMV that required IV antimicrobial therapy: Prevalence 21,6%). B. Bacterial infection that required IV antimicrobial therapy (Prevalence 58.8%). Statistics: Logistic regression analysis. Results: IgG, IgA, C3 and anti-PPS were significantly lower at day 7 as compared with the baseline study. At day 30 IgG, IgA and anti-PPS remained significantly lower. Immunological risk factors for opportunistic infections were: Pre-transplant IgGo1100 mg/dl (OR 4.95, CI95% 1.13-21.70, p¼0.038), day 7 IgGo600 mg/dL (OR 4.62; CI 95%: 1.06-20.13, p¼0.04), day 30 IgG o698 mg/dL (median value) (OR 5.44; CI 95%: 1.14-25.95, p¼0.033). Risk factors for bacterial infection: Pre-transplant C4o36 mg/dL (OR 4.90; CI 95%: 1.39-17.30, p¼0.013). Conclusions: Protocolized early immunologic monitoring of IgG is useful to identify lung recipients who are at risk of oportunistic infection. These patients deserve a more careful follow-up. 446 A Phase One, Open Label, Multi-Dose Study To Evaluate the Safety, Tolerability, and Biologic Effects of Three Doses of IW001 in Patients with Idiopathic Pulmonary Fibrosis (IPF) K. Rothhaar,1 T. Chew,1 S. Frye,1 M. Klemsz,1,2 W. Lange,1 D.S. Wilkes.1,2 1ImmuneWorks, Indianapolis, IN; 2Indiana University School of Medicine, Indianapolis, IN. Purpose: IW001, an oral solution of Type V collagen (col(V)), is a therapeutic agent in clinical development for IPF by ImmuneWorks. ImmuneWorks scientists believe that lung injury might result in the exposure of a normally hidden protein to the immune system, such as col(V). The immune system may recognize this sequestered protein as foreign, initiating an autoimmune cascade, resulting in an attack on the lung. As the autoimmune response expands, a fibrotic response would follow in an attempt to heal the lung. Lung transplantation is the only viable treatment that has shown survival benefit for IPF patients but the survival benefit is still complicated by significant early mortality rates, especially within the first year. High incidence of col(V) autoreactivity was found with IPF patients and associated with a higher incidence of PGD. Pre-clinical studies showed that col(V)induced immune tolerance abrogated acute rejection in a rat lung transplant model. Methods and Materials: ImmuneWorks conducted an open label, multicenter, Phase I clinical trial in IPF patients who tested positive for anti-col(V) antibodies. Study was designed to evaluate the safety, tolerability, and biological/clinical effects of a three doses (0.1mg, 0.5mg, 1.0mg) of IW001, when administered once daily orally for 24 weeks. Results: About 40% of IPF patients screened for this study tested positive for anti-Col(V) IgG. A total of 30 IPF patients were enrolled in one of three IW001 dose treatment groups. Absolute changes in %FVC pred from baseline to week 24 were determined and showed a trend toward the stabilization of the lung function with IW001 doses at both 0.5mg and 1.0mg/day. Additional biomarkers will be discussed. Conclusions: Our phase I results have demonstrated that IW001 is safe and well tolerated with no unexpected adverse events. IW001 may lead to a possible stabilization of lung function, underscoring the potential of col(V)-induced tolerance to be an effective therapeutic strategy in IPF. 447 Predicting Lung Transplant Waitlist Survival with the Lung Allocation Score in British Columbia, Canada A. Hirji,1 J. Yee,2 M. Sadatsafavi,3 L.G. Singer,4 R.D. Levy.1 1 Respiratory Division, Department of Medicine and British Columbia Transplant, University of British Columbia, Vancouver, BC, Canada; 2 Department of Thoracic Surgery, University of British Columbia, Vancouver, BC, Canada; 3Faculty of Medicine, University of British
The Journal of Heart and Lung Transplantation, Vol 32, No 4S, April 2013
extubation, significant reduction in respiratory complications, a trend toward lower transfusion requirement and improved overall survival. Graft survival was significantly improved with the use of ECMO. F1 Further longitudinal data is necessary. 444 Role of HLA-G Expression as a Predictive Marker of a Low Risk of Bronchiolitis Obliterans Syndrome in Lung Transplant Recipients: A 3-Year Prospective Study 1,2 G. Thabut,1 I. Krawice,2 E. Carosella,2 N. Rouas-Freiss.2 O. Brugiere, 1 ˆ Service de Pneumologie B et Transplantation Pulmonaire. Hopital CEA, Bichat, Paris, France; 2Laboratoire d’Hemato-Immunologie, ˆ Hopital Saint-Louis, Paris, France. Purpose: In lung Tx, the graft expression of the tolerogenic HLA-G molecule has been shown to be associated to a stable clinical condition observed at the date of tissue sampling. To evaluate the role of HLA-G as a predictive marker of graft tolerance, we planned a 3-year prospective study in a LTx recipients cohort to analyze if early expression HLA-G is associated to short and long-term functional stability of the graft, that is, a lower incidence of acute rejection (AR) or bronchiolitis obliterans syndrome (BOS). Methods and Materials: 41 LTx recipients were included and followed up 3 years post-LTx. Expression of HLA-G was analyzed by immunohistochemistry in the graft tissues from TBBx and dosage of soluble HLAG (sHLA-G) in plasma was performed by ELISA both at 3 and 12 months post-Tx in stable patients. Patients were classified first as those with or without histological detection of HLA-G in the graft at 3 and/or 12 months (hHLA-Gþ or - patients) and second as those with or without trough level sHLA-G 4 25 ng/ml at 3 and/or 12 months (sHLA-G þ or - patients). Freedom from BOS (by log-rank test) and an AR score were compared between both hHLA-G þ or - and sHLA-G þ or – patients. Results: Freedom from BOS at 3 year post-LTx was significantly higher for hHLA-G þ patients (n ¼ 21) compared to hHLA-G - patients (n ¼ 20) (p o 0.05, Figure 1) but did not differ for sHLA-G þ and sHLA-G – patients. No difference was observed for an ARS between hHLA-G þ or – patients and between sHLA-G þ and sHLA-G- patients (p ¼ ns). In addition, median through levels of sHLA-G was higher in hHLA-G þ patients compared to to hHLA-G – ones (p ¼ 0.02). Conclusions: Expression of HLA-G in the graft of stable LTx recipients seems predictive of a lower risk of BOS in long-term follow-up. An isolated dosage of sHLA-G seems of no clinical value as a predictive marker. 445 IgG Immunologic Monitoring To Identify Lung Recipients at Risk of Oportunistic Infections: Prospective Multicenter Study E. Sarmiento,1 J. Cifrian,2 R. Laporta,3 P. Ussetti,3 C. Bravo,4 S. Lopez,4 P. Morales,5 A. de Pablos,6 M. Jaramillo,1 J. Navarro,1 J. Rodriguez-Molina,1 J. Carbone.1 1Hospital General Universitario de Valdecilla, Gregorio Maran˜on, Madrid, Spain; 2Hospital Marques Santander, Spain; 3Hospital Universitario Puerta de Hierro, Madrid, Spain; 4Hospital Vall de Hebron, Barcelona, Spain; 5Hospital La Fe, Valencia, Spain; 6Hospital Universitario Doce de Octubre, Madrid, Spain. Purpose: Infection is a leading cause of morbidity and mortality in the first year following lung transplantation. However, reliable markers performed at fixed times before and after transplantation to detect patients at risk for developing these complications are lacking. The purpose of this study is to define the kinetics of humoral immunity parameters, and to evaluate the usefulness of assessment of these parameters in the identification of recipients at risk of developing severe infections after transplantation. Methods and Materials: We prospectively analyzed 97 adult lung recipients from May 2009 to May 2011 performed at 5 centers in Spain. Immunological studies were performed before transplantation and at 7 and 30 days after transplantation. The protocol included total immunoglobulin levels (IgG, IgM, IgA, nephelometry), complement factors (C3 and C4, nephelometry) and specific antibody titers to
pneumococcal polysaccharides (anti-PPS, ELISA, IgG: 23 serotypes), and to cytomegalovirus (ELISA, IgG). Clinical follow-up was performed over a 6-month period. Definition of outcomes: A. Opportunistic infections (including fungal and CMV that required IV antimicrobial therapy: Prevalence 21,6%). B. Bacterial infection that required IV antimicrobial therapy (Prevalence 58.8%). Statistics: Logistic regression analysis. Results: IgG, IgA, C3 and anti-PPS were significantly lower at day 7 as compared with the baseline study. At day 30 IgG, IgA and anti-PPS remained significantly lower. Immunological risk factors for opportunistic infections were: Pre-transplant IgGo1100 mg/dl (OR 4.95, CI95% 1.13-21.70, p¼0.038), day 7 IgGo600 mg/dL (OR 4.62; CI 95%: 1.06-20.13, p¼0.04), day 30 IgG o698 mg/dL (median value) (OR 5.44; CI 95%: 1.14-25.95, p¼0.033). Risk factors for bacterial infection: Pre-transplant C4o36 mg/dL (OR 4.90; CI 95%: 1.39-17.30, p¼0.013). Conclusions: Protocolized early immunologic monitoring of IgG is useful to identify lung recipients who are at risk of oportunistic infection. These patients deserve a more careful follow-up. 446 A Phase One, Open Label, Multi-Dose Study To Evaluate the Safety, Tolerability, and Biologic Effects of Three Doses of IW001 in Patients with Idiopathic Pulmonary Fibrosis (IPF) K. Rothhaar,1 T. Chew,1 S. Frye,1 M. Klemsz,1,2 W. Lange,1 D.S. Wilkes.1,2 1ImmuneWorks, Indianapolis, IN; 2Indiana University School of Medicine, Indianapolis, IN. Purpose: IW001, an oral solution of Type V collagen (col(V)), is a therapeutic agent in clinical development for IPF by ImmuneWorks. ImmuneWorks scientists believe that lung injury might result in the exposure of a normally hidden protein to the immune system, such as col(V). The immune system may recognize this sequestered protein as foreign, initiating an autoimmune cascade, resulting in an attack on the lung. As the autoimmune response expands, a fibrotic response would follow in an attempt to heal the lung. Lung transplantation is the only viable treatment that has shown survival benefit for IPF patients but the survival benefit is still complicated by significant early mortality rates, especially within the first year. High incidence of col(V) autoreactivity was found with IPF patients and associated with a higher incidence of PGD. Pre-clinical studies showed that col(V)induced immune tolerance abrogated acute rejection in a rat lung transplant model. Methods and Materials: ImmuneWorks conducted an open label, multicenter, Phase I clinical trial in IPF patients who tested positive for anti-col(V) antibodies. Study was designed to evaluate the safety, tolerability, and biological/clinical effects of a three doses (0.1mg, 0.5mg, 1.0mg) of IW001, when administered once daily orally for 24 weeks. Results: About 40% of IPF patients screened for this study tested positive for anti-Col(V) IgG. A total of 30 IPF patients were enrolled in one of three IW001 dose treatment groups. Absolute changes in %FVC pred from baseline to week 24 were determined and showed a trend toward the stabilization of the lung function with IW001 doses at both 0.5mg and 1.0mg/day. Additional biomarkers will be discussed. Conclusions: Our phase I results have demonstrated that IW001 is safe and well tolerated with no unexpected adverse events. IW001 may lead to a possible stabilization of lung function, underscoring the potential of col(V)-induced tolerance to be an effective therapeutic strategy in IPF. 447 Predicting Lung Transplant Waitlist Survival with the Lung Allocation Score in British Columbia, Canada A. Hirji,1 J. Yee,2 M. Sadatsafavi,3 L.G. Singer,4 R.D. Levy.1 1 Respiratory Division, Department of Medicine and British Columbia Transplant, University of British Columbia, Vancouver, BC, Canada; 2 Department of Thoracic Surgery, University of British Columbia, Vancouver, BC, Canada; 3Faculty of Medicine, University of British