Chronic Rejection 2 BOS (Bronchiolitis Obliterans Syndrome) Below are some recent ideas and research that is being done about BOS. I will include the article web site address when possible. Also, various treatments exist, but every center is different on the regime they use. Below you will find a list of treatments that various centers use. You may want to suggest them to your center and see if they are willing to look into it for you.
Effect of switching from cyclosporine to tacrolimus on exhaled nitric oxide and pulmonary function in patients with chronic rejection after lung transplantation - Geert M. Verleden MD, PhD, -Previous studies have demonstrated that shifting immunosuppressive therapy from cyclosporine (CyA) to tacrolimus (FK) may arrest the decline in forced expiratory volume in 1 second (FEV1) during chronic rejection after lung transplantation. Exhaled nitric oxide (eNO) has been shown to be elevated during chronic rejection. We report the concomitant stabilization of FEV1 and decrease in eNO after changing from CyA to FK therapy in patients with chronic rejection after lung transplantation. Methods -We used a prospective design. The study included 10 lung transplant patients (5 men and 5 women), mean age 44 ± 14 years at time of transplantation, with a progressive decline in FEV1 that was attributed to chronic rejection. Four patients underwent heart–lung transplantation and 3 had a sequential single and 3 a single-lung transplantation. The switch from CyA to FK occurred at 36 ± 23 months after transplantation (Time 0). The eNO was measured using a Chemiluminescence analyzer, according to standardized European Respiratory Society (ERS) criteria. Results - At Time 0, there were 6 patients in bronchiolitis obliterans syndrome (BOS) Stage 0-p, with a mean decline in FEV1 of 15 ± 3%; 2 in BOS Stage 1; and 2 in BOS Stage 2. Compared with the best post-operative FEV1, there was a progressive and significant decline until Time 0, from 2.56 ± 0.9 liters to 2.03 ± 0.94 liters (p = 0.0047). Thereafter, FEV1 stabilized: 2.03 ± 0.94 liters at Time 0 and 2.05 ± 0.94 liters 6 months later (p = non-significant). Concomitantly, there was a gradual increase in eNO during the 6 months before Time 0, from 11.4 ± 2.5 ppb at the time of best FEV1 to 20.5 ± 14.8 ppb at Time 0. After switching, there was a non-significant decline in eNO, from 20.5 ± 14.8 ppb to 14.9 ± 5.4 ppb. There was no significant difference in eNO levels between the patients in BOS Stage 0-p and patients in higher BOS stages at either timepoint in the study. Conclusions - This study illustrates that a switch from CyA to FK can stabilize pulmonary function in lung transplant patients with chronic rejection. This stabilization of FEV1 is accompanied by a decrease in eNO, indicating that this treatment shift can reduce inflammation of airways during the course of chronic rejection. Consequently, measuring eNO may be extremely valuable in guiding the treatment of chronic rejection after lung transplantation. Corresponding author. Reprint requests: Geert M. Verleden, MD, Department of Respiratory Diseases and Lung Transplantation Unit, University Hospital Gasthuisberg, 49 Herestraat, B-3000 , Leuven, , Belgium. Telephone: +32-16-34-68-00. Fax: +32-16-34-68-03.
Hidden Markov models for the onset and progression of bronchiolitis obliterans syndrome in lung transplant recipients. (Statistics in Medicine, 2002, 21: 113-128) Chronic rejection in lung transplant recipients is monitored by repeated measurement of forced expiratory volume in one second (FEV1). This marker is measured at irregular intervals and is also affected by covariates and short- term fluctuations. Staged Markov models are frequently used to describe the progression of chronic diseases. Definition of BOS in terms of forced expiratory volume in one second. The models presented in this paper are useful for assessing the natural history of the disease among a population. However, they are less suitable for predicting lung function on an individual basis using observed FEV1, history and thus assisting clinical intervention. That is, we are able to predict the proportion of cases who may progress to BOS in any year with acceptable accuracy, but we do not claim that these methods can be used to predict which individuals progress. For individual-level prediction it is most useful to focus on the FEV1 marker itself as the primary indicator of disease status.
Infectious etiology of bronchiolitis obliterans after lung transplantation (Current Opinion in Organ Transplantation 2003; 8(3):239-242) -- Regis A. Vilchez, MD, James Dauber, MD; Shimon Kusne, MD - Survival and allograft function in lung transplant recipients are limited by the development of bronchiolitis obliterans. The precise pathogenesis of bronchiolitis obliterans remains unknown. However, studies indicate that epithelial injury in the lung allograft can be induced by a variety of factors, including infections. Indeed, infection is among the most significant complications in lung transplant recipients, and some infectious agents are recognized to trigger allograft injury. Cytomegalovirus is an immunomodulating herpesvirus that causes an upregulation of human leukocyte antigen class I and intracellular adhesion molecule I in the epithelial cells of the lung allograft, resulting in activation of T helper and cytotoxic T cells. Respiratory viruses activate inflammatory mechanisms in the transplant lung that may lead to acute allograft rejection during and after respiratory viral infections. More importantly, data show the development of bronchiolitis obliterans after infection with these common pathogens. This review examines the published data implicating viruses and other infectious pathogens in the development of bronchiolitis obliterans in lung transplant recipients.
Clinical significance of anti human leukocyte antigen antibodies in lung transplantation (Current Opinion in Organ Transplantation 2003; 8(3):217-221)
The clinical success of human lung transplantation is limited by the development of bronchiolitis obliterans syndrome, a pulmonary specific manifestation of chronic allograft rejection. Although the etiology of bronchiolitis obliterans syndrome is not well understood, there is increasing evidence for a role of antibody to human leukocyte antigens in the development of this condition. This review critically evaluates recent publications that have investigated the clinical significance of anti human leukocyte antigen antibody in lung transplant recipients. Recent findings: A striking association has been observed between the development of antibody to donor human leukocyte antigen and bronchiolitis obliterans syndrome in some lung transplant patients. Indirect presentation of donor human leukocyte antigen may be critical to the development of anti human leukocyte antigen antibody. In human airway epithelia cultured in vitro, anti human leukocyte antigen antibody-ligand interactions induce fibroproliferative and apoptotic responses, implying a mechanistic role for antibody in the development of bronchiolitis obliterans syndrome. Summary: The response to allogenic solid organ transplant appears complex, involving both cellular and humoral components. Emerging evidence supports a pathogenic role for antibody to donor human leukocyte antigen in the development of chronic lung transplant rejection. Additional research is needed to better understand mechanisms of antibody production, further describe cellular effects of antibody-ligand interactions, and, importantly, explain why anti human leukocyte antigen antibody is detectable in only a subset of patients with bronchiolitis obliterans syndrome.
Microvascular changes in small airways predispose to obliterative bronchiolitis after lung transplantation (ADDED 9/20/04) -There is strong evidence that obliterative bronchiolitis (OB) in lung transplant recipients is related to acute rejection as graded by parenchymal perivascular infiltrates. OB (chronic rejection) is a small airways, rather than a parenchymal, scarring process. Conclusions OB after lung transplantation is associated with a decrease in microvascular supply to the small airway. This ischemic event may lead to airway damage or increase the tendency to repair by scarring. The small airways then appear to respond to this insult by angiogenesis, which may either occur too late to prevent permanent airway damage or be inadequate in restoring adequate blood supply to the airway. (Source: The Journal of Heart and Lung Transplantation May 2004)
Role of autoimmunity in organ allograft rejection: a focus on immunity to type V collagen in the pathogenesis of lung transplant rejection (ADDED 9/20/04) Alloimmunity to donor antigens is established as the primary mechanism that mediates rejection responses. However, newer immunosuppressive regimens designed to abrogate alloimmune activation have not improved survival. This data indicates that transplant rejection involves both alloimmune and autoimmune responses. (Source: Am J Physiol Lung Cell Mol Physiol 2004)
Prediction of lung-transplant rejection by hepatocyte growth factor Hepatocyte growth factor (HGF) (ADDED 9/20/04) We investigated whether HGF could be an accurate marker for prediction of lung-graft rejection. Patients with rejection had significantly higher concentrations than all other groups (3972 ng/L [1463], p<0·0001). Logistic regression identified HGF as a predictor for lung graft rejection (p=0·012). After steroid treatment, HGF concentrations returned almost to the preoperative values within 3 days. Interpretation HGF might be a marker for graft rejection in lung transplantation. A potential link between viral infection, mainly cytomegalovirus, and HGF, however, remains to be investigated
Long-term azithromycin use for treatment of bronchiolitis obliterans syndrome in lung transplant recipients
Short-term improvement in lung function was observed in 5 of 6 lung transplant recipients with bronchiolitis obliterans syndrome (BOS) who were treated with oral azithromycin. We assessed the long-term effect (mean duration 10 months) of treatment with oral azthromycin in 11 lung transplant recipients with BOS. Mean forced expiratory volume in 1 second (FEV1) was 40 ± 9% at initiation of azithromycin treatment, 39 ± 10% after 1 month, 39 ± 12% after 4 months, 38 ± 10% after 7 months and 38 ± 10% after 10 months, respectively (statistically non-significant for all data). We conclude that long-term administration with oral azithromycin does not reverse BOS in lung transplant recipients, but may slowprogression of the disease. (Source: The Journal of Heart and Lung Transplantation)
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