Biomedical subjects

Murali M Chakinala

Publications and source records attributed to Murali M Chakinala.

15 recordsLinked to original sources

PubMed2006

Impact of immediate primary lung allograft dysfunction on bronchiolitis obliterans syndrome.

RATIONALE: Primary graft dysfunction is a common complication after lung transplantation and a significant risk factor for short- and long-term mortality. OBJECTIVE: We examined the impact of primary graft dysfunction on bronchiolitis obliterans syndrome. METHODS: We performed a retrospective cohort study of 334 adult lung transplant recipients at our program and graded the severity of primary graft dysfunction according to the International Society for Heart and Lung Transplantation definition. We evaluated the impact of primary graft dysfunction on acute rejection, lymphocytic bronchitis, and bronchiolitis obliterans syndrome stage 1, using univariable and multivariable Cox proportional hazards models. MAIN RESULTS: Among the 334 recipients, 65 did not have primary graft dysfunction (grade 0), 130 had grade 1, 69 had grade 2, and 70 had grade 3. In the univariable analysis, all grades of primary graft dysfunction were associated with a significantly increased risk of bronchiolitis obliterans syndrome stage 1 (grade 1: relative risk [RR] = 1.73; grade 2: RR = 2.13; and grade 3: RR = 2.53, compared with grade 0). The multivariable model demonstrated that the increased risk of bronchiolitis obliterans syndrome associated with primary graft dysfunction was independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections. However, there was no association between primary graft dysfunction and acute rejection or lymphocytic bronchitis. CONCLUSIONS: Primary graft dysfunction is associated with an increased risk of bronchiolitis obliterans syndrome independent of acute rejection, lymphocytic bronchitis, and community-acquired respiratory viral infections, and this risk is directly related to the severity of primary graft dysfunction.

Adult↗

PubMed2006

IL-12 p80 is an innate epithelial cell effector that mediates chronic allograft dysfunction.

RATIONALE: Bronchiolitis obliterans syndrome is the leading cause of chronic lung allograft dysfunction. We have demonstrated that respiratory viral infection is a bronchiolitis obliterans syndrome risk factor and virus-dependent injury induces expression of innate airway epithelial genes belonging to the interleukin (IL)-12 family. Thus, we hypothesized that epithelial cell IL-12 family members could mediate lung allograft dysfunction. OBJECTIVES: We used mouse and human allograft specimens to evaluate the role of epithelial cell IL-12 family members in allograft dysfunction associated with and without viral infection. METHODS: Murine and human IL-12 family members were characterized and manipulated in allografts and then correlated with epithelial cell injury, immune cell accumulation, and collagen deposition. RESULTS: In a mouse model of lung transplantation, concurrent viral infection and allogeneic transplantation increased epithelial injury and this was followed by exaggerated accumulation of macrophages and collagen deposition. This virus-driven allograft dysfunction was associated with an epithelial innate response manifested by a synergistic increase in the production of the macrophage chemoattractant IL-12 p80 (p80), but not IL-12 or IL-23. Blockade or overexpression of donor epithelial p80 resulted in a corresponding abrogation or enhancement of macrophage accumulation and allograft dysfunction. We extended these findings to human recipients with viral infection and transplant bronchitis and again observed excessive epithelial p80 expression that correlated with increased macrophage accumulation. CONCLUSIONS: These experiments support a role for an enhanced epithelial innate response as a central process in allograft dysfunction and identify the macrophage chemoattractant p80 as an innate epithelial effector of disease progression.

Animals↗

PubMed2006

Thrombotic microangiopathy after lung transplantation.

BACKGROUND: Thrombotic microangiopathy (TMA) is a well-recognized complication after transplantation. The purpose of this study was to describe our center's experience with this complication after lung transplantation. METHODS: We retrospectively reviewed cases of TMA among patients who underwent lung transplantation between January 1, 1999 and December 31, 2003 (n = 257). The cases were characterized and the outcomes were analyzed. Univariate and multivariate Cox regression models were constructed to identify potential risk factors for TMA. RESULTS: Twenty-four cases of TMA developed in 20 recipients. Thirteen cases occurred in the setting of another illness and 11 cases were isolated complications. Multivariate Cox regression models identified female gender, history of TMA, and the immunosuppressive regimen as independent predictors of TMA. Maintenance immunosuppression with the combination of a calcineurin inhibitor and sirolimus carried a significantly higher risk of TMA than a calcineurin inhibitor alone. After the diagnosis of TMA, calcineurin inhibitors were stopped in 18 cases; however, in 6 cases in which the onset of TMA coincided with the addition of sirolimus to a calcineurin inhibitor, only sirolimus was discontinued. Plasmapheresis was performed for severe cases (n = 10). TMA remitted in all cases, and an alternate calcineurin inhibitor was introduced in 14 cases. TMA recurred in 4 recipients, a median 253 days after the initial episode. The median survival after the onset of TMA was 377 days. CONCLUSION: TMA is a serious complication after lung transplantation, and the risk is highest when sirolimus is used in combination with a calcineurin inhibitor.

Female↗

PubMed2005

The significance of a single episode of minimal acute rejection after lung transplantation.

BACKGROUND: Bronchiolitis obliterans syndrome (BOS) remains the leading obstacle to better long-term outcomes after lung transplantation. Acute rejection has been identified as the primary risk factor for BOS, but the impact of minimal acute rejection, especially a solitary episode, has usually been discounted as clinically insignificant. METHODS: We performed a retrospective cohort study of 259 adult lung transplant recipients to determine the risk of BOS associated with a single episode of A1 rejection, without recurrence or subsequent progression to a higher grade. The cohort was divided into 3 groups based on the severity of acute rejection (none, single episode of A1, and single episode of A2). We determined the risks of BOS stages 1, 2, 3, and death for each group using univariate and multivariate Cox regression analyses. RESULTS: A solitary episode of A1 rejection was a significant risk factor for BOS stages 1 and 2, but not stage 3 or death, in the univariate analysis. Multivariate Cox regression models confirmed that the risk of BOS attributable to a single episode of A1 rejection was independent of other potential risk factors, such as community acquired respiratory viral infections, number of HLA mismatches, and cytomegalovirus pneumonitis. Likewise, univariate and multivariate analyses demonstrated that a single episode of A2 rejection was a significant risk factor for all stages of BOS but not death. CONCLUSIONS: A single episode of minimal acute rejection without recurrence or subsequent progression to a higher grade is a significant predictor of BOS independent of other risk factors.

Adult↗

PubMed2005

Pneumonia in the solid organ transplant patient.

As the field of solid organ transplantation has grown, so has the importance of infectious complications in this select group of patients. Chronic immunosuppression compromises the natural host defenses that typically prevent lower respiratory tract infections and makes the solid organ transplant recipient especially susceptible to pneumonia. Evaluation of pneumonia in this population differs owing to the potential for opportunistic infections. Lung transplant recipients are particularly susceptible to pneumonia and pose unique diagnostic dilemmas. An understanding of the time line for the different key pathogens after transplantation aids the initial evaluation and management.

Humans↗

PubMed2005

Reliability for grading acute rejection and airway inflammation after lung transplantation.

BACKGROUND: The Lung Rejection Study Group (LRSG) created a scheme for grading acute allograft rejection in 1990 and then revised it in 1996, but virtually no studies have evaluated the reliability of this formulation. This investigation assessed the reliability of the current LRSG system by determining inter- and intrareader agreement for grading transbronchial biopsy samples from lung transplant recipients. METHODS: Biopsy samples from a cohort of 204 recipients were reviewed and classified by a single pathologist who was blinded to original interpretations. The "A" and "B" rejection grades from this contemporary review were compared with original grades by the kappa statistic. RESULTS: For "A" grading, weighted kappa was 0.65 (95% confidence interval [CI] 0.60-0.70) for interreader agreement (n = 529 specimens) and 0.65 (95% CI 0.53-0.76) for intrareader agreement (n = 97 specimens). For "B" grading, weighted kappa was 0.26 (95% CI 0.14-0.39) for interreader agreement (n = 164 specimens) and 0.33 (95% CI 0.15-0.51) for intrareader agreement (n = 58 specimens). CONCLUSIONS: On the basis of the analysis of the LRSG scheme, "A" grades exhibit very good reliability, but "B" grades have only fair reliability, and steps to improve this shortcoming should be taken.

Acute Disease↗

PubMed2005

A comparison of basiliximab and anti-thymocyte globulin as induction agents after lung transplantation.

BACKGROUND: Interleukin-2 receptor antagonists have supplanted polyclonal antibody preparations as the most frequently used induction agents after lung transplantation, but the relative efficacy of these agents has not been firmly established. METHODS: We retrospectively analyzed the efficacy of basiliximab compared with antithymocyte globulin among 157 adult lung transplant recipients at our center. RESULTS: At 3, 6, and 12 months after transplantation, the median cumulative acute rejection A scores for the basiliximab group (2, 2, and 3, respectively) were significantly higher than those for the anti-thymocyte globulin group (1, 1, and 2, respectively; p = 0.003, 0.004, and 0.033, respectively). In addition, basiliximab recipients were more likely to develop acute rejection grade > or = A2 than anti-thymocyte globulin recipients; in fact, 60% of basiliximab recipients compared with 38% of anti-thymocyte globulin recipients developed their first episode of acute rejection grade > or = A2 in the first 100 days after transplantation (log-rank p = 0.04). Furthermore, basiliximab recipients were more likely to develop bronchiolitis obliterans syndrome than anti-thymocyte globulin recipients (log-rank p = 0.036). Two years after transplantation, 36% of basiliximab recipients and 26% of anti-thymocyte globulin recipients developed bronchiolitis obliterans syndrome. However, there were no significant differences in the incidences of cytomegalovirus viremia and pneumonitis between the 2 groups (p = 0.86 and 0.89, respectively). CONCLUSIONS: Induction with anti-thymocyte globulin is associated with a lower burden of acute rejection and bronchiolitis obliterans syndrome compared with basiliximab, without a significant difference in the incidence of cytomegalovirus infections.

Adult↗

PubMed2005

Changing the prognosis of pulmonary arterial hypertension: impact of medical therapy.

Pulmonary arterial hypertension (PAH) is a progressive arteriopathy of the pulmonary circulation that can affect a wide group of patients. Presentation and natural history of PAH are intimately linked to progressive right ventricular failure. Historically, survival in PAH has been poor, especially for patients with PAH associated with progressive systemic sclerosis and human immunodeficiency virus. Oral, subcutaneous, and intravenous therapies that have emerged during the last decade can improve symptoms and hemodynamics. This review explores the impact of these therapies on prognosis in PAH, which ultimately rests on the ability to reverse the pulmonary arteriopathy and preserve right ventricular function.

Anticoagulants↗

PubMed2005

Minimal acute rejection after lung transplantation: a risk for bronchiolitis obliterans syndrome.

Bronchiolitis obliterans syndrome (BOS) is a major cause of lung allograft dysfunction. Although previous studies have identified mild to severe rejection (grade>or=A2) as a risk factor for BOS, the role of minimal rejection (grade A1) remains unclear. To determine if A1 rejection by itself is a risk factor for BOS, we performed a retrospective cohort study on 228 adult lung transplant recipients over a 7-year period. Cohorts were defined by their most severe rejection episode (none, A1 only, and >or=A2) and analyzed for the subsequent development and progression of BOS using univariate and multivariate time-dependent Cox regression analysis. In the univariate model, the occurrence of isolated minimal rejection was a risk factor for all stages of BOS. Similarly, multivariate models that included HLA mismatch, cytomegalovirus pneumonitis, community acquired viral infection, underlying disease and type of transplant demonstrated that A1 rejection was a distinct risk factor for BOS. Furthermore, the associated risk with A1 rejection was slightly greater than the risk from >or=A2 and treatment of A1 rejection decreased the risk for subsequent BOS stage 1. We conclude that minimal rejection is associated with an increased risk for BOS development and progression that is comparable to A2 rejection.

Adolescent↗

PubMed2004

Respiratory viral infections are a distinct risk for bronchiolitis obliterans syndrome and death.

Bronchiolitis obliterans syndrome (BOS) is the major obstacle to long-term survival after lung transplantation, in part because its pathogenesis is poorly understood and treatment options are limited. To identify unique risk factors for BOS and death, we performed a retrospective cohort study on 259 consecutive adult lung transplant recipients over a 5-year period. The demographic and clinical characteristics of this population were analyzed for an association between BOS or death and potential risk factors, including community-acquired respiratory viral (CARV) infections, acute rejection, and cytomegalovirus pneumonitis. Respiratory syncytial virus, parainfluenza, influenza, and adenovirus accounted for 21 CARV infections. Univariate and multivariate time-dependent Cox regression analyses demonstrated that this CARV group was more likely to develop BOS, death, and death from BOS. Furthermore, these trends were more pronounced in patients with evidence of lower respiratory tract-CARV (lower-CARV) infections. Notably, the CARV and lower-CARV infections were risk factors for BOS, death, and death from BOS distinct from the risk attributable to acute rejection. Identification of CARV and lower-CARV infections as BOS and mortality risk factors has important clinical implications and may provide insight into disease pathogenesis and accelerate the development of novel treatment strategies to modify post-CARV BOS.

Bronchiolitis Obliterans↗

PubMed2004

Abdominal-pelvic lymphoproliferative disease after lung transplantation: presentation and outcome.

BACKGROUND: Lymphoproliferative disease (LPD) is a well-recognized complication after lung transplantation. However, its presentation in the abdomen and pelvis has not been previously detailed. METHODS: We retrospectively identified cases of abdominal-pelvic LPD in lung transplant recipients. The cases were characterized clinically, and the outcomes were analyzed. RESULTS: Abdominal-pelvic LPD was identified in 19 of 603 adult patients who underwent lung or heart-lung transplantation at Barnes-Jewish Hospital between July 1, 1988 and December 31, 2001. The median time from transplantation to the onset of LPD was 5.8 years. Three cases presented early after transplantation (median, 175 days), and 16 cases presented late (median, 2,255 days). The time to diagnosis of LPD was significantly shorter for Epstein-Barr virus (EBV)-seronegative than for EBV-seropositive recipients (median, 175 vs. 2255 days; log-rank, P<0.001). Seventeen cases were non-Hodgkin's lymphomas, one was a Burkitt's lymphoma, and one was an atypical lymphoid proliferation. Among the 19 cases, 12 involved the gastrointestinal tract and 7 occurred in other sites. Immunosuppressive therapy was decreased in all patients. Eleven underwent surgical resection, and nine received chemotherapy. Sixteen patients have died, and 14 deaths were attributable to LPD. The median time from the diagnosis of LPD to death was 68 days. CONCLUSIONS: Abdominal-pelvic LPD is typically a late complication after lung transplantation; however, when it occurs early, it may be related to a primary EBV infection. This form of LPD is most frequently a non-Hodgkin's lymphoma, and despite aggressive therapy, the prognosis is poor.

Abdomen↗

PubMed2004

Yield of surveillance bronchoscopy for acute rejection and lymphocytic bronchitis/bronchiolitis after lung transplantation.

BACKGROUND: Better understanding of the timing and pattern of surveillance bronchoscopy findings after lung transplantation could influence the timing and frequency of surveillance bronchoscopy. We present our surveillance bronchoscopy experience and test the hypothesis that patients not encountering early acute rejection or lymphocytic bronchitis/bronchiolitis are less likely to have subsequent occult occurrences in the 1st year after lung transplantation. METHODS: We conducted a retrospective study of 204 patients who underword transplantation between 1996 and 2000. Based on contemporary biopsy-specimen grading in the first 100 days, we formed 2 groups: No Early Rejection and Early Rejection. We compared subsequent yields of surveillance bronchoscopy and the incidence of acute rejection or of lymphocytic bronchitis/bronchiolitis. RESULTS: We reviewed 645 biopsies taken from 204 recipients during the first 100 days to classify patients into a No Early Rejection Group (n=67) or an Early Rejection Group (n=137). Yield of surveillance bronchoscopy for acute rejection or lymphocytic bronchitis/bronchiolitis was 31% with the greatest yield during the first 30 days (45%), and then decreasing to 26% (p <0.001). After Day 100, 71% of occult acute rejection episodes involved minimal (A1) lesions. Yield of surveillance bronchoscopy after Day 100 was 20% in the No Early Rejection Group and was 27% in the Early Rejection Group (p=0.22). Incidence of acute rejection or lymphocytic bronchitis/bronchiolitis after Day 100 was 41% in the No Early Rejection Group and was 50% in the Early Rejection Group (p=0.17). CONCLUSION: Surveillance bronchoscopy detects occult acute rejection or lymphocytic bronchitis/bronchiolitis in approximately one-third of biopsy specimens during the 1st year, with the majority of late abnormalities being minimal (A1) rejection. The absence of acute rejection or lymphocytic bronchitis/bronchiolitis during the first 100 days does not predict freedom from such events in the remainder of the 1st year.

Acute Disease↗

PubMed2004

Community acquired respiratory viral infections after lung transplantation: clinical features and long-term consequences.

Community acquired respiratory viruses (CARVs) are increasingly recognized as serious threats to lung transplant recipients. While CARVs such as respiratory syncytial virus, parainfluenza, influenza, and adenovirus usually cause self-limited illnesses in immunocompetent subjects, infections in the transplant recipient can be dramatic. As transplant recipients live longer and diagnostic methods improve, the burden of CARVs will undoubtedly increase. Because of limited therapeutic options, some patients may succumb to CARV infections, while many survivors develop chronic allograft dysfunction. Recognition of this latter phenomenon has implicated CARVs in the pathogenesis of bronchiolitis obliterans.

Bronchiolitis Obliterans↗

PubMed2003

The predictive value of bronchiolitis obliterans syndrome stage 0-p.

Bronchiolitis obliterans syndrome (BOS) remains the main cause of graft loss after lung transplantation. Stage 0-p was recently added to the staging criteria to detect early deterioration in allograft function that might presage BOS stage 1. We assessed the predictive value of stage 0-p by retrospectively analyzing spirometric data for 203 adult bilateral lung transplant recipients. The FEV(1) criterion for stage 0-p had a positive predictive value of 79% and a negative predictive value of 82%. In contrast, the FEF(25-75%) criterion for stage 0-p had a positive predictive value of 52% and a negative predictive value of 72%. Fifty-seven percent of subjects who developed stage 0-p by the FEV(1) criterion progressed to stage 1 within 1 year, whereas only 37% of those who developed stage 0-p by the FEF(25-75%) criterion progressed to stage 1 within 1 year. We conclude that the FEV(1) criterion for stage 0-p is a reasonable predictor of BOS stage 1 after bilateral lung transplantation, but the FEF(25-75%) criterion for stage 0-p is not predictive of BOS stage 1 after bilateral lung transplantation.

Bronchiolitis Obliterans↗

PubMed2003

Acute allograft rejection after lung transplantation: diagnosis and therapy.

Acute rejection remains a significant problem after lung transplantation. While it generally is a treatable condition, significant resources and therapies are directed toward its prevention and resolution. Its larger significance undoubtedly rests in its contribution to the pathogenesis of BOS. Significant questions regarding the origins of AR, the role of LBB, alternative histologic appearances of acute allograft injury, and optimal therapy remain. Controversy regarding the utility of surveillance bronchoscopy and preemptive treatment of occult AR persists because of lack of conclusive evidence. Future investigations might resolve these matters and provide more efficacious and less toxic therapies that will hopefully reduce the impact of chronic rejection and improve long-term outcomes.

Acute Disease↗