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Purpose of Review: The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH)., Recent Findings: Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease., Summary: The utility of PAH-specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases.

Background: Acute lung rejection is a risk factor for chronic rejection, which jeopardizes long-term recipient survival. Presently, acute rejection is diagnosed with the use of transbronchial lung biopsies, which are invasive, expensive, and subject to sampling error. We seek to improve acute rejection diagnostics by identifying genes whose expression in bronchoalveolar lavage (BAL) cells best classifies acute rejection versus no rejection., Methods: BAL samples were analyzed from 32 subjects whose concurrent histology showed acute rejection (n=14) or no rejection (n=18). Gene expression was measured with Affymetrix microarrays. Quantitative real-time polymerase chain reaction confirmed the microarray results for selected genes. The nearest shrunken centroid method with 10-fold cross validation defined the classification model. A total of 250 iterations of the algorithm were performed to determine the misclassification error rate and the most influential genes in determining classifiers., Results: The estimated overall misclassification rate was <20%. Seven transcripts were present in every classifier, and 52 transcripts were present in >70% of classifiers; these transcripts are related to T-cell function, cytotoxic CD8 activity, and granulocyte degranulation. Eleven of the 52 genes were analyzed with quantitative real-time polymerase chain reaction; all were found to significantly different between the groups, with 10 of 11 increased in acute rejection samples. The proportions of lymphocytes and neutrophils in BAL samples increased in acute rejection but did not outperform the gene-based classifier., Conclusions: There is a prominent acute rejection-associated signature in BAL cells characterized by increased T-cell, CD8 cytotoxic cell, and neutrophil gene expression. These findings lay the foundation for development of rapid PCR-based assays of gene expression for clinical acute rejection diagnosis.

Goal: The goal of this study was to assess the efficacy of sirolimus in lung-transplant recipients., Methods: The study was designed as a single center, consecutive case study of lung-transplant recipients treated with sirolimus, tacrolimus, and prednisone. All study subjects also received an HMG-CoA reductase inhibitor, and prophylaxis for cytomegalovirus and Pneumocystis carinii., Results: A total of 15 subjects were enrolled in the study. Within 6 months, significant airway complications occurred in four subjects, three of whom died. At that point, the investigators terminated enrollment in the study. The study population was compared retrospectively with a group of 83 consecutive lung recipients treated with cyclosporine (n=64) or tacrolimus (n=19), mycophenolate mofetil, and prednisone. This confirmed an increased incidence of airway dehiscence and reduced survival in the sirolimus-treated patients. Sirolimus-treated patients had a low incidence of acute rejection. No significant differences were noted in the incidence of bacterial or fungal bronchopulmonary infections., Conclusions: We observed an unexpectedly high incidence of postoperative airway dehiscence in lung-transplant recipients treated with sirolimus, in combination with tacrolimus, prednisone, and an HMG-CoA inhibitor. Further studies will be needed to determine the safety and efficacy of using sirolimus after complete airway healing has occurred.

Background: Chronic allograft rejection manifested as bronchiolitis obliterans syndrome (BOS) is the leading cause of late death after lung transplantation. Although increasing evidence suggests an association between anti-human leukocyte antigens (HLA) antibodies and chronic rejection of kidney or heart allografts, the clinical significance of anti-HLA antibodies in lung recipients is less clear, especially in previously unsensitized recipients. The use of flow cytometry based panel reactive antibody (flow-PRA) provides a highly sensitive means to identify the development of de novo anti-HLA antibodies in lung recipients., Methods: Flow-PRA testing was used to analyze the pre- and posttransplant sera in stable BOS free lung recipients who survived at least 6 months. Patients without prior sensitization as defined by a negative pretransplant flow-PRA were analyzed posttransplant for the presence of anti-HLA antibodies by flow-PRA. A proportional hazards model was used to determine the impact of anti-HLA antibody on BOS risk., Results: Sera from 90 recipients at Duke University with negative pretransplant flow-PRA were tested by flow-PRA at various time points after transplant. Sera from 11% (10/90) of recipients were found to contain anti-HLA antibodies detectable by flow-PRA. Nine patients (90%) developed anti-HLA antibodies specific for donor antigens, and one patient developed anti-HLA class II antibodies, not specific to donor antigens. Among the nine patients with donor antigen specific antibodies, flow-PRA specificity analysis demonstrated eight were specific for class II antigens and one for class I antigens. In a multivariate model that controls for other BOS risk factors, a positive posttransplant flow-PRA was significantly associated with BOS grades 1,2, or 3 (hazard ratios [HR] 3.19; 95% confidence interval [CI]: 1.41-7.12, P=0.005) and BOS grade 2 or 3 (HR 4.08; 95% CI: 1.66-10.04, P=0.002). Four patients with de novo anti-HLA antibodies died during follow-up; all four had BOS. Among BOS patients, the presence of anti-HLA antibodies was associated with a significantly worse survival (P =0.05, log-rank test)., Conclusions: Although uncommon, previously unsensitized lung transplant recipients can develop anti-HLA antibodies to donor class II antigens. The development of de novo anti-HLA antibodies significantly increases the risk for BOS, independent of other posttransplant events. Furthermore, de novo anti-HLA antibodies identify BOS patients with significantly worse survival. Additional studies are needed to determine if class II-directed anti-HLA antibodies contribute mechanistically to the chronic rejection process in lung recipients.

Background: Up to 50% of human lung allografts develop chronic rejection manifested as obliterative bronchiolitis (OB). This complication frequently progresses despite maximal immunosuppression, suggesting that, once initiated, factors other than alloimmunity play a role in its progression. In animals, heterotopically transplanted allograft airways develop obliterative airway disease (OAD), an immunologically mediated lesion that is used as a preclinical model of OB. We sought to determine whether OAD would progress even after removal from the alloimmune environment., Methods: Tracheas from Lewis rats were transplanted subcutaneously into Brown Norway recipients to create allografts. After 7 or 14 days of alloimmune stimulus, these allografts were removed and retransplanted into an isogeneic environment for an additional 21 days. Histology was assessed at each time point, with quantitation of the airway epithelium and intraluminal fibroproliferation., Results: Allografts exposed to 14 days of alloimmune stimulus had a significant loss of airway epithelium compared with grafts exposed to only 7 days ( <0.001). There was little fibroproliferation seen in either of these groups. After retransplantation, the grafts initially exposed to 7 days of alloimmune stimulus had few abnormalities. In contrast, the group exposed initially to 14 days of alloimmunity and retransplanted had near complete obliteration of the lumen with fibroproliferation (96.9% occlusion, =0.001) and absent airway epithelium., Conclusions: OAD progresses despite removal of alloimmunity if the initial period of alloimmune injury is sufficient. Airway epithelial loss correlated with progression to fibroproliferation, suggesting that the epithelium plays a significant role in the pathogenesis of OB.

Background: One third of human lung allografts develop chronic rejection manifested as obliterative bronchiolitis. Heterotopically transplanted allogeneic murine tracheas develop obliterative airway disease (OAD) leading to a lesion resembling human obliterative bronchiolitis. The purpose of this study was to determine the T-cell and major histocompatibility complex (MHC) molecule requirements of murine OAD., Methods: BALB/c allografts and C57BL/6 (B6) isografts were transplanted into B6 severe combined immunodeficient (SCID) and B6 wild-type (WT) recipients. MHC class I-discrepant bm1 grafts, class II-discrepant bm12 grafts, and F1(bm1 x bm12) (F1) grafts also were transplanted into B6 WT recipients. Grafts were harvested between days 5 and 56 following transplantation and evaluated histologically., Results: Complete MHC-disparate allografts placed in WT recipients had significantly more disease than similar allografts in SCID recipients, and the latter were indistinguishable from isografts in either WT or SCID recipients, indicating a lymphocyte dependence on the disease development. Pathology was significantly more severe in bm1 and F1 allografts than in isografts recovered from B6 recipients, but bm12 allografts appeared no different than isografts. T-cell infiltrates in these bm12 allografts contained only CD4+ cells, whereas infiltrates in the BALB/c, bm1, and F1 allografts manifesting OAD contained both CD4+ and CD8+ cells. No grafts had significant B-cell infiltration., Conclusions: These findings suggest that OAD relies on a host T-cell response that includes CD8+ cells, directed against allo-class I-bearing donor cells within the graft.

Background: Organ donors and transplant recipients are routinely tested for ABO compatibility. ABO-identical organs are preferred, but occasionally the use of an ABO-compatible but nonidentical donor is clinically warranted. In heart-lung transplantation, the incidence of hemolysis from donor-derived anti-ABO antibodies is as high as 70%. The incidence of hemolysis for lung-only transplantation is not known. Our current posttransplantation transfusion policy for ABO-compatible but nonidentical lung-only transplant recipients is, when indicated, to use donor ABO group red blood cells., Methods: To evaluate the efficacy of our transfusion policy, we reviewed our experience from 1986-96. One heart-lung transplant, four single lung transplant, and three bilateral single lung transplant recipients received ABO-compatible but nonidentical organs., Results: The heart-lung transplant recipient developed a positive direct antiglobulin test (DAT), with anti-A eluted, and severe hemolysis on postoperative day 8 requiring plasma and whole blood exchange. Four of six lung-only transplant patients tested developed a positive DAT with anti-A eluted. Two early lung-only patients, who did not receive donor ABO group red blood cells, demonstrated clinical and laboratory evidence of hemolysis. Three bilateral lung transplant recipients were followed prospectively. The first patient had a negative DAT. The next two patients developed positive DATs on postoperative day 8 and 10, respectively. No evidence of hemolysis was detected in any of these cases., Conclusions: These results confirm that donor-derived anti-ABO antibodies develop with lung-only transplants. Our current transfusion policy is justified for both heart-lung and lung recipients of ABO-compatible but nonidentical organs. A high index of suspicion for donor-derived antibody causing hemolysis and communication with blood bank personnel are mandatory in this setting.

Obliterative bronchiolitis (OB), an important threat to the long-term survival of lung transplant recipients, is characterized histologically by fibroproliferation within small airways. The pathogenesis of OB is thought to involve chronic allograft rejection, and therapy frequently includes augmentation of immunosuppression. We have developed a model that reproduces the pathologic lesion of OB and allows study of interventions designed to limit airway fibrosis. In this model, heterotopic transplantation of murine airways into immune-mismatched recipients results in epithelial abnormalities and fibroproliferation in the airway lumen, changes not seen in heterotopic isografts. Cyclosporine (CsA) inhibits activation and proliferation of T lymphocytes and is commonly administered after lung transplantation. We hypothesized that use of CsA in our model system would reduce fibroproliferation in tracheal allografts. To test this hypothesis, murine tracheas were transplanted heterotopically into allo matched and allomismatched recipients, and then treated with varying doses (5, 10, 15, or 25 mg/kg i.p. q.d.) of CsA. Controls included allografts and isografts not treated with CsA. After 30 days, tracheas were harvested and examined histologically. CsA markedly reduced the development of fibroproliferation in allografts (19% in treated allografts versus 90% in untreated allografts, P<0.0001), but did not reduce inflammation or airway epithelial cell injury. High-dose (25 mg/kg/day) CsA was more effective than lower doses in reducing fibroproliferation (0% in high dose versus 29% in low dose, P=0.04). These findings demonstrate that CsA significantly reduces development of the pathologic lesion of OB, and supports the role of alloimmunity in the pathogenesis of this disease.

We have shown in lung recipients that high levels of peripheral blood allogeneic microchimerism at 12 to 18 months posttransplant correlated with donor antigen-specific hyporeactivity (i.e., decreased proliferative response to donor antigen in MLC while response to 3rd-party cells remains unchanged); both parameters correlated with an obliterative bronchiolitis (OB)-free state. We have expanded these studies to determine any association of sequential microchimerism levels with concomitant clinical events. In this preliminary study of 7 lung recipients, we used limiting-dilution PCR to quantify peripheral blood microchimerism at serial timepoints ranging from 3 to >48 months posttransplant. These levels were compared with a variety of immunologic and clinical parameters: acute rejection, CMV infection, OB, donor antigen-specific hyporeactivity, and pulmonary function. Pulmonary function was measured per the International Society of Heart and Lung Transplantation: "current FEV1/ baseline FEV1" (FEV1: forced expiratory volume in 1 second). Of the clinical parameters, the association between microchimerism and pulmonary function was the most striking. We observed dynamic patterns of peripheral microchimerism, which reflected the general rise and fall of FEV1. In all 7 recipients, chimerism and FEV1 were high very early posttransplant, then dropped at various rates and to various degrees. After its initial decline, microchimerism increased with FEV1 for the 1 hyporesponsive recipient; for the other 6 recipients, both values declined. These results illustrate, for the first time, that the fluctuation of peripheral blood microchimerism levels is associated with the recipient's clinical condition.

Although their relative importance and interaction are unclear, donor antigen(Ag)*-specific hyporeactivity and allogeneic microchimerism have been associated with improved long-term graft outcome and a lower incidence of chronic rejection in solid organ transplant recipients. We have postulated that a critical level of donor antigen, for a critical time period, is necessary to develop and maintain donor antigen-specific hyporeactivity; both the level and the time may differ by organ transplanted. In our current study, we tested donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism in liver and kidney recipients and compared these values with our previous findings in lung recipients. We tested 25 liver recipients at 12 to 29 months posttransplant: 10 (40%) had developed donor antigen-specific hyporeactivity; 5 (20%), peripheral blood allogeneic microchimerism. For all but 1 of the chimeric and hyporeactive recipients, the level of donor cells was very low (< 1:20,000). Five hyporeactive recipients and all 15 donor antigen-responsive recipients did not have detectable levels of peripheral blood microchimerism. No chronic rejection has developed in any of these recipients to date--however, a lower incidence of acute rejection was observed for those recipients with donor antigen-specific hyporeactivity (30% versus 60% without) or with peripheral blood allogeneic microchimerism (20% versus 55% without) (P = ns). These results differ from our previous findings in 19 lung recipients: at 12 to 18 months posttransplant, 35% of them had developed donor antigen-specific hyporeactivity; 47%, peripheral blood allogeneic microchimerism. All donor antigen-specific hyporeactivity recipients as well as some donor antigen-responsive recipients had peripheral blood allogeneic microchimerism. We expanded our current study to include 26 recipients and a quantitative estimate of the level of allogeneic microchimerism. We observed that the hyporesponsive recipients tended to have higher levels of donor cells in their peripheral blood (> 1:6,000) than did the responsive recipients. We previously reported that 22% of kidney recipients had developed donor antigen-specific hyporeactivity at 12 to 18 months posttransplant. In our current study of 33 kidney recipients, we observed peripheral blood allogeneic microchimerism in 7 (21%) at 12 to 18 months posttransplant. The level of donor cells was very low (approximately 1:75,000), with no correlation between donor antigen-specific hyporeactivity and peripheral blood allogeneic microchimerism at the time point tested. These studies emphasize the organ-specific nature of the development of donor antigen-specific hyporeactivity and the persistence of peripheral blood allogeneic microchimerism. Donor antigen-specific hyporeactivity correlates with very low levels of donor cells in liver recipients, while a higher critical level of donor cells is important in lung recipients. Additional sequential early posttransplant studies are necessary to further define the possible interrelationship between donor antigen and the development and maintenance of donor antigen-specific hyporeactivity.

The primed lymphocyte test (PLT) has been used to detect donor antigen-specific reactivity of bronchoalveolar lavage (BAL) lymphocytes associated with acute lung rejection and obliterative bronchiolitis (OB). To identify more precisely the immunopathogenetic events related to these processes, we have determined the PLT alloreactivity of 162 BAL specimens from 40 recipients as being directed against individual class I or class II antigens. We used selected homozygous typing cells representing the specific HLA class I and II antigens expressed by the recipient and donor cells. Our previous studies demonstrated a predominant CD8+ cell population mediating class I donor antigen-specific reactivity, correlating with OB in 3 out of 3 recipients tested, and a predominant CD4+ cell population mediating class II donor antigen-specific reactivity, correlating with acute rejection episodes in 13 out of 15 recipients tested. The obstructive airway disease OB, which is frequently fatal, is identified histologically by the presence of small airway inflammation and fibrosis of the lamina propria and lumen, and is characterized clinically by rapidly progressive airflow obstruction. However, a subgroup of patients with histologically proven OB demonstrates stabilization or only minimal progression of airflow limitation after augmentation of their immunosuppressive regimen, usually with high-dose methylprednisolone. To further characterize this subgroup, we tested the BAL-derived lymphocytes from 4 of these patients and observed PLT reactivity that correlated with the class II antigens of the donor, in contrast to the predominant donor class I antigen-specific PLT reactivity of patients with progressive OB. The distinct patterns of PLT reactivity observed for the BAL-derived lymphocytes from patients with the progressive versus the less progressive form of OB suggest that more than one immune process or perhaps different cell targets are involved. Alternatively, these clinical and in vitro findings may represent different stages of the same disease process. Taken together, these results suggest that distinct immunopathogenetic events may be occurring during acute lung rejection and OB.

Objective: To assess complications of bronchoalveolar lavage in the intubated, mechanically ventilated patient., Design: A retrospective, consecutive case series., Setting: Medical, surgical, and bone marrow transplant critical care units at a university teaching hospital., Patients: Ninety-nine consecutive critically ill, mechanically ventilated patients undergoing bronchoalveolar lavage were included in the study., Interventions: All patients underwent bronchoalveolar lavage using a standard method designed to maximize the safety of the procedure., Measurements: Each patient's hospital chart was reviewed for immediate and delayed medical complications of the procedure, including cardiac arrhythmias, bleeding, and hemodynamic disturbances. Specific indices of lung mechanics (peak inspiratory airway pressure and static compliance) and oxygenation (alveolar to arterial oxygen tension gradient [P(A-a)O2] and the ratio of FIO2/PaO2) were measured before and 4 hrs after bronchoalveolar lavage to assess durable physiologic consequences of the procedure., Results: No complications occurred that required premature termination of bronchoalveolar lavage. Three patients exhibited adverse effects (hypotension in two and wheezing in one) immediately after the procedure, all of which resolved promptly with treatment. No statistically significant changes were observed in the variables of arterial oxygenation or pulmonary mechanics. Although the sample mean did not change significantly for any of the oxygen variables, 19% of the patients experienced widening of the P(A-a)O2 by greater than 100 torr (greater than 13.3 kPa). A systematic analysis indicated that there was no statistically significant relationship between readily available clinical variables (including duration of mechanical ventilation before bronchoalveolar lavage and prebronchoalveolar lavage P[A-a]O2), and deterioration in oxygenation after the procedure., Conclusions: We conclude that bronchoalveolar lavage is a well-tolerated procedure in critically ill, mechanically ventilated patients, provided that risk factors for complications are corrected before the procedure and one adheres to procedural guidelines focused on patient safety. Clinically important complications are uncommon. Some patients exhibit deterioration in oxygen after bronchoalveolar lavage; this occurrence cannot be predicted before the procedure.

Heart-lung transplantation (HLT) and lung transplantation (LT) are effective treatment modalities for patients with advanced pulmonary parenchymal or vascular disease. Lung transplantation offers potential advantages over HLT, including reduced pretransplant waiting time and improved efficiency of organ utilization, and is currently being offered to patients formerly treated by HLT. To explore the relative merits of these procedures, the authors examined the results in 44 procedures (23 HLT and 21 LT) in 42 patients transplanted at their institution. Heart-lung transplant recipients included 20 adults and three children (ages 5,5 and 3). Most HLT patients had primary pulmonary hypertension (PPH) (n = 9) or Eisenmenger's syndrome (ES) (n = 8). Twenty-two of twenty-three patients have been long-term survivors (mean follow-up = 17.8 months, Kapaln-Meier survival at 12 months = 85%). Obliterative bronchiolitis (OB) has occurred in five patients (22%), and all have died. Of 21 LTs in 19 patients, nine had obstructive and eight had restrictive lung diseases. Three single-LT (SLT) patients had PPH, and one had ES secondary to a ventricular septal defect. Mean pulmonary artery pressures fell from 55 +/- 6 mm Hg before SLT to 21 +/- 3 mm Hg after SLT; p less than 0.001. Three pediatric patients (ages 4, 10, 17, and 17[re-transplant]) have undergone four SLTs. With mean follow-up of 6.4 months, LT patients have survival at 12 months of 80% (Kaplan-Meier). Lung transplant patients wait a far shorter time for their transplant than do HLT patients (166 vs. 384 days, p less than 0.03). Three patients (19%) have evidence of OB after SLT, with one death. By virtue of equal intermediate-term outcomes, shorter waiting times, and better use of donor organs in comparison with HLT, LT should be offered whenever possible to patients with end-stage pulmonary parenchymal or vascular disease. The authors' pediatric LT and HLT experience (7 treatments in 6 patients) is the largest reported to date and demonstrates the utility of these procedures in this group. Chronic rejection (OB) remains the greatest impediment to long-term survival in both LT and HLT pts.

Acute lung injury induced by respiratory syncytial virus (RSV) is a major cause of morbidity and mortality in patients who have undergone bone marrow transplantation. Twenty-nine of the 74 patients who received bone marrow transplants at the University of Minnesota during a 1-year period developed evidence of acute lung injury, and RSV was identified as the cause in 8. We discuss the clinical course of these 8 patients and offer a clinical approach to RSV infection occurring after bone marrow transplantation. We also review the immune response to infection with RSV and relate this information to the nature and degree of immunosuppression present in patients undergoing this type of transplantation. We found bronchoalveolar lavage with rapid antigen detection to be particularly useful for the prompt diagnosis of this serious infection. The virus was obtained from the lower respiratory tract of each patient and was identified in lavage effluent by culture and by antigen detection (ELISA). The mean time to a positive culture was 6 days, while detection of antigens of respiratory syncytial virus by ELISA was completed within 18 hours in all cases. The clinical progression of the illness in immunocompromised patients appears to be the same as in non-immunocompromised persons: upper respiratory tract infection and illness precede lower respiratory tract infection and acute lung injury. Seven of our 8 patients had upper respiratory tract symptoms or abnormal sinus radiographs, and upper respiratory specimens (cultures and ELISA from nasopharynx, throat, and sputum) were positive in 5 of 8 patients. Six patients developed RSV-induced lung injury before marrow engraftment; 4 of them had respiratory failure requiring mechanical ventilation and died, including 3 in whom RSV was eliminated from the lower respiratory tract following treatment with ribavirin aerosol. Two additional pre-engraftment patients had only relatively mild lung injury 4 days after beginning treatment with ribavirin for RSV infection in the upper respiratory tract. Their recovery suggests that early treatment may ameliorate RSV-induced lung injury. The remaining 2 patients developed lung injury after marrow engraftment. Both of these patients had clear chest radiographs, responded clinically to ribavirin, and survived. RSV is a potentially treatable cause of life-threatening lung injury, if the physician is aggressive in identifying the virus in the upper respiratory tract before evidence of lung injury appears. Rapid detection methods are essential when bone marrow transplant patients have fever along with signs, symptoms, or radiographic indications of nasal or sinus disorders.(ABSTRACT TRUNCATED AT 400 WORDS)