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Biomedical subjects

I L Paradis

Publications and source records attributed to I L Paradis.

At least 37 records · Page 2Linked to original sources
PubMed1993

Infection after lung transplantation.

Infections have been and still are the major cause of morbidity and mortality after lung transplantation. Nevertheless, the negative impact of infection on outcome has lessened considerably over the last decade because of lessons learned in the prevention, identification, and treatment of infection. Antibiotics tailored to the results of cultures and stains of respiratory-tract secretions obtained from both the donor and recipient have markedly decreased the prevalence of bacterial pneumonia early after lung transplantation. Ganciclovir treatment has reduced the mortality of cytomegalovirus (CMV) disease from 27% to 1%. Ganciclovir as prophylaxis has modestly reduced the prevalence of CMV illness from 80% to 60%. Pneumocystis infection has been nearly eliminated with low-dose trimethropin/sulfamethoxazole prophylaxis. Treating all Candida/Aspergillus isolates from respiratory-tract secretions with fluconazole or itraconazole has reduced the prevalence of fungus infections from 14% to 5%. Challenges still remain. The ideal regimen to prevent CMV illness is yet to be determined, and treating all fungal isolates from the allograft is not cost effective. Recurrent airway infection and late bacterial pneumonia caused by Pseudomonas species when obliterative bronchiolitis is present remain a major cause of concern. Surely the next decade will provide new insights into these problems.

Anti-Bacterial Agents↗
PubMed1992

Subclinical pneumonitis due to Pneumocystis carinii in a young adult with elevated antibody titers to Epstein-Barr virus.

Pneumocystis carinii was recovered from the lungs of a 20-year-old woman in apparent good health who had volunteered to undergo bronchoalveolar lavage (BAL) as a normal control subject. Total and differential cell counts in the BAL fluid revealed a significantly increased number and proportion of T lymphocytes, although the CD4:CD8 ratio was in the normal range. Despite the lack of specific antibiotic therapy, in a subsequent lavage no P. carinii were recovered, and the total and differential cell counts returned to normal, suggesting that the infection had resolved. Serologic evaluation revealed no evidence of human immunodeficiency virus infection, although elevated titers of antibodies to Epstein-Barr virus were demonstrated, suggesting ongoing or resolving viral infection. These findings suggest that P. carinii may cause subclinical pneumonitis even in the absence of a clinically evident immune deficient state. Furthermore, an increase in cell count and in the proportion of lymphocytes in an otherwise unremarkable BAL may indicate the presence of P. carinii in the airways and may be the only sign of subclinical infection of the respiratory tract by this organism.

Adult↗
PubMed1992

Ganciclovir prophylaxis for cytomegalovirus infections in pulmonary allograft recipients.

Cytomegalovirus (CMV) is a substantial cause of morbidity in pulmonary allograft recipients. In an attempt to decrease the prevalence of this infection, we treated 13 recipients at risk for cytomegalovirus with 3 wk of intravenous ganciclovir (5 mg/kg twice a day for 14 days, starting 5 days after the procedure, followed by 1 wk of the drug at a dose of 5 mg/kg/day). Following the ganciclovir course, patients received oral acyclovir, 800 mg three times a day for at least 2 months more. CMV infections developed in 5 recipients (38%), and none of these episodes occurred during the ganciclovir therapy. Neither of the 2 deaths in this group could be attributed to CMV. In comparison, the prevalence of CMV in the preceding cohort of 11 transplant recipients who were administered acyclovir alone was 91% (p << 0.01 by log-rank test), and there were 3 deaths due to viral infections (p = 0.08 by Fisher's exact test). Groups were similar in terms of immunosuppression and renal function during treatment, and none of the recipients developed leukopenia. We conclude that ganciclovir prophylaxis is well tolerated and appears to have considerable efficacy for prevention of CMV infections in pulmonary transplant recipients.

Administration, Oral↗
PubMed1992

Sequelae of cytomegalovirus pulmonary infections in lung allograft recipients.

Indirect effects of cytomegalovirus (CMV) infections in lung transplant recipients (LTX) have not previously been described in detail. We compared spirometric results, development of chronic rejection, rates of respiratory superinfections, and mortality as long as 2 yr after transplantation, between 62 LTX who never developed CMV (CMV-) and 56 LTX with a history of CMV pulmonary infections (CMV+). Initial spirometric parameters were near identical for both groups, but determinations > or = 6 months after transplantation showed that expiratory flows of the CMV+ were significantly reduced. Actuarial prevalences of chronic allograft rejection (CR) at 2 yr were highest among CMV+ with biopsy-proved pneumonitis (74%) compared with 22% among CMV- (p < 0.038). Bacterial or fungal pneumonias developed in 58.9% of the CMV+, whereas the rate among CMV- was 38.7% (p < 0.05). Only 36% of LTX with CMV pneumonitis lived 2 yr compared with 70% survival for CMV- (p < 0.016). Ganciclovir treatment of CMV infections decreased rates of respiratory superinfections and improved survival of patients, but it did not appear to affect subsequent development of CR. We conclude that CMV pulmonary infections among LTX result in serious late sequelae and that current treatment is ineffectual for prevention of viral-associated CR in these patients.

Adult↗
PubMed1992

Flow cytometric analysis of lymphocyte phenotypes in bronchoalveolar lavage fluid: comparison of a two-color technique with a standard immunoperoxidase assay.

Characterization of lymphocytes in bronchoalveolar fluid has provided insight into the pathogenesis of many pulmonary diseases. Identification of lymphocyte phenotypes has become highly successful due to development of specific monoclonal antibodies and reliable methods for detecting labeled cells such as flow cytometry (FCM) and immunocytochemistry. FCM permits rapid screening of many cells, but this analysis may be confounded by heterogeneity in the size and granularity of the cells being evaluated. Such heterogeneity may lead to exclusion of cells of interest and inclusion of unwanted cells. Often peripheral blood leukocytes are used to define the gate for lung lymphocytes, but this gate may be inappropriate due to considerable variation in size and granularity of cells in bronchoalveolar lavage (BAL) fluid. Here we report an alternative method for generating a gate which employed fluorescence and side scatter signals to analyze lymphocyte subsets in BAL fluid by FCM. This gating technique avoids the pitfalls inherent in using the conventional lymphocyte gate to analyze lung cells. To validate this approach, we compared the results generated by this gate and those from the conventional forward/side light scatter gate to results derived from an immunocytochemical technique (ABC) that has been extensively employed in our laboratory to identify lymphocyte subsets in blood and lavage fluid. FCM tended to underestimate the proportions of T-cell subsets compared with ABC when the conventional gate was used. Counting only cells that stained with fluorescein-conjugated anti-CD45 antibody and that had side scatter properties of lymphocytes, however, resulted in excellent agreement between FCM and ABC. It appears that the CD45+/side scatter gate includes the vast majority of lymphocytes in BAL fluid while excluding most of the nonlymphoid cells that contaminate the conventional gate. It was this latter group of cells, and erythrocytes in particular, that led to the artificially low values for lymphocyte phenotypes in BAL fluid by FCM when the conventional lymphocyte gate was used. Although erythrocytes in BAL fluid may be eliminated by hypotonic lysis, this may also result in contamination of the conventional lymphocyte gate with nuclear debris and particulates from macrophages. Despite these advantages, the fluorescence/side scatter gate may not always be optimal for the evaluation of T lymphocytes if BAL fluid contains CD45+, nonlymphoid cells with low side light scatter. In these instances, additional antibodies such as anti-CD14 and anti-CD11 may be employed to determine the size of contaminant monocytic cells and neutrophils.(ABSTRACT TRUNCATED AT 400 WORDS)

Bronchoalveolar Lavage Fluid↗
PubMed1992

Lung transplantation at the University of Pittsburgh.

Lung transplantation appears to be a therapeutic alternative for selected patients with end-stage pulmonary vascular and/or parenchymal disease. The greatest impediment to transplantation remains the availability of donor organs. This has become more significant as additional transplant centers become operational. The primary cause of death has been infection, and this most frequently occurs in the early post-transplant period. Significant progress has been made in curbing the morbidity and mortality from bacterial pneumonia and CMV infection, and this is the primary reason for improved survival rates. If the recipient survives the initial hospital stay, the likelihood of survival at 5 years is approximately 80%. The primary long-term complication is obliterative bronchiolitis which is poorly understood and difficult to treat. Nevertheless, the improvement in survival provides impetus to refine and improve the procedure so that survival can reach that attained by recipients of other major organ allografts.

Academic Medical Centers↗
PubMed1991

Similarity of pulmonary rejection patterns among heart-lung and double-lung transplant recipients.

The transbronchial biopsy and clinical courses of 9 double-lung and 1 single-lung recipients surviving greater than 10 days were analyzed and compared to those of 15 heart-lung transplants performed during the same time period. Of these, 8 isolated lung (LT) and 11 heart-lung transplant (HLT) recipients survived greater than 50 days and were at risk of developing obliterative bronchiolitis believed to be a form of chronic rejection. Cyclosporine-based immunosuppression, in combination with azathioprine and steroids, was used for 22 of 25 patients. Two double-lung recipients and 1 heart-lung patient received FK506 as the sole immunosuppressive agent; 90% and 62% of LT, and 67% and 54% of HLT recipients developed acute and chronic rejection, respectively (P = NS). The average time to first episode of acute (30.2 days [LT] versus 21.5 days [HLT]) and chronic rejection (146 days [LT] versus 193.7 days [HLT]) was not different between groups (P = NS). Age (34.2 [LT] versus 29.1 [HLT]) and sex (M:F, 5:5 [LT] versus 5:10 [HLT]) were also not found to be discriminators. The histologic diagnosis of chronic rejection was associated with significant declines in FEV1.0 and FEF25-75 (P less than 0.02). There was only one instance of cardiac rejection among the heart-lung transplant recipients. Heart-lung and isolated lung transplant patients appear to be at similar risk for developing acute or chronic pulmonary rejection.

Adult↗
PubMed1991

Cytomegalovirus serologic status and postoperative infection correlated with risk of developing chronic rejection after pulmonary transplantation.

Twenty-seven patients received pulmonary transplants during the period since we began routine use of cytomegalovirus-seronegative blood products for CMV-seronegative recipients. Preoperative serologic status of the recipient and the occurrence of cytomegalovirus infection in the postoperative period were correlated with development of obliterative bronchiolitis (OB) as diagnosed by transbronchial biopsy (TBB). Patients included 20 heart-lung and 7 double-lung recipients. OB occurred in 18 of 27 patients. All 3 CMV seronegative recipients receiving lungs from a seropositive donor and 9 of 10 CMV recipients seropositive at the time of transplantation developed OB compared with only 6 of 14 CMV seronegative patients receiving seronegative grafts (P = 0.018). CMV infection occurred in 10/27 patients, of whom 5 were asymptomatic; 90% of these patients developed OB. Donor-specific alloreactivity, based on primed lymphocyte testing (PLT) of bronchoalveolar lavage cells was found at the time of diagnosis of OB in 23 of 27 patients. A positive PLT was significantly associated with the presence of OB (P = 0.017). We conclude that preoperative seropositive status for CMV, grafting of organs from seropositive donors, and postoperative CMV infection are significant risk factors for developing OB. That OB is, in part, an immunologically mediated form of injury and represents chronic rejection is supported by the presence of donor-specific alloreactivity in BAL lymphocytes from all recipients with OB.

Antibodies, Viral↗
PubMed1991

Does histologic acute rejection in lung allografts predict the development of bronchiolitis obliterans?

Clinical acute lung rejection (AR) occurs in lung allografts usually within 50 days after transplantation. While perivascular infiltrates characterize AR, with moderate-to-severe acute rejection small airway injury occurs. We investigated the significance of small airway injury in AR and its relationship to the development of bronchiolitis obliterans (OB) in 11 recipients of combined heart-lung or double-lung allografts. In general, the intensity and persistence of early acute rejection episodes associated with injury to bronchioles correlated with the development of histologic bronchiolitis obliterans. Early AR may "prime" lymphocytes for subsequent respiratory epithelial injury and airway fibrosis late in the postoperative period.

Adult↗
PubMed1991

Alveolar macrophage migration after lung transplantation.

Pulmonary infection is a major source of morbidity and mortality in recipients of lung allografts. The alveolar macrophage plays an important role in pulmonary host defense, and to fulfill this role it must have the ability to orient and migrate in the direction of a stimulus. Thus migratory activity was measured in cells recovered from lung transplant recipients by bronchoalveolar lavage. The primary patient group consisted of recipients who had no evidence of infection or rejection at the time of bronchoalveolar lavage. These patients were further subdivided into an early postoperative group (less than 6 wk posttransplant) and a late postoperative group (greater than 6 wk posttransplant). Other categories included patients with chronic rejection and a small group of patients with Pneumocystis carinii pneumonia. Alveolar macrophages recovered by bronchoalveolar lavage were assayed for migratory response to N-formylmethlonylphenylalanine and endotoxin-activated human serum. Stimulated migration of cells from healthy recipients obtained in the late postoperative course was similar to that of normal control subjects, but stimulated migration of cells from healthy recipients in the early postoperative period and those undergoing chronic rejection was greater than expected. Spontaneous migration was similar in all groups except those with P. carinii pneumonia, in whom it was greatly increased. We conclude that alveolar macrophage migration is not impaired in lung allograft recipients without apparent signs of infection or rejection and is in fact increased during periods of possible macrophage activation (shortly after transplantation and during chronic rejection).

Bronchoalveolar Lavage Fluid↗
PubMed1991

The effect of obliterative bronchiolitis on breathing pattern during exercise in recipients of heart-lung transplants.

The more rapid and shallow ventilation pattern seen during exercise in patients with obstructive and/or restrictive lung disease has been attributed by some investigators to the effects of vagal afferents from intrapulmonary receptors. Recipients of heart-lung transplants (HLTR) offer a unique opportunity to test this hypothesis since they have denervated lungs and may develop obliterative bronchiolitis after organ rejection. We thus compared the ventilation responses to incremental bicycle ergometry of five HLTR with relatively normal pulmonary function (HLTR-N) and four with bronchiolitis obliterans (HLTR-O). We compared the slopes of the linear portion of the tidal volume versus inspired minute ventilation relationship of both groups. The rate of rise of tidal volume (VT) (slope of VT versus VI) was greater in HLTR-N (0.31 +/- 0.004) than in HLTR-O (0.023 +/- 0.007) (p less than 0.05). This corresponded to a slower increase in respiratory rate (RR) (slope of RR versus Vl/cm) in HLTR-N (0.055 +/- 0.005) than in HLTR-O (0.083 +/- 0.019) (p less than 0.01). Furthermore, values for VT, inspiratory time (TI), and duty cycle (TI/Ttot) measured during exercise at the VT break point were all significantly lower in the HLTR-O than in HLTR-N. We also evaluated the ability of HLTR with lung disease to regulate their ultimate level of ventilation during maximal exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1991

Accessory cell function of blood monocytes and alveolar macrophages after human lung transplantation.

Infection is a major complication of organ transplantation, and the lung is the most common site in recipients of a pulmonary allograft. The generation of an immune response both systemically and in the lungs is a major line of defense against infection. Therefore, we examined the ability of blood monocytes (BM) and alveolar macrophages (AM) recovered from lung transplant recipients without evidence of infection or rejection and from normal subjects to act as accessory cells in mitogen- and antigen-induced proliferation of autologous lymphocytes (Ly) and to stimulate an allogeneic (MLR) and autologous mixed lymphocyte reaction (AMLR). Proliferation of autologous Ly in the presence of mitogen and antigen and of allogeneic Ly stimulated by BM was significantly reduced in the lung recipients when compared with those in the normal subjects. Impaired Ly proliferation may result from inadequate presentation of antigen by recipient BM, heightened suppressive activity of BM, or the inability of recipient Ly to respond to proliferative signals. We believe that our results strongly support a role for inadequate presentation of antigen by BM. Inadequate antigen-driven stimulation could be one reason why transplant recipients have an increased susceptibility to infection. Somewhat unexpected was the finding that AM from lung recipients functioned nearly as well as AM from normal subjects as accessory cells. Although they failed to support mitogen-induced stimulation normally, AM from lung recipients were as efficient as autologous BM and AM from normal subjects in supporting Ly proliferation for soluble antigen and alloantigen.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1990

Potential role of dendritic cells in bronchiolitis obliterans in heart-lung transplantation.

Dendritic cells are essential for the activation of the type IV immunological reactions that are intrinsic to rejection of transplanted organs. We evaluated the number of dendritic cells in the recipient and donor portions of the trachea and donor bronchi of 6 heart-lung transplant recipients, 3 of whom had evidence of bronchiolitis obliterans, a presumed manifestation of chronic rejection of the lung. As compared with recipients without bronchiolitis obliterans, patients with it showed a significant increase in the number of S100-protein-positive dendritic cells in the tracheal and bronchial epithelium and submucosa of the donor organs. This finding of increased accessory cells in the transplanted mucosa provides support for the belief that bronchiolitis obliterans is an immunologically mediated form of chronic rejection.

Bronchi↗
PubMed1990

Proliferative responses of bronchoalveolar lavage lymphocytes from heart-lung transplant patients.

Donor-specific alloreactivity of bronchoalveolar lavage (BAL) lymphocytes was evaluated in the immunologic monitoring of lung transplant patients. The study dealt with 161 BAL performed on 28 transplant recipients. Unseparated BAL cells, separated BAL lymphocytes, and PBL were tested for donor-specific proliferative responses in 3-day primed lymphocyte testing (PLT), and for nonspecific proliferative responsiveness to exogenous IL-2. The proliferation data were analyzed for correlation with the status of the lung allograft assessed clinically, histologically, and by pulmonary function testing. Positive PLT responses of BAL lymphocytes were observed in 20 of 22 acute rejection episodes (91%) and in 24 of 35 cases (69%) when chronic rejection was diagnosed. During clinical quiescence donor-specific proliferative activity was demonstrated in only 4 of 35 cases (11%). Thus, acute rejection and chronic rejection correlated significantly (P less than 0.001) with donor-specific PLT reactivity of BAL lymphocytes. Though significant association with rejection was observed for the alloreactivity of unseparated BAL cells and PBL, the sensitivity of the PLT test with these cells was significantly lower than that with BAL lymphocytes. Similarly, the IL-2 proliferative activity of BAL lymphocytes was significantly increased during acute and chronic rejection. However, this test had lower sensitivity and specificity than did the donor-specific PLT. These findings suggest the usefulness of the donor-specific PLT of BAL lymphocytes as a reliable method for monitoring pulmonary rejection.

Adolescent↗
PubMed1990

Infectious complications in pulmonary allograft recipients.

This article has outlined the features of the major types of infections encountered in pulmonary allograft recipients. Virtually any pathogen can cause infection in these immunocompromised subjects, and there is a distinct propensity for these organisms to invade the transplanted lung. As is the case with other major organ recipients, there is a temporal sequence in the types of infection lung allograft recipients contract. Bacteria are the most frequent cause of pneumonia in the first postoperative month. After this period, infection with CMV, particularly CMV pneumonitis, becomes most common. Following the "window" for CMV infection, the risk for infestation with P. carinii becomes the primary concern. The latter two types of infection pose a double risk for the recipient: (1) morbidity and mortality from the infection itself and (2) chronic rejection following on the heels of these infections and producing morbidity and mortality on its own. Pulmonary allograft recipients are also susceptible to fungi, particularly C. albicans. Although these infections rarely produce an overwhelming pneumonia, they nonetheless carry a grave prognosis because they usually become widely disseminated. Better selection of donor lungs and prophylactic measures such as the use of broad-spectrum antibiotics and amphotericin B in the early postoperative period, the use of CMV-negative blood products in seronegative recipients, and the chronic administration of trimethoprim-sulfamethoxazole have reduced the rate of infection with bacteria, fungi, CMV (primary infections only), and P. carinii, respectively. Despite these relative successes, however, the risk for infection of the allograft remains high because the defense mechanisms in the lung allograft are breached by the effects of surgery, the "allogeneic environment" in the allograft and systemic immunosuppression, and the fact that chronic rejection causes structural changes that predispose to bacterial colonization of the airways and the need for increased levels of immunosuppression. Despite the formidable barrier that infection of the lung allograft poses, the procedure of pulmonary transplantation clearly holds sufficient promise that all efforts possible should be made to hurdle this barrier. Achieving such a goal would ensure a place for pulmonary transplantation in the armamentarium of treatment for irreversible pulmonary disease.

Bacterial Infections↗
PubMed1989

Posttransplant lymphoproliferative disorders in heart-lung transplant recipients: primary presentation in the allograft.

Heart-lung transplant recipients are predisposed to acute rejection episodes, bronchiolitis obliterans, and opportunistic infections. In 9.4% of recipients at the University of Pittsburgh, a posttransplant lymphoproliferative disorder (PTLD) developed, and in 60% of cases, it presented in the allografted lungs and was associated with primary infection by Epstein-Barr virus (EBV). The PTLD is histologically indistinguishable from a primary pulmonary lymphoma and consists of a mixed population of large lymphoid cells, immunoblasts, and plasma cells. Two cases of PTLD were monoclonal with immunohistochemical and Southern blot analysis. Despite this, there was clinical recovery with reduced immunosuppression and acyclovir. We discuss the role of EBV in the development of PTLD and the pathogenesis of primary presentation in the allograft.

Adolescent↗