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J H Dauber

Publications and source records attributed to J H Dauber.

At least 37 records · Page 2Linked to original sources

Lung transplantation: implications for the general internist.

The modern era of lung transplantation was ushered in on the wings of discoveries in new immunosuppressive agents and surgical technique. It has allowed those with end-stage organ disease to have a second chance at life. Even though still in its youth relative to other solid organ transplants, it is gaining momentum and promises to be a continuing area of growth and development. Although over 2,700 lung transplants have been done in the last 13 years worldwide, the lack of availability of donor organs is the major factor slowing the rapid expansion of this field of endeavor. Primary care physicians may have an impact on this problem by raising the awareness for organ donation in their patients and patients' families. Although initially performed almost exclusively for those with pulmonary vascular disease, indications have now expanded to include interstitial disease, septic lung disease, and emphysema, with the latter being the major reason for transplantation today. Unfortunately, at experienced institutions with long waiting lists, 20% or more of candidates do not survive to transplantation. With proper care and selection of transplant candidates it is hoped that more will survive to benefit from this treatment. The primary care physician will likely be assuming a greater role in the management of transplant candidates as their numbers increase. The care of transplant recipients, although often complex, is frequently rewarding. For the most part it is performed at transplant centers, but a role for the recipient's local physician in this process is also growing in the era of managed care. This chapter has also highlighted how the recipient's local physician can participate in postoperative care. Strict attention needs to be paid to any and all signs of organ rejection or infection because both can have devastating consequences. Awareness of the medications used in this population, their side effects, and drug interactions is essential. Despite the recent advances in pharmacologic therapy, organ rejection continues to be problematic. This is especially the case with the entity of chronic rejection because it frequently fails to respond long-term to therapy and accounts for a significant percentage of late mortality. Although infections continue to be the primary cause of both early and late mortality in these recipients, proper care and postoperative prophylaxis can lessen the incidence. Likewise, early and aggressive treatment of infections in recipients can be lifesaving. Despite all the potential problems, patients receiving lung transplants are living longer and return to productive lives. Between 50% and 60% are now living between 3 and 4 years, and one can only anticipate that this will continue to climb as our understanding of infections, medications, and the body's immunoregulatory system improves. As techniques for donor organ allocation and organ preservation improve, it is hoped that all those with end-stage lung disorders may have the opportunity to benefit from this expanding technology.

Humans↗

The importance of bronchoscopy with transbronchial biopsy and bronchoalveolar lavage in the management of lung transplant recipients.

Medical and surgical advances have made lung transplantation a feasible therapy for end-stage lung disease. Fiberoptic bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial lung biopsy (TBBx) is an accepted technique for detecting clinically evident rejection and infection in the allograft of symptomatic recipients. The role of TBBx and BAL in managing asymptomatic recipients is less defined. We retrospectively examined the role of bronchoscopy with TBBx and BAL in 1124 bronchoscopy procedures that were performed on 161 lung transplant recipients between January 1, 1988, and December 31, 1993. Bronchoscopy was performed when there was a change in the recipient's clinical condition, to assess the response of the allograft to a prior therapy, and under a surveillance protocol for detecting asymptomatic rejection or infection. Surveillance bronchoscopy was performed according to the following schedule: 10-14 days after transplantation, every 3 mo during the first year, every 4 mo during the second year, and at 6-mo intervals thereafter. Surveillance bronchoscopies were defined as procedures where the physician felt that there was no infection or rejection in the allograft on the basis of a standardized clinical evaluation, which excluded the results of the TBBx and BAL. We compared the clinical impression recorded by the physician on the day of the procedure with the final diagnosis determined after the results of the TBBx and BAL were known. We found unsuspected rejection and/or infection that required therapy in 25% (90/355) of all surveillance bronchoscopy procedures. Most episodes (61/90, 68%) of unsuspected rejection and/or infection occurred in the first 6 mo after transplantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗

Mixed allogeneic chimerism in lung allograft recipients.

Microchimerism in lung allograft recipients was studied in the autopsies of nine female recipients of male lung grafts who had survived for more than 1 month after transplantation. Using a Y chromosome-specific probe tissues were studied for the presence of donor cells that had migrated beyond the graft itself. They were quantitated by cell counting to give absolute numbers of cells per organ volume. While donor cells were disseminated throughout the body, their numbers were small. These absolute numbers should be studied in a larger group of recipients to determine if they correlate with prognosis and the development of bronchiolitis obliterans.

Adult↗

Case report: fluconazole therapy in histoplasma mediastinal granuloma.

A 41-year-old man presented with night sweats, fever, and substernal chest pain approximately 5 months after being treated for community-acquired pneumonia. Chest radiograph revealed a mediastinal mass that was confirmed by computed tomography (CT) of the thorax. During surgery, enlarged paratracheal lymph nodes and a mass surrounding the right lower lobe bronchus and bronchus intermedius were found. Multiple biopsies from the mass showed that it consisted mainly of acellular fibrous tissue, but a small number of fungal forms typical of Histoplasma capsulatum were seen at the edged of the fibrotic reaction. The lymph nodes contained granulomatous inflammation and areas of necrosis, but no organisms were identified. The patient was treated with fluconazole for 6 weeks with resolution of symptoms. After completion of therapy, a follow-up CT scan of the thorax showed involution of the mediastinal mass. There has been no recurrence of symptoms or radiographic abnormalities for 24 months since cessation of fluconazole. This case illustrates isolated mediastinal involvement by histoplasmosis and suggests that therapy with fluconazole at this stage may prevent the often devastating late complications of mediastinal fibrosis.

Adult↗

Benefits of posttransplantation monitoring of interleukin 6 in lung transplantation.

To determine the predictive diagnostic value of interleukin 6 (IL-6) monitoring in lung and heart-lung transplants, we measured posttransplantation serum IL-6 levels in 17 adult lung or heart-lung transplant recipients. Posttransplantation IL-6 elevation patterns were classified into 4 groups: serum IL-6 level remained negative throughout the monitoring period (group 1; n = 1; 6%); several sharp spikes with normal baseline (group 2; n = 9; 53%); persistently high level of serum IL-6 (group 3; n = 3; 18%); and several sharp spikes of serum IL-6 elevation with abnormally high baseline (group 4; n = 4; 24%). One patient without an elevation of IL-6 (group 1) did not experience any episodes of rejection or infection. Nine patients in group 2 had 19 IL-6 spikes, 13 of which were associated with histopathologically or clinically diagnosed rejection, 3 with acute bronchitis, and 1 with diffuse alveolar damage. Three patients in group 3 had persistent infections including cytomegalovirus infection, toxic megacolon, and repeated bacterial infection during the monitoring period, and 4 in group 4 died within 3 months after transplantation. From this study it appears that a spiked elevation of IL-6 could have a predictive value in diagnosing rejection, and persistently high levels of IL-6 indicate the presence of infection. Thus, IL-6 monitoring is beneficial for lung transplant recipients.

Adult↗

Recurrence of sarcoidosis in pulmonary allograft recipients.

Lung transplantation is a potentially curative therapy for the end-stage pulmonary sequelae of sarcoidosis. We reviewed the course of five lung allograft recipients with underlying sarcoidosis (S) at the University of Pittsburgh Medical Center and compared them with a control group (C) of 44 contemporaneous transplant recipients with other respiratory diseases. Sarcoid granulomata have developed in the allografts of 4 S, although these lesions have not yet been demonstrated to result in clinically significant abnormalities. In comparison with C, sarcoidosis patients had significantly greater mean grades of acute rejection during the first 3 months after transplantation (2.1 +/- 0.3 versus 1.6 +/- 0.1, S and C, respectively, p < 0.042) and larger proportions of lung biopsies showing more than mild acute rejection (40 versus 18%, p < 0.012) and lymphocytic bronchitis (30 versus 13%, p = 0.02), as well as a greater percentage of polymorphonuclear leukocytes in BAL returns (34.9 +/- 5.4 versus 19.0 +/- 1.6, p < 0.01). The two groups did not differ, however, in frequency of obliterative bronchiolitis, survival, or pulmonary function. We conclude that lung transplant recipients with underlying sarcoidosis are very likely to develop recurrent disease in the allograft and have more severe acute rejection responses, especially in the first weeks after transplantation. Pulmonary transplantation appears to be an efficacious therapy for end-stage sarcoidosis, but the long-term sequelae of the increased acute rejection and recurrent sarcoidosis in the allograft remain to be determined.

Adult↗

Enhanced secretion of immune-modulating cytokines by human lung fibroblasts during in vitro infection with Mycoplasma fermentans.

Fibroblasts may play an important role in the modulation of immune and inflammatory responses through elaboration of cytokines. To test this hypothesis, human lung fibroblasts were isolated from transbronchial biopsy specimens and assayed for production of interleukin-6 (IL-6) and granulocyte/macrophage colony-stimulating factor (GM-CSF). The sources of fibroblasts included lung allografts, recipient lungs obtained at time of transplant, and normal lung tissue removed during tumor resection. During the course of these studies, several early-passage fibroblasts from transplant recipients were observed to contain mycoplasma (MP)-like organisms as detected by extranuclear fluorescent staining with Hoechst 33258. Positive staining cultures were associated with isolation of Mycoplasma fermentans. IL-6 and GM-GSF as measured by ELISA were found to be elevated over 50-fold in conditioned medium from MP-infected fibroblasts as compared with noninfected lines. Treatment of cells with mycoplasma removal agent (MRA) eliminated extranuclear Hoechst fluorescence and significantly reduced the production of these cytokines. Tumor necrosis factor-beta (TNF-beta) induction of IL-6 and GM-CSF was amplified synergistically in infected cultures. No additional production of IL-6 or GM-CSF was observed in infected cultures treated with interferon-gamma (IFN-gamma) despite the ability of IFN-gamma to modestly induce IL-6 in uninfected cultures. Thus, in vitro infection of lung fibroblasts with MP represents a potent stimulus for the production of inflammatory cytokines and, therefore, necessitates rigorous control for these organisms in cell culture studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Cell Cycle↗

Acute rejection of lung allografts with various immunosuppressive protocols.

Between February 1990 and December 1991, 69 patients who survived for a minimum of 5 days after single-lung (27), double-lung (32), or heart-lung transplantation (10) were studied to learn the incidence and severity of acute rejection and the possible effects of various immunosuppressive protocols on this rejection. Acute rejection was less common (2.1 versus 3.1 episodes/patient) after transplantation in those 30 candidates who received rabbit antithymocyte globulin for the first 5 postoperative days versus the 28 who were maintained on cyclosporine, azathioprine, and prednisone alone (p < 0.05), but no patient escaped at least one episode. Patients given cyclosporine received more 3-day courses of methylprednisolone (p < 0.02) than those given rabbit antithymocyte globulin (2.5 versus 1.7 courses). Although no disadvantage in terms of infectious morbidity was noted in the rabbit antithymocyte globulin group, no obvious intermediate advantage was noted in survival (85% at 12 months) or grade of rejection or airway flows. The most common histopathologic grades were mild (A2) and moderate (A3); the average grade was A2.3. FK 506 was tested in 11 patients, and early results are promising relative to low early and likely fewer late episodes of rejection. No differences were noted in the likelihood of rejection for any procedures.

Acute Disease↗

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↗

Nasal cannula and transtracheal oxygen delivery. A comparison of patient response after 6 months of each technique.

The purpose of this study was to compare the efficacy of transtracheal (TT) oxygen delivery to that of nasal cannula delivery in subjects with chronic obstructive pulmonary disease (COPD). Twenty subjects (14 men, 6 women) were followed for 6 months during nasal cannula delivery. A TT catheter was then inserted, and measurements were repeated during TT use. With TT delivery, subjects required 45% less oxygen at rest and 39% less during exercise (p less than 0.0001). Oxygen use, measured by pounds of oxygen delivered to the home, also decreased, but the magnitude of change was less than anticipated (mean, 14%; range, +4% to -32%). Hospital days decreased from 12 +/- 10 during nasal cannula use to 4 +/- 6 during TT use (p less than 0.002). Exercise tolerance, as measured by a 12-min walk distance, was greater during TT use (p less than 0.0001). No change was seen in spirometry or acid-base balance. Also, no change was seen in Profile of Mood States, Sickness Impact Profile or Katz Adjustment Scale scores. Some problems were encountered relating to use of the catheter (displacement, mucus balls), but they were minor, and most were confined to the initial 2 months of TT use when the tract was immature. Our experience suggests that, in addition to decreasing oxygen flow rate, use of TT delivery may confer benefits that result in improved exercise tolerance and decreased hospitalization in patients with COPD.

Catheterization↗

Tumor necrosis factor-alpha production by alveolar macrophages in heart-lung transplant recipients.

Tumor necrosis factor-alpha (TNF alpha) is a cytokine produced by mononuclear cells that amplifies inflammation and modulates expression of Class I and Class II histocompatibility antigens. Because of these properties, this cytokine may exert a central role in both the defense and the rejection of the transplanted lung. Utilizing an ELISA technique, we measured TNF alpha in vivo and in vitro in several compartments of lung transplant recipients and in normal subjects that included serum, bronchoalveolar lavage fluid (BAL), and media conditioned by alveolar macrophages (AM) and by autologous peripheral blood monocytes (PBM). Overall, stimulated production of TNF alpha by AM from lung recipients in vitro was less than that of cells from normal subjects in response to lipopolysaccharide (LPS) challenge, and stimulated production of TNF alpha by AM harvested during conditions of infection or acute and chronic rejection was less than that by cells from healthy lung recipients. AM from normal subjects and allograft recipients produced substantially more TNF alpha than autologous PBM, but release in vitro by PBM from recipients was the same as that from cells of normal subjects who were not immunosuppressed. Thus, systemic immunosuppression does not seem to affect the production of TNF alpha by PBM in vitro, but it may reduce production by AM, indicating different effects of immunosuppression on different compartments of mononuclear cells. This mediator was not detected at elevated levels in serum, and it was undetectable in BAL fluid. We conclude that AM from lung recipients are capable of producing TNF alpha, which would influence the defense and immunogenicity of the allograft.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

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↗

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↗

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↗

The use of a short-length transtracheal oxygen catheter in patients of small stature with restrictive lung disease.

Transtracheal oxygen therapy is being used with increasing frequency because it is an effective mode of oxygen delivery and is well tolerated by patients. An increase in cough and mild intermittent hemoptysis are not uncommon in the early postinsertion period but usually resolve spontaneously. Herein we present two individuals of short stature with restrictive lung disease who had persistence of excessive cough and mild hemoptysis after insertion of a standard catheter (SCOOP). Bronchoscopic evaluation in one revealed erosions of the mucosa over the carina and take-off of the right main-stem bronchus. Symptoms resolved in both individuals following placement of a shorter catheter. We suggest that greater consideration be given to matching transtracheal catheter length to patient lung size, particularly in the face of severe restrictive lung disease.

Adult↗

The deficient migration in vitro of lung macrophages from newborn rats normalizes after three days of maturation in situ.

Because there are functional deficiencies in neonatal phagocytes, we investigated age-dependent differences in the directed migration of rat pulmonary macrophages (PM). Directed migration of PMs from newborn (less than 24 h old) rats towards partially purified rat C5a was lower than that of PMs from adults, but reached adult levels by the third post-natal day. Calculation of the dose of C5a resulting in a half-maximal migratory response (ED-50) revealed that the ED-50s for all age groups studied were similar. These results suggest that responding PMs at all times after birth have comparable sensitivity to C5a, but that a lower percentage of newborn PMs migrate toward this factor because of defects in either signal transduction or cell motility.

Aging↗

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↗