Janet R. Maurer

INTERNATIONAL GUIDELINES FOR THE SELECTION OF LUNG TRANSPLANT CANDIDATES

12. Paris W, Muchmore J, Pribil A, Zuhdi N, Cooper DK. Study of the relative incidences of psychosocial factors before and after transplantation and the influence of posttransplantation psychosocial factors on heart transplantation outcome. J Heart Lung Transplant 1994; 13: 424. 13. Chacko RC, Harper RG, Kunik M, Young J. Relationship of psychiatric morbidity and psychosocial factors in organ transplant candidates. Psychosomatics 1996; 37: 100. 14. Frazier P, et al. Correlates of non-compliance among renal transplant recipients. Clin Transplant 1994; 8: 550. 15. Chacko RC, Harper RG, Gotto J, Young J. Psychiatric interview and psychometric predictors of cardiac transplant survival. Am J Psychiatry 1996; 153: 1607. 16. Twillmann RK, Manetto C, Wellisch DK, Wolcott DL. The transplant evaluation rating scale: a revision of the psychosocial levels system for evaluating organ transplant candidates. Psychosomatics 1993; 34: 144. 17. Olbrisch ME, Levenson JL, Hamer R. The PACT: a rating scale for the study of clinical decision-making in psychosocial screening of organ transplant candidates. Clin Transplant 1989; 3: 164. 18. Hecker J, Norvell N, Hills H. Psychologic assessment of candidates for heart transplantation: toward a normative data base. J Heart Transplant 1989; 8(2): 171. 19. Levenson JL, Olbrisch ME. Psychosocial evaluation of organ transplant candidates: a comparative survey of process, criteria, and outcomes in heart, liver, and kidney transplantation. Psychosomatics 1993; 34(4): 314.

Anxiety and Depression in COPD: Current Understanding, Unanswered Questions, and Research Needs

BACKGROUND Approximately 60 million people in the United States live with one of four chronic conditions: heart disease, diabetes, chronic respiratory disease, and major depression. Anxiety and depression are very common comorbidities in COPD and have significant impact on patients, their families, society, and the course of the disease. METHODS We report the proceedings of a multidisciplinary workshop on anxiety and depression in COPD that aimed to shed light on the current understanding of these comorbidities, and outline unanswered questions and areas of future research needs. RESULTS Estimates of prevalence of anxiety and depression in COPD vary widely but are generally higher than those reported in some other advanced chronic diseases. Untreated and undetected anxiety and depressive symptoms may increase physical disability, morbidity, and health-care utilization. Several patient, physician, and system barriers contribute to the underdiagnosis of these disorders in patients with COPD. While few published studies demonstrate that these disorders associated with COPD respond well to appropriate pharmacologic and nonpharmacologic therapy, only a small proportion of COPD patients with these disorders receive effective treatment. CONCLUSION Future research is needed to address the impact, early detection, and management of anxiety and depression in COPD.BACKGROUND Approximately 60 million people in the United States live with one of four chronic conditions: heart disease, diabetes, chronic respiratory disease, and major depression. Anxiety and depression are very common comorbidities in COPD and have significant impact on patients, their families, society, and the course of the disease. METHODS We report the proceedings of a multidisciplinary workshop on anxiety and depression in COPD that aimed to shed light on the current understanding of these comorbidities, and outline unanswered questions and areas of future research needs. RESULTS Estimates of prevalence of anxiety and depression in COPD vary widely but are generally higher than those reported in some other advanced chronic diseases. Untreated and undetected anxiety and depressive symptoms may increase physical disability, morbidity, and health-care utilization. Several patient, physician, and system barriers contribute to the underdiagnosis of these disorders in patients with COPD. While few published studies demonstrate that these disorders associated with COPD respond well to appropriate pharmacologic and nonpharmacologic therapy, only a small proportion of COPD patients with these disorders receive effective treatment. CONCLUSION Future research is needed to address the impact, early detection, and management of anxiety and depression in COPD.

Cytomegalovirus Infection Is a Risk Factor for Invasive Aspergillosis in Lung Transplant Recipients

Invasive aspergillosis (IA) remains a major cause of morbidity and mortality following solid organ transplantation. To assess the incidence of IA following lung transplantation and to identify risk factors for its occurrence, we performed a case-control study involving 101 patients undergoing lung transplantation at our institution from 1990 to 1995 and reviewed the findings. Fourteen patients (14%) developed IA. The mean time from transplantation to diagnosis was 15 months. Nine patients died; the mean time to death from diagnosis was 13 days. Risk factors associated with developing IA included concomitant cytomegalovirus (CMV) pneumonia or viremia and culture isolation of Aspergillus species from a respiratory tract specimen after lung transplantation. Optimal strategies to prevent IA in lung transplant recipients remain to be determined, but prevention of aspergillus airway colonization and CMV viremia and disease after transplantation may be important targets for prophylactic interventions.

Hypogammaglobulinemia in lung transplant recipients

Background. Infectious complications continue to represent a significant source of morbidity and mortality in lung transplant recipients.Identifying specific, remediable immune defects is of potential value. After one lung transplant patient with recurrent infections was noted to be severely hypogammaglobulinemic, a screening program for humoral immune defects was instituted. The objectives were to define the prevalence of hypogammaglobulinemia in lung transplant recipients, assess levels of antibody to specific pathogens, and correlate infectious disease outcomes and survival with immunoglobulin levels. Methods. All lung transplant recipients followed at a single center between October 1996 and June 1999 underwent a posttransplant humoral immune status survey as part of routine posttransplant follow-up. This survey consists of total immunoglobulin levels (IgG, IgM, IgA), IgG subclasses (IgG1–4), and antibody titers to Pneumococcus, diphtheria, and tetanus. Since February 1997, this survey has been incorporated into the pretransplant evaluation as well. Humoral survey results for October 1996 through July 1999 were recorded, and clinical information on major infectious disease outcomes was obtained from chart reviews, discharge summaries, the Cleveland Clinic Unified Transplant Database, and review of all microbiological studies and pathology results for each patient. Results. Of 67 patients with humoral immune surveys drawn posttransplant, 47 (70%) had IgG levels less than 600 mg/dl (normal 717-1410 mg/dl), of which 25 (37%) had IgG levels less than 400 mg/dl (“lowest IgG group”) and 22 (33%) had IgG levels between 400 and 600 mg/dl (“moderately low IgG group”). A total of 20 patients (30%) had IgG levels of more than 600 mg/dl (“normal IgG group”). Infections that were significantly more common in the lowest IgG group, and more common in the moderately low IgG group than the normal IgG group, included: number of pneumonias (P =0.0006), bacteremias (P =0.02), total bacterial infections (P =0.002), tissue-invasive cytomegalovirus (P =0.01), invasive aspergillosis (P =0.001), total fungal infections (P =0.001), and total infections (P =0.006). Median hospital days per posttransplant year was significantly different in the three groups (11.0 vs. 7.4 vs. 2.8 days, P =0.0003.) Invasive aspergillosis occurred in 44% of the lowest IgG group, 9% of the moderately low IgG group, and 0% of the normal IgG group (P <0.001). Survival was poorest in the lowest IgG group and intermediate in the moderately low IgG group. IgG subclass deficiencies occurred in a variety of patterns. Hypogammaglobulinemic patients lacked protective responses to Pneumococcus in 14/47 (30%), diphtheria in 15%, and tetanus in 19%. In a group of 48 patients screened pretransplant, 90% had normal immunoglobulin levels. Conclusions. Hypogammaglobulinemia in lung transplant recipients is more common than has been previously recognized. An IgG level of less than 400 mg/dl identifies a group at extremely high risk of bacterial and fungal infections, tissue-invasive cytomegalovirus, and poorer survival. Immunoglobulin monitoring may offer an opportunity for intensive surveillance, tapering of immunosuppression, and preemptive therapy for infection.

Cyclosporine Nephrotoxicity In Lung Transplant Recipients

End-stage lung disease has been treated successfully by lung transplantation (LTXP) at our institution since 1983. We report on the renal function of 30 LTXP recipients who were followed for at least 6 months (mean, 39 months; range, 6–60 months). All patients received quadruple immunosuppressive therapy including cyclosporine A, with a trough serum level (RIA) between 150 and 250 ng/ml for the first 6 months between 125 and 150 mg/ml after 6 months. The mean serum creatinine (SeCr) increased from a baseline value of 75±3.5 to 182±13.9 μM at the end of the follow-up. The greatest change in SeCr occurred within the first 6 months post LTXP. Fifteen of 30 patients who were initially normotensive required at least one antihypertensive medication post LTXP. By the end of the followup, 9 patients had SeCr > 200 μM. Two patients in this institution have progressed to end-stage renal disease requiring dialytic therapy. CsA nephrotoxicity has emerged as a major source of morbidity in the lung transplant population. Nephrotoxicity occurs early, and there does not appear to be any trend toward reversibility despite a lowering of the dose. Renal parenchymal injury may be progressive, despite an apparent plateau of the SeCr in some patients.

The humoral immune response to influenza vaccination in lung transplant patients

The purpose of this study was to evaluate the humoral immune response to influenza vaccination in lung transplant recipients. Antibody levels to the three viral antigens included in the 1999–2000 trivalent influenza vaccine (A/Sydney/5/97-like (H3N2), A/Beijing262/95-like (H1N1), and B/Yamanashi/16/98) were measured before and 4 weeks postvaccination in 43 lung transplant recipients and 21 healthy adult controls. The ability to develop protective antibody levels, a serological response, and the magnitude of change in levels were assessed. The humoral immune response to influenza vaccination was significantly lower in the transplant group for all three viral antigens. To A/Sydney, 95% of the control group and 40% of the transplant group developed protective levels (p=0.0009); to A/Beijing, 71% of the control group and 30% of the transplant group developed protective levels (p=0.004); and to B/Yamanashi, 48% of the control group and 19% of the transplant group developed protective levels (p=0.02). Those receiving cyclosporine had lower antibody responses when compared to those receiving tacrolimus (r=−0.3056, p=0.0463). The humoral immune response to influenza vaccination in lung transplant recipients is poor. Lung transplant recipients receiving cyclosporine may have a lower antibody response than those receiving tacrolimus. Alternative prevention strategies may be needed.

Clinical characteristics of 13 solid organ transplant recipients with ganciclovir‐resistant cytomegalovirus infection

Abstract: Background. Ganciclovir‐resistant (GCV‐R) cytomegalovirus (CMV) is now being reported with increasing frequency in solid organ transplant recipients. Objective. To describe the clinical characteristics and outcomes of all solid organ transplant patients with GCV‐R CMV seen between 1990 and 2000 at a single center. Methods. Patients with clinically suspected GCV resistance had viral isolates subjected to phenotypic analysis by plaque reduction assay, and also genotypic analysis. Medical records of the 13 patients with GCV‐R CMV were reviewed for demographic, microbiologic, clinical, and pathologic data. Results. Thirteen patients were identified, including 5 kidney, 1 heart, and 7 lung transplant recipients. All but one patient (92%) were CMV donor seropositive, recipient negative (D+/R–), and 11/13 (85%) had tissue‐invasive CMV. CMV viremia was recurrent in 9/13 (69%); in 2 others, the first CMV episode was fatal. Overall, 9/13 (69%) of patients have died, all of CMV or its complications. Of the 10 who received foscarnet, only one survived. All patients had received GCV‐based prophylactic regimens; 8/13 patients (62%) had received CMV hyperimmune globulin (CMVIG) as part of prophylaxis, 6/13 (46%) had received oral ganciclovir, and 5/13 (38%) had received intermittent (3×/week) IV ganciclovir for prophylaxis. Conclusions. GCV‐R CMV is associated with CMV D+/R– status, tissue‐invasive disease, and high mortality even with foscarnet therapy. Exposure to less than fully therapeutic levels of GCV, in the form of oral or intermittent IV GCV, is common. The use of CMVIG in prophylaxis does not appear to prevent resistance. Further work remains to be done to elucidate the risk factors and optimal mode of prophylaxis and treatment for GCV‐R CMV.

Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation.

Bronchiolitis obliterans syndrome (BOS) is a common occurrence following lung transplantation and is one of the most important impediments to long-term graft viability. Cytolytic therapy has been used as treatment for BOS, but there is little data documenting efficacy. Furthermore, these agents have been associated with significant adverse effects. Charts of 15 patients who received an antilymphocyte preparation (ALP) for BOS were reviewed. Forced expiratory volume-1 second (FEV1) and stage of BOS were compared before and after treatment. Complications of ALP were recorded from the charts. Two of 15 patients had an improvement in FEV1, 5/15 exhibited no change, and 8/15 continued to decline. There was no pattern associating stage of BOS with likelihood of response to ALP. All patients received antimicrobial prophylaxis and did not experience infectious complications following administration of the ALP. ALP for the treatment of BOS results in an arrest or improvement of FEV1 in approximately 50% of patients. Infectious complications are uncommon when antimicrobial prophylaxis is administered.

A randomized controlled trial of verapamil on cyclosporine nephrotoxicity in heart and lung transplant recipients.

BACKGROUND Cyclosporine (CsA) is a potent immunosuppressive drug widely used in organ transplantation and in the treatment of autoimmune diseases (1, 2). However, its common nephrotoxic effect is a major limiting factor. Short-term CsA treatment has been shown to cause reversible renal vasoconstriction, whereas long-term treatment can lead to an afferent arteriolopathy and chronic renal failure. METHODS We performed a randomized controlled trial to examine the short-term renal effects of verapamil in 32 CsA-treated heart or lung transplant recipients. Sixteen patients each were randomized to receive a 6-week course of verapamil or control treatment (atenolol in hypertensive patients and placebo in normotensive patients) 1-2 months after transplantation. An 8-hr sequential clearance study of inulin and p-aminohippuric acid for estimating glomerular filtration rate and renal plasma flow, respectively, was performed at baseline and at completion of study. The integral area under the curve of the clearance parameter over 8 hr was then calculated to generate a clearance-time index. RESULTS There was no difference in the clearance-time indices for inulin and p-aminohippuric acid between the two groups at baseline. However, at the completion of study, the within-group change in the glomerular filtration rate clearance-time index was different between the verapamil and control groups (48+/-20 vs. -35+/-17 ml/min/1.73 m2 x hr, respectively; P=0.0038). A similar trend was seen for renal plasma flow, but did not reach statistical significance. Mean arterial blood pressure and whole-blood CsA levels did not differ between the two groups during the study. Verapamil treatment was also associated with a decrease in CsA dose requirement (7.6+/-0.58 mg/kg/day at baseline vs. 4.6+/-0.40 mg/kg/day at completion; P<0.001) without any significant change in trough whole blood CsA levels. Rejection episodes did not differ between the two groups. CONCLUSIONS The use of verapamil in the heart or lung transplant recipients may therefore provide both renal protective effects and cost savings.

A Comparison Of Preoperative And Postoperative Nutritional States Of Lung Transplant Recipients

Malnutrition is a documented problem in some types of end stage lung disease (ESLD). Recently, isolated lung transplants have successfully reversed the respiratory failure of patients suffering from ESLD. In this study, we compare the preoperative and postoperative nutritional states of lung transplant recipients using weight-to-height ratios, anthropometric measurements, subjective global assessment, and biochemical blood values. Patients with emphysema, cystic fibrosis, and other types of bronchiectasis, but not patients with pulmonary fibrosis or pulmonary hypertension, were malnourished preoperatively. All groups had normal biochemical profiles. Caloric intake of patients with cystic fibrosis and bronchiectasis was increased above predicted basal energy expenditure levels. By six months to one year postoperatively, all groups of malnourished patients had significantly improved their nutritional status. Emphysema patients improved nutrition by maintaining preoperative caloric intake levels—however, both cystic fibrosis and bronchiectasis patients were able to achieve the same goal with significantly decreased caloric intakes. We conclude that malnourished ESLD patients receiving isolated lung grafts are able to achieve normal nutrition within one year posttransplant. Since this occurs in all cases with a reduced, or at best maintained, caloric intake, more study is needed to elucidate the factors that contribute to ESLD malnutrition.