Marcus T. Haug

The incidence of invasive aspergillosis among solid organ transplant recipients and implications for prophylaxis in lung transplants

Abstract: Background. Invasive aspergillosis (IA) is associated with significant morbidity and mortality in solid organ transplant recipients but data on the incidence rates stratified by type of solid organ are limited. Objective. To describe the attack rates and incidence of IA in solid organ transplant recipients, and the impact of universal Aspergillus prophylaxis (aerosolized amphotericin B or oral itraconazole) in lung transplant recipients. Patients. The 2046 patients who received solid organ transplants at the Cleveland Clinic Foundation from January 1990 through 1999 were studied. Methods. Cases were ascertained through computerized records of microbiology, cytology, and pathology reports. Definite IA was defined as a positive culture and pathology showing septate hyphae. Probable IA was clinical disease and either a positive culture or histopathology. Disseminated IA was defined as involvement of two or more noncontiguous anatomic sites. Results. We identified 33 cases of IA (28% disseminated) in 2046 patients (attack rate = 1.6%) for an incidence of 4.8 cases per 1000 patient‐years (33 cases/6813 pt‐years). Both the attack and the incidence rates were significantly higher for lung transplant recipients vs. other transplant recipients: lung 12.8% (24 cases/188 patients) or 40.5 cases/1000‐pt year vs. heart 0.4% (3/686) or 1.4 per 1000‐pt year vs. liver 0.7% (3/439) or 2.1 per 1000‐pt year vs. renal 0.4% (3/733) or 1.2 per 1000‐pt year (P < 0.01). The incidence of IA was highest during the first year after transplantation for all categories, but cases occurred after the first year of transplantation only in lung transplant recipients. The attack rate of IA in lung transplant recipients was significantly lower after institution of routine Aspergillus prophylaxis (4.9% vs. 18.2%, P < 0.05). Conclusions. The highest incidence and attack rate of invasive aspergillosis among solid organ transplant recipients occurs in lung transplant recipients and supports the routine use of Aspergillus prophylaxis for at least one year after transplantation in this group.

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.

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.

Review of select transplant subpopulations at high risk of failure from standard immunosuppressive therapy.

Despite improvements in short‐term graft and patient survival rates for solid organ transplants, certain subgroups of transplant recipients experience poorer clinical outcome compared to the general population. Groups including pediatrics, African‐Americans, diabetics, cystic fibrosis patients, and pregnant women require special considerations when designing immunosuppressive regimens that optimize transplant outcomes. Problems specific to pediatric transplant recipients include altered pharmacokinetics of immunosuppressive drugs, such as cyclosporine (CsA) and tacrolimus (poor absorption, increased metabolism, rapid clearance), the need to restore growth post‐transplantation, and a high incidence of drug‐related adverse effects. African‐Americans have decreased drug absorption and bioavailability, high immunologic responsiveness, and a high incidence of post‐transplant diabetes mellitus. Diabetics and cystic fibrosis patients exhibit poor absorption of immunosuppressive agents, which may lead to underimmunosuppression and subsequent graft rejection. Pregnant women undergo physiologic changes that can alter the pharmacokinetics of immunosuppressives, thus requiring careful clinical management to minimize the risks of either under‐ or overimmunosuppression to mother and child. To achieve an optimal post‐transplant outcome in these high‐risk patients, the problems specific to each group must be addressed, and immunosuppressive therapy individualized accordingly. Drug formulation greatly impacts upon pharmacokinetics and the resultant level of immunosuppression. Thus, a formulation with improved absorption (e.g., CsA for microemulsion), higher bioavailability, and less pharmacokinetic variability may facilitate patient management and lead to more favorable outcomes, especially in groups demonstrating low and variable bioavailability. Other strategies aimed at improving transplant outcome include the use of higher immunosuppressive doses, different combinations of immunosuppressive agents, more frequent monitoring, and management of concurrent disease states.

Insulin antibodies and hypoglycemia in diabetic patients. Can a quantitative analysis of antibody binding predict the risk of hypoglycemia

We report a noninsulin-dependent diabetes mellitus (NIDDM) patient with spontaneous, severe hypoglycemic reactions and the presence of insulin antibodies. He had a remote antecedent history of beef-pork insulin therapy as well as exposure to hydralazine. Detailed insulin binding kinetic studies were performed in this patient as well as in six other insulintreated diabetic patients with anti-insulin antibodies (three with and three without an obvious cause of hypoglycemia). Sera from the current patient and five of the six other diabetic patients (one NIDDM, four IDDM) revealed two types of binding sites: high-affinity with low capacity (Kd′, 0.4–12.4×10−9 mol/L; binding capacity, 0.6–659 mU/L) and low-affinity with high capacity (Kd′, 0.3 to 35.7×10−7 mol/L; binding capacity; 202–113,680 mU/L). One NIDDM patient had only high-affinity antibodies (Kd′ 22.9 ×10−9 mol/L; binding capacity of 78 mU/L). Type of diabetes mellitus, insulin antibody titers or their binding capacities, insulin levels (total, bound, or free), and bioavailable insulin were not related to hypoglycemic reactions. Two calculated values by the method described tended to discriminate patients with and without hypoglycemia. The calculated amount of low-affinity antibody bound insulin ranged from 69.4–2090 mU/L vs <4–70.6 mU/L in patients with and without hypoglycemia, respectively. The best discrimination was afforded by the percent saturation of low-affinity binding sites; values were clearly higher in the patients with hypoglycemia (2.5–34.4 %) than in those without hypoglycemia (not detectable, 0.06, 0.15 %). Consideration of the possible drug-associated insulin antibody formation in insulin-treated diabetics and the novel quantitative analysis of the antibody binding kinetics should prove, helpful in evaluating patients with high insulin antibody titers and assessing the risk of hypoglycemia.

Cystic fibrosis patients with and without central nervous system complications following lung transplantation.

Central nervous system (CNS) complications occur more frequently in cystic fibrosis (CF) patients than other lung transplant recipients. The purpose of this study was to compare CF patients with and without CNS complications following lung transplantation, to identify risk factors for CNS events. Records of 21 patients with CF who underwent lung transplant between 1991–1996 were reviewed. Data were collected on multiple variables, including: age at transplant; gender; cytomegalovirus (CMV) status; cholesterol and triglyceride levels; sinusitis; percent ideal body weight (IBW); body mass index (BMI); augmented immunosuppression, acute lung rejection episodes (ALR); cyclosporine doses; electrolytes; magnesium, blood urea nitrogen (BUN), and creatinine levels; and 6‐month survival. CNS complications identified were seizures, severe headaches (HA), strokes, or confusional episodes.

Enhanced cyclosporine-itraconazole interaction with cola in lung transplant recipients.

Background: Invasive aspergillosis is a major cause of morbidity and mortality in lung transplant recipients (LTR), occurring in up to 15% of patients post‐transplant. The 14% aspergillus incidence at the Cleveland Clinic Foundation prompted institution of universal prophylaxis with oral itraconazole (ICZ) in 1997. We report our experience with two protocols of ICZ administration in non‐cystic fibrosis LTR and the interaction with cyclosporine (CSA). 
Methods: Group 1 patients (n=12) were administered ICZ capsules in a fasting or fed state, with or without a histamine‐2 (H‐2) receptor antagonist or proton pump inhibitor. Group 2 patients (n=12) received the same protocol as group I, but in a fed state with a carbonated beverage (cola) to increase acidity in the stomach to enhance absorption of ICZ. The ICZ dose was 200 mg/d, given as one daily dose. A historical control group (n=10) did not receive chemoprophylaxis with ICZ. CSA daily doses, dose intervals, concentration, cost, and random ICZ levels were documented over a 4‐month period of time and compared using generalized estimating equations. 
Results: The daily CSA mg/kg/d dose decreased over time in all three groups, but no differences were found between the three groups. The CSA dosing interval over time was significantly prolonged in group 2 compared to group 1 or the control group (p≤0.003). Over time, there was no difference in CSA concentration between all groups. There was no difference in cost over time between the three groups; however, the mean cost of CSA therapy was significantly lower in group 2 compared to the control group (p=0.025). Group 2 administered ICZ with cola had greater random blood concentrations of ICZ (p=0.019). 
Conclusions: ICZ capsules administered in a fed state with a cola resulted in greater random levels of ICZ, a decrease in cost/d of CSA, and a prolongation of CSA dosing interval. Although daily CSA dosage trended lower in group 2, it did not reach statistical significance. We believe these changes in CSA dosing over time reflect increased absorption of ICZ and recommend verifying ICZ absorption with an itraconazole level, especially when CSA intervals are not prolonged.

Does the donor-recipient ABO blood group compatibility status predict subsequent lung transplantation outcomes?

BACKGROUND The study was conducted to compare lung transplantation outcomes between ABO-identical (AI) and ABO-compatible (AC) recipients. METHODS Charts of lung allograft recipients transplanted between February, 1990 and October, 1995 were reviewed. Standard triple-drug immunosuppression and general antimicrobial prophylaxis were provided. Surveillance spirometry was administered every three months. Flexible bronchoscopy (FB) with transbronchial biopsies (TBBs) were undertaken for clinical indications. Time to event analysis on acute (AR) and chronic (CR) rejection and actuarial survival were determined by Kaplan-Meier analysis. Cumulative curves were compared with a log rank test. Comparisons of age, maximum forced expiratory volume in one second (FEV1) in the single (SLT) and double (DLT) lung recipients, duration of intensive care unit and hospital stay were carried out using the Wilcoxon Rank Sum test. Gender, race, underlying diagnoses, cytomegalovirus (CMV) status and pulmonary reimplantation response (PRR) were compared by Chi-square or Fishers exact test where appropriate. RESULTS Of the 100 lung recipients (age = 42.5 +/- 13.4 years; M:F = 50:50), 64 were AI and 36 AC. Median follow-up was 22 (range = 0-78) months. Outcome did not differ significantly between the 2 groups in terms of intensive care unit and hospital stay, PRR incidence and grade, incidence and frequencies of AR, median time and grade of first AR, maximum FEV1 for SLT and DLT recipients, incidence of CR and survival at 12 months. CONCLUSIONS As the donor supply remains limited, this could considerably simplify the logistics of future transplantation.

Cyclosporine disposition and long-term renal function in a 500-pound kidney transplant recipient.

Patient size has been suggested as a risk factor in kidney transplantation. We have followed a recipient of a cadaver kidney who became massively obese (232 kg, 511 lbs) 5 years posttransplantation. He has maintained stable renal function with no rejection episodes and at 5 years has a measured serum creatinine of 2.2 mg/dL, creatinine clearance 42 mL/min, and urinary protein excretion of 320 mg/24h. Both oral and intravenous cyclosporine (Sandimmune) pharmacokinetic studies were done on a steady-state dose of 150 mg, which represents 0.65 mg/kg per dose. The patient exhibited very high bioavailability, F = 95%, and an oral elimination T1/2 of over 21 hours. These data confirm that stable cyclosporine delivery in very obese recipients can be sustained by dosing normalized to the ideal body weight and trough level monitoring.