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< or =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.

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.

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.

Cystic fibrosis and bronchiectasis: selection, timing, and outcome.

Of the nearly 30,000 Cystic Fibrosis (CF) patients alive in the United States, more than 300 die each year. Of CF deaths at least 75% are from respiratory failure due to bronchiectasis. CF patients make up about 40% of the patients undergoing bilateral transplant. Because of the shortage of donor organs relative to the demand for them, it is important to choose candidates who are in the "transplant window.'' International criteria have been developed to assist in proper selection of potential candidates, but new data suggest that some refinement of current criteria may improve this process. Appropriate prognostic models, however, are not yet completely validated. Bronchiectasis patients are usually evaluated according to the same protocols as CF patients because no large studies exist that would allow us to derive separate prognostic indicators. Outcomes for CF patients are comparable to those for other diagnoses, except in the case of living donor recipients, which are slightly lower. CF patients may face particular issues following transplant-like infections and some immunosuppression complications possibly related to their underlying disease process. In addition, CF patients seem to be at particular risk of posttransplant lymphoproliferative disorder.

The spectrum of colonic complications in a lung transplant population.

BACKGROUND: Abdominal complications are recognized as a common complication of solid organ transplantation. These complications can range from gastritis with minor morbidity to viscus perforation and death. This study addresses specifically colonic complications in lung transplant patients to highlight their high incidence and significant morbidity and mortality in this population. METHODS: Data was obtained from a prospectively gathered database on 210 patients who underwent isolated lung transplantation between February 1, 1990, and July 10, 2000 at the Cleveland Clinic Foundation. Chronic diarrhea without a specific colonic lesion and infectious diarrheas except for CMV disease was excluded from the analysis. RESULTS: Twenty-seven of the 210 transplant recipients (13 percent) developed a colonic complication. The sex distribution of complications was 14 males and 13 females. The colonic complications noted were diverticulitis (9), CMV colitis (5), colon cancer/precancerous polyps (4), post transplant lymphoproliferative disorder (4), megacolon (4), colon rupture (2). One patient had concurrent CMV colitis and diverticulitis. Documented perforations occurred in seven patients and surgical resection was required in 11 patients. Of the 27 patients, 10 died and nine of the deaths were directly attributable to the colonic complication. CONCLUSIONS: Colonic complications are common post lung transplant and result in excessive morbidity and mortality in this population. Strategies to reduce this risk should be put in place in lung transplant centers.

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 Fisher's 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.

Native lung pneumonectomy for invasive pulmonary aspergillosis following lung transplantation: a case report.

Pulmonary aspergillosis occurs most commonly as a consequence of immunosuppression in recipients of pulmonary transplantation and is associated with a high mortality. It affects the native lung more commonly than the transplanted lung in single lung transplant patients. Infection often progresses despite aggressive medical therapy. The cornerstone of treatment of acute, semi-invasive, and invasive pulmonary aspergillosis (IPA) is medical, with intravenous amphotericin B, and oral itraconazole either as isolated or combined therapy. While newer, and more expensive liposomal forms of amphotericin B have been used to enhance tissue penetration and minimize renal toxicity, an appreciable improvement in clinical outcome has not been reported. The role of surgery in localized pulmonary aspergillus infection is well recognized, but remains undefined in immunosuppressed patients. We report a case where a pneumonectomy was performed for progressive, refractory angioinvasive aspergillosis in a lung transplant recipient whose disease progressed despite conventional antifungal therapy.

Chest wall arteriovenous fistula: an unusual complication after chest tube placement.

Posttraumatic arteriovenous fistulas can form between vessels of the thorax that have sustained loss of integrity to the vessel wall. Although most are caused by injuries as a consequence of missile penetration or stab wounds, iatrogenic damage is a potential cause. Herein we present a case of a systemic arteriovenous fistula involving an intercostal artery and subcutaneous vein after chest tube placement.

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.

Central nervous system complications after lung transplantation.

PURPOSE: This study describes the central nervous system (CNS) events after lung transplantation. METHODS: A chart review of all lung transplant recipients (LTR) to collect the clinical and neuroimaging data for CNS events defined as seizures, severe headaches, confusion, or stroke. RESULTS: Twenty-six patients of 100 LTRs from 1990 through 1995 had a CNS event; more than one event occurred in 5 patients for a total of 32 events. Severe headache was most common, occurring in 14 patients, followed by seizures in 10, stroke in 5, and confusion in 3. The CNS event was related to infection in three of the 26 patients. Of all evaluations performed, magnetic resonance imaging (MRI) identified the most abnormalities, the most common being white matter changes consistent with cyclosporine toxicity. Cyclosporine levels were elevated in slightly more than half of the patients. Hypomagnesemia was present in three of 10 patients with seizures. Prognosis for recovery from these complications was good, with only five patients having ongoing problems with headaches, one requiring long term anticonvulsant therapy, three having minor or no limitations from stroke and no long-term problems with confusion. One patient with seizures resulting from an aspergilloma died. CONCLUSION: CNS events occur commonly in LTRs, mostly related to cyclosporine toxicity or infection. MRI identifies more abnormalities than computed tomography. These events were not consistently associated with documented high cyclosporine levels and hypomagnesemia. In spite of significantly abnormal MRIs, the functional outcome is favorable.

Nonpulmonary medical complications in the intermediate and long-term survivor.

This article deals with the nonpulmonary, non-infectious complications in intermediate and long-term survivors of lung transplantation. Although they are an infrequent cause of mortality, these disorders can cause significant morbidity in this population. Diseases associated with the gamut of medications used post-transplant are specifically discussed, as are diseases caused by the direct immunosuppressive action of some of these drugs. General care of transplant patients also entails attention to their underlying diseases, and to routine medical considerations common to all patients.

Aspergillus infection in single and double lung transplant recipients.

To investigate the clinical manifestations of Aspergillus infections in lung transplant recipients, we reviewed the mycology and autopsy reports of all double (DLT=93) and single (SLT=48) lung transplant recipients from November 1983 to May 1993. Positive Aspergillus cultures were identified in 22% of the recipients (DLT=21, SLT=10). Colonization alone was present in 19 recipients (DLT=16, SLT=3). Complicated Aspergillus infection included Aspergillus bronchitis (DLT=1, SLT=1), aspergilloma (SLT=2), pulmonary invasive aspergillosis (DLT=1, SLT=2), disseminated aspergillosis (DLT=1, SLT=2), empyema (DLT=1), and a retroperitoneal abscess (DLT=1). Symptoms were seen only in patients with complicated lung infections and CXR abnormalities began in the native lung of four SLT recipients. Twenty patients survived (DLT=17, SLT=3) and 11 died (DLT=4, SLT=7) of disseminated aspergillosis (SLT=2), pulmonary invasive disease (DLT=1), bronchiolitis obliterans (DLT=2, SLT=2, CMV pneumonitis (SLT=1), diffuse alveolar damage (SLT=2), and hyperacute rejection (DLT=1). Complicated infection and mortality were more common in SLTs than DLTs (P<0.05). We conclude that infection with Aspergillus is not infrequent in the lung transplantation population. Single lung recipients develop more complicated infection than double lung recipients after Aspergillus infection with native lung being a potential source of infection.

Diaphragmatic paralysis: a complication of lung transplantation.

BACKGROUND: Damage to the phrenic nerve, either unilaterally or bilaterally, is a well-documented complication of cardiac operation, but less commonly reported after lung transplantation. METHODS: A retrospective review of 185 single and sequential single lung transplant procedures was performed at The Toronto Hospital. Objective confirmation (fluoroscopy or ultrasound) of diaphragmatic paralysis was found in 6 patients. Paralysis was unilateral in 5 patients (all were left sided) and bilateral in 1 patient. RESULTS: The average length of ventilation was 8.2 +/- 9.2 days with an average intensive care unit stay of 11.2 +/- 10.6 days. Mean duration in the hospital was 37.5 +/- 11.1 days. The average length of intensive care unit stay and hospitalization were compared with all other sequential single transplantations performed from approximately the time of the first documented case of diaphragmatic paralysis. Intensive care unit stay and hospitalization for the other (no diaphragmatic paralysis) transplant recipients were significantly shorter (5.3 +/- 2.7 and 29.1 +/- 12.9 days, respectively; p < 0.05). One patient required noninvasive ventilatory assistance via bilevel positive airway pressure in the hospital. One other patient used bilevel positive airway pressure in the hospital and overnight for 6 months after discharge. All patients obtained acceptable lung function and were ambulatory upon discharge from the hospital. CONCLUSIONS: Clinically detectable diaphragmatic paralysis is an infrequent complication of lung transplantation and is associated with longer intensive care unit stay and hospitalization, but is not associated with significant adverse outcomes.

Lung transplantation in cystic fibrosis.

Since the mid-1980s, more than 500 isolated lung and more than 240 heart-lung transplantations have been performed in patients with cystic fibrosis and end-stage disease. Survival data in these patients are now comparable to those of the general transplantation population as physicians have learned to deal successfully with many issues unique to patients with cystic fibrosis. Resistant infections and bronchiolitis obliterans remain significant obstacles to overcome in order to improve patients outcomes and enhance posttransplant quality of life.