Performance of Candida real-time polymerase chain reaction, ß-D-glucan assay, and blood cultures in the diagnosis of invasive candidiasis.

BACKGROUND: The sensitivity of blood cultures for diagnosing invasive candidiasis (IC) is poor. METHODS: We performed a validated Candida real-time polymerase chain reaction (PCR) and the Fungitell 1,3-ß-D-glucan (BDG) assay on blood samples collected from prospectively identified patients with IC (n = 55) and hospitalized controls (n = 73). Patients with IC had candidemia (n = 17), deep-seated candidiasis (n = 33), or both (n = 5). Controls had mucosal candidiasis (n = 5), Candida colonization (n = 48), or no known Candida colonization (n = 20). RESULTS: PCR using plasma or sera was more sensitive than whole blood for diagnosing IC (P = .008). Plasma or sera PCR was more sensitive than BDG in diagnosing IC (80% vs 56%; P = .03), with comparable specificity (70% vs 73%; P = .31). The tests were similar in diagnosing candidemia (59% vs 68%; P = .77), but PCR was more sensitive for deep-seated candidiasis (89% vs 53%; P = .004). PCR and BDG were more sensitive than blood cultures among patients with deep-seated candidiasis (88% and 62% vs 17%; P = .0005 and .003, respectively). PCR and culture identified the same Candida species in 82% of patients. The sensitivity of blood cultures combined with PCR or BDG among patients with IC was 98% and 79%, respectively. CONCLUSIONS: Candida PCR and, to a lesser extent, BDG testing significantly enhanced the ability of blood cultures to diagnose IC.

Comparison of an Aspergillus real-time polymerase chain reaction assay with galactomannan testing of bronchoalvelolar lavage fluid for the diagnosis of invasive pulmonary aspergillosis in lung transplant recipients.

BACKGROUND: Early diagnosis and treatment of invasive pulmonary aspergillosis (IPA) improves outcome. METHODS: We compared the performance of publicly available pan-Aspergillus, Aspergillus fumigatus-, and Aspergillus terreus-specific real-time polymerase chain reaction (PCR) assays with the Platelia galactomannan (GM) assay in 150 bronchoalveolar lavage (BAL) samples from lung transplant recipients (16 proven/probable IPA, 26 Aspergillus colonization, 11 non-Aspergillus mold colonization, and 97 negative controls). RESULTS: The sensitivity and specificity of pan-Aspergillus PCR (optimal quantification cycle [Cq], ≤35.0 by receiver operating characteristic analysis) and GM (≥.5) for diagnosing IPA were 100% (95% confidence interval, 79%-100%) and 88% (79%-92%), and 93% (68%-100%) and 89% (82%-93%), respectively. The sensitivity and specificity of A. fumigatus-specific PCR were 85% (55%-89%) and 96% (91%-98%), respectively. A. terreus-specific PCR was positive for the 1 patient with IPA due to this species; specificity was 99% (148 of 149 samples). Aspergillus PCR identified 1 patient with IPA not diagnosed by GM. For BAL samples associated with Aspergillus colonization, the specificity of GM (92%) was higher than that of pan-Aspergillus PCR (50%; P = .003). Among negative control samples, the specificity of pan-Aspergillus PCR (97%) was higher than that of BAL GM (88%; P = .03). Positive results for both BAL PCR and GM testing improved the specificity to 97% with minimal detriment to sensitivity (93%). CONCLUSIONS: A recently developed pan-Aspergillus PCR assay and GM testing of BAL fluid may facilitate the diagnosis of IPA after lung transplantation. A. fumigatus- and A. terreus-specific real-time PCR assays may be useful in rapidly identifying the most common cause of IPA and a species that is intrinsically resistant to amphotericin B, respectively.

Posaconazole serum concentrations among cardiothoracic transplant recipients: factors impacting trough levels and correlation with clinical response to therapy.

Fifty-six serum posaconazole trough levels were measured in 17 cardiothoracic transplant recipients. Initial levels were ≤ 0.5, 0.51 to 0.99, and ≥ 1 µg/ml for 47, 29, and 24% of patients, respectively. Median trough levels associated with therapeutic success were higher than those associated with failure (1.55 versus 0.34 µg/ml; P = 0.006). Patients with levels consistently >0.5 µg/ml were more likely to have successful outcome (P = 0.055). Age ≥ 65 years, oral administration, and absence of proton pump inhibitors were associated with higher levels of posaconazole (P = 0.006, 0.006, and 0.001, respectively).

Effects of increased dose of diuretics on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of left ventricular systolic and diastolic function in 51 patients with symptomatic heart failure caused by reduced left ventricular ejection fraction treated with beta blockers and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers.

We investigated in 51 consecutive outpatients with symptomatic congestive heart failure caused by abnormal left ventricular (LV) ejection fraction treated with furosemide or torsemide (10% also with metolazone), beta blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 55% with spironolactone, and 18% with digoxin, the effects of doubling the dose of furosemide, torsemide, and metolazone on symptoms, weight, 6-minute walk distance, and echocardiographic measurements of LV systolic and diastolic function at 24 ± 6 days follow-up. At follow-up, the weight decreased from 70 ± 6 kg to 65 ± 6 kg (P < 0.001), the New York Heart Association functional class decreased from 2.9 ± 0.4 to 2.1 ± 0.2 (P < 0.001), the Minnesota With Heart Failure Questionnaire score decreased from 43 ± 7 to 28 ± 8 (P < 0.001), the 6-minute walk distance increased from 270 ± 46 m to 318 ± 44 m (P < 0.001), and there was no significant change in LV ejection fraction, LV end-diastolic dimension, LV end-systolic dimension, left atrial dimension, pulmonary artery systolic pressure, peak mitral early/ atrial ratio, mitral deceleration time, and velocity time interval. In conclusion, doubling the dose of diuretics in outpatients with symptomatic congestive heart failure caused a significant loss of weight and a significant improvement in symptoms and 6-minute walk distance but did not change LV systolic and diastolic function.

Effect of enhanced external counterpulsation on clinical symptoms, quality of life, 6-minute walking distance, and echocardiographic measurements of left ventricular systolic and diastolic function after 35 days of treatment and at 1-year follow up in 47 patients with chronic refractory angina pectoris.

In a prospective study, enhanced external counterpulsation (EECP) was performed for 1 hour each day for 35 days in 47 patients, mean age 61 +/- 8 years, with prior coronary revascularization who had chronic refractory angina pectoris despite antianginal drugs and who were not candidates for further coronary revascularization. Compared with baseline values, EECP significantly improved anginal symptoms, dyspnea on exertion, and quality of life after 35 days of treatment (P < 0.001) and at 1-year follow up (P < 0.001). Compared with the baseline value of 653 +/- 249 feet, EECP significantly improved the 6-minute walking distance to 1025 +/- 234 feet after 35 days of treatment (P < 0.001) and to 1040 +/- 221 feet at 1-year follow up (P < 0.001). However, EECP did not significantly affect left ventricular ejection fraction, left ventricular end-diastolic and end-systolic dimensions, left ventricular end-diastolic and end-systolic volumes, E/A ratio, isovolumic relaxation time, and deceleration time measured by two2-dimensional and Doppler echocardiography.

Age-specific complications among lung transplant recipients 60 years and older.

BACKGROUND: An age limit of 65 years has been suggested for lung transplantation (LTx). METHODS: We conducted a retrospective study of LTx recipients at our institution and compared survival rates among patients aged <60, 60 to 65, and >65 years. We identified common complications and risk factors for death among patients aged ≥ 60 years. RESULTS: Between January 2006 and May 2008, 126 of 268 (47%) of LTx recipients were aged >60 years, among whom 36% were 60 to 65 and 64% were >65 years. There were no differences in survival among patients aged <60, 60 to 65, and >65 years. Among older patients, the major complications were infections (78%), rejection (36%), thromboembolism (21%), bone fractures (12%), malignancies (10%), and drug toxicity (10%). Rejection was more common among patients who were aged 60 to 65, and malignancies and drug toxicity were more common among patients >65 years. Other complications did not differ by age group. Infections accounted for 69% of deaths within 12 months, and infection-related deaths did not differ among the groups. Major infections were the strongest independent risk factors for death (hazard ratio, 4.37), followed by cytomegalovirus mismatch (hazard ratio, 3.69) and pre-transplant coronary artery disease (hazard ratio, 2.43). CONCLUSIONS: Survival rates among LTx recipients were similar regardless of age, but specific complications among older patients differed by age. Selection for LTx should not be based strictly on an age cutoff, but rather individualized according to general health status and other risk factors. Further research on risk factors affecting outcomes, pharmacokinetics and dynamics, quality of life, and mechanisms of untoward events is needed among older LTx recipients.

Cytomegalovirus disease among donor-positive/recipient-negative lung transplant recipients in the era of valganciclovir prophylaxis.

BACKGROUND: Valganciclovir prophylaxis is advocated for lung transplant recipients, but its efficacy is unknown. METHODS: Retrospective review was done of 109 donor-positive/recipient-negative lung transplant patients who received alemtuzumab induction and valganciclovir for cytomegalovirus prophylaxis. RESULTS: Median duration of follow-up after transplant was 27 months. Valganciclovir dose reductions (< 900 mg/day or renal-equivalent) were required for 18 patients (17%) due to toxicity, most commonly for neutropenia (n = 15) or gastrointestinal symptoms (n = 2). Of the 109 patients, 34 (31%) had no CMV infections, 45 (41%) had asymptomatic viremia, and 30 (27%) had CMV disease. CMV disease developed off prophylaxis in 10 patients (18%) at a median of 8.7 months after transplant and 2 months after valganciclovir discontinuation. Breakthrough disease occurred during prophylaxis in 10 patients (9%) at a median of 6.7 months. Patients with asymptomatic viremia or no CMV infection received prophylaxis for median 8.6 and 8.7 months, respectively. Risk factors for CMV disease by univariate analysis were increased age (p = 0.01), single-lung transplant (p = 0.03), chronic obstructive pulmonary disease (p = 0.05), reduced-dose valganciclovir (p = 0.001), and less than 6 months of prophylaxis (p = 0.005). By multivariate analysis, advanced age (p = 0.01) and reduced-dose valganciclovir (p = 0.0006) were independent risk factors for CMV disease. CMV disease developed in 4 patients (4%) due to ganciclovir-resistant viruses. CMV-attributable mortality was 5% (5 of 109), including 100% (4 of 4) with ganciclovir-resistant disease. CONCLUSIONS: Valganciclovir prophylaxis among donor-positive/recipient-negative lung transplant recipients delayed but did not eliminate CMV disease or CMV-related deaths and was limited by toxicity and ganciclovir-resistance. Our experience suggests that valganciclovir at reduced-doses or for less than 6 months is sub-optimal in preventing CMV disease.

Voriconazole exposure and geographic location are independent risk factors for squamous cell carcinoma of the skin among lung transplant recipients.

BACKGROUND: Skin cancer, in particular squamous cell carcinoma (SCC), is the most common malignancy after solid-organ transplantation. SCC has been reported in immunosuppressed patients receiving voriconazole, but the agent has not been shown to be a risk factor. Universal voriconazole prophylaxis and alemtuzumab induction are standard in our lung transplant program. METHODS: We performed a retrospective, case-control study (matched 1:3) among lung transplant recipients at our center from 2003 to 2008. RESULTS: SCC was diagnosed in 3.1% (17 of 543) of patients at a median follow-up of 36 months. Median time to development of SCC was 19 months post-transplant. Risk factors for SCC by univariate analysis included older age (p = 0.02), residence in locations with high levels of sun exposure (p = 0.0001), single-lung transplant (p = 0.02) and duration (p = 0.03) and cumulative dose (p = 0.03) of voriconazole. Duration of voriconazole (hazard ratio [HR] = 2.1; p = 0.04) and residence in locations with high sun exposure (HR = 3.8; p = 0.0004) were independent risk factors by multivariate analysis. SCC lesions were located on the head and neck in 94% of cases, and 53% had multiple lesions. All patients were treated with surgery. At least one independent lesion developed subsequently in 47% of patients. Local spread and distant metastases each occurred in 7% of cases. There were no deaths among the cases. CONCLUSIONS: Voriconazole exposure is a risk factor for SCC after lung transplantation, particularly among older patients living in areas with high sun exposure. Voriconazole should be used cautiously in these patients.

Impact of mold infections in explanted lungs on outcomes of lung transplantation.

INTRODUCTION: Little is known about the incidence or significance of mold infections in the explanted lungs of lung transplant recipients. METHOD: We reviewed the histopathology of the explanted lungs from 304 patients who underwent lung transplantation at our institution from 2005 to 2007 and received alemtuzumab induction therapy and posttransplant voriconazole prophylaxis. RESULTS: Invasive mold infections were present in the explanted lungs of 5% (14 of 304) of patients, including chronic necrotizing pneumonias (n=7), mycetomas (n=4), and invasive fungal pneumonias (n=3). Only 21% (3 of 14) received immunosuppressive therapy within 1 year before lung transplantation, suggesting that lung damage itself predisposed patients to mold infections. The risk of mold infection was higher in patients with cystic fibrosis (11%, 4 of 35) than other underlying lung diseases (4%, 10 of 269). Pulmonary mold infections were not diagnosed or suspected in 57% (8 of 14) of patients. Despite secondary voriconazole prophylaxis, fungal infections developed in 43% (6 of 14) of patients with mold infections of the explanted lungs compared with 14% (42 of 290) of patients without mold infections (P=0.01). Three patients developed invasive fungal infections while on voriconazole prophylaxis and three developed fungal infections more than 8 months after the discontinuation of voriconazole. The mortality attributable to invasive fungal infections among patients with mold infections of the explanted lungs was 29% (4 of 14). CONCLUSION: Invasive mold infections in the explanted lungs are often not recognized before lung transplantation and are associated with poor outcomes.