Daniel R. Kaul

Assessment of Cytomegalovirus-Specific Cell-Mediated Immunity for the Prediction of Cytomegalovirus Disease in High-Risk Solid-Organ Transplant Recipients: A Multicenter Cohort Study

BACKGROUND Cytomegalovirus (CMV) disease remains an important problem in solid-organ transplant recipients, with the greatest risk among donor CMV-seropositive, recipient-seronegative (D(+)/R(-)) patients. CMV-specific cell-mediated immunity may be able to predict which patients will develop CMV disease. METHODS We prospectively included D(+)/R(-) patients who received antiviral prophylaxis. We used the Quantiferon-CMV assay to measure interferon-γ levels following in vitro stimulation with CMV antigens. The test was performed at the end of prophylaxis and 1 and 2 months later. The primary outcome was the incidence of CMV disease at 12 months after transplant. We calculated positive and negative predictive values of the assay for protection from CMV disease. RESULTS Overall, 28 of 127 (22%) patients developed CMV disease. Of 124 evaluable patients, 31 (25%) had a positive result, 81 (65.3%) had a negative result, and 12 (9.7%) had an indeterminate result (negative mitogen and CMV antigen) with the Quantiferon-CMV assay. At 12 months, patients with a positive result had a subsequent lower incidence of CMV disease than patients with a negative and an indeterminate result (6.4% vs 22.2% vs 58.3%, respectively; P < .001). Positive and negative predictive values of the assay for protection from CMV disease were 0.90 (95% confidence interval [CI], .74-.98) and 0.27 (95% CI, .18-.37), respectively. CONCLUSIONS This assay may be useful to predict if patients are at low, intermediate, or high risk for the development of subsequent CMV disease after prophylaxis. CLINICAL TRIALS REGISTRATION NCT00817908.

First Report of Successful Treatment of Multidrug‐Resistant Cytomegalovirus Disease with the Novel Anti‐CMV Compound AIC246

We report the first case of cytomegalovirus (CMV) disease treated with AIC246, a novel anti‐CMV compound which targets the viral terminase complex and remains active against virus resistant to DNA polymerase inhibitors. A lung transplant recipient developed refractory multidrug‐resistant CMV disease involving the lungs, gastrointestinal tract and retina. His disease progressed despite treatment with all DNA polymerase inhibitors; multiple agents reported to have activity against CMV in case series, and reduction in his immunosuppressive medications. AIC246 which is in clinical development was obtained for emergency use, and combined with additional reduction in immunosuppression resulted in rapid clinical, virological and radiological resolution of disease. The patient has remained free of CMV disease or viremia off treatment for greater than 3 months. In summary AIC246, while still in development, may be a promising alternative to current therapies.

Low-dose cidofovir treatment of BK virus-associated hemorrhagic cystitis in recipients of hematopoietic stem cell transplant

In recipients of hematopoietic stem cell transplants (HSCTs), BK virus (BKV) has been associated with late-onset hemorrhagic cystitis (HC). In our institution, HSCT recipients with BKV-associated HC are treated with 1 mg/kg of cidofovir weekly. We identified HSCT recipients with BKV-associated HC, treated with weekly cidofovir. Microbiological response was defined as at least a one log reduction in urinary BKV viral load; clinical response was defined as improvement in symptoms and stability or reduction in the grade of cystitis. Nineteen allogeneic HSCT patients received a mean of 4.5 weekly doses of cidofovir. HC occurred at a mean of 68.7 days after transplant. A clinical response was detected in 16/19 (84%) patients, and 9/19 (47%) had a measurable microbiological response (8/10 nonresponders had a BKV viral load above the upper limit of the assay before treatment). Fourteen out of nineteen (74%) patients had no significant increase in serum creatinine. Five patients with renal dysfunction resolved after completion of the therapy and removal of other nephrotoxic agents. We conclude that weekly low-dose cidofovir appears to be a safe treatment option for BKV-associated HC. Although the efficacy of low-dose cidofovir is not proven, a prospective trial is warranted.

Association between sarcopenia and the risk of serious infection among adults undergoing liver transplantation

Although sarcopenia (muscle loss) is associated with increased mortality after liver transplantation, its influence on other complications is less well understood. We examined the association between sarcopenia and the risk of severe posttransplant infections among adult liver transplant recipients. By calculating the total psoas area (TPA) on preoperative computed tomography scans, we assessed sarcopenia among 207 liver transplant recipients. The presence or absence of a severe posttransplant infection was determined by a review of the medical chart. The influence of posttransplant infections on overall survival was also assessed. We identified 196 episodes of severe infections among 111 patients. Fifty‐six patients had more than 1 infection. The median time to the development of an infection was 27 days (interquartile range = 13‐62 days). When the patients were grouped by TPA tertiles, patients in the lowest tertile had a greater than 4‐fold higher chance of developing a severe infection in comparison with patients in the highest tertile (odds ratio = 4.6, 95% confidence interval =  2.25‐9.53). In a multivariate analysis, recipient age (hazard ratio = 1.04, P = 0.02), pretransplant TPA (hazard ratio = 0.38, P < 0.01), and pretransplant total bilirubin level (hazard ratio = 1.05, P = 0.02) were independently associated with the risk of developing severe infections. Patients with severe posttransplant infections had worse 1‐year survival than patients without infections (76% versus 92%, P = 0.003). In conclusion, among patients undergoing liver transplantation, a lower TPA was associated with a heightened risk for posttransplant infectious complications and mortality. Future efforts should focus on approaches for assessing and mitigating vulnerability in patients undergoing transplantation. Liver Transpl 19:1396–1402, 2013.

Infectious disease emergencies

This article reviews principles of recognition and management of a selection of commonly encountered infectious disease emergencies, including sepsis, necrotizing soft tissue infections, acute meningitis, and the emerging issue of severe Clostridium difficile colitis. Less common but potentially deadly environmentally acquired or zoonotic pathogens are discussed, as are special patient populations, including the febrile returning traveler and the asplenic patient.

HIV Protease Inhibitors: Advances in Therapy and Adverse Reactions, Including Metabolic Complications

Protease inhibitors (PIs) effectively inhibit replication of the human immunodeficiency virus (HIV), and reduce mortality and prolong survival in patients with HIV infection. Newer PIs saquinavir (soft gelatin capsule) and amprenavir, as well as other PIs, may be effective when administered twice/day. Adverse reactions may occur, as well as metabolic complications and interactions between PIs and other drugs, including other PIs. The strategy of combining PIs is based on specific pharmacologic interactions among the agents.

Histoplasmosis After Solid Organ Transplant

BACKGROUND To improve our understanding of risk factors, management, diagnosis, and outcomes associated with histoplasmosis after solid organ transplant (SOT), we report a large series of histoplasmosis occurring after SOT. METHODS All cases of histoplasmosis in SOT recipients diagnosed between 1 January 2003 and 31 December 2010 at 24 institutions were identified. Demographic, clinical, and laboratory data were collected. RESULTS One hundred fifty-two cases were identified: kidney (51%), liver (16%), kidney/pancreas (14%), heart (9%), lung (5%), pancreas (2%), and other (2%). The median time from transplant to diagnosis was 27 months, but 34% were diagnosed in the first year after transplant. Twenty-eight percent of patients had severe disease (requiring intensive care unit admission); 81% had disseminated disease. Urine Histoplasma antigen detection was the most sensitive diagnostic method, positive in 132 of 142 patients (93%). An amphotericin formulation was administered initially to 73% of patients for a median duration of 2 weeks; step-down therapy with an azole was continued for a median duration of 12 months. Ten percent of patients died due to histoplasmosis with 72% of deaths occurring in the first month after diagnosis; older age and severe disease were risk factors for death from histoplasmosis. Relapse occurred in 6% of patients. CONCLUSIONS Although late cases occur, the first year after SOT is the period of highest risk for histoplasmosis. In patients who survive the first month after diagnosis, treatment with an amphotericin formulation followed by an azole for 12 months is usually successful, with only rare relapse.

Kiss of Death

n engl j med 360;24 nejm.org june 11, 2009 2564 From the Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver (B.B.G., W.J.J.); the Division of Infectious Disease (D.R.K.), Department of Internal Medicine (S.S.), and Department of Veterans Affairs Health Services Research and Development Center of Excellence and Department of Medicine (S.S.) — all at the University of Michigan, Ann Arbor; and the Department of Medicine, National Jewish Medical and Research Center, Denver (W.J.J.). Address reprint requests to Dr. Graham at the University of Colorado Health Sciences Center, 4200 E. 9th Ave., Box C-272, Denver, CO, 80262, or at brian. graham@uchsc.edu.

Six-Month Prophylaxis Is Cost Effective in Transplant Patients at High Risk for Cytomegalovirus Infection

The risk of late-onset cytomegalovirus (CMV) infection remains a concern in seronegative kidney and/or pancreas transplant recipients of seropositive organs despite the use of antiviral prophylaxis. The optimal duration of prophylaxis is unknown. We studied the cost effectiveness of 6- versus 3-mo prophylaxis with valganciclovir. A total of 222 seronegative recipients of seropositive kidney and/or pancreas transplants received valganciclovir prophylaxis for either 3 or 6 mo during two consecutive time periods. We assessed the incidence of CMV infection and disease 12 mo after completion of prophylaxis and performed cost-effectiveness analyses. The overall incidence of CMV infection and disease was 26.7% and 24.4% in the 3-mo group and 20.9% and 12.1% in the 6-mo group, respectively. Six-month prophylaxis was associated with a statistically significant reduction in risk for CMV disease (HR, 0.35; 95% CI, 0.17 to 0.72), but not infection (HR, 0.65; 95% CI, 0.37 to 1.14). Cost-effectiveness analyses showed that 6-mo prophylaxis combined with a one-time viremia determination at the end of the prophylaxis period incurred an incremental cost of

Recurrence of Mycobacterium avium Infection in Patients Receiving Highly Active Antiretroviral Therapy and Antimycobacterial Agents

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