Lora D. Thomas

A prospective longitudinal study of polyomavirus shedding in lung-transplant recipients.

BACKGROUND Polyomavirus infection causes renal dysfunction after kidney transplantation, but it has not been thoroughly investigated in nonrenal solid-organ transplantation. METHODS Fifty lung-transplant recipients provided prospective urine and blood samples over the course of 17 months. Samples were analyzed for BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) using conventional polymerase chain reaction (PCR), sequence analysis, and quantitative real-time PCR. RESULTS Thirty-one (62%) of 50 patients had polyomavirus detected in at least 1 urine specimen, including 16 (32%) for BKV, 12 (24%) for JCV, and 6 (12%) for SV40. Mean BKV loads (5.0 log(10) copies/mL) did not differ from those of JCV (5.7 log(10) copies/mL; P=.38), but SV40 loads (2.5 log(10) copies/mL) were lower than those of BKV (P=.006) and JCV (P=.002). Blood samples were negative. Infection with individual polyomaviruses or polyomavirus infection in aggregate was not associated with reduced creatinine clearance. Patients not shedding polyomavirus had better survival than patients shedding polyomavirus (P=.049). CONCLUSIONS Polyomaviruses BKV and JCV were commonly detected in urine from lung-transplant recipients. SV40 was found in 12% of patients but was shed at a lower frequency and with lower viral loads than the other viruses. Polyomavirus infection was not associated with renal dysfunction.

Human ehrlichiosis in transplant recipients.

To characterize the impact of immunosuppression on human ehrlichiosis, we reviewed cases of ehrlichiosis occurring in transplant recipients and immunocompetent patients at three hospitals in Nashville, Tennessee. Between 1998 and 2006, 15 transplant patients were identified as having ehrlichiosis, diagnosed either by whole blood polymerase chain reaction (PCR) (n = 14) or serology (n = 1). They were compared with 43 immunocompetent patients diagnosed by whole blood PCR. We retrospectively collected demographic and clinical information. The species of Ehrlichia (E. ewingii or E. chaffeensis) was determined for patients diagnosed by PCR. The 15 transplant recipients with ehrlichiosis included 7 kidney recipients, 6 heart recipients, 1 liver recipient and 1 lung recipient. Transplant recipients had more infections with E. ewingii than immunocompetent patients (23% vs. 5%, p = 0.08). Transplant recipients experienced less rash (0% vs. 36%, p = 0.006) and presented with significantly lower hepatic enzymes, but more leukopenia and renal dysfunction than immunocompetent patients. Doxycycline therapy was started within 48 h of presentation in 73% of transplant recipients and 78% of immunocompetent patients (p = 0.7). No patient died in either group. Ehrlichia infections can occur in transplant recipients who live in an endemic area. With prompt treatment, the infected transplant recipients in our study had similar, favorable outcomes compared to immunocompetent patients.

Polyomavirus Infection and Its Impact on Renal Function and Long-Term Outcomes after Lung Transplantation

Background. Polyomavirus infection causes nephropathy after kidney transplantation but has not been thoroughly investigated in nonrenal organ transplantation. Methods. Ninety lung transplant recipients were enrolled, and they provided urine samples for over 4.5 years. Samples were analyzed for BK virus (BKV), JC virus (JCV), and simian virus 40 (SV40) by conventional and quantitative real-time polymerase chain reaction. Results. Fifty-nine (66%) patients had polyomavirus detected at least once, including 38 patients (42%) for BKV, 25 patients (28%) for JCV, and six patients (7%) for SV40. Frequency of virus shedding in serial urine samples by patients positive at least once varied significantly among viruses: JCV, 64%; BKV, 48%; and SV40, 14%. Urinary viral loads for BKV (105.4 copies/mL) and JCV (106.0 copies/mL) were higher than for SV40 (102.5 copies/mL; P=0.001 and 0.0003, respectively). Polyomavirus infection was associated with a pretransplant diagnosis of chronic obstructive pulmonary disease (odds ratio 6.0; P=0.016) but was less common in patients with a history of acute rejection (odds ratio 0.28; P=0.016). SV40 infection was associated with sirolimus-based immunosuppression (P=0.037). Reduced survival was noted for patients with BKV infection (P=0.03). Patients with polyomavirus infection did not have worse renal function than those without infection, but in patients with BKV infection, creatinine clearances were lower at times when viral shedding was detected (P=0.038). Conclusions. BKV and JCV were commonly detected in the urine of lung transplant recipients; SV40 was found at low frequency. No definite impact of polyomavirus infection on renal function was documented. BKV infection was associated with poorer survival.

Long-term outcomes of cytomegalovirus infection and disease after lung or heart–lung transplantation with a delayed ganciclovir regimen

Abstract:  Background:  Information is limited on long‐term outcomes after preemptive use of ganciclovir to control cytomegalovirus (CMV) infection in lung transplantation.

Interactions between Antiinfective Agents and Immunosuppressants

Infectious diseases are among the leading complications of immunosuppression for solid organ transplantation. The first few months posttransplant are particularly critical because immunosuppression is usually at high levels, acute rejection episodes are most likely to occur during this time frame requiring further increases in immunosuppression and patients are receiving antiinfective prophylaxis. While drug interactions are an important consideration for the life of the recipient, the high incidence of infections during the first year posttransplant make vigilance for drug interactions crucial during this period. Optimal treatment of specific infections, therefore, should be guided not only by knowledge of the pathogen’s susceptibility to antimicrobial agents, but also by the effects the agents will have on the pharmacokinetics of immunosuppressants the patient is receiving and potential additive or synergistic toxicities. Table 1 provides summary information on interactions between antiinfectives and immunosuppressants, an indication of their severity, suggested actions by the clinician, the weight of evidence supporting these effects and suggested actions. The following discussion describes these interactions in more detail, focusing on the most severe, and suggests approaches to alternative treatment.

Histoplasmosis in Patients With Cell-Mediated Immunodeficiency: Human Immunodeficiency Virus Infection, Organ Transplantation, and Tumor Necrosis Factor-α Inhibition.

Background. Histoplasmosis causes severe disease in patients with defects of cell-mediated immunity. It is not known whether outcomes vary related to the type of immunodeficiency or class of antifungal treatment. Methods. We reviewed cases of active histoplasmosis that occurred at Vanderbilt University Medical Center from July 1999 to June 2012 in patients with human immunodeficiency virus (HIV) infection, a history of transplantation, or tumor necrosis factor (TNF)-α inhibitor use. These groups were compared for differences in clinical presentation and outcomes. In addition, outcomes were related to the initial choice of treatment. Results. Ninety cases were identified (56 HIV, 23 transplant, 11 TNF-α inhibitor). Tumor necrosis factor-α patients had milder disease, shorter courses of therapy, and fewer relapses than HIV patients. Histoplasma antigenuria was highly prevalent in all groups (HIV 88%, transplant 95%, TNF-α 91%). Organ transplant recipients received amphotericin B formulation as initial therapy less often than other groups (22% vs 57% HIV vs 55% TNF-α; P = .006). Treatment failures only occurred in patients with severe disease. The failure rate was similar whether patients received initial amphotericin or triazole therapy. Ninety-day histoplasmosis-related mortality was 9% for all groups and did not vary significantly with choice of initial treatment. Conclusions. Histoplasmosis caused milder disease in patients receiving TNF-α inhibitors than patients with HIV or solid organ transplantation. Treatment failures and mortality only occurred in patients with severe disease and did not vary based on type of immunosuppression or choice of initial therapy.

311 – Risk Factors and Approaches to Infections in Transplant Recipients

Successful clinical organ transplantation dates from 1954, when the immunologic barrier to transplantation was ingeniously circumvented in a few patients with kidney failure by using organs from donors who were identical twins with the patients. Subsequently, transplantation of organs from genetically different individuals was attempted with lymphoid irradiation to suppress the recipient’s immune response to the allograft, but these efforts met with only occasional success. In the early 1960s, immunosuppressive regimens employing azathioprine and corticosteroids were introduced. These provided more effective control of allograft rejection that not only was sustainable but could be adjusted according to an individual patient’s circumstances. This development catapulted kidney transplantation beyond the experimental stage, and both living-related and cadaveric renal transplantation became part of regular clinical practice. Attempts at heart and liver transplantation proved more challenging, and these clinical efforts remained limited to a few dedicated programs for more than a decade. The next major watershed in the development of transplantation was the introduction of cyclosporine in the early 1980s. This development ushered in a marked expansion of heart and liver transplantation, promoted further growth of renal transplantation, and made lung transplantation possible. Currently, more than 28,000 solid organ transplantations are performed yearly in the United States, and most patients retain the grafts and survive many years after transplantation. As a result, patients with various types of transplants are now routinely encountered in general practice. Except for issues related to the function and rejection of the transplanted organ, infections are the most important problem after transplantation. The clinical manifestations of infection are variable and depend on the infecting pathogen, the prior immune status of the host, the type of transplantation, the time after transplantation, and the level of pharmacologic immunosuppression. With this complexity in mind, it is useful to address some general principles that may aid in the diagnosis, management, and understanding of infections after transplantation. The occurrence of infection requires a susceptible host and an available pathogen. Transplant recipients are not equally susceptible to all pathogens. For instance, most enteroviruses do not appear to infect transplant recipients with greater frequency or severity than they do normal hosts. A transplant recipient also may be quite susceptible to a given pathogen but may have a low risk of infection because of lack of exposure. For example, tuberculosis is rarely encountered at most transplantation centers in developed countries, but it can be a major problem in transplant recipients in parts of the world and in clinical settings in which infection cannot be avoided. Likewise, transplant recipients with no past exposure to cytomegalovirus (CMV) who receive organs from CMV-seronegative donors are at low risk for CMV infection, whatever their level of immunosuppression. In clinical practice, the clinician can and should use this sort of information to assess each patient’s individual susceptibility to important pathogens. Infections are most frequent and most varied during the first 6 months after transplantation. During this period, patients have all the risk factors for infection (Table 310-1): They may still be affected— either directly or indirectly—by their underlying disease; because they have undergone major surgery and been in the intensive care unit, they are at risk for wound and other nosocomial infections; and because they have received large doses of immunosuppressive drugs, the allograft may be malfunctioning as a result of rejection or other factors. This early period also covers the time of highest risk for infection by opportunistic microorganisms such as CMV and Nocardia, Aspergillus, Pneumocystis, or Toxoplasma organisms. These pathogens received much attention in the early literature on transplantation-related infections; more recently, their clinical impact has been diminished by the widespread use of antimicrobial prophylactic regimens early after transplantation. These regimens have virtually eliminated some infectious complications, such as Pneumocystis pneumonia, and have provided substantial but still imperfect control of others, such as CMV disease. With time—usually about 6 to 9 months after transplantation—the risk of infection tends to decrease. The level of vigilance may therefore be reduced, except for individual patients whose risk has remained high because of continued requirement for high doses of immunosuppression.