Search

Ehrlichiosis has been infrequently described as transmissible through organ transplantation. Two donor-derived clusters of ehrlichiosis are described here. During the summer of 2020, 2 cases of ehrlichiosis were reported to the Organ Procurement and Transplantation Network (OPTN) and the Centers for Disease Control and Prevention (CDC) for investigation. Additional transplant centers were contacted to investigate similar illness in other recipients and samples were sent to the CDC. Two kidney recipients from a common donor developed fatal ehrlichiosis-induced hemophagocytic lymphocytic histiocytosis. Two kidney recipients and a liver recipient from another common donor developed ehrlichiosis. All 3 were successfully treated. Clinicians should consider donor-derived ehrlichiosis when evaluating recipients with fever early after transplantation after more common causes are ruled out, especially if the donor has epidemiological risk factors for infection. Suspected cases should be reported to the organ procurement organization and the OPTN for further investigation by public health authorities.

Background Invasive mold infections (IMIs) remain a significant cause of morbidity and mortality in patients with acute leukemia (AL) and those undergoing hematopoietic stem cell transplantation (HSCT). We describe the epidemiology of IMIs, the incidence of IMI in patients with acute myelogenous Leukemia (AML) post HSCT, and risk factors for mortality. Methods Patients were identified using ICD9 and ICD10 codes using a University of Kansas internal database from 2009-2019, microbiology records, and an AML HSCT database and were followed through May 1st, 2020. Patients’ electronic medical records were reviewed for inclusion. IMI was defined as proven or probable using the 2009 National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) guidelines. Incidence was calculated as IMI cases/100-person-years. Risk factors for overall mortality were evaluated using a Cox regression model. Results We included 138 patients: 79 developed IMI after HSCT (8 autologous, 71 allogeneic) and 59 developed IMI after AL diagnosis. Seventeen of the AL patients underwent HSCT after IMI diagnosis (12 within 100 days of IMI). Proven IMI occurred in 45 (32.6%) and probable IMI occurred in 93 (67.4%) patients. The most common prophylactic agent prior to IMI diagnosis was fluconazole (31.2%), with 21.0% receiving none. Aspergillus was the most commonly identified mold with 91 (65.9%) cases. The average treatment duration was 101 (range 0 - 799) days. The incidence of IMI in patients with AML who underwent HSCT was 2.35 cases/100 person-years. All-cause mortality among patients with AL or HSCT who developed IMI was 23.1% at 6 weeks, 34.1% at 12 weeks, and 61.2% at 1 year. On univariate Cox model, Karnofsky performance status > 70 was associated with lower mortality (hazard ratio (HR) 0.317, 95% confidence interval (CI) [0.110, 0.914]) among HSCT recipients. ICU admission within 7 days prior to IMI diagnosis (HR 6.469, 95% CI [1.779, 23.530]) and each one point increase in BMI (HR 1.051, CI [1.001, 1.103]) were associated with increased mortality in the AL group. Figure 1 - Invasive mold infections by pathogen in HSCT-recipients and acute leukemia patients from 2009-2019. Figure 2 - Antifungal prophylactic agents prescribed for at least one week at time of IMI diagnosis Table 1 - Univariate survival analysis calculated using a Cox proportional-hazards regression model among patients who developed IMI after HSCT and patients who developed IMI after acute leukemia diagnosis Conclusion IMIs are associated with significant mortality in HSCT recipients and AL patients; patients at higher risk for mortality include those with lower baseline Karnofsky scores, recent ICU admissions, and higher BMI at time of IMI diagnosis. Disclosures Wissam El Atrouni, MD, ViiV (Advisor or Review Panel member)

Clinical manifestations of human parvovirus B19 infection can vary widely and may be atypical in solid organ transplant (SOT) recipients. However, disease is apparent when there is destruction of erythrocyte progenitor cells leading to severe acute or chronic anemia with lack of an appropriate reticulocyte response in the setting of active parvovirus B19 infection. Serology may not reliably establish the diagnosis. High-level viremia is more likely to be associated with symptomatic disease. Conversely, ongoing DNAemia after infection may not be clinically significant, if detected at low levels. Despite lack of robust data, intravenous immunoglobulin (IVIG) is frequently used for the treatment of SOT recipients with symptomatic parvovirus B19 infection. Although the optimal dosage and duration of IVIG is not known, most patients receive a total of 2 g/kg over a period of 2-5 days. A daily dose of 1 g/kg or more seems to be associated with higher incidence of toxicity. Application of standard and droplet isolation precautions remains the cornerstone for preventing human parvovirus B19 transmission. Additional research is needed to assess the efficacy of current and novel therapies and to develop a safe and effective parvovirus B19 vaccine.

The outcomes and optimal management of cirrhotic patients who develop cryptococcosis before transplantation are not fully known.We conducted a multicenter study involving consecutive patients with cirrhosis and cryptococcosis between January 2000 and March 2014. Data collected were generated as standard of care.In all, 112 patients were followed until death or up to 9 years. Disseminated disease and fungemia were present in 76.8% (86/112) and 90-day mortality was 57.1% (64/112). Of the 39 patients listed for transplant, 20.5% (8) underwent liver transplantation, including 2 with active but unrecognized disease before transplantation. Median duration of pretransplant antifungal therapy and posttransplant therapy was 43 days (interquartile range, 8-130 days) and 272 days (interquartile range, 180-630 days), respectively. Transplantation was associated with lower mortality (P = 0.002). None of the transplant recipients developed disease progression during the median follow-up of 3.5 years with a survival rate of 87.5%.Cryptococcosis in patients with cirrhosis has grave prognosis. Our findings suggest that transplantation after recent cryptococcal disease may not be a categorical exclusion and may be cautiously undertaken in liver transplant candidates who are otherwise deemed clinically stable.

Neutropenic sepsis is a common clinical entity occurring in postchemotherapy patients. Infection may not be the cause of fever in such patients after neutrophil-count recov- ery. Herein, we present two patients who developed fever during the neutropenic phase of induction chemotherapy and were treated with broad-spectrum antibiotics until they were no longer febrile and had recovered their neutrophil count. Being off antibiotics, they redeveloped fever within 48-72 hours. These fevers seemed to be secondary to postinfectious inflammatory response and not infection, supported by the fact that adequate antibiotic treatment was given and the collected fluid contained neutrophils but the cultures were negative. We hypothesize an explanation for this phenomenon based on the "homing of neutrophils" to bone marrow, which involves chemoattraction of CXC chemokine receptor (CXCR)-4 expressed on neutrophils towards the chemokine stromal cell-derived factor (SDF)-1 (CXCL12) expressed constitutively by bone marrow. Literature has shown that elevation of SDF-1 levels at injured/inflamed sites might create a similar gradient. This gradient results in the migration of neutrophils to the sites of previous injury/inflammation, leading to the formation of sterile abscesses. Based on our cases, we also conclude that antibiotics do not prevent the formation or treat such sterile "abscesses"; however, the drainage of these "abscesses" and treatment with anti-inflammatory agents are useful in such cases.

Characteristics of cirrhosis-associated cryptococcosis first diagnosed after death are not fully known. In a multicenter study, data generated as standard of care was systematically collected in 113 consecutive patients with cirrhosis and cryptococcosis followed for 80 patient-years. The diagnosis of cryptococcosis was first established after death in 15.9% (18/113) of the patients. Compared to cases diagnosed while alive, these patients had higher MELD score (33 vs. 22, P = .029) and higher rate of cryptococcemia (75.0% vs. 41.9%, P = .027). Cases diagnosed after death, in comparison to those diagnosed during life were more likely to present with shock (OR 3.42, 95% CI 1.18-9.90, P = .023), require mechanical ventilation at admission (OR 8.5, 95% CI 2.74-26.38, P = .001), less likely to undergo testing for serum cryptococcal antigen (OR 0.07, 95% CI 0.02-0.21, P < .001) and have positive antigen when the test was performed (OR 0.07, 95% CI 0.01-0.60, P = .016). In a subset of cirrhotic patients with advanced liver disease cryptococcosis was first recognized after death. These patients had the characteristics of presenting with fulminant fungemia, were less likely to have positive serum cryptococcal antigen and posed a diagnostic challenge for care providers.

Solid organ and hematopoietic stem cell transplant recipients are uniquely predisposed to develop clinical illness, often with increased severity, due to a variety of common and opportunistic viruses. Patients may acquire viral infections from the donor (donor-derived infections), from reactivation of endogenous latent virus, or from the community. Herpes viruses, most notably cytomegalovirus and Epstein Barr virus, are the most common among opportunistic viral pathogens that cause infection after solid organ and hematopoietic stem cell transplantation. The polyoma BK virus causes opportunistic clinical syndromes predominantly in kidney and allogeneic hematopoietic stem cell transplant recipients. The agents of viral hepatitis B and C present unique challenges particularly among liver transplant recipients. Respiratory viral illnesses due to influenza, respiratory syncytial virus, and parainfluenza virus may affect all types of transplant recipients, although severe clinical disease is observed more commonly among lung and allogeneic hematopoietic stem cell transplant recipients. Less common viral infections affecting transplant recipients include those caused by adenoviruses, parvovirus B19, and West Nile virus. Treatment for viruses with proven effective antiviral drug therapies should be complemented by reduction in the degree of immunosuppression. For others with no proven antiviral drugs for therapy, reduction in the degree of immunosuppression remains as the sole effective strategy for management. Prevention of viral infections is therefore of utmost importance, and this may be accomplished through vaccination, antiviral strategies, and aggressive infection control measures.

Background Liver transplantation is increasingly performed in patients aged ≥65 years. Per the United Network for Organ Sharing data, infections are the leading primary and contributory cause of death in older liver transplant (LT) recipients. This study aims to describe the epidemiology and outcomes of infections within the first 200 days of LT in older adults. Methods We performed a retrospective, observational multi-center study of patients aged ≥65 years who underwent primary LT from January 1, 2010 to June 30, 2015. Data collection included patient demographics, co-morbidities, transplant data, infection event in 200 days of LT and death. Severe infection was defined as the presence of sepsis, septic shock, or sepsis with multi-organ failure. Results A total of 255 patients met inclusion criteria with median follow-up of 690 days (range 1– 2095). The mean age was 67.6 years (SD 2.4). Majority were male (67%) and white (85%). Frequent indications of LT were hepatocellular carcinoma (46%) and hepatitis C (32%). The median MELD score at the time of LT was 22 (range 6–47). Only 3% of recipients received thymoglobulin for induction. Acute rejection within 200 days of LT occurred in 31 (12%); graft failure in 8 (3%); and re-transplantation in 5 (2%). One hundred twenty-seven patients (50%) developed 274 infections; 63 (25%) had 1 infection and 64 (25%) had ≥ 2 infections. Median time to first infection after LT was 26 days [IQR 9–72]. Out of 274 infections, 182 (66%) occurred in Conclusion Infections are common in this older LT cohort and occurred mainly in the early post-LT period. OIs were infrequent except for CMV. Despite concerns for immunosuppression and immunosenescence, the outcome of infection within the 200 days of LT was overall favorable. Disclosures All authors: No reported disclosures.

Background Hepatitis C virus (HCV) core and nonstructural (NS) 3 proteins induce inflammation and immunity through a toll-like receptor (TLR) 2-dependent pathway. Individuals with the R753Q single-nucleotide polymorphism (SNP) in the TLR2 gene have increased the risk of allograft failure after liver transplantation for chronic hepatitis C. Methods To test the hypothesis that R753Q SNP impairs TLR2 recognition of HCV proteins, a series of in vitro experiments were performed wherein stable clones of wild-type TLR2-deficient human embryonic kidney (HEK) 293 cells and HEK293 cells transfected with wild-type (HEK293-TLR2) or variant TLR2 genes (HEK293-TLR2-R753Q) were stimulated with HCV core and NS3 proteins. Cellular activation was assessed by nuclear factor-kappa B-driven luciferase activity, cytokine secretion, and gene upregulation. Results Compared with TLR2-deficient HEK293 cells, HEK293-TLR2 cells had marked nuclear factor-kappa B-driven luciferase activity, had modest to marked upregulation in TLR2 signaling-associated genes, and secreted large quantities of interleukin-8 during exposure to HCV core and NS3 proteins. In contrast, HEK293-TLR2-R753Q cells did not respond to stimulation with HCV and behaved similarly like TLR2-deficient HEK293 cells. Conclusion R753Q SNP impairs TLR2-mediated immune recognition of HCV core and NS3 proteins. This biologic defect may account for the predisposition of patients to develop allograft failure after liver transplantation for chronic hepatitis C.

R.D. Boyce, P.J. Deziel, C.C. Otley, M.P. Wilhelm, A.J. Eid, N.L. Wengenack, R.R. Razonable. Phaeohyphomycosis due to Alternaria species in transplant recipients. Transpl Infect Dis 2010: 12: 242–250. All rights reserved Abstract: Alternaria species are members of a heterogenous group of dematiaceous fungi that rarely cause opportunistic infections in transplant recipients. During a 20-year period from 1989 to 2008, 8 solid organ transplant recipients (63% males; median age, 48 years) developed Alternaria species infections at the Mayo Clinic. All patients were highly immunocompromised as evidenced by their receipt of multiple transplants, treatment of acute and chronic allograft rejection, and occurrence of other opportunistic infections. All patients presented with non-tender erythematous or violaceous skin papules, nodules, or pustules in exposed areas of the extremities. No case of visceral dissemination was observed. Itraconazole was the most common drug used for treatment, although voriconazole, posaconazole, and caspofungin could potentially be useful based on our limited clinical data and in vitro antifungal susceptibility testing. One patient was treated with voriconazole, while another patient who was refractory to itraconazole had rapid resolution of lesions after the addition of caspofungin. Attempts at antifungal therapy alone were unsuccessful; all patients eventually required surgical excision of lesions. In conclusion, Alternaria species are rare but increasingly recognized opportunistic infections among highly immunocompromised transplant recipients. Wide excisional surgery combined with prolonged systemic antifungal therapy and reduction in immunosuppressive regimens provided the best chance of cure. Although itraconazole remains the most common drug for treatment, this case series highlights the potential clinical utility of caspofungin, voriconazole, and posaconazole as alternative regimens.

Cytomegalovirus (CMV)-specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV-specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine-flow cytometry, we enumerated interferon-gamma producing CMV-specific CD4+ and CD8+ T cells at serial time points among CMV-mismatched (D+/R-) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (+ or - SD) time of 151 (+ or - 33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue-invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R-) status (HR: 13, 95% CI: 1.6-106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1-27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change-over-time in CMV-specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE-1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV-specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV-specific T cell assays will need to be assessed in a larger cohort of CMV D+/R- kidney recipients who remain at high-risk of delayed-onset CMV disease.

Arthurs SK, Eid AJ, Deziel PJ, Marshall WF, Cassivi SD, Walker RC, Razonable RR. The impact of invasive fungal diseases on survival after lung transplantation. Clin Transplant 2010: 24: 341–348. © 2009 John Wiley & Sons A/S. Abstract: Background: Recipients of lung transplants are at high risk of infectious complications. We investigated the epidemiology of infections after lung transplantation and determined their impact on survival. Methods: We retrospectively reviewed the medical records of patients who underwent lung transplantation at Mayo Clinic (Rochester) during 1990–2005. Survival analyses were performed using Kaplan–Meier estimation and Cox proportional hazard modeling. Results: Sixty-nine lung transplants were performed during the 16-yr study period. The mean (±SD) patient age was 50.5 ± 9.7 yr; 45% were male. During the mean (±SD) follow-up period of 1188 (±1288) d, the cumulative percentage of patients with infections were: bacteria (52%), cytomegalovirus (CMV) (49%), other viruses (32%), fungi (19%), mycobacteria (7%), and Pneumocystis jiroveci (1%). The median survival time after lung transplantation was 5.02 yr. Kaplan–Meier estimation of one-, three-, and five-yr survival was 80%, 61%, and 50%, respectively. Overall, 37 (54%) patients died due to graft rejection and failure (35%), invasive fungal diseases (16%), post-transplant lymphoproliferative disorder and other malignancies (14%), cardiovascular diseases (5%), CMV disease (3%), bacterial infection (3%), or other causes (24%). Survival analysis using Kaplan–Meier estimation showed that invasive fungal disease (Aspergillus sp., n = 9, Candida sp., n = 2, Alternaria sp., n = 1, Rhizopus sp., n = 1, and/or Mucor sp., n = 1) was significantly associated with mortality (p = 0.0104). After adjusting for age and graft rejection, invasive fungal disease remains a significant predictor of mortality (p = 0.0262). Conclusion: Invasive fungal disease is significantly associated with all-cause mortality after lung transplantation. An aggressive antifungal preventive strategy may lead to improved survival after lung transplantation.

Infections due to Mycobacterium marinum are rarely encountered following organ and tissue transplantation. Herein, we report a case of M. marinum infection in a kidney and pancreas transplant recipient who manifested clinically with multiple locally spreading sporotrichoid-like cutaneous nodules in his left forearm. In order to provide a general overview of post-transplant M. marinum infections, we reviewed and summarized all previously reported cases of this infection that occurred after transplantation. Including our index case, all 6 cases presented with multiple cutaneous and subcutaneous nodules that had spread locally in the involved extremity. One patient had lesions located in non-contiguous body sites suggesting either systemic dissemination or multiple sites of inoculation. In all but 1 patient, the cutaneous nodules appeared in an ascending pattern and following exposure to fish tanks or after contact with the marine environment. The diagnosis of M. marinum infection was suspected on clinical grounds and confirmed by mycobacterial culture. Treatment consisted of at least 2 active antibiotics (such as rifamycins, ethambutol, tetracyclines, or macrolides) for 4-9 months, resulting in clinical cure or improvement. Relapse was observed in 1 patient despite completing 6 months of antibiotic therapy. One patient had surgical excision of the lesions. In conclusion, M. marinum should be considered as the cause of cutaneous and subcutaneous nodules in transplant recipients, particularly in the context of fish tank or marine exposure. Compared with the immunocompetent hosts, M. marinum infection may have a more aggressive clinical course after transplantation, and may require a longer duration of antibiotic treatment. Early diagnosis and treatment may prevent local spread and potential systemic dissemination.

Purpose of reviewDespite advances in its management, cytomegalovirus remains a significant pathogen that influences the outcome of solid organ transplantation. Herein, the current epidemiology of cytomegalovirus disease and its prevention and treatment are discussed.Recent findingsAntiviral prophyla

Background Cytomegalovirus (CMV)-seronegative recipients of cardiac allografts from CMV-seropositive donors (CMV D + /R − ) are at highest risk of CMV disease after transplantation. This study was conducted to investigate the incidence, clinical features, risk factors and outcome of delayed-onset primary CMV disease in cardiac recipients who received anti-CMV prophylaxis. Methods This study enrolled all CMV D + /R − cardiac recipients during the period from 2000 to 2004. The medical records of patients were reviewed to assess clinical variables and outcomes. The data were analyzed using descriptive statistics and survival analysis. Results During the 5-year study period, a total of 31 cardiac recipients had CMV D + /R − serostatus (mean age ± SD: 49.2 ± 13.7 years; 74% male). All patients received oral ganciclovir ( n = 6) or valganciclovir ( n = 25) prophylaxis for a median duration of 95 days (interquartile range: 90 to 100). No breakthrough CMV disease was observed. However, 9 (29%) patients developed delayed-onset primary CMV disease (3 with CMV syndrome, 6 with gastrointestinal disease) during the period from 120 to 444 days after transplantation. No demographic or clinical variable was significantly associated with delayed-onset primary CMV disease. However, acute rejection with a severity of Grade ≥2 showed a trend toward association with CMV disease (hazards ratio: 2.46; 95% confidence interval: 0.66 to 9.2; p = 0.18). During the mean (±SD) follow-up period of 2.9 (±1.68) years, 3 patients died. CMV disease was not associated with all-cause mortality. Conclusions In the contemporary era of anti-viral prophylaxis, delayed-onset primary CMV disease remains a common complication among CMV D + /R − cardiac recipients. This finding warrants a better strategy for CMV prevention.

Background: Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir-resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug-resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis. Methods: The medical records of all CMV D+/R− kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug-resistant CMV were reviewed. Results: During a four-yr-study period, a total of 225 CMV D+/R− transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty-five (29%) of the 225 patients developed delayed-onset primary CMV disease, including nine (14%) suspected to have drug-resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue-invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug-associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow-up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug-resistant CMV. Conclusions: Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug-resistant CMV is not uncommon in CMV D+/R− solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug-resistant CMV on the successful outcome of organ transplantation.

Background. Experimental models suggest that immune cells recognize hepatitis C virus (HCV) through toll-like receptor (TLR)-2 and TLR4. We assessed the association between the single nucleotide polymorphism in genes that encode for these receptors and the outcome of liver transplantation for chronic HCV. Methods. A historical cohort of 92 liver transplant patients with chronic HCV were screened for TLR2 Arg753Gln and TLR4 Asp299Gly and Thr399Ile polymorphisms. The results were correlated with the predefined composite primary outcome of cirrhosis, retransplantation, and death. Statistical analysis was performed using Kaplan-Meier estimation and Cox proportional hazard model. Results. The mean patient age was 49 ± 9 years. Sixty percent were male and 84% were white. Twelve (13%) patients had TLR2 Arg753Gln and 32 (35%) had TLR4 Asp299Gly and/or Thr399Ile polymorphism. During the mean follow-up period of 32 months after liver transplantation, the composite primary outcome occurred in 19 (24%) of 80 patients without TLR2 polymorphism, one (14%) of seven patients with heterozygous TLR2 polymorphism, and in all five (100%) patients with homozygous TLR2 polymorphism (P=0.0007). Time-to-event analysis showed a significant association between homozygous TLR2 polymorphism and the primary outcome (P

Cytomegalovirus (CMV) retinitis is a sight-threatening illness that results from the reactivation of CMV in the retina of patients with end-stage AIDS. Valganciclovir, a prodrug of ganciclovir, is indicated as induction therapy at a dose of 900 mg twice daily for 3 weeks, and maintenance therapy at a dose of 900 mg once daily for CMV retinitis in patients with AIDS. After oral administration, valganciclovir is rapidly absorbed and extensively hydrolyzed to ganciclovir by intestinal and hepatic esterase enzymes. The bioavailability of ganciclovir after oral administration of valganciclovir is tenfold higher than oral ganciclovir. At a dose of 900 mg once daily, valganciclovir provides systemic exposure of ganciclovir comparable to intravenous ganciclovir (5 mg/kg daily). The most common adverse events of valganciclovir are myelosuppression and gastrointestinal symptoms. Prolonged valganciclovir administration could lead to the emergence of ganciclovir-resistant CMV. The use of highly active antiretroviral ...

Background. Histoplasmosis is a common fungal infection in the southeastern, mid-Atlantic, and central states; however, its presentation can be atypical.Case Presentation. We report a case ofHistoplasma capsulatuminfection presenting as slowly progressive weakness in the lower extremities, followed by the development of numbness below the midthoracic area, urinary incontinence, and slurred speech. Brain MRI showed leptomeningeal enhancement, predominantly linear, involving the basal cisterns, the brainstem, and spinal cord. Cerebrospinal fluid analysis showed lymphocytic pleocytosis.Discussion. CNS histoplasmosis is usually seen in patients with disseminated histoplasmosis. Isolated CNS histoplasmosis is rarely seen, especially in immunocompetent patients.Conclusions. Histoplasmosis should be considered in the differential diagnosis of patients experiencing slowly progressive neurological deficit.

Background. During primary infection, human herpesvirus-6 (HHV-6) may become integrated into the chromosome. This entity, termed chromosomally integrated HHV-6 (CIHHV-6), is often mistaken as active infection and treated unnecessarily. The prevalence of CIHHV-6 in kidney transplant recipients is not known. Methods. We performed quantitative HHV-6 polymerase chain reaction assay on whole blood samples collected from 47 kidney recipients. CIHHV-6 was defined as HHV-6 DNA levels >1 3 10 6 genomes/mL. Results. One of 47 kidney recipients was found to have CIHHV-6. The prevalence of CIHHV-6 was calculated at 2.1% (95% confidence interval

This chapter reviews the role of toll-like receptors (TLRs) in innate antiviral responses and in coordinating the antiviral adaptive immune system, and discusses the potential for TLRs as novel molecular targets for antiviral immunomodulatory therapy. A mutation in the Toll gene in Drosophila that results in defective protein was associated with reduced survival after fungal infection. The chapter discusses TLR recognition of pathogen-associated molecular patterns, TLR signaling pathway, biological outcomes of TLR activation, and TLRs and the pathogenesis of selected viral pathogens. The potential role for TLR-7 and TLR-8 in HSV pathogenesis is highlighted by ongoing research efforts to control herpes simplex virus (HSV) infections with the use of small-molecule TLR-7 and TLR-8 agonists. Many viruses, however, have evolved to develop strategies that block the effector mechanisms induced through TLR signaling pathways. Coronavirus, a contagious viral pathogen that causes the highly fatal severe acute respiratory syndrome (SARS), has an attenuated ability to induce type I interferons (IFNs), which are essential for the efficient control of the infection, because it has developed a TLR evasion mechanism characterized by failure of IRF-3 activation. The chapter describes TLRs as targets for immunomodulation and antiviral therapies. The successful clinical development of imiquimod, the prototype TLR immune response-modifying drug, provides a solid example of the promise and remarkable potential that TLR modulators have in bringing novel antiviral therapeutic strategies in the clinical setting.

Increasing numbers of immunocompromised patients have led to a corresponding rise in the incidence of invasive Aspergillus infections. Despite advances in antifungal therapy coupled with reduction in immunosuppression, invasive aspergillosis is associated with significant morbidity and mortality. Although surgical debulking has proven effective in difficult-to-treat cases, patient comorbidities may prevent such intervention. Non-invasive alternatives to surgery are needed. Microwave ablation has many advantages over other ablative techniques, including convection profile, faster heating time, and higher intra-lesion temperatures, which may be associated with greater therapeutic efficacy. We report a case of microwave ablation as an adjunct to medical therapy in angioinvasive renal aspergilloma.

Osteomyelitis can affect every bone and is heterogeneous in its pathophysiology and presentation. When the diagnosis is clinically suspected, further studies such as serum inflammatory markers and imaging studies should be performed. Magnetic resonance imaging can be very useful in establishing the diagnosis and determining the extent of infection. When possible, bone specimens should be obtained and cultured prior to the initiation of antimicrobial therapy. Surgical debridement is often required for chronic or contiguous osteomyelitis for successful eradication of the infection. The ultimate test-of-cure is the lack of clinical relapse after the discontinuation of antimicrobials.

Despite remarkable advances in the diagnostic and therapeutic modalities for its management, cytomegalovirus (CMV) remains one of the most important pathogens impacting on the outcome of transplantation. Not only does CMV directly cause morbidity and occasional mortality, it also influences many short-term and long-term indirect effects that collectively contribute to reduced allograft and patient survival. Prevention of CMV infection and disease is therefore key in ensuring the successful outcome of solid organ transplantation (SOT). In this regard, antiviral prophylaxis and pre-emptive therapy are similarly effective in preventing CMV disease after transplantation. However, current guidelines prefer antiviral prophylaxis over pre-emptive therapy in preventing CMV disease in high-risk SOT recipients, such as CMV-seronegative recipients of organs from CMV-seropositive donors (CMV D+/R-), and lung, intestinal and pancreas transplant recipients. Antiviral prophylaxis has the benefits of reducing not only the incidence of CMV disease, but also the indirect effects of CMV on allograft and patient survival. The major drawback of antiviral prophylaxis is delayed-onset CMV disease, which occurs in 15-38% of CMV D+/R- SOT recipients who received 3 months of prophylaxis. Allograft rejection, over-immunosuppression and lack of CMV-specific immunity are factors that predispose patients to delayed-onset CMV disease. A recent randomized trial in CMV D+/R- kidney recipients demonstrates a significant reduction in the incidence of CMV disease when valganciclovir prophylaxis is extended to 200 days (compared with the standard 100 days) after transplantation; however, the safety and cost of this prolonged approach has yet to be assessed. In some studies, delayed-onset CMV disease has been significantly associated with allograft loss and mortality. In the vast majority of patients, CMV disease responds to treatment with intravenous ganciclovir. Recently, oral valganciclovir was demonstrated to have an efficacy that is comparable to intravenous ganciclovir in treating mild to moderate cases of CMV disease in SOT recipients. Reduction in the degree of immunosuppression should complement antiviral treatment of CMV disease. Although it remains rare, ganciclovir-resistant CMV disease is increasingly seen in clinical practice, potentially fostered by the prolonged use of antivirals in high-risk over-immunosuppressed transplant recipients. Treatment of drug-resistant CMV is currently non-standardized and may include foscarnet, cidofovir, CMV hyperimmune globulins or leflunomide. The investigational drug marivabir had the potential to treat ganciclovir-resistant CMV disease as it acts through a different mechanism. However, the recent phase III clinical trial in allogeneic bone marrow transplant recipients showed that maribavir was not significantly better than placebo for the prevention of CMV disease. Similarly, the preliminary data in a liver transplant population suggests that maribavir was inferior to oral ganciclovir for the prevention of CMV disease. This article reviews the recent data and other developments in the management of CMV infection after SOT.

Cytomegalovirus (CMV)-specific cellular immunity is essential in controlling CMV infection after transplantation. We investigated whether CMV-specific T cell levels predict CMV DNAemia after kidney transplantation. Using cytokine-flow cytometry, we enumerated interferon-gamma producing CMV-specific CD4+ and CD8+ T cells at serial time points among CMV-mismatched (D+/R-) and seropositive (R+) kidney recipients who received 3 months of valganciclovir prophylaxis. Among 44 patients, eight (18%) developed CMV DNAemia at a mean (+ or - SD) time of 151 (+ or - 33) days after transplantation, including two (5%) with CMV syndrome and three (7%) with tissue-invasive CMV disease. Cox proportional hazards regression analysis showed that CMV mismatch (D+/R-) status (HR: 13, 95% CI: 1.6-106.4; P = 0.02) and diabetes mellitus (HR: 5.6; 95%CI: 1.1-27.9; P = 0.03) were significantly associated with CMV DNAemia. In contrast, the percentage or change-over-time in CMV-specific CD4+ [pp65 (P = 0.45), or CMV lysate (P = 0.22)] and CD8+ [pp65 (P = 0.43), or IE-1 (P = 0.37)] T cells were not significantly associated with CMV DNAemia. CMV-specific T cell assays have limited clinical utility among CMV R+ kidney recipients who received valganciclovir prophylaxis. On the other hand, the clinical utility of CMV-specific T cell assays will need to be assessed in a larger cohort of CMV D+/R- kidney recipients who remain at high-risk of delayed-onset CMV disease.

Primary gastrointestinal cytomegalovirus (CMV) disease after solid organ transplantation (SOT) is difficult to treat and may relapse. Herein, we reviewed the clinical records of CMV D+/R- SOT recipients with biopsy-proven gastrointestinal CMV disease to determine predictors of relapse. The population consisted of 26 kidney (13 [50%]), liver (10 [38%]) and heart (3 [12%]) transplant recipients who developed gastrointestinal CMV disease at a median of 54 (interquartile range [IQR]: 40-70) days after stopping antiviral prophylaxis. Except for one patient, all received induction intravenous ganciclovir (mean+/-SD, 33.8+/-19.3 days) followed by valganciclovir (27.5+/-13.3 days) in 18 patients. Ten patients further received valganciclovir maintenance therapy (41.6+/-28.6 days). The median times to CMV PCR negativity in blood was 22.5 days (IQR: 16.5-30.7) and to normal endoscopic findings was 27.0 days (IQR: 21.0-33.5). CMV relapse, which occurred in seven (27%) patients, was significantly associated with extensive disease (p=0.03). CMV seroconversion, viral load, treatment duration, maintenance therapy and endoscopic findings at the end of therapy were not significantly associated with CMV relapse. In conclusion, an extensive involvement of the gastrointestinal tract was significantly associated with CMV relapse. However, endoscopic evidence of resolution of gastrointestinal disease did not necessarily translate into a lower risk of CMV relapse.

Background. Deficiencies in cytomegalovirus (CMV)-specific T lymphocytes impair the immunologic response against CMV reactivation after allogeneic hematopoietic stem cell transplantation (HSCT). Methods. A time-dependent analysis was conducted to determine the association between the percentages and kinetics of interferon-gamma-producing CMV-specific CD4+ and CD8+ T lymphocytes and CMV viremia among 30 allogeneic HSCT recipients. Results. Higher percentages of CD4+ T lymphocytes activated with CMVpp65 (hazard ratio [HR]: 2.06; 95% confidence interval [95% CI]: 1.18–3.6; P=0.011) and CMV lysate (HR: 1.18; 95% CI: 0.99–1.42; P=0.072), and higher percentages of CD8+ T lymphocytes activated by CMV immediate early-1 (HR: 1.2; 95% CI: 1.01–1.43; P=0.038) and CMVpp65 (HR: 1.12; 95% CI: 1.0–1.27; P=0.060) were associated with time-to-CMV viremia. Furthermore, a higher degree in the decline of CMV lysate-activated CD4+ T lymphocytes (HR: 1.14; 95% CI: 0.96–1.36; P=0.125) and CMVpp65-activated CD8+ T lymphocytes (HR: 1.36; 95% CI: 1.03–1.78; P=0.031) was suggestive of or significantly associated with time-to-CMV viremia. Conclusions. Higher levels of CMV-specific CD4+ and CD8+ T lymphocytes were associated with subsequent CMV viremia after HSCT. The association between CMV viremia and the degree of decline in CMV-specific T lymphocytes suggests that severe disruption in homeostatic CMV-specific immune environment contributes to the immunopathogenesis of CMV after allogeneic HSCT.

Recipients of lung transplants are at high risk of infectious complications. We investigated the epidemiology of infections after lung transplantation and determined their impact on survival.We retrospectively reviewed the medical records of patients who underwent lung transplantation at Mayo Clinic (Rochester) during 1990-2005. Survival analyses were performed using Kaplan-Meier estimation and Cox proportional hazard modeling.Sixty-nine lung transplants were performed during the 16-yr study period. The mean (+/-SD) patient age was 50.5 +/- 9.7 yr; 45% were male. During the mean (+/-SD) follow-up period of 1188 (+/-1288) d, the cumulative percentage of patients with infections were: bacteria (52%), cytomegalovirus (CMV) (49%), other viruses (32%), fungi (19%), mycobacteria (7%), and Pneumocystis jiroveci (1%). The median survival time after lung transplantation was 5.02 yr. Kaplan-Meier estimation of one-, three-, and five-yr survival was 80%, 61%, and 50%, respectively. Overall, 37 (54%) patients died due to graft rejection and failure (35%), invasive fungal diseases (16%), post-transplant lymphoproliferative disorder and other malignancies (14%), cardiovascular diseases (5%), CMV disease (3%), bacterial infection (3%), or other causes (24%). Survival analysis using Kaplan-Meier estimation showed that invasive fungal disease (Aspergillus sp., n = 9, Candida sp., n = 2, Alternaria sp., n = 1, Rhizopus sp., n = 1, and/or Mucor sp., n = 1) was significantly associated with mortality (p = 0.0104). After adjusting for age and graft rejection, invasive fungal disease remains a significant predictor of mortality (p = 0.0262).Invasive fungal disease is significantly associated with all-cause mortality after lung transplantation. An aggressive antifungal preventive strategy may lead to improved survival after lung transplantation.

Valganciclovir prophylaxis is reportedly associated with a low incidence of ganciclovir-resistant cytomegalovirus (CMV). We assessed the incidence, clinical features, and outcome of drug-resistant CMV among solid organ transplant patients who received valganciclovir prophylaxis.The medical records of all CMV D+/R- kidney, pancreas, liver, and heart recipients were screened for CMV disease, and the clinical course and outcomes of patients with drug-resistant CMV were reviewed.During a four-yr-study period, a total of 225 CMV D+/R- transplant patients received valganciclovir prophylaxis for a median of 92 d. Sixty-five (29%) of the 225 patients developed delayed-onset primary CMV disease, including nine (14%) suspected to have drug-resistant virus. Four (6.2%) had confirmed UL97 or UL54 mutations. All except one patient manifested gastrointestinal tissue-invasive disease. Together with reduction in immunosuppression, intravenous foscarnet with or without CMV hyperimmunoglobulin was the most common treatment. Drug-associated nephrotoxicity was commonly observed and resulted in allograft loss in two patients. During the mean follow-up of 2.2 yr, allograft loss and mortality occurred in two of four patients with proven and in three of five patients with clinically suspected drug-resistant CMV.Cytomegalovirus disease because of clinically suspected or genotypically confirmed drug-resistant CMV is not uncommon in CMV D+/R- solid organ transplant patients who received valganciclovir prophylaxis. Because of its significant morbidity and mortality, an optimized strategy of CMV prevention is warranted to reduce the negative impact of drug-resistant CMV on the successful outcome of organ transplantation.

Background. During the contemporary era of antiviral prophylaxis, the impact of delayed-onset primary cytomegalovirus (CMV) disease on the outcome of kidney transplantation is not known. We evaluated the incidence, clinical features, risk factors, and outcomes of CMV disease among high-risk kidney transplant recipients. Methods. The medical records of CMV-seronegative recipients of kidney transplants from CMV-seropositive donors were reviewed. Cox proportional hazards regression was used to identify factors associated with CMV disease and to assess its impact on allograft loss and mortality. Results. None of the 176 CMV-seronegative recipients of kidney transplants from CMV-seropositive donors developed breakthrough CMV disease during a median of 92 days (interquartile range, 90-92 days) of oral ganciclovir or valganciclovir prophylaxis. Thereafter, 51 patients (29%) developed CMV disease at a median of 61 days (interquartile range, 40-143 days) after stopping antiviral prophylaxis. Early-onset bacterial and fungal infection (hazard ratio, 3.61; 95% confidence interval, 1.78-7.33; P

Clinical practice guidelines recommend antiviral prophylaxis to cytomegalovirus (CMV) donor-positive/recipient-negative (D+/R-) liver transplant recipients. We assessed the outcome of this strategy by determining the incidence, clinical features, and risk factors of CMV disease among CMV D+/R- liver transplant recipients who received antiviral prophylaxis. Sixty-seven CMV D+/R- liver transplant recipients (mean age+/-standard deviation: 49.5+/-11.4 years; 75% male) received oral ganciclovir [n=9 (13%)] or valganciclovir [n=58 (87%)] prophylaxis for a median duration of 92 days (interquartile range: 91-100). No breakthrough CMV disease was observed during antiviral prophylaxis. However, primary CMV disease was observed in 2%, 25%, 27%, 27%, and 29% of patients at 1, 3, 6, 12, and 24 months, respectively, after antiviral prophylaxis was stopped. The incidence of delayed-onset primary CMV disease was similar between those who received oral ganciclovir and valganciclovir. Nine (47%) patients had CMV syndrome, 8 (42%) had gastrointestinal CMV disease, and 2 (11%) had CMV hepatitis. Female patients (P=0.01) and younger age at transplant (P=0.03) were associated with an increased risk, whereas diabetes mellitus (P

Background. Polyomavirus-associated nephropathy (PVAN) is a significant cause of allograft loss after renal transplantation. A noninvasive assay that can guide the evaluation of PVAN would be of clinical value. We compared the utility of BK virus (BKV) polymerase chain reaction (PCR) and urine cytology in screening for concurrent PVAN. Methods. We used PCR to test urine and plasma samples from renal recipients simultaneously for BKV DNA. Additionally, we tested urine samples for decoy cells. Sample results were correlated with biopsy-proven PVAN. Receiver-operator characteristic curves were used to determine viral load thresholds associated with concurrent PVAN. Results. In this cross-sectional study, BKV viruria, viremia, and urinary decoy cells were detected in 24%, 9%, and 13% of renal recipients, respectively. Among 114 patients who had renal allograft biopsy, four (3.5%) were diagnosed with PVAN. Using pathology as gold standard for the diagnosis of PVAN, BKV viremia threshold of >1.6E+04 copies/mL had 100% sensitivity, 96% specificity, 50% positive predictive value, and 100% negative predictive value. A BKV viruria threshold of >2.5E+07 copies/mL had 100% sensitivity, 92% specificity, 31% positive predictive value, and 100% negative predictive value. In contrast, urine decoy cells had 25% sensitivity, 84% specificity, 5% positive predictive value, and 97% negative predictive value for the diagnosis of concurrent PVAN. Conclusion. BKV PCR may be a clinically useful noninvasive test to identify renal recipients with concurrent PVAN. BKV DNA >1.6E+04 copies/mL of plasma and >2.5E+07 copies/mL of urine were highly associated with concurrent PVAN whereas a negative PCR test makes the diagnosis of PVAN highly unlikely.

Cytomegalovirus (CMV) infection of the retina is a rarely encountered end-organ disease after transplantation. In order to describe the clinical characteristics and outcomes of CMV retinitis after hematopoietic stem cell and solid organ transplantation, we performed a retrospective review of all cases of CMV retinitis at the Mayo Clinic (Rochester, Minnesota) during 1990-2004. During this 15-year period, CMV retinitis was diagnosed in 14 eyes of 9 patients who had received kidney (n=5), liver (n=2), heart (n=1), and autologous hematopoietic stem cell transplant (n=1). The mean age of the patients was 58 (standard deviation+/-11) years; 6 were male. The median time to diagnosis of CMV retinitis was 9 months (range, 4 months to 13 years) after transplantation. Four (44%) patients had concomitant pneumonitis or hepatitis. Five (55%) patients had bilateral retinitis. Retinal involvement wasor=10% in 8 eyes,10% butor=50% in 4 eyes, and50% in 2 eyes. All patients received induction therapy with intravenous ganciclovir (n=8) or foscarnet (n=1) for a median of 43 days (range, 14-100 days) followed by maintenance therapy with intravenous or oral ganciclovir for a median of 88 days (range, 36-943 days) in 6 (67%) patients. One patient developed bilateral immune recovery uveitis during treatment, and later on progressed to develop rhegmatogenous retinal detachment. During the mean follow-up period of 20 months, visual acuity improved in 4 (28.5%), was stable in 4 (28.5%), and worsened in 6 (43%) eyes. CMV retinitis recurred in 2 patients. In conclusion, CMV retinitis is a rare, progressive, and highly morbid infectious complication of transplantation. The severity of clinical disease at the time of diagnosis may predict poor outcome. Hence, early intervention may be crucial to prevent its progression to irreversible visual loss.

Background Prosthetic joint infection (PJI) due to rapidly growing mycobacteria (RGM) is only occasionally encountered in clinical practice. Therefore, the optimal clinical management for this condition is unknown. Methods The medical records of patients who had PJI due to RGM during 1969-2006 were reviewed to summarize its clinical characteristics, treatment, and outcome. Results Eight patients developed 9 episodes of PJI (7 episodes involving the knee and 1 each involving the hip or elbow) due to RGM at a median of 312 weeks (range, 1-170 weeks) after prosthesis implantation. Patients presented with joint pain (7 patients), joint swelling (7 patients), and fever (3 patients), accompanied by an elevated erythrocyte sedimentation rate (median, 70.5 mm/h) and C-reactive protein level (median, 6 mg/dL). Mycobacterium chelonae (n=3), Mycobacterium abscessus (n=2), Mycobacterium fortuitum (n=3), and Mycobacterium smegmatis (n=1) were isolated from the 9 infected joints. Seven of 9 prostheses were resected, whereas 2 were retained after surgical debridement. Six of 8 patients received > or = 1 active antimicrobial agent for at least 6 months. During a median follow-up period of 33 weeks (range, 2.6-326 weeks) after surgical intervention, no clinical or microbiological relapses were observed. Reimplantation was performed successfully for 2 of 6 patients who underwent resection arthroplasty. The 2 patients with retained prosthesis continued to receive prolonged courses of suppressive antimicrobial therapy. Conclusions RGM is a rare cause of PJI that should be suspected in patients with negative results of routine bacterial cultures. The combination of resection arthroplasty and antimicrobial therapy is the preferred approach. However, in cases involving retained prosthetic components, RGM infection may be suppressed with lifelong courses of effective antibiotic therapy.

Background. Experimental data suggest that cytomegalovirus (CMV) initiates innate immunity through the activation of Toll-like receptor 2 (TLR2). To assess the clinical relevance of this experimental observation, we assessed the association between the specific single-nucleotide polymorphism that results in the substitution of arginine for glutamine in position 753 of TLR2 (the TLR2 Arg753Gln polymorphism) and CMV replication and disease after liver transplantation. Methods. Ninety-two liver transplant recipients with chronic hepatitis C were screened for the presence of the TLR2 Arg753Gln polymorphism. CMV load was determined in serially collected blood samples using CMV DNA polymerase chain reaction. Kaplan-Meier estimation and univariable and multivariable stepwise Cox proportional hazard models were used to assess associations. Results. The degree of CMV replication, as measured by CMV load, was significantly higher in patients who were homozygous (mean maximum viral load, 37,059 copies/mL) and heterozygous (mean maximum viral load, 29,718 copies/mL) for this polymorphism, compared with patients without the TLR2 Arg753Gln polymorphism (mean maximum viral load, 3252 copies/mL; P =.003). Kaplan-Meier survival analysis demonstrated an association between being homozygous for the TLR2 Arg753Gln polymorphism and CMV disease (P =.04). A multivariate Cox proportional hazard model demonstrated a trend towards a higher risk of CMV disease among patients who were homozygous for the TLR2 Arg753Gln polymorphism (hazard ratio, 1.91 [95% confidence interval, 0.91-3.40]; P =.08) after adjusting for patient age, CMV serostatus, and allograft rejection. Conclusions. TLR2 Arg753Gln polymorphism is possibly associated with CMV replication and disease after liver transplantation. This novel clinical observation supports the potential role of TLR2 in the immunologic control of CMV infection in humans.

In the era of highly active antiretroviral therapy, long-term complications of HIV infection and antiretroviral therapy deserve heightened attention. Morphologic and metabolic complications seen during the course of HIV infection encompass a variety of entities that may share a common pathophysiologic pathway. This review article will discuss clinical syndromes such as wasting, lipoatrophy/lipohypertrophy, polymetabolic syndrome as well as hyperlipidemia, cardiovascular disease, lactic acidosis, and metabolic bone disease in HIV-infected patients.

Background. Infections with parvovirus B19 (PVB19) can cause significant morbidity in transplant recipients. Methods. To characterize the epidemiology and clinical spectrum of posttransplant PVB19 infection, we reviewed all cases at our institution during a 16-year period, summarized the data from 91 cases published in the medical literature, and performed longitudinal molecular surveillance for PVB19 DNAemia among 47 solid organ and hematopoietic stem cell transplant recipients. Results. The median time to onset of PVB19 disease was 7 weeks after transplantation. Anemia, leukopenia, and thrombocytopenia were present in 98.8%, 37.5%, and 21.0% of patients, respectively. Hepatitis, myocarditis, and pneumonitis were also reported in association with PVB19 disease. Allograft tissue loss or dysfunction was observed at the time of PVB19 disease in 10% of cases. At the onset of disease, PVB19 IgM serological test results were negative in 29% of cases. Almost all patients (96%) with anti-PVB19 IgM had a positive PVB19 polymerase chain reaction assay result. Intravenous immunoglobulin was the most commonly used treatment modality. Three of 98 patients died of myocarditis and cardiogenic shock associated with PVB19 disease. Molecular surveillance throughout the first year after transplantation did not reveal PVB19 DNAemia in 47 anemic solid organ and hematopoietic stem cell transplant patients. Conclusions. PVB19 is a rare but clinically significant infection that manifests as refractory anemia during the posttransplantation period. The use of polymerase chain reaction for diagnosis is particularly helpful in immunosuppressed transplant patients who may fail to mount antibodies against PVB19 during active infection.