International survey of human herpes virus 8 screening and management in solid organ transplantation.

BACKGROUND: HHV-8/Kaposi Sarcoma herpesvirus has been associated with a broad spectrum of diseases in solid organ transplant (SOT) recipients. Primary donor-derived infection can be associated with severe and rapidly fatal non-neoplastic disease, and diagnosis is made with high HHV-8 DNAemia. METHODS: We carried out an international survey to investigate the current approach to HHV-8 screening, and management in SOT since a protocol has not been established by international guidelines. RESULTS: A total of 51 transplant centers from 15 countries filled out the survey. HHV-8-associated diseases in SOT have been diagnosed during the previous 5 years in 67% of centers. Pretransplant serological screening is performed in 17 centers (33%), and posttransplant HHV-8 nucleic acid testing (NAT) monitoring is performed in 21 centers (41%). Performing HHV-8 NAT monitoring and serological screening were found associated with having diagnosed in the previous 5 years a non-malignant HHV-8-associated disease. CONCLUSIONS: Serological pretransplant screening of donors and recipients and post-transplant HHV-8 NAT monitoring recommendations should be standardized. Even though serological assays are not optimal, they could contribute to increasing knowledge on epidemiology and management of HHV-8-associated diseases after SOT.

Pneumocystis jirovecii: a review with a focus on prevention and treatment.

Introduction: Pneumocystis jirovecii (PJ) is an opportunistic fungal pathogen that can cause severe pneumonia in immunocompromised hosts. Risk factors for Pneumocystis jirovecii pneumonia (PJP) include HIV, organ transplant, malignancy, certain inflammatory or rheumatologic conditions, and associated therapies and conditions that result in cell-mediated immune deficiency. Clinical signs of PJP are nonspecific and definitive diagnosis requires direct detection of the organism in lower respiratory secretions or tissue. First-line therapy for prophylaxis and treatment remains trimethoprim-sulfamethoxazole (TMP-SMX), though intolerance or allergy, and rarely treatment failure, may necessitate alternate therapeutics, such as dapsone, pentamidine, atovaquone, clindamycin, primaquine and most recently, echinocandins as adjunctive therapy. In people living with HIV (PLWH), adjunctive corticosteroid use in treatment has shown a mortality benefit.Areas covered: This review article covers the epidemiology, pathophysiology, diagnosis, microbiology, prophylaxis indications, prophylactic therapies, and treatments.Expert opinion: TMP-SMX has been first-line therapy for treating and preventing pneumocystis for decades. However, its adverse effects are not uncommon, particularly during treatment. Second-line therapies may be better tolerated, but often sacrifice efficacy. Echinocandins show some promise for new combination therapies; however, further studies are needed to define optimal antimicrobial therapy for PJP as well as the role of corticosteroids in those without HIV.

Granuloma in the explanted lungs: Infectious causes and impact on post-lung transplant mycobacterial infection.

INTRODUCTION: The significance of granuloma in explanted lungs of lung transplant recipients (LTR) on the development of post-transplant mycobacterial infection is unclear. METHODS: A retrospective review comparing LTRs and heart-lung transplant (H-LTR) recipients with granuloma in the explanted lungs between 2000 and 2012 (excluding those LTRs with granuloma due to sarcoidosis) and LTRs or H-LTRs without granuloma. Patients were followed for 2 years post-transplant. RESULTS: A total of 144 LTRs and 4 H-LTRs with granulomas (75 necrotizing and 73 non-necrotizing) and a comparator cohort of 144 LTRs and 4 H-LTRs without granuloma were analyzed. In LTRs with granulomas, identification of infectious organisms was more common by histopathology (35 AFB and 22 fungal) compared to cultures (six NTM and seven fungal) taken around time of the transplant. LTRs with granulomas were more likely to have pre-transplant non-tuberculous mycobacteria (NTM) infection compared to LTRs without granuloma; P < .01. In the multivariate analysis, having granuloma or positive mycobacterial cultures at time of transplant were associated with increased risk of post-transplant mycobacterial infection (HR = 1.8 95% CI [1.024-3.154]; P = .041 and HR = 2.083 95% CI [1.011-4.292]; P = .047). Although there was a trend toward increase mycobacterial disease in those with granulomas P = .056, there was no difference in survival post-transplantation between those with or without granuloma in the explanted lung; P = .886. CONCLUSION: The presence of granuloma in the explanted lungs of LTRs or positive mycobacterial cultures at time of transplant is associated with an increased risk of mycobacterial infection post-transplant.

Non-tuberculous mycobacteria in lung transplant recipients: Prevalence, risk factors, and impact on survival and chronic lung allograft dysfunction.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are environmental organisms that colonize or infect lung transplant recipients. Because of differences in populations studied and geographical diversity of species, risk factors for infection and its impact on patient outcomes post transplant are conflicting in the literature. METHODS: We reviewed the charts of 375 lung transplant recipients at the University of Alberta Hospital (Edmonton, Canada) between 2005 and 2014 to assess NTM epidemiology and risk factors. NTM positivity was determined from a laboratory database. The impact of NTM on patient and graft survival was tested by multivariate Cox regression analysis. RESULTS: Non-tuberculous mycobacteria were cultured from 26 patients before and 17 patients after transplant. The most commonly isolated species were Mycobacterium avium complex (55%) and Mycobacterium abscessus (20%). Five-year mortality was significantly higher in those infected with NTM after transplant (P = .016), but there was no difference in chronic lung allograft dysfunction (CLAD) at 5 years (P = .999). Cystic fibrosis and lower body mass index were associated with pre-transplant but not post-transplant NTM. CONCLUSIONS: Isolation of NTM occurred in 7% of patients before and 4.5% of patients after transplant. In this cohort, NTM isolation was associated with increased risk of death but not CLAD onset at 5 years.

Xanthogranulomatous prostatitis presenting as Pseudomonas aeruginosa prostatic abscesses: An uncommon complication after kidney transplantation.

Xanthogranulomatous (XG) prostatitis is a rare form of granulomatous prostatitis characterized by a benign inflammatory process of non-specific etiology that clinically may mimic carcinoma. Few cases have been reported in the English language medical literature, with only four reported cases presenting as prostatic abscesses. A 70-year-old male with type 2 diabetes mellitus and two previous kidney transplants presented with septic shock secondary to Pseudomonas aeruginosa bacteremia 4 days after undergoing a cystoscopy. Despite appropriate antimicrobial therapy, P. aeruginosa persisted in the blood for a total of 7 days. There were no indwelling prosthetic devices, no complicated pyelonephritis, and no endovascular sources of infection. Upon repeat clinical assessment, the patient reported pelvic pain. A digital rectal examination revealed prostatic tenderness and an endorectal ultrasound confirmed multiple prostatic abscesses. An ultrasound-guided transrectal needle aspirate drained scant purulent fluid and cultures grew the same phenotypic strain of P. aeruginosa. For definitive source control, the patient underwent transurethral resection of the prostate with unroofing of prostatic abscesses. The pathological findings were diagnostic of XG prostatitis. Given the rather acute presentation of this case, our hypothesis is that the prior urological instrumentation likely facilitated bacterial translocation and created the ideal environment for the development of pseudomonal prostatic abscesses resulting in XG inflammation and necrosis. XG prostatitis is a rare entity of uncertain etiology that can result in prostatic abscesses, and surgery is required for definitive diagnosis and management.

The Changing Epidemiology of Posttransplant Lymphoproliferative Disorder in Adult Solid Organ Transplant Recipients Over 30 Years: A Single-center Experience.

BACKGROUND: Posttransplant lymphoproliferative disorders (PTLD) are a complication of solid organ transplantation (SOT) associated with Epstein-Barr virus (EBV). METHODS: We analyzed the incidence of and risk factors for PTLD among adult SOT recipients at our center over 30 years (1984-2013). We also compared PTLD incidence before and after a prevention strategy of EBV viral load monitoring in EBV serology mismatched patients was adapted in 2001 (ie, transplant era 1 [1983-2001] vs era 2 [2002-2013]). RESULTS: Among 4171 SOT patients, 109 developed PTLD. Cumulative incidence at 1, 10, and 20 years posttransplant was 0.95, 2.3, and 3.5 per 100 person-years, respectively. Beyond the first year peak of almost exclusively EBV-positive PTLD, a lower incidence of PTLD, predominantly EBV negative, persisted for 20 years. Thoracic transplant (hazard ratio [HR], 2.1; P = 0.007) and negative EBV serology (HR, 7.7; P < 0.001) were independent risk factors for PTLD on multivariate Cox regression analysis. EBV seronegativity significantly increased risk of early (HR, 18.5) and EBV-positive PTLD (HR, 14.2), as well as late (HR, 4.9) and EBV-negative PTLD (HR, 3.6) on univariate analyses. Risk of early PTLD was significantly reduced in the recent transplant era (0.8% era 2 vs 1.9% era 1 at 5 years, P = 0.002); this reduction was seen in recent era EBV seropositive (P = 0.035 at 5 years) but not seronegative recipients (P = 0.90 year 5), suggesting lack of impact of viral load monitoring. CONCLUSIONS: Adult SOT recipients face a prolonged risk of late PTLD, whereas risk of early PTLD may have declined in recent years.

Mycobacterium branderi infection: Case report and literature review of an unusual and difficult-to-treat non-tuberculous mycobacterium.

A 67-year-old man with significant smoking history presented with fever, unintentional weight loss, night sweats, productive cough, and progressive dyspnea. Multiple respiratory specimens grew Mycobacterium branderi. Computed tomography scanning of the chest revealed a cavitary right upper lung lesion. Bronchoscopy and thoracoscopic biopsy were negative for malignancy but showed necrotizing granulomatous inflammation, which was culture negative. Due to clinical and radiologic progression despite therapy with clarithromycin, ethambutol and moxifloxacin, the lesion was surgically resected and the patient's symptoms resolved. Mycobacteria were seen in histopathology but did not grow from resected tissue. The patient received an additional 6 months of medical therapy and remains asymptomatic 1 month after completing antimicrobials. Cases of M. branderi causing human infection are very rarely reported. This is a novel case of multi-drug resistant M. branderi pulmonary infection in an apparently immunocompetent patient, progressive despite medical therapy and requiring surgical resection for definitive management.

Infective endocarditis in patients with an implanted transcatheter aortic valve: Clinical characteristics and outcome of a new entity.

AIMS: This study reports one case and review the literature on TAVI-associated endocarditis (TAVIE), to describe its clinical picture and to perform an analysis on prognostic factors. METHODS AND RESULTS: A MEDLINE search from January 2002 to October 2014 revealed 31 cases of TAVIE, including 1 from our hospital. Median age was 81 years (IQR, 78-85), 53% of patients were males and the median age-adjusted Charlson score was 7 (IQR, 5-8). Heart failure was recorded in 42%, embolic events in 19%, and periannular complications in 45%. The most common causative agent was Enterococcus spp (36%). Ten patients (32%) underwent surgery and nine patients died (29%). The prognostic factors for 6-month mortality were heart failure (HR, 9.97 [3.7-24.5]; p = 0.001), periannular complications (HR, 11.82 [3.3-41.3]; p = 0.004), and nonenterococcal/streptococcal etiology (HR, 4.76 [2.1-11.1]; p = 0.03). In patients with heart failure who did not undergo surgery, mortality was 89% (8 out of 9); in those who did undergo surgery, mortality was 0% (p < 0.001). CONCLUSIONS: TAVIE is an emerging entity with high mortality. Patients with heart failure who did not undergo surgery had a higher probability of dying. Surgical treatment provided better outcomes even in patients in whom surgery had previously been ruled out.

Randomized trial of micafungin for the prevention of invasive fungal infection in high-risk liver transplant recipients.

BACKGROUND: Invasive fungal infection (IFI) following liver transplant is associated with significant morbidity and mortality. Antifungal prophylaxis is rational for liver transplant patients at high IFI risk. METHODS: In this open-label, noninferiority study, patients were randomized 1:1 to receive intravenous micafungin 100 mg or center-specific standard care (fluconazole, liposomal amphotericin B, or caspofungin) posttransplant. The primary endpoint was clinical success (absence of a proven/probable IFI and no need for additional antifungals) at end of prophylaxis (EOP). Noninferiority (10% margin) of micafungin vs standard care was assessed in the per protocol and full analysis sets. Safety assessments included adverse events and liver and kidney function tests. RESULTS: The full analysis set comprised 344 patients (172 micafungin; 172 standard care). Mean age was 51.2 years; 48.0% had a Model for End-Stage Liver Disease score ≥20. At EOP (mean treatment duration, 17 days), clinical success was 98.6% for micafungin and 99.3% for standard care (Δ standard care - micafungin [95% confidence interval], 0.7% [-2.7% to 4.4%]) in the per protocol set and 96.5% and 93.6%, respectively (-2.9% [-8.0% to 1.9%]), in the full analysis set. Incidences of drug-related adverse events for micafungin and standard care were 11.6% and 16.3%, leading to discontinuation in 6.4% and 11.6% of cases, respectively. At EOP, liver function tests were similar but creatinine clearance was higher in micafungin- vs standard care-treated patients. CONCLUSIONS: Micafungin was noninferior to standard care as antifungal prophylaxis in liver transplant patients at high risk for IFI. Adverse event profiles and liver function at EOP were similar, although kidney function was better with micafungin. CLINICAL TRIALS REGISTRATION: NCT01058174.

Candida norvegensis fungemia in a liver transplant recipient.

BACKGROUND: The incidence of candidemia due to non-Candida albicans Candida species has been progressively increasing in recent years. The use of fluconazole as antifungal prophylaxis has been described as a risk factor for the development of infections by fluconazole resistant Candida strains. We report a case of Candida norvegensis bloodstream infection in a liver transplant recipient. CASE REPORT: A 61-year-old man, who received a third liver allograft and became worse with the onset of ischemic cholangiopathy and recurrent episodes of cholangitis, was admitted to our hospital due to the development of intra-abdominal abscesses. He received multiple antibiotic schemes, and after 3 months he was discharged, maintaining parenteral antibiotic at home. While he was on fluconazole prophylaxis, a breakthrough candidemia due to C. norvegensis occurred. In vitro susceptibilities of the isolate to several antifungal agents were as follows: amphotericin B MIC 0.5 mg/l, flucytosine 64 mg/l, fluconazole 64 mg/l, itraconazole 4 mg/l, voriconazole 0.75 mg/l, and caspofungin 0.047 mg/l. He was treated with anidulafungin with resolution of candidemia. CONCLUSIONS: The use of fluconazole for antifungal prophylaxis may lead to the emergence of fluconazole-resistant Candida infections, with C. norvegensis being a possible emerging pathogen in organ transplant recipients.

Genetic variants of innate immune receptors and infections after liver transplantation.

Infection is the leading cause of complication after liver transplantation, causing morbidity and mortality in the first months after surgery. Allograft rejection is mediated through adaptive immunological responses, and thus immunosuppressive therapy is necessary after transplantation. In this setting, the presence of genetic variants of innate immunity receptors may increase the risk of post-transplant infection, in comparison with patients carrying wild-type alleles. Numerous studies have investigated the role of genetic variants of innate immune receptors and the risk of complication after liver transplantation, but their results are discordant. Toll-like receptors and mannose-binding lectin are arguably the most important studied molecules; however, many other receptors could increase the risk of infection after transplantation. In this article, we review the published studies analyzing the impact of genetic variants in the innate immune system on the development of infectious complications after liver transplantation.

[Infections and fingolimod]. / Infecciones y fingolimod.

INTRODUCTION: Fingolimod is the first approved drug with oral availability for the treatment of relapsing multiple sclerosis. AIMS: To review the mechanism of action of fingolimod and its relationship with the development of infections. To propose preventive measures for those patients who are receiving the drug or will initiate a new treatment. In addition, the role of fingolimod in the development of progressive multifocal leukoencephalopathy on the basis of recent knowledge of its pathophysiology will be discussed. DEVELOPMENT: The mechanism of action of fingolimod is based on an antagonic effect on the sphingosine 1-phospate receptors that will generate an inhibition of the egress of naive and central memory lymphocytes into the bloodstream, allowing the free recirculation of memory effectors T lymphocytes. This effect will produce lymphopenia. Fingolimod-associated lymphopenia is a consequence of lymphocyte redistribution, and it is selective and reversible. There is no evidence of higher number of opportunistic and non-opportunistic infections in comparison to placebo or interferon beta-1a in patients receiving fingolimod. However, two patients developed severe herpetic infections under fingolimod. CONCLUSIONS: Fingolimod induce a selective and reversible lymphopenia that, taking into account the most recent available data, does not seem to be associated with higher risk of opportunistic infections due to a preservation of immuno-surveillance. The risk of herpesvirus infection should be taken into consideration and more studies are warranted to confirm if an association of these infections with the use of fingolimod exists.

[Guidelines for the treatment of invasive fungal disease by Aspergillus spp. and other fungi issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC). 2011 Update]. / Recomendaciones sobre el tratamiento de la enfermedad fúngica invasiva por Aspergillus spp. y otros hongos filamentosos de la Sociedad Española de Enfermedades Infecciosas y Microbiología Clínica (SEIMC). Actualización 2011.

The guidelines on the treatment of invasive fungal disease by Aspergillus spp. and other fungi issued by the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) are presented. These recommendations are focused on four clinical categories: oncology-haematology patients, solid organ transplant recipients, patients admitted to intensive care units, and children. An extensive review is made of therapeutical advances and scientific evidence in these settings. These guidelines have been prepared according the SEIMC consensus rules by a working group composed of specialists in infectious diseases, clinical microbiology, critical care medicine, paediatrics and oncology-haematology. Specific recommendations on the prevention of fungal infections in these patients are included.

Non-myeloablative hematopoietic stem cell transplantation in the treatment of severe idiopathic CD4+ lymphocytopenia.

A 40-year-old man with severe chronic idiopathic CD4+ lymphocytopenia complicated with opportunistic infections was successfully treated with non-myeloablative allogeneic hematopoietic stem cell transplantation. After conditioning with fludarabine plus low dose of total-body irradiation, CD34+ peripheral blood stem cells obtained by leukapheresis from his HLA-identical sister were infused. T cell and myeloid complete chimerism was achieved at day +28 and remained stable during the follow-up period. The patient did not develop infectious complications during the procedure. At 35 months of follow-up, his CD4+ T cell count was 1019 cells per microliter. Non-myeloablative allogeneic hematopoietic stem cell transplantation should be considered a treatment option for patients with severe forms of idiopathic CD4+ lymphocytopenia.

Patients at risk of complications of Staphylococcus aureus bloodstream infection.

Staphylococcus aureus is one of the most common causative pathogens of bloodstream infections (BSIs). In approximately one-half of patients with S. aureus BSI, no portal of entry can be documented. This group of patients has a high risk of developing septic metastases. Similarly, patient populations at high risk of S. aureus BSI and BSI-associated complications include patients receiving hemodialysis, injection drug users, patients with diabetes, and patients with preexisting cardiac conditions or other comorbidities. One of the most severe complications of S. aureus BSI is infective endocarditis, and S. aureus is now the most common cause of infective endocarditis in the developed world. Patients with methicillin-resistant S. aureus BSI or infective endocarditis have higher rates of mortality, compared with patients with methicillin-susceptible S. aureus infection. Nasal carriage is the most important source of S. aureus BSI. Better eradication and control strategies, including nasal decolonization and more-active antibiotics, are needed to combat S. aureus BSIs.

Immune reconstitution syndrome after voriconazole treatment for cryptococcal meningitis in a liver transplant recipient.

A new entity that comprises symptomatic worsening of an infectious or inflammatory process despite appropriate treatment was described a few years ago in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy. This entity was defined as immune reconstitution syndrome, and it is believed to result from an intense inflammatory reaction in patients with an appropriately treated infection who recover immunological status. Recently, immune reconstitution syndrome has also been described in transplant recipients, although information is scarce because of its low incidence. Here we describe a new case of immune reconstitution syndrome in a liver transplant recipient after successful treatment of cryptococcal meningitis.