Tuberculosis and Transplantation.

Mycobacterium tuberculosis is a major opportunistic pathogen in transplant recipients. Compared to that in the general population, the frequency of tuberculosis (TB) is 10 to 40 times higher in hematopoietic stem cell transplant (HSCT) recipients and 20 to 74 times higher in solid-organ transplant (SOT) recipients. Transplant recipients with TB are also more likely to develop disseminated disease, have longer time to definitive diagnosis, require more invasive diagnostic procedures, and experience greater anti-TB treatment-related toxicity than the general population. Specific risk factors for TB in SOT recipients include previous exposure to M. tuberculosis (positive tuberculin skin tests and/or residual TB lesions in pretransplant chest X ray) and the intensity of immunosuppression (use of antilymphocyte antibodies, type of basal immunosuppression, and intensification of immunosuppressive therapy for allograft rejection). Risk factors in HSCT recipients are allogeneic transplantation from an unrelated donor; chronic graft-versus-host disease treated with corticosteroids; unrelated or mismatched allograft; pretransplant conditioning using total body irradiation, busulfan, or cyclophosphamide; and type and stage of primary hematological disorder. Transplant recipients with evidence of prior exposure to M. tuberculosis should receive treatment appropriate for latent TB infection. Optimal management of active TB disease is particularly challenging due to significant drug interactions between the anti-TB agents and the immunosuppressive therapy. In this chapter, we address the epidemiology, clinical presentation, diagnostic considerations, and management strategies for TB in SOT and HSCT recipients.

Role of mTOR inhibitors for the control of viral infection in solid organ transplant recipients.

Appropriate post-transplant immunosuppressive regimens that avoid acute rejection, while reducing risk of viral reactivation, have been sought, but remain a chimera. Recent evidence suggesting potential regulatory and antiviral effects of mammalian target of rapamycin inhibitors (mTORi) is of great interest. Although the concept of an immunosuppressive drug with antiviral properties is not new, little effort has been made to put the evidence together to assess the management of immunosuppressive therapy in the presence of a viral infection. This review was developed to gather the evidence on antiviral activity of the mTORi against the viruses that most commonly reactivate in adult solid organ recipients: cytomegalovirus (CMV), polyomavirus, Epstein-Barr virus (EBV), human herpesvirus 8 (HHV8), and hepatitis C virus (HCV). A rapid review methodology and evaluation of quality and consistency of evidence based on the GRADE system was used. The existing literature was variable in nature, although indicating a potential advantage of mTORi in CMV, polyomavirus, and HHV8 infection, and a most doubtful relation with EBV and HCV infection. Several recommendations about the management of these infections are presented that can change certain current patterns of immunosuppression and help to improve the prognosis of the direct and indirect effects of viral infection in solid organ recipients.

Common Genetic Polymorphisms within NFκB-Related Genes and the Risk of Developing Invasive Aspergillosis.

Invasive Aspergillosis (IA) is an opportunistic infection caused by Aspergillus, a ubiquitously present airborne pathogenic mold. A growing number of studies suggest a major host genetic component in disease susceptibility. Here, we evaluated whether 14 single-nucleotide polymorphisms within NFκB1, NFκB2, RelA, RelB, Rel, and IRF4 genes influence the risk of IA in a population of 834 high-risk patients (157 IA and 677 non-IA) recruited through a collaborative effort involving the aspBIOmics consortium and four European clinical institutions. No significant overall associations between selected SNPs and the risk of IA were found in this large cohort. Although a hematopoietic stem cell transplantation (HSCT)-stratified analysis revealed that carriers of the IRF4 rs12203592T/T genotype had a six-fold increased risk of developing the infection when compared with those carrying the C allele (ORREC = 6.24, 95%CI 1.25-31.2, P = 0.026), the association of this variant with IA risk did not reach significance at experiment-wide significant threshold. In addition, we found an association of the IRF4AATC and IRF4GGTC haplotypes (not including the IRF4 rs12203592T risk allele) with a decreased risk of IA but the magnitude of the association was similar to the one observed in the single-SNP analysis, which indicated that the haplotypic effect on IA risk was likely due to the IRF4 rs12203592 SNP. Finally, no evidence of significant interactions among the genetic markers tested and the risk of IA was found. These results suggest that the SNPs on the studied genes do not have a clinically relevant impact on the risk of developing IA.

Varicella-zoster virus (VZV) infection as a possible cause of Ogilvie's syndrome in an immunocompromised host.

We describe an immunodeficient adult with Ogilvie's syndrome preceding a disseminated papulovesicular skin rash in whom varicella-zoster virus infection was demonstrated by PCR assay in cutaneous and colonic biopsy specimens. In view of the significant morbidity and mortality that this condition carries, early and accurate molecular diagnosis and timely treatment are strongly recommended.

Epstein-Barr virus DNAemia is an early surrogate marker of the net state of immunosuppresion in solid organ transplant recipients.

BACKGROUND: Epstein-Barr virus (EBV) DNAemia (EBVd) may be a surrogate marker of the net state of immunosuppression after solid organ transplantation (SOT). METHODS: A sample of 81 SOT recipients (53 renal, 21 liver, and 7 cardiac) from our institution (2003-2004) surviving more than 180 days was analyzed. EBVd was monitored in whole blood within the first 6 months using a real-time polymerase chain reaction assay. Using a Cox proportional hazards model, duration and magnitude of EBVd were assessed as potential surrogate markers for the occurrence of late adverse events (>6 months): graft dysfunction, graft loss, death, and immunosuppression-related adverse events (IRAE), defined by the occurrence of solid organ tumor and opportunistic and severe infections. RESULTS: A median of 10 blood samples per patient was screened. A total of 68 (84%) patients had detectable EBVd. Persistent EBVd (>30 days) was found in 40 (49.4%) and high EBVd (>1500 copies/mL) in 35 (43.3%). Multivariate analyses showed that persistent EVBd and high EBVd levels were independently related to the development of IRAE (hazard ratio, 2.95 and 4.32, respectively), whereas no significant associations were observed with late graft dysfunction or graft loss. CONCLUSIONS: Persistent and high levels of EBVd within the first 6 months after SOT are surrogate markers of increased risk of IRAE.

Effect of maintenance immunosuppressive drugs on virus pathobiology: evidence and potential mechanisms.

Recent evidence suggesting a potential anti-CMV effect of mTORis is of great interest to the transplant community. However, the concept of an immunosuppressant with antiviral properties is not new, with many accounts of the antiviral properties of several agents over the years. Despite these reports, to date, there has been little effort to collate the evidence into a fuller picture. This manuscript was developed to gather the evidence of antiviral activity of the agents that comprise a typical immunosuppressive regimen against viruses that commonly reactivate following transplant (HHV1 and 2, VZV, EBV, CMV and HHV6, 7, and 8, HCV, HBV, BKV, HIV, HPV, and parvovirus). Appropriate immunosuppressive regimens posttransplant that avoid acute rejection while reducing risk of viral reactivation are also reviewed. The existing literature was disparate in nature, although indicating a possible stimulatory effect of tacrolimus on BKV, potentiation of viral reactivation by steroids, and a potential advantage of mammalian target of rapamycin (mTOR) inhibition in several viral infections, including BKV, HPV, and several herpesviruses.

Hepatitis C and renal transplantation.

PURPOSE OF REVIEW: The purpose of this review is to describe the new insights of hepatitis C virus (HCV) infection and renal transplantation. RECENT FINDINGS: HCV is its most frequent cause of liver disease after transplantation. In the long run, HCV infection can lead to cirrhosis, hepatocarcinoma and death in some patients. As interferon is generally contraindicated after transplantation, the best way to treat patients is before transplantation. Long-term patient and graft survival rates are lower in HCV-positive patients than in HCV-negative graft recipients. HCV infection is an independent risk factor for death and graft loss. Mortality is higher, mainly as a result of cardiovascular complications, liver disease and infections but is lower than in HCV-positive patients on the transplant waiting list. New-onset diabetes after transplantation (NODAT), and HCV-related glomerulonephritis, together with chronic rejection and notably transplant glomerulopathy can contribute to graft failure. Despite this factor, transplantation is the best option for the HCV-positive patient on dialysis. Renal transplantation with kidneys from donors with positive anti-HCV antibodies into HCV RNA-positive recipients seems to be safe in the long term. SUMMARY: Renal transplantation is the therapy of choice for dialysis patients with HCV infection. To improve the results, a careful follow-up in the outpatient clinic for early detection of HCV-related complications is mandatory.

[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.

Selective intestinal decontamination with fluoroquinolones for the prevention of early bacterial infections after liver transplantation.

The role of selective intestinal decontamination with fluoroquinolones (FQ-SID) in the prevention of early bacterial infections (EBIs) in liver transplant recipients (LTRs) is unknown. We used the online database of the Spanish Network of Infection in Transplantation/Spanish Network for Research in Infectious Diseases, which prospectively analyzed 1010 LTRs from 12 Spanish hospitals from September 2003 to February 2005. We compared the incidence and etiology of EBIs (30 days after transplantation) in 415 LTRs from 4 centers that used FQ-SID (>7 days) and in 595 LTRs from 8 hospitals that did not use FQ-SID. A multivariate logistic regression analysis (including an adjustment for the transplant center factor) was performed to evaluate the potential protective factor of FQ-SID in the development of EBIs. We reported 266 EBI episodes in 252 LTRs (incidence = 24.9%). There were no differences in the incidence of EBIs between patients in the FQ-SID group and patients not in the FQ-SID group [109/415 (26.3%) versus 143/595 (24%), P = 0.9]. Although LTRs who received FQ-SID had a lower incidence of infections due to enteric bacteria (2.7% versus 6.5%, P = 0.007) and a higher incidence of infections due to nonfermenting gram-negative bacilli (6.6% versus 2.6%, P = 0.004), these findings could not be confirmed after an adjustment by the center factor in the multivariate models. We found no significant differences in the incidence of enterococcal infections (3.4% with FQ-SID versus 3.9% without FQ-SID, P = 0.5). Multivariate analysis did not confirm any protective effect of FQ-SID against the development of EBIs by enteric bacteria. In conclusion, FQ-SID does not reduce the incidence of EBIs in LTRs and could be withheld from this group of patients.

Systematic screening and treatment of asymptomatic bacteriuria in renal transplant recipients.

We sought to examine the impact of asymptomatic bacteriuria on renal transplant outcome by retrospectively analyzing 189 renal transplant recipients for whom systematic screening uncovered 298 episodes of asymptomatic bacteriuria in 96 recipients. These patients were treated and all were followed for 36 months. Significant risk factors included female gender, glomerulonephritis as the disease that led to transplantation, and double renal transplant. There were no differences in serum creatinine, creatinine clearance, or proteinuria between patients with and without bacteriuria. The incidence of pyelonephritis in these patients was 7.6 episodes per 100 patient-years compared with 1.07 in those without asymptomatic bacteriuria. Between two to five and more than five bacteriuria episodes were significant independent factors associated with pyelonephritis whereas more than five episodes was a significant independent factor associated with rejection. Thus, we found no differences in renal function prognosis between patients who do not develop asymptomatic bacteriuria and those uncovered by systematic screening and who received treatment following kidney transplantation. Despite this treatment, the incidence of pyelonephritis was much higher in the group of patients with detected asymptomatic bacteriuria.

Rhino-orbital-cerebral zygomycosis in solid organ transplant recipients.

BACKGROUND: Rhino-orbital-cerebral disease is a significant manifestation of zygomycosis in solid organ transplant (SOT) recipients. However, its characteristics and outcome are not well addressed. METHODS: SOT recipients with zygomycosis as per the European Organization for Research and Treatment in Cancer and the Mycoses Study Group criteria in a cohort study at our centers published previously and those identified with a PubMed search from the 1950s to November 2009 were studied. Patients with mycosis involving the sinuses, orbits, or central nervous system (CNS) were included. RESULTS: Patients comprised a total of 90 SOT recipients with rhino-orbital-cerebral zygomycosis, including 13 in our cohort and 77 in the literature. CNS disease occurred in 57% (51 of 90). Overall mortality was 52.3% (46 of 88), and the mortality in patients with CNS disease was 73.5% (36 of 49). In logistic regression analysis, older age (odds ratio [OR] 1.12, 95% confidence interval [CI] 1.04-1.21, P=0.002) was associated with a higher mortality rate, whereas lipid formulations of amphotericin B compared with amphotericin B deoxycholate (OR 0.09, 95% CI 0.02-0.50, P=0.006) and surgery (OR 0.12, 95% CI 0.01-0.94, P=0.043) were independently associated with an improved survival even when controlled for CNS involvement and the era of diagnosis of disease. CONCLUSIONS: Rhino-orbital-cerebral zygomycosis, particularly CNS disease, is associated with substantial mortality rate in SOT recipients. Older age is a significant risk factor for mortality, whereas lipid formulations of amphotericin B and surgery improved outcomes.

Clinical implications of respiratory virus infections in solid organ transplant recipients: a prospective study.

BACKGROUND: There is limited information about clinical consequences of respiratory virus infections (RVI) in solid organ transplant recipients. No prospective epidemiological study has been published previously. METHODS: We selected a cohort of 152 transplant recipients (cardiac, hepatic and renal transplant recipients). Median time from transplantation was 17 months (range 1-50). They were prospectively followed-up for RVI during 7 months (October to April). Clinical and microbiological evaluation (cell culture, shell vial and polymerase chain reaction technique) of each RVI episode was made. RESULTS: We detected 81 RVI (0.91 episodes/patient/year). Complications were detected in 15/81 episodes (18.5%): acute bronchitis (10 cases), pneumonia (three cases; 3.7% of RVI episodes) and bacterial sinusitis (2 cases). In 4 of 81 episodes (5%), patients needed hospitalization. A respiratory virus was isolated in 17 of 68 nasopharyngeal samples (six respiratory syncytial virus, six influenza, four picornavirus, one adenovirus). Fever presented an 83% positive predictive value for the diagnosis of influenza virus infection among those with a positive microbiological isolation. There were no episodes of acute rejection coincidentally with RVI. Only 54% of the subjects had been previously vaccinated against influenza. CONCLUSIONS: Incidence of RVI among solid organ transplant recipients is similar to general population but complications are higher. A relationship between RVI and rejection was not detected. The rate of influenza vaccination was lower than expected. The presence of fever in a transplant recipient with RVI strongly suggests influenza infection.

Effect of penicillin resistance of Streptococcus pneumoniae on the presentation, prognosis, and treatment of pneumococcal endocarditis in adults.

We performed a clinical study of pneumococcal endocarditis (PE) in adults at 15 major Spanish hospitals during a 21-year period (1978-1998). During this time, 63 patients had PE due to Streptococcus pneumoniae diagnosed. Of the 63 isolates recovered from these patients, 24 (38%) and 6 (10%) showed resistance to penicillin (minimum inhibitory concentration [MIC], 0.1-4 microg/mL) and cefotaxime (MIC, 1 microg/mL), respectively. Twenty-two (35%) of the patients died. Left-side heart failure, but not penicillin resistance, was independently associated with a higher risk of death (odds ratio, 1.33; 95% confidence interval, 1.04-1.71; P=.026). Patients without meningitis who had PE due to penicillin-resistant S. pneumoniae could be treated with high-dose penicillin or a third-generation cephalosporin if the MIC for penicillin was < or =1 microg/mL. For patients with concurrent meningitis, high doses of cefotaxime could be used if the MIC for cefotaxime was < or =1 microg/mL. Early recognition of heart failure and surgery may help to decrease mortality.