Major Infectious Complications Research Articles

Plasma Transfusion Is Associated With Postoperative Infectious Complications Following Esophageal Resection Surgery: A Retrospective Cohort Study

To examine the association between blood component transfusions and the incidence of major postoperative infections in patients undergoing esophageal resection surgery. Retrospective cohort study. Single academic tertiary referral center. All patients who underwent esophagectomy from 2005 through 2009. The primary outcome was the incidence of major postoperative infection, defined as pneumonia, bloodstream infection, and/or a surgical site infection occurring within 30 days postoperatively. In total, 465 patients were evaluated. One hundred thirty-eight patients (29.7%) received a blood transfusion before the onset of a major postoperative infection or during a similar exposure interval in those with no such complications. Univariate analysis showed a significant association between any blood component transfusion and postoperative infection (transfused v nontransfused 31.9% v 13.2%; odds ratio = 3.1, 95% confidence interval = 1.9-5.0; p < 0.01). This association was lost on multivariate analysis. Subgroup analysis with multivariate adjustment identified a significant association between high plasma volume blood component transfusions and postoperative infection (odds ratio = 4.2, 95% confidence interval = 1.2-15.8; p = 0.03). With multivariate adjustment, red blood cell administration was no longer associated with major postoperative infectious complications. High plasma volume blood component transfusions were associated with the development of major postoperative infectious complications in patients undergoing esophageal resection surgery. In contrast, red blood cell transfusion was not associated with infectious complications.

Clinical and epidemiological risk factors for ventilator-associated pneumonia in a cohort of critically ill patients

Ventilator-associated pneumonia (VAP) represents a major infectious complication in the ICU. The aim of this study is to identify risk factors for VAP acquisition.

Unanswered Questions in HIV Hematology

Hematological abnormalities are common manifestations of HIV infection that are regularly encountered in the clinical setting. Although initially recognized with the first descriptions of HIV infection over 30 years ago, our understanding of the epidemiology, natural history, and treatment of these blood disorders continues to evolve. Aggressive lymphomas such as diffuse large B-cell lymphoma and primary CNS lymphoma have decreased since the introduction of combination antiretroviral therapy (cART), though these and other HIV-associated malignancies continue to a have a major impact on the morbidity and mortality of persons with HIV. Other blood disorders frequently associated with HIV include cytopenias, particularly anemia and thrombocytopenia. In this special issue, studies investigating hematologic diseases associated with HIV infection are discussed. The diagnosis, treatment, and prognosis of Hodgkin lymphoma (HL) in the era of cART are reviewed by Jacobson and Abramson. Unlike non-Hodgkin lymphomas (NHL), the incidence of HL in HIV-infected patients has not decreased in the cART era. However, the introduction of cART has allowed the delivery of full doses of chemotherapy with significantly improved outcomes. Despite these advances, patients with HIV-associated HL remain at risk of treatment-related toxicity, and interactions between antiretroviral and chemotherapeutic agents necessitate careful attention to supportive care. Two papers focus on HIV-associated Burkitt lymphoma (BL). Though the outcome of HIV-NHL has improved substantially in the cART era, the outcome of HIV-BL with standard chemotherapy remains poor. J. A. Rodrigo et al. describe the combined experience in four Canadian centers treating patients with HIV-BL with the CODOX-M/IVAC regimen with or without rituximab in the modern era. In this study, intensive chemotherapy with CODOX-M/IVAC ± R yielded acceptable toxicity and favorable survival rates. A. M. Petrich et al. review the larger picture in the treatment of HIV-BL in the paper entitled “paradigms and controversies in the treatment of HIV-related Burkitt lymphoma.” In this paper, available data on the treatment of patients with HIV-BL with current BL-directed chemotherapy regimens are discussed in detail, including Hyper-CVAD, dose-adjusted EPOCH, the PETHEMA regimen, and CODOX-M/IVAC. Areas of uncertainty in the treatment of these patients include the addition of rituximab to chemotherapy regimens, the optimal approach to patients with relapsed or refractory BL and the role of stem cell transplantation, the appropriate approach to older patients and patients with central nervous system involvement, and the role of antiretroviral therapy and supportive care. An intriguing and pressing challenge in the management of patients with both malignant and nonmalignant hematologic disorders in HIV infection is the optimal approach to be taken in the developing world. This topic is addressed by M. Ulrickson et al. in the paper “Epidemiology, diagnosis, and treatment of HIV-associated NHL in resource-limited settings.” The epidemiology of NHL in Africa is compared to that of the US, and discrepancies in survival highlighted by cancer registries are discussed. Challenges in managing patients with NHL in resource-limited settings include diagnostic challenges due to limited access to a full battery of immunohistochemical tests and limited molecular testing. Treatment challenges include limited access to antiretroviral regimens, prophylactic agents, IV infusion centers, and a higher incidence of major infectious complications including tuberculosis and hepatitis B. Response assessments are further limited by a lack of ready access to cross-sectional imaging in some regions. Despite these challenges, progress has been made in developing tolerable and effective treatment regimens appropriate to these circumstances, and these important advances are reviewed. A common nonmalignant complication of HIV infection is immune thrombocytopenia (ITP). The characteristics of HIV-associated ITP were documented prior to the cART era, and the optimal treatment beyond cART is unknown. For this reason, K. L. S. Ambler et al. present a retrospective cohort study reviewing individuals with severe HIV-associated ITP diagnosed in the cART era. Their series is the largest such report of severe HIV-ITP in the post-cART era. The major finding from this study was that, although the various treatments were well tolerated and most patients achieved a safe platelet count, nearly all patients (87%) required retreatment for recurrence of severe ITP. This highlights that new approaches to the treatment of ITP in this population are needed. The intent of this special issue was to initiate interest in and further inquiry into the many hematologic complications faced by persons living with HIV. In addition to the topics discussed in this issue, areas for future exploration include the approach to management of patients with less common lymphoproliferative disorders such as indolent NHL, paraproteinemias, and Castleman disease, as well as non-malignant causes of cytopenias and their management. Heather A. Leitch Jeremy S. Abramson Matthew C. Cheung Lisa K. Hicks

Cytomegalovirus-Specific T Cells Are Elicited Early After Umbilical Cord Blood Transplant but Fail to Expand In Vivo and Control Virus Replication

Abstract 1974Cytomegalovirus (CMV) is a major infectious complication in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT) and has been linked to deficiencies of virus-specific T cell immunity. Compared to bone marrow or peripheral blood stem cell transplants, recipients of single or double umbilical cord blood transplants (UCBT) receive lower numbers of donor T cells that have not previously been primed to CMV and are at increased risk for early and recurrent CMV infections. At our institution, the rate of CMV reactivation in CMV seropositive patients undergoing CBT is close to 100% with standard dose Acyclovir as prophylaxis [Delaney unpublished data]. Here, we systematically analyzed the kinetics of recovery, durability, and specificity of CMV-specific CD8+ and CD4+ T cell responses in UCBT recipients. CD8 T cell responses to CMV were analyzed by interferon γ (IFN-γ) intracellular cytokine staining after stimulating recipient peripheral blood mononuclear cells (PBMC) obtained at various time points after CBT with autologous patient fibroblasts infected with the RV798 virus, which is a mutant CMV strain that lacks the viral US genes that downregulate class I MHC and can present all potentially immunogenic epitopes of the virus. The mean absolute CD8 T cell counts were 59, 93 and 213 cells/μl and the mean CD4 T cell counts were 154, 223 and 397 cells/μl in PBMC at day 56, 180 and 365 respectively. Direct assays of PBMC after a 4–6 hour stimulation with RV798-infected fibroblasts did not detect a significant frequency of IFN-γ+ CD8+ T cells in CBT recipients, in contrast to normal CMV+ donors that exhibited frequencies of CD8+ T cells of 2–10%. However, IFN-γ+ CMV specific CD8 T cells were readily detectable in PBMC obtained as early as day 42 after UCBT from 8 out of 8 CMV positive CBT recipients after a 10 day stimulation with RV798 infected fibroblasts. These responses were sustained at multiple time points through day 365 post transplant. This result was not a consequence of in vitro priming of CD8 T cells by prolonged stimulation with RV798 since we did not detect a CMV-specific T cell response in 3 out of 3 CMV seronegative recipients at any time through day 365 with the same assay. To assess CD4+ T cell responses, we performed lymphoproliferative assays (LPA) by stimulating patient PBMC obtained at the same time points with whole CMV antigen. The proportion of patients with a positive response at day 56, 80, 180 and 365 was 0.38, 0.50, 0.88, and 1.0 respectively. All of the CMV positive CBT recipients in our study had multiple occurrences of CMV reactivation throughout the first year post CBT requiring antiviral drug therapy.The CMV-specific CD8 T cell response in normal CMV+ individuals recognizes a large number of distinct dominant and subdominant antigens and a potential explanation for the failure to control CMV after CBT is that the T cell response may not be sufficiently diverse. We analyzed the specificity of CMV specific CD8+ T cells that developed after CBT in 4 recipients by assessing recognition of COS cells transfected with the class I HLA restricting alleles and with a CMV plasmid library consisting of 142 ORFs, subdivided into pools. A response was seen in 3 out of 4 patients to at least 3 different CMV antigens by day 80 post CBT, including previously defined dominant epitopes in pp65 and this diversity was maintained through 6–12 months post transplant. One patient had a less diverse response early post CBT and the response changed over time to include recognition of new epitopes.Collectively, our results demonstrate that CD8+ and CD4+ T cells are primed to CMV antigens very early after CBT despite the infusion of limited numbers of naïve T cells and the administration of post transplant immunosuppression. The inability to control CMV infection may be due to a quantitative deficiency of CMV-specific T cells resulting from the inability of CMV-specific T cells to expand in vivo to numbers sufficient to eliminate virus replication. Disclosures:No relevant conflicts of interest to declare.

PREGNANCY OUTCOME In GENETIC Subtypes of CONGENITAL Neutropenia

Abstract 4722Severe congenital neutropenia (CN) comprises a heterogeneous group of disorders with a common hematological and clinical phenotype characterized by a maturation arrest of myelopoiesis at the level of the promyelocyte / myelocyte stage with peripheral blood absolute neutrophil counts (ANC) below 0.5 ′ 109/l and early onset of bacterial infections. Current data on the molecular causes have demonstrated that CN is a multigene disorder with more than 10 genes described to date. Genetic analyses in autosomal dominant and sporadic cases of CN indicate that the majority of these cases are attributable to mutations in the elastase 2 (ELANE) gene encoding neutrophil elastase. However, mutations in the ELANE gene do not discriminate between patients with CN and patients with cyclic neutropenia (CyN). Since 1987, recombinant human Granulocyte-Colony stimulating factor (G-CSF) is available for the treatment of CN. Independent of the genetic subtype, more than 90% of patients respond well to G-CSF with sustained increase of absolute neutrophil counts and prolonged life expectancy. Since our first patients have reached adulthood the desire for parenthood arises. To-date there is only limited data on the infectious risk for affected mothers and their children due to G-CSF treatment during pregnancy.In this study we assessed the outcome of pregnancies reported to the SCNIR in Europe since 1994 with regard to:1.The neutropenia status in newborns of mothers and fathers with different genetic CN subtypes as an indicator for inheritance.2.The impact of G-CSF treatment on maternal and newborn complications in women of all neutropenia subtypes with or without G-CSF treatment during pregnancy.Since 1994 the SCNIR has collected long-term follow-up data of 510 patients with severe chronic neutropenia subtypes. 3 patients are diagnosed with congenital (71 ELANE-CN, 31 HAX1, 9 GC6PC3, 47 SDS, 117 unknown, 45 other), 66 with cyclic and 82 with idiopathic neutropenia. Adulthood was reached by 144 out of 304 CN patients. These include 38 ELANE-CN patients (male:14, female:24) and 11 ELA-CyN patients (male: 5, female:6).A total of 20 pregnancies in 12 mothers and 13 newborns by 7 fathers with different genetic subtypes of CN have been reported. Among them are pregnancies of 11 women with ELANE-CN, 8 with ELANE-CyN, 1 with SDS, 13 with an unknown genetic origin of CN (n=9) or CyN (n=4). No pregnancies were reported in patients with HAX1 or G6PC3 although 7 of these patients have reached adulthood.Data on neutropenia status was documented in 24 out of 31 live births. Neutropenia in newborns was diagnosed in 16 out of 30 live births from parents with genetic subtypes of CN. In 8 of the 16 affected newborns neutropenia was related to ELANE mutations. One mother registered with SDS delivered a healthy child.During pregnancy 17 women received G-CSF treatment (CN=11, CyN=4, IDN=2). Regardless of any cytokine treatment no major infectious complications were reported in our cohort. 24 of 31 reported pregnancies resulted in life births. 5 spontaneous terminations occurred in women with respectively without exposure to G-CSF. In addition, 2 still births were reported in women with idiopathic neutropenia, but G-CSF exposure remains unknown. Conclusion:The proportion of newborns with congenital neutropenia indicates the pattern of inheritance by their parents and reveals the need for genetic counseling. However, the acceptance of having affected children may reflect the high quality of life due to G-CSF treatment in affected parents. G-CSF treatment during pregnancy is well tolerated. In terms of G-CSF treatment, no differences in infectious complications during pregnancy in women with or without G-CSF administration were reported in our cohort. Interestingly, the proportion of women receiving G-CSF during pregnancy is highest among the CN subtype indicating the severe clinical phenotype. We therefore recommend the application of G-CSF in patients with severe chronic neutropenia during pregnancy. Disclosures:No relevant conflicts of interest to declare.

Factors associated with major infections in patients with granulomatosis with polyangiitis and systemic lupus erythematosus treated for deep organ involvement

This study is an audit and a comparison of major infective complications in patients with granulomatosis with polyangiitis (GPA) and systemic lupus erythematosis (SLE). Data were collected on consecutive patients attending a single treatment approach, multidisciplinary vasculitis centre who met diagnostic criteria for GPA and SLE from 01/01/2006 to 30/06/2006. Immunosuppressive treatment is used in this clinic with guidelines targeting avoidance of neutropenia. For each patient, documentation was made of disease presentation, organ involvement and therapy used. A history of major infections requiring hospital admission and intravenous antimicrobials pre- and post-diagnosis was recorded. Patients with GPA received a higher cumulative dose of cyclophosphamide, had a higher median age, shorter period of follow-up and had lower mean and nadir absolute lymphocyte counts and nadir neutrophil counts. GPA patients had more major infections per patient years (P = 0.0027) and respiratory tract infections (P = 0.0031) per patient years. Relative risk (RR) of major infection was significantly increased with methylprednisolone, RR 11.1 (P = <0.0001), cyclophosphamide, RR 2.0 (P = 0.0246) and the intensive phase of treatment, RR 13.3 (P = <0.0001). Marked lymphopenia was common in both groups during follow-up and was associated with an increased risk of major infection (P = 0.0020). Major infections, in particular respiratory tract infections, are more common in those treated for GPA than SLE. This may be due to a combination of factors including greater doses and duration of methyprednisolone and cyclophosphamide. We recommend treatment strategies that aim not only to avoid neutropenia but that also identify lymphopenia as a risk factor for major infection.

Comparing Postcesarean Infectious Complication Rates Using Two Different Skin Preparations

To estimate whether a new preoperative skin preparation protocol decreases postcesarean delivery infectious complications. We performed a retrospective cohort study. A povidone-iodine (13%) scrub followed by povidone-iodine (10%) paint (SCRUB+PAINT) protocol was compared with standard paint alone (PAINT). Patients and outcomes were identified using diagnosis-related group and International Classification of Diseases, 9th Revision, Clinical Modification coding. Monthly infection rates before the new protocol (October 1, 2007-September 30, 2008) were compared with rates after the protocol (January 1, 2009-December 31, 2009). The primary and secondary outcomes were major puerperal infection and a composite of major puerperal infection and infectious wound complications. Poisson regression was used to model monthly infection rates over time while controlling for confounders known to contribute to infectious risk. Data from 2,143 patients (PAINT: n=1,139; SCRUB+PAINT: n=1,004) were included in the analysis. There was no significant secular trend of decreasing infections over time before initiating SCRUB+PAINT (P=.42). SCRUB+PAINT was associated with a decrease in major puerperal infection (3.4 compared with 5.4/100 cesarean deliveries, P=.03) and composite wound infection (5.5 compared with 7.8/100 cesarean deliveries, P=.03) compared with PAINT alone. SCRUB+PAINT resulted in a 38% reduction in major puerperal infection (incident rate ratio 0.62 [0.42-0.93], P=.02) and a 31% reduction in composite wound infection (incident rate ratio 0.69 [0.50-0.96], P=.03) after controlling for confounders and fluctuations in the rates over time. The SCRUB+PAINT protocol is associated with a decrease in the rate of postcesarean delivery infectious complications compared with using povidone-iodine topical paint alone.

Preoperative Systemic Inflammation and Infectious Complications After Resection of Colorectal Liver Metastases

Postoperative complications are associated with a poor long-term prognosis after resection of colorectal liver metastases via an undetermined mechanism. The preoperative systemic inflammatory response, itself a predictor of poor survival, was recently shown to independently predict postoperative infectious complications after primary colorectal cancer resection. To examine the association of postoperative infectious complications with preoperative systemic inflammation and survival in patients undergoing resection of colorectal liver metastases. Retrospective study based on a prospectively updated database. A United Kingdom tertiary referral hepatobiliary unit. A total of 202 consecutive patients with colorectal liver metastases undergoing hepatectomy between January 1, 2000, and April 30, 2006. Multivariable analyses were performed to correlate preoperative and operative variables with postoperative complications and to correlate complications with long-term survival after metastasectomy. Ninety-day mortality and morbidity were 2.0% and 25.7%, respectively. The preoperative systemic inflammatory response independently predicted the development of infectious complications (P = .009) and major infectious complications (P = .005) after hepatectomy, along with performance of trisectionectomy. Infectious complications were associated with poor long-term survival after metastasectomy but lost independent significance when systemic inflammatory variables were included in multivariable analyses. The preoperative systemic inflammatory response independently predicts the development of infectious complications after colorectal liver metastases resection. Although infectious complications are associated with adverse long-term prognosis after hepatectomy, they lacked independent prognostic value when systemic inflammatory variables were also considered, suggesting that much of their prognostic value arises from their association with the preoperative systemic inflammatory response.

Conséquences nutritionnelles de la chirurgie en oncogériatrie. Étude descriptive et prospective

Objective To analyse the evolution of nutritional parameters after cancer surgery in the elderly, to review patient management practices and evaluate risk factors of postoperative complications. Methods Prospective and descriptive study of a monocentric cohort of patients aged 70 years or more. Nutritional status was evaluated before surgery (D–1). Nutritional parameters were noted at D5, D10, at hospital discharge (HD) and one month later (HD1m). Results Seventy-one patients (aged 75 ± 4.7 years) were included. At preoperative assessment, 22 patients (31%) were found malnourished; three of these were severely malnourished but did not receive preoperative artificial nutritional support. Thirteen patients had oral immunonutrition (13 of 29 indications) and two had nutritional support. The surgery was major in 52 cases. Postoperative nutritional support was given to 16 patients. Eleven patients had major infectious complications and 13 had major non-infectious complications. At HD, 42 patients (60.0%) were found malnourished (nine had severe malnutrition); at HD1m, 42 patients were malnourished (five had severe malnutrition). Survival rates were 94.4% at one month and 83.1% at one year. In this limited cohort of patients, no risk factor of postoperative complications could be identified. Conclusions Cancer surgery, even when major, is feasible in the elderly, but clinical management practices, particularly perioperative nutritional support, need to be improved. Earlier nutritional and geriatric evaluation would be needed in order to provide appropriate management.

Infectious Complications after Neurosurgery: Mainly Focusing on Ventriculitis and Meningitis

Ventriculitis and nosocomial meningitis are major infectious complications after neurosurgery. Determining whether fever after neurosurgery is infectious origin or not should be meticulously performed. Cell index >5 could be a reliable parameter for the decision to empirical treatment before micr...

Fibrin glue in the endoscopic treatment of fistulae and anastomotic leakages of the gastrointestinal tract

Fistulae or leakages of anastomotic junctions of the gastrointestinal tract used to be an indication for surgery. However, patients often are severely ill and endoscopic therapeutic options have been suggested to avoid surgical intervention. This is a retrospective analysis of fibrin glue application in the treatment of gastrointestinal fistulae or anastomotic leakages. The aim of this study was to investigate the value of fibrin glue in the treatment of gastrointestinal fistulae and leakages. From September 1996 to November 2002, 52 patients with gastrointestinal fistulae or insufficiencies have been treated endoscopically including the use of fibrin glue (Tissucol Duo S®, Baxter, Unterschleissheim, Germany). Clinical data comprising concomitant therapies and results were analysed by chart review. Twenty-six lesions were located in the oesophagus or gastroesophageal junction, 4 in the stomach, 7 in the small intestine, 13 colorectal and 2 in the pancreas. The duration of treatment ranged from 12 to 1,765 days. Two to 81 ml fibrin glue (median 8.5) was used in 1-40 sessions (median 4). All patients received antibiotics; additional endoscopic options were frequently applied. Endoscopic therapy cured 55.7% patients (n = 29); 36.5% (n = 19) were cured with fibrin glue as sole endoscopic option. In 23.1% (n = 12), surgical intervention became necessary. Patients without major infectious complications tended to have a higher cure rate without surgery (87.5% vs. 50%). Eleven patients died (21.1%). Endoscopic therapy is a valuable option in the treatment of fistulae and anastomotic insufficiencies of the gastrointestinal tract. It usually is applied repeatedly. Fibrin glue is a mainstay of this procedure. Major infectious complications seem to define a subgroup of patients with poorer outcome.

Everolimus and Mycophenolate as GvHD Prophylaxis Results In Improved Control of Advanced Disease and Reduced Bacterial and Fungal Infectious Complications After Allogeneic Stem Cell Transplantation

AbstractAbstract 1264Tolerance induction together with sustained disease control remain to be critical for longterm survivors after allogeneic hematopoietic cell transplantation (HCT). Regulatory T cells (Tregs) are involved in the regulation of graft versus host disease (GvHD) and graft versus leukemia effect (GvL). Although calcineurin inhibitors are frequently being used for the prevention of GvHD, tolerance induction might be hampered in HCT patients due to deteriorated Treg function. Data from animal models of HCT suggest that inhibition of the mammalian target of rapamycin (mTOR) results not only in suppressed T cell alloreactivity but also in sustained Treg function. On the other hand severe reduction of T cell alloreactivity might result in diminished control of especially advanced malignant disease. To explore the clinical efficacy of a calcineurin-free GvHD prophylaxis regimen, we initiated a phase I/II monocenter trial using everolimus and mycophenolate-sodium (MMF-Na) as GvHD prophylaxis in patients undergoing allogeneic HCT with peripheral stem cell (PBSC) grafts after reduced toxicity and standard conditioning. 28 patients were included (median age: 49,2 years, range: 21–65). The diagnoses were: AML/MDS (n=16), ALL (n=3), CML/MPS (n=3), T-PLL (n=1), NHL/CLL (n=6). At the time of transplantation 22/28 (78%) patients were at high risk (not in CR1/CP, untreated) for early relapse. Conditioning included fludarabin based reduced intensity (n=24) or standard regimens containing busulfan (n=2) or clofarabine (n=2). Four CR1 patients received additional alemtuzumab (total 10mg) for GvHD prophylaxis. PBSC grafts were obtained from unrelated (n=20) and related (n=8) HLA-matched donors. No graft failure occurred. Engraftment kinetics for myeloid cells were normal, patients without alemtuzumab showed rapid reconstitution of the T cell compartment with median cell counts of >200 CD4+ cells/μl at day +30 together with complete donor chimerism in 15/18 evaluable patients. No grade IV/V toxicities (according to CTC criteria) were observed due to the study medication. After a median follow up of 9 months, 3 relapses of 24 patients with CR after HCT (12,5%) occurred, of those one AML patient could be salvaged with withdrawal of immunosuppression. Nine patients have died. The causes were underlying malignant disease (n=2), GvHD (n=2), viral infections (n=3 with two cases of HHV6 associated encephalitis), post-surgery thrombembolism (n=1), and one unknown. Treatment related mortality after 100 days is 14,2%, after 1 year 21,4%. Due to the early recovery of T cell immunity mild forms of acute skin GvHD were common early after reconsitution, while acute GvHD Grade III-IV could be observed in 8/26 patients. Chronic GvHD occurred in 15/22 patients (68%) with moderate and severe forms in n=10 and n=3 patients, respectively. Cytomegalovirus (CMV) reactivation could be seen in 5/20 patients at risk, while no CMV disease developed. Importantly, in the first year after HCT no severe bacterial or fungal infections were observed even in cases with prolonged everolimus treatment. The whole cohort experienced a median overall survival of 20 months, median progression free survival was 19 months. In conclusion, GvHD prophylaxis with everolimus and MMF-Na is feasible but results in an increased frequency of moderate chronic GvHD without major bacterial and fungal infectious complications. Since this sustained alloreactivity might reduce the risk of relapse this regimen could be suited for patients undergoing HCT with advanced or uncontrolled malignant disease. Disclosures:No relevant conflicts of interest to declare.

Calcium Phosphate Cements in Skull Reconstruction: A Meta-Analysis

This work addresses the controversy regarding the indications and results of calcium phosphate cements in skull reconstruction through a meta-analysis of the published literature. A PubMed search for articles reporting the use of calcium phosphate cements for skull reconstruction was performed. Data collected included age, volume of cement, defect size, material used, length of follow-up, placement in communication with paranasal sinuses or in irradiated fields, and complications. Nineteen articles met the authors' inclusion criteria. The mean rates of complications were as follows: total complications, 13 percent (range, 0 to 62 percent); major complications, 9 percent (range, 0 to 62 percent); minor complications, 2 percent (range, 0 to 5 percent); infection, 5 percent (range, 0 to 22 percent); reoperation, 14 percent (range, 0 to 62 percent); and secondary surgery for contour correction, 1 percent (range, 0 to 12 percent). There was significant heterogeneity in the estimated rate of total and major complications, infection, and reoperation (p < 0.001), but minor complications and secondary contour correction had less heterogeneity (p = 0.58 and p = 0.78, respectively). Radiotherapy and communication with the paranasal sinuses significantly increased the complication rate (p < 0.05). Duration between surgery and complications averaged 17.5 months (range, 1 to 89 months). When mean complication rate and complication range of calcium phosphate cements in our meta-analysis were compared with previous large cranioplasty studies using methylmethacrylate or autogenous bone, calcium phosphate fared no better, and sometimes fared worse, than these other modalities. Calcium phosphate, therefore, should only be used selectively, and prospective long-term studies are needed to further refine its role in skull reconstruction.

Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

Improvement in Renal Function After Late Conversion to Sirolimus-Based Immunosuppression in Composite Tissue Allotransplantation

Cytomegalovirus infection after kidney transplantation, susceptibility to CMV-infection in association with HLA-genotype — Doctoral dissertation summary

Abstract Cytomegalovirus infection is a major infectious complication of transplant recipients, causing significant morbidity and mortality. It is possible to treat this infection effectively only if we know the direct and indirect effects of it, if we take the risk-factors into account, and use sensitive and reliable diagnostic methods for early establishment of diagnosis. In order to avoid severe CMV-infection, it is possible to administer prophylactic therapy. For prophylaxis planning it is important to know the CMV-seroprevalence of Hungarian population and its characteristics. Our results have shown that the seroprevalence of Hungarian population is high: 86%. The primary CMV-infection in Hungary occurs in childhood or in early adulthood, till age of 20 years the seroprevalence is 72%. CMV-seronegative recipients should be transplanted using organs of seronegative donors, however, the chance obtaining the graft from a CMV-seronegative donor was shown to be 2% only. Since such seromatching is rear, we have to know that the constellation of negative recipient and positive donor is the highest risk-factor for developing severe primary CMV-infection. While investigating data of 147 CMV-seronegative recipients from high-risk group it has been established that CMV-infection prophylaxis is essential for high risk patients in the early post-transplant period of 3 months, the administration of any of investigated prophylactic protocols is advantageous in comparing with prophylaxis free management of those patients (P=0.006). The study has also proven that monoprophylaxis with ganciclovir or valganciclovir is the most effective and cost-effective procedure as compared to other protocols (P=0.006). It is important to take into consideration that in prophylactic groups the “late-onset” CMV-infection occurred often (25.4%), and that there were no signs of seroconversion after the primary CMV-infection in 14% of the patients. For the first time it has been found and proven that the female sex is a risk factor for CMV-infection (P=0.0006). Genetic variability influences susceptibility to infectious diseases and HLA-molecules are critical for viral antigen uptaking, processing and presenting. Our data of 129 of high-risk patients suggest that recipients positive for HLA-DQ3 are more susceptible to CMV-infection than a comparable group of patients negative for this HLA-type. This result was not due to rejection and/or treatment for rejection and was not influenced by induction therapy or number of HLA-mismatches. The multivariate Cox Regression analysis has shown that HLA-DQ3 positivity is an independent predictor of primary CMV-infection in CMV-seronegative recipients with seropositive donor grafts (P=0.001). The cognition of HLA-DQ3 is useful in the prediction of acute CMV-infection in high-risk patients, and should influence the planning of the patients' management.

High efficacy and low toxicity of short-course oral valganciclovir as pre-emptive therapy for hematopoietic stem cell transplant cytomegalovirus infection

Cytomegalovirus (CMV) infection is a major infectious complication post-allogeneic hematopoietic stem cell transplantation (HSCT). CMV seropositivity in Eastern Mediterranean and certain Asian countries is reported to be close to 100%; hence, the need for effective pre-emptive treatment strategy that has low toxicity. Valganciclovir (VGC) is a prodrug of ganciclovir with high bioavailability. HSCT patients with documented CMV infection (as defined by positive CMV antigenemia) were treated as outpatients with VGC at a starting dose of 900 mg twice daily for 1 week. Those who were antigenemia negative after one week received 900 mg once daily for another week and treatment was subsequently discontinued. Those who were positive after one week of therapy continued on the twice-daily treatment schedule for another week and changed to a daily schedule once they converted to antigenemia negativity. From January 2004 to December 2007, 47 HSCT patients received preemptive treatment with VGC for 61 episodes of CMV infection. The antigenemia range was 1 to 700 infected cells/slide. Complete responses were observed in 92% and 97% after the 1st and 2nd week of treatment, respectively. Three percent of the episodes were considered refractory, requiring alternative therapy. No CMV disease was observed in this cohort. Neutropenia was the main observed toxicity, requiring granulocyte-colony stimulating factor in 8 episodes. Outpatient treatment of CMV infection with "short-course oral VGC" given as a one-week twice-daily treatment and one week once daily maintenance is a highly effective therapy with minimal toxicity. These results require validation in a larger, randomized study.

Cytomegalovirus infection/disease after hematopoietic stem cell transplantation

Cytomegalovirus (CMV) disease has historically been a main cause of death after allogeneic hematopoietic stem cell transplantation (HSCT). Since the introduction of prophylactic or preemptive therapy against CMV, the incidence of CMV disease has been successfully reduced. However, breakthrough CMV disease, particularly CMV gastrointestinal disease, remains one of the major infectious complications. Administration of an antiviral agent, ganciclovir, is often associated with myelotoxicity in HSCT recipients, and delayed immune reconstitution against CMV. Delayed immune reconstitution is a possible cause of the increasing incidence of late (more than 3 months after transplant) CMV disease after HSCT in this era of preemptive therapy. Foscarnet and valganciclovir are the available alternatives to intravenous ganciclovir. Foscarnet is not myelotoxic and has a toxicity profile different from ganciclovir. Valganciclovir, a prodrug of ganciclovir, has a higher bioavailability than oral ganciclovir and could be of clinical use, particularly in the outpatient setting or for patients requiring long-term antiviral therapy. Recent technological developments have enabled the visualization and isolation of CMV-specific T cells. Using these techniques, an individualized approach could be conducted based on each patient's immune reconstitution against CMV. In this review, we summarize the recent progress and current knowledge of CMV infection and disease after allogeneic HSCT.

Safety of transperineal 14‐core systematic prostate biopsy in diabetic men

To examine whether the transrectal ultrasound-guided transperineal 14-core prostate biopsy can be carried out safely in diabetic men and to determine adequate antimicrobial prophylaxis protocol in this setting. The present study included 539 men, 135 with concurrent diabetes mellitus (DM) and 404 without DM, who underwent transperineal extended 14-core biopsy due to elevated prostate-specific antigen > or = 2.5 ng/mL and/or abnormal digital rectal examination. Any complication requiring prolonged hospitalization or rehospitalization during the 4-week post-biopsy period was considered major. All other complications were considered minor. Intensity of antimicrobial prophylaxis was prospectively reduced in a stepwise manner down to single dose of oral levofloxacin. Except for DM, there was no significant difference in clinical background between the diabetic and non-diabetic men. The procedure was completed in all revealing prostate cancer in 42% of the diabetic men and 36% of the non-diabetic men (P = 0.23). Incidence of minor or major complications was not significantly different between the two groups. Minor complications were observed in 15.6% and 16.6% of each group, respectively, with voiding disturbance being the most common. No infectious major complication was observed regardless of the presence of DM. In the diabetic men, there was no statistical difference in incidence of biopsy-related complications according to modality of DM treatment, HbA1c level or antimicrobial prophylaxis protocol. Transperineal 14-core biopsy can be carried out without major infectious complications in diabetic men. Oral levofloxacin 300 mg once before the procedure seems to represent an effective antimicrobial prophylaxis in diabetic men without other risk of infection.

Malnutrition, Inflammation: Which Parameter Is Interesting to Detect in Planned Oncologic Surgery?

We are grateful to Dr. Muscaritoli and colleagues [1] for their comment and their recommendation concerning the need to assess inflammation parameters before surgery, especially C-reactive protein (CRP), and we totally agree with their advice. This point was recently confirmed in the study published this year by Moyes et al. [2], in which the Glasgow prognostic score (GPS) [3] using albumin (Alb) and C-reactive protein (CRP) values to determine the level of risk, was significantly associated with an increased risk of developing a postoperative infection during elective surgery in 385 colorectal cancer resections (odds ratio [OR] = 1.75; 95% confidence interval [CI] = 1.17–2.63; p = 0.007). The goals of our study were to detect easily collected data on nutritional parameters that would allow us to define a group for which a nutritional treatment could reduce the number of complications after surgery. In the course of our study [4] CRP data were collected before surgery in 76% of the cases. Three CRP threshold values were studied: [15, [50, and 100 mg/l. In the univariate analysis, only a CRP value of [50 mg/l was found to be associated with total major complications (TMC) (p = 0.02), with major infectious complications (p = 0.03) and with major non-infectious complications (p = 0.05). No statistically significant relationship was found for a CRP value [15 mg/l or for CRP [ 100 mg/l. In the multivariate analysis, CRP was no longer associated with the occurrence of postoperative complications. We also analyzed the frequency of complications according to the Prognostic Inflammatory Nutritional Index: [PINI = CRP (mg/l) 9 orosomucoid (mg/l)]/[albumin g/ l 9 transthyretin (mg/l)], determined before surgery. Overall, PINI values were obtained for 72% of the patients. A relationship with the frequency of TMC was found only in the univariate analysis (p = 0.04), not in the multivariate analysis. As reported by some authors [5], as well as by Dr. Muscaritoli, albumin is dependent not only on the patient’s nutritional status but also on the inflammatory status. McMillan et al. [3] obtained better survival at 3 years in colorectal cancer patients using the GPS: 86% for a GPS 0 (Alb [ 35 g/l and CRP \ 10 mg l), 71% for a GPS 1 (Alb \ 35 g/l or CRP \ 10 mg/l), and 46% for a GPS 2 (Alb \ 35 g/l and CRP [ 10 mg/l) (p \ 0.0001). After analyzing our results according to the same threshold values, a similar role was found for the inflammatory factor. Major complications were more frequent (p = 0.03) for the highest GPS values; respectively, 23, 31, and 47% for a GPS of 0, 1, and 2. In the study by McMillan et al. [3], only 16/109 patients had an isolated low albumin level without elevation of CRP. The survival of these patients at 3 months (94%) was similar to that of the patients with a GPS 0 (84%). In our study, 14 patients had an Alb \ 35 without elevated CRP with 43% of TMC, and 35 patients had elevated CRP without a low albumin level with 29% of TMC. These groups were too small to allow statistical comparisons, but when we performed a chi square test adjusted for CRP, it showed that Alb was correlated with TMC (p = 0.02), whereas this was not the case for CRP when adjusted for Alb. The results of the multivariate analysis, as well as the chi square test, show that a low albumin level is a risk factor for TMC, independent of the inflammation status S. Antoun (&) A. Rey Institut Gustave-Roussy, Villejuif, France e-mail: sami.antoun@igr.fr

Postoperative hyperglycaemia of diabetic patients undergoing cardiac surgery – a clinical audit

Previous studies have shown that hyperglycaemia is associated with postoperative complications in cardiac surgical patients. Conversely, well-controlled glucose levels are said to reduce major infectious complications in diabetic patients. The purpose of this clinical audit was to evaluate the blood glucose levels of diabetic patients undergoing cardiac surgery and to determine the effectiveness of postoperative glycaemic control. A group of 150 patients from a large Irish cardiac surgery centre was selected by convenience sampling. An audit tool was designed to capture the patients' blood glucose levels, treatment regimes and postoperative complications. The findings showed major variations between 'high', 'good' and 'borderline' blood glucose levels in the pre- and postoperative phase. Although blood glucose testing practices seemed inconsistent, mean levels measured 'borderline'. Furthermore, the treatment regimes varied greatly and suggest a lack of consensus regarding the management of postoperative hyperglycaemia. A total of 52% (n = 78) patients developed 114 complications with a level of 21.4% (n = 32) postoperative wound infections. The findings from this audit highlight the importance of regular blood glucose testing to enable early detection of hyperglycaemia and timely initiation of appropriate treatments regimes for diabetic patients undergoing cardiac surgery. Findings also show that hyperglycaemia derangement may make a difference in the recovery phase. While patients will benefit from lesser wound infections, hospitals might save costs involved with treating postoperative complications. More consistent blood glucose testing might be achieved through the use of evidence-based protocols. However, the education of staff is as important as it develops knowledge on the complex metabolic interactions of diabetic patients undergoing cardiac surgery. While this means investing in staff education and policy development, costs for daily care and expensive treatments for complications will be saved as patient recovery will be speedier and less eventful.