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Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and/or a defective antibody response to T-dependent and T-independent antigens. CVID response to immunization depends on the antigen type, the vaccine mechanism, and the specific patient immune defect. In CVID patients, humoral and cellular responses to the currently used COVID-19 vaccines remain unexplored. Eighteen CVID subjects receiving 2-dose anti-SARS-CoV-2 vaccines were prospectively studied. S1-antibodies and S1-specific IFN-γ T cell response were determined by ELISA and FluoroSpot, respectively. The immune response was measured before the administration and after each dose of the vaccine, and it was compared to the response of 50 healthy controls (HC). The development of humoral and cellular responses was slower in CVID patients compared with HC. After completing vaccination, 83% of CVID patients had S1-specific antibodies and 83% had S1-specific T cells compared with 100% and 98% of HC (p = 0.014 and p = 0.062, respectively), but neutralizing antibodies were detected only in 50% of the patients. The strength of both humoral and cellular responses was significantly lower in CVID compared with HC, after the first and second doses of the vaccine. Absent or discordant humoral and cellular responses were associated with previous history of autoimmunity and/or lymphoproliferation. Among the three patients lacking humoral response, two had received recent therapy with anti-B cell antibodies. Further studies are needed to understand if the response to COVID-19 vaccination in CVID patients is protective enough. The 2-dose vaccine schedule and possibly a third dose might be especially necessary to achieve full immune response in these patients.

During the last decade, many studies have demonstrated the role of CMV specific T-cell immune response on controlling CMV replication and dissemination. In fact, it is well established that transplanted patients lacking CMV-specific T-cell immunity have an increased occurrence of CMV replication episodes and CMV-related complications. In this context, the use of adoptive transfer of CMV-specific T-cells has been widely investigated and applied to Hematopoietic Stem Cell Transplant patients and may be useful as a therapeutic alternative, to reconstitute the CMV specific T-cell response and to control CMV viremia in patients receiving a transplantation. However, only few authors have explored the use of T-cell adoptive transfer in SOT recipients. We propose a novel review in which we provide an overview of the impact of using CMV-specific T-cell adoptive transfer on the control of CMV infection in SOT recipients, the different approaches to stimulate, isolate and expand CMV-specific T-cells developed over the years and a discussion of the possible use of CMV adoptive cellular therapy in this SOT population. Given the timeliness and importance of this topic, we believe that such an analysis will provide important insights into CMV infection and its treatment/prevention. This study was supported by the Spanish Ministry of Science, Innovation and University, Instituto de Salud Carlos III Grant/Award Numbers: PI17CIII-00014 (MPY110/18); DTS18CIII/00006 (MPY127/19); PI20-009 (MPY303/20). This work was supported by Plan Nacional de I + D+i 2013‐2016 and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministry of Science, Innovation and University, Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0009), co-financed by European Development Regional Fund ‘A way to achieve Europe’. EG-R is supported by the Sara Borrell Program (CD18CIII/00007), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades. FM is supported by the PFIS Program (F18III/00013), Instituto de Salud Carlos III, Ministerio de Ciencia, Innovación y Universidades. MN is supported by the FPU program (FPU19/05927), Ministerio de Ciencia, Innovación y Universidades. Sí

Primary infection and/or reactivation of cytomegalovirus (CMV) in kidney transplant recipients (KTR) favour rejection and mortality. T follicular helper cells (TFH) could contribute to protection against CMV. Circulatory TFH (cTFH) were studied pre-transplantation and early post-transplantation in 90 CMV seropositive KTR not receiving antithymocyte globulin or antiviral prophylaxis, followed-up for one year. Patients who presented CMV infection had significantly lower cTFH and activated cTFH pre-transplant and early post-transplantation. Pre-transplantation activated cTFH were also lower within patients who developed CMV disease. Pre- and 14 days post-transplant activated cTFH were an independent protective factor for CMV infection (HR 0.41, p=0.01; and 0.52, p=0.02, respectively). KTR with low cTFH 7 days post-transplantation (

Factor de impacto: 5,858 Q1 Tyrosine kinase inhibitors (TKIs) are successfully used in clinic to treat chronic myeloid leukemia (CML). Our group previously described that CD4+ T cells from patients with CML on treatment with TKIs such as dasatinib were resistant to HIV-1 infection ex vivo. The main mechanism for this antiviral activity was primarily based on the inhibition of SAMHD1 phosphorylation, which preserves the activity against HIV-1 of this innate immune factor. Approximately 50% CML patients who achieved a deep molecular response (DMR) may safely withdraw TKI treatment without molecular recurrence. Therefore, it has been speculated that TKIs may induce a potent antileukemic response that is maintained in most patients even one year after treatment interruption (TI). Subsequent to in vitro T-cell activation, we observed that SAMHD1 was phosphorylated in CD4+ T cells from CML patients who withdrew TKI treatment more than one year earlier, which indicated that these cells were now susceptible to HIV-1 infection. Importantly, these patients were seronegative for HIV-1 and seropositive for cytomegalovirus (CMV), but without CMV viremia. Although activated CD4+ T cells from CML patients on TI were apparently permissive to HIV-1 infection ex vivo, the frequency of proviral integration was reduced more than 12-fold on average when these cells were infected ex vivo in comparison with cells isolated from untreated, healthy donors. This reduced susceptibility to infection could be related to an enhanced NK-dependent cytotoxic activity, which was increased 8-fold on average when CD4+ T cells were infected ex vivo with HIV-1 in the presence of autologous NK cells. Enhanced cytotoxic activity was also observed in CD8 + T cells from these patients, which showed 8-fold increased expression of TCRγδ and more than 18-fold increased production of IFNγ upon activation with CMV peptides. In conclusion, treatment with TKIs induced a potent antileukemic response that may also have antiviral effects against HIV-1 and CMV, suggesting that transient use of TKIs in HIV-infected patients could develop a sustained antiviral response that would potentially interfere with HIV-1 reservoir dynamics. This work was supported by NIH grant R01AI143567; the Spanish Ministry of Economy and Competitiveness (SAF2016-78480-R); the Spanish AIDS Research Network RD16CIII/0002/0001 that is included in Acción Estratégica en Salud, Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica 2016-2020, Instituto de Salud Carlos III, European Region Development Fund (ERDF). The work of María Rosa López-Huertas and Sara Rodríguez-Mora is financed by NIH grant R01AI143567. The work of Lorena Vigón is supported by a pre-doctoral grant from Instituto de Salud Carlos III (FIS PI16CIII/00034-ISCIII-FEDER). The work of Elena Mateos is supported by the Spanish Ministry of Economy and Competitiveness SAF2016-78480-R. Sí

[Introduction] Our goal was to study whether influenza vaccination induced antibody mediated rejection in a large cohort of solid organ transplant recipients (SOTR)., [Methods] Serum anti-Human Leukocyte Antigen (HLA) antibodies were determined using class I and class II antibody-coated latex beads (FlowPRATM Screening Test) by flow cytometry. Anti-HLA antibody specificity was determined using the single-antigen bead flow cytometry (SAFC) assay and assignation of donor specific antibodies (DSA) was performed by virtual-crossmatch., [Results] We studied a cohort of 490 SOTR that received an influenza vaccination from 2009 to 2013: 110 (22.4%) received the pandemic adjuvanted vaccine, 59 (12%) within the first 6 months post-transplantation, 185 (37.7%) more than 6 months after transplantation and 136 (27.7%) received two vaccination doses. Overall, no differences of anti-HLA antibodies were found after immunization in patients that received the adjuvanted vaccine, within the first 6 months post-transplantation, or based on the type of organ transplanted. However, the second immunization dose increased the percentage of patients positive for anti-HLA class I significantly compared with patients with one dose (14.6% vs. 3.8%; P = 0.003). Patients with pre-existing antibodies before vaccination (15.7% for anti-HLA class I and 15.9% for class II) did not increase reactivity after immunization. A group of 75 (14.4%) patients developed de novo anti-HLA antibodies, however, only 5 (1.02%) of them were DSA, and none experienced allograft rejection. Only two (0.4%) patients were diagnosed with graft rejection with favorable outcomes and neither of them developed DSA., [Conclusion] Our results suggest that influenza vaccination is not associated with graft rejection in this cohort of SOTR., This study was funded by the Consejería de Salud (Grant Number: PI-0119-2012), Ministerio de Economía y Competitividad, Instituto de Salud Carlos III (Grant Numbers: GR09/0041, PI14-00165, and MPY110/18) and co-financed by European Development Regional Fund “A way to achieve Europe” ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD12/0015/0001).

Background Seasonal influenza infection may cause significant morbidity and mortality in transplant recipients. The purpose of this study was to assess the epidemiology of symptomatic influenza infection posttransplant and determine risk factors for severe disease. Methods Twenty centers in the United States, Canada, and Spain prospectively enrolled solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT) recipients with microbiologically confirmed influenza over 5 consecutive years (2010-2015). Demographics, microbiology data, and outcomes were collected. Serial nasopharyngeal swabs were collected at diagnosis and upto 28 days, and quantitative polymerase chain reaction for influenza A was performed. Results We enrolled 616 patients with confirmed influenza (477 SOT; 139 HSCT). Pneumonia at presentation was in 134 of 606 (22.1%) patients. Antiviral therapy was given to 94.1% for a median of 5 days (range, 1-42 days); 66.5% patients were hospitalized and 11.0% required intensive care unit (ICU) care. The receipt of vaccine in the same influenza season was associated with a decrease in disease severity as determined by the presence of pneumonia (odds ratio [OR], 0.34 [95% confidence interval {CI}, .21-.55], P < .001) and ICU admission (OR, 0.49 [95% CI, .26-.90], P = .023). Similarly, early antiviral treatment (within 48 hours) was associated with improved outcomes. In patients with influenza A, pneumonia, ICU admission, and not being immunized were also associated with higher viral loads at presentation (P = .018, P = .008, and P = .024, respectively). Conclusions Annual influenza vaccination and early antiviral therapy are associated with a significant reduction in influenza-associated morbidity, and should be emphasized as strategies to improve outcomes of transplant recipients.

Background Some studies have suggested that rATG treatment may be associated with an increased incidence of CMV infection and delayed CMV immune response. However, the evidences supporting this matter are scarce. This study aims to characterize the kinetic of the CMV-specific T-cell immune response before and after rATG induction therapy and the relationship with the development of CMV infection in CMV-seropositive kidney transplant recipients. Methods An observational prospective study of CMV-seropositive kidney transplant patients that received rATG induction therapy was performed. A pretransplant sample was obtained before the surgery to determine the CMV-specific immunity. CMV viral load (by PCR) and CMV-specific T-cell immune response (by flow cytometry) were determined during the follow-up at 0.5, 1, 2, 3, 6, and 12 months post transplantation. Results A total of 23 patients were included in the study. CMV prophylaxis was administrated for a media of 90 days after transplantation. At the end of follow-up, 18 (78.3%) patients had CMV-specific immunity with a median value of 0.31% CD8+ CD69+ INF-γ+ T cells at a median of 16 weeks post transplantation. Five patients never acquired CMV-specific immunity. No statistically significant association between CMV infection and CMV-specific T-cell immune response (P = .086) was observed. However, patients with positive pretransplant CMV-specific immunity developed earlier immunity and achieved higher levels of CD8+ CD69+ INF-γ+ T-cell post-transplantation than patients with negative pretransplant immunity. Conclusions CMV-specific immune monitoring in addition to CMV-serology may be useful to stratify patient's risk of CMV infection before transplantation.

Background Seasonal influenza virus vaccination should be considered in all pediatric patients with rheumatic diseases. Few studies have addressed influenza vaccination safety and efficacy in this group. We aim to prospectively evaluate immunogenicity and safety of the trivalent inactivated influenza vaccine including A/H1N1, A/H3N2 and B strains in children with juvenile idiopathic arthritis (JIA) receiving biological therapy. Methods Thirty-five children diagnosed with JIA and 6 healthy siblings were included. Serum samples were collected prior to, 4-8 weeks and one year after vaccination. Microneutralization assays were used to determine neutralizing antibody titers. The type and duration of therapy were analyzed to determine its effect on vaccine response. Clinical data of the participants were collected throughout the study including severe adverse events (SAE) and adverse events following immunization (AEFI). Results Twenty-five patients (74.3%) received biological treatment for JIA; anti TNF-α was prescribed in 15, anti IL-1 receptor in 4 and anti IL-6 receptor therapy in 6 children. The seroprotection rate 4-8 weeks after vaccination in the JIA group was 96% for influenza A/(H1N1)pdm and influenza A/H3N2, and 88% for influenza B. No differences were found in GMT, seroprotection and seroconversion rates for the three influenza strains between the control group and patients receiving biological therapy. Furthermore, long-term seroprotection at 12 months after vaccination was similar in patients receiving either biological or non-biological treatments. No SAEs were observed. Conclusions In this study, influenza vaccination was safe and immunogenic in children with JIA receiving biological therapy. Electronic supplementary material The online version of this article (doi:10.1186/s12969-017-0190-0) contains supplementary material, which is available to authorized users.

Summary Objectives The most frequent adverse events associated with valganciclovir treatment are hematological disturbances such as neutropenia. However, the consequences of neutropenia are unknown. We investigated the clinical impact of neutropenia during CMV preemptive therapy and its relationship with the length of antiviral therapy. Methods An observational, prospective cohort of 67 solid organ transplant recipients receiving CMV preemptive therapy was studied. Results Severe neutropenia occurred in 21.8% of the patients at a median of three weeks after initiating antiviral therapy. No association was observed between neutropenia and infection risk in these patients. Liver transplant recipients had 6.7 fold increased risk of neutropenia during CMV therapy compared to kidney transplant recipients ( p = 0.012). Patients who developed severe neutropenia received antiviral therapy a median of six days longer than patient who did not ( p = 0.457). Conclusions Despite the frequency of neutropenia during CMV preemptive therapy, the incidence of infections is not increased. Adjusting the length of preemptive therapy during the episodes of viremia may be recommended, especially in patients with concurrent risk factors for neutropenia such as liver recipients. Further trials are warranted to confirm the safety of this approach.

We present the case of a previously healthy 15-month-old girl with acute adenovirus infection who had features of severe bacterial sepsis and meningitis. Real-time qPCR done on cerebrospinal fluid identified adenovirus as the causative agent allowing stopping antibiotic treatment. The patient subsequently recovered without sequelae. An overview of published and unpublished data on adenovirus central nervous system infection in immunocompetent children is presented.

Background Influenza vaccine effectiveness is not optimal in solid organ transplant recipients (SOTR). We hypothesized that a booster dose might increase it. Methods TRANSGRIPE 1-2 is a phase 3, randomized, controlled, multicenter, open-label clinical trial. Patients were randomly assigned (1:1 stratified by study site, type of organ, and time since transplantation) to receive 1 dose (control group) or 2 doses (booster group) of the influenza vaccine 5 weeks apart. Results A total of 499 SOTR were enrolled. Although seroconversion at 10 weeks did not meet significance in the modified intention-to-treat population, seroconversion rates were significantly higher in the booster arm for the per-protocol population (53.8% vs 37.6% for influenza A(H1N1)pdm; 48.1% vs 32.3% for influenza A(H3N2); and 90.7% vs 75% for influenza B; P < .05). Furthermore, seroprotection at 10 weeks was higher in the booster group: 54% vs 43.2% for A(H1N1)pdm; 56.9% vs 45.5% for A(H3N2); and 83.4% vs 71.8% for influenza B (P < .05). The number needed to treat to seroprotect 1 patient was

Aim and method The aim of this study was to describe the clinical characteristics and outcome of pandemic influenza A H1N1/2009 (pH1N1) infection, in a retrospective cohort of pediatric patients with kidney and/or liver transplant and confirmed pH1N1 infection from June to December 2009, diagnosed in 2 Spanish teaching hospitals. Results Forty-nine patients were included. Pneumonia was diagnosed in 4 patients (8.2%), and 3 of them required respiratory support. There were no related deaths. Conclusion Antiviral treatment within 48 h was associated with a lower likelihood of pneumonia (0/38, 0%) than treatment started after 48 h (4/11, 36.3%) (P

Knowledge of donor and recipient (D/R) cytomegalovirus (CMV) serostatus is critical for risk stratification of CMV infection and disease in transplant recipients, particularly in the solid organ transplantation (SOT) setting. Despite its broad availability and the success of it use, the risk stratification based on the D/R serostatus is not free of limitations since there are a nondepreciable number of patients that are not accurately categorized by this approach. In fact, up to 20% of seropositive SOT recipients, classically considered at intermediate risk, develop episodes of CMV infection and disease after transplantation. Here, we provide an overview of additional donor and recipient factors that may have utility in identifying patients at risk for post-transplant CMV infection. Specifically, we summarize our current understanding regarding the potential use of use CMV-specific T-cell-mediated immunity, neutralizing antibodies and host genetics that may influence the risk of CMV infection and disease. We provide an overview of the benefits and limitations associated with using these immunological factors in risk stratification and propose specific variables that could be analyzed at the pretransplant evaluation to improve the identification of patients with increased individual susceptibility. Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Grant/Award Numbers: PI12‐ 1992, PI14‐0165, PI15‐0060, PI17CIII‐ 00014/ PI17‐01120/ PI17‐01097; Spanish Ministry of Economy and Competitiveness, Instituto de Salud Carlos III, Proyecto Integrado de Excelencia, Grant/Award Number: PIE 13/00045; Instituto de Salud Carlos III; Spanish Ministry of Economy and Competitiveness; “Juan Rodés”, Grant/Award Number: JR14/ 00036; Spanish Network for the Research in Infectious Diseases, Grant/Award Number: RD12/0015; European Development Regional Fund; Ministerio de Economía y Competitividad; Fondo de Investigación Sanitaria; Proyecto Integrado de Excelencia, Grant/Award Number: 13/00045

Summary Real-time polymerase chain reaction (PCR)-based approaches have not been assessed in terms of their ability to detect patients colonized by Acinetobacter baumannii during active surveillance. This prospective, double-blind study demonstrated that a real-time PCR assay had high sensitivity (100%) and specificity (91.2%) compared with conventional culture for detecting A. baumannii in 397 active surveillance samples, and provided results within 3h. Receiver-operator curve analyses demonstrated that the technique has diagnostic accuracy of 97.7% (95% confidence interval 96.0–99.3%). This method could facilitate the rapid implementation of infection control measures for preventing the transmission of A. baumannii .

Cytomegalovirus (CMV) infection remains a major complication of solid organ transplantation. Because of management of CMV is variable among transplant centers, in 2011 the Spanish Transplantation Infection Study Group (GESITRA) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC) developed consensus guidelines for the prevention and treatment of CMV infection in solid organ transplant recipients. Since then, new publications have clarified or questioned the aspects covered in the previous document. For that reason, a panel of experts revised the evidence on CMV management, including immunological monitoring, diagnostics, prevention, vaccines, indirect effects, treatment, drug resistance, immunotherapy, investigational drugs, and pediatric issues. This document summarizes the recommendations.

CMV DNA loads measured by the new Abbott RealTime CMV PCR were significantly higher than those quantitated by the Abbott CMV PCR kit (approximately 1 log(10)), and provided a better estimate of the actual CMV load present in plasma specimens as inferred by the use of the WHO standard.

Preventing influenza infection early after transplantation is essential, given the disease's high mortality. A multicentre prospective cohort study in adult solid organ transplant recipients (SOTR) receiving the influenza vaccine during four consecutive influenza seasons (2009–2013) was performed to assess the immunogenicity and safety of influenza vaccination in SOTR before and 6 months after transplantation. A total of 798 SOTR, 130 of them vaccinated within 6 months of transplantation and 668 of them vaccinated more than 6 months since transplantation. Seroprotection was similar in both groups: 73.1% vs. 76.5% for A/(H1N1)pdm (p 0.49), 67.5% vs. 74.1% for A/H3N2 (p 0.17) and 84.2% vs. 85.2% for influenza B (p 0.80), respectively. Geometric mean titres after vaccination did not differ among groups: 117.32 (95% confidence interval (CI) 81.52, 168.83) vs. 87.43 (95% CI 72.87, 104.91) for A/(H1N1)pdm, 120.45 (95% CI 82.17, 176.57) vs. 97.86 (95% CI 81.34, 117.44) for A/H3N2 and 143.32 (95% CI 103.46, 198.53) vs. 145.54 (95% CI 122.35, 174.24) for influenza B, respectively. After adjusting for confounding factors, time since transplantation was not associated with response to vaccination. No cases of rejection or severe adverse events were detected in patients vaccinated within the first 6 months after transplantation. In conclusion, influenza vaccination within the first 6 months after transplantation is as safe and immunogenic as vaccination thereafter. Thus, administration of the influenza vaccine can be recommended as soon as 1 month after transplantation.

Little is known about cytomegalovirus (CMV) infection after face transplantation, since only two of the 11 cases of face transplantation reported worldwide have documented a CMV infection after transplantation. Herein, we present the first report of a composite-tissue face allotransplant recipient at high risk for CMV infection (D + /R − [CMV serpositive donor positive/CMV seronegative receptor]) undergoing preemptive treatment. Preemptive treatment was safe and effective for controlling CMV infection and thus promoting early acquisition of a CMV-specific immune response that protected the patient from late-onset CMV disease.

Summary The aim of this study was to characterize timing, kinetic, and magnitude of CMV-specific immune response after hematopoietic stem cell transplantation (HSCT) and its ability to predict CMV replication and clinical outcomes. Using cell surface and intracellular cytokine staining by flow cytometry, CMV-specific T-cell response was measured in blood, while CMV viral load and chimerism were determined by real-time PCR. Patients that reconstituted CMV-specific T-cell response within 6 weeks after Allo-SCT showed a more robust immune response (CD8+: 0.7 cells/μl vs. 0.3/μl; P-value = 0.01), less incidence of CMV replication (33% vs. 89.5%; P-value = 0.007), reduced viral loads (1.81 log copies/ml vs. 0 copies/ml; P-value = 0.04), and better overall survival (72%; CI: 0.53–0.96 vs. 42% CI: 0.24–0.71; P-value = 0.07) than patients with a delayed immune reconstitution. Viremic patients had significantly higher transplant-related mortality than nonviremic patients after 1 year (33% CI: 0.15–0.52 vs. 0% CI: 0.05–0.34; P-value = 0.01). Risk factors independently associated with viral replication were receptor pretransplant CMV-positive serostatus (P-value = 0.02) and acquiring CMV-specific T-cell response after 6 weeks post-transplantation (P-value = 0.009). In conclusion, timing of acquiring a positive CMV-specific T-cell immune response after transplantation may identify patients with different risk for viral replication and different clinical outcomes, including survival.

OBJECTIVE To assess the impact of blips and persistent viremia episodes on cell-associated HIV-DNA reservoir in extensively pretreated patients receiving ritonavir-boosted darunavir monotherapy (MtDRV/rtv) for 24 months. DESIGN AND METHODS Patients from the MonDAR prospective study (NCT01606722) who received at least 6 months of MtDRV/rtv and had at least two available peripheral blood mononuclear cells (PBMCs) samples were selected and classified according to the viral outcome as continuous undetectable viremia (cUV; n = 40), blips (n = 31), intermittent viremia (IV; n = 23), and virological failure (VF, two consecutive viral loads >200 copies/ml; n = 20). Proviral HIV-DNA was quantified by real-time PCR in PBMCs samples at baseline, and months 6, 12, 18 and 24. Additionally, HIV-DNA levels were exhaustively analyzed at virological failure and blip episodes. RESULTS The HIV-DNA levels remained constant during the 24 months in every group. Neither blips nor intermittent viremia influenced the HIV-DNA levels at short-term or at middle term. By contrast, virological failure episodes gave rise to a significant increase in proviral DNA (2.15 vs. 2.32 log10 HIV-DNA copies/10 PBMCs; P = 0.042). Basal proviral DNA levels more than 2 log10 copies/10 PBMCs predicted the time to viral rebound at any given cut-off point (>20, >50, and >200 copies/ml. HR: 3.02, 2.61, and 3.02, respectively; P ≤ 0.03. Besides, an adherence less than 95% was also strongly associated with virological failure (HR, 3.17; P = 0.021). CONCLUSION Blip episodes and intermittent viremia did not affect the cellular HIV reservoir dynamic during MtDRV/rtv. Higher adherence and an HIV-DNA levels less than 2 log10 copies/10 PBMCs at baseline were associated with a lower risk of virological failure.

Summary Despite advances in prevention, cytomegalovirus (CMV) recurrence is an important challenge in high-risk organ recipients. The present study prospectively evaluates the impact of CMV-specific T-cell immune response and secondary prophylaxis on the risk of recurrence in a cohort of CMV high-risk organ recipients and whether it is possible to determine a safe standardized viral load value below which CMV disease is unlikely. Thirty-nine recipients were included. Thirty-six had primary infections, and 88.9% recurred. Rate and duration of recurrent CMV infection was similar in patients with and without secondary prophylaxis: 57.9% vs. 53.6%, P = 0.770 and 16 vs. 15 days, P = 0.786, respectively. The only factor independently associated with no episodes of CMV recurrence was the acquisition of CMV-specific T-cell immune response (OR: 0.151, 95% CI: 0.028–0.815; P = 0.028). Cytomegalovirus diseases (N = 5) occurred in patients with CMV viral load above 1500 IU/ml who did not follow the planned monitorization schedule. Our observations suggest that episodes of recurrent CMV infection are common after preemptive therapy despite secondary prophylaxis and that CMV-specific T-cell immune response is associated with a decreased risk of recurrent infections. Preemptive therapy may be safe in patients at high risk for CMV infection with strict close monitoring of the CMV viral load.

The aim of this study was to assess the immunogenicity of a vaccine against this virus in a prospective cohort of transplanted pediatric patients without previous influenza infection who received one dose of MF59®-adjuvanted pandemic H1N1/2009 vaccine. Seventeen patients who were being regularly followed up at the Outpatient Clinic of the Children's Transplant Unit (liver and kidney transplantation) in Hospital Universitari Vall d'Hebron (Barcelona) were included. Seroconversion was demonstrated in 15 of 17 (88.2%) vaccinated children. There were no rejection episodes or major adverse events. The MF59(®) -adjuvanted pandemic H1N1/2009 vaccine was safe and elicited an adequate response.

Before the advent of the influenza A(H1N1)pdm virus in 2009, the information available about the clinical manifestations and prognosis of influenza in immunosuppressed patients was scarce. With the 2009 pandemic, knowledge of the behavior, severity and importance of antiviral therapy for influenza A infection in immunocompromised hosts has increased considerably. The aim of the present manuscript is to review the main challenges of influenza in the most representative immunosuppressed populations such as solid organ transplant recipients, hematopoietic stem cell transplant recipients, patients with solid and hematological cancer and human immunodeficiency virus infected patients.

Background Valganciclovir preemptive therapy guided by the viral load is the current strategy recommended for preventing CMV disease in CMV-seropositive Solid Organ Transplant Recipients (SOTR) at lower risk for developing CMV infection. However, universal viral load cut-off has not been established for initiating therapy. Objectives Our goal was to define and validate a standardized cut-off determined in plasma by real-time PCR assay for initiating preemptive therapy in this population. Study design A prospective cohort study of consecutive cases of CMV-seropositive SOTR was carried out. The cut-off value was determined in a derivation cohort and was validated in the validation cohort. Viral loads were determined using the Quant CMV LightCycler 2.0 real-time PCR System (Roche Applied Science) and results were standardized using the WHO International Standard for human CMV. Results A viral load of 3983 IU/ml (2600 copies/ml) was established as the optimal cut-off for initiating preemptive therapy in a cohort of 141 patients with 982 tests and validated in a cohort of 252 recipients with a total of 2022 test. This cut-off had a 99.6% NPV indicating that the great majority of patients at lower risk will not develop CMV disease without specific antiviral therapy. The high sensitivity and specificity (89.9% and 88.9%, respectively) and the relatively small numbers of patients with CMV disease confirm that real-time PCR was optimal. Conclusions We have established a cut-off viral load for starting preemptive therapy for CMV-seropositive SOT recipients. Our results emphasized the importance of a mandatory follow-up protocol for CMV-seropositive patients receiving preemptive treatment.

BACKGROUND Little is known about the long-term antibody response to the 2009-H1N1 vaccine in solid organ transplant recipients (SOTR) and its clinical repercussion on the efficacy of following 2010-2011 influenza vaccine. METHODS We performed a multicenter prospective study in SOTR receiving one dose of the nonadjuvant 2010-2011 seasonal influenza vaccine and determined the immunological response at 5 weeks after vaccination. RESULTS One hundred SOTR were included. Long-term antibody titers to the previous vaccine were only detected in one third of the patients. Patients with baseline titers had significantly higher seroprotection for the 2009-H1N1 strain (100% vs. 73%, relative risks [RR] 1.37, 95% confidence intervals [CI] 1.19-1.57; P=0.006), for H3N2 strain (100% vs. 62.2%, RR 1.61, 95% CI 1.36-1.90; P=0.005), and for B strain (100% vs. 69%; P=0.02). The seroconversion rate in patients with baseline titers was 90.9% vs. 73% (RR 2.97, 95% CI 0.75-11.74; P=0.07) for the 2009-H1N1 strain, 92.2% vs. 62.2% (RR 5.29, 95% CI 0.8-35.7; P=0.02) for the H3N2 strain, and 58.3% vs. 69% (P=0.45) for the B strain. CONCLUSIONS SOTR response to the 2010-2011 influenza vaccine was not optimal. The response was related to baseline titers; however, most of the patients did not exhibit detectable antibodies at vaccination lacking long-term response. New strategies are necessary to improve vaccination efficacy.

Cytomegalovirus (CMV) end-organ disease is a serious complication after stem cell transplantation (SCT) (Boeckh M, 2003). Within the first one hundred days after SCT, 50% of recipients develop CMV infection determined by positive antigenemia and 65 to 86.5% when viral replication is determined by real-time PCR (RT-PCR) (Ljungman et al., 2006; Solano et al., 2001). Described risk factors for CMV infection concern donor type, graft source, positive CMV serostatus of donor and recipient, CD34+ graft selection, preconditioning regimen, GvHD prophylaxis regimen, incidence of acute and chronic GvHD and prophylaxis and treatment for GvHD (Ljungman et al., 2002; Ozdemir et al., 2007). Pre-emptive therapy is currently based on viral replication determined by either antigenemia or RT-PCR (Drew, 2007). Although antigenemia has been extensively used (Drew, 2007), RT-PCR has been shown to be more sensitive (Hakki et al., 2003; Solano et al., 2001).

Objectives: After the last pandemic the knowledge regarding influenza A infection has improved however, the outcomes of influenza B infection remain poorly studied. The aim of this study was to compare the features of influenza B versus influenza A(H1N1)pdm09 infections during the 2010-2011 epidemic-season., Methods: A prospective, observational-cohort of adults with laboratory-confirmed influenza infection during the 2010-2011 epidemic-season was studied., Results: Fifty cases of influenza B and 80 of influenza A(H1N1)pdm09 infection were enrolled. Among patients with influenza B, the median age was 34 years-old (23-64), 30% pregnant, 24% obese, 34% transplant recipients and 14% with bacterial co-infection. Twenty-eight percent of patients had pneumonia with alveolar localized pattern and five (10%) died. Pneumonia was associated with delayed antiviral therapy, older age, higher Charlson score, invasive mechanical ventilation and bacterial co-infection. Obesity and pregnancy were not associated with complicated influenza B infection. The proportion of pneumonia, admission to the ICU and mortality did not differ between cases of influenza A(H1N1)pdm09 and influenza B infection., Conclusions: Influenza B infection causes severe infection and it is associated with pneumonia or death, similar to influenza A(H1N1)pdm09 infection. Rapid diagnosis and early antiviral therapy are necessary for managing influenza pneumonia during epidemic periods. © 2012 The British Infection Association., This work was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (GR09/0041) and - co-financed by European Development Regional Fund >A way to achieve Europe> ERDF, Spanish Network for the Research in Infectious Diseases (REIPI RD06/0008). P.P-R. was funded by Instituto de Salud Carlos III, Programme Miguel Servet (CP05/00226).

Cordero, E. et al., Concern has been raised regarding the response to vaccination in solid organ transplant recipients (SOTR) undergoing immunosuppressant regimens and the possibility of rejection related to the immune response associated with pandemic influenza H1N1–2009 vaccination. The goal of this study was to assess the immunogenicity, efficacy and safety of the pandemic vaccine in SOTR.We performed a multicenter prospective study in SOTR receiving the pandemic vaccine. Immunological response was determined in serum 5 weeks after vaccination by microneutralization assays, and immunoglobulins were measured by ELISA. Three hundred and forty-six SOTR were included. Preexisting seroprotection was detected in 13.6% of cases and rates of seroconversion and seroprotection after vaccination were 73.1% and 82.9%, respectively. Patients with baseline antibody titers had better geometric mean titers (GMT)-post after pandemic vaccination (339.4 vs. 121.4, p < 0.001). Younger age, liver disease andm-TOR inhibitor therapywere independently associated with lower seroprotection and GMT-post. There were no major adverse effects or rejection episodes. Pandemic vaccine was safe in SOTR and elicited an adequate response, although lower than in healthy individuals. This is the first study describing a decreased response after vaccination in patients receiving mTOR inhibitors who presented lower seroprotection rates and lower GMT-post., This work was supported by the Fondo de Investigación Sanitaria (PI050226/2005 and PI060521/2006);Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III (GR09/0041) and Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III – cofinanced by European Development Regional Fund "A way to achieve Europe" ERDF, SpanishNetwork for the Research in Infectious Diseases (REIPI RD06/0008/0000).

This work was supported by the Ministerio de Ciencia e Innovación, Instituto de Salud Carlos III, cofinanced by European Development Regional Fund “A Way To Achieve Europe,” Spanish Network for Research in Infectious Pathology (REIPI RD06/0008/0000). M.J.M. is supported by the Programme Juan de la Cierva from the Ministerio de Ciencia e Innovación of Spain. P.P.-R. is supported by the Instituto de Salud Carlos III, Programme Miguel Servet CP05/00226.

Optimizing treatment for patients with persistent low-level viremia is complicated because most genotyping tests are validated for viral loads >1000 copies per milliliter. In this study, genotypes of 92 treatment-experienced patients with persistent low-level viremia were determined using an in-house assay. Based on the resistance profiles obtained from genotyping and patient pharmacologic history, patients were either maintained on their antiviral regimen (n = 51) or received an optimized regimen (n = 41). In the group receiving optimized treatment, undetectable viral loads were achieved in 73.2% at 6 months and at 90.2% at 1 year, indicating that treatment guided by genotyping of patients with low-level viremia is effective in achieving viral suppression.

Carta al editor

Cytomegalovirus (CMV) end-organ disease is a serious, frequent complication after allogenic stem cell transplantation (Allo-SCT). There are two prevention strategies: universal prophylaxis and preemptive therapy. Preemptive therapy is administered based on the results of sensitive techniques that detect the viral infection. We analyzed 41 peripheral blood Allo-SCT recipients: 34 received prophylaxis and seven preemptive treatment. Viral infections determined using real-time polymerase chain reaction (RT-PCR) assays occurred at an overall incidence of 65.8%. The viral loads quantified by RT-PCR were compared among the prophylaxis versus the preemptive group. Overall, the median viral load was significantly higher in the preemptive compared with the prophlylaxis group (P = .002). Furthermore, within the first 100 days posttransplantation, viral load values were higher among patients undergoing preemptive therapy (P = .009).

Solid organ transplant (SOT) recipients are at greater risk than the general population for complications and mortality from influenza infection.Researchers and clinicians with experience in SOT infections have developed this consensus document in collaboration with several Spanish scientific societies and study networks related to transplant management. We conducted a systematic review to assess the management and prevention of influenza infection in SOT recipients. Evidence levels based on the available literature are given for each recommendation. This article was written in accordance with international recommendations on consensus statements and the recommendations of the Appraisal of Guidelines for Research and Evaluation II (AGREE II).Recommendations are provided on the procurement of organs from donors with suspected or confirmed influenza infection. We highlight the importance of the possibility of influenza infection in any SOT recipient presenting upper or lower respiratory symptoms, including pneumonia. The importance of early antiviral treatment of SOT recipients with suspected or confirmed influenza infection and the necessity of annual influenza vaccination are emphasized. The microbiological techniques for diagnosis of influenza infection are reviewed. Guidelines for the use of antiviral prophylaxis in inpatients and outpatients are provided. Recommendations for household contacts of SOT recipients with influenza infection and health care workers in close contact with transplant patients are also included. Finally antiviral dose adjustment guidelines are presented for cases of impaired renal function and for pediatric populations.The latest scientific information available regarding influenza infection in the context of SOT is incorporated into this document.

Abstract 1281 Background: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). The quality of the post-transplant immune reconstitution plays a crucial role in the development of both, post-transplant infections and relapse of the underlying disease, two of the main factors conditioning post-transplant mortality and hence final survival. The relationship between viral replication and CMV specific immune reconstitution has not been completely unveiled. This knowledge would allow identifying patients at risk for developing CMV disease and eventually improving their clinical management. Objectives: to analyze the relationship between CMV replication and specific CMV immune reconstitution and the potential influence of this relationship in main clinical outcomes. Patients and Methods: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Blood samples were collected from one week before transplant, weekly during the first three months after transplant, every other week from month three to six and monthly from month seven to complete one year of follow up. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry with surface markers and intracellular cytokine staining. The percentage of activated CD4+, CD8+ and CD3+ T cells expressing CD69 were considered positive when IFN-’Y cytokine secretion was over 0.25%. Chimerism of the isolated CD8+ T cell subpopulation was determined by PCR. CD69 expression and cytokine secretion were compared in both CD4+ and CD8+ T cells between the different time points and both subsets of patients by the Wilcoxon test. CMV viral load reduction without treatment administration was compared by Wilcoxon test. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). Results: Twenty-six patients were enrolled in the study with a median age of 33 years (range:15-61). We identified two groups of patients. A first group of 18 (69.2%) patients developed CMV infection and acquired CMV-specific T cell response by median week 8 (range:1-22; Figure 1A). The decline in the incidence of CMV replication episodes correlated with the acquisition of CMV-specific T cell response (Linear regresion r2=0.781, Pearson correlation p=0.01). A second group of 8 patients (30.8%) never developed CMV infection after the transplant, with a median value of 2 weeks (range:1-7; Figure 1B). The time of the acquisition of CMV-specific T cell response for the group with viremia and for the non-viremic group (week 2 vs. week 8) was statistically different (p= 0.01). Fifteen per cent of the patients (n=4) developed end-organ disease. Three out of five patients with end-organ disease developed replication CMV episodes over 10,000 copies/ml, while only 1 out of 13 patients with no end-organ disease developed viral loads under 10,000 copies/ml (p=0.04). The percentage of positive CD8+ T cells expressing IFN-γ in the patients that developed disease tended to be lower than in the patients that did not develop disease (median percentage of IFN-g positive CD8 T cells 0.3 vs. 0.5, respectively). The chimerism of the CD8+ T cells subpopulation after acquiring the specific immune response was of complete donor origin for all the patients. Conclusions: Developing donor-derived T-cell mediated CMV-specific immune response within the following two weeks after the transplant is inversely associated with the development CMV infection. The level of CMV viral load may predict end-organ disease. The use of a tool to determine T-cell mediated CMV-specific immune response in the clinical practice may help to improve the management of these patients, avoiding unnecessary treatments, and predicting clinical outcomes. Disclosures: No relevant conflicts of interest to declare.

Abstract 4539 BACKGROUND: Cytomegalovirus (CMV) end-organ disease is a serious complication after allogeneic stem cell transplantation (Allo-SCT). Described risk factors for CMV infection are pretransplant CMV seropositive status of the recipient, non related donor or umbilical cord transplant, depleted lymphocyte graft, high intensity conditioning regimen, severe graft versus host disease (GVHD), CD34+ selection of the graft and delayed CMV specific immune reconstitution. OBJETIVES: To identify different profiles of allogeneic stem cell recipients based on their previously described risk factors for CMV infection and its association with their clinical outcomes. PATIENTS AND METHODS: A prospective study of consecutive recipients of Allo-SCT was performed from June 2008 through December 2009 at a single institution. Patients were sequentially monitored both clinically and analytically. CMV viral load was determined by real time PCR and CMV-specific T cell response was determined by flow cytometry. Non-normal distribution data were expressed as median values (range). Chi-square test or Fisher exact test were used to compare differences between groups of categorical data. Differences were considered statistically significant for p-values < 0.05. All statistical analyses were performed using SPSS 16.0 software (Chicago, IL). RESULTS: Twenty-six patients were included with a median age of 33 years (range:15-61). The donor was an identical sibling in 42.3%, unrelated donor in 53.8% and a mismatched family member in 3.8%. The source was peripheral blood 76.9%, cord blood 15.4% and bone marrow in 7.7%. Previous positive serostatus for CMV was 76.9% in recipients, and 53.8% in donors. The conditioning regimen was myeloablative in 57.7% and reduced-intensity in 42.3%. Graf versus host disease (GvHD) prophylaxis was cyclosporine (CsA) plus methotrexate (MTX) in 57.7% and CsA plus mycophenolate mofetil (MMF) in 42.3%. The incidence of acute GvHD was 76.9% and chronic GvHD was 53.8%. Treatment of GVHD was steroids plus CsA or tacrolimus and/or MMF in 76.9% of acute and 46.2% of chronic GvHD. Previously described risk factors for developing CMV infection were compared between patients developing (n=18) and non-developing (n=8) CMV infection. A higher risk for developing CMV infection was associated with previous CMV positive serostatus of the recipient (84% in viremic patients vs. 16% in non-viremic patients; p=0.01) and CsA plus MMF as GvHD prophylaxis (90.9% vs. 9.1%; p=0.04). We analyzed whether having several risk factors for developing CMV infection has an effect on the risk for developing CMV replication after the transplant. Patients that presented four or more risk factors, developed viral replication more frequently than patients having less than four risk factors (91.6% vs. 8.3%; p=0.02). Patients who acquired an earlier specific CMV immune reconstitution did not developed CMV replication, opposite to those with later immune reconstitution (week 2 vs. week 8, p= 0.01). Overall survival at one year was of 44.4% in the group with viral replication, and 100% in the group with no viral replication, p=0.014 (Figure 1). CONCLUSIONS: Patients that did not developed episodes of CMV replication after the transplant presented less than four risk factors for developing CMV infection, developed an early T-cell mediated CMV immune response and had better overall survival. The development of CMV specific immunity able to control CMV replication may be considered as a paradigm of post-transplant immune reconstitution with potential influence on overall survival. Disclosures: No relevant conflicts of interest to declare.