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Background With improvements in survival rates, health-related quality of life is an important outcome parameter to evaluate the effectiveness of transplantation. We aimed to identify potential immunologic abnormalities as factors associated with poorer health-related quality of life at distinct scales of the 36-Item Short Form Health Survey in heart transplant recipients long term after transplantation. Methods One hundred heart transplant recipients were evaluated in a single center. Short-form 36 questionnaires were sent by mail to participants. All patients were clinically and immunologically evaluated after the first year of heart transplantation. Results A high prevalence of several immunologic abnormalities persisted even after the first year of transplantation, including IgG hypogammaglobulinemia, low IgG-specific antipneumococcal antibodies, C4 hypocomplementemia, CD8 T-cell lymphocytopenia, and CD19 B-cell lymphocytopenia. Older recipients (>55 years), posttransplant diabetes, digestive complications, and posttransplant infections were associated with lower physical functioning scores (scale 55 years), pretransplant diabetes, pretransplant arterial hypertension, posttransplant digestive complications, and lower CD8 counts were associated with lower physical role scores (scale Conclusion In a single center study, lower CD8 cell counts were found to be associated with poorer health status in heart recipients after the first year of transplantation.

Bacterial infections are the most frequent infectious complications among solid organ recipients. These complications are associated with a high morbidity and mortality, despite recent advances in antimicrobial prophylaxis in the transplant setting. New therapeutic modalities are warranted. We present here a retrospective study based on medical records review of 2 solid organ recipients that were treated with mucosal bacterial immunotherapy because of recurrent bacterial respiratory infections long time after transplantation. A successful decrease of the frequency of bacterial respiratory infections during a period of up to 8 years was observed in one of the patients. We suggest that clinical trials in this field are warranted.

La radiación electromagnética está presente en nuestra vida sin darnos cuenta: en los conectores eléctricos, el teléfono celular, el sol, el agua que tomamos, existen campos magnéticos que son de origen natural y artificial necesario para facilitar las actividades de la vida diaria. Utilizamos radiación para curar enfermedades, hacer diagnósticos clínicos, comunicarnos, generar energía eléctrica, diagnosticar el clima espacial y su impacto en la tierra. En líneas generales podemos decir que la radiación genera beneficios para el ser humano. Sin embargo, cuando esta proviene de fuentes radiactivas generadas por el desarrollo científico puede crear efectos irreparables adversos para la salud. En este sentido, en el presente texto queremos distinguir como un uso indiscriminado de estas fuentes naturales pueden provocar daños irreparables.

BACKGROUND We performed a multicenter study to assess the association between secondary antibody deficiency (immunoglobulin G [IgG] hypogammaglobulinemia combined with low levels of specific antibodies) and development of infection in kidney transplantation. METHODS We prospectively analyzed 250 adult kidney recipients at four centers. The assessment points were before transplantation and 7 and 30 days after transplantation. The immune parameters were as follows: IgG, IgA, and IgM and complement factors C3 and C4 tested by nephelometry; specific IgG antibodies to cytomegalovirus (CMV) and IgG and IgG2 antibodies to pneumococcal polysaccharide (anti-PPS) determined using enzyme-linked immunosorbent assay. The clinical follow-up period lasted 6 months. The clinical outcomes were CMV disease and recurrent bacterial infections requiring antimicrobial therapy. STATISTICS Multivariate logistic regression. RESULTS At day 7, IgG hypogammaglobulinemia (IgG levels

Esta obra recoge algunas experiencias de formacion en recreacion de promotores ludicos del pais y presenta un profundo analisis en torno a la pertinencia de la recreacion en diversos contextos en los que la relacion con los ninos exige agentes de cambio creativos y reflexivos. En ese sentido, se revisan aspectos de la ensenanza de orden teorico y empirico postulados por autores de diferentes tendencias de la recreacion y el ocio que facilitan la construccion de propuestas o modelos de educacion de la recreacion. A su vez, se expone puntos de vista concretos acerca de la produccion de conocimiento y, por tanto, de realizacion practica del ocio en el contexto latinoamericano y, en particular, colombiano. Finalmente, este libro propone opciones concretas para el desarrollo practico del ocio en torno a la lectura recreativa y se analiza criticamente la idea convencional acerca del acoplamiento de objetos tecnicos en el cuerpo humano.

Purpose Bacterial infections are the most frequent infectious complications after heart transplantation. IgA and IgM serological response to the 23-valent pneumococcal polysaccharide vaccine (PPSV23) can be used to assess antibody function against T-cell independent type-2 antigens (anti-PPS). We evaluated if IgA and IgM anti-PPS titers after vaccination in a cohort of heart recipients were associated with the risk for development of bacterial infections. Methods A prospective follow-up study of 151 adult heart recipients (124 male, 27 female, mean age: 58 years) at a single center. The study population received one injection of PPSV23 before transplantation. Specific IgA and IgM anti-PPS were measured in pre and post vaccination sera before transplantation by ELISA (2-3 weeks interval between pre and post vaccination samples) and at distinct times after transplantation (day 7, 30, 90, 180). ELISA plate contained the 23 antigens of the pneumococcal vaccine. The prevalence of bacterial infections was registered during the first 6 months after transplantation. Results During follow-up 32 patients (21%) developed bacterial infectious complications that required IV drug therapy in hospital. Mean anti-PPS titers were significantly lower in transplanted patients who developed bacterial infections as compared with heart recipients who remained free of bacterial infections: after vaccination before transplantation (IgA anti-PPS, 12±10 vs 27±51 mg/dL, p=0.031), at day 7 after transplantation (IgA anti-PPS, 6±5 vs 13±12 mg/dL, p=0.01), at day 30 after transplantation (IgA anti-PPS, 6±5 vs 19±34 mg/dL, p=0.003 and IgM anti-PPS, 6±4 vs 14±19 mg/dL, p=0.002), at day 90 (IgA anti-PPS, 4±2 vs 17±10 mg/dL, p=0.003 and IgM anti-PPS, 7±4 vs 13±8 mg/dL, p=0.04) and at day 180 (IgA anti-PPS, 3±1 vs 15±9 mg/dL, p=0.003). Conclusion Low IgA and IgM anti-polysaccharide responses may predispose heart recipients to develop bacterial infections. IgA anti-PPS as a biomarker warrants validation in a multicenter study.

Purpose Infection is a cause of death in solid organ transplantation. Secondary antibody deficiency is a risk factor of severe infection in solid organ transplantation. In a multicenter randomized clinical trial we evaluated the efficacy and safety of an intravenous immunoglobulin (IVIG) protocol to decrease the rate of re-infection in solid organ recipients with severe infections and secondary antibody deficiency. Methods Adult patients (20 Heart, 12 Lung, 5 Kidney, 3 Liver Recipients) with post transplant severe infections and secondary antibody deficiency (IgG levels Results The primary outcome measure (rate of re-infection) was significantly lower in patients randomized to receive IVIG as compared with patients receiving only conventional antimicrobial therapy (35.3 vs 68.4%, chi-square test, p=0.047). Time to reach normal IgG (IgG > 750 mg/dL) was shorter in IVIG group (55±44 vs 93±42 days, p=0.06). Significantly higher levels of specific anti-cytomegalovirus, anti-clostridium difficile toxins A and B was demonstrated at visit 7 in patients who received IVIG as compared with patients that were treated with antimicrobial therapy alone. Conclusion In a randomized clinical trial we have preliminarily demonstrated that IVIG is associated with reconstitution of distinct specific antibodies and with a lower rate of re-infection in solid organ transplantation with severe infection and secondary antibody deficiency.

Purpose Along with infections, rejection and graft vasculopathy, malignancies comprise a major complication after heart transplant, with a rate of occurrence of over 30% in 10 years. Skin cancers and posttransplant lymphoproliferative disorder are more common in adults. The risk factors for development of a malignancy after heart transplant are the same as for the nontransplant population. Identification of biomarkers that assess post-transplant risk is needed to improve long-term outcomes following heart transplantation. Methods We performed a single center, cohort study of 281 heart transplant recipients followed for a mean time of 9.5 years (2-19 years post-transplant). Mean age was 54.5, male 71.5%. The primary endpoint was development of neoplasia (27.2%). 8.2% developed metastasis. We serially measured funcionally distinct lymphocyte subsets in peripheral blood. We correlated assay results with the outcomes of neoplasia and development of metastasis. Lymphocyte subsets were assessed by four-colour flow-cytometry before transplantation at the time of inclusion in waiting list, at day 7 and 30 after heart transplantation. Results Clinical risk factors of cancer were age, smoking, obesity, ischemic etiology and post-transplant infections. We observed the following abnormalities in heart recipients who developed cancer: lower percentages of naive B-cells and lower mean fluorescence intensity (MFI) of toll like receptor (TLR) 4 on B-cells before transplantation (p=0.01 and p=0.049, respectively); lower non switched memory B-cell percentages and lower MFI of TLR4 on B-cells at 7 days after transplantation (p Conclusion Immunological abnormalities of B-cells and of TLR4 expression on B-cells and CD8 T-cells were observed in heart recipients who developed cancer after heart transplantation. These results suggest a role of these abnormalities in the predisposition to cancer that warrants further evaluation.

BACKGROUND: Infection is still a leading cause of death during the first year after lung transplantation. We performed a multicenter study among teaching hospitals to assess monitoring of early humoral immunity as a means of identifying lung recipients at risk of serious infections. METHODS: We prospectively analyzed 82 adult lung recipients at 5 centers in Spain. Data were collected before transplantation and at 7 and 30 days after transplantation. Biomarkers included IgG, IgM, IgA, complement factors C3 and C4, titers of antibodies to pneumococcal polysaccharide antigens (IgG, IgA, IgM) and antibodies to cytomegalovirus (IgG), and serum B-cell activating factor (BAFF) levels. The clinical follow-up period lasted 6 months. Clinical outcomes were bacterial infections requiring intravenous anti-microbial agents, cytomegalovirus (CMV) disease, and fungal infections requiring therapy. RESULTS: We found that 33 patients (40.2%) developed at least 1 serious bacterial infection, 8 patients (9.8%) had CMV disease, and 10 patients (12.2%) had fungal infections. Lower IgM antibody levels against pneumococcal polysaccharide antigens at Day 7 (defined as

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Granulomatous Lymphocytic Interstitial Lung Disease (GLILD) is an inflammatory pulmonary complication of common variable immunodeficiency (CVID) with distinctive patterns in the biopsy; Granulomatous Disease, Lymphocytic Interstitial Disease, Follicular Bronchiolitis and Organizing Pneumonitis. Without the proper treatment this complication will lead to important pulmonary dysfunction due to fibrosis. Although this process has been well recognized, protocols for a standardized treatment, and the proper timing for the use of immune modulation as well as the maintenance time with monoclonal antibodies are an unclear topic. Case presentation: We present the case of a 57-year-old female patient with CVID. During the evaluation of an episode of autoimmune hemolytic anemia, she presented concomitantly radiological and histopathological features of GLILD. She was treated successfully with Rituximab monotherapy without any complications and is currently asymptomatic. Conclusion: We conclude that the use of Rituximab as single therapy, modulates the lymphocytic infiltration of the lung parenchyma and stops the progression and organization of the damage mediated by B cells and indirectly by T cells, and it could be used as monotherapy in the proper timing of the diagnostic process.

Purpose The identification of pre-transplant biomarkers to assess the risk of post transplant infections in lung transplantation is of interest. The anti-inflammatory cytokine interleukin-10 (IL-10) was investigated in this study. Higher IL-10 plasma levels have been associated with prolonged CMV clearance in lung recipients. In other clinical setings higher IL-10 levels have been found to be a predictor of clinical outcome in sepsis. In this study we evaluated the relationship between pre-transplant IL-10 serum concentration and the development of infections occurring after lung transplantation. Methods In a prospective follow-up multicenter study, 87 patients in 5 centers were included to identify potential biomarkers of risk for development of post transplant infections. 82 patients were transplanted. 41 patients (50%) developed at least one infection episode that required intravenous drug therapy during the first 6 months after transplantation. Pre-transplant IL-10 was measured with an enzyme-linked immunosorbent assay in blood. IL-10 levels were then correlated with the prevalence of infections. Results The distribution of post transplant infections was as follows: bacterial (67,35%), fungal (20,41%), viral (10,20%). Patients who developed infections disclosed significantly higher levels of pre-transplant serum IL-10: 43,26 ± 39,55 pg/ml vs. 21,70 ± 23,34 pg/ml; p 29 pg/ml were at higher risk of having post transplant infections (Logistic regression relative hazard 3.64 (p= 0.021; 95% confidence interval: 1.28- 10.87). Conclusion We demostrated that in lung recipients with pre-transplant higher levels of serum IL-10, the prevalence of post-transplant infections was higher which suggest a potential role of individual anti-inflammatory responses in the predisposition to infection.

Background Specific anticytomegalovirus (anti-CMV) intravenous immunoglobulin (IVIG) has the potential to influence the immune response, but its complex mode of action has not been well evaluated. Methods An immunologic study of 6 CMV-seronegative heart transplant patients receiving anti-CMV prophylaxis with the use of ganciclovir and CMV-IVIG (150 mg/kg within 24 hours after transplantation and 100 mg/kg on days 2, 7, 14, 22, 35, 56, and 77 after transplantation) was performed in a single center. Lymphocyte subsets were evaluated by means of 4-color flow cytometry at the time of inclusion in the waiting list and at 3 months after transplantation. Results High-risk heart recipients receiving CMV-IVIG showed a clear reduction in the frequency of activated CD4+CD38+DR+ T-helper cells at 3 months after transplantation compared with a group of 27 untreated control subjects who received only anti-CMV prophylaxis with the use of ganciclovir. In this study, an increase of CD19+CD27−IgM+IgD+ naive B cells was also observed in seronegative recipients after prophylaxis with the use of CMV-IVIG but not in control subjects. None of the CMV-IVIG–treated recipients developed acute cellular rejection during the 1st 6 months after transplantation. Conclusions The immune modulation of activated CD4+ lymphocyte and of naive B-cell subsets after CMV-IVIG use should be further evaluated in future prospective studies with higher numbers of patients.

Background Autoantibodies, low complement levels and higher NK cell counts are present in a subset of women with recurrent pregnancy loss (RPL). The combination of these abnormalities might be a surrogate profile for the presence of a subclinical inflammatory or autoimmune condition. Objectives In a cohort of women with unexplained RPL we evaluated if an immunological profile combining innate and adaptive immunity mediators was associated with the presence of distinct clinical characteristics that are commonly observed in autoimmune diseases and if it was a risk factor for developing these diseases. In a small subset of women with the immunological profile we evaluated the activation status of CD4+ and CD8+ cells. Methods We evaluated 366 women with RPL defined as 2 or more pregnancy losses and 93 control women. We defined the immune profile as the presence of 2 or more of the following abnormalities: Peripheral blood NK cell percentages >15%, positive antiphospholipid antibodies, positive antinuclear antibodies, positive anti-thyroid antibodies, low complement C3 levels and low C4 complement levels. Evolution to autoimmune diseases was detected during follow-up. Lymphocyte subsets were evaluated by flow-cytometry. Statistics: Chi-square test. Logistic regression. Results The prevalence of women with 2 or more immunological abnormalities was 57 out of 366 women (15.6%) and was significantly higher than in control women. Demographic clinical characteristics were similar in women with 2 or more immunological abnormalities as compared with women with only one immunological alteration or no abnormalities. The presence of the immunological profile was significantly associated with the presence of the following clinical characteristics: Leucopenia (p=0.048), lymphopenia (p=0.007), livedo reticularis (p=0.01), cutaneous rash (p=0.009), and arthritis (p=0.001). During follow-up 17 patients (4.6%) developed an inflammatory or autoimmune disease that was not present at the time of the diagnose of RPL including SLE and lupus like disease. Women with the immunological profile were at higher risk for evolution into these diseases: OR 4.19, 95% confidence interval 1.52–11.51, p=0.0055. In 10 women with the immunological profile we observed significantly higher levels of CD4+DR+ and CD8+DR+ T-cells as compared with women without the immune profile. Conclusions A subgroup of women with unexplained RPL are at risk of developing clinical characteristics of an inflammatory or autoimmune disease. In this regard, the immunological evaluation of women with RPL might be necessary not only to identify a potential cause of abortion but also to identify women that could require a more careful clinical follow-up. Higher CD4+DR+ and CD8+DR+ T-cells might be a pathogenic pathway leading to development of autoimmune diseases in RPL women. References Viallard JF, Bloch-Michel C, Neau-Cransac M, Taupin JL, Garrigue S, Miossec V, Mercie P, Pellegrin JL, Moreau JF. HLA-DR expression on lymphocyte subsets as a marker of disease activity in patients with systemic lupus erythematosus. Clin Exp Immunol. 2001;125(3):485–91. CD8+DR+ T-Cells and C3 Complement Serum Concentration as Potential Biomarkers in Thrombotic Antiphospholipid Syndrome. Sarmiento E, Dale J, Arraya M, Gallego A, Lanio N, Navarro J, Carbone J. Autoimmune Dis. 2014. Acknowledgements Research Funds. Fundacion Salud 2000. Madrid Spain. Disclosure of Interest None declared

[Abstract] BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG

Purpose The IgG antibody response against polysaccharide microbial antigens is enriched for IgG2 antibodies, which possess characteristics that are likely to enhance opsonisation of these antigens. IgG2 molecules are more effective than other IgG subclasses in opsonising antigens with a high epitope density. Lower IgG2 concentration has been found to be a risk factor of death after community acquired pneumonia. Infection is still a major cause of death during the first year after heart transplantation. In this study we evaluated the prevalence of IgG2 insufficiency in heart recipients before transplantation and its relationship with the risk for development of severe deadly infections. Methods 119 patients evaluated in a single center were included. Prospective follow-up was performed to identify the clinical outcomes: early deadly infections during the first month and deadly infections during the follow-up after transplantation. In this study using the Binding Site nephelometry test, IgG2 insufficiency was defined as IgG2 levels below 2.72 mg/dL. Results In the pre-transplant evaluation 46 (38.7%) patients were found to have IgG2 insufficiency. Early deadly infections were more prevalent among patients with IgG2 insufficiency (RH 2.68, 95% CI 1.10-6.53, p=0.029). Use of mechanical ventilation, pre-transplant infections and pre transplant use of ventricular assist devices were risk factors of early deadly infections. In multivariate regression analysis IgG2 insufficiency remained in the model (RH 4.18, 95% CI 1.20-14.47, p=0.024). IgG2 insuficiency was also a risk factor of deadly infections (RH 4.27, 95% CI 1.37-13.26, p=0.012) and a risk factor of 1-year all-cause mortality (RH 2.68, 95% CI 1.10-6.53, p=0.029). Conclusion Pre-transplant IgG2 insufficiency is a risk factor of bad outcome after transplantation. This immunological biomarker warrants evaluation in a multicenter study.

We evaluated the potential role of serum B-cell activating factor (BAFF) as a biomarker in HIV infection and analyzed the relationship between BAFF concentration and the immunophenotypic activation status of T-cells. We tested the hypothesis that higher serum BAFF concentrations are associated with risk for development of AIDS in HIV positive individuals. Forty-one HIV patients (CDC category A 17, category B 24) were evaluated retrospectively. Serum BAFF concentrations were assessed using a commercial enzyme-linked immunosorbent assay. Cox regression was used to estimate the probability for development of AIDS. Patients with higher BAFF concentrations (2100 pg/mL) were at greater risk of developing AIDS (relative hazard 5.69; p = 0.0033). BAFF levels were independently associated with risk of AIDS after adjustment by clinical risk factors. Serum BAFF was correlated with activated T-cell subsets and with neopterin levels. BAFF is a good candidate for further evaluation as a nonspecific surrogate marker in HIV infection.

Despite advances in anti-microbial prophylaxis, infection continues to be one of the most important barriers for long-term survival in solid organ transplantation. According to the 2013 report of the International Society for Heart and Lung Transplantation Registry, infections were the main cause of death in heart recipients between 1 month and 1 year after transplantation 1. Heart recipients who develop an infection before post-transplantation discharge have a higher risk of death at 5 years even if they survive the first year 1. Methods to identify heart recipients at risk of infection could allow physicians to make targeted adjustments to immunosuppressive strategy and prophylaxis aimed at decreasing patient morbidity 2. Biomarkers for the identification of transplant recipients at risk of infection must be validated clinically in large prospective multi-centre studies using standardized measurement techniques and evaluation methods. Immunoglobulin (Ig)G hypogammaglobulinaemia was investigated as a risk factor for infection in heart recipients by Avery and collaborators at the Cleveland Clinic in retrospective single-centre studies 3. We have confirmed these findings in prospective single-centre studies evaluating the role of IgG hypogammaglobulinaemia as a risk factor of severe infection in heart recipients who received non-cytolytic induction therapy with anti-CD25 monoclonal antibodies 4,5. In a recent prospective multi-centre national study, we assessed the usefulness of a panel of humoral immunity biomarkers in 267 heart recipients in Spain 6. Our study confirmed that monitoring IgG and distinct humoral immunity profiles (for example, combining IgG and C3 determinations) after transplantation can help to identify a subgroup of patients at greater risk of infection. Transplant recipients with moderate IgG hypogammaglobulinaemia and C3 hypocomplementaemia 1 month after transplantation were at greater risk of infection. In this study, most infections occurred during the first 3 months post-transplantation 6, suggesting that identification and management of risk factors would be most effective early after transplantation. The role of IgG hypogammaglobulinaemia as a risk factor for infection has also been confirmed in a recently published meta-analysis by Florescu and collaborators 7. In this study, severe IgG hypogammaglobulinaemia (defined as IgG 400 mg/dl. Opportunities for designing prevention trials that target the management of risk factors for infection in solid organ transplantation should be explored fully. In clinical trials, the use of biomarkers may allow close monitoring of response to treatment and also enable the selection of patients most likely to respond to specific therapies. An important aspect of IgG hypogammaglobulinaemia is that it is a risk factor that can be managed by replacing infusions of intravenous immunoglobulin (IVIg). The Cleveland Clinic group observed that prophylactic administration of specific anti-CMV IVIg in heart recipients with moderate hypogammaglobulinaemia (IgG

Background: Off-label use of intravenous immunoglobulin has been reported for the treatment of recurrent spontaneous pregnancy loss and selected cases of multiple sclerosis. However, the use of subcutaneous immunoglobulin has not been reported in these settings. Methods and results: We report on tolerability and clinical efficacy of subcutaneous immunoglobulin therapy in a woman with the unusual association of IgG4 subclass deficiency, C4 hypocomplementemia, localized scleroderma, unexplained spontaneous pregnancy loss and multiple sclerosis. Weekly infusions of subcutaneous immunoglobulin were self-administered at home (6 grams/week, Hizentra®) during the next pregnancy after abortion. Interferon beta-1a for the treatment of relapsing-remitting multiple sclerosis was stopped before pregnancy. During pregnancy only subcutaneous immunoglobulin was administered. The patient was found to have 4% of CD3+CD16/CD56+ (Natural Killer (NK) /T cells). The patient delivered a healthy baby (Apgar score 9 at 5 minutes) at 37 weeks gestation. During pregnancy and 3 months follow-up after delivery no multiple sclerosis flare-ups were observed. NK-T cell percentages remained stable. Conclusions: Our observation indicates that subcutaneous immunoglobulin therapy was well tolerated and efficacious in a selected case of unexplained abortion and multiple sclerosis.

The analysis of proliferative responses using 5,6-carboxyfluorescein diacetate succinimidyl ester (CFSE) in flow cytometry is widely used to assess lymphocyte function. The aim of this study was to evaluate nonspecific and specific lymphoproliferative responses using CFSE in heart recipients before and after transplantation and their association with the development of infection. We used four-color flow cytometry to measure the response of peripheral CD3+, CD4+, and CD8+ T cells to phytohemagglutinin mitogen (PHA), tetanus toxoid, hepatitis B, and influenza vaccines using a CFSE proliferation assay in 12 heart recipients and 8 healthy control subjects. Recipients were prospectively evaluated. Immunological studies were performed before and at 3 months after transplantation. A 12-month clinical follow-up examination sought to detect the prevalence of severe infectious complications. Heart recipients (infected [n = 7] and uninfected [n = 5]) disclosed significantly lower percentages of proliferative responses than healthy controls against PHA at both study points. Baseline CD3+, CD4+, and CD8+, antitetanus proliferative responses were significantly lower in infected heart recipients than controls. Patients who developed infections displayed significantly lower percentages of CD3+CFSE and CD8+CFSE cells to PHA mitogen at 3 months after transplantation versus those without infections. In conclusion, nonspecific T-cell reactivity to PHA was lower in heart recipients with posttransplantation infections.

Background Infection remains a source of mortality in heart recipients. We previously reported that post-transplant immunoglobulin G (IgG) quantification can help identify the risk for infection. We assessed whether other standardized parameters of humoral and cellular immunity could prove useful when identifying patients at risk of infection. Methods We prospectively studied 133 heart recipients over a 12-month period. Forty-eight patients had at least one episode of severe infection. An event was defined as an infection requiring intravenous antimicrobial therapy. Results Cox regression analysis revealed an association between the risk of developing infection and the following: lower IgG2 subclass levels (day 7: relative hazard [RH] 1.71; day 30: RH 1.76), lower IgA levels (day 7: RH 1.61; day 30: RH 1.91), lower complement C3 values (day 7: RH 1.25), lower CD3 absolute counts (day 30: RH 1.10), lower absolute natural killer [NK] cell count (day 7: RH 1.24), and lower IgG concentrations (day 7: RH 1.31; day 30: RH 1.36). Cox regression bivariate analysis revealed that lower day 7 C3 levels, IgG2 concentration, and absolute NK cell count remained significant after adjustment for total IgG levels. Conclusions Data suggest that early immune monitoring including C3, IgG2, and NK cell testing in addition to IgG concentrations is useful when attempting to identify the risk of infection in heart transplant recipients.

Human cytomegalovirus (CMV) active infection (CMV infection) poses serious risks to CMV-seropositive heart transplant recipients. We evaluated the usefulness of simultaneous assessment of CMV-specific values for parameters of the humoral (antibodies) and cellular (CD4+ and CD8+ T-cells) immune responses in the identification of heart recipients at risk of developing CMV infection after transplantation. We prospectively studied 38 CMV-seropositive heart recipients. Anti-CMV antibody titers were assessed using enzyme-linked immunosorbent assays. CD4+ and CD8+ T-cell responses to overlapping peptide pools of the CMV proteins pp65 and immediate early protein-1 (IE1) were evaluated by flow cytometry. Immunological studies were performed before transplantation and at 30 days after transplantation. Patients with CMV infection were compared with heart recipients without CMV infection. During the 6-month follow-up period, 13 (34.2%) patients developed CMV infection. At baseline, the mean anti-CMV-IgG antibody titer was lower in patients who developed CMV infection. This difference remained at 30 days after transplantation. One month after transplantation, the mean percentage of IE1-specific CD8+ T cells that are IFNg-positive (CD8/IFNg + IE1) was lower in CMV-infected patients. The predictive value of these variables at 30 days was increased when they were combined. Cox regression analysis revealed an association between the risk of developing CMV infection and the combination marker (low anti-CMV titer [

Immunoglobulin G (IgG) hypogammaglobulinemia (HGG) is a risk factor for development of severe infections after heart transplantation. We performed a clinical trial to preliminarily evaluate the efficacy and safety of early administration of intravenous immunoglobulin (IVIG) for prevention of severe infection in heart recipients with post-transplant IgG HGG.Twelve heart recipients with IgG HGG detected in a screening phase of the clinical trial (IgG500 mg/dL) were recruited. Patients received IVIG (Flebogamma 5%), as follows: 2 doses of 200 mg/kg followed by up to 5 additional doses of 300 mg/kg to maintain IgG750 mg/dL. IgG and specific antibody titers to distinct microorganisms were tested during follow-up. The primary outcome measure was development of severe infection during the study period. Data on the primary outcome were matched with those of 13 recipients with post-transplant HGG who were not included in the clinical trial and with those of 11 recipients who did not develop HGG during the same study period.Mean time to detection of HGG was 15 days. IgG and specific antibody reconstitution (anti-cytomegalovirus, anti-Haemophilus influenza, and anti-hepatitis B surface antigen antibodies) was observed in IVIG-treated patients. Severe infection was detected in 3 of 12 (25%) IVIG-treated recipients, in 10 of 13 (77%) HGG non-IVIG patients, and in 2 of 11 (18%) non-HGG patients (log-rank, 15.31; P=.0005). No severe IVIG-related side effects were recorded.Data from this study demonstrate that prophylactic IVIG replacement therapy safely modulates HGG and specific antimicrobial antibodies. Our data also preliminarily suggest that IVIG replacement therapy might decrease the incidence of severe infection in heart recipients with HGG.

Immunosuppressive and biologic therapies are costly and can involve a considerable risk of infection. Noninvasive diagnostic tools for early prediction of infection before and after administration of these therapies are of major interest. Serial longitudinal immune monitoring would provide data on immunocompetence and complement clinical follow-up protocols. Biomarkers of immune response may be useful to identify patients at risk of developing infection and who could be candidates for immunosuppressant dose reduction. This article focuses on the potential use of biomarkers of immune response to predict development of infection after immunosuppressive and biologic therapies in selected settings of autoimmune disease (rituximab for treatment of rheumatoid arthritis) and solid organ transplantation.

Secondary antibody deficiency has been associated with risk of invasive fungal infections in solid organ transplantation. Single center, multicenter and metanalysis studies have tested this association. Therapy of these infectious complications in the presence of a secondary antibody deficiency after transplantation remain a challenge for transplant teams. Currently, there are no guidelines for the management of this combined clinical scenario. We report the case of a patient with severe secondary immunodeficiency before and after heart transplantation who developed several infectious complications including cardiac invasive aspergillosis who had a long-term survival after combination therapy of antimicrobial drugs and prolonged intravenous immunoglobulin replacement therapy.

Tumor necrosis factor (TNF)-alpha inhibitors (infliximab, adalimumab, and etanercept) used in immune-mediated inflammatory diseases such as rheumatoid arthritis, Crohn's disease, or psoriatic arthritis have the potential to increase the risk of infectious complications. Pulmonary infections are one of the most frequent complications associated with the use of TNF inhibitors. This article provides an overview of the distinct types of infectious pulmonary complications seen in patients using these anticytokine drugs.

Objetive.Few studies have assessed immunophenotypic abnormalities on lymphocyte subsets in patients with antiphospholipid syndrome (APS). We performed an extended immunological study to define alterations of distinct T, B, and natural killer (NK) cell subsets in obstetric patients with APS and their relationship with APS–associated complications.Methods.Patients and controls: 36 women with APS [Sydney criteria, Group A1 without thrombosis (n = 26), Group A2 with thrombosis (n = 10)]; and 36 age matched women with recurrent abortion without antiphospholipid antibodies (disease controls; Group B), 36 healthy parous women (healthy controls; Group C), and 36 healthy nonparous women (healthy controls; Group D). Thrombotic events occurred after history of abortions in all A2 women. Three-color whole-blood flow cytometry was used to characterize the distinct immunophenotypes.Results.A1 patients had significantly higher percentages of CD4+CD45RA–CCR7+ central memory cells (A1 vs D), higher percentages of activated CD4+CD25+ T cells (A1 vs D), and lower percentages and absolute counts of CD4+CD45RA–CCR7– effector memory cells (A1 vs D). GroupA2 patients had higher percentages and absolute numbers of CD19+CD27–IgD+ naive B cells (A2 vs A1 vs all controls), lower percentages and absolute numbers of CD3–CD56+CD16+ NK cells (A2 vs all controls), and higher percentages of activated CD4+DR+ (A2 vs all controls), CD8+DR+ (A2 vs A1 vs C vs D), CD4+CD38+DR+ (A2 vs D), and CD4+CD25+DR+ T cells (A2 vs all controls). Increased percentages of CD8+DR+ T cells [relative risk (RR) 2.43, 95% CI 1.09–5.44, p = 0.02] and of naive B cells (RR 3.05, 95% CI 1.30–7.11, p = 0.009) were associated with development of thrombosis.Conclusion.In obstetric patients with APS we documented significant changes in T, B, and NK cell homeostasis. Increased levels of CD8+DR+ and CD19+CD27–IgD+ cells might identify obstetric patients with APS at risk of having thrombosis.

Infections are relevant complications that cause morbidity in solid organ transplantation and autoimmune diseases. Infection represents a leading single cause of death in these patients. Identification of patients at risk for development of infections and specific intervention to decrease infection risk might lead to better outcomes, though one needs first to evaluate the presence of risk factors for infection. Underlying disease itself, activity of the disease, presence of co-morbidities, transplantation procedures along with immunosuppressive and immunomodulatory therapies may be associated with an increased risk of infections. Among host factors, there are no reliable immunological markers to predict infections. Immune monitoring (assessment of immunocompetence) to estimate the risk of infection has so far not been performed routinely, with the only exception of neutrophil counts, tuberculin skin testing and serological evaluation of donor and recipients of transplants for anti-cytomegalovirus IgG antibodies. However, alterations of specific and non specific humoral and cellular immunity may be associated with a higher risk of infection among immunosuppressed patients. We review studies that have been designed to assess immune monitoring for prediction of infections in patients with selected solid organ transplantations and systemic autoimmune diseases.

We performed a retrospective cross-sectional study to ascertain the prevalence of immunological abnormalities in women with recurrent spontaneous abortions (RSA). The women had previously undergone karyotyping of the couple and ultrasonography to investigate anatomic uterine anomalies before immunological study. Routine immunologic monitoring for circulating antiphospholipid antibodies (aPL, n=333) [anticardiolipin antibodies (aCL), lupus anticoagulant (LA)], antibeta-2 glycoprotein-I antibodies (n=139), antinuclear antibodies (n=333), antithyroid antibodies (n=180) and percentages of natural killer (NK) cells in peripheral blood (n=189) was carried out in 333 consecutive patients with two or more (range 2-12) RSA. aPL positivity (mean-high value aCL or LA) was 15.9%. The frequency of positive antinuclear antibody tests at a titer of 1:160 or higher was 6%. Elevated levels of CD56+/CD16+CD3 2 lymphocytes (>18%) were observed in 11.1% of the patients studied. Anti-thyroid antibody positivity was found in 4% of women. Overall, 28.5% of women had at least one immunological abnormality. Women with RSA had significant autoimmune and alloimmune alterations involving functionally distinct autoantibodies and peripheral blood NK cells.

Hypogammaglobulinemia has been proposed to be a risk factor for infection after heart transplantation (OHT). Infection is a leading cause of morbility and mortality among these patients. In a retrospective study we analyzed the impact of substitutive therapy with nonspecific intravenous immunoglobulin (IVIG) on the outcomes of heart transplant patients with infections. We analyzed the outcome of 123 consecutive heart transplant recipients in our center from June 1996 to November 2005. Their mean age was 53 years (range = 22 to 69 years), and the mean follow-up = 51 months, (range = 1 to 124 months). Twenty-nine patients with hypogammaglobulinemia (mean serum immunoglobulin G levels = 480 mg/dL) experienced severe infections due to cytomegalovirus (CMV) disease, n = 4; CMV disease + another infection, n = 6; CMV infection, n = 4; CMV infection + other infection, n = 3; pulmonary nocardiosis, n = 2; recurrent pneumonia, n = 2; clostridium-difficile-associated diarrhea, n = 2; pulmonary tuberculosis, n = 1; bacterial infections, n = 5. They were treated with IVIG (400 mg/kg every 21 days) with the goal to reach normal serum immunoglobulin G levels (>700 mg/dL). Overall (n = 123), a logistic regression analysis showed IVIG therapy to be associated with a decreased risk of death [odds ratio (OR) = 0.204, 95% confidence interval (CI) = 0.04 to 0.92, P = .03]. Among patients who developed infections during follow-up (n = 70), IVIG therapy was also associated with a lower risk of death (OR = 0.104, CI = 0.02 to 0.50, P = .0047). When we stratified patients with CMV disease (n = 24) according to the presence (n = 10) or absence (n = 14) of IVIG therapy, the mortality rate of IVIG-treated patients was 20% versus 71% for non-IVIG treated patients [OR = 0.06, CI = 0.0060 to 0.63, P = .01]. The use of nonspecific IVIG in OHT with hypogammaglobulinemia and infections might reduce the risk of death. Randomized studies in a larger cohort of patients are necessary to confirm these results.

Although severe infectious complications are rare, it is important to properly screen patients for predisposing conditions before beginning treatment with infliximab. We assessed immunity markers that might provide prognostic value for the development of infection in Crohn's disease patients after treatment with infliximab. In a prospective study, 34 fistulizing Crohn's disease patients (mean age 37 years) were studied. Patients were scheduled to receive three infusions of infliximab (5 mg/kg) at weeks 0, 2, and 6. Immunologic studies: Serum immunoglobulin (IgG, IgA, IgM), IgG-subclasses, and complement (C3, C4, factor B) determined by nephelometry; CD3+, CD3+CD4+, CD3+CD8+, CD19+, and CD56+CD3- lymphocyte subsets performed by flow cytometry. During a mean follow-up of 56 months, 1 patient had disseminated tuberculosis and 2 patients had severe bacterial infections. The presence of infection was associated with significantly higher IgM (246 vs. 121 mg/dL; Mann-Whitney test, P = 0.01), lower C3 (64 vs. 118, P = 0.02), lower C4 concentrations (12 vs. 25, P = 0.02), and with decreased levels of CD19 B cells (47 vs. 290, P = 0.03) in the baseline study. Further prospective studies in a larger number of patients are suggested to examine whether early monitoring of immunocompetence might help to identify the risk of infection in patients treated with infliximab.