Elizabeth Sarmiento

IgG monitoring to identify the risk for development of infection in heart transplant recipients.

Abstract: Infectious complication represents a significant source of morbidity and mortality in heart transplant recipients. To assess humoral immunity markers that can predict the development of infection, 38 consecutive recipients of heart transplants performed at a single center were prospectively studied. Induction therapy included daclizumab. Immunoglobulin (IgG, IgA, IgM) and complement factors (C3, C4, and factor B) were performed by nephelometry in peripheral blood samples obtained before transplantation, and 7 days and 1 month after transplantation. During a mean follow‐up of 16.9 months, 13 patients had at least one episode of infection (34.2%). Eight of these were cytomegalovirus (CMV) infections treated with intravenous ganciclovir, 2 were bacterial pneumonia, 1 patient had bacterial septicemia, 1 patient had urinary tract infection, and 1 patient had pulmonary nocardiosis. No significant association was found between infection and age, sex, immunosuppression, CMV serostatus of donor and recipient, or treated rejection episodes. Pre‐transplant IgG (below median value=1140 mg/dL; relative risk [RR] 3.69; 95% confidence interval [CI] 1.01–13.54; P=0.04) and post‐transplant IgG levels at day 7 (below median value=679 mg/dL; RR 11.21; CI 1.04–89.48; P=0.022) were associated with an increase in the risk for developing infections. Early monitoring of immunoglobulin levels might help to identify the risk for developing infection in heart transplantation.

Partial response to anti-CD20 monoclonal antibody treatment of severe immune thrombocytopenic purpura in a patient with common variable immunodeficiency.

Abstract: Immune thrombocytopenic purpura (ITP), alone or in combination with autoimmune hemolytic anemia (Evans syndrome) and/or autoimmune neutropenia, is frequent in patients with common variable immunodeficiency (CVID). A 34‐year‐old man with CVID had long‐standing unresponsive ITP. The patient had a 9‐year history of CVID on substitutive therapy with intravenous immunoglobulin (IVIG). The clinical course of CVID was complicated with refractory fistulizing inflammatory bowel disease, nodular regenerative hyperplasia of the liver, splenomegaly, severe portal hypertension, and hypercatabolism of IgG. ITP was refractory to medical therapy, including different combinations of corticosteroids, high‐dose IVIG, azathioprine, and vincristine. Splenectomy was not performed because of severe portal hypertension. He received a total five doses of rituximab, a monoclonal antibody directed against CD20 antigen, at a dose of 375 mg/m2. After an initially slow response, his platelet count increased to more than 50,000/μL by the fourth week of infusion. Therapy was well tolerated, and B lymphocytes were effectively depleted from the peripheral blood. The patient was completely tapered off glucocorticoids and maintained platelets at above 40,000/μL. The patient has not taken immunosuppressive agents for 11 months. Early treatment with rituximab might be an option for patients with CVID and ITP that do not respond to other treatments or for patients for whom a splenectomy is contraindicated.

Immunological risk factors for infection after immunosuppressive and biologic therapies

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.

Humoral and cellular immune monitoring might be useful to identify liver transplant recipients at risk for development of infection

Abstract: Orthotopic liver transplantation (OLT) is a successful therapy for patients with end‐stage liver disease, and infection remains a significant cause of morbidity and mortality for patients undergoing this procedure. To assess humoral and cellular immunity markers as potential risk factors for development of infection, 46 consecutive liver transplant recipients (hepatitis C virus cirrhosis [n=17], alcoholic liver disease [n=15], hepatocellular carcinoma [n=9], autoimmune hepatitis [n=2], and other [n=3]) performed at a single center were prospectively studied. Maintenance therapy included tacrolimus (n=37) or cyclosporine (n=9) and prednisone. During follow‐up, 27 patients had at least 1 episode of infection (58.7%). Pre‐OLT immunoglobulin G (IgG) hypergammaglobulinemia (relative risk [RR] 2.78; 95% confidence interval [CI], 1.17–6.60, P=0.02), pre‐OLT IgA hypergammaglobulinemia (RR 2.77, CI=1.24–6.19, P=0.012), and pre‐OLT C3 hypocomplementemia (RR 3.02, CI=1.21–7.55, P=0.018) were associated with an increased risk for development of infection. Monitoring of Ig and complement levels might help to identify the risk of developing infection in OLT.

Quantitative Abnormalities of Peripheral Blood Distinct T, B, and Natural Killer Cell Subsets and Clinical Findings in Obstetric Antiphospholipid Syndrome

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.

Immune monitoring of anti cytomegalovirus antibodies and risk of cytomegalovirus disease in heart transplantation.

We sought to determine whether quantitative assessment of anti-cytomegalovirus (CMV) antibodies could be useful to identify patients at risk of cytomegalovirus (CMV) disease after heart transplantation (HT). 75 patients who underwent HT at a single health care center were prospectively studied. Induction therapy included 2 doses of daclizumab and maintenance tacrolimus (n=42) or cyclosporine (n=29), mycophenolate mofetil and prednisone. All patients received prophylaxis with gancyclovir or valganciclovir. Anti-CMV intravenous immunoglobulin (CMV-IG) was added in high risk patients (CMV D+/R- serostatus). Serial determinations of anti-CMV antibodies, immunoglobulins (IgG, IgA, IgM) and IgG-subclasses were analysed. CMV infection was based on detection of the virus by antigenemia. CMV disease consisted of detection of signs or symptoms attributable to this microorganism. Ten patients (13.3%) developed CMV disease. Mean time of development of CMV disease was 3.4+/-1.6 months. In Cox regression analysis, patients with low baseline anti-CMV titers (<4.26 natural logarithm of titer, RH: 8.1, 95%CI: 1.93-34.1, p=0.004) and recipients with 1-month post-HT IgG hypogammaglobulinemia (IgG<500 mg/dl, RH: 4.49, 95%CI: 1.26-15.94, p=0.02) were at higher risk of having CMV disease. Despite use of prophylactic CMV-IG, D+/R- patients showed significantly lower titers of anti-CMV antibodies at 7 d, 30 d and 90 d post HT as compared with HT recipients without infections. Four out of 6 of these patients developed late CMV disease. Monitoring of specific anti-CMV antibodies on the bedside warrants further evaluation as a potential tool to identify heart transplant recipients at higher risk of CMV disease.

Restoration of humoral immunity after intravenous immunoglobulin replacement therapy in heart recipients with post-transplant antibody deficiency and severe infections

IgG hypogammaglobulinemia is a risk factor for infection in heart recipients. We assessed reconstitution of humoral immunity after non‐specific intravenous immunoglobulin (IVIg) replacement therapy administered to treat secondary IgG hypogammaglobulinemia in heart recipients with severe infections. The study population comprised 55 heart recipients who were administered IVIg (IVIg group) and 55 heart recipients with no severe infectious complications (control group). An event was defined as a severe infection requiring intravenous drug therapy during the first year after transplantation. The IVIg protocol comprised non‐specific 5% pasteurized IVIg at a dose of 300–400 mg/kg/months. IgG titers were lower in the IVIg group than in controls at seven d (577 vs. 778 mg/dL, p < 0.001) and at one month (553 vs. 684, p = 0.003). After IVIg therapy, IgG concentrations were similar in both groups at three months (681 vs. 737, p = 0.25) and at six months (736 vs. 769, p = 0.46). At three months, the IVIg group had higher levels of antitetanus toxoid and anti‐HBs (ELISA, 2.07 ± 2.11 vs. 0.60 ± 1.24 mg/dL [p = 0.003] and 42 ± 40 vs. 11 ± 31 IU/mL [p = 0.005], respectively) than controls. The mean number of infectious complications was significantly lower after IVIG therapy in the IVIG group. IVIg was associated with restoration of humoral immunity in heart recipients with post‐transplant IgG hypogammaglobulinemia and severe infections.

Immunophenotypic profile of T cells in common variable immunodeficiency: is there an association with different clinical findings?

BACKGROUND A system based on the B-cell phenotype has recently been proposed to classify patients suffering from common variable immunodeficiency (CVID). Immunophenotypic T-cell abnormalities have also been correlated with clinical findings, although they have never been used in classification strategies. OBJECTIVE To simultaneously assess T and B-cell subset abnormalities in CVID patients and their relationship with clinical findings. To identify potential immunophenotypic T-cell abnormalities that could be further evaluated in multicenter studies. PATIENTS AND METHODS Peripheral blood lymphocytes from 21 CVID patients and 21 healthy donors were stained for T and B-cell subsets, analyzed by flow cytometry, and correlated with clinical characteristics. RESULTS Patients classified as MB0 (CD19/CD27+ < 11 %) showed higher percentages of CD4/ CD45RA (87 % vs 67 %, p = 0.028) and lower percentages of CD8/CD45RA+CCR7+ (10 % vs 26 %, p = 0.028) and CD4/CD25+ T-cells (36 % vs 62 %, p = 0.034) than MB2 patients. Even though our cohort was small, we observed a higher prevalence of distinct clinical complications of CVID in patients with B and T-cell abnormalities. Nonmalignant lymphoproliferative disorders and IgG hypercatabolism were more frequently observed in MB0 patients. A higher prevalence of splenomegaly was observed among CVID patients with increased levels of CD4/CD45RA, activated CD4/CD38+DR+, CD8/DR+, and CD8/CD38+ T-cells, as well as in those with lower percentages of CD4/CD45RA+CCR7+ and CD4/CD25+ T-cells. Lymphoproliferative disorders were more prevalent among CVID patients with higher CD4/CD45RA percentages. CONCLUSION The study of T-cell subsets warrants further evaluation as a potential tool to better identify CVID patients with distinct clinical profiles.

Evaluation of an immunological score to assess the risk of severe infection in heart recipients

We previously reported how specific humoral and cellular immunological markers that are readily available in clinical practice can be used to identify heart transplant recipients (HTR) at risk of developing severe infections. In this study, we perform an extended analysis to identify immunological profiles that could prove to be superior to individual markers in assessing the risk of infection early after heart transplantation.

Decreased levels of serum complement C3 and natural killer cells add to the predictive value of total immunoglobulin G for severe infection in heart transplant recipients

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.