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.

Utility of oligoclonal IgG band detection for MS diagnosis in daily clinical practice.

An early and accurate diagnosis of multiple sclerosis (MS) is very important, since it allows early treatment initiation, which reduces the activity of the disease. Oligoclonal IgG band (OCGB) detection is a good ancillary tool for MS diagnosis. However, it was argued that its usefulness was limited by the high interlaboratory variability. In the last years, different techniques for OCGB detection have appeared. We performed a blinded aleatorized multicenter study in 19 Spanish hospitals to assess the accuracy and reproducibility of OCGB detection in this new scenario. We studied cerebrospinal fluid (CSF) and serum samples from 114 neurological patients. Every hospital contributed to the study with triplicated pairs of CSF and serum samples of six patients and analyzed 18 different samples. Global analysis rendered a sensitivity of 92.1%, a specificity of 95.1% and a Kappa value of 0.81. This shows that current techniques for OCGB detection have good accuracy and a high interlaboratory reproducibility and thus, represent a good tool for MS diagnosis. When we analyzed separately the different techniques used for OCGB detection, the highest concordance was observed in western blot with alkaline phosphatase detection (kappa=0.91). This indicates that high sensitivity techniques improve the reproducibility of this assay.

Humoral and cellular monitoring to predict the development of infection in Crohn's disease patients beginning treatment with infliximab.

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.

Hypocomplementemia in the absence of autoantibodies in women with recurrent pregnancy loss.

BACKGROUND: Accumulating data suggest an immunopathogenic role for the complement system as a causative element in pregnancy loss (PL). Formation of pathogenic antibodies with activation of the classical pathway may have a role, but this mechanism fails to characterize the majority of cases with recurrent PL. We established the prevalence of hypocomplementemia without circulating autoantibodies in women with recurrent PL. METHODS: In a retrospective case control study, 201 women with recurrent PL (two or more PL) and 30 healthy women who had normal pregnancies but no PL were studied. Serum levels of C3, C4, and factor B were determined by nephelometry. Total hemolytic activity of the complement system (CH100) was investigated by radial immunodiffusion test. RESULTS: The prevalence of hypocomplementemia [low levels of C3, C4, FB or CH100 (with normal concentrations of C3, C4 and FB)] was significantly higher in women with recurrent PL (22.4%) in comparison with controls (6.6%; p = 0.019). C3, C4, FB hypocomplementemia or low CH100 were observed in 13 (6.5%), 19 (9.4%), 13 (6.5%) and 7 (3.5%) women with recurrent PL, respectively. Among patients with C3, C4, FB or CH100 hypocomplementemia, 10, 18, 12 and 5 patients had no circulating autoantibodies [antinuclear antibodies, anticardiolipin antibodies or antithyroid antibodies], respectively. In all, hypocomplementemia, in the absence of autoantibodies, was observed in 38 (18.9%) women with recurrent PL in a significantly higher frequency than controls (n = 2, p = 0.049). CONCLUSIONS: Hypocomplementemia, in the absence of autoantibodies was observed in a group of women with recurrent PL which might suggest a role of the complement system in the pathogenesis of PL in these patients.

[Systemic autoimmune disease in patients with uveitis]. / Enfermedad autoinmune sistémica en pacientes con uveítis.

OBJECTIVE: A descriptive study was conducted on patients with uveitis to determine the frequency of associated autoimmune systemic diseases. METHODS: 64 patients with uveitis were studied. The patients were not known to have an underlying autoimmune systemic disease prior to the diagnosis of uveitis. All patients had the following immunological tests performed: serum immunoglobulins, complement components, circulating immune complexes (CIC), antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA), anti-cardiolipin antibodies (ACA) and major histocompatibilty complex antigens. RESULTS: A relationship with a sub-clinical autoimmune systemic disorder could be presumed in eleven cases (17.2%). This was defined by positive autoantibodies (ANA, ANCA or ACA) in the presence of complement consumption, hyper-gammaglobulinemia or increased CIC without clinical criteria of a defined autoimmune disease. A definite association with systemic autoimmune disease was defined in four patients (6.25%). The observed autoimmune systemic diseases were Sjögren's syndrome (n=2, 3.13%), anti-phospholipid syndrome associated with lupus-like disease (n=1, 1.6%), and systemic vasculitis (n=1, 1.6%). Lupus-like disease (n=4, 6.25%) was also observed. CONCLUSION: In a significant proportion of patients with uveitis an autoimmune systemic disorder may be present and should be looked for.

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

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.

Enfermedad autoinmune sistémica en pacientes con uveítis / Systemic autoimmune disease in patients with uveitis

Objetivo: La realización de un estudio descriptivoen pacientes con uveítis para establecer la frecuenciade enfermedad autoimmune sistémica asociada.Métodos: Se incluyeron en el estudio 64 pacientescon uveítis. Ninguno de los pacientes estudiadostenia una enfermedad autoinmune sistémica conocidaantes del diagnóstico de uveítis. A todos lospacientes se les realizó un protocolo diagnósticoque incluyó las siguientes pruebas inmunológicas:inmunoglobulinas séricas, factores del complemento,inmunocomplejos circulantes (ICC), anticuerposantinucleares (ANA), anticuerpos anticitoplasma deneutrófilos (ANCA), anticuerpos anticardiolipina(ACA) y antígenos del complejo mayor de histocompatibilidad.Resultados: En once casos (17,2%) se objetivóasociación con un proceso autoinmune subclínicocaracterizado por la positividad de autoanticuerpos(ANA, ANCA o ACA) en presencia de consumo decomplemento, hipergammaglobulinemia o ICC elevados, sin que los pacientes cumpliesen criteriosclínicos de una enfermedad autoinmune. Se encontróuna asociación definitiva con enfermedadautoimmune sistémica en cuatro pacientes (6,25%).Las enfermedades autoinmunes observadas fueronel síndrome de Sjögren (n=2, 3,13%), síndromeantifosfolípido asociado a enfermedad lupus like(n=1, 1,6%) y vasculitis sistémica (n=1, 1,6%).También se observó un grupo de pacientes conenfermedad lupus like (n=4, 6,25%).Conclusión: En una proporción de pacientes conuveítis puede existir un proceso autoimmune sistémicosubyacente

Objective: A descriptive study was conducted on patients with uveitis to determine the frequency of associated autoimmune systemic diseases. Methods: 64 patients with uveitis were studied. The patients were not known to have an underlying autoimmune systemic disease prior to the diagnosis of uveitis. All patients had the following immunological tests performed: serum immunoglobulins, complement components, circulating immune complexes (CIC), antinuclear antibodies (ANA), antineutrophil cytoplasmic antibodies (ANCA), anticardiolipin antibodies (ACA) and major histocompatibilty complex antigens. Results: A relationship with a sub-clinical autoimmune systemic disorder could be presumed in eleven cases (17.2%). This was defined by positive autoantibodies (ANA, ANCA or ACA) in the presence of complement consumption, hyper-gammaglobulinemia or increased CIC without clinical criteria of a defined autoimmune disease. A definite association with systemic autoimmune disease was defined in four patients (6.25%). The observed autoimmune systemic diseases were Sjögren’s syndrome (n=2, 3.13%), anti-phospholipid syndrome associated with lupus-like disease (n=1, 1.6%), and systemic vasculitis (n=1, 1.6%). Lupus-like disease (n=4, 6.25%) was also observed. Conclusion: In a significant proportion of patients with uveitis an autoimmune systemic disorder may be present and should be looked for

Discordance between anti-beta2-glycoprotein-I and anti-cardiolipin antibodies in patients with clinical criteria of antiphospholipid syndrome.

OBJECTIVES: Clinical and immunological features of patients with clinical manifestations of the antiphospholipid syndrome (APS) with anti-beta2-glycoprotein-I antibodies (anti-beta2-GP-I) but without anticardiolipin antibodies (aCL) or any other autoimmune condition are not well documented. We sought to determine the clinical significance of positive anti-beta2-GP-I with negative aCL. METHODS: From July 2002 through July 2003, 1,179 serum samples obtained in our hospital from the Community of Madrid were tested for anti-beta2-GP-I and aCL by enzyme-linked immunosorbent assay. Clinical records of patients with discordant anti-beta2-GP-I and aCL were retrospectively analysed. RESULTS: A total of 56 patients with discordant anti-beta2-GP-I and aCL were identified. By logistic regression analysis, after adjusting for age, sex and risk factors of thrombosis, the risk for developing APS criteria associated with anti-beta2-GP-I was significant [odds ratio 3.88; 95% confidence interval (CI): 1.05-14.27; p = 0.04). 15 out of 56 patients (26.8%) had positive anti-beta2-GP-I and negative aCL. 5 out of 15 anti-beta2-GP-I-positive patients had clinical APS without serological nor clinical evidence of any autoimmune disease. CONCLUSION: Determination of anti-beta2-GP-I should be considered in individual cases with clinical manifestations of primary APS and repeated negative results on conventional antiphospholipid antibody test.

Hypogammaglobulinemia after heart transplantation: use of intravenous immunoglobulin replacement therapy in relapsing CMV disease.

Secondary hypogammaglobulinemia after heart transplantation may follow immunosuppressive therapy with the resultant increased risk of infections, including cytomegalovirus (CMV) disease. There is limited information on the use of intravenous immunoglobulin replacement therapy (IVIG) in heart-transplanted patients with hypogammaglobulinemia and CMV disease. We present data on five consecutive heart-transplanted patients with relapsing CMV disease, four of whom developed gastrointestinal disease. The immunosuppressive regimen included prednisone, cyclosporine A, azathioprine, mycophenolate mofetil, tacrolimus and antithymocyte globulin (ATG). Evaluation revealed CMV antigenemia. All the patients had been treated with intravenous ganciclovir. In addition, hyperimmune CMV immunoglobulin was administered in three patients. Significantly reduced levels of immunoglobulin G (IgG) were observed in the patients as compared with 15 heart-transplanted individuals without CMV disease [mean IgG levels: 323+/-18 and 639+/-63 mg/dl, respectively (p=0.003)]. IVIG [FLEBOGAMMA], 200-400 mg/kg every 21 days with the goal of maintaining normal serum IgG levels, was added for the treatment of CMV disease. Selected batches with the highest anti-CMV titers were set apart for the treatment of the patients. IVIG treatment, in combination with antiviral therapy, proved able to control CMV disease. There was a favorable clinical response and the patients became free of gastrointestinal symptoms. Detection of CMV antigens was negative after treatment. During IVIG therapy no immediate or delayed adverse effects were observed. Even if our survey was limited to five cases, the results suggest that addition of IVIG to antiviral chemotherapy might improve outcome in heart-transplanted patients with hypogammaglobulinemia and CMV disease.

[Atypical presentation of common variable immunodeficiency without infections]. / Presentación atípica de inmunodeficiencia variable común sin clínica infecciosa.

BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency disease, the hallmark of which is hypogammaglobulinemia and poor specific antibody responses. Patients usually have recurrent bacterial infections, but there are a number of other comorbid disorders, including autoimmune disease and neoplasms. Most patients are diagnosed as adults, and delay in identifying the antibody defect is common. In the present report, we illustrate atypical initial presentation without infections in CVID. CLINICAL OBSERVATION: In 5 out of 30 patients with CVID (16.6 %) diagnosed in our hospital in the Autonomous Community of Madrid, the first manifestation of immunodeficiency was not an infection. Three patients presented with immune cytopenias (thrombocytopenic purpura [n = 2] and hemolytic anemia [n = 1]); one patient had pernicious anemia and one patient had insulin-dependent diabetes as the first clinical feature of CVID. Four patients had IgG levels below 400 mg/dl. CONCLUSIONS: Atypical presentations of CVID must be recognized to prevent delayed diagnosis. Presentation of CVID as an autoimmune disease in the absence of recurrent infections prompts us to suggest baseline testing of immunoglobulin levels in patients presenting with autoimmune disorders.

B cell function after haploidentical in utero bone marrow transplantation in a patient with severe combined immunodeficiency.

An in utero paternal CD34(+) cell transplant was performed in a T-B+NK+ SCID fetus. We report here the results of the 3-year humoral immune reconstitution study. The methods used were ApoB VNTR typing, flow cytometry, nephelometry, hemagglutination, ELISA, ELISPOT and lymphoproliferative assays. The T cells were of donor origin whereas monocytes, B and NK cells were of host origin. Peripheral B cell counts and IgM levels were normal since birth. IVIG therapy was required at 5 months of age until 2 years old. IgA levels > or =20 mg/dl were detected from month 17 post transplantation. Isohemagglutinins were present since month 8 post transplantation, the highest titers (anti-A:1/128, anti-B:1/32) were obtained at month 33 post-transplantation. After immunization with rHBsAg, circulating anti-HBsAg IgG secreting cells and a 7.8-fold increase in serum anti-HBsAg Ab were detected. We conclude that split chimerism following in utero haploidentical BMT allows complete humoral immune reconstitution in a T-B+NK+ SCID patient.

Antiphospholipid antibodies: a risk factor for occlusive retinal vascular disorders. Comparison with ocular inflammatory diseases.

OBJECTIVE: To evaluate the prevalence of antiphospholipid antibodies (aPL) together with immunological characteristics of patients with occlusive retinal vascular disorders (ORVD) with and without risk factors (systemic arterial hypertension, diabetes mellitus, hyperlipidemia, and embolizing cardiac disease) for retinal occlusions compared to patients with ocular inflammatory diseases (OID) and healthy controls. METHODS: Sixty-eight patients with ORVD, 45 patients with OID, and 49 healthy persons were prospectively studied. Serologic studies included determination of anticardiolipin antibodies, lupus anticoagulant, antinuclear antibodies (ANA), levels of complement 4 and 3, total hemolytic complement (CH100), and circulating immune complexes (CIC). RESULTS: Elevated levels of aPL were detected in 16 (24%) patients with ORVD compared to 4 (9%) patients with OID (OR 3.15, p < 0.05) and 4 (8%) controls (OR 3.46, p < 0.05). No significant differences were seen in the prevalence of aPL comparing risk factor-positive patients with ORVD (8 of 33, 24%) to risk factor-free patients with ORVD (8 of 35, 23%). A higher frequency of positive ANA, elevated IgA, and increased CIC were detected in aPL positive patients with ORVD compared to patients with OID. CONCLUSION: Detection of aPL in patients with ORVD may help determine which patients are eligible for prophylactic treatment. An immunologic profile characterized by high prevalence of ANA, CIC, and elevated IgA distinguishes ORVD patients with aPL from inflammatory ophthalmologic disorders.