Thawed plasma (TP) as a substitute for intravenous immune globulin (IVIG) to prevent hypogammaglobulinemia post-therapeutic plasma exchange.

Intravenous immune globulin (IVIG) is a common treatment given after plasma exchange procedures to either prevent secondary hypogammaglobulinemia or as an adjunctive treatment for organ transplant rejection. However, side-effects are relatively common with this medication during and after infusion. This case-report describes our alternative to IVIG infusions post-plasma exchange. We hypothesize that in patients unable to tolerate IVIG, using thawed plasma as a replacement fluid provides a suitable increase in the patients post procedure immunoglobulin G (IgG) levels for patients with secondary hypogammaglobulinemia that are unable to tolerate IVIG infusions.

The Expanding Field of Secondary Antibody Deficiency: Causes, Diagnosis, and Management.

Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.

A national survey of screening and management of hypogammaglobulinemia in Canadian transplantation centers.

BACKGROUND: Infection remains one of the most common transplant-related causes of death in patients undergoing transplantation. Secondary hypogammaglobulinemia (HGG) as a component of immune suppression and deficiency is associated with both solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT). Available data and clinical experience for the supplementation of immunoglobulin (Ig) in these patients is conflicting, and differing clinical opinion accounts for non-uniform practice in the use of Ig treatment. We aimed to survey lead transplant practitioners for current practice around polyvalent Ig use in post-transplant recipients across Canada. METHODS: We performed a survey study using short questionnaires to estimate rate of screening of HGG, use of polyvalent Ig, and physician's opinion on Ig treatment and infection prevention. Directors of 24 SOT and 23 HCT centers across Canada were invited to participate in the survey via an electronic mail. RESULTS: Overall response rate was 63.8%. Twenty percent of SOT programs routinely measured Ig levels pre-transplant compared to 33% of allogeneic (allo-) and 21% of autologous (auto-) HCT programs. Post-transplant Ig levels were measured in 13%, 75%, and 29% in SOT, allo-HCT, and auto-HCT, respectively. The SOT and auto-HCT groups indicated that they do not prescribe Ig therapy (100% and 86%), contrary to the allo-HCT group (42%). Of the respondents in the SOT, allo-HCT, and auto-HCT groups, 60%, 67%, and 36%, respectively, thought infections could be prevented with intravenous immunoglobulins (IVIg). A majority of respondents indicated they would be interested in participating in a randomized controlled trial evaluating the use of IVIg in the SOT and in both HCT groups (100%, 83%, and 57%, respectively). CONCLUSIONS: Our study shows significant variation in practice between SOT and HCT centers with respect to screening and management of HGG. There is willingness to participate in a randomized controlled trial to address whether Ig treatment reduces infection in post-transplant recipients.

Clinical outcomes of immunoglobulin use in solid organ transplant recipients: protocol for a systematic review and meta-analysis.

BACKGROUND: Transplantation improves survival and the quality of life of patients with end-stage organ failure. Infection, due to surgical issues, host factors such as diabetes, immunosuppression, and hypogammaglobulinemia, is a major post-transplant complication. Clinical outcomes of prophylaxis or treatment of hypogammaglobulinemia in solid organ transplant recipients are not well established and are in need of further study. METHODS/DESIGN: We will conduct a systematic review of studies investigating clinically relevant outcomes of immunoglobulin use either as prophylaxis or treatment of hypogammaglobulinemia after solid organ transplantation. Both randomized and non-randomized studies (excluding case reports and case series of less than 20 subjects) will be included. Outcomes of interest will include the overall rate of infection, hospital admission, hospital length of stay, intensive care unit admission, 1-year all-cause mortality, incidence of acute organ rejection, allograft survival within 1 year, and adverse events. We will search MEDLINE, Embase, the Cochrane Central Register of Controlled Trials, Transplant library, and the International Clinical Trials Registry Platform for randomized and non-randomized studies on adult solid organ transplant patients who received prophylactic immunoglobulin or immunoglobulin treatment. Two reviewers will conduct all screening and data collection independently. We will assess study level of risk of bias using the Cochrane Risk of Bias Assessment Tool for randomized controlled trials and for non-randomized studies. If meta-analysis of outcome data is deemed appropriate, we will use random effects models to combine data for continuous and dichotomous measures. DISCUSSION: The results of this systematic review may inform guideline development for measuring immunoglobulin level and use of immunoglobulin in solid organ transplant patients and highlight areas for further research. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42015017620.

Potential role of post-transplant hypogammaglobulinemia in the risk of Clostridium difficile infection after kidney transplantation: a case-control study.

PURPOSE: To identify reversible risk factors for Clostridium difficile infection (CDI) after kidney transplantation (KT) that could lead to a reduction in its incidence and associated complications. METHODS: We performed a single-center case-control study in which 41 patients undergoing KT between February 2009 and July 2013 who developed a first episode of post-transplant CDI were included as cases. Patients transplanted at the same calendar day (± 2 weeks) as each case with no evidence of CDI and comparable risk exposure period were chosen as controls (2:1 ratio). Serum immunoglobulin and complement levels were systematically measured at baseline and months 1 and 6 after transplantation. RESULTS: Multivariate regression analysis identified age-adjusted Charlson comorbidity index (odds ratio [OR] per unitary increment 1.31; P value = 0.043), delayed graft function (OR 2.76; P value = 0.039), prior cytomegalovirus (CMV) disease (OR 6.85; P value = 0.011) and prior acute graft rejection (OR 5.92; P value = 0.008) as risk factors for post-transplant CDI. Cases with their first episode of CDI occurring beyond the first month were more likely to have IgG hypogammaglobulinemia (HGG) at month 1 (P value = 0.002), whereas cases with CDI beyond the sixth month were more likely to have HGG of any class at month 6 (P value = 0.003). Poor outcome (graft loss and/or all-cause mortality) was more common among cases (adjusted hazard ratio 5.69; P value = 0.001). CONCLUSION: The occurrence of CDI exerts a detrimental effect on graft and patient outcome. Post-transplant HGG was a potentially modifiable risk factor for CDI in KT recipients.

Retrospective analysis of weekly intravenous immunoglobulin prophylaxis versus intravenous immunoglobulin by IgG level monitoring in hematopoietic stem cell transplant recipients.

Patients undergoing allogeneic hematopoietic stem cell transplant (allo HCT) have a higher incidence of infections partly due to secondary hypogammaglobulinemia. We evaluated the role of IVIG in allo HCT patients who received prophylactic IVIG 200 mg/kg once weekly regardless of IgG level (Group 1, n = 115) compared with patients who received IVIG based on IgG level <400 mg/dL (Group 2, n = 114). Primary endpoints were the utilization of IVIG, incidence of veno-occlusive disease (VOD), graft-versus-host disease (GVHD), and documented infections within the first 100 days after allo HCT. Patients in both groups were similar except for a higher number of matched unrelated donor (MUD) transplants in Group 2 (62 vs. 41, P = 0.01). There were no significant differences in the incidence all grades of GVHD (55 vs. 50), VOD (2 vs. 0) or infections in the two groups except for a higher incidence of para-influenza infections in group 1 (9 vs. 0, P = 0.003) coinciding with the flu season. We recommend monthly monitoring of IgG level and replacement only if IgG level is <400 mg/dL.

Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies.

Primary immunodeficiency disease (PIDD) associated with hypogammaglobulinemia is typically treated with immunoglobulin replacement therapy. When administered as intravenous immunoglobulin (IVIG), an IgG trough occurs prior to the next replacement dose. While frequently measured, IgG trough levels required to minimize infection risk are not established. To address this question, all available studies evaluating trough IgG and pneumonia incidence in PIDD patients with hypogammaglobulinemia receiving IVIG were quantitatively combined by meta-analysis. Seventeen studies with 676 total patients and 2,127 patient-years of follow-up were included. Pneumonia incidence declined by 27% with each 100mg/dL increment in trough IgG (incidence rate ratio, 0.726; 95% confidence interval, 0.658-0.801). Pneumonia incidence with maintenance of 500 mg/dL IgG trough levels (0.113 cases per patient-year) was 5-fold that with 1000 mg/dL (0.023 cases per patient-year). This meta-analysis provides evidence that pneumonia risk can be progressively reduced by higher trough IgG levels up to at least 1000 mg/dL.

Immunoglobulin prophylaxis in hematological malignancies and hematopoietic stem cell transplantation.

BACKGROUND: Patients undergoing hematopoietic stem cell transplantation (HSCT) and those with lymphoproliferative disorders (LPD) have a higher incidence of infections due to secondary hypogammaglobulinemia. One approach is the prophylactic administration of intravenous immunoglobulins (IVIG). Randomized controlled trials (RCTs) showed conflicting results in terms of type, schedule, dose and hematological patients benefiting from IVIG. We therefore performed a systematic review and meta-analysis to evaluate the role of IVIG in these patients. OBJECTIVES: To determine whether prophylaxis with IVIG reduces mortality or affects other outcomes in patients with hematological malignancies. SEARCH STRATEGY: PubMed (January 1966 to December 2007), CENTRAL (The Cochrane Library, up to 2007, issue 1), LILACS and conference proceedings published between 2002-2007 were searched. The terms "immunoglobulins" or "gammaglobulins" or specific gammaglobulins and similar and the terms "hematologic neoplasms" or "hematologic malignancies" or "transplant" or "autotransplant" or "allotransplant" or "bone marrow transplant" or "peripheral stem cell transplant" and similar were selected. References of all included trials and reviews identified were scanned for additional trials. SELECTION CRITERIA: All RCTs comparing prophylaxis of IVIG with placebo, no treatment or another immunoglobulin preparation, different administration schedules or doses for patients with hematological malignancies were included. One author screened all abstracts identified through the search strategy and two reviewers independently inspected each reference identified by the search and applied inclusion criteria. DATA COLLECTION AND ANALYSIS: For each trial, results were expressed as relative risks (RR) with 95% confidence intervals (CI) for dichotomous data and weighted mean differences for continuous data. We conducted meta-analysis, where enough similar trials were available, using the fixed- effects model, unless significant heterogeneity was present. We performed sensitivity analyses to assess the effect of individual methodological quality measures on effect estimates, including allocation generation, concealment and blinding. MAIN RESULTS: Forty trials were included: thirty included HSCT patients and ten included patients LPD. When polyvalent immunoglobulins or hyperimmune cytomegalovirus (CMV)-IVIG was compared to control for HSCT, there was no difference in all-cause mortality. Polyvalent immunoglobulins significantly reduced the risk for interstitial pneumonitis but increased the risk for veno-occlusive disease and adverse events. In LPD, no benefit in terms of mortality IVIG could be demonstrated but there was a decrease in clinically and microbiologically documented infections. AUTHORS' CONCLUSIONS: In patients undergoing HSCT, routine prophylaxis with IVIG is not supported. Its use may be considered in LPD patients with hypogammaglobulinemia and recurrent infections, for reduction of clinically documented infections.

The effectiveness of intravenous human immunoglobulin treatment after plasmapheresis in restoring serum immunoglobulin levels: a preliminary study.

This study was performed to examine the effects of intravenous human immunoglobulin (IVIG) on the level of serum immunoglobulin G (IgG) and its subclasses after plasmapheresis in patients with autoimmune disorders. Twenty-nine patients with predominantly rheumatoid arthritis were enrolled in this study. The plasmapheresis was performed by the use of double-filtration plasmapheresis (DFPP). Immediately after DFPP, IVIG (2.5 g, 50 ml) was intravenously administered. The treatment with IVIG had almost no effect on subjective and objective symptoms. Immediately after DFPP, the total of serum IgG was decreased by approximately 40%. After 24 h, the total of serum IgG recovered to 16% reduction in IVIG-treated patients whereas it remained at 32% reduction in nontreated patients. The beneficial effect of IVIG was significantly observed in patients who had shown 1,000-1,800 mg/dl IgG in their sera. After DFPP, IgG subclasses were decreased without change in the ratio of subclasses. Twenty percent to 30% of IgG subclasses were supplemented by the treatment with IVIG without change in the ratio of subclasses. These results suggested that the treatment with IVIG at minimal amount was safe and effective to supplement IgG for hypogammaglobulinemia after DFPP.

Inmunizaciones e inmunocomprometidos / Immunizations and immnunocompromised

Este artículo es una revisión de los lineamientos para la vacunación de niños que padecen inmunodeficiencia. No obstante que los pacientes con algún grado de inmunocompromiso se benefician con la aplicación de vacunas, existe un desconocimiento sobre su inmunización. Es muy frecuente que estos niños carezcan de vacunas que los protegerían de enfermedades endémicas. El especialista que se dedica a la atención médica de pacientes con inmunodeficiencias congénitas o las secundarias a cáncer, insuficiencia renal e infección debe valorar la conveniencia de inmunizarlo. Cuando se sospecha inmunodeficiencia están contraindicadas las vacunas de virus o bacterias vivas, hasta que se elabore un diagnóstico de certeza. En general se considera que los pacientes con alteraciones en la función inmune tiene una menor respuesta a la aplicación de las vacunas. La respuesta inmunológica es compleja y requiere la integración de todos los componentes del sistema inmune incluyendo células presentadoras de antígeno, células B y células T. Una regla general aceptada es que la vacunación con microorganismos muertos y toxoides posee poco riesgo de enfermedad, mientras que las vacunas de bacterias y virus vivos están contraindicadas. Sin embargo, estas generalizaciones son muy amplias ya que cada paciente con inmunodeficiencia requiere valorarse en forma individual. Diferentes patologías afectan funciones inmunes e incluso grupos de pacientes con un mismo diagnóstico pueden encontrarse en diferentes estadios clínicos y con diferentes niveles de inmunosupresión. El propósito de este trabajo es proponer esquemas de vacunación para niños con agammaglobulinemia, inmunodeficiencia secundaria a infección por el VIH, terapia con esteroides, asplenia, cáncer e insuficiencia renal

Infection and immunity in chronic lymphocytic leukemia.

Patients having chronic lymphocytic leukemia (CLL) are at increased risk for infectious morbidity and mortality. The predisposition to infections in CLL patients has many components, including both immunodeficiency related to the leukemia itself (humoral and cellular immune dysfunction) and the results of cumulative immunosuppression related to CLL treatment. The risk of infectious complications increases with the duration of CLL, reflecting the natural history of the disease and the cumulative immunosuppression related to its treatment. Hence, in early, untreated CLL, the infectious risk is mainly related to hypogammaglobulinemia, and infections by encapsulated bacteria are common. However, in patients having advanced CLL, particularly those who receive the newer purine analogues, neutropenia and defects in cell-mediated immunity appear to be the major predisposing factors. An expanded spectrum of pathogens, including opportunistic fungi, Pneumocystis carinii, Listeria monocytogenes, mycobacteria, and herpesviruses, are seen in that setting. The changing spectrum of infections in this latter group of patients mandates a newer approach to prophylaxis and therapy.