Immunoglobulin Infusion Research Articles

Common variable immunodeficiency (CVI): case report

The CVI is the second most common primary immunodeficiency. The prevalence of CIV in the world is approximately 1:25,000. The age of presentation of ICV has peaks in the first decade if life and the beginning of the third decade. Both sexes are affected. Diagnostic criteria according to ESID/PAGID are: - recurrent infections; -age more 4 years; -reduced levels of IgG; decrease of IgA and/or IgM; exclusion of the other causes of hypogammaglobulinemia; - no isohemaglutininas and response to the vaccine. Five clinical phenotypes are described: only infections, autoimmunity, polyclonal lymphocytic infiltration, malignancy and enteropathy. The treatament of patients with CVI is performed with the use of an infusion of immunoglobulin.

Humoral Immunity and Plasma Cell Changes in Patients Responding to CD19-Specific Chimeric Antigen Receptor (CAR)-Modified T-Cell Adoptive Immunotherapy

Introduction: T cells engineered to express chimeric antigen receptors (CARs) recognizing CD19 (CART19) can eliminate malignant cells in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). We and other groups have shown that persistent tumor eradication by CD19-specific T cell immunotherapy is accompanied by normal B-cell aplasia. It is assumed that responding patients cannot make new antibody responses post-successful CART19 treatment; however, the status of previously established humoral immunity in these patients is currently unknown. Understanding the consequence of successful CART19 therapy on established humoral immunity has implications for both the clinical management of CART19-treated patients as well as the potential application of this therapy to non-malignant diseases such as autoimmunity and transplantation.Methods: We performed a prospective, observational study of adult and pediatric patients with ALL and adults with relapsed/refractory CLL, who were enrolled in clinical trials of CART19 at our institution. Serum antibody titers to previously-generated vaccine or vaccine-related pathogens (Streptococcus pneumoniae, Tetanus toxoid, Hemophilus influenza type-B (HIB), Measles, Mumps, and Rubella) were determined along with a quantitative assessment of B-cell and plasma cell frequencies in blood and bone marrow aspirates. Specimens were collected during pre-established study assessments or additional time points when collected as required for clinical management. Due to the challenges of assessing plasma cells, multiple methods were employed for their quantification in fresh specimens including flow cytometry and immunohistochemistry (IHC). Flow cytometric assessment of plasma cells was performed on freshly obtained marrow samples. Only patients with at least 3 months of B-cell aplasia in the absence of regular intravenous immunoglobulin (IVIg) infusions were included in the study.Results: All patients had no evidence of leukemia or peripheral B cells post-CART19 infusion at the time of this study. Compared to pre-CART19 serum titers, antibodies to S. pneumoniae remained stable or increased in 9 of 12 patients despite lack of circulating B-cells. Antibody titers to Tetanus toxoid were stable or increased in 13 of 14 patients. Anti-HIB levels were stable or increased in 9 of 11 patients and antibodies to Measles, Mumps and Rubella were stable or increased in 12 of 13, 11 of 13, and 12 of 13 patients, respectively. Flow cytometric analysis of bone marrow aspirates after CART19 infusion revealed three patients with persistence of CD38+ CD138+ plasma cells (at 1, 3 and 9 months post infusion, respectively) despite a complete absence of peripheral CD19+ B cells. In 9 patients, CD20 and CD138 IHC analysis of bone marrow core biopsies revealed a decrease in plasma cell (ranges: 1-5% pre-CART19, 0-<1% post-CART19), consistent with our previously published data. Finally, in another subset of patients, neither B cells nor plasma cells were detectable by flow cytometry of aspirate material or IHC of core biopsies collected either pre- or post-CART19 treatment.Conclusions: The stable or increased titers of antibodies to previous vaccines are surprising and may, in part, reflect improved marrow function as a result of leukemia eradication. The demonstration of plasma cells in a subset of patients in the absence of detectable tumor or normal B cells provides strong evidence for the existence of a population of plasma cells that are resistant to lysis by CART19 cells. This is consistent with antibody titers to previously generated vaccine antigens, which remain stable despite effective CART19 treatment. The additional finding of a decrease in CD138+ cells in several patients by IHC suggests that some populations of plasma cells are either targeted directly by CART19 or have a short half-life (e.g. plasmablasts); CD138 is not sufficient to distinguish these populations. Overall, these results indicate that long-lived plasma cells are resistant to CART19, likely due to a loss of CD19 during plasma cell differentiation. Continued analysis of remaining plasma cells in the absence of ongoing B-cell maturation as a result of CART19 persistence may provide important information on turnover rates of these long-lived cells in humans. DisclosuresBhoj:Novartis: Research Funding. Milone:Novartis: Patents & Royalties, Research Funding. June:Novartis: Research Funding, Royalty income Patents & Royalties. Porter:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Lacey:Novartis: Research Funding. Mahnke:Novartis: Research Funding.

Robust Immune Reconstitution in Children with Severe Primary Immunodeficiency after Reduced-Intensity Conditioning Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for severe primary immunodeficiency diseases (PID), but it is still unclear what is the optimal transplant approach. To help answer this question, the stem cell transplant team at Ann & Robert H. Lurie Children’s Hospital of Chicago (formerly Children’s Memorial Hospital) evaluated the risks and benefits of a reduced-intensity conditioning (RIC) transplant approach for treatment of severe PID. Between 2000 and 2013, 42 children with severe PID were treated with allogeneic HSCT following a RIC regimen consisting of fludarabine (30mg/m2/day x 6), rabbit anti-thymocyte globulin (once daily x 4), and intravenous busulfan (once daily x 2). Total busulfan exposure, as measured by the plasma concentration-time area-under-the-curve (AUC), was targeted individually for each patient at 4000 µM*min/day in an earlier cohort (n=14), and 5000 in a later cohort (n=28). Patients were treated in an ambulatory setting and were hospitalized only for specific medical or social reasons. There were 31 male and 11 female patients. The median age at the time of transplant was 8.2 months (range 1 month-17.4 years). The median weight was 7.6 kg (range 2.5-81.5 kg). Patients were diagnosed with severe combined immunodeficiency (n=17), Wiscott-Aldrich syndrome (n=7), hyper-IgM syndrome (n=5), major histocompatibility complex II deficiency (n=3), X-linked lymphoproliferative disease (n=3), NEMO syndrome (n=2), Omenn syndrome, reticular dysgenesis, Chediak-Higashi syndrome, IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, and IPEX-like syndrome (n=1 each). Fourteen patients had related donors and 28 had unrelated donors. Twenty-eight patients received peripheral blood HSC, 12 received cord blood, and 2 received bone marrow as the source of HSC. All patients tolerated the conditioning regimen with minimal nausea, vomiting, or pain. No severe mucositis, sinusoidal occlusion syndrome, seizure, grade III/IV acute GVHD or extensive chronic GVHD were seen. In most patients, the engraftment was rapid, with ANC ≥ 500 at a median of +15 days post-transplant, following a nadir at day +10 with a median ANC nadir of 60. In the AUC 4000 cohort, 2 patients (14%) developed primary graft failure and 2 patients (14%) developed immune-mediated secondary graft failure; in the AUC 5000 cohort, 2 patient (7%) developed primary graft failure and 1 patient developed secondary graft failure after primary EBV infection. Two patients died from complications associated with primary graft failure, 2 from complications caused by EBV infections, and 2 from complications related to their underlying diseases in the early post-transplant period. Kaplan–Meier analysis shows overall and event-free survival rates of 81.9% and 73.6%, respectively, at a median follow-up of 4.3 years. Most engrafted patients have stable donor chimerism over time. At a mean of 3.5 years post-transplant, the median donor chimerism in total white blood cells was 97% and the first and third quartiles were 77% and 99%, respectively. Engrafted patients demonstrated robust immune reconstitution with B and T cell counts normalized by 3 months and 9 months post-transplant, and CD45RA+ naive T cells by 1 year. Between 1 to 4 years post-transplant, the median absolute CD4+, CD8+ and CD19+ cell counts were 1388, 976 and 720 per mm3, respectively, percentage of CD45RA+ naive CD4 and CD8 cells were 68% and 81%, and endogenous IgG and IgM levels were 840 and 97 mg/dL. T cells showed regular responses to antigen and mitogen stimulation and exhibited normal TCRVβ repertoires. Endogenous IgG levels returned to normal by day +100, and no intravenous immunoglobulin infusion was required after day +100 in all but 1 patients. Positive vaccine-specific antibody responses were seen in patients after reimmunization at 12-24 months post-transplant. Clinically, patients have normal growth and development and do not exhibit increased susceptibility to infection. Our data showed that HSCT after RIC offers an optimal treatment for severe PID by providing robust post-transplant immune reconstitution while minimizing side effects. To reduce the risk of graft failure, we recommend a targeted busulfan AUC of 5000 µM*min/day for 2 days. DisclosuresNo relevant conflicts of interest to declare.

Successfull Engraftment and Clearance of Donor Specific Antibodies after Haploidentical Related Stem Cell Transplantation for an Adult Patient with Sickle Cell Disease

Introduction: Sickle cell disease (SCD) is one of the most common genetic disorders in the world and despite advances in best supportive care it remains a disease with high risk of morbidity and mortality. Allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative treatment modality. Reports of adults are limited because of the lack of suitable matched donors and the high treatment related toxicity (TRT) after conventional myeloablative conditioning regimen resulting from the accumulated disease specific end organ damage. Initial reports of non myeloablative conditioning regimen showed disappointing results because of the high risk of graft failure (GF) and disease recurrence. Recently, the development of reduced toxicity conditioning regimen (RTC) with lower TRT and the use of haploidentical family donors has widened the applicability of alloHSCT. Since SCD patients (pt) are highly alloimmunosized, donor HLA-specific antibodies (DSA) are often detectable and might compromise engraftment in HLA mismatched transplants.Material and Methods: We report a twenty two year old male pt with severe sickle cell-ß thalassemia and chronic blood transfusion related alloimmunization who received a family donor bone marrow alloHSCT from his haploidentical father. To reduce the risk of graft rejection, the preparative regimen consisted in a prephase-conditioning sequential immunoablation using two courses of a four day immunosuppressive treatment with fludarabine 40 mg/m2/d and dexamethasone 40 mg/d, six and three weeks before the start of the RIT conditioning regimen consisting of antithymocyte globuline (ATG, rabbit) 1.5 mg/kg from days -12 to -10; thiotepa 5 mg/kg on day -9; fludarabine 40 mg/m2 and intravenous busulfan 100 mg/kg from days -6 to -3. Graft versus host disease (GVHD) prophylaxis was provided by posttransplantation cyclophosphamide 50 mg/kg on day +3 and +4; cyclosporine and mycofenolate mofetil were started at day +5. The transplant work-up program included routine HLA antibody screening and prophylactic desensitization treatment with Rituxan combined with high dose immunoglobulin infusions after each cycle of immunoablation; additionally, plasmapheresis were performed at day -13 and -1, as well as one cycle of red blood cell exchange before the start of the RIT. Disease response was weekly measured by HbS levels using hemoglobin electrophoresis. Chimerism studies were done monthly by peripheral blood isolated CD3+ cells PCR analysis of variable number of nucleotide tandem repeats. DSA were examined using the luminex-based single antigen assay and MFI>=1000 were considered positive.Results: The time to neutrophil recovery over 500 x 103/mm3 and platelet recovery over 50 x 103/mm3 were 29 and 43 days respectively; transfusion independency was reached at day +36. No GF occurred with predominantly donor mixed chimerism (82%) at last follow-up. HbS levels (baseline 68%) continuously decreased after the start of the preparative regimen to < 1% at day +77. DSA were substantially reduced after desensitization treatment and importantly dropped down further after alloHSCT to undetectable levels. Of note, no increase of DSA posttransplantation was observed. With a follow up of 140 days, the pt developed no GVHD or early TRT.Conclusions: We presume that our preparative regimen approach in association with posttransplantation cyclophosphamide provides sufficient T-cell depletion and tolerance induction to enhance durable donor engraftment. The presence of DSA should not be a barrier to HLA haploidentical related alloHSCT. DisclosuresNo relevant conflicts of interest to declare.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

Common variable immunodeficiency (CVID): new genetic insight and unanswered questions.

Kawasaki disease with Glucose-6-Phosphate Dehydrogenase deficiency, case report

Kawasaki disease (KD) is an acute, self-limited vasculitis of unknown etiology that occurs predominantly in infants and children younger than 5years of age. Coronary artery abnormalities are the most serious complication.Based on the literatures infusion of Intravenous Immunoglobulin of 2g/kg and a high dose of oral aspirin up to 100mg/kg/day are the standard treatment for Kawasaki disease in the acute stage, and should be followed by antiplatelet dose of aspirin for thrombocytosis. Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is an inherited X-linked hereditary disorder, and aspirin can induce hemolysis in patients with G6PD deficiency. We report a case of a 5year and 8month old male with KD and G6PD deficiency.

Transient neonatal liver disease after maternal antenatal intravenous Ig infusions in gestational alloimmune liver disease associated with neonatal haemochromatosis.

Neonatal haemochromatosis is a rare gestational disease that results in severe foetal liver disease with extrahepatic iron overload, sparing the reticuloendothelial system. Recurrence can be prevented with intravenous immunoglobulin (IVIG) infusions during pregnancy, supporting an alloimmune aetiology. The aim of the study was to assess the effect of antenatal treatment with IVIG infusion on the outcome of pregnancies in women with a history of documented neonatal haemochromatosis likely owing to gestational alloimmune disease and to analyse IVIG tolerance. From 2004 to 2012, 8 pregnant women were treated with IVIG at 1 g/kg body weight weekly from 18 weeks' gestation until birth in a prospective multicentre study. All 8 neonates born to the treated women survived. Five developed mild neonatal liver disease with hepatomegaly (n = 1), hyperechogenic liver (n = 2), abnormal liver function tests (n = 1), raised serum ferritin (n = 3) and α-fetoprotein (n = 5) levels, or mild iron overload on liver magnetic resonance imaging (n = 1). Ferritin and α-fetoprotein levels normalised before 14 days and 2 months, respectively. A per-mother-basis analysis comparing outcomes of treated (n = 8) and untreated (n = 9) gestations showed a significant improvement in the survival of neonates with gestational IVIG therapy (survival 8/8 vs 0/9, P < 0.001). Adverse effects of IVIG infusion occurred in 5 mothers leading to discontinuation of treatment in 1 case. Preterm neonates born before 37 weeks' gestation had a decreased risk of neonatal liver disease (P = 0.04). Antenatal treatment with IVIG infusion in women at risk for gestational alloimmune disease recurrence improves the outcome of pregnancies despite mild signs of transient neonatal liver disease.

Case report: Follow-up, diagnosis, clinical evidence, laboratory evaluation, and treatment of Idiopathic thrombocytopenia using human Intravenous Immunglobulin in a terrier dog

The aim of the present case report is to describe the outcome, hematological and biochemical changes of treatment of idiopathic thrombocytopenia in a Terrier dog using human intravenous immunglobulin. The complete blood count, serum biochemistry, indirect immunofluorescence antibody and direct coomb’s tests, radiography and sonography were performed. Laboratory findings indicated sever thrombocytopenia (<15×103/µl) and mild leukocytosis. Increase in the erythrocyte sedimentation rate and total protein concentration were last up to 19 and 14 days, respectively .After it, areduction was observed and no relapse was reported. This case report provides the first successful treatment and clinical evidence of a terrier dog with idiopathic thrombocytopenia in which no underlying etiology has been identified. It was concluded that human intravenous immunoglobulin infusion (1 g/kg) is a safe treatment with a significant increase in platelet count without increase in hospitalization and the cost of patient care.

P10.01 * PARANEOPLASTIC BRAINSTEM ENCEPHALITIS AS PRESENTING SYMPTOM OF MERKEL CELL CARCINOMA (MCC) FOLLOWED BY INTRACRANIAL AND LEPTOMENINGEAL DIFFUSION

CASE REPORT: A 52 years-old man was hospitalized for dizziness and dysarthria, followed by sleepiness, ataxia and dysphagia with forced rest in bed and need of parenteral nutrition. Neurological examination revealed bilateral lateral nystagmus, positive Romberg's sign, gait ataxia. Magnetic resonance imaging (MRI) of the brain was negative. Cerebrospinal fluid examination showed increased protein and normal count cells; PCR for neurotropic viruses was negative. Neoplastic markers and onconeuronal antibodies resulted negative. Findings on computed tomography of the chest and abdomen were normal. PET scan showed high metabolic activity in axillary and inguinocrural right lymph nodes. Excisional biopsy of the inguinal lymph node documented metastasis from a malignant neuroendocrine cutaneous neoplasia cromogranina A, CK 20 EMA and Synaptophysin positive. This profile was consistent with metastatic MCC. No skin lesions were detected. A diagnosis of paraneoplastic brainstem encephalitis was formulated: the patient was treated with intravenous infusion of immunoglobulins with partial benefit. The primitive neoplasm was treated with a combination therapy of Etoposide 100 mg/mq administered for three days and Cisplatin 75 mg/mq for one day in a 21-day-cycle. One month after the first cycle the patient recovered autonomous deambulation and normal feeding. About five months later the patient complained of dysarthria, dysphagia and ataxia. A brain MRI revealed a pineal lesion with contrast enhancement. Cerebrospinal fluid examination revealed 50 mononucleate cells per field, protein level of 47 mg/dl. Cytofluorimetric study of CSF showed 7% of CD45 negative cells, EMA (epithelial membrane antigen) positive cells consistent with leptomeningeal invasion. The patient deteriorated rapidly: he presented an epileptic seizure followed by coma and a few days after he deceased. Discussion and conclusion Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous neurondocrine tumor. Literature reports few cases of paraneoplastic complications and also CNS metastasis are rare. In this case report, the onset of neurological symptoms lead to a diagnosis of a MCC. A paraneoplastic disease was supposed because of normal neuroradiological and laboratory findings although onconeuronal antibodies were absent. The rapid clinical response to treatment (both intravenous immunoglobulins and chemotherapy) seemed to confirm that view. The relapse of symtoms was caused by intracranial and leptomeningeal localization with poor prognosis. In the case described the MCC reveals a high affinity for CNS, both indirectly (an immune response against neuronal proteins expressed by the tumor cells is supposed to be the cause of the paraneoplastic syndrome) and directly with neurometastatic progression. In our knowledge this is the first case described of MCC with this high tropism for CNS.

Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States.

Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100,000 births. To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia, and document early institution of effective treatments. Epidemiological and retrospective observational study. Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data, and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3,030,083 newborns screened with a TREC test. Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58,000 infants (95% CI, 1/46,000-1/80,000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87% (45/52), 92% (45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. Newborn screening in 11 programs in the United States identified SCID in 1 in 58,000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined.

Enhancing Patient Flexibility of Subcutaneous Immunoglobulin G Dosing: Pharmacokinetic Outcomes of Various Maintenance and Loading Regimens in the Treatment of Primary Immunodeficiency.

IntroductionStandard treatment for patients with primary immunodeficiency (PID) is monthly intravenous immunoglobulin (IVIG), or weekly/biweekly subcutaneous immunoglobulin (SCIG) infusion. We used population pharmacokinetic modeling to predict immunoglobulin G (IgG) exposure following a broad range of SCIG dosing regimens for initiation and maintenance therapy in patients with PID.MethodsSimulations of SCIG dosing were performed to predict IgG concentration–time profiles and exposure metrics [steady-state area under the IgG concentration–time curve (AUC), IgG peak concentration (C max), and IgG trough concentration (C min) ratios] for various infusion regimens.ResultsThe equivalent of a weekly SCIG maintenance dose administered one, two, three, five, or seven times per week, or biweekly produced overlapping steady-state concentration–time profiles and similar AUC, C max, and C min values [95% confidence interval (CI) for ratios was 0.98–1.03, 0.95–1.09, and 0.92–1.08, respectively]. Administration every 3 or 4 weeks resulted in higher peaks and lower troughs; the 95% CI of the AUC, C max, and C min ratios was 0.97–1.04, 1.07–1.26, and 0.86–0.95, respectively. IgG levels >7 g/L were reached within 1 week using a loading dose regimen in which the weekly maintenance dose was administered five times in the first week of treatment. In patients with very low endogenous IgG levels, administering 1.5 times the weekly maintenance dose five times in the first week of treatment resulted in a similar response.ConclusionsThe same total weekly SCIG dose can be administered at different intervals, from daily to biweekly, with minimal impact on serum IgG levels. Several SCIG loading regimens rapidly achieve adequate serum IgG levels in treatment-naïve patients.Electronic supplementary materialThe online version of this article (doi:10.1007/s13554-014-0018-0) contains supplementary material, which is available to authorized users.

Intraventricular human immunoglobulin distributes extensively but fails to modify amyloid in a mouse model of amyloid deposition.

Intravenous immunoglobulin infusions into Alzheimer patients have been found to provide cognitive benefit over a period of 6 mo in open label studies. One suggestion has been that these preparations contain small amounts of antibodies directed against monomeric and oligomeric Aβ which underlie their effectiveness in patients. To test this hypothesis, we infused Gammagard, a version of intravenous immunoglobulin (IVIG), into the lateral ventricle of amyloid precursor protein (APP) transgenic mice with pre-existing amyloid deposits. Mice were infused over 4 weeks, and tested behaviorally for the last 2 weeks of treatment. Brains were analyzed for histopathology. We found widespread distribution of human-immunoglobulin G (h-IgG) staining in the mouse forebrain, including cerebral cortices and hippocampus. Some cortical neurons appeared to concentrate the h-IgG, but we did not detect evidence of amyloid plaque labeling by h-IgG. The IVIG-treated mice had no change in phenotype compared to saline-infused animals with respect to activity, learning and memory, or amyloid deposition. APP mice infused with an anti-Aβ monoclonal antibody did show some reduction in amyloid deposits. These data do not support the argument that anti-Aβ antibodies in IVIG preparations are responsible for cognitive benefits seen with these preparations.

Antibody levels to tetanus, diphtheria, measles and varicella in patients with primary immunodeficiency undergoing intravenous immunoglobulin therapy: a prospective study.

BackgroundPatients with antibody deficiencies depend on the presence of a variety of antibody specificities in intravenous immunoglobulin (IVIG) to ensure continued protection against pathogens. Few studies have examined levels of antibodies to specific pathogens in IVIG preparations and little is known about the specific antibody levels in patients under regular IVIG treatment. The current study determined the range of antibodies to tetanus, diphtheria, measles and varicella in IVIG products and the levels of these antibodies in patients undergoing IVIG treatment.MethodsWe selected 21 patients with primary antibody deficiencies who were receiving regular therapy with IVIG. Over a period of one year, we collected four blood samples from each patient (every 3 months), immediately before immunoglobulin infusion. We also collected samples from the IVIG preparation the patients received the month prior to blood collection. Antibody levels to tetanus, diphtheria, measles and varicella virus were measured in plasma and IVIG samples. Total IgG levels were determined in plasma samples.ResultsAntibody levels to tetanus, diphtheria, varicella virus and measles showed considerable variation in different IVIG lots, but they were similar when compared between commercial preparations. All patients presented with protective levels of antibodies specific for tetanus, measles and varicella. Some patients had suboptimal diphtheria antibody levels. There was a significant correlation between serum and IVIG antibodies to all pathogens, except tetanus. There was a significant correlation between diphtheria and varicella antibodies with total IgG levels, but there was no significant correlation with antibodies to tetanus or measles.ConclusionsThe study confirmed the variation in specific antibody levels between batches of the same brand of IVIG. Apart from the most common infections to which these patients are susceptible, health care providers must be aware of other vaccine preventable diseases, which still exist globally.

Acute encephalopathy due to true hyponatremia and hyperammonemia after fast infusion of intravenous immunoglobulin

Acute encephalopathy due to true hyponatremia and hyperammonemia after fast infusion of intravenous immunoglobulin

Post-exposure passive immunisation for preventing measles.

Measles outbreaks continue to occur in countries with high vaccination coverage. Passive immunisation is generally considered to prevent measles in someone who is not immune and has been exposed to infection. Estimates of effectiveness have varied and no minimum effective dose has been determined. To assess the effectiveness and safety of intramuscular injection or intravenous infusion of immunoglobulins (passive immunisation) for preventing measles when administered to exposed susceptible people before the onset of symptoms. We searched CENTRAL (2013, Issue 7), MEDLINE (1946 to July week 5, 2013), CINAHL (1981 to August 2013) and EMBASE (1974 to August 2013). We included randomised controlled trials (RCTs), quasi-RCTs and prospective, controlled (cohort) studies if: participants were susceptible and exposed to measles, polyclonal immunoglobulins derived from human sera or plasma were administered intramuscularly or intravenously as the only intervention in at least one group and the number of subsequent measles cases was measured. We excluded studies of other sources of immunoglobulins. Two authors independently extracted data and critically appraised the included studies. We attempted to contact study authors for missing information. We described the results of studies not included in meta-analyses. We included one RCT, two quasi-RCTs and 10 cohort studies (3925 participants). No studies were rated as low risk of bias for all criteria. Critical appraisal was constrained by a lack of information in most studies. The overall quality of the evidence was moderate.Seven studies (1432 participants) assessed cases of measles after immunoglobulin versus no treatment. Heterogeneity was explained by subgrouping according to the blood product used as an approximation of dose of immunoglobulin. When given within seven days of exposure, immunoglobulins were effective at preventing measles: gamma globulin (risk ratio (RR) 0.17, 95% confidence interval (CI) 0.08 to 0.36), convalescent serum (RR 0.21, 95% CI 0.15 to 0.29 to RR 0.49, 95% CI 0.44 to 0.54) and adult serum (RR 0.52, 95% CI 0.45 to 0.59). The differences in the effectiveness of different blood products were supported by studies not included in the meta-analysis and by two studies (702 participants) that found gamma globulin more effective than serum (RR 0.56, 95% CI 0.46 to 0.69).Based on three studies (893 participants) immunoglobulin was effective at preventing death due to measles compared to no treatment (RR 0.24, 95% CI 0.13 to 0.44).Two studies included measles vaccine alone among the intervention groups. Meta-analysis could not be undertaken. Both studies suggested the vaccine was more effective than gamma globulin.No serious adverse events were observed in any of the included studies, although reporting of adverse events was poor overall. Non-serious adverse events included transient fever, rash, muscle stiffness, local redness and induration. Passive immunisation within seven days of exposure is effective at preventing measles, with the risk for non-immune people up to 83% less than if no treatment is given. Given an attack rate of 45 per 1000 (per the control group of the most recent included study), gamma globulin compared to no treatment has an absolute risk reduction (ARR) of 37 per 1000 and a number needed to treat to benefit (NNTB) of 27. Given an attack rate of 759 per 1000 (per the attack rate of the other included study assessing gamma globulin), the ARR of gamma globulin compared to no treatment is 629 and the NNTB is two.It seems the dose of immunoglobulin administered impacts on effectiveness. A minimum effective dose of measles-specific antibodies could not be identified.Passive immunisation is effective at preventing deaths from measles, reducing the risk by 76% compared to no treatment. Whether the benefits of passive immunisation vary among subgroups of non-immune exposed people could not be determined.Due to a paucity of evidence comparing vaccine to passive immunisation, no firm conclusions can be drawn regarding relative effectiveness.The included studies were not specifically designed to detect adverse events.Future research should consider the effectiveness of passive immunisation for preventing measles in high-risk populations such as pregnant women, immunocompromised people and infants. Further efforts should be made to determine the minimum effective dose of measles-specific antibodies for post-exposure prophylaxis and the relative effectiveness of vaccine compared to immunoglobulin.

Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients

Intravenous immunoglobulin replacement therapy represents the standard treatment for hypogammaglobulinemia secondary to B-cell lymphoproliferative disorders. Subcutaneous immunoglobulin infusion is an effective, safe and well-tolerated treatment approach in primary immunodeficiencies but no extensive data are available on their use in secondary hypogammaglobulinemia, a frequent phenomenon occurring after treatment with anti-CD20 monoclonal antibodies in lymphoproliferative disorders. In this retrospective study we evaluated efficacy (serum IgG trough levels, incidence of infections per year, need for antibiotics) and safety (number of adverse events) of intravenous (300 mg/kg/4 weeks) versus subcutaneous (75 mg/kg/week) immunoglobulin replacement therapy in 61 patients. In addition, the impact of the infusion methods on quality of life was compared. All patients were treated with subcutaneous immunoglobulin, and 33 out of them had been previously treated with intravenous immunoglobulin. Both treatments appeared to be effective in replacing Ig production deficiency and in reducing the incidence of infectious events and the need for antibiotics. Subcutaneous immunoglobulin obtained a superior benefit when compared to intravenous immunoglobulin achieving higher IgG trough levels, lower incidence of overall infection and need for antibiotics. The incidence of serious bacterial infections was similar with both infusion ways. As expected, a lower number of adverse events was registered with subcutaneous immunoglobulin, compared to intravenous immunoglobulin, with no serious adverse events. Finally, we observed an improvement in health-related quality of life parameters after the switch to subcutaneous immunoglobulin. Our results suggest that subcutaneous immunoglobulin is safe and effective in patients with hypogammaglobulinemia associated to lymphoproliferative disorders.

Infliximab for intensification of primary therapy for Kawasaki disease: a phase 3 randomised, double-blind, placebo-controlled trial

Kawasaki disease, the most common cause of acquired heart disease in developed countries, is a self-limited vasculitis that is treated with high doses of intravenous immunoglobulin. Resistance to intravenous immunoglobulin in Kawasaki disease increases the risk of coronary artery aneurysms. We assessed whether the addition of infliximab to standard therapy (intravenous immunoglobulin and aspirin) in acute Kawasaki disease reduces the rate of treatment resistance. We undertook a phase 3, randomised, double-blind, placebo-controlled trial in two children's hospitals in the USA to assess the addition of infliximab (5 mg per kg) to standard therapy. Eligible participants were children aged 4 weeks-17 years who had a fever (temperature ≥38·0°C) for 3-10 days and met American Heart Association criteria for Kawasaki disease. Participants were randomly allocated in 1:1 ratio to two treatment groups: infliximab 5 mg/kg at 1 mg/mL intravenously over 2 h or placebo (normal saline 5 mL/kg, administered intravenously). Randomisation was based on a randomly permuted block design (block sizes 2 and 4), stratified by age, sex, and centre. Patients, treating physicians and staff, study team members, and echocardiographers were all masked to treament assignment. The primary outcome was the difference between the groups in treatment resistance defined as a temperature of 38·0°C or higher at 36 h to 7 days after completion of the infusion of intravenous immunoglobulin. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00760435. 196 patients were enrolled and randomised: 98 to the infliximab group and 98 to placebo. One patient in the placebo group was withdrawn from the study because of hypotension before receiving treatment. Treatment resistance rate did not differ significantly (11 [11·2%] for infliximab and 11 [11·3%] for placebo; p=0·81). Compared with the placebo group, participants given infliximab had fewer days of fever (median 1 day for infliximab vs 2 days for placebo; p<0·0001). At week 2, infliximab-treated patients had greater mean reductions in erythrocyte sedimentation rate (p=0·009) and a two-fold greater decrease in Z score of the left anterior descending artery (p=0·045) than did those in the placebo group, but this difference was not significant at week 5. Participants in the infliximab group had a greater mean reduction in C-reactive protein concentration (p=0·0003) and in absolute neutrophil count (p=0·024) at 24 h after treatment than did those given placebo, but by week 2 this difference was not significant. At week 5, none of the laboratory values differed significantly compared with baseline. No significant differences were recorded between the two groups at any timepoint in proximal right coronary artery Z scores, age-adjusted haemoglobin values, duration of hospital stay, or any other laboratory markers of inflammation measured. No reactions to intravenous immunoglobulin infusion occurred in patients treated with infliximab compared with 13 (13·4%) patients given placebo (p<0·0001). No serious adverse events were directly attributable to infliximab infusion. The addition of infliximab to primary treatment in acute Kawasaki disease did not reduce treatment resistance. However, it was safe and well tolerated and reduced fever duration, some markers of inflammation, left anterior descending coronary artery Z score, and intravenous immunoglobulin reaction rates. US Food and Drug Administration, Robert Wood Johnson Foundation, and Janssen Biotech.

Case report: passive transfer of hepatitis B antibodies from intravenous immunoglobulin

BackgroundPrior to initiating immunosuppressive therapy in the treatment of autoimmune inflammatory conditions, it is a requirement to screen for certain viral serology, including hepatitis B (HBV). A positive result may indicate the need for antiviral therapy, or contraindicate immunosuppression all together. An accurate interpretation of serological markers is therefore imperative in order to treat patients appropriately. We present a case of passive anti-HBV antibody transfer following intravenous immunoglobulin (IVIg) infusion, in which misinterpretation of serology results almost led to inappropriate treatment with antiviral therapy and the withholding of immunosuppressive agents. This phenomenon has been previously reported, but awareness remains limited.Case presentationA 50 year old Caucasian gentleman with a history of allogeneic haematopoietic stem cell transplant for transformed follicular lymphoma was admitted to hospital with recurrent respiratory tract infections. Investigation found him to be hypogammaglobulinaemic, and he was thus given 1 g/kg of intravenous immunoglobulin. The patient also disclosed a 3-week history of painful, swollen joints, leading to a diagnosis of seronegative inflammatory polyarthritis. Prior to initiating long term immunosuppression, viral screening found hepatitis B serology suggestive of past infection, with positive results for both anti-HBc and anti-HBs antibody, but negative HBV DNA. In response, prednisolone was weaned and the local hepatology team recommended commencement of lamivudine. Having been unable to identify a source of infection, the case was reported to the local blood centre, who tested a remaining vial from the same batch of IVIg and found it to be anti-HBc and anti-HBs positive. Fortunately the blood products were identified and tested prior to the patient initiating HBV treatment, and the effect of a delay in starting disease-modifying therapy was inconsequential in light of an excellent response to first-line therapies.ConclusionMisinterpretation of serology results following IVIg infusion may lead to significant patient harm, including unnecessary antiviral administration, the withholding of treatments, and psychosocial damage. This is especially pertinent at a time when we have an ever increasing number of patients being treated with IVIg for a wide array of immune-mediated disease. Passive antibody transfer should be considered wherever unexpected serological changes are identified.

Recurrent thrombosis prevention with intravenous immunoglobulin and hydroxychloroquine during pregnancy in a patient with history of catastrophic antiphospholipid syndrome and pregnancy loss

We report a case of a 36-year old patient with prior history of thrombosis in a setting of antiphospholipid antibody syndrome (APS) as well as pregnancy-associated catastrophic antiphospholipid syndrome (CAPS), resulting in multi-organ infarction and pregnancy loss. The episode of CAPS occurred while she was receiving antepartum low-dose aspirin and therapeutic-dose enoxaparin. This patient presented again at 6weeks gestation and ultrasounds were consistent with fetal growth restriction, concerning for placental insufficiency and thrombosis. This time, hydroxychloroquine and monthly intravenous immunoglobulin (IVIG) infusions were added to her prophylaxis regimen, resulting in a successful delivery. Platelet count and antiphospholipid antibody titers were routinely monitored throughout pregnancy as markers of disease activity for APS. Current thromboprophylaxis guidelines do not address therapeutic options to prevent further pregnancy morbidity in women who develop recurrent episodes of thrombosis or CAPS despite receiving adequate anti-thrombotic treatment. Use of hydroxychloroquine and IVIG has been associated with good outcomes in this subset of patients.

Efficacy and Safety of IgPro20, a Subcutaneous Immunoglobulin, in Japanese Patients with Primary Immunodeficiency Diseases

PurposeIntravenous (IVIG) and subcutaneous (SCIG) immunoglobulin infusions are widely used for the treatment of patients with primary immunodeficiency (PID) worldwide. This prospective, multicenter, open-label, single-arm Phase III study evaluated the efficacy, tolerability, and safety of IgPro20 (Hizentra®; L-proline–stabilized 20 % human SCIG) in adult and pediatric Japanese patients with PID.MethodsPatients received three IVIG infusions at 3–4-week intervals followed by a dose-equivalent switch to weekly SCIG infusions. A 12-week wash-in/wash-out period was followed by a 12-week SCIG efficacy period. The primary efficacy endpoint was the comparison of total serum IgG trough levels during the IVIG and SCIG efficacy periods by calculating the geometric mean ratio (GMR).ResultsThe GMR of IgG trough levels on SCIG versus IVIG was 1.09 (2-sided 90 % confidence interval: 1.06–1.13). No serious bacterial infections were reported. Eleven patients (52.4 %) had infectious episodes with an overall rate of 2.98 infections/patient/year; 7 patients (33.3 %) missed school/work/daycare due to infection (3.48 days/patient/year). Sixteen patients (76.2 %) were treated with antibiotics for an adverse event (AE; 47.6 %) or prophylaxis (23.8 %), resulting in 167.42 days/patient/year of antibiotic use. During SCIG treatment, 24 patients (96.0 %) had 269 AEs (0.461 AEs per/infusion) including local reactions as the most common AE (20 patients, 80.0 %). Local tolerability of IgPro20 was assessed as “very good” or “good” after 85.4 % of SCIG infusions. One patient (4.0 %) experienced a serious AE of moderate severity (bacterial infection) that was considered unrelated to study medication.ConclusionIgPro20 was effective and well tolerated in Japanese patients with PID.