IgM-enriched Intravenous Immunoglobulin Research Articles

Potential role of IgM-enriched immunoglobulin as adjuvant treatment in severe SARS-CoV-2 infection.

Severe COVID-19 patients are characterized by a dysregulated host response to an infection, with uncontrolled pro- and anti- inflammatory pathway activation. Consistent proportion of patients require admission in intensive care units and are at risk of progression to severe forms of disease. These patients are generally admitted during later stages of the disease, when effective antiviral and monoclonal antibody are not indicated. We aimed to assess the potential role of IgM-enriched intra venous immunoglobulins (IGAM) preparations in this setting. This retrospective, observational case-controlled study was conducted at a single-center University Hospital of Udine in the Friuli Venezia Giulia Region of Italy. Patients referring to the center between March 2020 and April 2021 was included. During the study period, patient who received Pentaglobin® IGAM treatment (N.=56), administered as compassionate use, was compared with a control group (N.=169) to assess, by propensity score analysis, clinical outcome. Untreated controls required, respect to patient treated with IGAM therapy, longer time to hospitalization with no significant differences in death and orotracheal intubation requirement. Significant differences in the two cohort were in: SOFA was higher in treated, while D-dimer and P/F ratio was better in the treatment cohort. Multivariate logistic regression analysis performed on the "matched sample," obtained by a weighting propensity score approach, identify, as significant protective factor for death outcome, the Pentaglobin® treatment (0.820 [0.698-0.963], P=0.016) and low C-reactive protein (1.001 [1.000-1.002], P=0.031) value while the delay of onset hospitalization is associate with a worst outcome (0.983 [0.967-0.999], P=0.041). The present study offers a significant insight concerning the use of IgM-enriched immunoglobulin preparations in patients with SARS-CoV-2 severe infection and also could identifying the specific immunological and biochemical profile of the patient who can more benefit from this therapeutic option.

Lung transplantation despite preformed donor-specific antihuman leukocyte antigen antibodies: a 9-year single-center experience

Pretransplant allosensitization to human leukocyte antigens (HLA) increases the recipient’s waiting list time and mortality in lung transplantation. Rather than waiting for crossmatch-negative donors, since 2013, recipients with preformed donor-specific antiHLA antibodies (pfDSA) have been managed with repeated IgA- and IgM-enriched intravenous immunoglobulin (IgGAM) infusions, usually in combination with plasmapheresis before IgGAM and a single dose of antiCD20 antibody. This retrospective study presents our 9-year experience with patients transplanted with pfDSA. Records of patients transplanted between February 2013 and May 2022 were reviewed. Outcomes were compared between patients with pfDSA and those without any de novo donor-specific antiHLA antibodies. The median follow-up time was 50 months. Of the 1,043 patients who had undergone lung transplantation, 758 (72.7%) did not develop any early donor-specific antiHLA antibodies, and 62 (5.9%) patients exhibited pfDSA. Among the 52 (84%) patients who completed treatment, pfDSA was cleared in 38 (73%). In pfDSA vs control patients and at 8-year follow-up, respectively, graft survival (%) was 75 vs 65 (P = .493) and freedom from chronic lung allograft dysfunction (%) was 63 vs 65 (P = .525). In lung transplantation, crossing the preformed HLA-antibody barrier is safe using a treatment protocol based on IgGAM. Patients with pfDSA have a good 8-year graft survival rate and freedom from chronic lung allograft dysfunction, similar to control patients.

Treatment with IgM-enriched intravenous immunoglobulins enhances clearance of stroke-associated bacterial lung infection.

Post-stroke infection is a common complication of stroke that is associated with poor outcome. We previously reported that stroke induces an ablation of multiple sub-populations of B cells and reduces levels of immunoglobulin M (IgM) antibody, which coincides with the development of spontaneous bacterial pneumonia. The loss of IgM after stroke could be an important determinant of infection susceptibility and highlights this pathway as a target for intervention. We treated mice with a replacement dose of IgM-enriched intravenous immunoglobulin (IgM-IVIg) prior to and 24 h after middle cerebral artery occlusion (MCAO) and allowed them to recover for 2- or 5-day post-surgery. Treatment with IgM-IVIg enhanced bacterial clearance from the lung after MCAO and improved lung pathology but did not impact brain infarct volume. IgM-IVIg treatment induced immunomodulatory effects systemically, including rescue of splenic plasma B cell numbers and endogenous mouse IgM and IgA circulating immunoglobulin concentrations that were reduced by MCAO. Treatment attenuated MCAO-induced elevation of selected pro-inflammatory cytokines in the lung. IgM-IVIg treatment did not increase the number of lung mononuclear phagocytes or directly modulate macrophage phagocytic capacity but enhanced phagocytosis of Staphylococcus aureus bioparticles in vitro. Low-dose IgM-IVIg contributes to increased clearance of spontaneous lung bacteria after MCAO likely via increasing availability of antibody in the lung to enhance opsonophagocytic activity. Immunomodulatory effects of IgM-IVIg treatment may also contribute to reduced levels of damage in the lung after MCAO. IgM-IVIg shows promise as an antibacterial and immunomodulatory agent to use in the treatment of post-stroke infection.

Outcomes of Newborn Infants with Neonatal Sepsis Receiving IgM-Enriched Intravenous Immunoglobulin as Adjunctive Treatment

Background: Neonatal sepsis is a major cause of morbidities and mortality in newborn infants. Adjunctive treatment with IgM-enriched intravenous immunoglobulins (IgM-enriched IVIG) may improve the outcomes of the newborn infants with neonatal sepsis. However, there is limited data with regards to the outcomes of newborn infants receiving this treatment. Objective: To evaluate the outcomes of the newborn infants with neonatal sepsis receiving IgM-enriched IVIG. Materials and Methods: A retrospective cohort study was done in newborn infants aged 28 days or younger diagnosed with either culture-proven sepsis or clinical sepsis at Srinagarind Hospital between 2012 and 2018. The outcomes with regards to death and morbidities were compared between newborn infants received IgM-enriched IVIG versus a control group. Results: Ninety-six newborn infants were eligible for the present study. Culture-proven sepsis group consisted of 20 newborn, which five of them had early-onset sepsis (EOS) and 15 had late-onset sepsis (LOS). There were 76 newborn infants in clinical sepsis group, which 36 had EOS and 40 had LOS. IgM-enriched IVIG was given to 12 (60%) newborn infants with culture-proven sepsis and 10 (13.2%) newborn infants with clinical sepsis. Among newborn infants diagnosed with culture-proven EOS and LOS, there was no significant differences in morbidities, mortality, length of hospital stay, and hospital cost between the intervention and the control group. In newborn infants diagnosed with clinical sepsis, subgroup analysis showed that in clinical LOS, the intervention group had significantly higher rate of death at 25% versus 0% (OR 6.3; 95% CI 3.0 to 13.2, p<0.05) and hospital cost with a mean of 601,155 versus 279,777 Baht (p<0.05) in comparison to the control group. Conclusion: IgM-enriched IVIG failed to demonstrate benefit as an adjunctive treatment for newborn infants with neonatal sepsis. It also failed to show reduction in length of hospital stay and hospital cost. Routine prescription of IgM-enriched IVIG in neonatal sepsis is not recommended. Keywords: Neonatal sepsis; IgM-enriched IVIG; Outcomes

Heart Transplantation After Infection of Left Ventricular Assist Devices: Effects of IGM-Enriched Human Immunoglobulin as Adjuvant Therapy

<h3>Purpose</h3> Infections are common and feared in patients with left ventricular assist device (LVAD) support. As the infected components cannot easily explanted, therapy is often insufficient and patients require heart transplantation (HTx). However, immunosuppression can aggravate the present infective complications. IgM-enriched intravenous human immunoglobulin (IGM-IVIG) conveys multiple anti-infective effects and may serve as an adjuvant therapy in these patients. <h3>Methods</h3> Between January and August 2021 a total of n=35 patients underwent HTx in our department. Of those, n=4 patients (p1-4) had a present infection of a left ventricular assist device. Immediately after HTx, laboratory parameters including immunoglobulins were evaluated and patients received 3 ml/kg body weight IGM-IVIG (Pentaglobin®, Biotest AG, Dreieich, Germany). IGM-IVIG application was repeated with 5 mg/kg body weight per day if immunoglobulins were below the reference range. Immunosuppression consisted of tacrolimus, mycophenolate mofetil and prednisolone. <h3>Results</h3> While P1, 2 and 4 suffered from driveline infection due caused by Pseudomonas aeruginosa or Staphylococcus aureus, P3 suffered from pericardial abscess close to the device, however microbiology could not identify germs. All patients were treated with antibiotics and had sufficient immunoglobulin concentrations before and after the IgM-IVIG application. Therefore, every patient only received IgM-IVIG once directly postoperative. While in P2-4 a raise in immunoglobulin concentration was observed after IgM-IVIG (mean increase of IgG=232 mg/dl (29 %), IgA=28 mg/dl (14 %), IgM=21 mg/dl (36 %), concentration in P1 dropped by about 40 %. This was most likely associated with severe bleeding complications of the patient. None of the patient suffered from postoperative infective complications or therapy-related adverse events. <h3>Conclusion</h3> Adjuvant application of IgM-IVIG is safe and feasible in patients undergoing HTx after LVAD infection. Although our results cover only a small proportion of patients, we were able to report adequate immunoglobulin concentrations and sufficient postoperative immune response in every patient.

Perioperative Desensitization with IgA- and IgM-Enriched Human Immunoglobulins Allows Safe Lung Transplantation in Patients with Preformed Donor Specific Antibodies

<h3>Purpose</h3> Pretransplant sensitization to human leukocyte antigens (HLA) increases the recipient waiting list time and mortality in lung transplantation. Instead of awaiting crossmatch-negative donors, since 2013, recipients with preformed anti-HLA donor specific antibodies (pfDSA) have been managed peri-transplant at our institution with repeated IgA- and IgM-enriched intravenous immunoglobulin infusions (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks thereafter to a maximum of 6 months), usually in combination with plasmapheresis (PE) before IgGAM and a single dose of anti-CD20 antibody (375mg/m², Rituximab) after the first IgGAM infusion. This study presents the 8-year results of this protocol in patients transplanted with pfDSA. <h3>Methods</h3> Records of patients transplanted at our institution between 02/2013 and 10/2021 were reviewed. Outcomes were compared between patients with pfDSA (pfDSA group) and those without any early DSA (control group)<i>.</i> Patients without pfDSA who developed DSA only post transplantation (n=219) were excluded from the analysis. Median follow-up was 47 (21-73) months. <h3>Results</h3> Of the 994 transplanted patients, 55 (5%) patients exhibited pfDSA and 721 (73%) did not develop any early DSA. Among these 55 patients, 40 (73%) patients possessed pfDSA against class II HLA antigens and 17 (31%) patients against class I antigens (2 patients against both classes). Twelve (22%) patients showed a positive retrospective CDC crossmatch and 21 (38%) patients developed additional de-novo DSA after transplantation. Forty-four (80%) patients were treated with PE and 45 (82%) patients with Rituximab. At follow-up end, treatment was completed in 45 (82%) patients (still on treatment, n=4; in-hospital deaths, n=2; treatment interrupted earlier as intended by protocol, n=4). In these 45 patients, IgGAM treatment cleared DSA in 33 (73%) patients, with 4 (12%) patients showing the same DSA recurrence. In pfDSA vs. control patients and at 5-year follow-up, respectively, graft survival (%) was 83 vs. 76 (p=0.40) and freedom from chronic lung allograft dysfunction (%) 72 vs. 72 (p=0.62). <h3>Conclusion</h3> In lung transplantation, a treatment protocol based on IgGAM allowed transplanting patients with preformed DSA with good 5-year graft survival similar to control patients.

Pediatric scrub typhus complicated by cytokine storm, hyperferritinemia, and cerebral infarcts: A case report

Hyperferritinemia has been associated with increased mortality in severe sepsis and also described with scrub typhus. We describe a case of a 10-year-old child with acute febrile illness, altered sensorium, seizures, and left hemiparesis, along with septic shock. The child had markedly elevated inflammatory markers, along with hyperferritinemia and increased D-dimer. Serological tests for scrub typhus were positive. The child was started on doxycycline along with supportive management. In view of hyperferritinemic sepsis with accompanying cytokine storm, septic shock, and disseminated intravascular coagulopathy, IgM-enriched intravenous immunoglobulin and dexamethasone were administered with good outcome. Neuroimaging revealed cerebral infarcts managed with low-molecular-weight heparin and aspirin. The child was discharged with normal sensorium and with improving left hemiparesis. Early use of immunomodulatory drugs in such atypical presentations in scrub typhus may reduce mortality, and further research is warranted.

Seven-Year Clinical Results of an IgA-and IgM-Enriched Human Immunoglobulin-Based Therapy for Antibody-Mediated Rejection after Lung Transplantation

Purpose Development of anti-HLA donor specific antibodies early after lung transplantation (eDSA) has been associated with antibody-mediated rejection (AMR) and poor graft survival. Since 2013, our institution has employed successive infusions of IgA- and IgM-enriched intravenous immunoglobulins (IgGAM, first infusion: 2gr/kg, then 0.5gr/kg once every 4 weeks for a maximum of 6 months) as 1st line treatment in such cases. Asymptomatic eDSA development (possible subclinical AMR) was treated with IgGAM only. Patients with concomitant graft dysfunction (possible clinical AMR) or positive crossmatch additionally receive 5 sessions of plasmapheresis pre-IgGAM, and a single dose of anti-CD20 antibody (Rituximab) afterwards. This study was presents 7-year results of this IgGAM-based protocol. Methods Records of patients transplanted between 02/2013 and 10/2020 were reviewed. Outcomes were compared between patients with eDSA and treated with IgGAM (IgGAM group) and those without eDSA (control group). Median follow-up was 41 (18-64) months. Results he 913 transplanted recipients, 224 (25%) patients were included in the IgGAM group and 667 (73%) the control group. The remaining 22 (2%) patients (13 patients with eDSA but not treated, and 9 patients treated only with tPE and Rituximab) were excluded. Forty-one (18%) IgGAM patients exhibited pre-formed eDSA and 16 (7%) patients showed a positive retrospective crossmatch. Thirty-six (16%) patients showed concomitant graft dysfunction (possible clinical AMR). Median time to eDSA detection was 14 days post-transplant. At follow-up end, treatment was completed in 204 (91%) patients (ongoing treatment, n=7; in-hospital deaths, n=4; treatment prematurely interrupted, n=9). In these 204 patients, IgGAM treatment cleared eDSA in 184 (90%) patients. Twenty-five (12%) patients developed eDSA recurrence at a median of 9 months after completing treatment. Clearance was less effective in patients with preformed eDSA (p Conclusion In lung recipients, treatment of eDSA with IgGAM yielded high eDSA clearance. Patients with eDSA and IgGAM-treatment have good 7-year graft survival similar to control patients.

Use of Intravenous Immunoglobulins in Sepsis Therapy-A Clinical View.

Sepsis is a life-threatening organ dysfunction, defined by a dysregulated host immune response to infection. During sepsis, the finely tuned system of immunity, inflammation and anti-inflammation is disturbed in a variety of ways. Both pro-inflammatory and anti-inflammatory pathways are upregulated, activation of the coagulation cascade and complement and sepsis-induced lymphopenia occur. Due to the manifold interactions in this network, the use of IgM-enriched intravenous immunoglobulins seems to be a promising therapeutic approach. Unfortunately, there is still a lack of evidence-based data to answer the important questions of appropriate patient populations, optimal timing and dosage of intravenous immunoglobulins. With this review, we aim to provide an overview of the role of immunoglobulins, with emphasis on IgM-enriched formulations, in the therapy of adult patients with sepsis and septic shock.

Treatment of Anti-HLA Donor-Specific Antibodies in Heart Transplantation: A Single-Center Experience

The presence of anti-HLA donor specific antibodies (DSA) after heart transplantation is associated with antibody-mediated rejection (AMR) and poor graft survival. Aim of this study was to present the results of our treatment protocol of DSA in heart transplantation. Since late 2016, at our institution, heart-transplanted patients with DSA but without graft dysfunction (Group 1) were treated with IgA- and IgM-enriched intravenous immunoglobulins (IgGAM) only (first infusion: 2g/kg, then 0.5g/kg once every 4 weeks for a maximum of 6 months). Patients with DSA and graft dysfunction (Group 2, clinical AMR) were treated with additional 5 sessions of plasmapheresis (PE) before IgGAM and a single a single dose of anti-CD20 antibody (Rituximab, 375mg/m2) after the first IgGAM infusion. Highly allosensitized (PRA>50%) patients showing preformed DSA (pfDSA), i.e. a positive virtual crossmatch (Group 3), were treated with an intraoperative single dose of the IL-6 receptor antibody Tocilizumab (10mg/kg), in addition to 5 sessions of PE, IgGAM infusions and a single Rituximab dose, as aforementioned. Among the 72 patients transplanted between 10/2016 and 10/2019, 3 (4%) patients formed Group 1, 8 (11%) patients Group 2, and 12 (17%) patients Group 3. Group 1 patients developed de novo DSA 31, 145 and 28 days after transplantation, were treated with IgGAM, which cleared DSA in all patients, were alive and did not show any episode of biopsy-confirmed rejection (ISHLT Grade R>1) at the end of follow-up. Group 2 patients developed de novo DSA at a median of 207 days after transplantation and showed graft dysfunction requiring ECMO support in 4 cases. Five (63%) patients died in-hospital. Among the 3 surviving patients, DSA were cleared in one patient. Group 3 patients showed pfDSA with >50% pre-transplant PRA. Post-transplant, patients did not show severe primary graft dysfunction, but one patient died in-hospital of pneumonia. pfDSA were cleared in 5 (42%) patients. At follow-up, all discharged patients survived, and 3 patients showed at least one episode of ISHLT Grade R>1 rejection or of minimal AMR (pAMR 1+). In heart transplantation, clinical AMR showed a dismal prognosis, despite treatment. Early diagnosis and preemptive treatment of DSA should be pursued. Transplantation across positive crossmatch barriers can be feasible and safe.

Clinical, laboratory features and prognosis of children receiving IgM-enriched immunoglobulin (3 days vs. 5 days) as adjuvant treatment for serious infectious disease in pediatric intensive care unit: a retrospective single-center experience (PIGMENT study)

ABSTRACT Introduction Although there are studies about sepsis treatment in different age groups, data on immunoglobulin-M (IgM)-enriched intravenous immunoglobulin use in pediatric intensive care units (PICUs) are limited. The aim of this study was to evaluate the clinical features and prognoses of children receiving IgM-enriched intravenous immunoglobulin to treat sepsis, septic shock, and multi-organ failure. Method We extracted data from the medical records of 254 children who received IgM-enriched intravenous immunoglobulin infusion (104 children for 3 days, 150 children for 5 days) in addition to standard treatment between 2010 and 2017. Results When the 5-day vs. 3-day IgM-enriched immunoglobulin treatments were compared, the mortality rate was shown to be lower in patients who received the longer duration of treatment (p < .001). Better outcomes were observed among children with septic shock (p < .01). Conclusion Our clinical work with 5-days IgM-enriched intravenous immunoglobulin may reveal a survival benefit of this treatment for children with septic shock.

Intravenous immunoglobulin for suspected or proven infection in neonates.

Neonates are at higher risk of infection due to immuno-incompetence. Maternal transport of immunoglobulins to the fetus mainly occurs after 32 weeks' gestation, and endogenous synthesis begins several months after birth. Administration of intravenous immunoglobulin (IVIG) provides immunoglobulin G (IgG) that can bind to cell surface receptors, provide opsonic activity, activate complement, promote antibody-dependent cytotoxicity and improve neutrophilic chemo-luminescence. Theoretically, infectious morbidity and mortality could be reduced by the administration of IVIG. To assess the effects of IVIG on mortality and morbidity caused by suspected or proven infection at study entry in neonates. To assess in a subgroup analysis the effects of IgM-enriched IVIG on mortality from suspected infection. For this update, MEDLINE, EMBASE, The Cochrane Library, CINAHL, trial registries, Web of Science, reference lists of identified studies, meta-analyses and personal files were searched in 2013. No language restrictions were applied. Randomised or quasi-randomised controlled trials involving newborn infants (< 28 days old); IVIG for treatment of suspected or proven bacterial or fungal infection compared with placebo or no intervention; and where one of the following outcomes was reported, mortality, length of hospital stay or psychomotor development at follow-up. Statistical analyses included typical risk ratio (RR), risk difference (RD), weighted mean difference (WMD), number needed to treat for an additional beneficial outcome (NNTB) or an additional harmful outcome (NNTH), all with 95% confidence intervals (CIs), and the I2 statistic to examine for statistical heterogeneity. The updated search identified one published study that was previously ongoing. A total of 9 studies evaluating 3973 infants were included in this review. Mortality during hospital stay in infants with clinically suspected infection was not significantly different after IVIG treatment (9 studies (n = 2527); typical RR 0.95, 95% CI 0.80 to 1.13; typical RD -0.01, 95% CI - 0.04 to 0.02; I2 = 23% for RR and 29% for RD). Death or major disability at 2 years corrected age was not significantly different in infants with suspected infection after IVIG treatment (1 study (n = 1985); RR 0.98, 95% CI 0.88 to 1.09; RD -0.01, 95% CI -0.05 to 0.03). Mortality during hospital stay was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1446); RR 0.95, 95% CI 0.74 to 1.21; RD -0.01, 95% CI -0.04 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with proven infection at trial entry (1 trial (n = 1393); RR 1.03, 95% CI 0.91 to 1.18; RD 0.01, 95% CI -0.04 to 0.06). Mortality during hospital stay in infants with clinically suspected or proven infection at trial entry was not significantly different after IVIG treatment (1 study (n = 3493); RR 1.00, 95% CI 0.86 to 1.16; RD 0.00, 95% CI - 0.02 to 0.03). Death or major disability at 2 years corrected age was not significantly different after IVIG treatment in infants with suspected or proven infection at trial entry (1 study (n = 3493); RR 1.00, 95% CI 0.92 to 1.09; RD -0.00, 95% CI -0.03 to 0.03). Length of hospital stay was not reduced for infants with suspected or proven infection at trial entry (1 study (n = 3493); mean difference (MD) 0.00 days, 95% CI -0.61 to 0.61). No significant difference in mortality during hospital stay after administration of IgM-enriched IVIG for suspected infection at trial entry was reported in 4 studies (n = 266) (typical RR 0.68, 95% CI 0.39 to 1.20; RD -0.06, 95% CI -0.14 to 0.02; I2 = 17% for RR and 53% for RD). The undisputable results of the INIS trial, which enrolled 3493 infants, and our meta-analyses (n = 3973) showed no reduction in mortality during hospital stay, or death or major disability at two years of age in infants with suspected or proven infection. Although based on a small sample size (n = 266), this update provides additional evidence that IgM-enriched IVIG does not significantly reduce mortality during hospital stay in infants with suspected infection. Routine administration of IVIG or IgM-enriched IVIG to prevent mortality in infants with suspected or proven neonatal infection is not recommended. No further research is recommended.

Five-Year Results of an IgA and IgM-Enriched Human Immunoglobulin G-Based Therapy for Early Anti-HLA Donor Specific Antibodies in 158 Lung-Transplanted Patients

Purpose The development of anti-HLA donor specific antibodies early after lung transplantation (eDSA) is associated with antibody-mediated rejection (AMR) and poor graft survival. At our institution, since 2013, we have treated patients with eDSA with successive infusions (first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks for a maximum of 6 months) of IgA and IgM-enriched human intravenous immunoglobulins G (Pentaglobin®, IgGAM), combined in some cases with a single dose of anti-CD20 antibody (Rituximab) and plasmapheresis (PE) or immunoabsorption. Aims of this study were to present the 5-year results of the IgGAM-based therapy and its impact on graft survival. Methods Records of patients transplanted at our institution between 03/2013 and 10/2018 were reviewed. Outcomes of patients with eDSA and treated with IgGAM (IgGAM group) and without eDSA(control group) were compared using the product-limit method of Kaplan-Meier and the log-rank test. Median (IQR) follow-up amounted to 29 (14, 48) months. Results During the study period, among the 705 transplanted patients, 158 (22%) patients formed the IgGAM group and 530 (75%) the control group. Among the remaining 17 (3%) patients, 10 patients developed eDSA but were not treated and 7 were treated only with PE and Rituximab, and thus were not considered in the study. Among the 158 IgGAM patients, 132 (84%) showed only eDSA (possible subclinical AMR) and were pre-emptively treated. The remaining 26 (16%) patients showed graft dysfunction concomitant with eDSA (possible clinical AMR). Median time to eDSA detection was 14 (11, 20) days after transplantation. As of October 2018, treatment was completed in 138 (87%) patients. IgGAM treatment cleared eDSA in 126 (91%) patients (median time 3 months), 15 (12%) patients showing eDSA recurrence at a median of 9 months after treatment end. During treatment time, freedom from biopsy-confirmed rejection (%) was 72 vs. 65 in IgGAM vs. control patients. At 5 years, graft survival (%) was 71 vs. 75 (p=0.74) and freedom from CLAD 84 vs. 70 (p=0.28) in IgGAM vs. control patients, respectively. Conclusion After lung transplantation, a IgGAM-based treatment for eDSA yielded high eDSA clearance. IgGAM patients showed improved 5-year CLAD-free survival in comparison to control patients. Graft survival was similar between groups.

Five-Year Experience with Treatment of Early Donor Specific Anti-HLA Antibodies in Pediatric Lung Transplant Recipients

Purpose Experience with treatment of early donor specific anti-HLA antibodies (eDSA) after lung transplantation in children is very limited. At our institution, since 2013, we have treated patients with eDSA with successive infusions (first infusion: 2gr/kg, then 0.5gr/kg every 4 weeks for a maximum of 6 months) of IgA and IgM-enriched human intravenous immunoglobulins (Pentaglobin, IgGAM), combined in some cases with a single dose of anti-CD20 antibody (Rituximab) and plasmapheresis (PE) or immunoabsorption. Aim of this study was to present the 5-year results of the IgGAM-based therapy in pediatric lung recipients. Methods Records of pediatric ( Results During the study period, among the 60 lung-transplanted pediatric patients (median age 13 years), 26 (43%) formed the IgGAM group and 33 (55%) the control group. One (2%) patient was treated only with PE and Rituximab and not considered in the study. Among the 26 IgGAM patients, 14 (54%) showed only eDSA (possible subclinical antibody-mediated rejection, AMR). The remaining 12 (46%) patients showed graft dysfunction concomitant with eDSA (possible clinical AMR). Median time to eDSA detection was 23 (14, 64) days after transplantation. As of October 2018, treatment was completed in 23 (88%) patients. Under IgGAM treatment eDSA cleared in 22 (96%) patients. At follow-up, 5 (20%) IgGAM vs. 5 (15%) control patients developed hypogammaglobulinemia requiring substitution (p=0.73). No IgGAM vs. 3 (10%) control patients developed post-transplant lymphoproliferative disease (p=0.25). At 5 years, graft survival (%) was 76 vs. 84 (p=0.78); freedom (%) from chronic lung allograft rejection (CLAD) was 88 vs. 75 (p=0.54), and from infection requiring hospitalization 53 vs. 23 (p= 0.021), in IgGAM vs. control patients, respectively. Conclusion After lung transplantation, an IgGAM-based treatment for eDSA yielded high eDSA clearance while decreasing the risk of severe infections. IgGAM patients showed 5-year CLAD-free survival at least as good as control patients without eDSA.

IgM-enriched Human Intravenous Immunoglobulin for Treatment of Early Antibody Mediated Rejection after Heart Transplantation

IgM-enriched Human Intravenous Immunoglobulin for Treatment of Early Antibody Mediated Rejection after Heart Transplantation

Preemptive treatment of early donor-specific antibodies with IgA- and IgM-enriched intravenous human immunoglobulins in lung transplantation.

This retrospective study presents our 4‐year experience of preemptive treatment of early anti‐HLA donor specific antibodies with IgA‐ and IgM‐enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti‐CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4‐year follow‐up, respectively, graft survival (%) was 79 versus 81 (P = .59), freedom (%) from biopsy‐confirmed rejection 57 versus 53 (P = .34), and from chronic lung allograft dysfunction 82 versus 78 (P = .83). After lung transplantation, patients with early donor‐specific antibodies and treated with IgA‐ and IgM‐enriched immunoglobulins had 4‐year graft survival similar to patients without antibodies and showed high antibody clearance.

Pantaglubulin Usefulness in Critical Care

Intravenous immunoglobulin (IVIg) products are available preparations of immunoglobulins extracted from plasma pools obtained from more than 1,000 healthy donors per lot. The inhibitory capacity of the IgGMA preparation was more potent than the capacity of an IVIgG preparation. IgM-enriched IVIg used in different cases of severe sepsis and polyneuromyopathy but the effectiveness was not the same. Although IgM-enriched IVIg has some adverse effect on the kidney.

Efficacy of intravenous immunoglobulin in the adjuvant treatment of patients with severe sepsis: a Meta analysis

To investigate the possibility of improving the prognosis of patients with severe sepsis by different kinds of intravenous immunoglobulin (IVIG). PubMed database, EMBase, Cochrane clinical trial database, CNKI, and Wangfang database etc were retrieved. The search time was from database creation to September 2015,which included all prospective studies of the effectiveness of IVIG compared with non-IVIG in all adult patients with severe sepsis. Main end-point parameter was total mortality rate; secondary end-point parameters were short-term (＜ 7 days) mortality,28-day mortality, length of intensive care unit (ICU) and hospital stay, and mortality due to septic shock or multiple organ failure (MOF). RevMan 5.3 was used for Meta analysis. Finally,16 prospective studies including 12 randomized controlled trails (RCT) and 4 prospective cohort studies were enrolled, referred to 1 819 patients, 892 patients were in IVIG group, 927 patients receiving human albumin, placebo or blank control were in control group. Compared with the control group, IVIG could reduce the total mortality rate of patients with severe sepsis [relative risk (RR) =0.71,95％ confidence interval (95％CI) =0.57-0.87,P =0.001].After the high-risk research was eliminated, it was shown that the IVIG could reduce the total mortality rate in patients with severe sepsis (RR =0.80, 95％CI =0.65-0.98, P =0.03).But IVIG could not reduce the 28-day mortality rate (RR =0.60, 95％CI =0.35-1.04, P =0.07), short-term mortality rate (RR =1.06, 95％CI =0.76-1.46,P =0.74), the mortality rate of septic shock (RR =0.55, 95％CI =0.29-1.03, P =0.06) and the mortality rate of MOF (RR =0.91, 95％CI =0.63-1.33, P =0.64).In fact, the length of stay in ICU [weighted mean difference (WMD) =-0.02, 95％CI =-0.03-0.25, P =0.86] and the total length of stay in hospital (WMD =-2.34,95％CI =-7.05-2.37,P =0.33) were similar. In subgroup, the 28-day mortality rate of patients with severe sepsis in the IgM group (RR =0.50, 95％CI =0.25-1.01, P =0.05) was significantly lower than that of IgG group (RR =0.72, 95％CI =0.40-1.30, P =0.28). IVIG can reduce the total mortality rate of patients with severe sepsis. Compared with IgG, IgM-enriched IVIG has certain advantages in patients with severe sepsis, but cannot reduce the short-term mortality rate, mortality rate of septic shock and MOF, and also cannot shorten the length of ICU stay and the total length of hospital day.

Igm-enriched polyclonal immunoglobulins in an experimental model of gram negative pneumonia developing septic shock

Severe pneumonia is a major challenge in the Intensive Care Unit, as it is characterized by high morbidity and mortality. A high rate of patients with pneumonia, in particular ventilator-associated poneumonia, develops septic shock. Although some interesting results have been reported in uncontrolled studies where IgM-enriched human intravenous immunoglobulins were added to the standard treatment of septic shock, a well-conducted clinical trial is missing[1]. Also, physiopathological data supporting such a trial are presently insufficient.

Role of Pentoxifylline and/or IgM-Enriched Intravenous Immunoglobulin in the Management of Neonatal Sepsis

To investigate the effectivity of pentoxifylline (PTX) and immunoglobulin M (IgM)-enriched intravenous immunoglobulin (IVIG) therapy in the treatment of neonatal sepsis (NS), alone or in combination. This was a prospective, double-blind, controlled study. Newborns with suspicion of sepsis were enrolled in the study. The patients were separated into four groups according to treatment protocol: Group 1 = placebo, Group 2 = pentoxifylline, Group 3 = IgM-enriched IVIG, and Group 4 = pentoxifylline + IgM-enriched IVIG. Blood samples were taken for C-reactive protein, interleukin-6, neutrophil CD64 expression, and tumor necrosis factor-alfa measurements immediately before treatment (1st day), and measurements were repeated on the 2nd and 4th days of the therapy. A total of 204 patients, 51 in each group, were recruited into the study. There were no significant differences for symptoms of sepsis among groups, except lethargy. No significant differences were observed among the groups according to laboratory data. Overall mortality rate was 8.8%. The rates of morbidities and mortality among study groups were similar. PTX and IgM-enriched IVIG therapies, either alone or in combination, did not reduce the rates of morbidities and mortality in NS.