IVIG Infusion Research Articles

M413 COVID-19 IN A PATIENT WITH CVID AND CONTRAINDICATIONS TO SEVERAL POTENTIAL TREATMENTS

Despite nearly 18 million cases of SARS-CoV-2 thus far, there is minimal information regarding treatment in patients with common variable immunodeficiency (CVID), such as presented here. A 59-year-old male with CVID was receiving IVIG infusion when RN noted lethargy, fever, and cough. Chest Xray showed bilateral lower lobe opacities. Labs significant for lymphopenia to 0.5, CRP 4.9, CK 23, ESR 22. SARS-CoV-2 testing positive. Given history of atrial fibrillation, hypertension, severe back pain, and 10.5-pack-year smoking history, patient requested to be DNR/DNI. Patient eventually required high flow oxygen with 70% FiO2 at 35L/min. Hydroxychloroquine initiated, but Qtc became prolonged. He received vitamin C and enrolled in convalescent plasma trial. Patient’s respiratory status worsened with increasing hypoxia. D-dimer increased to 7.63, ferritin to 2862, and LDH to 533. Prone position poorly tolerated. BiPAP recommended, but patient increasingly anxious and declined, requesting to go home to die. Within 2 days of receiving plasma, mentation improved; within 9 days oxygen requirements decreased; discharge occurred after 24 days in the hospital. Patient subsequently admitted for severe back pain and found to be still SARS-CoV-2 positive, 8.5 weeks from initial test. However, he continued asymptomatic on room air with improved chest xray. This patient had contraindications to several potential medications, physical limitations with proning, and slow recovery after receiving convalescent plasma, though he did not require ventilator support. There was evidence of hyperinflammation secondary to COVID-19, and it is unknown to what degree immunodeficiency may have been protective against a severe cytokine storm. Further investigation necessary.

Tregitopes regulate the tolerogenic immune response and decrease the foetal death rate in abortion-prone mouse matings

The imbalance in immune tolerance may cause the variety of reproductive failures. An intravenous immunoglobulin infusion (IVIg) therapy is used to improve the live birth rate in women suffering from recurrent pregnancy loss, recurrent spontaneous abortions and recurrent implantation failures. However, the results of IVIg studies are still inconclusive as IVIg infusion in women suffering from pregnancy loss is sometimes ineffective. One of the mechanisms of action of this treatment is inhibition of B cells differentiation and expansion of Tregs and secretion of interleukin 10. It was proposed that immunomodulatory effects of IVIg may be attributed to tregitopes - self-IgG-derived epitopes present in the structure of immunoglobulins. Similarly to IVIg, tregitopes cause the expansion of Tregs and secretion of antigen-specific effector cytokine response. Here, we studied whether the administration of mouse tregitope 167 and/or 289 can prevent abortions in mouse abortion-prone mouse matings. We revealed that tregitopes reduce the foetal death rate. This may be driven by observed higher pool of peripheral Tregs, increased production of IL-10 by Tregs and Bregs and/or maintaining the tolerogenic phenotype of antigen-presenting cells. We believe that our findings may indicate a potential alternative to IVIg for therapeutic intervention in case of pregnancy failures.

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter.

Solid organ transplant recipients may be at a high risk for SARS‐CoV‐2 infection and poor associated outcomes. We herein report our initial experience with solid organ transplant recipients with SARS‐CoV‐2 infection at two centers during the first 3 weeks of the outbreak in New York City. Baseline characteristics, clinical presentation, antiviral and immunosuppressive management were compared between patients with mild/moderate and severe disease (defined as ICU admission, intubation or death). Ninety patients were analyzed with a median age of 57 years. Forty‐six were kidney recipients, 17 lung, 13 liver, 9 heart, and 5 dual‐organ transplants. The most common presenting symptoms were fever (70%), cough (59%), and dyspnea (43%). Twenty‐two (24%) had mild, 41 (46%) moderate, and 27 (30%) severe disease. Among the 68 hospitalized patients, 12% required non‐rebreather and 35% required intubation. 91% received hydroxychloroquine, 66% azithromycin, 3% remdesivir, 21% tocilizumab, and 24% bolus steroids. Sixteen patients died (18% overall, 24% of hospitalized, 52% of ICU) and 37 (54%) were discharged. In this initial cohort, transplant recipients with COVID‐19 appear to have more severe outcomes, although testing limitations likely led to undercounting of mild/asymptomatic cases. As this outbreak unfolds, COVID‐19 has the potential to severely impact solid organ transplant recipients.

Immunotherapy for GRIN2A and GRIN2D-related epileptic encephalopathy

BackgroundGRIN-related developmental-epileptic encephalopathies are associated with a spectrum of neurodevelopmental disorders, including intellectual disability, epilepsy including continuous spike-and-wave during sleep syndrome (CSWS), or epilepsy-aphasia spectrum phenotypes such as in Landau-Kleffner syndrome. Efficacy of IVIG treatment was recently reported in a patient with LKS related to GRIN2A mutation. Aim and MethodsWe describe the efficacy of Immunotherapy in 5 consecutive patients (4 males, age range 6 months-13 years) with molecularly confirmed GRIN-related epileptic encephalopathy (4 with GRIN2A- related epilepsy-aphasia spectrum/epileptic encephalopathy with CSWS, accompanied by verbal, communicative and behavioural regression, and one patient with GRIN2D – related infantile developmental-epileptic encephalopathy). All patients had global developmental delay/ intellectual disability in various degrees, and were resistant to anticonvulsants, but none of the patients had frequent clinical seizures. All patients received monthly infusion of IVIG 2 g/ kg for 6 months; 2 patients were also treated with high-dose corticosteroids. ResultsNormalization or near normalization of the EEG was noted in 3 patients, from whom 2 had mild improvement in verbal abilities and communication skills. Perceptual/spatial abilities, as well as executive functions and attention span, remained significantly impaired. Conclusionaccording to this preliminary, open-label study, Immunotherapy may lead to a clinical and electrographic improvement in patients with GRIN-related developmental-epileptic encephalopathies. Further studies to validate the efficacy of immunotherapy and the potential role of autoimmunity in GRIN-related disorders are needed.

Intravenous Immunoglobulin Infusion Reactions in Kawasaki Disease Patients Who Undergo Sedation.

Although IVIG infusions are usually well tolerated, reactions can include hypotension, chills, and, rarely, anaphylactic reactions. Risk of adverse reactions correlates with dose and rate of IVIG infusion. An echocardiogram is the preferred imaging modality to detect coronary artery changes in acute Kawasaki disease (KD), but the quality of the study can be compromised if a child moves much during the imaging procedure. Thus, sedation is often required for children younger than 3 years of age. There is concern regarding coadministration of IVIG and sedatives. Therefore, the purpose of this analysis is to determine when the majority of IVIG infusion reactions occur to help find the optimal time to safely perform a sedated echocardiogram in patients with KD. This is a retrospective, single-center analysis of patients with KD administered IVIG at Rady Children's Hospital San Diego from November 1, 2013, to October 31, 2016. Of the 260 subjects in this study, 34 (13%) had an IVIG infusion reaction consisting of either chills or hypotension. There were no anaphylactic reactions. All infusion reactions occurred within 4 hours of starting IVIG. No hypotension reactions occurred after 4 hours. All subjects were able to complete their IVIG infusion without any further complications. Given that the maximum IVIG infusion rate is reached at 1.5 hours per our hospital's policy and that the overwhelming majority of infusion reactions occurred within the first 4 hours, we found it is safe to coadminister IVIG with sedation 4 hours after initiation of IVIG infusion.

Pediatric Motor Inflammatory Neuropathy: The Role of Antiphospholipid Antibodies

We report the clinical case of a nine-year-old girl who presented with progressive motor neuropathy, revealed via the detection of a higher delay in F-wave recording using digitalized nerve conduction/electromyography. Since the lupus anticoagulant (LAC) positivity, detected using diluted Russell viper venom time (dRVVT), switched to persistent serological anticardiolipin immunoglobulin G (IgG) positivity, a possible non-thrombotic antiphospholipid antibody (aPL)-related clinical manifestation was suspected, and intravenous immunoglobulin treatment (IVIG) was started. The IVIG treatment was well tolerated and the complete resolution of motor impairment was obtained after the third IVIG infusion. Our findings suggest that it could be useful to check for antiphospholipid antibodies in children with a rapid onset of progressive neurological signs in order to provide the beneficial use of IVIG in the treatment of pediatric aPL neurological conditions.

Desensitization Therapy for Patients with DSA Receiving Haploidentical (Haplo) Stem Cell Transplantation

<h3>Introduction</h3> The effect of desensitization therapy on patients with Donor-specific Anti-HLA Antibodies (DSA) for patients receiving Haplo transplantation are unknown. <h3>Methods</h3> Data of all 51 patients with DSA receiving Haplo transplantation between 11/2010-1/2019 at MD Anderson Cancer Center (N=41) and City of Hope (N=10) were included. Patients received desensitization with plasma exchange (PE), rituximab (R), and IVIg +/- buffy coat (BC) infused on day-1, as previously described by us (Ciurea SO. BBMT.2018:53:521). We analyzed transplant outcomes for DSA treated patients vs. those without DSA receiving Haplo transplant in the same period of time (control; N=345). <h3>Results</h3> The median age of patients with DSA was 51 years (range 19-69) and 47 years (range 18-72) in control group (p=0.15). There were no significant differences in diagnosis, remission status at transplant, DRI and ABO matching between 2 groups. RIC conditioning was used in 28% and 43% in DSA and control group, respectively (p=0.03) whereas 67% and 82% respectively (p=0.02) received marrow stem cell. Median levels of DSA on single antigen assay before desensitization was 5556 MFI (range 2360-28688). Of 51 patients with DSA, 37 (72.5%) DSA patients received desensitization with PE, R and IVIg, and 27/37 (73%) patients also received BC infusion before transplant. Twenty of 37 (54%) desensitized patients had DSA >5000 MFI and 14 out of them had complement binding DSA suggested by a positive C1q assay. Cumulative incidence (CI) of neutrophil engraftment at 28 days for patients who had DSA>5000 MFI and received desensitization was 75% compared with 91% in those without DSA (p=0.12) (Figure 1A) while 1-year NRM was 32% vs. 29% (p=0.57) (Figure 1B) and 1-year OS was 54% vs. 58%, respectively (p=0.18) (Figure 1C). The engraftment rate is significantly improved with desensitization treatment as our previous study demonstrated that only 46% of patients with DSA>5000 MFI achieved engraftment (Ciurea SO. BBMT.2015;21:1392). Remarkably, patients with DSA 2000-10000 who received treatment had 83% engraftment vs. 91% (p=0.86). Among 14 patients who had C1q+ DSA, 8 patients had persistently positive C1q after desensitization and only 4 engrafted, 2 had primary graft failure and 2 died before engraftment with CI of engraftment at 28 days of 43% (p=0.09 compared with control group). Persistent C1q positivity was associated with significantly higher NRM (37% vs. 29% at 1 year, p=0.01) and lower OS (33% vs. 58% at 1 year, p=0.002) compared with control group (Figure 1D). These significances persisted after adjusting for other factors in multivariable analysis. <h3>Conclusions</h3> Treatment with PE, R, IVIg and BC infusion is an effective strategy to desensitize patients with DSA before haploidentical transplantation. Patients who remain C1q+ at transplantation have high risk for engraftment failure and should not proceed to transplantation.

EP.19Anti-HMGCR positive necrotizing myopathy presenting in childhood

A 12-year-old girl, previously healthy, was hospitalized because of progressive proximal weakness for a few months. CK was 17000U/L. There were only minor skin changes, but an initial muscle biopsy was reported to have changes possibly compatible with dermatomyositis. Treatment was started with prednisolone and methotrexate, without adequate improvement. A biopsy two years later did not exclude the diagnosis of a muscular dystrophy. The fast development of weakness did not however really fit clinically. A neuromuscular gene panel analysis (328 genes) did not reveal the etiology, and ANA- and ANCA tests were negative. She gradually became weaker. At the age of 15,5y, she could not walk any longer, her upper extremities were weak, and she could not shift position in bed. She also had pain in her legs, and breathing and swallowing were affected. She was still on prednisolone, but methotrexate had been stopped. A new biopsy showed more extensive, chronic myopathic changes and acute changes, with fibers in different stages of necrosis. CK was 2600 U/L. MRI of total body disclosed generalized edema and patchy infiltration of fat in all visible muscles, combined with muscle atrophy. It was then suggested to test for HMGCR antibodies which were positive. The patient was started on IVIG infusions in addition to previous therapy and restarted methotrexate. She improved gradually. After one year she could walk with assistance, swallowing was normal, and respiration was much improved. HMGCR associated necrotizing autoimmune myopathy (NAM) may well occur without statin exposure. However, the disease is rare in childhood. A muscle biopsy with scattered necrotic fibers without inflammatory infiltrate should raise the suspicion of the disease. Because it is treatment responsive, HMGCR associated NAM is an important differential diagnosis also in children when the clinical picture, imaging and laboratory findings are in the borderline between a myositis and a muscular dystrophy.

2. Pregnancy and myositis

2. Pregnancy and myositis

Argatroban-refractory, Heparin-induced Thrombocytopenia after Coronary Intervention with Radial Artery Occlusion.

Heparin induced thrombocytopenia (HIT) is serious disorder that occurs in a small percentage of patients following exposure to heparin. HIT can further be classified into two types: HIT type 1 and type 2. Type 2 HIT is a potentially life threatening with clinically significant outcomes. It presents with thrombocytopenia and evidence of thrombus formation in the presence of antibody formation. Additionally, several variations of HIT exist, including delayed onset HIT and refractory HIT, known collectively as autoimmune HIT (aHIT). Here we present a case of delayed onset and refractory HIT in a patient with little heparin exposure, discovered only after cardiac intervention for suspected STEMI. Significant thrombotic events occurred thereafter, including radial artery stenosis and intracardiac thrombus. Treatment with argatroban was ineffective. Significant resolution of thrombocytopenia was seen several weeks after infusion with IVIG, thus depicting further suspicion for refractory HIT. IVIG for aHIT treatment is traditionally chosen only if the disease process is refractory to other anticoagulation efforts due to the potential risk for increasing thrombotic risk with IVIG infusion. Our case illistrate the rare presentation of aHIT and the use if IVIG to successfully treat thrombocytopenia in refractory HIT.

086 Clinical, investigational and treatment factors do not determine prognosis of patients with inflammatory neuropathies

IntroductionIdentifying patients who need long-term immunoglobulin (IVIg) treatment in patient with inflammatory neuropathies is essential as recent treatment trials show a remission rate of up to 40%.AimsCompare retrospective data on clinical, investigational and treatment factors in patients who have ceased IVIg with patients who have failed a cessation trial.Methods15 patients who successfully suspended IVIg infusions were compared with 15 in whom decreasing or stopping IVIg was unsuccessful.Results30 patients (12 with CIDP and 3 with MMN in both groups) were diagnosed 39.5 months from onset of symptoms in the successful group vs. 40.7 months in the unsuccessful group (p=0.953). There was a significant difference in the summed upper limb sensory amplitudes on electrophysiology prior to starting IVIg between the patients with CIDP (17.4 mV vs. 9.8mV p=0.007). There was no difference in the average doses between the groups. A successful cessation trial was attempted at a mean of 60.5 months post starting treatment, compared with 60 months in the unsuccessful patients.ConclusionThere is a need for objective biomarker to measure disease activity because other than one neurophysiology marker, other factors did not help predict a successful cessation trial of IVIg.

Rituximab-based maintenance therapy in Waldenström macroglobulinemia: A case control study.

7559 Background: Waldenström macroglobulinemia (WM) is a rare indolent lymphoma commonly treated with rituximab (R)-based therapy. The use of rituximab maintenance (mR) in WM is controversial. We present a case-control study of patients (pts) with WM treated with mR. Methods: Pts evaluated at Mayo Clinic, Rochester with active WM that received mR between 1/2000 &amp; 6/2018 were included. Cases comprised pts who received mR following R-based induction as primary therapy. Cases were matched based on the time of diagnosis in 1:2 ratio with a control group treated with R-based primary induction therapy without mR. Time to event analyses were performed from initiation of R-based induction. Results: Of 776 pts with active WM, 42 (5%) cases received mR and 84 pts were selected as controls. The median follow-up and the proportion of high risk pts were comparable between the two cohorts (Table). Pts in the mR cohort show a trend toward longer time to next therapy (TTNT) and a significantly longer overall survival (OS) compared to the control group (Table). The R-based induction therapies were comparable in the two cohorts (p = 0.6). Median duration of mR was 1.9 yrs (95% CI 1.6-2) and mR was used most frequently every (q) 2 (range 1-6) months. Of the 42 mR pts, 25 (60%) received an R-based combination for induction and 17 (40%) received R monotherapy as induction. Five (12%) pts discontinued mR due to toxicity, infections were reported in 13 pts (31%) during mR therapy and 3 pts (7%) received IVIg infusions for recurrent infections. Conclusions: R-based induction followed by mR demonstrates a longer OS in WM compared to R-treated control population not receiving mR, albeit at a high rate of infections. Despite limitations of a retrospective study, with a heterogeneously treated cohort, these data add to the body of literature supporting Rituximab maintenance. Results from an ongoing randomized controlled trial are awaited. [Table: see text]

Indirect-comparison meta-analysis of treatment options for patients with refractory Kawasaki disease

BackgroundThere is limited information available regarding the clinical management of intravenous immunoglobulin-resistant Kawasaki disease (KD). We aimed to evaluate the optimal treatment options for patients with refractory KD by presenting an indirect-comparison meta-analysis.MethodsPubMed, EMBASE, Web of Science, and the Cochrane Database were searched on August 31, 2018. Unpublished studies were also searched in ProQuest Dissertations & Theses and through manual retrieval strategies. Randomized concurrent controlled trials (RCTs), high-quality non-randomized concurrent controlled trials (non-RCTs), and retrospective studies associated with AEs were included. The quality of all eligible studies was assessed using Cochrane collaboration’s tool and non-randomized study guidelines. Risk ratios (RR) with 95% confidence intervals (CIs) for dichotomous outcomes were estimated in our analysis. GRADE profiler 3.6.1 was used to assess the evidence profile.ResultsTwelve studies involving 372 immunoglobulin-resistant KD patients were identified and analyzed. Neither infliximab nor intravenous pulse methylprednisolone (IVMP) was significantly more effective than second IVIG infusion with respect to lowering coronary artery lesions (CALs) (infliximab, 0.85, 0.43–1.69; IVMP, 0.99, 0.52–1.88) and treatment resistance (infliximab, 0.43, 0.21–0.89; IVMP, 1.16, 0.33–4.13). No significant differences were found between infliximab and IVMP in the incidence rate of CALs (0.70, 0.27–1.81), the treatment resistance (0.37, 0.09–1.60), the rates of coronary artery aneurysm (4.13, 0.38–45.22) and the coronary artery dilatation (0.45, 0.10–1.99). Furthermore, compared with second IVIG infusion, both infliximab and IVMP showed significant effectiveness in antipyretic effects (infliximab, 1.52, 1.16–1.99; IVMP, 1.29, 0.77–2.15). However, Infliximab was noninferior to IVMP on antipyretic effects (1.18, 0.66–2.15). IVMP treatment showed significant association with fewer AEs than second IVIG infusion (0.49, 0.26–0.94) and infliximab (2.34, 1.07–5.09). No significant differences were noted between infliximab treatment and second IVIG infusion (1.06, 0.69–1.63).ConclusionsInfliximab, IVMP, and second IVIG infusion showed no significant differences in the cardioprotective effect or the rate of treatment resistance. Infliximab and IVMP treatment were more effective than second IVIG infusion regarding antipyretic effects. IVMP treatment may have an advantage due to its lower total rate of AEs associated with drug infusion.Trial registrationThe study has been registered on PROSPERO (CRD42016039693).

Successful liver retransplantation due to acute AMR with 18 hours anhepatic period, complicated by the necrotizing pancreatitis

Introduction: This case describes the successful re-LTx (with 18 hours anhepatic period) performed due to severe AMR on the 10th POD. On the 7th day after re-LTx ischemic necrotizing pancreatitis developed. The patient died 20 days after the re-LTx due to the septic shock. Method: The patient S., aged 58, was transplanted due to NASH-related cirrhosis (MELD 23, hepatorenal syndrome). LTx was performed from non-marginal DBD. Result: First four postoperative days (PODs) were uneventful. From 5th till 10th PODs liver graft function progressively deteriorated with the level of AST/ALT of 5500 / 5300 U/l and INR of 3.6 on the 10th POD. Despite the sequential steroid pulse therapy, IVIG infusion and plasmapheresis, performed from the 6th to the 9th PODs, liver graft failure with multi-organ failure was developed on the 10th POD. The recipient was transferred to the operation theatre: the total graft necrosis was revealed (histologically C4d-positive antibody mediated rejection); hepatectomy and temporary portacaval shunt were performed. After this the patient condition was stabilized and the patient has been waiting for the liver graft in the operating theatre. Liver retransplantation from marginal DBD (graft steatosis - 60 %) was performed after 18 hours of anhepatic period. Early postoperative period was complicated by Enterococcus spp serous peritonitis, successfully treated by planned relaparotomies and antibiotic treatment. The second liver graft function was adequate. On the 7th day after re-LTx pancreonecrosis with necrosis of the mesentery of the descending colon was revealed. Despite provided intensive care the patient died 30 days after the 1st LTx. Conclusion: The aim - to verify on what step incorrect tactics was applied (if it was): 1. a) Classic technique vs Piggy-back in patients with severe HRS? b) Should we avoid Tac in patients with RRT in early postoperative period? c) Could we save that sort of patient?

Intravenous immunoglobulins for rheumatic disorders and thromboembolic events-a case series and review of the literature.

To report the temporal association between a series of thromboembolic events and intravenous immunoglobulin infusion in patients with rheumatic diseases, and to review the literature on the subject. The clinical presentation, course, and outcome of thromboembolic events occurring post-immunoglobulin infusion in nine patients is described. A web-based literature review using the PubMed database from 1996 to 2017 was performed, searching for the keywords: thrombosis, thromboembolism, intravenous immunoglobulin, pulmonary embolism, deep vein thrombosis, cerebrovascular event, and acute myocardial infarction. Nine patients who had suffered a thromboembolic event within a week after receiving an intravenous immunoglobulin infusion (Omr-IgG-am™, OMRIX) were identified among our joint cohort. All patients except one were female ranging in age from 22 to 69years. Five had progressive systemic sclerosis (one of them had progressive systemic sclerosis with antiphospholipid syndrome, and another had an overlap of progressive systemic sclerosis with systemic lupus erythematosus), the sixth had monoclonal IgM autoimmune neuropathy, the seventh had systemic lupus erythematosus with antiphospholipid syndrome, the eighth had granulomatosis with polyangiitis (GPA) and the ninth had overlap autoimmune syndrome. Six of the patients had an arterial thrombosis: an acute myocardial infarction in four, a brachial artery thrombosis in the fifth, and a cerebrovascular attack in the sixth. Three patients sustained a venous thrombosis and/or an acute pulmonary embolism (one of them had a DVT with the PE). Two events occurred during the IVIG infusion, three within an hour after the last infusion of the 5-day course, one occurred a few hours after the initiation of the IVIG therapy, another occurred 3days after receiving the final infusion of the 10th course, and two events occurred a week after the treatment course has ended. Fifty-five percent of the patients had no thrombogenic risk factors other than their rheumatic condition, and most of them had received numerous, uneventful IVIG treatment courses before sustaining the thromboembolic event. No immediate deaths occurred among this cohort. Thromboembolic events after IVIG infusions, although infrequent, may occur in rheumatic patients, even in the absence of other recognizable risk factors for thromboembolism. The reported events had occurred despite complying with recommended guidelines for IVIG administration, which include a lengthy 8-h infusion and division of the total dose. No correlation was found between the number and frequency of the infusions to the thromboembolic events. Heightened awareness of possible thromboembolic events in rheumatic patients is encouraged for at least a week following IVIG administration.

Protective Role Immunoglobulin Replacement Therapy in Chronic Lymphocytic Leukemia: FOCUS on Subcutaneous Immunoglobulin Formulations

INTRODUCTION. Secondary antibody deficiency is a common complication in chronic lymphocytic leukemia (CLL) that could be present at diagnosis or can be acquired during the follow-up due to CLL progression, perturbation of non-neoplastic immune system and chemoimmunotherapy. Despite new and active target therapies a significant amount of CLL patients still develops severe and life-threatening infections. Intravenous immunoglobulin (IG) (IVIG) replacement therapy (IGRT) has been proven to be an effective supportive treatment in patients with primary and secondary antibody deficiency such as CLL. Subcutaneous immunoglobulin (SCIG) is a new valid treatment option that allows patients self-administration without access to the clinic which proved to be as effective as IVIG in primary immunodeficiencies. However, the activity SCIG is CLL patients with IG defect has been little investigated.The aim of this study was to retrospectively evaluate IG levels, infection rate and safety of patients treated with SCIG as compared to those managed with IVIG.METHODS. Inclusion criteria were: diagnosis of CLL according to iwCLL guideline, age >18 years, received at least 1 IVIG or SCIG infusion. IGRT was started according to hospital policies in patient with severe symptomatic hypogammaglobulinemia. The physician was responsible for the choice between IGRT formulations (the first patient received SCIG since Nov 2008). IG levels (IgG, IgA and IgM) were recorded within 3 months before starting IGRT (baseline), after 6 months and within three months from the last available follow-up. Continuous variables were compared with Wilcoxon's tests while categorical variables with Fisher's exact or Chi-square tests when appropriate. Time to IGRT discontinuation was calculated from the beginning IGRT to death or discontinuation (event) or last available follow-up /(censored).RESULTS. We gathered data from 116 CLL patients followed in 2 hematology centers who received IGRT: 63% were male, the median age at diagnosis was 58 years, 77 were at Binet A stage, 48% and 16% were unmutated IGHV and harbor TP53 abnormalities, respectively. 91% received at least one therapies, the median numbers of treatments were 3 (range 0-9) and 36% died during the follow-up due to infections in 22 cases, CLL progression in 5, Richter transformation in 6 patients and 9 other causes such as second cancers or major bleedings. Forty-nine patients received IVIG and 88 SCIG (41 the 20% formulation and 47 the 16% drugs).Despite similar basal and +6 months IgG levels, patients treated with SCIG achieved significant higher serum IgG at last available follow-up (3.99, 5.67 and 5.4 g/L vs 3.89, 6.07 and 6.22 g/L for IVIG and SCIG, p=0.0009). Both IgA and IgM levels remained stable during replacement therapy.While the number of grade 3-4 infections remain stable during IVIG (both 80% before and after IVIG), they decrease with SCIG (88% vs 64%, p<0.0019). Furthermore, the incidence of all and grade 3-4 infections decreased to 0.59 and 0.17, and 0.30 and 0.13 events/people/year with IVIG and SCIG, respectively. Incidences of infections was not higher in patients receiving oral inhibitors (i.e. ibrutinib, idelalisib and venetoclax).Adverse events during SCIG infusions occurred in 11% of subjects, most commonly skin reaction and pruritus. They were mild, limited to the site of infusion and easily to manage. Bruising did not increase during concomitant treatment of SCIG and ibrutinib.After a median duration of IGRT of 3.7 years (4.7 for IVIG and 3.1 for SCIG) 71% of subjects managed with IGEV discontinued therapy as compared to 36% of SC formulation (p<0.0001), 16% due to death in the former group as opposite to 9% of the latter. The estimated 3-year time to IGRT discontinuation were 44% vs 29% for IVIG and SCIG, respectively (p=0.2089). 29 patients shit from IVIG to SCIG, while none to opposite. We also observed that patients who shift from IVIG to SCIG were able to achieved higher IgG levels at last follow-up (median IgG 4.76 vs 6.62g/L, p<0.0001).CONCLUSIONS. In this study we described the clinical and biological characteristics of the bigger population with CLL and secondary hypogammaglobulinemia receiving IGRT. We demonstrated that SCIG are well tolerated, non-inferior to IVIG, they also allow to reach higher IgG through levels and to decrease the incidence of severe infections even during continuous CLL therapies. DisclosuresVisentin:janssen: Consultancy, Honoraria. Mauro:abbvie: Other: board member; janssen: Other: board member. Foà:ROCHE: Other: ADVISORY BOARD, Speakers Bureau; AMGEN: Other: ADVISORY BOARD; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; NOVARTIS: Speakers Bureau. Trentin:Gilead: Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria; Janssen: Research Funding.

NECROTIZING FASCIITIS SECONDARY TO CLOSTRIDIUM SEPTICUM IN A PATIENT WITH MYD88 DEFICIENCY

Introduction MyD88 deficiency impairs toll-like receptor and interleukin-1 receptor mediated immunity. This results in bacterial infections of the upper respiratory tract and skin and predisposes patients to invasive infection with pyogenic bacteria. Clostridium septicum is an anaerobic bacteria that rarely affects children. This case discusses a patient with MyD88 deficiency presenting with necrotizing fasciitis secondary to Clostridium septicum. Case Description Our patient is a 9-year old female with known MyD88 deficiency and history of multiple invasive bacterial infections. She presented with knee and abdominal pain and had extensive subcutaneous air on x-ray. She was immediately taken to the operating room for debridement and wound VAC placement and was found to have necrotizing fasciitis, necrotizing myositis, and necrotizing cellulitis secondary to Clostridium septicum. She was started on broad spectrum antibiotics that were later narrowed based on culture sensitivities. She then developed further extension of her disease and antibiotics were adjusted. Throughout her hospitalization she underwent numerous debridements, hyperbaric oxygen therapy, and multiple IVIG infusions. Antibiotic therapy was adjusted throughout hospitalization and narrowed by time of discharge. Discussion This patient's presentation of necrotizing fasciitis, necrotizing myositis, and necrotizing cellulitis secondary to Clostridium septicum is unique. This organism is typically found to infect adults with malignant disease, such as colorectal cancer. In other reported pediatric cases of Clostridium septicum, it has been associated with neutropenia. This case is important to report, as it may lead to discovery of additional pathways in which MyD88 deficiency may alter immune response. MyD88 deficiency impairs toll-like receptor and interleukin-1 receptor mediated immunity. This results in bacterial infections of the upper respiratory tract and skin and predisposes patients to invasive infection with pyogenic bacteria. Clostridium septicum is an anaerobic bacteria that rarely affects children. This case discusses a patient with MyD88 deficiency presenting with necrotizing fasciitis secondary to Clostridium septicum. Our patient is a 9-year old female with known MyD88 deficiency and history of multiple invasive bacterial infections. She presented with knee and abdominal pain and had extensive subcutaneous air on x-ray. She was immediately taken to the operating room for debridement and wound VAC placement and was found to have necrotizing fasciitis, necrotizing myositis, and necrotizing cellulitis secondary to Clostridium septicum. She was started on broad spectrum antibiotics that were later narrowed based on culture sensitivities. She then developed further extension of her disease and antibiotics were adjusted. Throughout her hospitalization she underwent numerous debridements, hyperbaric oxygen therapy, and multiple IVIG infusions. Antibiotic therapy was adjusted throughout hospitalization and narrowed by time of discharge. This patient's presentation of necrotizing fasciitis, necrotizing myositis, and necrotizing cellulitis secondary to Clostridium septicum is unique. This organism is typically found to infect adults with malignant disease, such as colorectal cancer. In other reported pediatric cases of Clostridium septicum, it has been associated with neutropenia. This case is important to report, as it may lead to discovery of additional pathways in which MyD88 deficiency may alter immune response.

IgG levels in Kawasaki disease and its association with clinical outcomes.

Previous studies have suggested an association of IgG levels (before and after IVIG infusion) with clinical outcomes in Kawasaki disease. A retrospective analysis was performed that included 418 patients with KD admitted to Tokyo Women's Medical University Yachiyo Medical Center to evaluate pre- and post-IVIG IgG levels and its relation to outcomes. All patients received an initial IVIG infusion and aspirin; IgG levels were measured in 350 patients before IVIG (pre-IVIG IgG levels) and in 373 patients 48h after starting IVIG infusion (post-IVIG IgG levels). Media and standard deviation of the pre- and post-IVIG IgG levels were reported and classified according to age. Also, IgG z-scores were calculated according to normal values of IgG by age. The number of cases and corresponding percentage of non-responders were reported by age and total patients. The association of pre-IVIG, post-IVIG IgG levels and post-IVIG IgG level/pre-IVIG IgG level ratio with no-response was evaluated by simple logistic regression model based on the IgG z-score, and regression coefficient, X2 value, p, and R2 of Nagelkerke were reported. Pre-IVIG and post-IVIG IgG levels presented an association with non-responders with statistical significance. This association was more evident between post-IVIG IgG levels and non-responders. Regarding coronary alterations, it was not possible to perform an adequate statistical analysis due the small number of patients. Pre- and post-IVIG infusion IgG levels could be an important biomarker in KD as well as in other inflammatory conditions. Higher IgG levels could be associated with a more effective immunomodulatory action and associated with better clinical outcomes.

WED 223 Predicting disease activity in inflammatory neuropathies

BackgroundThere is currently no accurate way to determine who will need long-term immunoglobulin (IVIg) treatment in chronic inflammatory demyelinating polyneuropathy (CIDP) and multifocal motor neuropathy (MMN).AimsRetrospectively compare clinical, investigational and treatment factors in patients who have successfully ceased IVIg with patients who have active disease.Methods15 patients who have successfully suspended IVIg infusions were compared with 15 in whom decreasing the IVIg dose was unsuccessful.Results30 patients (12 with CIDP and 3 with MMN in both groups) were diagnosed 39.5 months from onset of symptoms in the successful group vs 40.7 months in the unsuccessful group (p=0.953). There was a significant difference in the summed upper limb sensory amplitudes on electrophysiology prior to starting IVIg between the patients with CIDP (17.4 mV vs 9.8 mV p=0.007). There was no difference between the average doses between the groups. A successful cessation trial was attempted at a mean of 60.5 months post starting treatment, compared with 60 months in the unsuccessful patients.ConclusionOther than the differences in initial upper limb amplitudes, other factors did not help predict a successful cessation trial of IVIg. This reinforces the need for an objective biomarker to measure disease activity.

P148 Precise definition of HLA-antibody by ruling out false positive reactivity from luminex single antigen assay in supporting succesful thoracic organ transplantation

False positive antigen specificities (FPAS) from the Luminex Single Antigen (LSA) Assay are difficult to identify due to multiple interfering factors and various corresponding resolving approaches. Over calling antibodies limits a patient’s access to deceased donor organs and can result in erroneous immune therapy. Here we report how to properly identify and resolve FPAS from LSA assays to precisely provide HLA-antibody results in supporting Thoracic Organ Transplantation (TOT). We retrospectively studied 66 TOT cases that had suspected FPAS reactions with LSA assays. The initial antibody work up was tested by LSA and FlowPRA Screening Beads. Discordance between the two assays and/or ambiguity were verified by Luminex Phenotype Beads. LSA was used for all antibody follow up. If an obvious antibody increase was observed, further investigation for sensitizing events and/or possible interfering medication (such as IvIg), warranted additional testing. Detailed approaches for FPAS identification and resolution are listed in Table 1a. Of the 66 FPAS cases, 56 (85%) were caused by denatured antigen (dAg) and 10 (15%) were due to IvIg infusion. The distribution of complete FPAS and partial FPAS (the mixture of true positive and FPAS) from dAg and IvIg were almost equal, 54% vs 46% and 50% vs 50%, respectively. The FPAS dAg patterns with highest occurring frequencies were Cw1, Cw12, Cw15 (27%) from class I and DP1, DP11, DP13, DP6, DQ4 (34%) from class II. The elimination of FPAS reduced the average PRA by 67% from dAg and 78% from IvIg interference. 22 cases received TOT after FPAS were ruled out (Table 1b). FPAS is the prevalent issue of LSA when false negativity is eliminated by serum EDTA treatment. Alternative assays by multiple platforms, supplementary LSA data analysis, and referencing clinical records are warranted for ruling out FPAS. This provides precise antibody testing results for successful access to TOT.