IVIG Treatment Research Articles

Extending the functional characteristics of naturally occurring autoantibodies against β-Amyloid, Prion Protein and α-Synuclein.

BackgroundAbnormal aggregation of proteins induces neuronal cell loss in neurodegenerative disorders such as Alzheimer’s Disease, Creutzfeldt-Jakob Disease and Parkinson’s Disease. Specific stimuli initialize conformational changes in physiological proteins, causing intra- or extracellular protein aggregation. We and other groups have identified naturally occurring autoantibodies (nAbs) as part of the human antibody pool that are able to prevent peptide fibrillation. These nAbs show a rescue effect following exposure of toxic aggregates on neurons, and they support microglial uptake of aggregated peptides.ObjectiveIdentification of a putative common epitope among the relevant proteins β-Amyloid, α-Synuclein and Prion Protein for the respective nAbs.Material and methodsBinding affinity between the aforementioned proteins and nAbs was tested by Dot Blot, ELISA and SPR-technology. Furthermore, the functionality of the protein-nAbs-complexes was studied in Thioflavin-T assays and microglial uptake experiments to study dependent inhibition of protein aggregation and enhancement of Fcγ mediated uptake by microglial cells.Resultsβ-Amyloid and Prion Protein fragment showed considerable binding affinity and functional efficacy for all applied nAbs. Thereby, no significant difference within the different nAbs was detected. In contrast, α-Synuclein was bound exclusively by nAbs-α-Synuclein, which was reproduced in all binding studies. Surprisingly, functional assays with α-Synuclein revealed no significant effect of nAbs in comparison to IVIg treatment. However, all applied nAbs as well as IVIg show a minimal functionality on the microglial uptake of α-Synuclein.ConclusionnAbs-Aβ, nAbs-PrP possibly display comparable affinity to the same structural epitope within Aβ and PrP106-126 A117V whereas the epitope recognized by nAbs-α-Syn is only present in α-Syn. The structural similarity of Aβ and PrP fragment promotes the outline for an efficient antibody for the treatment of several neurodegenerative disorders and extend the functional characteristics of the investigated nAbs.

Establishment of a new scoring model for IVIG non-response of Kawasaki disease

Objective To analyze the possible risk factors of IVIG non-response of Kawasaki disease(KD), Shanghai Children′s Hospital and Shanghai Junze Software develop an research platform, which is based on E-Science model.Through the mathematical model by integrating the risk factors to explore the method of effective prediction for IVIG non-response, and to provide the clinical basis for timely and effective treatment and prognosis of the disease. Methods The data of KD children who were hospitalized in Shanghai Children′s Hospital from January 2013 to November 2016 were included.The indexes included gender, age, time of IVIG treatment, and laboratory examinations.The multivariate logistic regression was used to analyze the influencing factors of IVIG non-response.The indexes in the model were deduced according to the independent variables of the logistic regression equation.The ROC curve and the area under the curve were calculated for the new prediction model.The sensitivity and specificity of the new prediction model were calculated according to the cutoff value.Finally, the new model was compared with the Kobayashi and Egami scoring model. Results The levels of CRP, NLR, LDH, ALB and FDP in children with KD were influencing factors for IVIG non-response(P<0.05). According to the logistic regression equation, the sensitivity and specificity of the model used to predict IVIG non- response were 69.7% and 80.4%, respectively, and the area under the ROC curve was 0.825(95% CI: 0.769-0.882). Kobayashi and Egami scoring models were tested, the sensitivity and specificity of the new scoring system were better than previous ones. Conclusion The scoring model established in this study has a good effect in predicting IVIG non-response in KD patients and could be used in clinical practice, and it is worthy to be validated and adjusted by large-scale data. Key words: E-Science; Kawasaki disease; IVIG no response; Scoring model

Oral fingolimod for chronic inflammatory demyelinating polyradiculoneuropathy (FORCIDP Trial): a double-blind, multicentre, randomised controlled trial

Fingolimod is approved for the treatment of relapsing-remitting multiple sclerosis and was effective in experimental autoimmune neuritis in rats, a possible model for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). We aimed to evaluate the efficacy of fingolimod in delaying disability progression in patients with CIDP who withdrew from currently effective treatments (intravenous immunoglobulin [IVIg] or corticosteroids). This double-blind, multicentre, randomised, placebo-controlled, parallel-group, event-driven study was done at 48 neurology centres in Australia, Canada, Israel, Japan, the USA, and nine countries in Europe. Participants with CIDP who were receiving IVIg or corticosteroids were randomly assigned (1:1) to once-daily oral fingolimod 0·5 mg or placebo. Owing to the event-driven design, treatment duration was flexible and could be up to 4·5 years. Randomisation was done with an automated interactive voice response-web response system and was stratified by Inflammatory Neuropathy Cause and Treatment (INCAT) disability scale scores. Previous IVIg treatment was discontinued after one final course ending the day before the first dose of fingolimod or placebo was given, whereas corticosteroids were tapered off over 8 weeks after randomisation. The primary endpoint was time to first confirmed worsening (≥1 point increase on the adjusted INCAT disability scale score versus baseline) and was assessed in the full analysis set, which consisted of all patients who underwent randomisation and had at least one efficacy assessment for the primary analysis. The survival distribution functions of time to first worsening were estimated within each treatment group according to the Kaplan-Meier survival distribution function and compared with a stratified log-rank test. The trial is registered with ClinicalTrials.gov, number NCT01625182. Of 106 participants randomly assigned between Jan 24, 2013, and March 10, 2016, 54 received fingolimod (41 who had been receiving IVIg and 13 who had been receiving corticosteroids) and 52 received placebo (41 who had been receiving IVIg and 11 who had been receiving corticosteroids). The trial ended for futility as recommended by an independent data monitoring committee after an interim analysis when 44 confirmed worsening events had occurred. At the end of the study, the survival estimate of the proportion of participants free from confirmed worsening was not significantly different between the fingolimod group (42%, 95% CI 23-60) and the placebo group (43%, 28-59; p=0·91). Adverse events occurred in 41 (76%) participants receiving fingolimod and 44 (85%) on placebo, and serious adverse events occurred in nine (17%) and four (8%) patients, respectively. The most common adverse events with fingolimod were headache (12 [22%] patients), hypertension (ten [19%]), and extremity pain (seven [13%]). Adverse events leading to study discontinuation occurred in seven (13%) participants on fingolimod and none on placebo. Fingolimod 0·5 mg once-daily was not better than placebo for the treatment of CIDP. Future trial designs should take account of the possibility that if IVIg is stopped abruptly, some patients might relapse soon afterwards whereas others might remain in remission. Novartis Pharma.

Biweekly Hizentra\xae in Primary Immunodeficiency: a Multicenter, Observational Cohort Study (IBIS)

Immunoglobulin G (IgG) replacement therapy is a standard treatment for patients with primary immunodeficiency diseases (PIDs). Hizentra®, a 20% human subcutaneous IgG (SCIG), is approved for biweekly administration for PIDs. The aim of the multicenter IBIS study was to prospectively investigate the efficacy of biweekly Hizentra® compared with previous IVIG or SCIG treatment regimens in patients with PIDs. The study consisted of a 12-month retrospective period followed by 12-month prospective observational period. The main endpoints included pre-infusion IgG concentrations, proportion of patients with serious bacterial infections (SBIs), other infections, hospitalizations due to PID-related illnesses, and days with antibiotics during the study periods. Of the 36 patients enrolled in the study, 35 patients continued the study (mean age 26.1 ± 14.4 years; 68.6% male). The mean pre-infusion IgG levels for prior immunoglobulin regimens during the retrospective period (7.84 ± 2.09 g/L) and the prospective period (8.55 ± 1.76 g/L) did not show any significant variations (p = 0.4964). The mean annual rate of SBIs/patient was 0.063 ± 0.246 for both prospective and retrospective periods. No hospitalizations related to PIDs were reported during the prospective period versus one in the retrospective period. All patients were either very (76.5%) or quite (23.5%) satisfied with biweekly Hizentra® at the end of the study. In conclusion, the IBIS study provided real-world evidence on the efficacy of biweekly Hizentra® in patients with PIDs, thus verifying the data generated by the pharmacometric modeling and simulation study in a normal clinical setting.

Treatment options in myocarditis and inflammatory cardiomyopathy

For myocarditis and inflammatory cardiomyopathy, an etiologically driven treatment is today the best option beyond heart failure therapy. Prerequisites for this are noninvasive and invasive biomarkers including endomyocardial biopsy and polymerase chain reaction on cardiotropic agents. Imaging by Doppler echocardiography and cardiac magnetic resonance imaging as well as cardiac biomarkers such as C‑reactive protein, N‑terminal pro-B-type natriuretic peptide , and troponins can contribute to the clinical work-up of the syndrome but not toward elucidating the underlying cause or pathogenetic process. This review summarizes the phases and clinical features of myocarditis and gives an up-to-date short overview of the current treatment options starting with heart failure and antiarrhythmic therapy. Although inflammation in myocardial disease can resolve spontaneously, often specific treatment directed against the causative agent is required. For fulminant, acute, and chronic autoreactive myocarditis, immunosuppressive treatment has proven to be beneficial in the TIMIC and ESETCID trials; for viral cardiomyopathy and myocarditis, intravenous immunoglobulin IgG subtype and polyvalent intravenous immunoglobulins IgG, IgA, and IgM can frequently resolve inflammation. However, despite the elimination of inflammation, the eradication of parvovirus B19 and human herpesvirus-6 is still a challenge, for which ivIg treatment can become a future key player.

Delayed intravenous immunoglobulin treatment increased the risk of coronary artery lesions in children with Kawasaki disease at different status

ABSTRACT Objective: Kawasaki disease (KD) is a systemic vasculitis with serious complications, especially the development of coronary artery lesions (CALs). The aim of this study was to identify the risk for the development of CALs with IVIG treatment of KD >10 days after illness onset in patients with different KD status, and explore potential moderators of the association between delayed treatment and CALs. Methods: We performed a retrospective review of the medical records of KD patients. All patients were divided into two groups (conventional therapy group and delayed therapy group, IVIG treatment ≤10 days vs >10 days). We compared the demographic and clinical characteristics, laboratory data, and analyzed risk factors for CALs in patients who received IVIG treatment >10 days, and determined whether different status of KD modified the effects of delayed IVIG treatment on CALs. Results: In the delayed IVIG treatment group, children were more likely to develop CALs and the proportion of incomplete KD was higher, compared with the conventional therapy group. The number of children younger than 12 months or older than 61 months was higher and children had higher BMI and were more likely to receive steroids before diagnosis in the delayed IVIG treatment group compared with the conventional therapy group. Delayed IVIG treatment was an independent risk factor for the development of CALs (adjusted OR = 2.90, 95%CI = 1.42, 5.91). Delayed therapy children with higher levels of C-reactive protein (>79 mg/L) and erythrocyte sedimentation rate (>34 mm/h) had the highest risk for developing CALs (OR = 5.68, 95%CI: 1.17, 27.59; OR = 4.11, 95%CI: 1.62, 10.46, respectively). Conclusion: Delayed IVIG treatment was an independent risk factor for the development of CALs. Children in the delayed IVIG treatment group with higher levels of CRP and ESR (CRP >79 mg/L, ESR >34 mm/h) had the greatest likelihood of developing CALs.

Changes and significance of histone acetylation associated with forkhead box P3 gene during the acute phase of Kawasaki disease

Objective To investigate the histone acetylation status of forkhead box P3(Foxp3) gene and its roles in immunological pathogenesis of Kawasaki disease(KD). Methods Forty-two children with KD and 32 age-matched healthy children consented to participate in this study as a control group.Co-immunoprecipitation and real-time PCR were performed to determine acetylation levels of histone H4 associated with Foxp3 gene and binding abilities of Kruppel like factor 10(KLF10) and p300/CBP-associated factor (PCAF) with Foxp3 gene in CD4+ T cells.The proportion of CD4+ CD25high Foxp3+ cells (Treg) and protein levels of Foxp3, KLF10, PCAF, phosphated SMAD family member 2/3(pSmad2/3) and itchy E3 ubiquitin protein ligase(Itch) were analyzed by flow cytometry.Quantitative real-time PCR was used to evaluate the levels of Foxp3, transforming growth factor-β1 receptor Ⅱ (TGF-βRⅡ), transforming growth factor-β1 receptor Ⅰ(TGF-βRⅠ), tyrosine kinase 2(Tyk2), SH2 domain-containing protein-tyrosine phosphatase-2(SHP2) and cytotoxic T-lymphocyte-associated protein 4(CTLA4) mRNA in Treg.Plasma concentrations of TGF-β and interleukin-6(IL-6) were measured by enzyme-linked immunosorbent assay. Results (1)Compared with the control group, the proportion of Treg, expression levels of Foxp3 and TGF-β, and histone acetylation levels of Foxp3 promoter decreased remarkably during acute KD, and the differences were all statistically significant(all P<0.05), and restored after IVIG therapy(all P<0.05). Meanwhile, the 5 indexes aforementioned in KD patients with coronary artery lesions (KD-CAL+ ) were lower than those without coronary artery lesions(KD-CAL-), and the differences were all statistically significant (all P<0.05). (2)Compared with the control group, protein levels of KLF10 and PCAF in Treg cells, and their binding abilities with Foxp3 gene were significantly down-regulated during acute KD, and the differences were all statistically significant(all P<0.05), and restored to some extent after IVIG treatment(all P<0.05). Positive correlations between protein levels of KLF10 and PCAF, and mRNA level of Foxp3 were detected in acute KD patients (r=0.47, 0.59, all P<0.05). Furthermore, protein levels of KLF10 and PCAF and their binding abilities with Foxp3 gene in KD-CAL+ group were lower than those in KD-CAL- group, and the differences were all statistically significant(all P<0.05). (3) Compared with the control group, the plasma concentration of TGF-β and expressions of TGF-βRⅡ/Ⅰ, pSmad2/3, Itch, CTLA4 and SHP2 in Treg were down-regulated during the acute phase of KD, and the differences were all statistically significant(all P<0.05), as well as plasma concentration of IL-6 and expression its downstream molecule Tyk2 increased remarkably in patients with acute KD(all P<0.05). All the indexes mentioned before restored significantly after IVIG treatment (all P<0.05). Simultaneously, the 7 former indexes in KD-CAL+ group were found to be lower than those in KD-CAL- group, while 2 indexes of the latter in KD-CAL+ group were higher than those in KD-CAL- group, and the differences were all statistically significant(all P<0.05). Conclusion Histone hypoacetylation of Foxp3 promoter might be one of the important factors contributing to insufficiency and dysfunction of regulatory T cells during acute Kawasaki disease. Key words: Kawasaki disease; Foxp3; Histone; Acetylation; Immune

Platform Session – Electromyography: Nerve ultrasound for the identification of treatment-responsive chronic neuropathies without nerve conduction abnormalities

We aimed to determine whether nerve ultrasound can improve detection of potentially treatable chronic inflammatory neuropathies in patients that have normal nerve conduction study (NCS). Diagnostic consensus criteria for inflammatory neuropathies primarily rely on NCS results that indicate multifocal demyelination. However, additional supportive criteria are developed to identify these treatable inflammatory neuropathies. In this study we examined the additional value of sonography in the detection of treatable inflammatory neuropathies. We analysed 240 incident patients with clinical suspicion of chronic inflammatory neuropathy; work-up consisted of routine ancillary investigations recommended in the diagnostic consensus guidelines and a standardized sonographic protocol assessing arm nerves and brachial plexus. All patients without any demyelinating features on NCS, but with sonographic abnormalities fitting inflammatory neuropathy and a clinical phenotype totally compatible with chronic inflammatory demyelinating polyneuropathy (CIDP), Lewis Sumner Syndrome (LSS), or multifocal motor neuropathy (MMN), received standard treatment with IVIg. Treatment effect was evaluated by routine clinical examination and hand grip or myometry. We found 17 patients (7%) with a clinical phenotype compatible with CIDP (n = 10), LSS (n = 1) and MMN (n = 6, with 3 positive for anti-GM1 auto-antibodies), sonographic nerve enlargement of proximal median nerve segments and/or cervical (nerve) roots, yet negative NCS (2 only axonal loss, 15 normal). An abnormal MRI of brachial plexus was found in 9/17 patients (53%) and an elevated protein content of cerebrospinal fluid in 9/17 patients (53%). All 17 patients showed objective improvement on IVIG treatment. Our study suggests that nerve ultrasound may help to improve detection of treatment-responsive chronic neuropathies, even in patients not fulfilling the diagnostic NCS and other supportive criteria, including MRI of the brachial plexus. Therefore, future revisions of the diagnostic consensus criteria may include sonography as complementary technique to NCS and MRI.

Neutropenia after intravenous immunoglobulin therapy is associated with coronary artery lesions in children with Kawasaki disease: a case control study

BackgroundTo evaluate differences in laboratory parameters, clinical presentation, and incidence of coronary artery lesions (CAL) between children with neutropenic and non-neutropenic Kawasaki disease (KD).MethodsAll consecutive KD patients that presented to the Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University in Wenzhou, China between January 2005 and December 2015 were included in this study. Patients were divided into two groups (KD with neutropenia (NKD) and KD without neutropenia (NNKD)) based on whether or not they developed neutropenia during the course of treatment. We compared differences in clinical manifestations, laboratory parameters, and treatment protocols between groups. We also evaluated the relationship between neutropenia with immunoglobulin dosage and incidence of CAL.ResultsAn IVIG treatment regimen of 2 g/kg*1d was associated with a lower incidence of neutropenia compared to the 1 g/kg*2d protocol. The incidence of CAL was higher in KD patients with neutropenia than in those without. Subgroup analysis showed no difference in the incidence of CAL among the different age groups between KD patients with and without neutropenia.ConclusionsFollow up ultrasonic echocardiography should be performed in KD patients with neutropenia in order to allow for early detection of CAL and timely intervention.

High albumin level is a predictor of favorable response to immunotherapy in autoimmune encephalitis

There is no known biomarker that predicts the response to immune therapy in autoimmune synaptic encephalitis. Thus, we investigated serum albumin as a prognostic biomarker of early immune therapies in patients with autoimmune encephalitis. We enrolled patients who were diagnosed with definite autoimmune encephalitis and underwent IVIg treatment at Seoul National University Hospital from 2012 to 2017. Patients were dichotomized according to serum albumin prior to IVIg administration with a cut-off level of 4.0 g/dL, which was the median value of 50% of patients. Seventeen (53.1%) of the 32 patients with definite autoimmune encephalitis who received IVIg treatment in our hospital had low serum albumin (<4.0 g/dL). The initial disease severity (mRS ≥ 4) was the sole factor that predicted low albumin in autoimmune encephalitis patients using multivariate analysis (P = 0.013). The low albumin group exhibited a worse response to immune therapy at the third and fourth weeks from IVIg administration (P < 0.01 and P = 0.012, respectively), and recovery to activities of daily life without assistance was faster in the high albumin group (log-rank test for trend, P < 0.01). Our study found that pretreatment low serum albumin was a significant indicator of autoimmune encephalitis prognosis in the short-term and long-term.

A child with subcorneal pustular dermatosis responded to IVIG treatment (Sneddon-Wilkinson disease).

Subcorneal pustular dermatosis (SPD) is a rare, chronic, recurrent dermatosis characterised by sterile pustules. It develops mainly in middle-aged or elder women, but is also rarely seen in children. The exact aetiology of the disease is unknown. In literature, cases associated with IgA gammopathy have been reported. In this article; we report a case of a five-year-old girl who was diagnosed as SPD by clinical features, histopathological characteristics, and direct immunofluorescence analysis results. IgA was high, and IgG-IgM and CD19+ B cell were low. We noticed that during IVIG treatment for immunodeficiency, dermatological symptoms were recovered rapidly. Clinical profile of SPD and its association with systemic diseases may provide early detection of immune dysfunction.

A Case of Acute Hepatitis in Patient With Guillain-Barre Syndrome

Introduction: Differential diagnosis for acute hepatitis (AH) is broad. AH in association with Guillain Barre Syndrome (GBS) was studied in a prospective study in the Netherlands in 1996 which showed significant elevation of liver enzymes patients with GBS in comparison to control. This association was even more prominent in the subgroup of patients who received IVIG for treatment. Here we report the first case of acute hepatitis in a patient with GBS who received IVIG. Case description: A 24-year-old female with no significant past medical history presented to Loma Linda Hospital emergency room with four-day history of increasing weakness in bilateral lower extremities. The patient had no history of alcohol or drug use. On physical examination, she noted to have diminished strength bilateral lower extremities. No stigmata of chronic liver disease. EMG showed a picture of acute demyelination. Spinal fluid showed albumin cytologic dissociation consistent with GBS. Initial liver function panel showed AST=75, ALT=111, ALP=64 Total bilirubin=0.5 on day one of hospital stay and before receiving any treatment. However, patient continued to have rising liver enzymes especially after receiving IVIG. Patient had extensive negative work up including acute viral hepatitis panel, CMV IgM, IgG and PCR, EBV serology and PCR as well as HSV PCR. Upon discharge, she continued to have elevated liver enzymes; AST=191, ALT =213, ALP= 69 and total bilirubin of 0.5 consistent with acute hepatitis, likely due to underlying GBS and IVIG treatment. Liver enzymes completely normalized 8 weeks after discharge. Discussion: Liver function abnormalities associated with GBS have been attributed to the antecedent infections, mainly CMV and EBV. Recently few case reports mentioned association of GBS with acute hepatitis E infection. However, no previous case reports in the USA described acute hepatitis associated with GBS. New elevation in liver transaminases in association with a new onset GBS should be investigated to rule out other causes of AH including antecedent infections. Although a rare finding, further studies are needed to better understand the pathophysiology of AH in patients with GBS.

Seeing the Forest for the Trees: A Case of an Atypical Bacterial Pneumonia Leading to the Diagnosis of CVID

SESSION TITLE: Other Infections SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Combined Variable Immunodeficiency Disorder (CVID) in adults is a rare but frequently lethal disease due to its low clinical suspicion and heterogeneous presentation. We present a patient in septic shock due to multifocal bacterial pneumonia who was ultimately diagnosed with CVID. CASE PRESENTATION: A 34-year old female with no significant past medical history presented for 2 days of worsening shortness of breath preceded by 2 weeks of productive coughs, fevers, chills, and fatigue. On presentation, she was found to have absent left lung sounds and underwent an immediate chest tube thoracostomy for a pneumothorax. A subsequent CT showing bilateral multifocal cystic consolidations and a large loculated effusion in the left lung base. Initial labs showed a moderate leukocytosis with neutrophilia. The patient was admitted to the ICU for septic shock secondary to a bilateral necrotizing pneumonia and required a second chest tube to drain her left lung effusion. Pleural fluid, blood, and sputum cultures grew out Prevotella and Achromobacter. The patient ultimately required emergent intubation for hypoxic respiratory failure, and was found to have severe hypogammaglobinemia correlating with CVID on labratory results. On later questioning, the patient recalled that she had recurrent annual sinus infections since adolescence and was once told by a physician she had an illness that’s description correlated with autoimmune hemolytic anemia. Allergy & Immunology and Infectious Disease were immediately consulted, and the patient was started on amphotericin B, ciprofloxacin, and meropenem in addition to undergoing 2 rounds of IVIG treatment. The patient was ultimately transferred out of the ICU in stable condition and discharged home with close follow-up for further workup of her CVID. DISCUSSION: The mean age of onset for CVID in females is 27-years old, with a typical delay in diagnosis of 6-7 years. The spectrum of initial presentation is wide, including sinopulmonary infections, autoimmune diseases, and even malignancy, making diagnosis difficult. However, early detection is essential as the mean age of mortality in females is 44-years old, with delay to diagnosis being one of the biggest risk factors for mortality. CONCLUSIONS: We present a case of a previously undiagnosed female with CVID presenting with severe bilateral necrotizing bacterial pneumonia requiring an extensive ICU stay with multiple invasive interventions. Early detection of her CVID may have prevented this near-fatal encounter, and serves as valuable evidence for the need to regularly consider immunodeficiency disorders in adults with recurrent infections. Reference #1: Gathmann B, Mahlaoui N, Ceredih, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116-126. Reference #2: Resnick ES, Moshier EL, Godbold JH, Cunningham-Rundles C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood. 2012;119(7):1650-1657. DISCLOSURE: The following authors have nothing to disclose: Lakshay Jain, Sami Bashour, Harman Kular, Simon Yau, Purvesh Patel, Nicola Hanania No Product/Research Disclosure Information

Joint glucocorticoid clinical analysis of initial treatment of Kawasaki disease

Objective To investigate the advantages of glucocorticoid combined with traditional methods and to explore glucocorticoid use in appropriate time in the whole course of the disease and the appropriate dose. Methods With reference to Kawasaki disease(KD)diagnostic criteria, 363 cases of patients with KD were enrolled, and divided into conventional treatment group and combined hormone group randomly.Combined hormone group according to clinical manifestations can be divided into sub groups as typical KD and atypical KD group.We analyzed respectively before and after 1 week treatment in two groups of children with the onset of age, gender, heating duration after treatment, IVIG treatment time, hospitalization days and total hospitalization expenses, tips and course of acute stage, recovery period the relevant indexes to the test, and coronary artery lesion(CAL)in one month. Results Thermal process after treatment, hospitalization duration and hospitalization expenses decreased significantly in combined hormone group compared with conventional treatment group.The difference between the two, in the clinical laboratory indexes and CAL have no obvious difference.In different types of KD, the thermal process after treatment, hospitalization days and hospitalization expenses, have decreased significantly in typical KD sub group when treating with combined hormone therapy comparing with hormone therapy atypical sub group.Other clinical laboratory indexes and CAL have no obvious differences in compared between the sub groups. Conclusion Combined hormone therapy for KD patients, plays an important role in shortening the thermal process after treatment and reducing the hospitalization expense. Key words: Kawasaki disease; Glucocorticoids; Intravenous gamma globulin

P 37 Rare treatable cause of ulnar nerve paresis after critical illness detected by nerve ultrasound

We report a case of neuropathy of the right ulnar nerve first diagnosed after intensive care unit treatment including ventilation and hemodialysis due to a status epilepticus. A 37-year-old caucasian male presented with convulsive status epilepticus. Since he underwent surgical treatment of a left cerebral arteriovenous malformation 11 years ago he suffered on symptomatic epilepsy. Some weeks before he decide to stop his antiepileptic drugs. Following admission to the intensive care unit (ICU), the antiepileptic medication (valproate, phenytoin) was without successfully alleviating seizures. The patient was finally anaesthetized and intubated to secure airway. Medication of propofol and midazolam resulted in a burst supression pattern on EEG. Finally a combination of levetiracetam and phenytoin was given. EEG was than without epileptic activity. Unfortunately patient suffered pneumonia, consecutive sepsis with renal failure and required hemodialysis for 13 days. ICU treatment was successfull and weaning of mechanical ventilation was achieved after 4 weeks. When patient was awake he noted weakness and paraesthesias of his right hand. Because of general weakness following severe disease it was thought to be a symptom of a critical illness neuropathy. After admission to rehabilitation clinic general weakness improved rapidly, but a sensorimotor ulnar paresis persisted. All muscles of the right hand supplied by the ulnar nerve showed weakness and atrophy equally. Electromyography of the right abductor digiti minimi muscle (ABDM) showed fibrillation potentials and positive sharp waves. Neurography showed slow nerve conduction velocity (NCV) oft he right ulnar nerve of the foream (36 m/s; left: 51 m/s), but normal NCV oft he upper arm. Compound motor action potential (CMAP) oft he right ABDM was strongly diminished (0,3 mV; left 6 mV) on all sites of stimulation. There were neither sensory nerve action potential nor F-waves obtainable oft he right ulnar nerve. Left ulnar nerve and median nerve bilaterally showed normal findings. There were no clinical signs of involvement of other peripheral nerves. Nerve sonography was performed to rule out local compression, for example caused by synovial cyst. Ulnar nerve showed a 3-4-fold thickening of the cross sectional area (CSA) beginning in the distal forearm up to the distal upperarm. Nearly all fascicles showed discontinuous hypoechoic hyperthrophy. Neither other nerves nor brachial plexus showed abnormal findings on nerve sonography. Laboratory investigations did not reveal any pathology concerning focal hypertrophic neuropathy. Despite the monofocal pattern diagnosis of multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) was made. At that time the symptoms of the ulnar paresis remained unchanged since 3 month. We introduced IVIG treatment and patient responded well. This case demonstrates the diagnostic power of nerve sonography in addition to routine investigations in the detection of a curable focal neuropathy. It should be used in any case of focal neuropathy if no other diagnosis can be made safely.

OR40 Applying single-cell mass cytometry to investigate the immune system of highly sensitized patients who undergo intravenous immunoglobulin desensitization treatment

Aim To identify potential immune markers for predicting and monitoring IVIG desensitization by CyTOF technology. Methods CyTOF: A panel of 37 antibodies against phenotypic and functional immune makers were labelled with metals and used to define 27 cell populations by Single-cell mass cytometry. Applying Cytobank ( http://www.cytobank.org ) (Chen and Kotecha, 2014), visualizing cellular features of interest across all the cells in a dataset were manually gated and clustered cell population according to the proper cell markers. SEM (Significance Analysis of Microarrays) paired algorithms was used for the data statistical analysis. Results Two highly sensitized patient frozen PBMC samples were tested in vitro and in vivo by CyTOF. The expression of HLA-class I (HLA-I) decreased in all cell populations after incubating patient PMBC (in vitro sample) with 2.5%IVIG for 16 h. Excepting B cells, the expression of HLA-I also decreased after 15 courses of IVIG treatment (in vivo sample). IVIG treatment increased inhibitory Fc receptor CD32IIb expression significantly on basophils, myeloid dendritic cells (DC), and all B cells (especially memory B cells) in vivo; and increased CD56 and CD25 expressions on NK cells and Treg cells respectively. Conclusions IVIG treatment significantly increases inhibitory markers expression on APC cells and activated Treg cells in desensitization patient. Inhibitory Fc receptor CD32IIb, CD56, CD25, and HLA-I could be useful immune marker for predicting and monitoring IVIG efficacy in desensitization.

P057 Factors THA impact downregulation of HLA antibodies in heart transplant candidates

Aim The presence of HLA antibodies in highly sensitized heart transplant candidates is a barrier that can prevent these individuals from receiving a lifesaving transplant. In an effort to downregulate their HLA antibodies, many candidates are treated with high-dose intravenous immunoglobulin. While this therapeutic approach to downregulation is successful in some subjects, others show no response. In this study, we attempted to identify factors associated with the successful downregulation of HLA antibodies in highly sensitized candidates eligible for heart transplantation. Methods Fifteen heart transplant candidates (ages 25–66) in this retrospective chart review had calculated panel reactive antibody (cPRA) levels ranging from 41 to 100%. In an effort to downregulate HLA antibodies, all subjects received monthly IVIG (2 g/kg; number of doses ranged from 2 to 25). Data evaluated included gender, age, race, BMI, ventricular assist device (VAD) type, desensitization regimen, PRA levels, antibodies present prior to and after IVIG, as well as history of blood transfusions, pregnancies, and previous transplants. Patients were considered responders to IVIG therapy if their original cPRA level decreased by ⩾50%, and non-responders if the decrease in cPRA was Results Patients included in this study had all received a VAD with a mean cPRA of 79.6 prior to IVIG treatment. IVIG efficacy was demonstrated by lower cPRA values ( p p = 0.005) in the responder group. Compared with the non-responder group, responders were more likely to be male ( p = 0.036) and females without previous pregnancies ( p = 0.036). Trends towards responsivenss were also seen with white race (0.106) and greater number of IVIG doses ( p = 0.085). Download high-res image (289KB) Download full-size image Conclusions IVIG is an appropriate treatment for highly sensitized patients eligible for heart transplant with patient-specific characteristics including male gender and pregnancy status, making certain patients more responsive to therapy than others.

Acute autonomic neuropathy with severe gastrointestinal symptoms in children: a case series

BackgroundAcute autonomic neuropathy (AAN) is rare disorder with anecdotal report, especially for childhood onset patients. Misdiagnosis or delays in treatment can always be found in clinical practice. We conducted this study to give a description of the manifestations and treatment of AAN in children and therefore help clinicians to make the accurate diagnosis early so that the prognosis of the patients can be improved.MethodsA systematic record from 3 clinical centers was used to identify 11 subject, 3 males and 8 females, with clinical diagnosed AAN.ResultThe age ranged from 2 years and 4 months to 14 years and 6 months (mean, 9 ± 3.6 years old) and the course from onset to diagnosis ranged from 7 days to 8 months. All children shared prominent initial symptoms, 7 with frequent vomiting and 4 with motor dysfunctions. The condition of 9 patients improved after treatment of IVIg and intravenous glucocorticoid.ConclusionThe clinical manifestations of AAN are diverse, generalized, and non-specific. Gastrointestinal disorders were the most common initial symptoms. Symptoms of gastrointestinal system and abnormal secretion of glands were severe and more common than other symptoms. The mechanism of AAN remains unknown. Although IVIg and intravenous glucocorticoid can be used in clinical practice, there is still no treatment recommendation and further study is needed.

S40 Diagnosis and follow-up of TTR-FAP: Common misdiagnoses

Transthyretin familial amyloid polyneuropathy (TTR-FAP) is a highly disabling, life threatening disease characterized by progressive sensorimotor and autonomic neuropathy. The profile of the disease is inadequately understood at present. Variable clinical features, lack of awareness among physicians and limited access to genetic screening can all contribute to high rates of misdiagnosis and poorer patient outcomes. Existing treatment options and emerging therapies opened a new era in the management of TTR-FAP. Time to diagnosis can be more than 4 years especially, in non-endemic areas. The common misdiagnoses include diabetic neuropathy which is sensory neuropathy with small fiber predominance and autonomic symptoms and signs. TTR-FAP should be kept in mind in CIDP cases not responding to conventional immunosuppressives and IVIg treatment. Idiopathic axonal neuropathies constitute a large group of undiagnosed polyneuropathies. A thorough investigation, including missing points of the family and patient history can lead to TTR-FAP diagnosis in some cases. AL amylodosis can also be confusing in the elderly. Other differential diagnosis possibilities include HSAN, Fabry’s disease and leprous neuropathy. As ATTR is an irreversible and progressive disease, diagnosing patients and initiating treatment as early as possible are essential. Delay in the time to diagnosis is a major obstacle to the optimal management of TTR-FAP.

Risk Factors of Resistance to Intravenous Immunoglobulin in Patients with Kawasaki : A Cross-Sectional Study over a 10 Year Period (2006 - 2016)

Abstract Introduction: Kawasaki is an acute vasculitis and is the most common cause of acquired heart disease in children. About 25% of patients remain infected and febrile despite receiving intravenous immunoglobulin and aspirin. The aim of this study was to investigate the clinical and laboratory predictive resistance factors for intravenous immunoglobulin in patients with Kawasaki hospitalized in Khorramabad Shahid Madani Hospital. Materials and Methods: Patients were divided into two groups: a) responders to IVIG treatment, consisting of 47 patients (90/4 %); and b) resistant to treatment, consisting of 5 patients (9.6%), and the difference between clinical manifestations and laboratory findings of the two groups were examined and the results were statistically analyzed. Results: 52 patients with Kawasaki diagnosis were gauged. In the treatment-resistant group (9.6%), the number of clinical symptoms was lower than that of KAU diagnosis criteria, but this difference was not statistically significant between the two groups. Laboratory tests evaluation showed that the mean of ESR and CRP were higher in the treatment-resistant group and the mean of serum sodium in this group was lower than that of the responder group. Discussion and Conclusion: High ESR and CRP and lower serum sodium levels can be considered as predictors of resistance to intravenous immunoglobulin therapy in patients with Kawasaki. Keywords Author Keywords:Kawasaki disease; immunoglobulin resistance; acute vasculitis KeyWords Plus:DISEASE; CHILDREN