IVIG Group Research Articles

Intravenous immunoglobulin fails to improve ARDS in patients undergoing ECMO therapy

BackgroundAcute respiratory distress syndrome (ARDS) is associated with high mortality rates. ARDS patients suffer from severe hypoxemia, and extracorporeal membrane oxygenation (ECMO) therapy may be necessary to ensure oxygenation. ARDS has various etiologies, including trauma, ischemia-reperfusion injury or infections of various origins, and the associated immunological responses may vary. To support the immunological response in this patient collective, we used intravenous IgM immunoglobulin therapy to enhance the likelihood of pulmonary recovery.MethodsARDS patients admitted to the intensive care unit (ICU) who were placed on ECMO and treated with (IVIG group; n = 29) or without (control group; n = 28) intravenous IgM-enriched immunoglobulins for 3 days in the initial stages of ARDS were analyzed retrospectively.ResultsThe baseline characteristics did not differ between the groups, although the IVIG group showed a significantly reduced oxygenation index compared to the control group. We found no differences in the length of ICU stay or ventilation parameters. We did not find a significant difference between the groups for the extent of inflammation or for overall survival.ConclusionWe conclude that administration of IgM-enriched immunoglobulins as an additional therapy did not have a beneficial effect in patients with severe ARDS requiring ECMO support.Trial registrationClinical Trials: NCT02961166; retrospectively registered.

A randomized double-blind trial of intravenous immunoglobulin for bullous pemphigoid

BackgroundPatients with steroid-resistant bullous pemphigoid (BP) require an appropriate treatment option. ObjectiveA multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of high-dose intravenous immunoglobulin (IVIG; 400mg/kg/day for 5days) in BP patients who showed no symptomatic improvement with prednisolone (≥0.4mg/kg/day) administered. MethodsWe evaluated the efficacy using the disease activity score on day15 (DAS15) as a primary endpoint, and changes in the DAS over time, the anti-BP180 antibody titer, and safety for a period of 57days as secondary endpoints. ResultsWe enrolled 56 patients in this study. The DAS15 was 12.5 points lower in the IVIG group than in the placebo group (p=0.089). The mean DAS of the IVIG group was constantly lower than that of the placebo group throughout the course of observation, and a post hoc analysis of covariance revealed a significant difference (p=0.041). Furthermore, when analyzed only in severe cases (DAS≥40), the DAS15 differed significantly (p=0.046). The anti-BP180 antibody titers showed no difference between the two groups. ConclusionIVIG provides a beneficial therapeutic outcome for patients with BP who are resistant to steroid therapy.

Rituximab in Combination With Bortezomib, Plasmapheresis, and High-Dose IVIG to Treat Antibody-Mediated Renal Allograft Rejection.

BackgroundCurrent treatment strategies for antibody-mediated renal allograft rejection (AMR) are not sufficiently effective. In most centers, “standard of care” treatment includes plasmapheresis (PPH) and IVIG preparations. Since several years, modern therapeutics targeting B cells and plasma cells have become available. We investigated, whether combined administration of rituximab and bortezomib in addition to PPH and high-dose IVIG is useful.MethodsBetween November 2011 and January 2013, we treated 10 consecutive patients with biopsy-proven AMR with rituximab (500 mg), bortezomib (4× 1.3 mg/m2), PPH (6×), and high-dose IVIG (1.5 g/kg) (group A). This group was compared with a group of 11 consecutive patients treated with an identical regimen without rituximab between July 2010 and November 2011 (group B).ResultsMedian follow-up was 41(33-46) months in group A and 55(47-63) months in group B. At 40 months after treatment, graft survival was 60% in group A and 64% in group B, respectively (P = 0.87). Before and after treatment, serum creatinine, estimated glomerular filtration rate, and proteinuria were not different between groups. A significant reduction in donor-specific HLA antibody mean fluorescence intensity was observed in group A (25.2%, P = 0.046) and B (38.3%, P = 0.01) at 3 months posttreatment. In group A, more patients suffered from side effects compared with group B (infections: 70% vs 18%, P = 0.02).ConclusionsThe addition of rituximab to bortezomib, PPH, and high-dose IVIG did not further improve graft survival. Instead, we observed an increase of side effects. Therefore, combined administration of bortezomib and rituximab in addition to PPH and IVIG should be regarded with caution.

Effects of pooled human immunoglobulins in an animal model of neuromyelitis optica with chronic application of autoantibodies to aquaporin 4.

Effects of pooled human immunoglobulins in an animal model of neuromyelitis optica with chronic application of autoantibodies to aquaporin 4.

Low-dose intravenous immunoglobulin treatment for complex regional pain syndrome (LIPS): study protocol for a randomized controlled trial.

BackgroundLongstanding complex regional pain syndrome (CRPS) is refractory to treatment with established analgesic drugs in most cases, and for many patients, alternative pain treatment approaches, such as with neuromodulation devices or rehabilitation methods, also do not work. The development of novel, effective treatment technologies is, therefore, important. There are preliminary data suggesting that low-dose immunoglobulin treatment may significantly reduce pain from longstanding CRPS.Methods/DesignLIPS is a multicentre (United Kingdom), double-blind, randomised parallel group, placebo-controlled trial, designed to evaluate the efficacy, safety, and tolerability of intravenous immunoglobulin (IVIg) 0.5 g/kg plus standard treatment, versus matched placebo plus standard treatment in 108 patients with longstanding complex regional pain syndrome. Participants with moderate or severe CRPS of between 1 and 5 years duration will be randomly allocated to receive IVIg 0.5 g/kg (IntratectTM 50 g/l solution for infusion) or matching placebo administered day 1 and day 22 after randomisation, followed by two optional doses of open-label medication on day 43 after randomisation and on day 64 after randomisation. The primary outcome is the patients’ pain intensity in the IVIG group compared with the placebo group, between 6 and 42 days after randomisation. The primary trial objective is to confirm the efficacy and confidently determine the effect size of the IVIG treatment technology in this group of patients.Trial registrationISRCTN42179756 (Registered 28 June 13).Electronic supplementary materialThe online version of this article (doi:10.1186/1745-6215-15-404) contains supplementary material, which is available to authorized users.

Effects of intravenous human immunoglobulin on late hyporegenerative anemia secondary to rhesus hemolytic disease of the newborn

Background and objectives: To determine the effects of intravenous immunoglob-ulin (IVIg) on the course of late hyporegenerative anemia and the requirement for exchange transfusions, phototherapy and top-up red blood cell transfusions due to rhesus hemolytic dis-ease of the newborn (Rh-HDN). Patients and methods: This is retrospective cohort study of newborns with Rh-HDN who were treated with or without IVIg. Relevant maternal and neonatal data were obtained and analyzed. All infants were followed up as outpatients for a period of 2-3 months, and during the follow ups, complete blood counts (RBCs) were performed every two weeks to diagnose late hyporegenerative anemia. Results: Sixty-six infants with Rh-HDN were enrolled in this study (42 in the IVIg group and 24 in the no-IVIg group). We observed no significant differences between the two groups in terms of maternal age, number of previous children affected with Rh-HDN, intrauterine transfusions, gestational age (GA), birth weight (BW), Apgar scores at the 1st or 5th minutes, exchange transfusions, or days on phototherapy. The serum bilirubin immediately after birth and the maximum serum bilirubin during the hospital course were significantly higher in the IVIG group (P = 0.0035 and P = 0.0225, respectively). Although there were no statistically significant dif-ferences, there was a trend toward the late anemia in the IVIg group being diagnosed and resolved earlier than in the no-IVIg group. Additionally, a greater proportion of the IVIg group required three or more top-up transfusions compared to the no-IVIg group, but this difference was not statistically significant. Conclusion: IVIg might have had an effect on the early development of late anemia and might have shortened the duration of late anemia relative to the infants who did not receive IVIg. The exchange transfusions and the days on phototherapy were not affected by IVIg.

Induction Of Tolerance To FVIII Using Nanoparticles In a Murine Model Of Hemophilia A

Anti-FVIII inhibitor development is currently considered the most serious side effect in the treatment of hemophilia A patients. In this study, we sought to address this problem by determining the efficacy of a novel tolerogenic protocol utilizing nanoparticle formulations provided by Selecta Biosciences. Thus, hemophilia A mice (FVIII KO, n = 6-8) were treated weekly for five weeks through intravenous route with 1 µg recombinant human FVIII (rFVIII), plus immune modulating agent coupled nanoparticles or control nanoparticles (coded F1 or F2 or F3). An additional control group was included, in which the mice were treated on the same schedule with high dose IVIG + rFVIII. As expected, all the mice in the control group (later revealed to be F3) developed high levels anti-FVIII IgG after the five treatments, with the average levels at 21.2 ± 4.4 µg/ml. Both the F1 and F2 nanoparticle treatments effectively prevented the anti-FVIII inhibitory antibody development throughout the course of the 5-week treatment. One week after the final treatment, the majority (5/7) of both F1 and F2 groups remained undetectable for anti-FVIII IgG antibodies. Consistent with this pattern, the anti-FVIII inhibitor titers for the F1, F2, F3 and IVIG groups were 42.3 ± 9.9, 14.3 ± 7.2, 92.9 ± 2.5, and 30.3 ± 5.6 Bethesda Units (BU)/ml, respectively after another 7 days (p < 0.01 for F1 and F2 vs. F3). To determine the duration of the FVIII-tolerance, the mice were challenged twice with rFVIII (1µg) 29 and 53 days after the final nanoparticle treatment. After the first FVIII challenge, the inhibitor titers for the F1, F2, F3 and IVIG groups were 81.3 ± 10.8, 33.1 ± 13.2, 84.1 ± 2.2 (p = 0.41 for F1 vs. F3; and p < 0.01 for F2 vs. F3), and 50.6 ± 9.7 BU/ml, respectively. Remarkably, the FVIII-tolerance in F2 group was sustained even after additional FVIII challenges ∼ 2 months later, when the effect in IVIG group was completely lost. A therapeutic protocol using mice pre-immunized with FVIII also led to substantial reductions in anti-FVIII titers. In conclusion, the concomitant Selecta F2 nanoparticle treatments not only significantly prevented the anti-FVIII inhibitory antibody development during the treatments, but also resulted in long-term FVIII-tolerance, suggesting a potential clinical application. (Supported in part by a grant-in-aid from Selecta Bioscience and by HL061883) Disclosures:Griset:Selecta Biosciences: Employment, Equity Ownership. Maldonado:Selecta Biosciences: Employment, Equity Ownership. Kishimoto:Selecta Biosciences: Employment, Equity Ownership. Scott:Selecta Biosciences: Research Funding.

Triptolide as an Alternative to IVIG Therapy for Kawasaki Disease in a Mouse Model

Kawasaki disease is treated by immunoglobulin therapy, which has adverse side effects like renal damage. The aim of the present study was to explore the effectiveness of triptolide, a compound derived from threewingnut that has anti-inflammatory effects, on the treatment of Kawasaki disease in a mouse model. Animal experiment. A mouse model of Kawasaki disease was established through exposure to Candida albicans by intraperitoneal injection. Exposed mice were then randomly divided into several groups (each n=15): model group (saline-treated), low- or high-dose triptolide groups (0.2 mg/kg or 0.4 mg/kg, respectively), and IVIG (high-dose immunoglobulin) group (1 g/kg body weight). Unexposed mice served as an additional control group. Nine weeks from the initial exposure, mice were euthanised and coronary tissues and blood samples were harvested. The rate of apoptosis was detected by TUNEL, and ICAM-1 expression was detected by immunohistochemistry in coronary endothelial cells. Serum TNF-α levels were detected by ELISA. Compared to mice in the (unexposed) control group, apoptosis of endothelial cells, ICAM-1 expression, and serum TNF-α levels were significantly increased in all exposed mice (p<0.05), confirming the presence of disease. However, treatment with triptolide or IVIG significantly lowered these measures compared to untreated exposed mice (model group; p<0.05). Triptolide treatment reduces markers of coronary endothelial inflammation in a mouse model of Kawasaki disease, similar to IVIG treatment, and therefore may be a useful alternative therapy for this disease.

Steroid Pulse Therapy for Children With Intravenous Immunoglobulin Therapy–Resistant Kawasaki Disease: A Prospective Study

Patients with Kawasaki disease (KD) who did not respond to the initial IVIG are known to have higher risk for developing coronary arterial lesions (CALs). Our aim is to clarify whether patients with initial IVIG resistant KD may benefit from methylprednisolone pulse therapy (MPT) in comparison with re- treatment of IVIG (2nd IVIG). A total of 237 patients (median age: 2 years 2 months; range 1 months-10 years) with KD were initially treated with IVIG (2 g/kg). Among them, 41 patients (22 %) were assessed as IVIG resistance: these patients were allocated to either group A receiving MPT (n = 14) or group B receiving the 2nd IVIG (n = 27). Patients with resistant to the additional therapy (MPT or 2nd IVIG) were received second IVIG (group A) or MPT (group B). Changes in leukocyte count, C-reactive protein and albumin before and after an additional therapy were significantly greater in group A than those in group B. However, the prevalence of CALs did not differ between the groups (36 % in group A and 26 % in group B, p > 0.05). There was no significant difference in the medical cost between the groups (median cost: 92,032 JPY in group A and 97,331 JPY in group B). MPT does not reduce the risk of development to CAL and does not seem to be beneficial as single agent therapy for IVIG resistant KD.

Changes in quality of life scores with intravenous immunoglobulin or plasmapheresis in patients with myasthenia gravis

BackgroundIntravenous immunoglobulin (IVIG) and plasmapheresis (plasma exchange (PLEX)) have comparable efficacy in reducing the Quantitative Myasthenia Gravis Score for disease severity (QMGS) in patients with moderate to severe myasthenia gravis...

EFFECTS OF FCγRIIIA ON AORTIC ATHEROSCLEROTIC PLAQUE DESTABILISATION IN APOE−/− MICE

ObjectivesOur previous studies suggest that Fc receptor III A of immunoglobulin G (FcγRIIIA, also named CD16) is closely correlated to coronary heart disease (CHD). However, the mechanism responsible for FcγRIIIA's...

The Effects of Adjuvant Immunoglobulin M-Enriched Immunoglobulin Therapy on Mortality Rate and Renal Function in Sepsis-Induced Multiple Organ Dysfunction Syndrome: Retrospective Analysis of Intensive Care Unit Patients

To determine the effect of immunoglobulin (Ig)M-enriched Ig therapy on mortality rate and renal function in sepsis-induced multiple organ dysfunction syndrome (MODS), using the Acute Physiology and Chronic Health Evaluation II (APACHE II) score. Retrospective study of patients with sepsis-induced MODS treated with standard antibiotic plus supportive therapy (control group) or IgM-enriched Ig therapy adjuvant to control group therapy (IVIg group). Total length of stay in the intensive care unit (ICU), overall mortality rate and 28-day case fatality rate (CFR), as well as APACHE II scores and renal function parameters at day 1 and day 4 of therapy, were recorded. A total of 118 patients were included (control group, n = 62; IVIg group, n = 56). In both groups, day 4 APACHE II scores decreased significantly compared with day 1 scores; the effect of treatment on renal function was minimal. Length of ICU stay, overall mortality rate and 28-day CFR were significantly lower in the IVIg group compared with the control group. Adding IgM-enriched Ig therapy to standard therapy for MODS improved general clinical conditions and significantly reduced APACHE II scores, overall mortality rate and 28-day CFR, although effects on renal function were minimal.

Restoration of humoral immunity after intravenous immunoglobulin replacement therapy in heart recipients with post‐transplant antibody deficiency and severe infections

IgG hypogammaglobulinemia is a risk factor for infection in heart recipients. We assessed reconstitution of humoral immunity after non-specific intravenous immunoglobulin (IVIg) replacement therapy administered to treat secondary IgG hypogammaglobulinemia in heart recipients with severe infections. The study population comprised 55 heart recipients who were administered IVIg (IVIg group) and 55 heart recipients with no severe infectious complications (control group). An event was defined as a severe infection requiring intravenous drug therapy during the first year after transplantation. The IVIg protocol comprised non-specific 5% pasteurized IVIg at a dose of 300-400 mg/kg/months. IgG titers were lower in the IVIg group than in controls at seven d (577 vs. 778 mg/dL, p < 0.001) and at one month (553 vs. 684, p = 0.003). After IVIg therapy, IgG concentrations were similar in both groups at three months (681 vs. 737, p = 0.25) and at six months (736 vs. 769, p = 0.46). At three months, the IVIg group had higher levels of antitetanus toxoid and anti-HBs (ELISA, 2.07 ± 2.11 vs. 0.60 ± 1.24 mg/dL [p = 0.003] and 42 ± 40 vs. 11 ± 31 IU/mL [p = 0.005], respectively) than controls. The mean number of infectious complications was significantly lower after IVIG therapy in the IVIG group. IVIg was associated with restoration of humoral immunity in heart recipients with post-transplant IgG hypogammaglobulinemia and severe infections.

No neurorestorative effect of IVIg in a mouse model of Parkinson Disease (75.6)

Abstract Immunotherapies have been proposed as a therapeutic strategy for the treatment of Parkinson disease (PD). Intravenous immunoglobulin preparation (IVIg) is used for the treatment of immunodeficiency and autoimmune diseases. Here, we investigated the effect of IVIg treatment on the dopaminergic (DAergic) nigrostriatal system after MPTP-induced denervation in mice. Mice received 4 MPTP injections (15 mg/Kg) at 2-hour intervals followed by a 14 days treatment with IVIg. IVIg injections led to a 21,6% increase in TReg cells in vehicle group (p&amp;lt;0.05) and minimal specific immune response. As expected, MPTP insult induced a significant 80% and 84% depletion of striatal dopamine content (p&amp;lt;0.01), as well as a 31% and 45% nigral DAergic neuron loss (p&amp;lt;0.001) in the Control and IVIg group, respectively. Moreover, two-way ANOVA analyses revealed a significant downregulating effect of IVIg on striatal tyrosine hydroxylase protein level (-16%, p&amp;lt;0.05) and on the number of nigral DAergic neurons (-29%, p&amp;lt;0.05), paralleling the toxic effect of MPTP. Collectively, our results provide no evidence of a neurorestorative effect of IVIg on the nigrostriatal system of the MPTP-treated mouse, and suggest that we need to proceed with caution before treating PD patients with IVIg.

1636 Intravenous immunoglobulin to treat Japanese encephalitis; a randomised controlled trial in Nepalese children

BackgroundJapanese encephalitis virus (JEV) causes 35 000–50 000 cases and 10 000 deaths every year and is the most important cause of encephalitis worldwide. There is no known antiviral treatment...

Abstract 9271: Significance of Primary Therapy With Intravenous Immunoglobulin Plus Prednisolone For Severe Kawasaki Disease: Result From Japanese Multicenter Randomized Clinical Trial.

Background Recent re-assessment reports have suggested that primary corticosteroid therapy for severe Kawasaki disease patients might be beneficial. Methods We conducted a multicenter, prospective, randomized, open, blinded-endpoints, and parallel-group study to determine whether the addition of prednisolone to conventional intravenous immunoglobulin therapy for severe Kawasaki disease reduces the risk of coronary artery abnormality. Between September 2008 and December 2010, 248 severe Kawasaki disease patients with risk score ≥5 points were randomly assigned to receive either intravenous immunoglobulin (IVIG group; n = 123) or intravenous immunoglobulin plus prednisolone (IVIG+PSL group; n = 125). The primary endpoint was presence of coronary artery abnormality during study period. Secondary endpoints included incidence of coronary artery abnormality at week 4, Z score of coronary arteries, duration of fever after enrollment, need for additional rescue therapy, serum levels of C-reactive protein (CRP) at weeks 1 and 2 after enrollment, and severe adverse events. Results Incidence of coronary artery abnormality during study periodt was significantly lower in the IVIG+PSL group than in the IVIG group (3% vs 23%, respectively; P&lt;0.001). Similarly, incidence of coronary artery abnormality at week 4 after enrollment was significantly lower in the IVIG+PSL group than in the IVIG group (3% vs 13%, respectively; P=0.014). Furthermore, IVIG+PSL group had shorter duration of fever after enrollment (P&lt;0.001), lower risk of need for additional rescue therapy (P&lt;0.001), and lower CRP level at weeks 1 and 2 (both P&lt;0.001) compared with IVIG group. Incidence of severe adverse events was similar in the two groups. Conclusions Intravenous immunoglobulin plus prednisolone is superior to intravenous immunoglobulin alone to prevent coronary artery abnormality in patients with severe Kawasaki disease. (UMIN-CTR Number, UMIN000000940.)

Correlation between Fc γ R III a and aortic atherosclerotic plaque destabilization in ApoE knockout mice and intervention effects of effective components of Chuanxiong Rhizome and Red Peony Root

To explore the correlation between Fc γ RIII A (CD16A) and aortic atherosclerotic plaque destabilization in apoE knockout (apoE KO) mice and the intervention effects of effective components of chuanxiong rhizome and red peony root. Eight 8-week-old male C57BL/6J mice were selected as the control group. Forty 8-week-old male apoE KO mice were randomly divided into the model group, apoE KO + intraperitoneal injection immunoglobulin group (IVIG), apoE KO + simvastatin group (Sm), apoE KO + high dosage of xiongshao capsule (XSC) group (XSCH), and apoE KO + low dosage of XSC group (XSCL), 8 mice in each group. Mice in the control group were put on a normal diet, and others were fed with a high-fat diet. After 10-week different interventions, monocyte CD16 expression was detected by flow cytometry, aortic matrix metalloproteinase-9 (MMP-9) mRNA expression was detected using reverse transcription polymerase chain reaction, and serum tumor necrosis factor (TNF)-α level was detected using enzyme-linked immunosorbent assay. Compared with the control group, monocyte CD16 expression, aortic MMP-9 mRNA expression, and serum TNF-α level in the model group increased obviously (P<0.01). Injections of apoE KO mice with intraperitoneal immunoglobulin during a 5-day period significantly reduced the monocyte CD16 expression, aortic MMP-9 mRNA expression, and serum TNF-α level (P<0.01 or 0.05) over a 10-week period of high-fat diet. Indices above in the Sm group, XSCH group, and XSCL group decreased in a different degree. Of them, the aortic MMP-9 mRNA expression in XSCH group was lower than that in Sm group (P<0.05) and the monocyte CD16 expression and serum TNF-α level showed no significant difference between XSCH group and Sm group (P>0.05). Correlation analyses suggested positive correlation between monocyte CD16 expression and aortic MMP-9 mRNA expression or serum TNF-α level in IVIG group, XSCH group, and XSCL group. FcγR III A mediates systemic inflammation in the progression of coronary heart disease with blood stasis syndrome. XSC could stabilize atherosclerotic plaque by suppressing inflammation and its target was relative with FcγRIII A.

Treatment guidelines for Guillain-Barré Syndrome

Guillain–Barre syndrome (GBS) is an acute onset, usually monophasic immune-mediated disorder of the peripheral nervous system. The term GBS is often considered to be synonymous with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), but with the increasing recognition of variants over the past few decades, the number of diseases that fall under the rubric GBS have grown to include axonal variants and more restricted variants, such as Miller Fisher syndrome (MFS) [Table 1].[1] Table 1 Guillain–Barre syndrome—clinical variants Epidemiology The reported incidence rates for GBS are 1–2 per 100,000 population.[2–4] The lifetime likelihood of any individual acquiring GBS is 1:1000.[5] The subtypes of GBS have different incidence rates in different parts of the world. In Europe and North America AIDP is dominant contributing to 90% of the cases. In contrast in China and Japan AMAN being the most common subtype.[6,7] The picture is intermediate when we look at other population. In Indian series the incidence of AIDP and AMAN are virtually equal although AMAN is more common in younger patients.[8] There seems to be a slight preponderance of AIDP in studies by Gupta et al[9] and by Meena et al (unpublished data from NIMS, Hyderabad). Available Indian literature indicates a peak incidence between June–July and Sept–October.[10] In western countries, GBS is common in the 5th decade,[11] but in India it occurs more commonly at a younger age.[10,12] GBS is equally common in men and women and can occur at any age. There is a male preponderance among the hospitalized population.[10,12]

The effects of adjuvant therapies for sepsis on hepatic and renal function: a retrospective analysis of 108 ICU patients

As liver and kidney failure have a direct effect on mortality, morbidity, and intensive care unit (ICU) length of stay in sepsis patients, maintaining their functions or minimizing the degree of failure should be one of the most important goals of therapy. In this retrospective study we investigated the effects of recently introduced adjuvant therapies on hepatorenal functions in septic ICU patients. Materials and methods: We conducted comparative and retrospective data analysis of 108 patients with sepsis that were followed-up during a 2-year period in the ICU. We recorded AST, ALT, ALP, albumin, bilirubin, and INR in order to evaluate variations in hepatic functions, and we recorded creatinine, BUN, and mean hourly urinary output in order to evaluate variations in renal functions in patients that received standard antibiotherapy only (ST group), in those that received polyvalent IgM-enriched immunoglobulin therapy added to standard antibiotherapy (IVIg group), and in those that received recombinant human-activated protein C therapy added to standard antibiotherapy (APC group). Variables at the beginning of the treatments and 96 h post-treatment were assessed. Results: In total, 108 patients were analyzed (IVIg group: n = 20 in; APC: group n = 22; ST group: n = 66). The groups were homogeneous in terms of initial hepatic and renal functions, according to AST, ALT, albumin, INR, bilirubin, BUN, creatinine, and mean hourly urinary output. In the APC group the AST level at 96 h was significantly lower than that at baseline (0 h), and in the ST group 96-h bilirubin was lower than that at baseline (0 h) (P = 0.035 and P = 0.015, respectively). Conclusion: We retrospectively observed that the adjuvant therapies did not improve hepatorenal functions in our ICU septic patients.

Intravenous Immunoglobulins Reverse Acute Vaso-Occlusive Crises in Sickle Cell Mice through Rapid Inhibition of Neutrophil Adhesion.

Previous studies using intravital microscopy in a sickle cell disease (SCD) mouse model suggest that adherent leukocytes (WBCs) play a key role in vaso-occlusion by capturing circulating erythrocytes (RBCs) in venules. Commercial intravenous human gamma globulin (IVIG) given prior to the inflammatory stimuli increased microcirculatory blood flow and improved survival (Blood 2004 103(6):2397–400). To mimic the clinical situation where SCD patients seek medical attention after the onset of symptoms, we have developed an in vivo model in which the therapeutic intervention was administered after in the inflammatory challenge. Berkeley SCD bone marrow was transplanted into irradiated C57BL/6 to generate age- and gender-matched genetically identical cohorts of SCD mice. Fully engrafted male SCD mice were treated with TNF-α and prepared for intravital microscopy examination of the cremaster muscle. Seventy minutes following administration of TNF-α (0.5 μg i.p.), IVIG (800 mg/kg) or an equivalent volume of control PBS or albumin (800 mg/kg) was administered by a programmable syringe pump. Twenty minutes after IVIG, PBS, or albumin exposure, 8–10 venules were recorded over a period of 60 min with each venule recorded continuously for at least 3 min. IVIG significantly increased the number of rolling leukocytes (2–3 fold, p<0.05) compared to control groups treated with albumin or PBS. Moreover, further analyses of leukocyte behavior revealed that IVIG significantly increased rolling velocities, indicating that it alters adhesion pathways involved in slow rolling. In contrast, the number of WBCs adherent to the endothelium was reduced by ∼50% in the IVIG group (p<0.05). The effect of IVIG on leukocyte adhesion was rapid, being statistically significant in the first ∼10 min after completion of IVIG infusion. The number of adherent WBCs increased progressively over time in the PBS group but remained lower throughout the recording period in the IVIG group. To assess the effect of IVIG on sickle RBC adhesion, we quantified the interactions between circulating RBCs and adherent WBCs, and found that IVIG dramatically reduced the number of RBC-WBC interactions by 10–19 fold (p<0.05). These effects resulted in improved microcirculatory blood flow and Kaplan-Meier curves revealed a dramatic improvement in survival of sickle cell mice in the IVIG-treated sickle cell mice compared to control groups. Longer survival correlated positively with blood flow (p=0.003) and negatively with the number of adherent WBCs (p=0.01) and RBC-WBC interactions (p=0.05). In order to exclude the possibility that irradiation and graft-versus-host disease were confounding factors, we treated parental (non-transplanted) sickle mice with IVIG, and found similar results, although statistical significance was only reached for RBC-WBC interactions (p<0.001) due to the small number of mice. In addition, IVIG treatment reduced the number of adherent WBCs recruited in wild-type C57BL/6 mice (p<0.002). Using multichannel digital fluorescence videomicroscopy that we recently developed (Nat Methods. 2007 4:219–22), we found that IVIG affected specifically the recruitment of adherent neutrophils, but did not change the number of adherent monocytes or lymphocytes. Thus, these results suggest that IVIG may improve VOC by inhibiting neutrophil activation, and underscore the encouraging possibility that therapeutic interventions initiated when patients have an established crisis may change the outcome of acute episodes, preventing their progression into life-threatening complications.