IVIg a new frontier in immuno-modulation in sepsis

  1. Reza Nejat MD FCCM
    IVIg a new frontier in immuno-modulation in sepsis
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    • 1. Reza Nejat, M.D., Anesthesiologist, FCCM, Assistant Professor, SBMU
    • 2. IVIg in Sepsis § SIRS: The definition, ú Any two or more of the followings: Body temperature> 38° c or 90/min Respiratory Rate> 20/min or PaCO2 12000/mm³ or 10% § Sepsis: Infection-induced SIRS ú Mortality: 22%-76%
    • 3. IVIg in Sepsis § The development of sepsis: ú a complex interaction between the infecting microorganism and the host response; ú the harmful consequences of dys-regulated immune response § Severe sepsis is associated with altered homeostasis characterized by: ú activation of inflammation, ú enhancement of coagulation ú impairment of fibrinolysis
    • 4. IVIg in Sepsis SIRS or CARS § Increased inflammatory response: ú systemic inflammatory response syndrome (SIRS), § more recently, secondary immune suppression, ú compensative anti-inflammatory response syndrome (CARS), ú equally capable to contribute to organ damage and lead patients to exitus
    • 5. IVIg in Sepsis § Sequential pro-inflammatory and the anti- inflammatory responses ú proinflammatory, cytokine storm : Tumor necrosis factor (TNF), interleukin 1 (IL-1) IL-6, able to induce ú Anti-inflammatory mechanism: damage of the adaptive and innate immune system, loss of CD4 and CD8 T lymphocytes, B cells and dendritic cells induced by apoptotic events
    • 6. IVIg in Sepsis § Relevance of Pro- and Anti- inflammatory phases is conditioned by: ú Genetic asset, ú age, ú comorbidities, ú nutritional status § The hyperergic phase: in the young, § the immunosuppressive phase: in the elderly
    • 7. IVIg in Sepsis § History ú Started in 1950s after 2nd WW IM use in prevention of viral infections Extended to patients with immunodefficiencies § Introduction of IVIg ú With proteolytic enzymes!!! ú Later; methods to maintain the integrity of the molecules ú Later on; intact and unchanged molecule (3rd generation)
    • 8. IVIg in Sepsis § IVIg: ú Contain specific Abs against various viruses, bacteria and toxins ú Exerts opsonic effect ú Complement activating effect ú Neutralizes activity of toxins and viruses ú Suppresses pro-inflammatory cytokines ú Ab-dependent bactericidal-enhancing function ú Increases the susceptibility to antimicrobial agents
    • 9. IVIg in Sepsis § Intravenous immunoglobulin (IVIg) is therapeutic preparation mainly including human IgG collected from a large number of healthy donors ú Mouthon L, Lortholary O. ; Clin Microbiol Infect 2003;9:333. § In the last three decades IVIg has been also increasingly used for the treatment of various autoimmune and systemic inflammatory diseases, and currently as an immune-modulator mainly in off label use ú Gelfand EW; N Engl J Med 2012;367:2015–25 ú [3] Salemi S, et al; Int Rev Immunol 2014;28
    • 10. IVIg in Sepsis § More than 75% of the intravenous immune globulin in the United States administered to patients with autoimmune or inflammatory conditions.
    • 11. IVIg in Sepsis § Diseases for Which Intravenous Immune Globulin Has Been Shown to Be Beneficial: § FDA-approved indications: ú Primary immunodeficiency disease ú Chronic lymphocytic leukemia ú Pediatric HIV infection ú Kawasaki’s disease ú Allogeneic bone marrow transplantation ú Chronic inflammatory demyelinating polyneuropathy ú Kidney transplantation involving a recipient with a high antibody titer ú or an ABO-incompatible donor ú Multifocal motor neuropathy
    • 12. IVIg in Sepsis § Additional approved indications with criteria ú Neuromuscular disorders ú Guillain–Barré syndrome ú Relapsing–remitting multiple sclerosis ú Myasthenia gravis ú Refractory polymyositis ú Polyradiculoneuropathy ú Lambert–Eaton myasthenic syndrome ú Opsoclonus–myoclonus ú Birdshot retinopathy ú Refractory dermatomyositis ú Hematologic disorders ú Autoimmune hemolytic anemia ú Severe anemia associated with parvovirus B19 ú Autoimmune neutropenia ú Neonatal alloimmune thrombocytopenia
    • 13. IVIg in Sepsis § Additional approved indications with criteria ú HIV-associated thrombocytopenia ú Graft-versus-host disease ú Cytomegalovirus infection or interstitial pneumonia in patients ú undergoing ú bone marrow transplantation ú Dermatologic disorders ú Pemphigus vulgaris ú Pemphigus foliaceus ú Bullous pemphigoid ú Mucous-membrane (cicatricial) pemphigoid ú Epidermolysis bullosa acquisita ú Toxic epidermal necrolysis or Stevens–Johnson syndrome ú Necrotizing fasciitis
    • 14. IVIg in Sepsis § the anti-inflammatory potential of intravenous immune globulin in Kawasaki’s disease has been well described. ú fever often abates, ú reductions in several inflammatory markers ú decreases in the production of proinflammatory cytokines tumor necrosis factor α [TNF-α], interleukin-1α, interleukin-6 ú down-regulation of adhesion molecule and chemokine chemokine-receptor expression ú the neutralization of super-antigens
    • 15. IVIg in Sepsis § IVIg in Burn ú Replacement therapy with IVIg resulted in elevation of serum Igs, yet, no reduction of infections and/or mortality – Shirani K.Z., et al; Am J Med, March, Suppl. 3A, 76: 175, 1984 – Waymack J.P., et al; Burns 15: 71, 1989
    • 16. IVIg in Sepsis § IVIg in Burn § Patients with burn treated with IVIg in addition to ABs had a SIGNIFICANT reduction in mortality due to infection § 50% reduction in hospital stay § Accordingly, it was believed that in addition to proper hydration, early escharectomy and grafting, and specific AB therapy IVIgs is an invaluable tool in management of burned patients ú Olivia R. G., et al; Ann Medit Bums Club- vol VI- n.I- March 1993 Juan Fernandes Hospital, Buenos Aires, Argentina
    • 17. IVIg in Sepsis § The clinical experience of IVIG use in ú Toxic epidermal necrolysis (TEN) ú Stevens-Johnson syndrome (SJS) is positive in most cases § Average dose ú (TEN: 800mg±400mg/kg/day for 4.0±1.0 days) ú (SJS: 800mg±200mg/kg/day for 3.4±1.0 days) Mittman N, et al: Am J Clin Dermatol: 2006:7(6): 359-68
    • 18. IVIg in Sepsis § The clinical experience of IVIG use in ú Toxic epidermal necrolysis (TEN) ú Stevens-Johnson syndrome (SJS) § is positive in most cases Mittman N, et al: Am J Clin Dermatol: 2006:7(6): 359-68 § Mortality of 0% among 13 IVIg-treated TENs patients, in whom mortality was significantly lower than predicted by SCORTEN Aires DJ, et al; J Drugs Dermatology: 2013 Jun 1;12(6); 679-84
    • 19. IVIg in Sepsis § Blood level of gamma globulin: ú Reduced in early stages of sepsis Due to depressed production, leakage, consumption ú Reduced level is associated with high incidence of shock and mortality ú Mortality improved if anti- microbials are appropriate and IVIg is additionally administered
    • 20. IVIg in Sepsis § Four RCT since 2000 on IVIg administration against sepsis and septic shock: 1. Masaoka T, et al: The efficacy of IVIg in combination therapy with antibiotics for severe infection. Jpn J Chemother 2000, 48: 199-217 2. Darenberg J , et al : IVIg G therapy in STTSS : a European randomized, double-blind placebo-controlled trial. Clin Infect Dis 2003, 37: 333-340 3. Hentrich M, et al: IgMA-enriched immunoglobulin in neutropenic patients with sepsis syndrome and septic shock : a randomized , controlled, multiple-center trial. Crit Care Med 2006, 34: 1319-1325 4. Werden K, et al: Score-based IgG therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35: 2693-2701
    • 21. IVIg in Sepsis § Two reports in four RCT since 2000 on IVIg administration against sepsis and septic shock: ú RCT in patients with refractory infections complicated with mainly blood diseases. ú Reported defervescence effects and prognosis improvement ú 5 grams/day for 3 days Masaoka T, et al: The efficacy of IVIg in combination therapy with antibiotics for severe infection. Jpn J Chemother 2000, 48: 199-217
    • 22. IVIg in Sepsis § Two reports in four RCT since 2000 on IVIg administration against sepsis and septic shock: ú Significant improvement in APACHE II score. ú Significant improvement in ICU survival. ú Reduction of the duration on mechanical ventilation. ú 2 days of IVIg: day 1: 600mg/kg, day 2: 300 mg/kg Werden K, et al: Score-based IgG therapy of patients with sepsis: the SBITS study. Crit Care Med 2007, 35: 2693-2701
    • 23. IVIg in Sepsis § An 18-month, open-label, follow-up study of 2 4 patients with Alzheimer ’s Disease receiving intravenous immune globulin showed a reduction in ventricular enlargement on MRI and an improvement in cogniton scores. ú Relkin N, et al; Neurology 2010;75:380.
    • 24. IVIg in Sepsis § The ways in which intravenous immune globulin exerts its immuno-modulatory and anti-inflammatory effects remain unclear, with many pathways in the innate and adaptive immune systems being potentially targeted
    • 25. IVIg in Sepsis F(ab)2-mediated activities Fc-dependent activities Suppression or neutralization of cytokines Blockade of the FcRn Neutralization of activated complement components Modulation of activating FcγRs Restoration of idiotypic/anti-idiotypic networks Up-regulation of inhibitory FcγRIIB Blockade of leukocyte- adhesionmolecule binding Immunomodulation by sialylated IgG Targeting of specific immune cellsurface receptors Increase proliferation and immunosuppressive effect of Tregs Modulation of maturation and function of dendritic cells Hindrance of natural-killer cell activity
    • 26. IVIg in Sepsis § Administered immune globulin can exert both anti- inflammatory and pro- inflammatory effects, depending on the interacting partner. ú Anti-inflammatory activities: at relatively high doses, ú Pro-inflammatory activities: atlowdoses
    • 27. IVIg in Sepsis § The binding of IgG to potentially harmful complement fragments (C3a, C3b, C4b, and C5a) blocks deposition of these fragments on target tissues, § thus preventing subsequent immune damage that arises from cell destruction or aggravated inflammation.
    • 28. IVIg in Sepsis § Polyvalent IVIg improves: ú Opsonization, ú prevent nonspecific complement activation, ú Protect against the antibiotic-induced endotoxin release, and ú Neutralize endotoxin as well as a wide variety of superantigens Sriskandan S, et al; J Antimicrob Chemother 2006;58:117–24.
    • 29. IVIg in Sepsis § Protective effect of IVIg administration in animal models of DIC and organ failure after infusion of lipopolysaccharide (LPS) was shown. § This beneficial effect might be due to attenuation of the overshooting pro- inflammatory state with decreased plasma levels of TNF and IL-6.
    • 30. IVIg in Sepsis § It has been reported also that the damage of the microcirculatory flow induced by LPS could benefit from treatment with IVIg.
    • 31. IVIg in Sepsis § IVIg administration probably can: ú Modulate different T cell subsets, in particular Th- 17 and regulatory T ú Inhibits the proliferation and maturation of human Th17 cells, as well as their cytokine profile (decreased production of IL-17A, IL-17F, IL-21) ú Suppress the effect of CD4+CD25+ T cells presented the decrease of TNF-α production by stimulated CD4+CD25− T cells was further increased by adding IVIg to cell culture ú Establish an increase of the proliferation of Treg cells
    • 32. IVIg in Sepsis § Catalytic Antibodies ú Immunoglobulins endowed with a capacity to hydrolyze an antigenic substrate. ú Of the IgG and IgM isotypes are part of naturally occurring antibodies ú Participate in the removal of metabolic wastes ú Protect from bacterial infections through their intrinsic ability to convert molecular oxygen into hydrogen peroxide and ozone
    • 33. IVIg in Sepsis § IgG catalytic activity from 34 consecutive patients with severe sepsis or septic shock was assessed. § The cumulative rate of survival was higher among patients with high catalytic rates of IgG as compared with patients with low catalytic rates (p < 0.05). Lacroix-Desmazes S, et al. Proc Natl Acad SciUSA2005;102:4109–13.
    • 34. IVIg in Sepsis § Patients most likely to benefit from IgM-enriched IVIG are: ú Gram-negative septic shock patients. ú Gram-positive bacteria in severe highly invasive group A streptococcal (GAS) infections, In particular streptococcal toxic shock syndrome (STSS) associated with necrotizing fasciitis or myositis in which IVIg administration accepted by FDA
    • 35. IVIg in Sepsis § IVIG has the ability to: ú Facilitate opsonization of Streptococci ú Neutralize a wide variety of superantigens ú Suppresse GAS supernatant- induced T cell activation and inhibits pro-inflammatory cytokines production
    • 36. IVIg in Sepsis § IgM-enriched IVIg, as well as purified serum IgA and IgM, is more efficient than standard IgG IVIg in neutralizing the streptococcal superantigen § It implies that an IgM-enriched IVIg preparation could potentially be more efficacious than standard IgG IVIg in superantigen-mediated sepsis Norrby-Teglund A, et al; Clin Infect Dis 2000;31:1175–82. Norrby-Teglund A, et al; J Intern Med 2006;260:509–16.
    • 37. IVIg in Sepsis § Effectiveness of IVIg in patients with severe sepsis and septic shock could be time-dependent. § Berlot et al. analyzed 129 patients with severe sepsis and septic shock and observed that: ú The surviving patients showed lesser delay in the administration of IgM and IgA enriched polyclonal intravenous immunoglobulins compared with patients did not survive (23 vs. 63 h, p
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