3/29/2014 Update on Practical Aspects of Gammaglobulin in PID Jack Routes MD Professor of Pediatrics and Medicine Chief, Allergy and Clinical Immunology Medical College of Wisconsin Disclosures/Attestation • Baxter Pharmaceuticals: PI initiated grant • NIH Learning Objectives • To know the risk factors for the minor and serious adverse effects of intravenous gammaglobulin (IVIG). • To be knowledgeable in the use of IVIG or subcutaneous immunoglobulin (SCIG) in the treatment of primary immunodeficiency disorders (PIDD). • To understand the advantages and disadvantages of IVIG or SCIG in the treatment PIDD. 1 3/29/2014 Table Summary of Ig Preparations in USA http://primaryimmune.org/ treatment-information/immunoglobulin-products FDA Indications: IVIG • Treatment of primary immune deficiency disorders (PIDD) • Treatment of ITP • Prevention of coronary artery aneurysms in Kawasaki’s Disease • Chronic inflammatory demyelinating polyneuropathy • Prevention of bacterial infections in patients with CLL • Prevention of pneumonitis and GVHD following bone marrow transplantation • Kidney transplantation (ABO incompatible, high Ab recipient) • Reduction in bacterial infections in children with HIV-1 infection Common Uses IVIG/SCIG • • • • • • • • • • • • Primary immunodeficiency diseases (that result in defect in antibody responses) Secondary immunodeficiency conditions (with impaired antibody responses) B-cell leukemia Use of chemotherapy or radiotherapy Autoimmune syndromes Hematologic: ITP, autoimmune hemolytic anemia Rheumatologic: RA, vasculitis, Kawasaki disease, uveitis, SLE Endocrinologic: Autoimmune diabetes mellitus, Graves ophthalmopathy Neurologic: Guillain-Barre´ syndrome, chronic inflammatory demyelinating polyneuropathy, myasthenia gravis, dermatomyositis Dermatologic: TEN, Steven-Johnson syndrome Kidney transplantation (ABO incompatible, high Ab recipient) Infectious diseases – CMV – Rotavirus – Parvovirus B19 – HIV infection JACI: 2010;125:S314-23 2 3/29/2014 Classification for PIDD using IVIG/SCIG Category B cells IgG Content IgG Quality Examples I Absent/Dec reased Absent Absent Agammaglobulinemia SCID II Present Low Low Hyper IgM Syndrome (all forms) CVID III Present Normal Low NEMO Specific Ab Deficiency IV Present Low Normal Transient Hypogam. Infancy adapted from: http://www.immunodeficiencysearch.com/ivig-replacement#!__ivig-replacement Background Questions • What is the optimal dose of antibody replacement in XLA and CVID? – Adjustment of dose based on trough levels? – Adjustment of dose based on break-through infections? (treat the patient not a level?) • Does Ab replacement therapy prevent chronic lung disease and sinus disease Meta-analysis: IVIG/SCIG • Meta-analysis SCIG (13 studies) or IVIG (17 studies): major focus on relationship between serum IgG and pneumonia • For every increase in 100 mg/dl trough, 27% decrease in incidence pneumonia • Incidence pneumonia associated with level of 500 mg/dl was 5 fold increased vs. 1000/mg/dl • Increase 121 mg/dl trough for every increase of 100 mg/dl/month (IVIG); less (.89 mg/dl) for SCIG. • Recent Canadian consensus document: recommended trough level of at least 700mg/dl Clin. Exp. Immunol. 169: 172–181, 2012 (SCIG) and Clin. Immunol. 137:21-30, 2010 (IVIG) 3 3/29/2014 Background • Hypothesis: each patient requires individualized dose to prevent infection • Prospective study of 90 patients with CVID and 15 patients XLA over 22 years • Single center • Dose IgG (SCIG/IVIG) increased based on “break through infections” • Relationship between dose, trough IgG and infection free intervals examined J. Allergy Clin Immunol 125:1354-1360, 2010 Study Design • Initial dose: 0.4 mg/kg or 0.6mg/kg/month (bronchiectasis, BE) • Increase dose IgG-0.15mg/kg/month – 1 serious infection/yr- requires IV Abx • (“Infection score 3”-serious infection) – 3 moderate infections/year-requires oral Abx or conjunctivitis. • (“Infection score 2”-moderate infection) J. Allergy Clin Immunol 125:1354-1360, 2010 Outcome Measurements • Determined the dose/mean trough level to prevent infection (to an acceptable rate) for a period of one year – Infection score <4.5 – Infection score <2.5 – Infection score =0 • 885 periods, 741 patient years J. Allergy Clin Immunol 125:1354-1360, 2010 4 3/29/2014 Outcome Measurements (cont.,) • Also analyzed patients on basis of: – dx (XLA, CVID) – Bronchiectasis (BE) – Splenomegaly – Clinical phenotype: • No other disease, enteropathy, cytopenias, polyclonal lymphoproliferation, autoimmune, malignancy J. Allergy Clin Immunol 125:1354-1360, 2010 Results • Weak but statistically significant relationship between dose or trough of IgG required to prevent infection at ANY of the 3 infection scores • Dose required to prevent infection was unique to the individuals and influenced by secondary complications • The presence of ANY disease related phenotype required a higher dose of IgG to prevent infection J. Allergy Clin Immunol 125:1354-1360, 2010 Results (cont.,) • Compared to pts without bronchiectasis (BE), pts. with BE required about a 2 fold higher dose to maintain an equivalent trough IgG • Infection scores in patients with and without BE were similar • Patients with splenomegaly also required a higher dose to maintain equivalent trough levels J. Allergy Clin Immunol 125:1354-1360, 2010 5 3/29/2014 Summary • The high degree of patient heterogeneity contributes to distinct doses of Ig required to prevent infection in CVID • Certain conditions (splenomegaly, BE) require higher doses to achieve similar troughs as patients w/o these conditions • When dosing IgG replacement, you treat the patient not a level. Study Background • Multicenter prospective study of 224 patients with CVID • Define spectrum of illness at the clinical onset and over follow-up (mean time: 11 years) • Long term effects of immunoglobulin treatment. J. Clin. Immunol. 27: 308-316, 2007 Results • Mean age at the time of diagnosis was 26.6 years. • The mean age at the onset of symptoms was 16.9 years, implying a mean diagnostic delay of 8.9 years. • Morbidity due to CVID, including chronic lung and sinus disease increased with time despite Rx with IVIG J. Clin. Immunol. 27: 308-316, 2007 6 3/29/2014 Chronic Lung Disease and Sinus Disease Progress Despite Ab Replacement Chronic Lung Disease N=224 pts. (CVID) Mean f/u 11 yrs. Chronic Sinus Disease J. Clin. Immunol. 27: 308-316, 2007 and J Clin Immunol. 31:315-22, 2011 At Dx Development during F/u Safety of IVIG Against Infectious Agents Viral Safety-Donor Restrictions • HCV outbreak from IVIG (1984-USA) changed FDA requirements for IVIG production • Donors are not from large metro areas (note: each lot of IVIG/SCIG pooled serum of at least 1,000 donors, some preparations >10,000 donors) • Not lived in Great Britain > 6mos 1986-present • Careful H&P-not acutely ill, exclude known high risk groups • Screened for HIV-1 p24 Ag, HBVAg, antibodies to HIV-1/2, syphilis, HCV and PCR for HBV • Units are not released for 6 months until donor has been retested for above pathogens 7 3/29/2014 Safety Against Pathogens • Heat Rx with stabilizers • Detergent solubilization (enveloped viruses) • Caprylic acid (enveloped viruses) • Pepsin and low pH • Deep filtration/nanofiltrations: deep filtration common to all IVIG and thought to remove prion proteins Factors in IVIG Influencing Adverse Events • Sodium content • Type and concentration of sugar • Osmolarity and osmolality • pH • Volume Load • IgA concentration • Lyophilized vs. liquid? • Dose: Immunomodulatory (2gm/kg/month) vs. Replacement (0.4-0.6 gm/kg/month) 8 3/29/2014 Typical Infusion Rates IVIG • Children < 6yo: 0.5mg/kg/hr increase by 0.5 mg/kg/hr every 15min up to MAX of 3mg/kg/hr • Older Children/Adults: 0.5mg/kg/hr increase by 0.5-1 mg/kg/hr every 15min up to MAX of 4mg/kg/hr IgG Preparations: SCIG vs IVIG • Aggregated Igs likely responsible for many minor adverse events (AE) • Newer preparations IVIG markedly reduced aggregated Igs • Subcutaneous only Ig (SCIG) preparations SHOULD NOT be given IV (Hizentra in US) • Currently Gammagard Liquid, Gamunex-C, Gammaked for SCIG and IV routes • IVIG preparations appear to be safe given via sc route (not FDA approved) AE to IVIG • Most commonly occur during initiation of IVIG • Recent bacterial infection increased AE • Depending on IVIG used, some start with lower concentration IVIG (5%) with first dose • Low infusion rates initial dose (0.5mg/kg/min1.0 mg/kg/min increase 15’-30’ to maximum of 2.5 mg/kg/min) • Healthy older children/adults may tolerate higher infusion rates with later infusions (4mg/kg/min) 9 3/29/2014 Common AE to IVIG • Most AE infusion rate related • Headache (most common), anxiety • Fever and/or chills, flushing • Tachycardia and/or palpitations • Chest tightness/pain, shortness of breath/bronchospasm • Nausea, abdominal pain • Back pain, myalgias, arthralgias • Mild hypotension Adverse Events IVIG: Children • Prospective study of 348 infusions in 58 children • Headache most common AE • Delayed AE more common than immediate AE Arch. Dis. Child. 2006;91;651-6 Treatment of Mild Adverse Events • For immediate reaction: stop infusion, give an antihistamine and NSAID or acetaminophen • Resume infusion in 15’-20’ at slower rate • Consider pretreatment if problem persists: antihistamines, NSAI and corticosteroids • Make sure patient well hydrated before infusion • Recommend non-sedating anti-histamines if adult and driving (not Benadryl!) • Consider alternative brand of IVIG or SCIT if problem persists 10 3/29/2014 Adverse Reactions IVIGAseptic Meningitis • More common with immunomodulatory doses of IVIG (2 gm/kg) • Prior hx migraine risk factor • Sxns usually develop within 24h of infusion • Nuchal rigidity, headache, photophobia--fever uncommon • CSF: increased IgG/pleocytosis Adverse Reactions : Possibly Related to IgA in IVIG • Most AE do not appear to be related to IgA content in IVIG • IgG or IgE Abs in patient directed against IgA in IVIG • Immunologic mechanisms – Anaphylactic: IgE Abs to IgA – Serum sickness like illness • Systemic reactions with administration of IVIG or within 72 hrs—most occur in adults. • Predisposed patients: Specific antibody deficiency with IgA deficiency (< 10mg/dl), ? CVID patients with absent IgA • Most (all?) CVID patients with absent IgA cannot make specific IgE • Consider substituting low IgA product or SCIG ( JACI 129:628-634, 2011) Severe Adverse Reactions IVIGCardiovascular system • Thromboembolic: Deep vein thrombosis, pulmonary embolism, stroke, central retinal vein occlusion • Myocardial ischemia/infarction • Stroke • Pulmonary edema 11 3/29/2014 Severe Adverse Events (SAE) IVIG: Cardiovascular system • Etiology unclear-likely increased viscosity of blood • IVIG risk factors – High osmolarity or high salt concentration – Lypholized product? • FDA states insufficient data to clearly implicate lyophilized products – High infusion rate – Immunomodulatory doses of IVIG SAE Patient Risk Factors: Cardiovascular System • Dehydration • Renal disease • Diabetes • Pre-existing cardiovascular disease • Advanced age • Prior thromboembolic events • Patient immobilization AE: IVIG-Renal AE • Varied from mild azotemia to acute renal failure, osmotic nephrosis and death • Patient risk factors: – Age (mean 60.5 yrs) – Pre-existing renal disease – Diabetes mellitus – Dehydration – Sepsis – Other nephrotoxic drugs • IVIG risk factors: – 90% occurred with sucrose-containing IVIG!!!!! – High osmolarity IVIG also risk factor – Most received immunomodulatory doses of IVIG 12 3/29/2014 SAE: IVIG-Renal Mechanism • IVIG acute renal failure usually occurs within 1 week of IVIG • Oliguric > non-oliguric renal failure • 30% require short-term hemodialysis • Majority return to normal renal function within 2 weeks. • Acute Renal Failure Bx: Vacuolization and swelling of proximal tubules consistent with osmotic nephrosis • Sucrose is not metabolized by the kidney and accumulate at tubular epithelium leading to accumulation, osmotic damage/nephrosis Summary: SAE and IVIG • High Risk Patients: Extremes of age, preexisting heart or renal disease, diabetes, dehydration • Dose of IVIG (Immunomodulatory dose at greater risk) • Avoid high salt, high osmolarity, sucrose containing IVIG in these patients Advantages SCIG vs. IVIG • Decreased systemic side effects • Possible reduction AE due to anti-IgA Abs • More consistent levels of IgG in blood-no IgG “trough” levels • IV access is not needed • Easier and likely safer administration at home • Improved quality of life • Some believe safer in patients with or prone to develop renal disease (acute protein load), heart disease or other risk factors 13 3/29/2014 Contraindications SCIG • Severe thrombocytopenia • Bleeding disorder • Anticoagulant therapy • Diffuse severe skin disease (severe eczema) • Limited subcutaneous tissue Disadvantages SCIG vs. IVIG • Local side effects (swelling, erythema, itching) at the site of infusion is common • Poor choice in child/adult that is needle phobic • Increased long-term exposure to needles • Assuring patient compliance (home administration) • Need for pump to deliver Ig SCIG-PK • Dose absorbed and redistributed slowly • The amount of IgG administered over time is generally equivalent • FDA mandated AUC equivalency for Vivaglobin requiring 1.37X dose of IVIG (trough IVIG: 768 mg/dl; trough SCIG 1040 mg/dl) • Mean half life 40.6 days • Approximately 6 months of therapy is needed to achieve a steady state 14 3/29/2014 Serum Levels IgG: IVIG vs. SCIG A. B. IVIG SCIG SCIG: Establishing the Regimen • Establish dose: if new patient (400-600 mg/kg/month); if on IVIG some use same dose while others correct for AUC (1.37X IVIG dose) • Patient preferences – Number infusions per week (generally 1x/week) – Volume per infusion – Number of sites per infusion (simultaneous sites or rotate sites) – Volume per site – Total time per infusion SCIG: Infusion Rate & Volume/Site • FDA Trial: limits 20 ml/hr and 15 ml/site (published 20-35 ml/site) • Berger reports mean 0.176 ml/site/hr average infusion (12 ml/hr-70 Kg adult; 3.5 ml/hr-20-kg child) • Larger volumes may be given over longer period of time • Trend is for faster infusion, some patients “push” SCIG and do not use pump 15 3/29/2014 SCIG: Local Reactions Infusion-site Reactions (%) • Swelling at site of infusion most common side effect • Mild rarely requires discontinuation • Decreases with time Immunol Allergy Clin N Am 28 (2008) 779–802 SCIG: Where to Administer • Careful instructions to patients with clinic administration until competent and sure no serious AE (first 2-4 infusions) • Anterior abdominal wall to flanks (most frequent), anterior or inner thighs, backs of arms • Guideline: site ok if can “pinch and inch” • Most important: draw back syringe BEFORE administering Ig • Reminder: the FDA approved forms of SCIG cannot be used for IVIG SCIG: Safety and Efficacy • Several studies indicate similar efficacy to IVIG • Appears to have less systemic side effects than IVIG • Several studies suggest better QOL on SCIG vs IVIG • Alternative therapy in patients who desire home therapy or have serious systemic AE with IVIG 16 3/29/2014 Brand Name: Which is Better? Immunol Allergy Clin N Am 28 (2008) 765–778 • No convincing studies that one brand of IVIG is better at reducing infection than another Further Reading • Immunology Clinics of NA, Nov. 2008: Entire November issue devoted to replacement Ig • JACI 117: S525-553, 2006: Evidence based review by AAAAI • Concise Review. Bringing immunoglobulin knowledge up to date: how should we treat today? Clin Exp Immunol 166:16-25, 2011. • Concensus review on use of IVIG. Clin Immunol 135:255-263, 2011. 17