Immunomodulatory Therapy for Severe Influenza Going Beyond Antivirals Patrick Wieruszewski, PharmD PGY2 Critical Care Resident Pharmacy Grand Rounds September 5, 2017 2017 MFMER slide-1
Objectives Review the mechanisms of benefit in using immune therapies for influenza virus Determine the role of immune therapies in the treatment of severe influenza Identify safety concerns of immune therapies 2017 MFMER slide-2
Influenza Virus Surface glycoproteins Hemagglutinin Neuraminidase Viral mutation Genetic drift Antigenic shift Airborne (droplet), surfaces Inhalation Mouth, nose by touch Neuraminidase Hemagglutinin 2017 MFMER slide-3
Pathobiology Corti et al. Curr Opin Virol 2017;24:60-9. 2017 MFMER slide-4
Bronchial hyperreactivity Bacterial superinfection Distal airway obstruction Respiratory Compromise Severe alveolar inflammation Impaired diffusion capacity Falsey et al. Clin Infect Dis 2006;42:518-24. Levenson et al. N Engl J Med 2013;369:2253-8. Utell et al. Am Rev Respir Dis 1980;121:233-41. 2017 MFMER slide-5
Severe Influenza Disease Minor bronchiolar infection Normal lungs Diffuse pulmonary infection, cytokines Alveolar hemorrhage Kobasa et al. Nature 2004;431:703-7. 2017 MFMER slide-6
Question 1 I am familiar with and have recommended the use of blood products and/or derived immunoglobulins in the treatment of infectious diseases True False 2017 MFMER slide-7
Immunotherapy Corti et al. Curr Opin Virol 2017;24:60-9. 2017 MFMER slide-8
Immune Therapies Convalescent Plasma Intravenous Immunoglobulin Hyperimmune Globulin 2017 MFMER slide-9
Convalescent Plasma (CP) Whole blood collected from individuals suffering illness during the recovery phase Immunogenicity measured by hemagglutinininhibition (neutralizing antibody inhibition) Use dates back to the 1918 Spanish influenza pandemic Utilized in many other infectious diseases (Ebola, SARS coronavirus, RSV) SARS = severe acute respiratory syndrome RSV = respiratory syncytial virus Luke et al. Crit Care Med 2010;38:e66-73. Marano et al. Blood Transfus 2016;14:152-7. 2017 MFMER slide-10
CP in H5N1 31 y/o healthy male Fever, chills, cough, clear sputum Large opacities left lower lung Tracheal aspirate PCR H5N1 (A/Shenzhen/406H/2006) Convalescent plasma donor A/chicken/Hong Kong/282/2006 >99% homology of hemagglutinin genes Hemagglutinin inhibition, 1:80 PCR = polymerase chain reaction Zhou et al. N Engl J Med 2007;357:1450-1. 2017 MFMER slide-11
Temperature ( o C) Viral load (copies x 100/ml) 41 40 CP in H5N1 Viral load Temperature 1600 39 1200 38 800 37 36 35 0 5 10 15 20 25 Symptom onset Oseltamivir Day Convalescent plasma 400 0 Zhou et al. N Engl J Med 2007;357:1450-1. 2017 MFMER slide-12
CP During 2009 H1N1 Pandemic Design Prospective cohort (n = 93) Population Deterioration despite optimal antiviral therapy ICU admission within 7d of symptom onset Exclusion Intervention Minors Hypersensitivity to Ig or known IgA deficiency Standard antiviral therapy PLUS CP with HA inhibition titer 1:160 (n = 20) No CP (n = 73) HA = hemagglutinin Hung et al. Clin Infect Dis 2011;52:447-56. 2017 MFMER slide-13
2009 H1N1 Pandemic Results Demographics Middle-aged Minimal comorbidities Severity of illness Mechanical ventilation (93%) Stress dose steroids (41%) ECMO (13%) Dead (n = 44) Alive (n = 49) p-value Convalescent Plasma 4 (9%) 16 (33%) 0.01 Acute renal failure 17 (40%) 8 (18%) 0.02 CP associated with reduced viral load and inflammatory markers ECMO = extracorporeal membrane oxygenation Hung et al. Clin Infect Dis 2011;52:447-56. 2017 MFMER slide-14
CP Phase II Design Multicenter, randomized, phase II (n = 98) Population Exclusion Intervention Severe Influenza Hypoxia (SaO 2 < 93%) Tachypnea (RR > 20 bpm) ABO-compatible CP not available or allergy Condition not able to tolerate 500cc fluid Influenza not primary reason for acute illness Standard of care PLUS CP 2 units, HA inhibition titer 1:40 (n = 49) No CP (n = 49) HA = hemagglutinin Beigel et al. Lancet Respir Med 2017;5:500-11. 2017 MFMER slide-15
CP Phase II Results Demographics Middle-aged Moderate comorbidities Dismiss home without home health Not hospitalized, resume normal activities Severity of illness O 2 requirement (82%) ARDS (38%) ICU admission (58%) CP (n = 49) No CP (n = 49) p-value 21 (50%) 14 (33%) 0.029 17 (40%) 8 (18%) 0.02 No differences in ICU admission, ICU or hospital LOS, need for supplemental O 2, mechanical ventilation, or adverse events ARDS = acute respiratory distress syndrome LOS = length of stay Beigel et al. Lancet Respir Med 2017;5:500-11. 2017 MFMER slide-16
Normalized respiratory status Normalized respiratory status Early Administration Plasma > 4 days Plasma 4 days Standard > 4 days 1.0 Plasma 1.0 Standard 4 days 0.8 Standard 0.8 0.6 0.6 0.4 0.4 0.2 0.2 p = 0.069 p = 0.038 0 0 0 14 28 0 14 28 Days Days Beigel et al. Lancet Respir Med 2017;5:500-11. 2017 MFMER slide-17
Limitations Underpowered, un-blinded Non-pandemic setting Both groups received neuraminidase inhibitors Variability in hemagglutinin inhibition of plasma Effects of hemagglutinin inhibition unknown Effective titer/dose unknown Did not evaluate bacterial super-infection Beigel et al. Lancet Respir Med 2017;5:500-11. 2017 MFMER slide-18
Safety Considerations Transfusion reactions Volume expansion Transfusionrelated lung injury Convalescent Plasma Thromboembolism Antibodydependent enhancement Blood borne infections Beigel et al. Lancet Respir Med 2017;5:500-11. Lee et al. Lancet Respir Med 2017;5:e27. 2017 MFMER slide-19
Intravenous Immunoglobulin (IVIg) Pooled serum IgG from thousands of donors Initially thought to contain anti-influenza antibodies Found to have protective effects independent of hemagglutinin inhibition Large amounts of carbohydrate-binding antibodies Sialylated antibody decoys Rockman et al. EBioMedicine 2017;19:119-27. Huang et al. Oncotarget 2016;7:15606-17. von Gunten et al. J Allergy Clin Immunol 2009;123:1268-76. 2017 MFMER slide-20
IVIg in H1N1 59 y/o healthy male High-grade fever, sore throat, fatigue Day 1 Antibiotics for pneumonia Day 6 ventilatory requirements IVIg 0.4 gm/kg x 5d Day 14 Extubated Day 3 Worsening, required intubation Oseltamivir started Day 8 ventilatory requirements Chong et al. J Microbiol Immunol Infect 2011;44:319-22. 2017 MFMER slide-21
Geometric Mean Titer Cross-Reactive Neutralizing Antibodies 40 35 40 35 One Dose p < 0.001 40 35 Two Doses 30 30 30 25 25 25 p = 0.004 20 20 20 15 10 15 10 p < 0.001 15 10 p < 0.001 5 5 5 0 1 2 4 IVIg concentration (g/dl) 0 Pre-IVIg Post-IVIg MN titer HA titer 0 Pre-IVIg Post-IVIg MN = microneutralization HA = hemagglutinin Hong et al. Pediatr Infect Dis 2011;30:67-9. 2017 MFMER slide-22
Hyperimmune Globulin (hivig) Polyclonal antibodies obtained from vaccinated patients or those recovered from disease Usually fractionated from convalescent blood products High-titer hemagglutinin antibodies Frequently used in other viral diseases (e.g., cytomegalovirus globulin) Marano et al. Blood Transfus 2016;14:152-7. 2017 MFMER slide-23
hivig During H1N1 2009 Pandemic Design Multicenter, randomized, double-blind (n = 34) Population Exclusion Intervention Deterioration despite standard of care (antiviral) ICU admission & positive pressure ventilation Within 7d of symptom onset Minors Hypersensitivity to Ig or known IgA deficiency Moribund hivig 0.4 gm/kg, HA antibody titer 1:640 (n = 17) IVIg 0.4 gm/kg, HA antibody titer 1:20 (n = 17) Hung et al. Chest 2013;144:464-73. 2017 MFMER slide-24
Viral Load (log 10 copies/cc) Survival 2009 H1N1 Pandemic Results Demographics Middle-aged 5 Minimal comorbidities p = 0.04 p = 0.02 Severity of illness Mechanical ventilation (94%) ECMO (35%) 1.0 4 3 IVIg hivig 0.8 0.6 2 0.4 0.2 p = 0.02 1 0 Day 5 Day 7 0 0 10 20 Day Hung et al. Chest 2013;144:464-73. 2017 MFMER slide-25
Limitations Small sample size Many excluded for late ICU admission No report of adverse reactions Long-term outcomes unknown Ideal dosage of hivig not determined Immune response not measured Hung et al. Chest 2013;144:464-73. 2017 MFMER slide-26
Hemagglutinin Antibody Titer (rgmt) INSIGHT FLU Group Pharmacokinetic analysis of evolution of HA inhibition antibody titer with hivig (n = 31) hivig 0.25 gm/kg vs. placebo 3 different strains/titers (1:640, 1:320, 1:160) 500 400 300 200 100 * hivig Placebo 0 0 14 28 *significant, no p-value Pre-infusion Day rgmt = reciprocal geometric mean INSIGHT FLU005 Pilot Group. J Infect Dis 2016;213:574-8. 2017 MFMER slide-27
IVIg Safety Considerations Infusionrelated reactions Anaphylaxis IVIg Acute kidney injury Hemolytic anemia Thromboembolism Gelfand. N Engl J Med 2012;367:2015-25 Stiehm. Transfus Med Rev 2013;27:171-8. 2017 MFMER slide-28
Question 2 Which of the following is NOT a proposed mechanism of immune therapies in treating influenza disease? A. Prevent release of newly formed virions B. Inhibit activating proteases C. Direct damage to viral RNA D. Inhibit viral fusion and internalization E. Block binding to sialic acid receptors 2017 MFMER slide-29
Convalescent Plasma Greatest experience in influenza Potentially best option during a pandemic Issues with blood products Type & crossmatch required Hyperimmune Globulin HAI Ongoing trials Demonstrated immune response Most time consuming production Potentially dangerous for laboratory personnel HAI **** IgG Quicker availability Readily available Well-known safety profile Benefit extrapolated from theoretical mechanisms Intravenous Immunoglobulin HAI = hemagglutinin inhibition **** = Not compared as monotherapy 2017 MFMER slide-30
Should We Use Them? Proposed mechanisms suggest benefit in severe disease Limited scope experiences show potential benefit in varying outcomes May be most attractive for pandemic scenario resulting from new mutant strains Convalescent plasma may be most realistic Infrastructure to operationalize may be biggest challenge moving forward 2017 MFMER slide-31
Question 3 Which of the following are safety concerns with the use of convalescent blood products? A. Thromboembolic disease B. Blood borne infection C. Transfusion-related lung injury D. Volume overload E. All of the above 2017 MFMER slide-32
Conclusion Immune therapies may provide multifactorial benefit for treating influenza disease Immunomodulatory therapies are potentially a viable therapeutic option for severe influenza in a pandemic situation Limited safety data exist for immune therapies in influenza and must be extrapolated from other indications 2017 MFMER slide-33
The worst pandemic in modern history was the Spanish flu of 1918, which killed tens of millions of people. Today, with how interconnected the world is, it would spread faster. Bill Gates, 2014 2017 MFMER slide-34
Immunomodulatory Therapy for Severe Influenza Going Beyond Antivirals Patrick Wieruszewski, PharmD Wieruszewski.Patrick@mayo.edu Pharmacy Grand Rounds September 5, 2017 2017 MFMER slide-35