M. Ulanova, S. Gravelle, N. Hawdon, S. Malik, D. Vergidis, and W. McCready

1. Risk of invasive H. influenzae disease in patients with chronic renal failure: a call for vaccination? M. Ulanova, S. Gravelle, N. Hawdon, S. Malik, D. Vergidis, and W. McCready Lake Superior

2. Secondary Immunodeficiency States • The immune system’s ability to fight infections is compromised • Result of severe chronic organ diseases, aging, or use of immunosuppressive therapies Chronic liver disease Chronic kidney disease Diabetes mellitus Leukemias Multiple myeloma Bone marrow transplantation Cytostatic drugs, corticosteroids, etc Examples:

3. Chronic Kidney Disease (CKD) • Among ≥65 yr old adults in USA, 20% have CKD • ESRD: stage 5 CKD requiring renal replacement therapy • Over 700,000 ESRD patients by 2015 (USA) • In ESRD patients, 1-yr mortality: 20% 5-yr mortality: over 60% • Increased prevalence of ESRD in Aboriginal people in Canada; mainly caused by diabetic nephropathy • In Northwestern Ontario, 36.6% of ESRD patients undergoing dialysis: Aboriginal (2008)

4. Impaired Host Immune Response in ESRD Patients • Decreased granulocyte and monocyte/macrophage phagocytic function • Defective antigen presentation by monocytes and macrophages • Reduced antibody production by B lymphocytes • Impaired T-cell mediated immunity

5. Factors Causing Immune Dysfunction in ESRD Patients • The uremic state and its metabolic consequences • Accumulation of toxic waste products • Chronic malnutrition and anemia • Underlying diseases which led to renal failure • Immunosuppressive drugs used to treat and control underlying diseases • Dialysis procedure • Multiple blood transfusions

6. Risk Factors of Infection in Kidney Disease • Impaired Immune Response • T- and B-lymphocytes • Neutrophils • Monocytes • Comorbid Conditions • Advanced Age • Diabetes Mellitus • Other Systemic Diseases Decreased Vaccine Responsiveness Immunosuppressive Therapy ACUTE INFECTION Disruption of Cutaneus Barriers Increased Exposure to Infectious Agents

7. Infections in ESRD • Second major cause of death • Most common: 1) urinary tract infections, 2) pneumonia, 3) sepsis • Also cellulitis, peritonitis, endocarditis, meningitis • Annual mortality rates in the dialysis population compared with the general population: • 10-fold higher for pneumonia (Sarnak et al, Chest, 2001) • 100-fold higher for sepsis (Sarnak et al, Kidney Int, 2000)

8. Vaccinations recommended for adults with CKD and patients undergoing dialysis • Pneumococcal 23-valent polysaccharide vaccine • Influenza vaccine • Hepatitis virus B vaccine • Varicella vaccine According to The Canadian Immunization Guide (2006)

9. Haemophilus influenzae • Gram-negative bacterium • The polysaccharide capsule protects bacteria from host defense • Six serotypes of encapsulated H. influenzae: a, b, c, d, e, f Most virulent: Hib • Non-encapsulated H.influenzae www.wadsworth.org/databank/images/haemophilus

10. Haemophilus influenzae • Nasopharyngeal colonization in healthy individuals • Cause invasive diseases: meningitis, sepsis, and bacteremic pneumonia, mainly in children • Circulating IgG antibody: the major defense mechanism • Natural immunity develops with age • Young children: delay in immune responses • Pediatric vaccine against H. influenzae type b (Hib): dramatic decline in disease incidence • Adult vaccination is recommended for high-risk groups (e.g. asplenia) • In some Aboriginal populations: increased susceptibility to invasive H. influenzae disease

11. Our recent findings: high incidence of invasive H. influenzae disease caused by non-type b strains in Northwestern Ontario • 38 cases of invasive H. influenzae disease • High ncidence rate: 2.98/100.000 in 2004, 2006, and 2007 • Increased prevalence of the disease among 1) First Nations children <5 yr 2) Adults with predisposing medical conditions Invasive H. influenzae disease: Northwestern Ontario 2002-2008 Invasive Hibdisease: Ontario1989-2004* Brown V, Madden S, Kelly L, Jamieson F, Tsang R, Ulanova M. Invasive Haemophilus influenzae disease caused by non-type b strains in Northwestern Ontario, Canada, 2002-2008. Clin Infect Dis 2009, 49:1240-1243.

12. Do patients with diabetic nephropathy and ESRD have an increased risk of invasive H. influenzae type bdisease? Rationale: • Diabetic nephropathy: the most common cause of chronic renal failure • Both diabetes and ESRD cause immunosuppression • Hib continues circulating in Canada • Adults have not been immunized against Hib • Cases of peritonitis caused by Hib are described

13. Methodology 28 ESRD patients with type 2 diabetes mellitus (DM) undergoing peritoneal or haemodialysis (50% First Nations, age 37-83) 15 patients with DM and normal kidney function (age 45-76) 38 healthy controls (42% First Nations, age 22-77) Analysis of serum IgG antibody levels against H. influenzae type b (Hib) capsular polysaccharide (ELISA) Antibody level ensuring long-term protection: 1 mg/ml

14. Morbidity in ESRD Patients

15. Serum IgG antibody levels to H. influenzae type b P<0.05

16. Antibody against H. influenzae type bin patients with ESRD and diabetes mellitus Over 60% of patients with ESRD lack protective anti-Hib antibodies

17. Discussion With pediatric Hib vaccine widely used, circulation of Hib is decreasing Decreased natural exposure to Hib in non-vaccinated individuals Lack of natural boosting of anti-Hib immunity

18. Discussion ESRD patients are immunocompromized (secondary immunodeficiency) With pediatric Hib vaccine widely used, circulation of Hib is decreasing Decreased natural exposure to Hib in non-vaccinated individuals Increased risk of Hib invasive disease Lack of natural boosting of anti-Hib immunity

19. Conclusions • Pediatric Hib vaccine is safe and efficient in adults • It may be beneficial to immunize adult ESRD patients with the pediatric Hib vaccine to achieve protective antibody level • Next questions: • Can vaccination provide long-lasting protection? • What about other groups of ESRD patients?

20. Acknowledgements Financial Support: Founding Dean Summer Medical Student Research Award to Sean Gravelle Dr McCready’s NOSM Internal Research Funding Dr Ulanova’s NOSM Internal Research Funding Patients at TBRHSC Renal Services and Dr Malik’s Office Volunteers: healthy controls Donna Newhouse Personnel at TBRHSC and physicians’ offices