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

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

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)

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

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 Factors Causing Immune Dysfunction in ESRD Patients

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

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) fold higher for sepsis (Sarnak et al, Kidney Int, 2000)

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)

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 Haemophilus influenzae /images/haemophilus

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 Haemophilus influenzae

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/ 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 Invasive Hib disease: Ontario * 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, Clin Infect Dis 2009, 49:

Do patients with diabetic nephropathy and ESRD have an increased risk of invasive H. influenzae type b disease? 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

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) Methodology Analysis of serum IgG antibody levels against H. influenzae type b (Hib) capsular polysaccharide (ELISA) Antibody level ensuring long-term protection: 1  g/ml

Morbidity in ESRD Patients Type 2 Diabetes Mellitus25/25 Cardiovascular Disease18/25 COPD7/25 Hypothyroidism3/25 Mental Illness3/25 Multiple Infectious Episodes20/25 Pneumonia9/25 Sepsis6/25 Cellulitis/Infected Ulcers5/25 Urinary Tract Infection3/25 Septic Arthritis1/25 Osteomyelitis1/25 Peritonitis1/25 Otitis media1/25

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

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

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 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 ESRD patients are immunocompromized (secondary immunodeficiency) Increased risk of Hib invasive disease Discussion

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? Conclusions

Acknowledgements Patients at TBRHSC Renal Services and Dr Malik’s Office Volunteers: healthy controls Donna Newhouse Personnel at TBRHSC and physicians’ offices 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