Transcript Risk of invasive H. influenzae disease in patients with chronic renal

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
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
Examples:
Chronic liver disease
Chronic kidney disease
Diabetes mellitus
Leukemias
Multiple myeloma
Bone marrow transplantation
Cytostatic drugs, corticosteroids, etc
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
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
Risk Factors of Infection in Kidney
Disease
Comorbid
Conditions
• Advanced Age
• Diabetes Mellitus
• Other Systemic
Diseases
Impaired Immune
Response
• T- and Blymphocytes
• Neutrophils
• Monocytes
Decreased Vaccine
Responsiveness
Increased
Exposure to
Infectious Agents
ACUTE
INFECTION
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
- 100-fold higher for sepsis
(Sarnak et al, Chest, 2001)
(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)
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
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
Our recent findings: high incidence of invasive
H. influenzae disease caused by non-type b strains in
Northwestern Ontario
Incidence Rate per 100, 000
3.5
3
2.5
2
Invasive H. influenzae
disease: Northwestern
Ontario 2002-2008
1.5
1
0.5
Invasive Hib disease:
Ontario1989-2004*
0
1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008
Year
*Public Health Agency of Canada Notifiable Diseases, 2006
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.
• 38 cases of invasive
H. influenzae disease
• High ncidence rate:
H.2.98/100.000
influenzae
in 2004,
Northwestern Ontario
2006, and 2007
Hib Ontario
• Increased prevalence
of the disease among
1) First Nations children
<5 yr
2) Adults with
predisposing medical
conditions
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
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
Morbidity in ESRD
Patients
Type 2 Diabetes Mellitus
25/25
Cardiovascular Disease
18/25
COPD
7/25
Hypothyroidism
Mental Illness
Multiple Infectious Episodes
20/25
Pneumonia
9/25
Sepsis
6/25
Cellulitis/Infected Ulcers
5/25
Urinary Tract Infection
3/25
Septic Arthritis
1/25
Osteomyelitis
1/25
Peritonitis
1/25
Otitis media
1/25
3/25
3/25
Serum IgG antibody levels to H. influenzae
type b
Median
2.41
2.73
0.47
Range
0 - 8.1
0 - 13.5
0 - 22.0
P<0.05
Antibody against H. influenzae type b in patients
with ESRD and diabetes mellitus
Patient Group
Controls
Lack of protective
Ab (1 mg/ml)
13% (5 out of 38 )
Diabetes Mellitus
33% (5 out of 15)
ESRD + Diabetes
61% (17 out of 28)
Over 60% of patients with ESRD lack
protective anti-Hib antibodies
Discussion
With pediatric Hib vaccine
widely used, circulation of
Hib is decreasing
Decreased natural
exposure to Hib in nonvaccinated individuals
Lack of natural boosting
of anti-Hib immunity
Discussion
With pediatric Hib vaccine
widely used, circulation of
Hib is decreasing
ESRD patients are
immunocompromized
(secondary
immunodeficiency)
Decreased natural
exposure to Hib in nonvaccinated individuals
Lack of natural boosting
of anti-Hib immunity
Increased risk of Hib
invasive disease
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?
Acknowledgements
Financial Support:
Patients at TBRHSC Renal
Services and Dr Malik’s
Office
Volunteers: healthy controls
Donna Newhouse
Personnel at TBRHSC and
physicians’ offices
Founding Dean Summer
Medical Student Research
Award to Sean Gravelle
Dr McCready’s NOSM
Internal Research Funding
Dr Ulanova’s NOSM Internal
Research Funding