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 diseaseChronic kidney diseaseDiabetes mellitusLeukemiasMultiple myelomaBone marrow transplantationCytostatic 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)

- 100-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

www.wadsworth.org/databank/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: 2.98/100.000 in 2004, 2006, and 2007

• Increased prevalence of the disease among 1) First Nations children <5 yr 2) Adults with predisposing medical conditions

0

0.5

1

1.5

2

2.5

3

3.5

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Incide

nce Ra

te per 1

00, 00

0

Year

Hib Ontario

H. influenzae Northwestern Ontario

*Public Health Agency of Canada Notifiable Diseases, 2006

0

0.5

1

1.5

2

2.5

3

3.5

1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008

Incide

nce Ra

te per 1

00, 00

0

Year

Hib Ontario

H. influenzae Northwestern Ontario

*Public Health Agency of Canada Notifiable Diseases, 2006

Invasive H. influenzae disease: Northwestern

Ontario 2002-2008

Invasive Hib disease:

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.

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 Mellitus 25/25

Cardiovascular Disease 18/25

COPD 7/25

Hypothyroidism 3/25

Mental Illness 3/25

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

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 GroupLack of protective

Ab (1 g/ml)

Controls 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

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