PNEUMOCOCCAL DISEASE: A MAJOR HEALTH THREAT

1
PNEUMOCOCCAL DISEASE A MAJOR HEALTH THREAT

• Pneumococcal disease caused by Streptococcus
  pneumoniae
• Pneumococcal disease a major threat to health
• Non-invasive diseases (e.g. otitis media,
  pneumonia)
• Invasive diseases (e.g. bacteraemia, meningitis)
• Invasive pneumococcal disease is serious and has
  a high risk of mortality
• Groups at high risk include elderly persons,
  persons with chronic diseases, asplenic
  patients, immunocompromised patients

1.2
2
DISEASES CAUSED BY STREPTOCOCCUS PNEUMONIAE
PNEUMOCOCCAL INFECTION

• Non-invasive disease
• Sinusitis (sinuses)
• Otitis media (middle ear)
• Pneumonia (lungs)

• Invasive disease
• Bacteraemia (blood)
• Meningitis (CNS)
• Endocarditis (heart)
• Peritonitis (body cavity)
• Septic arthritis (bones and joints)
• Others (appendicitis, salpingitis, soft-tissue
  infections)

Musher, in Principles and Practice of
Infectious Diseases, 1995
2.13
3
PNEUMOCOCCUS TRANSMISSION AND COLONISATION
Fedson, Musher, in Vaccines, 1994 Musher, in
Principles and Practice of Infectious Diseases,
1995
2.4
4
PNEUMOCOCCUS PATHOGENESIS
Salyers, Whitt, in Bacterial Pathogenesis, 1994
2.6
5
PNEUMOCOCCAL EPIDEMIOLOGY AT-RISK GROUPS (1)

• ELDERLY PERSONS
• Laboratory reports of bacteraemic pneumococcal
  infection per 100 000 population, by age group,
  in England and Wales

1986
1982
1992
Bacteraemia
35
30
25
Reports per 100 000 population
20
15
10
5
19
1019
2044
4564
6569
7074
75
Age (yrs)
lt1
Aszkenasy et al., CDR Review, 1995
CDSC Communicable Disease Surveillance Centre
3.5
6
THE OVERLAP BETWEEN PNEUMOCOCCAL PNEUMONIA AND
INVASIVE PNEUMOCOCCAL DISEASE
5.6
Fedson DS. Drugs Aging 1999.
7
PNEUMOCOCCAL DISEASE PNEUMONIA (4)

• Complications
• Bacteraemia in 15-30 of patients with
  pneumonia1,2
• high mortality despite appropriate antibiotic
  therapy
• overall case fatality rate 15-20 for
  pneumococcal bacteraemia
• higher case fatality rates (30-40) for elderly
  persons and other vulnerable groups
• Spread of pneumococci in the blood to other
  normally sterile sites can cause other invasive
  pneumococcal diseases (e.g. meningitis)
• Empyema (pus in the pleural cavity) in about 2
  of cases3

1 Salyers, Whitt, in Bacterial Pathogenesis,
1994 2 Fedson, Musher, in Vaccines, 1994 3
Musher, Clin Infect Dis, 1992
2.17
8
PNEUMOCOCCAL DISEASE MENINGITIS (1)

• Meningitis
• Inflammation of the meninges (membranes
  surrounding the brain)
• Can be caused by a range of microorganisms, as
  well as be a manifestation of some non-infectious
  diseases
• Pneumococcal meningitis
• Invasive pneumococcal disease
• Generally, pneumococci invade the CNS from the
  blood stream
• Signs and symptoms1
• Early stages fever, irritability, neck
  stiffness, drowsiness
• Later stages headache, seizures, coma
• The signs and symptoms are not specific to
  pneumococcal disease

1 Salyers, Whitt, in Bacterial Pathogenesis,
1994
2.18
9
PNEUMOCOCCAL DISEASE MENINGITIS (2)

• Pneumococcal meningitis¾a high risk of mortality
• Case-fatality rate about 30 in adults1
• Higher (about 55) in older patients and other
  vulnerable groups2
• Disability among survivors1
• Learning disability
• Hearing loss
• Blindness
• Paralysis

1 Fedson, Musher, in Vaccines, 1994 2 CDC, MMWR,
1989
2.19
10
INTRODUCTION PNEUMOCOCCAL DISEASE (2)
Pathogenic agents in bacterial meningitis in
persons aged ³ 60 years in the USA
Group B streptococcus 3
Haemophilus influenzae 4
Others 26
Streptococcus pneumoniae 49
Neisseria meningitidis 4
Listeria monocytogenes 14
Wenger et al., J Infect Dis, 1990
1.4
11
EPIDEMIOLOGY INVASIVE PNEUMOCOCCAL DISEASE (3)

• PNEUMOCOCCAL MENINGITIS1,2
• Annual incidence 1-2/100 000 persons
• Higher among young children and elderly persons
• at least 10 times the incidence among an elderly
  (³60 years) population than among younger adults
  (20-29 years of age)2
• Case-fatality rates are high
• about 30 in adults and 6 in children3

1 CDC, MMWR, 1997 2 Wenger et al., J Infect Dis,
1990 3 Fedson, Musher, in Vaccines, 1994
3.3
12
PNEUMOCOCCAL DISEASE MEDICAL MANAGEMENT (1)

• Hospitalisation
• Often required in high-risk groups and/or in
  severe forms of pneumococcal disease
• Sometimes admission to an intensive care unit is
  necessary
• Empiric treatment using broad-spectrum
  antimicrobial agents
• To cover all possible bacterial aetiological
  agents
• To overcome increasing antimicrobial resistance
  to antibiotics
• High-cost management

2.21
13
PNEUMOCOCCAL DISEASEA SUMMARY

• S. pneumoniae
• A bacterium surrounded by a polysaccharide
  capsule that protects it from phagocytosis
• Many different serotypes
• Pneumococcal disease
• Invasive pneumococcal disease is serious and has
  a high risk of mortality
• Risk factors include old age, chronic illness,
  asplenia and immunodeficiency
• Mortality remains high despite appropriate
  antibiotic therapy
• S. pneumoniae resistance to antimicrobials is
  increasing (with concomitant increasing cost of
  management)
• Prevention of pneumococcal disease among
  high-risk groups is a priority

2.24
14
PNEUMOCOCCUS DIVERSITY OF SEROTYPES

• There are at least 90 different serotypes of
• S. pneumoniae1,2
• Each has a capsule of a different chemical
  composition
• Each stimulates the production of a different
  antibody
• Only a minority of serotypes cause most cases of
  human disease
• 8-10 cause two-thirds of serious pneumococcal
  infections in adults3

1 Fedson, Musher, in Vaccines, 1994 2 Henrichsen,
J Clin Microbiol, 1995 3 UK DoH, Immunisation
Against Infectious Disease, 1996
2.3
15
PNEUMOCOCCAL VACCINES ANTIGEN COMPOSITION

• 23-valent pneumococcal vaccine contains purified
  capsular polysaccharides derived from 23 S.
  pneumoniae serotypes1
• 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A,11A, 12F,
  14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, 33F
• Serotype coverage2,3
• 85-90 of serotypes responsible for all cases of
  invasive pneumococcal disease
• Vaccine includes major serotypes that have
  developed antimicrobial resistance
• Cross protection within some serotypes1
• For example, antibody response to serotype 6B
  protects against serotype 6A, which is not in the
  vaccine

1 CDC, MMWR, 1989 2 Fedson, Musher, in Vaccines,
1994 3 Geslin et al., Méd Mal Infect, 1992
5.2
16
PNEUMOCOCCAL VACCINES IMMUNE RESPONSE

• Vaccine stimulates 23 type-specific anti-capsular
  antibodies1
• Antibodies aid the destruction of pneumococci by
  white blood cells
• The immune response in most elderly patients ³ 65
  years of age
• is as good as that of healthy younger adults1
• is variable according to serotypes2
• The response is decreased in
• immunosuppressed individuals (e.g. patients with
  leukaemia, lymphoma, multiple myeloma, or AIDS)3
• Antibody levels generally last 5 years or more4
• Note it is inappropriate to use 23-valent
  vaccine in children under 2 years of age, because
  the immune response in this age group is poor 3

1 Fedson, Musher, in Vaccines, 19942 Rubins et
al., Infect Immun, 19993 CDC, MMWR ,19974
Butler et al., JAMA ,1993
5.3
17
PNEUMOCOCCAL VACCINES OVERVIEW OF EFFECTIVENESS

• Case-control and indirect cohort studies on the
  effectiveness of the pneumococcal vaccine in
  preventing invasive pneumococcal disease

Type of infection Location Vaccine
Source (no of cases) efficacy (95 CI) All
serotypes Connecticut (1054) 47 (30-59) Shapiro
et al. 1991 Philadelphia (122) 70 (37-86) Sims
et al. 1988 Charlottesville (85) 81 (34-94) Farr
et al. 1995 Alaska (159) 64 (32-81) Davidson
et al.1994 Vaccine type Connecticut (983) 56
(42-67) Shapiro et al. 1991 VT-related Denver
(89) -21 (-221-55) Forrester et al. 1987 Alaska
(87) 79 (49-92) Davidson et al. 1994 CDC
57 (45-66) Butler et al. 1993
only patients with pneumococcal isolates from
normally sterile body sites were included. VT
indicates vaccine-type pneumococcal infection.
unpublished observations. indirect cohort
study 515 vaccinated and 2322 unvaccinated
subjects.
Fedson, in The Clinical Impact of Pneumococcal
disease and Strategies for its Prevention, 1995
5.14
18
PNEUMOCOCCAL VACCINES CLINICAL EFFECTIVENESS

• Estimation of effectiveness of pneumococcal
  vaccination in preventing invasive pneumococcal
  disease caused by vaccine serotypes
• US Centers for Disease Control study in 2837
  patients (³ 5 years old) by underlying illness,
  1978-1992

Overall effectiveness of 57
95 CI
75
Immunocompetent, gt65 years (70,373)
57-85
84
50-95
Diabetes mellitus (9,122)
23-90
73
Coronary vascular disease (15,73)
65
26-83
Chronic pulmonary disease (50,186)
14-95
77
Anatomic asplenia (89,23)
69
17-88
Congestive heart failure (20,96)
Underlying disease/condition (no of isolates from
vaccinated, unvaccinated subjects)
Note data are for patients who received
14-valent or 23-valent vaccine. Overall
effectiveness for patients receiving 23-valent
vaccine was 60.
5.13
Butler et al., JAMA ,1993
19
PNEUMOCOCCAL DISEASE PREVENTION VACCINATION
RECOMMENDATIONS

• WHO view (Technical Advisory Group convened by
  WHO Regional Office for Europe, 1988)1
• Pneumococcal vaccination should be recommended
  for all elderly persons (aged ³60-65 years) and
  for persons of any age at high risk of acquiring
  pneumococcal infection
• National recommendations
• Many countries recommend vaccination for specific
  at-risk groups or conditions
• Some countries recommend vaccination for elderly
  persons aged
• ³60 years Belgium, Germany, Iceland
• ³65 years Denmark, Finland, Norway, Sweden,
  USA, Canada, New Zealand

1 Fedson et al., Infection 1989
4.3
20
PNEUMOCOCCAL DISEASE PREVENTION VACCINATION
RECOMMENDATIONS
Pneumococcal vaccination recommendations in the
USA Europe (1997 data)

• Immunocompromised Cardiopulmonary Nurs
  ing Age gt
• Country Asplenia Haematological HIV diabetes,
  renal Other home 65 years
• Austria l - - l l - -
• Belgium l l l l l l l
• Denmark l l l l - - l
• Finland l l l l l - l
• France l l - l l - -
• Germany l l - l - - -
• Iceland l l - l l l l
• Ireland l l l l l - -
• Italy l - l - - - -
• Luxembourg l l l l l l l
• Netherlands l - -
• Norway l l l l l - l
• Sweden l l l l l - l
• Switzerland l l l l l - -
• UK l l l l l - -
• USA l l l l l l l

recommended for any person at increased risk
because of chronic illness. Austria not
diabetes mellitus or renal disease France not
heart disease. Belgium, Iceland ³60 years
Luxembourg ³55 years. - not recommended. There
are no national recommendations for Greece,
Portugal or Spain. For Switzerland,
recommendations are from an advisory note only in
the national vaccination recommendations
4.4
D Fedson, personal communication, 1997
21
PNEUMOCOCCAL DISEASE PREVENTION OPPORTUNITIES
FOR VACCINATION
Who When Age ³65 years and/or persons at
risk Regular return visits to general
practitioners or hospitals Concomitantly with
influenza vaccine (at a different injection
site) Discharge from hospital Residency in
nursing home or other chronic care
facility Persons undergoing splenectomy, 2
weeks before elective surgery, organ
chemotherapy transplantation, cancer
chemotherapy, immunosuppressive
treatment Persons with HIV infection On
diagnosis of HIV positivity
CDC, MMWR, 1997
4.5
22
PNEUMOCOCCAL DISEASE PREVENTION OVERALL
VACCINATION RATES

• Pneumococcal vaccination rates in the USA, Canada
  and western Europe in 1996

USA
OthersSpain (5)Portugal (0)Netherlands
(3)Italy (2)Ireland (5)Greece(2)Germany (5)
Canada
Belgium
UK
Sweden
Norway
Finland
Iceland
Austria
France
Switzerland
Denmark

Others
0
40
80
120
160
200
240
280
Fedson, Clin Infect Dis, in press
Doses of pneumococcal vaccine distributed per 10
000 population
4.6
23
PNEUMOCOCCAL DISEASE PREVENTION
PHARMACOECONOMICS

• The cost-effectiveness of vaccination to prevent
  pneumococcal bacteraemia in persons aged ³65
  years was recently evaluated in the USA

Net medical expenditure per QALY gained for
single pneumococcal vaccination was compared with
treatment of the disease if it occurred
Vaccination was COST-SAVING in each age group
analysed (65-74, 75-84, ³85 years)
'Based on preventing bacteraemia alone, these
results lend strong support to US policies for
universal pneumococcal vaccination for elderly
people'
Sisk et al., JAMA, 1997
4.7
24
PNEUMOCOCCAL DISEASE CONCLUSIONS

• Pneumococcal disease
• Major cause of morbidity and mortality worldwide
• Diagnosis not always made and difficult to
  establish
• Treatment may be complicated by antibiotic
  resistance
• Management can be costly
• Prevention by vaccination is a priority in
  populations who are at risk
• The elderly
• Patients with chronic cardiovascular, pulmonary,
  renal, hepatic and metabolic disorders
• Patients who are immunocompromised
• Patients with asplenia

7.1