1. Streptococcus pneumonia (pneumococcus)
Sir William Osler
Streptococcus pneumonia (pneumococcus)
“the captain of all the men of death”
“Pneumonia may well be called the friend of the aged. Taken off by it in an acute, short, not often painful illness, the old man escapes those ‘cold gradations of decay’ so distressing of himself and to his friends”
Pneumococcal pneumonia is estimated to affect one in a thousand adults each year and has a case fatality ratio of 10 to 20% (World Health Organization, 1999).
Each year in England and Wales, one person per thousand is admitted to
hospital with community-acquired pneumonia (CAP) [1] and four times as many cases are treated outside hospital [2].
In subjects aged <65 yrs, pneumonia kills as often as all other infectious diseases combined [6].

2. 1-2 million deaths per year Half in children
Pneumonia
1-2 million deaths per year
Half in children
Commonest infectious cause of death in
developed countries
About 1 in 500 people age >55yr per annum
Sir William Osler
Streptococcus pneumonia (poneumococcus)
“the captain of all the men of death”
“Pneumonia may well be called the friend of the aged. Taken off by it in an acute, short, not often painful illness, the old man escapes those ‘cold gradations of decay’ so distressing of himself and to his friends”
Among people aged 55 years and older, the incidence per 1000 person-years was 1·7 in those with no underlying
disease, 3·4 with one underlying disease, and 15·0 with three underlying diseases.2 (Mantani)

3. Pneumonia Severity : CURB 65
1068 patients admitted to 3 hospitals
9% mortality at 30 days
Lim Thorax 2008

4. Pneumococcal disease and age
IPD cases are defined by the isolation of S. pneumoniae from the blood, cerebrospinal fluid (CSF), or other normally
sterile sites

5. Risks of Pneumococcal disease
OR (95%CI)
Males ( )
Smoker ( )
Less than high school 2.8 ( )
<6yr child in day care 3.0 ( )
Chronic disease 2.6 ( )
COPD, diabetes, cirrhosis,
heart failure)
Case control study Atlanta, Baltimore, Ontario
228 cases of Invasive pneumococcal disease
Excluded immunosuppressed inc cancer
Nuorti New Eng J Med 2001

6. 10% of healthy adults.
20–40% of healthy children
60% of infants and children in nurseries

7. Toffee apple 92 different serotypes
About 66% of the serious infections in adults and about 80% of invasive infections in children are caused by eight to ten capsular types (Health Protection Agency, 2003).
In the USA and most of the more developed countries, the serotypes commonly causing bacteraemic disease in adults are 3, 4, 7, 8, and Types 1 and 5 are more commonly reported in less developed countries.14 Transmissibility also varies by serotype.15 Serotype 1 is 20 times more infectious than serotype 9.15 Rapid spread of particular serotypes is seen in family cluster studies.16 The virulence of pneumococcal serotypes varies.17 For example, serotype 3 is noted as a cause of bronchopneumonia, and serotype 18 is seen more commonly as a cause of meningitis (mantani)
92 different serotypes
70 % of adult infection and 80% of childhood infection caused by 10 types

8. Polysaccharide vaccine (23 valent) Pneumovax II
Conjugated polysaccharide vaccine
Prevanar (13 valent)
£8.32
23 types included account for about 96% of the pneumococcal isolates that cause serious infection in the UK (Health Protection Agency, 2003).
The antibody responses to PPSV23 and PCV7 were statistically comparable for 58% (n = 42), whereas PCV7 responses were statistically higher than PPSV23 responses in 42% (n = 30) –Grabenstein
Because vaccination with polysaccharide antigens does not establish T-cell-mediated immune memory, the immune response to revaccination is not expected to be higher than the response after primary vaccination. (Grabenstein)
£ (x 3)

9. Components of pneumococcal vaccines
23 valent Polysaccharide vaccine
78% of serotypes age group 18-49
76% of serotypes age group 50-64
66% of serotypes age group >64
13 valent conjugate vaccine
53% of serotypes age group 18-49
49% of serotypes age group 50-64
44% of serotypes age group >64
In 2008 in the US, the serotypes in PCV13 caused 53%, 49% and 44% of IPD cases among persons aged 18–49 years, 50–64 years, and ≥65 years, respectively. Serotypes in PPSV23 caused 78%, 76%, and 66% of IPD cases among persons in these age groups (Grabenstein)
These seven serotypes are responsible for 80% of pneumococcal infections in children living in developed countries.(Toll)
Of the ∼92 different S. pneumoniae serotypes, 7 of the most common serotypes causing IPD in children are included in PCV7 (4, 6B, 9V, 14, 18C, 19F, and 23F). The 23-valent PPV includes those 7 serotypes, as well as an additional 16 (1, 2, 3, 5, 7F, 8, 9N, 10A, 11A, 12F, 15B, 17F, 19A, 20, 22F, and 33F), which were selected primarily because of their contribution to IPD in adults

10. Pneumococcal vaccine timelines
valent polysaccharide vaccine
1983 current 23 valent polysaccharide vaccine
1992 vaccine recommended for at risk groups
2002 conjugate vaccine 7 for at-risk children <2yr
2003 polysaccharide vaccine for everyone ≥ 65 yr
2004 conjugate vaccine for at-risk children <5 yr
2006 routine childhood immunisation
valent conjugate vaccine introduced

11. Effectiveness of pneumococcal vaccine
Isolation of PCV-7 pneumococcal strains in those age <2yr
Public Health England

12. Adverse effects Fever nausea, headache 1:1000 Deaths 0
Local reaction (unable to lift arm)
First vaccine %
Reimmunisation %
Elderly female, lax skin 10%
From postlicensing case reports, systemic effects of fever (temperature up to 40C), chills,
nausea, and headache have been reported as occurring with a frequency of one per Patients required
acute hospital investigation and medical support for about 2 days. No deaths have been reported. A mild reaction thatinterferes with arm movement occurs in 1% of primary
vaccinees.53 Information from sufficient numbers on the
risk of adverse events from revaccination is limited. In one
of the few studies, 1% of 900 first-time vaccinees and 5% of
500 people revaccinated 5 or more years after primary
vaccination were not able to lift their arms above their
heads.54 1% in both groups developed high temperatures
but none required hospital admission. No increase in
admission rates was noted in a revaccinated cohort of just
over 1000 compared with first-time-vaccinated
elderly US Medicare patients.55 A report of a clinical trial of
revaccination in the USA noted that about 10% of patients
developed severe erythema similar in effect to cellulitis of
the arm, exclusively in older women women with loose upper arm
skin and poor muscle tone.56 (Mantani)
Mantani Lancet 2003

13. Invasive pneumococcal disease vs pneumonia

14. Pneumococcal bacteraemia and outcome of pneumonia
125 subjects with bacteremic
1,847 subjects without
Time to achieve clinical stability
Probability of dying
Time to discharge
Bordon Chest 2008

15. Effective against invasive pneumococcal disease (IPD)
25 studies 18 RCTs with 64,852 subjects;
7 non-RCTs with 62,294 subjects)
Effective against invasive pneumococcal disease (IPD)
74% reduction (OR 0.26, 95% CI 0.14 to 0.45)
Effective against pneumonia in low-income countries
46% reduction (OR 0.54, 95% CI 0.43 to 0.67)
No significant effect against pneumonia in high-income countries
(OR 0.71, 95% CI 0.45 to 1.12)
Less effective in adults with chronic illness
(OR 0.93, 95% CI 0.73 to 1.19)
No reduction in mortality
(OR 0.90, 95% CI 0.74 to 1.09)

17. Duration of protection from pneumococcal polysaccharide vaccine
Pneumococcal antibody levels
Vaccine effectiveness (%)
by age and time from vaccination
< >5
< >5
< >5
Antibody levels fall with time
Evidence of falling effectiveness inconsistent Shapiro NEJM1991 vs Butler JAMA 1993
Mostly evidence is that revaccination is not as effective as first in inducing antibodies – hyporesponsiveness – but that does not necesserily correlate with clinical effectiveness
<
Shapiro New Eng J Med 1991

18. Effectiveness of pneumococcal vaccine
Isolation of PCV-7 pneumococcal strains in those age <2yr
Public Health England

19. Herd effectiveness of pneumococcal vaccine
Isolation of PCV-7 pneumococcal strains in those age >5yr
Public Health England

20. Emergence of non PCV-7 pneumococcal strains
Isolation of non- PCV-7 pneumococcal strains in those age >5yr
Capsular switching probably arises through
trans formation of capsular genes from one serotype to
another.18,138–140 Such events could arm an intrinsically
virulent strain of S pneumoniae previously encapsulated
with a vaccine- related serotype with a new antigenic
polysaccharide coat to avoid vaccine-induced immune
recognition.
Serotype 19A S pneumoniae is a specifi c
concern.136 This serotype has expanded greatly since
introduction of the conjugate pneumococcal vaccine,138,139
and has much virulence potential as a pulmonary and
extrapulmonary pathogen. Moreover, it has the propensity
to acquire multiple drug-resistance genes, complicating
Public Health England

21. Pneumococcal promiscuity

22. Pneumococal vaccine in adults
Effectiveness against pneumonia is uncertain
Stops bacteraemia
May just stop bacteraemia
Duration of effectiveness is uncertain
Changing epidemiology of pneumococcal disease

26. Death from pneumonia in metal working occupations 1930-1963

27. Death from pneumonia in metal working occupations 1970-1972

28. Death from pneumonia in metal working occupations 1979-1990

29. Death from pneumonia in metal working occupations 1991-2000
Pneumococcal and unspecified lobar pneumonia (ICD 481)
Bronchopneumonia (ICD 481)
Other pneumonias (ICD 480, 482-3, 486)

30. Welders are also more commonly admitted to hospital with CAP, especially lobar pneumonia, as demonstrated by a large case control study from the West Midlands.4

31. Effects of metal fume exposure
Consistent x 2-3 increased risk of pneumonia
Hasn’t decreased since the 1930s
Only when actively exposed
Confined to lobar/ pneumococcal pneumonia
WHY ?

33. Iron and welding Iron facilitates bacterial growth
Fifty years ago Schade and Caroline discovered that iron binding proteins, present in blood and the whites of eggs, could inhibit bacterial growth in vitro.
Later on, others showed that animals injected with iron were more susceptible to infection than untreated controls,
and that the well known antibacterial effects of body fluids could be abolished in vitro by adding iron.‘
free radical injury: in vivo iron dependent reduction of hydrogen peroxide generates hydroxyl radicals
Studies have shown that metal particles, or carbon coated with metals, can be cytotoxic to macrophages,19 20 and short term inhalation experiments in animals have produced a cytotoxic response at ambient concentrations down to 0.1 mg/m.n
Most of the body's iron stores are intracellular-in ferritin, haemosiderin or
haem; and the extracellular fraction is bound to high affinity iron binding proteins-transferrin in serum and lactoferrin in external secretions.9
These proteins have large association constants, and are only partially saturated under normal circumstances (30% to 40% in the case of serum transferring, so the amount of free iron in equilibrium with iron binding proteins is thought to be as low as 10-'8 M.'0
Iron facilitates bacterial growth
Iron increases inflammation
Iron is toxic to macrophages

34. The Iron war during infection
Pathogens adapt to obtain Iron
Produce haemolysins which liberate iron from haem
Produce proteolytic proteins that break down transferrin and lactoferrin
producing their own low molecular weight iron chelators,
Host organisms restrict iron availability during infection.
Lactoferrin, ferratin bind iron
Decreased binding to transferrin
Macrophages ingest Fe-transferrin
Reduced release of Fe from macrophages
Decreased absorption of Iron ;" " while the amount of iron bound

35. Welding and pneumonia 75,000 welders in the UK
40-50 hospital admissions pa because of fume
2 deaths pa
Source : HSE

36. PPV (single 0.5ml dose in those who have not received PPV previously) should be considered for those at risk of frequent or continuous occupational exposure to metal fume (e.g. welders) taking into account the exposure control measures in place. Vaccination may reduce the risk of invasive pneumococcal disease but should not replace the need for measures to prevent or reduce exposure.
In response to growing evidence on risk, the Joint Committee on Vaccination and Immunisations (JCVI), on behalf of the Department of Health in England, recommended in 2011 that all welders be offered a single dose of the pneumococcal polysaccharide vaccine PPV-23.7 This advice was modified in 2012, extending recommended use to a broader range of workers with exposure to metal fumes. Further details and a discussion of the potential strengths and limitations of PPV-23 vaccination in at-risk occupations have been published elsewhere.1

37. Pneumococcal disease 1 in 5000 welders/yr Vaccine reduces risk by 75%
Effect lasts 10 yr
Vaccinating 600 welders will prevent 1 case pa
If 1 in 8 die
Vaccinating 5000 welders will prevent 1 death pa
In the USA, pneumococcal vaccination of people aged 65 years and older was estimated to be cost-saving,4 with
the assumption that hospital-admission costs associated with bacteraemia were saved, and that vaccine efficacy
against bacteraemia was 47% overall based on estimates of efficacy specific for age and duration from the casecontrol
study by Shapiro and colleagues.45 In Europe, the cost per year of life gained was estimated as –33 000
ecus, with the same estimates of vaccine efficacy.51 (Mantani)
Britain has some 70,000 at-risk workers in welding occupations. Other at-risk groups include a range of workers who share occupational exposure to metal fumes in common (eg moulders and core makers, and furnace men in foundries).2,3
Deaths from pneumonia in young adults are rare,
as are deaths due to IPD [14,15], but the analysis by
Palmer et al. [13] found that the attributable mortality
from metal fume (45.3 excess deaths) in England and
Wales during 1991–2000 was not trivial compared with
an estimated 62.6 deaths from occupational asthma over
the same period. Using data from various sources, the
Health & Safety Executive has since made a similar estimate
of attributable mortality [16].

39. Number needed to treat Stopping smoking to prevent IHD death 8
Warfarin in AF to prevent stroke
Treat BP >/90 to prevent vasc event
Mammograms to save 1 cancer death 1,600
Aspirin to prevent AMI/stroke 1,667
Osteoporosis Rx to prevent # Fem > 60 yr 1,945
Regular seat belt use to prevent death ,000