Dr.T.V.Rao MD

STREPTOCOCCUS PNEUMONIA (PNEUMOCOCCUS)

UPDATE

DR.T.V.RAO MD 1

• S. pneumoniae first

isolated by Pasteur in

1881

• Confused with other

causes of pneumonia

until discovery of Gram

stain in 1884

• More than 80 serotypes

described by 1940

• First U.S. vaccine in

1977

HISTORY OF PNEUMOCOCCAL DISEASE

DR.T.V.RAO MD 2

• Streptococcus

pneumoniae

(pneumococcus)

• Gram-positive,

encapsulated

diplococcus

• Capsular swelling

observed when reacted

with type-specific

antisera (Quelling

reaction)

STREPTOCOCCUS PNEUMONIAE

DR.T.V.RAO MD 3

• Capsular

swelling

observed when

reacted with

type-specific

antisera (Quelling reaction)

QUELLING REACTION

DR.T.V.RAO MD 4

IMPORTANT FOR MODELLING: PNEUMOCOCCAL SEROTYPES

• Based on properties of capsular polysaccharides

• Immunologically distinct and basis for classification

• > 40 serogroups (e.g. group 19)

• > 90 serotypes (e.g. types 19A, 19C, 19F)

• No immunologic cross-reactivity between serogroups

• Some cross-reactivity within some serogroups and some cross-

protection

• Geographical and temporal variation

• Some more immunogenic than others

DR.T.V.RAO MD 5

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

Meningitis

Pneumonia

Pericarditis

Septicemia

Osteomyelitis

Otits media

Sinusitis

Endocarditis

Peritonitis

Arthritis

CLINICAL MANIFESTATIONS

DR.T.V.RAO MD 7

PNEUMOCOCCUS CAUSE MULTIORGAN

DISEASE

DR.T.V.RAO MD 8

DISEASES CAUSED BY STREPTOCOCCUS PNEUMONIAE

Non-invasive disease

• Sinusitis (sinuses)

• Otitis media (middle ear)

• Pneumonia (lungs)

Musher, in Principles and Practice of Infectious Diseases, 1995

Invasive disease

• Bacteraemia (blood)

• Meningitis (CNS)

• Endocarditis (heart)

• Peritonitis (body cavity)

• Septic arthritis (bones and joints)

• Others (appendicitis, salpingitis,

soft-tissue infections)

PNEUMOCOCCAL INFECTION

• Abrupt onset

• Fever

• Shaking chills

• Pleuritic chest pain

• Productive cough

• Dyspnea, tachypnea,

hypoxia

PNEUMOCOCCAL PNEUMONIA

CLINICAL FEATURES

DR.T.V.RAO MD 10

• Bacteremia without known site of

infection most common clinical

presentation

• S. pneumoniae leading cause of

bacterial meningitis among

children younger than 5 years of

age

• Highest rate of meningitis among

children younger than 1 year of

age

• Common cause of acute otitis

media

PNEUMOCOCCAL DISEASE IN CHILDREN

DR.T.V.RAO MD 11

• Decreased immune function

• Asplenia (functional or anatomic)

• Chronic heart, pulmonary, liver or renal disease

• Cigarette smoking

• Cerebrospinal fluid (CSF) leak

CONDITIONS THAT INCREASE RISK FOR

INVASIVE PNEUMOCOCCAL DISEASE

DR.T.V.RAO MD 12

• S. pneumoniae is the most common cause of community-acquired bacterial pneumonia

• >500,000 cases annually

25%-35% require hospitalization

10%-25% have concomitant bacteremia

LOWER RESPIRATORY TRACT

INFECTIONS

DR.T.V.RAO MD 13

• Bacteremia most common

clinical presentation among

children younger than 2

years

• Most common cause of

bacterial meningitis in the

U.S.

• Highest rate of meningitis

among children younger

than 2 years

INVASIVE PNEUMOCOCCAL

DISEASE

DR.T.V.RAO MD 14

• Functional or

anatomic asplenia

• Sickle cell disease

• HIV infection

• Out-of-home group

child care

• Certain racial and

ethnic groups

CHILDREN AT INCREASED RISK OF

INVASIVE PNEUMOCOCCAL DISEASE

DR.T.V.RAO MD 15

SIGNIFICANT DISEASE BURDEN IN CHILDREN

Otitis media

Pneumonia

Bacteremia

Meningitis

Disease severity

No

nin

vasiv

e

Invasiv

e

Estimated number

of cases per year (US)

5–7 million

71,000

17,000

1,400

Prevalence

Incre

ases

MMWR. 1997;46:1-24. DR.T.V.RAO MD 16

• Common etiological agents: Streptococcus pneumoniae

• Clinical presentation: Abrupt onset with fever, cough, production of purulent sputum, dyspnea, and Pleuritic chest pain

• Recommended diagnostics: Chest X-ray, blood culture, FBC, gram stain of sputum, sputum culture and sensitivity

• Common findings: X-ray may show pneumonic consolidation, infiltrates, or pleural effusion; leukocytosis; blood cultures may be positive

Bacterial Pneumonia

DR.T.V.RAO MD 17

COMMON CAUSE OF PNEUMONIA-

STREPTOCOCCUS PNEUMONIA

DR.T.V.RAO MD 18

• From colonisation to

invasion of middle ear

through the eustachian

tube

• Facilitated by previous viral

infection

• Mostly in young children

with immature immune

defence

• Day-care centre (DCC)

attendance and prior antibiotic

treatment are risk factors

ACUTE OTITIS MEDIA

DR.T.V.RAO MD 19

• Bacterial growth in normally

sterile fluids

• Blood (pneumonia,

meningitis, endocarditis)

• CSF (meningitis)

• Joint fluids (artritis)

• Pleural fluid (pleuritis)

• Peritoneal fluid (peritonitis)

INVASIVE PNEUMOCOCCAL DISEASE

(IPD)

DR.T.V.RAO MD 20

PNEUMOCOCCAL DISEASE: PNEUMONIA AND COMPLICATIONS

•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

IMPACT OF COMPETITION

• Pneumococcal strains also compete with each

other. The increase in the prevalence of previously

uncommon serotypes in populations in which the

pneumococcal CPS conjugate vaccine is

extensively used (a phenomenon that is referred to

as serotype replacement) suggests that nonvaccine

pneumococcal types are being out-competed by the

serotypes that are present in the vaccine. One

mechanism that could underlie this intra-species

competition is the strain-specific activity of

pneumococcal Bacteriocins, which are known as

pneumocins.

• Chest X-ray

• Culture and

staining

• Biochemical tests

of isolated

organism

DIAGNOSIS OF STREPTOCOCCUS

PNEUMONIA

CULTURING OF S.PNEUMONIAE

DR.T.V.RAO MD 24

• Streptococcus pneumoniae is a fastidious bacterium, growing best in 5%

carbon dioxide. Nearly 20% of fresh clinical isolates require fully anaerobic

conditions. In all cases, growth requires a source of catalase (e.g. blood) to

neutralize the large amount of hydrogen peroxide produced by the

bacteria. In complex media containing blood, at 37°C, the bacterium has a

doubling time of 20-30 minute

• On agar, pneumococci grow as glistening colonies, about 1 mm in diameter.

Two serotypes, types 3 and 37, are mucoid. Pneumococci spontaneously

undergo a genetically determined, phase variation from opaque to

transparent colonies at a rate of 1 in 105 . The transparent colony type is

adapted to colonization of the nasopharynx, whereas the opaque variant is

suited for survival in blood. The chemical basis for the difference in colony

appearance is not known, but significant difference in surface protein

expression between the two types has been shown.

CULTURING OF S.PNEUMONIAE (CONT)

DR.T.V.RAO MD 25

• Streptococcus pneumoniae is a fermentative

aerotolerant anaerobe. It is usually cultured in media that

contain blood. On blood agar, colonies characteristically

produce a zone of alpha (green) haemolysis, which

differentiates S. pneumoniae from the group A (beta haemolytic)

streptococcus, but not from commensal alpha haemolytic

(viridans) streptococci which are co-inhabitants of the upper

respiratory tract. Special tests such as inulin fermentation, bile

solubility, and optochin (an antibiotic) sensitivity must be

routinely employed to differentiate the pneumococcus from

Streptococcus viridans

DRUG-RESISTANT S.PNEUMONIAE

• Mortality associated with S. pneumoniae dropped with

advent of penicillin in the 1940’s

• During the 1960’s, isolates of S.Pneumoniae moderately

resistant to penicillin appeared

• Isolates with high-level resistance emerged in the 1970’s

• 60-fold increase in 1992 vs 1987

• Prevalence of drug-resistant strains continues to

increase -- up to 35% in some communities

DR.T.V.RAO MD 26

23F

23F

23F

23F

23F

SPREAD OF INTERNATIONAL EPIDEMIC

CLONES

DR.T.V.RAO MD 27

• Prevention of life-

threatening and prevalent

pneumococcal disease

• Reduction of disease

transmission

• Reduction of carriage

• Reduction of antibiotic

resistance

• Retention of antibiotic

effectiveness

RATIONALE FOR VACCINATION AGAINST

STREPTOCOCCUS PNEUMONIA

DR.T.V.RAO MD 28

NEW PROTEIN-CONJUGATED VACCINES • T cell-dependent immune response

• Immunological memory

• Booster response

• Immunogenic also in young children

• 7-11 of 90 serotypes

• Protects against invasive disease in all age groups (type-specific)

• Protects against AOM (type-specific)

• Effective against carriage

• Licensed in USA February 2000 & European approval February 2001

DR.T.V.RAO MD 29

PNEUMOCOCCAL POLYSACCHARIDE

VACCINE

• 14-valent pneumococcal vaccine licensed in 1977

• 23-valent preparation licensed in 1983

• 23-valent vaccines cover 85%-90% of serotypes that cause invasive pneumococcal infections

• 23-valent vaccines contain serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F

• 6 serotypes most frequently associated with drug-resistant infection: 6B, 9V, 14, 19A, and 23F

DR.T.V.RAO MD 30

ADVERSE REACTIONS TO PNEUMOCOCCAL

VACCINE Low incidence of adverse reactions

• ~50% of patients experience mild, local reactions, usually lasting

<48 hours

• More severe local reactions, moderate systemic reactions, and

severe systemic reactions are rare

• ~33% of 7531 vaccine recipients had local reactions and none had

severe febrile or anaphylactic reactions

CDC. MMWR.February 1989;38:64-68, 73-76

CDC. MMWR. April 1997;46(RR-8):1-24

Fine et al. Arch Intern Med. 1994;154:2666-2677

DR.T.V.RAO MD 31

• All adults >65 years

• Immunocompetent persons >2

years with:

Chronic cardiovascular

disease

Chronic pulmonary disease

Diabetes mellitus

Alcoholism

Chronic liver disease

CSF leaks

CDC RECOMMENDATIONS

DR.T.V.RAO MD 32

• Persons >2 years living

in special environments

or social settings, such

as:

Nursing homes

Chronic-care

facilities

Alaskan Natives

Certain Native

American populations

CDC RECOMMENDATIONS

DR.T.V.RAO MD 33

DURATION OF PROTECTION

• Full antibody response occurs in 2-3 week

• Antibody levels remain elevated for at least 5 years

• May decrease to preimmunization levels within 10 years

• May decline within 3-5 years in children, within 5-10 years in elderly, splenectomy and renal dialysis patients, transplant recipients

• Duration of protection suggests revaccination for some patients

CDC.MMWR.February 1989;38:64-68, 73-76

DR.T.V.RAO MD 34

REVACCINATION GUIDELINES

Revaccinate persons who:

• Are >65 years of age, if vaccinated >5 years earlier and

aged <65 years when first vaccinated

• Are 2-64 years and at high risk for serious pneumococcal

infection

• Are at high risk and have shown a rapid decline in

antibody levels, if first vaccinated >5 years earlier

Revaccination is not routinely recommended for most

patients

DR.T.V.RAO MD 35

CDC RECOMMENDATIONS

• Immunocompromised persons >2 years with:

Functional or anatomic asplenia

HIV, AIDS

Leukemia, lymphoma, Hodgkin’s disease, multiple myeloma

Generalized malignancy

Chronic renal failure, nephrotic syndrome

Receiving immunosuppressive chemotherapy, radiation

Organ and bone marrow transplant patients

DR.T.V.RAO MD 36

• Protection by

pneumococcal

polysaccharide vaccine

may not be lifelong

• One-time revaccination

after >5 years is

recommended for

persons >65 years

vaccinated at <65 years

Jackson et al. JAMA. 1999;281:243-248

REVACCINATION OF THE ELDERLY

DR.T.V.RAO MD 37

Current pneumococcal conjugate vaccines are effective against the specific serotypes included in the vaccines, but do not protect against all pneumococcal serotypes. Furthermore, they are complicated and relatively expensive to produce, which makes it difficult for poorer countries in urgent need to be able to afford them without assistance.

ACCELERATING NEW VACCINE DEVELOPMENT AGAINST

PNEUMONIA AND OTHER PNEUMOCOCCAL DISEASES

DR.T.V.RAO MD 38

PATH is an international non-profit

organization that creates

sustainable, culturally relevant

solutions, enabling communities

worldwide to break longstanding

cycles of poor health. By

collaborating with diverse public-

and private-sector partners, we help

provide appropriate health

technologies and vital strategies that

change the way people think and

act. Our work improves global health

and well-being.

DR.T.V.RAO MD 39

DR.T.V.RAO MD 40

• PATH is pursuing a number of approaches to develop pneumococcal vaccines that will be effective and affordable in the countries that most urgently need them. The pneumococcal vaccine project at PATH partners with scientists and manufacturers to advance their research toward preventing this childhood disease.

• One approach that holds particular promise is the development of “common protein” vaccines. Vaccines containing proteins that are common to all pneumococcus serotypes could provide broad protection to children worldwide. PATH is also partnering to develop an inactivated whole cell vaccine against pneumococcus that could provide affordable and broad protection for children.

IMPORTANT FOR MODELLING:

VACCINE EFFECT ON ANTIBIOTIC RESISTANCE

• Reduction of antibiotics consumption (15-20% Israel)

• Reduction of carriage of antibiotic-resistant bacteria

• Vaccine types = child serotypes = resistant types

• Herd immunity: decreased carriage in siblings

• Reduction of infection with antibiotic resistant bacteria

• But the bacteria will fight back

• Serotype replacement to non-vaccine types

• They will eventually also become resistant

DR.T.V.RAO MD 41

PNEUMOCOCCAL DISEASE: MUCH NEGLECTED IN

DEVELOPING WORLD CAUSES MORBIDITY AND MORTALITY

•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

DR.T.V.RAO MD 43

• Programme created by Dr.T.V.Rao MD

for Medical and Health Care Workers in

the Developing World

• Email

• doctortvrao@gmail.com