101115 bcg ppt - Hospital Authorityicidportal.ha.org.hk/Home/File?path=/Training... · – Case detection rate ≥70% – Treatment success rate ≥85% • By 2015 : – ↓TB prevalence

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BCG(Bacille Calmette Guérin)

General Overview

Tuberculosis & Chest Service

Public Health Services Branch

Centre for Health Protection

Department of Health

Hong Kong SAR

Tuberculosis

April 1993: WHO declared TB as a global emergency

GLOBAL PROBLEM

PREVALENCE OF TB INFECTION 1.7 BILLION

PREVALENCE OF TB CASES 16-20 MILLION

ANNUAL INCIDENCE OF TB 8 MILLION

ANNUAL DEATHS FROM TB 3 MILLION

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Global Plan to Stop TB

(2006-2015)

Goals/ Targets:

– Millennium Development Goal (MDG) 6• Target 8: halt and begin to reverse the

incidence of TB by 2015

– Targets linked to MDGs:• By 2005:

– Case detection rate ≥70%

– Treatment success rate ≥85%

• By 2015:

– ↓TB prevalence & death rates by 50%

(relative to 1990)

• By 2050– eliminate TB (1/1,000,000)

DOTS StrategyLaunched in 2006 by WHO with six

components:

1. Pursuing high-quality DOTS expansion

and enhancement

2. Addressing TB/HIV, MDR-TB and other

challenges

3. Contributing to health system

strengthening

4. Engaging all care providers

5. Empowering people with TB, and

communities

6. Enabling and promoting research

STOP TB Strategy

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TB notification in Hong Kong (1952 - 2009)

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100

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52

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00

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ate

(p

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2009 TB notification rate

= 76.6 per 100,000

(provisional figures)

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Countries in Western Pacific Region(WHO Classification)(for Adaptation of the DOTS Strategy)

• Group 1: high TB burden• Mainland China

• Group 2: intermediate TB burden and good health infrastructure

• Hong Kong *

• Singapore, Japan, Malaysia, Macao, Brunei, Korea

• Group 3: Pacific Island Countries (PIC) with populations smaller than 1 million

• Group 4: Industrialised countries with low TB burden and low incidence

• Australia, New Zealand

CONTROL OF TUBERCULOSISCONTROL OF TUBERCULOSIS

IN HONG KONGIN HONG KONG

StrategiesStrategies

- Case finding: passive vs active

- Effective chemotherapy: DOTS

- Treatment of latent TB infection (preventive treatment or chemoprophylaxis)

- BCG vaccination

- (Health education)

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MDR-TB and XDR-TB

• MDR-TB (multidrug-resistant TB) (耐多藥結核病)• resistant to at least H (isoniazid) and R (rifampicin)

• XDR-TB (extensively drug-resistant TB) (廣泛耐藥性結核病):– (Oct 06 WHO definition) resistant to

• any fluoroquinolone, and

• at least one of the 3 injectable second-line drugs (capreomycin, kanamycin, and amikacin),

• in addition to MDR-TB

• Global figures [WHO 2007 estimation]:• MDR-TB: 490,000

• XDR-TB: 40,000

Cavity

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Miliary TB

BCG (Bacille Calmette-Guérin)

• Development:– 1908: Nocard isolated a strain – known as “Lait Nocard”, which caused

bovine tuberculous mastitis

– 1921: after 13 years of successive subculturing the strain by Albert Calmetteand Camille Guérin � first developed BCG

• Produced by several laboratories round the world – different strain: different viability, immunogenicity, reactogenicity, and residual virulence� Now: four main strains accounting for >90% of current vaccines:

- French Pasteur strain 1173P2 (international reference strain)

- Danish (Copenhagen) strain 1131

- Glaxo strain 1077

- Tokyo strain 172

• 1921: Oral BCG vaccine– Contaminated with virulent TB bacillus in 1929 in Germany � 72 deaths

among 251 vaccinated children

• 1927: Intradermal BCG

• 1939: Multiple puncture vaccination

• 1948: WHO and UNICEF: encouraged BCG vaccination campaigns all over the world

• 1974: WHO launched EPI

• At present: nearly 100 million children vaccinated with BCG every year

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• Efficacy:– Several clinical trials (after 1930):

• efficacy between 0 and 80%

• Largest trial in Madras: no protection

– Case control studies• Efficacy between 16 and 73%

• Protection for pulmonary TB: 10 to 66%

• Protection for TBM and miliary TB: consistently high, >50%

– Meta-analyses• Protection for TBM and miliary TB: 72 to 100%, with a

summary estimate of 86%

• Protection for all forms of TB: summary estimates:– 51% (RCT, randomised controlled trial)

– 50% (case-control studies)

• Protection for pulmonary TB:– Heterogeneous

– Several RCTs: -88 and 79%

Estimates of BCG

efficacy against

different forms of TB

and leprosy, from

clinical trials (CT), case

control (CC), cohort

(COH) and household

contact studies (HH).

(Fine PEM et al. WHO/V&B/99.23; 1999:1-42)

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• Hypothesis for heterogeneity in protective efficacy:

– Biological variability of BCG vaccine due to different strains

– Exposure to environmental mycobacteria

• Higher efficacy rates if far away from the equator (with low or no prevalence of EM)

• Meta-analysis: 41% of the discrepancy in the estimated efficacy is due to latitude

– Route of infection

• Protective if the disease results from primary infection (TBM, disseminated TB)

• Lower if exogenous reinfection

– Other factors

• Related to use of the vaccine: viability, dose, route of administration

• Host factors: nutritional status, other infections, genetic aspects

Results of meta-analyses on BCG efficacy (TB Manual 2006)

Colditz GA 1994

Brewer TF 2000All ages71% (47-84%)Overall TB death

Colditz GA 1994

Brewer TF 2000All ages51% (30-66%)Overall TB risk

Rodrigues LC 1993All ages, 6 case control

studies

75% (61-84%)Disseminated TB

Rodrigues LC 1993All ages, 7 RCTs86% (65-95%)Meningeal TB and

disseminated TB

Colditz GA 19953 Case control studies in

newborns and infants

83% (58-93%)Laboratory confirmed

TB



78% (58-88%)Disseminated TB



64% (30-82%)Meningeal TB

Colditz GA 19955 RCTs in newborns and

infants

65% (12-86%)Death



52% (38-64%)TB at all sites

Colditz GA 19954 RCTs in newborns and

infants

74% (62-83%)TB at all sites

ReferenceRemarksEfficacy (95% CI)Target disease

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Meta-analysis on childhood TBM and miliary TB(Bourdin B. Lancet 2006)

In 2002, estimations:

• 100.5 million BCG vaccinations given to infants

• TB meningitis: 29729 cases prevented

≡ 3435 vaccinations to prevent 1 case

• Miliary TB: 11486 cases prevented

≡ 9314 vaccinations to prevent 1 case

• US$2-3 per dose

• US$206 (150-272) per year of healthy life gained


• Length of protective efficacy

– According to literature, protective efficacy decreases with time

– Study in UK by MRC between 1950 and 1970:• First 5 years: protection around 84%

• Between 10 and 15 years: 59% (Hart PD 1977)

– Study in US:• 77% decreasing to 52% during a 6-decade follow up (Aronson

NE 2004)

– Study in Brazil:• protection by neonatal vaccination against all forms of TB

lasts for 15 to 20 years (Barreto ML 2005)

– Meta-analysis (1998)• Efficacy wanes with time, lasts probably no longer than 15

years

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BCGPrevious Vaccination Policies

1. At birth• WHO EPI

2. Once in childhood or adolescence• E.g., UK (targeted vaccination for those at greatest risk)

3. Repeated/booster BCG vaccination• Not recommended now.

4. No routine BCG vaccination• E.g., US: BCG only for selective use among high risk

individuals

BCG• Revaccination

– Some countries (Russia, Portugal, Chile, Hungary) used repeated BCG vaccination – based on assumption that protection decreases with time.

– Hungary (1959): reported decrease in TB incidence after use of revaccination introduced (methodology flaw?)

– Chile, Finland, Malawi, Brazil, Japan – no evidence for efficacy of a second dose

– WHO recommends use of one dose of BCG vaccine against TB only; booster dose has no proven additional protective effect (WHO 1995)

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• Study in HK:– Revaccination of school children did not confer further

protection against TB

– RR = 1.28 (95% CI = 0.92 – 1.77)

• ACI (Advisory Committee on Immunisation of DH in HK (2000):– BCG for all newborns in HK

– For children under age 15 and residing in HK, and who have never had BCG vaccination before, direct BCG vaccination is recommended and prior TST is not required

– Local BCG revaccination programme for primary school children in HK stopped in 2000

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• BCG vaccine supplied by DH free of charge to HA & private hospitals

• Danish 1331 (intradermal injection) (Statens Serum Institut)

• In turn, statistics are provided to DH on coverage of BCG vaccination in newborns.

• BCG:– Intradermally at the insertion of deltoid on the left arm

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BCG vaccination coverage

Infant mortality rate

(All causes)Infant mortality rate

(TB)

BCG for HCW in Hong Kong(TB Manual 2006) (HA Task force 2003) (ACI 2004)

• In Hong Kong, the bulk of the population has received BCG vaccination at some point in time.

• In health care settings, a comprehensive infection control programme should be the priority and routine vaccination of HCW is not recommended.

• Nevertheless, for HCW who have never received BCG before, they should be counselled on the risks and benefits associated with BCG vaccination, as well as the possible roles of tuberculin surveillance and treatment of LTBI.

• Under special high risk circumstances, e.g., situations with a high risk of exposure to MDR-TB, BCG may be considered for previously unvaccinated individuals who are tuberculin tested to be negative and are thus likely to be free of past TB infection.

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• Administration:

– Oral vaccine• requires a much higher dose

• Effective dose difficult to control as some mycobacteria are inactivated by gastric acid

• Reports of cervical lymphadenopathy and middle ear infection

– Subcutaneous injection• Should be avoided as it may produce large abscesses

– Percutaneous injection• Spread vaccine over left arm

• Heat-sterilised number 3 straight suture needle: 20 times (4 rows of 5 punctures)

– Intradermal:• Delivered dose better controlled

• More effective in inducing tuberculin reaction

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• BCG scar

– BCG vaccination leaves a typical scar

• high sensitivity and specificity of the scar as an indicator of

previous BCG vaccination

– 17 – 25% do not have a scar

– No evidence of association between scar and protection

vs TB

– Size of scar:

• Bears a correlation with PPD response before vaccination

• Smaller scar associated with a small BCG dose

• Larger with increase in number of doses

Tuberculin Skin Test and BCG

• Positive TST (delayed type hypersensitivity)– Does not mean immunity induced by BCG (CMI

cellular mediated immunity)

– Induration >15 mm more related to TB infection than BCG vaccination

– Tuberculin reactivity after vaccination decreases with time

– Tuberculin response lower after neonatal BCG vaccination than after postneonatal vaccination

• IGRA (interferon-gamma release assay)– (QuantiFERON TB Gold Test, Tspot TB test)

– Specific tests and not confounded by BCG

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Adverse reactions:

• Local reactions to BCG vaccines:– Superficial scar in most recipients

– ↑chance of keloid (esp if near acromion process)

– Rarely ulceration and regional LN enlargement

• Severe reactions:– Osteitis

– Disseminated infection is rare and only occurs in patients with impaired immunity

�Defined as BCG disease that presents in an HIV-infected child within 3 months

after the initiation of highly active antiretroviral therapy (HAART) with/without

immunological or viral proof of immune reconstitution

BCG IRIS

�BCG confirmed from >1 remote site, as described under distant disease, and/or

from at least 1 blood or bone marrow culture.

Disseminated disease

�Involvement of any site beyond a local or regional ipsilateral process. This

includes any of the following: BCG confirmed from at least 1 distant site beyond

the vaccination site, e.g. pulmonary secretions (gastric aspirate, tracheal aspirate),

cerebrospinal fluid, urine, osteitis, and distant skin lesion.

Distant disease

�Involvement of any regional lymph nodes or other regional lesions beyond the

vaccination site: ipsilateral axillary, supraclavicular, cervical and upper arm glands.

Lymph node involvement must conform to EPI definition and may include

enlargement, suppuration and fistula formation.

Regional disease

A local process at the site of vaccination. This includes any of the following

�BCG infection site abscess conforming to EPI definitions: ≧10 mm X 10 mm

�Severe BCG scar ulceration

Local BCG disease

DescriptionCategory

EPI, Expanded Programme on Immunization

EPI criteria for local or regional BCG disease: (1) Ipsilateral LN ≧15 X 15 mm; (2) Suppurative ipsilateral axiallry lymphadenitis;

(3) Injection site abscess of ≧10 mm; (4) Nonresolving BCG papule

Classification of BCG Disease(Hesseling AC et al. Clin Infect Dis 2006)

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Adverse events of BCG vaccination

• Ulcers at vaccination site:

– Inappropriate application, e.g,

• Subcutaneous injection

• Excessive dose

• Secondary contamination at puncture site

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Lawrence CM, Summerly ME. Keloid formation after BCG vaccination. The Practitioner. 1982;226:326-328.

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• BCG lymphadenitis

– Prospective study of two million vaccinations (1979-81) estimated risk to be 0.387 per 1000 for infant (age <1)

– [Other studies of regional suppurative lymphadenitis: incidence of 0.1 per 1000 to 5 per 1000 vaccinated children in some developing countries.]

– Among 6000 reported cases, majority occurred within first 5 months after vaccination

– Factors:• Vaccine strain (e.g., more reactogenic Pasteur strain, less reactogenic

Glaxo strain)

• Total number of viable and non-viable bacilli in the vaccine preparation

• Dose of BCG given

• Age of person receiving the vaccine (more common among newborns than older children)

– Treatment:• No consensus

• Antimicrobial (erythromycin/ INH) to no treatment

• Uncomplicated cases generally resolve spontaneously on observation



• Osteitis:

– Incidence of 0.6 to 46 cases per one

million vaccinated children

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• Disseminated infection:

– Rare, may result in death

– Incidence ranges from 0.19 to 1.56 per one

million vaccinees

– Esp in children with congenital or acquired

immunodeficiency who are mistakenly

vaccinated

Major contraindications to BCG vaccination

• Relative or temporary in some literature:

– BW < 2 kg

– Skin reactions at the vaccination site

– Severe diseases

– Use of immunosuppresants

– Febrile condition

• Absolute

– Acquired or congenital immunodeficiencies

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BCG VACCINATION FOR THE HIV-INFECTED

• BCG

– live attenuated bacterial vaccine

– not to be given to AIDS patient

• Diagnosis of HIV infection in newborns

– Difficult (maternal Ab passively transferred to infant in utero)

– Need sophisticated and costly investigations [e.g., direct demonstration of

the HIV virus (HIV DNA, HIV RNA and p24 antigens)]

• WHO Revised BCG vaccination guidelines for infants at risk for HIV

infection (Wkly Epidemiol Rec 2007;83:193-6)

– ‘For infants who are already HIV infected when vaccinated with BCG

vaccine, the benefits of potentially preventing severe TB are outweighed

by the risks associated with the use of BCG vaccine’.

“The use of BCG Vaccine in HIV Infected Patients”(SCAS) (Nov 2009)

Recommendations:

• Recommend against BCG vaccination in all HIV-infected patients.

• For HIV-exposed infants, a delayed approach is recommended – vaccination is delayed in those known to have been exposed to HIV in utero or during birth, until HIV is ruled out (mostly within 6 months by nucleic acid amplification tests)

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• Other uses:– Immune modulator:

• Treatment of some neoplasms (e.g., bladder cancer)

– Leprosy• Efficacy ranging from 20% to 80%

• Some studies show that BCG offers greater protection against leprosy than TB

– Buruli Ulcer• M. ulcerans infection

– Protection against:• Ancylostomiasis and other helminth infections

– Atopy:• Decrease in frequency of atopy among children vaccinated

with BCG

New Vaccine Development

• Limited and controversial efficacy of BCG

• Deciphering of the whole genome of M. tuberculosis

(Nature 1998)

• Approaches:

– Live attenuated vaccine:

by deleting the gene

responsible for

virulence

– Subunit vaccine

– DNA vaccine

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Chapter 15

BCG vaccination

Professional Manual 2006

(available for download at www.info.gov.hk/tb_chest)

THANK YOU!

www.info.gov.hk/tb_chest

STOP TBSTOP TB STOP TBSTOP TB

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101115 bcg ppt - Hospital Authorityicidportal.ha.org.hk/Home/File?path=/Training... · – Case detection rate ≥70% – Treatment success rate ≥85% • By 2015 : – ↓TB prevalence