TUBERCULOSIS...
the disease in children and implications for the
care of today’s child... from a clinician’s view.
H. S. Patterson, M. D.
TB IN CHILDREN
OBJECTIVES
• Understand, in simple terms, the pathophysiology and clinical course of TB in
children.
• Understand the difference between
TB infection and TB disease.
• Understand how to make the diagnosis of
TB in a child.
TB IN CHILDREN
OUTLINE
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•
•
•
•
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historical and epidemiologic perspectives
diagnostic considerations
natural course
mortality/complications
why prophylaxis?
look alike
TUBERCULOSIS...
The greatest killer of all time...
The captain of all these men of death...
...during this century and the last,
one billion people have died from tuberculosis
TUBERCULOSIS...
“The White Plague”
Oliver Wendell Holmes Sr, 1861
WHO is this famous Georgian
who died of TB and how old was
he when he died?
Leading causes of death in U.S.
1900
CAUSE
Flu & Pneumonia
Tuberculosis
Diarrhea/Enteritis
DEATH RATE
202/100,000
194/100,000
140/100,000
TB epidemiology in perspective
• approximately 1/3 of the world’s
population is infected with m. tuberculosis
• there are approximately 8 million new cases
of (active)TB per year, world wide
• 2.9 million deaths occur annually from TB
• 1987-1991, in US, number of cases of
active TB in children less than 5 years of
age, increased 49%
2000
1500
1000
500
0
1985
1986
1987
1988
1989
1990
1991
Annual number of cases of tuberculosis in children
less than 15 years of age in the United States
2000
1900
1800
1700
1600
1981
1983
1985
1987
1989
Tuberculosis deaths by year, United States, 1980-1989
(National Health Statistics)
TB RISK FACTORS
•
•
•
•
•
crowding
decreased access to health care
lower socio-economic status
HIV
? race
Historical TB
1000
100
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
1000
100
1804 Laennec associates lesions,
describes “phthsis”
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
100
1804 Laennec associates lesions,
describes “phthsis”
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
1882, Koch discovers
mycobacterium tuberculosis
100
1804 Laennec associates lesions,
describes “phthsis”
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
1882, Koch discovers
mycobacterium tuberculosis
100
1917 Flu pandemic
1804 Laennec associates lesions,
describes “phthsis”
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
1839, Shoenlein recognized “tubercle” as
fundamental lesion, ergo “tuberculosis”.
1000
1882, Koch discovers
mycobacterium tuberculosis
100
1917 Flu pandemic
1804 Laennec associates lesions,
describes “phthsis”
50
MORTALITY
rate per 100,000
10
Tb evidenced in 4,000 BC
5
1946, Streptomycin used as antibiotic
1
0.5
1700
1750
1800
1850
1900
1950
YEAR
Mortality from tuberculosis in developed countries
2000
Upstate New York
30000
26000
REPORTED
TB CASES
US
actual
22000
18000
expected
1981
1983
1985
YEAR
1987
30000
26000
REPORTED
TB CASES
US
actual
22000
HIV related
18000
expected
1981
1983
1985
YEAR
1987
Natural history of tuberculosis in a newly
infected (adult) contact (infection is not necessarily disease)
NO INFECTION
CONTACT
Defenses
NO DISEASE (90%)
INFECTION
EARLY DISEASE (5%)
Cell-mediated
immunity
DISEASE
LATE DISEASE
(5%)
DIAGNOSIS: CMI
NO INFECTION
CONTACT
Defenses
INFECTION
cell-mediated
immunity
NO DISEASE (90%)
EARLY DISEASE (5%)
DISEASE
LATE DISEASE
(5%)
DIAGNOSIS: CMI
NO INFECTION
CONTACT
Defenses
INFECTION
cell-mediated
immunity
NO DISEASE (90%)
EARLY DISEASE (5%)
DISEASE
LATE DISEASE
PPD positive
(5%)
The TB Skin Test: MATERIALS
• OLD TUBERCULIN
– culture of TB bacillus in glycol peptone broth
– TB “tine” test
• PURIFIED PROTEIN DERIVATIVE (PPD)
– TB bacillus grown in Long’s media, filtered after
heating
– adopted by WHO as standard in 1950
– PPD-S 1952
– dose = 5 IU
The TB (Mantoux) Skin Test
• Intra-dermal
– quality control important
– trained practioner necessary
• Delayed hypersensitivity
– cell mediated
– 48-72 hours
• False negative
– immuno-compromized conditions
– measles/measles immunizations
• Nonspecific reactions
– increase >10 IU
– cross reactions, atypical MB
Factors causing decreased ability to
respond to tuberculin
•
Factors related to the person being tested
– Infections
• Viral (measles, mumps, chickenpox)
• Bacterial (typhoid fever, brucelosis, typhus, pertussis, overwhelming TB,
• Fungal (South American blastomycosis)
– Live virus vaccinations (MMR)
– Metabolic derangements (chronic renal failure)
– Nutritional factors (severe protein depletion)
– Diseases affecting lymphid organs (Hodgkin’s lymphoma, chronic lymphocytic
leukemia, sarcoidosis)
– Drugs (corticosteroids, other immunosuppressive agents)
– Age (newborn, elderly)
– Recent overwhelming infection with M. tuberculosis
– Stress (surgery, burns, mental illness, graft versus host reactions)
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•
•
Factors related to the tuberculin used
Factors related to the method of administration
Factors related to reading the test and recording results
Indications for skin test screening
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•
•
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Persons with signs and/or symptoms suggestive of tuberculosis disease
Recent contacts of persons known or suspected to have tuberculosis
Persons with undiagnosed upper lobe fibrotic lesions
Persons infected with HIV
Alcoholics and intravenous drug abusers
Persons with medical conditions known to increase the risk of disesase if
infection has occurred:
– silicosis, gastrectomy, jejunoileal bypasss, significant weight loss
below IBW, chronic renal failure, diabetes mellitus, high dose
corticosteroid treatment or other immunosuppressive therapy,
leukemia, lymphoma, malignancy
• Groups at high risk of infection:
– Latin America, Oceana, medically underserved populations, residents
of long term care facilities
• Groups that would pose a significant risk to others if diseased: employees
of health care facilities, schools, child care facilities
ATS/CDC
TB PATHOPHYSIOLOGY
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•
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systemic infection
primary infection/disease
progressive primary disease
miliary disease
meningitis
chronic TB (re-activation)
Inhalation of Infected
Droplet Nuclei
non-specific bronchopneumonia
1) skin test sensitization
2) resistance to exogenous reinfection
3) lympho-hematogenous spread
complete resolution
(rare)
progression
massive necrosis
(rare)
healing with granuloma formation
stable
breakdown with development of
(re-activation)TB DISEASE
TB: PRIMARY Infection
• 95% of cases begin
with pulmonary focus
• usually a SINGLE
focus
• hypersensitivity
develops 2 to 6 weeks
– until then, focus may
grow larger
– hypersensitivity brings
caseation
Tissue Specimens Obtained at Autopsy from the Patient
Jha, A. K. et al. N Engl J Med 2004;350:2399-2404
PRIMARY Infection:
Lympho-hematogenous spread
• 8-14 weeks after onset of TB
• usually occult
• Mantoux positive during this
phase
• body wide seeding occurs
during this phase
– bone, kidney, meninges etc.
– 3% of children with nl CXR’s
develop calcifications in lung
apices (SIMON FOCI)
Jha, A. K. et al. N Engl J Med 2004;350:2399-2404
PRIMARY TB:
endo-bronchial consequences
• lymph nodes draining primary infection site
become involved
• lymph node capsule becomes adherent to
bronchial wall
– infection can progress to ulceration into the
bronchial wall
– bronchial compression occurs with more than
one node at same level
– with healing, bronchial constriction/stenosis
can occur
INFECTION TO ENDO-BRONCHIAL DISEASE
TO STENOSIS
HEALED PRIMARY INFECTION
SIMON FOCI
CALCIFIED nodes
and peripheral lesion
(Ghon complex)
other VISCERAL sites
USUAL PROGRESSION
OF PRIMARY INFECTION
infection
lympho-hematogenous
spread
healed PRIMARY
infection
PROGRESSIVE PRIMARY
TB(DISEASE)
• occasional (3.7%) local progression, despite
hypersensitivity (more common in younger pt)
• can be cavitary
• can have endo-bronchial spread
• similar in appearance to adult type, “reactivation”
disease
• 2/3 of cases progress to death in the untreated
PROGRESSIVE PRIMARY DISEASE
lymph node involvement
cavitation
pleural effusion
Progressive Primary Disease
ENDOBRONCHIAL SPREAD
WITH SUBSEQUENT
BRONCHOPNEUMONIA
Disseminated TB pneumonia
MILIARY Disease
Generalized Hematogenous Tuberculosis
• generalized dissemination through
bloodstream
– caseous focus ruptures into blood vessel
– growth of tubercle within the blood vessel
– may be acute, occult or chronic
• uniformly fatal if not treated
• rare
• usually occurs in the first 4 months after
primary infection
MILIARY Disease
• millet seed appearance on
X-ray
• Mantoux positive?
• Most children still have
active primary complex
when miliary disease
strikes
• most develop meningitis
Major sites of extra-pulmonary tuberculosis
among children in the United States
SITES
lymphatics
meninges
pleura
miliary
skeletal
other
%
67
13
6
5
4
5
Avg. Age
5y
3y
16y
1y
5y
Clin Chest Med 1989, Am. Rev. Resp. Dis, 1990
TB MENINGITIS
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•
•
•
•
primary seeding
caseous lesion adjacent meninges
growth/discharge
usually insidious
prophylaxis is preventive
TB MENINGITIS
• 40% of cases ocur within 3 months of
estimated onset of TB
– rarely < 1 month
• 90% with TB menningitis PPD positive
– 94% of these have positive CXR’s
• average duration from meningitis diagnosis
to death (untreated) 19.5 days
CHRONIC PULMONARY TB
(re-activation/adult type)
• occurs only after primary infection
– 0.5-10 % incidence (7% by Lincoln)
– usually not less than 1 year of age
– most cases occur when primary infection
aquired after 7 years of age
• minute areas of bronchopneumonia
• tissue hypersensitivity - cavity formation
• few symptoms early on in disease
12
10
8
6
4
2
0
0
2
4
6
8
10
12
14
16
18
20
Age in years
Annual risk of developing chronic pulmonary tuberculosis
among survivors of pulmonary primary tuberculosis
(Dis Chest 38:473, 1960)
Major sites of extrapulmonary tuberculosis
among children in the United States
SITES
lymphatics
meninges
pleura
miliary
skeletal
other
%
67
13
6
5
4
5
Avg. Age
5y
3y
16y
1y
5y
Clin Chest Med 1989, Am. Rev. Resp. Dis, 1990
DEATHS from TB in children
(natural course of the disease)
• higher incidence in younger children
• 25% of children will die in the untreated
state
• 90% of the deaths will occur in the first
year
INH PROPHYLAXIS
• the best prophylaxis is AVOIDING exposure
• for patients with quiescent, uncomplicated,
non-active disease
• reduces antigen load, thereby decreasing
risk of (re)activation
PULMONARY TUBERCULOSIS
LOOK ALIKE...
TB like manifestations
TB IN CHILDREN
SUMMARY
• There is no such thing as a positive PPD from just
“being exposed” to the disease
• primary vs reactivation disease
• children with primary TB are rarely
“communicable”
• untreated, there is high morbidity and mortality
• children with quiescent disease deserve prophylaxis
• prophylaxis is “essentially” curative