Transcript Tuberculin Skin Test

TB in Children
Oscar Roberto Santos Punla
Medical Clerk
Etiology
Mycobacteria
• acid-fast bacilli, obligate aerobes,
slow-growing
• Contain high molecular weight
mycolic acids in their cell walls (lipidrich cell wall (resistant to bactericidal
action of antibiotics)
Classified into:
• M. tuberculosis complex
• M. tuberculosis
• M. bovis
Nontuberculous mycobacteria
• (M. avium-intracellulare; M. kansasii)
• Mycobacterium bovis
– causes primary pulmonary as well as
primary GI TB
Epidemiology
• One third of the world’s population is infected
• TB kills 5,000 people a day – 2-3 million each year
• HIV and TB co-infection is producing explosive
epidemics
• Hundreds of thousands of children will become TB
orphans this year
• MDR threatens global TB control
TB Global Burden
•
•
•
•
•
•
•
2006 9.2 M new cases
4.1 M  new smear (+) cases
0.7 M HIV (+)
14.4 M prevalent cases
1 M children < 15 years
0.5 M MDR-TB cases
1.5 M deaths
WHO Global TB Control 2008
Background
• Tuberculosis (TB) is increasing among adults in
many areas
• TB is major cause of childhood morbidity and
mortality worldwide
• Limited information on epidemiology of TB in
children
TB in Children
• WHO estimate of TB in children
– 1.3 million annual cases
– 450,000 deaths
• 15% of TB in low-income countries children vs.
6% in United States
Childhood TB…
Why is it neglected?
• Difficulty confirming the diagnosis by
microbiology
• Lack of family-centered approach internationally
• Children rarely contagious – public health “deadend”
• Perceived lack of scientific study
• Disinterest of pediatricians
• Misplaced faith in BCG vaccines
Childhood TB
Why is it important?
– Health problem in children
– May later contribute to epidemic
Childhood TB as Sentinel Event
• Indicates recent transmission in a community
• Rapid progression from infection to disease
“A deterioration in the control of TB thus immediately
hurts the youngest generation” (Rieder, 1997)
• Children are future reservoir of disease
Childhood TB diagnosed by:
Combination of :
• Contact with infectious adult case
• Symptoms and signs
• Positive tuberculin skin test
• Suspicious CXR
• Bacteriological confirmation
• Serology
Transmission
Incubation Period
• 2-12 weeks from infection to development of
a (+) skin test
• risk of developing TB disease is highest during
the 6 months after infection and remains high
for 2 years
• many years may elapse between latent TB and
disease
Pathogenesis of Tuberculosis
• Organisms contained in droplet nuclei land in
the alveoli
• Infectious dose probably < 10 organisms
• Organisms ingested by macrophages,
transported to regional [hilar, mediastinal,
cervical] lymph nodes
• Lymphohematogenous dissemination of
organisms occurs early – meninges, apices of
lungs, lymph nodes, other organs
Predisposing Factors
• chronic illness
• malnutrition
• fatigue
Risk of Progression to Disease
• Age
– 43% in infants (children < 1 yr)
– 25% in children aged one to five years
– 15% in adolescents
– 10% in adults
• Recent Infection
• Malnutrition
• Immunosuppression, particularly HIV
Timetable of Pediatric Tuberculosis
•
•
•
•
•
•
Miliary and Meningeal 2 – 6 months
Pulmonary 2 – 12 months
Lymph node 2 – 12 months
Pleural effusion 3 – 12 months
Skeletal 6 months – 2 years
Renal 1 – 5 years
Transmission
• marker of
contagiousness: (+)
bacilli in sputum
• children <12 years old
with 1° PTB are not
contagious:
1. pulmonary lesions are
small
2. cough is minimal or
nonexistent
3. little or no expulsion of
bacilli
Bacilli in sputum
Features of Contagious
Pediatric Tuberculosis
•
•
•
•
•
Cavitary lung lesion
Sputum production
Positive acid-fast stain of sputum smear
Bronchoscopy
Draining lesions or surgical drainage of an
abscess
Are Children With Tuberculosis Ever
Contagious?
Difficult to answer in the community
• Orphanages – caretaker with TB led to
transmission; a child with TB did not
• Schools – only 2 reported “epidemics” caused
by children <13 years old
• Children’s Hospitals – rare case reports of
transmission, all with special circumstances,
none has been patient -to -patient
Genetics of Pediatric Tuberculosis
• Houston study of 184 families with 1(143) or
multiple (41) cases of tuberculosis diseases
• Examined 3 genes : NRAMP1 (protective in
adults), VDR (vitamin D receptor), MBL
(mannose binding ligand)
• Compared genetic and standard
epidemiologic information to determine
influences on expressions of tuberculosis in
children
NRAMP1 Genetics And
Pediatric Tuberculosis
1. The attributable risk of NRAMP1 gene variation
was 85% among tuberculosis-infected children.
[high frequency of the risk allele]
2. NRAMP1 and VDR genes acted as “progressor”
alleles, mediating the development of
tuberculosis infection to disease
3. The NRAMP1 effect was minimal in families with
more than one case of disease, negating the
common technique of general scanning in
multiplex families to determine the effect of
genes on host response.
Challenges for Surveillance
•
•
•
•
Difficult diagnosis of childhood TB
Lack of standard case definition
Increased extrapulmonary disease
Low public health priority of childhood TB
We’re All in the Same Boat
“Successful TB control in the
U.S. …depends on the
development of effective
strategies to control and
prevent disease among
foreign-born persons.”
Source: CDC. Controlling TB in the
United States, 2005
Tuberculosis Cases by Race/Ethnicity: California,
2006
American Indian/
Alaska Native
Black
9 (0.3%)
208 (7.5%)
White
267 (9.6%)
Hispanic
1,068 (38.4%)
Unknown
4 (0.1%)
Asian/Pacific Islander
1,223 (44.0%)
The Paradox of Tuberculosis
By use of drugs and BCG vaccines, we can:
• cure tuberculosis disease
• prevent progression of infection to disease
• prevent a high proportion of life-threatening
childhood tuberculosis
Yet, tuberculosis remains one of the three biggest
scourges of humans, and our inability to control
it remains our biggest health failure.
DIRECTLY OBSERVED THERAPY
FOR PEDIATRIC TUBERCULOSIS
• Means a “dispassionate” 3rd party is
Physically present when medications are taken
• Standard of care for tuberculosis disease
• Encouraged for high risk LTBI: contacts of
cases, infants, HIV-infected or immune
compromised
Clinical Forms of PTB
(PPS Consensus)
• Pulmonary/Endothoracic TB
• Extrapulmonary TB
Clinical Forms
 Pulmonary
Tuberculosis (PTB)
- refers to disease
involving the lung
parenchyma
Clinical Forms-Pulmonary
• Asymptomatic or Latent TB Infection
(LTBI)
• Primary Pulmonary TB
• Progressive Primary Tuberculosis
• Reactivation Tuberculosis
• Endobronchial TB
• Miliary TB
• Pleurisy with effusion
Latent Tuberculosis Infection (LTBI)
• M. tuberculosis infection in a person who
has a positive TST result, no physical
findings of disease and chest radiograph
findings that are normal or reveal
evidence of healed infection (e.g.
granulomas or calcification in the lung,
hilar lymph nodes or both).
• such patients are non-infectious
Clinical Forms of TB
Report of the Committee on Infectious
Diseases, AAP 2003
Primary Pulmonary TB
• involves a primary complex and its
progression
• most frequent: presence of enlarged
lymph nodes without primary focus visible
radiographically
Primary Pulmonary
Tuberculosis
Progressive Primary Tuberculosis
• with local progression of the primary complex
 caseation enlarges, liquefies and
disseminates its contents into the bronchi 
new foci
• pneumonia, atelectasis, air trapping, stenosis,
bronchiectasis
• retractions, wheezes, crackles, localized
decreased breath sounds
Progressive Pulmonary TB
Reactivation Tuberculosis
• Rare in childhood; may
occur in adolescents
• More common in children
who acquire the initial
infection after 7 yrs of age
• CXR: extensive infiltrates or
thick walled cavities
• Hx: fever, cough,
hemoptysis, weight loss
• PE: minor or absent
Extensive Cavitary Disease
Endobronchial TB
Extrabronchial or
Extraluminal
• hyperemic and
edematous lymph
nodes impinge upon
the wall of a
bronchus  occlude
the lumen usually
RML bronchus
Endobronchial TB
• occurs more frequently
• adherence of LN’s with spread of the
disease through the airway wall 
ulceration of mucosa  granulation
tissue  obstruct lumen usually the
RML or RUL bronchus
• Treatment: add Prednisone 1-2
mg/kg/day for 6-12 weeks
Miliary TB
• infants and young children affected as a
complication of primary TB
• bacilli spreads via lymphatics to capillaries of
most organ system (oxygenated: liver, spleen,
marrow and brain )
• mandatory tests include lumbar tap and
funduscopy
• size of millet lesions varies with the host’s
immune status, the larger lesions are found in
immunocompromised patients
Miliary TB
• death occurs in 4-12 weeks if untreated
usually 2° to meningitis
• fever resolves in 2-3 weeks of
chemotherapy
• X-ray lesions improve in 5-10 weeks
• Treatment: add prednisone to mitigate
alveolocapillary block
Miliary TB
Pleural Effusion
• older children, unilateral
• either as a
hypersensitivity reaction
or as an extension of
subpleural focus or TB
of the spine
• onset is acute with high
fever and chest pain
• serous pleural effusion
and a (+) PPD
Clinical Forms-Extrapulmonary
Extrapulmonary
- refers to tuberculosis of
other organs other than
the lungs e.g. pleura,
lymph nodes, abdomen,
genitourinary tract, skin,
joints and bones, meninges
-
If patient has both pulmonary and
extrapulmonary TB, it should be classified as
Pulmonary TB
e.g. Miliary TB
Treatment of TB:
Guidelines for National Programmes, WHO,
2003
Classification (Stages)
TB Exposure
• (+) exposure to an adult or adolescent
with active TB
TB Infection
• (+) Mantoux test
• with or without exposure, normal CXR,
no signs and symptoms
TB Disease
3 or more of the following
– exposure to an adult/adolescent with
active TB
– (+) Mantoux test
– signs and symptoms suggestive of TB
– abnormal CXR suggestive of TB
– laboratory findings suggestive of TB
(histological, cytological, biochemical,
immunological and/or molecular)
Clinical Signs/Symptoms
(any 1 or 2 or more are
considered positive)
• Cough of more than
2 weeks duration
Clinical Signs/Symptoms
(any 1 or 2 or more are
considered positive)
• Fever of more than 2
weeks duration
Clinical Signs/Symptoms
(any 1 or 2 or more are
considered positive)
• painless cervical
and/or other
lymphadenopathies
Clinical Signs/Symptoms
(any 1 or 2 or more are
considered positive)
• poor weight gain
Clinical Signs/Symptoms
(any 1 or 2 or more are
considered positive)
failure to make a quick
return to normal health
after an infection
(measles, tonsillitis,
whooping cough)
failure to respond to
appropriate antibiotic
therapy (pneumonia,
otitis media)
Tuberculin Skin Test
• Most widely used method to determine
– Latent TB infection
– Infected persons
– Those who do not have the disease
• A measure of a person’s cellular immune
responsiveness
• Features include:
– Delayed course
– Indurated character
– Occasional vesiculation and necrosis
Tuberculin Skin Test
• based on a delayed type of hypersensitivity
reaction (DTH), manifested as an indurated area at
the site of the intradermal injection which usually
begins within 5 to 6 hours of administration, as
previously sensitized lymphocytes, monocytes and
macrophages infiltrate the site.
• an immediate wheal and flare reaction may occur
but usually disappears by 24 hours and should not
be interpreted as a positive reaction.
• only the area of induration should be measured.
Menzier, RI. Tuberculin Skin Testing.
Tuberculosis: A Comprehensive International Approach
2000:279-322
Tuberculin Skin Test
• In most children, tuberculin reaction first
appear 3-6 weeks, and occasionally up to 3
months, after initial infection
Tuberculin Skin Test
• PPD-RT23
– 2-TU (tuberculin unit), the WHO standardized
dose for Mantoux tuberculin testing
– Most widely used tuberculin skin test in the world
– bioequivalent 5 TU of PPD-S
• PPD-S
– Standard tuberculin preparation
Tuberculin Skin Test
• As a rule of thumb, 0.1 ml of the 2-TU of RT-23
will have a tuberculin reactivity similar to 0.1
ml of the 5 TU PPD-S.
Method of Mantoux Testing
Interpretation of PPD
• WHO Consensus
–  10mm is considered positive in high risk
individuals
Mantoux Test Interpretation
False Negative Reactions False Positive Reactions
1. Viral, Bacterial, Fungal,
Early TB Infection, Severe
TB disease
2. Live virus vaccines
1. Exposure to NTM
3. Metabolic, Malignancies
3. Transfusion with whole
blood from donors with
known positive TST
4. Corticosteroids,
Immunosuppressive drugs
5. Technical factors and
interpretation
4. Inexperienced or biased
reader
5. Increasing mm induration
2. BCG vaccine
Phenomena related to TST
• Anergy
– Absence of reaction does NOT rule out TB
– A decrease or disappearance of the DTH (delayed type
hypersensitivity) responses to TST in immunosuppressed
individuals
• Skin test conversion
– Indicative of recent infection
– An increase in reaction size of ≥10mm induration within 2
years with previously negative TST reaction
• Boosted reaction
Boosting Effect
• Overtime the effect of DTH to mycobacterial
antigens may wane and thus a TST could be
negative. However, with subsequent TSTs, the
DTH response may be stimulated by PPD and
result in a positive reaction – boosting
phenomenon.
• Increase in TST size caused by repetitive TSTs in
an individual previously sensitized to mycobacterial
antigens, particularly BCG & NTM.
• Boosting is minimized if TSTs are placed <1 week
apart.
• No boosting occurs if person has not been infected
with mycobacterial antigens.
Radiologic Findings in Tuberculosis
Radiologic Findings in Tuberculosis
“ A clear chest x-ray does not rule out the
existence of a small focus of progressive
tuberculosis; nor are there pathognomonic
roentgen features in a fresh primary
tuberculous complex. Moreover, not all
shadows are tuberculous infiltrates.”
Mita Pardo de Tavera (1975)
CHEST X-RAYS
• considered essential to assess children and adolescents
with positive TST for pulmonary TB
LTBI. Chest x-rays are usually normal but findings may
include dense nodules with calcifications (i.e. a ghon
complex) calcified non-enlarged regional lymph nodes or
both or pleural thickening (i.e. scarring)
ATS targeted tuberculin testing and
LTBI. Am J Respi Care Med.
2000;161
AAP Tuberculosis Red Book: 2003 Report
Committee on Infectious Diseases
2003:642-660
treatment of
of the
Radiologic Findings in PTB
• In its complete form, the primary complex is
composed of the following; however, NOT ALL
features are necessary to make the diagnosis.
– Size and shape in the radiolucent lung
– Enlarged regional nodes
– Lymphangitis
– A localized pleural effusion
Lateral chest x-rays improved the accuracy of detecting
hilar adenopathy in children 1 month - 12 years of
age.
176 culture confirmed cases of TB disease
46% (81 of 176) had adenopathy visible on CXR
49% (40 of 81) visible on both frontal & lateral
views
24% (19 of 81) only on frontal view
27% (22 of 81) only on lateral view
Imuts KJA et al. Value of
Adolescent Chest Radiographs
in Tuberculosis in
Children.
Pediatr Radiol 1994;24:478-480
Radiologic Findings in PTB
•
•
•
•
Parenchymal involvement
Lymph node involvement
Airway involvement
Pleural involvement
Parenchymal involvement
• Acinar consolidation
– Typical
– Homogenous density with ill defined margins
– Predominantly in the upper lobes
• Atelectasis
– In the anterior segments of the RU and RM lobes due
to bronchial compression of the enlarged lymph
nodes
– An entire lobe, often the RML, may be affected
Lymph Node involvement
• Hilar or paratracheal lymph node enlargement
is the radiologic finding that clearly
differentiates primary from post-primary
tuberculosis
• Usually unilateral
• Highly suggestive is the large size of the
adenitis relative to the insignificant size of the
primary lung focus
Lymph Node involvement
Radiologic Findings in TB
Airway Involvement
• Tracheobronchial involvement is common
• Bronchial obstruction due to tuberculous LN
may present radiographically as
– Hyperaeration
– Segmental atelectasis – usually in the RML
– Collapse-consolidation lesions
Pleural involvement
• Very common
• Usually localized, contiguous to the primary
foci
• May also be generalized, as seen in
progressive types of PTB
Resolution of Radiographic Changes
Pulmonary infiltrates
Hilar adenopathy
Pleural effusion
Hyperaeration in
endobroncial TB
Miliary TB
Usually clears in 2-9
months
Usually clears in 2-3
years
Complete resorption in
about 6-12 weeks
Improve as early as 3
weeks
After several months
CT Scans
Chest CT Scan may show enlarged or
prominent mediastinal or hilar adenopathy
not demonstrable on chest x-ray.
Can demonstrate endobronchial disease,
pericardial invasion, early cavitation or
bronchiectasis.
Neri N et al. Diagnosis of Pediatric
Tuberculosis in the Modern Era. Pediatr
1999;18:122-126
Infect Dis J.
Mycobacteriology and New Diagnostic
Tests for TB
Mycobacteriology of Childhood TB
Obtain cultures
Lowenstein – Jensen
Bactec Method
sputum, gastric lavage,
bronchoalveolar lavage, body
fluid
New diagnostic tests for TB
1. Immunoassays for mycobacterial
antibodies and myobacterial
antigens (ELISA)
New diagnostic tests for TB
2. Polymerase Chain Reaction (PCR)
New diagnostic tests for TB
3. DNA Probes
Skin Test
New Tests
CT Scan
Chest X-ray
Culture
MANAGEMENT
FIRST LINE ANTI-TB DRUGS
•
•
•
•
•
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Streptomycin (S)
Ethambutol (E)
SECOND LINE ANTI-TB DRUGS
•
•
•
•
•
•
1. Kanamycin
2. Capreomycin
3. Viomycin
4. Thiacetazone
5. Ethionamide
6. Cycloserine
• 7. Para-aminocalicyclic acid
(PAS)
• 8. Terizodone
• 9. Ofloxacin
• 10. Ciprofloxacin
• 11. Amikacin
• 12. Rifabutin
MAIN PROPERTIES OF
ANTI-TB DRUGS
1. Bactericidal activity
2. Sterilizing activity
3. Ability to prevent or delay
emergence of resistance
RELATIVE BACTERICIDAL ACTIVITY
OF FIRST LINE ANTITUBERCULOSIS DRUGS
DRUGS
Rapidly growing
extracellular
organisms
(neutral pH)
Slowly growing
extracellular
organisms
(neutral pH)
Slowly growing
intracellular
organisms
(acid pH)
H
++
+/-
+
R
++
+
+
Z
0
0
+++
S
+++
+/-
0
E
+/-
0
+/-
PRINCIPLES OF CHEMOTHERAPY
OF TUBERCULOSIS
S, H, R
rapidly growing
extracellular bacilli
Inadequate Adequate
Treatment Bactericidal
Action
Treatment
Failure
Z, R, H
slowly growing intracellular and in
closed caseous lesions
Adequate
sterilizing
Inadequate treatment
late growth of
action
persisters
Elimination of elimination of
extracellular
persisters
bacilli
Relapse
LASTING CURE OF TUBERCULOSIS
Preventive Therapy of Childhood
Tuberculosis
TB Exposure
Yes
(+)
Repeat MTX
after 3 months
(-)
D/C INH,If no
BCG scar, Give
BCG
Start H
(+) CXR &/or S/Sx
suggestive of TB
No
TB Infection II
cont H for 6
months
Yes
PTB III- multiple
drug therapy
Interruptions in Therapy
Interruption in initial phase
yes
<14 days >14 days
no
% planned doses in continuation phase completed
Continue tx,
restart
<80%
>80%
if total not
completed in 3 mos,
duration of
additional tx may not
restart
interruption
be necessary
<3 months
>3 months
continue tx, if not
completed in 6 mos,
start from beginning
restart
American Thoracic Society: Treatment of Tuberculosis 2003
Indication for Baseline Liver Function Test and
Monthly Interval Monitoring
•
•
•
•
concurrent and recent liver disease
clinical evidence of hepatotoxicity
pregnancy or within 6 weeks postpartum
if more than 3-5x elevated, D/C INH
Pathogenesis of Tuberculosis
TB in Children