Transcript tuberculosis - Children`s Hospital of Michigan

Chokechai Rongkavilit
Pediatric Infectious Diseases
Why do we need to know TB?
Over 1/3 of world population is infected with TB.
1% of world population will become infected each year.
Previous epidemic and continued immigration have
resulted in a large number of latent TB in US.
Development of active TB in persons with latent infection
poses a continual threat of transmission.
Dye C, et al. JAMA 1999;282:677
Transmission and Pathogenesis
Transmission of M. tuberculosis
• Spread by droplet nuclei
• Expelled when person with infectious TB coughs,
sneezes, speaks, or sings
• Close contacts at highest risk of becoming infected
• Transmission occurs from person with infectious
TB disease (not latent TB infection)
How contagious is TB?
10 secondary cases arise annually from 1 untreated
smear-positive case.
Index case
Increased PPD + rate in household
contacts (above age-matched control)
Smear +
30%-50%
Smear -/culture + 5%
Smear -/culture -
0-8%
~50% of all TB cases are smear negative.
Styblo K. Bull Int Union Tuberc 1978;53:53
How contagious is TB?
Transmission is influenced by

Number of AFB excreted from the source case (cavitary
or laryngeal TB)

Duration of exposure

Closeness of exposure
TB infection requires only 1-5 AFB deposited in
terminal alveolus.
TB Case Rates, United States,
2002
D.C.
< 3.5 (year 2000 target)
3.6 - 5.2
> 5.2 (national average)
Rate: cases per 100,000
25000
20000
15000
Year
1
9
0
9
7
9
5
1994
0
1990
9
3
9
1
9
9
8
5
7
8
1986
1998
2
1982
8
3
10000
8
No. of Cases
Reported TB Cases
United States, 1982-2002
2002
Epidemiology
Recent increase in TB cases, including MDR-TB, in US
(peak in 1992)

Deteriorating public health infrastructure

Inadequate institutional control of TB

Urban crowding

Epidemic of HIV

Immigration
After 1992, TB cases decrease in US.
Cantwell MF, et al. JAMA 1994;272:535
Reported TB Cases by Age
Group United States, 2002
<15 yrs (6%)
65+ yrs
(21%)
45-64 yrs
(28%)
15-24 yrs (10%)
25-44 yrs
(35%)
Reported TB Cases by
Race/Ethnicity
United States, 2002
Hispanic
(27%)
White, non-Hispanic
(20%)
American Indian/
Alaska Native (1%)
Black, non-Hispanic
(30%)
Asian/Pacific Islander
(22%)
Number of TB Cases in
U.S.-born vs. Foreign-born
Persons
United States, 1992-2002
20000
15000
10000
5000
0
1992
1994
1996
U.S.-born
1998
2000
Foreign-born
2002
Trends in TB Cases in Foreignborn Persons, United States,
1986-2002
No. of Cases
Percentage
10,000
60
50
8,000
40
30
20
6,000
4,000
2,000
10
0
0
1986 1988 1990 1992 1994 1996 1998 2000 2002
No. of Cases
Percentage of Total Cases
Countries of Birth for Foreignborn Persons Reported with
TB
United States, 2002
Other
Countries
Mexico
(25%)
(38%)
Philippines
(11%)
S. Korea
Vietnam
(3%) Haiti
India (8%)
(3%) China
(5%)
(7%)
Length of U.S. Residence Prior
to TB Diagnosis, United
States, 2002
100%
80%
60%
40%
20%
0%
All
Philippines
<1 yr
1- 4 yrs
Mexico
>5 yrs
Vietnam
Pediatric TB in USA
Nelson LJ. Pediatr. 2004;114:333
Pediatric TB in USA
In 2001, TB case rate in
children
<5 y:
2.8 per 100,000
5-9 y:
1.0 per 100,000
10-14 y: 0.9 per 100,000
Resist
US-born
Foreign-born
INH
6.4%
10.9%
MDR
1.4%
2.8%
Nelson LJ. Pediatr. 2004;114:333
Testing for
TB Disease and Infection
Purpose of Targeted Testing
•
Find persons with LTBI who would benefit from
treatment
•
Find persons with TB disease who would benefit
from treatment
•
Groups that are not high risk for TB should not be
tested routinely
Risk-Assessment Questionnaires
Place of birth
Travel
Exposure to TB cases
Close contact with a person with +PPD
Jail, shelter, illegal drug use, HIV
Household members born/traveling outside US
PPD is + in 6% of those with at least 1 risk factor vs 0.1% of
those without any risk factors.
Supplement to Pediatrics; Oct 2004
PPD
Purified protein products from M. tuberculosis (5
TU)
Stimulation of sensitized T-lymphocyte
delayed-type hypersensitivity
Response occurs at 2-10 weeks after TB infection
Sensitivity 75-90%

poor nutrition

overwhelming acute illness

immunosuppression
Administering the Tuberculin Skin Test
• Inject intradermally 0.1 ml of 5
TU PPD tuberculin
• Produce wheal 6 mm to 10 mm
in diameter (do not place control)
• Do not recap, bend, or break
needles, or remove needles from syringes
• Follow universal precautions for infection control
Reading the Tuberculin Skin Test
• Read reaction 48-72 hours after
injection
• Measure only induration
• Record reaction in millimeters
PPD
Ballpoint Pen Method
Diameter of induration
Classifying the Tuberculin Reaction
5 mm is classified as positive in
•
Recent contacts of known or suspected TB case
•
Persons clinical or radiographic findings consistent
with active or previously active TB
•
Immunosuppressed patients: HIV
Classifying the Tuberculin Reaction (cont.)
10 mm is classified as positive in
Risk for disseminated disease
• Concomitant medical conditions: DM, malnutrition, CRF,
lymphoma
•
Those < 4 years old
Risk for exposure to TB
•
•
Born or travel to a country with high prevalence of TB
Frequent exposure to cases with risk factors for TB
•
HIV, homeless, illegal drug use, immigrants
Classifying the Tuberculin
Reaction (cont.)
15 mm is classified as positive in
• Persons with no known risk factors for TB
• Targeted skin testing programs should only be
conducted among high-risk groups
PPD
Cutoff value
5 mm
 immunocompromised host
 recent exposure to infectious case
 high probability of infection (abnormal CXR)
15 mm
 low risk of TB
10 mm

others
Factors that May Affect the
Skin Test Reaction
Type of Reaction
False-positive
False-negative
Possible Cause
Nontuberculous mycobacteria
BCG vaccination
Anergy
Recent TB infection
Very young age (< 6 months old)
Live-virus vaccination
Overwhelming TB disease
Sensitivity of PPD: 80-96%
Anergy
• The use of control skin-test antigens has several
limitations and IS NOT RECOMMENDED
• It has not been standardized
• The diagnosis of anergy has not been associated
with high risk of developing TB
Diagnosis of TB
Evaluation for TB
•
Medical history
•
Physical examination
•
Mantoux tuberculin skin test
•
Chest radiograph
•
Bacteriologic or histologic exam
“Clinical judgement”
Tuberculosis is one of the great imitator.
Common Sites of TB Disease
•
Lungs
•
Pleura
•
Central nervous system
•
Lymphatic system
•
Genitourinary systems
•
Bones and joints
•
Disseminated (miliary TB)
Systemic Symptoms of TB
•
Fever
•
Chills
•
Night sweats
•
Appetite loss
•
Weight loss
•
Easy fatigability
Conditions That Increase the Risk of
Progression to TB Disease
•
•
•
•
•
•
•
•
•
HIV infection
Substance abuse
Recent infection
Chest radiograph findings suggestive of previous TB
Diabetes mellitus
Immunosuppressed
End-stage renal disease
Chronic malabsorption syndromes
Low body weight (10% or more below the ideal)
Estimated HIV Coinfection in
Persons Reported with TB
United States, 1993-2001
% Coinfection
30
20
10
0
1993 1994 1995 1996 1997 1998 1999 2000 2001
All Ages
Aged 25 - 44
Note: Minimum estimates based on reported HIV-positive status
among all TB cases in the age group. All 2001 cases from California
have an unknown HIV status.
Chest Radiograph
•
•
Abnormalities often seen in apical
or posterior segments of upper
lobe or superior segments of
lower lobe
Non-specific findings in children
•
May have unusual appearance in
HIV-positive persons
•
Cannot confirm diagnosis of TB
Arrow points to cavity in
patient's right upper lobe.
Specimen Collection
•
Obtain 3 sputum specimens for smear examination
and culture
•
Persons unable to cough up sputum, induce
sputum, bronchoscopy or gastric aspiration
•
Follow infection control precautions during
specimen collection
AFB smear
AFB (shown in red) are tubercle bacilli
Cultures
•
Use to confirm diagnosis of TB
•
Culture all specimens, even if smear negative
•
Results in 4 to 14 days when liquid medium
systems used
Colonies of M. tuberculosis growing on media
Drug Susceptibility Testing
•
Drug susceptibility testing on initial M. tuberculosis
isolate
•
Repeat for patients who
- Do not respond to therapy
- Have positive cultures despite 2 months of therapy
•
Promptly forward results to the health department
Persons at Increased Risk for
Drug Resistance
•
History of treatment with TB drugs
•
Contacts of persons with drug-resistant TB
•
Foreign-born persons from high prevalent drug
resistant areas
•
Smears or cultures remain positive despite
2 months of TB treatment
•
Received inadequate treatment regimens for
>2 weeks
Data Collection and Analysis
•
TB reporting required in every state
•
All new cases and suspected cases promptly
reported to health department
•
All drug susceptibility results sent to health
department
Treatment of Latent TB Infection (LTBI)
Treatment of LTBI with Isoniazid (INH)
• 9-month regimen considered optimal
• Children should receive 9 months of therapy
• Can be given twice-weekly if directly observed
LTBI = PPD+ with normal H & P & CXR
Treatment of LTBI with a Rifamycin
and Pyrazinamide (PZA)
HIV-Positive Persons
•
A rifamycin and PZA daily for 2 months
•
Administration of rifampin (RIF) contraindicated with some
HIV drugs
HIV-Negative Persons
•
Clinical trials have not been conducted
•
Daily RIF and PZA for 2 months
•
May be given twice weekly
Contacts of INH-Resistant TB
•
Treatment with a rifamycin and PZA
•
If unable to tolerate PZA, 4-month regimen of daily RIF
•
HIV-positive persons: 2 month regimen with a rifamycin and
PZA
Contacts of Multidrug-Resistant TB
•
Use 2 drugs to which the infecting organism has
demonstrated susceptibility
•
Treat for 6 months or observe without treatment
(HIV-negative)
•
Treat HIV-positive persons for 12 months
•
Follow for 2 years regardless of treatment
Monitoring Patients
Baseline laboratory testing
•
Not routinely indicated
•
Baseline hepatic measurements for
- Patients whose initial evaluation suggests a liver disorder
- Patients with HIV infection
- Pregnant women and those in immediate postpartum period
- Patients with history of chronic liver disorder
Treatment of TB Disease
Basic Principles of Treatment
•
Provide safest, most effective therapy in shortest time
•
Multiple drugs to which the organisms are susceptible
•
Never add single drug to failing regimen
•
Ensure adherence to therapy
Adherence
•
Nonadherence is a major problem in TB control
•
Use case management and directly observed
therapy (DOT) to ensure patients complete treatment
Directly Observed Therapy (DOT)
High cure rate up to 95% even in resourcepoor countries
Prevent additional spread
Prevent development of drug resistance
Cost-effective
Directly Observed Therapy (DOT)
•
Health care worker watches patient swallow each
dose of medication
•
Consider DOT for all patients
•
DOT should be used with all intermittent regimens
•
DOT can lead to reductions in relapse and acquired
drug resistance
•
Use DOT with other measures to promote adherence
100%
Mode of Treatment
Administration in Persons
Reported with TB United
States, 1993-2000
80%
60%
40%
20%
0%
1993
1994
1995
DOT only
1996
1997
DOT + SA
1998
1999
SA only
Directly observed therapy (DOT); Self-administered therapy (SA)
2000
Completion of TB Therapy
United States, 1993-2000
100
*
80
60
40
20
0
1993 1994 1995 1996 1997 1998 1999 2000
Completed
Completed in 1 yr or less
*Healthy People 2010 target: Completed in 1 yr or less
Note: Persons with initial isolate resistant to rifampin and children under 15
years old with meningeal, bone or joint, or miliary disease excluded.
Treatment of TB for HIV-Negative Persons
• Include four drugs in initial regimen
- Isoniazid (INH)
- Rifampin (RIF)
- Pyrazinamide (PZA)
- Ethambutol (EMB) or streptomycin (SM)
• Adjust regimen when drug susceptibility results are
Known (6 months)
Extrapulmonary TB
•
In most cases, treat with same regimens
used for pulmonary TB
Bone and Joint TB, Miliary TB,
or TB Meningitis in Children
•
Treat for a minimum of 12 months
Treatment Regimens for TB
Resistant Only to INH
HIV-Negative Persons
•
Carefully supervise and manage treatment to avoid
development of MDR TB
•
Discontinue INH and continue RIF, PZA, and EMB
or SM for the entire 6 months
•
Or, treat with RIF and EMB for 12 months
HIV-Positive Persons
•
Regimen should consist of a rifamycin, PZA, and EMB
Multidrug-Resistant TB (MDR TB)
•
Presents difficult treatment problems
•
Treatment must be individualized
•
Clinicians unfamiliar with treatment of MDR TB should
seek expert consultation
•
Always use DOT (or hospitalization) to ensure adherence
Monitoring for Adverse Reactions
•
Baseline measurements
•
Monitor patients at least monthly
•
Monitoring for adverse reactions must be
individualized
•
Instruct patients to immediately report adverse
reactions
Monitoring Response to Treatment
• Monitor patients bacteriologically monthly until
cultures convert to negative
• After 3 months of therapy, if cultures are positive
or symptoms do not resolve, reevaluate for
- Potential drug-resistant disease
- Nonadherence to drug regimen
• If cultures do not convert to negative despite 3
months of therapy, consider initiating DOT
Infection Control in Health Care Settings
Infectiousness
Patients should be considered infectious if they
•
Are coughing
•
Are undergoing cough-inducing or aerosol-generating
procedures, or
•
Have sputum smears positive for acid-fast bacilli and they
•Are not receiving therapy
•Have just started therapy, or
•Have poor clinical response to therapy
Who should be placed in
isolation?
Most children with TB do not require isolation.
Children with cough and
 Cavitary pulmonary TB
 Positive smears
 Laryngeal involvement
 Extensive pulmonary TB
Adult household contacts (until proved not to have
contagious TB)
AAP Red Book 2000
How to isolate the patient?
Transmitted by airborne droplet nuclei
small particles < 5 µm which suspend in air for long
periods
Private room with negative-pressure
ventilation
Respirator mask
Engineering Controls
To prevent spread and reduce concentration of infectious
droplet nuclei
• Use ventilation systems in TB isolation rooms
• Use HEPA filtration and ultraviolet irradiation with other
infection control measures
Personal Respiratory Protection
Use in areas where increased risk of exposure:
•
TB isolation rooms
•
Rooms where cough-inducing procedures are done
•
Homes of infectious TB patients
When does the patient become
noncontagious?
It is difficult to determine an absolute moment at
which a pt on therapy becomes non-contagious.
Discontinuation of isolation should be based on

clinical improvement after appropriate treatment

3 negative smears collected on different days

For MDR TB, need 3 negative cultures
Multidrug Resistant Tuberculosis
Red = hot spot
Yellow = outbreak
Multidrug-Resistant TB (MDR TB) Remains a
Serious Public Health Concern
• Resistance to INH 4% in 46 states and District
of Columbia (DC) during 1993-1998
• 45 states and DC reported at least one MDR TB
case during 1993-1998
Primary Anti-TB Drug
Resistance
United States, 1993-2002
% Resistant
10
5
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
Isoniazid
MDR TB
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.
Percentage
Primary Isoniazid Resistance in
U.S.-born vs. Foreign-born
Persons
14
United States, 1993-2002
12
10
8
6
4
2
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
U.S.-born
Foreign-born
Note: Based on initial isolates from persons with no prior history of TB.
% Resistant
Primary MDR TB in
U.S.-born vs. Foreign-born
Persons, United States, 19932002
3
2
1
0
1993 1994 1995 1996 1997 1998 1999 2000 2001 2002
U.S.-born
Foreign-born
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.
When to suspect drug-resistant
TB?
Contacts of patient with drug-resistant TB
Contacts of patient with prior treatment for TB
Prior treatment for TB
Persistent +AFB after 2-3 months of therapy
Foreign-born
Residents in area with high prevalence of drugresistant TB (INH resistance rate  4%)
Take-home messages
Always keep TB in differential diagnoses
Aggressive work-up and treatment
Use DOT
Aggressive search for source and contact cases
If in doubt, isolate the patient