1. TUBERCULOSIS
Chokechai Rongkavilit
Pediatric Infectious Diseases

2. 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

3. Transmission and Pathogenesis

4. 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)

5. How contagious is TB?
10 secondary cases arise annually from 1 untreated smear-positive case.
~50% of all TB cases are smear negative.
Styblo K. Bull Int Union Tuberc 1978;53:53

6. 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.

8. TB Case Rates, United States, 2002
D.C.
< 3.5 (year 2000 target)
> 5.2 (national average)
Rate: cases per 100,000

9. Reported TB Cases United States, 1982-2002
No. of Cases
1982
1986
1990
1994
1998
2002
Year

10. 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

11. Reported TB Cases by Age Group United States, 2002
<15 yrs (6%)
65+ yrs
(21%)
15-24 yrs (10%)
25-44 yrs
(35%)
45-64 yrs
(28%)

12. Reported TB Cases by Race/Ethnicity United States, 2002
White, non-Hispanic
(20%)
Hispanic
(27%)
American Indian/
Alaska Native (1%)
Asian/Pacific Islander
(22%)
Black, non-Hispanic
(30%)

13. Number of TB Cases in U. S. -born vs
Number of TB Cases in U.S.-born vs. Foreign-born Persons United States,
No. of Cases

14. Trends in TB Cases in Foreign-born Persons, United States, 1986-2002
No. of Cases
Percentage

15. Countries of Birth for Foreign-born Persons Reported with TB United States, 2002
Other
Countries
(38%)
Mexico
(25%)
Philippines
(11%)
S. Korea
(3%)
Vietnam
(8%)
Haiti
(3%)
India
(7%)
China
(5%)

16. Length of U.S. Residence Prior to TB Diagnosis, United States, 2002

17. Pediatric TB in USA
Nelson LJ. Pediatr. 2004;114:333

18. 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

19. TB Disease and Infection
Testing for
TB Disease and Infection

20. 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

21. 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

22. 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

23. 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

24. Reading the Tuberculin Skin Test
Read reaction hours after
injection
Measure only induration
Record reaction in millimeters

25. PPD
Ballpoint Pen Method
Diameter of induration

26. 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

27. 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

28. 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

29. 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

30. Factors that May Affect the
Skin Test Reaction
Type of Reaction Possible Cause
False-positive Nontuberculous mycobacteria
BCG vaccination
Anergy
False-negative Recent TB infection
Very young age (< 6 months old)
Live-virus vaccination
Overwhelming TB disease
Sensitivity of PPD: 80-96%

31. 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

32. Diagnosis of TB

33. Tuberculosis is one of the great imitator.
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.

34. Common Sites of TB Disease
Lungs
Pleura
Central nervous system
Lymphatic system
Genitourinary systems
Bones and joints
Disseminated (miliary TB)

35. Systemic Symptoms of TB
Fever
Chills
Night sweats
Appetite loss
Weight loss
Easy fatigability

36. 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)

37. Estimated HIV Coinfection in Persons Reported with TB United States, 1993-2001
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.

38. 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.

39. 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

40. AFB smear
AFB (shown in red) are tubercle bacilli

41. 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

42. 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

43. 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

44. 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

45. Treatment of Latent TB Infection (LTBI)

46. 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

47. 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

48. Contacts of Multidrug-Resistant TB
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

49. 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

50. Treatment of TB Disease

51. 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

52. Adherence Nonadherence is a major problem in TB control
Use case management and directly observed
therapy (DOT) to ensure patients complete treatment

53. Directly Observed Therapy (DOT)
High cure rate up to 95% even in resource-poor countries
Prevent additional spread
Prevent development of drug resistance
Cost-effective

54. 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

55. Mode of Treatment Administration in Persons Reported with TB United States, 1993-2000
Directly observed therapy (DOT); Self-administered therapy (SA)

56. Completion of TB Therapy United States, 1993-2000*
Percentage
*Healthy People 2010 target: Completed in 1 yr or less
Note: Persons with initial isolate resistant to rifampin and children under years old with meningeal, bone or joint, or miliary disease excluded.

57. 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)

58. Bone and Joint TB, Miliary TB, or TB Meningitis in Children
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

59. 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

60. 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

61. 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

62. 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

63. Infection Control in Health Care Settings

64. 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

65. 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

66. 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

67. 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

68. 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

69. 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

70. Multidrug Resistant Tuberculosis
Red = hot spot
Yellow = outbreak

71. Multidrug-Resistant TB (MDR TB) Remains a
Serious Public Health Concern
Resistance to INH 4% in 46 states and District
of Columbia (DC) during
45 states and DC reported at least one MDR TB
case during

72. Primary Anti-TB Drug Resistance United States, 1993-2002
% Resistant
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.

73. Primary Isoniazid Resistance in U. S. -born vs
Primary Isoniazid Resistance in U.S.-born vs. Foreign-born Persons United States,
Percentage
Note: Based on initial isolates from persons with no prior history of TB.

74. Primary MDR TB in U. S. -born vs
Primary MDR TB in U.S.-born vs. Foreign-born Persons, United States,
% Resistant
Note: Based on initial isolates from persons with no prior history of TB.
MDR TB defined as resistance to at least isoniazid and rifampin.

75. 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 drug-resistant TB (INH resistance rate  4%)

76. 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