TUBERCULOSIS

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TUBERCULOSIS
Chokechai Rongkavilit Pediatric Infectious
Diseases

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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 1999282677
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Transmission and Pathogenesis
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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)

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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 19785353
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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.

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(No Transcript)
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TB Case Rates, United States, 2002
D.C.
lt 3.5 (year 2000 target)
3.6 - 5.2
gt 5.2 (national average)
Rate cases per 100,000
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Reported TB Cases United States, 1982-2002
No. of Cases
1982
1986
1990
1994
1998
2002
Year
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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 1994272535
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Reported TB Cases by Age Group United States, 2002
lt15 yrs (6)
65 yrs (21)
15-24 yrs (10)
25-44 yrs (35)
45-64 yrs (28)
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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)
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Number of TB Cases inU.S.-born vs. Foreign-born
Persons United States, 1992-2002
No. of Cases
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Trends in TB Cases in Foreign-born Persons,
United States, 1986-2002
No. of Cases
Percentage
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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)
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Length of U.S. Residence Prior to TB Diagnosis,
United States, 2002
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Pediatric TB in USA

Nelson LJ. Pediatr. 2004114333
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Pediatric TB in USA

• In 2001, TB case rate in children
• lt5 y 2.8 per 100,000
• 5-9 y 1.0 per 100,000
• 10-14 y 0.9 per 100,000

Nelson LJ. Pediatr. 2004114333
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Testing for TB Disease and Infection
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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

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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
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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

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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

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Reading the Tuberculin Skin Test

• Read reaction 48-72 hours after
• injection
• Measure only induration
• Record reaction in millimeters

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PPD
Ballpoint Pen Method
Diameter of induration
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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

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Classifying the Tuberculin Reaction (cont.)

• ?10 mm is classified as positive in
• Risk for disseminated disease
• Concomitant medical conditions DM, malnutrition,
  CRF, lymphoma
• Those lt 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

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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

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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

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

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Diagnosis of TB
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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.
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Common Sites of TB Disease

• Lungs
• Pleura
• Central nervous system
• Lymphatic system
• Genitourinary systems
• Bones and joints
• Disseminated (miliary TB)

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Systemic Symptoms of TB

• Fever
• Chills
• Night sweats
• Appetite loss
• Weight loss
• Easy fatigability

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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)

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Estimated HIV Coinfection in Persons Reported
with TBUnited States, 1993-2001
Coinfection
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.
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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.
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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

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AFB smear
AFB (shown in red) are tubercle bacilli
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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
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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

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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
• gt2 weeks

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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

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Treatment of Latent TB Infection (LTBI)
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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
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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

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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

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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

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Treatment of TB Disease
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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

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Adherence

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

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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

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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

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Mode of Treatment Administration in Persons
Reported with TB United States, 1993-2000
Directly observed therapy (DOT)
Self-administered therapy (SA)
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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 15 years
old with meningeal, bone or joint, or miliary
disease excluded.
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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)

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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

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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

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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

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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

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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

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Infection Control in Health Care Settings
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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

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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
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How to isolate the patient?

• Transmitted by airborne droplet nuclei
• small particles lt 5 µm which suspend in air for
  long periods
• Private room with negative-pressure ventilation
• Respirator mask

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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

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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

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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

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Multidrug Resistant Tuberculosis
Red hot spot Yellow outbreak
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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

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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.
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Primary Isoniazid Resistance in U.S.-born vs.
Foreign-born Persons United States, 1993-2002
Percentage
Note Based on initial isolates from persons with
no prior history of TB.
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Primary MDR TB inU.S.-born vs. Foreign-born
Persons, 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.
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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)

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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