Chokechai RongkavilitPediatric 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.

Styblo K. Bull Int Union Tuberc 1978;53:53

Index case Increased PPD + rate in householdcontacts (above age-matched control)

Smear + 30%-50%

Smear -/culture + 5%

Smear -/culture - 0-8%

~50% of all TB cases are smear negative.

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

< 3.5 (year 2000 target)

3.6 - 5.2

> 5.2 (national average)

D.C.

Rate: cases per 100,000

Reported TB Cases United States, 1982-2002

10000

15000

20000

25000

83 85 87 89 91 93 95 97 99

2001

Year

1982 1986 1990 1994 1998 2002

No

. of

Ca

ses

EpidemiologyRecent increase in TB cases, including MDR-TB, in US (peak in 1992)Deteriorating public health infrastructure Inadequate institutional control of TBUrban crowdingEpidemic 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

25-44 yrs (35%)

<15 yrs (6%)

15-24 yrs (10%)

45-64 yrs (28%)

65+ yrs (21%)

Reported TB Cases by Race/Ethnicity

United States, 2002

Hispanic(27%)

Black, non-Hispanic(30%)

Asian/Pacific Islander(22%)

White, non-Hispanic(20%)

American Indian/ Alaska Native (1%)

Number of TB Cases inU.S.-born vs. Foreign-born Persons

United States, 1992-2002

0

5000

10000

15000

20000

1992 1994 1996 1998 2000 2002

U.S.-born Foreign-born

No

. o

f C

ases

Trends in TB Cases in Foreign-born Persons, United States, 1986-2002

0

2,000

4,000

6,000

8,000

10,000

1986 1988 1990 1992 1994 1996 1998 2000 20020

10

20

30

40

50

60

No. of Cases Percentage of Total Cases

No. of Cases Percentage

Countries of Birth for Foreign-born Persons Reported with TB

United States, 2002

Mexico(25%)

Philippines(11%)

Vietnam(8%)India

(7%)China

(5%)

Haiti(3%)

S. Korea(3%)

OtherCountries

(38%)

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

2002

0%

20%

40%

60%

80%

100%

All Philippines Mexico Vietnam

<1 yr 1- 4 yrs >5 yrs

Pediatric TB in USA

Nelson LJ. Pediatr. 2004;114:333

Pediatric TB in USAIn 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 birthTravelExposure to TB casesClose contact with a person with +PPDJail, shelter, illegal drug use, HIVHousehold 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 5TU PPD tuberculin

•Produce wheal 6 mm to 10 mm in diameter (do not place control)

•Do not recap, bend, or breakneedles, 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

Diameter of induration

Ballpoint Pen Method

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

PPDCutoff value

5 mm immunocompromised host recent exposure to infectious casehigh probability of infection (abnormal CXR)

15 mm low risk of TB

10 mmothers

Factors that May Affect the Skin Test Reaction

Type of Reaction Possible CauseFalse-positive Nontuberculous mycobacteria BCG vaccination

AnergyFalse-negative 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 TBUnited States, 1993-2001

0

10

20

30

1993 1994 1995 1996 1997 1998 1999 2000 2001

All Ages Aged 25 - 44

% C

oin

fect

ion

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 resource-

poor 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

Mode of Treatment Administration in Persons

Reported with TB United States, 1993-2000

0%

20%

40%

60%

80%

100%

1993 1994 1995 1996 1997 1998 1999 2000

DOT only DOT + SA SA onlyDirectly observed therapy (DOT); Self-administered therapy (SA)

Completion of TB Therapy United States, 1993-2000

0

20

40

60

80

100

1993 1994 1995 1996 1997 1998 1999 2000

Completed 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.

Per

cen

tag

e *

*Healthy People 2010 target: Completed in 1 yr or less

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 TBPositive smearsLaryngeal involvementExtensive 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 nucleismall 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 spotYellow = outbreak

•Resistance to INH 4% in 46 states and Districtof Columbia (DC) during 1993-1998

•45 states and DC reported at least one MDR TB case during 1993-1998

Multidrug-Resistant TB (MDR TB) Remains a Serious Public Health Concern

Primary Anti-TB Drug Resistance

United States, 1993-2002

0

5

10

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

Isoniazid MDR TB

% R

esis

tan

t

Note: Based on initial isolates from persons with no prior history of TB.MDR TB defined as resistance to at least isoniazid and rifampin.

Primary Isoniazid Resistance in U.S.-born vs. Foreign-born Persons

United States, 1993-2002

02468

101214

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

U.S.-born Foreign-born

Pe

rce

nta

ge

Note: Based on initial isolates from persons with no prior history of TB.

Primary MDR TB inU.S.-born vs. Foreign-born

Persons, United States, 1993-2002

0

1

2

3

1993 1994 1995 1996 1997 1998 1999 2000 2001 2002

U.S.-born Foreign-born

% R

esis

tan

t

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 drug-resistant 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