Primary Care Management of

Latent Tuberculosis Infection

in the Foreign-Born
Investigators
• Carey Jackson MD, MPH University of Washington
• Jenny Pang MD, MPH, Seattle-King County
Department of Public Health
• Nick DeLuca PhD, Centers for Disease Control and
Prevention (CDC)
• Stacey Bryant RN, Research Coordinator

Public Health
Seattle & King County
 Active TB Disease
• Tubercle bacilli in the body
• Usually positive skin test
• Infectious (before
treatment)
• Symptoms of TB
• Chest x-ray usually
abnormal
• Sputum smears and
cultures usually positive
Granuloma breaks • An active “case” of TB
down and tubercle
escape and multiply
 Symptoms of Active TB Disease
Systemic Pulmonary
Symptoms Symptoms
• Weight loss • Coughing (duration of
• Fatigue ≥ 3 weeks)
• Fever • Chest pain (when
• Night sweats breathing or coughing)
• Hemoptysis
• Chills
Latent TB Infection (LTBI)

LTBI is the presence of

M. tuberculosis organisms
(tubercle bacilli)
without symptoms or
radiographic evidence of
active TB disease
Latent TB Infection (LTBI)
• Tubercle bacilli in the
body
• Usually positive skin test
• NOT infectious
• No symptoms
• Normal chest X-ray
• Sputum smears and
cultures are negative
• Not a “case” of TB
Epidemiology
Active TB Incidence Worldwide, 2005

2 billion infected with LTBI!

(Active TB all forms [per 100,000 population per year])

Source: WHO Stop TB Department,
website: http://www.who.int/globalatlas/interactiveMapping/MainFrame2.asp
 TB Case Rates,* United States, 2006

D.C.

< 3.5 (year 2000 target)

15 million infected 3.6–4.6
with LTBI! > 4.6 (national average)
*Cases per 100,000.
 Trends in TB Cases in Foreign-born
Persons, United States, 1986–2006*
No. of Cases Percentage
10,000 60
8,000 50
40
6,000
30
4,000
20
2,000 10
0 0
86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06

No. of Cases Percentage of Total Cases

57% of cases in 2006 were foreign-born

*Updated as of April 6, 2007.
Percentage of TB Cases Among Foreign-
born Persons, United States*

1996 2006

DC DC

>50%
25%–49%
<25%
*Updated as of April 6, 2007.
 TB Rates in Countries of Birth
2005
600
506
500
344
Per 100,000

400
291 305
300
200
168 175
100 119
100
4.6 23
0

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Source: World Health Organization

 TB Case Rates by Age Group
and Sex, United States, 2006
Cases per 100,000
12
10
8
6
4
2
0
<15 yrs 15–24 yrs 25–44 yrs 45–64 yrs >65 yrs

Male Female

Highest Incidence is in 65+

 Percent of Foreign-born with TB by Time of
Residence in U.S. Prior to Diagnosis,* 2006
Over HALF of active TB cases in the Foreign-Born
have been in the US more than 5 years!
100%
80%
60%
40%
20%
0%
All Mexico Philippines Viet Nam

<1 yr 1–4 yrs >5 yrs

*Data exclude foreign-born TB patients for when length of
residence in the U.S. prior to diagnosis was unknown.
Countries of Birth of Foreign-born
Persons Reported with TB
United States, 2006

Mexico
Other (25%)
Countries
(38%)

Philippines
(11%)

Guatemala
(3%) Viet Nam
Haiti (8%)
India
(3%) China
(5%) (7%)
Latent TB Infection Testing
 Flow Chart for Latent TB Infection (LTBI) in Primary Care
Patient with risk factors
for LTBI
Note: Evaluate patient for
TST (PPD) LTBI testing and treatment
regardless of BCG status

Negative Positive Rule out active TB disease

before treatment for LTBI is
started
No treatment; History/HIV risk,
Document status in physical exam,
medical record chest x-ray

Normal Abnormal

Refer to TB clinic Treatment of

for evaluation Positive active TB
of active TB by TB clinic

Candidate for
Negative
LTBI Treatment
 Who Should Be Tested
Know the TB status of your at risk patients.
Who is considered What countries are
at risk? considered TB endemic?
Foreign born • All of Asia except Japan
patients from • All of Central and South
TB endemic America
countries, • All of Africa
where prior TB • All of Eastern Europe
exposure is
(Yes, that is practically
almost certain
the whole world)
 Other Groups At High Risk for TB
Groups
• Close contacts of Active TB cases
• Usually taken care of by TB clinic
• Healthcare workers who serve high risk
clients
• Residents & employees of congregate
settings
• Medically underserved/low-income groups:
• Homeless
• Migrant workers
• Street drug users
• Children with parents who have risk factors
 Medical Conditions that
Put People at High Risk for TB
Medical Conditions
• HIV +
• Renal dialysis
• Immunocompromised
(>15 mg prednisone qd for 1 month or more)
• Diabetes mellitus
• Silicosis
• Cancer of the head and neck
• Hematologic and reticuloendothelial diseases
• Intestinal bypass or gastrectomy
• Chronic malabsorption syndromes
• Low body weight
• Organ Transplant
Who needs repeat LTBI testing?

1) Healthcare workers
2) Close contacts to infectious TB cases
3) Frequent travelers to abroad
• If baseline TST is negative, consider
retesting your patients that have
extended travel to high risk areas.
• Do symptom review upon return and
possibly retesting 8-10 week after
return.
Reading the Tuberculin Skin Test
(TST)
• Measure reaction in 48 to 72
hours
• Measure induration,
not erythema (redness)
• Record reaction in
millimeters, not “negative”
or “positive”
• Ensure trained health care
professional measures and
interprets the TST (PPD)
 Interpreting the TST (PPD)

A positive TST (PPD) is determined by

• The size of the induration
• The patient’s risk factors
 Interpreting Tuberculin Skin Test Reactions
5 mm 10 mm 15 mm
or greater or greater or greater
• HIV positive persons • Immigrants from high- No known
• Recent contacts of prevalence areas risk factors
persons with active • Injection drug users
tuberculosis • Residents and employees* of
• Fibrotic changes on high-risk congregate settings
chest radiograph, • Personnel in
consistent with mycobacteriology
tuberculosis laboratories
• Patients with organ • Persons with clinical
transplants and other conditions that place them at
immunosuppressed high risk
patients • Children: <4 years of age; all
exposed to adults at high-risk

(Note: the CDC discourages testing of people at low risk for infection.)
 Interpreting IGRA’s
• 1) Not entirely sensitive to detect TB--
about 70% sensitive and >90% specific
• 2) Cannot distinguish latent TB from
active TB
• 3)For LTBI---Useful because of
specificity of assay to distinguish a
false positive TST from a true positive
in testing a foreign-born population
where BCG vaccination is routinely
used. 
 Interpreting IGRA’s
•  
• 4)In low prevalence LTBI populations,
such has health care workers born in
the US--the jury is still out to whether
using these assay is feasible and cost
effective
•     a) CDC is studying this question
currently through TBESC
    b)  preliminary data shows that there
could be a reversion from QFN positive
to QFN negative and vice versa with
serial testing over time
 Interpreting IGRA’s
•  5) ? MAI distinction--maybe, but not well
studied.
•  6) Discordance in testing someone for LTBI----  
TST negative and QFN positive-- No one knows
what will happen to these patients.  A long term
follow-up study needs to see if TB develops in
these patients.
• 7) Elispot is labor intensive and require
processing the same day.  Current
QuantiFERON -TB In Tube does not.  It requires
an incubator, if specimen is not processed the
same day.
 TB screening for those coming to US
1) Refugees and Immigrants
In Country of Origin
• Evaluated for active TB ONLY
In the US
• Those applying for an adjustment of status are
evaluated for LTBI but treatment is NOT mandated
2) Visitors, students, temporary workers,
undocumented
• Not evaluated

The Immigration Process does not take care of

Latent TB Infection (LTBI) for you!
 BCG
Should persons who have been vaccinated with BCG
(Bacille Calmette-Guerin) be tested for LTBI
• According to CDC guidelines, persons who have
received BCG should be tested for LTBI as
otherwise indicated

How should the results be interpreted?

• Positive TST should be assumed to be due to TB
infection, not BCG, and treatment should be
recommended, unless contraindicated

Source: CDC TB Fact Sheet “BCG Vaccine” 2006.

 Literature Review on BCG
2006
• 1500 papers reviewed from 1980-2005
• Data demonstrate that the TST (PPD)
performs well on BCG vaccinated adult
(15+) patients and on patients from
high and intermediate incidence
countries
• The effect of the BCG vaccine on TST
(PPD) reaction decreases with
increasing time since vaccination.
 Literature Review on BCG
2006 (cont.)
Conclusion:
• “Adults (15+) from intermediate and
high-incidence countries are at high
risk for LTBI and the results of
tuberculin testing can be interpreted in
the same manner, regardless of
vaccination status.”

Source: Joos, TJ et al. 2006. “Tuberculin reactivity in bacille Calmette-Guerin vaccinated populations: a compilation
of international data.” The International Journal of Tuberculosis and Lung Disease, Volume 10, Number 8, August 2006 .
 Treatment for
Latent Tuberculosis
Infection (LTBI)
 Who Should be Treated for
Latent TB Infection (LTBI)?
Anyone who has been diagnosed with latent
TB infection is a candidate for treatment, if
they also fulfill the following criteria:
• Willing and able to complete a full course of
therapy
• Available to be monitored during the full
course of treatment
• No medical contraindications such as active
liver disease
(Note: careful assessment to rule out the possibility of
active TB disease is always necessary before
treatment for LTBI is started.)
 Risk Factors for Progression from Latent
TB Infection (LTBI) to Active TB Disease
Medical Conditions
Your patient’s TB infection may be latent now,
but many factors could increase the risk of progression

• Immunosuppression • Silicosis
• Lymphoma, • Gastrectomy/
leukemia jejunoileal bypass
• Diabetes • Head and neck cancer
• Renal dialysis • HIV +
• Malnutrition
Risk Factors for Progression from Latent TB
Infection (LTBI) to Active TB Disease (cont.)
Drugs
Immunosuppressive agents
• Steroids (not inhaled) (prednisone
>15 mg/day for 1 month or more)
• Cancer chemotherapy
• Cyclosporine
• Anti-Rheumatics*
• Etanercept (Enbrel)
• Infliximab (Remicade)
• Adalimumab (Humira TM)
• Anakinra (Kineret)
* Brassard, P. 2006. Antirheumatics Drugs and the Risk of Tuberculosis. CID 2006:43 (15
September).
 Case Example of Progression from
LTBI to Active TB
Case #1:
• 68 yo Chinese man with latent
TB untreated
• Hx of Hepatitis B with low level
activity
• Family history of colon cancer
• Developed adenocarcinoma
of the colon and was receiving
chemotherapy
• Developed hemoptysis and was thought
to have a lung metastasis
• Bronchoscopy aspirate grew TB
 Case Example of Progression from
LTBI to Active TB
Case #2
• 66 yo Vietnamese female
with latent TB (untreated),
diabetes inflammatory
arthritis, and depression/
PTSD
• Developed idiopathic thrombocytopenic purpura
and began to have bleeding
• Treated with systemic high dose steroids in the
hospital and developed milliary TB
• Died of complications
Source: from practice of PI, Carey Jackson, MD. Internal Medicine. International Clinic,
Harborview Medical Center, Seattle, Washington.
 Current Treatment for LTBI
Preferred Regimen
Drug Dose Frequency Duration

Isoniazid 300 mg Daily 9 months

(INH)

A minimum of 270 doses

must be administered
within 12 months
 Alternative Regimens for LTBI
Drug Dose Frequency Duration Other
Isoniazid 900 mg Twice weekly 9 months DOT
Isoniazid 300 mg Daily 6 months
Isoniazid 900 mg Twice weekly 6 months DOT
Rifampin 600 mg Daily 4 months
 No Longer Recommended
Regimen for LTBI

Rifampin plus pyrazinamide x 2

months

This regimen has been associated with

increased risk of severe hepatic injury
and death

Source: “Update: Adverse Event Data and Revised American Thoracic Society/CDC
Recommendations Against the Use of Rifampin and Pyrazinamide for Treatment of Latent
Tuberculosis Infection---United States, 2003”; MMWR, August 8, 2003 / 52(31);735-739.
 Monitoring of Patients on
Treatment for LTBI
• Baseline and monthly laboratory testing not
needed except for patients with
• HIV infection
• Pregnancy or within 3 months post-partum
• History of liver disease/heavy alcohol use
• Patient on chemotherapy
• Evaluate patients monthly for
• Adherence to treatment
• Symptoms of hepatitis (fatigue, weight loss,
nausea, vomiting, jaundice)
 Treatment of Patients
35 Years of Age and Older
• The CDC changed its guideline in 2000
and now encourages treatment of LTBI
in all age groups
• Use clinical judgment in treating older
patients

*CDC/ATS Guidelines: Morbidity and Mortality Weekly Report

(MMWR), “Targeted Tuberculin Testing and Treatment of Latent
Tuberculosis Infection.” June 9, 2000
 Hepatic Adverse Drug Effects of
Isoniazid (INH)
• Frequent (~5%): Liver Enzyme Elevations

• Infrequent (~0.1%): Hepatitis

Large Scale Study:

• 11,141 treated with INH from 1989-1995
• 11 had hepatitis, no deaths
• Overall rate was 1 per 1000 (or 0.1%)

(Nolan CM, Goldberg SV, Buskin SE. JAMA. 1999 Mar 17;281(11):1014-8.)
 Patients with Chronic Hepatitis B
But No Active Liver Disease
Yes, they can receive treatment for LTBI

• Baseline liver function tests and at 1 month

• If the tests are normal at 1 month, no further
testing is necessary unless symptoms
develop
• If the tests are elevated at 1 month, continue
monthly testing as long as levels are
abnormal
• If any one of the liver function tests exceeds
3-5 times the upper limit of normal at any
time, strongly consider stopping therapy
 Counseling a Patient with LTBI
Don’t Say:
• “You’ve been
“exposed” to TB
so you need to be
treated.”
Say Instead:
• “You have been exposed AND infected
with the TB bacteria. But don’t
worry…”
 Counseling a Patient with LTBI (cont.)

Good news:
• “You do not have
the disease and you
are not contagious
to anyone.”

Bad news:
• “However, it is sleeping in your body and if
you don’t treat it now it can wake up later
and make you very ill and contagious to
others.”
Counseling a Patient with LTBI (cont.)
Why get treated?
• “Treatment will prevent
future disease and
protect you and those
close to you.”
Warning
• “Taking medication for 9 months is a long
time but it takes that long to kill all the TB
germs.”
• “ TB germs are ‘TOUGH bugs’ … so take
your medicine correctly and completely.”
Summary
Meeting the Challenge of LTBI
For every patient
• Assess TB risk factors
• If risk is present, perform TST (PPD)
• If TST (PPD) is positive, rule out active TB
disease
• If active TB disease is ruled out, evaluate
as candidate for LTBI treatment
• If good candidate, initiate treatment for
LTBI
• If treatment is initiated, ensure completion
Meeting the Challenge of LTBI (cont.)
• Latent TB Infection should be treated as a condition
in itself which is a precursor to a serious and
potentially fatal disease
• Much the same way we treat hypertension as a
condition in itself because it significantly heightens
risk of heart disease, renal failure, and stroke or
place infants in car seats because of the significant
risk of injury without them, so should we approach
latent TB infection
• While the condition in itself is asymptomatic, the
risks assumed by ignoring it are substantial
 Physicians Caring for
At Risk Populations

• Always include TB in the DDX

• “THINK TB” and “TB RISK”
 Acknowledgements
The following individuals provided consultation and
review of this presentation:
• Masa Narita MD, TB Controller for Seattle-King
County Public Health
• John Bernardo, MD – Tuberculosis Control Officer,
Massachusetts Department of Public Health
• L. Masae Kawamura - MD, Director TB Control
Section, San Francisco Department of Public Health
• Stephen Weis, DO –Director of Tuberculosis and
Refugee Services for Tarrant County Health
Department, Texas
Without the help of the following
individuals, this project would not have
been possible:
• Lan Nguyen
• Ed Chow
• Jessie Wing
• Ximena Urrutia-Rojas
• Jeff Caballero
• Sharon Sharnprapai
 References
1. CDC Fact Sheet. “BCG Vaccine”. 2006. In Division of
TB Elimination Fact Sheets. Retrieved 11-22-06 from:
www.cdc.gov/nchstp/tb/pubs/tbfactsheets/250120.htm
2. DSHS/Public Health Service/CDC. 2006. “TB 101 for
Healthcare Providers.” PPT.
3. DTBE/CDC. 2005. “Targeted Tuberculin Testing
and Treatment of Latent Tuberculosis Infection”. In
Division of Tuberculosis Elimination. Retrieved 9-16-06
from: www.cdc.gov/nchstp/tb/pubs/slidesets/slides.htm
4. DTBE/CDC. 2005. “Tuberculosis in the United States:
National Surveillance System Highlights from 2004”. In
Division of Tuberculosis Elimination. Retrieved 9-16-06
from:
www.cdc.gov/nchstp/tb/pubs/slidesets/surv/surv2004/d
efault.htm
 References (cont.)
5. Hong, SW. 2001. “Preventing Nosocomial
Mycobacterium tuberculosis Transmission in
International Settings”. Emerging Infectious
Diseases. Vol. 7, No. 2, March-April 2001
6. Joos, TJ; Miller WC; Murdoch, DM. 2006.
“Tuberculin reactivity in bacille Calmette-Guerin
vaccinated populations: a compilation of
international data.” The International Journal of
Tuberculosis and Lung Disease, Volume 10,
Number 8, August 2006, pp. 883-891.
7. Kawamura, L. Masae. 2006. “Targeted Testing and
Treatment of Tuberculosis”. In Francis J. Curry
National Tuberculosis Center. Retrieved 9-16-06
from:
www.nationaltbcenter.edu/testing_ltbi/presentation
.cfm
 References (cont.)
8. World Health Organization. 2005. Global Health
Atlas. Accessed 10-2-06 from:
www.who.int/globalatlas/dataQuery/default.asp
9. Update: Adverse Event Data and Revised American
Thoracic Society/CDC Recommendations Against
the Use of Rifampin and Pyrazinamide for
Treatment of Latent Tuberculosis Infection---United
States, 2003 MMWR, August 8, 2003 / 52(31);735-
739. Assessed 2-2-07 from
http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5
231a4.htm