Transcript View - Department of Medicine

TB (Infection) or not TB?
Who should we screen and treat?
Primary Care Conference
August 31, 2005
K. Mae Hla, M.D., M.H.S.
Learning Objectives
• Review guidelines for testing and treatment of
LTBI using case examples
• Evaluate the rationale for targeted TST
• Discuss factors influencing TST results and
interpretations
• Assess the evidence of current treatment
recommendations for LTBI
• Updates on new tests and treatment
recommendations
Case #1
43 year old female physician who underwent
routine annual testing at UWHC:
PPD was 10 mm. Previous year’s PPD was 0 mm.
No known history of exposure but works with high
risk patients
No history of BCG
No history of cough, low grade fever, night sweats
or weight loss
What would you do with this patient?
 Consider the test positive

 Consider the test negative
 Consider a Chest X-ray

 Disregard test results if chest x-ray is
negative since she’s older than 35 years
Case #2
• 32 year old man arrived from India 2
years ago
• TB tested during pre-employment exam
• 23 mm induration
• H/o BCG in childhood
• No symptoms of active TB
What would you do with this patient?
 Positive TST is due to BCG
 Old positive PPD
 No need to consider for INH treatment
since due to either of the above
 Disregard BCG and recommend INH

What would you do now?
 Positive TB test is due to BCG
 Old positive PPD
 No need to consider for INH treatment
since due to either of the above
 Disregard BCG and recommend INH –
end of story
 Test further

Case # 3
• 28 y.o. woman with SLE, ESRD, S/P
kidney transplant on immunosuppressive
therapy
• PPD placed during hospitalization with
acute lung infiltrate was 6 mm
• Is this PPD positive or negative?
Case # 4
36 y.o. diabetic male, PPD 13 mm, recently in
prison, known exposure to INH resistant TB, no
known prior PPDs, no acute symptoms, CXRnegative.
 Is this person at risk of developing TB?
 What are his risk factors?
 What would you recommend he be treated
with?
Case # 5
• 30 y.o. male seen in clinic for
naturalization physical
• Country of origin: England
• Hx of BCG at age 13
• PPD: 11 mm induration, never been
tested in past
• CXR normal
Case # 5
 Consider his PPD positive
 Consider his PPD negative

 Consider his pos PPD to be due to BCG
and not recommend INH
 Disregard BCG and consider 9 months
of INH
Case # 6
35 y.o. HIV positive male, PPD negative
for past 2 yrs, tested 6 mm now; no
known exposure history, no acute
symptoms, CXR negative for active or old
TB.
Is his PPD negative or positive?
How likely is he to develop active TB?
General Principles in Screening
• The disease is common (prior probability)
• The test is both accurate and reliable
• Treating the disease at an early phase
will lead to improved outcome compared
to that of treating it only when it manifests
itself as active disease
• Treatment is feasible and not harmful
Reported TB Cases
United States, 1953 - 1998
100,000
Cases
(Log Scale)
70,000
*
50,000
*
30,000
20,000
10,000
53
60
70
80
Year
*Change in case definition
90
98
Recent Cases per 100,000 population
Reported Cases of TB by Country of Birth United States, 1986-1998
40
35
30
25
Foreign-born
20
15
10
All Cases
5
0
U.S.-born
86 87 88 89 90 91 92 93 94 95 96 97 98
Year
Areas of Concern
• TB cases continue to be reported in every state
• Drug-resistant cases reported in almost every
state
• Estimated 10-15 million persons in U.S.
infected with M. tuberculosis
– Without intervention, about 10% will develop TB
disease at some point in life
Targeted TB Testing
• Identify persons with LTBI who would benefit
by treatment of LTBI
• Find persons with TB disease who would
benefit from treatment
• Groups that are not high risk for TB should
not be tested routinely
• All testing activities should be accompanied
by plan for follow-up care
Who should we screen?
High Risk Groups for LTBI
Groups that should be tested for LTBI
regardless of age:
• Persons at higher risk for exposure to or
infection with TB
• Persons at higher risk for TB once
infected
Persons at Higher Risk for Exposure
to or Infection with TB
• Close contacts of person known or suspected to
have TB
• Foreign-born persons from areas where TB is
common
• Residents and employees of high-risk congregate
settings
• Health care workers (HCWs) who serve high-risk
clients
Persons at Higher Risk for Exposure
to or Infection with TB (cont.)
• Medically underserved, low-income
populations
• High-risk racial or ethnic minority
populations
• Children exposed to adults in high-risk
categories
• Persons who inject illicit drugs
TB Case Rates* according to the length of Residence in the U.S.
for Foreign-Born Persons, 1986-1993
World Region of Origin
TB
Case
Rates
Rates US
Residence
<5 yr
Rates US
Residence
>5 yr
United States
8.1
--
--
Established market
economies
4.7
6.0
4.7
Former socialist economies of
Europe
11.2
14.9
13.7
India
55.6
108.2
35.8
Latin America
33.7
68.4
30.8
Mainland China
40.6
89.7
30.7
Middle East
22.1
47.3
15.2
Other Asian countries
81.8
207.5
41.1
Sub-Saharan Africa
58.4
108.9
26.4
Total foreign-born
30.6
66.3
21.7
* Rates are per 100,000 person-years, adjusted for age.
Persons at Higher Risk of Developing
TB Disease once Infected
• HIV infected
• Recently infected (converted within 2 yr)
• Persons with certain medical conditions
• Persons who inject illicit drugs
• History of inadequately treated TB
Incidence of active TB in persons with a
positive PPD by selected risk factors
Risk Factor
TB Cases/1,000 person-years
Recent TB infection
Infection <1 yr past
Infection 1-7 yr past
Human immunodeficiency virus
(HIV) infection
Injection drug use
HIV seropositive
HIV seronegative or unknown
12.9
1.6
35.0-162
76.0
10.0
Relative risk* for developing active TB
by selected clinical conditions
Clinical Condition
Silicosis
Diabetes mellitus
Chronic renal failure/hemodialysis
Relative Risk
30
2.0-4.1
10.0-25.3
*Relative to control population; independent of TB test status
Relative risk* for developing active TB
by selected clinical conditions
Clinical Condition
Gastrectomy
Jejunoileal bypass
Solid organ transplantation
Renal
Cardiac
Carcinoma of head or neck
Relative Risk
2-5
27-63
37
20-74
16
*Relative to control population; independent of TB test status
Are HCWs at high risk of LTBI?
• Prevalence of TB in the community, facility,
institution
• Contact with high risk patients (HIV positive
pts., injection drug users, homeless pts.)
• Increased risk in certain occupational
groups (respiratory therapists)
• Individual risk factors (diverse workforce)
Test accuracy and reliability
•
•
•
•
Prior probability of disease
Method of administration
Timing of reading
Interpretation
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 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
Classifying the Tuberculin Reaction
>5 mm is classified as positive in
• HIV-positive persons
• Recent contacts of TB case
• Persons with fibrotic changes on chest
radiograph consistent with old healed TB
• Patients with organ transplants and other
immunosuppressed patients
>10 mm is classified as positive in
• Recent arrivals from high-prevalence countries
• Injection drug users
• Residents and employees of high-risk congregate
settings (hospitals, prison, NH)
• Mycobacteriology laboratory personnel
• Persons with clinical conditions that place them at
high risk
• Children <4 years of age, or children and
adolescents exposed to high-risk adults
Classifying the Tuberculin Reaction
(cont.)
>15 mm is classified as positive in
• Persons with no known risk factors for TB
• HCWs otherwise at low risk for TB disease
and who received baseline testing at start of
employment
Factors that May Affect the Skin Test Reaction
Type of Reaction
Possible Cause
False-positive
Nontuberculous mycobacteria
BCG vaccination
False-negative
Anergy
Recent TB infection
Very young age (<6 months old)
Live-virus vaccination
Overwhelming TB disease
Errors in application & interpretation
Boosting
• Some people with LTBI may have negative
skin test reaction when tested years after
infection
• Initial skin test may stimulate (boost) ability
to react to tuberculin
• Positive reactions to subsequent tests may
be misinterpreted as a new infection
Two-Step Testing
Use two-step testing for initial skin testing of adults
who will be retested periodically
• If first test positive, consider the person
infected
• If first test negative, give second test 1-3
weeks later
• If second test positive, consider person
infected
• If second test negative, consider person
uninfected
BCG Vaccination and TST
• Tuberculin skin testing is not contraindicated
in BCG-vaccinated persons
• Treatment for LTBI should be considered for
any BCG- vaccinated person whose skin
test reaction is >10 mm, if any of these
circumstances are present:
- Was contact of person with infectious TB
- Was born or has resided in a country with high
TB prevalence
- Is continually exposed to populations where TB
prevalence is high
BCG Effect vs. LTBI
• Case # 2
– Likely LTBI given country of origin and
recent arrival
• Case # 5
– Likely BCG effect
New Test for Detecting LTBI
• QuantiFERON (QFT)– FDA approved in 2001
– in vitro cytokine assay
– quantification of interferon-gamma released
from sensitized lymphocytes in whole blood
incubated overnight with PPD from M.TB
– will not detect M. Bovis strains used in BCG
– QFT results: % Tuberculin response: cut point
of 15% for people with identified risk, 30% for
people with no identified risk for infection
QuantiFERON-TB Test
• Advantages
– Less subjective than interpretation of the TST
– Requires single patient visit
– Helps in detecting LTBI in patients who have
had BCG
– Does not boost anamnestic immune responses
– Maybe more efficient and cost effective than
TSTs in screening HCWs for infection with
M.TB
QuantiFERON-TB Test (QFT)
• Disadvantages
– limited laboratory and clinical experience
– process within 12 hours after blood collection
– ability of QFT in predicting progression to TB
disease not evaluated
– confirmation of a positive QFT with TST
recommended especially if probability of LTBI
low
– active TB still needs to be ruled out
Who Should We Treat?
• Persons who are at very high risk of
developing TB once infected should be
given treatment regardless of age
Patients who should be treated if their
TST result is >5, regardless of age
• HIV-positive persons
• Recent contacts of TB case
• Persons with fibrotic changes on chest
radiograph consistent with old healed TB
• Patients with organ transplants and other
immunosuppressed patients
Consider treatment if TST >10 mm
• Recent immigrants from high-prevalence countries
• Injection drug users
• Residents and employees of high-risk congregate
settings
• Mycobacteriology laboratory personnel
• Persons with clinical conditions that place them at
high risk
• Persons living in areas with high incidence of TB
• Children <5 years of age, or children and
adolescents exposed to high-risk adults
Efficacy of INH in treating LTBI
• Many RCTs of isoniazid in 1950-1960
• Industrialized and developing countries
• involving >100,000 participants at risk for
TB
– Children with primary TB, contacts of TB
cases, positive PPDs, institutionalized
pts,and persons with inactive TB
Efficacy of Treatment with 12
months of INH
• Decrease in TB among all participants
varied from 25 to 92%
• In analysis restricted to compliant
persons, protective efficacy was
approximately 90%
Efficacy of various durations of isoniazid
preventive therapy for persons with fibrotic
lesions, by length of treatment (IUAT Trial, 1969-77)
5 yr TB incidence* (% reduction)
Group
All participants
(n = 27,830)
Adherent participants
(n = 21,635)
Fibrotic lesions <2cm2
(n = 18,663)
Fibrotic lesions >2cm2
(n = 8,428)
Placebo
12 wk
24 wk
52 wk
11.3 (21)
5.0 (65)
3.6 (75)
15
9.4 (31)
4.7 (69)
1.1 (93)
11.6
9.2 (20)
4.0 (66)
4.2 (64)
21.3
16.2 (24)
7.0 (67)
2.4 (89)
14.3
Strength of Treatment
Recommendations
Rating (A-E)
A. Preferred; should generally be offered
B. Alternative; acceptable to offer
C. Offer when preferred or alternative
regimens cannot be given
D. Should generally not be offered
E. Should never be offered
Quality of Evidence Supporting
Recommendation
Evidence (I-III)
I.
At least one randomized trial with clinical
endpoints
II. Clinical trials that either are not randomized
or were conducted in other populations
III. Expert opinion
Rating and Evidence
Drugs
Duration
(mo)
Interval
HIV-
HIV+
Isoniazid
9
Daily
Twice weekly
A (II)
B (II)
A (II)
B (II)
Isoniazid
6
Daily
Twice weekly
B (I)
B (II)
C (I)
C (I)
Rifampin
4
Daily
B (II)
B (III)
Rifampinpyrazinamide
Generally should not be offered for treating
LTBI in both HIV positive and negative (D/II)*
* As revised in the ATS/CDC update, MMWR 2003 & JAMA 2005
Treatment of LTBI with Isoniazid (INH)
• 9-month regimen considered optimal
• Children, HIV infected persons and those
with CXR evidence of prior TB (fibrotic
lesions) should receive 9 months of therapy
• Can be given twice-weekly only if directly
observed
• 6-month regimen is an acceptable alternative
Treatment of LTBI with Rifampin
• 4-month regimen considered acceptable as
alternative
• Can be given twice-weekly only if directly
observed
• Persons with HIV infection, and with CD4 cell
counts <100 should not be treated with
intermittent regimens, and should receive
DOT, if feasible
Treatment of LTBI with Rifampin
and Pyrazinamide (RZ)
• Reports of severe liver injury and death
• CDC & ATS have revised previous
recommendations
• RZ should generally not be offered for treatment
of LTBI for both HIV positive and negative
• Use only after consultation with infectious disease,
if potential benefits outweigh risk and patient has
no contraindications
Contacts of INH-Resistant TB
• Treatment with Rifampin, 4 month
continuous regimen
• HIV infected: should not administer protease
inhibitors or delavirdine concurrently with
rifampin. Rifabutin could be used instead
with appropriate dose adjustments
MDR TB Cases, 1993 - 1998
None
> 1 case
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
Pregnancy and Breast-feeding
• INH daily or twice weekly
• Pyridoxine supplementation
• Breast-feeding not contraindicated
Adverse Effects
• INH
– rash, elevated LFTs, hepatitis, peripheral
neuropathy, mild CNS effects, drug interactions
• Rifampin
– rash, hepatitis, fever, thrombocytopenia, drug
interactions with PIs or NNRTIs
• Pyrazinamide
– GI upset, hepatitis, rash, arthralgias, gout (rare)
Monitoring Patients
Before treatment for LTBI is started, clinicians
should
• R/O possibility of TB disease with CXR
• Determine history of Rx for LTBI or disease
• Determine contraindications to treatment:
medications and medical history
• Recommend HIV testing if risk factors are
present
• Use State and Local Health Departments
Monitoring Patients (cont.)
• Baseline laboratory testing not routinely
indicated
• Baseline hepatic measurements indicated
for
• Patients whose initial evaluation suggests a
liver disorder or regular use of alcohol
• Patients with HIV infection
• Pregnant women and those in immediate
postpartum period
• Patients with history of chronic liver disorder
Monitoring Patients (cont.)
At least monthly (public health nurse), evaluate for
• Adherence to prescribed regimen is major
determinant of outcome of treatment
• Signs and symptoms of active TB disease
• Signs and symptoms of hepatitis
• Prompt evaluation of side effects and changes in
treatment crucial
Guidelines!!!
Sigourney Weaver:
Bill Murray:
Sigourney Weaver:
Bill Murray:
“I am Zule. Do you want this body?”
“Is this a trick question?”
“Take me now!”
“I make it a rule never to get involved
with possessed people”
[Sigourney Weaver kisses Bill Murray fiercely]
Bill Murray:
“Actually, it’s more of a guideline
than a rule”
References
• Am J Respir Crit Care Med 2000;161:S221-247
• Targeted Tuberculin Testing and Treatment of Latent TB
Infection. MMWR Weekly Report. DHHS. CDC. 2000;49:151
• Guidelines for Using the QuantiFERON TB test for
diagnosing Latent TB infection. MMWR 2003;52;15-18
• Update: Adverse Event Data and Revised ATS/CDC
Recommendations against use of Rifampin and
Pyrazinamide for Treatment of Latent TB Infection-United
States, 2003 MMWR 2003:52(31) 735-739
• Update on the Treatment of Tuberculosis and Latent
Tuberculosis infection. Blumberg H. et al JAMA 2005;293
(22) 2776-2784