Download Targeted Testing and Treatment of Latent TB Infection

Targeted Testing and
Treatment of Latent TB
Infection
L. Masae Kawamura, MD
Director, TB Control Section, San Francisco
Department of Public Health
Francis J. Curry National Tuberculosis Center
University of California, San Francisco
Introduction
L. Masae Kawamura, MD
2
Diagnosing TB infection and
disease is a primary care
issue…..
3
↛
Preventing TB is a primary care
issue…
Know the TB status of your at risk patients
Ensure evaluation and treatment
4
Meeting the challenge of LTBI
• 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
Source: Carey Jackson, MD. Internal Medicine. International Clinic, Harborview Medical
Center, Seattle, Washington.
5
TB is global
6
TB is local: “Hot spots” in San Francisco
Tenderloin/SoMarket: Homeless hotspot
Chinatown: old and new immigrant hot spot
Click the
diagram
to expand
7
U.S.A.
“Tuberculosis is a social disease with medical implications”
–Sir William Osler
§
§
§
§
~11 million infected individuals *
Pool of infected individuals grows by 400,000
per year due to legal immigration
Over 50% of total cases are foreign-born
Over 80% of US-born cases occur among
racial and ethnic minorities
*Bennett et al. Am J Respir Crit Care Med 2008; 177:348-355
8
Making the connection:
Risk of infection and disease
progression
§
Risk of infection
-prior exposure to TB
-current/recent exposure to TB
-ongoing/chronic exposure
§
Risk of disease progression
-medical risk factors
9
Targeted testing = Strategic screening of those
at highest risk of TB infection and TB disease
Intersection of risks: TB infection, medical, and population risks
TB
RISK OF EXPOSURE
Foreign-born
Homeless, urban poor
Elderly US-born
MEDICAL RISKS
AIDS, diabetes, renal dialysis,
cancer, Immunosuppressive
drugs, organ transplant,
prior TB
Adapted slide: originally created by Jenny Flood, MD and staff, California Dept. of Public Health
10
Failing to meet the challenge: Case #1
Primary
33-year-old
yr old son:
son:+PPD
+PPD
asymptomatic
asymptomatic
Reactivation
28-year-old mom from Central
American, coughing for 3
months. Failed to follow up for
LTBI treatment refill 2.5 years
before
11
Groups at high risk for TB infection
Groups
• Close contacts of active TB cases
- Risk associated with disease burden and presence of
cough of the source case
• Residents & employees of congregate settings
- Correctional facilities (inmates and staff), nursing homes, longterm care facilities, renal dialysis units
• Healthcare workers
• Medically underserved/low-income groups
-
Homeless or marginally housed
Migrant workers
Street drug users
Children with parents who have risk factors
12
Testing by risk of infection
Who is considered
at risk?
•Foreign-born
patients from TB
endemic countries,
where prior TB
exposure is almost
certain
• Frequent or
prolonged travel to
these areas
What countries are
considered TB endemic?
• All of Asia except Japan
• All of Central and South
America
• All of Africa
• All of Eastern Europe
(Yes, that is practically
the whole world)
13
Refugee and immigrant screening
The immigration process does not take care of
Latent TB Infection (LTBI) for you!
In Country of Origin
• Adults evaluated for active TB ONLY
• NEW: Children <15 yrs and contacts screened with TST
in some countries but no LTBI treatment
In the US
• Those entering the US as suspects are
expected to follow up with the local health
dept but NOT mandated
• Those applying for an adjustment of status are
evaluated for LTBI but
treatment is NOT mandated
Not evaluated
• Visitors, students, temporary workers, undocumented
14
LTBI: Medical conditions that
increase risk of progression
Medical Conditions
• HIV +
• Prior TB (lung fibrosis consistent with
old TB)
15
LTBI: Medical conditions that
increase risk of progression (2)
Medical Conditions
• Children under 5
• Recent infection (contacts and
converters)
16
LTBI: Medical conditions that
increase risk of progression (3)
Medical Conditions
•
•
•
•
•
•
•
•
•
•
Diabetes mellitus
Cancer of the head and neck
Hematologic and reticuloendothelial diseases
Intestinal bypass or gastrectomy
Chronic malabsorption syndromes
Low body weight – malnutrition
Renal dialysis
Silicosis
Alcoholism
NEW - Tobacco users*
*Lin HH, Ezzati M, Murray M. PLoS Med. 2007;4(1):e20
Slama K, Chiang CY, Enarson DA, Hassmiller K, Fanning A, Gupta P, Ray C. Int J Tuberc Lung Dis.
2007;11(10):1049-61
Bates MN, Khalakdina A, Pai M, Chang L, Lessa F, Smith KR. Arch Intern Med. 2007;167(4):335-42
17
Quantification of TB risks
Risk factor
Estimated increased risk
(Compared control population with +TST)
Advanced HIV infection*
Anti-TNF agents**
Old, healed TB*
Diabetes mellitus***
Tobacco (ever smokers)****
Chronic renal failure*
Silicosis*
Gastrectomy *
Underweight*
* Horsburgh CR, N Eng J Med. 2004; 350(20) :2060-2067
**Gossec L, et al. Ann Rheum Dis. 2009; 68:1680-1685
***Jeon CY, Murray MB. PLoS Med. 2008; 5(7): e152. Review
****Lin HH, Ezzati M, Murray MB. PLoS Med. 2007;4(1):e20
9.9
7.9
5.2
3.1
2.69
2.4
1.7
1.4
1.6
18
LTBI: Immunosupressive agents that
increase risk of progression
Immunosuppressive agents
•
•
•
•
Steroids (not inhaled) (eg. >15 mg prednisone QD >3 wks)
Cancer chemotherapy
Cyclosporine and others drugs used in organ transplant
Anti-Rheumatics*
•Etanercept (Enbrel)
•Infliximab (Remicade)
•Adalimumab (Humira TM)
•Anakinra (Kineret)
*Brassard P, Kezouh A, Suissa S.
Antirheumatic drugs and the risk of tuberculosis. Clin Infect Dis.
2006 ;43(6):717-22.
19
How often do I screen my patient for TB?
§ Retesting: dependent on ongoing risk of TB
exposure
§ Frequency: dependent on degree of chronic TB
exposure (use local epidemiology)
– Annual testing*: HCWs, long-term care residents,
shelter or homeless CBO or substance recovery
program staff
– Q 6 month testing*: TB clinic frontline staff, ER
workers, pulmonologists performing bronchoscopy
– Periodic testing*: extended travel to high risk area
*Need to correlate with local epidemiologic data
20
Flowchart:
Evaluation to treatment of LTBI
Assess TB risks
no
yes
STOP
Tuberculin test + symptom review
Negative
Positive
Chest x-ray
Normal
Treatment
not indicated
Candidate for
Rx of latent TB
Abnormal
Evaluate for
active TB
21
Diagnostic tools for tuberculosis infection
TB Skin Test (TST)
Interferon Gamma Release
Assays (IGRAs)
22
In vivo and in vitro diagnostic
tests TST – in vivo
Presentation of
mycobacterial antigens
IFN-g
TNF-a
IL-8, etc.
IGRA – in vitro
IFN-g
Antigen
presenting
cell
Memory
T-cell
TNF-a
Andersen P, et al. Lancet. 2000;356:1099-104
IL-8, etc.
23
Mantoux tuberculin skin test –
Key points
• TST should not be performed on
someone with documented history of a
positive test
• TST should be read and interpreted by
a trained healthcare professional
• TB disease must be ruled out before
initiating treatment for LTBI
24
Reading the TST
• Measure reaction in 48 to 72
hours
• Measure induration,
not erythema (redness)
• Record reaction in millimeters,
not “negative” or “positive”
• Positive reactions can be
read for up to 7 days
• Negative reactions can be read
accurately for only 72 hours
25
Interpreting tuberculin skin test reactions
5 mm
or greater
• HIV positive persons
• Recent contacts of
persons with active
tuberculosis
• Fibrotic changes on
chest radiograph,
consistent with
tuberculosis
• Patients with organ
transplants and other
immunosuppressed
patients
10 mm
or greater
• Immigrants from highprevalence areas
• Injection drug users
• Residents and employees of
high-risk congregate settings
• Personnel in mycobacteriology
laboratories
• Persons with clinical conditions
that place them at high risk
• Children: <4 years of age; all
exposed to adults at high-risk
15 mm
or greater
No known
risk factors
Why did
you test
this
person?
Note: the CDC discourages testing of people at low risk for infection.
26
Tuberculin skin test interpretation:
Tuberculin skin test conversion
§ Signifies new infection
§ CDC definition:
>10 mm increase within 2-year period
§ Problems with interpretation:
conversions may actually represent
boosted reactions in some individuals
27
TB IGRAs
Interferon Gamma Release Assays
• Indirect test for M. tuberculosis infection using whole
blood
• Test for cell-mediated immune response (not antibody
response)
• Highly specific: Not affected by prior BCG vaccination
and most environmental mycobacteria
BCG X 2 in Chinese orphanage
TST positive , QFT-G negative
LTBI treatment avoided
28
3 FDA-approved highly specific
IGRAs
QuantiFERON®-TB Gold (Cellestis Ltd., Carnegie,
Australia)
• FDA cleared late 2004
• Uses ESAT-6 and CFP-10 as antigens
QuantiFERON®-TB In-Tube
• FDA approved in Dec. 2007
• Uses 3 antigens affixed to inside of tube
- Adds TB7.7 (RD4) antigen to ESAT-6 and
CFP-10
T-SpotTBÔ (Oxford Immunotec, Oxford, UK)
• FDA conditionally approved in Aug. 2008
• Use 2 antigens: ESAT-6 and CFP-10
29
IGRAs: Species specificity of
ESAT-6 and CFP-10
Tuberculosis
complex
M tuberculosis
M africanum
M bovis
BCG substrain
gothenburg
moreau
tice
tokyo
danish
glaxo
montreal
pasteur
Antigens
ESAT
CFP
+
+
+
+
+
+
-
-
Environmental
strains
M abcessus
M avium
M branderi
M celatum
M chelonae
M fortuitum
M gordonii
M intracellulare
M kansasii
M malmoense
M marinum
M oenavense
M scrofulaceum
M smegmatis
M szulgai
M terrae
M vaccae
M xenopi
Antigens
ESAT
CFP
+
+
+
-
+
+
+
-
30
Interferon Gamma Release Assays
vs. tuberculin skin test
IGRA
•
•
•
•
•
•
•
In vitro
Single antigens
No boosting
Not affected by BCG
Result with one patient
visit
Minimal inter-reader
variability
Results: one standard
for all
TST
•
•
•
•
•
•
•
In vivo
Multiple antigens
Boosting
BCG may affect results
Two patient visits
required for result
Significant inter-reader
variability
Results: different cut
points based on risk
31
Current IGRAs
QuantiFERON® (QFT):
Whole blood incubated with MTB
specific antigens -> free IFN-γ
release is measured (ELISA)
0.35
IU/
ml
POS
NEG
QFT-TB Gold In-Tube
TB Antigens
CONTROL
+ CONTROL
-
T-Spot®.TB:
T-cells incubated with MTB specific
antigens; IFN-γ releasing cells are
counted (ELISPOT-based
technology)
32
IGRAs: Interpreting results
Positive
QuantiFERON®
-TB Gold
QuantiFERON®
-TB In-Tube
≥0.35*
T Spot TB Ô
≥8
Negative
<0.35 *
Gray Zone
None
Indeterminate
Controls fail:
High Nil
Poor Mitogen
response
spots*
<8
5-7 spots* same as above
spots*
* (TB Ag - Nil) and assumes appropriate control responses
33
2009 IGRA CDC Guidelines
§
IGRAs can be used in all situations where the skin test is
currently being used
§
IGRAs preferred:
§ BCG vaccinated persons
§ Persons unlikely to return for a TST reading
§ Low risk individuals
§
Like the TST, clinical judgment required when interpreting
Θ
IGRA results in children <5yrs, immunocompromised persons,
and TB suspects
§
TST preferred in children <5yrs
§
When maximum sensitivity needed → acceptable to use both
TST and IGRA
§
Lab should report quantitative results
34
IGRAs: Managing & interpreting results
Contact investigation:* Repeat test as you would the
TST if initial QFT-G is negative, at 8-10 weeks
Managing indeterminate results:* Repeat QFT-G
or place TST or do nothing
Definition of a QFT conversion:* Defined as
change from negative to positive result
*Guidelines for using the QuantiFERON-TB Gold test for detecting Mycobacterium
tuberculosis infection, United States. MMWR. 2005 Dec 16;54(RR-15):49-55
Areas of ongoing research:
•
•
Quantitative definition for “IGRA converter”
Quantitative response to treatment
(promising but not yet clinically relevant)
35
IGRA performance compared to
TST
Performance
characteristics
TST
IFN-gamma assays
Est. sensitivity
75-91%
80-95%
Est. specificity
80-90%
95-100%
Correlates with exposure Often no
Yes
Results change with Rx
Usually yes
??
36
Comparing different IGRAs
QFT-GIT
Tspots (≥ 6 spots)
Characteristics
QFT-G
Est. sensitivity (%)
74-79 *
81
93
Est. specificity (%)
99
99
88
Correlates with exposure
yes
yes
yes
and risk factors
Immunocompromised
>indet
> indet
<indet
*Pai M, Zwerling A, Menzies D. Ann Intern Med. 2008;149(3):177-84
If not designated, data from compiled research up to 8/08
37
Can IGRAs replace the TB skin test?
Current data indicate….
• Contacts: yes
• Screening BCG vaccinated individuals:
yes, preferred!
• Screening low risk individuals: yes
• Screening the homeless and other poorly
adherent populations: yes, preferred!
• Serial testing: yes, with caveat
38
What to expect when you switch to
IGRAs
• Significant decrease in the positive rate
and further work-up
• Unnecessary testing and retesting!
• Serial testing (excluding contact
investigation and active cases)
Ø Unexpected positives that require further investigation
(e.g. repeat testing, review of quantitative results)
Ø Beware of “wobblers”, results that hover around the
baseline
39
TST and IGRA test interpretation:
False-negative or indeterminate results
Host factors affecting TST and likely IGRAs
§ HIV- low CD4, no ARVs
§ Recent TB infection (<10 weeks)
§ Infections (viral, fungal, bacterial)
§ Other illness affecting lymphoid organs
§ Live virus vaccination
§ Immunosuppressive drugs
§ Overwhelming TB
§ Age (newborn, elderly)
40
TST and IGRA test interpretation:
False-negative or indeterminate results
(2)
TST technical factors
§ The tuberculin used (i.e., improper storage,
contamination)
§ Improper method of administration, reading
and/or recording of results
IGRA technical factors
§
§
§
§
Insufficient blood volume
Insufficient mixing
Endotoxin in lab tubes
Lab errors
41
TST: False-positive results
§
Cross-reactions and boosted reactions from atypical
mycobacterial infections and BCG
§
History of BCG vaccination, especially if recent (<1 yr)
or multiple
§
Misinterpretation of immediate hypersensitivity to
tuberculin
§
Switching tuberculin products (tubersol with applisol)
IGRA: False-positive results
§
Cross-reactions from M. kansasii, M. szulgai, and M.
marinum
§
Product failure: Endotoxin traces in tubes
§
Lab errors
42
TST and IGRAs are tools,
not panaceas
Screening individuals who are likely to have
false-negative TB test results
(young infants, HIV+s, immunosuppressed)
§
Chest x-ray – look for evidence of TB infection (e.g.,
hilar calcification, upper lobe fibrosis, calcified
granuloma)
§
Symptom review
§
Assess TB risk factors
§
Decision to provide LTBI treatment in the absence of
a positive TB test should be based on risk of true
infection, chest x-ray findings, individual and public
health implications
43
Does this remicade candidate have LTBI?
TST = negative
QFT = negative
asymptomatic
44
Treatment for
Latent Tuberculosis
Infection (LTBI)
Current guidelines for TB prevention
§ DECISION TO TEST IS DECISION TO
TREAT!
§ No 35-year-old cut-off
§ 9 months of INH preferred over 6 months
§ Baseline laboratory monitoring not
routinely indicated
46
Failing to meet the LTBI challenge
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 miliary TB
• Died of complications
Source:
Carey Jackson, MD. Internal Medicine. International Clinic, Harborview Medical
Center, Seattle, Washington
47
Who should be treated for
Latent TB Infection (LTBI)?
Note: Careful assessment to rule out the possibility of
active TB disease is always necessary before treatment
for LTBI is started.
• 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
48
Clinical trials of isoniazid treatment
of LTBI
Efficacy of INH based on duration of
treatment and compliance
Duration
of INH
5-year risk
reduction
Compliance
Reduction
if compliant
3 mos
21%
87%
31%
6 mos
65%
78%
69%
12 mos
75%
68%
93%
Bull World Health Organ. 1982;60(4):555-64
49
INH for LTBI
How long is enough?
Calculated curve
Calculated values
Observed values
5
4
Cases
per 100
• Lower TB rates
among those who took
0-9 mo
3
• No extra increase
among those who took
>9 mo
2
1
0
0
6
12
18
24
Months of Treatment
Comstock GW. Int J Tuberc Lung Dis. 1999 Oct;3(10):847-50
50
Current treatment for LTBI
Drug
Isoniazid
(INH)
Dose
Max:
300 mg
Children/
adolescents
10-15mg/kg
300 mg if
over 20 kg
Frequency
Daily
Duration
9 months
Preferred for everyone
6 months is “acceptable”
for:
• Immunocompetent
adults without scarring
on chest radiograph
• Programs unable to
deliver 9 months
A minimum of 270 doses must be administered within 12 months
51
Alternative regimens for LTBI
Drug
Dose
Frequency
Duration
Requirements
Isoniazid
900 mg
Adults-15 mg/kg
Children 20-40mg/kg
Twice weekly
9 months
DOT
Isoniazid
900 mg
Twice weekly
6 months
DOT
Rifampin
with or
without INH*
600 mg
Adults-10 mg/kg
Children 10-20
mg/kg
Daily
4 months
Immunocompetent
Rifampin
600 mg
Daily
6 months
Children or
immunocompromised
*Combined use with rifampin/INH x 4 months is the preferred regimen by some TB
programs for patients with abnormal CXRs consistent with old TB
52
Severe liver injury:
2-month Rifampin-Pyrazinamide LTBI regimen
53
Hepatic adverse drug effects of
isoniazid (INH)
• Frequent (10-20%): Asymptomatic liver enzyme
elevations
- Levels usually return to normal after completion of
treatment
MMWR June 9, 2000; 49(No. RR-6): 39
• 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
0.1%!
Nolan CM, Goldberg SV, Buskin SE. JAMA. 1999;281(11):1014-8.
54
Monitoring of patients on LTBI
treatment
Baseline and monthly laboratory testing not
needed except for patients with:
•
•
•
•
•
HIV infection
Pregnancy or postpartum (1st 3 months after delivery)
History of liver disease/heavy alcohol use
Chemotherapy
Taking other medication that is potentially liver toxic
Monthly monitoring:
• Adherence with therapy
• Symptoms of adverse drug reactions: “Nausea,
anorexia, fatigue, yellow skin or eyes, dark urine?
Allergic reactions?”
• Plans to continue treatment
55
INH and peripheral neuropathy:
Who needs Vitamin B6 (pyridoxine)
• Adults:
•
•
•
•
•
•
Diabetes
Uremia
Alcoholism
HIV
Malnutrition
Pregnant or
breastfeeding
• Seizure disorder
• Children:
• Exclusively breastfed
• Milk and meat deficient
diet
• Symptomatic HIV
• Anyone with symptoms
of peripheral
neuropathy
56
What about drug resistant LTBI,
refusal of treatment, or intolerance?
Contacts of INH-resistant TB: 4-6 months of rifampin
(longer for children and immunocompromised)
Contacts of MDR-TB: Consult an expert! Regimen
based on index cases susceptibility results
If treatment is not available, refused or not tolerated
Thoroughly educate patient:
• TB signs and symptoms and how, when, and where to go if
they develop
• Current and future risk of TB if medical risks develop
• Close clinical monitoring for 2 years is recommended for
contacts and converters
57
Treatment of LTBI in special situations
• Use rifabutin when rifampin is contraindicated
or compromises patient care because of drugdrug interactions
(eg. HIV on protease inhibitors, methadone
users, transplant patients on cyclosporin, etc)
• For persons intolerant of INH, use 4 months of
rifampin (6 months for children and
immunocompromised)
• Pregnancy is not a contraindication to LTBI
treatment with INH or rifampin
58
TB window prophylaxis
Window: time between TB infection and fully developed
cellular immunity (TB test is falsely negative)
Who needs window prophylaxis?
• High-risk TB contacts (young children and
immunocompromised/HIV+) with initial ΘTB test and
significant TB exposure
When can window treatment be discontinued?
• HIV-negative children: 8-10 weeks after contact broken to
untreated case and repeat TB test negative
• Immunocompromised/HIV: Unclear; repeat testing may not
be helpful because of false negative results
59
Retreatment of Latent TB Infection
• Re-infection can occur
• Serious issue for immunocompromised
individuals
• Definitely recommended for persons with
chronic immune suppression (e.g. HIV
infection, drug induced, etc.)
• Retreatment should be based on the severity
of exposure, health status, and age of patient
60
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…”
61
Counseling a patient with LTBI (2)
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.”
62
Counseling a Patient with LTBI (3)
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.”
63
Counseling a patient with LTBI (4)
“INH treatment is safe but all medications, even
over-the-counter drugs, can have side effects”
“Be safe “
§ “Avoid alcohol and acetominophen-containing
products”
§ “Stop treatment and seek care immediately if
anorexia, nausea or a diffuse rash develops
(symptoms are reversible!)”
Prior to leaving the office:
Ensure that your patient understands what to
monitor for and what to do if side effects occur
64
Meeting the challenge
of LTBI
For every patient…
§ Assess TB risk factors
§ If risk is present, perform a TB test
§ If TB test 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 monthly
monitoring and completion
65
Summary
§ TB will remain a primary care issue until better
§
control is established outside of the U.S.
Targeted testing and treatment of LTBI is a key
strategy to eliminate TB in the U.S.
§ The specificity of the new blood test for TB offers a
significant advance in our ability to accurately
diagnose LTBI
§ Final pearl: Absence of TST reaction or negative
IGRA does not exclude disease
66
Resources for TB medical
consultation
§ Local TB program
§ Your Regional Training and Medical
Consultation Center
§ For the Western Region:
Francis J. Curry National TB Center
TB Warmline (415) 502-4700 or (877) 390-6682
67