The Challenges and Pitfalls
in Diagnosing or
Misdiagnosing
Tuberculosis: Are the Days
of the TB Skin Test Over?
Theodore F. Them, MD, MS, PhD, MPH, FACOEM
Chief, Section of Occupational
& Environmental Medicine
Guthrie Clinic, Ltd
Sayre, Pennsylvania
Roy F. Chemaly, MD, MPH, FIDSA, FACP
Professor of Medicine
Director, Infection Control Section
Director, Antimicrobial Stewardship Program
University of Texas – MD Anderson Cancer Center
Houston, Texas
Objectives
By the end of this presentation, the attendee
should be able to:
• Explain the consequences of misdiagnosing active
or latent TB.
• Describe the currently available tests and their
place in TB diagnosis.
• Recognize the limitations of different TB screening
strategies.
• Discuss how certain patient populations might
benefit from the use of an IGRA in place of the
TST for TB screening.
2
Tuberculosis Testing
Currently 2 methods are available for the
detection of M. tuberculosis infection in the US:
• Mantoux tuberculin skin test (TST)
• Interferon-gamma release assays (IGRAs)
• CDC guidelines1 allow the use of IGRAs or the
TST for screening healthcare workers
3
Issues Affecting TST Utility1
• False-Positive Results
– Foreign-born persons (BCG vaccinated) account for 64.6% of all TB
cases in US
– Exposure to other mycobacteria
– Unknown cause
• False-Negative Results
– Immunosuppression
• AIDS
• Cancer
• Anti-TNF
• Transplant
• Noncompliance
– Failure to return for TST interpretation
1. Centers for Disease Control and Prevention. MMWR. 2014.
4
Tuberculin Skin Test (TST) vs
Interferon-Gamma Release Assays (IGRAs)
TST
•2 visits required (minimum)
•Method: injection into skin
•Results affected by BCG
•Results in 48−72 hours
•Subjective results
•Can cause booster
phenomenon
IGRAs
• 1 visit required
• Method: blood draw
• Results not affected by BCG
• Next-day results
• Objective results
• Does not cause booster
phenomenon
5
Commercially Available IGRAs
QuantiFERON®-TB Gold1
The T-SPOT®.TB Test2
•
ELISA technology
•
ELISPOT technology
•
Measures IFN-γ release
•
Enumerates effector T cells
•
“One and done”
•
“One and done”
•
PI sensitivity: 88.2%
•
PI sensitivity: 95.6%
•
PI specificity: 99.1%
•
PI specificity: 97.1%
•
“Real-world” specificity: 98%−98.9%3,4
•
“Real-world” specificity: 98.9%−99.1%5,6
•
3 specialized tubes
•
1 standard tube
•
Provides qualitative results
•
•
Sample stability: 16 hours
Provides quantitative and qualitative
results
•
No FDA-approved borderline category
•
FDA-approved borderline category
•
Can be run in hospital lab
•
Sample stability: 32 hours
•
Available nationally through reference
laboratories (eg, Quest)
•
Can be run in hospital lab
•
Available nationally through Oxford
Diagnostic Laboratories®
1. QuantiFERON-TB Gold Package Insert. Cellestis, Inc. Valencia, CA. Doc. No.
US05990301L, March 2013.
2. T-SPOT.TB Package Insert. Marlborough, MA: Oxford Immunotec; 2010.
3. Schablon A, et al. BMC Infect Dis. 2011;(11):245-252.
4. Pai M, et al. Ann Intern Med. 2008;149(3):177-184.
5. Wang SH, et al. Scand J Infect Dis. 2010;42(11-12):845-850.
6. Bienek DR, et al. Int J Tuberc Lung Dis. 2009;13(11):1416-1421.
T-SPOT and Oxford Diagnostic Laboratories are registered trademarks of
Oxford Immunotec, Ltd.
6
QuantiFERON is a registered trademark of Cellestis, Inc.
QuantiFERON®TB Gold
QuantiFERON is a registered trademark of Cellestis, Inc.
Blood Collection for QFT® Testing1
• Collection tubes include:
– Nil control (grey cap)
– TB antigen (red cap)
– Mitogen control (purple cap)
• Tubes require shaking (10 times each) to mix blood with
antigens coated on the inside of the tubes, but too much
shaking could cause aberrant results.
• Blood in collection tubes must be incubated for 16−24
hours at 37°C within 16 hours of collection.2,3
1. QuantiFERON-TB Gold Package Insert. Cellestis, Inc. Valencia, CA. Doc. No. US05990301L, March 2013.
2. Herrera V, et al. J Clin Microbiol. 2010;48(8):2672-2676.
3. Doberne D, et al. J Clin Microbiol. 2011;49(8):3061-3064.
QFT is a registered trademark of Cellestis, Inc.
8
The T-SPOT®. TB
Test
T-SPOT is a registered trademark of Oxford Immunotec, Ltd.
Blood Collection for T-SPOT®.TB1
• Standard phlebotomy techniques
• Uses a standard lithium or sodium heparin tube
• Less sensitive to preanalytical variables than QFT
–
–
–
–
–
–
Time from collection to analysis
No specialized tubes needed
No specific order of draw
No shaking of tubes
No incubation required
Specimens maintained at room temperature
for up to 32 hours
1. T-SPOT.TB Package Insert. Marlborough, MA: Oxford Immunotec; 2013.
T-SPOT is a registered trademark of Oxford Immunotec, Ltd.
10
Consideration of IGRA Logistics
Phlebotomy Steps
QuantiFERON®-TB Gold1
T-SPOT®.TB Test2
Collection tubes
3 specialized tubes
Standard tube
Tubes drawn in specific
order
Required; Nil, TB antigen, mitogen
N/A
Blood volume
1 mL (0.8−1.2 mL); under- or
Fill 6-mL tube
overfilling outside the 0.8- to 1.2-mL
range may lead to erroneous results
Shake collection tubes
Required; shake the tubes up and
down 10 times
Not required
Purge tube with butterfly
Required when a butterfly needle is
used
Not required
Sample stability
Specimens must be incubated as
Up to 32 hours
soon as possible but within 16 hours
1. QuantiFERON-TB Gold Package Insert. Cellestis, Inc. Valencia, CA. Doc. No. US05990301L, March 2013.
2. T-SPOT.TB Package Insert. Marlborough, MA: Oxford Immunotec; 2010.
T-SPOT is a registered trademark of Oxford Immunotec, Ltd. QuantiFERON is a registered trademark of Cellestis, Inc.
11
Targeted Testing
High-Risk
Populations
for TB
Targeted TB Testing
• Close contacts of persons known or suspected to have TB
disease
• Foreign-born from areas of high incidence TB disease (Latin
America, Africa, Asia, Eastern Europe, and Russia)
• Persons who travel to areas with a high prevalence of TB
disease
• Residents and employees of high-risk congregate settings
(correctional facilities, long-term care facilities, homeless shelters)
• Healthcare workers who serve clients or patients who are at
increased risk for TB disease
• Specific populations defined locally as having increased
incidence of latent M-TB (possibly including medically underserved, low-income
populations, or persons who abuse drugs or alcohol)
13
TB in the US: 2012 Data1
• 9588 new TB cases in US
(case rate of 3.0)
• TB rate among foreignborn (FB) was 13x higher
than US-born
• 4 states account for onehalf of all reported cases:
–
–
–
–
California
Texas
New York
Florida
1. Centers for Disease Control and Prevention. www.cdc.gov/mmwr/preview/mmwrhtml/mm6211a2.htm?s_cid=mm6211a2_e.
14
TB in the US: 2013 Data¹
TB population statistics:
• 54.2% of 6172 FB persons with TB originated
from Mexico, Philippines, India, Vietnam, and
China
• 6.8% reported as HIV+
• 5.7% reported being homeless in past year
• 3.9% confined to correctional facility at time of
diagnosis
• Every 100 contacts not treated will lead to 3 new
cases of TB in 1−2 years.1
1. Centers for Disease Control and Prevention. Trends in Tuberculosis – United States, 2013. MMWR. 2014.
Screening TB Contacts: Acceptance of Diagnosis1
• The results of this study: Grinsdale J, et al. Int J
Tuberc Lung Dis. 2011;15(12):1614–1619.
• Contacts tested with QFT were more likely to
complete evaluation (64% vs 56%).
• Infected contacts started (89% vs 72%) and
completed (70% vs 53%) LTBI treatment more often
in group tested with QFT.
• Positive QFT results, but not positive TST results,
correlated with the intensity, proximity, and duration
of TB exposure.
1.
.
16
Clinical
Implications with
Suboptimal
Testing:
Employee Health
Case
Case Study
• 41-year-old male Indian nurse who started work at a Cancer Center
September 2012. Was referred with a diagnosis of pneumonia.
• PMHx: February 2012, he started having a cough with off and on
sputum production. He was diagnosed with bronchitis and received
2 courses of azithromycin with no improvement.
• Referred to a pulmonologist had chest x-ray done in March 2012
and a PPD skin test, which were both negative ; received
cefuroxime and later on Levaquin with no improvement.
• At that point, he was diagnosed with possible asthma, and was
started on inhaled steroids.
• His cough got a little bit better initially and started to get worse
again.
Case Study
• December 2012: Worsening cough and
hemoptysis now.
• Saw another pulmonologist in February 2013
for a second opinion. No chest x-ray was done.
Was prescribed another course of an
antibiotic with no improvement.
Case Study
• Past Social History:
– Born and raised in India. He immigrated to Canada in
2005 and then moved to the US few years later.
– Working since September 2012 as a nurse on the Stem
Cell Transplant Units.
– Exposure to an active case of TB 35 years ago when he
was a child (his uncle had active TB).
– The patient had multiple PPD skin tests, which were
negative. He received the BCG vaccine as well.
– He is married and he has 2 kids (9-month-old and 6year-old).
Case Study
• May 2013: He went back to India for a
vacation. He saw an internist who did a ZiehlNeelsen stain on 3 sputum specimens, which
came back positive for AFB. His chest x-ray
showed bilateral infiltrates.
• After return to the USA had a positive
Quantiferon -TB test done.
May 2013; before therapy
October 2013; while on therapy
Testing Special
Patient
Populations
Using IGRAs
Issues Affecting LTBI Diagnosis1
• LTBI is difficult to diagnose in
immunocompromised patients.
• Risk for progression to active TB is greater in
immunocompromised patients.
• No gold standard exists to diagnose LTBI.
– TST performs particularly poorly in
immunocompromised patients because of an
increased likelihood for false-negative results.
1. Redelman-Sidi G, et al. Am J Respir Crit Care Med. 2013;188(4):422-431.
Advantages of IGRAs
• Results are numerical and thus less subject to
reader bias.
• No need for a follow-up visit for reading of
results.
• Not affected by BCG vaccination status as they
use TB-specific antigens that are not present in
BCG.
• Whatever test for TB you use, understand the
variables that affect test results, so that you can
manage them and get the most accurate results
possible.