Transcript Current FAQ*s in Tuberculosis

TUBERCULOSIS UPDATE - 2016
Lauri D. Thrupp M.D.
Outline
A.
B.
C.
D.
Current Epidemiology
MDR
Diagnostics: IGRA & NAAT Update
Latent TB
E. Spectrum of Disease including extrapulmonary, and
Dx & Management Issues
F. Therapy
G. Respiratory Isolation
H. Summary Dx and Management - Handout
A. Current Epidemiology
Introduction
• Worldwide, 1/3 of the population is infected
with TB
• 10 – 15 million people in the US are infected
• 9,563 TB cases reported in US in 2015,
2,137 (22.3%) of which were in California
• Of TB cases in California in 2015:
– 81% occur among foreign-born
– 22 multidrug-resistant (MDR) TB cases
and no extensively drug-resistant (XDR)
TB cases.
– Highest rates in those > 65 year old
TB Case Rates,* United States, 2014
D.C.
10-15 million infected
with LTBI!
*Cases per 100,000.
< 3.0 (2014 national average)
>3.0
Trends in TB Cases in Foreign-born Persons,
United States, 1993 – 2015*
No. of Cases
Percentage
9000
70%
8000
60%
7000
50%
6000
5000
40%
4000
30%
3000
20%
2000
10%
1000
0
0%
Number of Cases
Percent of Total Cases
66.2% of U.S. cases in 2015 were foreign-born
Number of Reported Tuberculosis Cases,
Orange County, 1993 - 2015
500
430
Number of Cases
400
364
336
330
298
300
278
246
248
242
273
217
246
200
230
230
209
197
226
224
210
187
192
187
162
100
0
'93 '94 '95 '96 '97 '98 '99 '00 '01 '02 '03 '04 '05 '06 '07 '08 '09 '10 '11 '12 '13 '14 '15
Reporting Year
Characteristics of Active TB Cases
Orange County, 2015
Place of Birth
Foreign-born
90%
US-born
10%
Foreign-born TB Cases
by Country of Birth
Orange County, 2015
RISK FACTORS FOR ACTIVE TB IN CALIF*
Condition
# in Calif
F.Born
Risk Ratio for active TB
DM
2M
35%
2–4x
RA
200K
17%
12 x
HIV
100K
14%
8x
ESRD
50K
25%
10 – 25 x
Transplant
35K
22%
20 – 74 x
L
i
* Jennifer Flood, Calif DPH
B. MDR TB
Multi-Drug Resistant TB (MDR-TB) Cases
by Race/Ethnicity,
Orange County, 2008 - 2013
Number of MDR-TB cases
7
6
5
4
3
2
1
0
2008
2009
2010
2011
Year of Report
Vietnamese
In 2011, 1 XDR-TB case was reported in Orange County.
Hispanic
Filipino
2012
Korean
2013
Drug Resistant TB
• Multidrug resistant (MDR) TB - TB that is
resistant to at least INH and Rifampin
• Extensively Drug Resistant (XDR) TB - TB
that is resistant to INH, Rifampin, an
injectable agent and a fluoroquinolone
Recognition - Who is at higher risk of
MDR-TB?
• History of previous TB treatment, particularly if
after 1980, when Rifampin became widely
used
• Foreign born patients from countries or
ethnicities with high prevalence of MDR-TB
• Poor response to standard 4 drug regimen
(culture remains + after 2 months of treatment)
• Known exposure to MDR-TB case
• HIV positive (higher incidence of Rifampin
monoresistance)
10. D.M. – 15 year old US born high school
student varsity basketball player. Grandmother
pulm TB 2013, (who had contact of friend with
peritoneal TB, MDR). DM had neg PPD and CXR
in May, converted PPD pos. in July.
C. Diagnostics: IGRA & NAAT Update
IGRA Blood Tests
(quantiferon, Tspot)
• Replacement for Tuberculin Skin Test (PPD)
• In vitro assay of 8-IF production from T-cells
upon exposure to specific M. tbc antigens
(ESAT-6 and CFP 10), in parallel comparison
with control antigens
• Should distinguish true infection with M. tbc from
positive TST due to BCG immunization or
infection with other mycobacteria (exception: M.
kansasii and M. marinum)
IGRAs: Interpreting Results
Positive
QuantiFERON®
-TB Gold
QuantiFERON®
-TB In-Tube
T Spot TB 
≥0.35*
Negative
<0.35 *
Gray Zone
None
Indeterminate
Controls fail:
High Nil
Poor Mitogen
response
≥8
spots*
<8
5-7 spots* same as above
spots*
* (TB Ag - Nil) and assumes appropriate control responses
IGRA Performance Compared to TST
Performance
Characteristics
TST
IFN-γ 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
??
Sensitivity of Cepheid (“Xpert”)
Specificity
US
TB culture
Positive
AFB sm+/TB+
AFB sm-/TB+
85%
97%
59%
99%
(75/88)
(59/61)
(16/27)
(526/530)
Luetkemeyer CID 2016
IGRA’s for TB Screening of HCW (2)
Site
M
Reversion Rates (No LTBI Rx)
Stanford
1600
39%
CDC
106
76%
Canada
13
62%
Arkansas
69
45%
IGRA’s for TB Screening of HCW (1)
Conversion Rates (%)
Site
M
TST
IGRA
Stanford
8200
0.4%
4.4%
CDC (4 Hosp)
2300
0.9%
6.1%
Canada
240
0
5.3%
Arkansas
2200
0.1%
3.2%
Direct detection of M. tuberculosis in
Clinical Material
• Commercial nucleic acid amplification tests
(NAAT) for M. tb are now available, including
– Gen-Probe Amplified Mycobacterium TB
Direct (AMTD) (for smear + or smear -) and
– GeneXpert (Cepheid)
• These tests are designed to amplify and detect
DNA specific to M.tb
• The sensitivity of these methods allows for direct
detection of M.tb in clinical specimens
RATE OF TB TRANSMISSION TO CONTACTS
Birmingham, U.K.
• Contacts = 850, from 111 index patients
• Contact Transmission – 165/850 (19%)
Active Disease
17
Latent TBI
148
• Risk of Transmission – Odds Ratio:
Smear positive
1.33
TTD < 9 days
2.56
___________________________
P < .001
_______________________________________________________________
O’Shea CID 2014:59, 177
40
TIME TO DETECTION, AFB, AND NAAT
UCIMC, (n=30 cult pos cases)
Time to Detection (Days)
30
20
low
transmission
risk
10
higher
transmission
risk
0
0(-)
0(+)
1(+)
2(+)
Sputum AFB (NAAT)
3(+)
4(+)
D. Latent TB
Latent TB Infection- the “lite”
version
More than 80 % of TB Cases in the US are
due to reactivation of LTBI
Progression of TB Infection
• 10% of infected persons with normal
immune systems develop TB at some point
in life
• Certain medical conditions increase risk that
TB infection will progress to TB disease
• HIV strongest risk factor for development of
TB if infected
– Risk of developing TB disease 7% to
10% each year
Treatment of Latent TB Infection
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 Int J Tuberc Lung Dis. 1999;10:847
Prevent TB Study (3 HP vs 9 H)
• Open labeled, randomized trial comparing 3
months of INH/Rifapentine (15 mg/k each)
given once a week by DOT versus 9 months of
INH by SAT
• Subjects followed for 33 months after
enrollment
• Primary endpoint: Culture confirmed TB in
patients > 18 yo and culture confirmed or
clinical TB in patients < 18 yo
Conclusions
• The 3 HP TB rate was half that of 9H
• 3 HP by DOT was at least as effective as
9H by SAT
• 3 HP completion rate was significantly
higher than 9H- 82 % vs 69 %
• 3 HP was safe relative to 9H-fewer rates of
adverse events, less hepatotoxicity
E. Spectrum of Disease including
Extrapulmonary, and Dx &
Management Issues
Employee in High-Risk Setting
9. I.W. – 18 year old student from Kenya,
healthy, completely asymptomatic, exc had a
brief “cold” lasting several days about 2 weeks
ago. Screened for job as live-in caretaker. PPD
30mm. Work-up?
Meningitis&Pulm TB + MAC
3. A.N. – 20 year old Vietnamese university
honor student, admitted to Community Hospital
with mental disturbance, HA. CSF x2, 60w, 28
Gluc., neg cult and neg AFB. No response to
bact. meningitis Rx, became comatose,
responded to ventriculostomy. TB Rx started incl
steroid taper. Gradual improvement on Rx but
N & V and persistent neurol problems. Adm UCI
6 weeks later – CSF W50, still PMN, Gluc 40, Prot
300.
GI & Undiagnosed Pulm TB, No LTB Rx
9. H.J. – 72 year old retired university chemistry
professor, originally from China. Presented with
abdominal pain, bloating, weight loss. Also had
long term mild chronic cough. CT showed distal
ileum thickening suggesting Crohn’s Dis.
Colonoscopy showed ileocecal mass, Bx AFB
pos. Then chest x-Ray done – bilat. cavitary dis.
and sputums 4+ AFB.
Pulmonary, No Latent TB Rx
11. R.B – 21 year US born Hispanic man referred
from Health Dept because of 2 month cough with
yellow sputum, plus some chest pain. Abnormal
chest xRay found by drug rehab facility. Known
positive PPD in prior jail, but 4 months earlier xRay
?? normal. Family Hx neg re TB
Adm afebrile, no chills, sweats, hemoptysis or
weight loss. PE unremarkable. WBC 17, alb 3.0.
Prior outside xRay 3 weeks ago RUL and LLL
infiltrates. New xRay RUL cavity. Plan?
Pregnancy & Pulmonary, ?etiol
1. G.T. – 30 year old Philippine-born woman, 18
weeks pregnant, in community hospital for 3
weeks with dry cough, fevers, and intermittent
spotting. PPD neg. x-ray “interstitial infiltrates”.
Sputum cult NF. No response to courses of
azithro, and no response to Zosyn. Sputum AFB
neg. Next steps?
Pulmonary
8. M.O. – 76 year Hispanic man non-smoker,
adm with 3 weeks productive cough, chills,
fever, 30 lb wt loss. Antibiotics from PCP no
help. On ED x-Ray LUL cavity and 4 drug TB
therapy started. QF pos. Then 3 sputums neg
AFB, one grew few colonies aspergillus, another
2 yeasts. Next step?
Pitfalls in TB Diagnosis
• Patients may not display classic clinical
symptoms of TB
• TST/IGRA: may not be reactive in patients
with active disease or immunocompromised
state
• CXR: may appear normal in
immunocompromised patients with active TB
• Sputum exams: smears will be negative if low
numbers of AFB present
• TAKE HOME MESSAGE: don’t be mislead by
negative test results if you have a high
suspicion for TB!
Diagnosis Of Tuberculosis
Bronchoscopy vs. 3 Induced Sputum(IS)
Sensitivity of Bronchoscopy
TB culture
73 %
NPV
Sensitivity of 3 IS TB culture
87%
NPV
96%
91%
C Anderson, N Inhaber, and D Menzies (1995) Comparison of Sputum induction
with fiber-optic bronchoscopy in the diagnosis of tuberculosis., AJRCCM 152 (5 PT 1), p. 1570-4
TB of Bone
4. R.G. – 56 year old Hispanic woman with
severe osteomyelitis and destructive arthritis of
the right hip and acetabulum. PPD pos. Total hip
replacement and debridement 7 years ago
gradually failed with recurrence of osteomyelitic
changes on x-Ray. Biopsy showed granulomas,
neg. AFB. TB Rx without new surgery produced
dramatic improvement.
7. M.L. – 37 year old Vietnamese man with
alleged history of sarcoidosis and prior steroid
Rx. Presented with several months ankle pain,
grad. increasing, with “mass” on x-Ray. PPD pos.
6. P.W. – 80 year old US born caucasian woman;
work-up for cough and SOB showed anterior
mediastinal peribronchial mass. PPD neg. Three
sputums neg AFB smear. BAL neg AFB. Next
steps?
5. A.H. – 49 year Vietnamese woman with
vertebral T 7-8 and extensive paravertebral
involvement, including early neurologic signs.
Medical Rx poorly tolerated, requiring three
years of Rx but clinically improved.
F. Therapy
Antituberculosis Drugs
First-Line Drugs
Second-Line Drugs
• Isoniazid (INH)
• Streptomycin
• Rifampin (RIF)
• Cycloserine
• Pyrazinamide (PZA)
• p-Aminosalicylic acid
• Ethambutol (EMB)
• Ethionamide
• Rifabutin* (RBT)
• Amikacin or kanamycin*
• Rifapentine (RPT)
• Capreomycin
• Levofloxacin*
• Moxifloxacin*
• Gatifloxacin*
* Not approved by the U.S. Food and Drug Administration for use in the
treatment of TB
Antituberculosis Drugs
“Third-Line Drugs”
•Clofazamine
•Linezolid
•Amoxicillin/calvulinate
•Clarithromycin
•Imipenem
New Drug recently approved for treatment of MDR-TB
•Diarylquinolines (TMC-207)- bedaquilline (Sirturo)
Treatment Regimens
• Four regimens recommended for treatment
of culture-positive TB, with different options
for dosing intervals in continuation phase
• Initial phase: standard four drug regimens
(INH, RIF, PZA, EMB), for 2 months,
(except one regimen that excludes PZA)
• Continuation phase: additional 4 months or
(7 months for some patients)
Am J Resp Crit Care Med 2003; 167: 603-662