Lauri D. Thrupp M.D.

A. Current Epidemiology
B. MDR
C. Diagnostics: IGRA & NAAT Update
D. Latent TB
E. Spectrum of Disease including extrapulmonary, and
Dx & Management Issues
F. Therapy
G. Respiratory Isolation
H. Summary Dx and Management - Handout

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
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
Percentage
70%
60%
50%
40%
30%
20%
10%
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
400
430
364
336
330
300
273
200
298
246
246
278
230
248
230
242
226
217
210
197
224
209
192
187
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
US-born
90%
10%

Foreign-born TB Cases by Country of Birth
Orange County, 2015

RISK FACTORS FOR ACTIVE TB IN CALIF*
Condition
DM
RA
HIV
ESRD 50K
L
Transplant 35K
* Jennifer Flood, Calif DPH
# in Calif
2M
200K
100K
F.Born
35%
17%
14%
25%
22%
Risk Ratio for active TB
2 – 4 x
12 x
8 x
10 – 25 x
20 – 74 x i

Multi-Drug Resistant TB (MDR-TB) Cases by Race/Ethnicity,
Orange County, 2008 - 2013
5
4
3
2
7
6
1
0
2008 2009 2010 2011
Year of Report
Vietnamese Hispanic Filipino Korean
In 2011, 1 XDR-TB case was reported in Orange County.
2012 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.

(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
QuantiFERON ®
-TB Gold
QuantiFERON
®
-TB In-Tube
Positive Negative Gray Zone Indeterminate
≥ 0.35
* <0.35 *
None
Controls fail:
High Nil
Poor Mitogen response
T Spot TB
 ≥ 8 spots*
< 8 spots*
5-7 spots* same as above
* (TB Ag - Nil) and assumes appropriate control responses

IGRA Performance Compared to TST
Performance
Characteristics
Est. sensitivity (%)
TST
Est. specificity (%)
75-91
80-90
Correlates with exposure Often no
Results change with Rx ??
IFNγ Assays
80-95
95-100
Yes
Usually yes

Sensitivity of Cepheid (“Xpert”)
Specificity
US
TB culture
Positive
AFB sm+/TB+ AFB sm-/TB+
85%
(75/88)
97%
(59/61)
59%
(16/27)
99%
(526/530)
Luetkemeyer CID 2016

Site
Stanford
CDC
Canada
Arkansas
M
1600
106
13
69
Reversion Rates (No LTBI Rx)
39%
76%
62%
45%

Site M TST IGRA
Stanford 8200 0.4% 4.4%
CDC (4 Hosp)
Canada
Arkansas
2300
240
2200
0.9%
0
0.1%
6.1%
5.3%
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
TTD < 9 days
1.33
2.56
___________________________
P < .001
_______________________________________________________________
O’Shea CID 2014:59, 177

40
30
TIME TO DETECTION, AFB, AND NAAT
UCIMC, (n=30 cult pos cases)
20
10
0
0(-) 0(+) 1(+) 2(+)
Sputum AFB (NAAT)
3(+) 4(+) low transmission risk higher transmission risk

lite
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

Cases per 100
3
2
5
4
1
0
0
Treatment of Latent TB Infection
How long is enough?
Calculated curve
Calculated values
Observed values
• Lower TB rates among those who took 0-9 mo
• No extra increase among those who took >9 mo
6 12 18
Months of Treatment
24
Comstock Int J Tuberc Lung Dis. 1999;10:847

• 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

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?

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.

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.

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?

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?

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 NPV
TB culture
73 % 91%
Sensitivity of 3 IS TB culture NPV
87% 96%
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

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.

Antituberculosis Drugs
First-Line Drugs
• Isoniazid (INH)
• Rifampin (RIF)
• Pyrazinamide (PZA)
• Ethambutol (EMB)
• Rifabutin* (RBT)
• Rifapentine (RPT)
Second-Line Drugs
• Streptomycin
• Cycloserine
• p-Aminosalicylic acid
• Ethionamide
• Amikacin or kanamycin*
• Capreomycin
• Levofloxacin*
• Moxifloxacin*
• Gatifloxacin *
* Not approved by the U.S. Food and Drug Administration for use in the treatment of TB

Antituberculosis Drugs
“ ThirdLine 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