[PDF] - What the Primary Physician Topics for Discussion Should Know about PDF Document

SLIDE 1

What the Primary Physician Should Know about Tuberculosis

Henry F. Chambers, M.D Professor of Medicine, UCSF

Topics for Discussion

Epidemiology
Common disease presentations
Diagnosis of active TB
Screening for latent TB infection

Global Impact of TB - 2012

World population 7,100,000,000
Number infected with TB: 2,340,000,000
New reported cases of active TB:

– 2012: 8,600,000 (121 per 100,000) – 2011: 9,400,000 (140 per 100,000) – US rate 3.4/100,000

New MDR cases (9.6% XDR): 450,000
1,300,000 deaths

– 45% reduction from 1990 to 2012 – #2 cause of death worldwide from infectious disease

TB Case Rates,* United States, 2012

*Cases per 100,000.

< 3.2 (2012 national average) >3.2

D.C.

9,945 cases for ~350,000 Primary Care MDs

TB Case Rates by Race/Ethnicity,* United States, 2003–2012**

*All races are non-Hispanic. **Updated as of June 10, 2013.

Cases per 100,000

0.0 ¡ 5.0 ¡ 10.0 ¡ 15.0 ¡ 20.0 ¡ 25.0 ¡ 30.0 ¡ 35.0 ¡ 2003 ¡ 2004 ¡ 2005 ¡ 2006 ¡ 2007 ¡ 2008 ¡ 2009 ¡ 2010 ¡ 2011 ¡ 2012 ¡

Hispanic ¡or ¡La7no ¡ American ¡Indian ¡or ¡Alaska ¡Na7ve ¡ Asian ¡ Black ¡or ¡African ¡American ¡ Na7ve ¡Hawaiian ¡or ¡Other ¡Pacific ¡Islander ¡ White ¡

Number of TB Cases in U.S.-born vs. Foreign-born Persons, United States, 1993–2012*

*Updated as of June 10, 2013

No. of Cases

0 ¡ 5,000 ¡ 10,000 ¡ 15,000 ¡ 20,000 ¡ 1993 ¡ 1994 ¡ 1995 ¡ 1996 ¡ 1997 ¡ 1998 ¡ 1999 ¡ 2000 ¡ 2001 ¡ 2002 ¡ 2003 ¡ 2004 ¡ 2005 ¡ 2006 ¡ 2007 ¡ 2008 ¡ 2009 ¡ 2010 ¡ 2011 ¡ 2012 ¡ U.S.-‑born ¡ Foreign-‑born ¡

SLIDE 2

Trends in TB Cases in Foreign-born Persons, United States, 1992 – 2012*

*Updated as of June 10, 2013

No. of Cases

Percentage 0 ¡ 10 ¡ 20 ¡ 30 ¡ 40 ¡ 50 ¡ 60 ¡ 70 ¡ 0 ¡ 1,000 ¡ 2,000 ¡ 3,000 ¡ 4,000 ¡ 5,000 ¡ 6,000 ¡ 7,000 ¡ 8,000 ¡ 9,000 ¡ 10,000 ¡

1 9 9 2 ¡ 1 9 9 3 ¡ 1 9 9 4 ¡ 1 9 9 5 ¡ 1 9 9 6 ¡ 1 9 9 7 ¡ 1 9 9 8 ¡ 1 9 9 9 ¡ 2 ¡ 2 1 ¡ 2 2 ¡ 2 3 ¡ 2 4 ¡ 2 5 ¡ 2 6 ¡ 2 7 ¡ 2 8 ¡ 2 9 ¡ 2 1 ¡ 2 1 1 ¡ 2 1 2 ¡ Number ¡of ¡Cases ¡ Percentage ¡of ¡Total ¡Cases ¡

TB Case Rates by Age Group and Sex, United States, 2012

Cases per 100,000

0.0 1.0 2.0 3.0 4.0 5.0 6.0 7.0 8.0 Under 5 5 - 14 15 - 24 25 - 44 45 - 64 ≥65 Male Female

Active Tuberculosis

Pulmonary tuberculosis: 85% of all

cases

The infectious form of the disease
Clinical suspicion based on

– Signs, symptoms, setting – Chest x-ray

20 40 60 80 100 120 All cases Expul Percent Extrapulmonary Pulmonary Other Bone/jt Miliary GU Pleural Lymphatic

Sites of TB Infection Case Presentation

63 y/o inmate transferred from jail for r/o TB
No fever, cough, weight loss
12 mm + PPD, HIV negative
Prior work-up

– 2/2001: AFB smear/culture neg x3 – 4/2005: AFB smear/culture neg x3 – 8/2005: AFB smear/culture neg x3 – 3/2010: AFB smear/culture neg x1 – 9/2010: AFB smear/culture neg x4 CXR: LUL nodular infiltrate, slight volume loss, maybe slightly worse since prior film

SLIDE 3

What is your estimate of the likelihood of active TB in this case?

1. 75% or higher
2. 50-75%
3. 25-50%
4. 5-25%
5. < 5%

Work-Up

CXR: LUL nodular infiltrate, slight

volume loss, maybe slightly worse since prior film?

Sputum examination

– Routine: OF on culture and Gram-stain – AFB x2 and BAL x1: no AFB – GenProbe Amplified MTD test: negative

What is your revised estimate of the likelihood of active TB in this case?

1. 75% or higher
2. 50-75%
3. 25-50%
4. 5-25%
5. < 5%

Diagnosis of TB

SLIDE 4

Performance of Diagnostic Tests for Pulmonary TB

Sensitivity Specificity AFB smear 60% 99% NAA test 85% 99% Culture 90% 99% PPD (or QTF) 60% 10%

Xpert MTB/RIF Test Performance

Sensitivity Specificity Smear pos. TB 95-98% 99% Smear neg. TB 60-72% Rifampin “R” 98-99% 99-100%

NEJM 361:1005, 2010; Am J Crit Care Med 184:132, 2011

Organism Burden in TB

Cavitary TB Pulmonary infiltrate Lymphadenopathy 106 - 107 cfu/g 104 - 105 cfu/g 102 - 104 cfu/g

Detection Thresholds of Tests for TB Diagnosis

Positive smear Positive NAA test Positive culture 104 - 105 cfu/ml 101 - 102 cfu/ml 101 cfu/ml

Performance of NAAT for Diagnosis of Pulmonary TB

Pre-test probability PPV NPV 90% 100% 43% 75% 98% 69% 50% 96% 87% 25% 91% 95% 5% 57% 99%

Clinical Course

Patient was discharged back to jail
Treatment for tuberculosis withheld

pending results of work-up

16 days after discharge, one sputum

culture and the BAL specimen were reported positive for Mtb!

SLIDE 5

Extrapulmonary TB Forms of Extrapulmonary Tuberculosis

Cervical lymphadenitis
Tuberculous pleuritis
Other rarer birds

Differential Dx of Cervical Adenitis

Tuberculosis
Non-tuberculous mycobacterial infection
Kikuchi-Fujimoto’s syndrome (histiocytic

necrotizing lymphadenitis)

Staph or strep infection
Cat scratch
Lymphoma, other tumor
Other: syphilis, HIV, tularemia, listeria,

plague

Tuberculous Adenitis

Clinically presentation not distinctive
Constitutional symptoms not usually present
Seen in children, young adults > adults
PPD + in 75-80%
Chest x-ray abnormality (15-20%) favors

MTB

Foreign-born patient more likely to have

MTB

SLIDE 6

Work-up of Suspected TB Adenitis

Tuberculin test
Check HIV serology
Chest x-ray to r/o pulmonary TB
Respiratory isolation for patients with

pulmonary symptoms, pulmonary TB

Notify tuberculosis control

Diagnosis of TB Adenitis

Tissue is the issue

– to exclude other etiologies – for sensitivity testing

FNA

– Characteristic granulomas in 80% – Culture + in 40-70% – Smear + < 50%

Biopsy: partial vs. total excision

Treatment of TB Cervical Adenitis

Responsive to medical therapy alone
If excisional surgery performed,

medical therapy still must be given

Paradoxical “worsening” can occur;

needle aspiration effective management

Sinus track formation, non-healing

wounds may benefit from surgery

Similar Scenario for TB Pleuritis

Unilateral, benign, lymphocytic effusion
Primary infection, newly + PPD
Fluid usually smear and culture

negative

Pleural biopsy culture positive ~60%,

with granulomas ~80%

Treat as for adenitis or pulmonary TB

Principles of Therapy

Start 4 drugs (RIPE) for suspected active TB
Never use a single drug for treating active TB:

resistance can emerge (1 mutant in 104 to 106)

Never add a single drug to a failing regimen
Consult and expert and/or local health

department

Francis Curry National TB Center: http://

www.nationaltbcenter.edu/

Bedaquiline

Treatment of TB caused by MDR or

XDR strains of MTBtuberculosis

DOT: 400 mg once daily for 2 weeks,

then 200 mg 3 x/week for 22 weeks,

– Taken with food and – Always in combination with other anti-TB medications.

Monitor for QTc prolongation

Lancet 380:986, 2012; Antimicrob Agents Chemother 56:3271, 2012; NEJM 360:2397, 2009

SLIDE 7

Screening for Latent TB Infection (LTBI) Case Presentation

LV is a 58 y/o female from Ukraine

referred for treatment of hypertension and diabetes

She is otherwise well
She gives a history of BCG vaccination

as a teen

What is the best course of action?

1. The patient should be screened for LTBI with a

tuberculin test

2. The patient should not be screened for LTBI

because she is not a candidate for INH prophylaxis due to her age

3. The patient should not be screened because

with prior BCG vaccination the tuberculin test will be false positive

4. The patient should be screened for LTBI by

chest x-ray

LTBI: Goals of Screening

Identify active cases
Identify infected persons likely to benefit

from treatment of latent TB infection (LTBI)

Surveillance

Who Should Be Screened?

Persons with increased risk of TB infection
Persons with increased risk of progression
Not the general population

Increased Risk of Infection

Recent contacts of an active TB case

– About 30% are infected

Foreign-born persons from high TB

prevalence areas

– Asia, Mexico, Middle East, Central and South America, Africa, Eastern Europe

Medically underserved, low-income, racial

and ethnic minorities

Others: HCW, residents of congregate living

settings

SLIDE 8

Increased Risk of Progression

Children < 5 years old
Recent infection (contacts and converters
HIV+
Prior TB
Various medical conditions:

– Diabetes, hematologic/reticuloendotheial diseases, intestinal or gastric bypass, renal dialysis – Malabsorption syndromes, malnutrition, silicosis, alcoholism, smokers – Immunosuppression, anti-TNF agents – > 15 mg prednisone QD for > 3 wks

Risk of Progression

Risk Factor Increase in risk (+TST) AIDS/Advanced HIV 9.9 Anti-TNF agent 7.9 Old TB, untreated 5.2 Diabetes 3.1 Smoker 2.7 Underweight 1.6

Flowchart: Evaluation and Treatment of LTBI

TB Risk?

Tuberculin Test + symptom review Negative Positive Chest x-ray Normal Abnormal STOP

No Yes

Treatment not indicated R/o active TB Candidate for Rx

f LTBI

Diagnosis of LTBI

TB Skin Test (TST) QuantiFERON Blood Test (QFT)

Reading the TST

Measure reaction in 48

to 72 hours

Measure induration, not

erythema

Record reaction in

millimeters, not as “negative” or “positive”

Positive reactions can

be read for up to 7 days

Negative reactions can

be read accurately for

nly 72 hours

TST Positivity

5 mm + PPD

– HIV, immunocompromised, contacts, abnl CXR

10 mm + PPD

– Those at increased risk of infection: IVDU, health care workers, foreign born, children < 4 yo, high-risk medical conditions

15 mm +PPD

– Persons not at risk (why did you do the test?)

SLIDE 9

TST Conversion

Signifies new infection
> 10 mm increase within 2-year period
Conversions may represent boosted

reactions in some individuals

Tuberculin Skin Test

Should NOT be performed on someone with

a documented history of a positive test

Should be applied, read, and interpreted by

a trained health professional

RULE OUT active TB before treating for

LTBI

– CXR for all – Sputum AFB smear and culture if abnormal

Interferon Gamma Release Assays (IGRA)

Indirect test for M. tuberculosis

infection using whole blood

Tests for generation of interferon

gamma by cell-mediated immunity (not antibody)

Highly specific: not affected by prior

BCG vaccination

Andersen, et al. Lancet 356:1099, 2000

FDA Approved Interferon Gamma Release Assays (IGRA)

Quantiferon-TB Gold (Cellestis, Ltd)

– Uses ESAT-6 and CFP-10 as antigens

Quantiferon-TB Gold In-tube (QFT-

GIT)

– Uses ESAT-6, CFP-10 and TB7.7 (RD4) as antigens affixed to inside of tube

T-Spot-TB (Oxford Immunotec)

– Uses ESAT-6 and CFP-10

IGRAS: Species Specificity of ESAT-6 and CFP-10

Mycobacterial species ESAT-6 CFP-10

M. tuberculosis

+ +

M. africanum

+ +

M. bovis

+ + BCG strains

M. avium-intracellulare
M. abscessus
M. smegmatis
M. kansasii

+ +

M. marinum

+ +

M. szulgai

+ +

SLIDE 10

Quantiferon-Gold Advantages

Requires a single patient visit to draw a

blood sample

Results within 24 hours
No boosting
Is not subject to reader bias that can
ccur with TST
Is not affected by prior BCG

Performance of IGRA vs TST

Performance characteristics TST IGRA

Sensitivity 75-91% 80-95% Specificity 80-90% 95-100% Correlates with exposure Often no Yes Results change with Rx ?? Usually yes

When Should You Use IGRA?

Can be used in all circumstances in which the

TST is currently used, including

– contact investigations – evaluation of recent immigrants who have had BCG vaccination – TB screening of health care workers – others undergoing serial evaluation for M. tuberculosis

Caution should be used when testing certain

populations (i.e., children < 5 years old, immunocompromised) because of limited data in use IGRAs

QFT-GIT Screening of HCWs

Manufacturer's IFN-gamma cutoff ≥0.35 IU/ml may be too low for low prevalence settings, inflating positivity and conversion rates, and a higher cut-off may be more appropriate

Am J Respir Crit Care Med 188:1005, 2013

Current Guidelines for Treatment

f LTBI
Decision to test is decision to treat
No 35 year-old cut-off
9 months of INH preferred over 6

months

Baseline lab monitoring not routinely

indicated

Efficacy of INH Treatment of LTBI

Duration

f INH

5-yr risk reduction Complianc e Reduction if compliant

3 mo 21% 87% 31% 6 mo 65% 78% 69% 9 mo 75% 68% 93%

Bull World Health Organ 60:555, 1982

SLIDE 11

Rifapentine (Rfp) + INH for Rx of LTBI

Regimen TB rate Compliance AE* (hepatitis)

INH 300 mg qd x 9 mo 15/3745 69% 3.7% (0.4%) Rfp 900 mg + INH 900 mg qwk x 3 mo§ 7/3986 82% 4.9% (2.7%)

NEJM 365:2155, 2011

* Treatment ending

§ DOT

What is the best course of action?

1. The patient should be offered a tuberculin test to

screen for LTBI

2. The patient should not be screened for LTBI

because she is not a candidate for INH prophylaxis due to her age

3. The patient should not be screened with