# Presentation: 045188

## Tuberculosis from a Clinician’s Perspective

- Charles L. Daley, M.D.
- University of California, San Francisco
- F. J. Curry National TB Center

- Epidemiology and Laboratory Priorities

## Tuberculosis from a Clinician’s Perspective

- Epidemiology
- Transmission and Pathogenesis
- Diagnosis and Treatment of Tuberculosis
- Diagnosis and Treatment Latent TB Infection (LTBI)
- Laboratory Priorities-A Clinician’s Perspective

## The Global Resurgence of Tuberculosis

- “The microbe is nothing:
-  the terrain, everything.”
-     – L. Pasteur, 1822-1895

## Magnitude of Tuberculosis

- Prevalence of infection                  2 billion
- Annual number of new cases        8 million
- Annual case rate                      60.6/100,000
- Tuberculosis deaths*                     2 million
- % preventable deaths                    26

- *Does not include TB/HIV deaths

## Estimated TB Incidence Rates, 1997

## WHO Global ProjectPrevalence of MDR-TB in Previously Treated

- 0	20	  40	   60	    80	     100%

-     **United States**
-               Uganda
- Russian (Tomsk)
-         Puerto Rico
- China (Zhejiang)
-               Estonia
-                     Italy
-       Sierra Leone
-    China (Henan)
- Russia (Ivanovo)
-              Uruguay

- Any drug resistance other than MDR

- MDR-TB

## Global Distribution Of HIV/MTB

- 301,000

- 1

- 10,000

- GLOBAL

- T

- OT

- AL:  3.1 MILLION

- 2,400,000

- 7,000

- 48,000

- 8,000

- 200,000

- 4,000

- 440,000

- 62,000

- GLOBAL

- T

- OT

- AL:  10.7 MILLION

- 7,302,006

- 107,000

- 84,000

- 5,000

- 2,364,000

- 307,000

## Tuberculosis Cases in the U.S.1980-2000

- Source: CDC

## TB Case Rates in the U.S, 2000

_**<**_** 3.5 (year 2000 target)**

**3.6 - 5.8**

**> 5.8 (national average)**

**D.C.**

- Rate: cases per 100,000

## Number of TB CasesUS-born vs. Foreign-born  , 1992-2000

**No. of Cases**

## TB Cases In The United StatesAge 24-44, by HIV Status, 1998

*Reporting **	**	**	**	**	**	**	**	**	** Total **	**	**	**	*_*Cases with HIV Status*_*	**	**	**	**  %*
_*Area*_*	**	**	**	**	**	**	**	**	**	**	**	**	**	**	**	*_*Cases*_*	**	**	**	**	**	**   *_*No.*_*	**	**	**	**	**	**	**	**	*_*%*_*	**	**	**	**          *_*HIV  +*_
- Alabama											 107									  85									79.4									12.9
- Florida														544								 457								84.0							   	46.8
- Georgia													228							  	174								76.3									 29.9
- Louisiana										 132							   103								78.0									 18.4
- Maryland										  	112								 	  92								82.1									 28.3
- New York City				   652								  548								84.0									 39.6
- Oregon															71								 	  	 60								84.5									 13.3

- Source: CDC

## Transmission and Pathogenesis of TB

- Continued containment (90%)

- No infection (70%)

*Adequate*

- Non-immunologic

-       defenses

*Inadequate*

- Infection (30%)

*Inadequate*

*Adequate*

- Containment (95%)

- Early progression (5%)

- Late progression(5%)

*Inadequate*

- Immunologic

- defenses

*Adequate*

## Diagnosis of Tuberculosis

- 400 B.C.	Clinical observation and   			deduction - Hipprocates
- 1761		Percussion - Anenbrugger
- 1819		Ausculation - Laennec
- 1882		Microscopic examination and 			culture - Koch
- 1895		Xrays - Rontgen

## Sensitivity and SpecificityA Laboratory Perspective

- Sensitivity - The percentage of patients with the disease who have a positive test
- Specificity - The percentage of patients without disease who have a negative test

## Predictive ValuesA Clinician’s Perspective

- Positive predictive value (PPV) - The percentage of patients with a positive test who have the disease
- Negative predictive value (NPV) - The percentage of patients with a negative test who do not have the disease

## Prevalence of Disease vs. Predictive Value

- 100
-   80
-   60
-   40
-   20
-     0

- 0	20	  40	    60	     80	     100

- Prevalence of disease

- PV
- (%)

- Positive

- Negative

## TB or Not TB?

## Diagnostic Work-Up of TB Suspect

- AFB X 3

- Smear +

- Smear –

- Treatment

- ?

## Predictive Value of a Positive AFB Smear

- Initiate treatment for TB

- Culture, Speciation, Susceptibility Testing

*M. tuberculosis*

- 50-90%

- Continue treatment

- Tailor treatment

- Nontuberculous

- mycobacteria

- 10-50%

## Clinical Decision Making with Negative AFB Smears

- Low

- Moderate

- No Rx,

- wait for

- culture

- result

- Assess the following:

- Initiate Rx

- Invasive diagnostic procedure;

- bronchoscopy, FNA

- •

- clinical/immune status

- •

- risk of transmission

- •

- side-effects of Rx

- High

## Direct Amplification TestsSmear Positive Specimens

-   Perform DAT

- Positive DAT

- Negative DAT

-  MTB

- 100%

- NTM

- 0%

- NTM

-  90%

-  MTB

-  10%

- Direct Amplification TestsSmear Positive Specimens

## Diagnosis of TuberculosisRole of Clinical Suspicion

- Prospective multicenter trial
- 7 sites (6 in U.S. and 1 in Switerzland)
- 338 TB suspects were enrolled
- Patients were stratified by clinical investigators to be at:
- Low (≤ 25%)
- Intermediate (26-75%)
- High (>75%) risk of TB

- Catanzaro A, et al. JAMA 2000;283:639

## Diagnosis of TuberculosisRole of Clinical Suspicion

- 			   *Low**	**       Intermediate**	** High*
*	**	**	**(n= 224)**	**(n=68)**	**	**(n=46*)
- Prevalence of TB	     5%		   29%		   87%
- Started on drugs	   11%		   49%		   98%

-  Among 338 suspects, 72 had TB
- 	45 (63%) had ≥ 2 positive cultures
- 	20 (28%) had one positive culture
- 	  7 (10%) had not positive cultures

- Catanzaro A, et al. JAMA 2000;283:639

## Diagnosis of TuberculosisRole of Clinical Suspicion

- 100
-   80
-   60
-   40
-   20
-     0

-    5

-   29

-   87

- %

- Overall

- TB Prevalence, %

- PPV

- NPV

- 100
-   80
-   60
-   40
-   20
-     0

-    5

-   29

-   87

- Overall

- MTD

- AFB smear

## Treatment of TuberculosisUnscientific and Probably Ineffective

- Wolf’s liver boiled in wine
- Flesh of a she-ass with broth
- Smoke of dried cow dung
- Elephant’s blood
- Woman’s milk
- Mice boiled in salt and oil

## Treatment of TuberculosisSan Francisco General Hospital

## Treatment of TuberculosisStandard Regimen

- *Streptomycin may be substituted

- Isoniazid

- Rifampin

- Pyrazinamide

- Ethambutol*

- 0	1	  2	     3	        4	          5          6

- months

- Initial Phase		     Continuation Phase

## Tuberculosis Tip of the Iceberg

- TB infection

- Active cases

- Total Population

## Tuberculin Skin TestingMantoux Method

## Quanti-FERON-TB Test

-    Nil
- antigen

-  Hu
- PPD

-  Av
- PPD

-    Rec
- antigens

- Mitogen
-  control

- Add simulation
- antigens to blood

- Quanti-FERON-TB Test

- Dispense blood into wells

- Specific T cells
- respond and produce
- gamma-interferon

- ELISA

## Quanti-FERON-TB TestImpact of BCG Vaccination

- 				    *% Agreement**	**         kappa*
*	**	**	**Overall       TST+**	**   TST-**	*
- Total Population	  84.7	        64.8	   90.2		0.55
- Unvaccinated	  88.1	        64.5	   91.3		0.50
- Unk. Vaccination	  82.2	        72.1	   88.0		0.61
- BCG Vaccinated	  70.1	        61.5	   81.8		0.41

- Mazurek G, et al. JAMA 2001

## Quanti-FERON-TB TestDiscordance: +TST, –QFT

*Variable**	**        Category**	**Relative Risk**	**         P-value*
- Race		          White		        1.0
- 		          Hispanic	        1.24		0.63
- 		          Black		        1.69		0.15
- 		          Asian		        2.33		0.03
- 		          Other		        0.61		0.66
- History of BCG        None		        1.0
- 		          Unknown	        2.49		0.03
- 		          Vaccinated	        6.92		0.00
- MAC by QFT	          No		        1.0
- 		          Yes		        2.64		0.008

- Mazurek G, et al. JAMA 2001

## ESAT-6 ELISPOT AssayContacts Stratified by Exposure

- Lalvani, et al. Lancet 2001;357:2017-21

- •50 healthy contacts with
- well-defined degrees
- of exposure
- •ESAT-6 correlated with
- degree of exposure
- •ESAT-6 was not
- correlated with BCG
- status

## Treatment of LTBIDrug Regimens

*Regimen                 Duration               Interval               **	**	**            (months)**	**	*
- Isoniazid	                  9	               Daily
- 				                   Twice-wkly
- Isoniazid                      6                       Daily
- 				                   Twice-wkly
- Rifampin-PZA              2	               Daily
- 		                 2-3                Twice-wkly
- Rifampin	                  4                       Daily

- ATS/CDC AJRCCM 2000

## Laboratory Priorities A Clinician’s Perspective

- Services offered - The more the merrier
- Turn around time - The quicker the better
- Communication - It’s a good thing
- Costs?

## Laboratory PrioritiesA Clinician’s Perspective

*Test**	**	**	**     Positive **	**	**         Negative*
*	**	**	**characteristics**	**	**     characteristics*
- Smear			Rapid			      Not sensitive
- 			Inexpensive
- 			+ Infectiousness
- Culture			Definitive diagnosis	     Slow
- Susceptibility		Identifies drug resist.	     Slow
-   tests
- Amplification 		Rapid			     Expensive
-   tests			Sensitive and specific	     – Infectiousness

## Drug Susceptibility TestingPriorities

- Isoniazid
- Low and high concentrations?
- Rifampin
- Pyrazinamide
- Ethambutol
- ?Streptomycin?

## Communication

- Communication is essential for patient care
- Speed of reporting results must be balanced against the reporting of accurate results
- In suspected cross-contamination, the clinician should be informed immediately

## A Clinician’ Laboratory Wish List

- Diagnosis and treatment of TB
- Rapid identification-species specific
- Correlate with infectiousness of patient
- Rapid drug susceptibility testing
- Determine response to therapy
- Diagnosis and treatment of LTBI
- Rapid and accurate determination of infection
- Test to predict progression to active TB

## Genome of M. tuberculosis