Juzar Ali M.D., FRCP(C), FCCP(Russell C. Klein M.D.  LSU ALUMNI Professor of Medicine)

Vice Chair (Clinical) Department of MedicineDirector: LSU Chest & LSU-Wetmore TB ClinicsSection of Pulmonary & Critical Care Medicine

Louisiana State University Health Sciences CenterNEW ORLEANS

April 2008

The Alphabet Soup in TB and MOTT

ObjectivesObjectives

At the end of this presentation, the participants will be able to:

• (a) Review issues related to LTBI, BCG and INF-G• (b) Appreciate the importance of DOTS and

DOSE • (c) Gain a better understanding of MDRTB and

XDRTB• (d) Be informed about MOTT

Sm + C – Sm - C+ Sm – C--

DOTDOTS

DRTBMDRTBXDRTB

LTBI ; BCG ; INF-G

MOTT

DOST?

TUBERCULOSISTUBERCULOSIS

• ACTIVE DISEASE

• LATENT INFECTION

PUBLIC HEALTHPUBLIC HEALTHCLASSIFICATIONCLASSIFICATION

• Class 0 No Exposure, No Infection

• Class 1 Exposure , No Infection

• Class II Infection , No Disease

• Class III Current Disease

• Class IV No Current Disease

• Class V Suspect

Part A : LTBI

Latent TB InfectionLatent TB InfectionDefinition?Definition?

• A paucibacillary infection with no detectable bacilli present

• Animal models: Bacilli “stunted” due to nutritional depletion, hypoxia or genetic factors

Ref: Mol Micro 2002 ; 43: 717

Annu Rev Microbio 2001; 55: 133-163

The triple issues of LTBIThe triple issues of LTBI

LTBI

BCG

PPD/ TST INFγ

*Poor Specificity in BCG vaccinated persons*Low sensitivity in Immune compromised hosts*Logistical drawbacks*Overall no show rate 40%* At Wetmore 21%** completion rate

Based on Mycobacterial genomics and antigenicSpecific T cell responseDeleted segment ROD1Early secretory antigenic target-6 ESAT-6Culture filtrate Protein 10 CFP-10Checking for the “TB footprint”Technical & Cost ?

ELISPOT testELISA Quantiferon Gold

BCG

PPD & BCGPPD & BCG

• Except in children, the size of the PPD reaction bears no relationship to active TB

• BCG induced reactions are smaller and tend to wane more quickly than reactions caused by naturally occurring infections

• History of BCG is “generally” ignored

Contacts : variable data*Contacts : variable data*

Association of prevalence of TB Reactions with closeness of contact among household contacts of new smear positive PTB patients

Close intimate close regular not close sporadic

42 % + 34 % + 13 % **+** 16 % healthy population sample all household contact 30 %

Lutong & BeiShandong MU ChinaIUTLD 2000 4 ( 3 ) 275

*+ = > 5 mm, 10, 7.5 * CID 2007:44

Risk factors for TB infection among Risk factors for TB infection among household contactshousehold contacts

• Cross sectional study; 342 index cases and their 500 household contacts identified. Prevalence of TB infection among household contacts was 47.80 %

• Multivariate analysis: close contact; exposure to a female index case; exposure to cavitary disease; a crowded household and those with 3 + smear grade

South East Asian journal of Tropical Med 2004 June

• addendum: HIV ? Younger patients, males ( Am J Epi 2001; 154: 934-43 )

Other recent data Other recent data

• Prevalence of TB Infection among household* contacts was 34 % if smear positive and 10.7 % if only culture positive

• If culture negative: it was 7 %

* close relatives or friends 4 %

Comstock GW : Epidemiology of TB 2000

Nosocomial TransmissionNosocomial Transmission

• Delays in diagnosis and treatment

• Median duration between onset of symptoms and initiation of treatment was 44 days ( Australia , Turkey )

• USA: 6-14 days ( One study )

• Only 16 % of patients isolated

• N95 vs surgical masks and leakage issues

• “Ladies and gentlemen, thank you for flying with us……”

Air travelAir travel

• Quality of air better than most similar

enclosed places on ground• 20-30 air exchanges per hour ( 6-12 per hour in

hospitals isolation room• 50% recycled cabin air through HEPA filters• 99% of particulate matter 0.1-0.3 μm• 2 rows/8 hours limit• Problem when waiting/parked on ground etc

Transmission factorsTransmission factors

• Infectiousness of the index case

• Duration of exposure

• Proximity and closeness of the contact

Essentially the same

Quantiferon TB Gold -1Quantiferon TB Gold -1

• Unaffected by BCG and NTM• TB-specific antigens are only present in M.TB• INF-Gamma in whole blood with an ELISA

measurement• 90% SENSITIVITY IN Culture + TB• 98% SPECIFICITY IN Culture + TB www.cellestis.com

Further references : lancet 2004 Dec Volume 4;

QUANTIFERON GOLD - 2QUANTIFERON GOLD - 2INF-Gamma based assayINF-Gamma based assay

• Advantages: More Specific ,( BCG/MOTT), One visit; good correlation with TST

• Disadvantages: Technical, Analysis software, Blood, Cost,Usage, Refrigerated

• Components: ESAT-6 antigen, CFP-antigens

• Limitations: Not tested in IM states/children

ELISPOT & ELISAELISPOT & ELISA

• Both tests have higher specificity than TST• Higher diagnostic sensitivity than TST 70-97%

• Further increase in sensitivity with T cell INF γ release assay (TIGRA)

• ?? Decreased levels as a marker for treatment response???

Ref: Lalvani Chest 2007;131:1898-1906

Relative Increased Risk for developing Relative Increased Risk for developing Active TB by selected conditionsActive TB by selected conditions

• Silicosis………………… 30%• DM……………………… 2-4 %• CRF…………………….. 10-25%• Gastrectomy…………… .2-5%• J-I Bypass………………. 27-63%• Solid Organ Transplant….37% / 70%• Carcinoma of head or neck 16%

A “positive” PPD: suggested planA “positive” PPD: suggested plan

QUANTIFY RULE OUTACTIVE DISEASE

RULE OUTEXTRA-PULM DIS

SIZE OF PPDIN CHILDREN

LTBI

DOCUMENT SYMPTOMSH/P

ROSLN EXAM

GO BACKTo STEPS B&CIF IN DOUBT

RISK OF ADR

CHECK HIV CXR CORELATEWITH CXR

PRE-LAB

STRATIFYRISK,CHECKINDEX CASE

SPUTUM PRE-TEST? IF SURE GO TOSTEP E

TREAT FOR LTBI

CONCLUDE:IF POSITIVESTEPS B-E

PRE-TEST?TREAT FOR TB ?

TREAT? FOR TB MONITORSIDE EFFECTS

A : DATA B: EVALUATE C: SCAN D : RECAP E: TREAT

JALI

steps

Part B: Active Disease Specific Diagnosis & “DOST” Treatment Issues & DOTS

Latest National Statistics* MMWR Latest National Statistics* MMWR 20072007

• 13767 TB cases in 2007 @ 4.6 per 100K

• 3.2 % decline from 2005

• Less decline than previously ( 7.3 % )

• Highest rates in FB individuals

• Blacks 8.4 times higher

• Asians 2 times higher

• Hispanics 7.6 times higher than whites

Contd…Contd…

• Mainly from Mexico, Philippines, Vietnam , China and India

• 124 MDRTB in 2005

• FB 81 % of MDRTB

• XRDTB: 17 cases reported between 2000 -2006

“In the future it will not be difficult to decide what is tuberculosis and what is not. The demonstration of tubercle bacilli ….will settle the question”

Robert Koch

Verily thou dost DOTS*

But pray, dost thou DOST**

and this is not Shakespeare

DOTS*: Direct Observed Therapy Strategy

DOST**: Direct Observed Induced Sputum Test

JValidated by Swiss studySee reference quoted. &CID 2007;44:1415-20

SputumSputum

• Timing & Technique : “DOST” *

• Character

• Quantity

• Labeling as Induced sputum looks like saliva and may be discarded by lab

• To be AFB positive we need 10000 organisms /cc of sputum

Yaeger et al Am Rev 1966;95 998-1004 * my term

VolumeVolume

• Sputum > 5 cc • 1849 patients 39 month period sensitivity

was 92 % when volume was > 5 cc• 3486 patients 24 month period when all

sputum processed regardless of volume Sensitivity was 72 .5 %

Warren et al Am J Respir CC 2000 May; 161(5): 1559-52

Direct vs. conc. smears Direct vs. conc. smears

• 2693 specimens evaluated; 353 were culture positive .

• Of them :

• Sensitivity of direct smear 34- 42 %

• Sensitivity of conc. smear 58- 71 %

Peterson et al J Clin Micro 1999 37 ( 11)

The issuesThe issues

• Little supervision; the “give the cup” approach• Bacterial contamination• Only 30 % positivity in the first sputum although

incremental yield beyond 3 is doubtful• ( S:47%/C:74% to S:58%/ C: 90%) • Depends upon cavitary disease or non cavitary

disease• Single vs.24-72 hour pooled specimen: No

difference except increased bacterial contamination (2%) increased to 15 %

Krasnow et al Appl Micro 1969;18:915-917Kestle DG et al Am J Clin Path 1967;48:347-349

2 vs. 32 vs. 3

• Screening TB suspects using 2 sputum smears

• 2 smear :186 / 1152 16 % suspects were smear positive

• 3 smear: 173/1106 ( 16 % ) were smear positive

Harries et al NTB control Prog Liver pool

In J Tb 2000 4 (1) 36-40

The second and the third smearThe second and the third smear

• Incremental yield from a third serial smear ranged from 0.7 % to 7.2 5 Between 122- 796 smears are required to identify one additional case with a third serial sputum smear.

• Incremental yield from second serial follow up smear ranged from 4.5 % to 26.9 % and 164-2133 slides were reqd. to identify one additional failure with a second serial smear.

IUATLD 2005 Vol 9 # 4 Reider and Chang

Sputum Induction (SI )Sputum Induction (SI )

• SI produced a positive smear in 29 % of patients with suspected TB who were previously been smear negative or unable to expectorate

Harrtoung et al S AFR Med J 2002 Jun 92 (6)

Comparison of SI with FOB Comparison of SI with FOB

• 101 patients• High prevalence area ( Brazil )• **In both HIV and non HIV patients;• Sen & NPV For FOB 73% & 91 % resp.• Sen. & NPV for SI 87 % and 91 % resp.• with kappa value 0.92

Anderson et al Am J Resp CC 1995 , Nov 152 Conde et al Am Rev 2000 Dec**

In Endobronchial DiseaseIn Endobronchial Disease

• 50 smear negative TB ( India )

• Br. Aspirate and Post bronch sputum positive in 12 and 14 cases respectively

• Bronch was positive in 28, being the only positive sample

• 45/ 50 were culture positive with brushings

Chawla et al Eur Respi J 1988 Oct (9)

BulletsBullets

• 2 sputum smears as good as 3 even for infection control purposes but….

• Volume of sputum 5cc or more improves sensitivity

• If ES negative; SI adds up to 19-30 % in sensitivity in suspected cases

• FOB with Bronchial washing if less than 50 cc, there is no difference in sensitivity

• FOB with BAL better if return more than 50 cc and sensitivity increased if PCR also done

Ref: Thorax 2002 : 57 1010 Nelson et al J Clin Micro 1999 36 (2)

The success of DOTS

Completion range of Rx strategiesCompletion range of Rx strategies

0

10

20

30

40

50

60

70

80

90

100

SAT Mod. DOT DOT E DOT

JAMA 1998; 279: 943-948

The Real Life Algorithm* .. 2/4 or 2/7 or 3/3

Dx of TB (Class 3 or 5 Start RIPE DOT DAILY/Bi weekly*

RIPE******* Culture back ********** Pan sensitive ***RIP(drop E) 2 month Sputum culture negative

***Drop PZA *** RI ******0…… 2-4 weeks……..6 weeks 8-12 wks …….6mths ………….9mths* Check dosage

Smear negative………….Smear negative………….Looks like……..Looks like……..

Looks like TB but is smear negative!

High Index ofsuspicion

Low Index of suspicion

No ATT; pursue other Dx

Culture NegativeNo CXR change

? Rx for LTBI

RIPE Rx

If cultures +…..continue protocol Rx If cultures negative

If Improved,CompleteRx

If no changeComplete Rx?Reevaluate

Part C: DRUG RESISTANT TB

Primary drug-resistance is said to occur in a patient who has never received antituberculosis therapy.

Secondary resistance refers to the development of resistance during or following chemotherapy, for what had previously been drug-susceptible

tuberculosis

• DRTB: The term "drug-resistant tuberculosis" refers to cases of tuberculosis caused by an isolate of Mycobacterium tuberculosis, which is resistant to one of the first-line antituberculosis drugs: isoniazid, rifampin, pyrazinamide, or ethambutol.

• Multidrug-resistant tuberculosis (MDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid and rifampin, and possibly additional chemotherapeutic agents.

• Extensively drug-resistant tuberculosis (XDR-TB) is caused by an isolate of M. tuberculosis, which is resistant to at least isoniazid, rifampin, fluoroquinolones, and either aminoglycosides (amikacin, kanamycin) or capreomycin, or both

The Story of MDRTBThe Story of MDRTB

• Exists and ongoing throughout the world over the years.. Russia, Far East, South Asia; Globally 400K cases reported

• 1990s Several outbreaks in hospitals and correctional facilities in NY and Florida; Mostly HIV, 80% mortality; Dx-Death time 4-16 weeks

• Nosocomial transmission; not more contagious but more difficult to treat

• Lower cure rate and Cost differential

XDRTB in the limelightXDRTB in the limelight

Lancet 2006: Gandhi et al

Dx-Death period: 16 days

HIV population

This report summarizes the results of that survey, which determined that, during 2000--2004, of 17,690 TB isolates, 20% were MDR and 2% were XDR.

Population-based data on drug susceptibility of TB isolates were obtained from the United States (for 1993--2004), Latvia (for 2000--2002), and South Korea (for 2004), where 4%, 19%, and 15% of MDR TB cases, respectively, were XDR.

MMWR 3/200655(11);301-305

                                                       

Public Health & Research agenda Public Health & Research agenda for TB Controlfor TB Control

• Streamline rapid diagnostic methods: more studies on INF-γ tests• Shorten and simplify Rx for DS TB• Improve Rx for DR TB• Efficient and effective Dx & RX and registry for LTBI• Once a week regimens• Combination of Moxifloxacin and Rifapentine?• Improved drug delivery system• ?Nutritional supplements; • Identification of predictors of relapse• Identification of predictors of non- compliance!!!!• Cytokine inhibitors / Role of arginase / iNO• ?INF-γ /Interleukin 2 administration

At a Public Health levelAt a Public Health level

LabSupport

Clinics

FieldWorkers

Academia CommunityMDs

State/Public Health Experts

$$ Priorities

Politics

Patient care Societal /Public Health

Pivotal roles or the “Bermuda Triangle”

TB control: As simple as thisTB control: As simple as this

Thank you; J

As far fetched as this ?As far fetched as this ?