TUBERCULOSIS

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The Alphabet Soup in TB and MOTT
Juzar Ali M.D., FRCP(C), FCCP (Russell C. Klein
M.D.  LSU ALUMNI Professor of Medicine) Vice
Chair (Clinical) Department of Medicine Director
LSU Chest LSU-Wetmore TB Clinics Section of
Pulmonary  Critical Care Medicine Louisiana
State University Health Sciences Center NEW
ORLEANS April 2008
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Objectives

• 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

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Sm C Sm - C Sm C--
MOTT
DRTB MDRTB XDRTB
DOT DOTS
DOST?
LTBI BCG INF-G
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TUBERCULOSIS

• ACTIVE DISEASE
• LATENT INFECTION

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PUBLIC HEALTHCLASSIFICATION

• 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

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• Part A LTBI

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Latent TB InfectionDefinition?

• 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

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The triple issues of LTBI

BCG
BCG
LTBI
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
antigenic Specific T cell response Deleted
segment ROD1 Early secretory antigenic target-6
ESAT-6 Culture filtrate Protein 10
CFP-10 Checking for the TB footprint Technical
Cost ?
ELISPOT test ELISA Quantiferon Gold
INF?
PPD/ TST
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PPD 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

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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 Bei Shandong MU China IUTLD 2000 4 ( 3 )
275
gt 5 mm, 10, 7.5
CID 200744
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Risk factors for TB infection among household
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 )

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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

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Nosocomial 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

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• Ladies and gentlemen, thank you for flying with
  us

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Air 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

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Transmission factors
Essentially the same

• Infectiousness of the index case
• Duration of exposure
• Proximity and closeness of the contact

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Quantiferon 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
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QUANTIFERON GOLD - 2INF-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

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ELISPOT ELISA

• Both tests have higher specificity than TST
• Higher diagnostic sensitivity than TST 70-97
• Further increase in sensitivity with T cell INF ?
  release assay (TIGRA)
• ?? Decreased levels as a marker for treatment
  response???

Ref Lalvani Chest 20071311898-1906
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Relative Increased Risk for developing Active 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

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A positive PPD suggested plan
JALI
A DATA B EVALUATE C
SCAN D RECAP E TREAT
QUANTIFY RULE OUT ACTIVE DISEASE RULE OUT EXTRA-PULM DIS SIZE OF PPD IN CHILDREN LTBI
DOCUMENT SYMPTOMS H/P ROS LN EXAM GO BACK To STEPS BC IF IN DOUBT RISK OF ADR
CHECK HIV CXR CORELATE WITH CXR PRE-LAB
STRATIFY RISK,CHECK INDEX CASE SPUTUM PRE-TEST? IF SURE GO TO STEP E TREAT FOR LTBI
CONCLUDE IF POSITIVE STEPS B-E PRE-TEST? TREAT FOR TB ? TREAT? FOR TB MONITOR SIDE EFFECTS
steps
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• Part B
• Active Disease
• Specific Diagnosis DOST
• Treatment Issues DOTS

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Latest National Statistics MMWR 2007

• 13767 TB cases in 2007 _at_ 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

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Contd

• Mainly from Mexico, Philippines, Vietnam , China
  and India
• 124 MDRTB in 2005
• FB 81 of MDRTB
• XRDTB 17 cases reported between 2000 -2006

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• 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

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• 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

J
Validated by Swiss study See reference quoted.
CID 2007441415-20
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Sputum

• 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 196695 998-1004
  my term

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Volume

• Sputum gt 5 cc
• 1849 patients 39 month period sensitivity was
  92 when volume was gt 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

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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)

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The issues

• Little supervision the give the cup approach
• Bacterial contamination
• Only 30 positivity in the first sputum although
  incremental yield beyond 3 is doubtful
• ( S47/C74 to S58/ 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 196918915-917
• Kestle DG et al Am J Clin Path 196748347-349

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2 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

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The 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

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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)

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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

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In 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)

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Bullets

• 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)

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The success of DOTS
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Completion range of Rx strategies
JAMA 1998 279 943-948
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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


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Smear negative.Looks like..
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Looks like TB but is smear negative!
Low Index of suspicion
High Index of suspicion
RIPE Rx
No ATT pursue other Dx
If cultures ..continue protocol Rx
If cultures negative
Culture Negative No CXR change
If Improved, Complete Rx
If no change Complete Rx? Reevaluate
? Rx for LTBI
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• Part C DRUG RESISTANT TB

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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
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• 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

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The 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

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XDRTB in the limelight

• Lancet 2006 Gandhi et al
• Dx-Death period 16 days
• HIV population

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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 3/2006 55(11)301-305
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Public Health Research agenda for TB Control

• Streamline rapid diagnostic methods more studies
  on INF-? 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-? /Interleukin 2 administration

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At a Public Health level
Societal / Public Health
Patient care
State/Public Health Experts
Clinics
Politics
Lab Support
Field Workers
Community MDs
Academia

Priorities
Pivotal roles or the Bermuda Triangle
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TB control As simple as this
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As far fetched as this ?
Thank you J