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
Objectives
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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--
DRTB
MDRTB
XDRTB
DOT
DOTS
DOST?
LTBI ; BCG ; INF-G
MOTT
TUBERCULOSIS
• ACTIVE DISEASE
• LATENT INFECTION
PUBLIC HEALTH
CLASSIFICATION
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Class 0
Class 1
Class II
Class III
Class IV
Class V
No Exposure, No Infection
Exposure , No Infection
Infection , No Disease
Current Disease
No Current Disease
Suspect
Part A : LTBI
Latent TB Infection
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 LTBI
BCG
BCG
*Poor Specificity in BCG vaccinated persons
*Low sensitivity in Immune compromised hosts
*Logistical drawbacks
*Overall no show rate 40%*
At Wetmore 21%** completion rate
LTBI
PPD/ TST
Based on Mycobacterial genomics and antigen
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 ?
INFγ
ELISPOT test
ELISA Quantiferon Gold
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
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
42 % +
** 16 % healthy population sample
Lutong & Bei
Shandong MU China
IUTLD 2000 4 ( 3 ) 275
34 % +
not close sporadic
13 % **+
all household contact 30 %
*+ = > 5 mm, 10, 7.5
* CID 2007:44
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 )
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 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 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 factors
Essentially the same
• Infectiousness of the index case
• Duration of exposure
• Proximity and closeness of the contact
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;
QUANTIFERON GOLD - 2
INF-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, CFPantigens
• Limitations: Not tested in IM
states/children
ELISPOT & 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
Active TB by selected conditions
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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%
JALI
A “positive” PPD: suggested plan
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 B&C
IF IN DOUBT
RISK OF ADR
CHECK HIV
CXR
CORELATE
WITH CXR
STRATIFY
RISK,CHECK
INDEX CASE
SPUTUM
PRE-TEST?
CONCLUDE:
IF POSITIVE
STEPS B-E
PRE-TEST?
TREAT FOR
TB ?
TREAT? FOR TB
steps
PRE-LAB
IF SURE GO TO
STEP E
TREAT FOR
LTBI
MONITOR
SIDE EFFECTS
Part B:
Active Disease
Specific Diagnosis & “DOST”
Treatment Issues & DOTS
Latest National Statistics* MMWR
2007
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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…
• 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
J
Validated by Swiss study
See reference quoted. &
CID 2007;44:1415-20
Sputum
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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
Volume
• 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
• 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 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;18:915-917
Kestle DG et al Am J Clin Path 1967;48:347-349
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
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 1642133 slides were reqd. to identify one additional
failure with a second serial smear.
IUATLD 2005 Vol 9 # 4 Reider and Chang
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
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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 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)
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)
The success of DOTS
Completion range of Rx strategies
100
90
80
70
60
50
40
30
20
10
0
SAT
Mod. DOT
JAMA 1998; 279: 943-948
DOT
E DOT
The Real Life Algorithm*
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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
0…… 2-4 weeks……..6 weeks 8-12 wks
* Check dosage
*** RI ******
…….6mths
………….9mths
Smear negative………….
Looks like……..
Looks like TB but is smear negative!
High Index of
suspicion
RIPE Rx
If cultures +…..continue protocol Rx
If cultures negative
If Improved,
Complete
Rx
If no change
Complete Rx?
Reevaluate
Low Index of
suspicion
No ATT;
pursue other
Dx
Culture Negative
No CXR change
? Rx for LTBI
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 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 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 3/2006
55(11);301-305
Public Health & Research agenda
for TB Control
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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 level
Societal /
Public Health
Patient care
Clinics
State/Public Health
Experts
Politics
Lab
Field
Academia Community $$
Support Workers
MDs
Pivotal roles or the “Bermuda Triangle”
Priorities
TB control: As simple as this
As far fetched as this ?
Thank you; J