100
100
100
100
100
100
200
200
200
200
200
200
300
300
300
300
300
300
400
400
400
400
400
400
500
500
500
500
500
500
Jeopardy Value
Extraction of DNA; hybridization of
labeled PCR products with
oligonucleotide probes; according to the
CDC, this must be performed on at least
one respiratory specimen from each
patient with clinical suspicion of TB,
where diagnosis has not yet been
established
What are nucleic
acid amplification
tests?
Jeopardy Value
3% to 7% of sputum
specimens have this,
Less than 50% of labs do this
What are tests for
NAA inhibitors?
NAA
• CDC recommends that standardized NAA
testing be performed on at least one
respiratory specimen from each patient
with clinical suspicion of TB, where Dx
has not yet been established, and for
whom the result will alter management
and TB control measures/contact
investigations
MMWR Jan 2009/58(01);7-10
NAA
Ampl MTB direct test
MTD (Gen-probe)
Enhanced Amplicor (Roche)
test
Greater PPV /NPV and SS in smear positive cases ) 80-95%
Lower sensitivity and PPV in smear negative cases 50% appx
Earlier Detection
Less inappropriate use of FQ as empiric monotherapy for pneumonia
Reliance by MDs: 20-50% of cases
NAA testing should be considered as Critical test value notification
Report time less than 48 hours.
If clinical suspicion is low, do not do NAA as PPV low
If clinical suspicion moderate or high: single NAA negative should not be relied upon
MMWR Jan 2009
Interpretation of NAA
CLINICAL
SUSPICION
AFB smear
NAA result
HIGH
positive
positive
MTB (PPV 95%)
Rx Isolate and
Contact investigation
HIGH
Negative
positive
Repeat NAA; if
positive or clinical
suspicion high: Rx
as TB as above
Positive
negative
Repeat; test for Inhibitors,
if none
This is probably MOTT
If Inhibitors present NAA
no use
Decision to Rx ??
Adapted from AJRD 1997 #155 ; 1804
Jeopardy Value
This is based on
mycobacterial genomics and
antigen specific T cell
response, Antigenic targets
include ESAT-6 and CFP-10
What is the IGRA
test based on?
The blood test for TB
Global caution!!
IGRA* update
Advantages
Disadvantages
TIGRA preferred but TST acceptable
Homeless /Transitional Care/ Substance
abusers
TST is preferred
Children less than 5 years of age
Equally acceptable:
Contact screening* ( although higher PPV
and NPV seen ( 3% vs. 13 % and 99% vs..
ILH current priority list
100% when compared with TST 5mm
1. Employees
Am j Resp Crit Care 2011 jan
2. Immune compromised patients
3. Patients with Hx of BCG
4. Specific cases where differential Dx of pneumonia includes TB or MAC
5. Referral from Transitional Homes/ Shelters to UCC
)
Relationship of timing of TST to TIGRA: Variable conflicting data ; Present consensus : no effect on either test results or booster phenomenon or false positivity
Ref MMWR /CDC Rep 2010 : 59 (RR-5 :1-28
Jeopardy Value
NTM/MOTT
BCG
Technique
What are the
drawbacks of
TST/Mantoux
test/PPD?
No cross-reactivity to BCG and most NTMs
Antigens
Tuberculosis Complex
Antigens
Environmental Strains
ESAT-6
CFP 10
ESAT-6
CFP 10
M. tuberculosis
+
+
M. abcessus
-
-
M. africanum
+
+
M. avium
-
-
M. bovis
+
+
M. branderi
-
-
M. celatum
-
-
BCG substrain
gothenburg
-
-
M. chelonae
-
-
moreau
-
-
M. fortuitum
-
-
tice
-
-
M. gordonae
+
+
tokyo
-
-
M. intracellulare
-
-
danish
-
-
M. kansasii
+
+
glaxo
-
-
M. malmoense
-
-
montreal
-
-
M. marinum
+
+
pasteur
-
-
M. oenavense
-
-
M. scrofulaceum
-
-
M. smegmatis
-
-
M. szulgai
+
+
M. terrae
-
-
M. vaccae
-
-
M. xenopii
-
-
Watch for M. MSGK
Updated CDC Guidelines
CDC guidelines1 allow the use of IGRA or TST for screening
healthcare workers:
 “An IGRA or a TST may be used without preference for periodic
screening of persons who might have occupational exposure to M.
tuberculosis (eg, surveillance programs for healthcare workers).”
 IGRA preferred testing for groups with low rates of return
 IGRA preferred testing for individuals who have received
BCG
 “Prior to implementing IGRAs, each institution and tuberculosiscontrol program should evaluate the availability, overall cost, and
benefits of IGRAs for their own setting.”
 LSU/ILH guidelines : When DDx includes
Pneumonia/MAC/MOTT
 & with employees screening
1. Updated Guidelines for Using Interferon Gamma Release Assays to Detect Mycobacterium tuberculosis Infection - 2010. CDC MMWR 59 RR-5.
Commercially Available IGRAs
QuantiFERON®-TB Gold In-Tube1
The T-SPOT®.TB Test2

ELISA technology
ELISpot technology

Measures IFN-γ release
Enumerates effector T cells

“One and done”
“One and done”

PI sensitivity: 88.2%
PI sensitivity: 95.6%

PI specificity: 99.1%
PI specificity: 97.1%

3 specialized tubes
1 standard tube

Provides qualitative results
Provides quantitative and qualitative results

Sample stability: 16 hours
FDA-approved borderline category

Can be run in hospital lab
Sample stability: 32 hours

Available nationally through reference
laboratories (eg, Quest)
Can be run in hospital lab
Available nationally through Oxford
Diagnostic Laboratories®
1. QuantiFERON-TB Gold Package Insert. Cellestis, Inc. Valencia, CA. Doc. No. US05990301K, July 2011.
2. T-SPOT.TB Package Insert. Marlborough, MA: Oxford Immunotec; 2010. T-SPOT is a registered trademark of Oxford Immunotec, Ltd. QuantiFERON is a
registered trademark of Cellestis, Inc.
Questions We Ask ?
• TST and IGRAs : predictors of disease : General
• Does quantifying help in either case ?
• Specific Quantification in TB spot test : Culture filtrate
protein 10 spot count, but not early secretary antigenic target 6
spot count, was significantly associated with subsequent TB
development. ( Hongkong study in silicotic pts )
• Issue of discordance & Borderline data
• Effect of Smoking Negative effect of smoking on the performance of the QuantiFERON TB gold in
•
tube test BMC Infectious Diseases 2012, 12:379 doi:10.1186/1471-2334-12-379
•
IMPORTANCE OF DEFINITION OF CONVERTORS OR REVERSION
SPECIALLY IN HCWs
Challenges of IGRAs conversion in serial testing of HCW : Fong et al Chest 2012 ;142 (1): 55-62
Active Vs latent
•
IGRA responses are higher in active disease than in LTBI
–
However, there is a very large overlap in the results so it will not be possible to use IGRAs to
differentiate between active disease and latent infection
Chee et al Eur J Clin Microbiol
Infect Dis (2008)
Janssens et al ERJ (2007)
T-SPOT.TB spot numbers in subjects with active
disease compared to LTBI (TST+ve and TST-ve)
T-SPOT.TB spot numbers in subjects
with active disease compared to LTBI
Explaining discordant results; TNF screening
70 subjects attending a rheumatology
clinic in Athens
•
All candidates for anti-TNF therapy
•
43/70 on immunosuppressive drugs
•
15/70 had co-morbid conditions (e.g.
chronic liver disease, diabetes, COPD)
•
Results of TST and the T-SPOT.TB test
compared, multivariate analysis used to
analyse discordant results
TST
T-SPOT.TB
•
+
-
Total
+
12
4
16
-
15
39
54
Total
27
43
70
Vassilopoulus et al., J Rheumatology (2008)
“(BCG) vaccination was associated with TST+/Elispot– discordant
results (p = 0.01), whereas steroid use was linked to TST–/Elispot+
discordant results (p = 0.04).”
Jeopardy Value
Must check for active TB
Do not forget to look for
extra- pulm TB
What do you do before
starting treatment for
latent TB?
JALI
A “positive” TST / IGRA : suggested plan
A : DATA
steps
QUANTIFY
ASSESS
BORDERLINE
B: EVALUATE
C: SCAN
D : RECAP
E: TREAT
RULE OUT
ACTIVE
DISEASE
RULE OUT
EXTRA-PULM
DISEASE
SIZE OF TST: is it
helpful?
IN CHILDREN;
Degree of IGRA
??
Dx; LTBI
Should we offer
Rx? Based on
many factors
DOCUMENT
SYMPTOMS
H/P
ROS
LN EXAM
GO BACK
to STEPS B&C
IF IN DOUBT
RISK OF ADR*
CHECK HIV
CXR
CT Scan if needed
CORRELATE
with Chest
imaging
STRATIFY
RISK, CHECK
SOURCE CASE
WHY???
SPUTUM
INDUCE if
needed
PRE-TEST
PROBABILITY?
CONCLUDE
AFTER FULL
EVALUATION:
IF POSITIVE
STEPS B-E
PRE-TEST
PROBABILITY?
TREAT FOR
ACTIVE
TB ?
TREAT FOR TB ?
INDETERMINATE
DISCORDANT
RESULTS
PRE-LAB
CHECK
IF SURE GO TO
STEP E
TREAT FOR
LTBI.
ASSESS
RISK BENEFIT
RATIO
MONITOR
SIDE EFFECTS*
AND Rx
*ATS 2006 DILI consensus statement
Jeopardy Value
Must be DOT and it is not
treatment for active TB
What is
chemoprophylaxis
for latent TB by
intermittent
therapy?
Ripaentine / INH weekly
Jeopardy Value
13% to 22% of cohort
can acquire disease
form this group
What is
Smear negative TB?
The hidden reservoir of TB
• Smear negative cases: 13-22 % of cohort can
acquire disease from smear negative contacts
• Undocumented immigrants with prolonged
symptoms with poor access to health care
( CID 2008 Tostmann et al)
(Achkar et al Clin Infec Dis 2008 Nov)
Delay in Dx, Index of suspicion ( Surgical specialties)
Am J Med science 340 Nov 2010)
Note:
Infectious period 3 months prior to onset of symptoms
Only 20% of contacts with LTBI complete Rx.; Need to expand contact screening for Smear negative TB
(
Suspect cases
ILH data
• Suspect TB cases require Resp
Isolation
• Average cost of care 20 K per pt
• ALOS : may be as high as 22.7 days
When to hospitalize and when to discharge
Basis : NYC Health Dept criteria
IN-Patient
ED
Latent TB
TB
When to discharge
Avoid weekends
Check pt infection and clinical factors
Co morbid conditions
Home and follow up situations.
Depends upon where discharged to
Low Suspicion
For TB
When to admit?
Cavitary disease / Hx Substance abuse
Unstable medical /psych /social conditions
or unclear follow up situations
Jeopardy Value
Compliance
No DOT
Increase bacterial burden
Development of secondary
resistance
Malabsorption of Drugs
Host variation in response to drugs
“lab error”
What are
The causes of
delayed sputum
conversion and/or
treatment failure?
Therapy
•
Ideal Rx:
DOT “RIPE”
Duration: 6 months …..* 9 months in
special case scenarios
* When sputum culture is still positive at the end of 2 months
* CXR showed cavitary disease/ Initial high bacterial load
* When initial induction phase did not include PZA
* When induction phase was not “standard” i.e. once weekly
doses
Jeopardy Value
Sputum culture is
positive after 2 months
Cavitary, heavy smear
positive disease
PZA of RIPE not used.
When
Do you extend
treatment beyond 6
months?
Jeopardy Value
No SM
No PZA in USA
9 months at least
Vitamin B6 a must
What is
TB treatment in
pregnant womem?
Jeopardy Value
Side effects may be due to
longer intervals of dosing
rather then the actual dose
We may be using a lower
dose than is needed
What is
Rifampin and ?
issues with
standard dosage?
Jeopardy Value
23% of MDR-TB
are this
What is
XDR-TB?
RISK Factors for DR; MDRTB and
XDRTB
• Inadequate Rx protocols and non
compliance
• Question of low level resistance and
importance there of
• Previous TB Rx OR 11; HIV OR 3 ,
Homelessness OR 3, ETOH abuse OR 2
( Annals June 2009 )
• Rifampin Resistance is an excellent
marker for MDRTB
Where are we moving forward ?
• Old drugs ; Newer drugs and newer class of drugs ( focus has
moved to out of USA to Japan , India )
• Other approaches : targeting MTB proteins*
• Drug delivery : Inhaled administration
• Revisit Rifampins ( Dose, toxicity concerns ( immunologic and idiosyncratic ) , association with PZA ,
•
Drug levels, D-D interaction )
Caution about Flouroquinoles
Mitnick et al NJMRC Denver Expert Opinion Pharmacoth 2009
( *Nature 2009 : Lin et al )
Jeopardy Value
KatG gene
aphC gene
What is the
the genetic basis of
INH resistance?
Detecting drug resistance
􀂄 Rifampicin resistance: Mutations in β subunit of RNA
polymerase
􀂄 >90% of mutations in 81 base pair region
􀂄
Isoniazid resistance – more complex
􀂄 katG gene (peroxidase) mutations
􀂄 inhA gene mutations – cell wall synthesis
􀂄 others - aphC gene mutations
􀂄PCR-based detection
􀂄 GenoType MTBDRplus (Hain Lifescience)
􀂄
USED RECENTLY AT WETMORE
Jeopardy Value
It is not coming soon
It is here
90% sensitive/specific
What is
The XPERT Test?
Detecting drug resistance
􀂄 Rifampicin resistance: Mutations in β subunit of RNA polymerase
􀂄 >90% of mutations in 81 base pair region
􀂄
Isoniazid resistance – more complex
􀂄 katG gene (peroxidase) mutations
􀂄 inhA gene mutations – cell wall synthesis
􀂄 others - aphC gene mutations
PZA : mutations in gene pncA
􀂄
􀂄 PCR-based detection line probe assay
􀂄 GenoType MTBDRplus (Hain Lifescience)
XPERT Testing FIND Inititative
It is not coming soon, it is here ( 90% S/S)*
* NEJM , Eur Pub June 2011
􀂄
Jeopardy Value
•
•
•
•
•
Delayed conversion
Increased bacterial load
??Erratic Drug response and levels
Increased rates
Double jeopardy
Relapse of PTB after sputum
conversion after SCC
• Followed for 3 years
• 3.29 %
• Those who became smear negative after 3
months of Rx had a relapse rate of 8.8 %
• Relapse rate about 10 % in Diabetics
CDC data from NC Public health dept
High risk for treatment failure or
relapse
HIV / DM
When second line Rx used
**Cavitation on initial CXR
**Positive Sputum Culture after 8 weeks
of Rx.
** When PZA is not used in the
Intensive phase
US PHSS 22 TB Consortium trial 1993-2002 cohort and ATS guidelines
Relapses
• In nearly all patients with TB caused by
drug susceptible organisms and who are
treated with Rif –containing regimens using
DOT Rx, relapses occur with susceptible
organisms
Jeopardy Value
Dec levels Reported in TB patients
Decreased levels /Receptor polymorphism
associated with increase susceptibility to MTB
Can suppress intracellular growth of MTB in
vitro
Induces expression of autophagy, phagosomal
maturation, antimicrobial peptides such as
cathelicidin
Enhances the activity of PZA
What is
Vitamin D?
VITAMIN D
• TB and nutritional deficiency : A historical fact
• Vit D deficiency reported in TB pts
• Vit D receptor polymorphism associated with
increased susceptibility to MTB
• Vit D can suppress intracellular growth of MTB in
vitro
• Vit D also induced expression of autophagy,
phagosomal maturation, antimicrobial peptides
(cathelicidin,
• Enhanced activity of PZA
•
Amer Jour Med Sciences 341 June 2011 Science Tran s Med Oct 11
Jeopardy Value
Seen in at least one TB
drug in about 46% of
cases
Data shows significant
scatter
What are
Low drug levels?
Done at wetmore
•*Thee et al In J Tuberc 2007 (9) 937
•**Um et al In J Tuberc 2007
•*** Kimerling et al Chest 1998
Drug levels
• Due to PK and PD variability it is better to use
Body surface* area ,especially in children to
decide dosage and achieve better therapeutic
levels
• **Low 2 hr serum conc of at least one Anti TB
drug was seen in about 46%
• INH associated with acetyl INH/INH ratio and
ETH associated with Cr Cl;
• However significant scatter noted, many
variables such as ETOH use , fixed combination
etc and hence clinical relevance unclear.
Importance of looking at the therapeutic level
range
Done at wetmore
•*Thee et al In J Tuberc 2007 (9) 937
•**Um et al In J Tuberc 2007
Drug levels
• Body weight or Body surface* especially in
children
• **Low 2 hr serum conc was 46% INH and
Rifampin mainly associated with dose/kg
weight
• INH associated with acetyl INH/INH ratio
and ETH associated with Cr Cl;
• However significant scatter noted and
clinical relevance unclear
Drug Level Testing in TB Patients
2009 - 2012
50
45
40
# Pts tested = 47
35
30
27
25
21
20
15
15
10
5
3
2
1
0
1
Low Level Drugs
INH
RIF
EMB
PZA
Rb
INH & RIF
INH,RIF,PZA
Positive Culture Conversion to Negative:
Nml Levels vs. Low Drug Levels
7
9
Conversion data not avail/Xtra Pulm
22
Low level Conversion > 3 mos
Low level Conversion </= 3 mos
Nml level Conversion > 3 mos
1
Nml level Conversion </= 3 mos
8
0
5
10
15
# Pts tested = 47
20
25
Observation
• We observed at Wetmore Clinic in our
random , haphazard analysis that TB
patients with DM were requiring higher
dosage of TB Meds based on their drug
level data . This was specially seen with
PZA and Rifampin
Hypothesis
• Patients who have diabetes and TB have
lower blood drug levels of PZA , compared
to patients with TB without DM
• WE are looking at Rifampin levels and data
, but do not have that yet
PZA levels
Descriptive Statistics
N
Minimum
Maximum
Mean
Std. Deviation
INH
245
0
25
6.53
4.943
RIF
242
0
34
10.09
7.052
PZA
117
0
100
40.13
19.806
67
Valid N (listwise)
1. There were repeats and missing data cases among those 117 cases. Once the data was cleaned,
this was the outcome:
Group Statistics
PZA
DIABSTATUS
N
Mean
Std. Deviation
Std. Error Mean
1.0
5
34.800
13.4425
6.0117
.0
38
49.921
24.0106
3.8950
2. Of the 117 instances, 43 were true PZA individual cases.
Independent Samples Test
Levene's Test for Equality of
t-test for Equality of Means
Variances
F
Equal variances assumed
PZA
Equal variances not assumed
2.924
Sig.
.095
t
df
Sig. (2-
Mean
Std. Error
tailed)
Difference
Difference
95% Confidence Interval of the
Difference
Lower
Upper
-1.370
41
.178
-15.1211
11.0333
-37.4032
7.1611
-2.111
7.912
.068
-15.1211
7.1632
-31.6712
1.4291
3. Once the data is cleaned and analyzed, the significance level rises to above 0.05, meaning there is
no significant association. There is no difference between the PZA levels of those that are diabetic
versus the non-diabetic group.
Verbal communication A Ghaffar MD MPH&TM 2013
TUBERCULOSIS DISEASE:
DRUG LEVEL TESTING
CRITERIA FOR TESTING
1)Recurrent MTB disease of any site
2)MTB cases not converting to negative sputum smear @ 4 weeks
3)MTB cases not converting to negative sputum culture @ 8 weeks
4)MTB case with known drug resistant organisms
6)MTB case with HIV co-infection
7)MTB cases with abnormal Drug Blood Level results
8)Other MTB cases with administrative approval
Drug levels that should be tested include INH, Rifampin or Rifabutin, PZA and Moxifloxacin.
Other drugs can be tested upon administrative approval.
Drug levels ? Some questions
• Present practice; why the doses? RIF specially*
•
•
•
•
( Ingen et al CID 2011: 3 reasons
Drug conc above MIC, Fear of side effects, economic
600mg is at a lower end of the dose response curve; side effects not dose related :
idiosyncratic and immunological more, cost?)
Weight/gender/genetic variations/BSA may determine different dose
• Any reason to change practice since in most
cases of Rx failure , causes are multifactorial
• Side effects may be due to longer intervals of
dosage rather than dose
• Importance of tailoring Rx
• Do we re-set the clock?
Jeopardy Value
??
??
•Exposure
•Human to human
transmission
•Latent disease
•Pauci bacillary ?
•Reactivation
•Relapse
vs.
•Environmental/
Ingestion
•No H-H transmission
•Pauci bacillary
•Mixed infection
•Indolent
•New Infection
3 to 10 % incidence in clinical and
laboratory settings and data
•
What are NTMs
MYCOBACTERIUM
TUBERCULOSIS AND MOTT
Over the course of 4 years, data were collected on
Mycobacterium tuberculosis and MOTT, basically to compare
the number of patients infected with each of these organisms.
Patients with MTB are provided treatment at no cost through
the Public Health System. However, those unlucky patients
diagnosed with MOTT are on there own when it comes to
seeking treatment for their condition.
DUAL INFECTIONS
• As noted in the previous chart, there were 10
dual infections. Eight (8) of these were MTB
and Mycobacterium Avium Complex (MAC),
one (1) was MTB and Mycobacterium
fortuitum and one (1) was MTB and
Mycobacterium kansasii.
Relapse of PTB after sputum conversion
after SCC
• Followed for 3 years
• 3.29 %
• Those who became smear negative
after 3 months of Rx had a relapse
rate of 8.8 %
CDC data from NC Public health dept
High risk for treatment failure or relapse
HIV / DM* BMC Med 2011
When second line Rx used
**Cavitation on initial CXR
**Positive Sputum Culture after 8
weeks of Rx.
** When PZA is not used in the
Intensive phase
US PHSS 22 TB Consortium trial 1993-2002 cohort and ATS
guidelines
Pulmonary Disease
M. abscessus : Worldwide; may be found concomitant with
MAC
M. asiaticum* Rarely isolated
M. avium complex Worldwide; most common NTM pathogen
in U.S.
M. celatum* Cross-reactivity with TB-DNA probe
M. kansasii : U.S., Europe, South Africa, coal-mining regions
M. chelonae Pulm Disease ??
.
M. fortuitum Associated with aspiration
Contaminant
M Szulgai and M Chelonae and Eye disease
When the last ATS statement about NTM was prepared in 1997,
there were approximately 50 NTM species that had been identified.
Currently, more than 125 NTM species have been cataloged***
The increase relates to
**improved microbiologic techniques and identification
w cases of NTM lung disease may significantly exceed case rates for
in some communities and regions
,
**advances in molecular techniques with the development and
acceptance of 16S rRNA gene sequencing as a standard for
defining new species.
***Clinical significance??
•
Jeopardy Value
Photochromogen
•
Scotochromogen
•
• Non- chromogen
• What is the Runyon Classification of
Mycobacterial Disease ?
Classification of mycobacterial species commonly causing human disease
M. tuberculosis
complex
Slowly growing mycobacteria
M. tuberculosis
M. kansasii
M. bovis
M. marinum
M. africanum
Scotochromogens, Runyon group II
M. microti
M. gordonae
M. leprae
Photochromogens, Runyon* group I
M. scrofulaceum
Nonchromogens, Runyon group III
M. avium complex
M. avium
M. intracellulare
M. scrofulaceum
M. terrae complex
M. ulcerans
M. xenopi
M. simiae
M. malmoense
M. szulgai
M. asiaticum
Rapidly growing mycobacteria
Runyon group IV
M. fortuitum
The “Staph”
of mycobacteria
M. chelonae
M. abscessus
Pulmonary Disease
M. abscessus : Worldwide; may be found concomitant with
MAC
M. asiaticum* Rarely isolated
M. avium complex Worldwide; most common NTM pathogen
in U.S.
M. celatum* Cross-reactivity with TB-DNA probe
M. kansasii : U.S., Europe, South Africa, coal-mining regions
M. chelonae Pulm Disease ??
.
M. fortuitum Associated with aspiration
Contaminant
M Szulgai and M Chelonae and Eye disease
**Lung disease due to NTM occurs commonly in structural lung
disease, such as chronic obstructive pulmonary disease (COPD),
bronchiectasis, CF, pneumoconiosis, prior TB, pulmonary alveolar
proteinosis, and esophageal motility disorders
**Abnormal CF genotypes, CFTR Gene mutation and _1-antitrypsin (AAT) phenotypes
may predispose some patients to NTM infection
**NTM lung disease also occurs in women without clearly recognized
predisposing factors There is also an association between bronchiectasis, nodular
pulmonary NTM infections and a particular body habitus,
predominantly in postmenopausal women (e.g., pectus
excavatum, scoliosis, mitral valve prolapse)
“A mean MAC machine in the thin and lean”
**Bronchiectasis and NTM infection,
usually MAC, often coexist, making causality difficult to
determine. These patients may carry multiple MAC strains over
time, suggesting either polyclonal infection or recurrent infection
with distinct strains). It is unclear whether this problem is
due to local abnormalities (e.g., bronchiectasis) or to immune defects
Am J Respir CC M 178; 1066-1074 , 2008 NHLBI
Semi-quantitative analysis of smears can be useful for diagnostic
and post Rx follow up purposes.
The burden of organisms in clinical
material is usually reflected by the number of organisms seen
on microscopic examination of stained smears.
Environmental
contamination, which usually involves small numbers of organisms,
rarely results in a positive smear examination.
Previous studies have indicated that specimens with a high number o
mycobacteria isolated by culture are associated with positive
mears and, conversely, specimens with a low number of mycobacteri
isolated by culture are less likely to have positive smears
ATS Recommendations:
1. As much material as possible for NTM culture should be
provided with clear instructions to the laboratory to culture
for mycobacteria (C, III).
2. All cultures for NTM should include both a rapid detection
broth (liquid) media technique and solid media cultures
(C, III).
3. Quantification of the number of colonies on plated culture
media should be performed to aid clinical diagnosis (C,III).
4. Supplemented culture media and special culture conditions
(lower incubation temperatures) should be used for
material cultured from skin lesions, joints, and bone (A,II
5. The time (in days) to detection of mycobacterial growth
should be stated on the laboratory report (C, III).
Tumor Necrosis Factor Inhibition & NTM
IFN-_ and IL-12 control mycobacteria in large part through the
up-regulation of tumor necrosis factor (TNF)-_ made predominantly
by monocytes/macrophages.
The risk posed by TNF-_ blocking agents for predisposing to NTM
infections or promoting progression of active NTM infection is
unknown.
Expert opinion
is that patients with active NTM disease should receive TNF-_
blocking agents only if they are also receiving adequate therapy
for the NTM disease.
Pathophysiology of Bronchiectasis
related to mycobacterial disease
•
•
•
•
•
•
The inflammation /infection cascade
Interleukin,8, neutrophils, unopposed elastase and proteases
The effect of trans mural inflammation, edema, crater formation, ulceration,
Neo vacularization leading to permanent parenchymal damage
Different properties of sputum in dilated airways
Variance in mycobacterial genetic pool
Variance in strains
Jeopardy Value
•
•
•
•
•
•
•
? Colonizer
Indolent disease
Nodular Disease
Bronchiectasis
Fibro cavitary Disease
MDR disease
Hypersensitivity
What are the many faces of NTM
specially MAC ?
A 52-year old Caucasian woman sought medical attention due to chronic cough. Physical
exam was unremarkable. Sputum culture revealed light growth with few colonies of
Mycobacterium avium complex (MAC). Repeat sputum cultures later again revealed a few
colonies of MAC. The patient was treated symptomatically and followed clinically by serial
sputum test (s) and radiographic evaluation. No specific therapy for MAC was initiated and the
patient did well, remaining asymptomatic.
: Wheezing; Dx Asthma
CXR Nodular opacities ? TB Started RIPE
Tr Bx Bx: Granulamatous Inflammation
Br Wash: MAC
MAC “Hot tub Lung” ;
or
Sarcoidosis with MAC?
: Culture positive TB on Rx;
Subsequent 7 sputa all culture negative for TB ,
positive for MAC
Figure 6
A 76- year old Caucasian woman, smoker, with past
history of TB, treated completely in the 1960’s, was seen
with cough and minimal shortness of breath. Pulmonary
function tests revealed moderate obstructive airways
dysfunction. Sputum tests revealed moderate growth of
Mycobacterium avium complex on repeated
examinations. The patient was placed on daily treatment
with clarithromycin and ethambutol with bronchodilators.
She remained stable on this regimen without any acute
exacerbations. Serial sputum cultures intermittently
revealed light growth of Mycobacterium avium complex.
A 65-year old woman with a history of nonspecific interstitial pneumonitis (NSIP) and pulmonary fibrosis
and with documented Mycobacterium avium complex (MAC) on repeated sputum cultures since 2003
was admitted in March 2006 with increasing dyspnea and respiratory failure. Prior to admission she had
had multiple sputum cultures which were positive for MAC and sensitive only to high dose
clarithromycin, ethambutol and rifabutin with which she was treated for 18 months. Due to concomitant
and repeated growth of methicillin-resistant Staphylococcus aureus (MRSA), she was also given
linezolid intermittently. She was admitted to the hospital and treated empirically with broad-spectrum
antibiotics while her MAC treatment was continued due to persistently positive sputum cultures. She
failed to respond to therapy and died after a month of hospitalization due to progressive respiratory
failure
.
MAN!! The Mycobacterial Highway
TB? RIPE
MK
MAC
MC
A
A 42-year old man with history of treated TB in 1980 developed fibrocavitary MAC infection in 1993. His treatment with
ethambutol, rifabutin and clarithromycin was erratic due to non-adherence. He was admitted to the hospital in March 2004
with increasing cough, night sweats and a ten pound weight loss. No culture and sensitivity data were available. With the
history of erratic treatment, presumed macrolide resistance and unilateral fibrocavitary right sided disease, he was
evaluated for surgical excision and pneumonectomy. His pulmonary function tests revealed a FEV1 of 1.4 L and a split
perfusion pulmonary scan showed one percent perfusion of the right lung and 99% of blood flow to the left lung. The
patient had a complicated operative and perioperative course and died of respiratory failure after a month long stay in the
ICU.
A 50-year old man with severe COPD and bronchiectasis was on long term treatment for
Mycobacterium avium complex pulmonary disease (MAC-PD) initially and later for macrolideresistant MAC (MRMAC). He was admitted in moderately severe respiratory distress with fever and
increasing cough. In addition to the multiple drugs used for the treatment of this patient though the
course of his illness, therapeutic trials of thalidomide, interferon gamma and high dose mefloquine
were given. Due to progressive bilateral disease and poor pulmonary function, surgery was not
considered. (The patient later died of respiratory failure and overwhelming infection)
.
ENVIRONMENTAL LUNG DISEASE OUTPATIENT CLINIC
NON-TUBERCULOUS MYCOBATERIAL DISEASE NTM PROTOCOL
Identify which NTM the patient has
Check for predisposing factors
Check environmental factors/ contacts and history
Check for systemic immune deficiencies
Check for local structural deficiencies
Stage the patient based on clinical, radiographic and bacteriological data.
Staging & Mgm plan
Stage 1 – Mild intermittent disease: surveillance and environmental controls
Stage 2 – Mild to moderate disease: above measures in addition to emphasizing bronchial toilet
Stage 3 – Moderate disease: surveillance, environmental controls, bronchial toilet plus oral treatment thrice weekly
Stage 4 – Moderate to severe disease: surveillance: environmental controls, bronchial toilet, oral DAILY treatment plus inhaled
antibiotics
Stage 5 – Severe disease – surveillance, environmental controls, bronchial toilet, daily oral customized treatment, inhaled antibiotics
with surgical options always to be kept in mind
Questions we need to ask when considering the treatment regimen of these patients:
What will the benefit of the treatment be to the patient?
What are the goals of this therapy?
What are the criteria of the outcome?
What will be the duration of treatment?
What are the expected side effects/tolerance in this patient?
What will we do to address these?
Developed: May, 2013
By: Juzar Ali, MD & Maureen S. Vincent, CLSS
LSUHSC Section of Pulmonary/Critical Care Medicine
Jeopardy Value
THIS IS THE CORNERSTONE OF DRUG
REGIMEN in MAC
•
WHAT IS A MACROLIDE /AZOLIDE?
Isolates of MAC have only a single copy of the ribosome, and hence,
macrolide monotherapy carries a significant risk of the development
of mutational resistance.
All high-level
clarithromycin-resistant isolates have mutations in the adenine
at position 2058 or 2059 of the 23S rRNA gene, which is the
presumed macrolide binding site on the ribosomal unit
Suggested algorithm for Culture &
Sensitivity
Macrolide/Azolide Sensitive
No
Yes
Rx with macrolide/Azolide
Do Expanded Sensitivity
Combination double or triple Consider combination Rx
Drug Rx
sensitivity
Such as Rif /Rb with Eth
MANAGEMENT OPTIONS
Step 1: Diagnosis & Clinical Classification**
** Ref: 5. American Thoracic Society Documents: Mycobacterial Diseases Subcommittee. The Official Statement of the American Thoracic Society (ATS)
and the Infectious Diseases Society of America (IDSA) Am J Respir Crit Care Med Vol 175. pp 367–416, 2007
** Ref 9 Chitty S, Ali J. Mycobacterium Avium Complex Pulmonary Disease in immune competent patients. Southern Medical Journal June 2005, 98 (6) pp
646-652
Step 2: CATEGORIZE GROUP
Surveillance Group
Treatment Group
Suppressive treatment Group
Clinical and chest-imaging
follow-up with serial sputum
cultures and colony counts;
?also applicable in the “Hot
Tub Lung Group”
Based on risk-benefit analysis:
Suppressive treatment with two
drugs: ETHAMBUTOL & MACROLODE
Aggressive treatment group
FOCAL DISEASE
3 drugs +- SURGERY
DIFFUSE NODULAR
BRONCHIECTASIS
3 DRUGS THRICE
WEEKLY
FIBROCAVITARY
DISEASE
3 DRUGS DAILY plus IV
AMINOGLYCOSIDE
COMPLEX
MACROLIDE RESISTANT
CUSTOMIZED
PROTOCOL
Recommendations:
1. Surgical resection of limited (focal) disease in a patient
with adequate cardiopulmonary reserve to withstand partial
or complete lung resection can be successful in combination
with multidrug treatment regimens for treating
MAC lung disease (B, II).
2. Surgical resection of a solitary pulmonary nodule due to
MAC is considered curative (C, III).
3. Mycobacterial lung disease surgery should be performed
in centers with expertise in both medical and surgical management
of mycobacterial diseases (C, III).
Factors contributing
to the poor response to therapy included cavitary disease,
previous treatment for MAC lung disease, and a history of
chronic obstructive lung disease or bronchiectasis and
macrolide resistance
Helps establish prognosis, goals and expectations of therapy
Treatment of M. abscessus pulmonary disease.
There are no drug regimens of proven or predictable
efficacy for treatment of M. abscessus lung disease.
Multidrug regimens that include clarithromycin 1,000
mg/day may cause symptomatic improvement and disease
regression.
Surgical resection of localized disease combined with
multidrug clarithromycin-based therapy offers the best
chance for cure of this disease.
Summary For NTM
• Environmental Surveillance
• Underlying immune or structural lung defect
• Focus on type of clinical-radiologic disease : Bronchiectasis, F/C ,
Nodular etc
• Specific identification of NTM and source search
• Consistent quantification smear/colony count
• Stratification of risk/benefit of Rx
• Goals of Rx and outcomes be established
• Customized approach ( “step ladder method ramping it up ” )based on
tolerance and compliance with Rx and without compromising overall
regimen;
• Watch drug- drug interaction
• ? role of drug levels?
Challenges
Identification characteristics
Macrophage barrier to Rx
Hydrophobicity of MOTT with drugs being hydrophilic in
nature; eg: more hydrophobic drugs i.e rifabutin as
opposed to rifampin
Cell wall associated permeability barrier specially seen in M.
Chelonei ; hence ethambutol specially in combination a
better choice
Lack of correlation in vitro and therapeutic efficacy
Multi strain sero variance specially in AIDS and patients with
nodular / bronchiectasis disease pattern**
Theory of adaptive resistance due to continual exposure eg:
pigmentation /proteins when clofazimine is used
Confused ?
So am I , most of the time; and if I am not , I consider myself lucky
Thank you , JA