Transcript TB in Your Practice: Focus on Co-Morbidities

Jayne Ash Address
TB in Your Practice: Focus
on Co-Morbidities
Gisela Schecter, MD, MPH
CA Dept of Public Health
May 6, 2010
I
have no conflicts of interest to declare
Who was Jayne Ash?
 Executive
Director of strategic planning for
CTCA from 1998-2001
 Graduate of the N.C. School of PH
 Jazz singer
 Great facilitator


On task
Great sense of humor
 Died
tragically in 2001
60 years ago
Now
 Highest
incidence of TB is in > 65 y.o.,
many of whom have concurrent diseases
 A new disease has put people at
increased risk of TB
 New therapies that modulate immunity put
people at increased risk of TB
 Lifestyle choices put people at risk for TB
 Co-morbidity is the rule, not the exception
TB is not your patient’s only problem





Diabetes Mellitus
Smoking
Chronic Kidney Disease and Hemodialysis
HIV infection
(Immunosuppressive therapies)
 Tuberculosis
and Diabetes Mellitus
LTBI and Progression to Active TB

The frequent association of DM and TB has
been observed for over 2,000 years
 Systematic




Review from Harvard, 2008
13 observational studies that reported an ageadjusted estimate of assoc. between TB and DM
Almost 1.8 million participants
3 Cohort studies gave RR of 3.11 (CI 2.27-4.6)
10 Case/control studies Odds Ratios ranged from
1.16-7.83
Jeon CY, PLos Med. 2008
LTBI and Progression to Active TB
 Diabetic


Contacts
A Hong Kong study examined 4661 close
contacts to TB cases
Both early (within 3 months) and late
(followed for 5 years) disease in contacts was
strongly associated with diabetes in the
contact (RR= 3.44)
Lee MS, Int J Tuberc Lung Dis. 2008
LTBI and Progression to Active TB
 Why
are patients with diabetes at
increased risk of TB?




Impaired cell-mediated immunity
Renal failure
Micronutrient deficiency
Pulmonary microangiopathy
Harries AD, Trans Royal S of Trop Med & Hyg. 2009
Presentation and Diagnosis
 Diabetes
and Radiological Presentation of
Pulmonary TB

Cavitary lung lesions
• Yes DM; 50.8%
• No DM; 39%

Lower lobe lung lesions
• Yes DM; 23.5% lower lobe lesions only
• No DM; 2.4% lower lobe lesions only
Shaikh MA, Saudi Med J, 2003
Presentation and Diagnosis
 More




advanced disease
Patients with DM are more frequently smear +
Cavitary findings
Hemoptysis is more common
Fever more common
Is this a result of delay in diagnosis or
more rapid disease progression?
Wang CS, Epidemiol Infect, 2008
Response to Treatment

Old Dogma: Despite increased risk of
progression to active TB if infected, diabetic
patients did just as well.
 5 new studies
 Baltimore: delayed culture conversion, higher
mortality
 Texas: delayed sputum culture conversion
 Taiwan: higher mortality
 Indonesia: slower smear and culture
conversion
 Shanghai: significantly higher relapse rate
Response to Treatment
 Data
on drug resistance is less clear with
some studies showing increased drug
resistance in patients with DM, but others
not
 Patients with DM may be at increased risk
of acquired drug resistance
 Acquired MDR TB is infrequent in CA, but
anecdotally, the 2 most recent cases were
among persons with DM
Rifampin and DM
 Comparison
of 17 age and sex matched
persons with and without DM. (All had
TB)

AUC 12.3 mg x h/L TB and DM
 AUC 25.9 mg x h/L TB only
 Peak
levels also about half in Diabetics
 Low levels associated with higher body
weight and poor glucose control
Nijland HM, Clin Infect Dis, 2006
Case 1
 64
yo Hmong woman diagnosed with
extensive, smear + pan-sensitive tuberculosis
in August, 2009
 Longstanding, poorly controlled DM
 Began RIPE 8/31/09
 Smears improved gradually and became
negative in October, 2009
 Cultures remained +
Case 1
 Late
January 2010, smears again +
 Culture sent for molecular beacons and DST
 Molecular beacon showed no INH resistance
mutations in katG or inhA, results for Rif were
initially inconclusive, but repeat test showed
rpoB Rif mutation
 Culture very slow growing, but DST report in
late March showed INH and Rif resistant
Case 1
 What
happened?
 Without informing DOT staff, patient had
developed almost daily vomiting after taking
TB meds
 Why?
 Poorly controlled diabetic patients frequently
have gastroparesis
 Rifampin levels are lower even w/o vomiting
Effect of TB treatment on DM

Rifampin raises blood glucose levels even in
non diabetics
 Rifampin activates the CYP450 enzyme system
 Sulfonorylureas and thiozolidinediones are
metabolized by this same system.
 Blood levels of these drugs significantly lowered
by Rifampin
When treating TB in a patient with
DM remember:

Both PZA and EMB need adjustment for renal
impairment; check serum Cr (renal dys-function
common in DM)
 INH peripheral neuropathy is more common in
diabetics: always supplement Vitamin B6
 Follow patients closely and monitor for sputum
conversion
 Consider extending treatment to 9 months if risk
factors for relapse such as slow sputum conversion
OR cavitary CXR are present
When treating TB in a patient with
DM remember:
 Just
as we recommend screening TB patients
for HIV, screen for DM when TB is diagnosed
 Repeat serum glucose after one month
 Monitor for polyuria/polydipsia during
treatment
 Follow diabetes closely and adjust diabetic
medications to bring blood sugar as close to
normal as possible
When treating TB in a patient with
DM remember:
 At
treatment end, be aware that diabetic
medications may need to be adjusted
downward
Recommendations for TB
screening and LTBI treatment
 Screen
all diabetics at risk for TB infection for
LTBI (and active TB), at diagnosis of DM and
periodically, as local epi dictates
 Strongly encourage LTBI treatment if TST
and/or IGRA is positive.
 Contacts with DM should be given high
priority for evaluation and LTBI treatment
TB and Diabetes Mellitus

DM increases risk of LTBI progressing to disease
 Diabetic patients need LTBI screening and rx
 TB may present differently in diabetics
 Diabetics clear sputum more slowly and have higher
mortality
 Consider prolonging treatment to 9 months if risk factors
for relapse such as either delayed sputum conversion
OR cavitary CXR are present
 Consider obtaining Rifampin blood levels
 Monitor diabetic control closely
 Use B6 if on INH
Tobacco and
Tuberculosis
Is there a problem?
Tobacco use is the leading preventable
cause of death in the world

Tobacco use is a risk factor for 6 of the 8 leading
causes of death in the world
 Ischemic heart disease, cerebral vascular
disease, COPD, lower respiratory infections,
lung cancer
AND
Tuberculosis
The tobacco epidemic is about to get much
worse
 Tobacco
currently kills
about 5 million/year but
this will increase to 10
million/year in a few
decades
 Total deaths attributable
to tobacco in the 21st
century are estimated
to be 1 billion
Tobacco and Development
 Tobacco


and Poverty: A vicious circle
The poor are the ones who smoke the most
Smoking worsens poverty due to:
• Money spent of tobacco can’t be used for food or
other essential items
• Increased illness and health care costs
 Smoking
accounts for much of the
mortality gap between rich and poor
High burden TB countries are those
with high-burden tobacco use
 40%
of new and relapsed TB cases live in
just 2 countries, India and China
 >40% of smokers live in those same two
countries
So what is the association
between tobacco exposure
and tuberculosis?
A Qualitative Systematic Review Jointly
Conducted by WHO and IUATLD
 Selection

of articles:
All English language journal articles on tobacco
exposure and tuberculosis available in:
• PubMed from 1954 through 2005
• The Union data base of TB articles since 1918
 42
articles containing 50 studies were
included in the review.
Main Results of the Systematic
Review
The effects of tobacco use on TB outcomes are independent
of the effects of alcohol use, SES, age, sex and other
potential confounders

Exposure to tobacco smoke is significantly
related to TB infection:



Eight studies investigated tuberculosis infection
All of the studies of infection found significant effects
of exposure to tobacco
Odds ratios ranging from 1.03 to 3.20
Main Results of the Systematic
Review
 Passive
or active exposure to tobacco
smoke is significantly associated with a
new and/or recurrent tuberculosis disease:

24 studies explored the relationship between
tobacco smoke exposure and new and/or
recurrent tuberculosis disease:
• Of 19 studies with significant results for active
exposure, odds ratios ranged from 1.01 to 6.26
• Of 4 studies with significant effects for passive
exposure, odds ratios ranged from 1.6 to 9.3
Main Results of the Systematic
Review
 Active
smoking is significantly associated
with tuberculosis mortality:



5 studies investigated the role of exposure to
tobacco smoke and tuberculosis mortality
All of the mortality studies found significant
relationships with tobacco use.
Risk ratios ranging from 1.02 to 6.62
A Nationally Representative CaseControl Study of Smoking and Death in
India
 Smoking
will cause about 930,000 deaths
in India in 2010 and smoking could also be
a cause of many of the deaths from TB
 38% of total numbers of deaths associated
with smoking will be caused by TB
Prabhat, NEJM 2008
Mechanisms underlying the Association
between Tobacco and TB
 Smoking
may attenuate mycobactericidal
activities including oxidative stress in the
lung tissues
 Mechanical disruption of cilia function and
other clearance mechanisms in the
tracheobronchial system
 Nicotine turns off the production of TNFalpha by macrophages in the lungs
(decreasing local levels of TNF-alpha might reactivate LTBI)
1) Pai, Expert Rev Anti Infect Ther, 2007; 2) Davis, Trans Roy Soc Trop Med Hygiene, 2006
The New Stop TB Strategy
 WHO
developed a new Stop TB strategy
in 2006, recognizing that prevention of the
most frequent risk factors is an important
contributor to TB control
 Any reduction in the prevalence of tobacco
smoking should benefit TB control
 We in the health care system must play an
important role in reducing both of these
epidemics
What can we do?
MPOWER: Six policies to Reverse
the Tobacco Epidemic
 Monitor
tobacco use and prevention
policies
 Protect people from tobacco smoke
 Offer help to quit tobacco use
 Warm about the dangers of tobacco
 Enforce bans on tobacco advertising,
promotion, and sponsorship
 Raise taxes on tobacco
Treatment of tobacco dependence
is effective
Effectiveness data for smoking cessation interventions (abstinence for at least 6
months) Cochrane Reviews
Interventions
Comparator
Odds Ratio
Self-help
No intervention
1.24
Physician advice
No advice
1.74
Physician intensive
advice
Minimal advice
1.44
Group behavior rx No intervention
2.17
NRT
Placebo or non-ART
1.58
Telephone counseling
No telephone c.
1.41
 Can
we reduce both morbidity and
mortality from TB by increasing our efforts
to reduce smoking?
DOTS
+
MPOWER
=
TB
Raviglione, M.
RR if factor
present
Prevalence of
factor
Population
attributable risk
Malnutrition
3.0
17%
25%
D. M.
3.0
3.4%
6%
Smoking
2.6
18%
23%
HIV
8.3
1%
7%
TB and Renal Disease
 Impaired CMI
with cutaneous anergy rates of
30-80% in ESRD
 Risk of active TB 7-52 X higher than general
population
 2004 Kaiser Permanente study: Active TB in
their dialysis patients 11.3 X rate in California
population as a whole
Renal Disease
TB Treatment Principals
 For




INH and RIF not affected and dose adjustments are
not necessary (metabolized by the liver)
EMB, PZA and levofloxacin: use usual daily dose,
but decrease frequency to 3 X weekly
Give all drugs immediately after dialysis
Always use vitamin B6 with INH
 For

CrCl < 30 ml/min:
CrCl > 30, but <70 ml/min:
Monitor closely for EMB optic neuropathy
First Line Agents and Hemodialysis
Drug
Isoniazid
Change
frequency?
NO
Removed by
hemodialysis
+
Rifampin
NO
NO
Ethambutol
YES
+
Pyrazinamide
YES
+++
TB and Renal Disease
 Resources:


http://www.ctca.org/guidelines/New_Renal_Dialysis_Guid
elines_02_22_08.pdf
http://www.thoracic.org/sections/publications/statements/pa
ges/mtpi/rr5211.html
TB Treatment Doses and Intervals in ESRD
TB and Renal Disease



Prevention is the key!
All patients with renal impairment should have
baseline TST or IGRA to assess for LTBI,
ideally before CrCL < 30 ml/min
If LTBI present, must be very strongly
encouraged to complete LTBI Rx
• INH 300 mg daily or 900 mg twice or thrice weekly
after dialysis for 9 months
• Rifampin 600 mg daily or twice or thrice weekly for
4 months
HIV related Tuberculosis
 WHO
estimates that TB is cause of death
for 13% of persons with AIDS
 Risk of progression to active TB if LTBI
present is about 10% per annum
 Occurs even with relatively high CD4
counts
 Presentation influenced by degree of
immunodeficiency
CXR Pattern: Early vs. Advanced HIV
Early HIV
Advanced HIV
(CD4 >200)
(CD4 <200)
“Typical”
(Reactivation)
“Atypical”
(Primary)
Infiltrate
Upper lobes
Lower lobes,
multiple sites,
or miliary
Cavitation
Common
Uncommon
Adenopathy
Uncommon
Common
Effusion
Uncommon
More common
Pattern
Adenitis and Consolidation
Courtesy M. Gotway, MD
HIV related Tuberculosis
 When
CD4 < 200, extra pulmonary TB
(lymphadenitis, pleuritis, pericarditis, and
meningitis) with or without pulmonary
disease found > 50% of patients
 Can present with high fevers, rapid
progression, sepsis syndrome
HIV related Tuberculosis

Screen all persons for LTBI at time of HIV
diagnosis
 If initial CD4 < 200 and LTBI test negative,
repeat screening after ART begun and CD4 >
200
 Annual screening only if at risk for repeated or
ongoing exposure to persons with active TB
 Screening Tests:


TST; 5 mm or greater reaction is positive
Interferon Gamma Release Assays (IGRAs)
HIV related Tuberculosis
 Treat
for LTBI if no evidence of active TB
AND:



Any positive diagnostic test for LTBI without
prior treatment
Close contact of infectious TB case,
regardless of TST or IGRA result
History of untreated or inadequately treated
healed TB (old fibrotic lesions on CXR)
 Preferred
9 months
regimen is INH 300 mg daily for
HIV related Tuberculosis

Initiation of ART in Patients with Active TB:

Always start TB treatment immediately
CD4 count Timing of ART Initiation
<100
After 2 or more weeks of TB rx
100-200
After 2-8 weeks of TB rx
201-350
During maintenance phase of TB rx
> 350
After completion of TB rx
CDC: MMWR, Guidelines for Prev/Treat of Opp Inf in HIV-
HIV related Tuberculosis
 Efavirenz
based ART is preferred
 If pregnant or under 3 years of age,
Nevirapine is the NNRTI of choice
 If patient is already on a protease inhibitor
based regimen or a PI must be used, then
Rifabutin may be used instead of Rifampin
Case 2

A 40 year-old man presents with fever for 4
weeks, cough with bloody sputum, night
sweats and weight loss of 7kg
 Chest X-ray shows right mid lung infiltrate
 Sputum AFB is positive
 His HIV test is positive and CD4 is180 cell/cu
mm
 RIPE is begun
Case 2



When seen after 8 weeks
of treatment, his fevers,
night sweats, and cough
have stopped and he has
gained 5kg
His TB regimen is
changed to isoniazid and
rifampin
Atripla is begun
(efavirenz, tenofovir,
emtricitabine)
X-ray shows improvement
Case 2
 The
patient returns 1 month after starting
Atripla
 He says that his fever, cough and night
sweats have “come back” “
 He has taken the Atripla as prescribed but
thinks they are making him more sick and
would like to stop them
Case 2






The patient has had
excellent adherence and
denies nausea, vomiting
or diarrhea
His oxygen saturation
comes back at 96% on
room air
Heart rate, respiratory
rate and other vital signs
are normal
Some axillary nodes are
present
Sputum smear is 1+ AFB
NSAIDS given
NEW CHEST X RAY
Case 2






2 weeks later he is worse
Sputum cultures have
converted to negative
Sputum smear is still 1+
AFB
On physical exam is
tachypneic
Respiratory rate is elevated
and oxygen saturations is
90% on room air
Crackles heard in right lung
field
X-ray shows worsening
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Paradoxical
worsening of symptoms after
initiating ART (or sometimes TB rx itself)
 Remains a major problem, particularly if
initial CD4 count low
 Usually occurs 1-3 months into ART
 Greatest risk if ART started in first 2
months of TB rx, and/or CD4 < 100
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Signs/symptoms




High fevers
Worsening respiratory status, parenchymal
infiltrates, pleural effusions
Increase in lymphadenopathy
Breakthrough meningitis or CNS lesions
 Evaluate
thoroughly for other possible
causes, especially TB treatment failure
Immune Reconstitution
Inflammatory Syndrome (IRIS)
 Treat
with NSAIDS if mild to moderate
 Use steroids if severe (1mg/kg of
prednisone daily with gradual taper)
 Try not to change anti-TB or ARV therapy
In Summary

Many, if not most of our TB patients now
have significant co morbidities
 Our colleagues in the private sector will need
to remember TB in order to promptly
diagnose, or better yet, prevent TB
 Epidemics of DM and HIV, and ongoing
tobacco use place large numbers of patients
at risk for TB
 Co morbid conditions complicate the
treatment of TB
 TB Prevention is key