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Tuberculosis
February 21, 2007
Timothy R. Sterling, M.D.
Vanderbilt University Medical Center
Director of TB Research, Nashville-Davidson
Metro Health Department
Overview
• TB Epidemiology
– TB/HIV
– Drug Resistance
• Diagnosis of TB
• TB Treatment
– Treatment Regimens
– TB/HIV
• Diagnosis and Treatment of Latent Infection
• Infection control
Global TB Epidemiology
2004
• Estimated # new TB cases:
8.9 million
• Estimated # prevalent cases:
14.6 million
• Estimated # deaths:
1.7 million
• Estimated # infections:
2 billion
– 33% of population
WHO Report 2006. Global tuberculosis control. WHO/HTM/TB/2006.362
Estimated number of new TB cases, 2004
Estimated number of
new cases (all forms)
0 - 999
1000 - 9999
10 000 – 99 999
100 000 - 999 999
1 000 000 or more
No estimate
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning
the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for whic h there may not yet be full agreement.
 WHO 2005. All rights reserved
WHO Report 2006. Global tuberculosis control. WHO/HTM/TB/2006.362
Estimated TB incidence rates, 2004
Estimated new TB
cases (all forms) per
100 000 population
0 - 24
25 - 49
50 - 99
100 - 299
300 or more
No estimate
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization
concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for whic h there may not yet be full agreement.
 WHO 2005. All rights reserved
WHO Report 2006. Global tuberculosis control. WHO/HTM/TB/2006.362
Impact of HIV on
TB Epidemiology
• HIV responsible for the global TB
resurgence
– sub-Saharan Africa
Estimated HIV prevalence in new adult TB cases
HIV prevalence in TB
cases, 15-49 years (%)
0-4
5 - 19
20 - 49
50 or more
No estimate
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the
legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries.
Dotted lines on maps represent approximate border lines for whic h there may not yet be full agreement.
 WHO 2005. All rights reserved
Global Incidence of MDR-TB
Resistance to INH + rifampin
• TB cases in 2004
– Resistance surveys for:
• New cases (90 countries)
• Previously treated cases (77 countries)
– Logistic regression estimated rate among all 184 countries in the world
• Global estimates:
– 424,203 cases in 2004
– 4.3% of all new and previously treated TB cases
• China, India, Russian Federation accounted for 62% of
estimated global burden of MDR-TB
WHO—Zignol M et al. J Infect Dis 2006;194:479-85.
Multidrug-Resistant Tuberculosis
• Global “hotspots”: Russia, Latvia, India,
Dominican Republic
• Risk factors:
– prior TB treatment
– noncompliance
– adding one drug to failing regimen
– HIV?; outbreaks among AIDS patients
• Treatment: 18-24 months
– complex regimens
XDR TB
Extensively Drug Resistant
Revised WHO Case Definition (Oct 11, 2006):
Resistance to at least isoniazid and
rifampin (MDR) plus resistance to:
• Fluoroquinolones +
• 1 of the second-line injectable drugs
– amikacin, kanamycin, or capreomycin
Diagnosis of Tuberculosis
•
•
•
•
Clinical signs/symptoms
Chest radiograph
Microscopy
Culture
– DNA probe after growth in culture
• Nucleic acid amplification
Sputum
• Sputum expectoration
– 3 samples
• Every 8 hours, with 1 specimen in early AM
– For hospitalized patients; more convenient though few data
• Sputum induction
– In persons from whom expectorated sputum cannot be obtained or is
smear-negative
– Repeated sputum induction (3-4) increases yield
– Cost-effective, even in resource-poor countries
• Bronchoscopy
– Unclear whether yield is greater than with repeated sputum induction
– Consider when sputum induction negative but CXR suggests TB
Microscopy
• Techniques:
– Acid-Fast (Ziehl-Neelsen; Kinyoun)
– Fluorochrome (auramine-rhodamine)
• Faster, easier to interpret
• Sputum
– + smear requires 5,000-10,000 bacilli/ml
– 50% (34-80%) sensitive; nonspecific
• Extrapulmonary specimens
– Lower sensitivity
Diagnosis of TB
Culture
• 80% sensitive; 98% specific
• Solid media:
– 7H-11, Lowenstein-Jensen
– 21-42 days required for growth
• Liquid media:
– 7H-12 Bactec (radiometric); MGIT (fluorescent)
– 5-10 days for growth
• DNA probe once growth in culture:
– M. tuberculosis complex, MAI, M. kansasii, M.
gordonae
Diagnosis of TB
Nucleic Acid Amplification
• FDA-approved for respiratory specimens
from untreated patients
AFB smear +
AFB smear neg
Sensitivity
95%
48%
Specificity
98%
95%
• Greater sensitivity if TB suspected
clinically
Diagnosis of TB
Nucleic Acid Amplification
• Does not replace need to obtain AFB
smear and culture
• If high index of suspicion but NAA
negative, TB has not been ruled out
• Expensive
• Extrapulmonary specimens: limited data,
but less sensitive
Treatment of TB
• Goal of therapy:
– kill M. tuberculosis, prevent resistance + relapse
• Induction phase:
– Isoniazid kills 95% of organisms (growing rapidly) during
first 2 days of treatment
– RIF, PZA then supplant INH in cidal role during the 2month induction phase (slowly metabolizing bacilli)
• Continuation phase
– Rifampin primarily effective against persistent bacilli,
though INH also cidal
Mitchison DA. IJTLD 2000;4:796-806
Treatment of TB
• Culture-positive pulmonary tuberculosis
caused by drug-susceptible organisms
– American Thoracic Society
– Centers for Disease Control & Prevention
– Infectious Diseases Society of America
Am J Respir Crit Care Med 2003;167:603-62
Initial Treatment Regimens
Drug Combinations and Dosing Intervals
Initial
2 weeks
HRZE daily
+
6 weeks
HRZE 2x/wk
Continuation
18 weeks
HR 2x/week
H/RPT 1x/week*
Rating
HIV- HIV+
A (II) B (II)
B (I)
E (I)
* no cavity on initial CXR, and smear-negative after 2 months.Extend Rx if cx+ at 2 mos
H: isoniazid
R: rifampin
Z: pyrazinamide
E: ethambutol
RPT: rifapentine
Additional Points
• Ethambutol can be discontinued as soon as
susceptibility to isoniazid + rifampin
demonstrated
• Obtain monthly sputum cultures until 2
consecutive negative cultures
– Culture after 2 months of treatment VERY
important
• HIV testing recommended in all patients
Optimal Duration of TB Treatment
Regardless of HIV status
Site of Disease
Pulmonary
Bone/joint
CNS/meningeal
Other extrpulmonary
Duration
6 months*
6-9 months
9-12 months
6 months
*Extend to 9 months if cavitary and culture + at 2 months
American Thoracic Society, Centers for Disease Control, IDSA.
Treatment of Tuberculosis. AJRCCM 2003;167:603-62
Renal Failure
• Drugs excreted by kidneys:
– ethambutol
– pyrazinamide (metabolites)
• Maintain dose, but increase interval:
– Thrice-weekly dosing
• Administer drugs after hemodialysis (DOT)
– Pyrazinamide, cycloserine dialyzed out
Hepatic Disease
Treatment when underlying liver disease
• Treat with standard therapy
• Other options:
– RZE x 6 months
– HRE x 9 months
– RE (+/- FQ) x 12 months (no data)
• Check baseline transaminases, bili, alk 
– Follow closely, along with symptoms
H: isoniazid
R: rifampin
Z: pyrazinamide
E: ethambutol
FQ:fluoroquinolone
Hepatic Disease
Treatment when hepatitis develops on therapy
• Stop treatment:
– isoniazid, rifampin, pyrazinamide
• Check hepatitis A, B, C serology
• Assess for other hepatotoxins
– alcohol
– acetominophen
• Could continue treatment with ethambutol,
aminoglycoside, fluoroquinolone
• Sequential drug rechallenge of 1st-line agents
when AST < 2x upper limit of normal
Pregnancy
• No aminoglycosides
– Congenital deafness
• Pyrazinamide:
– U.S.:
– WHO, IUATLD:
probably OK
OK
• Breastfeeding fine with 1st-line agents
Children
• Treatment same as in adult, except:
– No ethambutol if visual acuity cannot be
monitored, unless:
• High risk of drug resistance (INH)
• Upper lobe infiltrate/cavity (higher organism burden)
• Cultures often difficult to obtain
• Rely on susceptibilities of presumed source case
Recommendations for Treatment
of TB in HIV-Infected Patients
• TB/HIV patients with CD4 < 100 should not
receive once- or twice- weekly therapy
– Daily therapy during induction
– Daily or thrice-weekly therapy during
continuation
MMWR 2002;51:214-5
Treatment of TB/HIV
Drug Interactions
• Possible combinations:
– rifampin + efavirenz
– rifabutin + ritonavir-boosted protease inhibitors
• Avoid these combinations:
– rifampin + : saquinavir, indinavir, nelfinavir, amprenavir (fos),
atazanavir, or delavridine
– rifabutin +: delavridine, saquinavir
• Nucleoside/tide reverse transcriptase inhibitors and
enfuvirtide not affected rifamycins, so can be given
Immune Reconstitution
Inflammatory Syndrome
• Clinical Manifestations
– Constitutional: fever, weight loss,
– Pulmonary: cough, increased infiltrates
– Extrapulmonary:
• Lymphatic: increased cervical, intra-thoracic, intra-abdominal
adenopathy
• Serositis: pleural, pericardial effusions
• CNS: expanding tuberculomas
• Other: soft tissue, bone abscesses, skin, +PPD
Risk Factors for IRIS
In (roughly) decreasing order of importance
• HAART initiation within 2 months of starting
anti-tuberculosis treatment
• Disseminated/extrapulmonary TB
• Low baseline CD4 (< 100/mm3)--trend, but consistent
• Increase in CD4% on HAART
• HIV-1 RNA decline on HAART
• Antiretroviral therapy-naïve
Narita 1998, Wendel 2001, Navas 2002, Breen 2004, Breton 2004, Burman 2004, Shelburne 2005
Diagnosis of M. tuberculosis infection
Tuberculin skin test (TST)
• Tuberculin=broth culture filtrate of tubercle bacilli
– Purified protein derivative (PPD), a standardized form of tuberculin,
was introduced in 1934
• Contains ~ 200 antigens, including those shared by M. bovis BCG and
non-tuberculous mycobacteria
• T-cells sensitized by M. tuberculosis infection respond to M.
tuberculosis antigens in PPD and release IFN-
– Cutaneous induration due to delayed-type hypersenstivity to
intradermal injection of PPD
• Positive test determined by determining mm of induration
– Inter- and intra-reader variability
– Possible human error
Tuberculin Skin Test
• Sensitivity:
– Presumably high in latently infected persons with
normal immune response
• Decreased in immunocompromised patients:
– HIV (CD4 < 100), corticosteroids, other immunosuppressants,
young children (< 1 year)
• False negative until 8-12 weeks after infection
• Specificity:
– False positives due to environmental mycobacteria,
BCG
• Decreased specificity and positive predictive value in
populations at low risk for TB infection
• Improved specificity if greater mm induration for + test
Interferon- Release Assays
• Detection of IFN- or IFN--producing T-cells after stimulation
of sensitized T-cells by M. tuberculosis antigens
– Assesses cell-mediated immunity
• Early-generation tests used PPD as the stimulus
– As non-specific as the TST
• More recent assays have used synthetic peptides of 2 proteins
present in M. tuberculosis, but not BCG or most nontuberculous mycobacteria (NTM):
– Early secretory antigen target 6 (ESAT-6)
– Culture filtrate protein-10 (CFP-10)
CDC Guidelines
QuantiFERON-TB Gold
• Can be used in all circumstances in which TST
used:
– Contact investigations, recent immigrants (BCG), serial
testing (e.g., health-care workers)
• TB risk among persons with + test unknown
• Limited data:
–
–
–
–
–
Immunocompromised (e.g., HIV)
Close contacts
Persons at  risk of progressing to TB
Children (no data in persons < 17 years old)
Persons who undergo periodic screening (HCW)
MMWR 2005;54(RR-15):49-55.
Indications for
Treatment of Latent Infection
• Perform skin testing only on persons at
high risk for progression to active TB
• If persons in these high-risk groups are
latently infected (i.e. PPD+), treat
regardless of age
Am J Resp Crit Care Med 2000;161:S221
Treatment of Latent TB Infection
2000 ATS/CDC
Regimen
INH qD x 9 months
INH biw x 9 months
INH qD x 6 months
INH biw x 6 months
HIVAII
BII
BI
BII
HIV+
AII
BII
CI
CII
A: preferred
I: Randomized Clinical Trial
B: acceptable alternative
II: nonRCT
C: offer when cannot give A,B
III: expert opinion
Treatment of Latent TB Infection
2000 ATS/CDC
Regimen
HIV-
HIV+
RIF qD x 4 months
BII
BIII
A: preferred
B: acceptable alternative
C: offer when cannot give A,B
I: Randomized Clinical Trial
II: nonRCT
III: expert opinion
Initiating Respiratory Isolation
• Policies vary at different hospitals
• Cough > 2 weeks and abnormal CXR
– Additional symptoms c/w TB
• Epidemiology suggestive of TB:
– Recent TB exposure
– Incarceration
– HIV (10% may have negative CXR)
Discontinuing Respiratory Isolation
TB suspects
• CDC guidelines:
– 3 negative AFB smears
– Collected at least 8 (not 24) hours apart
– At least one collection during early AM
• Based on expert opinion, not evidence
• To get patients out of isolation in < 48 hours
– Another diagnosis assigned
– Infectious TB unlikely
MMWR 2005;54(RR-17): 1-121.
When to Refer a TB Suspect to the
Health Department
• EARLY
• As soon as they start anti-TB therapy
• Allows for:
– TB Clinic staff to visit patient in hospital
• Establish rapport
• Review medications, drug-drug interactions
Nashville Metro Health Department TB clinic telephone #: 340-5650
When Can a TB Suspect be
Discharged?
• On appropriate anti-TB treatment
• Health department notified and follow-up,
treatment plan in place
• Stable residence at verifiable address
When Can a TB Suspect be
Discharged?
• They can be discharged before they have 3
negative smears unless “home” includes:
– Young children (< 5 y.o.)
– Immunocompromised (e.g., HIV)
– Prison
– Nursing home
– Homeless shelter