Tuberculosis February 21, 2007

Timothy R. Sterling, M.D.

Vanderbilt University Medical CenterDirector 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 Epidemiology2004

• 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

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on th e part of the World Health Organization concerning the legal status of any country, territory, city or area or of i ts 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

0 - 9991000 - 999910 000 – 99 999100 000 - 999 999

No estimate1 000 000 or more

Estimated number of new cases (all forms)

WHO Report 2006. Global tuberculosis control. WHO/HTM/TB/2006.362

Estimated TB incidence rates, 2004

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on th e 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

0 - 2425 - 4950 - 99100 - 299

No estimate300 or more

Estimated new TB cases (all forms) per 100 000 population

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

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on th e 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

HIV prevalence in TB cases, 15-49 years (%)

0 - 45 - 1920 - 4950 or moreNo estimate

Global Incidence of MDR-TBResistance 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 TBCulture

• 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

Sensitivity Specificity

AFB smear + 95% 98% AFB smear neg 48% 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 2-

month 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 RegimensDrug Combinations and Dosing Intervals

Initial Continuation Rating2 weeks 18 weeks HIV- HIV+HRZE daily HR 2x/week A (II) B (II)+ H/RPT 1x/week* B (I) E (I)6 weeksHRZE 2x/wk

* no cavity on initial CXR, and smear-negative after 2 months.Extend Rx if cx+ at 2 mos

H: isoniazid R: rifampin RPT: rifapentine

Z: pyrazinamide E: ethambutol

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 TreatmentRegardless of HIV status

Site of Disease Duration

Pulmonary 6 months*

Bone/joint 6-9 months

CNS/meningeal 9-12 months

Other extrpulmonary 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 DiseaseTreatment 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 FQ:fluoroquinolone

Z: pyrazinamide E: ethambutol

Hepatic DiseaseTreatment 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.: probably OK– WHO, IUATLD: 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/HIVDrug 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 IRISIn (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 non-tuberculous mycobacteria (NTM):– Early secretory antigen target 6 (ESAT-6)– Culture filtrate protein-10 (CFP-10)

CDC GuidelinesQuantiFERON-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 Infection2000 ATS/CDC

Regimen HIV- HIV+ INH qD x 9 monthsAII AII INH biw x 9 months BII BII INH qD x 6 monthsBI CI INH biw x 6 months BII 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 Infection2000 ATS/CDC

Regimen HIV- HIV+

RIF qD x 4 months BII BIII

A: preferred I: Randomized Clinical Trial

B: acceptable alternative II: nonRCT C: offer when cannot give A,B 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 IsolationTB 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