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Tuberculosis Today. James S. Seebass, D.O. Oklahoma State University Center for Health Sciences • College of Osteopathic Medicine. Global Burden of Tuberculosis. ~ 8 million new cases of active TB/year 2-3 million deaths worldwide/year 1 in 3 persons with Mycobacterium tb infection

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Tuberculosis Today

James S. Seebass, D.O.

Oklahoma State University

Center for Health Sciences • College of Osteopathic Medicine


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Global Burden of Tuberculosis

  • ~ 8 million new cases of active TB/year

  • 2-3 million deaths worldwide/year

  • 1 in 3 persons with Mycobacterium tb infection

  • 22 high TB burden countries; hot spots for MDR with drug resistance as high as 14%*


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Transmission and Pathogenesis of Tuberculosis


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Transmission of Tuberculosis

“In approaching the consumptive one breathes

pernicious air. One takes the disease because

there is in this air something disease-producing”

Aristotle


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Transmission of Tuberculosis Generation of Droplet Nuclei

  • One cough produces 500 droplets

  • The average tuberculosis (TB) patient generates 75,000 droplets per day before therapy

  • This drops to 25 infectious droplets per day within 2 weeks of effective therapy


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Transmission of Tuberculosis

CASE

CONTACT

Site of TB

Cough

Bacillary load

Treatment

Ventilation

Filtration

U.V. light

Closeness and

duration of contact

Immune status

Previous infection


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Tuberculin Reactivity Among Contacts by Index Status

Contact status

Index Status Household Casual

(n=858) (n=4207)

Sm +, Cx + 20.2% 3.7%

Sm –, Cx + 1.1% 0.2%

Van Geuns, et al. BIUAT 1975;50:107


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Likelihood of Developing TB In Contacts by Index Status

TB Among Contacts

Index Status Close Casual Close Casual

(Ages: 0 -14 yrs) (Ages: 15 - 29 yrs)

Sm +, Cx + 38% 24% 11% 6%

Sm –, Cx + 18% 18% 1% 3%

Grzybowski S, et al. BIUAT. 1975;60:90


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Effects of Therapy on M. tuberculosis


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General Issues: Clinical Suspicion

  • To diagnose TB you must first think of TB

  • Knowing when to consider TB in the differential diagnosis = knowing who is at risk

    • risk for infection

    • risk for disease


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General Issues: Clinical Suspicion (2)

  • Risk for infection

    • Homeless or unstably housed

    • Foreign-born from high prevalence country

    • Residence in institution

    • Healthcare worker

    • Contact with pulmonary TB patient


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General Issues: Clinical Suspicion (3)

  • Risk for disease

    • HIV infection

    • CXR with fibrotic lesions consistent with old TB

    • Substance abuse

    • Diabetes mellitus

    • Chronic renal failure

    • Immunosuppressive therapy (equivalent to 15 mg prednisone/day for at least 1 month)


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General Issues: Clinical Suspicion (4)

  • Risk for disease (continued)

    • Solid organ transplant recipients

    • Silicosis

    • Hematologic malignancies

    • Head and neck cancers

    • Malnutrition

    • Gastrectomy or jejunoileal bypass

    • Prior TB disease


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Risk Factor

How many times higher is the risk of TB disease

HIV/AIDS

113-170

Diabetes

4.1

“old TB” on CXR

13.6

Chronic renal failure

25

Other conditions

3-16

Risk for Development of TB Disease


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Who Should Be Screened:“TARGETED TESTING”

Screening should be targeted to those at higher risk of TB

  • Populations with increased rates of TB infection

  • Persons with increased risk of progression to active TB if infected

  • NOT the general population


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New Tuberculosis Guidelines: Tuberculin Testing

Criteria for Tuberculin Positivity

>5 mm>10 mm>15 mm

HIV infection Recent immigrants No risk

Contact to Injection drug users

active TB case Children

Abnormal CXR High risk medical

15 mg/day prednisone conditions

for 1 month Residents and employees homes, hospitals of jails/nursing


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Risk of Infection

Recent contacts of infectious TB cases:

  • 4-5% risk of developing active disease within the first 1-2 years

  • Risk may double if contact is < 4 years old

  • Nationwide about 20% of TB contacts are infected


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Risk of Infection (2)

Foreign born persons:

  • High and intermediate incidence (Asia and Pacific Islands, Africa, Central and South America, Eastern Europe, Middle East)

  • Emphasis on newcomers to the U.S. (<5 years)


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Risk of Infection (3)

Medically underserved/low-income groups:

  • Homeless

  • Migrant workers

  • Low-cost hotel dwellers or crowded impoverished living conditions

  • Street drug users

  • Racial and ethnic minorities

  • Children with parents that have TB risk factors


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Risk of Infection (4)

  • Pregnant women belonging to any risk groups or if the local TB epidemiologic situation warrants it

  • Correctional facilities (inmates and staff)

  • Healthcare workers

  • Nursing home

  • Long-term care facilities

  • Renal dialysis units


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Risk of Progression

HIV infection:

  • Screen as early as possible (anergy increases as HIV disease advances)

  • Screen every 6-12 months; thereafter depends on lifestyle and environment

  • Exceptionally high rate of reactivation (7-10% per year)

  • Rapid development to active disease from new infection


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Risk of Progression (2)

Individuals with abnormal chest x-ray compatible with past TB regardlessof age

  • Risk of active disease is 10 times that of a person with a normal x-ray and no other risk factors

  • Annual reactivation rate: 0.3  1.5% versus .05  0.1%

  • PPD and sputum part of screening in spite of stability of chest x-ray and history of treatment


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Risk of Progression (3)

Recent infection:

  • 4-5% risk of developing active disease within the first 1-2 years

    Infants and children < 4 years of age

  • 40% progression to disease in infants younger than 12 months


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Risk of Progression (4)

Medical conditions:

  • Immunosuppressive therapy (including anti-TNF-alpha, e.g. infliximab)

  • Lymphoma, leukemia

  • Injection drug use

  • Diabetes

  • Malnutrition

  • Renal failure

  • Silicosis

  • Alcoholism


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Frequency of Screening

  • Retesting: dependent on ongoing risk of TB exposure

  • Frequency: dependent on degree of chronic TB exposure (use local epidemiology)

    • Annual testing*: healthcare workers, long-term care residents, shelter or homeless program or substance recovery program staff

    • Q 6 month testing*: TB clinic frontline staff, ER workers, pulmonologists performing bronchoscopy

      *Need to correlate with local epidemiologic data


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Tuberculin Skin Test Interpretation: False-Negative Results

  • Host factors

    • HIV

    • Recent TB infection (<3 months)

    • Infections (viral, fungal, bacterial)

    • Other illness affecting lymphoid organs

    • Live virus vaccination

    • Immunosuppressive drugs

    • Overwhelming TB

    • Age (newborn, elderly)


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Tuberculin Skin Test Interpretation: False-Negative Results (2)

  • Technical factors

    • The tuberculin used (i.e., improper storage, contamination)

    • Improper method of administration, reading and/or recording of results


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Tuberculin Skin Test Interpretation: False-Positive Results (3)

Causes

  • Cross-reactions from atypical mycobacterial infections

  • Recent or multiple BCG vaccination

  • Misinterpretation of immediate hypersensitivity to tuberculin

  • Switching tuberculin products (tubersol with applisol)


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Tuberculin Skin Test Interpretation

Absence of PPD reaction

DOES NOT EXCLUDE DISEASE


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TST Interpretation: Boosted Reaction

  • Delayed hypersensitivity to tuberculin in some individuals may gradually wane over time

  • Initial PPD may be “falsely negative”

  • A booster response may incorrectly be interpreted as a “conversion”


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BCG Vaccination and Interpretation of the Tuberculin Skin Test

  • CDC recommendation:

  • Ignore history of BCG when interpreting the skin test

  • Consult TB experts if confused (my recommendation)


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Tuberculosis Screening Flowchart

At-risk person

Tuberculin test + symptom review

Negative

Positive

Chest x-ray

Normal

Abnormal

Candidate for Rx of latent TB

Treatment

not indicated

Evaluate for active TB


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“A Rose by Any Other Name”

Terms no longer in use:

  • prophylaxis

  • chemoprophylaxis

  • preventive therapy

  • preventive treatment

Rose du jour: Treatment of latent tuberculosis infection

LTBI


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New Guidelines for TB Prevention: Changes From the Past

  • DECISION TO TEST IS DECISION TO TREAT!

  • No 35-year-old cut-off

  • 9 months of INH preferred over 6 months

  • New alternatives to INH (rifampin-based regimens)

  • Baseline laboratory monitoring not routinely indicated


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Completion of INH Treatment for LTBI

  • Based on total number of doses, not duration

  • Need to take 270 doses within 12 months for 9 month regimen

  • Need to take 180 doses within 9 months for 6 month regimen



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Isoniazid-Induced Hepatitis

N=13,838

Hepatitis

Age (yr) Cases/1000

< 20 0.0

20-34 3.0

35-49 12.0

50-64 23.0

> 64 8.0

N=11,141

Hepatitis

Age (yr)Cases/1000

0-14 0.0

15-34 0.8

35-64 2.1

≥65 2.8

Nolan CL et al. JAMA 1999;281:10140

Kopanoff et al. Am Rev Resp Dis 1976;117:991


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Clinical Presentation: Site of Disease

Reported TB Cases by Form of Disease United States, 2001

Both (7.4%)

Extrapulmonary (20.1%)

Pleural (18.3%)

Lymphatic (42.5%)

Pulmonary (72.5%)

Other (12.3%)

Bone/joint (10.2%)

Peritoneal (4.6%)

Meningeal (6.0%)

Genitourinary (5.9%)


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Clinical Presentation: Pulmonary Symptoms and Signs

  • Cough – 40-80%

  • Sputum production

  • Pleuritic chest pain

  • Hemoptysis – does not always indicate active disease


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Clinical Presentation: Systemic Symptoms and Signs (2)

  • Fever – 65-80%

  • Chills/sweats

  • Fatigue/malaise

  • Anorexia/weight loss

  • No symptoms – 10-20%


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Radiographic Presentation: Pulmonary Tuberculosis

Primary Post-primary

Location of infiltrates Upper: Lower 60:40 85% upper Usually upper in children

Cavitation Rare Often present

Adenopathy Adults ~30% Rare Children-common

Effusion May be present May be present


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Laboratory Diagnosis: Predictive Value of a Positive Smear

Smear positive for AFB

Initiate treatment for TB

Culture and Speciation

M. tuberculosis

Non-tuberculous

50-90%

mycobacteria

10-50%

Continue treatment

Adjust treatment


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Approach to a Patient Suspected of Having TB: AFB Smear Negative

Smear negative for AFB

High

Low

Moderate

Assess the following:

No Rx,

Initiate Rx

clinical/immune status

wait for

risk of transmission

culture

side-effects of Rx

result

Invasive diagnostic procedure;

bronchoscopy, FNA


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Antituberculosis Drugs NegativeIn the United States

First-line Drugs Second-line Drugs

Isoniazid Cycloserine

Rifampin Ethionamide

Rifapentine Levofloxacin*

Rifabutin* Moxifloxacin*

Ethambutol Gatifloxacin*

Pyrazinamide p-Aminosalicylic acid

Streptomycin

Amikacin/kanamycin*

Capreomycin

* Not approved by the United States Food and Drug Administration for use

in the treatment of tuberculosis.


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Treatment of Tuberculosis NegativeRelative Activities of Drugs

Agent Early bactericidal Preventing Sterilizing

activity drug resistance activity

Isoniazid ++++ +++ ++

Rifampin ++ +++ ++++

Pyrazinamide + + +++

Streptomycin ++ ++ ++

Ethambutol ++ – +++ ++ +

Highest ++++, High +++, Intermediate ++, Low +


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Treatment of Tuberculosis NegativeStandard Regimen

Initial Phase Continuation Phase

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6

months


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Recommended Regimens Negative

Initial Continuation Rating

Reg. Drugs Interval/Dose Reg. Drugs Interval/Doses HIV- HIV+

1 INH 7 days/wk (56) 1a INH/RIF 7 days/wk (126) AI AII

RIF or 5 days/wk (40) or 5 days/wk (90)

EMB 1b INH/RIF 2X weekly (36) AI AII

PZA 1c INH/RPT* once weekly (18) BI EI

2 INH 7 days/wk (14) 2a INH/RIF 2X weekly (36) AII BII

RIF then 2X weekly (12) 2b INH/RPT* once weekly (18) BI EI

EMB

PZA

*RPT - Only for HIV (–) persons without cavitation who are smear (– ) by 2 mos


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Recommended Regimens Negative

Initial Continuation Rating

Reg. Drugs Interval/Dose Reg. Drugs Interval/Doses HIV- HIV+

3 INH 3X weekly (24) 3a INH/RIF 3X weekly (54) BI BII

RIF

EMB

PZA

4 INH 7 days/wk (56) 4a INH/RIF 7 days/wk (217) CI CII

RIF or 5 days/wk (40) or 5 days/wk (155)

EMB 4b INH/RIF 2X weekly (62) CI CII


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Treatment of Tuberculosis NegativeExtending Therapy

Initial Continuation Phase

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2* 3 4 5 6 7 8 9

months

*If culture positive at 2 mos, extend continuation phase from 4 to 7 mos


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Isoniazid Negative

  • Pharmacokinetics

    • Bactericidal

    • Absorption – well absorbed

    • Distribution – widely distributed, penetrates caseous tissue; CSF concentrations = serum concentrations

    • Elimination – primarily hepatic thus no need to adjust in renal insufficiency

    • Adverse effects: hepatotoxicity (< 3%), risk  w/EtOH,age, rifampin therapy; peripheral neuropathy: risk  EtOH, malnourished; rare: lupus-like syndrome


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Isoniazid Negative

  • INH administered with Phenytoin or Tegretol results in levels of the anti-seizure medications

    • Monitor blood levels of seizure meds

  • Altered drug absorption w/antacids

  • Pharmacodynamic interaction

    • Concomitant use of meds w/similar toxicity profiles

  • Herbal drug interaction: melatonin, an herbal product used for insomnia/jet lag may increase INH levels


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Bacteriostatic Negative

Absorption – good [PO only]

Distribution – minimal CSF penetration

Elimination – ~80% excreted kidneys

dosage adjustment necessary in renal dysfunction

HD dose: 15-25 mg/kg/dose three times/week

No significant CYP-450 interactions

Altered drug absorption w/antacids – stagger administration

OK with food

Adverse effects

Optic neuritis, red-green color blindness [dose related]

Test baseline acuity and color discrimination

Ethambutol


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Pyrazinamide Negative

  • Bactericidal

  • Absorption – good

  • Distribution – works best in acidic environment

  • CSF concentrations = serum concentrations

  • Elimination – hepatic

    • HD dose: 25 to 35 mg/kg/dose three times/week

  • No significant CYP-450 interaction

  • Adverse effects: hepatitis, GI upset, polyarthralgia, rash, hyperuricemia


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Rifampin Negative

  • Bactericidal

  • Pharmacokinetics

    • Absorption – well absorbed

    • Distribution – penetrates well into most tissue (CNS)

    • Elimination – primarily hepatic thus no need to adjust in renal insufficiency

  • Adverse effects: GI upset, flu-like syndrome, hepatotoxicity, thrombocytopenia, anemia

  • Orange discoloration of body fluids


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