Tuberculosis Today Tuberculosis Today

James S. Seebass, D.O.Oklahoma State University

Center for Health Sciences • College of Osteopathic Medicine

James S. Seebass, D.O.Oklahoma State University

Center for Health Sciences • College of Osteopathic Medicine

Global Burden of Tuberculosis 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%*

~ 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%*

Transmission and Pathogenesis

of Tuberculosis

Transmission and Pathogenesis

of Tuberculosis

Transmission of TuberculosisTransmission of Tuberculosis

“In approaching the consumptive one breathes pernicious air. One takes the disease becausethere is in this air something disease-producing”

Aristotle

Transmission of Tuberculosis Generation of Droplet Nuclei

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

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

Transmission of TuberculosisTransmission of Tuberculosis

CASE CONTACT

Site of TBCoughBacillary loadTreatment

Closeness and duration of contactImmune statusPrevious infection

VentilationFiltrationU.V. light

Tuberculin Reactivity Among Contacts by Index Status

Tuberculin Reactivity Among Contacts by Index Status

Contact statusIndex 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

Likelihood of Developing TB In Contacts by Index StatusLikelihood of Developing TB In Contacts by Index Status

TB Among ContactsIndex 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

Effects of Therapy on M. tuberculosis

Effects of Therapy on M. tuberculosis

0

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1 2 4 6 8 10 12 14 16 18 20 22 24

Weeks

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1 2 4 6 8 10 12 14 16 18 20 22 24

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General Issues: Clinical SuspicionGeneral 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

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

General Issues: Clinical Suspicion (2)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

Risk for infection Homeless or unstably housed Foreign-born from high prevalence country Residence in institution Healthcare worker Contact with pulmonary TB patient

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)

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)

General Issues: Clinical Suspicion (3)

Risk for disease (continued) Solid organ transplant recipients Silicosis Hematologic malignancies Head and neck cancers Malnutrition Gastrectomy or jejunoileal bypass Prior TB disease

Risk for disease (continued) Solid organ transplant recipients Silicosis Hematologic malignancies Head and neck cancers Malnutrition Gastrectomy or jejunoileal bypass Prior TB disease

General Issues: Clinical Suspicion (4)

Risk for Development of TB DiseaseRisk for Development of TB Disease

3-16Other conditions

25Chronic renal failure

13.6“old TB” on CXR

4.1Diabetes

113-170HIV/AIDS

How many times higher is the risk

of TB disease

Risk Factor

Who Should Be Screened:“TARGETED TESTING”

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

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

New Tuberculosis Guidelines: Tuberculin Testing

New Tuberculosis Guidelines: Tuberculin TestingCriteria 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

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

Risk of InfectionRisk 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

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

Risk of Infection (2)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)

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)

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

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

Risk of Infection (3)

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

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

Risk of Infection (4)

Risk of ProgressionRisk 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

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

Risk of Progression (2)Risk of Progression (2)

Individuals with abnormal chest x-ray compatible with past TB regardless of 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

Individuals with abnormal chest x-ray compatible with past TB regardless of 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

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

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

Risk of Progression (3)

Medical conditions: Immunosuppressive therapy

(including anti-TNF-alpha, e.g. infliximab) Lymphoma, leukemia Injection drug use Diabetes Malnutrition Renal failure Silicosis Alcoholism

Medical conditions: Immunosuppressive therapy

(including anti-TNF-alpha, e.g. infliximab) Lymphoma, leukemia Injection drug use Diabetes Malnutrition Renal failure Silicosis Alcoholism

Risk of Progression (4)

Frequency of ScreeningFrequency 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

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

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)

Tuberculin Skin Test Interpretation: False-Negative Results

Technical factors

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

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

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

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

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)

Causes

Cross-reactions from atypical mycobacterial infections

Recent or multiple BCG vaccination

Misinterpretation of immediate hypersensitivity to tuberculin

Switching tuberculin products (tubersol with applisol)

Absence of PPD reaction

DOES NOT EXCLUDE DISEASE

Tuberculin Skin Test Interpretation

TST Interpretation: Boosted Reaction

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”

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”

CDC recommendation:

Ignore history of BCG when interpreting the skin test

Consult TB experts if confused (my recommendation)

BCG Vaccination and Interpretation of the Tuberculin Skin Test

Tuberculosis Screening FlowchartTuberculosis Screening Flowchart

Evaluate for active TB

At-risk person

Tuberculin test + symptom review

Negative Positive

Chest x-ray

Normal Abnormal

Treatmentnot indicated

Candidate for Rx of latent TB

“A Rose by Any Other Name”“A Rose by Any Other Name”

Terms no longer in use: prophylaxis chemoprophylaxis preventive therapy preventive treatment

Terms no longer in use: prophylaxis chemoprophylaxis preventive therapy preventive treatment

Rose du jour: Treatment of latent tuberculosis infection LTBI

New Guidelines for TB Prevention: Changes From the Past

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

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

Completion of INH Treatment for LTBICompletion 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

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

Clinical Trials of Isoniazid Preventive Therapy

Clinical Trials of Isoniazid Preventive Therapy

Year

Num

ber

of C

ases

0 2 4 6 8 10

Placebo

Isoniazid

500

400

300

200

100

00 2 4 6 8 10

Placebo

Isoniazid

500

400

300

200

100

0

Isoniazid-Induced HepatitisIsoniazid-Induced Hepatitis

N=13,838

HepatitisAge (yr) Cases/1000

< 20 0.020-34 3.035-49 12.050-64 23.0> 64 8.0

N=11,141

HepatitisAge (yr) Cases/1000

0-14 0.015-34 0.835-64 2.1≥65 2.8

Nolan CL et al. JAMA 1999;281:10140Kopanoff et al. Am Rev Resp Dis 1976;117:991

Pulmonary (72.5%)

Extrapulmonary (20.1%)

Both (7.4%)

Pleural (18.3%)

Lymphatic (42.5%)

Bone/joint (10.2%)

Genitourinary (5.9%) Meningeal (6.0%)

Peritoneal (4.6%)

Other (12.3%)

Clinical Presentation: Site of DiseaseClinical Presentation: Site of DiseaseReported TB Cases by Form of Disease United States, 2001

Clinical Presentation: Pulmonary Symptoms and Signs

Clinical Presentation: Pulmonary Symptoms and Signs

Cough – 40-80% Sputum production Pleuritic chest pain Hemoptysis – does not always indicate active

disease

Cough – 40-80% Sputum production Pleuritic chest pain Hemoptysis – does not always indicate active

disease

Clinical Presentation: Systemic Symptoms and Signs (2)

Clinical Presentation: Systemic Symptoms and Signs (2)

Fever – 65-80% Chills/sweats Fatigue/malaise Anorexia/weight loss No symptoms – 10-20%

Fever – 65-80% Chills/sweats Fatigue/malaise Anorexia/weight loss No symptoms – 10-20%

Radiographic Presentation: Pulmonary Tuberculosis

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

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

Smear positive for AFB

Initiate treatment for TB

Culture and Speciation

M. tuberculosis50-90%

Continue treatment Adjust treatment

Non-tuberculous mycobacteria

10-50%

Laboratory Diagnosis: Predictive Value of a Positive Smear

Smear negative for AFB

Low Moderate

No Rx, wait for culture result

Assess the following: Initiate Rx

Invasive diagnostic procedure; bronchoscopy, FNA

•clinical/immune status

•risk of transmission

•side-effects of Rx

High

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

Antituberculosis Drugs In the United States

Antituberculosis Drugs In 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.

Treatment of TuberculosisRelative Activities of Drugs

Treatment of TuberculosisRelative Activities of Drugs

Agent Early bactericidal Preventing Sterilizing activity drug resistance activity

Isoniazid ++++ +++ ++Rifampin ++ +++ ++++Pyrazinamide + + +++Streptomycin ++ ++ ++Ethambutol ++ – +++ ++ +Highest ++++, High +++, Intermediate ++, Low +

Treatment of TuberculosisStandard Regimen

Treatment of TuberculosisStandard Regimen

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6

months

Initial Phase Continuation Phase

Recommended RegimensRecommended Regimens

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

Recommended RegimensRecommended Regimens

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

Treatment of TuberculosisExtending Therapy

Treatment of TuberculosisExtending Therapy

Isoniazid

Rifampin

PyrazinamideEthambutol

0 1 2* 3 4 5 6 7 8 9months

Initial Continuation Phase

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

IsoniazidIsoniazid

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

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

Isoniazid Isoniazid

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

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

Bacteriostatic 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

Bacteriostatic 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

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

PyrazinamidePyrazinamide

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

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

RifampinRifampin 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

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