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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
Tuberculosis Today

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%*
transmission of tuberculosis
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

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
transmission of tuberculosis7
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

tuberculin reactivity among contacts by index status
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

likelihood of developing tb in contacts by index status
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

general issues clinical suspicion
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
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
general issues clinical suspicion 3
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)
general issues clinical suspicion 4
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
risk for development of tb disease

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
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
new tuberculosis guidelines tuberculin testing
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

risk of infection
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
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)
risk of infection 3
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
risk of infection 4
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
risk of progression
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
risk of progression 2
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
risk of progression 3
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
risk of progression 4
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
frequency of screening
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

tuberculin skin test interpretation false negative results
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)
tuberculin skin test interpretation false negative results 2
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
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)
tuberculin skin test interpretation
Tuberculin Skin Test Interpretation

Absence of PPD reaction

DOES NOT EXCLUDE DISEASE

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”
bcg vaccination and interpretation of the tuberculin skin test
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)
tuberculosis screening flowchart
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

a rose by any other name
“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

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
completion of inh treatment for ltbi
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
isoniazid induced hepatitis
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

clinical presentation site of disease
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%)

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
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%
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

laboratory diagnosis predictive value of a positive smear
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

approach to a patient suspected of having tb afb smear negative
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

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 tuberculosis relative 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 tuberculosis standard regimen
Treatment of TuberculosisStandard Regimen

Initial Phase Continuation Phase

Isoniazid

Rifampin

Pyrazinamide

Ethambutol

0 1 2 3 4 5 6

months

recommended regimens
Recommended 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 regimens51
Recommended 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 tuberculosis extending therapy
Treatment of TuberculosisExtending 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

isoniazid
Isoniazid
  • 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
isoniazid54
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
slide55
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

Ethambutol

pyrazinamide
Pyrazinamide
  • 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
rifampin
Rifampin
  • 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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