Tuberculosis Today

1
Tuberculosis Today

• James S. Seebass, D.O.
• Oklahoma State University
• Center for Health Sciences College of
  Osteopathic Medicine

2
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

3
Transmission and Pathogenesis of Tuberculosis
4
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
5
(No Transcript)
6
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

7
Transmission of Tuberculosis
CASE
CONTACT
Site of TB Cough Bacillary load Treatment
Closeness and duration of contact Immune
status Previous infection
Ventilation Filtration U.V. light
8
Tuberculin Reactivity Among Contacts by Index
Status
Contact status Index Status Household
Casual (n858) (n4207) Sm , Cx
20.2 3.7 Sm , Cx 1.1 0.2
Van Geuns, et al. BIUAT 197550107
9
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. 19756090
10
Effects of Therapy on M. tuberculosis
11
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

12
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

13
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)

14
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

15
Risk for Development of TB Disease
16
Who Should Be ScreenedTARGETED 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

17
New Tuberculosis Guidelines Tuberculin Testing

• Criteria for Tuberculin Positivity
• gt5 mm gt10 mm
  gt15 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

18
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 lt 4 years old
• Nationwide about 20 of TB contacts are infected

19
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. (lt5 years)

20
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

21
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

22
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

23
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

24
Risk of Progression (3)

• Recent infection
• 4-5 risk of developing active disease within the
  first 1-2 years
• Infants and children lt 4 years of age
• 40 progression to disease in infants younger
  than 12 months

25
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

26
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

27
Tuberculin Skin Test Interpretation
False-Negative Results

• Host factors
• HIV
• Recent TB infection (lt3 months)
• Infections (viral, fungal, bacterial)
• Other illness affecting lymphoid organs
• Live virus vaccination
• Immunosuppressive drugs
• Overwhelming TB
• Age (newborn, elderly)

28
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

29
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)

30
Tuberculin Skin Test Interpretation
Absence of PPD reaction DOES NOT EXCLUDE DISEASE
31
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

32
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)

33
Tuberculosis Screening Flowchart
At-risk person
Tuberculin test symptom review
Negative
Positive
Chest x-ray
Normal
Abnormal
Candidate for Rx of latent TB
Evaluate for active TB
Treatment not indicated
34
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
35
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

36
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

37
Clinical Trials of Isoniazid Preventive Therapy
Number of Cases
Year
38
Isoniazid-Induced Hepatitis
N13,838 Hepatitis Age
(yr) Cases/1000 lt 20 0.0 20-34
3.0 35-49 12.0 50-64 23.0 gt 64 8.0
N11,141 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 199928110140
Kopanoff et al. Am Rev Resp Dis 1976117991
39
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)
40
Clinical Presentation Pulmonary Symptoms and
Signs

• Cough 40-80
• Sputum production
• Pleuritic chest pain
• Hemoptysis does not always indicate active
  disease

41
Clinical Presentation Systemic Symptoms and
Signs (2)

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

42
Radiographic Presentation Pulmonary Tuberculosis

• Primary Post-primary
• Location of infiltrates Upper Lower 6040 85
  upper Usually upper in children
• Cavitation Rare Often
  present
• Adenopathy Adults 30 Rare Children-common
• Effusion May be present May be present

43
(No Transcript)
44
(No Transcript)
45
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
46
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
47
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.
48
Treatment of TuberculosisRelative Activities of
Drugs
Agent Early bactericidal Preventing
Sterilizing activity
drug resistance activity Isoniazid
Rifampin
Pyrazinamide
Streptomycin Ethambutol

Highest , High , Intermediate , Low
49
Treatment of TuberculosisStandard Regimen
Initial Phase Continuation Phase
Isoniazid
Rifampin
Pyrazinamide
Ethambutol
0 1 2 3 4 5
6
months
50
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
51
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
52
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
53
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 (lt 3), risk ?
  w/EtOH,age, rifampin therapy peripheral
  neuropathy risk ? EtOH, malnourished rare
  lupus-like syndrome

54
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

55
Ethambutol

• 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

56
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

57
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