Tuberculosis

Daniel Hart, MD
Assistant Professor of Medicine
February 20th, 2007
Overview

 Epidemiology
 Transmission/Pathogenesis
 Skin Testing/Quantiferon Testing
 Active TB
 Latent TB
 Treatment in Special Situations
 Patient Monitoring on Therapy
 Infection Prevention (Isolation Protocols)
Epidemiology

 Most cases in the US are due to

reactivation, especially amongst immigrants
 Highest risk of progression to active TB is
within 2 years of seroconversion
 Increase in incidence in late 1980s-early 90s
largely due to HIV
 Needs to be reported to the health
department
Microbiology

 Aerobic
 Bacillus (rod-shaped)
 Non-spore forming
 Non-motile
 Cell wall – mycolic acid – retains acid fast
stain
 Growth - doubling time of 15-20 hrs.
 3-8 weeks for growth on solid media
Transmission
 Transmitted by airborne particles 1-5
microns in size
 Ease of transmission depends on duration
and proximity of contact as well as the
number of bacteria excreted
 Infection can result from only 1-5 bacteria
entering a terminal alveolus
 Only those with active pulmonary TB are
infectious
Pathogenesis
– Inhalation -> phagocytosis by alveolar
macrophages
– Bacterial multiplication occurs intracellularly
– Lymphatic spread to regional lymph nodes or
hematogenous dissemination
– Immune response results in granuloma formation
(containment of infection)
– Cell death in the granuloma results in caseous
necrosis
– Bacteria can remain dormant in the granuloma
Pathogenesis

– Medical conditions that increase risk for

active TB:
 Chronic renal failure
 Diabetes mellitus

 Silicosis

 Leukemias/lymphomas

 Carcinoma of the head/neck or lung

 Weight loss > 10% of ideal body weight

 Gastrectomy/jejunoileal bypass
TB Skin Testing

 PPD – purified protein derivative of

tuberculin (antigenic)
 Delayed type hypersensitivity reaction
 PPD may not become “positive” until 3
months after exposure
 Boosting effect
Skin Test Interpretation

 PPD >/= 5 mm:

– HIV patients
– Recent contacts of someone with TB
– Fibrotic changes on CXR c/w prior TB
– Organ transplant recipients
– Immunosuppressed (includes patients
receiving the equivalent of 15 mg/day or
more of prednisone for one month or
more)
Skin Test Interpretation
 PPD >/= 10 mm:
– Recent immigrants (< 5 years) from high
prevalence areas (Eastern Europe, Latin
America, Asia, Africa)
– IV drug users
– Residents and employees of high risk facilities
(hospitals, nursing homes, homeless shelters,
prisons)
– Children < 4 years of age
– Mycobacteriology lab personnel
Skin Test Interpretation

 PPD >/= 10 mm:

– People with medical conditions that place
them at high risk for active TB
 Chronic renal failure
 Diabetes mellitus

 Silicosis

 Leukemias/lymphomas

 Carcinoma of the head/neck or lung

 Weight loss > 10% of ideal body weight

 Gastrectomy/jejunoileal bypass
Skin Test Interpretation

 PPD >/= 15 mm:

– Low risk people
– Routine tuberculin testing not
recommended for low risk populations
Skin Test Intrepretation

 False positives:
– Non-tuberculous mycobacterial infection
– BCG vaccination
 False negatives:
– HIV
– Malnutrition
– Steroid therapy
– Recent infection
BCG

 Bacille Calmette-Guerin vaccination:

 Live attenuated mycobacterial strain derived
from M. bovis
 Can yield false positives to PPD – less likely
as time from vaccination increases
 Reactions > 20 mm likely are true

 CDC advises that the PPD be interpreted by

the same guidelines (ignore the BCG history)
Quantiferon Testing

 Whole blood in vitro test:

– Lymphocytes release IFN gamma in
presence of 2 TB antigens
 Will be positive in latent or active TB
 Advantages:
– No error in interpretation
– No follow-up in 48-72 hours
– No boosting
– Not affected by BCG
Quantiferon Testing

 Disadvantages:
– Must be processed within 12 hours of
collection
– False + with atypical mycobacteria
– Too many indeterminate results with
current version (Q-Gold)
– May be less reliable in pregnant women,
children, and immunocompromised
– Does not distinguish between active and
latent TB
Tuberculosis

 Active:  Latent:
– Positive skin test or – Positive skin test or
Quantiferon test Quantiferon test
– Symptoms – No symptoms
– Signs – No signs
– Abnormal CXR – Normal CXR
 Exceptions: Nodules,
pleural scarring
Symptoms/Signs

– Fever
– Night sweats
– Cough
– Hemoptysis
– Pleurisy
– Anorexia
– Weight loss
– Fatigue
Tuberculosis
 Commonly affects the lungs/pleura
 Extrapulmonary sites:
 Lymph nodes – cervical most common-
scrofula
 Bones/joints – spine most common – Pott’s
 GU system – sterile pyuria
 CNS – Elevated CSF WBC (lymphocytes
predominant), low glucose, and high protein
in TB meningitis (insidious onset)
 Abdomen
 Pericardium

 Practically any organ can be involved

Miliary TB

 Hematogenous dissemination of TB
 Commonly affects the lungs, liver, spleen,
bone marrow, kidneys, and adrenals
 Can occur at the time of primary infection or
reactivation
 CXR – diffuse nodules <2 mm
 PPD and sputum for AFB can be negative -
bone marrow or liver biopsy may be helpful
Diagnosis of Active TB

 Acid fast stain of sputum

 Sputum AFB culture (culture needed
for drug susceptibility)
 Radiographic imaging (CXR, CT)
 PCR/NAT
 Fluid Aspiration
 Tissue biopsy – higher yield than fluid
CXR Findings

 Primary TB:
 Lower or middle lobe infiltrates
 Reactivated TB:
 Apical infiltrates/cavitation
 Latent TB:
 Usually normal
 Nodules in hilar area or upper lobes

 Pleural scarring/thickening
Treatment

 Before 1940s: open air (sanatorium)

 1946: streptomycin
 1952: isoniazid
 1970: rifampin
Treatment of Active TB
 Four drug regimen for first 2 months:
 INH 300 mg
 Rifampin 600 mg
 PZA 15-30 mg/kg
 Ethambutol 15-25 mg/kg or streptomycin 15
mg/kg
 Two drug regimen for next 4 months:
 INH and rifampin
 If the TB is not resistant (or < 4%
resistance in the community): INH,
rifampin, and PZA for the first 2
months can be used
Treatment of Active TB

 INH resistant TB:

– Rifampin, PZA, and ethambutol for 6
months
 Rifampin resistant TB:
– INH, PZA, and streptomycin for 9 months
or INH and ethambutol for 18 months
 MDR/XDR TB:
– Based on susceptibility patterns
Blumberg, HM; IDSA
Factors in Treatment of
Latent TB
 Age:
 Previously, low risk patients older than 35
were not treated – higher risk of drug-
induced hepatitis
 “Decision to tuberculin test is a decision to
treat”
 Weigh risks/benefits of treatment in low risk
patients
 Liver disease:
 End stage liver disease and active hepatitis
are relative contraindications to treatment
Treatment of Latent TB

 Efficacy of 90% if all the medications

are taken
 60-70% rates when the drugs are self-
administered
 Protective effect will last probably for
life but at least 20 years
Treatment of Latent TB

 Need to exclude active disease before

treatment (avoids single drug therapy
of active TB)
 CXR – if changes consistent with TB, send
AFB sputum culture
 Single drug therapy appropriate for
latent TB – bacterial load much lower
compared with active TB
Treatment of Latent TB
 Regimens:
– Isoniazid (INH) daily or twice weekly
under directly observed therapy (esp. if
adherence is an issue)
 9 months of treatment is optimal
 At least 6 months is needed
 12 months if treatment is interrupted

– Rifampin daily
 4 months of treatment
 Alternative regimen for those exposed to an
INH resistant patient
Treatment of Latent TB

 Regimens:
– Rifampin/PZA for 2 months
 Similar in safety and efficacy to 12 month
regimen of INH
 No longer recommended due to hepatic
toxicity (including liver failure leading to
death)
Treatment of Latent TB

 Regimens: Multi-Drug Resistant TB

– Therapy based on susceptibility pattern of
the index case if information available
– 2 drug therapy for 12 months
 PZA plus
 Ethambutol or

 Fluoroquinolone with anti-TB activity

Treatment of Latent TB

 If INH treatment is interrupted, an

additional 3 months should be given
 If interruption is >3 months, re-start
treatment
 If a treated person is re-exposed to
someone with TB, repeat treatment is
not needed unless the patient is HIV+
Treatment – Special
Situations
 HIV:
 Up to 20% of patients with CD4 counts < 200
can have a normal CXR with active TB – send
sputum before treatment
 Recent contact with someone with active TB:
treat regardless of PPD result
 Anergy testing not recommended
 Extrapulmonary TB more common
 Immune reconstitution
 Same treatment regimens (except rifabutin
instead of rifampin for patients on PIs)
Treatment – Special
Situations
 Pregnancy:
– No evidence that PPD testing is harmful
– INH: not teratogenic; hepatotoxicity may be
more likely
– Rifampin: generally considered safe – reports of
hemorrhage in the newborn
– Ethambutol: okay
– Streptomycin: avoid (congenital deafness)
– PZA: no published safety data
– Breast-feeding is not contraindicated
Treatment – Special
Situations
 Pregnancy:
– Active TB – treat
– Latent TB (immunocompetent host) –
defer therapy until after delivery
– Latent TB (HIV or recent converter) –
immediate therapy with INH
Monitoring on Treatment

 INH: Side effects

 Abdominal pain, nausea, vomiting
 Dark urine

 Icterus

 Easy bruising/bleeding

 Arthralgias

 Rash

 Paresthesias/weakness – peripheral
neuropathy is less likely with pyridoxine
 Anorexia/fatigue
Monitoring on Treatment

 INH
– Elevated transaminases in 10-20% of
cases – especially with EtOH
– Should be withheld if transaminases
increase more than 3x the upper limit of
normal when associated with symptoms
or 5x the upper limit of normal in
asymptomatic patients
Monitoring on Treatment

 Rifampin: Side effects

– GI upset
– Thrombocytopenia
– Hepatitis
– Flu-like syndrome – if taken irregularly
– Multiple drug interactions
– Orange bodily secretions due to excretion
Monitoring on Treatment

 PZA: Side effects

– GI upset
– Hepatitis
– Arthralgias
– Hyperuricemia – acute gout uncommon
 Ethambutol:
– Optic neuritis: reversible decreased red-green
color perception and visual acuity
– Not hepatotoxic
Adherence

 Decreases with duration of therapy

whereas efficacy increases with length
of treatment
 Factors:
 Side effects
 Complexity of regimen (active TB)
 Perception (especially in latent TB)

 Directly Observed Therapy – especially

in twice weekly regimens
Infection Prevention

 If active pulmonary TB is suspected:

– AFB isolation
– Negative pressure
– Particulate respirator masks
 Isolation not required for:
– Latent TB
– Extrapulmonary TB
Infection Prevention

 Isolation can be discontinued:

– If AFB smears x 3 are negative
– An alternative diagnosis is made
 If patient has active TB, then:
– After 2 weeks of effective therapy
– Resolution of cough, fever
– Negative or “less positive” AFB smears