Med II
Tuberculosis
Denise
Etiologic Agent
 Mycobacterium tuberculosis: most frequent, most impt
agent of human agent
 M. bovis: once an impt cause of TB transmitted by
unpasteurized milk
 M. africanum
 M. microti: “vole” bacillus, less virulent, rarely
encountered
 M. canettii
Mycobacterium tuberculosis
 Rod-shaped, nonspore-forming, thin aerobic bacterium
(0.5umx3um)
 Acid fast: due to high content of mycolic acids, long-chain
cross-linked FAs and other cell wall lipids (also exhibited
by Nocardia, Rhodococcus, Legionella, Isospora,
Crypstosporidium
 Genome sequence: ~4000 genes + GC content
From Exposure to Infection
 M. tuberculosis: transmitted by droplet nuclei, which are
aerosolized by coughing, sneezing or speaking  remain
suspended in the air for several hours  gain direct
access to the terminal passages when inhaled
 Impt determinants of transmission:
a. intimacy and duration of contact
b. degree of infectiousness of the case
c. shared environment of the contact
 Pxs with sputum containing AFB visible by microscopy:
highly infectious; they often have cavitary pulmonary
disease or TB of the respiratory tract
 Pxs with sputum smear (-)/culture (+): less infectious
 Pxs culture (-) + extrapulmonary TB: noninfectious
From Infection to Disease
 Primary TB: clinical illness ff infection; common among
children up to 4 years old; may be severe and
disseminated; usually not transmissible
 Majority of infected individuals develop TB within the first
year or two after infection
 Secondary TB: dormant bacilli that has persist for years
before reactivating; often infectious
 Age: impt determinant of the risk of disease after
infection
 Late adolescence & early adulthood: highest
incidence of TB
 Among women peaks at 25-34 y/o
 Risk may ↑ in elderly due to waning immunity &
comorbidity
 HIV co-infection: most potent risk factor for TB
Pathogenesis & Immunity
 Inhaled bacilli trapped in the upper airways and expelled
by ciliated mucosal cells and some reach the alveoli
 In the alveoli, activated alveolar macrophages ingest the
bacilli  association of C2a with the bacterial cell wall 
C3b opsonization of the bacteria  recognition by the
macrophages  phagocytosis
 Genes to confer virulence to M. Tb:
 katG—encodes for catalase protective against
oxidative stress
 rpoV—main sigma factor initiating transcription
 erp—CHON required for multiplication
 Initial stage of host-bacterium interaction: host’s
macrophages contain bacillary multiplication by producing
proteolytic enzymes and cytokines or the bacilli begin to
multiply  their growth quickly kills the macrophages
which lyse  monocytes ingest bacilli released from the
macrophages
 2-4 wks after infection: 2 more host responses: tissue-
damaging response (due to delayed type hypersensitivity)
+ macrophage-activating response (cell-mediated
phenomenon)
 With the dev’t of specific immunity & the accumulation of
large #s of activated macrophages  granulomatous
lesions form (contains lymphocytes, epithelioid cells &
giant cells)
 Bacillary antigens  stimulate T lymphocytes  release
lymphokines  aggregate around the lesion’s center 
neutralize tubercle bacilli  necrotic material resembles
soft cheese (caseous necrosis)  healed lesions undergo
calcification
 Bacilli transported by macrophages to regional lymph
nodes: same evolution in other organs & they tend to heal
 In young children with poor natural immunity,
hematogenous dissemination may result in fatal military
TB or TB meningitis
 Cell mediated immunity confers protection against M. Tb
 Humoral immunity: no defined role in protection
 Macrophages: directly phagocytize tubercle
bacilli
 T cells (CD4+): protection thru prod’n of
lymphokines
 Macrophages secrete a number of cytokines:
 Il-6: cause hyperglobulinemia
 TNF-a: kill mycobacteria, formation of
granuloma, fever, weight loss
 Macrophages: critical in processing and presenting
antigens to T lymphocytes  proliferation on CD4+
lymphocytes  that is why in HIV-infected ones, inability
to contain mycobacterial proliferation is apparent
 Reactive CD4+ T cells  produce cytokines of the TH1
pattern and participate in MHC class II-restricted killing of
cells infected with M. Tb
 M. Tb possesses various CHON antigens present in the
cytoplasm and cell wall
 Coincident with the appearance of immunity, DTH to M.
Tb develops: basis of the PPD skin test
 Cellular mechanisms responsible for PPD reactivity:
related to previously sensitized CD4+ lymphocytes which
are attracted to the skin-test site
Clinical Manifestations
Primary TB
(1) Primary Disease
 Results from an initial infection with tubercle bacilli
 In areas of high TB prevalence, often seen in children and
frequently localized to the middle and lower lung zones
 Lesion after infection: peripheral and accompanied by
hilar or paratracheal lymphadenopathy
 Small calcified nodule—Ghon lesion
 In immunocompromised & malnourished, primary Tb may
progress rapidly to clinical illness
 Initial lesion ↑ in size
 Pleural effusion—due to penetration of bacilli into the
pleural space from an adjacent subpleural focus
 Progressive primary TB: primary site enlarges  central
portion goes necrotic  acute cavitation develops
 In young children, hilar or mediastinal lymphadenopathy
due to the spread of the bacilli from the lung parenchyma
thru lymphatic vessels develop
 Enlarged lymph nodes may  compress bronchi 
obstruction  segmental or lobar collapse
 Partial obstruction: may cause emphysema &
bronchiectasis
 Hematogenous dissemination: common & symptomatic,
may result in severe manifestations
(2) Postprimary Disease
 Results from endogenous reactivation of latent infection
 Localized to the apical and posterior segments of the
upper lobes where the high O2 conc favors mycobacterial
growth
 With cavity formation, liquefied necrotic contents are
ultimately discharged into the airways  satellite lesions
within the lungs that may in turn undergo cavitation

 Tuberculous pneumonia: massive involvement of
pulmonary segments or lobes with coalescence of lesions
 Nonspecific S/S: night sweats, weight loss, anorexia,
general malaise & weakness
 Cough: in the majority of cases
 Massive hemoptysis: due to erosion of a fully patent vessel
located in the wall of a cavity; may also result from
rupture of a dilated vessel in a cavity (Rasmussen’s
aneurysm) or from aspergilloma formation in an old cavity
 Pleuritic chest pain: in pxs with subpleural parenchymal
lesions but can also result from muscle strain due to
persistent coughing
 PE: of limited use in PTB
Extrapulmonary TB
In order of frequency:
a. lymph nodes
b. pleura
c. genitourinary tract
d. bones
e. joints
f. meninges
g. peritoneum
h. pericardium
A. Lymph Node TB (Tuberculous Lymphadenitis)
 Most common presentation of extrapulmonary TB
 Mainly due to M. Tb
 Presents as painless swelling of the lymph nodes, most
commonly at cervical and supraclavicular sites (scrofula)
 Discrete in early disease but may be inflamed and have a
fistulous tract draining caseous material
 Diagnosis: FNAB
B. Pleural TB
 Penetration by tubercle bacilli into the pleural space
 PE: dullness to percussion & absence of breath sounds
 CXR reveals effusion & some shows parenchymal lesion
 Thoracentesis: to ascertain nature of effusion
 Fluid can be straw-colored, sometimes hemorrhagic; can
be an exudate with a CHON conc >50% of that in serum, a
normal to low glucose conc, pH < 7.2, detectable WBCs
 Neutrophils: early stage, Mononuclear cells: late stage
 Tuberculous empyema: less common complication; due
to a rupture of a cavity, with delivery of a large # of
organisms into the pleural space or of a bronchopleural
fistula
 CXR: pyopneumothorax with an air-fluid level
 Effusion: purulent, thick, contains large #s of
lymphocytes
 AFB smear and culture is often (+)
C. TB of the Upper Airways
 Nearly always a complication of advanced cavitary
pulmonary TB
 May involve larynx, pharynx, epiglottis
 S/S: hoarseness, dysphagia, chronic productive cough
 Acid-fast smear often (+)
 Can may have similar features but is usually painless
D. Genitourinary TB
 ~15% of all extrapulmonary cases; due to hematogenous
seeding ff primary infection
 Common presentations: urinary frequency, dysuria,
hematuria, flank pain
 Discovered only after severe destructive lesions of the
kidneys
 Diagnosis: IV pyelogram; when calcifications and ureteral
strictures are present, they are suggestive of GUT TB
 More common in females affecting the fallopian tubes and
endometrium that may cause infertility, pelvic pain and
menstrual abnormalities
 Responds well to chemotherapy
E. Skeletal TB
 Pathogenesis related to reactivation of hematogenous foci
or spread from adjacent paravertebral lymph nodes
 Weight bearing joints: affected most commonly
 Spinal TB (Pott’s disease or tuberculous spondylitis)—
involved two or more adjacent vertebral bodies
 Upper thoracic spine: most common site of spinal TB in
children; lower thoracic and upper lumbar vertebrae in
adults
 Kyphosis: with collapse of vertebral bodies in advanced
disease
 CT or MRI: reveals the characteristic lesion and suggest its
etiology
 Diagnosis: aspiration of the abscess or bone biopsy
 Paraplegia: catastrophic complication of Pott’s disease
 TB of the hip joints causes pain and limping
 TB of the knee: pain and swelling ff trauma
 If unrecognized bones may be destroyed
F. Tuberculous Meningitis & Tuberculoma
 TB of the CNS: ~5%
 Results from the hematogenous spread of primary or
Postprimary pulmonary disease or from rupture of a
subependymal tubercle into the subarachnoid space
 Common presentations: headache, mental changes or
acutely as confusion, lethargy, altered sensorium and
neck rigidity
 Evolves over 1-2 weeks
 Paresis of CNs: frequent finding
 Involvement of cerebral arteries  focal ischemia
 Hydrocephalus: common
 Diagnosis: Lumbar puncture
 CSF content:
 High leukocyte count (predominance of
lymphocytes)
 CHON content of 1-8g/dL
 Low glucose conc
 AFB on direct smear of CSF sediment
 Culture: diagnostics in 80% of cases
 Tx: glucocorticoids (dexamethasone) enhance the chances
of survival and reduce the frequency of neurologic
sequelae
G. GIT TB
 Pathogenetic mechanisms:
 Swallowing of sputum with direct seeding
 Hematogenous spread
 Ingestion of milk from cows affected by bovine TB
 Terminal ileum & cecum: sites most commonly involved
 Common presentations: abdominal pain, diarrhea,
obstruction, hematochezia and palpable mass in the
abdomen, fever, night sweats, weight loss
 Tuberculous peritonitis: follows either from the direct
spread of tubercle bacilli from ruptured lymph nodes and
intraabdominal organs or hematogenous seeding
 Diagnosis of tuberculous peritonitis: paracentesis
H. Pericardial TB
 Due to direct progression of a primary focus within the
pericardium, to reactivation of latent focus, or to rupture
of an adjacent lymph node
 Subacute onset
 Effusion develops in many cases
 Diagnosis: pericardiocentesis under echocardiographic
guidance
 Fluid subject for biochemical, cytological and
microbiologic study; exudative in nature
 Tx. Glucocorticoids in the management of acute disease,
reducing effusion, facilitating hemodynamic recovery and
thus ↓ mortality
I. Miliary or Disseminated TB
 Due to hematogenous spread of tubercle bacilli
  In children, due to primary infection. IN adults, due to
either recent infection or reactivation of old disseminated
foci
 Lesions are usually yellowish granulomas (1-2mm)
 Clinical manifestations: fever, night sweats, anorexia,
weakness and weight loss
 Pxs may have cough and some have abdominal symptoms
 PE: hepatomegaly, splenomegaly, lymphadenopathy
 CXR: miliary reticulonodular pattern; large infiltrates;
interstitial infiltrates, pleural effusion
 Sputum smear (-) in 80% of cases
 Diagnosis: bronchoalveolar lavage and transbronchial
biopsy
HIV-Associated TB
 TB can appear at any stage of HIV infection
 When cell mediated immunity is only partially
compromised, PTB presents with upper lobe infiltrates &
cavitation without significant lymphadenopathy or pleural
effusion
 In late stages, a primary TB pattern with diffuse
interstitial or miliary infiltrates, little or no cavitation and
intrathoracic lymphadenopathy is more common
 Extrapulmonary TB forms are lymphatic, disseminated,
pleural and pericardial
 Diagnosis is difficult due to ↑ frequency of sputum smear
(-)and atypical CXR findings, lack of classic granuloma and
(-) PPD skin tests
Diagnosis
 Key to diagnosis: high index of suspicion
 Diagnosis is first entertained when the CXR of a px is
abnormal
 If the px has no complicating medical conditions that
favor immunosuppression, the CXR may show the typical
picture of upper lobe infiltrates with cavitation
 The longer the delay between the onset of symptoms and
the diagnosis, the more likely is the finding of cavitary
disease
 AFB Microscopy:
 Presumptive diagnosis is based on this
 Auramine-rhodamine staining and fluorescence
microscopy—commonly used by modern labs
 Staining with Kinyoun or Ziehl-Neelsen basic
fuchsin dyes—more traditional, satisfactory but
time consuming
 3 sputum specimens, collected preferably early in
the morning
 Mycobacterial culture
 Definitive diagnosis is based on this
 A sputum specimen obtained from a patient with a
productive cough
 Specimens may be inoculated onto egg- or agar-
based medium (e.g., Lowenstein-Jensen or
Middlebrook 7H10) & incubated at 37°C under 5%
CO2
 Because most species of mycobacteria, including
M. tuberculosis, grow slowly, 4 to 8 weeks may be
required before growth is detected
 Nucleic Acid Amplification
 Permit the diagnosis of tuberculosis in as little as
several hours
 Applicability is limited by low sensitivity (lower
than culture, but higher than AFB18 smear
microscopy) & high cost
 Most useful for the rapid confirmation of
tuberculosis in persons with AFB-positive sputa
 May also have utility for the diagnosis of AFB-(-)
pulmonary & extrapulmonary TB in selected pxs
 Drug Susceptibility Testing
 Initial isolate of M. Tb should be tested for
susceptibility to HRE
 May be conducted directly (with the clinical
specimen) or indirectly (with mycobacterial
cultures) on solid or liquid medium
 Radiographic Procedures
 Although the "classic" picture is that of upper lobe
disease with infiltrates and cavities, virtually any
radiographic pattern — from a normal film or a
solitary pulmonary nodule to diffuse alveolar
infiltrates in a patient with ARDS — may be seen
 PPD Skin Testing & Diagnosis of Latent TB Infection
 Most widely used in screening for M. tuberculosis
infection
 Test is of limited value in the diagnosis of active
TB because of its low sensitivity & specificity
 (+) rxns obtained:
- when px have been infected with M. Tb but
do not have active disease
- when pxs have been sensitized by
nontuberculous mycobacteria
 Cytokine Release Assays
 Requires overnight incubation of a peripheral-
blood sample with PPD & control antigens followed
by measurement of IFN released by sensitized
lymphocytes in an ELISA
 Add’l Diagnostic Procedures
 Sputum induction by ultrasonic nebulization of
hypertonic saline: for pxs who cannot produce a
sputum
 fiberoptic bronchoscopy with bronchial brushings
or transbronchial biopsy of the lesion
 Bronchoalveolar lavage of a lung segment
containing an abnormality may also be performed
 Adjunctive Diagnostic Test
 Serologic diagnosis based on detection of Ab to a
variety of mycobacterial Ags
Treatment
 2 aims of TB:
- interrupt TB transmission by rendering pxs
noninfectious
- prevent morbidity & mortality by curing pxs with TB
disease
 4 first-line agents: HRZE
- well absorbed after oral administration
- peak serum levels: 2-4h
- complete elimination within 24h
- recommended on the basis of their:
 bactericidal activity (ability to rapidly reduce
the number of viable organisms and render
patients noninfectious)
 sterilizing activity (ability to kill all bacilli and
thus sterilize the affected organ, measured in
terms of the ability to prevent relapses)
 low rate of induction of drug resistance
 Second line agents:
- injectables: streptomycin (formerly a first-line
agent), kanamycin, amikacin, and capreomycin
- oral: ethionamide, cycloserine, and
paraaminosalicylic acid
- fluoroquinolone antibiotics have become the most
commonly used second-line drugs: levofloxacin,
gatifloxacin, moxifloxacin
 Regimens: initial phase & a continuation phase
- Initial phase: the majority of the tubercle bacilli are
killed, symptoms resolve & the px becomes
noninfectious
- Continuation phase: required to eliminate persisting
mycobacteria & prevent relapse
- Tx regimen of choice: 2-month initial phase of HRZE
followed by a 4-month continuation phase of HR
- Tx may be daily or 3x weekly or twice weekly ff an
initial phase of daily therapy
- Continuation phase of once-weekly rifapentine &
isoniazid: equally effective for HIV-seronegative
patients with noncavitary PTB who have (-) sputum
cultures at 2mos
 Pxs with PTB & delayed sputum-culture conversion: tx
extended by 3mos, for a total course of 9mos
 Pxs with sputum culture-(-) PTB: tx may be reduced to a
total of 4mos
 To prevent isoniazid-related neuropathy, pyridoxine (10 to
25 mg/d) should be added to the regimen given to persons
at high risk of vitamin B6 deficiency
 Lack of adherence to tx: most impt impediment to cure
 Direct observation of tx & provision of FDC products:
addition to measures addressing noncompliance
- FDC products: H/R, H/R/Z & H/R/Z/E
 - Strongly recommended as a means of minimizing the
likelihood of prescription error and of the
development of drug resistance as the result of
monotherapy
Monitoring Tx Response & Drug Toxicity
 Bacteriologic evaluation: preferred method
 Sputum examined monthly until cultures become (-)
- With the recommended regimen, >80% of pxs will
have (-) sputum cultures at the end of the 2nd month
of tx
 In some pxs, especially those with extensive cavitary
disease & large # of organisms, AFB smear conversion may
follow culture conversion
 When a px's sputum cultures remain (+) at 3mos, tx
failure & drug resistance should be suspected
 After the completion of tx, neither sputum examination
nor CXR is recommended for follow-up purposes
 Hepatitis: most common adverse rxn
- All adult pxs should undergo baseline assessment of
liver function (e.g., measurement of serum levels of
hepatic aminotransferases & serum bilirubin)
 Hypersensitivity: require discontinuation of all drugs
rechallenge to determine which agent is the culprit
 Hyperuricemia & arthralgia: caused by pyrazinamide can
usually be managed by the administration acetylsalicylic
acid; if gouty arthritis develops, pyrazinamide should be
stopped
Tx Failure & Relapse
 Current isolate be tested for susceptibility to first- and
second-line agents
 Cardinal rule in the is deteriorating px: add more than
one drug at a time to a failing regimen: at least 2 &
preferably 3 drugs that have never been used & to which
the bacilli are likely to be susceptible should be added
 Mycobacterial strains infecting pxs who experience a
relapse after apparently successful tx are less likely to
have acquired drug resistance than are strains from pxs in
whom tx has failed
 It is prudent to begin the tx of all relapses with all five
first-line drugs pending the results of susceptibility testing
HIV-Associated TB
 Amithiozone: not recommended to HIV-infected pxs with
TB due to fatal skin rxns
 3 impt considerations relevant to TB tx in HIV pxs:
- an ↑ frequency of paradoxical rxns
- drug interactions between HAART & rifamycins
- dev’t of rifampin monoresistance with widely spaced
intermittent treatment
 HIV infected TB pxs: candidates for HAART
 Highly active antiretroviral therapy (HAART): paradoxical
rxns: exacerbations in S/S & lab or radiographic
manifestations of TB
 Pathogenesis of paradoxical rxns: immune response to
antigens released as bacilli are killed by effective
chemotherapy
 Glucocorticoids: used for more severe rxns
 Rifampin, a potent inducer of enzymes of the cytochrome
P450 system, lowers serum levels of many HIV protease
inhibitors & some nonnucleoside reverse transcriptase
inhibitors, essential drugs used in HAART regimens
Drug-Resistant TB
 Strains of M. TB resistant to individual drugs arise by
spontaneous point mutations in the mycobacterial
genome, which occur at low but predictable rates
 Because there is no cross-resistance among the commonly
used drugs, the probability that a strain will be resistant
to two drugs is the product of the probabilities of
resistance to each drug and thus is low
 Dev’t of drug-resistant TB: invariably the result of
monotherapy
 Primary drug resistance is that in a strain infecting a
patient who has not previously been treated
 Acquired resistance develops during tx with an
inappropriate regimen
 Although the 6-month regimen is generally effective for
pxs with initial isoniazid-resistant disease, it is prudent to
include ethambutol & pyrazinamide for the full 6mos
 For strains resistant to isoniazid and rifampin,
combinations of a fluoroquinolone, ethambutol,
pyrazinamide & streptomycin
 For pxs with bacilli resistant to all of the first-line agents,
cure may be attained with a combination of four second-
line drugs, including one injectable agent
Prevention of TB
BCG vaccination
 Safe & rarely causes serious complications
 Side effects: ulceration at vaccination site & regional
lymphadenitis
 Recommended for routine use at birth in countries with
high TB prevalence
Tx of Latent TB Infection
 Based on the results of a large # of randomized, placebo-
controlled clinical trials demonstrating 6-12mos course of
isoniazid reduces the risk of active TB in infected TB by
90%
 Optimal duration of tx: 9-10mos
 Candidates for tx of latent TB: identified by PPD skin
testing of persons in defined high risk-groups
 Reactions are read at 48 to 72 h as the transverse
diameter in millimeters of induration; the diameter of
erythema is not considered
 Area of induration =5mm in diameter: (+) reactions for
close contacts of infectious cases, persons with HIV
infection, persons receiving drugs that suppress the
immune system, & previously untreated persons whose
chest radiograph is consistent with healed TB
 10-mm cutoff is used to define positive reactions in most
other at-risk persons
 Infants & children who have come into contact with
infectious cases should be treated and should have a
repeat skin test 2 or 3 months after contact ends
 Isoniazid is administered at a daily dose of 5 mg/kg (up to
300 mg/d) for 9 months
 a 6-month period of treatment has been recommended in
the past and may be considered for HIV1-negative adults
with normal chest radiographs when financial
considerations are important
 An alternative regimen for adults is 4 months of daily
rifampin
 Isoniazid should not be given to persons with active liver
disease
Basics of Control
 Highest priority in any tuberculosis control program:
prompt detection of cases & the provision of short-course
chemotherapy to all TB pxs
 DOTS strategy promoted by the WHO:
(1) political commitment by the gov’t to sustained
TB control
(2) case detection through microscopic exam of
sputum from pxs who present to health care
facilities with cough of >2-3 wks' duration
(3) administration of standard short-course
chemotherapy to all sputum smear-(+) pxs under
proper case-management conditions, including
direct observation of drug ingestion
(4) establishment & maintenance of a system of
regular drug supply
(5) establishment & maintenance of an effective
surveillance & monitoring system that allows
assessment of tx outcomes