2017 COMMUNICABLE DISEASE

TUBERCULOSIS
HARRISON’S PRINCIPLES OF INTERNAL MEDICINE 19E

ETIOLOGIC AGENT
M. TUBERCULOSIS COMPLEX
- M. tuberculosis
- M bovis
o resistant to pyrazinamide
o once an important cause of TB transmitted by
unpasteurized milk
- M. caprae
- M. africanum
- M. microti
- M. pinnipedii
- M. mungi
- M. orygis
- M. canetti
M. TUBERCULOSIS
- Slow growing, facultative, obligate aerobe and intracellular
- Rod-shaped, non-spore-forming, thin aerobic bacterium
(0.5um x 3um)
- Neutral on Gram’s staining
o Cannot be decolorized by acid alcohol
- Grows in parallel groups called cords
- Humans are the only known reservoir
Acid-fast bacilli
- Mainly due to high content of mycolic acid, long-chain
cross-linked fatty acids, and other cell-wall lipids
- Other Organisms that are acid-fast: PATHOGENESIS
o Nocardia Risk of acquiring M. tuberculosis infection
o Legionella - Determined mainly by exogenous factors
o Isospora Risk of developing Disease after being infected:
o Cryptosporidium - Depends largely endogenous factors:
Cell Wall o Innate immunologic and nonimmunologic
- Cell Wall composed with arabinogalactan and defenses
peptidoglycan o Cell mediated immunity (CMI) function
o Very low permeability of the cell wall  reduced - Usual course from infection to disease is within 2 years
effectiveness of antibiotics INFECTION AND MACROPHAGE INVASION
- Lipoarabinomannan
- Majority of inhaled bacilli are trapped in the upper airways
o Involved in the pathogen-host interaction
and expelled by ciliated mucosal cells
o Facilitates survival within macrophages
- High guanin-plus-cytosine content o <10% each the alveoli
o Indicative of aerobic lifestyle - Alveolar macrophages that have not been activated
TRANSMISSION phagocytose the bacilli
- Droplet nuclei – MC o Enhanced by complement activation
o Aerosolized by coughing, sneezing, or speaking  Leads to opsonization of bacilli with C3
 3000 infectious nuclei per cough activation products (C3b and C3bi)
o Small droplets (<5-10um) may remain suspended - Adhesion of mycobacteria to macrophages:
in the air for several hours and may reach the o Complement receptors
terminal air passages when inhaled o Mannose receptor
Determinants of likelihood of transmission: o Ig GFc gamma receptor
- Contact with a person who has an infectious form of TB o Type A scavenger receptors
- Intimacy and duration of contact - Phagosome-lysosome fusion (phagosome) and
- Degree of infectiousness of the case
inflammatory cytokine production
- Shared environment
o Inhibits the production of PI3P
Infectious Patients:
- With cavitary pulmonary disease - Survival of M. tuberculosis depends on the reduced
- Laryngeal TB acidification d/t lack of assembly of a complete vesicular
- Sputum containinf 105 – 107 AFB/mL proton-adenosine triphosphatase
Who are patients who are less infectious: VIRULENCE OF TUBERCLE BACILLI
- Sputum smear-negative / culture positive TB KatG gene
- Culture-negative PTB - Encodes for a catalase/ peroxidase enzyme that protects
- Extrapulmonary TB against oxidative stress
- Patients with both HIV infection and TB - Required for isoniazid activation and subsequent
bactericidal activity
Region of Difference 1 (RD1)
- Encodes for key small protein antigens:
o Early secretory antigen-6 (ESAT-6)
o Culture filtrate protein-10 (CFP-10)

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 - Absence of this in vaccine strain M. bovis BCG  ke - Ghon Focus
attenuating mutation o Lesion forming after initial infection
Isocitrate lyase gne icl1 o Usually peripheral
- Encode in a key step in the glyoxylate shunt that facilitates o Accompanied by transient or paratracheal LAD
bacterial growth on fatty acid substrates - Ghon complex
- Required for the log-term persistence of M. tuberculosis o Ghon focus + pleural reaction + thickening +
infection in mice with chronic TB regional LAD
Protein CarD - Erythema Nodosum on the legs
- Essential for the control of rRNA transcription that is - Phlyctenular conjunctivitis
required for replication and persistence in the host cell - Pneumonia d/t rupture of LN into the airway
Sigma factor C and H (sigC and sigH) - Bronchiectasis
- Associated with normal bacterial growth in mice Postprimary (Adult-Type) disease – Reactivation/ Secondary TB
INNATE RESISTANCE TO INFECTION - Result from endogenous reactivation of distant LTBI or
Nramp1 (natural resistance-associated macrophage protein 1) recent infection
- Plays a regulatory role in resistance/ susceptibility to o 50% occurs during the 1st 18 months after infection
mycobacteria o Risk much higher among HIV-infected persons –
HOST RESPONSE, GRANULOMA FORMATION, AND most potent risk factor
LATENCY - Determinant of risk of disease after infection:
ESAT-6 protein o Age
- Induces secretion of matrix metalloproteinase 9 (MMP9) by  Peak among women: 25-34yo
nearby epithelial cells that are in contact with infected o Gender
macrophages  Women > men in ages 25-34yo
 Men > Women at older ages
MMP9 - Early (nonspecific and insidious):
- Stimulates recruitment of naïve macrophages o Diurnal fever and night sweats d/t defervescence
- Inducing granuloma maturation and bacterial growth o Weight loss
M. tuberculosis derived cAMP o Anorexia
- Disrupts cell signal transduction pathways and stimulates o General malaise
elevation in the secretion of TNF-alpha o Weakness
- Further proinflammatory cell recruitment - Cough (initially nonproductive and limited to the morning)
After 2-4 weeks after infection  host responses develop that inhibit - Hemoptysis
mycobacterial growth: o Erosion of blood vessel
- Macrophage-activating CMI response o Rupture of a dilated vessel in a cavity
o T-cell mediated phenomenon resulting in the (Rasmussen’s Aneurysm)
activation of macrophages that are capable of o Aspergilloma formation in an old cavity
killing and digesting tubercle bacilli - Pleuritic Chest Pain
- Tissue damaging response - Hematologic findings:
o Result of a delayed-type hypersensitivity reaction o Mild anemia
to various bacillary antigens o Leukocytosis
o Destroys unactivated macrophages that contain o Thrombocytosis
bacillary antigens - Slightly elevated CRP and/ or ESR
o Causes caseous necrosis of the involved tissues - Hyponatremia d/t SIADH
Granulomatous lesions (tubercles) DIAGNOSIS
- Consists of accumulations of lymphocytes and activated - High index of suspicion
macrophages that evolve toward epithelioid and giant o Night seats
cell morphologies o Weight loss
CLINICAL MANIFESTATIONS o Anorexia
PULMONARY TUBERCULOSIS o Unexplained fever and chills
Classification Primary TB Secondary o Chest pain
(Postprimary TB) o Fatigue
Age Children in the first few Late adolescence o Body malaise
years of life up to 4 yo and early - Chest radiograph
Immunocompromised adulthood o Upper lobe infiltrate with cavities
persons o Atypical in immunosuppressed patients
Transmissibility not associated with More infectious Definitive Diagnosis:
high-level transmissibility than primary - Identification of M tuberculosis in culture
disease - Identification of specific DNA sequence in NAAT
Lung Segment Middle and lower lung Usually localized to DIRECT SPUTUM SMEAR MICROSCOPY (DSSM) – AFB
Involved zone the apical and MICROSCOPY
posterior segments - Light microscopy of specimens stained with Ziehl-Neelsen
of the upper lobes o 2-3 sputum specimen collected early in the
morning
Superior segments
- Light emitting diode (LED) fluorescence microscope
of the lower lobe
NUCLEIC ACID AMPLIFICATION
Primary Disease - For rapid confirmation of TB in persons with AFB-positive
- Directly follows an infection specimens
- Asymptomatic or may present with fever and occasionally - For diagnosis of AFB-negative pulmonary and
pleuritic chest pain extrapulmonary TB

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Xpert MTB/RIF
- Can simultaneously detect TB and rifampin resistance in
<2h
- Initial diagnostic test in adults and children presumed to
have MDR-TB or HIV-assoc TB
- Initial test applied to CSF from patients in whom TB
meningitis is suspected and replacement test for selected
nonrespiratory specimen
MYCOBACTERIAL CULTURE
- 4-8 weeks required before growth is detected
DRUG SUSCEPTIBILITY TESTING
- Initial isolate should be tested for susceptibility to isoniazid
and rifampin
- Expanded susceptibility testing for 2nd-line anti-TB drugs is
mandatory when MDR-TB is found
Direct Susceptibility Testing
- Obtained rapidly on liquid medium (3 weeks)
Indirect Susceptibility Testing
- Testing on solid medium
- Result may be unavailable for ≥8weeks
PCR
- Amplifies resistance gene regions:
- Differentiates between other strains
RADIOGRAPHIC PROCEDURES
Classic CXR: upper lobe disease with infiltrates and cavities
CT scan
- useful in interpreting questionable findins
- helpful in some forms of extrapulmonary TB
MRI:
- useful in dx of intracranial TB
DIAGNOSIS OF LATENT M. TUBERCULOSIS INFECTION
TUBERCULIN SKIN TESTING
- most widely used screening for LTBI
- measures response to antigenic stimulation by T cells that
reside in the skin
- triggers a delayed hypersensitivity among those infected
Limitations:
- lack of mycobacterial species specificity
- inability to discriminate between LTBI and active disease
- Subjectivity of the skin-reaction interpretation
- Deterioration of product
- Batch-batch variation
False-Negative Reactions False-Positive Reactions
Immunosuppression Nontuberculous mycobacteria
Overwhelming TB BCG vaccination
Boosting Phenomenon
- Spurious TST conversion resulting from boosting of reactivity
on subsequent TST 1-5 weeks after initial test
IFN-GAMMA RELEASE ASSAY
- Measures response of recirculating memory T cells to
persisting bacilli producing antigenic signals
- More specific than TST as a result of less cross-reactivity
Potential Advantages:
- Logistical convenience
- Need for fewer patient visits to complete testing
- Avoidance of somewhat subjective measurements
TST VS. IGRA
IGRA
- preferred for most persons over 5yo who are being
screened for LTBI
TST
- preferred for LTBI testing under 5yo

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 Extrapulmonary Sites Mechanism Diagnosis Treatment
(in order of frequency)
Lymph Node (scrofula) Most common FNAB
- Posterior cervical Tuberculous Lymphadenitis Surgical excision biopsy***
- Supraclavicular
Pleura
- Pleural Effusion - Reflects recent primary infection CXR Glucocorticoids may
- Hypersensitivity response to Thoracentesis reduce duration of
mycobacterial Ag - Straw colored/ hemorrhagic fever and/ or fever
- Contiguous parenchymal - Exudate: protein >50% of that
spread in serum
- Normal to low glucose conc
- pH:7.3
- WBC 500-6000/uL (neutrophils
during early stage,
lymphocytes later)
- Absent mesothelial cells
- Lysozyme
Pleural Adenosine deaminase -
screening test
IFN- gamma measurement
Needle Biopsy

- Tuberculous - Rupture of a cavity with spillage CXR: hydropneumothorax Surgical Drainage

Empyema of a large number of organisms Pleural fluid: purulent, thick, with large Decortication (removal
into the pleural space numbers of lymphocytes of thickened visceral
- Complication: (+) Acid fast smears and culture pleura)
- May create a
bronchopleural fistula
- Pleural Fibrosis
- Restrictive lung disease
Genitourinary Tract - Female > Male PE: urinary frequency, dysuria, nocturia,
- Fallopian tube hematuria, flank or abdominal pain
- Endometrium Urinalysis: pyuria and hematuria
- Epididymis Imaging: deformities and obstructions;
calcification; urethral strictures
Culture: 3 morning urine specimen
Bones and Joints - Reactivation of hematogenous PE: kyphosis (gibbus), paravertebral
- Weight Bearing: foci cold abscess, upper spine  soft tissue
- Spine (40%) - Spread from adjacent mass; lower spine  psoas abscess
- Hips paravertebral LN CT/ MRI
- Knees - Involves 2 or more adjacent Aspiration
vertebral bodies Bone biopsy
- Children: upper thoracic spine Synovial fluid Exam:
- Adults: lower thoracic and Upper - Thick
lumbar vertebrae - High protein
- Variable cell count
CNS - Often in young children Glucocorticoids

- Meningitis - Hematogenous spread of Lumbar puncture

primary or postprimary PTB - High leukocyte count with
- Rupture of a subependymal lymphocyte predominance
tubercle into the subarachnoid - Protein 1-8g/L (100-800mg/dL)
space - Low glucose
CSF culture – gold standard
- Tuberculoma - Presents as 1 or more space PE: seizure and focal signs
occupying lesions CT/ MRI: contrast enhanced ring lesions
GI TB - Swallowing of sputum with direct Histo exam and cultre obtained
- Terminal Ileum seeding intraoperatively
- Cecum - Hematogenous spread
- Ingestion of milk from cows
- Tubercoulous - Direct spread of TB from Paracentesis
Peritonitis ruptured LN and intraab organs - High protein
- leukocytosis
Pericardium (Tuberculous - direct extension from adjacent Pericardiocentesis
Pericarditis) mediastinal or hilar LN or
hematogenous
TB of Upper Airways Complication of advanced cavitary Acid fast smear of sputum
- Larynx; Pharynx; TB Biopsy
Epiglottis

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 TREATMENT Impediment to cure: Lack of adherence to treatment
Goals: - Patient-related factors:
- Prevent morbidity and death by curing TB while preventing o Lack of belief that the illness is significant and/ or
emergence of drug resistance treatment will have a beneficial effect
- Interrupt transmission by rendering patients noninfectious o Existence of concomitant medical conditions
DRUGS o Lack of social support
o Fear of stigma and discrimination
1ST LINE DRUGS 2ND LINE DRUGS o Poverty
Isoniazid Fluoroquinolone o With attendant joblessness and homelessness
Rifampin Injectable - Provider-related factors that promote adherence:
Pyrazinamide Aminoglycoside o Support
- Augments potency of - Kanamycin o Education
isoniazid/ rifampin making it - Amikacin o Encouragement of patients and offering of
a 6-month course - Streptomycin convenient clinic hours
Ethambutol Capreomycin MONITORING TREATMENT RESPONSE AND DRUG
Ethionamide and TOXICITY
Prothionamide Measuring progress of TB control
Cycloserine and - Case detection rate
Terizidone - Treatment success rate
PAS Monitoring Treatment:
For patients with TB resistant to most of the 1st and 2nd line agents - Bacteriologic Evaluation (culture and/ or smear
(“group 5”) microscopy)
- Clofazimine o Essential in monitoring response to treatment for
- Linezolid TB
- Amoxicillin/ clavulanic Acid - Patient’s weight
- Clarithromycin - Sputum examined monthly until cultures become negative
- Carbapenems o 80% become negative at the end of 2nd month of
For severe case of MDR-TB treatment
- Diarylquinoline bedaquiline - AFB smear conversion
- Nitroimidazole delamanid o Lag behind culture conversion
 d/t expectoration and microscopic
visualization of dead bacilli
o undertaken at 2, 5, and 6 months
- Nucleic Acid Amplification
Not used to monitor treatment:
- Xpert MTB/ RIF
- Serial chest radiograph
o Changes may lag behind bacteriologic response
Drug Toxicity
- Hepatitis – most common
o All adult patient should undergo baseline LFT
o Stop treatment if:
REGIMEN  Symptomatic hepatitis
 Marked (5-6x) elevated s. AST/ALT
Initial (Intensive/ Continuation - Hypersensitivity
bactericidal) Phase (Sterilizing) Phase - Hyperuricemia and arthralgia (pyrazinamide)
Majority of the Eliminates persisting o Mgt: ASA
tubercle bacilli are mycobacteria and o Stop PZA if with gouty arthritis
killed prevent relapse - Autoimmune thrombocytopenia sec to rifampin
Symptoms Resolve - Optic neuritis with ethambutol
Patient becomes - Pruritus and GI upset
noninfectious TREATMENT FAILURE AND RELAPSE
Usual Agents 2 months 4 months Treatment Failure
- Isoniazide (H) - Isoniazid - Sputum smear and/ or culture remain positive after 3
- Rifampin (R) - Rifampin months of treatment
- Pyrazinamide (Z - Initial molecular testing for rifampin resistance
- Ethambutol € - If clinical condition is deteriorating  change in regimen:
Duration of treatment o Add more than 1 drug at a time to a failing
New smear or 2 months (HRZE) 4 months (HR) regimen
culture-positive  At least 2 and preferably 3 drugs that
case have never been used and to which the
bacilli are likely to be susceptible
New culture- o Patient may continue INH or RIF along with new
negative case agents pending the results of susceptibility tests
Pregnancy 2 months (HRE) 7 months (HR) Relapse
Relapses and 3 months (HRZES) 5 months (HRE) - A patient who has been declared cured of any form of TB
treatment in the past by a physician after 1 full course of anti-TB
default meds, and now has become sputum smear (+)
- Recurrence after apparently successful treatment
- Give all 4 1st line drugs + streptomycin
Return to treatment after default
- A patient who stops taking his medications for 2 months or
more and comes back to the clinic smear (+)

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 DRUG-RESISTANT TB DIRECTLY OBSERVED TREATMENT (DOTS)
- Arise by spontaneous point mutations in the mycobacterial Components:
genomes - Availability of quality assured sputum microscopy
- Almost the result of monotherapy - Uninterrupted supply of anti-TB drugs
Primary Drug resistance - Supervised treatment
- Develops in patient infected from the start by a drug- - Patient and program monitoring
resistant strain - Political will
Acquired Resistance
- Develops during treatment with an inappropriate regimen
MDR-TB
- Resistant to at least isoniazid and rifampin
- Initial Phase: 5 drugs x 8 months
o Later generation fluoroquinolone
o An injectable agent
o Ethionamide
o Cycloserine or PAS
o Pyrazinamide
- Optimal duration of treatment: at least 20 months
Agent Mutation
Isoniazid rpoB gene
Isoniazid katG gene & inhA gene
Pyrazinamide pncA gene
Ethambutol embB gene
Fluoroquinolones gyrA and B gene
Aminoglycosides rrs gene

SPECIAL CLINICAL SITUATIONS

Patient with CKD
- Should not receive aminoglycosides
- Ethambutol can be given if serum drug levels can be
monitored
- Dosage of isoniazid and pyrazinamide should be reduced
for all patients with severe CKD (except undergoing
hemodialysis)
Patient’s with Liver Disease
- Use of pyrazinamide should be avoided
Silicotuberculosis
- Extension of therapy by at least 2months
Pregnant
- 9 months of treatment with INH and RIF supplemented by
ethambutol for the 1st 2 months
- Streptomycin is contraindicated
o Damage to CN VIII
- Breastfeeding is not contraindicated

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