1. Tuberculosis

2. A Small Disclaimer…
This presentation will NOT teach you everything there is to know about tuberculosis

3. Image credit: National Library of Medicine
History of TB (1)
TB has affected humans for millennia
Historically known by a variety of names, including:
Consumption
Wasting disease
White plague
TB was a death sentence for many
Vintage image circa 1919
Image credit: National Library of Medicine 3 3

4. History of TB (2) Scientific Discoveries in 1800s
Until mid-1800s, many believed TB was hereditary
1865 Jean Antoine-Villemin proved TB was contagious
1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB
Mycobacterium tuberculosis
Image credit: Janice Haney Carr 4 4

5. History of TB (3) Sanatoriums
Before TB antibiotics, many patients were sent to sanatoriums
Patients followed a regimen of bed rest, open air, and sunshine
TB patients who could not afford sanatoriums often died at home
Sanatorium patients resting outside 5 5

6. Breakthrough in the Fight Against TB (1)
Drugs that could kill TB
bacteria were discovered
in 1940s and 1950s
Streptomycin (SM) discovered in 1943
Isoniazid (INH) and
p-aminosalicylic acid (PAS) discovered between 1943 and 1952 6 6

7. most common and important agent of human disease is M. tuberculosis.
M. bovis (characteristically resistant to pyrazinamide, once an important cause, currently the cause of a small percentage of cases worldwide)
M. microti : less virulent and rarely encountered
M. pinnipedii (seals and sea lions in the southern hemisphere and recently isolated from humans )
M. canettii (a rare isolate from East African cases that produces unusual smooth colonies on solid media)

8. neutral on Gram's staining.
M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic bacterium measuring 0.5μm by 3 μm
neutral on Gram's staining.
once stained, the bacilli cannot be decolorized by acid alcohol  due mainly to the organism’s high content of
mycolic acids,
long-chain cross-linked fatty acids,
other cell-wall lipids

9. cell wall, lipids are linked to underlying arabinogalactan and peptidoglycan. This structure confers very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics
cell wall, lipoarabinomannan, is involved in the pathogen-host interaction and facilitates the survival of M. tuberculosis within macrophages

10. Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei, and the protozoa Isospora and Cryptosporidium

12. TB Transmission (3)
TB is spread person to person through the air via droplet nuclei
M. tuberculosis may be expelled when an infectious person:
Coughs
Sneezes
Speaks
Sings
Transmission occurs when another person inhales droplet nuclei 12 12

13. Dots in air represent droplet nuclei containing
TB Transmission (4)
Dots in air represent droplet nuclei containing
M. tuberculosis 13

14. SOURCE CASE
Only patients with pulmonary tuberculosis can be regarded as infectious. (placenta, skin, milk)
Smear positive
Cavitary pulmonary disease
Endobronchial or laryngeal tuberculosis
Coughing(wearing mask with patient)
Use of chemotherapy (Isoniazide)
persons with both HIV infection and tuberculosis are less likely to have cavitations, they may be less infectious than persons without HIV co-infection.

15. A single bacillus in a tiny droplet nucleus is more hazardous than several bacilli in larger airborne particles
Coughing is the most effective mechanism for generating aerosols that create droplet nuclei.
Thin, watery secretions are more easily fragmented into small respirable droplets than is more viscous mucus.

16. Masks worn by persons exposed to an infectious source are less effective than are masks worn by patients, because most airborne droplet nuclei are much smaller than their parent droplets.

17. prevalence of PPD + among young contacts of patients with newly discovered tuberculosis increased as the radiographic extent of involvement increased
contacts of patients who have organisms + in sputum smears have a much higher prevalence of infection
patients who had positive sputum smears but who were receiving antituberculosis drugs were much less infectious for guinea pigs than were untreated patients.

18. under standard conditions of temperature and humidity indoors : survived
60% to 71% for 3 hours,
48% to 56% for 6 hours,
28% to 32% for 9 hours.
exposure to ultraviolet radiation kills tubercle bacilli

19. close contacts (generally household) 30% are infected, rate of tuberculosis is in the range of 15 per 1000
nonclose contacts (generally out-of-household)  15% are infected, 3 per 1000 nonclose contacts develop tuberculosis
Because the risk of tuberculosis is higher among close contacts, they should also be considered high-priority candidates for INH preventive therapy.

20. 2- nonimmunologic defenses ,
risk of developing disease after being infected depends on endogenous factors, such as the individual's:
innate
1- immunologic
2- nonimmunologic defenses ,
level of function of cell-mediated immunity (CMI)

21. FROM INFECTION TO DISEASE
PRIMARY TUBERCULOSIS -common among children (up to 4yr) -may be severe and disseminated -usually not transmissible -within two years after infection
SECONDARY TUBERCULOSIS -often infectious late adolescent and early adulthood -women(25-34yr)

22. risk is much higher among HIV-infected persons
one-third of cases of active tuberculosis in some inner-city communities
were due to recent transmission rather than to reactivation of latent infection.

23. Risk Factors for Active Tuberculosis
Recent infection (<1 year)
Fibrotic lesions (spontaneously healed)
Intravenous drug use
Gastrectomy
Jejunoileal bypass
Posttransplantation period (renal, cardiac)
Malnutrition and severe underweight
Silicosis
Lymphoma
Leukemia
Other malignancy
HIV
Hemophilia
CRF
Diabetes(insulin dependent)
Immunosuppresion

24. Infection and Macrophage Invasion
usually <10% of droplet nuclei reach the alveoli
Invasion of macrophages results largely from binding of the bacterial cell wall with a variety of macrophage cell-surface molecules
Phagocytosis is enhanced by complement activation leading to opsonization of bacilli

25. LAM inhibits the intracellular increase of Ca2+
LAM inhibits the intracellular increase of Ca2+. Thus the Ca2+/calmodulin pathway (leading to phagosome-lysosome fusion) is impaired, and the bacilli may survive within the phagosomes
replication begins and the macrophage eventually ruptures and releases its bacillary contents

26. Virulance of the bacillus
lipid rich cell wall
glycolipid capsule
genes confer virulance(katG,rpoV)
number of invading bacilli
katG gene encodes for catalase/peroxidase enzymes that protect against oxidative stress
rpoV is the main sigma factor initiating transcription of several genes

27. PATHOGENESIS
Host response tissue damage response(DTH) delayed-type hypersensitivity (DTH) reaction to various bacillary antigens; it destroys unactivated macrophages that contain multiplying bacilli but also causes caseous necrosis of the involved tissues
-macrophage activating response (T-cell mediated phenomenon) activation of macrophages that are capable of killing and digesting tubercle bacilli

28. Granuloma Formation
development of specific immunity and the accumulation of large numbers of activated lymphocytes and macrophages that evolve toward epithelioid and giant cell morphologies
the tissue-damaging response can limit mycobacterial growth within macrophages
growth is inhibited within this necrotic environment by low oxygen tension and low pH
some lesions may heal by fibrosis, with subsequent calcification, whereas inflammation and necrosis occur in other lesions.

29. The Delayed-Type Hypersensitivity Reaction
minority of cases, the macrophage-activating response is weak mycobacterial growth can be inhibited only by intensified DTH reactions, which lead to lung tissue destruction.
lesions enlarge and the surrounding tissue is progressively damaged cavities are formed liquefied caseous material, containing large numbers of bacilli, is drained through bronchi.

30. In young children with poor natural immunity, hematogenous dissemination may result in fatal miliary tuberculosis or tuberculous meningitis
early stages of infection, bacilli are transported by macrophages to regional lymph nodes gain access to the bloodstream and disseminate throughout the body.

31. CELL MEDIATED IMMUNITY
T lymphocyte,mainly Th1(CD4+)
Local macrophage
IL1- IL6 –TNFα- IL2- IFNγ
Active cell aggregate around lesion and effectively neutralize tubercle bacilli
Caseous necrosis
Viable bacilli may remain dormant
Healed lesion may undergo calcification (Ranke complex)

32. TST, which is used primarily for the detection of M
TST, which is used primarily for the detection of M. tuberculosis infection in persons without symptoms
related mainly to previously sensitized CD4+ T lymphocytes
DTH is associated with protective immunity , it by no means guarantees protection against reactivation
previous latent or active tuberculosis may not confer fully protective immunity

33. Interferon-γ Release Assays
Compared with the tuberculin skin test, the INF-γ release assays have the advantage of :
being accomplished with one patient visit,
being more specific
in the presence of BCG vaccination
infection with nontuberculous mycobacteria,
having less reader variability,
not recalling waned immunity

34. POSSIBLE OUTCOMES Immediate clearance of the organism
Chronic or latent infection
Primary disease
Reactivation

35. Condition associated with reactivation
HIV infection
End stage renal disease
Diabetes mellitus
Corticosteroid use
Diminution in CMI associated with old age Reactivation TB tends to be localized

36. Clinical manifeststion
Extra pulmonary tuberculosis
Tuberculous lymphadenitis
Pleural tuberculosis Upper airway tuberculosis Genitourinary tuberculosis Skeletal TB ,
Meningitis & tuberculoma
Gastrointestinal ,
Pericardial
Miliary or disseminated TB
Eye TB
Pulmonary tuberculosis -primary Secondary

37. Bacilli may reach any part of the body, but common sites include:
Sites of TB Disease (1)
Bacilli may reach any part of the body, but common sites include: 37 37

38. Sites of TB Disease (2) Location Frequency Pulmonary TB
Lungs
Most TB cases are pulmonary
Extrapulmonary TB
Places other than lungs such as:
Larynx
Lymph nodes
Pleura
Brain
Kidneys
Bones and joints
Found more often in:
HIV-infected or
other
immunosuppressed
persons
Young children
Miliary TB
Carried to all parts of body, through bloodstream
Rare 38 38

39. Module 1 – Transmission and Pathogenesis of Tuberculosis
TB Pathogenesis (4)
Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)
Module 1 – Transmission and Pathogenesis of Tuberculosis

40. TB Pathogenesis (5) Tubercle bacilli multiply in alveoli, where
infection begins
Module 1 – Transmission and Pathogenesis of Tuberculosis

41. Module 1 – Transmission and Pathogenesis of Tuberculosis
TB Pathogenesis (6)
A small number of tubercle bacilli enter bloodstream and spread throughout body
Module 1 – Transmission and Pathogenesis of Tuberculosis

42. TB Pathogenesis (7) LTBI
Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli
These cells form a barrier shell that keeps the bacilli contained and under control (LTBI)
Module 1 – Transmission and Pathogenesis of Tuberculosis

43. TB Pathogenesis (8) TB Disease
If the immune system CANNOT keep tubercle bacilli under control, bacilli begin to multiply rapidly and cause TB disease
This process can occur in different places in the body
Module 1 – Transmission and Pathogenesis of Tuberculosis

44. Latent TB Infection (LTBI) TB Disease (in the lungs)
LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli in the body
Active, multiplying tubercle bacilli in the body
TST or blood test results usually positive
Chest x-ray usually normal
Chest x-ray usually abnormal
Sputum smears and cultures negative
Sputum smears and cultures may be positive
No symptoms
Symptoms such as cough, fever, weight loss
Not infectious
Often infectious before treatment
Not a case of TB
A case of TB
Module 1 – Transmission and Pathogenesis of Tuberculosis

45. Signs and Symptoms of TB
Cough for more than three weeks
Coughing up blood
Unexplained weight loss
Night sweats
Fever
Feeling tired
Not everyone with TB looks really sick…

46. Systemic effcts Fever Malaise Weight loss pancytopenia Leukocytosis
Anemia
Leukopenia
hyponatremia

47. Primary pulmonary tuberculosis
Often seen in children
Frequently localized to middle and lower lung zone
Paratracheal or hilar lymphadenopathy
Progressive primary tuberculosis (cavation)
Pleural effusion, collapse lung, Bronchectasis
Dissemination ,may develop milliary tuberculosis and meningitis
Ghon lesion(healed lesion)

48. Secondary tuberculosis
Symptom: productive cough, hemoptysis, dyspnea, fever, night sweat
Signs: not specific,
dullness with decreased fermitus (pleural effusion),
rales,
sign of consolidation,
amphoric sound,clubbing

49. Chest.x.ray secondary tuberculosis
Apical and post. segments of the upper lobes(80-90%)
Superior segments of lower lobes
Infiltration and cavitary lesion
Nodules and branching linear densities (tree in bud)
Pleural effusion
Solitary nodule(atypical)

53. Other pulmonary presentation
Endobronchial tuberculosis
ARDS
Tuberculous pneumonitis (lower lobe)
Lower lobe TB(elderly,diabetes,renal and hepatic dis. ,corticosteroid)
Tuberculoma (rounded mass lesion)

54. Complication of pulmonary TB
Massive hemoptysis (rare)
Spontaneous pneumothorax
Empyema
Bronchectasis
Extensive pulmonary destruction
Tuberculosis of the upper airway(chronic productive cough, hoarseness,dysphagia)

55. Pleural tuberculosis
Hypersensitivity reaction to mycobacterial antigens in pleural space
Rupture or leakage from subpleural focus of disease
Ph.E:dullness to percussion and absence of breath sound

56. Pleural fluid characteristics
Exudative (ppl / pserum >0/5)
Normal or low glucose
PH<7/2
Lymph dominant
Mesothelial cell rare
AFB negative in smear
Fluid culture 30% positive
Biopsy with culture 70-80% diagnostic
ADA, IFN gamma

57. Miliary (disseminated) tuberculosis
Hematogenous spread of tubercle bacilli
Recent infection or reactivation
Yellowish granuloma up to 2mm

58. Clinical manifestation (miliaryTB)
History: fever, night sweat,anorexia, weakness,weight loss
PH.E: Hepatomegaly,Splenomegaly, lymphadenopathy, choroidal tubercle, menangismus

59. Diagnosis miliary TB CXR :miliary reticonodular pattern
Sputum smear negative in 80%
Anemia,leukopenia,leukocytosis
DIC
Elevated alk/ph, abnormal liver function test
Negative PPD(50%)
BAL and biopsy more positive

64. Clinicopathologic patterns
Acute miliary tuberculosis(typical caseating granuloma)
Cryptic miliary tuberculosis(more chronic, non specific clinical presentation)
Non reactive miliary TB(acute septicemic)
Risk factor: Age, alcohol abuse, malignancy, renal failure, CTD, diabetes, pregnancy, immunosuppresion

66. HIV-associated TB Presentation varies with the stage
Late stage: primary pattern with miliary infiltrate and lymphadenopathy , no cavitation
Higher incidence of extrapulmonary and pleural effusion
Sputum smear frequently negative
Lack of classic granuloma formation

68. Diagnosis Tuberculosis
High index suspicion
Chest.x.ray
AFB Microscopy:
three sputum specimens, collected in the early morning
Staining with ziehl neelsen or auramine-rhodamine

69. Diagnosis Culture: Egg based (lowenstein-jensen),
agar based (middelbrook);
4-8 week may be requird for growth
Liquid media with radiometric growth detection (bactec-460)
High pressure liquid chromatography of mycolic acid(2-3 week)
Nucleic acid amplification

70. regional lymphadenitis,
BCG VACCINATION
Derived from an attenuated strain of M.bovis
Efficacy from 80% to nil
Rarely complication:
ulceration,
regional lymphadenitis,
osteomyelitis,
dissemination

71. PPD Purified protein derivative PPD 5tu:0/1ml contain 0/0001mg
Mantoax method (interadermaly, volar surface)
Wheal 6-10mm
Reaction are read at 48 to72h(transverse diameter of induration in mm)
A second skin test administered 1week or more after the first(two-step)

72. Measuring TST Record induration (bump) only
Measure transverse (across arm)
Record: Date given, date read, mm

75. TB Classification System (1)
Based on pathogenesis of TB
Class
Type
Description
No TB exposure
Not infected
No history of TB exposure
Negative result to a TST or IGRA 1
TB exposure
No evidence of infection
History of TB exposure
Negative result to a TST (given at least 8-
10 weeks after exposure) or IGRA 2
TB infection
No TB disease
Positive result to a TST or IGRA
Negative smears and cultures (if done)
No clinical or x-ray evidence of active
TB disease
Module 1 – Transmission and Pathogenesis of Tuberculosis

76. TB Classification System (2)
Based on pathogenesis of TB
Class
Type
Description 3
TB, clinically active
Positive culture (if done) for M. tuberculosis Positive result to a TST or IGRA, and clinical, bacteriological, or x-ray evidence of TB disease 4
Previous TB disease (not clinically active)
Medical history of TB disease
Abnormal but stable x-ray findings
Positive result to a TST or IGRA
Negative smears and cultures (if done) No clinical or x-ray evidence of active TB disease 5
TB suspected
Signs and symptoms of TB disease, but evaluation not complete
Module 1 – Transmission and Pathogenesis of Tuberculosis

77. Short course treatment(6 month)
First line drugs: Rifampin, Isoniazid, Ethambutol, Pyrazinamid, streptomycin
Short course treatment(6 month)
2month initial phase (bactericidal): rifampin, isoniazid, ethambutol, pyrazinamide
4month continuation (sterilizing): rifampin and isoniazid

78. Treatment Pyridoxin (vit B6) should be given to: -ALCOHOLICS
-Malnurished
-pregnant and lactating woman
-chronic renal failure
-diabetes
-HIV infection

79. history of hepatic disease
Hepatitis
Most common adverse reaction
Baseline assessment of liver function in all adult patient
monitoring monthly :
Older patient
alcoholics
pregnancy
HIV
history of hepatic disease
Treatment should be stopped: symptomatic hepatitis or three to five fold elevation LFT

80. First Line Drugs INH : RIF: GI-upset,Drug Raised LFT Interactions
Hepatitis
Peripheral-neuropathy
Drug interactions
Mild effect on CNS
drug induced lupus
RIF:
GI-upset,Drug
Interactions
Hepatitis
Thrombocytopenia
Rash
Interstitial nephritis
Flu like

81. PZA:
Hepatitis, Rash
GI upset
Arthralgia
Hyperuricemia
rarerly gout
EMB:
Optic neuritis
SM :
Ototoxicity
Nephrotoxicity

82. Adjunctive corticosteroid
Meningitis
Pericarditis
Acute life threatening pulmonary tuberculosis
Low serum albumin
Severe weight loss
Adenitis in children

83. Monitoring response to treatment
Sputum culture monthly until become negative
AFB smear conversion may follow culture conversion
If culture not practical,AFB smear should be undertaken at 2,5and 6 months
Culture/smear positive after 3month and smear positive after 5months are indicative treatment failure
Serial c.x.ray not recommended ,except at the end of treatment

84. A cardinal rule in the latter situation
results of susceptibility testing are expected to become available within a few weeks changes in the regimen can be postponed until that time.
If the patient's clinical condition is deteriorating, an earlier change in regimen may be indicated.
A cardinal rule in the latter situation
always add more than one drug at a time to a failing regimen:
at least two and preferably three drugs that have never been used and to which the bacilli are likely to be susceptible
The patient may continue to take isoniazid and rifampin along with these new agents pending the results of susceptibility tests.

85. Patients who experience a recurrence after apparently successful treatment (relapses) are less likely to harbor drug-resistant strains than are patients in whom treatment has failed.
If the regimen administered initially does not contain rifampin, the probability of isoniazid resistance is high.
begin the treatment of all patients who have relapsed with all four first-line drugs plus streptomycin, pending the results of susceptibility testing.

86. Drug-Resistant TB
M. tuberculosis resistant to individual drugs  spontaneous point mutations in the mycobacterial genome
there is no cross-resistance among the commonly used drugs 
probability that a strain will be resistant to two drugs : product of the probabilities of resistance to each drug
drug-resistant TB is invariably the result of
Monotherapy —i.e., the failure of the health care provider to prescribe at least two drugs to which tubercle bacilli are susceptible
the patient to take properly prescribed therapy

87. Drug-resistant TB may be either primary or acquired
Primary : develops in a strain infecting a patient who has not previously been treated
Acquired : during treatment with an inappropriate regimen
Multidrug-resistant tuberculosis (MDR-TB)
defined as resistance to at least isoniazid and rifampin (also known as rifampicin in many countries),

88. Module 1 – Transmission and Pathogenesis of Tuberculosis
Drug-Resistant TB (3)
Mono-resistant
Resistant to any one TB treatment drug
Poly-resistant
Resistant to at least any 2 TB drugs (but not both isoniazid and rifampin)
Multidrug resistant
(MDR TB)
Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs
Extensively drug resistant
(XDR TB)
Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)
Module 1 – Transmission and Pathogenesis of Tuberculosis

89. MDR strains that are resistant to : all fluoroquinolones and
XDR-TB
MDR strains that are resistant to :
all fluoroquinolones and
at least one of three second-line injectable agents (amikacin, kanamycin, and capreomycin).
Drug-resistant TB can be prevented by adherence :
the inclusion of at least two bactericidal drugs to which the organism is susceptible
the use of fixed-drug-combination products
the verification that patients complete the prescribed course.