Download PBL Tuberculosis – Lecture by Dr Khalid Mahmud Ch

DR MUHAMMAD KHALID CHAUDHARY
MBBS, MCPS, FCCP (USA), FCPS (PULMONOLOGY)
ASSOCIATE PROFESSOR
INSTITUTE OF CHEST MEDICINE
KING EDWARD MEDICAL, UNIVERSITY /
MAYO HOSPITAL, LAHORE
TUBERCULOSIS
PROBLEM BASED LEARNING
CASE SCENARIO
A 24 year old paper factory worker presented
with 3 months history of COUGH, SPUTUM,
HAEMOPTYSIS, FEVER, NIGHT SWEATS, LOSS
OF WEIGHT and DECREASED APPETITE. He was
a non smoker and belonged to poor socioeconomic class. He was the youngest of the
family of 6 sharing two rooms. His mother
suffered from tuberculosis 2 years ago.
CASE SCENARIO- CLINICAL EXAMINATION
On examination he looked underweight
Pulse: 102/min
Temperature: 99.6 F
Respiratory Rate: 17/min
Examination of the chest revealed dullness to
percussion at the right upper chest and
crackles on the same area on auscultation
DIFFERENTIAL DIAGNOSIS
Pulmonary Tuberculosis (PTB)
Pneumonia
Bronchiectasis
CBC
Hb: 11 g/dl
TLC: Normal
ESR: 45 mm 1st hour
CHEST X-RAY
SPUTUM
AFB smear + (ZN Stain)
SPUTUM
AFB culture and sensitivity
DIAGNOSIS
PULMONARY TUBERCULOSIS
FACTS ABOUT TUBERCULOSIS
Most common cause of infectious disease related
mortality world wide
WHO estimates that two billion people have
latent TB
Three million deaths per year
At least one person infected every second
80% of TB patients are in 15-54 year age group
BURDEN OF TB
GLOBAL
PAKISTAN
Smear positive – 60 /100,000
Ranks 5th amongst 22 high burden
countries
Incidence – 231 (181) /100,000
(415800)
Smear positive – 81 /100,000
Prevalence – 206 /100,000
Prevalence – 373 (329) /100,000
Incidence – 136 /100,000
Mortality – 24 /100,000
Mortality – 40 /100,000
History of TB
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
History of TB (2)
Scientific Discoveries in 1800s
• Until mid-1800s, many
believed TB was
hereditary
• 1865 Jean AntoineVillemin proved TB was
contagious
• 1882 Robert Koch
discovered M.
tuberculosis, the
bacterium that causes TB
Mycobacterium tuberculosis
Image credit: Janice Haney Carr
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
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
Breakthrough in the Fight Against TB
(2)
• TB death rates in U.S. began to drop dramatically
• Each year, fewer people got TB
• Most TB sanatoriums in U.S. had closed by mid
1970s
TB Resurgence
• Increase in TB in mid 1980s
• Contributing factors:
– Inadequate funding for TB control
programs
– HIV epidemic
– Increased immigration from
countries where TB is common
– Spread in homeless shelters and
correctional facilities
– Increase and spread of multidrugresistant TB
March 16, 1992 Newsweek Magazine Cover
TB Prevention and Control Efforts
• Increased governmental funding for TB control programs
beginning in 1992
• Number of TB cases has steadily declined since 1993
28,000
26,000
24,000
No. of Cases
22,000
20,000
18,000
16,000
14,000
12,000
10,000
1984
1987
1990
1993
Year
1996
1999
Reported TB Cases, U.S., 1982-2008
2002
2005
2008
TB History Timeline
1993: TB cases decline due to
increased funding and enhanced TB
control efforts
1865:
Jean-Antoine
Villemin
proved TB is
contagious
1840
1860
1884:
First TB
sanatorium
established
in U.S.
1880
1900
1882:
Robert Koch discovers
M. tuberculosis
1943: Streptomycin
(SM) a drug used
to treat TB is
discovered
Mid-1970s: Most TB
sanatoriums in U.S.
closed
1920
1960
1940
1943-1952:
Two more drugs are
discovered to treat TB:
INH and PAS
1980
2000
Mid-1980s:
Unexpected rise in TB
cases
History of TB
Study Question 1.1
In what year was each of the following
discoveries made?
a. TB was proven to be contagious
1865
b. The bacterium that causes TB was discovered
1882
c.
The first drug that could kill TB was discovered
1943
TB Transmission
TB Transmission (1)
Transmission is defined as the spread of an organism,
such as M. tuberculosis, from one person to another.
TB Transmission (2)
Types of Mycobacteria
• M. tuberculosis causes most
TB cases in Pakistan
• Mycobacteria that cause TB:
–
–
–
–
–
M. tuberculosis
M. bovis
M. africanum
M. microti
M. canetti
• Mycobacteria that do not
cause TB
– e.g., M. avium complex
M. tuberculosis
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
TB Transmission (4)
Dots in air represent droplet nuclei containing
M. tuberculosis
TB Transmission (5)
• Probability that TB will be transmitted depends on:
– Infectiousness of person with TB disease
– Environment in which exposure occurred
– Length of exposure
– Virulence (strength) of the tubercle bacilli
• The best way to stop transmission is to:
– Isolate infectious persons
– Provide effective treatment to infectious persons as soon as
possible
TB Transmission
Study Question 1.2
What organism causes most TB disease in the
Pakistan?
M. tuberculosis
What are 4 other mycobacteria that cause TB
disease?
M. bovis, M. africanum, M. microti, and M.
canetti
TB Transmission
Study Question 1.3
How is TB spread?
TB is spread from person to person through the
air via droplet nuclei containing M. tuberculosis.
TB Transmission
Study Question 1.4
The probability that TB will be transmitted depends
on what four factors?
• Infectiousness of person with TB disease
• Environment in which exposure occurred
• Length of exposure
• Virulence (strength) of tubercle bacilli
Drug-Resistant TB
Drug-Resistant TB (1)
• Caused by M. tuberculosis
organisms resistant to at
least one TB treatment drug
–
–
–
–
Isoniazid (INH, H)
Rifampin (RIF, R)
Pyrazinamide (PZA, Z)
Ethambutol (EMB, E)
• Resistant means drugs can no
longer kill the bacteria
Drug-Resistant TB (2)
Primary
Resistance
Caused by person-to-person
transmission of drug-resistant
organisms
Secondary
Resistance
Develops during TB treatment:
• Patient was not
given appropriate
treatment regimen
OR
• Patient did not
follow treatment regimen as
prescribed
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)
Drug-resistant TB
Study Question 1.5
What is drug-resistant TB?
Drug-resistant TB is caused by M.
tuberculosis organisms that are resistant to at
least one TB treatment drug. Drugresistant
TB can be difficult to treat.
Drug-resistant TB
Study Question 1.6
What is the difference between primary and secondary
drug-resistant TB?
• Primary resistance is caused by person-to-person
transmission of drug-resistant organisms.
• Secondary resistance develops during TB
treatment. Either the patient was not treated
with the right TB drugs or the patient did not
follow the prescribed treatment regimen.
TB Pathogenesis
TB Pathogenesis (1)
Pathogenesis is defined as how an infection or disease
develops in the body.
TB Pathogenesis (2)
Latent TB Infection (LTBI)
• Occurs when tubercle bacilli are in the body, but the
immune system is keeping them under control
• Detected by the Mantoux tuberculin skin test (TST) or
by blood tests such as interferon-gamma release
assays (IGRAs) which include:
– QuantiFERON®-TB Gold test (QFT-G)
– QuantiFERON®-TB Gold In-Tube (QFT-GIT)
– T-Spot®.TB test (T-SPOT)
• People with LTBI are NOT infectious
TB Pathogenesis (3)
TB Disease
• Develops when immune system cannot keep tubercle
bacilli under control
– May develop very soon after infection or many
years after infection
• About 10% of all people with normal immune
systems who have LTBI will develop TB disease at
some point in their lives
• People with TB disease are often infectious
TB Pathogenesis (4)
Droplet nuclei containing tubercle bacilli are inhaled,
enter the lungs, and travel to small air sacs (alveoli)
TB Pathogenesis (5)
2
bronchiole
blood vessel
tubercle bacilli
alveoli
Tubercle bacilli multiply in alveoli, where
infection begins
TB Pathogenesis (6)
3
brain
bone
lung
kidney
A small number of tubercle bacilli enter
bloodstream and spread throughout body
TB Pathogenesis (7)
LTBI
4
special
immune cells
form a barrier
shell (in this
example,
bacilli are
in the lungs)
• 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)
TB Pathogenesis (8)
TB Disease
5
shell breaks
down and
tubercle
bacilli escape
and multiply
(in this example,
TB disease
develops in
the lungs)
• 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
LTBI vs. TB Disease
Latent TB Infection (LTBI)
TB Disease (in the lungs)
Inactive, contained tubercle bacilli Active, multiplying tubercle bacilli
in the body
in the body
TST or blood test results usually
positive
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
TB Pathogenesis
Study Question 1.7
When a person inhales air that contains droplet nuclei
containing M. tuberculosis, where do the droplet nuclei
go?
• Most of the larger droplet nuclei become lodged in
the upper respiratory tract, where infection is
unlikely to develop
• However, droplet nuclei may reach the small air sacs
of the lung (the alveoli), where infection begins
TB Pathogenesis
Study Question 1.8
After the tubercle bacilli reach the small air sacs of
the lung (the alveoli), what happens to them?
• Tubercle bacilli multiply in alveoli and some
enter the bloodstream and spread throughout
the body
• Bacilli may reach any part of the body
• Within 2 to 8 weeks, the immune system usually
intervenes, halting multiplication and
preventing further spread
TB Pathogenesis
Study Question 1.9
In people with LTBI (but not TB disease), how does
the immune system keep the tubercle bacilli under
control?
The immune system produces special
immune cells that surround the tubercle
bacilli. These cells form a shell that keeps the
bacilli contained and under control.
TB Pathogenesis
Study Question 1.10
How is LTBI detected?
LTBI is detected by the Mantoux tuberculin
skin test (TST) or blood tests such as
interferon-gamma release assays (IGRA), which
include the QuantiFERON®-TB test (QFT-G),
QuantiFERON®-TB Gold In-tube (QFT-GIT), or TSPOT.
TB Pathogenesis
Study Question 1.11
What are the major similarities and differences between LTBI
and TB disease? List characteristics of each.
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
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
TB Pathogenesis
Study Question 1.12
What happens if the immune system cannot keep
the tubercle bacilli under control and the bacilli
begin to multiply rapidly?
When this happens, TB disease
develops.
The risk that TB disease will develop is higher for
some people than
for others.
TB Pathogenesis
Sites of TB Disease
55
Sites of TB Disease (1)
Bacilli may reach any part of the body, but common sites
include:
Brain
Larynx
Bone
Lymph node
Pleura
Lung
Kidney
Spine
Sites of TB Disease (2)
Location
Pulmonary TB
Lungs
Extrapulmonary TB Places other than
lungs such as:
• Larynx
• Lymph nodes
• Pleura
• Brain
• Kidneys
• Bones and joints
Miliary TB
Carried to all parts
of body, through
bloodstream
Frequency
Most TB cases are
pulmonary
Found more often in:
• HIV-infected or
other
immunosuppressed
persons
• Young children
Uncommon
Sites for TB
Study Question 1.16
What part of the body is the most common
site for TB disease?
Lungs are the most common site
What are some other sites?
-
Larynx
Lymph nodes
Pleura (membrane around the lungs)
Brain
Kidneys
Bones and joints
Clinical Presentation
SYMPTOMS
• Young people, < 54 years in more than 80%
of cases
• Asymptomatic initially
• Tiredness, malaise, loss of appetite, weight
loss, Low grade fever
• Cough > 3 Weeks
• Sputum mucoid, purulent, blood stained
Clinical Presentation
SIGNS
• Emaciation
• Increased respiratory rate
• Dullness at affected area
• Crackles at affected area
• Tracheal deviation due to fibrosis
Diagnosis
•
•
•
•
•
•
•
•
•
History
Clinical Examination
Sputum Examination - smear and culture
Radiological Examination - CXR, CT.
Routine Blood
Tuberculin test
PCR test
Serological tests
Special Circumstances
– Gastric lavage &Throat swab in children
– Bronchial lavage and transbronchial biopsy
Sputum Examination
•
•
•
•
Ziehl- Nielson Staining (ZN staining)
Fluorescence Staining
Culture on L J Media – 3-8 weeks
Culture on Bectic Media – 3-6 days
AFB - Ziehl-Nielson stain
64
Colony Morphology – LJ Slant
Radiology
X-Ray suggestive of TB
•
•
•
•
•
•
Opacities in the upper zone
Bilateral infiltrates
Patchy or nodular shadow
Presence of cavities
Calcification
Opacities that persist after few weeks
70
Tuberculin testing
Mantoux test:
• Intradermal inj. Of 0.1 ml (10 units) PPD
• Diameter of induration is measured in mm at
48-72 hours.
• < 6 mm NEGATIVE
• > 1O mm POSITIVE (past or present
mycobacterial infection) If no BCG
• >15 mm POSITIVE if previous BCG
PPD Tuberculin Testing
PPD result after – 72 hours.
Tuberculin testing
Heaf test
• Widely used in survey work
• A drop of undiluted tuberculin ( 100,000 IU/
ml) placed on skin, and 6 needle punctures
are made through it with Heaf gun.
• Read after 3-7 days and graded as
Heaf test
Grade 1: 4-6 small raised red dots
Grade 2: Raised red ring with
normal skin in middle
Grade 3: Raised red circle
Grade 4 : Raised red circle with
blisters or ulcers
Grade 2-4: Positive if no BCG
Grade 3-4: Positive if previous BCG
PCR
• Theoretically capable of detecting a single
organism in a specimen of sputum
• Todate its role in clinical practice is not clear
• Sensitivity 80%, specificity 89-97% (less than
culture)
• Cost, delicate technique
• Serous cavity T.B
Basic principles of treatment
• Combination of antibiotics
–Rapid killing of mycobacteria
•Interruption of the chain of
transmission
–Prevention of drug resistance
• Long duration of treatment
–Sterilisation of lesions
•Prevention of relapse
Drugs Available For Treatment of
TB
• ESSENTIAL DRUGS
- Isoniazid (H)
- Rifampicin (R)
- Pyrazinamide (Z)
- Ethambutol (E)
- Streptomycin (S)
Recommended Regimens
• New Cases.
HRZE = 2 months intensive phase.
HR = 4 months continuation phase.
• Re-treatment Cases.
5 Drugs regimen
HRZES = initial 2 months.
HRZE = upto 3 months.
HRE = 5 months (continuation phase).
Module 1 – Transmission and Pathogenesis of Tuberculosis
84