Mohammad Tohidi M.D.

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Mohammad Tohidi M.D. Professor of Internal
Medicine Department of Pulmonary Diseases Ghaem
Hospital MUMS Mashhad IRAN
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Tuberculosis Transmission and Pathogenesis
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Case presentation

• 21Y O woman referred with the CC of cough for 2
  months.She has had small amount of yellow
  sputum,no fever night sweat hemoptysis, but she
  had 2 kg weight loss.Past medical HX was
  unremarkable.On PE she was slightly pale,but
  otherwise normal.She received antibiotics
  antitussive with no significant effect.

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Approach to the Patient Cough

• Chest radiography may be particularly helpful in
  suggesting or confirming the cause of the cough

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• What we should do next?

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Order the Lot!
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Approach to the Patient

• Evaluate based on likely clinical possibilities
• Sputum for AFB Stain culture
• PFT
• HRCT

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Approach to the Patient

• Sputum for AFB

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Diagnosis

• Pulmonary Tuberculosis

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Global Burden of Tuberculosis

• Tuberculosis (TB) remains the leading cause of
  death worldwide from a single infectious disease
  agent. Indeed up to 1/2 of the world's
  population(3.1 billion) is infected with TB.  The
  registered number of new cases of TB worldwide
  roughly correlates with economic conditions the
  highest incidences are seen in those countries of
  Africa, Asia, and Latin America with the lowest
  gross national products. WHO estimates that eight
  million people get TB every year, of whom 95
  live in developing countries. An estimated 2
  million people die from TB every year. 

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Etiology
M. tuberculosis M. bovis M. africanum M.
microti M. canettii M. caprae M. pinnipedii
Source CDC Public Health Image Library/Dr.
George P. Kubica
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Etiology
With the exception of M. pinnipedii, all of the
species in the Mycobacterium tuberculosis complex
have been shown to cause disease in humans
however, M. tuberculosis is by far the most
prevalent
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Characteristics of M. tuberculosis

• Slightly curved, rod shaped bacilli
• 0.2 - 0.5 microns in diameter 2 - 4 microns in
  length
• Acid fast - resists decolorization with
  acid/alcohol
• Multiplies slowly (every 18 - 24 hrs)

• Thick lipid cell wall
• Can remain dormant for decades
• Aerobic
• Non-motile

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Etiology (2)

• Mycobacteria commonly found in the environment
  rarely cause disease in humans and are not spread
  from person to person
• Mycobacteria other than tuberculosis (MOTT) most
  often cause disease in individuals with weakened
  immune systems
• Mycobacterium avium and M. intracellulare are the
  more common MOTT sometimes seen in patients
  co-infected with HIV

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Transmission of M.tb
Transmission of M.tb
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How is TB Transmitted?

• Person-to-person through the air by a person with
  TB disease of the lungs

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Transmission of M. tuberculosis
Millions of tubercle bacilli in lungs (mainly in
cavities) Coughing projects droplet nuclei into
the air that contain tubercle bacilli

• One cough can release 3,000 droplet nuclei
• One sneeze can release tens of thousands of
  droplet nuclei

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Transmission of M. tuberculosis
When a person with TB disease of the lungs or
larynx coughs, sneezes or sings, droplet nuclei
containing the TB bacilli are expelled into the
air These droplets or particles, called droplet
nuclei, are about 1 to 5 microns in diameter -
less than 1/5000 of an inch Droplet nuclei can
remain suspended in the air for several hours,
depending on the environment
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Transmission of M. tuberculosis
The average TB patient generates 75,000 droplets
per day before therapy This falls to 25
infectious droplets per day within two weeks of
effective therapy
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Fate of M. tb Aerosols

• Large droplets settle to the ground quickly
• Smaller droplets form droplet nuclei of 15 µ
  in diameter
• Droplet nuclei can remain airborne

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Fate of M. tb Aerosols

• When a person inhales air that contains droplets,
  most of the larger droplets become lodged in the
  upper respiratory tract (the nose and throat),
  where infection is unlikely to develop. However,
  the droplet nuclei may reach the small air sacs
  of the lung (the alveoli), where infection begins

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Fate of M. tb Aerosols

• The alveoli contain a type of white blood cell,
  called a macrophage, that eats up any foreign
  objects in the air sac. When the TB bacteria
  reaches the air sac it gets eaten up by the
  macrophage
• Once the TB bacteria is inside of the macrophage
  it begins to multiply

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TB Transmission and Pathogenesis

• ? Not everyone who is exposed to TB will become
  infected

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The Chance of Infection Increases

• When the concentration of TB bacteria circulating
  in the air is greater
• Coughing smear cavitary disease
• Exposure occurs indoors
• Poor air circulation and ventilation small,
  enclosed space
• Poor or no access to sunlight (UV light)

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The Chance of Infection Increases(2)

• The greater the time spent with the infectious
  person or breathing in air with infectious
  particles

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Transmission of Tuberculosis
CASE
CONTACT
Site of TB Cough Bacillary load Treatment
Closeness and duration of contact Immune
status Previous infection
Ventilation Filtration U.V. light
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TB Germs Cannot be Spread By

• Sharing dishes and utensils
• Using towels and linens
• Handling food
• Sharing cell phones
• Touching computer keyboard

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pathogenesis of TB
This next section describes the pathogenesis of
TB (the way TB infection and disease develop in
the body) At first, the tubercle bacilli
multiply in the alveoli and a small number enter
the bloodstream and spread throughout the body
(dissemination) Bacilli may reach any part of
the body, including areas where TB disease is
more likely to develop. These areas include the
upper portions of the lungs, as well as the
kidneys, the brain, and bone
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pathogenesis of TB
Disseminated TB refers to TB that simultaneously
involves multiple organs. While miliary is
given as an example of disseminated TB, it really
refers to a radiographic manifestation of
disseminated TB. Its important to note that not
all patients with disseminated TB have a miliary
pattern on CXR
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miliary tuberculosis
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Spread of TB to Other Parts of the Body

• Lungs (85 all cases)
• Pleura
• Central nervous system
• (e.g., brain, meninges)
• Lymph nodes
• Genitourinary system
• Bones and joints
• Disseminated
• (e.g., miliary)

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TB Can Affect Any Part of Your Body
Extrapulmonary TB
Brain
Pleura
Lymph Node
Spine
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Cell-mediated Immune Response
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• Within 2 to 10 weeks, however, the body's immune
  system usually intervenes, halting multiplication
  and preventing further spread
• The immune system is the system of cells and
  tissues in the body that protect the body from
  foreign substances

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Latent TB Infection (LTBI)

• Person
• Not ill
• Not contagious
• Normal chest x-ray
• Usually the tuberculin skin test is positive
• Germs
• Sleeping but still alive
• Surrounded (walled off) by bodys immune system

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• If the immune system is compromised, then the
  bacilli multiply and spread to other sites in the
  body. People who have TB infection but not TB
  disease are NOT infectious - in other words, they
  cannot spread the infection to other people
• Persons with LTBI have a low bacillary load
  (e.g., 103)
• It is very important to remember that TB
  infection is not considered a case of TB

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TB Transmission and Pathogenesis (2)

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If a person has a healthy immune system, the body
will wall off the bacteria and keep it asleep
(latent). In areas where the prevalence of HIV
is low, the majority of people exposed and
infected with TB are able to contain the
infection A small proportion, however, will
progress to primary, active TB disease. This
generally will be individuals with a weakened
immune system or, as with infant, sbecause their
immune system is not fully developed The highest
risk period for early progression to disease is
within the first year or two following infection
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Reactivation
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Reactivation

• This typically occurs when the immune system
  becomes weak allowing the TB bacteria to multiply
  out of the control of the immune system
• The TB bacteria can then escape from the
  granuloma and enter the airway
• This is the usual mechanism of development of
  active TB among adults

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Active TB Disease

• Germs
• Awake and multiplying
• Cause damage to the lungs
• Person
• Most often feels sick
• Contagious (before pills started)
• Usually have a positive tuberculin skin test
• Chest X-ray is often abnormal (with pulmonary TB)

Granuloma breaks down and tubercle escape and
multiply
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TB Transmission and Pathogenesis (3)

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Risk Assessment

• Evaluate for risk factors that increase the
  likelihood
• that a person may have LTBI (high prevalence)
• for progression of LTBI to active TB disease
  (high risk)

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General Issues Clinical Suspicion

• To diagnose TB you must first think of TB
• Knowing when to consider TB in the differential
  diagnosis knowing who is at risk
• risk for infection
• risk for disease

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High Prevalence for LTBI

• Known contact to person with TB disease
• Persons who live or spend time in certain
  congregate settings
• facilities for the elderly
• jails, prisons
• shelters for the homeless
• drug treatment centers
• Overcrowded habitation (housing)
• Persons born in countries with high prevalence of
  TB

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High Risk for Progression
Persons more likely to progress from LTBI to TB
disease include

• HIV-infected persons
• Persons with a history of prior, untreated TB or
  fibrotic lesions on chest X-ray
• Recent TB infection (within past 2 years)
• Injection drug users
• Age (very young or very old)

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High Risk for Progression (2)

• Persons with certain medical conditions such as
• Diabetes mellitus
• Chronic renal failure or on hemodialysis
• Solid organ transplantation
• Certain types of cancer (e.g., leukemia)
• Gastrectomy or jejunoileal bypass
• Underweight or malnourished persons
• Silicosis

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High Risk for Progression (3)

• Persons taking immunosuppressive agents
• Prolonged corticosteroid therapy (gt15mg daily for
  over 4 weeks)
• Cancer chemotherapy
• Cyclosporine
• Persons taking blocking agents against Tumor
  Necrosis Factor-Alpha
• Etanercept (Enbrel)
• Infliximab (Remicade)
• Adalimumab (HumiraTM)

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Risk for Development of TB Disease
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The Effects of Immune Suppression from HIV on TB

• Increased risk of reactivation of LTBI (10
  annual risk among HIV vs. 10 lifetime risk
  among HIV-negative individuals)
• More likely to have early progression to TB
  disease following infection
• TB can occur at any point in the progression of
  HIV infection (any CD4 ct.)
• High risk of recurrent TB (either relapse or
  re-infection)

Source TB/HIV A Clinical Manual. Second
Edition. WHO, 2004
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The Effects of TB on HIV Progression

• TB increases HIV replication by activating the
  immune system
• Co-infected persons often have very high HIV
  viral loads
• Immuno-suppression progresses more quickly, and
  survival may be shorter despite successful
  treatment of TB
• Co-infected patients have a shorter survival
  period than persons with HIV who never had TB
  disease

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Clinical Presentation Site of Disease
Reported TB Cases by Form of Disease United
States, 2001
Both (7.4)
Extrapulmonary (20.1)
Pleural (18.3)
Lymphatic (42.5)
PulPulPlnary (72.5) oary (72.5) ????mona (2.5)
Other (12.3)
Bone/joint (10.2)
Peritoneal (4.6)
Meningeal (6.0)
Genitourinary (5.9)
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Pulmonary manifestations of tuberculosis

• Pulmonary manifestations of tuberculosis (TB)
  include primary,
  Reactivation,
  Endobronchial,
  Lower lung
  field infection,
  Tuberculoma.

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PRIMARY TUBERCULOSIS

• Fever was the most common symptom
• Chest pain and pleuritic chest pain(25)
• One-half of patients with pleuritic chest pain
  had evidence of a pleural effusion
• fatigue, cough, arthralgias and
  pharyngitis(rare).
• The physical examination was usually normal
  pulmonary signs included pain to palpation and
  signs of an effusion.

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PRIMARY TUBERCULOSISRadiographic abnormalities

• hilar adenopathy, occurring in 65 percent
• Approximately one-third pleural effusions,
  typically within the first three to four months
  after infection
• Lower and upper lobe infiltrates were observed
  in 33 and 13 percent of adults, respectively.
  Most infiltrates resolved over months to years.
• the infiltrates progressed within the first year
  after skin test conversion, so-called progressive
  primary TB.
• Right middle lobe collapse may complicate the
  adenopathy.

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REACTIVATION TUBERCULOSIS

• Multiple terms have been used to describe this
  stage of TB chronic TB, postprimary disease,
  recrudescent TB, endogenous reinfection, and
  adult type progressive TB.

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REACTIVATION TUBERCULOSIS

• One-half to two-thirds of patients developed
  cough, weight loss and fatigue. Fever and night
  sweats or night sweats alone were present in
  approximately one-half. Chest pain and dyspnea
  each were reported in approximately one-third of
  patients, and hemoptysis in approximately
  one-quarter.
• Dyspnea can occur when patients have extensive
  parenchymal involvement, pleural effusions, or a
  pneumothorax.

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REACTIVATION TUBERCULOSISPresentation in the
elderly

• fever, sweats and hemoptysis were less common in
  the elderly, and these patients were less likely
  to have cavitary disease or a positive (PPD) skin
  test.

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REACTIVATION TUBERCULOSIS Radiographic
abnormalities

• reactivation TB typically involves the
  apical-posterior segments of the upper lobes (80
  to 90 percent of patients), followed in frequency
  by the superior segment of the lower lobes and
  the anterior segment of the upper lobes
• In recent large series of TB in adults, 70 to 87
  percent had the upper lobe infiltrates typical of
  reactivation 19 to 40 percent also had cavities,
  with visible air-fluid levels in as many as 20
  percent

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Pulmonary TB typically affects the upper zones of
the lung
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REACTIVATION TUBERCULOSIS Radiographic
abnormalities

• CT scan may show a cavity or centrilobular
  lesions, nodules and branching linear densities,
  sometimes called a "tree in bud" appearance.

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"atypical" radiographic patterns for adult TB

• Hilar adenopathy, sometimes associated with right
  middle lobe collapse
  Infiltrates or cavities in the middle or lower
  lung zones (see lower lung field TB below)
  Pleural effusions
  Solitary nodules
• the known increasing incidence of primary TB in
  adults, rather than "atypical" forms of TB.

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A normal chest radiograph in active pulmonary TB

• A normal chest radiograph is also possible even
  in active pulmonary TB. As an example, in one
  Canadian study of 518 patients with
  culture-proven pulmonary TB, 25 patients (5
  percent) had normal chest x-rays 23 of these
  patients had pulmonary symptoms at the time of
  the normal radiograph.

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ENDOBRONCHIAL TUBERCULOSIS

• 15 percent of patients had lesions in the
  tracheobronchial tree at rigid bronchoscopy and
  40 percent at autopsy.
• At least two mechanisms of developing
  endobronchial TB are possible
• Direct extension to the bronchi from an
  adjacent parenchymal focus, usually a cavity,
  Spread of organisms to the bronchi via infected
  sputum from a distant site.

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ENDOBRONCHIAL TUBERCULOSIS

• Complications of endobronchial TB can include
  Obstruction,
  Atelectasis (with or without secondary
  infections),
  Bronchiectasis,
  Tracheal or
  Bronchial stenosis .

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ENDOBRONCHIAL TUBERCULOSISSymptoms

• a barking cough, two-thirds of patients, often
  accompanied by sputum production. Patients
  rarely develop so-called bronchorrhea
• Lithoptysis
• Wheezing and hemoptysis
• Dyspnea, when present, may signal obstruction
  or atelectasis.
• The clinical manifestations can also be subacute
  or chronic, resembling bronchogenic carcinoma

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ENDOBRONCHIAL TUBERCULOSIS Radiographic
abnormalities

• The most common radiographic finding of
  endobronchial TB in adults is an upper lobe
  infiltrate and cavity with ipsilateral spread to
  the lower lobe and possibly to the superior
  segment of the contralateral lower lobe
• Extensive endobronchial TB can also be associated
  with bronchiectasis on CT scan.

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ENDOBRONCHIAL TUBERCULOSIS

• When endobronchial TB occurs in patients with
  primary disease, segmental atelectasis may be the
  only finding atelectasis is more frequent in the
  right middle lobe and the anterior segment of the
  right upper lobe.
• Because endobronchial lesions can exist without
  extensive parenchymal abnormalities, 10 to 20
  percent of patients may have normal chest
  radiographs

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ENDOBRONCHIAL TUBERCULOSIS

• While it would be natural to expect that rates of
  AFB smear positivity would be high with extensive
  endobronchial involvement, rates of 15 to 20
  percent have been reported. This lower rate may
  be due to bronchial inflammatory tissue which
  might prevent expectoration of infected secretions

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LOWER LUNG FIELD TUBERCULOSIS 

•  Lower lung field TB is defined as disease
  located below a line traced across the hila,
  including the perihilar regions, on a standard PA
  and lateral chest x-ray
• 2 to 9 percent in incidence in adults,

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LOWER LUNG FIELD TUBERCULOSIS

• Typical reactivation TB rarely involves the
  superior segments of the lower lobes.
  Endobronchial TB can affect lower lung fields in
  both primary infection, especially when adjacent
  lymph nodes are involved, and during
  reactivation, when spread from upper lobe disease
  secondarily infects the lower lung fields.
  
  Typical primary tuberculosis.
  A non-specific tuberculous
  pneumonitis,

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LOWER LUNG FIELD TUBERCULOSIS

• Compared to upper lobe TB, consolidation in the
  lower lobes tends to be more extensive and
  homogeneous. Cavitation may be present, and large
  cavities are reported.
• Elderly patients and those with diabetes, renal
  or hepatic disease, those receiving
  corticosteroids, and those with underlying
  silicosis appear most at risk for lower lobe TB.
  However, many patients have no underlying medical
  illnesses.

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COMPLICATIONS OF PULMONARY TUBERCULOSIS 

• Pulmonary complications of TB include hemoptysis,
  pneumothorax, bronchiectasis and extensive
  pulmonary destruction (including pulmonary
  gangrene).