Mohammad Tohidi M.D.

Professor of Internal Medicine

Department of Pulmonary Diseases

Ghaem Hospital MUMS Mashhad

IRAN

Mohammad Tohidi M.D.

Professor of Internal Medicine

Department of Pulmonary Diseases

Ghaem Hospital MUMS Mashhad

IRAN

Tuberculosis Transmission and Pathogenesis

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.

Approach to the Patient: Cough

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

What we should do next?

Order the Lot!

Approach to the Patient:

Evaluate based on likely clinical possibilities:

Sputum for AFB Stain &culture

PFTHRCT

Approach to the Patient

Sputum for AFB: ++++

Diagnosis

Pulmonary Tuberculosis

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. 

M. tuberculosisM. bovisM. africanumM. microtiM. canettiiM. caprae M. pinnipedii

Source: CDC Public Health Image Library/Dr. George P. Kubica

Etiology

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

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

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

Transmission

of M.tb

Transmission of M.tb

How is TB Transmitted?Person-to-person through the air by a person with TB disease of the lungs

Less frequently transmitted by:Ingestion of Mycobacterium bovis found in unpasteurized milk productsLaboratory accident

Source: CDC, 2000

Transmission of M. tuberculosis

One cough can release 3,000 droplet nuclei

One sneeze can release tens of thousands of droplet nuclei

Millions of tubercle bacilli in lungs (mainly in cavities)

Coughing projects droplet nuclei into the air that contain tubercle bacilli

Transmission of M. tuberculosisWhen 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

Transmission of M. tuberculosisThe 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

Fate of M. tb Aerosols

Large droplets settle to the ground quickly

Smaller droplets form “droplet nuclei” of 1–5 µ in diameter

Droplet nuclei can remain airborne

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

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 macrophageOnce the TB bacteria is inside of the macrophage it begins to multiply

TB Transmission and Pathogenesis

Exposure

No infection (70%)

Adequate

Non-specific immunity

Inadequate

Infection (30%)

Not everyone who is exposed to TB will become infected

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)

The Chance of Infection Increases…(2)

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

Transmission of Tuberculosis

CASE CONTACT

Site of TBCoughBacillary loadTreatment

Closeness and duration of contactImmune statusPrevious infection

VentilationFiltrationU.V. light

TB Germs Cannot be Spread By: Sharing dishes and utensils

Using towels and linens

Handling food

Sharing cell phones

Touching computer keyboard

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

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. It’s important to note that not all patients with disseminated TB have a miliary pattern on CXR

miliary tuberculosis

Spread of TB to Other Parts of the Body

1. Lungs (85% all cases)

2. Pleura

3. Central nervous system• (e.g., brain, meninges)

4. Lymph nodes

5. Genitourinary system

6. Bones and joints

7. Disseminated (e.g., miliary)

TB Can Affect Any Part of Your Body: Extrapulmonary TB

Pleura

Lymph Node

Brain

Spine

Cell-mediated Immune Response

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

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 body’s immune system

Latent TB Infection (LTBI)

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

Immunologic defenses

TB Transmission and Pathogenesis (2)

Exposure

No infection (70%)

Adequate

Non-specific immunity

Inadequate

Infection (30%)

Inadequate

Early progression (5%)

Adequate

Containment (95%)

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

Reactivation

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

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

TB

Immunologic defenses

Exposure

No infection (70%)

Adequate

Non-immunologic defense

Inadequate

Infection (30%)

Inadequate

Early progression (5%)

Adequate

Containment (95%)

Late progression(5%)

Inadequate

Immunologic defenses

Continued containment (90%)

Adequate

TB Transmission and Pathogenesis (3)

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)

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

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

High Risk for Progression

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)

Persons more likely to progress from LTBI to TB disease include:

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

High Risk for Progression (3)

Persons taking immunosuppressive agents:

Prolonged corticosteroid therapy (>15mg daily for over 4 weeks)

Cancer chemotherapy Cyclosporine

Persons taking blocking agents against Tumor Necrosis Factor-Alpha:

Etanercept (Enbrel®) Infliximab (Remicade®) Adalimumab (HumiraTM)

Risk for Development of TB Disease

3-16Other conditions

25Chronic renal failure

13.6“old TB” on CXR

4.1Diabetes

113-170HIV/AIDS

How many times higher is the risk

of TB disease

Risk Factor

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

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

PulPulPlnary (72.5%)oary (72.5%)

mona (2.5%)حححح

Extrapulmonary (20.1%)

Both (7.4%)

Pleural (18.3%)

Lymphatic (42.5%)

Bone/joint (10.2%)

Genitourinary (5.9%) Meningeal (6.0%)

Peritoneal (4.6%)

Other (12.3%)

Clinical Presentation: Site of DiseaseClinical Presentation: Site of Disease

Reported TB Cases by Form of Disease United States, 2001

Pulmonary manifestations of tuberculosis

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

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.

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.

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.

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.

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.

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

Pulmonary TB typically affects the upper zones of the lung

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.

"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.

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.

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.

ENDOBRONCHIAL TUBERCULOSIS

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

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

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.

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

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

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,

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,

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.

COMPLICATIONS OF PULMONARY TUBERCULOSIS 

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