1. 2009/2/26
Definition
Epidemiology
Etiology
Pulmonary Tuberculosis Transmission
Progression and development
Pathology
Clinical manifestations
The Department of Respiratory Ｍedicine
Laboratory tests and examinations
The first affiliated hospital of Sun Yat-sen University
Types of pulmonary tuberculosis
Diagnosis
Kejing Tang, M.D., Ph.D.
Differential Diagnosis (self-study)
Treatment
唐可京 2009/2/26
【Definition】 【Epidemiology】
A communicable disease caused by Global epidemic status
Mycobacterium tuberculosis (tubercle bacillus).
TB is one of the world’s deadliest diseases
Tuberculosis may involve multiple organs
y p g
One thi d f th
O third of the world’s population (two billion people i t t l) are i f t d
ld’ l ti (t billi l in total) infected.
such as the lung, liver, spleen, kidney, brain,
and bone. Each year, nearly 9 million new cases of TB, half of them are contagious.
Pulmonary tuberculosis is the most frequent TB currently holds the seventh place in the global ranking of causes of death.
site of involvement.
Each year, there are almost 3 million TB-related deaths worldwide.
Extrapulmonary tuberculosis is less frequent.
TB is the leading killer of people who are HIV infected.
Only pulmonary tuberculosis is infectious.
It is the single most important bacterial infection and the number
one infectious disease killer worldwide.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
【Epidemiology】 Most TB cases are in India and China（2002）
Epidemic status in China
Of all individuals infected worldwide, 22% are in China.
The characteristics:
High infection rate: nearly half of population (550 million) is infected < 1 000
1 000 to 9 999
High
Hi h mobidity
bidit 10 000 t 99 999
to
100 000 to 999 999
High resistance rate: primary resistance rate 18.6%, acquired ~ 46.5% 1 000 000 or more
No Estimate
High death rate: about 130 thousand cases died every year
Young people and adults are mainly involved
Notable difference of mobidity in different areas
Low mobidity in areas where DOTS (Directly Observed Treatment,
Short-Course) strategy was performed
The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World
Tang Kejing, SUMS Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or
boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement.
© WHO 2002
2009/2/26
1

2. 2009/2/26
【 Etiology 】
Bionomics of M. tuberculosis (1)
【Etiology】
Microscopic morphology
The tubercle bacillus was discovered by Koch in The bacteria are slender, slightly curved
1882. or straight, rod-shaped, non-encapsulated,
non-motile bacteria.
The Mycobacterium tuberculosis complex belongs
y p g The dimensions of the bacilli have been
to the family Mycobacteriaceae and includes the reported to be 1-10 μm in length (usually 3-5 μm),
subspecies M. tuberculosis, M. africanum, M. bovis and 0.2-0.6 μm in width.
Ziehl-Neelsen staining of
Mycobacterium tuberculosis
and M. microti.
growing in culture at 1000x
magnification.
More than 90% of human pulmonary tuberculosis is Acid fastness
caused by M. tuberculosis (and occasionally by M.
bovis and M. africanum).
Robert Koch Mycobacterium species are classified as acid-fast bacteria because the
(1843-1910) waxy cell wall make the mycobacteria have the resistance to decolorization
with acid-alcohol solutions after staining with carbol fuchsin
Tang Kejing, SUMS
2009/2/26 唐可京 2009/2/26
【 Etiology 】 【 Etiology 】
Bionomics of M. tuberculosis (2) Bionomics of M. tuberculosis (3)
Slow-growing Complicated structure
The generation time is 15 to 20 hours.
Constituents of M. tuberculosis are complex and mainly include
Visible colonies on a solid medium usually take 2 to 4 week. lipids, proteins and polysaccharides.
Each constituent has its role in the pathogenesis of tuberculosis.
tuberculosis
Powerful resistance
It can survive in a dry state for months or years, in a dark and humid room phospholipids caseous necrosis
for months, and in a low temperature condition like -40℃ for years.
lipoid substance fatty acid tuberculation
To kill： high pressure steam sterilization: 30 minutes at 120℃ (Best way)
waxes virulence, acid fastness
M.
easily destroyed by heat and ultraviolet light (UV) tuberculosis proteins reactinogen of allergy
70% alcohol: within 2 minutes polysaccharides antigen of immune responses
唐可京 2009/2/26 唐可京 2009/2/26
【Transmission】
【Transmission】
Susceptible population
Risk factors for tuberculosis include the following:
Source of infection
The most important source of infection is the patient with (secondary) Poverty, malnourishment, lack of medical facilities
pulmonary tuberculosis , and when he/she coughs, sneezes, speaks, Living with those who have active tuberculosis, people with
or sings. This person is usually sputum smear-positive. previously active tuberculosis but who have received inadequate
chemotherapy
Extrapulmonary TB is rarely contagious. Immigrants from high prevalence countries
Low income
Homeless
Route of transmission Crowded living conditions
Diseases producing a decrease in immunological status (diabetes,
Transmission is by inhalation of droplet nucleus. anticancer chemotherapy, receive immunosuppressive drug, HIV
disease)
Other routes of transmission such as through digestive tract, skin Health care workers
and intrauterine are comparatively rare.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 唐可京 2009/2/26
2

3. 2009/2/26
【Progression and development】
【Progression and development】 Primary Infection (1)
Only 10% of people infected with M. tuberculosis eventually Most common in infants and children, especially in developing
countries with high rates of malnutrition and poor medical care.
will develop active tuberculosis (when the body’s immune
Primary pulmonary tuberculosis results from an initial infection
system weakens)
y ) with tubercle bacillus through inhalation of droplet nucleus
nucleus.
Primary Infection Primary syndrome (primary tuberculosis): the lesion of primary
infiltration, and the enlargement of tracheobronchial lymph node
Postprimary (secondary ) tuberculosis Lymphatic and hematogenous dissemination of tuberculosis typically
occurs before the development of an effective immune response.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
【Progression and development】 【Progression and development】
Primary Infection (2) Immunity and delayed-type hypersensitivity
Immunity to tuberculosis:
Outcome: Native immunity
Acquired immunity—result from primary tuberculous infection or
Most lesions of disseminated and primary tuberculosis could heal, vaccination with BCG (Bacillus Calmette-Guerin)
although they may remain potential foci for later reactivation when
the body immunity function is suppressed.
Type of Immunity to tuberculosis:
Cell-mediated immunity: provides partial protection. Two types of cells
In infants and young children, especially with malnutrition or poor are essential: macrophages and T cells.
medical care, dissemination may result in miliary or meningeal Humoral immunity: has no defined role in protection.
tuberculosis—illnesses with potential for major mortality.
Delayed-type hypersensitivity
• a Th1 lymphocyte response to the antigens of the tubercle bacillus,
causing cell death and tissue damage or tissue necrosis.
• two types of phenomenon: tuberculin (PPD) test, Koch phenomenon
Tang Kejing, SUMS
2009/2/26 2009/2/26
【Progression and development】 【Progression and development】
Postprimary (secondary ) tuberculosis (1) Postprimary (secondary ) tuberculosis (2)
Occurs after a latent period of months or years following primary It may occur either by
infection.
Endogenous reactivation: means that dormant bacilli
The most common type in adults. persisting in tissues for months or years after primary infection start
to multiply.
Usually affects the lungs but can involve any part of the body.
body
Risk factors of reactivation:
Patients usually presents obvious clinical symptoms, cavities and
bacilli expelled, and are contagious (Most of patients are sputum • Patients with chronic disease causing general debility:
smear-positive.) alcoholism, malnutrition and diabetes mellitus
Without treatment, 25% of patients are spontaneously cured by
• Patients with cellular immunodeficiency:
the body’s defence mechanisms, 50% die within 5 years, and HIV infecion, immunosuppressant drug treatment
25% continue to excrete bacilli and remain sources of infection Exogenous reinfection: means a repeat infection in a person
for many years before dying. who has already previously had a primary infection.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26
3

4. 2009/2/26
【Pathology】
【Pathology】 Basic pathological findings (1)
Basic pathological findings Exudative lesions, proliferative lesions, and caseous
necrosis are the basic pathological changes of tuberculosis.
Transformation
T f ti These pathological changes existed simultaneously and
can transform reciprocally.
The disease as a whole may fluctuate between periods of
exacerbation and remission.
Tang Kejing, SUMS Tang Kejing, SUMS
【Pathology】 Tuberculous granuloma 【Pathology】
A typical appearance of proliferative lesions
Basic pathological findings (2)
At low power magnification.
Well-defined granulomas are seen here. The
follicle is surrounded by a crown of
Exudative lesions lymphocytes; in the centre are two giant cells
and a cluster of epithelioid cells.
~ ocurr in the initial or worse duration of tuberculous infection.
The localized, small appearance of these
granulomas suggests that the immune response
Proliferation—shows typically tuberculous granuloma is fairly
i f i l good.
d
~ ocurrs with strong resistance or in recovery stage of the body.
Caseous necrosis
~ appear in the condition of presence of strong toxic tuberculous bacilli At high power magnification.
in a large numbers and of hypersensitivity with weak resistance. Langhans giant cell is a committee of
macrophages with the nuclei lined up along one
edge of the cell.
Tang Kejing, SUMS
唐可京 2009/2/26
【Pathology】 【Pathology】
Tuberculous granuloma with caseous necrosis
Transformation
At low power magnification.
The caseating necrosis can be seen in the Before anti-tuberculosis chemotherapy, tuberculosis lesions
centre of the photo; at the exterior three represent slow recover, repeated exacerbation, and spread
giant cells and epithelioid cells can be seen.
easily.
Caseating necrosis is a fine-grained ,
homogeneous, eosinophilic necrosis . This lesion
is very specific to tuberculosis. Early exudative lesions: resolve almost completely with
chemotherapy.
Small areas of proliferative or caseous lesions: may be absorbed
to small or gradually become fibrosis.
Gross pathologic findings Liquefaction of caseous foci →cavity formation →satellite lesions
The caseous necrosis is extensive, and within the lungs
cavitation is prominent. Such patients can be
highly infectious. Some pulmonary lesions become fibrotic and may later calcify.
Tang Kejing, SUMS
唐可京 2009/2/26
4

5. 2009/2/26
【Clinical Manifestation】
【Clinical Manifestation】 1. Systemic symptoms
The onset of the disease is often nonspecific and insidious;
1. Systemic symptoms symptoms often develop slowly, over several weeks.
1. Fever
2.
2 Respiratory symptoms The most common symptom. The fever is a low grade fever and has a
characteristic afternoon peak with defervescence at night accompanied
by sweats.
3. Signs
2. Fatigue, night sweats, and loss of appetite and weight
~ are systemic symptoms consistent with both pulmonary and
4. Special performance extrapulmonary tuberculosis.
3. Menoxenia
Some female patients may have irregular menses
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
【Clinical Manifestation】
【Clinical Manifestation】
2. Respiratory symptoms 3. Signs (self-study)
Respiratory symptoms predominate The physical signs in patients with pulmonary tuberculosis are
nonspecific.
1. Cough and expectoration cough is the most common symptom. The
cough is nonspecific, usually nonproductive but persistent, and it may become Small extent of disease often no abnormal signs in the chest
productive of mucopurulent or blood-streaked sputum.
Widespread exudative process or caseous necrosis signs of lung
consolidation (reinforcement of tactile fremitus dull percussion note, bronchial
fremitus, note
2. Hemoptysis can be light, moderate or massive. Sudden massive hemoptysis breathing sound and fine rales)
resulting from erosion of a pulmonary artery by an advancing cavity was an
occasional terminal event in the pre-drug era but is now seldom seen. Big cavitary process hyperresonant note or tympanic resonance on percussion,
and bronchial breathing sound or bottle sound on auscultation.
3. Chest pain usually due to extension of inflammation to the parietal pleura Big extent of fibrosis tracheal deviation toward the affected side, chest wall
and often is described as dull and aching or pleuritic in nature. collapse of affected side, dull percussion note, diminished breath sound and moist
rales on auscultation.
4. Dyspnea is an uncommon feature; when present, it is usually caused by Tuberculous pleuritis signs of pleural effusion (tracheal deviation away from
extensive parenchymal disease, tracheobronchial obstruction, or a large pleural the side of the effusion, bulging of the chest wall, abatement of tactile fremitus,
effusion. percussive flatness and absent or attenuated breath sounds on auscultation.
Endobronchial tuberculosis local wheezes
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
【Clinical Manifestation】
4. Special performance 【 Laboratory tests and examinations】
Allergic symptoms
Tuberculous rheumatism (Poncet's disease): is an immunological reaction
to M. tuberculosis with resultant reactive polyarthritis. It is a rare aseptic form of 1. Bacteriological examination
arthritis observed in patients with active TB.
Follicular keratoconjunctivitis
j
2. Radiological
2 R di l i l examination
i ti
Unresponsive tuberculosis (tuberculous septicemia) 3. Tuberculin skin test
Seen in patients with extreme immune suppression.
Clinical manifestations: continued high fever, bone marrow suppression or
leukemoid reaction. Respiratory symptoms and chest X-ray findings are often not 4. Fiberoptic bronchoscopy
obvious or absent.
Often misdiagnosed as sepsis, leukemia, typhoid, and other connective tissue
diseases.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
5

6. 2009/2/26
【 Laboratory tests and examinations】 【 Laboratory tests and examinations】
1. Bacteriological examination
1. Bacteriological examination ② Sputum smear microscopy
Key examination in the diagnosis of pulmonary tuberculosis.
Because most cases of tuberculosis are pulmonary, examination of In order to detect M. tuberculosis in a sputum sample, in excess of 10,000
sputum is of primary importance. organisms per ml of sputum are required for smear positivity.
Other sources: pus, biopsy specimen of lung or bronchus, Acid-fast bacteria seen on smear may represent either M. tuberculosis or
nontuberculous mycobacteria.
bronchoalveolar lavage fluid
Acid-fast staining methods: Ziehl-Neelsen (ZN) stain.
① Collection of sputum samples p , p y p
This method is simple, rapid and fairly inexpensive.
Reporting on AFB (acid-fast bacilli) Microscopy (by Ziehl-Neelsen)
100%
100% 93%
Cumulative Positivity
81%
Number of bacilli seen Result reported
None per 300 oil immersion fields Negative
50%
1-2 per 100 oil immersion fields report exact number
The cumulative positivity of three 3-9 per 100 oil immersion fields +
0% sputum specimens could achieve 100%. 1-9 per 10 oil immersion field ++
First Second Third 1-9 per oil immersion field +++
It is best to obtain a series of early-morning Tang Kejing, SUMS > 9 per oil immersion field ++++
specimens collected on 3 consecutive days. 2009/2/26
【 Laboratory tests and examinations】 【 Laboratory tests and examinations】
1. Bacteriological examination 1. Bacteriological examination
③ Mycobacterial culture
Culture of M. tuberculosis has high sensitivity and specificity. Drug sensitivity
④ Molecular biology detection
tests can be performed at the same time.
Nucleic acid amplification tests
As culture is a complicated, relatively costly technique, which is slow to yield The unsatisfactory sensitivity is the major limitation of amplification-based
results, it is not suitable for rapid identification of the most potent sources of methods.
infection. Culture, supported by microscopy, still remains the gold standard, and
Liquid broth cultures require 1 to 3 weeks of incubation for detection of molecular methods only represent a useful support in some cases, to speed up
organisms, as compared to solid media, which require 3 to 8 weeks. the diagnosis of TB.
fingerprinting
DNA fi i ti
Commercial automated liquid broth systems (the BACTEC 460 TB system, the BACTEC 960
mycobacterial growth indicator tube (MGIT) system)
greatly facilitate mycobacterial culture. Nucleic acid probes
High-performance liquid chromatography (HPLC)
When growth has occurred on
culture, large, rounded, buff-
coloured “cauliflower like”
colonies are visible to the naked
eye on the surface of the culture
⑤ TB antigen and antibody detection
medium; they have a dry, rough
surface, and are isolated or There is still a need to improve the sensitivity or specificity of
confluent, depending on the commercial serological tests.
number of bacilli present in the
original sample.
【 Laboratory tests and examinations】 【 Laboratory tests and examinations】
2. Radiological examination 2. Radiological examination
Important for diagnosis. It is helpful in judging the ranges and
characteristics of pulmonary lesions, and is also helpful in evaluating
the therapeutic responses. Chest computed tomography
Chest X-ray Chest CT is particularly helpful in finding minor or occult
A posterior-anterior radiograph of the chest is the standard view used tuberculous lesions, and may also be helpful in differentiating
for the detection and description of chest abnormalities.
In pulmonary tuberculosis, radiographic abnormalities are often seen in different nodular lesions in the lungs.
the apical and posterior segments of the upper lobe or in the superior
segments of the lower lobe. However, lesions may appear anywhere in
the lungs and may differ in size, shape, density, and cavitation,
especially in immunosuppressed persons.
Old healed tuberculosis usually presents a different radiographic
appearance from active tuberculosis. Infiltration, caseous change and
cavitation are considered as active lesions.
唐可京 2009/2/26 唐可京 2009/2/26
6

7. 2009/2/26
【 Laboratory tests and examinations】 【 Laboratory tests and examinations】
3. Tuberculin skin test (TST) 3. Tuberculin skin test (TST)
How to judge the result
The standard method of determining whether a person is infected with
Less than 5 mm: not significant, or “negative”
M. tuberculosis.
Between 5 to 9 mm: weakly positive
Reagent：5-tuberculin unit (TU) of purified protein derivative (PPD)
Where to inject: Intradermal injection. About a third of the way Between 10 to 19 mm: positive
down on the volar aspect of the forearm Greater than 20 mm or there are water vacuoles and
When to read the result: should be read between 48 and 72 lymphangitis on the injection site: significant positive
hours after the injection
j
How to measure: The reaction should be measured in millimeters How to interpret the result
Measure induration
of the induration (palpable, raised, hardened area or swelling). The (not erythema)
Factors that May Affect the Skin Test Reaction
reader should not measure erythema (redness).
Type of Reaction Possible causes
False-positive Nontuberculous mycobacteria
BCG vaccination
False-negative HIV infected
Overwhelming TB disease
Severe or febrile illness
Viral infections (e.g. measles, chickenpox)
Live-virus vaccinations
Immunosuppressive therapy
唐可京 2009/2/26 2009/2/26
【 Laboratory tests and examinations】
4. Fiberoptic bronchoscopy
Diagnostic fiberoptic bronchoscopy with transbronchial biopsy
and bronchoalveolar lavage (BAL) is an efficient way to obtain
diagnostic materials when sputum does not suffice.
Tang Kejing, SUMS
唐可京 2009/2/26
【 Types of pulmonary tuberculosis 】 【 Types of pulmonary tuberculosis 】
According to Chinese Medical Association (CMA) (1999), According to Britain and USA, tuberculosis is classified as
tuberculosis is classified as five types. two types.
1. Primary pulmonary tuberculosis
Primary syndrome and intrathoracic lymphatic tuberculosis
2. Hematogenous disseminated pulmonary tuberculosis 1. Pulmonary tuberculosis
Acute, subacute, and chronic ~ Primary or postprimary (second) ~.
3. Postprimary or secondary pulmonary tuberculosis Both categories can lead to hematogenous spreading.
Infiltrative, chronic fibro-cavitary pulmonary tuberculosis, and
caseous pneumonitis
4. Tuberculous pleuritis 2. Extrapulmonary tuberculosis
Tuberculous dry pleurisy, tuberculous exudative pleurisy, and Virtually all organ systems may be affected.
tuberculous empyema
The sites include lymph nodes, pleura, genitourinary tract, bones
5. Other extrapulmonary tuberculosis and joints, meninges, peritoneum, pericardium, and so on.
In order of frequency: genitourinary tract, bones and joints,
meninges, peritoneum, and pericardium
2009/2/26 2009/2/26
7

8. 2009/2/26
【CMA types】 续：【诊断】
1. Primary pulmonary
tuberculosis
1. Primary pulmonary tuberculosis
Pathology and chest radiograph
Occurs in people (most often in children less than 5 years of age) Primary complex
who have not had any previous exposure to M. tuberculosis.
Typical lesion of primary pulmonary tuberculosis,
Includes primary complex and mediastinal lymphadenopathy consists of the primary lesion, lymphangitis
(Lymphatic s drain the bacilli to the hilar lymph
In the majority of cases ~ is asymptomatic, and goes unnoticed. nodes) and related hilar lymphadenopathy.
The primary complex (Ghon focus and
ipsilateral hilar lymphadenopathy)
Most patients recover completely without sequelae. Some of them
may, however, subsequently develop active tuberculosis Mediastinal lymphadenopathy
(reactivate) after a period of quiescence .
In some cases, isolated ~ may occur without any
visible changes in the pulmonary parenchyma.
Tang Kejing, SUMS
Tuberculosis of intrathoracic lymphonodes
【CMA types】
2. Hematogenous disseminated
2. Hematogenous disseminated pulmonary tuberculosis
pulmonary tuberculosis Pathology
Includes acute ~ (acute miliary tuberculosis) and subacute or chronic ~. Acute hematogenous disseminated
Acute hematogenous disseminated pulmonary tuberculosis pulmonary tuberculosis
Occurs most commonly in infants and children, and other immunologically Often demonstrates the miliary pattern of
incompetent individuals. extensive, small nodules resembling millet seeds, all
The onset often occurs within the first weeks after primary pulmonary tuberculosis.
tuberculosis the same size (most of the nodules are 2 mm in
In children, there is always widespread dissemination of the granulomas in other diameter) and spread symmetrically over both
organs. lungs.
If treatment is delayed, the prognosis may be badly affected, as many children have
accompanying meningitis. Subacute or chronic hematogenous
disseminated pulmonary tuberculosis
Subacute or chronic hematogenous disseminated pulmonary often demonstrates extensive, miliary or nodous
tuberculosis shadows of variable size, density and distribution,
The onset of ~ often develops insidiously without striking clinical symptoms. most frequently in the bilateral upper and middle
The body immunity of the patient is relatively good. lung zones, and existing simultaneously with fresh
Tang Kejing, SUMS
exudations, old indurations and calcified nodules.
2. Hematogenous 【CMA types】
disseminated pulmonary
tuberculosis
3. Secondary pulmonary tuberculosis
Chest radiograph
Acute hematogenous disseminated Characteristic features:
pulmonary tuberculosis
The lesions can present with a wide variety of radiographic
nodules iso-density
features and usually be present in the apical or posterior
iso-size
iso-distribution
segment of the upper lobes or the superior segment of the
lower lobes.
Subacute or chronic hematogenous Usually no intrathoracic lymphadenopathy .
disseminated pulmonary tuberculosis
Pulmonary lesions are usually localized, but may have
nodules aniso-density
extensive lung destruction with cavitation or caseous necrosis.
ansio-size
ansio-distribution Most of patients are sputum smear-positive.
Tang Kejing, SUMS
8

9. 2009/2/26
【CMA types】
【Diagnosis 】
Classifications based on pathology and chest radiograph
Infiltrative pulmonary tuberculosis 1. Medical history and clinical manifestations
Cavitary pulmonary tuberculosis
2. Diagnostic criteria
Tuberculoma
Bacillary positive
Bacillary-positive pulmonary tuberculosis
Caseous pneumonia
Bacillary-negative pulmonary tuberculosis
Fibro-cavitary pulmonary
tuberculosis 3. Judgement of activities
4. Classification and Record mode
Tang Kejing, SUMS
2009/2/26
【Diagnosis】 【Diagnosis】
2. Diagnostic criteria
1. Medical history and clinical manifestations
Bacillary-positive pulmonary tuberculosis
Symptoms and signs Patient can be diagnosed when the sputum smear and/or culture is
The symptoms of pulmonary TB may include a productive, prolonged positive with corresponding clinical manifestations and chest X-ray findings.
cough (duration of ≥ 3 weeks), chest pain, and hemoptysis. Systemic
symptoms of TB include fever, chills, night sweats, appetite loss, weight
Bacillary-negative pulmonary tuberculosis
loss, and easy fatigability. TB should be considered in persons who have g p
Can be diagnosed when examination results of a series of three sputum
these symptoms. smear microscopy and one sputum culture are all negative.
The physical signs in patients with pulmonary TB are nonspecific. The diagnosis of ~ should be based on criteria as follows:
History of TB exposure, infection, or disease ① Typical clinical symptoms and chest radiographic characteristics of
Past TB treatment pulmonary TB.
Demographic risk factors for TB: ② Exclusion of other non-tuberculous pulmonary diseases clinically.
③ A strong positive PPD-tuberculin (5TU) skin test and/or a positive
Country of origin, age, ethnic or racial group, occupation
serum anti-tuberculosis antibody.
Medical conditions that increase risk for TB disease: ④ Response to diagnostic anti-tuberculosis therapy.
HIV infection, use of medications that affect host immunity
Tang Kejing, SUMS
Having at least three criteria can diagnose as ~ clinically.
2009/2/26 2009/2/26
【Diagnosis】 【Diagnosis】
4. Classification and Record mode
3. Judgement of activities Tuberculosis is classified as five types in China in 1999
Primary pulmonary tuberculosis
Patients with pulmonary TB must be identified to be clinically active or Hematogenous disseminated pulmonary tuberculosis
inactive, and active patients should receive anti-tuberculosis therapy. Secondary pulmonary tuberculosis
Judgement of activities is based on the clinical features, chest X-ray Tuberculous pleurisy
findings and sputum bacteria examination. Other extrapulmonary tuberculosis
Signs of active pulmonary tuberculosis Recording mode of pulmonary tuberculosis
Sputum bacteria positive Pulmonary tuberculosis should be recorded in proper order and based on
Chest X-ray: Exudative lesions, exudative and proliferative lesions, Types: five types
caseous pneumonia, caseous change and cavitation Affected sites and range: left, right or both lungs
Bacteriologic status of sputum: smear (+) / (－) or culture (+) / (－). (No
Signs of inactive pulmonary tuberculosis sputum) or (Unexamined if no sputum)
Chest X-ray: Proliferative lesions, nodules and fibrotic lesions with well- History of chemotherapy: initial treatment, retreatment
demarcated, sharp margins, calcified nodular lesions (calcified For example:
granuloma ) or apical pleural thickening • Postprimary pulmonary tuberculosis of right upper lobe with positive
sputum smears in initial treatment.
Tang Kejing, SUMS
2009/2/26 2009/2/26
9

10. 2009/2/26
【Differential Diagnosis】 (Self-study)
The table shows possible alternative diagnoses.
Diagnosis Pointers to the correct diagnosis 【 Treatment】
Other infections, e.g.
Bacterial pneumonia usually shorter history, febrile, response to antibiotic
Lung abscess cough with large amounts of purulent
Chemotherapy of Tuberculosis
abscess with fluid level on CXR
Pneumocystis carinii often dry, non-productive cough with prominent
1. Principles of anti-tuberculosis chemotherapy
dyspnoea 2. Major effects of chemotherapy
Chronic obstructive airways risk factor (smoking), chronic symptoms, prominent g
3. Biological mechanisms of chemotherapy py
disease
di dyspnoea, generalized wheeze, signs of right h
d li d h i f i ht heartt
failure (e.g. ankle oedema) 4. Frequently used anti-tuberculosis drugs
Bronchiectasis coughing large amounts of purulent 5. Standardized tuberculosis treatment regimens
Bronchial carcinoma (lung cancer)risk factor (smoking, older age, previous mine-work) 6. Drug resistant pulmonary tuberculosis
Asthma intermittent symptoms, generalized expiratory
wheeze; symptoms wake the patient at night
Surgical treatment
Congestive cardiac failure symptoms of heart failure (dyspnoea, orthopnoea,
left ventricular failure paroxysmal nocturnal dyspnea, hemoptysis, oedema,
epigastric discomfort from hepatic congestion)
signs of heart failure
Symptomatic treatment
Diseases of mediastinum or hilus intrathoracic thyroid (right upper mediastinum )
of lung tumors of lymphatic tissue (middle mediastinum),
dermoid cyst，teratoma (anterior mediastinum) Tang Kejing, SUMS
Other febrile illness typhus, septicemia and leukemia 2009/2/26
【 Treatment】 【 Treatment】
Chemotherapy of Tuberculosis Chemotherapy of Tuberculosis
1. Principles of anti-tuberculosis chemotherapy 1. Principles of anti-tuberculosis chemotherapy
Aims of anti-tuberculosis drug treatment Guiding principles for effective treatment of tuberculosis
(1) Early: Early therapy for suspicious or confirmed cases may get
(1) to cure the patient of tuberculosis early efficacy, possible complete absorption, and less spreading.
(2) to prevent death from active tuberculosis or its late effects (2) Regular: resistance.
Regular administration to avoid drug resistance
(3) to prevent relapse of tuberculosis (3) Full-termed: Full course of therapy for the long generation time of
mycobacteria and their long periods of metabolic inactivity, such therapy
(4) to decrease transmission of tuberculosis to others ensure to enhance cure rate and lessen recurrent rate.
(5) to prevent the development of acquired drug resistance (4) Adequate: Adequate dosages provide the safest and most
effective therapy.
(5) Combined chemotherapy: Combined multiple drugs improve
efficacy and prevent drug resistance.
Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
【 Treatment】 【 Treatment】
Chemotherapy of Tuberculosis 2. Major effects of chemotherapy Chemotherapy of Tuberculosis
(1) Bactericidal activity
Isoniazid (INH) kills 90% of the total population of bacilli during the first few
days of treatment. It is most effective against the metabolically active,
The course of therapy is divided into two phases continuously growing bacilli.
Rifampicin (RFP) can kill the semidormant bacilli that isoniazid cannot.
Pyrazinamide (PZA) kills bacilli in an acid environment inside cells, e.g.
macrophages.
The initial or intensive phase (2 months)——agents are
used in combination to kill rapidly replicating populations of (2) Prevention of drug resistance
M. tuberculosis and to prevent the emergence of drug Isoniazid and rifampicin are most effective in preventing resistance to other
drugs.
resistance
Streptomycin (SM) and ethambutol (EMB) are slightly less effective.
The continuation phase (4 to 6 months)——utilizing (3) Sterilizing activity
sterilizing drugs to kill the less metabolically active and The ability of a drug to kill the last viable, often semidormant, bacterium
intermittently replicating populations inside the host.
Rifampicin and pyrazinamide are the most effective sterilizing drugs
Isoniazid is intermediate
Streptomycin (SM) and ethambutol (EMB) are the least effective
Tang Kejing, SUMS
2009/2/26
10

11. 2009/2/26
【 Treatment】 【 Treatment】
3. Biological mechanisms of chemotherapy Chemotherapy of Tuberculosis
(1)Anti-tuberculosis drugs act on different bacillary populations in 3. Biological mechanisms of chemotherapy
a patient with tuberculosis
(2) Drug resistance
The best protection against the selection of resistant organisms is the
Table. Different bacillary populations in a patient with tuberculosis use of at least two bactericidal drugs to which the organisms are sensitive.
Metabolism Location Biological features Active Clinical By giving initial chemotherapy with two or more drugs, the likelihood of
state drugs significance
drug resistant bacilli surviving in the bacterial population is extremely
A Metabolically Extracellular • replicate constantly and INH>>SM Reducing small.
group active, bacilli, found rapidly. >RFP>EMB infectiousness
continuously principally • strong virulence, big and
growing bacilli inside lung infectiousness and changed preventing
cavities g
into drug-resistant mutant acquired
q
bacilli easily. resistance (3) I t
Intermittent use
itt t
B Slowly- Intracellular Their multiplication is PZA>>RFP
group replicating bacilli bacilli, situated slowed down by the lack of >INH Mainly based on the delayed growing period of M. tuberculosis after
inside the oxygen and the acid pH of giving anti-tuberculosis drugs such as Isoniazid and Rifampicin.
macrophages the macrophage cytoplasm. Preventing
relapse
C Semidormant / which replicate in the tissues RFP>>INH
group bacilli very slowly and episodically,
(persisters) are metabolically inactive.
However, they are still alive, (4) Draught
and can start to multiply
once again as soon as the A high peak concentration of drugs in the serum played a more important
immune defence system role in the response to treatment than the maintenance of a continuous
weakens
inhibitory level of the drug.
D dormant bacilli / which fade away and die Generally /
group on their own. drug
resistent
【 Treatment】 Table . Doses and common adverse reactions to anti-tuberculosis drugs
Nomen Abbrevi- Daily dose Intermittent Mechanisms
4. Frequently used proprium ation （g） dose（g） of action Common adverse reactions
Isoniazid H，INH 0.3 0.6～0.8 DNA synthesis Peripheral neuropathy,
anti-tuberculosis drugs occasional hepatotoxicity
Rifampicin R，RFP 0.45～0.6* 0.6～0.9 mRNA Hepatitis, gastrointestinal
Isoniazid (INH) synthesis upset, skin eruptions,
Streptomycin (SM) thrombocytopenia
Discovery of antituberculosis drugs: Streptomycin S，SM 0.75～1.0△ 0.75～1.0 Protein Eighth nerve damage,
synthesis
nephrotoxicity
Pyrazinamide Z，PZA 1.5～2.0 2～3 Bacteriostasis Gastrointestinal upset,
1944: Streptomycin (S, SM) by hepatotoxicity,
pyrazinoic acid
1946: p-aminosalicylic acid (P, PAS) hyperuricemia, joint pain
Ethambutol E，EMB 0.75 1.0
0.75～1.0** 1.5 2.0
1.5～2.0 RNA synthesis Retrobulbar neuritis,
synthes s neur t s,
1950: Ethambutol (E, EMB)
1950 Eth b t l (E Rifampin (RFP) Rifapentine
Rif ti hyperuricemia, gout, skin rash,
drug fever, gastrointestinal
1951: Isoniazid (H, INH)
disturbance
1952: Pyrazinamide (Z, PZA) Para-aminosalicylic P，PAS 8～12*** 10～12 Intermediary Gastrointestinal intolerance,
metabolism hepatitis, hypersensitivity
1955: Cycloserine (环丝氨酸) acid
Protionamide 1321Th 0.5～0.75 0.5～1.0 Protein Gastrointestinal symptoms,
1956: Ethionamide(乙硫异烟胺)、kanamycin synthesis
hepatotoxicity
1962: Capreomycin(卷曲霉素) Ethambutol (EMB) p-aminosalicylic acid (PAS) Kanamycin K，KM 0.75～1.0△ 0.75～1.0 Protein Auditory and vestibular nerve
synthesis
1965: Rifampicin (R, RFP) damage, nephrotoxicity
Capreomycin Cp，CPM 0.75～1.0△ 0.75～1.0 Protein Auditory and vestibular nerve
synthesis
damage, nephrotoxicity
•*0.45 g if < 50 kg body weight，0.6 g if ≥ 50 kg；dosages of S、Z、Th are also regulated based on body weight；
•△ 0.75 g per time for aged people；
Pyrazinamide (PZA) •** 25 mg/kg for the initial 2 months; then decreased to 15 mg/kg；
Cycloserine •*** separated to twice per day（other drugs: once daily）.
【 Treatment】 【 Treatment】
Chemotherapy of Tuberculosis Chemotherapy of Tuberculosis
5. Standardized tuberculosis treatment regimens 6. Drug resistant pulmonary tuberculosis
There are many different possible anti-tuberculosis treatment regimens.
The recommended treatment regimen for drug resistant pulmonary
Directly observed treatment (DOT) is recommended for all patients and is
particularly essential when intermittent regimens are used. tuberculosis, especially multidrug-resistance pulmonary tuberculosis
(MDR-TB) should include at least 4 or 5 drugs, including 3 drugs which
(1) Recommended treatment regimens for new, smear-positive tuberculosis are active or never used previously in the initial phase, and 2 or 3 of the
cases, including new smear-negative cases with cavitation or miliary most active and best-tolerated drugs in the continuation phase.
tuberculosis
① Daily regimens：2HRZE/4HR An initial phase of at least 3 months should be followed by a
② Intermittent regimens：2H3R3Z3E3/4H3R3 continuation phase of 18 to 21 months.
(2) Recommended treatment regimens for smear-positive cases who need to
receive re-treatment Available drugs used in drug resistant pulmonary tuberculosis include
① Daily regimens： 2HRZSE/4~6HRE ofloxacin, levofloxacin, prothionamide (1321Th), para-aminosalicylic acid
② Intermittent regimens： 2H3R3Z3S3E3/6H3R3E3 (PAS), amikacin, capreomycin, etc.
(3) Recommended treatment regimens for new, smear-negative tuberculosis Directly observed treatment (DOT) should be performed during the
cases whole range of treatment.
① Daily regimens： 2HRZ/4HR
② Intermittent regimens： 2H3R3Z3/4H3R3 Tang Kejing, SUMS Tang Kejing, SUMS
2009/2/26 2009/2/26
11