Tuberculosis
Bálint Beatrix MD, PhD
SZTE, Dpt. of Pulmonology
Deszk
2014.
Tuberculosis
TB a chronic bacterial infection, causes more
deaths worldwide than any other infectious
disease.
TB is spread through the air and usually infects
the lungs, although other organs are sometimes
involved.
Some 2 billion people - one-third of the world's
population - are infected with the TB organism,
Mycobacterium tuberculosis.
History 1.
Paleopathological evidences
- skeletal TB, bone TB
Ancient greek physisians used the word PHTYSIS
8th-9th century ¼ of the european adults died from TB.
Germ theory:
-Robert Koch (1882)-Pathogenicity of Mycobacterium tuberculosis
-Konrad Röntgen (1892)- X ray
TB in the World (number of TB cases)
Románia
Oroszország
Portugália
Szerbia
Lengyelország
Magyarország
2005
Spanyolország
Szlovénia
2004
Nagy-Britannia
2003
Szlovákia
2002
Ausztria
Belgium
2001
Csehország
Franciaország
Németország
Hollandia
Finnország
Olaszország
Dánia
Svédország
% 000
Tbc incidencia Európában az elmúlt években
TB in EUROPE
2006
160,0
140,0
120,0
100,0
80,0
60,0
40,0
20,0
0,0
Causes of death of HIV positive patients
Mycobacterium tuberculosis
•
•
•
•
The causative agents for tuberculosis
Discovered by Robert Koch in 1882
~25 % of world’s population infected
25 million is infected in USA
Microbiology
Mycobacterium tuberculosis
obligate, aerobic parazite, acid-fast
slow growth
visible colonial growth: 4-6 weeks
INH resistant and sensitive strains are different
Direct examination
Ziehl-Neelsen stain:
4 m long and 0,2-0,5 m wide
10 000 organism/ml of sputumsmear positive
Culture of sputum/fluid
M. tuberculosis: growths slowly, lack of pigment, produces niacin
M. bovis: niacine negative
Drug sensitivity test.
Quick test: PCR, Bactec
Mode of spread
• TB is spread from in microscopic droplets person
to person — droplet nuclei — expelled from the
lungs when a TB sufferer coughs, sneezes, speaks,
sings, or laughs. Only people with active disease
are contagious.
• People are most likely to be contagious when their
sputum contains bacilli, when they cough
frequently and when the extent of their lung
disease, as revealed by a chest x-ray, is great.
* People who have been treated with appropriate drugs for at
least two weeks usually are not infectious.
Predisposing Factors
•
•
•
•
•
•
•
•
•
•
Babies and young children
HIV infection
substance abuse
diabetes mellitus
silicosis
cancer
leukemia or Hodgkin's disease
severe kidney disease
low body weight
certain medical treatments
– corticosteroid treatment
– organ transplants
– chemotherapy
HOW DOES TB DISEASE DEVELOP?
There are two possible ways a person can become sick with TB
disease:
1.A person who may have been infected with TB for years and has
been perfectly healthy. The time may come when this person
suffers a change in health. The cause may be another disease like
AIDS or diabetes. Or it may be drug or alcohol abuse or a lack of
health care because of homelessness.
Whatever the cause, when the body's ability to protect itself is
damaged, the TB infection can become TB disease. In this way, a
person may become sick with TB disease months or even years
after they first breathed in the TB germs.
2. A person first breathes in the TB germs the body is unable to
protect itself against the disease. The germs then develop into
active TB disease within weeks. (This way TB disease develops
happens much more quickly.)
Pathogenesis
The site of initial infection  alveoli  macrophages ingest the inhaled M. tuberculosis.
Some bacilli may be killed immediately; others may multiply within the macrophages.
During the 2 to 8 weeks after initial infection in people with intact immune systems,
macrophages present pieces of the bacilli, displayed on their cell surfaces, to the T cells
 release an elaborate array of chemical signals
cell-mediated hypersensitivity  T cells responds  tuberculin skin test (PPD test)
cell signals  inflammatory reactions;
 recruit and activate specialized cells to kill bacilli and
In HIV-infected people and in children, the bacilli spread to other sites in the body 
dissemination  life-threatening meningitis and other problems.
Pathogenesis 2.
The body's immune system maintains a standoff with the infection,
sometimes for years.
TB bacilli may persist within macrophages, but further multiplication
and spread of M. tuberculosis are confined.
Most people undergo complete healing of their initial infection,
and the tubercles calcify and lose their viability.
A positive TB skin test, and in some cases a chest x-ray,
may provide the only evidence of the infection.
If, the body's resistance is  because of aging, infections (HIV),
malnutrition,or other factors, the bacilli may break out of the tubercles
in the alveoli and cause active disease.
Pathogenesis 3.
(X ray)
Simon foci: The initial infection leaves
nodular scars in the apices of one or
both lungs, called which are the most
common seeds for later active TB.
Ghon foci: calcified scars of primary
infection and residual calcified hilar
lymph nodes.
Ghon komplex
Symptoms
Early TB (single or multiple nodule, caseous lesion)
- no symptomes
Progresszive TB (cavitation, pneumonitis)
- nonspecific symptomes: anorexia, fatigue, weight loss,
remittent fever,
night sweets
- cough, sputum (mucopurulent)
- haemoptysis
- chest pain (inflammation of parietal pleura)
Laboratory findings
IIn advanced TB!
- RBC 
- Se albumin 
- WBC 
- Sodium 
- Calcium 
Characteristic X-ray findings
•
•
•
•
Apical, subapical patchy infiltration
Bilateral upper lobe infiltration
Dissemination: miliary tb
Lower lobe TB
– cavitation or infiltration
– atelectesis, mass leasions, large cavitation with fluid,
pneumonic-like infiltration
• Non-specific
• Pleural effusion
Tbc: tuberculoma
Tb pneumonia
Tb hilar adenopathy
Miliary tb
Tb: miliary
Tb: cavity
Tb: cavity
Tb: cavity
Tb:progressive
Callus pleurae, residuum
Diagnosis
• X-ray findings
• Sputum/bronchoscopic lavage fluid smear +
Negatíve tuberculin test: can not exclude the infection
• Histology: TUBERCULOMA
• epitheloid cells,
•Langhans giant cells,
•lymphocytes,
•caseous lesion (necrosis)
•Definitive diagnosis
- culture
- specification of the organism
Extrapulmonary TB
(TB can involve any organ)
-TB of the tonsils, lymph nodes, abdominal organs, bones, and joints caused
by ingestion of milk infected with M. bovis. (slaughtering cows with milk)
*GENITOURINARY TUBERCULOSIS
-kidney pyelonephritis. (chronic, "sterile" routine culture-negative)
-epididymis or prostate gland, baldder, vesicles.
-Salpingo-oophoritis
* TUBERCULOUS MENINGITIS (TB to the subarachnoid space)
* MILIARY TUBERCULOSIS (Generalized Hematogenous or
Lymphohematogenous TB) Bone marrow involvement
* TUBERCULOUS PERITONITIS
*TUBERCULOUS PERICARDITIS
*TUBERCULOUS LYMPHADENITIS
*TUBERCULOSIS OF BONES AND JOINTS (Pott's disease)
*TUBERCULOSIS OF THE LIVER
Extrapulmonary TB according to the location
(Hungary 2007.)
Extrapulmonalis tuberculosis lokalizáció szerint
Pleuritis és egyéb
48%
Csont-izületi
13%
Nyirokcsomó
13%
Meningitis
3%
Hugy-ivarszervi
16%
History of chemotherapy
Streptomycin
Toxicity
Resistancy
Recidive infection
1946-1952
Isonicid
1952-1970
INH + PAS + Streptomycin
Treatment-18 months
Rifampicin
RMP + INH
RMP + INH + ETB
1970
9 months
6 months
Therapeutic agents for tb
•
•
•
•
•
•
First line therapy
Isoniazid
Rifampin
Pyrazinamide
Streptomycin
Ethambutol
•
•
•
•
•
•
Secund line therapy
Ethionamide
Cycloserine
PAS
Aminoglycosides
Capreomycin
Activity of antituberculous drug
Drug
Activity
pH
Site
Isoniazid
Rifampin
Pirazynamide
Ethambutol
cidal
cidal/static
cidal/sterilizing
cidal at 25 mg/kg
static at 15 mg/kg
cidal
neut-alk
neut-alk
acid
neut-alk
I/E
I/E
I/E
I/E
neut-alk
E
Streotomycin
I=Intracellular; E=Extracellular
Second line drugs
•
•
•
•
•
•
•
Aminoglycosides
Capreomycin
Ethionamide
PAS
Cycloserine
Ciprofloxacin
Ofloxacin
•
•
•
•
Thiocetazone
Imipenem
Ampicillin
Metronidazole
Characteristics of 2nd line drugs
•
•
•
•
•
Less effective drugs
Poor GI tolarence
Significant side effect profile
Not well studied
Some not readily available (PAS)
The principles of therapy
• Combination therapy
– kills more effectively
– Shortens therapy
• Prevents emergence of resistance:
– INH/RAMP  EMB SM  PZA
•
•
•
•
Treatment must be for a least six month
Bactericidal phase: 1 month
Strerilizing phase: months 3 through 6
Never add a single drug t a failing regimen
Initial therapy: four drugs
•
•
•
•
Isoniazid (INH)
300 mg daily
Rifampin (RIF)
600 mg daily
Pyrazinamide (PZA)25-30 mg daily
Ethambutol (EMB)25 mg initially
Therapeutic Regimens
•
•
•
•
•
Daily therapy
6 months
Daily treatment
180 doses
2-3 % relapse
• Short course
• 6 months
• Twice or three times
weekly
• 52-114 doses
• Equivalent relapse
Preventive therapy for
tuberculous infection
• Infection vs. active disease
• Lifetime risk for active disease
– Higher in children
– 10 % per year in HIV infected patients
• Mantoux skin test is the indicator of
infection
• Preventive therapy requires 6 months of
single drug therapy
• Isoniazid
Nontuberculous mycobacteria
• Pumonary disease
– M. avium, kansasii, abscessus, xenopi,
malmoense
• Lymphadenitis
– M. avium, scrofulaceum, malmoense
• Cutaneous disease
– M. marinum, fortuitum, chelonea, ulcerans
• Disseminated disease
– M. avium, kansasii,chelonea, haemophilum
Treatment of nontuberculous
mycobacteria
• The antituberculotic drugs are usually
not effective
• M. kansasii: INH, RIF, EMB
• M. avium: macrolide, Rifamycin, EMB
• Rapid growers: clarithromycin and 2nd
agents
History 2.
Outstanding representatives of the arts
and political life who suffered from TB
•
•
•
•
•
•
•
•
Balzac
Brontë sisters
Chekov
Chopin
Dostoevsky
Kafka
D.H. Lawrence
Sir Walter Scott
•
•
•
•
E. A. Poe
Voltaire
John Keats
Rembrandt’s wife
(Sashka) and his son
(Titus)
• Marquise de
Pompadur
• Napoleon II
Model: Simonetta Catanea died of TB at the age of 23.
Symptomes:whitish-pink colour of skin, small shoulders,
narrow thorax, low-placed and close breastssigns of phtisis