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Tuberculosis
Tuberculosis
Definition
An infectious disease caused by mycobacteria
of tuberculosis complex (Mycobacterium tuberculosis, M.bovis, M.africanum) and characterised by the formation of granulomas in infected
tissues and by cell - mediated hypersensitivity.
Most commonly a disease of the lungs but infections may occur at many tissue sides or
may disseminate.
Tb - epidemiology
1/3 world population is infected on Mycobacterium
tuberculosis
50% is smear-positive
incidence rate of Tb is growing at approximately 0,4%/
year, but much faster in Sub-Saharan Africa and in
countries of the former Soviet Union
TB - epidemiology
High risk groups in the United States include
immigrants from areas of the world where tb is
common
High-Risk Groups for TB Infection
Foreign-Born/Immigrants
Foreign-born
27%
U.S.-born
73%
1992
Foreign-born
59%
U.S.-born
41%
U.S.-born
41%
Foreign-born
59%
2008
Cases of TB in foreign-born and U.S.-born,
1992 and 2008
Tb - epidemiology
High - risk groups for TB:
patients infected with HIV (HIV is the strongest known risk
factor for developing TB disease)
prolonged therapy with corticosteroids, immunosupressive
therapy, such as tumor necrosis factor-alpha (TNF-α)
people infected with M.tuberculosis within past 2 years
(the highest risk of developing active TB in first 2 years)
Tb - epidemiology
High - risk groups for TB:
infants and children younger than 4 years old (due to
underdeveloped immune system)
-
-
people with medical conditions known to increase the
risk for TB
diabetes
silicosis
severe kidney disease
certain types of cancer
certain intestinal conditions
Tb - epidemiology
High - risk groups for TB:
immigrants from high endemic areas
people who inject drugs (injecting drugs may weaken
immune system)
people after transplantations
Tb - epidemiology
Additional factors :
homelessness
poverty
poor living conditions (lack of hygiene, malnutrition)
substance abuse
Tb - ethiology
Genus MYCOBACTERIUM
30 well – characterised and many
unclassified baccili
most – not pathogenic for humans
most – free living saprophytes
acid – fast
slow – growing (Lowenstein-Jansen
medium)
non - sporulating
Acid-fastness
is a physical property of some
bacteria referring to their
resistance to decolorization by
acids during staining procedures.
acid-fast organisms are difficult
to characterize using standard
microbiological techniques
high content of mycolic acid in
cell walls
Ziehl-Neelsen stain
Tb - transmission
human to human via respiratory route
consumption of contaminated cows’ milk
perinatal and wound transmission (very rare)
Tb - transmission
FACTORS AFFECTING THE POSSIBILITY OF
INFECTION
infectiousness of person with active TB
environment in which exposure occurred
length of exposure
virulence (strength) of the tubercle bacilli
genetic predisposition of an infected person
Tb - transmission
FACTORS THAT REDUCE THE RISK OF
INFECTION
isolation of contagious persons
adequate ventilation
effective treatment to infectious persons
as soon as possible
Tb - pathogenesis
Entry of tubercle bacilli into lungs (alveoli)
↓
alveoli – subpleural, middle to upper zones
↓
bacilli ingested by alveolar macrophages
(undergo slow multiplication)
↓
transport to the regional lymph nodes
↓
↓
stopping the dissemination
hematogenous
at the level of regional lymph nodes
dissemination
(kidney, CNS, lungs)
Tb - pathogenesis
Hematogenous disseminations
↓
↓
healing
potencial foci
of later reactivation
Tb - pathogenesis
2-8 weeks after primery infection (when bacilli multiply inside
macrofages)
→ development of cell mediated hypersensivity (positive
tuberculin skin test)
→ lymphocytes enter the areas of infection
→ chemotactic factors (interleukins, lymphokines)
→ monocytes enter the area
→ transformation into macrophages and histiolytic cells →
become organised into granulomas
Tb - pathogenesis
Granulomatous lesions consist of central area of
necrotic material of a cheesy nature, called
caseation, surrounded by epithelioid cells and
Langhans’ giant cells with multiple nuclei
Subsequently the area may hael completly and
become calcified
Mycobacteria may persist in
macrophages for years but their further
multiplication and spread is usu. confined (they are
dormant but capable of being activated)
Granulomatous leasion
Tb manifestations
1.
Primary tuberculosis
2.
Latent (dormant) TB infection (LTBI)
3.
Secondary tuberculosis
(recrudescence, adult type tb
- caused by reactivation or
less often by reinfection )
Primary tuberculosis
first infection with M. tuberculosis
usu. asymptomatic (90-95% unrecognised)
mild flu-like symptoms
small transient pleural effusion
enlargment of hilar lymph nodes may sometimes occur
positive tuberculin skin test and Quantiferon
Latent (dormant) infection
asymptomatic
positive tuberculine skin test
positive Quantiferon
People with latent TB infection are not infectious and
cannot spread TB bacteria to others. However, if TB
bacteria become active in the body and multiply, the
person will get sick with TB disease.
Reactivation pulmonary Tb
months to years after primary infection
often located in the upper lobes of the lungs (area where
bacteria have been able to persist in a dormant state
after spreading)
kidney, long bones, spine may be sites of reactivation
Reactivation pulmonary Tb
chest radiograph – infiltrates in
the apical and posterior
bronchopulmonary segments of
the upper lobes, caesation
necrosis, pulmonary cavities
with baccili)
may be unilateral or bilateral
Reactivation pulmonary Tb
gradual onset
tiredness, malaise, anorexia, loss of weight, fever,
drenching night sweats, anxiety
cough: non productive or mucoid, purulent or blood
stained
dull ache in the chest
occasionally hemoptysis
Tb - symptoms
EXTRAPULMONARY TUBERCULOSIS:
A.
B.
C.
D.
E.
F.
Lymph nodes – peripheral or hilar
Pleura – pleural effusion
Gastrointestinal tract – mainly the ileocaecal area, occ.
peritoneum
Genitourinary system – the kidney, may also cause
painless, craggy swellings of epididymis and
salpingitis, tubal abscesses and infertility in females
CNS
Skeletal system – arthritis and osteomyelitis with cold
abscess formation
Tb - symptoms
EXTRAPULMONARY TUBERCULOSIS:
F. Eye – chorioiditis, iridocyclitis, keratoconjunctivitis
G. Pericardium – constrictive pericarditis
H. Adenal glands – destruction and Addison’s disease
I. Skin – lupus vulgaris
Tb – diagnostics
History and phisical examination
Chest X-ray
Bacteriology (the diagnosis of tuberculosis is established
when tubercle bacici are identified in the sputum, urine,
body fluid, or tissues of the patient)
- sputum/ induced sputum/ bronchoalveolar lavage examination:
stain
culture: 4-8 weeks on classical media, detection using
radiometric tehniques
Identification of mycobacterial DNA-PCR
1.
2.
3.
Tb – diagnostics
4. Serologic tests (ELISA – IgG antibody to selected
mycobacterial antigens)
5. Chromatographic techniques (identify characteristic lipids)
6. Tuberculin test – Mantoux test
- is based on cell-mediated immunity
- mainly used for: A. contact tracing
B. BCG vaccination programmes
Tb – diagnostics
Mantoux test: PPD/OT test
PPD – purified protein derivative
OT – old tuberculin
•
•
•
•
tuberculin is applied intradermally on the forearm
forearm should be examined within 48-72 hours
reaction is transverse diameter of induration around
injection site assessed by gentle palpation
erythema (redness) is not measured
Tb – diagnostics
Tuberculin test is positive when induration is ≥ 5 mm for
persons likely to be infected :
-
people living with HIV
immunosupressed patients
people after organ transplantations
recent close contacts of people with infectious TB
people with chest X-ray findings suggestive of previous TB
disease
Tb – diagnostics
Tuberculin test is positive when induration is ≥ 10 mm for
persons from population groups at elevated risk of TB:
•
•
•
•
people who have recently come to US from areas
where TB is common
people who inject drugs
people with certain medical conditions that increase
risk for TB
children younger than 4 years old
Tb – diagnostics
Tuberculin test is positive when induration is ≥ 15 mm for
persons:
from low risk populations esp. in geographic areas
known to have a high prevalance of nonspecific
tuberculin reactivity
Tb - prevention
1. Nonspecific
2. Specific
A. Chemoprophylaxis
B. BCG vaccination
Bacillus Camelette Guerin is an attenuated strain
of M. bovis. It induces tuberculin hypersensivity.
Dermal reaction is usu. not as large as that which
follows natural infection, does not persist as long,
and varies strain to strain of vaccine.
Treatment of LTBI -chemoprophylaxis
Prophylactic antituberculous chemotherapy should
receive patients with positive
QuantiFERON and TBT with:
•
high risk for developing active TB disease
once inected with M.tuberculosis
Chemoprophylaxis
INH 300 mg/d (for children 5 mg/kg/d)
For 6 month
One single morning dose
Tb treatment
combinations of drugs are required, to prevent the
resistance during the course of therapy
(mycobacteria can develope the resistance to ant single
drug)
treatment must be administered for months to years
(depending on kinds of drugs), becourse the response of
mycobacterial infections to chemotherapy is slow
Tb - treatment
„First-line” drugs:
Isoniazid (INH), Rifampin (RIF), Pyrazinamide (PZA),
Ethambutol (EMB), Streptomycin (SM)
„Second-line” drugs:
A. In the case of resistance to the drugs of first choice
B. In case of failure of clinical response to conventional
therapy
Ethionamid, Capreomycin, Cycloserine,
Aminosalicylic Acid (PAS), Ciprofloxacin, Ofloxacin,
Rifabutin, Clofazimine
Tb treatment
•
•
•
•
Antituberculous drugs can be divided into:
bacteriostatics:
EM
bactericidal:
SM
INH (against rapidly growing mycobacteria)
RMP (against slowly growing organisms)
Tb - treatment
Tubercle baccilli exist in tuberculous patiens
in three pools:
extracellular pool (RMP, INH+SM)
intracellular pool (RMP, INH+ PZA)
necrotic caseum pool (RMP)
Tb treatment
INH (5 mg/kg/d - us. 300mg/d) + RMP (10 mg/kg/d – us.600mg/d)
+ PZA (25mg/kg/d) + EMB (15 mg/kg/d) or SM (15mg/kg/d)
for 2 month
followed by:
INH (5 mg/kg/d - us. 300mg/d) + RMP (10 mg/kg/d – us.600mg)
for 4 month
Adverse reactions of
antituberculous drugs:
INH
A.
B.
Allergy reactions – fever and skin rashes, lupus
erythematosus
Toxic effect – injury to the liver
In 10 to 20% of treated patients, serious in 1-2%
(transaminase value increases up to 3 to 4 times normal
Often asymptomatic, rare with loss of appetite, nausea,
vomiting, jaudince
Toxicity depends on age, is greater in alcoholic, during
pregnency and post-partum period,
Adverse reactions of
antituberculous drugs:
C. Peripheral neuropathy
Due to INH-induced pyridoxine deficiency
More frequent in alcoholic, poor nourished persons,
elderly
Daily dose of 25 to 50 mg of pyridoxine can prevent this
complications
D. Anemia
E. Agranulocytosis
Adverse reactions of
antituberculous drugs:
RIF
A.
B.
C.
D.
E.
Hepatitis ( transient increase of transaminase and
bilirubin) and cholestatic jaudince (rare)
Thrombocytopenia
Renal failure
Fever
Allergic reactions
Adverse reactions of
antituberculous drugs:
PZA
A.
B.
C.
Hepatotoxicity (1-5% patients) especially, when high
doses are used
Hiperurykemia
Gastrointestinal symptoms
Adverse reactions of
antituberculous drugs:
EMB
A. Can affect ocular nerve (first symptom is
inability to distinquish blue from green)
B. Hiperurykemia
Adverse reactions of
antituberculous drugs:
SM
A.
B.
C.
Nephrotoxicity – renal tubular damage
Ototoxicity
Vestibular damage
Drug-Resistant TB
50
Drug-Resistant TB
Caused by M. tuberculosis
organisms resistant to at
least one TB treatment drug
–
–
–
–
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)
Resistant means drugs can
no longer kill the bacteria
Drug-Resistant TB
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
poly-resistant - resistant to at least any 2 TB drugs (but
not both isoniazid and rifampin)
Drug-Resistant TB
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 any
one TB treatment drug
Percentage of MDR TB among new TB
cases (1994–2007)