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									Tuberculosis
          Tuberculosis
                  Definition

An infectious disease caused by mycobacteria
of tuberculosis complex (Mycobacterium tuber-
culosis, M.bovis, M.africanum) and characteri-
sed by the formation of granulomas in infected
tissues and by cell - mediated hypersensitivity.
 Most commonly a disease of the lungs but in-
   fections 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
            Foreign-born
                               59%
                27%         U.S.-born
                              41%          U.S.-born
U.S.-born                                    41%
  73%                               Foreign-born
                                        59%


       1992                         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.   Lymph nodes – peripheral or hilar
B.   Pleura – pleural effusion
C.   Gastrointestinal tract – mainly the ileocaecal area, occ.
     peritoneum
D.   Genitourinary system – the kidney, may also cause
     painless, craggy swellings of epididymis and
     salpingitis, tubal abscesses and infertility in females
E.   CNS
F.   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

1.   History and phisical examination
2.   Chest X-ray
3.   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
                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.    Allergy reactions – fever and skin rashes, lupus
      erythematosus
B.    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.    Hepatitis ( transient increase of transaminase and
      bilirubin) and cholestatic jaudince (rare)
B.    Thrombocytopenia
C.    Renal failure
D.    Fever
E.    Allergic reactions
             Adverse reactions of
            antituberculous drugs:

PZA
A.    Hepatotoxicity (1-5% patients) especially, when high
      doses are used
B.    Hiperurykemia
C.    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.   Nephrotoxicity – renal tubular damage
B.   Ototoxicity
C.   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)

								
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