TUBERCULOSIS TUBERCULOSIS tuberculosis is on

							TUBERCULOSIS
tuberculosis is on the increase in developed countries,
 AIDS
 use of immunosuppressive drugs
 decreased socio-economic conditions
 increased immigration of persons from areas of high
  endemicity.
 In developing countries it is 20-50 times more
  common.
 In 2004 there were 9 million new cases world-wide.
Epidemiology
 Tuberculosis is the world's leading cause of death from a
  single infectious disease,
 1.7 million deaths (without HIV infection) in 2004.
This is the result of:
 inadequate programmes for disease control with poorly
  supervised treatment
 multiple drug resistance (MDR), extensive drug resistant
  TB (XDR-TB)
 co-infection with HIV
 a rapid rise in the world's population of young adults - the
  age group with the highest mortality from tuberculosis
 overcrowding and poor nutrition.
Pathology
 The first infection with M. tuberculosis is known as primary
    tuberculosis.
    usually subpleural,
    often in the mid to upper zones (Ghon focus).
    Within an hour of reaching the lung, tubercle bacilli reach the
    draining lymph nodes at the hilum of the lung and a few escape into
    the bloodstream.
    In the initial reaction the alveolar macrophages ingest the
    bacillusThe bacteria proliferate inside the cells and the
    macrophages release chemokines and cytokines  attract neutrophil
    granulocytes, monocytes and other inflammatory cells. The
    macrophages present the antigen to the T lymphocytes development
    of cellular immunity that can be demonstrated 3-8 weeks after the
    initial infection by a positive reaction in the skin to an intradermal
    injection of protein from tubercle bacilli (tuberculin/PPD.
Primary tuberculosis.
• A delayed hypersensitivity-type reaction occurs, resulting in
  tissue necrosis, and at this stage the classical pathology of
  tuberculosis can be seen.
• Granulomatous lesions consist of a central area of necrotic
  material of a cheesy nature, called caseation, surrounded by
  epithelioid cells and Langhans' giant cells with multiple nuclei,
  both cells being derived from the macrophage.
• there is a varying degree of fibrosis. Subsequently the caseated
  areas heal completely and many become calcified.
• at least 20% of these calcified primary lesions contain tubercle
  bacilli, initially lying dormant but capable of being activated
  following depression of the host defence system (latent TB).
Clinical features and investigations
 Primary tuberculosis is symptomless in the great majority
    of individuals.
    Occasionally there may be a vague illness, sometimes
    associated with cough and wheeze.
   A small transient pleural effusion or erythema nodosum
    may occur, both representing hypersensitivity
    manifestations of the infective process.
   Enlargement of lymph nodes compressing the bronchi can
    give rise to collapse of segments or lobes of the lung
   persistent collapse can give rise to subsequent
    bronchiectasis, often in the middle lobe (Brock's syndrome
Miliary tuberculosis
 acute diffuse dissemination of tubercle bacilli via the bloodstream
    (haematogenous spread).
   It can be a difficult diagnosis to make, especially in older people
   It can lead on from a primary infection or reactivation of a latent focus due to
    immunosuppression for any reason, e.g. drugs, co-morbidity.
   This form of disseminated tuberculosis is universally fatal without treatment.
   It may present in an entirely non-specific manner with the gradual onset of
    vague ill-health, loss of weight and then fever.
   Occasionally the disease presents as tuberculous meningitis.
   Usually there are no abnormal physical signs in the early stages, although
    eventually the spleen and liver become enlarged.
   Choroidal tubercles are seen in the eyes. These lesions are about one-quarter of
    the diameter of the optic disc and are yellowish and slightly shiny and raised in
    nature, later becoming white in the centre. There may be one or many in each
    eye
Clinical features and investigations
 chest X-ray may be entirely normal in miliary tuberculosis as the
    tubercles are not visible until uniform miliary shadows 1-2 mm in
    diameter are seen throughout the lung; they have a hard outline.
    The lesions can increase in size up to 5-10 mm
   CT scanning may reveal lung parenchymal abnormalities at an
    earlier stage.
   The Mantoux test is usually positive but may be negative in 30-
    50% of people with very severe disease.
   Transbronchial biopsies are frequently positive before any
    abnormality is visible on the chest X-ray.
   Biopsy and culture of liver and bone marrow may be necessary in
    patients presenting with a pyrexia of unknown origin (PUO). A
    trial of antituberculous therapy can be used in individuals with a
    PUO.
Adult post-primary pulmonary
tuberculosis
 gradual onset of symptoms over weeks or months.
 Tiredness, malaise, anorexia and loss of weight together with a fever and cough
  remain the outstanding features of pulmonary tuberculosis.
 Drenching night sweats are rather uncommon and are more usually due to
  anxiety.
 Sputum in tuberculosis may be mucoid, purulent or blood-stained. Many
  patients suffer a dull ache in the chest and it is not uncommon for patients to
  complain of recurrent colds.

 A pleural effusion or pneumonia can be the presenting feature of tuberculosis.
 Physical examination reveals little. Finger clubbing is only present if the
  disease is advanced and associated with considerable production of purulent
  sputum.
 There are often no physical signs in the chest even in the presence of extensive
  radiological changes, Physical signs of an associated effusion, pneumonia or
  fibrosis may be present.
Investigations
 An abnormal chest X-ray is often found with no symptoms, but
    the reverse is extremely rare.
    The chest X-ray typically shows patchy or nodular shadows in
    the upper zones, loss of volume, and fibrosis with or without
    cavitation. Calcification may be present.
    A single X-ray does not give an indication of the activity of the
    disease.
   Very similar chest X-ray appearances occur in histoplasmosis and
    other fungal infections of the lung, including cryptococcosis,
    coccidioidomycosis, blastomycosis and aspergillosis, as well as in
    bronchial carcinoma or cavitating pulmonary infarcts.
   Lymph node presentation of tuberculosis : a tender lump or
    fluctuant mass, usually supraclavicular or in the anterior triangle
    of the neck
Diagnosis
 The diagnosis of tuberculosis is made on the basis of the following investigations:
 Imaging. Chest X-ray , and CT scan if necessary.
 Staining. The sputum is stained with an auramine-phenol fluorescent test. The Ziehl-
  Neelsen (ZN) stain for acid and alcohol-fast bacilli (AAFB) is less sensitive.
 Culture. The sputum is cultured on Lowenstein-Jensen or Middlebrook media for 4-8
  weeks. Liquid culture (Bactec (Becton-Dickinson)) is used in many laboratories and has
  the advantage of shorter culture times.
   Cultures to determine the sensitivity of the bacillus to antibiotics take a further 3-4
  weeks.
 Fibreoptic bronchoscopy with washings from the affected lobes is useful if no sputum
  is available.
  Transbronchial biopsies can also be obtained for histology and microbiological
  assessment.
 Biopsies of the pleura, lymph nodes and solid lesions within the lung (tuberculomas).
 Whole blood interferon-γ assay or skin tests
Treatment
 Bed rest does not affect the outcome of the disease.
 Some patients will require hospitalization for a brief period; these
    include
   ill patients,
    smear-positive,
   highly infectious patients (particularly with multidrug-resistant TB),
   those in whom the diagnosis is uncertain and those individuals from
    whom it is essential to gain cooperation.
   lack of patient compliance is a major reason why 5% of patients do not
    respond to treatment.
   In vitro resistance to one or more of the antituberculous drugs used to
    occur in fewer than 1% of patients in the UK, but the rate of resistance
    is gradually increasing (isoniazid resistance 4-6%, multidrug resistance
    1%).
Treatment
 Six-month regimen
 once-daily rifampicin 600 mg and isoniazid 300 mg is standard
    practice for patients with pulmonary and lymph node disease.
   These are given as combination tablets and are taken 30 minutes before
    breakfast, since the absorption of rifampicin is influenced by food.
   This is supplemented for the first 2 months by pyrazinamide at a dose
    of 1.5 g (bodyweight <50 kg) or 2.0 mg daily. Pyrazinamide is of
    particular value in treating mycobacteria present within macrophages,
    and for this reason it may have a very valuable effect on preventing
    subsequent relapse.
   Pyridoxine 10 mg daily is given to reduce the risk of isoniazid-induced
    neuropathy.
   Current recommendations advise the addition of ethambutol (using 15
    mg per day) if the risk of drug resistance is increased.
Treatment
 Longer regimens :
Treatment of bone tuberculosis should be continued for
  a total of 9 months
tuberculous meningitis for 1 year.

 The drugs used are the same as for pulmonary
 tuberculosis, with pyrazinamide prescribed for the
 first 2 months only and for drug-resistant disease
Drug-resistant organisms

 The development of resistance after initial drug sensitivity
  (secondary drug resistance) occurs in patients who do not
  comply with the treatment regimens.
 Primary drug resistance is seen in immigrants to the UK
  and those exposed to others infected with resistant
  organisms.
 The WHO defines two categories of drug resistance:
 multidrug resistance (MDR) - isoniazid, rifampicin
 extensive drug resistance (XDR) - isoniazid, rifampicin,
  quinolone and at least one of the following second-line
  drugs: kanamycin, capteomycin, amikacin.
 MDR and XDR is a world-wide major therapeutic problem with a high
    mortality and occurs mainly in HIV-infected patients.
   Nosocomial transmission of multidrug-resistant tuberculosis to
    healthcare workers and to other patients is recognized and poses a
    major public health problem.
   The drug treatment of suspected drug resistance in both HIV-positive
    and HIV-negative patients is as follows:
   with multiple drug resistance use at least three drugs to which
    the organism is sensitive
   with resistance to one of the four main drugs, use the other three.
   Therapy should be continued for up to 2 years and in HIV-positive
    patients for at least 12 months after negative cultures.
   Second-line drugs available for treatment of resistant M. tuberculosis
    are capreomycin, cycloserine, clarithromycin, azithromycin,
    ciprofloxacin, ofloxacin, ethionamide, kanamycin, amikacin,
    moxifloxacin and rifabutin
Unwanted effects of drug
treatment
 Rifampicin induces liver enzymes. The drug should be stopped only if
    the serum bilirubin becomes elevated or if transferases are >3×
    elevated, which is uncommon.
   Thrombocytopenia has been reported.
   Rifampicin stains body secretions pink and the patients should be
    warned of the change in colour of their urine, tears (contact lens) and
    sweat.
   Induction of liver enzymes means that concomitant drug treatment
    may be made less effective
   Isoniazid : At high doses it may produce a polyneuropathy but this is
    extremely rare (pyridoxine 10 mg daily). Occasionally, isoniazid gives
    rise to allergic reactions in the form of a skin rash and fever, with
    hepatitis occurring in fewer than 1% of cases. The latter, however, may
    be fatal if the drug is continued.
   Pyrazinamide :hepatic toxicity, though this is much rarer with present
    dosage schedules. may precipitate hyperuricaemic gout.
 Ethambutol : cause a dose-related optic retrobulbar
  neuritis that presents with colour blindness for green,
  reduction in visual acuity and a central scotoma
  (commoner at doses of 25 mg/kg).. All patients prescribed
  the drug should be seen by an ophthalmologist prior to
  treatment and doses of 15 mg/kg should be used.
 Streptomycin :can cause irreversible damage to the
  vestibular nerve. It is more likely to occur in the elderly and
  in those with renal impairment.
This drug is used only if patients are very ill, have multidrug-
  resistant TB or are not responding adequately to therapy
Prevention
 BCG vaccination :live attenuated vaccine derived from M. bovis (a
    bovine strain of Mycobacteria).
    Early trials showed that it decreases the risk of developing tuberculosis
    by about 70%.
   A recent study has shown that world-wide use of BCG is very cost-
    effective.
   BCG has been shown to be particularly effective in preventing miliary
    tuberculosis and tuberculous meningitis.
   In meta-analysis the overall protective efficacy is around 50%. This
    efficacy varies throughout the world from zero to 94% protection and
    appears to depend on latitude,
   This lack of efficacy is thought to be related to a number of local
    factors including the frequency of infection with environmental
    mycobacteria (e.g. M. fortuitum, M. kansasii), which may induce a
    degree of protection similar to but not enhanced by BCG.
The Mantoux test


Patients are tested with purified protein derivative (PPD) of Mycobacterium tuberculosis.




•The test is based on cell-mediated immunity with the development of induration and inflammation at the site of
infection due to infiltration with mainly T lymphocytes. The test can be falsely negative in patients with AIDS
because of impairment of delayed hypersensitivity. 0.1 mL of a 1 : 1000 strength PPD (equivalent to 10 tuberculin
units) is injected intradermally.
•The induration (not the erythema) is measured after 72 hours. The test is positive if the induration is 10 mm or
more in diameter.




Whole blood interferon-gamma assay (Quantiferon-TB gold and T-Spot-TB)
Body_ID: PB014020
•Can be used in all circumstances. In vitro T cell based assay
•T cells of individuals who have previously been sensitized to TB will produce IFN-γ when they are incubated with
TB antigens (e.g. PPD or early secretory antigen target-6 (ESAT-6))
•ELISA test or an enzyme-linked monospot assay
•Advantages
        •    No return visit to look at test result
        •    Negative in BCG immunized people
•Disadvantages
        •    Variable sensitivity and specificity
Prevention
 Tuberculosis is spread from person to person
 Screening procedures involve screening
 all close family members or
 other individuals who share the same kitchen and bathroom
  facilities.
 Close contacts at work or school may also be screened.

 The Mantoux test is the standard tuberculin skin test .
 Whole blood IFN-γ assays are being increasingly used. These
  have the advantage of just a single visit as it is an in vitro test.
  Early secretory antigenic target-6 (ESAT-6), is not present in
  BCG and thus the test is negative in patients previously
  immunized with BCG - unlike the skin test which is positive.
Prevention
In adults:
 even if a tuberculosis test is positive,
  chest X-ray is negative nothing more need be done.
 Chemoprophylaxis should be given in patients whose
  recent test conversion has been documented and for
  young adults (16-34 years) who are positive on
  tuberculosis testing without BCG history and found at
  new immigrant screening.
 In children, a positive test is usually taken as
 evidence of infection, and treatment is instituted.
Prevention
 In patients with HIV infection, who have not had BCG,
  chemoprophylaxis with isoniazid is given, reducing the relative risk of
  developing active TB by 40% in highly endemic areas.
 If the test is negative in children and young adults (<35 years), it is
  repeated at 6 weeks, and if it remains negative then BCG is
  administered.
 Children under the age of 1 year who have a family member with
  tuberculosis are given chemoprophylaxis with a daily dose of isoniazid
  5-10 mg/kg for 6 months together with immunization with a strain of
  BCG