Tuberculosis -History, Examination, Investigations and Treatment

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Tuberculosis is a chronic, granulomatous systemic infection caused by Mycobacterium complex (M.tuberculosis, M. bovis, M. canetti, M. africanum and M. microti). It is pulmonary in 80% of the cases whereas in 20% is extrapulmonary, among which the commonest is tuberculosis of lymph nodes.

Management of Tuberculosis

Multidisciplinary team should be involved comprising:

  1. General Physician
  2. Pulmonologist
  3. Thoracic Surgeon
  4. General Surgeon (Gastrointestinal complications)
  5. Anesthesiologist (severe respiratory distress)
  6. Orthopeadic surgeon (joint or bone involvement)
  7. Nephrologist (Urinary involvement)
  8. Urologist (Surgical complications of genitourinary system)
  9. Gynaecologist (Genitourinary involvement in females)
  10. Neurologist (Tuberculous meningitis or other forms of CNS involvement)
  11. Ophthalmologist (Eye involvement)
  12. Endocrinologist (Involvement of endocrine glands)

History:

Presenting complaints and associated symptoms:

  • Chronic cough greater than 3 weeks with sputum production
  • Low grade fever
  • Night sweats
  • Weight loss
  • Hemoptysis
  • Fatigue
  • Chest pain

Symptoms of extrapulmonary disease:

  • CNS Involvement:
    • Tuberculous Meningitis
      • Headache
      • Meningism
      • Drowsiness
      • Confusion
      • Seizures
      • Over 2-3 weeks
    • Hydrocephalus
    • Cranial nerve palsies
    • Space occupying lesions
    • Seizures (hyponatremia due to release of ADH like substances)
  • Skeletal tuberculosis:
    • Back pain
    • Stiffness
    • Cord compression
    • Monoarthritis
    • Chronic osteomyelitis
  • Genitourinary tuberculosis:
    • Flank pain
    • Dysuria
    • Frequency
    • Hematuria
    • Pyuria
    • Lower abdominal pain
    • Infertility
    • Scrotal mass
    • Perianal sinus
    • Genital ulcer
  • Gastrointestinal tuberculosis:
    • Non-healing oral and anal ulcers
    • Dysphagia
    • Abdominal pain
    • Abdominal mass
    • Malabsorption
    • Obstruction
    • Diarrhea
    • Hematochezia
  • Tuberculous Lymphadenopathy:
    • Painless, lump on the neck
  • Endocrine Involvement:
    • Addison’s disease
    • Diabetes mellitus
  • Ophthalmic Involvement:
    • Chorioretinitis

Past Medical History:

  • Previous treatment of Tuberculosis
  • Compliance
  • BCG vaccination
  • Malignancies (especially lymphoma, leukemias)
  • Any immunosuppressive condition e.g Corticosterioids, HIV, cytotoxic agents, anti-TNF agents
  • Diabetes mellitus (especially type I)
  • Chronic renal failure
  • Silicosis
  • Recent measles (increased risk of TB in children)
  • Any condition leading to malnutrition e.g malabsorption, pancreatic cancer
  • Deficiency of vitamin D and A

Past Surgical History

  • Segmentectomy, lobectomy and pneumonectomy
  • Gastrectomy
  • Jejuno-ileal bypass

Family History:

  • Tuberculosis
  • Treatment taken
  • Treatment completed
  • Other members involved

Socioeconomic history:

  • Hygiene and sanitation
  • Overcrowding

Personal History:

  • Smoking

Occupation History:

  • Sandblasting etc (i.e exposure to silicon)

Drug History:

  • Corticosteroids
  • Anti-TNF
  • Cytotoxics

Examination:

  • General Physical Examination:
    • Emaciated, weak
    • Tachypnea
    • Lymph nodes palpable (mostly cervical)
    • Clubbing if severe
    • Jaundice (military tuberculosis)
    • Pallor (anemia of chronic disorder, iron deficiency due to hemoptysis, malabsorption, bone marrow involvement)
    • Jugular venous pressure raised in case of pericardial involvement
  • Respiratory Examination:
    • Decreased movements of the chest (Collapse, pneumothorax, pain and pleural effusion)
    • Mediastinum shift to the affected side (collapse)
    • Mediastinum shift to opposite side (Tension pneumothorax due to cavitatory lesion)
    • Apex beat may shift (Tension pneumothorax/ collapse)
    • Decreased chest expansion (Collapse)
    • Vocal fremitus increased
    • Dull percussion note (collapse, consolidation)
    • Bronchial breathing (Consolidation)
    • Vocal resonance increased (Consolidation)
    • Pleural effusion:
      • Decreased vocal fremitus
      • Stony dull percussion note
      • Absent/reduced breathing sounds
      • Vocal resonance decreased
    • Cardiovascular Examination:
      • Shifted Apex beat
      • Increased pericardial dullness (Pericardial effusion)
      • Reduced heart sounds (Pericardial effusion)
    • Gastrointestinal Examination:
      • Mouth ulcers
      • Abdominal mass (right iliac fossa most common)
      • Hepatomegaly (miliary TB)
      • Splenomegaly (miliary TB)
      • Anal ulcers
    • Musculoskeletal System:
      • Spinal tenderness (Spinal TB)
      • Gibbus (Spinal TB)
      • Swelling of joint (hip, knee etc)
    • Genitourinary System:
      • Flank tenderness
      • Perineal Abscess
      • Genital ulcer
    • Neurological Examination:
      • Cranial nerve palsy
      • Signs of meningism
      • Signs of raised intracranial pressure

Investigations:

Diagnosis of Pulmonary Tuberculosis:

Anyone presenting with cough of greater than 3 weeks with sputum production should undergo investigations for diagnosis of pulmonary tuberculosis

Sputum smear:

  • 3 sputum examination* optimum
    • 1st spot sputum on the day of presentation
    • Early morning sample on 2nd day
    • Early morning (indoor) or spot sputum (outdoor) on 3rd day
  • Ziehl Nelson staining of the sputum
    • Requires 5,000-10,000 bacilli per mL
  • Advantages:
    • Cheap
    • Rapid
    • Easy to perform
  • Disadvantages:
    • Children, Elderly and HIV infected can produce sputum
    • Can not differentiate between dead or alive baciili
  • Alternately stained with auramine-rhodamine flouresecent stain
  • Sputum can be induced by hypertonic saline
  • Lastly Bronchoalveolar lavage can be used for the smear.
  • Transbronchial biopsy can also be taken for staining and culture
  • Gastric lavage or aspirate can also be used

*Ideally early morning sample is best for the detection of AFBs.

tuberculosis-management

Chest X-ray:

  • No pattern is absolutely typical of TB
  • 10-15% of culture positive TB patients are not diagnosed by x-
  • 40% of patients diagnosed as having TB on the basis of x-ray alone do not have active TB
  • Patterns:
    • Consolidation/collapse:
      • Pneumonia
      • Bronchial carcinoma
      • Pulmonary infarct
    • Cavitation:
      • Pneumonia/lung abscess
      • Lung cancer
      • Pulmonary infarct
      • Wegener’s granulomatosus
      • Progressive massive fibrosis
    • Miliary Diffuse:
      • Sarcoidosis
      • Malignancy
      • Pneumoconiosis
      • Infection (e.g histoplasmosis infection)
    • Pleural effusion/empyema:
      • Bacterial pneumonia
      • Pulmonary thromboembolism
      • Carcinoma
      • Connective tissue disease
    • Less common patterns:
      • Pneumothorax
      • Acute respiratory distress syndrome
      • Cor pulmonale
      • Localized emphysema

Culture: (Gold standard)

  • Need 10-100 bacilli/mL of sputum
  • Lowenstein-jenson medium or Brookfield medium (solid)
    • Colonies can be seen on surface of media
    • Give result in 8 weeks
  • BACTEC, MGIT liquid media
    • Yield culture relatively quickly (2 weeks).
    • Sensitivity can not be checked

Serological tests:

  • Not recommended because does not differentiate inactive and active disease
  • ELISA , Mycodot etc

Immunodiagnosis:

  • Mantoux test (tuberculin skin test)
    • Advantages
      • Simple
      • Low tech
      • Can be done by trained health worker in remote areas
      • Effect of BCG is minimal
      • Predictive value has been validated by longitudinal studies
    • Disadvantages:
      • Two visits
      • Subjective interpretation
      • Results take 48-72 hours
      • Cross reacts with BCG and other non tuberculous mycobacteria
      • Administration of second dose may cause false positive result due to boosting of immune response.
    • Quantiferon Gold (Interferon gamma releasing assays)
      • Advantages
        • Requires only one visit
        • Boosting effect eliminated by in vitro (ex vivo) testing
        • IGRA interpretation is objective
        • Results available within 24-48 hours
        • No cross reactivity with BCG or non-tuberculous mycobacteria
      • Disadvantages:
        • High tech
        • Requires specialized equipment
        • Expensive
      • Adenine deaminase (ADA) levels:
        • Pleural effusion (40-60 IU/L)
        • Easy to measure
        • Not expensive
        • Raised in cell mediated response
        • Sensitive and specific
        • Can be done on CSF and peritoneal fluid
      • PCR:
        • Advantages
          • Rapid (3-4 hours)
          • High sensitivity (10 bacilli/mL)
        • Disadvantages:
          • Expensive
          • Requires training and equipment
          • False positives
          • Can differentiate between dead or alive bacilli
        • Gene Xpert Mycobaterium tuberculosis (MTB)/ Resistance to RIfampicin (RIF) testing by automated nucleic acid amplification techniques (gene Xpert MTB/RIF by NAAT)
          • Target rpoB gene in mycobacterium
          • Result available within hours
          • Very high sensitivity and specificity (95%)
          • Tells about Rifampicin resistance as well
        • Drug Sensitivity testing

Other Investigations:

  • Complete Blood count
  • Liver Function Test
  • Renal Function Test
  • Color Vision testing
  • CT-scan chest (lung window)

Q: What does positive sputum and negative gene Xpert test implies?

A: Presence of atypical mycobacterium.

Culture positive, Normal X-ray indicates

  • Early disease
  • Endobronchial TB
  • Immunocompormised

Treatment of Pulmonary Tuberculosis:

Types of Tuberculosis according to drug sensitivity:

  • Drug Sensitive Tuberculosis: Sensitive to all 1st line drugs
  • Monoresistant Tuberculosis: Resistant to any of the 1st line drugs
  • Polydrug resistant Tuberculosis: Resistant to 2 or more drugs other than isoniazid and rifampicin
  • Multidrug resistant Tuberculosis: Resistant to Rifampicin and Isoniazid
  • Extensively resistant Tuberculosis: Resistant to Rifampicin, Isoniazid and fluoroquinolone or any of the injectables (Kanamycin, capreomycin and Amikacin)
  • Totally resistant Tuberculosis: All known 1st and 2nd line drugs.

Categories of TB:

  • Category I:
    • New cases
    • Extra-pulmonary
    • Others
    • Regimen: standard
  • Category II:
    • Retreatment cases:
      • Failure (DST mandatory)
      • Relapse (DST preferable)
      • Default (DST preferable)
    • If DST negative or unavailable (with low probability of MDR) regimen:
      • 2 months HRZES
      • 1 month HRZE
      • 5 Months HRE
    • If DST positive adjust regimen accordingly; may require MDR treatment.
    • If sputum positive after continuation means treatment failure and means MDR TB and patient becomes ineligible for Cat-II treatment

Standard Treatment:

  • Induction Phase: RIPE
    • Rifampicin
      • 10 mg/Kg per day (max 600mg)
      • 10mg/kg oral twice a week
    • Isoniazid
      • 5 mg/kg daily oral or I/M(max 300mg)
      • 15 mg/Kg 1-3 times a week oral or I/M(max 900mg)
      • Add pyridoxine 25 mg\day
    • Pyrazinamide
      • 15-30 mg/Kg daily (max 2g)
      • 50mg /Kg twice weekly (max 2g)
    • Ethambutol
      • 15mg/kg daily oral
    • For 2 months
  • Continuation Phase:
    • 2 drugs:
      • Rifampicin and Isoniazid for 4 months (6 months total)*

OR

  • Ethambutol and Isoniazid for 6 months (8 months total)+

OR

  • 3 drugs:
    • Isoniazid, Rifampicin and Ethambutol for 4 months (6months total)

*This therapy is given in those areas where the resistance to the isoniazid is high. In such cases there is a high chance of developing rifampicin resistance as well and consequently leading to Multi drug resistance.

+Usually given in America and Europe where resistance to isoniazid is low

Multidrug Resistance Treatment:

It can be blind (based on clinical scenario) or guided (based on culture or gene testing)

Principles:

  • At least 20 months duration
  • 5 Drugs:
    • 4 2nd line and pyrazinamide
    • 1 aminoglycoside
    • 1 fluoroquinolone
    • Others cycloserine and ethionamide
  • 8 months of intensive phase
    • Aminoglycoside (e.g amikacin or kanamycin)
      • 15-20 mg/Kg/day for 6days/weeks
      • 1g vial
    • Fluoroquinolone (e.g Levofloxacin, moxifloxacin)
      • Levofloxacin 7.5-10 mg/Kg
      • Give 500-1000 mg daily in single dose or 2 divided doses as tolerated
      • Levofloxacin 250 and 500 mg tablets
      • Moxifloxacin 400 mg tablets
    • Cycloserine:
      • 15-20 mg/Kg/day
      • 250 mg capsule
      • Begin 2 tab/day and increase gradually according to patient’s weight until maximum 1 g daily in 2 divided doses as tolerated.
      • Vitamin B6 200 mg daily or
      • 1 tab of vitamin B6 50 mg for each capsule of cycloserine given
    • Ethionamide
      • 15-20 mg/kg/day oral (max 1g)
      • 250 mg
      • Same as cycloserine
    • Pyrazinamide
      • 30-40 mg/Kg/day (max 2 g)
      • 500 mg tablet
    • 12 months of continuation phase
      • 3 drugs are retained and 2 are withdrawn
      • Usually pyrazinamide and aminoglycoside are discontinued
    • Bedaquiline:
      • Approved for use in MDR TB along in combination with four other drugs
      • Inhibits bacterial ATP synthease
      • WHO approves the use of drug under following conditions:
        • Treatment is administered in closely monitored conditions
        • Proper patient selection
        • Proper informed consent
        • Adherence to WHO recommendations for designing MDR-TB treatment regimes
        • Pharmocovigilance and proper management of adverse reactions and drug to drug interactions

WHO Definitions:

Case of Tuberculosis:

  • A patient in whom tuberculosis has been confirmed by bacteriology or diagnosed by a clinician.

Definitive Case:

  • A patient with positive culture for the mycobacterium tuberculosis complex. In countries where culture is not routinely available, a patient with two sputum smears positive for acid fast bacilli (AFB+) is also considered a definite case.

Pulmonary case:

  • A patient with tuberculosis disease involving the lung parenchyma

Smear-positive pulmonary case:

  • A patient with one or more initial sputum smear examinations (direct smear microscopy) AFB+

OR

  • One sputum examination AFB+ and radiographic abnormalities consistent with active pulmonary tuberculosis as determined by a clinician

Smear Negative pulmonary Case:

  • A patient with pulmonary tuberculosis no meeting the above criteria for smear positive disease.
  • Diagnostic criteria should include:
    • At least two sputum smear examinations negative for AFB
    • Radiographic abnormalities consistent with active pulmonary tuberculosis
    • No response to a course of broad spectrum antibiotics (except evidence of HIV)
    • Decision by a clinician to treat with a full course of antituberculous chemotherapy
    • Positive culture but negative AFB sputum examinations

Extrapulmonary case:

  • A patient with tuberculosis of organs other than lungs (e.g pleura, lymph nodes, abdomen, genitourinary tract, skin , joints, bones and meninges). Diagnosis should be based on:
    • One culture positive specimen
    • Histological or
    • Strong clinical evidence consistent with active extrapulmonary disease, followed by a decision by a clinician to treat with a full course of antituberculosis chemotherapy.
    • Absence of pulmonary disease

New Case:

  • A patient who has never had treatment for tuberculosis or
  • Who has taken antituberculosis drugs for less than a month

Re-treatment Case:

  • Further defined by the outcome of the last treatment.
  • A patient previously treated for TB who is started on a re-treatment regimen after previous treatment has failed or detection of MDR any time during treatment (treatment failure)
  • Who returns to treatment having previously defaulted (treatment after default)
  • Who was previously declared cured or treatment completed and is diagnosed with bacteriologically positive (sputum smear or culture) TB (relapse)
  • Not treated or inadequately treated latent tuberculosis. (Re-activation)

Cured:

  • A patient who was initially smear positive and who was smear negative in the last month of treatment and on at least one previous occasion.

Completed treatment:

  • A patient who completed treatment but did not meet the criteria for cure or failure.
  • Applies to:
    • Smear positive pulmonary TB
    • Smear negative pulmonary TB
    • Extrapulmonary TB

Died:

  • A patient who died from any cause during treatment

Failed:

  • A patient who was initially smear-positive and who remained smear-positive at month 5 or later during treatment.

Defaulted:

  • A patient whose treatment was interrupted for 2 consecutive months or more

Transferred out:

  • A patient who transferred to another reporting unit and for whom treatment outcome is not known

Successfully treated:

  • A patient who was cured or who completed treatment

Further Reading

Tuberculosis -The Basics

Spinal Tuberculosis (Pott’s Disease)