Tuberculosis

Introduction

• 1/3 of world population harbors bacterium
• High-risk individuals
  • Immigrants from high-prevalence countries
  • Patients with HIV
  • Residents and staff of prisons or homeless shelters
  • Alcoholics
  • IVDU
  • Elderly and NH patients

Pathophysiology

• Slow-growing aerobic rod that has acid-fast cell wall
• Obligate aerobe settling in areas of high O2 and high blood flow
• Droplet spread
• Persons with active TB who excrete bacteria in saliva or sputum are the most infectious
• 30% of patients actually become infected after droplet exposure

Pathophysiology

• Primary and latent infection
  • Cell-mediated immunity at regional lymph nodes leads to granulomas (tubercles)
  • Tubercles are a sign of primary infection and may progress to caseation necrosis and calficiation
  • Ghon complex = Calcified hilar lymph nodes
  • If tubercle fails to contain the infection, mycobacteria can spread by haematogenous, lymphatic or direct mechanical routes
  • Tendency is for survival in apical or posterior segments of upper lobe and superior segment of lower lobe, renal cortex, meninges, epiphyses of long bones and vertebrae
  • Can remain in these areas lying dormant for years (= latent infection)
  • Disease detected by positive tuberculin skin test (positive 1-2 months after exposure)
  • 1-13% of healthy patients with go on to develop active post-primary disease
  • Children and HIV positive patients have a 20% rate of post-primary infection

Pathophysiology

• Reactivation tuberculosis
  • As host defences weaken, unable to contain mycobacteria within tubercles with subsequent reactivation
  • Risk higher in HIV and those >50yo
  • 5% develop within 2 years of primary infection and 5% in later life
  • HIV confers a 5-10% risk of reactivation per year
  • Others at risk include those immunocompromised from carcinoma of solid organs, leukaemia, transplant or TNFalpha antagonists (etanercept/infliximab) or corticosteroids
  • Those with diabetes, haemodialysis, psoriasis and silicosis are also at increased risk

Clinical features

• Primary TB
  • Usually asymptomatic and detected by positive tuberculin skin test or CXR abnormality
  • May have fever, weight loss, malaise and chest pain with viral pneumonitis-type picture
  • Hilar adenopathy is present
  • If immunocompromised may be progressive and fatal
• Reactivation TB
  • Most commonly fever, malaise, night sweats, weight loss
  • Spread through lungs = cough, haemoptysis, dyspnoea, pleuritic chest pain
  • 20% will have extra-pulmonary manifestations
    • Painless lymphadenopathy (cervical lymphadenitis = scrofula)
    • Abdominal pain due to hepatosplenomegaly, peritoneal tubercles, prostatitis, epididymitis, orchitis
    • Adrenal insufficiency, bone pain with arthritis, osteomyelitis, pott’s disease, haematuria and meningitis
    • Pericarditis
    • Can mimic many other diseases

Diagnosis

• The goal in ED is to consider this in differential for any patient over 50 with pneumonia-like presentation, or those with HIV or immunocompromised in order to begin Ix and start respiratory precautions
• On CXR look carefully for upper lung field involvement, fibrocalcific changes, pleural capping or a calcified Ghon complex
• Once suspected, given empirical antibiotics for pneumonia, admit to isolation bed, institute airborne precautions, sputum cultures, tuberculin skin testing and test for HIV if status not known

Mantoux testing

• Intracutaneous injection of 0.1mL purified protein derivative info forearm
• Relies on delayed-type hypersensitivity reaction triggered in those with past infection or significant recent exposure
• Read at 48-72 hours by measuring extent of skin induration (not erythema or other skin changes)
• Those who have received BCG will have a positive test as will exposure to non-tuberculous mycobacterial infection
• False-negative in profound immunosuppression

Mantoux testing

• >=5mm positive in: HIV, close contact with TB, CXR suggestive of TB, immunosuppressed
• >=10mm positive if IVDU, high-prevalence groups, conditions that increase progression to active disease or <4yo
• >=15mm positive in all others
• If deemed positive, need to consider clinical, laboratory and CXR findings to ascertain if previous exposure, primary TB, latent TB or reactivation TB

Blood tests

• Interferon-gamma release assays (Quantiferon Gold)
  • Measures response to exposure to peptides present in all M. tuberculosis proteins, which trigger IFN-gamma release in host
  • More specific as proteins are absent in BCG and most non-tuberculous mycobacteria
  • Results in 16-24 hours
  • Especially helpful if follow-up is not reliable or if skin testing is not helpful or with known previous exposure e.g. healthcare worker
  • Positive test suggests immune recognition of TB and may be due to either current or remote past infection
  • If positive, sputum samples are required

Sputum testing

• Three samples (preferably early morning) are indicated to maximise yield
• May require saline nebulisation or gastric aspirates in children
• Bronchoscopy sometimes required
• Microscopy
  • 5000 bacilli/mL Ziehl-Neelsen acid-fast required for positive smear
  • Microscopy positive in 50% of pulmonary TB
  • Culture or molecular assays are then required to confirm acid-fast bacilli are in fact M. tuberculosis
    • Liquid culture is the most sensitive

Molecular assays

• Detect DNA specific for MTB
• Highly sensitive in smear positive samples but sensitivity drops to 50% if smear negative
• GeneXpert sensitivity is equivalent to solid culture and simultaneously detects rifampicin resistance

Drug-susceptibility testing

• First-line: Isoniazid, rifampicin, ethambutol, pyrazinamide, streptomycin
• Resistant strains then tested against second-line agents
• MDR-TB indicates resistance to both isoniazid and rifampicin

Detecting latent TB

• Mantoux and/or Quantiferon-Gold
• Allows treatment which reduces rate of progression to active TB by 60-90% and eliminates potential transmission

CXR

• Used to identify disease in those with pulmonary symptoms or after a positive skin test
• Most common finding is a normal CXR
• Primary infection
  • Parenchymal changes in any lung area with unilateral lymphadenopathy
  • Calcification, when present, is a late finding (see latent below)
  • Isolated ipsilateral hilar or mediastinal adenopathy may be the only finding
  • Pleural effusions are usually unilateral
• Latent TB
  • Upper lobe or hilar nodules and fibrotic lesions, which may be calcified
  • Bronchiectasis, volume loss and pleural scarring
  • Healed primary infection appears as Ghon foci, areas of scarring and calcification
• Reactivation infections
  • Classic cavitary or non-cavitary upper lobe or superior lower lobe lesions
  • Immunocompromised patients typically show findings consistent with primary disease

Treatment of active TB

• Isoniazid, Rifampicin, Ethambutol and Pyrazinamide for 8 weeks followed by two drug continuation therapy for 18-31 weeks
• Longer if immunosuppressed or those with extrapulmonary disease
• Isoniazid
  • Hepatotoxicity is common with increased risk in pre-existing liver disease, pregnancy, ethanol use, HIV and hepatitis C
  • Peripheral neuropathy also seen
• Rifampicin – Hepatitis, thrombocytopaenia, GI disturbances
• Ethambutol – Retrobulbar neuritis and peripheral neuropathy

Paradoxical reaction

• Immune reconstitution syndrome sometimes seen with initiation of therapy
• More common in HIV
• Fever, worsening respiratory status, lymphadenopathy, hepatosplenomegaly, ascites, meningitis and new/worsening CNS lesions may occur
• Hypercalcaemia can occur

Treatment of latent TB

• Isoniazid alone for 9 months

Disposition and follow-up

• Outpatient
  • Need home isolation insutrctions, primary care physician follow-up and TB clinic follow-up
• Hospital admission
  • If unwell, uncertain diagnosis, possible non-compliance, or active drug-resistant TB
• Directly observed therapy (DOT) is an alternative regime

TB and HIV

• HIV is the strongest risk factor for TB
• Patients with new diagnosis TB are 20x more likely to have HIV
• HIV patients are 20-30x more likely to develop TB than general population
• TB is a defining event of AIDS
• Rapid progression and drug resistance far more likely
• Successful antiretroviral therapy reduces incidence of TB and extrapulmonary TB
• Therefore, if considering TB = consider and test for HIV
• Drug interactions are a common issue

MDR-TB

• Resistance to at least isoniazid and rifampicin
• Due to spontaneous genetic mutation
• Risk factors
  • Previous TB treatment
  • Exposure to MDR-TB
  • Community isoniazid resistance >4%
  • Persistent symptoms or persistently positive sputum cultures after 4 months of standard therapy

XDR-TB

• Resistance to:
  • Isoniazid and rifampicin +
  • Any fluoroquinolone +
  • At least one injectable second-line agent
• Associated with poor outcomes and higher mortality

TB in children

• Primary TB often asymptomatic
• Classic presentations may be seen in older children
• Most common extrapulmonary manifestation is cervical lymphadenitis
• Yield of sputum culture and smears is lower and may require hypertonic saline nebulisation, gastric aspirates or gastric lavage
• QuantiferonGold and NAAT are not recommended for children under 5 (<2 in Australian Guidelines)

Miliary TB

• Seen in disseminated TB with multiple small lung lesions like millet seeds
• Also seen in histoplasmosis, malignancy, siderosis and sarcoidosis
• Higher mortality and seen in children, elderly and immunocompromised
• Miliary disease in primary TB is generally more rapid with multiorgan failure, shock and ARDS
• Miliary disease in reactivation TB tends to be chronic and non-specific

Tuberculous meningitis

• Often seen in children or immunosuppressed
• Subtle, subacute gradual fever, headache, cognitive impairment not accompanied by classical meningitis signs
• Focal neurological signs may be evident
• Long-term neurological dysfunction is common and VP shunts are required in 25% for hydrocephalus
• The key is requesting TB cultures and smears on CSF samples

Last Updated on October 28, 2020 by Andrew Crofton