Tuberculosis

Revised and reviewed 14 December 2016

OVERVIEW

• Tuberculosis (TB) is the most important infectious cause of death worldwide and is caused by the Mycobacterium tuberculosis complex
• Reasons for admission to ICU include respiratory failure, multiorgan failure and decreased consciousness associated with central nervous system disease
• Though treatable, mortality is high (>25%) in TB patients requiring ICU, and they often have prolonged ICU stays
• TB is uncommon in Australia and most developed countries

CAUSE

TB is caused by the aerobic acid fast bacilli of the M. tuberculosis complex

• M. tuberculosis is responsible for most cases in Australia
• A small number of cases result from other species that belong to the same complex, such as M. bovis, M. africanum. M. canetii and M. caprae 

PATHOGENESIS

Following TB exposure there are various potential outcomes

• No infection (70-90%) (immediate clearance)
•  Infection (10-30%)
  • active TB (10%, half of these developing within 5 years)
    • 98% cured if treated
    • 50% die within 2 years if untreated
  • latent infection (90%)
• Reactivation of latent infection

Primary disease

• may go unnoticed, e.g. pulmonary lesions healing, sometimes leaving traces of calcified scar tissue on CXR
• usually seen in children not previously exposed to TB (or to BCG vaccination)
• Bacilli within the lung generally survive initial cellular phagocytosis defence mechanisms, possibly due to their high lipid content capsules
• Ghon focus
  • “Tubercule” formation occurs due to a granulomatous response to chronic infection
  • most commonly appears as a 1-2cm sub-pleural lesion within the midzone region of either lung
  • Healing involves central “caseation” and fibrotic walling off of the lesion
  • Larger lesions may calcify
• Tuberculous lymphadenopathy
  • Lymphatic spread from the ghon focus occurs to the pulmonary hilar lymph nodes
• “Primary complex”
  • The combination of ghon focus and hilar lymphadenopathy
• Rapidly progressive pulmonary broncho-pneumonia
  • Occasionally occurs, due to rupture of a ghon focus
• Miliary TB
  • form of TB where there is haematological dissemination from focal infection into the blood
  • results in seeding of other areas of the lungs and multiple organs with TB bacilli
• Extrapulmonary TB
  • seeding through blood or lymphatic spread to produce extrapulmonary involvement
  • more common in AIDS/ immunosuppression
• Cell mediated immunty is induced
  • occurs during primary infection or following BCG vaccination
  • can be demonstrated by a positive tuberculin skin test, which is a delayed hypersensitivity reaction to tuberculoprotein

Secondary disease

• due to either reactivation of “latent” primary TB or re-infection
• usual site is the apex of the lung, or the apical segments of the lower lobes
• Extra-pulmonary spread may also eventually occur
• Lung lesions may:
  • Cavitate and lead to a rapidly progressive pulmonary broncho-pneumonia or a more devastating “military” TB
  • Erode adjacent blood vessels leading to hemoptysis, which may be massive

RISK FACTORS

Immune suppression

• HIV/ AIDS
• CRF
• malnutrition
• solid organ transplant
• prolonged steroid use
• other conditions of lower risk
  • IV drug users
  • Alcoholism
  • DM
  • Elderly

Other comorbidities

• silicosis
• gastrectomy
• jejunoilieal bypass
• chronic pulmonary disease

Epidemiology

• immigrants from countries with a high incidence of TB
  • e.g. Vietnam, India, China, Africa, Philippines, Eastern Europe, Pacific Islands
• Indigenous Australians in some locations
• institutional living
• close contact with a known case of active TB
• living in substandard, overcrowded conditions
• Institutionalised people including prisoners
• Health professionals

CLINICAL FEATURES

Suspect TB (and consider isolation) if:

• a cough persisted for 3 weeks or more
• other symptoms or signs compatible with active TB (see General)
• CXR changes consistent with pulmonary TB (often, previous X-rays need to be reviewed to look for new changes)
• if the patient has previously lived in a TB endemic country

General

• contact history and risk factors
• fever
• night sweats
• unexplained weight loss
• fatigue
• anorexia
• can effect any organ system!

Pulmonary tuberculosis

• cough and sputum
• haemoptysis
• chest wall pain
• SOB
• crackles (apical)
• recurrent pneumonia
• pleural effusions
• spontaneous pneumothorax

Tuberculosis of the CNS (meningitis and/or cerebral tuberculosis)

• vague illness for 2-8 weeks
• headache
• neck stiffness
• cranial nerve palsies
• papilloedema
• hemiplegia
• seizures
• hypdrocephalus
• hyponatraemia (SIADH / cerebral salt wasting)

Tuberculosis emergencies

• massive haemoptysis (e.g. Rasmussen aneurysm)
• airway obstruction (e.g. Laryngeal/retropharyngeal TB)
• respiratory failure (e.g. extensive pulmonary TB)
• pericardial tamponade
• small intestinal obstruction
• tuberculous meningitis
• status epilepticus, stroke or pituitary apoplexy due to cerebral tuberculomas
• DIC (e.g. miliary TB)
• shock and MODS (rare – “Landouzy septicaemia” from disseminated TB; adrenal insufficency from adrenal TB)

Other reasons for ICU admission of TB patients

• liver or renal failure due to drug reactions
• elective admission post-thoracic surgery
• comorbidities

INVESTIGATIONS

Early diagnosis of TB is important as delays in starting anti-tuberculosis therapy are associated with worse survival

• all patients suspected of pulmonary TB should have at least 2 sputum samples sent for investigation

Laboratory

• Culture of the bacillus (e.g. sputum, blood, CSF, pleural fluid, gastric lavage, bronchial washings, drainage of collections)
  • Takes a long time (2-4 weeks)
  • provides drug susceptibility information
• Identification of acid-fast bacilli (e.g. sputum, blood, CSF, pleural fluid, gastric lavage, bronchial washings, drainage of collections)
  • Ziehl-Neelsen stain
  • Sputum induction increases rates of TB detection
  • It appears to be as good as BAL
• Pleural fluid
  • total protein, glucose, WCC and differential, pH, adenosine deminase (if > 70U/L -> highly suggestive of Tb)
•  CSF (lumbar puncture)
  • high protein, low glucose and predominately lymphocytic CSF (TB menigitis)
• Nucleic acid amplification (e.g. PCR of sputum, CSF, pleural fluid)
  • Rapidly available
  • High specificity
  • Useful in ruling in rather than ruling out TB
  • If clinical suspicion is high, a negative NAA does not exclude TB
  • NAA results may remain positive for months
• Interferon-γ release assays (IGRAs) such as the quantiferon test
  • confirms TB exposure
  • cannot discriminate between latent and active TB
  • negative result does not exclude TB
  • positive result does not give drug sensitivities

Imaging

• CXR
  • patchy/nodular shadowing in upper zones, cavitation, calcification, hilar or mediastinal lymphadenopathy, diffuse millary shadowing
  • may be normal in extra-pulmonary TB
• CT or MRI Brain
  • thickening and enhancement of meninges in basilar region (TB menigitis)
  • cerebral tuberculomas

Other

• Histological identification of caseating granulomas (e.g. biopsy of lymph nodes, pleura or other affected tissue)

MANAGEMENT

Resuscitation

• address immediate life threats (see above)

Specific therapy

• Guided by an infectious diseases specialist
• Institute infection control measures (see below)
• Initial standard daily regimen (intensive phase)
  • Patients receive 4 anti-TB medications plus pyridoxine
    • Isoniazid (H)
      • 300 mg (child 10 mg/kg up to 300 mg) orally daily
    • Rifampicin (R)
      • 600 mg (adult less than 50 kg: 450 mg; child 10 mg/kg up to 600 mg) orally daily PLUS
    • Ethambutol (E)
      • 15 mg/kg orally daily (up to 1200 mg; in adults and children 6 years or older) PLUS
    • Pyrazindamide (Z)
      • 25 mg/kg (up to 2 g) orally daily
    • Pyridoxine
      • 25 mg orally daily
  • suitable for patients where there is no drug resistance suspected
  • often commenced prior to antibiotic sensitivities being available
  •  duration
    • minimum of two months, or
    • at least until sputum is smear-negative for pulmonary TB and, in culture positive cases, drug susceptibilities are known, whichever is longer
    • ethambutol can be ceased once the TB isolate is confirmed to be fully sensitive to first-line agents, even if this is before two months, and can be omitted if the isolate is known to be fully sensitive to first-line agents before
• Sterilisation phase for fully sensitive TB
  • total treatment course of six months (2HRZE/4HR) (“short course”)
  • certain patients are not suitable for “short course” therapy and typically require longer duration treatment:
    • the patient has not received HRZ for the complete initial treatment course
    • evidence of extensive disease, including extensive cavitation on CXR
    • patient is not fully adherent to medications
    • delayed clinical response to treatment, including persistent positive sputum smears two months into treatment
    • evidence of disseminated, central nervous system or skeletal disease (extrapulmonary TB – requires longer therapy)
    • the organism shows resistance to isoniazid, rifampicin or pyrazinamide
• Options for drug-resistant TB
  • isoniazid resistance (~10% of cases):
    • 2HRZE/7RZE or 2HRZE/10RE if pyrazinamide intolerant
  • Multi-drug resistant (MDR) and extended -drug resistant (XDR) TB:
    • requires specialist management
    • requires addition of ‘second line’ agents such as fluoroquinolones (e.g. moxifloxacin), amikacin, prothionamide and PAS
    • regimens are at least 18-24 months duration
• In Victoria directly observed intermittent short-course therapy (DOTS) is provided on a case-by-case basis

Adjuntive corticosteroids

•  used as an adjunct to anti- tuberculous drugs in certain TB infections to decrease the adverse effects of inflammation associated with TB infection and its treatment
• Definite indications
  • TB meningitis
  • TB pericarditis
  • HIV-associated immune-reconstitution syndrome causing clinical deterioration in a patient with active TB
  • adrenal insufficiency due to TB
• Controversial indications (have been used with anecdotal success, but evidence is limited evidence)
  • ureteric TB
  • extensive pulmonary TB
  • pleural TB
  • vertebral TB
  • paediatric intrapulmonary lymph node TB
• Regimen
  • prednisolone 60 mg/day (child 1–2 mg/kg) weaning over 6–12 weeks

Supportive care and monitoring

• TB patients requiring ICU have high rates of comorbidities and complications (of the disease and the therapy)

Disposition

• Patients with life-threatening presentations require ICU admission
• Consult infectious diseases specialist early
• Close follow up and serial investigations are requiring after stabilistation of the initial illness to ensure compliance with therapy and clearance of infection

INFECTION CONTROL AND THE HOSPITAL ENVIRONMENT

Hospitalisation of TB patients is not mandatory unless these factors dictate otherwise

• social conditions,
• coexisting medical conditions, or
• illness severity

Isolation practices for known or suspected TB patients

• When a patient needs to be transported or managed outside an isolation room, they should wear surgical masks to cover their mouth and nose during transport
• Aerosol isolation + standard contact isolation
• Isolation room (Class N room)
  • private (e.g. private bathroom)
  • door kept closed
  • negative pressure (12 air changes/h (ACH); 30 Pa if air lock, 15 Pa if no airlock)
  • warning signs on doors
  • air exhausted to outside environment (unless HEPA filter prior to recirculation to hospital environment)
  • minimise number of HCWs and visitors entering the room

Cough-inducing and aerosol-generating procedures

• Cough-inducing procedures include
  • endotracheal intubation and suction
  • diagnostic sputum induction
  • aerosol treatments (for example, pentamidine therapy)
  • bronchoscopy
• Procedures that may generate infectious aerosols include
  • irrigation of tuberculous abscesses
  • laboratory techniques such as homogenising or lyophilising of TB infected tissue
• Precautions
  • only perform procedures if necessary
  • Staff should wear masks and gloves
  • perform in isolation room
  • allow enough time for sufficient removal of airborne contaminants afterward (e.g. 35 min for a room with 12 ACH)
  • If intubated
    • bacterial filter and closed suction on circuit
  •  Bronchoscopy
    • minimise aerosols (paralyze, consider apnoeic ventilation during procedure)
  • Sputum specimens in biohazard bags

Staff

• use high filtration mask (N95 or N100)
• education for staff on symptoms
• staff screening: CXR, Mantoux (baseline and 2 months)
• early ID involvement in staff exposed

No restriction on the movement of patients with non-pulmonary disease

PROGNOSIS

• Overall, with appropriate therapy, TB has a 98% cure rate
• Patients requiring mechanical ventilation have up to a 69% mortality
• Worse mortality if:
  • older age
  • nosocomial pneumonia
  • TB destroyed lung
  • MODS
  • duration of symptoms >4 weeks
  • APACHE-II score >20

References and links

LITFL

• Total TB Extravaganza

Journal articles

• Hagan G, Nathani N. Clinical review: tuberculosis on the intensive care unit. Critical care. 17(5):240. 2013. [pubmed]
• Lange C, Abubakar I, Alffenaar JW, et al. Management of patients with multidrug-resistant/extensively drug-resistant tuberculosis in Europe: a TBNET consensus statement. The European Respiratory Journal. 44(1):23-63. 2014. [pubmed]
• Zumla A, Raviglione M, Hafner R, von Reyn CF. Tuberculosis. New England Journal of Medicine. 368(8):745-55. 2013. [pubmed]

FOAM and web resources

• CDNA National Guidelines for Public Health Management of TB (pdf)
• Management, prevention and control of tuberculosis – Guidelines for healthcare providers (Victoria, Australia) (pdf)