Non-pulmonary Tuberculosis

Tuberculosis is a chronic, recurrent infection that most often causes pulmonary disease, but it may also result in extrapulmonary disease, particularly involving the pleura, lymph nodes, genitourinary tract, skeleton, meninges, peritoneum, or pericardium. Tuberculosis is caused by infection with mycobacteria, most commonly Mycobacterium tuberculosis and M. bovis. Diagnosis of tuberculosis, especially non-pulmonary tuberculosis, may be difficult and a high index of suspicion is required in order to avoid delays in diagnosis.

• The annual incidence of tuberculosis is approximately 14 cases per 100,000 population, with about 43% of cases having non-pulmonary tuberculosis.¹
• The most frequent sites of extra-pulmonary disease in 2003 included extra-thoracic lymph nodes (18%), pleura (8%) and intra-thoracic lymph nodes (7%). Meningeal tuberculosis was reported in 2% of reported cases of tuberculosis.¹
• Non-pulmonary tuberculosis is more common in HIV-positive patients.
• Patients with other immunocompromised states (e.g. post-transplant, lymphoma, T-cell deficiencies) may also have an increased risk of extrapulmonary disease.
• Other groups at increased risk of tuberculosis include intravenous drug abuse, the homeless, prisoners, people living in poverty and overcrowded conditions, alcoholics, people who are malnourished, people with diabetes or renal disease, and the young (especially infants and those aged between 15 and 25 years) and the elderly.
• Tuberculous lymphadenitis, tuberculous meningitis, osteoarticular tuberculosis and miliary tuberculosis are some of the more well-recognised manifestations of non-pulmonary tuberculosis in childhood.²

• Disseminated tuberculosis (miliary TB)
  • Presentation usually non-specific with fever, anorexia, weight loss, night sweats and weakness.
  • Most affected patients will have pulmonary involvement.
  • Widespread involvement leads to altered mental state, meningismus, wasting, hepatosplenomegaly and lymphadenopathy.
• Peripheral lymphadenitis
  • Most often occurs in young adult females of minority races.
  • Systemic symptoms are usually absent.
  • Painless, unilateral discrete swelling of one or more lymph nodes, especially cervical or supraclavicular.
  • The overlying skin may become inflamed as the disease progresses.
• Mesenteric lymphadenitis
  • Tuberculous abdominal lymphadenopathy is common in HIV positive patients but rare in HIV negative patients.
  • May present with fever, abdominal pain and gastrointestinal obstruction. A mass may be palpable.
• Pleural tuberculosis
  • May cause pleurisy with a pleural effusion or tuberculous empyema, possibly leading to a bronchopleural fistula.
  • Presentation may be gradual or abrupt in onset and severe, causing fever, cough, pleuritic pain and sometimes dyspnoea.
• Renal tuberculosis
  • May present with dysuria, pyuria, haematuria, urinary frequency, and back and loin pain.
  • Genital tuberculosis
  • More common in women and may present with menstrual irregularity, abdominal pain and infertility. Ectopic pregnancies may occur.
  • In men, presents with a painless scrotal mass, orchitis, prostatitis or epididymitis.
• Tuberculous spondylitis
  • Systemic symptoms are often absent. Initial symptoms include back pain and stiffness.
  • Disease progression may lead to leg weakness or paraplegia.
  • Anterior wedging of two adjacent vertebrae with destruction of the intervening disc causes a tender prominence of the spine (gibbus).
• Peripheral osteoarticular tuberculosis
  • Pain in affected bone or joint, with swelling of involved and restricted movements of the involved joint.
  • Bone marrow involvement may cause pancytopaenia.
• Tuberculous meningitis
  • Initially presents with fatigue, malaise, intermittent headaches, and low grade fever.
  • Progresses over a few weeks to cause headaches, altered mental state and vomiting, and then to meningism. focal neurological signs due to involvement of cranial nerves and vasculitis.
  • Tuberculous meningitis may present with sudden severe meningitis progressing rapidly to coma and death.
• Spinal meningitis
  • May present with bladder or sphincter weakness, anaesthesia, paraesthesiae or weakness in the nerve root distribution.
• Gastrointestinal tuberculosis
  • May occur after swallowing of respiratory secretions or drinking of unpasteurized milk (M. bovis).
  • Any part of the gastrointestinal tract may be affected, from mouth to anus.
  • Oral tuberculosis may cause non-healing ulcers of the mouth or tongue.
  • Oesophageal involvement may present with dysphagia or massive haematemesis.
  • Ileo-caecal involvement presents with abdominal pain, anorexia, diarrhoea, obstruction, haemorrhage or a palpable mass.
  • May also cause infection in stomach, pancreas, biliary tract (ascending cholangitis) or liver (tuberculous hepatitis).
• Peritonitis
  • Fever, weight loss and anorexia, with abdominal pain and swelling (ascites).
• Pericardial tuberculosis
  • Presentation may be acute or insidious.
  • Non-specific symptoms include fever, weight loss and night sweats.
  • Local symptoms include cough, dyspnoea, orthopnoea, ankle swelling and chest pain.
  • Cardiac tamponade and cardiac constriction may occur.
• Cutaneous tuberculosis
  • Presentation is very variable, e.g. nodules or ulcers.
• Laryngitis
  • Dysphagia, otalgia, cough, wheezing and haemoptysis.
• Otitis
  • Hearing loss, painless discharge.
  • May present as facial nerve palsy.
• Ocular tuberculosis
  • Keratoconjunctivitis: pain and photophobia.
  • Choroidal: may be asymptomatic or cause decreased visual acuity. A choroidal tubercle may be seen.
  • Uveitis, iritis, and episcleritis: variable red, painful eye.
• Breast
  • Nodules, abscess or discrete masses.
• Adrenal gland
  • Addison's disease may occur with bilateral adrenal gland involvement.

• Tuberculin skin test: indicates infection with Mycobacterium tuberculosis.
• Blood tests that measure the T-cell reaction to specific tuberculosis antigens: under development. T cells with a memory for tuberculosis will produce gamma-interferon when incubated with tuberculosis antigens.
• All clinical samples suspected of containing mycobacteria (e.g. sputum, gastric washings, cerebrospinal fluid, blood, urine, material from abscesses) should be sent to the laboratory for acid-fast bacilli (AFB) staining and mycobacterial culture and for drug sensitivities. Multiple samples should be sent (at least 3).
• Samples should be sent for direct identification of mycobacteria using DNA amplification methods when prompt treatment is imperative, e.g. when the patient is immunocompromised.
• Chest X-ray: should be ordered in all patients with suspected pulmonary disease and non-pulmonary tuberculosis.
• CT or MRI scans: abdomen, chest, central nervous system. CT or MRI scans of the spine if skeletal tuberculosis is suspected. Plain x-rays of spine are often unhelpful with diagnosis.
• CSF analysis: in all patients with suspected meningeal tuberculosis.
• Abdominal ultrasound: gastrointestinal, genitourinary, peritonitis.
• Echocardiogram: pericardial involvement.
• Tissue biopsy may be required for mycobacterial culture and histology.
• HIV serology should be tested in all patients with tuberculosis.
• Check full blood count, renal function and electrolytes, and liver function tests.

• The standard recommended regimen:
  • 6 months of isoniazid and rifampicin supplemented in the first 2 months with pyrazinamide and ethambutol).
  • Fixed-dose combination tablets should be used as part of any TB treatment regimen.
  • The standard recommended regimen may be used during pregnancy and breast-feeding.
  • Streptomycin should not be given in pregnancy.
• Directly observed therapy (DOT) should be considered for patients who have adverse factors on their risk assessment, especially:
  • Street or shelter-dwelling homeless people with active tuberculosis.
  • Patients with likely poor adherence, especially those who have a history of non-adherence.
• Patients with active meningeal TB:
  • Initially 12 months treatment, comprising isoniazid, pyrazinamide, rifampicin and a fourth drug (e.g. ethambutol) for the first 2 months, followed by isoniazid and rifampicin for the rest of the treatment period.
  • Glucocorticoid treatment:
    • Adults: equivalent to prednisolone 20-40 mg if on rifampicin, otherwise 10-20 mg.
    • Children: equivalent to prednisolone 1-2 mg/kg, maximum 40 mg.
    • Gradual withdrawal of the glucocorticoid should start within 2-3 weeks of initiation.
• Peripheral lymph node TB:
  • The standard recommended regimen should be used (see above).
  • Patients with active peripheral lymph node TB who have had an affected gland surgically removed should still be treated with the standard recommended regimen.
  • Drug treatment should normally be stopped after 6 months, regardless of the appearance of new nodes, residual nodes or sinuses draining during treatment.
• Bone and joint TB:
  • The standard recommended regimen should be used (see above).
  • A CT or MRI scan should be performed on patients with active spinal TB who have neurological signs or symptoms. If there is direct spinal cord involvement, management should be as for meningeal TB (above).
  • In patients with spinal TB, anterior spinal fusion should not be performed routinely. it should be considered if there is spinal instability or evidence of spinal cord compression.
• Pericardial TB:
  • The standard recommended regimen should be used (see above).
  • In addition, glucocorticoid treatment should be given:
  • Adults: glucocorticoid equivalent to prednisolone at 60 mg/day.
  • Children: glucocorticoid equivalent to prednisolone 1mg/kg/day (maximum 40 mg/day).
  • Gradual withdrawal of the glucocorticoid should be considered, starting within 2-3 weeks of initiation.
• Disseminated (including miliary) TB:
  • The standard recommended regimen should be used (see above).
  • Treatment of disseminated (including miliary) TB should be started even if initial liver function tests are abnormal.
  • Patients should be tested for CNS involvement by:
    • CT or MRI scan and/or lumbar puncture for those with CNS signs or symptoms.
    • Lumbar puncture for those without CNS signs and symptoms.
  • If evidence of CNS involvement is detected, treatment should be the same as for meningeal TB.
• Other sites of infection:
  • The standard recommended regimen should be used (see above) for patients with:
    • Active genitourinary TB, or
    • Active TB of any site other than respiratory system, CNS, peripheral lymph nodes, bones and joints, pericardium and disseminated (including miliary) disease.

• Latent TB is when active TB has been excluded by chest X-ray and examination for people who are younger than 36 years, any age with HIV, any age and a healthcare worker, and are either:
  • Mantoux positive (6 mm or greater), and without prior BCG vaccination, or
  • Strongly Mantoux positive (15 mm or greater), interferon-gamma positive, and with prior BCG vaccination.
• Children aged 1-15 years who are strongly Mantoux positive (15 mm or greater), and interferon-gamma positive (if this test has been performed), and without prior BCG vaccination.
• People with evidence of TB scars on chest X-ray, and without a history of adequate treatment.
• People with HIV who are in close contact with people with sputum smear-positive respiratory TB should have active disease excluded and then be given treatment for latent TB infection. Mantoux testing may be unreliable in people with HIV.

Management

• Treatment for latent TB infection should not be started in close contacts of people with sputum smear-positive multi-drug resistant TB who are strongly Mantoux positive (15 mm or greater), as no regimen is of proven benefit, and only a small proportion of people infected will develop the disease. Long-term monitoring should be undertaken for active disease.
• People who have agreed to receive treatment for latent TB infection should be started on one of the following regimens:
  • Either 6 months of isoniazid or 3 months of rifampicin and isoniazid for people aged 16-35 not known to have HIV.
  • Either 6 months of isoniazid or 3 months of rifampicin and isoniazid for people older than 35 in whom treatment for latent TB infection is recommended, and who are not known to have HIV.
  • 6 months of isoniazid for people of any age who have HIV.
  • 6 months of rifampicin for contacts, aged 35 or younger, of people with isoniazid-resistant TB.

• Non-pulmonary tuberculosis tends to have a worse prognosis than pulmonary tuberculosis.
• Co-infection with HIV also adversely affects prognosis.
• Prognosis is adversely affected by non-compliance with therapy, extensive disease at the time of diagnosis and shorter duration of therapy.

• BCG vaccination: those now recommended to receive BCG are:⁴
  • All infants living in areas where the incidence of TB is 40/100,000 or greater.
  • Infants whose parents or grandparents were born in a country with a TB incidence of 40/100,000 or higher.
  • Previously unvaccinated new immigrants from high prevalence countries for TB.
  • Children who would otherwise have been offered BCG through the schools programme are now screened for TB risk factors, and tested and vaccinated if appropriate.
• Screening and appropriate treatment of close contacts (e.g. household, school, prison) of any person with active TB, irrespective of the site of infection.
• Prevention of tuberculosis in susceptible close contacts or those who have become tuberculin positive:
  • Isoniazid 300 mg daily for 6 months (child 5 mg/kg daily, maximum 300 mg daily), or
  • Isoniazid 300 mg daily and rifampicin 600 mg daily (450 mg if less than 50 kg) for 3 months. For children: isoniazid 5 mg/kg daily (maximum 300 mg daily) and rifampicin 10 mg/kg daily (maximum 450 mg daily if body-weight less than 50 kg; maximum 600 mg daily if body-weight over 50 kg), or
  • For isoniazid-resistant tuberculosis in patients under 35 years: rifampicin 600 mg daily (450 mg if less than 50 kg) for 6 months; child 10 mg/kg daily (maximum 450 mg daily if body-weight less than 50 kg; maximum 600 mg daily if body-weight over 50 kg)