RetourExtrapulmonary TB is active TB in organs other than the lungs. About 15% of the 7 million incident TB cases globally notified in 2018 were extrapulmonary TB; among WHO regions, prevalence ranged from 8% in the Western Pacific; to 15–17% in Africa, the Americas, Europe and South-East Asia; and to 24% in the Eastern Mediterranean (4). The WHO European Region is facing an increasing notification rate of extrapulmonary TB: in this region seven countries (Finland, the Netherlands, Norway, Sweden, Turkey, the United Kingdom and Uzbekistan) reported more than 30% of cases (40).
Overall, among both adults and children, about two of every three extrapulmonary TB cases are represented by pleural and lymph node TB (41). In settings with a high prevalence of HIV infection, lymph node TB represents about 10% of all TB cases (42). Osteoarticular, urogenital, intra-abdominal, pericardial and meningeal TB are less frequent (41). Tuberculous meningitis is important both for being clinically severe and for being largely preventable in children by vaccinating with bacille Calmette– Guérin (BCG), ideally at birth (43).
Compared with pulmonary TB, extrapulmonary TB is more difficult to diagnose because it can mimic other organ-specific diseases, clinical samples for bacteriological situations are difficult to obtain for culture, and digital imaging is not always available. In addition, extrapulmonary TB is often paucibacillary (41). Pericardial, meningeal and disseminated (miliary) TB forms are more likely to result in a fatal outcome.
7.1 Eligibility
Adults with extrapulmonary TB are eligible for the 6-month 2HRZE/4HR regimen, except for those with TB of the central nervous system, bone or joint, for which some expert groups suggest longer therapy (i.e. 9–12 months).
Children aged between 3 months and 16 years with extrapulmonary TB limited to peripheral lymph nodes (i.e. without involvement of other sites of disease) should be treated with the 4-month regimen (2HRZ(E)/2HR).
In children and adolescents with tuberculous meningitis, two alternative regimens can be used: a 12-month regimen (strong recommendation) and a 6-month regimen described below (conditionally recommended). The 6-month tuberculous meningitis regimen is not currently recommended for use in children and adolescents living with HIV.
7.2 Composition and duration of the regimen
Pulmonary and extrapulmonary TB disease in adults can be treated with the same regimens, the 6-month 2HRZE/4HR being the core regimen. Outside WHO recommendations, some experts suggest 9–12 months of treatment for tuberculous meningitis (given the serious risk of disability and mortality) (41), and 9 months of treatment for osteoarticular TB (given the difficulties in assessing treatment response) (41, 44–46).
Treatment of extrapulmonary TB is similar to that of pulmonary TB, being centred around the 6-month 2HRZE/4HR regimen; however, the regimen can be prolonged up to 12 months for tuberculous meningitis, osteoarticular TB or other types of extrapulmonary TB, as decided by clinicians. The 4-month 2HPMZ/2HPM regimen was not studied in extrapulmonary TB and thus cannot be recommended at this time. Furthermore, extrapulmonary TB is usually more difficult to diagnose, and evaluation of its outcomes can be more challenging because of the absence of bacteriological evidence in most patients and the need for cross-sectional imaging; hence, there is little quality evidence on this type of TB.
Following infection with M. tuberculosis, young children are at high risk of developing the most severe forms of disease, the most devastating being tuberculous meningitis, which predominantly affects young children (peak age of onset, 2–4 years). WHO currently recommends a 12-month regimen to treat tuberculous meningitis in children, comprising isoniazid, rifampicin, pyrazinamide and ethambutol given daily for the first 2 months, followed by isoniazid and rifampicin given daily for an additional 10 months (2HRZE/10HR) (19). Recommended doses to be used in this regimen are the same as those for the treatment of pulmonary TB. This regimen can be used in all children and adolescents, including those who are HIV-positive.
An alternative option of a shorter regimen is also conditionally recommended. This shorter regimen is recommended for children and adolescents with bacteriologically confirmed or clinically diagnosed tuberculous meningitis (without suspicion or evidence of MDR/RR-TB); it is a 6-month intensive regimen that comprises isoniazid, rifampicin, pyrazinamide and ethionamide (6HRZEto) (19). It is preferable to use child-friendly, dispersible and FDC medicines in children when possible.
In cases of non-severe TB, the 4-month 2HRZ(E)/2HR regimen (see Section 5 for details) can be used for children and adolescents with peripheral lymph node TB, intrathoracic lymph node TB without airway obstruction and uncomplicated TB pleural effusion (1).
Children with peripheral lymph node TB were included in the SHINE trial, and the results showed that the 4-month regimen (2HRZ(E)/2HR) can be used in children and adolescents aged between 3 months and 16 years with extrathoracic lymph node TB, which falls under the definition of non-severe TB (1). These results should provide reassurance for clinicians regarding a seemingly delayed clinical response to TB treatment, which is often seen in children with peripheral lymph node TB (where lymph nodes remain enlarged even after treatment).
7.3 Use of adjuvant steroids in the treatment of tuberculous meningitis and pericarditis
Treatment with corticosteroids is recommended for tuberculous meningitis and pericarditis because the benefits outweigh the potential harms of corticosteroid therapy (1, 22, 38, 44, 47).
In patients with tuberculous meningitis, evidence from RCTs (48–52) showed lower rates of mortality, death or severe disability, and disease relapse when patients were treated with steroids in addition to anti-TB treatment. The mortality benefit increased with the increasing severity of disease. Additionally, rates of AEs and severe AEs, including severe hepatitis, were lower in patients receiving steroids; hence, steroids should be given regardless of the severity of meningitis.
In patients with tuberculous pericarditis, a systematic review (53–60) found a benefit to steroid treatment in relation to death, constrictive pericarditis and treatment adherence. When the studies were considered individually, the largest (1400 patients) and most recent study – the Investigation of the Management of Pericarditis (IMPI) study – showed no benefit of steroids (55). However, a factor complicating these findings is HIV infection. In the IMPI study, 67% of subjects were HIV-positive and only 14% were on ART. This raises the question as to whether immunosuppressed patients may have had a different benefit from steroids when compared with HIV-negative people or people living with HIV who are on ART. In the IMPI study, a supplemental analysis of only HIV-negative patients showed a small mortality benefit with steroid treatment. However, another smaller study of 58 subjects, all of whom were HIV-positive, found that steroids reduced mortality (56). Other studies in the review did not address HIV and mortality.
With regard to the use of steroids in tuberculous pericarditis, in one study, an increase in HIV-related cancers (non-Hodgkin’s lymphoma and Kaposi sarcoma) was observed (55). However, this increase appeared to be caused by co-administration of immunotherapy (M. indicus pranii). The increase in cancers was not confirmed in another study (39). Practitioners should evaluate when intravenous steroids are necessary, and when oral formulations may be equally effective.
7.4 Considerations for implementation
Provider-initiated HIV testing is recommended as part of the evaluation of all TB patients and patients in whom the TB disease is suspected. HIV testing is especially important in people with or suspected of having extrapulmonary TB, because of the increased frequency of extrapulmonary involvement in those with immunosuppression. Extrapulmonary TB is considered to be WHO clinical stage 4 HIV disease.
Based on the severity of signs and symptoms, and the likelihood of potential sequelae, the patient may need frequent treatment monitoring or post-treatment follow-up (or both).
Although surgery is sometimes required for diagnosis, it plays little role in the treatment of extrapulmonary TB, being reserved for management of late complications of disease such as hydrocephalus, obstructive uropathy, constrictive pericarditis and neurological involvement from Pott’s disease (spinal TB). For large, fluctuant lymph nodes that appear to be about to drain spontaneously, aspiration or incision and drainage may be beneficial. To prevent further complications and to manage similar situations in a timely manner, clinical monitoring may be needed in selected patients.
Apart from these specific situations, there are no additional recommendations beyond the standard of care. Additional details on treatment monitoring are given in Section 9 of this document.