Review update: Xpert MTB/RIF Ultra assay for tuberculosis disease and rifampicin resistance in children

Xpert MTB/RIF Ultra assay for tuberculosis disease and rifampicin resistance in children

Why is improving the diagnosis of tuberculosis important?

Every year, an estimated one million children and young adolescents become ill with tuberculosis, and around 226,000 die from the disease. Tuberculosis is caused by the bacterium Mycobacterium tuberculosis and mostly affects the lungs (pulmonary tuberculosis), though it can affect other sites in the body (extrapulmonary tuberculosis). Signs and symptoms of pulmonary tuberculosis include cough, fever, night sweats, and weight loss. Signs and symptoms of extrapulmonary tuberculosis depend on the site of disease. When detected early and treated effectively, tuberculosis is largely curable.

Not recognizing tuberculosis (false negative) early may result in delayed diagnosis and treatment, severe illness, and death. An incorrect tuberculosis diagnosis (false positive) may result in anxiety, unnecessary treatment (which can involve medication side effects), and the possibility of missing alternative diagnoses which warrant treatment.

What was the aim of this review?

To determine the accuracy of Xpert Ultra in children with symptoms of tuberculosis for diagnosing pulmonary tuberculosis, tuberculous meningitis (affecting membranes that surround the brain and spinal cord), lymph node tuberculosis (a painful swelling of one or more lymph nodes, which are bean‐shaped structures that help fight infection), and rifampicin resistance.

What did this review study?

Xpert Ultra, a World Health Organization‐recommended rapid test that simultaneously detects tuberculosis and rifampicin resistance in adults and children with tuberculosis symptoms. Rifampicin is an important medicine used to treat tuberculosis. For tuberculosis diagnosis, we assessed results against two different benchmarks: tuberculosis culture (a method used to grow bacteria on nutrient‐rich media) and a composite definition based on symptoms, chest X‐ray, sputum microscopy (examination under a microscope of mucus and other matter coughed up from the lungs), and culture. For rifampicin resistance detection, we assessed results against drug susceptibility testing or line probe assay (a rapid laboratory‐based test for detecting tuberculosis bacteria).

What were the main results in this review?

We included 14 studies. For pulmonary tuberculosis, we analysed 335 data sets (around 26,000 participants). No studies evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis. Three studies evaluated Xpert Ultra accuracy for detection of rifampicin resistance.

For a population of 1000 children:

• where 100 have pulmonary tuberculosis in sputum according to culture results:

‐ 101 would be Xpert Ultra‐positive, and of these, 26 (26%) would not have pulmonary tuberculosis (false positive); and
‐ 899 would be Xpert Ultra‐negative, and of these, 25 (3%) would have tuberculosis (false negative).

• where 100 have pulmonary tuberculosis in gastric aspirate (collection of lung and oral secretions from the stomach) according to culture results:

‐ 97 would be Xpert Ultra‐positive, and of these, 27 (28%) would not have pulmonary tuberculosis (false positive); and
‐ 903 would be Xpert Ultra‐negative, and of these, 30 (3%) would have tuberculosis (false negative).

• where 100 have pulmonary tuberculosis in stool according to culture results:

‐ 74 would be Xpert Ultra‐positive and of these, 18 (24%) would not have pulmonary tuberculosis (false positive); and
‐ 926 would be Xpert Ultra‐negative, and of these, 44 (5%) would have tuberculosis (false negative).

• where 100 have pulmonary tuberculosis in nasopharyngeal aspirate (secretions from the uppermost part of the throat, behind the nose) according to culture results:

‐ 66 would be Xpert Ultra‐positive, and of these, 22 (33%) would not have pulmonary tuberculosis (false positive); and
‐ 934 would be Xpert Ultra‐negative, and of these, 56 (6%) would have tuberculosis (false negative).

Xpert Ultra accurately detected rifampicin resistance, but there were few studies and only three children with rifampicin resistance included.

How confident are we in the results of this review?

For pulmonary tuberculosis, we are fairly confident because we included studies from different countries and used two different benchmarks, though neither is perfect. However, the evidence base is still limited and there were few studies with few children for one of the specimen types (nasopharyngeal aspirate).

For rifampicin resistance, we identified few studies with very few children with rifampicin resistance, so we are less confident.

What children do the results of this review apply to?

Children and young adolescents (birth to 14 years) who are HIV‐positive or HIV‐negative, with signs or symptoms of pulmonary tuberculosis. The results also apply to children with severe pneumonia or malnutrition and tuberculosis symptoms. In this review, we did not identify any studies that evaluated Xpert Ultra accuracy for tuberculous meningitis or lymph node tuberculosis.

What are the implications of this review?

The results suggest that Xpert Ultra in sputum, gastric aspirate, stool, and nasopharyngeal aspirate is an accurate method for detecting pulmonary tuberculosis and rifampicin resistance in children.

Using Xpert Ultra in sputum, gastric aspirate, stool, and nasopharyngeal aspirate, the risk of missing a diagnosis of pulmonary tuberculosis (confirmed by culture) is low, suggesting that only a small number of children will not receive treatment. The risk of incorrectly diagnosing a child as having pulmonary tuberculosis is slightly higher. This may result in some children receiving unnecessary treatment.

How up to date is this review?

This review updates our previous review and includes evidence published up to 9 March 2021.

Kay AW, Ness T, Verkuijl SE, Viney K, Brands A, Masini T, González Fernández L, Eisenhut M, Detjen AK, Mandalakas AM, Steingart KR, Takwoingi Y. Xpert MTB/RIF Ultra assay for tuberculosis disease and rifampicin resistance in children. Cochrane Database of Systematic Reviews 2022, Issue 9. Art. No.: CD013359. DOI: 10.1002/14651858.CD013359.pub3.

The editorial base of the Cochrane Infectious Diseases Group is funded by UK aid from the UK government for the benefit of low- and middle-income countries (project number 300342-104). The views expressed do not necessarily reflect the UK government’s official policies.