Paediatric TB: should Xpert molecular test replace smear microscopy?

Xpert MTB/RIF rapid molecular diagnostic test is certainly superior to smear microscopy

October 31, 2013 02:26 am | Updated November 17, 2021 02:56 am IST

HIGHER SENSITIVITY: In a primary health care setting, Xpert diagnosed five times more positive cases than smear microscopy in children under 15 years

HIGHER SENSITIVITY: In a primary health care setting, Xpert diagnosed five times more positive cases than smear microscopy in children under 15 years

Unlike adults, children under five years of age are particularly vulnerable to getting infected with TB and may develop the disease very soon after infection. This is all the more true in the case of those from households where an adult has been recently diagnosed with sputum smear positive active pulmonary TB.

India’s Revised National TB Control Programme (RNTCP) estimates that children account for about 12 per cent of the total TB caseload in the country. As WHO had pointed out, the estimated caseload in India, like in other countries, is a gross underestimation.

The main reason is that correct diagnosis of pulmonary TB infection and disease in children, especially in those under five years, is a big challenge. For instance, unlike adults, young children are unable to produce sputum — the most vital and basic sample to confirm infection/disease.

As a rule, only very few TB bacilli are present in the sputum sample of young children. This is particularly true in the case of children who are less ill. Other diagnostic methods — tuberculin skin test and chest X-ray — have their own limitations and challenges. And clinical symptoms can only serve as a useful indicator but cannot be used in isolation as children exhibit non-specific symptoms.

First diagnostic tool

Smear microscopy is the first diagnostic tool used to microbiologically confirm TB infection/disease. Unfortunately, smear microscopy performs poorly in children, especially in those under five years.

The sensitivity of microscopy — depending on the child’s age, disease severity and mycobacterial burden — is about 15-20 per cent. Hence, even many active TB cases show up as sputum smear negative (meaning that the child is free of disease).

Culture is the gold standard in diagnosing TB. “[But] culture is not infallible — it has sensitivity limitations and takes time [several weeks] to yield a clinically useful result,” a November 5, 2012 paper published online in The Lancet points out. “Where optimum culture facilities are available, confirmation is delayed and the combination of sputum smear and culture tests still misses many cases of childhood tuberculosis.”

“The sensitivity of culture varies between 20 per cent and 60 per cent, depending on what you look at,” Dr. Anne Detjen, Technical Consultant, The Union North America Office, childhood TB/child lung health, said in an email to this Correspondent.

For these reasons, researchers are looking for an alternative test that is more sensitive than smear microscopy and takes less time than culture to yield useful results. And the one that is currently available is Xpert MTB/RIF — a rapid molecular test. In 2010, WHO endorsed Xpert for rapid diagnosis of drug-sensitive and multi-drug resistant TB. Several studies have been done to test its usefulness in diagnosing TB in children and the results appear encouraging.

A WHO policy update released a few days ago on the use of Xpert in adults and children with pulmonary and extrapulmonary TB clearly states that the “overall pooled sensitivity of Xpert MTB/RIF against culture in children presumed to have TB was 66 per cent in 10 studies where expectorated sputum (ES) or induced sputum (IS) was used and 66 per cent in seven studies where gastric lavage aspirates (GLA) were used.

Pooled specificity of Xpert MTB/RIF against culture as the reference standard was over 98 per cent.”

In the case of culture-negative specimens, the pooled sensitivity against clinical TB as the reference was very low at four per cent for ES or IS and 15 per cent for GLA.

“It is likely that the apparent poor performance of Xpert was the result of a clinical TB reference standard that lacked specificity,” the policy update notes.

Xpert’s sensitivity

Xpert’s sensitivity in ES/IS among children with smear-negative results ranged from 25 per cent to 86 per cent. But in the case of smear-positive results, the pooled sensitivity of Xpert in either ES or IS was 96 per cent. “The pooled sensitivity estimate in smear-positive children was 96 per cent and 55 per cent in smear-negative children. The findings were similar for Xpert in GLA, with an overall sensitivity of 95 per cent among smear-positive and 62 per cent among smear-negative children,” the update states.

“Xpert MTB/RIF may be used rather than conventional microscopy and culture as the initial diagnostic test in all children presumed to have TB (conditional recommendation acknowledging resource implications, very low-quality evidence),” states the update.

Systematic review

“We have indeed performed a systematic review and meta-analysis of available data on Xpert MTB/RIF in children that contributed to the revised WHO policy guidance,” Dr. Detjen said.

“The Xpert MTB/RIF Policy Guidance Update was reviewed by the WHO Guidelines Review Committee (GRC),” Dr. Christopher Gilpin, Scientist, Global TB programme, WHO, Geneva, said in an email to this Correspondent.

“The systematic reviews included studies with children below five years and stratified pooled sensitivity and specificity estimates for Xpert MTB/RIF (in expectorated and induced sputum) were determined for children aged 0-4 and 5-15 years. Xpert MTB/RIF in gastric lavage aspirates estimated accuracy for 0-4 year age group only,” Dr. Gilpin stated.

“Xpert performs clearly superiorly to smear microscopy but is not good in children that are culture negative,” Dr. Detjen noted.

She also pointed out other positive outcomes that would come once Xpert is made widely available. “It will increase the number of confirmed TB cases and can detect drug resistance. Health-care workers may actually start taking sputum specimens from children since the new tool is certainly more promising than microscopy. Currently, specimens are often not even taken in places where the only test that can be done is smear microscopy,” she pointed out.

Fewer TB bacilli needed

The reason why Xpert performs much better than microscopy is because fewer TB bacilli are required to be present in the sputum sample. If Xpert’s lower limit of detection is 131 colony forming units (CFU)/ml, and culture’s is 10-100 CFU/ml, it is much higher in the case of smear microscopy.

But Xpert is very unlikely to become available in India for contact screening of children. There are currently 32 Xpert diagnostic machines and the government is in the process of procuring 300 more. But these are only for testing drug-resistant TB.

(The Correspondent is a recipient of the 2013 REACH Lilly MDR-TB Partnership National Media Fellowship for Reporting on TB.)

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