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A Prospective Evaluation of a Three-Gene Host Response Signature to Classify Tuberculosis Severity in Children
Brittney Sweetser1,2, Esin Nkereuwem3, Jascent Nakafeero4
1Division of Pulmonary Diseases & Critical Care Medicine, University of California, Irvine, Orange, United States.
Insights
The Xpert MTB-Host Response (HR) test shows promise for assessing tuberculosis severity in children, nearing target accuracy in older children and confirmed cases. Further refinement is needed for younger children with less severe disease.
Area of Science:
- Infectious Diseases
- Pediatric Medicine
- Biomarker Discovery
Background:
- Accurate stratification of pediatric tuberculosis (TB) severity is crucial for appropriate treatment, yet point-of-care tools are lacking.
- Short-course treatment regimens may benefit children with non-severe TB, necessitating reliable methods to distinguish disease severity.
Purpose of the Study:
- To prospectively evaluate the Cepheid Xpert MTB-Host Response (HR) prototype cartridge for its ability to stratify TB severity in children with pulmonary TB (PTB).
- To assess if the Xpert-HR test could achieve World Health Organization (WHO) target accuracy (≥90% sensitivity, ≥70% specificity) for treatment optimization.
Main Methods:
- A prospective study involving 106 children (<15 years) with confirmed or unconfirmed PTB in The Gambia and Uganda.
- Severity was defined using WHO guidelines for a four-month, drug-susceptible regimen.
- Blood samples were tested using the HR cartridge for PCR-based detection of 3 mRNA genes, generating a TB score to classify severe TB.
Main Results:
- The Xpert-HR test demonstrated an Area Under the Curve (AUC) of 0.67, with 89.3% sensitivity and 29.5% specificity in all children with PTB.
- Near-target accuracy was observed in children with Confirmed TB (91.7% sensitivity, 62.5% specificity) and in children aged 5-9 years (100% sensitivity, 66.7% specificity).
- Lower specificity was noted in children with Unconfirmed TB (24.3%) and those younger than 5 years (28.2%).
Conclusions:
- The Xpert-HR test shows potential for stratifying PTB severity in older children and those with Confirmed TB, approaching WHO target accuracy.
- Lower specificity in children with Unconfirmed TB and younger children suggests a need for further optimization.
- Child-specific host response signatures may be required to enhance the test's performance in younger children with paucibacillary disease.
Background:
Children with non-severe TB may benefit from short-course treatment, but point-of-care tools are needed to stratify disease severity. We prospectively evaluated the Cepheid Xpert MTB-Host Response (HR) prototype cartridge for distinguishing TB severity in children with pulmonary TB (PTB) in The Gambia and Uganda.
Methods:
We included children <15 with microbiologically confirmed or clinically diagnosed unconfirmed PTB. Severity was defined using the World Health Organization (WHO) guidelines for a four-month, drug-susceptible regimen. Capillary or venous blood was tested with the HR cartridge for PCR-based detection of 3 mRNA genes and calculation of a TB score from cycle thresholds. We generated receiver operating characteristic curves with the TB score to classify severe TB and assessed if Xpert-HR could achieve the WHO target accuracy for treatment optimization (≥90% sensitivity, ≥70% specificity).
Results:
Among 106 children, the median age was 4 years (IQR 1-7), 56.6% were female, and 13.2% were living with HIV. In all children with PTB, Xpert-HR achieved an AUC of 0.67 (95% CI 0.55-0.78), with 89.3% sensitivity (95% CI 71.8-97.7) and 29.5% specificity (95% CI 19.7-40.9, cutoff ≤ -0.60). By confirmation status, Xpert-HR approached the target accuracy in children with Confirmed TB, with 62.5% specificity (95% CI 24.5-91.5) at 91.7% sensitivity (95% CI 61.5-99.8, cut-off ≤ -1.349). Among children with Unconfirmed TB, specificity was lower (24.3%, 95% CI 14.8-36.0) at 93.8% sensitivity (95% CI 69.8-99.8, cutoff ≤ -0.450). Target accuracy was almost achieved in children 5-9 regardless of confirmation status (100% sensitivity [95% CI 71.5-100], 66.7% specificity [95% CI 43.0-85.4], cutoff ≤ -1.35), but specificity (28.2%, 95% CI 18.6-39.5) was lower for children < 5 (92.9% sensitivity, 95% CI 76.5-99.1, cutoff ≤ -0.550).
Conclusions:
Xpert-HR approached the target accuracy to stratify PTB severity in older children and those with Confirmed TB but had lower specificity in children with Unconfirmed TB. Child-specific signatures may be needed to improve performance in younger children with paucibacillary disease.
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