Infections are a major cause of morbidity and mortality in pediatric cancer patients. And patients undergoing treatment for relapsed or refractory malignancies are known to be at high risk of life-threatening bloodstream infection (BSI).

To detect BSI, a blood culture is used to determine if pathogens are present. Although culture-based diagnostic techniques are important, this approach requires a significant load of live bacteria in the blood. In early bacteremia or focal infection preceding bacteremia, blood cultures are typically negative.

Delayed diagnosis and delayed optimal therapy of bloodstream infection is associated with increased morbidity and mortality. Novel diagnostic tools are needed to speed up the identification and characterization of these infections. Ideally, a predictive test would identify patients with impending bloodstream infection to enable pre-emptive antimicrobial therapy. However, today there is no validated test available.

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But a new, non-invasive blood test may change this.

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The results from the PREDSEQ study (NCT03226158) , a pilot phase study of high-risk pediatric leukemia patients vulnerable to serious, life-threatening infections, confirms that a novel, a non-invasive blood test, developed by Karius (Redwood City, CA), a life sciences company transforming infectious disease diagnostics by using genomics, is able to identify patients with bloodstream infections (BSI) before they have symptoms or a positive blood culture.[1][2]

Using next-generation sequencing (NGS), also known as high-throughput sequencing, the novel test detects microbial cell-free DNA in patient plasma from over 1,250 pathogens known to cause disease, including bacteria, DNA viruses, fungi, molds and eukaryotes.

Next generation sequencing of pathogens may be a tool to identify the presence of pathogen nucleic acids in sterile sites. In preliminary studies, next generation sequencing performed with blood culture appears to be sensitive and specific for diagnosis of BSI.

The reason why this approach can be successful is that pathogens leave traces of genomic DNA in the bloodstream. By sequencing these traces, scientists can identify these pathogens and help physicians treat acute infections.

In addition, NGS allow the sequencing of DNA and RNA much more quickly and cheaply than the previously used Sanger sequencing, and as such has revolutionized the study of genomics and molecular biology. And NGS of pathogens may be an effective tool to identify the presence of pathogen nucleic acids in sterile sites.

The researchers confirmed that in preliminary studies, next generation sequencing performed with blood culture appears to be sensitive and specific for diagnosis of BSI.

Karius test

The result of the test being developed by Karius enable pre-emptive treatment of bloodstream infections in high-risk pediatric cancer patients prior to onset of symptoms. This could reduce the serious consequences of bloodstream infections in these patients while also limiting their use of prophylactic antibiotics.

These outcome of the PREDSEQ study confirms the potential benefits of the Karius Test for predicting bloodstream infections prior to onset of symptoms in pediatric patients with a relapsed or refractory malignancy. This may also help to determining whether detection of pathogen DNA in blood could be used as a monitoring tool.

The PREDSEQ study was conducted in collaboration with researchers at St. Jude Children’s Research Hospital (Memphis, TN) and enrolled 31 pediatric patients receiving treatment for relapsed or refractory malignancy at high risk of serious infection in an IRB-approved prospective cohort study and sent blood samples to the Karius laboratory.

Prior to clinical symptoms

?The results of our study with St. Jude demonstrate the ability of the Karius Test to identify bloodstream infections prior to clinical symptoms,? noted David Hong, a pediatric infectious diseases doctor and Vice President of Medical Affairs and Clinical Development at Karius.

?Results from the PREDSEQ study further confirm the promise that the Karius Test could potentially be used as a monitoring tool in severely immunocompromised children to enable earlier detection of bloodstream infections.?

?We are excited to share the results of our research showing that plasma metagenomic sequencing appears to be sensitive for prediction of bloodstream infections from a broad range of pathogens, including bacteria that cause high mortality and morbidity among pediatric cancer patients,? noted Joshua Wolf, a pediatric infectious diseases doctor and associate faculty member at St. Jude.

?We have been looking for a ?crystal ball? to help identify patients who are about to get sick, and this is a step in the right direction,? Wolf further explained.

“Our leukemia treatment protocols are now curing a high percentage of children, making addressing the infectious complications of their treatment even more important as we aim to further increase survival rates,” said Charles Gawad, a leukemia specialist and assistant faculty member at St. Jude.

“This study shows that it may be possible to reduce these complications with the purposeful application of this exciting new technology,” Gawad added.

Study design

As part of the study, episodes of febrile neutropenia or documented infection were collected prospectively from medical records and BSI was defined according to National Healthcare Safety Network (NHSN) criteria. Control samples were defined as samples collected ?7 days before or after any fever or documented infection. After filtering human sequences, reads were aligned to a curated pathogen database, and organisms above a statistically significant threshold were reported by Karius.

A total of 11 BSI episodes occurred in 9 participants during the study period. Predictive sensitivity of NGS in the 2 days before onset of infection (n = 9) was 78% (95% CI 40 ? 99.7%), and diagnostic sensitivity on the day of infection (n = 11) was 82% (48 ? 98%). Specificity of NGS for development of fever or infection within 7 days (n = 10) was 80% (95% CI 44 ? 98%). NGS was positive up to 6 days prior to onset of BSI. In samples collected before or during documented infections, NGS also identified multiple additional uncultured bacteria and fungi.

Reference

[1] Goggin K, Inaba Y, Gonzalez-Pena V, Allison KJ, Lok Chan K, Hollemon D, Ahmed A, Hong D, et al. Prediction of Bloodstream Infection Prior to Onset of Symptoms by Plasma Metagenomic Sequencing in Pediatric Patients With Relapsed or Refractory Malignancy (PREDSEQ). Open Forum Infectious Diseases, Volume 5, Issue suppl_1, November 2018, Page S60, https://doi.org/10.1093/ofid/ofy209.141

[2] Next Generation Pathogen Sequencing for Prediction of Adverse Events – NCT03226158 [Clinical Trial]


Last Editorial Review: November 1, 2018

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