CAN SEPSIS PATIENTS BENEFIT FROM NGS IN CLINICAL SETTINGS?

Sepsis is the final common pathway to death for severe infectious diseases,” WHO (2020).

Sepsis is responsible for almost 20% of all deaths worldwide. This was higher than deaths caused by cancer in 2020. Even if patients survive to live another day, they have risks of developing long-term consequences of neurological, psychiatric, and functional disabilities. Sepsis costs a total of $13,4 billion in 2018, more than twice its cost in 2012 as reported by US Medicare. Sepsis is undoubtedly still a complex challenge up till now.

It is obvious we are nowhere near successful in controlling sepsis. Something has to change. It has to change quickly.

Next-generation sequencing (NGS) has confirmed its place in research fields, but its use in clinical settings is currently under massive investigation. Could NGS be the change that we are desperate to find? Could septic patients have a brighter future with the application of NGS in routine clinical settings?

Clinical manifestation of sepsis can mimic a wide range of other diseases. Detecting a clinically relevant pathogen will help settle the diagnosis. Confidently saying that there is no pathogen is also critical. For example, as many as 25% of patients with acute decompensated heart failure were misdiagnosed with sepsis. Imagine how a more sensitive diagnostic tool could prevent these patients from apparent harm by excluding them from aggressive sepsis management such as fluid administration or antimicrobial therapy.

The ability of culture media to grow microorganisms puts limitations on the blood culture method. There are currently over 1.400 known human pathogens ranging from viruses, bacteria, fungi, protozoa, and helminths. Standard culture-based methods can only detect a small fraction of these pathogens. It had a low positivity rate of around 20% to 50%, and up to 80% of blood cultures in sepsis patients stay undetected.

Detecting clinically relevant pathogen in complex cases with a lot of comorbidities and confusing symptoms is beyond difficult. Here is one example of a devastating case reported in China. A young man with previously proven HIV and Hepatitis B coinfection came with neurological symptoms. Doctors took cerebrospinal fluid (CSF) samples on the third day of care and did extensive laboratory tests for infections. They all came back as negative, but the patient’s condition worsened. They then submitted the CSF sample for metagenomics NGS (mNGS) on the same day. The result was positive for Varicella Zoster Virus. Finally, there was one question answered! Sadly, the young man died the day after. Imagine if the mNGS procedure was done on the first day of his admission.

Here’s another example of how NGS has the potential to help actual patients in clinical settings. A two-year-old boy with leukemia was admitted to a hospital for chemotherapy. During his stay, he developed a fever up to 40-50C. His CRP and PCT results showed marked bacterial systemic infection, but blood culture came back negative. Doctors decided to give him meropenem, vancomycin, caspofungin, and acyclovir. The symptoms persisted, so doctors changed the regimen. They gave him tobramycin, linezolid, and voriconazole for another week. These new regiments failed to make the boy’s condition better. Doctors then started to consider mycobacterial infection and performed related tests. All came back negative. Finally, doctors and parents both agreed on doing NGS test from his blood sample. The final result came back within 43 hours with high reads of Propionibacterium acnes. Doctors adjusted his regimen to P.acnes-specific therapy, and his condition recovered soon after. In this case, if done sooner, NGS would’ve prevented the administration of unnecessary antimicrobial drugs.

From those two cases, we can see how NGS technology implemented in clinical settings helped both the patients and clinicians. Micronbrane offers NGS technology to be utilized in clinical settings with their sequencing system PaRTI-Seq®. They also escalate the game with Devin®, which depletes host nucleated cells. Devin® reduces human DNA interference in less than ten minutes. Together, Devin® and PaRTI-SeqÒ can provide a result in less than 24 hours. That is a lot of time and money saved.

Besides identifying the culprit of an infection, NGS also promises further potential in the world of antimicrobial stewardship. Researchers found that NGS produces data that could predict phenotypic antimicrobial susceptibilities and resistance with good performance. A study shows that NGS had 96% sensitivity and 97% specificity in Escherichia coli and Klebsiella pneumonia isolates taken from patients’ blood samples.15

NGS’s ability to provide us with resistance genes information could be of great help for septic patients. Next-Generation Sequencing incorporated by Micronbrane into their PaRTI-Seq®, was reported to reduce the time needed by 20 hours compared to the conventional susceptibility testing method. NGS can help clinicians save lives by giving faster and more precise antimicrobial agents for septic patients.

Micronbrane brings NGS technology closer to sepsis patients, especially in East, South, and Southeast Asia, where the numbers are the highest.1 The incorporation of Devin® and PaRTI-Seq® by Micronbrane in clinical sepsis workflow will contribute more evidence that NGS can benefit septic patients in real-life clinical settings.