Sepsis and the genome

Recent studies on sepsis show that genomics could hold the key to faster diagnosis and treatment, as well as understanding why it occurs

A recent study has revealed that nanopore genome sequencing, a new technology that can analyse pathogen DNA present in the patient’s bloodstream, could test for sepsis and return results in a matter of hours, rather than days, dramatically improving the chance of survival for patients.

A second study has revealed that genomics can also be used to determine the cause of the condition. The findings suggest that our own DNA, and the proteins that package it, could trigger the overreaction of our immune system, leading to sepsis.

What is sepsis?

Sepsis is a life-threatening illness caused by the overreaction of an individual’s immune system after an infection, resulting in damage to organs and tissues. It is usually triggered by bacterial infections, such as pneumonia or urinary tract infections, but can also happen in response to viruses. According to The UK Sepsis Trust, it is responsible for more than 48,000 deaths annually in the UK.

Sepsis is treatable, and most patients recover, but early symptoms may resemble a common cold or flu, making it difficult to diagnose. Affected individuals can also decline rapidly, so the condition can be extremely dangerous if not detected.

In cases where treatment is not received, hyperinflammation can cause immune system suppression, organ failure and blood clots.

Harnessing genomics for faster diagnosis

Current practice in cases of sepsis is to give patients a broad-spectrum antibiotic when they arrive in hospital, and to send blood samples to discover the exact pathogen, so that targeted antibiotics can be prescribed. This process can take several days to provide results for treatment.

New research published in the Journal of Molecular Diagnostics details the use of nanopore genome sequencing to speed up this process. The approach used a combination of microbial cell-free DNA (cfDNA), a handheld sequencing device and a carefully designed bioinformatics pathway to return results within a few hours, enabling the most effective antibiotic to be administered to the patient much more quickly.

CfDNA are fragments of DNA floating in the bloodstream that have been released from dying cells. In patients with sepsis, this will include both the patient’s own DNA and the DNA of the bacteria causing the infection. Using cfDNA in a test is efficient because it cuts out the culturing step, allowing the pathogen’s DNA to be sequenced directly.

The researchers compared samples from four patients in intensive care who were affected by sepsis, and three who were not. The samples were analysed using the handheld nanopore sequencer, which was able to correctly identify bacterial, viral and fungal pathogens, and returned results within two to three hours.

A retrospective analysis also looked at 239 genomic samples using both nanopore sequencing and Illumina sequencing (the clinically validated technology used in the 100,000 Genomes Project) to compare the approaches. Despite being slightly less accurate than Illumina sequencing, the handheld sequencer could return results much faster, which could be crucial in making effective patient care decisions and preventing life-threatening consequences of late detection.

DNA’s role in the onset of sepsis

Another recent study looking at the causes of sepsis suggests that DNA, and the proteins used to package it, could be crucial in triggering the hyperimmune response that brings about its onset.

Inside our cells, DNA is stored in complexes tightly wrapped around histone proteins, and together these complexes are called chromatin. When cells die, their contents can be released into the bloodstream, and this is also true for chromatin.

The research, published in PLOS ONE, suggests that this cell-free chromatin (cfCh) can be integrated into the DNA of healthy cells causing disruption and cell death, leading to the release of more cfCh in a cascade effect.

To test this idea, the researchers targeted mice affected by sepsis and designed agents to inactivate cfCh. The results showed that these agents successfully reduced cfCh levels, as well as levels of inflammatory cytokines. The treatment had a significant impact on survival, with reduced inflammation of the spleen and thymus, and a reduction in liver and kidney damage, and blood clots.

The researchers are now planning a clinical trial to test their findings in humans.