The term “liquid biopsy” has come into common usage, and the concept is receiving significant attention in the diagnosis and treatment of cancer. Liquid biopsies have been evaluated in other clinical areas, including prenatal diagnostics, organ transplant, autoimmune disease, trauma, myocardial infarction and sepsis. Liquid biopsy has been defined as “the collection of samples of non-solid biological tissues – i.e., body fluids – to test and analyze for relevant markers in specific diseases.”
Invading microbes either die naturally or are killed by antibiotics and the body’s immune response. Upon death, microbial genetic material and nucleic acids are released into the bloodstream or other bodily fluids. Sequencing methods are then used to identify fragmented microbial cell-free DNA (mcfDNA), extracellular DNA that can come from any cell in the body.
As this field’s technology is advancing rapidly, close attention must be paid to ensure that any test results are accurate and reliable, for use in both clinical and insurance settings. Potential uses of liquid biopsy in non-cancer settings include screening, identification of diseases and treatment selection and prognosis. Using liquid biopsy as an initial screening tool could reduce exposing individuals to unnecessary further tests and possible higher morbidity risk.
Infectious diseases such as bloodstream infections, tuberculosis, fungal and parasitic infections, endocarditis, pneumonia, urinary tract infections and infections following organ transplants can potentially be identified using mcfDNA as a marker of infection. The ability to identify pathogens quickly using non-invasive screening methods may provide significant benefit to patient outcomes.
Researchers have developed several mcfDNA PCR-based tests that use blood and urine specimens to diagnose infections. The mcfDNA plasma test can detect more than 1,000 organisms in the bloodstream that are responsible for causing infection. It has shown sensitivity of 93% and specificity of 63%. The test is also able to detect probable cause of sepsis in nearly half of patients (49%), compared with 18% using blood culture and 38% using microbiology tests. It also provided better results in detecting pathogens from individuals who had received antimicrobial therapy within two weeks preceding presentation compared with blood culture (48% versus 20%).
There are, however, issues with using liquid biopsy for clinical diagnosis of infectious diseases. Concentrations of cfDNA vary considerably from person to person, and there can be a lack of quantitative results differentiating infection from potential contaminants. Differences between practice and protocols with liquid biopsy methodology, and cost of sequencing further complicate its implimentation.
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Elevated biomarker levels may be indicative of other pathological conditions, including infection, sepsis and autoimmune diseases. Sensitivity has been shown to be between 70% and 93% and specificity to be between 63% and 88% for mcfDNA liquid biopsy tests. cfDNA sequencing tests lack the ability to detect RNA virus pathogens such as human immunodeficiency virus (HIV), Zika, hepatitis C, respiratory syncytial virus (RSV), enteroviruses and norovirus.
Noninvasive prenatal testing (NIPT), which analyzes fetal cfDNA in the maternal bloodstream, is being more frequently used since 2011. It is used to screen for fetal chromosomal abnormalities and to detect other fetal and pregnancy-associated conditions such as preeclampsia, fetal growth restriction, congenital heart diseases and gestational diabetes. Fetal DNA shed into the mother’s bloodstream can also be sequenced to test for common chromosomal abnormalities such as trisomy 21 (Down syndrome), trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome) and monosomy X (Turner syndrome).
Extracellular Vesicles (EVs) are rudimentary cells, mostly isolated from blood plasma and serum. These are considered a promising liquid biopsy tool for noninvasive diagnosis of disease, as they contain microribonucleic acids (miRNAs), messenger RNAs (mRNAs), DNA, proteins and lipids. EVs derived from blood samples have shown the potential to diagnosis conditions such as Alzheimer’s disease, amyotrophic lateral sclerosis, Parkinson’s disease and Huntington’s disease. Saliva liquid biopsy testing may help diagnose conditions such as oral lichen planus, periodontitis and Sjogren’s syndrome, as elevated protein levels in saliva EV are involved in wound repair.
The rapid development of liquid biopsy technology, along with its potential for multiple clinical applications, including new cancer screening tests, has garnered significant attention in both medical and insurance literature. mcfDNA technology is already providing valuable diagnostic information, but further work will be needed to establish quantitative reference parameters to provide a clearer interpretation of results. Given their multiple potential uses, they will surely affect many aspects of insurance medicine and products. Thus, while currently presenting some challenges to the insurance industry, liquid biopsy technology also represents great opportunity. Insurers should seek ways to embrace and find opportunity with these promising developments in the emerging field of liquid biopsies.