One of the biggest challenges in addressing COVID-19 has been the variability in the degree and type of symptoms that infected individuals have presented. Though it’s still unclear how to treat COVID-19 most effectively, one thing is certain: not all patients will require the same form or level of treatment. Therefore, precision medicine will likely play an important role in managing the pandemic.
In a recently published paper, researchers at Michigan State University describe a precision medicine workflow that uses a combination of RNA-seq and targeted immune sequencing to identify biomarkers in patients that experience multiple organ dysfunction syndrome (MODS) in response to a variety of different infections or trauma1.
A role for immune sequencing in precision medicine
Precision/personalized medicine is an approach for disease treatment and prevention that relies heavily on accurate and timely genetic analysis. In contrast to one-size-fits-all approaches, precision medicine considers individual variability in the genes, environment, and lifestyle of each patient to help develop a highly personalized treatment plan for individual clinical needs. Precision medicine approaches can be particularly impactful in Intensive Care Units (ICUs) where patient outcome is dependent on rapid, comprehensive, and real-time diagnosis2.
Advanced next-generation sequencing (NGS) technologies such as whole-blood RNA sequencing (RNA-seq) have proven to be tremendously powerful in precision medicine workflows. However, traditional RNA-seq based precision medicine workflows focus largely on circulating RNA, while neglecting to account for the changing architecture of our cells —particularly immune cells—in response to disease or infection.
In order to better understand how the immune system is behaving in patients who present MODS, Prokop et al. developed a precision medicine workflow1 that incorporates immune repertoire sequencing using iRepertoire’s RepSeq+ platform. RepSeq+ enables simultaneous amplification of all seven B cell and T cell receptor chains. Unlike competing technologies, which typically focus on one or two chains at a time, RepSeq+ enables a comparison of the relative expression of the entire B and T cell repertoire.
One platform, multiple biological insights
Prokop et al. tested their workflow in 27 Pediatric Intensive Care Unit (PICU) patients presented with MODS1. They used PAXgene blood collection followed by multi-timepoint whole-blood (cellular/acellular) ribosomal-reduced RNA sequencing and RepSeq+ immune repertoire sequencing to simultaneously map viral/bacterial load, cell composition, and tissue damage biomarkers. To reflect the trajectory of critical illness in these patients, they collected the blood samples at days 0, 3, and 8—the acute, stabilization, and recovery phases of illness.
The cohort of PICU patients presenting MODS exhibited a broad etiology of disease that included various infections as well as environmental factors. The authors demonstrated that their workflow can be used to reveal the interplay between host genetics and viral/bacterial-induced mechanisms as well as diagnosing the cause of MODS. This investigation highlights the fact that since each MODS patient had an individual response, this group could qualify as a prime cohort for personalized/precision medicine strategy development. Further, the multi-parameter approach provided incredibly detailed and unexpected insights into the complex interplay between host genetics and viral/bacterial specific mechanisms.
Remarkably, they identified a unique case of virally induced genetics (VIG) in one of the 27 patients. In this patient, day 0 RNA-seq analysis was suggestive of viral induced hemophagocytic lymphohistiocytosis (HLH), which was confirmed by a bone marrow exam. HLH diagnosis usually takes several days. Additionally, using rapid whole-exome sequencing they identified a virus-induced splice variant associated with an autoinflammatory disorder called “Aicardi-Goutières syndrome,” which is a form of systemic lupus erythematosus (SLE). Using RepSeq+, they further confirmed that the use of this splice variant resulted in severe immune system dysfunction.
Applying the platform to COVID-19 research
MODS is of particular interest in light of the current pandemic. In the case of COVID-19 infections, only a small subset of patients will advance into multiple organ failure3. Having a complete profile for each patient like the one described above would not only confirm the diagnosis but would also help in identifying the co-infections and biomarkers of organ damage. This improved level of granularity could help in designing individual treatment regimens and ultimately reduce the risk of organ failure and mortality.
Adding immune repertoire sequencing to RNA-seq based precision medicine workflows provides the ability to study the unique response of a patient’s immune system in the context of their genetics and environmental factors. Such a multifactored approach can be an incredibly powerful tool for understanding and managing various diseases, including COVID-19. Ongoing work in COVID-19 conducted by iRepertoire and collaborators will continue to establish the relevance of immune sequencing technologies in a variety of clinical settings where precise and comprehensive analysis are prime factors in deciding the course of therapy.
1. Prokop, J. W. et al. Virus-induced genetics revealed by multidimensional precision medicine transcriptional workflow applicable to COVID-19. Physiological Genomics 52, 255–268 (2020). https://doi.org/10.1152/physiolgenomics.00045.2020
2. Chiu, C. Y. & Miller, S. A. Clinical metagenomics. Nature Reviews Genetics 20, 341–355 (2019). https://doi.org/10.1038/s41576-019-0113-7
3. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study – The Lancet. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30211-7/fulltext