Companion Diagnostics in Managing COVID-19

Edward Blair is a thought leader and long-term proponent of precision medicine in cancer, infectious disease and neurodegeneration as a result of deep experience in development and commercialisation of both therapeutics and diagnostics.

He is currently a Trustee Director of the Quadram Institute for Biotechnology (Norwich, UK), and was Chair of Virokine Therapeutics, CEO at GeneFirst Ltd. (Abingdon, UK) and CEO of Integrated Magnetic Systems Ltd. (Dundee, UK). Eddie has held Executive and Non-Executive Directorships at Public Limited Companies, through IPO in some cases. He also remains Managing Director of Integrated Medicines Ltd (IML; Cambridge, UK), a company co-founded in 2003 to enable personalised medicine by combining diagnostic-type testing with new and existing medicines. He undertakes contract work through Blair Biomedical Consulting (Cambridge, UK) and was recently contracted to UCB Pharma (Brussels, Belgium) to direct and manage their neurodegenerative disease biomarker strategies.

Introductory comments

The Coronavirus Infectious Disease pandemic that is believed to have emerged from Wuhan, China late in 2019 (COVID-19), has changed our lives forever and there is an expectation that the pathogen behind COVID-19, known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), will become endemic [1]. Thus, SARS-CoV2 may become like influenza requiring annual vaccinations against prevailing strains. Unlike influenza, SARS-CoV-2 infection carries a risk of chronic illness that persists long beyond the severe acute respiratory syndrome that results in immediate morbidity; this so-called ‘Long COVID’ carries many similarities to the chronic illness that follows acute sepsis, e.g., dysfunction in immune, cognitive, cardiovascular and renal systems [2,3].

Two further aspects of COVID-19 are that:

1. Several of the vaccines against the original strains of SARS-CoV2 have proven extremely effective in limiting severe disease [4,5] and asymptomatic transmission [6], and they also appear effective against variants emerging during 2020 in the UK, South Africa and Brazil [7].
2. SARS-CoV2, being an RNA virus with an error-prone replicase that lacks proofreading capability, is likely to exist as a constellation of ‘quasi-species’. As a result, immune-selection of escape variants from the quasi-species pool is likely to drive the emergence of vaccine-resistant and/or potentially more pathogenic variants. For example, despite a coordinated strategy that has seen around 50% of the Chilean population vaccinated, incomplete herd immunity may be driving an emergence of the disease associated with new variants [5,8].

Against this background, this commentary will consider how diagnostics might be deployed as companions to the management of COVID-19 through various interventions.

Acute infections

Prediction of Disease Severity Risk: Although age is the major determining host factor of disease severity, other socioeconomic factors and disease comorbidities also appear to contribute to the risk of developing disease, leading to hospitalisation and mortality. It is also clear that strains with higher affinities for the primary SARS-CoV2 cellular receptor, the Angiotensin-Converting Enzyme 2(ACE2), are more infectious and thus more contagious and result in a higher disease burden; it would be reasonable to expect that polymorphic variations in the ACE2 gene might also give rise to higher affinity binding by the virus and thus greater susceptibility to infection. The determination of viral genotype may also guide on transmission rates as well as predicting disease severity based on the dominant variant present. In addition to genetic predisposition to severe immune responses, non-genetic tests of prevailing cytokine profiles or other indicators of underlying inflammation may also guide on immediate risk of severe infection.

Prediction of response to vaccination and treatment: While prevalence of SARS-CoV2 variants in a given population provides useful surveillance information, the personalisation of viral genotyping will be informative in determining which vaccines may provide a therapeutic benefit to an individual, and will also provide a guide as to the ongoing effectiveness of antiviral treatments such as remdesivir. The certainty of treatment-resistant variants emerging means that alternate treatments and rapid companion diagnostics will be crucial in combatting acute infections. Similarly, host genetics per https://covid.genomicc.org/, as well as immuno-profiling, will be essential in guiding augmentative treatment options, such as the use of the JAK/ TYK2 inhibitors, baricitinib, upadacitinib and filgotinib [9] (although in this specific case, caution is advised [10]). At the time of writing, the association of current vaccines with an extremely rare and unlikely-to-occur specific type of blood clot in the brain (known as cerebral venous sinus thrombosis, CVST) occurring together with thrombocytopenia, is unclear, the development of diagnostics to also guide on the safety of interventions may gain greater utility.

Monitoring response and recovery: Neutralising antibodies (NAb) against SARS-CoV2 are an excellent indicator of protection from further high-morbidity infections [7] and so determination NAb titres would be a key diagnostic measure to assess the degree of recovery and the enduring level of protection. This in turn would guide on which further vaccinations or treatments could have utility for a given individual. If booster vaccination campaigns and/ or annual vaccinations do become regular features of managing COVID-19, then there may be utility in also assessing levels of NAb against the adenoviral vector component of several approved vaccines; high NAb against non-human adenoviruses will surely limit the effectiveness of the cognate vaccine.

Long COVID

Objective characterisation of maladies: Given that Long Covid embraces the dysfunction of many organs, particularly lungs, liver, kidneys, heart and nervous systems [2], the provision of integrated and precise diagnoses through objective diagnostic measures could provide a guide on the level of inter-disciplinary support that would be required to manage individual cases. Thus serum-based measurement of key biomarkers (protein, nucleic acid or metabolic) associated with respiratory, liver, renal, neurological and cardiac dysfunction could lead to targeted interventions. In addition, a broad intervention to suppress immunological or inflammatory system dysfunction, such as rheumatoid arthritis or inflammatory bowel disease treatments, could prove efficacious.

Monitoring disease ‘flares’ and long-term outcomes: As with post-sepsis syndrome [3], it is possible that Long Covid will also be characterised by more or less frequent worsening of disease pathologies and so, again, serum-based biomarker measurements may have substantial utility. It is also known that other infectious agents can predispose individuals to the development of chronic illness – respiratory syncytial virus and asthma, coxsackievirus and cardiomyopathy, and herpes simplex virus and neuralgia to name three examples – and so there may be an as yet uncharacterised chronic disease beyond Long Covid.

Concluding comments

Without doubt, companion diagnostics to guide understanding, management and intervention in COVID-19 have an immense and growing role as we gain greater understanding of the disease and its short- and long-term impact on health. The greatest impact may be in facilitating the return of societies to the global ‘new’ normal through surveillance, disease monitoring and health status management.