LONDON – A large scale prospective study has shown that increased blood plasma viscosity is correlated with disease severity and the likelihood of progression to organ failure, in patients who are hospitalized with COVID-19 infections.

Researchers at Addenbrooke’s Hospital in Cambridge, U.K. suggest this could be an easy but sensitive way to quickly triage patients admitted to hospital with symptoms of COVID-19. “This is significant, because to date there have been no other reported lab tests that are able to quantify individual disease burden,” they say.

The study involved 395 patients admitted with respiratory illness between April and May 2020. Of these, 171 had a polymerase chain reaction (PCR) test confirming they had contracted SARS-CoV-2, while 224 had a negative PCR test for the virus.

There was a significant difference in plasma viscosity between the two groups, but little difference in other blood count measures.

In comparison with non-COVID-19 patients, those who were COVID-19 positive had reduced lymphocyte counts, but there were no significant differences between leukocytes, platelet counts, neutrophil counts, or large unstained cell counts, between the two cohorts.

“A plasma viscosity result above the identified cut‐off is shown to have good correlation with disease progression. The measurement of plasma viscosity is a cheap and reliable test already available in many hematology laboratories. It is frequently performed alongside a routine full blood count, without the need for taking an additional blood sample,” the researchers say in a paper published in the International Journal of Laboratory Hematology, April 4.

Plasma viscosity is a sensitive index of plasma protein changes that result from inflammation or tissue damage and is a highly accurate indicator of conditions including infection, rheumatoid arthritis and tuberculosis. It is also used as a marker for subsequent adverse events in angina, stroke and peripheral occlusive vascular disease, according to Benson Viscometers Ltd. of Haverfordwest, U.K., which manufactured the viscometer used in the Addenbrooke’s study.

Unlike some other indicators and inflammatory markers, plasma viscosity is not affected by hematocrit variations, such as anemia or polycythemia, or by gender or age. “Other benefits of the test are that plasma viscosity becomes abnormal early in the disease, has a low incidence of false normal values, can be performed on a sample up to seven days old, is stable, technically reproducible and standardized, and that relatively small changes are significant for any individual,” a Benson’s spokesman told BioWorld.

Total plasma exchange

The Addenbrooke’s data add weight to evidence suggesting total plasma exchange would be an effective treatment for seriously ill COVID-19 patients, building on initial research carried out by clinicians at Atlanta-based Emory University. They had noted that the thromboses suffered by seriously ill COVID-19 patients did not respond to anticoagulant medication and it was suspected hyperviscosity syndrome might be the cause.

“We realized we needed to think beyond our typical testing strategies to understand why this might be happening,” said Cheryl Maier, assistant professor of coagulation and transfusion at Emory, commenting when the paper describing the findings was published in The Lancet in June 2020.

The Emory clinicians measured plasma viscosity in 15 critically ill COVID-19 patients admitted to intensive care who did not respond to anticoagulation. They had plasma viscosity levels ranging from 1.9-4.2 centipoise, putting them all above the normal range of 1.4-1.8 centipoise (centipoise is the international standard unit of dynamic viscosity).

The sickest patients, with viscosity more than double normal levels, were more likely to suffer from blood clots, and elevated plasma viscosity and organ failure assessment scores were strongly correlated.

A key cause of other types of hyperviscosity syndrome, as seen for example in leukemia or myeloproliferative disorders, is elevated fibrinogen. The Emory patients were found to have substantially increased amounts of the coagulation factor, with levels ranging from 459-1,188 mg/dL, when the normal range is 200-400 mg/dL.

There have been other reports in seriously ill COVID-19 patients of elevated fibrinogen, which, as the Emory researchers note, simultaneously increases plasma viscosity and provides the substrate for clot formation. Maier said it is necessary to understand if elevated plasma viscosity is a marker of disease, or is contributing to clotting.

Therapeutic plasma exchange is an established treatment for hyperviscosity, and given this, Maier and colleagues are assessing its use in treating what they are now referring to as COVID-19-related hyperviscosity.

In six critically ill COVID-19 patients with plasma viscosity levels ranging from 2.6-4.2 centipoise, total plasma exchange decreased plasma viscosity to a median of 1.6 centipoise. The therapy also reduced fibrinogen levels in five of the patients, according to initial data published in the April 2021 issue of Transfusion. The two sickest patients died, but a significant improvement in clinical status was observed in the other four.

While others have tested total plasma exchange to treat patients who are seriously ill with COVID-19, the rationale has been to reduce levels of circulating cytokines and other inflammatory factors. The Emory researchers say theirs is the first report to describe plasma exchange in COVID‐19 with the primary goal of reducing plasma viscosity. They are now conducting a randomized trial, testing total plasma exchange against standard of care.

Multicenter studies

For the Addenbrooke’s researchers, measuring plasma viscosity potentially is a sensitive means of discriminating between respiratory illness caused by SARS-CoV-2 and that of other etiologies, and for risk stratification of patients with COVID-19 infection.

The Emory studies reported to date are smaller and only included patients who were critically ill, the Addenbrooke’s researchers note. “Our study provides a broader evaluation of plasma viscosity levels in a range of symptomatic hospital inpatients,” they say.

To validate the work, the researchers aim to collect data on all inpatients who have a full blood count and plasma viscosity performed, to see if they can create a simple triage tool. They would also like to see a multicenter assessment, to confirm their results and to agree a standard for how plasma viscosity readings are interpreted in COVID-19 risk assessments.

“The test is available at a number of hospital laboratories across the U.K. and it really could change the way we handle COVID-19 patients who are admitted to hospital with a suspected infection with the virus,” the researchers say.

Plasma velocity is a long-standing test and reference ranges are well publicized, the Benson spokesman noted. The company will do what it can to support the COVID-19 research, he said. “There is no doubt that further studies and research into the work started by Addenbrooke’s will help further validate their findings and potentially see a standard range developed and agreed for COVID patients.”