Presently, to check the progression of COVID, physicians have to go by preliminary symptoms and other subjective clinical observations. But, a recent study has found that identifying and quantifying certain proteins in the patient's blood on admission will pave the way for a clearer decision whether the patient will suffer severe disease needing admission to ICU and other life supporting measures or not.

---

Last year, this day (March 11), the World Health Organization declared COVID-19 as a pandemic; the disease spread globally, and as of March 4, 2021, there were 115,820,427 cases and 2,572,887 deaths. For most patients, COVID-19 manifests like an upper respiratory tract, self-limited infection. However, the progression of COVID-19 in a large subset of patients to respiratory distress, multi-organ failure, and death has resulted in an enormous global impact.

A recent press release from Yale University highlighted an important factor. When patients with COVID-19 arrive in emergency rooms, there are relatively few ways for doctors to predict which ones are more likely to become critically ill and require intensive care and which ones are more likely to enjoy a quick recovery.

This is one of the most crucial pieces of information the physicians who closely observe the patients need for effective follow up. “As the death toll from COVID-19 exceeds 2.1 million worldwide (that was when the authors submitted the paper for publication; now the death toll exceeds 2.57 million!), it remains a pressing concern to understand how the disease causes such a wide spectrum of clinical outcomes," the authors noted in a press release from the university.

---

Biomarkers to predict severity

New research and development carried out by the researchers at Yale University identified a series of biomarkers, or biological signals, associated with white blood cell activation and obesity that can predict severe outcomes in COVID-19 patients.

The February 26 edition of Blood Advances, a journal published by the American Society of Hematology published their study. The science behind the programme appears to be well established.

According to Dr. Hyung Chun, the lead author and an associate professor of medicine in cardiovascular medicine and pathology and director of translational research at the Yale Pulmonary Vascular Disease Program, patients with high levels of these markers were much more likely to require care in the intensive care unit, require ventilation, or die due to their COVID-19.

“Previously, a few laboratory studies had identified possible indicators of severe COVID-19, including D-dimer levels, a measure of blood coagulation, and levels of proteins known as cytokines, which are released as part of inflammatory responses in the body. However, until now, no laboratory marker could predict which patients with COVID-19 would eventually become critically ill prior to showing clinical signs and symptoms of severe disease.” the press release clarified.

The response of Dr. Hyung Chun to a few questions from this writer appears at the end of this article.

---

Importance of blood profiling

In order to achieve a deeper understanding of the immunologic phenotypes of COVID-19 across the spectrum of disease severity, the researchers carried out proteomic profiling of blood obtained from patients hospitalised with COVID-19 and used a machine-learning algorithm to define the biomarkers that best discriminate between critically ill patients and those with milder disease.

They made a key discovery. They identified a unique neutrophil activation signature composed of neutrophil activators and neutrophil-derived effectors, which had the greatest power of all measured biomarkers to identify critically ill patients.

“These effector proteins were highly transcriptionally enriched in a developing neutrophil population that was recently identified specifically in critically ill COVID-19 patients and were strongly correlated with absolute neutrophil count (ANC) in our patient cohorts. This signature of neutrophil activation was predictive of in-hospital mortality and, most compellingly, was elevated at the time of hospital admission in patients who only later progressed to critical illness, thus preceding and predicting the onset of critical illness,” they concluded quoting appropriate references.

They identified neutrophil activation as a defining feature of severe COVID-19 that occurs before the onset of critical illness, implicating neutrophils as a central player in causing severe COVID-19 and highlighting opportunities to predict the disease clinically and to treat it by appropriate intervention.

---

The study

In the present study, Yale researchers used proteomic profiling -- a screen for multiple proteins within the blood -- to analyse samples taken from 100 patients who would go on to experience different levels of COVID-19 severity. In all cases, they collected the blood samples on the patients' first day of admission.

The researchers also used the Yale Department of Medicine COVID explorer database to evaluate laboratory results from 3325 COVID-19–positive patients admitted to the six hospitals within the Yale-New Haven Health System.

They included patients with a confirmed positive COVID-19 test within 14 days preceding hospitalisation in the cohort. This dataset combined all clinical variables extracted from the electronic medical record, including demographics, co-morbidities, procedures, and all laboratory values recorded during the hospitalization.

One of their key findings was that the COVID-19 patients who later became critically ill showed elevated levels of five proteins (resistin, lipocalin-2, HGF, IL-8, and G-CSF) that are associated with neutrophils, a type of white blood cell. Many of these proteins had previously been associated with obesity but not with COVID-19 or other viral illnesses.

Interestingly, the elevated neutrophil biomarkers for patients who would go on to experience more serious symptoms were evident before those symptoms appeared. All COVID-19 patients who were admitted or transferred to the ICU had elevated neutrophil activation markers, while these biomarkers remained low for patients who never developed a severe illness. None of the patients with lower neutrophil biomarker levels died.

"This is one of the first demonstrations that a set of biomarkers in the blood of COVID patients can predict eventual ICU admission, even before such patients become critically ill,” study author Dr. Alfred Lee, associate professor of medicine in haematology, Director of the Yale Medical Oncology-Hematology Fellowship Program, and a member of the Yale Cancer Center said in the press release from the university.

---

Value of early knowledge

Having early knowledge of these indicators could significantly improve patient treatment, the researchers said.

"If a diagnostic test [for these biomarkers] could be ordered early, it could give us a better sense of who is more likely to become critically ill and will benefit from a higher level of care and consideration for therapies that affect the immune system early on in their hospitalisation," said Chun. "Many of these drugs do carry potential side effects, and these tests may help identify those patients who would benefit the most."

---

COVID-19 & obesity

Another important highlight of the study was the connection between COVID-19 and obesity. The Centers for Disease Control and Prevention notes that obesity and severe obesity increase risk of severe illness from COVID-19. Obesity triples the risk of hospitalisation from COVID-19, and levels of body mass index have been found to correlate with the risk of death from COVID-19.

Neutrophils are inflammatory cells, said Lee, so it makes sense that they would be elevated in the context of both obesity -- which involves chronic, low-grade inflammation -- and COVID-19, which causes hyper-inflammation in the most severe cases, leading to tissue damage and organ failure.

"There are also signs that neutrophils might participate in thrombosis or blood clotting," said Lee, another troubling hallmark of COVID-19.

The researchers plan to study the relationship between biomarkers and COVID-19 by looking at patients who have recovered from acute illness.

---

Need for further research

"We are hoping these findings motivate other groups to look at their own patient populations," said Chun, adding that they'll need additional validation studies that would support developing diagnostic tests for these biomarkers.

"The evolution of our findings really shows the power of collaboration, which has emerged as one hopeful aspect of this devastating pandemic that we will continue to harness for the benefit of the patients," said Lee.

---

Earlier study

In an earlier study, scientists at Britain’s Francis Crick Institute and Germany’s Charite Universitaetsmedizin, Berlin found the proteins are present in different levels in COVID-19 patients, depending on the severity of their symptoms

In a study published in the journal Cell Systems (June 2020), researchers have found 27 key proteins in the blood of people infected with COVID-19 which they say could act as predictive biomarkers for how ill a patient could become with the disease.

They used mass spectrometry to rapidly identify and quantify the presence of various proteins in blood plasma from 31 COVID-19 patients at Berlin’s Charite hospital. They then validated their results in 17 other patients with COVID-19 at the same hospital, and in 15 healthy people who acted as controls.

The study by Yale scientists appeared to be more focussed; admittedly both of them are works in progress

---

Q&A with the study's lead author

This writer sent a few questions on some of the general details of the study to Dr. Hyung Chun. The questions and his responses are as follows:

Question 1: The description of the tests indicates that now it is a research and development endeavour using several instruments and related technologies. They may not be readily available in a typical pathology laboratory. Any comment?

Answer: This is correct. There is currently no diagnostic test that can be used for detecting the factors we identified to be important determinants of clinical outcomes in COVID-19 infection. Our hope is that such a diagnostic test can be developed to be used in the setting of early hospital course.

Question 2: Using the test, how quickly can a clinician get actionable inputs which guide the course of treatment for the patient?

Answer: Presently, treatment for patients hospitalised with COVID-19 depends primarily on their oxygen requirement. Once diagnostic tests can be developed, it can help identify those patients who may be at higher risk of developing severe disease before its onset, and also help identify those patients who would benefit from the treatments that are both approved and being developed.

Question 3: How soon is the test likely to become a part of the standard of care for treatment? What further measures are needed for the purpose?

Answer: A validated clinical diagnostic test needs to be developed. We are currently discussing with several companies who may be interested in developing such a test.

---

Let us hope that the efforts to arrive at a routinely usable test with the needed instruments will be successful and the virus will be vanquished. Once it is ready, COVID-19 patients will benefit directly. Their physicians may get, in advance, objective information to identify and treat the COVID-19 patients who may suffer from more severe disease. The entire approach is new and there are no low hanging fruits. These are maiden steps. So the research must continue.

Dr. K S Parthasarathy is a former Secretary of the Atomic Energy Regulatory Board and a former Raja Ramanna Fellow, Department of Atomic Energy. A Ph.D from University of Leeds, UK, he is a medical physicist with specialization in radiation safety and regulatory matters. He was a Research Associate in the University of Virginia Medical Centre, Charlottesville, USA. He served the International Atomic Energy Agency as an expert and member in its Technical and Advisory Committees