The NIH’s Researching COVID to Enhance Recovery (RECOVER) Initiative used a cohort study of more than 10,000 individuals with and without previous COVID-19 diagnoses and compared samples using 25 common laboratory tests in hopes a useful biomarker could be identified. They were unsuccessful.
Long COVID—or PASC—is an umbrella term for those with persistent post-COVID infection symptoms that negatively impact quality of life. Though it affects millions worldwide and has been called a major public health burden, the NIH/Langone study scientists noted one glaring problem: PASC is defined differently in the major tests they studied. This makes consistent diagnoses difficult.
The study brought to light possible roadblocks that prevented biomarker identification.
“This study is an important step toward defining long COVID beyond any one individual symptom,” said study author Leora Horwitz, MD (above), director of the Center for Healthcare Innovation and Delivery Science and co-principal investigator for the RECOVER CSC at NYU Langone, in a Langone Health news release. “This definition—which may evolve over time—will serve as a critical foundation for scientific discovery and treatment design.” In the future, clinical laboratories may be tasked with finding combinations of routine and reference tests that, together, enable a more precise and earlier diagnosis of long COVID. (Photo copyright: Yale School of Medicine.)
NIH/Langone Study Details
“The study … examined 25 routinely used and standardized laboratory tests chosen based on availability across institutions, prior literature, and clinical experience. These tests were conducted prospectively in laboratories that are certified by the Clinical Laboratory Improvement Amendments (CLIA). The samples were collected from 10,094 RECOVER-Adult participants, representing a diverse cohort from all over the US,” Inside Precision Medicine reported.
However, the scientists found no clinical laboratory “value” among the 25 tests examined that “reliably indicate previous infection, PASC, or the particular cluster type of PASC,” Inside Precision Medicine noted, adding that “Although some minor differences in the results of specific laboratory tests attempted to differentiate between individuals with and without a history of infection, these findings were generally clinically meaningless.”
“In a cohort study of more than 10,000 participants with and without prior SARS-CoV-2 infection, we found no evidence that any of 25 routine clinical laboratory values provide a reliable biomarker of prior infection, PASC, or the specific type of PASC cluster. … Overall, no evidence was found that any of the 25 routine clinical laboratory values assessed in this study could serve as a clinically useful biomarker of PASC,” the study authors wrote in Annals of Internal Medicine.
In addition to a vague definition of PASC, the NIH/Langone researchers noted a few other potential problems identifying a biomarker from the research.
“Use of only selected biomarkers, choice of comparison groups, if any (people who have recovered from PASC or healthy control participants); duration of symptoms; types of symptoms or phenotypes; and patient population features, such as sex, age, race, vaccination status, comorbidities, and severity of initial infection,” could be a cause for ambiguous results, the scientists wrote.
Future Research
“Understanding the basic biological underpinnings of persistent symptoms after SARS-CoV-2 infection will likely require a rigorous focus on investigations beyond routine clinical laboratory studies (for example, transcriptomics, proteomics, metabolomics) to identify novel biomarkers,” the study authors wrote in Annals of Internal Medicine.
“Our challenge is to discover biomarkers that can help us quickly and accurately diagnose long COVID to ensure people struggling with this disease receive the most appropriate care as soon as possible,” said David Goff, MD, PhD, director of the division of cardiovascular sciences at the NIH’s National Heart, Lung, and Blood Institute, in an NHLBI news release. “Long COVID symptoms can prevent someone from returning to work or school, and may even make everyday tasks a burden, so the ability for rapid diagnosis is key.”
“Approximately one in 20 US adults reported persisting symptoms after COVID-19 in June 2024, with 1.4% reporting significant limitations,” the NIH/Langone scientists wrote in their published study.
Astute clinical laboratory scientists will recognize this as possible future diagnostic testing. There is no shortage of need.
Doctors report difficulty differentiating COVID-19 from other viral infections, impacting clinical laboratory test orders
Because the SARS-CoV-2 coronavirus is in the same family of viruses that cause the common cold and influenza, virologists expected this virus—which caused the global COVID-19 pandemic—would evolve and mutate into a milder form of infection. Early evidence from this influenza season seems consistent with these expectations in ways that will influence how clinical laboratories offer tests for different respiratory viruses.
While new variants of the SARS-CoV-2 virus continue to appear, indications are that early in this flu season individuals infected with the more recent variants are experiencing milder symptoms when compared to the last few years. Doctors report they find it increasingly difficult to distinguish COVID-19 infections from allergies or the common cold because patients’ symptoms are less severe, according to NBC News.
This, of course, makes it challenging for doctors to know the most appropriate clinical laboratory tests to order to help them make accurate diagnoses.
“It isn’t the same typical symptoms that we were seeing before. It’s a lot of congestion, sometimes sneezing, usually a mild sore throat,” Erick Eiting, MD, Vice Chair of Operations for Emergency Medicine at Mount Sinai Hospital in New York City, told NBC News. “Just about everyone who I’ve seen has had really mild symptoms. The only way that we knew that it was COVID was because we happened to be testing them.” Knowing which tests for respiratory viruses that clinical laboratories need to perform may soon be the challenge for doctors. (Photo copyright: Mt. Sinai.)
Milder COVID-19 Symptoms Follow a Pattern
Previous hallmarks of a COVID-19 infection included:
Loss of taste,
loss of smell,
dry cough,
fever,
sore throat,
diarrhea,
body aches,
headaches.
However, physicians now observe milder symptoms of the infection that follow a distinct pattern and which are mostly concentrated in the upper respiratory tract.
Grace McComsey, MD, Vice President of Research and Associate Chief Scientific Officer at University Hospitals Health System (UH) in Cleveland, Ohio, told NBC News that some patients have described their throat pain as “a burning sensation like they never had, even with Strep in the past.”
“Then, as soon as the congestion happens, it seems like the throat gets better,” she added.
In addition to the congestion, some patients are experiencing:
headache,
fever,
chills,
fatigue,
muscle aches,
post-nasal drip.
McComsey noted that fatigue and muscle aches usually only last a couple of days, but that the congestion can sometimes last a few weeks. She also estimated that only around 10-20% of her newest COVID patients are losing their sense of smell or taste, whereas early in the pandemic that number was closer to 60-70% of her patients.
Doctors also noted that fewer patients are requiring hospitalization and that many recover without the use of antivirals or other treatments.
“Especially since July, when this recent mini-surge started, younger people that have upper respiratory symptoms—cough, runny nose, sore throat, fever and chills—99% of the time they go home with supportive care,” said Michael Daignault, MD, an emergency physician at Providence Saint Joseph Medical Center in Burbank, California.
Milder SARS-CoV-2 Variants Should Still be Taken Seriously
Doctors have varying opinions regarding why the current COVID-19 variants are milder. Some believe the recent variants simply aren’t as good at infecting the lungs as previous variants.
“Overall, the severity of COVID-19 is much lower than it was a year ago and two years ago,” Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, told NBC News. “That’s not because the variants are less robust. It’s because the immune responses are higher.”
McComsey added that she doesn’t think mild cases should be ignored as she is still seeing new cases of long COVID with rapid heart rate and exercise intolerance being among the most common lingering symptoms. Re-infections also add to the risks associated with long COVID.
“What we’re seeing in long COVID clinics is not just the older strains that continue to be symptomatic and not getting better—we’re adding to that number with the new strain as well,” McComsey said. “That’s why I’m not taking this new wave any less seriously.”
Clinical Laboratory COVID-19 Testing May Decrease
According to Andrew Read, PhD, Interim Senior Vice President for Research and Evan Pugh University Professor of Biology and Entomology at Pennsylvania State University, there is nothing unexpected or startling about the coronavirus acquiring new mutations.
“When a mutation confers an interesting new trick that’s got an advantage, it’s going to be popping up in many different places,” Read told the New York Times. “Everything we see is just consistent with how you imagine virus evolution proceeding in a situation where a new virus has jumped into a novel host population.”
Data from the Centers for Disease Control and Prevention’s COVID-19 Data Tracker—which reports weekly hospitalizations, deaths, emergency department (ED) visits, and COVID-19 test positivity results—shows infection trends fluctuating, but overall, they are decreasing.
For the week of October 21, 2023, there were 16,186 hospitalizations due to COVID-19 compared to the highest week recorded (January 15, 2022) with 150,674 hospitalizations nationwide.
The highest number of deaths reported in a single week were 25,974 for the week of January 8, 2021, while 637 patients perished from COVID-19 during the week of October 21, 2023.
In January of 2021, COVID accounted for 13.8% of all ED visits and in October 2023, COVID-19 was responsible for 1.3% of ED visits.
“What I think we’re seeing is the virus continuing to evolve, and then leading to waves of infection, hopefully mostly mild in severity,” Barouch told The New York Times.
As severity of COVID-19 infections continues to fall, so, presumably, will demand for COVID-19 testing which has been a source of revenue for clinical laboratories for several years.
