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.
Without the beneficial bacteria, infants can develop gut dysbiosis, which can lead to severe chronic diseases
Another key insight into how the human microbiome performs essential functions has been discovered by a research team at the University of California, Davis (UCD). They have learned that nearly all babies born in developed nations no longer have a specific strain of bacteria called B. infantis, which digests a certain type of sugar found in breast milk.
Microbiologists, clinical laboratory scientist, and pathologists will find the UCD researcher’s discovery to be a fascinating insight into a newly-understood function of the human microbiome. Assuming that further research confirms these early findings, it also could lead to a medical laboratory assay for use during pregnancy or after delivery that would enable physicians to determine if the newborn is missing this strain of bacteria and what therapies would be appropriate.
Babies in Developed Nations Lack Beneficial B. infantis Bacteria
“The central benefits of having a microbiota dominated by B. infantis is that it crowds all the other guys out—especially pathogenic bacteria, which can cause both acute illnesses and chronic inflammation that leads to disease,” UC Davis researcher Bruce German, PhD, Professor and Chemist, Food Science and Technology, told the New York Times.
The UC Davis researchers published their study findings in mSphere, a journal of the American Society for Microbiology. In their paper they note that Bifidobacterium Infantis or B. infantis, a beneficial bacteria that aids in digestion, is missing from the microbiomes of infants in developed nations, such as the United States.
The study hypothesized that the reduction and eventual absence of B. infantis in American babies was the consequence of three factors:
An increase in cesarean births;
Use of commercial formulas instead of breast milk; and,
Heightened use of antibiotics.
According to the New York Times, “Dr. German and his colleagues learned about the missing bacterium by studying breast milk. They found that the milk contains an abundance of oligosaccharides, carbohydrates that babies are incapable of digesting. Why would they be there if babies can’t digest them? They realized that these carbohydrates weren’t feeding the baby—they were feeding B. infantis.”
Good versus Bad Gut Bacteria
Because 70-80% of our immune system resides within our gastrointestinal tract, gut bacteria play an important role in our overall health. Breast milk contains essential probiotics and anti-inflammatory compounds that help “friendly” bacteria flourish in the infant gut.
There are more than two hundred different sugars or carbohydrates found in breast milk, known as human milk oligosaccharides (HMOs). They are one of the most copious components in breast milk but are completely indigestible by humans. So, why are they there?
Because they serve a critical role as food for microbes or prebiotics. Scientists have discovered that HMOs present in breast milk are there to feed the B. infantis, not to nourish the baby.
HMOs also act as a decoy to confuse undesirable bacteria from doing damage in the gut.
“Bad” bacteria are inclined to latch onto sugar molecules in intestinal cells. Because HMOs are very similar to those sugar molecules, the undesirable bacteria will instead latch onto the HMOs in a baby’s gut and leave vulnerable intestinal cells alone.
The primary benefits of B. infantis include:
Production of short-chain fatty acids. When infantis digests HMOs, some short-chain fatty acids are released, which provide energy and help control yeast and fungus growth.
Support for gut integrity. infantis signals gut cells in infants to generate proteins that fill gaps between intestinal cells. These gaps can be dangerous as they may allow toxins and bad bacteria to get into the bloodstream.
Keeping undesirable bacteria at bay. infantis consumes HMOs and usurps space in the gut so potentially dangerous bacteria cannot take up residence or cause problems.
Release of sialic acid. As it devours HMOs, infantis churns and releases sialic acid, a crucial nutrient for the brain development of infants.
Production of folate. infantis also produces folate, which is necessary for infant development and growth and the creation of red blood cells.
“The need for clinicians to have a quick and reliable method to determine Bifidobacterium levels in [a] baby’s gut, and an effective way to replace the right Bifidobacterium to correct dysbiosis when detected, are the critical next steps for infant health,” noted Jennifer Smilowitz, PhD (above), Associate Director of Human Studies Research Program for the Foods for Health Institute at UC Davis, and one of the study authors, in a news release. (Photo copyright: UC Davis.)
Alarming Changes to Infant Gut Microbiome
The UC Davis study is the latest example of new insights about the microbiome, which refers to the collected genetic material of human microbiota. This promising field of research is expected to lead to a better understanding of how human gut bacteria affects resistance to certain chronic diseases, such as cancer, and to new clinical laboratory treatments and drug therapies.
Different research initiatives involving the human microbiome continue to indicate that gut bacteria can be a source of useful biomarkers for improving the health of individuals. Dark Daily has covered the study of human microbiome and development of new cancer therapies based on that research for many years.
Microbiome research, however, sometimes uncovers negative findings as well.
Lack of B. infantis, a principle gut microbe, can contribute to gut dysbiosis, which has been linked to chronic health conditions such as:
Researchers observed that reduction in B. infantis in the infant gut also has resulted in a rise in the pH of infant fecal matter. An analysis of 14 clinical studies performed between 1926 and 2017 showed a startling increase of pH from 5.0 to 6.5 in infant stools.
“These alarming changes to the infant gut microbiome and thus, gut environment, may be due to modern medical practices like antibiotics, C-sections, and formula feeding,” Jennifer Smilowitz, PhD, Associate Director of Human Studies Research Program for the Foods for Health Institute at UC Davis, and one of the study authors, noted in a news release. “These are all potentially life-saving medical practices but have unintended consequences on the infant gut microbiome. As a result, certain pathogenic bacteria—those linked to higher risk of health issues, such as colic, eczema, allergies, diabetes, and obesity—thrive.”
The process by which the researchers in this study identified the missing bacteria illustrates how more refined ways to examine molecules in the body are providing streamlined tools to identify elements within the body and their interaction with each other.
This new insight is one more confirmation that the human microbiome will be the source of useful diagnostic biomarkers, associated with medical laboratory therapies that can improve the health of individual patients.
