Study of the 50 Omicron variants could lead to new approaches to clinical laboratory testing and medical treatments for long COVID
Patients infected with SARS-CoV-2 can usually expect the COVID-19 illness to subside within a couple of weeks. However, one Dutch patient remained infected with the coronavirus for 612 days and fought more than 50 mutations (aka, variants) before dying late last year of complications due to pre-existing conditions. This extreme case has given doctors, virologists, microbiologists, and clinical laboratories new insights into how the SARS-CoV-2 virus mutates and may lead to new treatments for long COVID.
The medication the patient was taking for his pre-existing conditions may have contributed to his body being unable to produce antibodies in response to three shots of the Moderna mRNA COVID vaccine he received.
Magda Vergouwe, MD, PhD candidate at the Center for Experimental and Molecular Medicine (CEMM), Amsterdam UMC, who lead a study into the patient, theorized that some of the medications the patient was on for his pre-existing conditions could have destroyed healthy cells alongside the abnormal cancer-causing B cells the drugs were meant to target.
“This case underscores the risk of persistent SARS-CoV-2 infections in immunocompromised individuals,” the researchers said prior to presenting their report about the case at a meeting of the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) in Barcelona, Spain, Time reported. “We emphasize the importance of continuing genomic surveillance of SARS-CoV-2 evolution in immunocompromised individuals with persistent infections.”
“Chronic infections and viral evolution [are] commonly described in [the] literature, and there are other cases of immunocompromised patients who have had [COVID] infections for hundreds of days,” Magda Vergouwe, MD, PhD candidate (above), Center for Experimental and Molecular Medicine at Amsterdam UMC, told Scientific American. “But this is unique due to the extreme length of the infection … and with the virus staying in his body for so long, it was possible for mutations to just develop and develop and develop.” Microbiologists, virologists, and clinical laboratories involved in testing patients with long COVID may want to follow this story. (Photo copyright: LinkedIn.)
Risks to Immunocompromised Patients
Pre-existing conditions increase the risk factor for COVID-19 infections. A 2021 study published in the Journal of the American Board of Family Medicine (JABFM) titled, “Prevalence of Pre-existing Conditions among Community Health Center Patients with COVID-19,” found that about 61% of that study’s test group had a pre-existing condition prior to the outbreak of the COVID-19 pandemic.
When the Dutch man was admitted to Amsterdam UMC with common and serious COVID-19 symptoms, such as shortness of breath, a cough, and low blood oxygen levels, he was prescribed sotrovimab (a monoclonal antibody) along with other COVID treatments.
About a month after being admitted his COVID-19 symptoms decreased, so he was first discharged to a rehab facility and then finally to his home. However, he continued to test positive for the coronavirus and developed other infections that may have been complicated by the persistent case of COVID-19.
The Amsterdam UMC doctors emphasized that the man ultimately succumbed to his pre-existing conditions and not necessarily COVID-19.
“It’s important to note that in the end he did not die from his COVID-19,” Vergouwe told Scientific American. “But he did keep it with him for a very long period of time until then, and this is why we made sure to sample [the virus in his body] as much as we could.”
One in Five Adults Develop Long COVID
Long COVID does not necessarily indicate an active infection. However, in as many as one in five US adults COVID symptoms persist after the acute phase of the infection is over, according to a study published recently in JAMA Network Open titled, “Epidemiologic Features of Recovery from SARS-CoV-2 Infection.”
“In this cohort study, more than one in five adults did not recover within three months of SARS-CoV-2 infection. Recovery within three months was less likely in women and those with pre-existing cardiovascular disease and more likely in those with COVID-19 vaccination or infection during the Omicron variant wave,” the JAMA authors wrote.
The origins of long COVID are not entirely clear, but according to the National Institutes of Health (NIH) it can develop when a patient is unable to sufficiently rest while battling off the initial virus. According to Vergouwe, the SARS-CoV-2 genome will always grow quicker when found in a patient with a compromised immune system.
Unique COVID-19 Mutations
More than 50 new mutations of the original Omicron variant were identified in the Dutch patient. According to Vergouwe, “while that number can sound shocking, mutations to the SARS-CoV-2 genome are expected to evolve more quickly in those who are immunocompromised (the average mutation rate of the virus is estimated to be two mutations per person per month),” Scientific American reported. “What does make these mutations unusual, she noted, is how their features differed vastly from mutations observed in other people with COVID. [Vergouwe] hypothesizes that the exceptional length of the individual’s infection, and his pre-existing conditions, allowed the virus to evolve extensively and uniquely.”
COVID-19 appears to be here to stay, and most clinical laboratory managers and pathologists understand why. As physicians continue to learn about the SARS-CoV-2 coronavirus, this is another example of how the knowledge about SARS-CoV-2 is growing as different individuals are infected with different variants of the virus.
HHS Office of Inspector General was the latest to examine the quality control problems that led to distribution of inaccurate test to clinical laboratories nationwide
Failure on the part of the Centers for Disease Control and Prevention (CDC) to produce accurate, dependable SARS-CoV-2 clinical laboratory test kits at the start of the COVID-19 pandemic continues to draw scrutiny and criticism of the actions taken by the federal agency.
In the early weeks of the COVID-19 pandemic, the CDC distributed faulty SARS-CoV-2 test kits to public health laboratories (PHLs), delaying the response to the outbreak at a critical juncture. That failure was widely publicized at the time. But within the past year, two reports have provided a more detailed look at the shortcomings that led to the snafu.
“We identified weaknesses in CDC’s COVID-19 test kit development processes and the agencywide laboratory quality processes that may have contributed to the failure of the initial COVID-19 test kits,” the OIG stated in its report.
Prior to the outbreak, the agency had internal documents that were supposed to provide guidance for how to respond to public health emergencies. However, “these documents do not address the development of a test kit,” the OIG stated.
“If the CDC can’t change, [its] importance in health in the nation will decline,” said microbiologist Jill Taylor, PhD (above), Senior Adviser for the Association of Public Health Laboratories in Washington, DC. “The coordination of public health emergency responses in the nation will be worse off.” Clinical laboratories that were blocked from developing their own SARS-CoV-2 test during the pandemic would certainly agree. (Photo copyright: Columbia University.)
Problems at the CDC’s RVD Lab
Much of the OIG’s report focused on the CDC’s Respiratory Virus Diagnostic (RVD) lab which was part of the CDC’s National Center for Immunization and Respiratory Diseases (NCIRD). The RVD lab had primary responsibility for developing, producing, and distributing the test kits. Because it was focused on research, it “was not set up to develop and manufacture test kits and therefore had no policies and procedures for developing and manufacturing test kits,” the report stated.
The RVD lab also lacked the staff and funding to handle test kit development in a public health emergency, the report stated. As a result, “the lead scientist not only managed but also participated in all test kit development processes,” the report stated. “In addition, when the initial test kit failed at some PHLs, the lead scientist was also responsible for troubleshooting and correcting the problem.”
To verify the test kit, the RVD lab needed samples of viral material from the agency’s Biotechnology Core Facility Branch (BCFB) CORE Lab, which also manufactured reagents for the kit.
“RVD Lab, which was under pressure to quickly create a test kit for the emerging health threat, insisted that CORE Lab deviate from its usual practices of segregating these two activities and fulfill orders for both reagents and viral material,” the report stated.
This increased the risk of contamination, the report said. An analysis by CDC scientists “did not determine whether a process error or contamination was at fault for the test kit failure; however, based on our interviews with CDC personnel, contamination could not be ruled out,” the report stated.
The report also cited the CDC’s lack of standardized systems for quality control and management of laboratory documents. Labs involved in test kit development used two different incompatible systems for tracking and managing documents, “resulting in staff being unable to distinguish between draft, obsolete, and current versions of laboratory procedures and forms.”
Outside Experts Weigh In
The OIG report followed an earlier review by the CDC’s Laboratory Workgroup (LW), which consists of 12 outside experts, including academics, clinical laboratory directors, state public health laboratory directors, and a science advisor from the Association of Public Health Laboratories. Members were appointed by the CDC Advisory Committee to the Director.
This group cited four major issues:
Lack of adequate planning: For the “rapid development, validation, manufacture, and distribution of a test for a novel pathogen.”
Ineffective governance: Three labs—the RVD Lab, CORE Lab, and Reagent and Diagnostic Services Branch—were involved in test kit development and manufacturing. “At no point, however, were these three laboratories brought together under unified leadership to develop the SARS-CoV-2 test,” the report stated.
Poor quality control and oversight: “Essentially, at the start of the pandemic, infectious disease clinical laboratories at CDC were not held to the same quality and regulatory standards that equivalent high-complexity public health, clinical and commercial reference laboratories in the United States are held,” the report stated.
Poor test design processes: The report noted that the test kit had three probes designed to bind to different parts of the SARS-CoV-2 nucleocapsid gene. The first two—N1 (topology) and N2 (intracellular localization)—were designed to match SARS-CoV-2 specifically, whereas the third—N3 (functions of the protein)—was designed to match all Sarbecoviruses, the family that includes SARS-CoV-2 as well as the coronavirus responsible for the 2002-2004 SARS outbreak.
The N1 probe was found to be contaminated, the group’s report stated, while the N3 probe was poorly designed. The report questioned the decision to include the N3 probe, which was not included in European tests.
Also lacking were “clearly defined pass/fail threshold criteria for test validation,” the report stated.
Advice to the CDC
Both reports made recommendations for changes at the CDC, but the LW’s were more far-reaching. For example, it advised the agency to establish a senior leader position “with major responsibility and authority for laboratories at the agency.” This individual would oversee a new Center that would “focus on clinical laboratory quality, laboratory safety, workforce training, readiness and response, and manufacturing.”
In addition, the CDC should consolidate its clinical diagnostic laboratories, the report advised, and “laboratories that follow a clinical quality management system should have separate technical staff and space from those that do not follow such a system, such as certain research laboratories.”
The report also called for collaboration with “high functioning public health laboratories, hospital and academic laboratories, and commercial reference laboratories.” For example, collaborating on test design and development “should eliminate the risk of a single point of failure for test design and validation,” the LW suggested.
CBS News reported in August that the CDC had already begun implementing some of the group’s suggestions, including agencywide quality standards and better coordination with state labs.
However, “recommendations for the agency to physically separate its clinical laboratories from its research laboratories, or to train researchers to uphold new quality standards, will be heavy lifts because they require continuous funding,” CBS News reported, citing an interview with Jim Pirkle, MD, PhD, Director, Division of Laboratory Sciences, National Center for Environmental Health, at the CDC.
Understanding why some people display no symptoms during a COVID-19 infection could lead to new precision medicine genetic tests medical labs could use to identify people with the mutated gene
New research from the University of California San Francisco (UCSF) may explain why some people could get COVID-19 but never test positive on a clinical laboratory test or develop symptoms despite exposure to the SARS-CoV-2 coronavirus.
According to the UCSF study, variations in a specific gene in a system of genes responsible for regulating the human immune system appears to be the factor in why about 10% of those who become infected with the virus are asymptomatic.
These scientific insights did not receive widespread news coverage but will be of interest to clinical laboratory managers and pathologists who oversee SARS-CoV-2 testing in their labs.
“Some people just don’t have symptoms at all,” Jill Hollenbach, PhD (above), Professor of Neurology atUCSF’s Weill Institute for Neurosciences and lead researcher in the study, told NBC News. “There’s something happening at a really fundamental level in the immune response that is helping those people to just completely wipe out this infection.” Identifying a genetic reason why some people are asymptomatic could lead to new precision medicine clinical laboratory diagnostics for COVID-19. (Photo copyright: Elena Zhukova /University of California San Francisco.)
Fortunate Gene Mutation
According to the Centers for Disease Control and Prevention’s (CDC) COVID Data Tracker, as of April 5, 2023, a total of 104,242,889 COVID-19 cases have been reported in the United States. However, according to a CDC Morbidity and Mortality Weekly Report (MMWR), “Traditional methods of disease surveillance do not capture all COVID-19 cases because some are asymptomatic, not diagnosed, or not reported; therefore, [knowing the true] proportion of the population with SARS-CoV-2 antibodies (i.e., seroprevalence) can improve understanding of population-level incidence of COVID-19.”
She also participates in the COVID-19 HLA and Immunogenetics Consortium, a group of academic researchers, clinical laboratory directors, journal editors, and others who examine the role of HLA variations in determining COVID-19 risk.
Hollenbach’s research identified an HLA variant—known as HLA-B*15:01—that causes the human immune system to react quickly to SARS-CoV-2 and “basically nuke the infection before you even start to have symptoms,” she told NPR.
“It’s definitely luck,” she added. “But, you know, this [gene] mutation is quite common. We estimate that maybe one in 10 people have it. And in people who are asymptomatic, that rises to one in five.”
“HLA variants are among the strongest reported associations with viral infections,” the UCSF study notes. So, the researchers theorized that HLA variations play a role in asymptomatic SARS-CoV-2 infections as well.
To conduct their study, shortly after the SARS-CoV-2 outbreak in 2020, the researchers recruited approximately 30,000 volunteer bone marrow donors from the National Marrow Donor Program to respond to periodic questions via a smartphone app or website. Because HLA variations can determine appropriate matches between donors and recipients, the database includes information about their HLA types.
Each week, respondents were asked to report if they had been tested for SARS-CoV-2. Each day, they were asked to report whether they had symptoms associated with COVID-19. “We were pretty stringent in our definition of asymptomatic,” Hollenbach told NBC News. “[The respondents couldn’t] even have a scratchy throat.”
The researchers eventually identified a cohort of 1,428 people who had tested positive for SARS-CoV-2 between February 2020 and April 30, 2021, before vaccines were widely available. Among these individuals, 136 reported no symptoms for two weeks before or two weeks after a positive test.
“Overall, one in five individuals (20%) who remained asymptomatic after infection carried HLA-B*15:01, compared to 9% among patients reporting symptoms,” the researchers wrote in their medRxiv preprint. Study participants with two copies of the gene were more than eight times more likely to be asymptomatic.
The UCSF researchers also looked at four other HLA variants and found none to be “significantly associated” with lack of symptoms. They confirmed their findings by reproducing the HLA-B association in two additional independent cohorts, one from an earlier study in the UK and the other consisting of San Francisco-area residents.
Individuals in the latter group had either tested positive for SARS-CoV-2 or reported COVID symptoms, and their DNA was analyzed to determine their HLA types.
Pre-existing T-Cell Immunity May Reduce Severity of COVID-19 Infection
The UCSF researchers also attempted to determine how HLA-B*15:01 plays a role in knocking out SARS-CoV-2 infections. They noted previous research that indicated previous exposure to seasonal coronaviruses, such as common cold viruses, could limit the severity of COVID-19. The scientists hypothesized that pre-existing T-cell immunity in HLA-B carriers may be the key.
The COVID-19 HLA and Immunogenetics Consortium website describes how HLA and T-cells work together to ward off disease. HLA “proteins are found on the surface of all cells except red-blood cells.” They’re “like windows into the inner workings of a cell,” and T-cells use the molecules to determine the presence of foreign proteins that are likely signs of infection. “Activated T-cells can kill infected cells, or activate B-cells, which produce antibodies in response to an infection,” the website explains.
Hollenbach’s research team analyzed T-cells from pre-pandemic individuals and observed that in more than half of HLA-B carriers, the T-cells were reactive to a SARS-CoV-2 peptide. The scientists corroborated the hypothesis by examining crystal structures of the HLA-B*15:01 molecule in the presence of coronavirus spike peptides from SARS-CoV-2 and two other human coronaviruses: OC43-CoV and HKU1-CoV.
“Altogether, our results strongly support the hypothesis that HLA-B*15:01 mediates asymptomatic COVID-19 disease via pre-existing T-cell immunity due to previous exposure to HKU1-CoV and OC43-CoV,” the researchers wrote.
Can Genes Prevent COVID-19 Infections?
Meanwhile, researchers at The Rockefeller University in New York City are attempting to go further and see if there are mutations that prevent people from getting infected in the first place. NPR reported that they were seeking participants for a study seeking to identify so-called “superdodger” genes.
Study participants identified as possibly having superdodger genes receive a kit designed to collect saliva samples, after which the researchers sequence the respondents’ genomes. “We hope that in a group of 2,000 to 4,000 people, some people will have genetic mutations that tell us why they’re resistant to infection,” Casanova told NPR.
All this genetic research is in very early stages. But results are promising and may lead to new precision medicine clinical laboratory tests for identifying people who are predisposed to having an asymptomatic response to COVID-19 infection. That in turn could help scientists learn how to moderate or even eliminate symptoms in those unfortunate people who suffer the typical symptoms of the disease.
These findings hint at the role of pre-existing conditions in raising the risk of an individual having a severe case of COVID-19 once infected
At the University of Michigan, a team of pathologists have been researching the factors that might cause some patients infected by SARS-CoV-2 to suffer persistent respiratory problems, often described as “long COVID.” They have identified factors that place some individuals at higher risk for these problems.
Little is known about how the SARS-CoV-2 coronavirus affects the body long-term. Millions of people who have survived COVID-19 infections are living with chronic symptoms, including persistent respiratory problems such as shortness of breath. However, until now, it was not clear what may be causing these symptoms in some people but not others, even after the coronavirus has completely cleared their bodies.
Now, anatomic pathologists at Michigan Medicine, formerly the University of Michigan Health, believe they may have discovered what is causing ongoing respiratory problems in some patients who have recovered from the COVID-19 infection—pre-existing conditions.
The researchers examined lung biopsies from COVID-19 patients who continued to experience lingering symptoms. They discovered in some individuals lung damage that was present prior to contracting the virus.
“Some of the early publications and popular press around long COVID has implied or assumed that once you had COVID, everything that happens next is COVID-related,” said anatomic pathologist and senior author of the study Jeffrey Myers, MD (above), Vice Chair for Clinical Affairs and Quality at Michigan Medicine, in a news release. “Of course, that might or might not be true,” he added. (Photo copyright: University of Michigan.)
The research team analyzed lung biopsies from 18 COVID-19 survivors who were still experiencing respiratory symptoms or had abnormal computed tomography (CT) scans after the virus was no longer present in their bodies. The researchers found ground glass opacities on the radiological scans of 14 of those patients.
According to the news release, this finding indicates there were “areas of the lungs that appear as a cloudy gray color as opposed to the dark color of normal air-filled lungs, on a chest X-ray or CT scan.”
The biopsies exhibited evidence of pre-existing lung scarring and proof of diffuse alveolar damage, which is typically seen in patients with acute respiratory illnesses. Only five of the patients examined in the study were known to have lung disease prior to their COVID-19 diagnoses.
The researchers found that the most common condition present in these 18 patients was usual interstitial pneumonia (UIP). This condition, also known clinically as idiopathic pulmonary fibrosis (IPF), is a common form of pulmonary fibrosis that is characterized by progressive scarring and stiffening of both lungs.
“We were seeing a lot of UIP, which isn’t the pattern we tend to associate with acute lung injury,” said Kristine Konopka, MD, Clinical Associate Professor at Michigan Medicine and lead author of the study, in the news release. “So, we think these are patients who had lung disease prior to COVID and maybe they just weren’t being followed by primary care physicians. They then had COVID, are still sick, and their UIP is finally being picked up.”
Could Patients Have Lung Disease and Not Know it?
“The notion,” Myers noted in the news release, “that a person could have chronic lung damage and not know it was unheard of until relatively recently.” He also explained that UIP/IPF is a progressive disease that gets worse with time and that an infection like COVID-19 can accelerate the illness to a more serious condition known as an acute exacerbation of IPF, which can lead to death.
“SARS-CoV-2 comes along and does to the lung, from a pathology perspective, exactly what happens with an acute exacerbation,” Myers said.
The researchers also stated that it’s impossible to determine for certain whether the SARS-CoV-2 virus caused the UIP/IPF without the existence of full clinical histories of the patients prior to their COVID-19 diagnoses. They hope their research will motivate clinicians to be cautious before automatically attributing respiratory symptoms to long COVID in survivors of the virus. It is possible that the lung damage was present prior to the coronavirus.
“You shouldn’t make assumptions but [instead] ask the right questions, the first of which would be ‘I wonder if this is really COVID?’ What you do after that depends on the answer to that question,” he added.
This research is an example of how pathologists can add insight and value into the deeper understanding of the processes involved in specific diseases. Dark Daily invites any of our readers who are aware of other pathologist-authored studies or published papers about COVID-19 to alert us to the availability of those works.
According to the Centers for Disease Control and Prevention (CDC), the 1918 influenza (aka, the Spanish Flu) pandemic took place worldwide between 1918 and 1919. It was caused by the H1N1 virus (A/H1N1), a subtype of the Influenza A virus, and infected approximately 500 million people worldwide (a third of the human population at the time). Fifty million people died. Many were children or otherwise healthy individuals, but people from all age groups perished.
The CDC calls the Spanish Flu the “deadliest pandemic of the 20th century.” Past pandemics have generally concluded after 2.5 to 3.5 years. That’s how long it takes for new viruses to mutate and become endemic diseases, Healthline reported.
The COVID-19 pandemic has been around for about that long. It stands to reason the natural end of the COVID-19 pandemic may be just around the corner. But is it? And is the Omicron variant an indicator that the COVID-19 pandemic is winding down?
“Our analysis suggests that in the US, this combination of characteristics would lead to Omicron replacing Delta as the dominant variant in the next few months and to a higher peak burden of disease than the country saw in the second half of 2021 (but likely below the peak reached in the winter of 2020-21),” the report states.
McKinsey analysts also acknowledged the possible impact of new therapeutics, COVID-19 vaccine booster doses, and public health measures on Omicron spread. “In the short term, an accelerated rollout of booster doses of COVID-19 vaccines is likely to be one of the best protections against an Omicron-fueled wave of the disease,” the analysts wrote.
Does How the Spanish Flu Came to an End Mirror the COVID-19 Pandemic?
Virologists and infectious disease experts explained that the Spanish Flu virus did what viruses still do: mutate and become less dangerous. Herd immunity also helped end the 1918 pandemic.
“The 1918 influenza virus eventually mutated to the point of not having a high number of deaths—eventually over three years or so. We may very well be witnessing this process with ongoing variants of SARS-CoV-2,” virologist Rodney Rohde, PhD, Director of the Clinical Laboratory Science Program at Texas State University, told Healthline.
Today’s flu strains have “ancestral links” to the 1918 flu, and thus, the SARS-CoV-2 coronavirus will most likely also leave its mark, The Boston Herald reported. “The coronavirus will evolve and hopefully morph into a seasonal illness to which we pay little mind, but it’s still too early to tell,” Todd Ellerin, MD (above,) Director of Infectious Diseases, South Shore Health, South Weymouth, Mass., told The Boston Herald. (Photo copyright: Greg Derr/The Patriot Ledger.)
“If you think about the way viruses behave, biologically, their reason for living is to replicate and spread, and there’s really no advantage for the virus to kill the host,” infectious disease specialist Keith Armitage, MD, Professor of Medicine, Division of Infectious Diseases at Case Western Reserve University, told Healthline. “The hope is, that if the pandemic doesn’t go away, we will get new variants that are highly contagious but don’t produce much of a clinical illness,” he added.
In “2021’s Top 10 Lab Stories Confirm Important Trends,” Dark Daily’s sister publication, The Dark Report (TDR), posed a similar question in its number one story of 2021: “COVID-19: Will it Become Endemic and a Respiratory Virus that Shows Up Every Year like Influenza?”
“The question of whether SARS-CoV-2 is a pandemic that fades, as did SARS in 2003, or becomes endemic and a respiratory virus that shows up every season like influenza and the common cold, is of major concern to clinical lab administrators. That’s because clinical labs and pathology groups must continue to serve physicians and patients with the usual menu of routine, reference, and esoteric testing,” TDR noted.
Clinical Laboratories to Continue COVID Testing
It would be most helpful for medical laboratories and pathology groups to have some idea of when the pandemic will end. Unfortunately, such predictions would not be very useful.
“Since COVID-19 infections have a high number of asymptomatic transmitters, we may not fully understand how societal and environmental pressures—masks, distancing, remote working, etc.—on the virus will allow it to evolve,” Rohde told Healthline.
For now, clinical laboratories will need to continue to remain prepared as COVID-19 cases rise and people seek SARS-COV-2 tests, vaccinations, and treatments. COVID-19 testing is likely to be in demand throughout the coming year. The current surge in demand for COVID-19 tests is putting additional stress on the supply chain.
“We know pandemics end; it’s just a matter of time,” Sara Paton, PhD, Associate Professor of Epidemiology, Wright State University, told the Journal-News. “It could be in 2022, maybe later in the year, but I can’t say for sure. It could be 2023.”
