Long COVID: which symptoms can be attributed to SARS-CoV-2 infection?

Authors: Christopher E Brightling Rachael A Evans Published:August 06, 2022DOI:https://doi.org/10.1016/S0140-6736(22)01385-X The Lancet

Mortality rates following SARS-CoV-2 infection have decreased as a consequence of public health policies, vaccination, and acute antiviral and anti-inflammatory therapies.1 However, in the wake of the pandemic, post-acute sequelae of COVID-19, or long COVID, has emerged: a chronic illness in people who have ongoing multidimensional symptomatology and disability weeks to years after the initial infection.2 Early reports of long COVID prevalence, summarized in a systematic review examining the frequency and variety of persistent symptoms after COVID-19, found that the median proportion of people who had at least one persistent symptom 60 days or more after diagnosis or at least 30 days after recovery from COVID-19 infection was 73%. 3 However, the estimated prevalence depends on the duration, population, and symptoms used to define long COVID. More recently, community-based studies have suggested a lower prevalence of persistent symptoms; 4 whereas among people who were hospitalised following COVID-19 infection, a high proportion do not fully recover (50–70%).56

The number of COVID-19 cases continues to rise and now exceeds 500 million worldwide.1 Consequently, the number of people with long COVID is similarly increasing. Indeed, the UK Office for National Statistics (ONS) survey up to May, 2022 estimated that 2 million people in the UK had self-reported long COVID. 8 Of these people, 72% reported having long COVID for at least 12 weeks, 42% for at least 1 year, and 19% for at least 2 years. Consistent with other studies, fatigue was the most common symptom in the ONS survey, followed by breathlessness, cough, and muscle ache.45678 Risk factors for long COVID are female sex, obesity, middle age (35–65 years), living in areas of greater socioeconomic deprivation, and the presence of another activity-limiting health condition.156 Importantly, health-care use is increased in those with long COVID, with increased general practitioner consultation rates.

How many of the symptoms currently attributed to long COVID actually represent pre-existent disease or are unrelated to COVID-19 is uncertain. Symptoms that were present before SARS-CoV-2 infection are often not recorded or assessed by recall. In The Lancet, Aranka V Ballering and colleagues 10  report the findings of a longitudinal cohort study conducted in the north of the Netherlands between April, 2020, and August, 2021, where 23 somatic symptoms were assessed using 24 repeated measurements in digital COVID-19 questionnaires. The study was embedded within the large, population-based Lifelines COVID-19 cohort. The main strengths of this study were that participants were their own control, with the pattern and severity of symptoms assessed before and 3–5 months after SARS-CoV-2 infection, and were also compared with a matched control group of COVID-19-negative participants. Of the 76 422 participants, 4231 (5·5%) had COVID-19 and were compared with 8462 matched controls. Participants had a mean age of 53·7 years (SD 12·9), 46 329 (60·8%) were female, and nearly all were of White ethnicity. The proportion of participants who had at least one core symptom of substantially increased severity to at least moderate was 21·4% (381 of 1782) in COVID-19-positive participants versus 8·7% (361 of 4130) in COVID-19-negative controls. Thus, this study found that core symptoms were attributed to COVID-19 in 12·7% of participants, or approximately one in eight. This is a major advance on previous long COVID prevalence estimates, as it includes a matched control group without SARS-CoV-2 infection and accounts for symptoms that were present before infection.

The pattern of symptomatology observed by Ballering and colleagues 0  was similar to previous reports, with fatigue and breathlessness among the most common symptoms, but other symptoms such as chest pain were more common in people who had COVID-19 than in COVID-19-negative controls. Ballering and colleagues10  propose a core symptom set to be considered as part of the case definition for long COVID. Although an agreed diagnostic core symptom set would inform clinical pathways and research, the study by Ballering and colleagues 10 did not fully consider the impact on mental health, it was conducted in one region in the Netherlands, and it did not include an ethnically diverse population; thus the concept of a core symptom set will require further validation. Importantly, the study by Ballering and colleagues 10  does not provide new mechanistic insights, which are key to uncovering new therapeutic targets. In other studies, clustering of patient-reported outcomes has identified different severity groups of long COVID and identified increased systemic inflammation in people with very severe long COVID.5, 6

 How patient-centred outcomes, together with biomarkers, can further refine long COVID diagnosis and inform precision medicine approaches warrants further consideration. Encouragingly, emerging data from other studies suggest that the proportion of newly infected people developing long COVID is reduced in people who have received vaccination before SARS-CoV-2 infection,11  and might be lower in people infected with the omicron variant than those infected with earlier variants.2

 Findings from the ONS survey suggested that vaccination following infection might reduce the symptom burden of long COVID after the first dose, with sustained improvement after a second dose13  Whether acute treatments for COVID-19 affect the likelihood of developing long COVID or its severity is unknown.

Current evidence supports the view that long COVID is common and can persist for at least 2 years after SARS-CoV-2 infection, although severe debilitating disease is present in a minority. The long COVID case definition needs to be further improved, potentially to describe different types of long COVID, of which better mechanistic understanding is crucial. This will lead to personalised multimodality treatments that can be implemented to manage the increasingly high number of people with long COVID.

CEB has received consultancy and or grants paid to his institution from GlaxoSmithKline, AstraZeneca, Boehringer Ingelheim, Novartis, Chiesi, Genentech, Roche, Sanofi, Regeneron, Mologic, and 4DPharma for asthma and chronic obstructive pulmonary disease research. RAE has received consultancy fees from AstraZeneca on the topic of long COVID and from GlaxoSmithKline on digital health, and speaker’s fees from Boehringer Ingelheim on long COVID. RAE holds a National Institute for Health and Care Research (NIHR) clinician scientist award CS-2016-16-020.

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9

COVID-19 INCREASING STROKE RISKS IN PEOPLE OF ALL AGES

Author: University of Utah Health Communications

The COVID-19 pandemic has been unpredictable as more is learned about the varied side effects of the virus. A typical respiratory infection, such as the flu, usually has a specific set of symptoms and potential complications. With COVID-19, the long-term effects range from neurological complications to loss of taste and smell, trouble focusing (“brain fog”), and chronic fatigue. Another surprising finding from several studies is the heightened risk of stroke and heart attack—and not just for older adults. People under the age of 50 appear to be at much higher risk of these complications too.

One study published in JAMA in April 2021 found that the risk of stroke was more than twice as high for COVID-19 patients when compared to people of the same age, sex, and ethnicity in the general population—82.6 cases per 100,000 people compared to 38.2 cases for those without a COVID-19 diagnosis. 

In another Swedish study published in the August 14, 2021 issue of The Lancet, researchers found that within a week of a COVID-19 diagnosis, a person’s risk of heart attack was three to eight times higher than normal, and their risk of stroke was three to six times higher. The study revealed these risks remained high for at least a month. The average age of people in the study was only 48 years. The data from those diagnosed was compared with 348,000 Swedish people in a similar age range who did not have the virus.

This trend is something Jonathan Kinzinger, DPT, a physical therapist and adjunct assistant professor at University of Utah Health who works with stroke patients at the Craig H. Neilsen Rehabilitation Hospital, has seen up close. 

“We are definitely seeing a huge increase in younger stroke survivors who are post-COVID diagnosis,” Kinzinger says. “We know that vascular complications go along with COVID infections, which can lead to strokes and other cardiovascular issues.”

group of researchers headed by Mark Ellul, PhD, NIHR Clinical Lecturer in Neurology at the Institute of Infection, Veterinary and Ecological Sciences from the University of Liverpool, first observed this in September 2020. They found that the number of patients admitted to the hospital with a large vessel stroke who also had a COVID-19 diagnosis was seven times higher than normal.

Similar findings have also come out of other countries, where the median age for patients who needed thrombectomy surgery to remove a blood clot was down across the board. In one New York Medical Center, the average age of patients with confirmed stroke and COVID-19 diagnosis was 63 years. The average age of stroke patients who tested negative for COVID was much higher (70 years), even when they controlled for age, sex, and other risk factors.

Researchers are still studying the cause of the increased risk. But doctors know that COVID-19 causes an inflammatory response that thickens a person’s blood. Thicker blood is more likely to clot, and clots can lead to stroke. Many of the young people who suffer a stroke after a COVID-19 diagnosis have few (and sometimes no) risk factors normally associated with stroke.

Sometimes these strokes don’t occur for several weeks after a COVID-19 diagnosis, and it’s impossible to predict who might be at risk. For patients recovering from COVID-19 and a stroke, there is the added challenge of an impaired cardio-respiratory system. “Not only are we dealing with strength, motor, and balance deficits that go along with stroke, we also have to work around respiratory issues, tracheostomies, and other complications,” Kinzinger says. Stroke recovery is physically and mentally challenging anyway, and these complications can increase recovery time.

“When someone has a stroke and they are under 50, their whole life is uprooted,” he says. “A lot of people have younger kids or spouses, they may have a career or they’re going to school, so it’s just such a different phase of life than someone who is older.”

What heart and stroke patients need to know about COVID-19 in 2022

Authors: Michael Merschel, American Heart Association News

Two years into the pandemic, researchers have learned a lot about how COVID-19 affects people with heart disease and stroke survivors. But like the coronavirus itself, what everyone needs to know keeps evolving.

“You can’t assume that what was true three months ago is true now,” said Dr. James de Lemos, a cardiologist at UT Southwestern Medical Center in Dallas. Thanks to the omicron variant, “it’s a fundamentally different pandemic than it was at Thanksgiving.”

Early data suggests omicron causes less severe illness but spreads more easily than its predecessors. So heart and stroke patients need to protect themselves, starting with understanding that COVID-19 still is a threat to their health.

“Early on, we recognized that the risk was higher for those with pre-existing cardiovascular disease,” said Dr. Biykem Bozkurt, a cardiologist at Baylor College of Medicine in Houston. According to the Centers for Disease Control and Prevention, people with conditions such as heart failure, coronary artery disease and possibly high blood pressure may be more likely to get severely ill from COVID-19. So can people who have diabetes, are overweight or are recovering from a stroke.

SARS-CoV-2, the virus that causes COVID-19, also has been linked to increased risk of several cardiovascular conditions. According to a September 2021 report from the CDC, people with COVID-19 are nearly 16 times more likely to have heart inflammation, or myocarditis, than uninfected people. The report found about 150 cases per 100,000 people with COVID-19 versus about nine cases per 100,000 people without the virus.

In addition, an August 2021 study in the New England Journal of Medicine showed people with the coronavirus may have a significantly higher, albeit rare, risk of intracranial hemorrhage, or brain bleeding; heart attack; and having an arrhythmia, or abnormal heartbeat.

Researchers don’t have full data on omicron’s effects yet, Bozkurt said, but it’s still affecting people who are vulnerable. “And that’s why the hospitals right now are full.”

The risks of any one person having a severe problem from the new variant are relatively small, de Lemos said. “But the flipside is, given how many people are getting infected right now, the cumulative number of people with COVID-19 complications is still very large.”

De Lemos, who helped create the American Heart Association’s COVID-19 Cardiovascular Disease Registry, said omicron “is obviously wildly more infectious and able to evade the vaccine to some extent, although it does appear that the vaccine seems to prevent severe infections and hospitalizations.”

And overall, “we don’t know a ton about specifically why certain patients with heart disease do less well,” he said, although understanding has evolved over time.

In the beginning, de Lemos said, doctors feared the virus directly infected the heart muscle. “That doesn’t really appear to be the case,” he said.

Instead, it appears that in severe cases, the virus is inflaming the lining of blood vessels of the heart and increasing the likelihood of clotting in the smallest vessels, he said.

COVID-19 also can overwhelm the heart by making it work harder to pump oxygenated blood through the body as the lungs are overwhelmed.

But as they’ve learned more about the coronavirus, doctors have gotten better at fighting it. For example, de Lemos said, they now work proactively to treat blood-clotting disorders in hospitalized patients. And although researchers are working to understand lingering effects known as “long COVID,” it appears long-term implications for the heart look favorable.

“The vast majority of people who have mild COVID infections really appear to have nothing to worry about with their hearts,” he said. “That’s good news, I think, and doesn’t get emphasized enough.”

People with existing heart conditions or a history of stroke still need to protect themselves, and have many ways of doing so.

“Number one: Get vaccinated,” said Bozkurt, who has studied COVID-19 vaccine side effects. “And please, do get a booster.” Reports of rare cases of vaccine-related myocarditis, particularly in younger males, should not dissuade anybody with an existing condition. Most people with pre-existing cardiovascular disease are not young adult males, she noted. And regardless of age, the benefits from vaccines outweigh the risks.

Given how the vaccines don’t seem to be as protective against the spread of omicron, de Lemos said if you’re a heart disease or stroke patient, hunker down for the next several weeks until this wave passes, “and then you’ll be able to re-emerge.”

Patients should avoid indoor crowds, he said, and use a KN95 mask or, when possible, an N95 mask instead of cloth masks when being in a crowd is necessary.

Bozkurt said heart and stroke patients should keep in contact with their health care team and continue taking medications as prescribed. Anybody with symptoms that could be heart-related should seek care immediately. “Do not delay,” she said.

Both doctors said it was important to get information from reliable sources. Some false remedies promoted on social media can actually damage the heart, Bozkurt said.

De Lemos acknowledged that even from reliable sources, advice can shift. “I would say that the information is written in pencil, not in pen, because things are changing so fast.” It can be frustrating for him, even as a scientist, when experts disagree or alter their recommendations, but “that’s the way science goes.”

And even as COVID-19 “remains a bizarrely arbitrary virus in terms of who gets sick and who doesn’t,” he’s optimistic.

“Think about all the progress we’ve made in a year or two, and the remarkable effect of the vaccines, the fact that we have drugs” that should help keep people out of hospitals. Heart and stroke patients need to be extra careful right now, but “as frustrating as it is, we will not be in this situation forever. We really won’t.”

Editor’s note: Because of the rapidly evolving events surrounding the coronavirus, the facts and advice presented in this story may have changed since publication. Visit Heart.org for the latest coverage, and check with the Centers for Disease Control and Prevention and local health officials for the most recent guidance.

If you have questions or comments about this story, please email editor@heart.org.

Researchers are working together to better understand and treat the syndrome

Authors:  SABRINA RICHARDS / FRED HUTCH NEWS SERVICE JANUARY 26, 2022

Robin Macnofsky’s first symptoms, in April 2020, were so mild she didn’t take a test for COVID-19, preferring to save it for someone who really needed it.

A few weeks later her chest tightened and her temperature spiked. These ebbed, but an even stronger wave hit: a high fever and exhaustion that left her bedbound in a days-long “zombie sleep.” Macnofsky tested positive for COVID-19 (likely from remaining viral genetic material). Her symptoms endured.

Previously a champion multi-tasker who could split her concentration in four directions, the then-59-year-old could no longer follow the plot of a TV episode or walk her dog. Her temperature waxed and waned.

A realization dawned: The end was nowhere in sight, and no one could tell her why.

Scientists studying the unfamiliar and unfurling COVID-19 pandemic also began to realize that for Macnofsky and many other COVID-19 patients, a long hospital stay or a short, mild illness were not the only outcomes. For some people, mild symptoms, quickly resolved, were just the beginning.

Researchers worldwide, including many at Fred Hutchinson Cancer Research Center and the University of Washington, are working to understand long COVID-19, the long-lasting effects of COVID-19 infection that can affect adults, teens and children. Hutch and UW investigators are building on deep expertise in immunology and infectious diseases like HIV to figure out what causes long COVID-19, who is at risk, and how to treat it. To do so, they’re tackling challenges that range from basic questions about how best to measure symptoms to uncovering the complex immunological interplay that may drive symptoms.

‘Something is different’

In March 2020, Julie Czartoski, a nurse practitioner working with Fred Hutch virology expert and Joel D. Meyers Endowed Chair holder Dr. Julie McElrath, helped McElrath quickly put together a study, the Seattle COVID Cohort Study, to look at COVID-19 in first responders and those infected with SARS-CoV-2, the virus that causes COVID-19. They wanted to know who was getting it, and how badly. Soon they opened the study to others in the community. Luckily, few participants who contracted the coronavirus had symptoms that warranted hospitalization. Most had relatively mild infections that cleared up quickly.

But that wasn’t the end. For many, symptoms persisted, even worsened. Participants reported lingering fevers, new joint pain, exhaustion and brain fog, among a grab bag of other symptoms. When an unexpected number of young, healthy firefighters reported atrial fibrillation — a rapid, abnormal heart rhythm — Czartoski knew something was up.

“It’s not unheard of in young adults, but to have so many was weird,” she said. “I remember texting Julie McElrath and saying, ‘Something is different, because these people are still sick.’”

Because of their fast action and prompt study enrollment, Czartoski and McElrath were early to recognize a truth that would eventually become clear to other scientists: COVID-19 can cast a long shadow.

More research and resources 

Many of the people in McElrath’s study who reported lasting problems had experienced mild, almost cold-like infections with SARS-CoV-2. Very few had been hospitalized.

It takes time to know for sure that a patient is suffering from long COVID-19. A week or two is not long enough to be sure their symptoms won’t clear up soon. Eventually, McElrath and her team found that about 30% of the coronavirus-positive participants in their study had lasting symptoms, or new symptoms attributed to COVID-19, that extended at least 60 days past their initial infection, Czartoski said.

Long COVID-19 dogs some patients, like Macnofsky, much longer, and their symptoms can be severe. After two different week-long hospital stays, in which she underwent terrifying procedures to remove nearly a liter of fluid pressing on her heart and then her lungs, Macnofsky took a leave of absence from her career as a community organizer. By early 2022, she still rations her energy and has yet to regain her prior multi-tasking abilities.

Time defines the syndrome and time challenges those suffering from it and the scientists working to untangle it. Also known as PASC, for post-acute sequelae of SARS-CoV-2 infection, long COVID-19 refers to symptoms that endure long after someone has recovered from their initial coronavirus infection. (The term “sequelae” refers to a disease’s aftereffects.) Symptoms can include fatigue, shortness of breath, brain fog, fever, anxiety and depression. COVID-19 patients who were sick enough to need ICU care may also be dealing with post-ICU syndrome, and it’s not yet clear how their experience will unfold differently from patients who were treated in the ICU for other causes.

For a health problem as mysterious and as complex as long COVID-19, progress requires scientific teamwork.

That’s why, in summer 2021, Dr. Rachel Bender Ignacio reached out to investigators across Fred Hutch and the University of Washington, inviting them to join a long COVID-19 working group to share challenges and solutions, and find collaborators to help investigate specific questions.

As medical director of the Hutch’s COVID-19 Clinical Research Center, or CCRC, Bender Ignacio had a good sense of who at both institutions were treating or studying the syndrome. She was also hearing from CCRC trial participants who had transitioned from acute to long COVID-19 and wanted to know how scientists were addressing it. “I have my ear to the ground,” she said.

Bender Ignacio felt that progress required stronger connections between clinicians and laboratory and translational scientists. Physicians needed a better understanding of the biological mechanisms driving long COVID-19 before they could move proposed treatments into clinical trials, and basic scientists could reveal those mechanisms but needed tissue samples and clinical insights from the people providing patient care.

“Bringing everyone together was the least I could do,” Bender Ignacio said.

The working group she put together is an example of international and multidisciplinary efforts to tackle the challenges that vex investigators studying long COVID-19, including how to best classify and diagnose the syndrome, what’s causing it, and how to treat it. The recently launched National Institutes of Health RECOVER initiative, aimed at understanding PASC, is giving the investigators in the field hope that standards may be forthcoming, said Dr. Eric Chow, a working group member and UW infectious diseases fellow who studies the damage that respiratory viruses can do outside the lungs.

The researchers who joined Bender Ignacio’s collective span disciplines and body systems, including the brain, heart and lungs. They include researchers and clinicians at UW and Harborview Medical Center, which opened one of the nation’s earliest clinics devoted to helping long COVID-19 patients. The working group members bring expertise in long-term complications from viral infections like HIV and influenza, and know how viruses or the immune reaction to them can damage the body. SARS-CoV-2 may be wreaking the most havoc right now, but it’s not the only virus that can upend sufferers’ lives: Many, including Bender Ignacio, have spent their careers studying the long-term effects of HIV.

Now the team is bringing their wide-ranging expertise to bear on the many questions of long-haul COVID-19, hoping to surmount its challenges and help patients.

Learning on the fly

Studying a little-understood problem in a rapidly shifting pandemic is incredibly challenging. At the beginning, scientists had no knowledge base to inform their data collection or study design. Every week or month brought new information that forced them to reassess the data they had already collected — and adjust their data-collection methods to incorporate new understanding.

“It’s like building a boat while you’re sailing it,” said working group and CCRC member Dr. James Andrews, a University of Washington rheumatologist who studies how sepsis, particularly severe cases requiring hospitalization, can lead to long-term disability.

The first challenge was realizing that a problem existed. Many of the long-haulers Czartoski interviewed for the Seattle COVID Cohort Study struggled to find help and even recognition of their symptoms, she said.

“In the beginning, a big part of my job was just listening,” Czartoski recalled.

Study participants wept as they described to her their crushing fatigue and debilitating symptoms, and the struggle to get health care providers to understand that their vague-seeming complaints posed a real problem. Macnofsky, too, found it difficult to get help for her constant fever, headaches, fatigue and brain fog.

In the beginning, no one knew what information would be important to understand why these patients were suffering and how to help.

A snapshot of data “is one piece of the whole puzzle,” said Hutch statistician Dr. Zoe Moodie, who helps design and analyze HIV vaccine trials and develops statistical methods to analyze immunological data. “Generally, the more pieces the better, and as time goes go on we learn which are the important pieces.”

Czartoski tackled the problem by collecting everything she could: “Sometimes [a symptom] didn’t seem important, then a week later I’d have five people reporting it.”

And sometimes the information that most impacts a patient’s life can seem negligible when committed to paper, she said. One person’s loss of smell or taste may seem like small potatoes compared to others’ chronic exhaustion and continual fevers. But such seemingly small symptoms can make life and some careers difficult: Firefighters smell phantom burning and parents who can no longer smell a dirty diaper. Once-favorite food now repells.

“And [those symptoms] are really tough on quality of life,” Czartoski noted. Depression can set in, straining a person’s long-term relationships, affecting quality of life and for some, the ability to hold down a job.

Initially, she had a limited systematized questionnaire, and took notes longhand while patients noted every symptom they could think of — whether they knew it related to their COVID-19 or not. As time passed, Czartoski and her colleagues were able to spot common symptoms that they added to an ever-expanding checklist. (Then, they had to get the checklist built into the study records system.)

The working group members brainstorm statistical and analytical strategies that could help, and which take into account the fact that not everyone’s data has been collected in the same way at the same time points during the course of their disease.

Even now, their efforts to untangle long COVID-19 are hampered by what they didn’t know six, 12, 18 months ago, Czartoski said.

“Researchers will ask about blood drawn a year and a half ago: Were they taking Tylenol?” she said. “It could change the immune response, but I don’t know!”

Fred Hutch HIV researchers Dr. Julie McElrath (left) and Dr. Rachel Bender Ignacio (right) are parlaying their expertise in viral infections and clinical trials to help patients suffering from long COVID-19. McElrath gathered a cohort of long-haulers who are helping researchers dig into the immune drivers of PASC. As the CCRC’s medical director, Bender Ignacio helps make crucial connections between basic and translational scientists working in the field.

Photos by Robert Hood / Hutch News Service

Finding the right box

Another major challenge that long COVID-19 researchers face is classification. Many studies are producing data on the syndrome, but if symptoms aren’t collected and classified similarly, trying to compare different studies will be like comparing apples and oranges.

Decisions about how to classify symptoms also affect how patients are grouped together and how the data is analyzed. One big concern: Should patients be grouped by symptom, or should symptoms be grouped by the organs they affect?

It’s a bit of a chicken-and-egg issue, but it gets into the problem of what’s behind long COVID-19 to begin with, said Chow, who began treating Macnofsky after her hospital stay. (The two teamed up to tell Macnofsky’s story in a dual first-person essay published in the scientific journal Open Forum Infectious Diseases.)

“For example, what about fatigue? Do you group everyone with fatigue together? But what if one person’s fatigue is caused by damage to the nervous system, another’s by damage to their heart, and someone else’s by lung damage,” said Chow, who at the start of the pandemic was part of the Centers for Disease Control and Prevention team that went to New York state to confirm COVID-19-associated multisystem inflammatory syndrome in children.

Even in cases where it’s clear the immune system is at fault, fatigue may not have a single cause. Energy-sucking immune activation could explain one person’s fatigue, but post-infection autoimmunity, in which their own tissues are under attack, could be the reason behind another’s, Andrews said.

Trying to find the biological similarities in data taken from these patients would be like trying to compare pages of text written in different languages: more likely to result in gibberish than to identify a helpful pattern.

And sometimes, symptoms may not even be the result of a person’s coronavirus infection. Part of the problem is the often-vague, widely varying collection of symptoms, many of which long COVID-19 shares with other chronic health problems, such as autoimmune diseases or chronic fatigue syndrome. Autoimmune diseases often strike in young adulthood. For some people, SARS-CoV-2 infection and an autoimmune diagnosis are just two pieces of unrelated bad luck.

“In a longitudinal cohort like this, nothing is ever completely clean,” Czartoski said.

Working group members share questions and strategies. Should they classify symptoms by severity score, or follow the CDC’s recommendations to classify symptoms by outcome measures in different areas? Members often draw on their or other members’ expertise in different disciplines, such as adapting questionnaires used by neurologists to assess cognitive difficulties. Czartoski recommended a severity scale long used by HIV researchers to assess how symptoms impact patients’ daily living.

The team also grapples with the challenges of classifying symptoms that may seem focused on a specific organ system, but are actually emblematic of a body-wide problem. Researchers noted that some simplification needs to occur to make it possible to analyze the reams of data that can be collected.

But sometimes it’s unclear what’s causing someone’s symptom — so researchers can’t classify symptoms by underlying cause. What then?

Members also keep an eye on trends in the wider scientific community to see if they can align with areas of growing consensus, the better to compare their results with other studies.

Who’s at risk for symptoms, and how long will they last?

But sorting out the logistical challenges of classification is just the first step. Long COVID-19 researchers want to understand why symptoms develop and who’s at risk. Why do some symptoms affect some patients but not others? Who will have a mild course, and who will suffer greatly? A deeper understanding, they hope, will shed light on why symptoms linger so long for some people, and how to predict how a patient’s experience will unfold.

UW neurologist Dr. Payal Patel is focusing on the cognitive symptoms of PASC.

“I want to know, what is the cause of the symptoms we see in PASC,” said Patel, who studies the continuing effects of infections of the central nervous system, including HIV. “We know PASC affects different organ systems. I’m trying to get a better clinical understanding of how it affects the brain.”

Without this, it’s difficult to give worried patients a clear picture of what they can expect from long COVID. Patel wants to better understand how long such symptoms last, who’s most at risk, and what’s causing them. Is brain fog caused primarily by immune dysfunction? Or could the clotting problems associated with COVID-19 have damaged the cells lining blood vessels in the brain? Patel and a team of scientists have studies underway to answer these questions.

This type of location-specific question can be very difficult to address, Chow noted. It’s relatively easy to take blood samples and look at general patterns of immune cells or antibodies floating through the blood. But what about problems that are occurring at a hard-to-reach spot, like tiny blood vessels in the brain or lungs?

Some working group members focus their research questions on specific areas of the body. With Patel, Andrews is trying to understand who’s most at risk for cognitive and physical impairments after COVID. Some patients’ fatigue is related to muscle wasting, known medically as sarcopenia, and Andrews wants to know what’s behind that and who’s at risk.

Role of the immune system in long COVID-19

Since it became understood that an overactive immune response (known as a “cytokine storm”) lurks behind some of COVID-19’s most dire complications, scientists have begun digging deeper into how the immune system responds to SARS-CoV-2. Macnofsky herself participated in a Benaroya Research Institute study looking at the immune response to the novel coronavirus.

Bender Ignacio’s working group is drawing on the Hutch’s longstanding expertise in immunology and infectious diseases and looking to the immune system for answers.

“We’re studying what natural infection looks like over time,” said Fred Hutch immunologist Dr. Maria Lemos, who studies immune responses in mucosal tissue like vaginal and nasal surfaces, where we first encounter many viruses. “People could have cold symptoms for nine days, then four moths later they’re diagnosed with a lung condition or a heart condition.”

To understand why, she and others on McElrath’s team are mapping the immune response to SARS-CoV-2 infection as it unfolds over months. With collaborators at Emory University in Atlanta, they’re charting the rise and fall of antibodies against the virus and how different immune-cell populations grow, shrink and morph over time.

By describing how these responses differ between people who did and did not develop long COVID-19, the researchers hope to identify key biomarkers, like specific inflammatory proteins, that help predict which patients will have persistent problems. Such biological predictors could help doctors intervene early, either to help connect patients with the right services to help them deal with symptoms, or (once scientists crack this problem) stave it off entirely.

McElrath’s team, with collaborators at Emory University and the Seattle-based Allen Institute for Immunology, has revealed some tantalizing immunological patterns, Lemos said, which the group posted on the preprint server biorxiv.org. The immune trajectory in many long-haulers looks startlingly unlike that seen in people who recover quickly and permanently.

“The alarm system of the immune system doesn’t get turned on as quickly in these people — but surprisingly it seems to remain on for way longer,” Lemos said. They’re currently putting together a paper for peer review at a scientific journal.

On top of this project, Moodie is working with investigators the Allen Institute to identify immunological signatures, including cellular features like proteins and gene expression, that distinguish long COVID-19 from acute COVID-19. Some patients — including Macnofsky — report improvement of symptoms after vaccination for COVID-19, and Moodie and her collaborators want to understand how vaccination may help their bodies resolve their chronic, damaging immune responses.

(Whether prior COVID-19 vaccination helps protect against developing long COVID-19 is still being explored. A recent study in The Lancet suggests that vaccinated people are less likely to have long-lasting symptoms after SARS-CoV-2 infection.)

Treatments for long-haulers?

Macnofsky said she’s recently been helped by six months of weekly pulmonary rehab sessions. It’s possible that early access to rehabilitative therapies could help prevent or alleviate severe long COVID-19 in others.

It is taking time for scientists at the Hutch and elsewhere to get a clear enough picture of what’s driving long COVID-19 to open clinical studies to address patients’ problems, but a few have begun.

The Seattle arm of a multi-center, Phase 2 trial of a drug called RSLV 132, is administered through the CCRC and headed by Andrews. (People interested in participating can contact the CCRC.) Developed by biotech company Resolve Therapeutics, the drug has already shown promise against fatigue in people with autoimmune diseases like Sjögren syndrome, and scientists hope long COVID-19 patients will also benefit.

“One of the exciting things about this study is that it’s taking a targeted therapy approach to treating symptoms,” Andrews said. “It’s targeting the mechanism behind fatigue — chronic inflammation — to see if it helps.”

In addition to testing whether RSLV 132 outperforms a placebo when it comes to alleviating fatigue in long COVID-19 patients, researchers will collect tissue samples that they’ll study to get a better picture of how it might be working (if it does), he said. If it turns out that some patients respond and some don’t, such samples could also help investigators figure out why.

And, if there’s a similar biological process underpinning the fatigue seen in long COVID and other diseases and syndromes, the study could benefit a wide array of patients, Andrews said.

That’s a hope that other members of the working group also harbor. One of the big questions, said Chow, is whether long COVID-19 patients are suffering from the same immunologic problems as patients with chronic fatigue syndrome, autoimmune diseases, or other virus-associated chronic damage. Or is there something unique about the biology behind long COVID-19?

Bender Ignacio sees potential for the close ties between the CCRC and the long COVID-19 working group to help fast-track promising treatments or treatment strategies that emerge from group members’ projects.  

Working toward a more certain future

One thing Chow hopes come from the studies is more predictability. Right now, clinicians struggle to determine whose symptoms will last, and whose will resolve. A better understanding of long COVID-19 subgroups will help clinicians guide patients toward the best therapies for them. Improving doctors’ ability to diagnose and clinically characterize long COVID-19 will also help improve insurance reimbursement, he said. Right now, he stressed the need to recognize and validate what patients with long COVID-19 face.

Macnofsky, who at one point couldn’t take a phone call from a friend without falling back into a zombie sleep, feels fortunate. She joined Facebook groups organized by long COVID-19 sufferers, where many reported not just horrible symptoms but job loss and crushing debt. Macnofsky’s leave of absence from her career was fully supported — emotionally and financially — by her husband. She’s recovered enough now to step back into some job duties, though not at her previous level. But she knows other patients who continue to suffer, with no idea when — or if — their symptoms will ever improve.

On top of everything else, her uncertain future is one of the biggest challenges Macnofsky faces Luckily, she said, her “keep calm and carry on” attitude (and compassionate family) are helping her ride her waves of symptoms.

“There’s a mental health component to being so ill,” Czartoski said. She still encourages patients to treat themselves gently and take it one day at a time. While most will improve with time, a few will worsen — and she still can’t tell someone which patient they’ll be. The answer will only come with more data.

“I’m still collecting everything I can,” Czartoski said.

USC researchers identify symptoms associated with increased risk for long COVID

Authors: Corinne Purtill Wed, July 20, 2022 Los Angeles Times Published Scientific Reports

From the start of the pandemic, patients and doctors alike have been frustrated by the sizable minority of coronavirus infections that turn into long COVID, a perplexing collection of lingering and often disabling symptoms that persist weeks, months or years after the initial infection subsides.

The condition has been reported in both children and adults; in those who had preexisting conditions and those in robust health; in patients hospitalized with COVID-19 and those who experienced only mild symptoms during their initial infection.

new study from researchers at USC offers some insights into the prevalence of long COVID and suggests some early clues for who might be more likely to develop long-term symptoms.

The study, published this month in Scientific Reports, found that 23% of people who had coronavirus infections between March 2020 and March 2021 were still reporting symptoms up to 12 weeks later.

Researchers recruited roughly 8,000 people, some infected and some not, to answer biweekly questions about their overall health and COVID-19 status. By the end of the yearlong survey period, they had a sample of 308 people who had gotten the disease at some point in the year.

After filtering out respondents with symptoms such as headache and fatigue prior to infection as a result of unrelated conditions like seasonal allergies, the team found that nearly 1 in 4 COVID-19 sufferers were still grappling with symptoms 12 weeks after becoming infected.

“These people are not able to do necessarily all the activities they would want to do, not able to fully work and take care of their families,” said Eileen Crimmins, a demographer at USC’s Leonard Davis School of Gerontology and a coauthor of the study.

“That’s an aspect of this disease that needs to be recognized, because it’s not really as benign as some people think,” she said. “Even people who have relatively few symptoms to start with can end up with long COVID.”

Determining who is at greater risk for long COVID has proved a challenge to demographers and healthcare providers.

Several previous studies have identified women as being at greater risk. But the USC study found no relationship in its sample between long COVID and age, gender, race or preexisting health conditions including cancer, diabetes, hypertension and heart disease.

It did note a higher risk in patients who had obesity prior to infection. And it also spotted some associations between specific symptoms people experienced during their initial infection and the likelihood of developing long COVID. Patients who reported sore throats, headaches and, intriguingly, hair loss after testing positive were more likely to have lingering symptoms months later.

“Our assumption is that that hair loss reflects extreme stress, potentially a reaction to a high fever or medications,” Crimmins said. “So it’s probably some indication of how severe the illness was.”

Because it covered only the first year of the pandemic, the study doesn’t account for two major developments: vaccines and variants. None of the COVID-19 patients in the sample were eligible for vaccines during the study period, and all were infected before the Alpha variant from the U.K reached U.S. shores.

While the study’s 308 respondents were representative of the population, no snapshot of a few hundred people can tell the whole story of the roughly 200 million people in the U.S. who have had the virus, according to estimates from the Centers for Disease Control and Prevention.

“The authors made a commendable effort to identify factors associated with long COVID,” said Dr. Alain Lekoubou Looti, a neurologist at Penn State University who was not involved with the study. “However, these factors may need to be confirmed in larger samples.”

The most common long COVID symptoms reported were headache, nasal congestion, abdominal pain, fatigue and diarrhea. But the study did not address many of the symptoms people living with long COVID describe as the most debilitating, said Hannah Davis, a co-founder of the Patient-Led Research Collaborative, a research group that focuses on the condition.

“We need work like this, but this work also indicates they aren’t very familiar with what long COVID is,” Davis said. “The list of symptoms are predominantly acute COVID symptoms and don’t include the most common symptoms of post-exertional malaise, cognitive dysfunction, memory loss, sensorimotor symptoms and others.”

Defining long COVID presents a challenge to those attempting to track or treat it. COVID-19 is a chimerical beast — symptoms evolve as the condition drags on, and can vary widely among patients.

The fluidity of long COVID makes it hard to gauge its prevalence. Various studies have placed the percentage of people reporting enduring symptoms 12 weeks after their initial infection at anywhere from 3% to 50%.

“We need a universal case definition before we can really understand the prevalence of long COVID. Right now, the definition varies wildly across studies, leading to a big range in prevalence estimates,” said Jana Hirschtick, an epidemiologist with the University of Michigan’s School of Public Health. “After all this time, we still don’t have a clear picture of who is at greatest risk.”

The absence of strict diagnostic criteria is also a major issue for patients attempting to seek treatment. At the moment, long COVID is considered an “exclusionary diagnosis,” meaning one that is given only after all other valid possibilities have been ruled out, said Melissa Pinto, an associate professor of nursing at UC Irvine who studies the condition. In the U.S., that can mean a long and expensive process of submitting to various tests and specialists.

For many long COVID patients, 12 weeks is just the beginning of a months- or years-long ordeal.

“I’ve known people that have had this now for 2½ years,” Pinto said. “There’s no safety net, really, for these individuals.”

New England Journal of Medicine: “Conspiracy Theory” confirmed

The America First Report breaks the story: July 12, 2022

Several recent studies have indicated the Covid-19 vaccines actually increase the risk of contracting the disease over time, but these studies have been ignored or even debunked by corporate media and Big Pharma for months. Now, they’ll have to contend with a new study published in the highly respected New England Journal of Medicine.

This study was huge in scale, sifting through data collected from over 100,000 people infected by the Omicron variant. It lends credibility to the statistical significance of the findings, which are absolutely startling. Here are the key points:

  • Those who have been “fully vaccinated” with two shots from Moderna or Pfizer are more likely to contract Covid-19 than those who have not been vaccinated at all
  • Booster shots offer protection approximately equal to natural immunity, but the benefits wane after 2-5 months
  • Natural immunity lasts for at least 300-days, which is the length of the study; it likely lasts much longer

This jibes with the current narrative coming from Big Pharma and their minions in government and corporate media that the jabs are supposed to mitigate the effects. But even that claim has been called into question as recent studies indicate the vaccinated may be dying even more than the unvaccinated. According to The Exposé:

The Government of Canada has confirmed that the vaccinated population account for 4 in every 5 Covid-19 deaths to have occurred across the country since the middle of February 2022, and 70% of those deaths have been among the triple vaccinated population.

Despite the scope of the study and the credibility of the source, it will not receive any attention from corporate media. It is imperative that our readers get the word out because this is an absolute narrative-buster for Big Pharma. Now more than ever, we must alert the people of the truth because we are on the verge of seeing millions of children under the age of five-years-old injected.

Children do not readily acquire this pathogen, spread to other children, spread to adults, take it home, get severely ill, or die from it. It is that simple. We know children tend not to transmit Covid-19 virus and that the concept of asymptomatic spread has been questioned severely, particularly for children.

Children, if infected, just do not spread Covid-19 to others readily, either to other children, other adults in their families or otherwise, nor to their teachers. This was demonstrated elegantly in a study performed in the French Alps. The pediatric literature is clear science on this. Overwhelming data shows that the SARS-CoV-2-associated burden of severe disease or death in children and adolescents is very low (statistically zero).

Swedish data by Ludvigsson reported on the 1,951,905 children in Sweden (as of December 31, 2020) who were 1 to 16 years of age who attended school with largely no lockdowns or masks. They found zero (0) deaths. “Despite Sweden’s having kept schools and preschools open, we found a low incidence of severe Covid-19 among schoolchildren and children of preschool age during the SARS-CoV-2 pandemic.”

recent German study (collating evidence from three sources 1) a national seroprevalence study (the SARSCoV-2 KIDS study), 2) the German statutory notification system and 3) a nationwide registry on children and adolescents hospitalized with either SARS-CoV-2 or Pediatric Inflammatory Multisystem Syndrome (PIMS-TS)) reported that there were zero (0) deaths in children 5 to 18 years old across the period of study.

Governments and public health officials have driven this pandemic of fear and propaganda. But parents willing to assess this purely from a benefit versus risk position might ask themselves: ‘If my child has little if any risk, near zero risk of severe sequelae or death, and thus no benefit from the vaccine, yet there could be potential harms and as yet unknown harms from the vaccine (as already reported in adults who have received the vaccines), then why would I subject my child to such a vaccine?

Because the life of your child (or yourself) is a price the purveyors of this genocide are entirely willing to pay in exchange for a nice, fat paycheck.

Comport yourselves accordingly.

Understanding COVID-19 through genome-wide association studies

Authors: Tom H. Karlsen  Nature Genetics volume 54, pages368–369 (2022)Cite this article

8742 Accesses 1 Citations 87 Altmetric

Defining the most appropriate phenotypes in genome-wide association studies of COVID-19 is challenging, and two new publications demonstrate how case-control definitions critically determine outcomes and downstream clinical utility of findings.

Exploring self-reported data from more than 700,000 participants in a direct-to-consumer ancestry genetics company, in this issue of Nature Genetics, Roberts et al. report how several commonly used phenotype definitions in COVID-19 genetics studies converge to represent either susceptibility to infection by the SARS-CoV-2 virus or risk of severe COVID-19 disease1. For pragmatic reasons, early genome-wide association studies (GWAS) in COVID-19 focused on hospitalized cases compared with unscreened and often previously genotyped controls2,3. While allowing for rapid assessments during the first and very challenging wave of the pandemic, such study designs are biased towards the biology of complications in COVID-19. The emphasis on patients with mild or no symptoms, including identification of household COVID-19 exposure as a high-risk measure, allowed the authors to conduct a deep investigation of susceptibility to SARS-CoV-2 infection through comparisons such as exposed individuals who tested positive for COVID-19 versus exposed individuals who tested negative. Not only did these assessments corroborate the controversial ABO locus as a bona fide susceptibility gene for SARS-CoV-2 infection2,4, they also suggested the presence of a hitherto unexplored pool of protective variants.

In a dedicated query of rare variants (minor allele frequency (MAF) < 0.005), also reported in this issue of Nature Genetics, Horowitz et al. identified an association signal between a non-coding X chromosome variant (rs190509934) upstream of angiotensin-converting enzyme 2 (ACE2) and protection against SARS-CoV-2 infection5. The authors go on to substantiate their finding using RNA sequencing – data from liver tissue, showing that the protective allele leads to an almost 40% reduction in ACE2 expression levels in carriers. The association inherently holds considerable plausibility, with the membrane-bound ACE2 serving as the binding site for the SARS-CoV-2 spike glycoprotein, initiating virus cell entry6. Furthermore, Horowitz et al.5 and Roberts et al.1 utilize rich phenotype data to dissect the chromosome 3p21.31 association into a susceptibility signal and a severity signal, which localize to SLC6A20 and LZTFL1, respectively, as also observed by others7SLC6A20 encodes the sodium–imino-acid (proline) transporter 1 (SIT1), which functionally interacts with ACE2 (ref. 8), and the risk allele has been shown to associate with increased expression of SLC6A20 (ref. 2). Along with data suggesting that the receptor-binding domain of the SARS-CoV-2 spike protein preferentially interacts with blood group A9, which is encoded by the risk variant at the ABO locus, genetics of the susceptibility to SARS-CoV-2 infection appear to converge on the cell entry apparatus for the virus.

Critical illness in COVID-19 develops in fewer than 10% of individuals infected with SARS-CoV-2 (ref. 10). Given the window from the first symptoms of COVID-19 to onset of severe disease with respiratory failure (typically about one week)10, prediction of a severe disease course following SARS-CoV-2 infection is of considerable clinical interest as well as from a therapeutic point of view. Reliable risk stratification may guide therapeutic interventions during this lead-in period, characterized by enhanced viral replication. These interventions potentially include antiviral therapies, convalescent plasma, neutralizing monoclonal antibodies or — possibly more important for hospitalized patients — immunomodulating drugs.

Horowitz et al. found that a high genetic risk score (top 10%) based on six established severity variants was associated with a 1.65-fold and 1.75-fold higher risk of severe disease, in individuals with or without the presence of clinical risk factors such as age and diabetes, respectively5. Others have found an odds ratio of 2.0 for the impact of the rs10490770 risk allele at the 3p21.31 locus on the combined end-point of death or severe respiratory failure in an overall COVID-19 patient population11, with almost double the effect size in individuals 60 years or younger (odds ratio of 3.5). These magnitudes are comparable with those associated with clinical risk factors. Findings of lower age in individuals homozygous for the chromosome 3p21.31 risk variant support enhanced utility of genetic risk stratification in the young patient population2.

The execution of GWAS in COVID-19 has been remarkably nimble, due in part to robust collaborative networks set up during past GWAS12, as well as the utilization of previously genotyped study populations such as the UK Biobank, AncestryDNA and 23andme1,3,4,5. The rapid phenotyping undertaken by several biobanks and direct-to-consumer genetics companies during the COVID-19 pandemic is unprecedented, and the resulting publications deserve acknowledgement as a form of ‘population-level testing’ for genetic clues in emerging diseases. The orchestration of projects by the COVID-19 Host Genetics Initiative has also been an important catalyzer of activities13. Figure 1 summarizes published and peer-reviewed GWAS articles on COVID-19. However, even at time of writing, the meta-analysis of the sixth data freeze of the COVID-19 Host Genetics Initiative has been released online, reporting on a total of 23 loci involving in COVID-19 susceptibility (7 loci) and severity (15 loci); adding 10 new loci to the consortium’s own publication only 3 months ago7. The 22-month period that has passed since the publication of the first COVID-19 GWAS2 appears even more impressive in comparison with the 7 years of Crohn’s disease genetics — spanning from the 2001 nucleotide-binding oligomerization domain 2 (NOD2) susceptibility gene discovery to a 2008 meta-analysis14,15 — that it took to achieve the same amount of insight. Further exemplified by the 20-year history of genetics of Crohn’s disease, translational studies of GWAS findings take time, but may reveal new and unexpected aspects of pathophysiology. It is in this context that the rapid unravelling of COVID-19 genetics becomes important. Some of the loci hold immediate biological plausibility (for example, ACE2 and some of the chemokines), whereas the underlying mechanisms of others remain obscure. Following this recent sprint of COVID-19 GWAS to which Horowitz et al.5 and Roberts et al.1 significantly contribute, the subsequent translational ultramarathon of biological studies can begin — and with this a deeper understanding of the pathophysiology of SARS-CoV-2 infection and its complications will emerge. Vaccination has proven the ultimate protection against SARS-CoV-2 infection. The hope is that the biological insights provided by COVID-19 GWAS will facilitate identification and development of novel treatment options of not only hospitalized and critically ill COVID-19 patients, but also treatment modalities that can prevent hospitalization.

figure 1
Fig. 1: Genetic loci from COVID-19 GWAS in peer-reviewed publications to date.

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THE MYSTERY OF LONG COVID: BRAIN FOG, FATIGUE, EVEN SEXUAL DYSFUNCTION

Duke doctors share insights on the illness during a media briefing

Authors: STEVE HARTSOE MARCH 9, 2022 IN RESEARCHMEDICINE

Thousands of COVID-19 survivors continue to grapple with symptoms many months after they were first infected. Brain fog, fatigue, even sexual dysfunction are among the symptoms people endure weeks and months after their acute COVID symptoms fade.

On some occasions, the virus reveals a pre-existing disease or causes another to inflict the patient.

But there is still much unknown about so-called long COVID, which ongoing research at Duke University and elsewhere aims to clarify.

Two Duke pulmonologists spoke Wednesday with the media about symptoms, treatments and what remains unknown about long COVID.

ON WHAT CONSTITUTES LONG COVID

Dr. Coral Giovacchini, a pulmonologist and critical care specialist with Duke Health and an assistant professor of medicine

“Groups have created different definitions and so what we initially mean now, when we talk about long COVID is symptoms that last beyond the four weeks of what we would consider the acute illness.”

“… And the NIH is defining this still currently as anything after four weeks, and this is an evolving definition for us.”

“Long COVID itself can include a host of different symptoms after the acute infection, it’s usually an extension of what you have sometimes from your acute infection, but can also include other new things. The most common things that we see are persistent fatigue and persistent shortness of breath symptoms, it can also include a bunch of different things like palpitations, things that we’ve heard referred to as brain fog, memory issues, ongoing insomnia problems, neuropathic problems and a host of different things.”

Dr. Loretta Que, a pulmonologist with Duke Health and a professor of medicine

“When you look at the literature and when you look at what we see here at Duke, the literature quotes anywhere from 10 to 50% of patients can have long COVID or developed long-COVID symptoms. I think, on average, it’s about 30% that’s quoted.”

“Over here Duke we’re seeing numbers that are similar to that, if you look at that also is somewhat dependent on the symptom that you’re describing post-COVID because if you look at brain fog, even up to 80% of patients are quoting brain fog after COVID, so it is, it is a burden on patients and it’s a problem that they’re trying to deal with and that we’re trying to help them with.”

DIFFICULTY CONFIRMING SYMPTOMS ARE LONG COVID AND NOT A DIFFERENT ILLNESS

Dr. Loretta Que

“What I’m seeing with COVID is something similar to what I see with other chronic illnesses, so if you look at diseases like Lyme disease, for example, a lot of these patients can develop prolonged fatigue, fibromyalgia — that’s muscle aches and pains — difficulty concentrating, difficulty breathing. So all of those symptoms that I see with chronic diseases I’m also seeing with COVID and long COVID.”

“How do you tell the difference? It’s hard to know. We assess the patient when they come in. Our clinic at Duke primarily focuses on the lung effects of COVID. And so, if someone comes in and they’re complaining about shortness of breath or chest discomfort … post-COVID then we see them. And we often find that if they had some form of lung disease prior to COVID, then whatever symptoms they had before COVID have been amplified after COVID.”

“I think what we’re seeing is a combination of the acute effects of COVID and then the amplification of disease after they’ve had COVID.”

“COVID can unmask disease, (it) can be something predating or can be something that’s been unmasked or something new.”

Dr. Coral Giovacchini

“Another part of the definition that’s evolving right is that we want to make sure that there’s not something else going on, and so it’s really important for patients to present if you have these symptoms rather than just saying, ‘Oh, I have ongoing long COVID or post-viral syndrome.’”

“Because, and you know, even though it feels like it through this pandemic time, not everything is COVID and you really want to make sure that what we’re treating and what we’re seeing is not something else that’s maybe being masked by what you might think is COVID.”

ARE THERE ANY RISK FACTORS THAT CAN PREDICT LONG COVID?

Dr. Coral Giovacchini

“That’s another interesting question, another part of the literature that is sort of evolving as we follow this along. I think what people think of as historical risk factors for severe disease, so things like age, underlying comorbidity, … high blood pressure and diabetes are not actually the things that pan out in terms of risk factors for COVID … or for long COVID for some people.”

“That’s been quite a surprise, when they develop symptoms later or have ongoing persistent symptoms and the most consistent thing that’s been panned out so far in some of the cohort studies, in the literature, is the number of symptoms that someone presents with.”

“So if somebody has more than five different types of symptoms that they’re presenting with, with their acute COVID infection, that may predispose (them) to ongoing long COVID and symptoms. They don’t necessarily need to be the same symptoms, but that probably is something that predisposes, regardless of the initial severity of your disease.”

“So even patients who are managed as outpatient or have mild disease but have a host of symptoms when they present, may be more likely to get long COVID symptoms in the future.”

“It’s certainly not something that means that you will develop long COVID if you have that many symptoms, it’s just that that’s something that we’re seeing as a potential risk factor.”

“I think the other surprising thing for some patients and people following this is that again, it does not relate to the severity of your disease, so these patients can have had mild disease, or maybe a short hospitalization and still end up with long COVID symptoms. They’re also tending to be younger patients than we think of as those who might get severe disease.”

“Patients who are showing up with long COVID symptoms tend to be on the younger end of that spectrum. So maybe in the 40 to 55 range and even younger patients we’ve seen this pan out.”

THE LIKELIHOOD BREAKTHROUGH INFECTIONS LEAD TO LONG COVID

Dr. Loretta Que

“Well, we still are seeing long covid post-vaccination. The numbers are way lower so (there’s a) marked reduction in these numbers of patients that are presenting and … seem to be different than what we see with those who have not been vaccinated. So the severity of their post COVID seems to be reduced.”

“… When I look at their lung findings on a CT scan or chest X-ray or lung-function studies, they are not as affected as those who have not been vaccinated.”

HOW EFEFCTIVE ARE ANTIVIRAL MEDICATIONS IN LIMITING LONG COVID?

Dr. Coral Giovacchini

“I think that’s the hope for a lot of folks, but it is certainly too soon to know if it’s going to have a difference in terms of long COVID symptoms. I think … the goal of antivirals is to reduce the severity of disease and reduce the symptom burden, but again, long COVID can happen in patients who may or may not have had severe disease, and so it’s an area that will be interesting to see how that unfolds in the future as more patients get treated with antivirals that are coming out.”

ARE LONG COVID SYMPTOMS AS SEVERE AS IN THE ACUTE COVID PHASE?

Dr. Coral Giovacchini

“I think, for a lot of patients, because for some patients fatigue that goes on for months can be extremely debilitating and maybe more ‘severe’ for them in terms of their daily functioning, than perhaps their initial respiratory symptoms were up front.”

“And so I think it just it depends on the type of symptom that the patient is dealing with. … For a lot of patients, that can be very severe in terms of their ongoing daily life ability to function, particularly some of the brain fog and mental effects.”

HOW DOES LONG COVID AFFECT CHILDREN – VACCINATED AND UNVACCINATED?

Dr. Loretta Que

“Long COVID in children is an issue and we still don’t know the long-term impact of that.”

Dr. Coral Giovacchini

“There are data that are now coming out of countries who had higher (cases of COVID) before we did, and so we have a little bit longer-term data.”

“Countries like Italy and Israel and the UK … have shown that long COVID in kids is evolving and is becoming an issue for them, with rates of about 40% of kids still having ongoing symptom effects at an average of 162 days. So in that five and a half, six months follow-up range most of their symptoms can be things like fatigue, like adults have, but are also turning into some of the cognitive effects like memory attention disorders in kids and some anxiety.”

“Now, there has been a lot of question of this in the literature as whether or not these mental effects are coven related or pandemic related, which is going to be a whole other thing to figure out, especially in the children population.”

“But it is certainly something to follow in kids because what we’ve historically been talking about again is that this is mild disease in kids so even the children who are … outpatients can have ongoing effects and it’s something that parents and pediatricians need to be watching out for in the future, as we follow these kids along.”

WILL DIAGNOSING LONG COVID BECOME EASIER OVER TIME?

Dr. Loretta Que

“A lot of what we do in medicine is trying to unravel these puzzles. I think that’s a great question, because we have a lot of ongoing research that’s been done to help us … better identify these patients and the NIH is devoting research dollars to the development of new research platforms to help us in this endeavor. Right now, it’s a broad constellation of symptoms. I suspect it’s going to continue being a broad constellation of symptoms, just like when anybody presents with viral-like illness and we have to do an evaluation, but it might be that in the future, we might have a more targeted approach to doing so. That’s our hope.”

ARE THERE LONG COVID SYMPTOMS THAT SURPRISED YOU?

Dr. Loretta Que

“I’ve seen patients with sexual dysfunction with long COVID. It’s not a strange abnormality, but it’s odd for me because I’m a lung doctor and they presented with sexual dysfunction and pain.”

Dr. Coral Giovacchini

“Yeah, … I have seen the same, and I think that can be shocking for some patients. I would go back to the ongoing taste abnormalities for patients. I think a lot of patients feel like that is a very strange manifestation, even if they didn’t have loss of smell or taste. Some of their favorite foods can just be almost intolerable to them going forward and it’s a challenging thing we don’t have a treatment for. And so it can also cause a lot of weight-loss problems in patients or weight gain, depending on their taste alterations.”

WHAT SHOULD PEOPLE DO IF THEY SUSPECT THEY HAVE LONG COVID?

Dr. Loretta Que

“There are multiple studies that (are) looking at long COVID and not just within the pulmonary division and so, if you go to the Duke Hospital website, you can look at some of the different trials that are ongoing and see which one you might qualify for.”

(COVID studies open at Duke: https://www.dukehealth.org/clinical-trials/directory?can=Noncancer&condition=COVID-19; COVID repository: https://www.dukehealth.org/clinical-trials/directory/pro00105316)

Faculty Participants

Coral Giovacchini, M.D.
Dr. Coral Giovacchini is a pulmonologist and critical care specialist with Duke Health and an assistant professor of medicine at the Duke University School of Medicine.

Loretta Que, M.D.
Dr. Loretta Que is a pulmonologist with Duke Health and a professor of medicine at the Duke University School of Medicine.

COVID long-haulers: Study shows who is most at risk, impact on local communities

Authors:  Hiroshima University Medical Express Posted June 9. 2022

A Japanese research team looking at COVID-19’s lingering impacts on survivors and local communities found that having a mild case of COVID-19, smoking status, comorbidities, or your sex aren’t significant predictors to tell if you are less likely to develop long-term symptoms, but age is.

“The prevalence of sequelae did not significantly differ by sex, severity of COVID-19, place of medical care, smoking status, or comorbidities,” the research team, led by Hiroshima University Professor and Executive Vice President Junko Tanaka, said in their findings published in Scientific Reports.

The cross-sectional study explored four areas to investigate what recovery and community life are like for COVID-19 survivors. These areas are the persistence of symptoms, psychological distress, impairments in work performance, and experiences of stigma and discrimination. Some 127 patients who recovered from COVID-19 at two hospitals in Hiroshima Prefecture, Japan participated in the study between August 2020 to March 2021.

Although they found that smoking history and comorbidities were not significantly related to the frequency of long-term symptoms in the multivariate analysis, the researchers believe that these factors should be continued to be examined in the future since only 18 were smokers among the study participants. As for comorbidities, hypertension was reported only in 19 of the participants and diabetes in 13.

COVID-19 severity is not a risk factor

Persistent symptoms of COVID-19 were identified in over half of the participants at a median of 29 days after onset. Meanwhile, half of those with mild cases experienced lingering symptoms.

“The most important finding is that the percentage of patients with some sequelae after approximately one month from the onset of COVID-19 was as high as 52%, and even among those with mild disease, the rate was as high as 49.5%,” study first-author Aya Sugiyama, assistant professor at Hiroshima University’s Graduate School of Biomedical and Health Sciences, said.

Their findings are consistent with previous studies reporting that 53% to 55% of non-hospitalized COVID-19 patients get lingering symptoms.

“Several reports have pointed out that COVID-19 severity is not associated with sequelae. These findings suggest that COVID-19 patients should be followed up for persistent symptoms regardless of the severity of COVID-19,” the researchers said.

Older age is a factor

The prevalence of lingering symptoms varied by age group in the study, but the researchers found that older patients are significantly more likely to become long-haulers compared to those aged 40 and below. This is consistent with previous studies showing that long-haul symptoms were more likely with increasing age.

They also discovered age-dependent differences in the prevalence of symptoms. Patients aged 60 and above were more likely than other age groups to report fatigue, palpitations, dry eyes or mouth, dyspnea, and sputum production.

The researchers noted how long-haul symptoms are common in organs with high ACE2 expression. ACE2, the major cell entry receptor for SARS-CoV-2, is extensively expressed in numerous human organs such as the mouth, liver, and lungs.

“COVID-19 affects various tissues and organs, such as those in the respiratory, cardiovascular, and neurological systems,” they stated in the paper.

Common symptoms reported by long-haulers in the study included disorders in their sense of smell (15%) and taste (14.2%), cough (14.2%), and fatigue (11%).

Recovery and community life

Their findings also found that sex was not a risk factor for long-haul COVID symptoms, a contrast to another study in the BMJ that pointed out how they are twice as common in females as in males.

Sex and the presence of long-haul symptoms, however, were found to be predictors of psychological distress. Some 45% of females and 17.9% of males scored ≥ 5 on the Kessler Psychological Distress Scale (K6), meaning the risk of psychological distress was higher in women than men.

Stigma and discrimination due to COVID-19 were reported by 43.3% of participants. The most common complaints were being treated as contagious despite being cured (61.8%), harmful rumors (29.1%), and verbal harassment (25.5%).

Meanwhile, 29.1% of study participants had possible impairments in their job performance, suggesting that post–COVID-19 conditions may influence productivity at work to only a limited extent.

The researchers noted how their findings revealed significant health impacts of long-haul COVID symptoms in local communities. They hope to conduct a large-scale and long-term study.

“We would like to elucidate how long the aftereffects last and whether the actual aftereffects differ by viral variant,” Sugiyama said.

Diabetes may increase long COVID risk; COVID while pregnant linked to baby brain development issues

Authors: Nancy Lapid Thu, June 9, 2022,

The following is a summary of some recent studies on COVID-19. They include research that warrants further study to corroborate the findings and that has yet to be certified by peer review.

Diabetes may increase the risk of long COVID, new analyses of seven previous studies suggest.

Researchers reviewed studies that tracked people for at least four weeks after COVID-19 recovery to see which individuals developed persistent symptoms associated with long COVID such as brain fog, skin conditions, depression, and shortness of breath. In three of the studies, people with diabetes were up to four times more likely to develop long COVID compared to people without diabetes, according to a presentation https://eppro02.ativ.me/web/page.php?page=IntHtml&project=ADA22&id=1683 on Sunday at the annual Scientific Sessions of the American Diabetes Association. The researchers said diabetes appears to be “a potent risk factor” for long COVID but their findings are preliminary because the studies used different methods, definitions of long COVID, and follow-up times, and some looked at hospitalized patients while others focused on people with milder cases of COVID-19.

“More high-quality studies across multiple populations and settings are needed to determine if diabetes is indeed a risk factor” for long COVID, the researchers said. “In the meantime, careful monitoring of people with diabetes… may be advised” after COVID-19.

COVID-19 in pregnancy linked with babies’ learning skills

Babies born to mothers who had COVID-19 while pregnant may be at higher than average risk for problems with brain development involved in learning, focusing, remembering, and developing social skills, researchers have found.

They studied 7,772 infants delivered in Massachusetts between March and September 2020, tracking the babies until age 12 months. During that time, 14.4% of the babies born to the 222 women with a positive coronavirus test during pregnancy were diagnosed with a neurodevelopmental disorder, compared to 8.7% of babies whose mothers avoided the virus while pregnant. After accounting for other neurodevelopmental risk factors, including preterm delivery, SARS-CoV-2 infection during pregnancy was linked with an 86% higher risk of a neurodevelopmental disorder diagnosis in offspring, the researchers reported on Thursday in JAMA Network Open https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2793178. The risk was more than doubled when the infection occurred in the third trimester.

The researchers point out that their study was brief and cannot rule out the possibility that additional neurodevelopmental effects will become apparent as the children grow up. On the other hand, they note, larger and more rigorous studies are needed to rule out other potential causes and prove that the coronavirus is to blame.

The rare but life-threatening inflammatory syndrome seen in some children after a coronavirus infection has become even more rare with the Omicron variant causing most infections and more kids vaccinated, according to a new study.

Researchers looked at data from Denmark on more than half a million children and adolescents infected after Omicron became dominant, about half of whom experienced breakthrough infections after vaccination. Overall, only one vaccinated child and 11 unvaccinated children developed Multisystem Inflammatory Syndrome in Children (MIS-C), which causes inflammation in the heart, lungs, kidneys and brain after a mild or asymptomatic SARS-CoV-2 infection. That translates to rates of 34.9 MIS-C cases per million unvaccinated children with COVID-19 and 3.7 cases per million vaccinated young COVID-19 patients, the researchers said on Wednesday in JAMA Pediatrics https://jamanetwork.com/journals/jamapediatrics/fullarticle/2793024. By comparison, rates of MIS-C cases when Delta was predominant were 290.7 per million unvaccinated infected kids and 101.5 per million among the vaccinated who had COVID, they said.

The fact that MIS-C risk was significantly lower in vaccinated children suggests the vaccine is helping to keep the immune system from causing the deadly inflammatory reaction that is an MIS-C hallmark, the researchers said.