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It’s been a puzzle since the beginning: What is long Covid anyway? Who has it and who doesn’t?

At the beginning of the pandemic, people who didn’t die or get well right away were relegated to some “not really” status – people (including doctors and spouses) refused to believe that they hadn’t gotten well. Friends and relatives accused them of malingering. People were told it was all in their head.

Now, two years out, the nation and the world have more or less acknowledged that long Covid exists. But what is it exactly?

A large number of people – maybe as many as 10 to 30 percent of people who contract Covid, by most estimates – will have long-lasting symptoms. Yet without a diagnosis or a cause for their symptoms, without a treatment plan, they are still at sea.

Symptoms include fatigue, respiratory distress, cardiac problems, “brain fog,” gastrointestinal problems, hair loss, loss of the sense of smell and taste, onset of autoimmune diseases, kidney problems, reproductive health issues and multiple others – a list of several hundred is included by a patient-led research collaborative group on their paper published in The Lancet.

I’ve spent a lot of time talking to long Covid patients about their health. Some have made modest steps toward recovery. Yet many, lacking a formal diagnosis, aare still ill and feel forgotten. Others have learned – now, two years out – that their doctors have no solutions. Many have lost jobs or are unable to work; generally, they have a hard time getting disability pay because they don’t have a diagnosis. And still, many are having a hard time getting people to believe them.

So here is an attempt to describe long Covid, to establish a taxonomy, if you will – with a journalism lens and with some science thrown in – in an attempt to make sense of the landscape.

First, what do you call it?

The language changes. “Long Covid” is used by many. Others don’t like this because it suggests that Covid persists as an ongoing illness, while their view is that the continuing symptoms are a consequence of the initial infection.

“Long-haul Covid” was used early on, but fewer people use that now because it seems to get confused with “long-haul” as in the trucking industry.

“Post-Covid” or “post-Covid syndrome” is embraced by some – but others object because they think there might be a continuing ongoing infection.

The National Institutes of Health chose to call the entire landscape “post-acute sequelae of Covid,” or PAS-C.

We generally use “long Covid” because that’s what we started out with.

Your Local Epidemiologist has an outline

I’m a huge fan of Katelyn Jetelina, who writes over at Substack as “Your Local Epidemiologist.” She did a series in early March that was very informative and down-to-earth about long Covid.

She breaks it down into three categories based on cause:

Direct cell damage, she writes, occurs when the virus enters cells, multiplies and eventually kills a cell or all the cells in an organ. “This initial and direct cell damage can cause lingering or ongoing symptoms,” she writes. “For example, SARS-CoV-2 has shown to directly cause cell damage to the heart, thus leading to long-lasting arrhythmias.

A second big group, she writes, is patients who had long hospitalizations and were bed-bound for weeks. “Patients can show muscle weakness, cognitive brain dysfunction, and psychosocial stress. This is not unique to SARS-CoV-2, as this phenomenon occurs during all types of hospitalizations. In the medical world, we call this post-ICU care syndrome.”

Third, after recovery from the acute phase of illness, some people have further symptoms, she adds. There are two major theories about this, she writes:

  1. Viral persistence (lingering virus): “There has been considerable evidence that some people harbor the virus in their tissue. These viral reservoirs can both cause direct damage to cells and leak viral particles into the blood, where they can create microclots, activate inflammation, and ultimately cause more damage,” she writes, in “different tissues, including the esophagus, thyroid, and spleen.”
  2. Immune system: “The second theory is that long COVID symptoms are driven by the immune system. This can be caused by micro-blood clots … which have been shown to conceal autoantibodies. Then the body starts attacking itself. The other thing that may happen is immune dysregulation. Even if the body cleared the virus, the immune system is off balance, allowing other dormant viruses to reactivate, like herpes or a parasite called Toxoplasma. These then drive chronic symptoms.”

She concludes, “In reality, the cause of long COVID for most people is likely a combination of pathways.”

The National Institutes of Health study

A national study called “RECOVER,” of “post-acute sequelae of Covid,” the N.I.H. name, was launched to define the landscape.

“RECOVER, a research initiative from the National Institutes of Health (NIH), seeks to understand, prevent, and treat PASC, including Long COVID. PASC stands for post-acute sequelae of SARS-CoV-2 and is a term scientists are using to study the potential consequences of a SARS-CoV-2 infection,” the Recover site says.

The effort is funded by tax dollars. The site says: “Congress gave $1.15 billion to N.I.H. to study the long-term health effects of SARS-CoV-2 infection in late December, 2020. … Money provided by the government for research or programs can be called grants, contracts, or awards, including subawards. Early in 2021, awards were given to 30 groups. This includes researchers from hospitals, health centers, and other places….

“In early fall 2021, the NIH gave $470 million to the RECOVER Clinical Science Core (CSC) to begin to put together a network of sites across the country to study Long COVID. The CSC is led by New York University (NYU) Langone Health and includes more than 100 researchers from more than 25 places that have hundreds of research sites across the country doing studies.”

Not a few critics

While the effort seems broad, it has recently come under criticism, Rachel Cohrs wrote recently in Stat.

“There is a growing chorus that the study itself is far too broad and too focused on observing patients — and that the agency can make more of a difference if it studies treatments and therapeutics, too,” she wrote.

“ ‘It’s maddening that the N.I.H. has decided to direct this massive amount of funding toward a four-year-long data collection project. … Their goals do not match the goals of people who are suffering,’ said Diana Berrent, founder of the long Covid patient group Survivor Corps.

“Even putting aside debate over the NIH study’s design, the enrollment numbers are minuscule. The study is meant to enroll 40,000 adults and children, but by March 18, it had signed up just 1,366 — 3% of the goal. And that’s after NIH gave nearly $470 million to New York University Langone Health in September to coordinate the recruitment effort,” Cohrs wrote.

“A Mount Sinai standalone patient registry has recruited almost 1,600 patients since spring 2020. And the Mayo Clinic pulled in more than 200 patients since Jan. 2021, and expects another 100 by the end of April. The recruitment at these facilities is

Patient-led research

In reporting for this article, I asked Dr. Dave Lee, a New York emergency room doctor who has done his own research on Covid, whose research he finds exemplary. (Disclosure: I took part in a study Lee was running on Covid in the summer of 2021.)

He said he looks to research by the Patient-Led Research Collaborative as groundbreaking. The patients leading the research, including Hannah Davis, Hannah Wei, Gina Assaf, Dr. Athena Akrami and Lisa McCorkell, all contracted Covid in March 2020. They are familiar with the trajectory of the disease, and also with the social, logistical and political issues surrounding it – for example, the lack of testing capacity early on resulted in a large number of patients with no positive proof that they had Covid, who were therefore excluded from studies of confirmed patients.

That group has done several studies and has an ongoing data collection effort.

One study, “Characterizing long COVID in an international cohort: 7 months of symptoms and their impact,” was published in The Lancet.

“Patients with Long COVID report prolonged, multisystem involvement and significant disability. By seven months, many patients have not yet recovered (mainly from systemic and neurological/cognitive symptoms), have not returned to previous levels of work, and continue to experience significant symptom burden,” the study said.

They added: “Overall symptom prevalence in 10 organ systems was estimated for a total of 203 symptoms (see Methods, Appendix A for list of symptoms). Table 3 summarizes these prevalence estimates for 18 categories (nine non-neuropsychiatric organ systems: systemic, reproductive/genitourinary/endocrine, cardiovascular, musculoskeletal, immunological and autoimmune, HEENT, pulmonary, gastrointestinal and dermatologic in Fig. 2, and nine neuropsychiatric sub-groups: cognitive dysfunction, speech and language, memory, headaches, smell and taste, sleep, emotion and mood, hallucinations, sensorimotor in Fig. 3, see Appendix F Table S6-S23 for raw data). Almost all participants experienced systemic (99.7%, 95% confidence interval 99.49% to 99.84%), and HEENT (100%) symptoms. Musculoskeletal, cardiovascular, gastrointestinal, pulmonary, and neuropsychiatric symptoms were prevalent in >85% of participants (further detail in Supplemental Tables S5-S21). The top three most debilitating symptoms listed by patients were: 1) fatigue (n>2652), 2) breathing issues (n>2242), and 3) cognitive dysfunction (n>1274). Participants experienced an average of 55.9+/- 25.5 (mean+/-STD) symptoms during their illness.”

Here’s a snapshot of part of their chart of symptoms. Their web site also has guidelines for Covid researchers to use a symptom list that corresponds with their research.

 

Patients express concern about NIH work

Reacting to the RECOVER work by the N.I.H., the Patient-Led Research Collaborative issued a list of concerns last November, in an open letter that is also posted on its site. The patient-led group objected to the methodology, to the words used, to the goals and many other points.

Among other points, the patient-led group wrote, “To our knowledge, there is no central, comprehensive, accountable, ongoing and staffed community/patient advocacy or engagement structure ensuring meaningful involvement of people with Long COVID. Any structure that may have been developed lacks transparency, as multiple central groups of patients with Long COVID are unclear what that structure is. Patient involvement can include being informed of research opportunities, recruited for outreach, or invited to one-off listening sessions. However, meaningful involvement must include deep and ongoing engagement with patient leaders who are accountable to both their communities and each other, in specific, defined positions ‘at the table’ with RECOVER investigators and staff.“

The patient-led group also wrote, “The recruitment of patient representatives was rushed and only provided three days’ notice with a requirement to attend daily, multi-hour meetings for the following two weeks. Rapid deadlines are also unreasonable when the population providing feedback is dealing with often debilitating symptoms. Patients were treated dismissively in conversation and often needed to say the same thing multiple times to be heard, if acknowledged at all. Patients’ lived and past expertise have been ignored, even when they have medicine and healthcare backgrounds, or are among the most central and knowledgeable of Long COVID leaders in networks with thousands of people around the United States and world.“

Further, the patient-led group wrote, the RECOVER initiative “shows a neglect of post-viral illness, and is not grounded in post-viral illness expertise or inquiry” including things like myalgic encephalitis- chronic fatigue syndrome.

It also places an emphasis on recovery, the group said, stigmatizing those who do not recover.

The emergency room doctor

Lee, who has studied various kinds of long Covid, has several general buckets for long Covid, based on symptoms in general.

One of those buckets is the post-viral autoimmune category: After being infected with Covid, a patient gets diabetes, Guillain-Barre syndrome, Kawasaki disease and so on. Lupus has been observed post-Covid, also.

Beyond that, he referred to “big clusters.”

Respiratory symptoms affect 70 to 80 percent of long covid patients, he said.

Another big cluster is dysautonomia symptoms, he said, or problems with the autonomic nervous system — governing involuntary body functions like digestion, heartbeat, breathing and so on. “That’s very broad – it encapsulates a lot of organ systems. It’s every involuntary function,” he said. “It crosses systems. So when you say ‘gastrointestinal,’ I don’t think of it as GI, but as dysautonomia.” The dysautonomia patients comprise about 20 to 30 percent of patients, he said.

A third big bucket, he said, is neurological. The brains of patients with long Covid from biobank and autopsy studies, plus NIH findings, show neurological damage. “All of the above can have elements of neurologic symptoms,” he added.

Vascular issues, clotting

The effects of vascular issues throughout the body are also interesting, he said. He thinks the microvascular thrombosis in the lung and brain is at the root of respiratory and neurological consequences.

“I think we clearly know there’s like endothelial activation, damage and potential vascular inflammation, and that kicks off the thrombotic process,” he said. “But what causes that is still not clear. I think it’s autoimmune, other people think it’s various things.

“What was surprising to me was that I saw this article in the New England Journal [of Medicine] in May 2020, where this person very clearly stated that based specialized testing of scans and stuff that it looked like patients had a vascular disease when they had COVID,” which was startling because at that time, it was widely assumed that Covid was respiratory. But to this day, some patients have clotting in their lungs he described as “microthrombi,” he said, which is why he is recruiting for a study about that.

“Honestly, I think COVID pneumonia is not so much a viral pneumonia, rather, it’s a post-viral autoimmune attack for the lungs, and typically disrupts the vessels causing thrombosis,“ he said.

Why is it so hard for medicine to figure out what’s going on? “people develop a specialty and expertise, and then it’s a challenge to recognize that maybe one doesn’t have all the answers,” Lee said. “So when a patient has a condition that doesn’t fit into all the square boxes that you learned about during training, you basically decide that the patient must not be thinking right. Because it doesn’t square with anything that you learned.”

A big topic of conversation among long Covid patients is inflammation — which is a term that encompasses a lot of situations.

‘Medium’ Covid

To further complicate matters, there are some people who aren’t completely flattened by their post-infection symptoms, but are still ill. One such person is Nina Feldman, reporter for NPR station WHYY in Philadelphia, who wrote about her experiences recently.

It is “very common to take weeks to fully recover — a condition I’ve been thinking of as ‘medium Covid,’ ” she wrote. She said she’d been reporting on Covid for months, but was completely surprised by her experiences of “what an infection would be like for a young, otherwise healthy person like me.”

“Like so many Americans, I got COVID-19 over Christmas. I was vaccinated and boosted, and my case was indeed mild: sore throat, sinus pressure and headache, extreme fatigue. After eight days, I was feeling better, and I tested negative two days in a row using rapid antigen tests. I was anxious to get back out into the world. …

“Not quite. Soon after ending my isolation, I had dinner at a friend’s house. One glass of wine left me feeling the next day like I’d had a whole bottle. I was bone-achingly exhausted but couldn’t sleep that night.

“In the days and weeks that followed, as I managed the insomnia, I was also contending with bouts of extreme fatigue brought on by physical activities that are usually easy and even energizing for me: going for a long walk in the cold, riding an exercise bike, taking a sauna. The waves of fatigue, which I started calling ‘crashes,’ felt like I was coming down with a sickness in real time: weakened muscles, body aches, the feeling that all you can do is lie down. The crashes lasted for a couple of days, I’d recover slowly, and the cycle would inevitably repeat when I would accidentally push myself beyond my new and unfamiliar limit. It took me about six weeks to start feeling better.”

Struggling to get a diagnosis

The difficulty in defining long Covid underpins a series of reflections by patients saying that their doctors refuse to believe them, their insurers refuse to pay, that their friends and spouses reject the idea that they’ve been so ill for so long – suggesting that the illness is all in their head.

Doctors are among the long Covid patients facing skepticism over their illness, David Tuller wrote recently in CodaStory.

“Given persistent shortages in protective gear, medical professionals in the U.K., U.S. and elsewhere have been hard-hit by Covid — and by long Covid, the disabling condition that can follow. Many have been shocked that their own clinicians and colleagues have dismissed or expressed disbelief about their continuing symptoms,” Tuller wrote.

“They are also angry that members of their profession are publicly hyping and researching the notion that long Covid is mainly generated by pandemic-related emotional and psychological distress. “

Jeanne Pinder

Jeanne Pinder  is the founder and CEO of ClearHealthCosts. She worked at The New York Times for almost 25 years as a reporter, editor and human resources executive, then volunteered for a buyout and founded...