Responses to Participant Questions

Response:

Dr. Nikolich: They were somewhat surprising because much of the literature was suggesting incidence in older
adults may be higher. But when we think about the mechanisms, and when we think about what you mentioned
about other post-viral syndromes, we are seeing similar curves of incidence, certainly in myalgic
encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long Lyme. I think that the issue of relatedness to
other post-infection syndromes is really, really important. In fact, my group has gotten some funding to study that
very topic. We’re not thinking that Long COVID is the same as ME/CFS, but they do share many features, so
distinguishing what is similar and what is not similar, particularly at the level of molecular signatures and the
potential mechanisms of the disease, is going to be very important going forward.

Response:

Dr. Nikolich: One would be to go to the weaknesses of our study, the limitations, and try to correct as many of
those as we can. One of those would be to study this very same group at another couple of time points, because
fortunately, with RECOVER being a longitudinal study, we do have more time points. We know about the evolution
of symptoms. A Long COVID trajectories manuscript will be published soon. I don’t know how much the authors
specifically focused on age, and that’s certainly something to revisit. The second limitation is about age-sensitive
questions, where we could re-contact and re-ask some of our participants and make sure that we don’t miss some
of the things that Dr. Russell mentioned. For example, was a respondent too tired answering question number 75
on the questionnaire, or was there some other reason why they didn’t want to go any further? The third really
important one is that, mechanistically, we think that lower responsiveness of their immune system and their
inflammatory system could be protecting older adults from Long COVID, and we can study that based on the
results of the samples that were collected across the study. So that is one of the things that we’re continuing to do
and hope to do in greater granularity.

Responses:

Dr. Russell: I think when you’re caring for an older adult, one of the biggest things is to not anchor on any
particular diagnosis. The clinical picture for everyone is very different and sometimes very complicated. It’s really
important to always have Long COVID as a possibility, but also make sure you’re not ruling out other things. One of
the examples I gave during my talk is whether brain fog could be a side effect of a medication. You wouldn’t want
to miss that, so I think it’s important to understand the symptom clusters and know that it’s definitely a possibility,
but I think it’s also important to really take a step back and look at the whole patient when making these diagnoses
to make sure you’re not missing anything.

Dr. Nikolich: Having these symptoms you mentioned might lead a practicing physician to think about if
somebody’s presenting with a prolonged history of loss of smell and taste that wasn’t there before, they should
probably consider Long COVID as part of their diagnostic set. But I couldn’t agree more that one of the worst things
that you can do is say, oh, I read this in a textbook, and this is how it’s going to be for this patient. For our geriatric
patients, that’s almost never the case. You really have to keep an open mind.

Responses:

Dr. Russell: I can start by saying that a lot of the management strategies are individualized now, based on focusing
on symptom relief and rehabilitation and multidisciplinary care. There are studies looking at potential
pharmacologic management of Long COVID, but they really are investigational at this point, so I know that there’s
some research, and perhaps Dr. Nikolich can go into more detail looking at things like metformin, low-dose
naltrexone, and colchicine.

Dr. Nikolich: The first round of RECOVER-based clinical trials has still not been unblinded, meaning that we don’t
know the results yet, and those were targeting virus and viral persistence, which is a difficult topic to study
because the virus is not very obvious. It’s actually hiding, and if it is still present, you need very sensitive laboratory
measures to detect it. If we don’t get a signal from that study, it may not mean that we have conclusively set that
issue aside. In the meantime, however, you mentioned many other studies, Dr. Russell, that metformin has shown
some anecdotal and early trial promise. Naltrexone has relieved symptoms in many people, and RECOVER-TLC is
prioritizing it for the next generation of clinical trials. Another important and interesting drug is baricitinib, which is
an immune suppressant. This drug trial could support (or not) our hypothesis that Long COVID may be immune
mediated, at least in some people. If so, baricitinib should quiet things down, and it may bring those high-risk
groups of 40 to 49 or 50 to 59 lower and closer to the older adults in how they manifest their symptoms. But for all
these treatments—first, none of them are specifically targeting older adults as of now. Second, one of the
problems that we’re facing in general with geriatric medicine is that in many clinical trials, older adults are
underenrolled. We don’t have enough of them, and they’re not targeted as a population. That is something that
we need to very carefully think about and make sure that any forward-going studies, particularly within RECOVER,
enroll enough people of the appropriate age groups. That goes for children as well. Pediatricians will tell you that
children don’t get enrolled enough, but older adults are even more underenrolled than children in many cases, so
we really need to understand what’s happening in these vulnerable groups. Eventually, what we would like to do,
which is completely consistent with what you have heard from Dr. Russell, is that we need to go to this level of
individualization and precision medicine, not only at the level of treatments, but also of enrollment into the trials.
In other words, by clinical symptoms and by molecular biomarkers, we need to know exactly what people’s profiles
are, and these different profiles are going to require different treatments. If people are coming with 200 to 300
symptoms, it’s unlikely that a single drug treatment will take care of all of them. We’re very likely to need
combinations of treatments, and we’re very likely going to need different combinations of treatments for different
clusters of symptoms and maybe biomarker signatures as well.

Responses: 

Dr. Russell: Speaking from our literature review standpoint, we were looking at papers that categorize patients
aged 65 or older. Sixty-five-plus is generally considered older. I did come across one paper in our literature review
that classified older than age 35 as older, which made me roll my eyes. But, generally speaking, 65 or above is
considered older.

Dr. Nikolich: I would add that aging is a continuous process. The first age-related change that happens in our body
happens to the gland called the thymus that sits above our heart; it’s making T cells. That gland basically loses 90%
of its mass and of its production of new T cells by the time we’re in puberty. Somebody could argue that this is the
beginning of aging, and immunologically, it probably is, actually. But 65 has always been considered a definition
that probably came more from the Social Security Administration than from anybody in science. Immunologically,
when people ask me, when is your immune system starting to age? Well, we know that at 45, it’s starting to age,
so not at 35. But if you analyze the death curves from these outbreaks of new infections, which is the best and the
most sensitive index for older adults, with coronavirus, West Nile virus, and a bunch of other infections including
SARS-CoV-1, you start seeing that the group of 45 to 54 is about 2 to 3 times more likely to die than those younger
than them. Then that gets worse and worse. It’s this logarithmic curve that goes very high up very quickly, so as I
mentioned, by the time you’re 85 with SARS-CoV-2 or other infections, you’d be 2 to 300 times more likely to die
than people in the 18 to 39 age group.

Response:

Dr. Nikolich: I have been, during acute COVID, very much on the forefront of that type of research, and it’s interesting. People with autoimmune diseases are more likely to have exaggerated immune reactions. A Long COVID story in that group, surprisingly, did not really show an enormous association. It was checkered. Some people had it, and some people didn’t. Even when you look at their responses to the vaccine, they were not uniformly compromised. So it’s a really interesting topic to study. I intend to bring this back to my colleagues and see if we can mine the RECOVER study and figure out some of these answers from the vast datasets that we have. It’s not a clearly settled issue. There’s not a clear link; there is no doubt that in the complex diseases, like Long COVID, ME/CFS, and others, there will be a genetic component. There will be people who are predisposed. Those would be the people who typically reacted to other infections even before Long COVID, with a lot of symptoms, like Guillain-Barré syndrome, for instance, and many others. But it’s not a simple association, and there is much to learn.

Responses:

Dr. Russell: One of the biggest things is just to make sure that you’re listening to your patients. Patients know their
bodies and what’s normal for them, and if they’re experiencing a symptom that is frustrating or causing them
difficulties, it’s important to really listen to it and think about the underlying cause, because I think it’s common for
older patients to feel like their concerns are not being heard. That’s the biggest message I’d want to leave: make
sure you’re really working with your patients and creating a plan that is supporting them moving forward.

Dr. Nikolich: I would just amplify that because this point really cannot be overemphasized in many ways. A patient
did not come to your office today to complain and waste your time. They came because they’re miserable. I think
what Dr. Russell has mentioned is that older adults are very often not heard for their own complaints. Long COVID
patients, certainly many of them, have been told that a lot of this is in their head, and that this is not real. This is
extremely real. It’s debilitating, it’s devastating, and it can really change and ruin people’s lives in many ways. We
have seen this over and over; so for everybody, for decisionmakers, for clinicians, do not ignore this one. We have
literally millions of people who are disabled with this disease, and in any age stratum, and we don’t even know
how this is going to play out with kids with Long COVID. Are they going to be really incapable of fully functioning
down the line, and to what extent? What can we do to make sure that they’re not and that we can help them? I
think across the board, this is an extremely serious disease, an extremely debilitating disease. The other point to
remind everybody of is that, although there will be some differences between Long COVID, Long Lyme, long flu,
ME-CFS, fibromyalgia, and so on; there will be a common basis as well for most of these people. People with
ME-CFS, fibromyalgia, and so on will tell you that there was a particular infection after which things went downhill.
But in all these diseases, the infecting microorganism may not be known, and even if it is, there simply are not
enough cases happening at the same time so that one can study them in a systematic way. For Long COVID, on the
other hand, this is the only group where we know that there was a virus, and which virus it was, and then right
after that virus, there were huge numbers of people who are disabled. So, the benefit of understanding how the
virus causes this prolonged and disabling disease in the case of Long COVID will definitely have positive impacts on
all these other diseases and should allow us to hopefully understand them deeper.

Responses:

Dr. Russell: I reviewed my notes from writing our literature review—approximately 4 to 5 papers supported severe
acute infection as a risk factor for every 1 paper that stated it wasn’t a risk factor. But you are correct—no matter
the severity of acute infection, patients are still suffering damage that puts them at risk of Long COVID.

Dr. Nikolich: The chances of developing Long COVID after severe COVID were between 40% and 70%. It was less,
and overall down to 5% to 10%, in milder disease. But it was still happening in those with mild and even
asymptomatic disease.

Response:

Dr. Nikolich: I am not aware of this type of data.

Response:

Dr. Nikolich: There are ongoing studies, including a published one from RECOVER, but the interaction of age and
sex was not specifically investigated. Females have a stronger predilection for autoimmunity, which peaks in
middle age (40–55), so that fits with our results of potentially lower incidence in older adults.

Response:

Dr. Russell: Absolutely. This is a common limitation for geriatric research in a world that is so driven by online surveys and technology.

Response:

Dr. Nikolich: We have run the analysis in both ways with similar results.

Response:

Dr. Russell: That is one of the aspects that makes diagnosing Long COVID in older adults so difficult and why it is so important to get a better understanding of how Long COVID more specifically presents in older adults.

Response:

Dr. Nikolich: Yes. We found that older adults dominantly had milder clusters.

Responses: 

Dr. Russell: Absolutely. A high fatality rate is one of the key factors that naturally reduces the prevalence of a disease and is a theory we have discussed when looking at the data.

Dr. Nikolich: Indeed. We have flagged this explanation in the “discussion” section of our paper. 

Response: 

Dr. Nikolich: By helping us formulate hypotheses that will be tested in clinical trials. We are in communication with
RECOVER-TLC on these issues.

Response:

Dr. Nikolich: Yes. These are in progress (we are directly studying herpesvirus reactivations).

Response:

Dr. Nikolich: Yes. The RECOVER-AUTONOMIC trial was done with IVIG. Results are still being analyzed. 

Response:

Dr. Nikolich: Yes.

Response: 

Dr. Nikolich: Many inflammatory and immune parameters are now being routinely examined in mechanistic studies and will be studied in clinical trials.

Response:

Dr. Nikolich: Yes. Reinfection is being studied as a separate risk factor.

Response:

Dr. Nikolich: This is an interesting possibility; it would need some piloting to support a full trial.