1/🧵Long-COVID Defined
🔸Let’s Unpack @NEJM
🔸Hear from patients
🔸We call LC a disease state
🔸It’s a clinical definition
🔸Adding Inclusion/Exclusion Criteria to our @theNASEM definition fosters great research definitions
🔸 I admit my early mistake…
bit.ly/3Ys30u0
🔸Let’s Unpack @NEJM
🔸Hear from patients
🔸We call LC a disease state
🔸It’s a clinical definition
🔸Adding Inclusion/Exclusion Criteria to our @theNASEM definition fosters great research definitions
🔸 I admit my early mistake…
bit.ly/3Ys30u0
2/ NASEM 2024 Long Covid Definition:
“Long Covid is an IACC occurring after SARS-CoV-2 infection & present >=3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”
Read caveats in text box…
“Long Covid is an IACC occurring after SARS-CoV-2 infection & present >=3 months as a continuous, relapsing and remitting, or progressive disease state that affects one or more organ systems.”
Read caveats in text box…
3/ Patients describing Long COVID – read text box
“My long Covid life remains terrifying. Last weekend I washed my car, dried it, put it back in the garage. Then I got violently sick and could hardly get up to get food. I was unable to read or even call my mom. I’m a shell of myself. But my physical issues aren’t half as bad as my brain problems. It’s hard to describe. You can say brain fog, but that doesn’t come close to doing it justice.”
“At work my brain is just begging for rest. I struggle with finding words and completing tasks in a timely manner. … I’ll be in a meeting and know exactly what I want to say before I say it. …I’ll get to a word, and I just cannot think of the word. I’ll just be like, ‘Give me a moment,’ and I’ll go through my brain cycling through words. This week the word was “consistent.” I couldn’t think of the word consistent. I kept thinking it was coincident or concentric or constant. I used to build prototypes multiple days a week, and now if I do anything in the lab, I’m pretty much wiped out for a week. …I mean, I’ve had to dig real deep. How much longer will I feel like this? I’m scared.”
“My long Covid life remains terrifying. Last weekend I washed my car, dried it, put it back in the garage. Then I got violently sick and could hardly get up to get food. I was unable to read or even call my mom. I’m a shell of myself. But my physical issues aren’t half as bad as my brain problems. It’s hard to describe. You can say brain fog, but that doesn’t come close to doing it justice.”
“At work my brain is just begging for rest. I struggle with finding words and completing tasks in a timely manner. … I’ll be in a meeting and know exactly what I want to say before I say it. …I’ll get to a word, and I just cannot think of the word. I’ll just be like, ‘Give me a moment,’ and I’ll go through my brain cycling through words. This week the word was “consistent.” I couldn’t think of the word consistent. I kept thinking it was coincident or concentric or constant. I used to build prototypes multiple days a week, and now if I do anything in the lab, I’m pretty much wiped out for a week. …I mean, I’ve had to dig real deep. How much longer will I feel like this? I’m scared.”
4/ Mea Culpa💥
I was wrong & wrote about it. In early 2020, I didn’t believe in Long COVID as a disease.
In this piece I write:
“As a clinician, one of us (Dr. Ely) can admit to early skepticism. Having worked with severely ill patients in the intensive care unit and researched their survivorship trajectories for 25 years, we found that the myriad signs and symptoms reported by patients with long Covid seemed to mirror those described by patients after critical illness. At first, it appeared plausible to attribute these numerous adverse outcomes — including cognitive impairment, neuromuscular disease, depression, and severe fatigue — to the acquired chronic disease state called the post intensive care syndrome (PICS). This hypothesis faltered when symptoms similar to PICS began cropping up in tens of thousands of patients from the first wave of the pandemic, most of whom had never been admitted to a hospital during their acute SARS-CoV-2 infection and reported only mild initial symptoms.”
I was wrong & wrote about it. In early 2020, I didn’t believe in Long COVID as a disease.
In this piece I write:
“As a clinician, one of us (Dr. Ely) can admit to early skepticism. Having worked with severely ill patients in the intensive care unit and researched their survivorship trajectories for 25 years, we found that the myriad signs and symptoms reported by patients with long Covid seemed to mirror those described by patients after critical illness. At first, it appeared plausible to attribute these numerous adverse outcomes — including cognitive impairment, neuromuscular disease, depression, and severe fatigue — to the acquired chronic disease state called the post intensive care syndrome (PICS). This hypothesis faltered when symptoms similar to PICS began cropping up in tens of thousands of patients from the first wave of the pandemic, most of whom had never been admitted to a hospital during their acute SARS-CoV-2 infection and reported only mild initial symptoms.”
5/ IACCs
Patients with LC join the ranks of millions before w chronic conditions in which associations with infections have been found (e.g., myalgic encephalomyelitis–chronic fatigue syndrome, post-treatment Lyme disease, and multiple sclerosis, among others). In preceding decades there was no pandemic to garner attention to their plight.
Patients with LC join the ranks of millions before w chronic conditions in which associations with infections have been found (e.g., myalgic encephalomyelitis–chronic fatigue syndrome, post-treatment Lyme disease, and multiple sclerosis, among others). In preceding decades there was no pandemic to garner attention to their plight.
6/ Creating this #LongCOVID @NASEM_Health definition:
More than 1300 people participated, including patients, caregivers, public health & health care professionals, researchers, policy and advocacy professionals, payers, health care business professionals, and public at large.
More than 1300 people participated, including patients, caregivers, public health & health care professionals, researchers, policy and advocacy professionals, payers, health care business professionals, and public at large.
7/ We will find treatments through GREAT RESEARCH
This 2024 NASEM Definition will be the gateway to get into research, yet it’s deliberately designed to be highly sensitive to allow patients “in the club” (that they never wanted to be in) by doctors and nurses, so for sure there will be a need add criteria to answer specific scientific hypotheses. We are doing that for our upcoming REVERSE-LC trial funded by the NIA to see if immunomodulation will improve the acquired neuropsychological dysfunction (#brainfog) in patients suffering LC.
This 2024 NASEM Definition will be the gateway to get into research, yet it’s deliberately designed to be highly sensitive to allow patients “in the club” (that they never wanted to be in) by doctors and nurses, so for sure there will be a need add criteria to answer specific scientific hypotheses. We are doing that for our upcoming REVERSE-LC trial funded by the NIA to see if immunomodulation will improve the acquired neuropsychological dysfunction (#brainfog) in patients suffering LC.
8/ INCLUSIVITY
The 2024 NASEM definition was crafted to be intentionally inclusive & communicated among all stakeholders. Because patients with acute SARS-CoV-2 infection may have residual symptoms for a couple months before recovery, the committee adopted the requirement that symptoms must have been present for at least 3 months to fulfill the definition. This 3-month period may begin after an interval of apparent recovery after acute infection. The definition incorporates an explicit statement on equity.
The 2024 NASEM definition was crafted to be intentionally inclusive & communicated among all stakeholders. Because patients with acute SARS-CoV-2 infection may have residual symptoms for a couple months before recovery, the committee adopted the requirement that symptoms must have been present for at least 3 months to fulfill the definition. This 3-month period may begin after an interval of apparent recovery after acute infection. The definition incorporates an explicit statement on equity.
9/ Sensitivity vs Specificity
Since it’s designed to be highly sensitive, there will be false positive diagnoses of LC. We wrote this into the NEJM paper:
“Because of its intentional inclusivity, the definition can lead to high diagnostic sensitivity (few false negatives) and low diagnostic specificity (more false positives). For this reason, the report5 stresses that applying the definition in clinical care depends on the experience and judgment of the clinician and careful consideration of alternative causes of a patient’s presentation. For many research purposes, additional eligibility criteria — such as specific age, other demographic features, presence of a specified set of symptoms, or documentation of previous SARS-CoV-2 infection — may be useful to test hypotheses regarding treatment or mechanisms of disease. In such a trial, all research participants will fit the 2024 NASEM definition, but not all patients who fit the definition will qualify as research participants. In general, erroneous classification of research participants with respect to the disease in question will reduce the statistical power of the trial to detect an effect.”
Since it’s designed to be highly sensitive, there will be false positive diagnoses of LC. We wrote this into the NEJM paper:
“Because of its intentional inclusivity, the definition can lead to high diagnostic sensitivity (few false negatives) and low diagnostic specificity (more false positives). For this reason, the report5 stresses that applying the definition in clinical care depends on the experience and judgment of the clinician and careful consideration of alternative causes of a patient’s presentation. For many research purposes, additional eligibility criteria — such as specific age, other demographic features, presence of a specified set of symptoms, or documentation of previous SARS-CoV-2 infection — may be useful to test hypotheses regarding treatment or mechanisms of disease. In such a trial, all research participants will fit the 2024 NASEM definition, but not all patients who fit the definition will qualify as research participants. In general, erroneous classification of research participants with respect to the disease in question will reduce the statistical power of the trial to detect an effect.”
10/ PROOF?
Why is proof not required for a diagnosis of Long COVID?
First, for research, proof will often be required…
but in clinical practice, by now, most people have had COVID. A requirement for proof of diagnosis could wrongly exclude many patients, because early antigen tests had many false negatives and patients who have performed home tests typically discard test strips. Furthermore, although antibody testing can sometimes indicate a past SARS-CoV-2 infection, there are notable limitations, including fluctuation or waning of antibody levels over time and across different assays, complications in antibody test results owing to vaccination against Covid-19, and the effects of sex and age on the sensitivity of antibody testing.
Why is proof not required for a diagnosis of Long COVID?
First, for research, proof will often be required…
but in clinical practice, by now, most people have had COVID. A requirement for proof of diagnosis could wrongly exclude many patients, because early antigen tests had many false negatives and patients who have performed home tests typically discard test strips. Furthermore, although antibody testing can sometimes indicate a past SARS-CoV-2 infection, there are notable limitations, including fluctuation or waning of antibody levels over time and across different assays, complications in antibody test results owing to vaccination against Covid-19, and the effects of sex and age on the sensitivity of antibody testing.
11/ Expert History Taking & Clinical Evaluation
Expert history taking and clinical judgment are required to assess patients who may have either exacerbation of baseline coexisting illnesses or de novo diseases. For example, in the case of neurologic disease, a 62-year-old man who has preexisting mild cognitive impairment may have accelerated brain atrophy on magnetic resonance imaging (MRI) with clinical progression to moderate dementia with long Covid. Likewise, 8 months after having SARS-CoV-2 infection, a cognitively and physically healthy 46-year-old woman may receive a diagnosis of mild neuropsychological impairment (i.e., “brain fog”) and post-exertional malaise that progresses over the next 2 years into mild dementia with disabling fatigue
Expert history taking and clinical judgment are required to assess patients who may have either exacerbation of baseline coexisting illnesses or de novo diseases. For example, in the case of neurologic disease, a 62-year-old man who has preexisting mild cognitive impairment may have accelerated brain atrophy on magnetic resonance imaging (MRI) with clinical progression to moderate dementia with long Covid. Likewise, 8 months after having SARS-CoV-2 infection, a cognitively and physically healthy 46-year-old woman may receive a diagnosis of mild neuropsychological impairment (i.e., “brain fog”) and post-exertional malaise that progresses over the next 2 years into mild dementia with disabling fatigue
12/fin
Conclusions
📌ALWAYS listen to patients📌They teach us and tell us what is wrong.
📌Let’s help them!
📌A standard definition will improve our understanding of the nature, scope &burden of LC
📌We’ve certainly under-reported & missed many deaths & great suffering from LC
📌This definition will be updated in <3 years when more data are available
📌We hope the 2024 NASEM definition will facilitate communication among patients, family members, and clinicians
Conclusions
📌ALWAYS listen to patients📌They teach us and tell us what is wrong.
📌Let’s help them!
📌A standard definition will improve our understanding of the nature, scope &burden of LC
📌We’ve certainly under-reported & missed many deaths & great suffering from LC
📌This definition will be updated in <3 years when more data are available
📌We hope the 2024 NASEM definition will facilitate communication among patients, family members, and clinicians
13/ NOTE: @TheLancet and the incomparable @TrishGreenhalgh just reported on Long COVID as well. Read their edifying insights and thoughts here. Her thread on this is super.
FREE ACCESS - bit.ly/3WwIJAG
kwnsfk27.r.eu-west-1.awstrack.me/L0/https:%2F%2…
FREE ACCESS - bit.ly/3WwIJAG
kwnsfk27.r.eu-west-1.awstrack.me/L0/https:%2F%2…
Many are asking me why we are making brain 🧠 function our primary outcome for the upcoming Reverse-LC trial funded by NIH…this 🧵👇 explains what a huge deal this is for #LongCOVID patients & science to justify…
https://twitter.com/weselymd/status/1501717860942553089
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