Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection, 2023, Thaweethai et al.

Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection

Spoiler: Everybody

Tanayott Thaweethai; Sarah E. Jolley; Elizabeth W. Karlson; Emily B. Levitan; Bruce Levy; Grace A. McComsey; Lisa McCorkell; Girish N. Nadkarni; Sairam Parthasarathy; Upinder Singh; Tiffany A. Walker; Caitlin A. Selvaggi; Daniel J. Shinnick; Carolin C. M. Schulte; Rachel Atchley-Challenner; Leora I. Horwitz; Andrea S. Foulkes; RECOVER Consortium Authors; RECOVER Consortium; Judith A. Aberg; Natalie L. Adolphi; Shreya Ahirwar; Shifa Ahmed; Neera Ahuja; Masanori Aikawa; Almary Akerlundh; Teresa T. Akintonwa; Aseel Al-Jadiri; Natalya Alekhina; Heather A. Algren; Akram N. Alshawabkeh; Nariman Ammar; Adit Anand; Brett R. Anderson; Lisa Aponte-Soto; Judy L. Aschner; Mary M. Atha; Andrew M. Atz; Robin L. Aupperle; Mirna Ayache; Eduardo Azziz-Baumgartner; L. C. Bailey; Fiona C. Baker; Venkataraman Balaraman; Jennifer A. Bandy; Dithi Banerjee; Deanna M. Barch; James M. Bardes; Jackson Barlocker; R. G. Barr; Arielle Baskin-Sommers; Sanjib Basu; Tracy A. Battaglia; Leah Baucom; Carmen J. Beamon; Casey L. Beaty; Noam D. Beckmann; Jasmine A. Berry; Nahid Bhadelia; Daksh Bhargava; Sultana Bhuiyan; Jiang Bian; Christian Bime; James M. Bjork; Lora J. Black; Catherine A. Blish; Jason P. Block; Amanda Bogie; Dawn Bolliger; William Bonaventura; Seuli Bose-Brill; Mary B. Bower; Andrew D. Boyd; Jerusha Boyineni; Steven B. Bradfute; Carolyn T. Bramante; M. D. Brannock; J. D. Bremner; Shari B. Brosnahan; Natalie C. Buchbinder; Elliott Bueler; Irina A. Buhimschi; Hulya Bukulmez; H. T. Bunnell; John B. Buse; Elizabeth A. Calhoun; Tingyi Cao; Michael D. Carrithers; Thomas W. Carton; Abigail Case; B.J. Casey; Faye Victoria C. Casimero; Lauren Castro; Teresa Cato; Patricia Ceger; Connie L. Cerullo; Linda Chang; Arunee A. Chang; Praneeth Chebrolu; Yong Chen; Li Qing Chen; Benjamin K. Chen; David Chestek; Robert F. Chew; Deena J. Chisolm; Dominic C. Chow; Maryanne R. Chrisant; Dimitri A. Christakis; Christopher G. Chute; Mine S. Cicek; Cheryl R. Clark; Duncan B. Clark; Geoffrey D. Clarke; Katharine N. Clouser; Thomas J. Connors; Judith A. Cook; Krista Coombs; Carlos Cordon-Cardo; Julie L. Costello; Lesley Cottrell; Kelly Cowan; Lindsay G. Cowell; Savannah Cranford; Jamie Cronin; Mollie R. Cummins; Hannah L. Curry; Viren D'Sa; Sean G. Dabney; Casey L. Daniel; Mirella Dapretto; Dawood Darbar; Paul M. Darden; Raktima Dasgupta; Soham Dasgupta; Felicia Davis Blakley; Katherine Dea; Sara J. Deakyne Davies; Lauren A. Decker; Ralph A. DeFronzo; Walter Dehority; Amelia N. Deitchman; James del Alcazar; Phoebe Del Boccio; Carlos del Rio; Marina Del Rios; Julie A. DeLisa; Sean C. Deoni; Maya Z. Diaz; John D. Dickinson; Audrey Dionne; Kathleen R. Diviak; Sarah E. Donohue; Michael J. Downey; Allen J. Dozor; Benard P. Dreyer; Kirsten B. Dummer; Matthew S. Durstenfeld; Mark S. Dworkin; Sherrie L. Edmonds; Matthew D. Elias; Jamie Elifritz; Evan Ellingworth; Amy J. Elliott; Angela M. Ellison; Mike L. Enger; Joaquin M. Espinosa; Shari Esquenazi-Karonika; Michael D. 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Whiteheart; Zanthia Wiley; Juan P. Wisnivesky; Lynn M. Yee; Sokratis Zisis

IMPORTANCE
SARS-CoV-2 infection is associated with persistent, relapsing, or new symptoms or other health effects occurring after acute infection, termed postacute sequelae of SARS-CoV-2 infection (PASC), also known as long COVID. Characterizing PASC requires analysis of prospectively and uniformly collected data from diverse uninfected and infected individuals.

OBJECTIVE
To develop a definition of PASC using self-reported symptoms and describe PASC frequencies across cohorts, vaccination status, and number of infections.

DESIGN, SETTING, AND PARTICIPANTS
Prospective observational cohort study of adults with and without SARS-CoV-2 infection at 85 enrolling sites (hospitals, health centers, community organizations) located in 33 states plus Washington, DC, and Puerto Rico. Participants who were enrolled in the RECOVER adult cohort before April 10, 2023, completed a symptom survey 6 months or more after acute symptom onset or test date. Selection included population-based, volunteer, and convenience sampling.

EXPOSURE
SARS-CoV-2 infection.

MAIN OUTCOMES AND MEASURES
PASC and 44 participant-reported symptoms (with severity thresholds).

RESULTS
A total of 9764 participants (89% SARS-CoV-2 infected; 71% female; 16% Hispanic/Latino; 15% non-Hispanic Black; median age, 47 years [IQR, 35-60]) met selection criteria. Adjusted odds ratios were 1.5 or greater (infected vs uninfected participants) for 37 symptoms. Symptoms contributing to PASC score included postexertional malaise, fatigue, brain fog, dizziness, gastrointestinal symptoms, palpitations, changes in sexual desire or capacity, loss of or change in smell or taste, thirst, chronic cough, chest pain, and abnormal movements. Among 2231 participants first infected on or after December 1, 2021, and enrolled within 30 days of infection, 224 (10% [95% CI, 8.8%-11%]) were PASC positive at 6 months.

CONCLUSIONS AND RELEVANCE
A definition of PASC was developed based on symptoms in a prospective cohort study. As a first step to providing a framework for other investigations, iterative refinement that further incorporates other clinical features is needed to support actionable definitions of PASC.

Link | PDF (JAMA)

 

Editorial Disentangling the Postacute Sequelae of SARS-CoV-2: E Unibus Pluram (From One, Many) —

 

Haven't read the paper so don't know how they asked about PEM. I suspect the 2 most likely explanations are

1) asymptomatic infections leading to a few 'healthy controls' actually having long covid and PEM

2) ambiguous definition of PEM resulting in some people with common-or-garden exertion intolerance mistakenly thinking they have PEM

 

If only someone had applied this sort of thinking to ME decades ago

 

I suspect that they used the DePaul Short Form PEM questionnaire which, as we have discussed in the past, is quite flawed.

 

I would assume that represents "uninfected" were actually infected - just not proven so. I was hoping sophisticated investigations could more accurately assess previous infection status: in particular SARS-CoV-2-specific T cells. I see though that, at least in children, there may be cross-reactivity with previous coronaviruses, so perhaps that wouldn't be reliable (thread for pre-print).

 

Summary thread on Twitter by a lead researcher within the RECOVER initiative that explains the methodology of the study: https://twitter.com/user/status/1661763345882525696


They developed a score (using LASSO) to classify participants as having long Covid or not based on a set of 12 symptoms. The score for each symptom accounted for the difference in its prevalence between patients versus controls.

With a cut-off total score of 12, they obtain a false positive rate (non-PASC controls misclassified as having PASC) of only 4%. PEM counts for 7 points and is the second highest-rated symptom behind smell/taste problems (8 points), whereas fatigue only scores 1 point.

 

Interestingly, non-long Covid ME/CFS patients diagnosed per the IOM or NICE criteria would score at least 11 points: PEM (7), brain fog (3), fatigue (1) — and most likely dizziness (1) and/or palpitations (2), in which case they would be classified as long Covid cases —.

 

Indeed. To me, this definition seems to delineate two major presentations of long Covid: people with PEM and autonomic issues, and people with respiratory and olfactory symptoms (the latter being most likely those with organic sequelae). The next step, in my view, would be to analyze to what extent they overlap — they may, for example, share cognitive symptoms (brain fog), thirst, fatigue and chest pain as common symptoms.

 

A very unusual study population:





This is at variance to other "Long Covid" studies where PASC is associated with higher deprivation numbers.

 

In Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2 (Preprint 2023), it was stated —

I think that's likely. It's also not uncommon for the LC Facebook groups to have people who "previously had ME", though often having recovered up until Covid.

 

Though does match this preprint from April.

 

But unfortunate that they did not report the prevalence rate of ME/CFS.

They only note that "Among infected participants meeting criteria for ME/CFS, 98%met the criteria for PASC." More interesting would be to know which % of PASC patients meets ME/CFS criteria. I assume they have this information but prefer to keep this information for a separate paper?