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

[SNT Gatchaman]

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. Evans; Danielle N. Evans; Julio C. Facelli; Camila S. Fang; E. Vincent S. Faustino; Maria E. Fayad Lara; Candace H. Feldman; Alexander G. Fiks; Rebecca Fineman; Aloke V. Finn; Melinda S. Fischer; Megan L. Fitzgerald; Valerie J. Flaherman; Thomas J. Flotte; Daniel Forsha; Meghan R. Fortune; John J. Foxe; Nicole Franks; Michael B. Freedman; Catherine E. Freeland; Naomi P. Friedman; Greta Fry; Margot Gage Witvliet; Emily J. Gallagher; Richard Gallagher; Hugh Garavan; Sunanda M. Gaur; Dylan G. Gee; Maria Laura Gennaro; Lynn B. Gerald; Saikat B. Ghosh; Joseph T. Giacino; Andrew T. Girvin; Stephanie L. Godfrey; Mark P. Goldberg; Steven N. Goodman; Howard S. Gordon; Ramkiran Gouripeddi; Paige Graham; Joey P. Granger; Kevin M. Gray; Tina Greimes; Rachel S. Gross; Nicholas Guthe; Evan Gutter; Stephanie Haasnoot; Emily C. Hadley; Melissa A. Haendel; Stephanie Hafner; Katia C. Halabi; Patrick C. Hanley; Ashraf S. Harahsheh; Michelle S. Harkins; Kimberly L. Hartwig; Keren Hasbani; Sharon Hasek; Kristine S. Hauser; Andrew C. Heath; Camden L. Hebson; Mary M. Heitzeg; Monica Hendrickson; Timothy J. Henrich; Alfonso C. Hernandez-Romieu; Christina M. Hester; Miranda Higginbotham; Sophia Hill; Kathryn Hirabayashi; On Ho; Laura Hobart-Porter; M. C. Hoffman; Maryann Holtcamp; Travis K. Hong; Benjamin D. Horne; Carol R. Horowitz; Daniel S. Hsia; Harvey Hsu; Priscilla Y. Hsue; Matthew Huentelman; Bryan E. Huerta; Jared D. Huling; Kathy Hummel; William G. Iacono; Alejandra L. Ibanez; Carmel Ibeawuchi; Katherine Irby; Nahed Ismail; Joanna Jacobus; Vanessa L. Jacoby; Leonard A. Jason; Vidhi Javia; Kyle J. Jennette; Terry L. Jernigan; Sihang Jiang; Naimin Jing; Jace D. Johnny; Nadia Johnson; Brandi Johnson; Brandon Johnson; Pei-Ni Jone; Suzanne E. Judd; Joy J. Juskowich; Edmond K. Kabagambe; David C. Kaelber; Diane G. Kanjilal; Mayank M. Kansal; Tyler J. Kasmarcak; Daniel Kaufman; Rika Kawakami; Dean L. Kellogg; Denise A. Kent; Deepshikha Kewlani; Dhruv Khullar; Keri S. Kim; Arthur Y. Kim; Patricia A. Kinser; Lawrence C. Kleinman; Elizabeth B. Klerman; Matthew J. Kluko; Stacey Knight; Misaki Kobayashi; Karla J. Kopp; Michael Koropsak; Jessica S. Kosut; Ellen Kraig; Amanda Krausert; Ana C. Krieger; Hema Krishna; Aparna Krishnamoorthy; Sankaran S. Krishnan; James P. Lahs; Angela R. Laird; Victoria Laleau; Michelle F. Lamendola-Essel; Jeremy Landeo-Gutierrez; Sean M. Lang; Christine L. Larson; James P. Lash; Jessica Lasky-Su; Gregory Laynor; Simon Lee; Grace M. Lee; F. E. Lee; Matthew A. Lee; Peter J. Leese; R. C. Lefebvre; Angelica J. Levreault; Kennedy C. Lewis; Lu Li; Peter Paul C. Lim; Janet Y. Lin; Krista M. Lisdahl; Matthew B. Litvack; Xiaokang Liu; Jennifer Lloyd; Jennifer K. Logue; Johanna J. Loomba; Vitaly Lorman; Yiwen Lu; Katelyn R. Ludwig; Allison M. Lutz; Jeri Mack; Abeer M. Mahmoud; Cheryl L. Maier; Shahdi K. Malakooti; Sergey Malchenko; Gail L. Mallett; Gabrielle Maranga; Megan W. Martel; Susanne P. Martin-Herz; Maria Martinez-Lage; Christine Maughan; Cammeo Mauntel-Medici; Heidi T. May; Kenneth H. Mayer; Diego R. Mazzotti; Caitryn M. McCallum; Brian W. McCrindle; Russell J. McCulloh; Dylan McDonald; Stephanie McInnis; Julie A. McMurry; Asuncion Mejias; Jonathan Melamed; Martha Menchaca; Alan L. Mendelsohn; Lucio Miele; Mitchell G. Miglis; Cris Milne; Joshua D. Milner; Roger A. Mitchell; Murray A. Mittleman; Sindhu Mohandas; Jonathan G. Monteiro; Vanessa Monzon; David J. Moreno; Lerraughn M. Morgan; Dmitry Morozyuk; Keith E. Morse; Erick Moyneur; Praveen C. Mudumbi; Eva M. Müller-Oehring; Naoko Muramatsu; Hugh Musick; Kshema Nagavedu; Erica R. Nahin; Anoop M. Nambiar; Benjamin H. Natelson; Michael C. Neale; Manette Ness-Cochinwala; Jane W. Newburger; Lisa T. Newman; Amber N. Nguyen; Lauren Nichols; Sheila M. Nolan; Seth Noland; Richard M. Novak; George T. O'Connor; John J. O'Keefe; Princess U. Ogbogu; Carlos R. Oliveira; Matthew E. Oster; Robert F. Padera; Henry H. Paik; Nathan M. Pajor; Huaqin Helen Pan; Deepti Pant; Andrew Partridge; Payal B. Patel; Saaya Patel; Khushboo Patel; Martin P. Paulus; Ronald M. Payne; Ann Pearman; Myriam Peralta-Carcelen; Nicolas L. Perez; Emily R. Pfaff; De-Ann M. Pillers; Chloe E. Pitsch; Neil H. Pliskin; Michael A. Portman; Radu Postelnicu; Jennifer S. Potter; Bellur S. Prabhakar; Priya Prahalad; Bharati Prasad; Barbara Predki; Alexander J. Preiss; Heather M. Prendergast; Davin K. Quinn; Yuri Quintana; Dustin J. Rabideau; Jonathan M. Radosta; Jeffrey Radwell; Hengameh Raissy; Ramaswamy Ramchandran; Isabelle Randall; Suchitra Rao; Amy Rapkiewicz; Sonja A. Rasmussen; Hanieh Razzaghi; Candida J. Rebello; Paulina A. Rebolledo; Neha V. Reddy; Unma M. Reddy; Cara Reedy; Jalees Rehman; R. R. Reichard; Kayleigh M. Reid; Jane E. Reusch; Kyung E. Rhee; Mary B. Rice; John-Ross R. Rizzo; Nadia R. Roan; Polly Robarts; Timothy R. Roberts; Nitza Rochez; Kathleen E. Rodgers; Colin M. Rogerson; Maria E. Romero; Johana M. Rosas; Erika B. Rosenzweig; Russell L. Rothman; Nadine G. Rouphael; Mark W. Russell; Melissa Rutherfoord; Arash A. Sabati; Samer B. Sader; Marzieh Salehi; Amy L. Salisbury; Barbara A. Sampson; Yamuna Sanil; Alice I. Sato; Sharon H. Saydah; Michael S. Schechter; Edward J. Schenck; Katherine I. Schlepphorst; Julia Schuchard; Tina L. Schuh; Jennifer A. Sculley; Alan C. Seifert; Anisha K. Sekar; Rangaraj Selvarangan; Sudha Seshadri; Howard D. Sesso; Dimpy P. Shah; Divya Shakti; Nancy L. Shapiro; Suchetha Sharma; Kumar Sharma; Shubhi Sharma; Kavita Sharma; Gwendolyn Shaw; Eyal Shemesh; Yishan Shen; Elizabeth Shenkman; Stephanie Shiau; Michelle Siciliano; Aylin Simsir; Veronica E. Smith; Jessica N. Snowden; Isaac H. Solomon; Leslie A. Spikes; Lindsay M. Squeglia; Shubhika Srivastava; Mary L. St. Jean; Kenneth A. Stapleford; Cheryl R. Stein; Michelle D. Stevenson; Sarah A. Stewart de Ramirez; Lauren E. Stiles; Aryeh Stock; Melissa S. Stockwell; James R. Stone; Jeran Stratford; Til Stürmer; Vignesh Subbian; Jun Sun; Mehul S. Suthar; Ashley Sylvera; David M. Systrom; Jacqueline Szmuszkovicz; Maria M. Talavera-Barber; Kelan G. Tantisira; Nancy Tartt; Tracy Terlinde; Ronald J. Teufel; Deepika Thacker; Mansi Thakrar; Stephen N. Thibodeau; Gelise L. Thomas; Moriah E. Thomason; Jiayi Tong; Robert Torres; Jessica Traenkner; Robin Tragus; Joel D. Trinity; Jena S. Tronieri; Andrea B. Troxel; Jennifer Truong; Dongngan T. Truong; Joel Tsevat; Mmekom M. Udosen; Kristen Unterberger; Paul J. Utz; Viola Vaccarino; Brittany B. Vallejos; Terry L. Vanden Hoek; Nita Vangeepuram; Jay K. Varma; Suzanne D. Vernon; Crystal M. Vidal; Sara Vivensi; Adam S. Vohra; Laura K. Wagner; Fei Wang; David Warburton; Megan R. Warner; Rebecca L. Watkins; Sara E. Watson; Ryan Webb; Ryan M. Weeks; Mark G. Weiner; Alan Werzberger; Shelby C. West; Jordan C. Weyer; Jennifer L. Wheeler; Kenneth J. Wilkins; Natasha J. Williams; Charles T. Williams; Erika S. Wimberly; Terra J. Winter; Scott C. Woller; Rachel Wong; Jeremy P. Wood; John C. Wood; Marion J. J. Wood; Qiong Wu; Yinglin Xia; Jie Xu; Samuel Yang; H. S. Yin; Hsiang S. Yin; Yun Jae Yoo; Chloe E. Young; Natalie M. Young; Chengxi Zang; William T. Zempsky; Bingyu Zhang; Yongkang Zhang; Dazheng Zhang; Emily Zimmerman; George A. Alba; Radica Alicic; Natasha Altman; Khamal Anglin; Urania Argueta; Hassan Ashktorab; Gaston Baslet; Ingrid V. Bassett; Lucinda Bateman; Brahmchetna Bedi; Shamik Bhattacharyya; Marie-Abele Bind; Andra L. Blomkalns; Hector Bonilla; Patricia A. Bush; Mario Castro; James Chan; Alexander W. Charney; Peter Chen; Lori B. Chibnik; Helen Y. Chu; Rebecca G. Clifton; Maged M. Costantine; Sushma K. Cribbs; Sylvia I. Davila Nieves; Steven G. Deeks; Alexandria Duven; Ivette F. Emery; Nathan Erdmann; Kristine M. Erlandson; Kacey C. Ernst; Rachael Farah-Abraham; Cheryl E. Farner; Elen M. Feuerriegel; Judes Fleurimont; Vivian Fonseca; Nicholas Franko; Vivian Gainer; Jennifer C. Gander; Edward M. Gardner; Linda N. Geng; Kelly S. Gibson; Minjoung Go; Jason D. Goldman; Halle Grebe; Frank L. Greenway; Mounira Habli; John Hafner; Jenny E. Han; Keith A. Hanson; James Heath; Carla Hernandez; Rachel Hess; Sally L. Hodder; Matthew K. Hoffman; Susan E. Hoover; Beatrice Huang; Brenna L. Hughes; Prasanna Jagannathan; Janice John; Michael R. Jordan; Stuart D. Katz; Elizabeth S. Kaufman; John D. Kelly; Sara W. Kelly; Megan M. Kemp; John P. Kirwan; Jonathan D. Klein; Kenneth S. Knox; Jerry A. Krishnan; Andre Kumar; Adeyinka O. Laiyemo; Allison A. Lambert; Margaret Lanca; Joyce K. Lee-Iannotti; Brian P. Logarbo; Michele T. Longo; Carlos A. Luciano; Karen Lutrick; Jason H. Maley; Jai G. Marathe; Vincent Marconi; Gailen D. Marshall; Christopher F. Martin; Yuri Matusov; Alem Mehari; Hector Mendez-Figueroa; Robin Mermelstein; Torri D. Metz; Richard Morse; Jarrod Mosier; Christian Mouchati; Janet Mullington; Shawn N. Murphy; Robert B. Neuman; Janko Z. Nikolich; Ighovwerha Ofotokun; Elizabeth Ojemakinde; Anna Palatnik; Kristy Palomares; Tanyalak Parimon; Samuel Parry; Jan E. Patterson; Thomas F. Patterson; Rachel E. Patzer; Michael J. Peluso; Priscilla Pemu; Christian M. Pettker; Beth A. Plunkett; Kristen Pogreba-Brown; Athena Poppas; John G. Quigley; Uma Reddy; Rebecca Reece; Harrison Reeder; W. B. Reeves; Eric M. Reiman; Franz Rischard; Jonathan Rosand; Dwight J. Rouse; Adam Ruff; George Saade; Grecio J. Sandoval; Shannon M. Schlater; Fitzgerald Shepherd; Zaki A. Sherif; Hyagriv Simhan; Nora G. Singer; Daniel W. Skupski; Amber Sowles; Jeffrey A. Sparks; Fatima I. Sukhera; Barbara S. Taylor; Larissa Teunis; Robert J. Thomas; John M. Thorp; Paul Thuluvath; Amberly Ticotsky; Alan T. Tita; Katherine R. Tuttle; Alfredo E. Urdaneta; Daisy Valdivieso; Timothy M. VanWagoner; Andrew Vasey; Monica Verduzco-Gutierrez; Zachary S. Wallace; Honorine D. Ward; David E. Warren; Steven J. Weiner; Shelley Welch; Sidney W. 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)

 

[SNT Gatchaman]

Symptoms (using severity thresholds) with more than 15% absolute difference in frequencies (infected vs uninfected) included postexertional malaise (PEM) (28% vs 7%; aOR, 5.2 [95% CI, 3.9-6.8]), fatigue (38% vs 17%; aOR, 2.9 [95% CI, 2.4-3.4]), dizziness (23% vs 7%; aOR, 3.4 [95% CI, 2.6-4.4]), brain fog (20% vs 4%; aOR, 4.5 [95% CI, 3.2-6.2]), and gastrointestinal (GI) symptoms (25% vs 10%; aOR, 2.7 [95% CI, 2.2-3.4]).

PASC subgroups that demonstrate overlap with conditions previously described in clinical practice are detailed here, including olfactory dysfunction, cardiopulmonary sequelae, neurocognitive impairment, ME/CFS, and dysautonomia and overlap with those reported by the National COVID Cohort Collaborative.

 

[SNT Gatchaman]

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

Another potential benefit of the RECOVER adult cohort study would be if future work finds characteristic biomarkers for the different phenotypes of postacute sequelae, and if those signatures are similar to biosignatures in other conditions, particularly of myalgic encephalomyelitis/chronic fatigue syndrome. This would create an opportunity to conduct studies relevant to that complex disorder with sample sizes not previously feasible, accelerating the ability to rapidly test various treatment strategies for this previously identified disabling condition.

 

[Trish]

The prevalence of PEM seem odd.
28% in the infected group vs 7% in the uninfected group.

I'm not sure what they were assessing as PEM, but a finding of 7% in the uninfected group seems remarkably high, given the pre pandemic prevalence of ME/CFS of well under 1%, and as far as I know there isn't a list of other diseases that would account for 6% prevalence of PEM, since we don't know of anything else that causes PEM.

Edit from eFigure2 in Supplement 3: For new onset PEM the frequencies were 28% and 4%.
I understand the uninfected group were volunteers, not a properly representative sample as required for epidemiology studies.

 

[Ravn]

The prevalence of PEM seem odd.
28% in the infected group vs 7% in the uninfected group.

I'm not sure what they were assessing as PEM, but a finding of 7% in the uninfected group seems remarkably high, given the pre pandemic prevalence of ME/CFS of well under 1%, and as far as I know there isn't a list of other diseases that would account for 6% prevalence of PEM, since we don't know of anything else that causes PEM.

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

 

[Ravn]

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

To optimize our understanding of the long-term impact of post–COVID-19 sequelae and to design and assess potential interventions, it is critically important to establish validated case definitions. Erroneous case definitions, and the resultant misclassification bias, could delay the correct diagnoses by clinicians, will decrease the likelihood of identifying the biological mechanisms underpinning these symptoms, might threaten the ability to demonstrate the efficacy of interventions, and could lead to misdirected, ineffective treatments.

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

 

[cassava7]

The prevalence of PEM seem odd.
28% in the infected group vs 7% in the uninfected group.

I'm not sure what they were assessing as PEM, but a finding of 7% in the uninfected group seems remarkably high, given the pre pandemic prevalence of ME/CFS of well under 1%, and as far as I know there isn't a list of other diseases that would account for 6% prevalence of PEM, since we don't know of anything else that causes PEM.

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

 

[Trish]

I agree with comments above about the huge value of the recognition of ME/CFS and PASC being properly defined for future research. And it's great to see a study that puts PEM and ME/CFS at the heart of the findings and the recognition that it needs more and better research.

The data is in Supplement 3.

On page 6
ME/CFS Definition
ME/CFS was identified using a definition based on the Institute of Medicine criteria. Participants were classified as having ME/CFS if they met all the following criteria:
A. Reported fatigue, reported severe or very severe fatigue on PROMIS Global-1071 Question 8, and had a PROMIS Global-10 physical health sub-score ≤10,
AND
B. Reported P-E Malaise,
AND
C. Reported Sleep disturbance and when asked “In the past 7 days, my sleep was refreshing”, the participant selected “Not at all”, “A little bit”, or “Somewhat”,
AND
D.
Either of the following:
a) Orthostatic intolerance (orthostatic tachycardia without orthostatic hypotension as obtained from the Active Standing Test)
OR
b) Reported brain fog and had a Neuro-QoL Cognition Score ≤40
___________________

Page 10 is a table of symptoms and how they were assessed:
PEM appears just to be assessed by this description in the RECOVER questionnaire:

Post-exertional malaise (Symptoms worse after even minor physical or mental effort)

It doesn't have any additional criteria to assess it, unlike fatigue which not only includes Fatigue (being very tired) in the RECOVER questionnaire, but also requires additional severity criteria: PROMIS Fatigue Score (moderate or worse)

PROMIS Fatigue Score (moderate or worse) This is question 8 of the PROMIS Global-10 questionnaire and is asked of all participants. The question is “In the past 7 days, how would you rate your fatigue on average?”. The responses are none, mild, moderate, severe, and very severe. A response of moderate, severe, or very severe means the participants meets the severity criteria

 

[SNT Gatchaman]

I'm not sure what they were assessing as PEM, but a finding of 7% in the uninfected group seems remarkably high, given the pre pandemic prevalence of ME/CFS of well under 1%, and as far as I know there isn't a list of other diseases that would account for 6% prevalence of PEM, since we don't know of anything else that causes PEM.

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).

 

[Trish]

I would assume that represents "uninfected" were actually infected - just not proven so.

I was assuming that too, but I think they did a blood test on the uninfected and if positive reclassified them as infected. I'm not sure how accurate that is. Also as in my postscript to my post, only 4% of the uninfected said their PEM was new onset, so maybe a few of the uninfected sample had pre-existing undiagnosed ME/CFS.

 

[cassava7]

Summary thread on Twitter by a lead researcher within the RECOVER initiative that explains the methodology of the study:

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.

 

[Trish]

 

[cassava7]

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 —.

 

[Trish]

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 either dizziness (1) and/or palpitations (2), in which case they would be classified as long Covid cases —.

And someone with a loss of sense of smell or taste and a persistent cough would also be diagnosed with long Covid, demonstrating very effectively that there need to be subcategories for research purposes.

 

[cassava7]

And someone with a loss of sense of smell or taste and a persistent cough would also be diagnosed with long Covid, demonstrating very effectively that there need to be subcategories for research purposes.

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.

 

[Trish]

I'm very pleased to see that long Covid is being researched according to physical symptoms, not psychological ones. Anxiety and depression were asked about but not in the main RECOVER questionnaire:

Anxiety (GAD-7>9) First, all participants answer the two-question GAD-2 (Generalized Anxiety Disorder) survey, which assesses how often the participant has been bothered by feeling nervous, anxious, or on edge or not being able to stop or control worrying over the past two weeks. If the sum of the scores to the 2 questions is <3, the participant automatically does not meet this severity criteria. If the sum of the scores is >=3, they receive the full 7-question survey, which includes 5 additional screening questions. The participant meets the severity criteria if the sum of the scores to all 7 questions is >9.

Depression (PHQ-8>9) First, all participants answer the two-question PHQ-2 survey, which assesses how often the participant has been bothered by having little interest or pleasure in doing things or feeling down, depressed, or hopeless over the past two weeks. If the sum of the scores to the 2 questions is <3, the participant automatically does not meet this severity criteria. If the sum of the scores is >=3, they receive the full 7-question survey, which includes 6 additional screening questions. The participant meets the severity criteria if the sum of the scores to all 8 questions is >9.

Nor do they appear in the list of symptoms to define PASC.

The results were:

In the whole cohort prevalence of symptom (eFigure 1):
Depression: infected: 11% uninfected: 5%
Anxiety: infected 12% : uninfected 6%:

In the whole cohort, prevalence of new onset of symptom (eFigure 2):
Depression: infected: 9% uninfected: 3%
Anxiety: infected: 8% uninfected: 3%

In PASC positive participants, ie those scoring at least 12 on the scale shown in the tweet in post #13 above:

Depression 29%
Anxiety 27%
________________________

 

[CRG]

A very unusual study population:





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

 

[SNT Gatchaman]

I was assuming that too, but I think they did a blood test on the uninfected and if positive reclassified them as infected. I'm not sure how accurate that is.

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

Most striking from our study was the finding that while fully recovered individuals exhibited coordinated humoral and cellular immune responses to SARS-CoV-2, this coordination was lost in the LC group. This finding is consistent with observations that about half of individuals with LC with no detectable SARS-CoV-2 antibodies have detectable SARS-CoV- 2-specific T cell responses. That improper crosstalk between T and B cells may be involved in the etiology of LC is also supported by our RNAseq data, which showed that a cluster of genes including both immunoglobulin synthesis and T cell function were co-upregulated in those without LC, but not in individuals with LC.

Also as in my postscript to my post, only 4% of the uninfected said their PEM was new onset, so maybe a few of the uninfected sample had pre-existing undiagnosed ME/CFS.

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.

 

[SNT Gatchaman]

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

Though does match this preprint from April.

 

[ME/CFS Skeptic]

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?