This is a preprint.

It has not yet been peer reviewed by a journal.

The National Library of Medicine is running a pilot to include preprints that result from research funded by NIH in PMC and PubMed.

[Preprint]. 2021 Mar 26:2021.03.20.21253896.

doi: 10.1101/2021.03.20.21253896.

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information

Halie M Rando^{1

2}, Tellen D Bennett³, James Brian Byrd⁴, Carolyn Bramante⁵, Tiffany J Callahan^{1

6}, Christopher G Chute⁷, Hannah E Davis⁸, Rachel Deer⁹, Joel Gagnier⁶, Farrukh M Koraishy¹⁰, Feifan Liu¹¹, Julie A McMurry¹, Richard A Moffitt¹², Emily R Pfaff¹³, Justin T Reese¹⁴, Rose Relevo¹⁵, Peter N Robinson^{16

17}, Joel H Saltz¹², Anthony Solomonides¹⁸, Anupam Sule¹⁹, Umit Topaloglu²⁰, Melissa A Haendel¹

Affiliations

¹ Center for Health AI, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.
³ Center for Health AI and Section of Informatics and Data Science, Department of Pediatrics, University of Colorado School of Medicine, University of Colorado, Aurora, CO, USA.
⁴ University of Minnesota, Minneapolis, MN, USA.
⁵ The University of Michigan at Ann Arbor, Ann Arbor, MI, USA.
⁶ Computational Bioscience, University of Colorado Anschutz Medical Campus, Boulder, CO, USA.
⁷ Schools of Medicine, Public Health, and Nursing, Johns Hopkins University, Baltimore, MD, USA.
⁸ Patient Led Research for COVID-19.
⁹ The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
¹⁰ Stony Brook University, Stony Brook, NY, USA.
¹¹ University of Massachusetts Medical School Worcester, Worcester, MA, USA.
¹² Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY, USA.
¹³ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
¹⁵ Oregon Health & Science University, Portland, OR, USA.
¹⁶ The Jackson Laboratory For Genomic Medicine, Farmington, CT, USA.
¹⁷ Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.
¹⁸ Research Institute, NorthShore University HealthSystem, Evanston, IL, USA.
¹⁹ Saint Joseph Mercy Health System, Ypsilanti, MI, USA.
²⁰ School of Medicine, Wake Forest University, Winston Salem, NC, USA.

PMID: 33791733
PMCID: PMC8010765
DOI: 10.1101/2021.03.20.21253896

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information

Halie M Rando et al. medRxiv. 2021.

[Preprint]. 2021 Mar 26:2021.03.20.21253896.

doi: 10.1101/2021.03.20.21253896.

Authors

Affiliations

¹ Center for Health AI, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
² Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, CO, USA.
³ Center for Health AI and Section of Informatics and Data Science, Department of Pediatrics, University of Colorado School of Medicine, University of Colorado, Aurora, CO, USA.
⁴ University of Minnesota, Minneapolis, MN, USA.
⁵ The University of Michigan at Ann Arbor, Ann Arbor, MI, USA.
⁶ Computational Bioscience, University of Colorado Anschutz Medical Campus, Boulder, CO, USA.
⁷ Schools of Medicine, Public Health, and Nursing, Johns Hopkins University, Baltimore, MD, USA.
⁸ Patient Led Research for COVID-19.
⁹ The University of Texas Medical Branch at Galveston, Galveston, TX, USA.
¹⁰ Stony Brook University, Stony Brook, NY, USA.
¹¹ University of Massachusetts Medical School Worcester, Worcester, MA, USA.
¹² Department of Biomedical Informatics, Stony Brook University, Stony Brook, NY, USA.
¹³ Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
¹⁴ Environmental Genomics and Systems Biology Division, Lawrence Berkeley National Laboratory, Berkeley, CA, USA.
¹⁵ Oregon Health & Science University, Portland, OR, USA.
¹⁶ The Jackson Laboratory For Genomic Medicine, Farmington, CT, USA.
¹⁷ Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.
¹⁸ Research Institute, NorthShore University HealthSystem, Evanston, IL, USA.
¹⁹ Saint Joseph Mercy Health System, Ypsilanti, MI, USA.
²⁰ School of Medicine, Wake Forest University, Winston Salem, NC, USA.

PMID: 33791733
PMCID: PMC8010765
DOI: 10.1101/2021.03.20.21253896

Abstract

Since late 2019, the novel coronavirus SARS-CoV-2 has introduced a wide array of health challenges globally. In addition to a complex acute presentation that can affect multiple organ systems, increasing evidence points to long-term sequelae being common and impactful. The worldwide scientific community is forging ahead to characterize a wide range of outcomes associated with SARS-CoV-2 infection; however the underlying assumptions in these studies have varied so widely that the resulting data are difficult to compareFormal definitions are needed in order to design robust and consistent studies of Long COVID that consistently capture variation in long-term outcomes. Even the condition itself goes by three terms, most widely "Long COVID", but also "COVID-19 syndrome (PACS)" or, "post-acute sequelae of SARS-CoV-2 infection (PASC)". In the present study, we investigate the definitions used in the literature published to date and compare them against data available from electronic health records and patient-reported information collected via surveys. Long COVID holds the potential to produce a second public health crisis on the heels of the pandemic itself. Proactive efforts to identify the characteristics of this heterogeneous condition are imperative for a rigorous scientific effort to investigate and mitigate this threat.

PubMed Disclaimer

Conflict of interest statement

Declaration of Conflicts of Interest Julie A. McMurry: Cofounder, Pryzm Health; Melissa A. Haendel: co-founder Pryzm Health

Figures

**Figure 1.. Heterogeneity of reported phenotypes for post-acute COVID-19 sequelae.**
Clinical and patient-reported symptoms, time course, and patients counts were extracted from the literature (see Supplemental Table 1. The author and year associated with each publication is provided in the first column. The second column indicates the exact phenotypes reported in each study, corresponding to symptoms and clinical indices. Symptoms and indices are categorized into phenotype groups. Most of the 142 symptoms or indices reported were unique to a single study. Examples of terms used are magnified in the pull-out. Supplemental Table 1 contains the literature extracted.

**Figure 2.**
Average frequency of constitutional symptoms (specific terms descending from HP:0025142, Constitutional symptom, which is defined as a symptom or manifestation indicating a systemic or general effect of a disease and that may affect the general well-being or status of an individual). Frequencies are given separately for the 19 researcher-led studies and two patient-led studies.

**Figure 3.**
Schematic illustrating the method used to identify patients for Long COVID analysis, mapping of these patients’ data to HPO via OMOP2OBO codesets, and looking for patients with HPO phenotypic features from the mapped data to define a potential Long COVID cohort.

See this image and copyright information in PMC

References

1. Puelles VG, Lütgehetmann M, Lindenmeyer MT, et al. Multiorgan and Renal Tropism of SARS-CoV-2. N Engl J Med 2020; 383: 590–2. - PMC - PubMed
1. Gavriatopoulou M, Korompoki E, Fotiou D, et al. Organ-specific manifestations of COVID-19 infection. Clin Exp Med 2020; 20: 493–506. - PMC - PubMed
1. Disser NP, De Micheli AJ, Schonk MM, et al. Musculoskeletal Consequences of COVID-19. J Bone Joint Surg Am 2020; 102: 1197–204. - PMC - PubMed
1. Abdullahi A, Candan SA, Abba MA, et al. Neurological and Musculoskeletal Features of COVID-19: A Systematic Review and Meta-Analysis. Front Neurol 2020; 11: 687. - PMC - PubMed
1. Ferrandi PJ, Alway SE, Mohamed JS. The interaction between SARS-CoV-2 and ACE2 may have consequences for skeletal muscle viral susceptibility and myopathies. J Appl Physiol 2020; 129: 864–7. - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

This is a preprint.

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information

Affiliations

Challenges in defining Long COVID: Striking differences across literature, Electronic Health Records, and patient-reported information

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Publication types

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Miscellaneous