Evolving phenotypes of non-hospitalized patients that indicate long COVID
Authors: Estiri Hossein , Strasser Zachary H. , Brat Gabriel A. , Semenov Yevgeniy R. ,   The Consortium for Characterization of COVID-19 by EHR (4CE), Aaron James R. , Agapito Giuseppe , Albayrak Adem , Alessiani Mario , Amendola Danilo F. , Anthony Li L. L. J. , Aronow Bruce J. , Ashraf Fatima , Atz Andrew , Avillach Paul , Balshi James , Beaulieu-Jones Brett K. , Bell Douglas S. , Bellasi Antonio , Bellazzi Riccardo , Benoit Vincent , Beraghi Michele , Sobrino José Luis Bernal , Bernaux Mélodie , Bey Romain , Martínez Alvar Blanco , Boeker Martin , Bonzel Clara-Lea , Booth John , Bosari Silvano , Bourgeois Florence T. , Bradford Robert L. , Brat Gabriel A. , Bréant Stéphane , Brown Nicholas W. , Bryant William A. , Bucalo Mauro , Burgun Anita , Cai Tianxi , Cannataro Mario , Carmona Aldo , Caucheteux Charlotte , Champ Julien , Chen Jin , Chen Krista , Chiovato Luca , Chiudinelli Lorenzo , Cho Kelly , Cimino James J. , Colicchio Tiago K. , Cormont Sylvie , Cossin Sébastien , Craig Jean B. , Bermúdez Juan Luis Cruz , Rojo Jaime Cruz , Dagliati Arianna , Daniar Mohamad , Daniel Christel , Davoudi Anahita , Devkota Batsal , Dubiel Julien , Esteve Loic , Estiri Hossein , Fan Shirley , Follett Robert W. , Gaiolla Paula S. A. , Ganslandt Thomas , Barrio Noelia García , Garmire Lana X. , Gehlenborg Nils , Geva Alon , Gradinger Tobias , Gramfort Alexandre , Griffier Romain , Griffon Nicolas , Grisel Olivier , Gutiérrez-Sacristán Alba , Hanauer David A. , Haverkamp Christian , He Bing , Henderson Darren W. , Hilka Martin , Holmes John H. , Hong Chuan , Horki Petar , Huling Kenneth M. , Hutch Meghan R. , Issitt Richard W. , Jannot Anne Sophie , Jouhet Vianney , Keller Mark S. , Kirchoff Katie , Klann Jeffrey G. , Kohane Isaac S. , Krantz Ian D. , Kraska Detlef , Krishnamurthy Ashok K. , L’Yi Sehi , Le Trang T. , Leblanc Judith , Leite Andressa R. R. , Lemaitre Guillaume , Lenert Leslie , Leprovost Damien , Liu Molei , Loh Ne Hooi Will , Lozano-Zahonero Sara , Luo Yuan , Lynch Kristine E. , Mahmood Sadiqa , Maidlow Sarah , Malovini Alberto , Mandl Kenneth D. , Mao Chengsheng , Maram Anupama , Martel Patricia , Masino Aaron J. , Mazzitelli Maria , Mensch Arthur , Milano Marianna , Minicucci Marcos F. , Moal Bertrand , Moore Jason H. , Moraleda Cinta , Morris Jeffrey S. , Morris Michele , Moshal Karyn L. , Mousavi Sajad , Mowery Danielle L. , Murad Douglas A. , Murphy Shawn N. , Naughton Thomas P. , Neuraz Antoine , Ngiam Kee Yuan , Norman James B. , Obeid Jihad , Okoshi Marina P. , Olson Karen L. , Omenn Gilbert S. , Orlova Nina , Ostasiewski Brian D. , Palmer Nathan P. , Paris Nicolas , Patel Lav P. , Jimenez Miguel Pedrera , Pfaff Emily R. , Pillion Danielle , Prokosch Hans U. , Prudente Robson A. , González Víctor Quirós , Ramoni Rachel B. , Raskin Maryna , Rieg Siegbert , Domínguez Gustavo Roig , Rojo Pablo , Sáez Carlos , Salamanca Elisa , Samayamuthu Malarkodi J. , Sandrin Arnaud , Santos Janaina C. C. , Savino Maria , Schriver Emily R. , Schubert Petra , Schuettler Juergen , Scudeller Luigia , Sebire Neil J. , Balazote Pablo Serrano , Serre Patricia , Serret-Larmande Arnaud , Shakeri Zahra , Silvio Domenick , Sliz Piotr , Son Jiyeon , Sonday Charles , South Andrew M. , Spiridou Anastasia , Tan Amelia L. M. , Tan Bryce W. Q. , Tan Byorn W. L. , Tanni Suzana E. , Taylor Deanne M. , Terriza Torres Ana I. , Tibollo Valentina , Tippmann Patric , Torti Carlo , Trecarichi Enrico M. , Tseng Yi-Ju , Vallejos Andrew K. , Varoquaux Gael , Vella Margaret E. , Verdy Guillaume , Vie Jill-Jênn , Visweswaran Shyam , Vitacca Michele , Wagholikar Kavishwar B. , Waitman Lemuel R. , Wang Xuan , Wassermann Demian , Weber Griffin M. , Xia Zongqi , Yehya Nadir , Yuan William , Zambelli Alberto , Zhang Harrison G. , Zoeller Daniel , Zucco Chiara , Patel Chirag J. , Murphy Shawn N. 
Published: September 2021

Background

For some SARS-CoV-2 survivors, recovery from the acute phase of the infection has been grueling with lingering effects. Many of the symptoms characterized as the post-acute sequelae of COVID-19 (PASC) could have multiple causes or are similarly seen in non-COVID patients. Accurate identification of PASC phenotypes will be important to guide future research and help the healthcare system focus its efforts and resources on adequately controlled age- and gender-specific sequelae of a COVID-19 infection.

Methods

In this retrospective electronic health record (EHR) cohort study, we applied a computational framework for knowledge discovery from clinical data, MLHO, to identify phenotypes that positively associate with a past positive reverse transcription-polymerase chain reaction (RT-PCR) test for COVID-19. We evaluated the post-test phenotypes in two temporal windows at 3–6 and 6–9 months after the test and by age and gender. Data from longitudinal diagnosis records stored in EHRs from Mass General Brigham in the Boston Metropolitan Area was used for the analyses. Statistical analyses were performed on data from March 2020 to June 2021. Study participants included over 96 thousand patients who had tested positive or negative for COVID-19 and were not hospitalized.

Results

We identified 33 phenotypes among different age/gender cohorts or time windows that were positively associated with past SARS-CoV-2 infection. All identified phenotypes were newly recorded in patients’ medical records 2 months or longer after a COVID-19 RT-PCR test in non-hospitalized patients regardless of the test result. Among these phenotypes, a new diagnosis record for anosmia and dysgeusia (OR 2.60, 95% CI [1.94–3.46]), alopecia (OR 3.09, 95% CI [2.53–3.76]), chest pain (OR 1.27, 95% CI [1.09–1.48]), chronic fatigue syndrome (OR 2.60, 95% CI [1.22–2.10]), shortness of breath (OR 1.41, 95% CI [1.22–1.64]), pneumonia (OR 1.66, 95% CI [1.28–2.16]), and type 2 diabetes mellitus (OR 1.41, 95% CI [1.22–1.64]) is one of the most significant indicators of a past COVID-19 infection. Additionally, more new phenotypes were found with increased confidence among the cohorts who were younger than 65.

Conclusions

The findings of this study confirm many of the post-COVID-19 symptoms and suggest that a variety of new diagnoses, including new diabetes mellitus and neurological disorder diagnoses, are more common among those with a history of COVID-19 than those without the infection. Additionally, more than 63% of PASC phenotypes were observed in patients under 65 years of age, pointing out the importance of vaccination to minimize the risk of debilitating post-acute sequelae of COVID-19 among younger adults.