Subphenotypes of Self-Reported Symptoms and Outcomes in Long COVID: a prospective cohort study with latent class analysis
Authors: Kitsios Georgios D. , Blacka Shawna , Jacobs Jana , Mirza Taaha , Naqvi Asma , Gentry Heather , Kessinger Cathy , Wang Xiaohong , Golubykh Konstantin , Qurashi Hafiz Muhammad Siddique , Dodia Akash , Risbano Michael , Benigno Michael , Emir Birol , Weinstein Edward , Bramson Candace , Jiang Lili , Dai Feng , Szigethy Eva , Mellors John , Methe Barbara , Sciurba Frank , Mehdi Nouraie Seyed , Morris Alison 
Published: August 2023

AbstractObjectiveTo characterize subphenotypes of self-reported symptoms and outcomes(SRSOs) in Post-acute sequelae of COVID-19(PASC).DesignProspective, observational cohort study of PASC subjects.SettingAcademic tertiary center from five clinical referral sources.ParticipantsAdults with COVID-19 ≥ 20 days before enrollment and presence of any new self-reported symptoms following COVID-19.ExposuresWe collected data on clinical variables and SRSOs via structured telephone interviews and performed standardized assessments with validated clinical numerical scales to capture psychological symptoms, neurocognitive functioning, and cardiopulmonary function. We collected saliva and stool samples for quantification of SARS-CoV-2 RNA via qPCR.Primary and Secondary outcomes of measureDescription of PASC SRSOs burden and duration, derivation of distinct PASC subphenotypes via latent class analysis (LCA), and relationship between viral load with SRSOs and PASC subphenotypes.ResultsBaseline data for 214 individuals were analyzed. The study visit took place at a median of 197.5 days after COVID-19 diagnosis, and participants reported ever having a median of 9/16 symptoms (interquartile range 6-11) after acute COVID, with muscle-aches, dyspnea, and headache being the most common. Fatigue, cognitive impairment, and dyspnea were experienced for a longer time. Participants had a lower burden of active symptoms (median 3, interquartile range 1-6) than those ever experienced (p<0.001). Unsupervised LCA of symptoms revealed three clinically-active PASC subphenotypes: a high burden constitutional symptoms (21.9%), a persistent loss/change of smell and taste (20.6%), and a minimal residual symptoms subphenotype (57.5%). Subphenotype assignments were strongly associated with self-assessments of global health, recovery and PASC impact on employment (p<0.001). Viral persistence (5.6% saliva and 1% stool samples positive) did not explain SRSOs or subphenotypes.ConclusionsWe identified distinct PASC subphenotypes and highlight that although most symptoms progressively resolve, specific PASC subpopulations are impacted by either high burden of constitutional symptoms or persistent olfactory/gustatory dysfunction, requiring prospective identification and targeted preventive or therapeutic interventions.Strengths and Limitations of this studyProspective cohort study with inclusive patient population with PASC symptomatology from different clinical sources and index severity of COVID-19.Structured telephone interviews and standardized assessments with validated clinical numerical scalesUnsupervised clustering analysis for data-driven derivation of PASC subphenotypes.Analyses based on self-reported symptoms and outcomes, but not on physiologic or imaging measurements.Non-invasive biospecimen for analysis of viral persistence may have missed viral signal in deep-seeded tissues.Key PointsQuestionAre there distinct subphenotypes of self-reported symptoms and outcomes in subjects with PASC and what if so, which factors predict them?FindingsThis prospective observational cohort study identified three distinct PASC clusters, comprising a high burden cluster with constitutional symptoms (21.9%), a cluster characterized by persistent loss/change of smell and taste (20.6%), and a minimal residual symptoms cluster (57.5%).MeaningPASC subphenotypes offer insights into the symptoms and outcomes experienced by individuals, and provide a framework for targeted study of preventive and therapeutic interventions.