Table of contents
Liane S. Canas PhD1 liane.dos_santos_canas at kcl.ac.uk), Erika Molteni PhD1, Jie Deng PhD1, Carole H. Sudre PhD2,3, Benjamin Murray MSc1, Eric Kerfoot PhD1, Michela Antonelli PhD1, Liyuan Chen MSc1, Khaled Rjoob PhD2, Joan Capdevila Pujol PhD4, Lorenzo Polidori MSc4, Anna May MSc4, Marc F. Osterdahl PhD5, Ronan Whiston PhD5, Nathan J. Cheetham PhD5, Vicky Bowyer MSc5, Prof Tim D. Spector PhD5, Prof Alexander Hammers PhD1, Prof Emma L. Duncan PhD5,6, Prof Sebastien Ourselin PhD1, Claire J. Steves PhD5, Marc Modat PhD1
- School of Biomedical Engineering & Imaging Sciences, King’s College London, London, UK.
- MRC Unit for Lifelong Health and Ageing, Department of Population Health Sciences, University College London, London, UK
- Centre for Medical Image Computing, Department of Computer Science, University College London, London, UK
- ZOE Limited London, UK
- Department of Twin Research and Genetic Epidemiology, King’s College London, London, UK.
- Department of Endocrinology, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Self-reported symptom studies rapidly increased our understanding of SARS-CoV-2 during the pandemic and enabled the monitoring of long-term effects of COVID-19 outside the hospital setting. It is now evident that post-COVID syndrome presents with heterogeneous profiles, which need characterisation to enable personalised care among the most affected survivors. This study describes post-COVID profiles, and how they relate to different viral variants and vaccination status.
In this prospective longitudinal cohort study, we analysed data from 336,652 subjects, with regular health reports through the Covid Symptom Study (CSS) smartphone application. These subjects had reported feeling physically normal for at least 30 days before testing positive for SARS-CoV-2. 9,323 individuals subsequently developed Long-COVID, defined as symptoms lasting longer than 28 days. 1,459 had post-COVID syndrome, defined as more than 12 weeks of symptoms. Clustering analysis of the time-series data was performed to identify distinct symptom profiles for post-COVID patients, across variants of SARS-CoV-2 and vaccination status at the time of infection. Clusters were then characterised based on symptom prevalence, duration, demography, and prior conditions (comorbidities). Using an independent testing sample with additional data (n=140), we investigated the impact of post-COVID symptom clusters on the lives of affected individuals.
We identified distinct profiles of symptoms for post-COVID syndrome within and across variants: four endotypes were identified for infections due to the wild-type variant; seven for the alpha variant; and five for delta. Across all variants, a cardiorespiratory cluster of symptoms was identified. A second cluster related to central neurological, and a third to cases with the most severe and debilitating multiorgan symptoms. Gastrointestinal symptoms clustered in no more than two specific phenotypes per viral variant. The three main clusters were confirmed in an independent testing sample, and their functional impact was assessed.
Unsupervised analysis identified different post-COVID profiles, characterised by differing symptom combinations, durations, and functional outcomes. Phenotypes were at least partially concordant with individuals’ reported experiences. Our classification may be useful to understand distinct mechanisms of the post-COVID syndrome, as well as subgroups of individuals at risk of prolonged debilitation.
We identified distinct self-reported symptom evolutions, or clusters, in individuals with more than 12 weeks of persisting symptoms after SARS CoV-2 infection, using a data-driven approach. Although multiple clusters were found across the three variants assessed, common features emerged for three clusters dominated by certain symptom groups: central neurological, cardiorespiratory, and systemic/inflammatory (Supplementary Table 1). Our findings may have relevance to individuals living with PCS, their health practitioners, and healthcare services, providing data to validate their illness and manage their expectations during its course. This work adds to the emerging evidence that PCS may have sub-types, possibly with differing pathophysiology. For any given individual, their condition may relate to a specific central/neurological process, to respiratory damage, or to a systemic inflammatory cause. Our study suggests that further investigation into mechanisms underlying PCS should consider subdividing affected individuals into different subgroups, which may increase the ability to identify distinct processes underlying these symptom clusters.
__Evidence before this study:))
We conducted a search in the PubMed Central database, with keywords: ("Long-COVID*" OR "post?covid*" OR "post?COVID*" OR postCOVID* OR postCovid*) AND (cluster* OR endotype* OR phenotype* OR sub?type* OR subtype).
On 15 June 2022, 161 documents were identified, of which 24 either provided descriptions of sub-types or proposed phenotypes of Long-COVID or post-COVID syndrome(s). These included 16 studies attempting manual sub-grouping of phenotypes, 6 deployments of unsupervised methods for patient clustering and automatic semantic phenotyping (unsupervised k-means=2; random forest classification; other=2), and two reports of uncommon presentations of Long-COVID/post-COVID syndrome. Overall, two to eight symptom profiles (clusters) were identified, with three recurring clusters. A cardiopulmonary syndrome was the predominant observation, manifesting with exertional intolerance and dyspnoea (n=10), fatigue (n=8), autonomic dysfunction, tachycardia or palpitations (n=5), lung radiological abnormalities including fibrosis (n=2), and.chest pain (n=1). A second common presentation consisted in persistent general autoimmune activation and proinflammatory state (n=2), comprising multi-organ mild sequelae (n=2), gastrointestinal symptoms (n=2), dermatological symptoms (n=2), and/or fever (n=1). A third syndrome was reported, with neurological or neuropsychiatric symptoms: brain fog or dizziness (n=2), poor memory or cognition (n=2), and other mental health issues including mood disorders (n=5), headache (n=2), central sensitization (n=1), paresthesia (n=1), autonomic dysfunction (n=1), fibromyalgia (n=2), and chronic pain or myalgias (n=6). Unsupervised clustering methods identified two to six different post-COVID phenotypes, mapping to the ones described above.
14 further documents focused on possible causes and/or mechanisms of disease underlying one or more manifestations of Long-COVID or post-COVID and identifying immune response dysregulation as a potential common element. All the other documents were beyond the scope of this work.
To our knowledge, there are no studies examining the symptom profile of post-COVID syndrome between different variants and vaccination status. Also, no studies reported the modelling of longitudinally collected symptoms, as time-series data, aiming at the characterisation of post-COVID syndrome.
Added-value of this study:
Our study aimed to identify symptom profiles for post-COVID syndrome across the dominant variants in 2020 and 2021, and across vaccination status at the time of infection, using a large sample with prospectively collected longitudinal self-reports of symptoms. For individuals developing 12 weeks or more of symptoms, we identified three main symptom profiles which were consistent across variants and by vaccination status, differing only in the ratio of individuals affected by each profile and symptom duration overall.
Implications of all the available evidence:
We demonstrate the existence of different post-COVID syndromes, which share commonalities across SARS-CoV-2 variant types in both symptoms themselves and how they evolved through the illness. We describe subgroups of patients with specific post-COVID presentations which might reflect different underlying pathophysiological mechanisms. Given the time-series component, our study is relevant for post-COVID prognostication, indicating how long certain symptoms last. These insights could aid in the development of personalised diagnosis and treatment, as well as helping policymakers plan for the delivery of care for people living with post-COVID syndrome.
Half as much Long-Haul with Omicron - June 2022
Long-COVID is now the biggest COVID concern - many studies
Long-Haul more prevalent among seniors - June - 2022
Long-haul fatigue, etc. common after viral infections (SARS1,2, MERS, Swine, 1918,...) even a decade later
Probably fewer long-haul COVID-19 problems when rejuvenated immune system (Vitamin D, etc.)– Dec 2020