Persistent somatic symptoms are key to individual illness perception at one year after COVID-19 (preprint)

Background: Sequelae of Coronavirus disease 2019 (COVID-19) were investigated by both patient-initiated and academic initiatives. Patient's subjective illness perceptions might differ from physician's clinical assessment results. Herein, we explored factors influencing patient's perception during COVID-19 recovery. Methods: Participants of the prospective observation CovILD study with persistent somatic symptoms or cardiopulmonary findings at the clinical follow-up one year after COVID-19 were analyzed (n = 74). Explanatory variables included baseline demographic and comorbidity data, COVID-19 course and one-year follow-up data of persistent somatic symptoms, physical performance, lung function testing (LFT), chest computed tomography (CT) and trans-thoracic echocardiography (TTE). Factors affecting illness perception (Brief Illness Perception Questionnaire, BIPQ) were identified by penalized multi-parameter regression and unsupervised clustering. Results: In modeling, 47% of overall illness perception variance at one year after COVID-19 was attributed to fatigue intensity, reduced physical performance, hair loss and baseline respiratory comorbidity. Overall illness perception was independent of LFT results, pulmonary lesions in CT or heart abnormality in TTE. As identified by clustering, persistent somatic symptom count, fatigue, diminished physical performance, dyspnea, hair loss and sleep problems at the one-year follow-up and severe acute COVID-19 were associated with the BIPQ domains of concern, emotional representation, complaints, disease timeline and consequences. Conclusion: Persistent somatic symptoms rather than clinical assessment results, revealing lung and heart abnormalities, impact on severity and quality of illness perception at one year after COVID-19 and may foster unhelpful coping mechanisms. Besides COVID-19 severity, individual illness perception should be taken into account when allocating rehabilitation and psychological therapy resources. Study registration: ClinicalTrials.gov: NCT04416100.

Distinct smell and taste disorder phenotype of post-acute COVID-19 sequelae (preprint)

Background Olfactory dysfunction (OD) often accompanies acute coronavirus disease 2019 (COVID-19) and its sequelae. Herein, we investigated OD during COVID-19 recovery in the context of other symptoms, quality of life, physical and mental health. Methods Symptom recovery patterns were analyzed in a bi-national, ambulatory COVID-19 survey (n = 906, ≥ 90 days follow-up) and a multi-center observational cross-sectional cohort of ambulatory and hospitalized individuals (n = 108, 360 days follow-up) with multi-dimensional scaling, association rule mining and partitioning around medoids clustering. Results Both in the ambulatory collective (72%, n = 655/906) and the cross-sectional ambulatory and hospitalized cohort (41%, n = 44/108) self-reported OD was frequent during acute COVID-19, displayed a slow recovery pace (ambulatory: 28 days, cross-sectional: 90 days median recovery time) and commonly co-occurred with taste disorders. In the ambulatory collective, a predominantly young, female, comorbidity-free group of convalescents with persistent OD and taste disorder (>90 days) was identified. This post-acute smell and taste disorder phenotype was characterized by a low frequency of other leading post-acute symptoms including fatigue, respiratory and neurocognitive complaints. Despite a protracted smell and taste dysfunction, this subset had high ratings of physical performance, mental health, and quality of life. Conclusion Our results underline the clinical heterogeneity of post-acute COVID-19 sequelae calling for tailored management strategies. The persistent smell and taste disorder phenotype may represent a distinct COVID-19 recovery pathway characterized by a good recovery of other COVID-19 related symptoms. Study registration ClinicalTrials.gov: NCT04661462 (ambulatory collective), NCT04416100 (cross-sectional cohort).

A global systematic analysis of the occurrence, severity, and recovery pattern of long COVID in 2020 and 2021 (preprint)

ImportanceWhile much of the attention on the COVID-19 pandemic was directed at the daily counts of cases and those with serious disease overwhelming health services, increasingly, reports have appeared of people who experience debilitating symptoms after the initial infection. This is popularly known as long COVID. ObjectiveTo estimate by country and territory of the number of patients affected by long COVID in 2020 and 2021, the severity of their symptoms and expected pattern of recovery DesignWe jointly analyzed ten ongoing cohort studies in ten countries for the occurrence of three major symptom clusters of long COVID among representative COVID cases. The defining symptoms of the three clusters (fatigue, cognitive problems, and shortness of breath) are explicitly mentioned in the WHO clinical case definition. For incidence of long COVID, we adopted the minimum duration after infection of three months from the WHO case definition. We pooled data from the contributing studies, two large medical record databases in the United States, and findings from 44 published studies using a Bayesian meta-regression tool. We separately estimated occurrence and pattern of recovery in patients with milder acute infections and those hospitalized. We estimated the incidence and prevalence of long COVID globally and by country in 2020 and 2021 as well as the severity-weighted prevalence using disability weights from the Global Burden of Disease study. ResultsAnalyses are based on detailed information for 1906 community infections and 10526 hospitalized patients from the ten collaborating cohorts, three of which included children. We added published data on 37262 community infections and 9540 hospitalized patients as well as ICD-coded medical record data concerning 1.3 million infections. Globally, in 2020 and 2021, 144.7 million (95% uncertainty interval [UI] 54.8-312.9) people suffered from any of the three symptom clusters of long COVID. This corresponds to 3.69% (1.38-7.96) of all infections. The fatigue, respiratory, and cognitive clusters occurred in 51.0% (16.9-92.4), 60.4% (18.9-89.1), and 35.4% (9.4-75.1) of long COVID cases, respectively. Those with milder acute COVID-19 cases had a quicker estimated recovery (median duration 3.99 months [IQR 3.84-4.20]) than those admitted for the acute infection (median duration 8.84 months [IQR 8.10-9.78]). At twelve months, 15.1% (10.3-21.1) continued to experience long COVID symptoms. Conclusions and relevanceThe occurrence of debilitating ongoing symptoms of COVID-19 is common. Knowing how many people are affected, and for how long, is important to plan for rehabilitative services and support to return to social activities, places of learning, and the workplace when symptoms start to wane. Key PointsO_ST_ABSQuestionC_ST_ABSWhat are the extent and nature of the most common long COVID symptoms by country in 2020 and 2021? FindingsGlobally, 144.7 million people experienced one or more of three symptom clusters (fatigue; cognitive problems; and ongoing respiratory problems) of long COVID three months after infection, in 2020 and 2021. Most cases arose from milder infections. At 12 months after infection, 15.1% of these cases had not yet recovered. MeaningThe substantial number of people with long COVID are in need of rehabilitative care and support to transition back into the workplace or education when symptoms start to wane.

Who is at risk of poor mental health following COVID-19 outpatient management? (preprint)

BackgroundCOVID-19 convalescents are at risk of developing a de novo mental health disorder or of worsening of a pre-existing one. The objectives of our study was to phenotype individuals at highest risk of mental health disorders among COVID-19 outpatients. MethodsWe conducted a binational online survey study with adult non-hospitalized COVID-19 convalescents (Austria/AT: n=1157, Italy/IT: n= 893). Primary endpoints were positive screening for depression and anxiety (PHQ-4, Patient Health Questionnaire) and self-perceived overall mental health and quality of life rated with 4 point Likert scales. Psychosocial stress was surveyed with a modified PHQ stress module. Associations of the mental health with socio-demographic variables, COVID-19 course and recovery data were assessed by multi-parameter random forest and serial univariable modeling. Mental disorder risk subsets were defined by self-organizing map and hierarchical clustering algorithms. The survey analyses are publicly available (https://im2-ibk.shinyapps.io/mental_health_dashboard/). ResultsIn the study cohorts, 4.6 (IT)/6% (AT) of participants reported depression and/or anxiety before to infection. At a median of 79 days (AT)/96 days (IT) post COVID-19 onset, 12.4 (AT)/19.3% (IT) of subjects were screened positive for anxiety and 17.3 (AT)/23.2% (IT) for depression. Over one-fifth of the respondents rated their overall mental health (AT: 21.8%, IT: 24.1%) or quality of life (AT: 20.3%, IT: 25.9%) as fair or poor. In both study collectives, psychosocial stress, high numbers of acute and persistent COVID-19 complaints and the presence of acute neurocognitive symptoms (impaired concentration, confusion, forgetfulness) were the strongest correlates of deteriorating mental health and poor quality of life. In clustering analysis, these variables defined a high risk subset with particularly high propensity of post-COVID-19 mental health impairment and decreased quality of life. Pre-existing depression or anxiety was associated with an increased symptom burden during acute COVID-19 and recovery. ConclusionOur study revealed a bidirectional relationship between COVID-19 symptoms and mental health. We put forward specific acute symptoms of the disease as red flags of mental health deterioration which should prompt general practitioners to identify COVID-19 patients who may benefit from early psychological and psychiatric intervention. Trial registrationClinicalTrials.gov: NCT04661462.

Phenotyping of acute and persistent COVID-19 features in the outpatient setting: exploratory analysis of an international cross-sectional online survey (preprint)

BACKGROUNDLong COVID, defined as presence of COVID-19 related symptoms 28 days or more after the onset of acute SARS-CoV-2 infection, is an emerging challenge to healthcare systems. The objective of this study was to phenotype recovery trajectories of non-hospitalized COVID-19 individuals. METHODSWe performed an international, multi-center, exploratory online survey study on demographics, comorbidities, COVID-19 symptoms and recovery status of non-hospitalized SARS-CoV-2 infected adults (Austria: n=1157), and Italy: n= 893). RESULTSWorking age subjects (Austria median: 43 yrs (IQR: 31 - 53), Italy: 45 yrs (IQR: 35 - 55)) and females (65.1% and 68.3%) predominated the study cohorts. Course of acute COVID-19 was characterized by a high symptom burden (median 13 (IQR: 9 - 18) and 13 (7 - 18) out of 44 features queried), a 47.6 - 49.3% rate of symptom persistence beyond 28 days and 20.9 - 31.9% relapse rate. By cluster analysis, two acute symptom phenotypes could be discerned: the non-specific infection phenotype and the multi-organ phenotype (MOP), the latter encompassing multiple neurological, cardiopulmonary, gastrointestinal and dermatological features. Clustering of long COVID subjects yielded three distinct subgroups, with a subset of 48.7 - 55 % long COVID individuals particularly affected by post-acute MOP symptoms. The number and presence of specific acute MOP symptoms and pre-existing multi-morbidity was linked to elevated risk of long COVID. CONCLUSIONThe consistent findings of two independent cohorts further delineate patterns of acute and post-acute COVID-19 and emphasize the importance of symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources. Key PointsO_ST_ABSQuestionC_ST_ABSWhich acute symptom patterns of acute COVID-19 are associated with prolonged symptom persistence, symptom relapse or physical performance impairment? FindingsIn this multicenter international comparative survey study on non-hospitalized SARS- CoV-2 infected adults (Austria: n = 1157, Italy: n = 893) we identified distinct and reproducible phenotypes of acute and persistent features. Acute multi-organ symptoms including neurological and cardiopulmonary manifestations are linked to elevated risk of long COVID. MeaningThese findings suggest to employ symptom phenotyping of home-isolated COVID-19 patients to predict protracted convalescence and to allocate medical resources.

Neurological Outcome and Quality of Life Three Months after COVID-19: A Prospective Observational Cohort Study (preprint)

BACKGROUND: Increasing evidence suggests the involvement of the central and peripheral nervous system in patients with coronavirus disease 2019 (COVID-19). Little is known about neurological outcomes and quality of life (QoL) after recovery from acute infection.METHODS: In this prospective, multicentre, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16-item Sniffin-Sticks-test), cognitive deficits (Montreal Cognitive Assessment), QoL (36-item Short Form), and mental health (Hospital Anxiety and Depression Scale, Post-traumatic Stress Disorder Checklist-5) three months after disease onset.FINDINGS: Of 135 COVID-19 patients included, 31 (23%) required ICU-care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient-care (mild) during acute disease. At three-month follow-up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID-19. These included poly-neuro/myopathy (n=16, 12%), mild encephalopathy (n=2, 2%), parkinsonism (n=1, 1%), orthostatic hypotension (n=1, 1%), Guillain-Barré-Syndrome (n=1, 1%) and ischemic stroke (n=1, 1%). Self-reported hyposmia/anosmia was noted in 23/135 patients (17%), which was significantly lower compared to those documented during acute COVID-19 (44%; p<0·001). Interestingly, objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at three-month follow-up. In ICU patients, encephalopathy significantly improved over time (from 29% (9/31) during acute disease to 3% (1/31) at follow-up, p=0·008). At follow-up, cognitive deficits were apparent in 23% (29/124), and QoL was impaired in 31% (28/90). Assessment of mental health revealed symptoms of depression, anxiety and post-traumatic stress disorders in 11%, 25%, and 11%, respectively.INTERPRETATION: Despite recovery from acute infection, neurological symptoms were prevalent at three-months follow-up. Above all, smelling disorders were persistent in a large proportion of patients. Our results urge for further studies investigating the onset and evolution of neurological diseases following COVID-19 infection to develop strategies for secondary prevention.TRIAL REGISTRATION: ClinicalTrials.gov (NCT04416100)FUNDING: Not applicable.DECLARATION OF INTERESTS: KS reports grants from FWF Austrian Science Fund, grants from Michael J. Fox Foundation, grants from International Parkinson and Movement Disorder Society, personal fees from Teva, personal fees from UCB, personal fees from Lundbeck, personal fees from AOP Orphan Pharmaceuticals AG, personal fees from Abbvie, personal fees from Roche, personal fees from Grünenthal; all outside the submitted work. PM reports grants from TWF (Tyrolean Science Fund), grants from Medtronic, personal fees from Boston Scientific, all outside the submitted work. The other authors have nothing to disclose. All other authors declare no competing interests.ETHICS APPROVAL STATEMENT: The conduct of the study was approved by the local ethics committee (Medical University of Innsbruck, EK Nr: 1103/2020). Written informed consent was obtained from all patients according to local regulations.