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).

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.

Investigating phenotypes of pulmonary COVID-19 recovery – a longitudinal observational prospective multicenter trial (preprint)

Background COVID-19 is associated with long-term pulmonary symptoms and may result in chronic pulmonary impairment. The optimal procedures to prevent, identify, monitor, and treat these pulmonary sequelae are elusive. Research question To characterize the kinetics of pulmonary recovery, risk factors and constellations of clinical features linked to persisting radiological lung findings after COVID-19. Study design and methods A longitudinal, prospective, multicenter, observational cohort study including COVID-19 patients (n = 108). Longitudinal pulmonary imaging and functional readouts, symptom prevalence, clinical and laboratory parameters were collected during acute COVID-19 and at 60-, 100- and 180-days follow-up visits. Recovery kinetics and risk factors were investigated by logistic regression. Classification of clinical features and study participants was accomplished by k-means clustering, the k-nearest neighbors (kNN), and naive Bayes algorithms. Results At the six-month follow-up, 51.9% of participants reported persistent symptoms with physical performance impairment (27.8%) and dyspnea (24.1%) being the most frequent. Structural lung abnormalities were still present in 45.4% of the collective, ranging from 12% in the outpatients to 78% in the subjects treated at the ICU during acute infection. The strongest risk factors of persisting lung findings were elevated interleukin-6 (IL6) and C-reactive protein (CRP) during recovery and hospitalization during acute COVID-19. Clustering analysis revealed association of the lung lesions with increased anti-S1/S2 antibody, IL6, CRP, and D-dimer levels at the early follow-up suggesting non-resolving inflammation as a mechanism of the perturbed recovery. Finally, we demonstrate the robustness of risk class assignment and prediction of individual risk of delayed lung recovery employing clustering and machine learning algorithms. Interpretation Severity of acute infection, and systemic inflammation is strongly linked to persistent post-COVID-19 lung abnormality. Automated screening of multi-parameter health record data may assist the identification of patients at risk of delayed pulmonary recovery and optimize COVID-19 follow-up management. Clinical Trial Registration ClinicalTrials.gov: NCT04416100