Clinical phenotypes and quality of life to define post-COVID-19 syndrome: a cluster analysis of the multinational, prospective ORCHESTRA cohort

Abstract

Background: Lack of specific definitions of clinical characteristics, disease severity, and risk and preventive factors of post-COVID-19 syndrome (PCS) severely impacts research and discovery of new preventive and therapeutics drugs.

Methods: This prospective multicenter cohort study was conducted from February 2020 to June 2022 in 5 countries, enrolling SARS-CoV-2 out- and in-patients followed at 3-, 6-, and 12-month from diagnosis, with assessment of clinical and biochemical features, antibody (Ab) response, Variant of Concern (VoC), and physical and mental quality of life (QoL). Outcome of interest was identification of risk and protective factors of PCS by clinical phenotype, setting, severity of disease, treatment, and vaccination status. We used SF-36 questionnaire to assess evolution in QoL index during follow-up and unsupervised machine learning algorithms (principal component analysis, PCA) to explore symptom clusters. Severity of PCS was defined by clinical phenotype and QoL. We also used generalized linear models to analyse the impact of PCS on QoL and associated risk and preventive factors. CT registration number: NCT05097677.

Findings: Among 1796 patients enrolled, 1030 (57%) suffered from at least one symptom at 12-month. PCA identified 4 clinical phenotypes: chronic fatigue-like syndrome (CFs: fatigue, headache and memory loss, 757 patients, 42%), respiratory syndrome (REs: cough and dyspnoea, 502, 23%); chronic pain syndrome (CPs: arthralgia and myalgia, 399, 22%); and neurosensorial syndrome (NSs: alteration in taste and smell, 197, 11%). Determinants of clinical phenotypes were different (all comparisons p < 0.05): being female increased risk of CPs, NSs, and CFs; chronic pulmonary diseases of REs; neurological symptoms at SARS-CoV-2 diagnosis of REs, NSs, and CFs; oxygen therapy of CFs and REs; and gastrointestinal symptoms at SARS-CoV-2 diagnosis of CFs. Early treatment of SARS-CoV-2 infection with monoclonal Ab (all clinical phenotypes), corticosteroids therapy for mild/severe cases (NSs), and SARS-CoV-2 vaccination (CPs) were less likely to be associated to PCS (all comparisons p < 0.05). Highest reduction in QoL was detected in REs and CPs (43.57 and 43.86 vs 57.32 in PCS-negative controls, p < 0.001). Female sex (p < 0.001), gastrointestinal symptoms (p = 0.034) and renal complications (p = 0.002) during the acute infection were likely to increase risk of severe PCS (QoL <50). Vaccination and early treatment with monoclonal Ab reduced the risk of severe PCS (p = 0.01 and p = 0.03, respectively).

Interpretation: Our study provides new evidence suggesting that PCS can be classified by clinical phenotypes with different impact on QoL, underlying possible different pathogenic mechanisms. We identified factors associated to each clinical phenotype and to severe PCS. These results might help in designing pathogenesis studies and in selecting high-risk patients for inclusion in therapeutic and management clinical trials.

Funding: The study received funding from the Horizon 2020 ORCHESTRA project, grant 101016167; from the Netherlands Organisation for Health Research and Development (ZonMw), grant 10430012010023; from Inserm, REACTing (REsearch & ACtion emergING infectious diseases) consortium and the French Ministry of Health, grant PHRC 20-0424.

Keywords: COVID-19; Long-term sequelae; Post-COVID syndrome; Prediction model; SARS-CoV-2.

Fig. 1

Relative frequency of symptoms across the population subgroups according to the demographic features and comorbidities. Each value corresponds to the percentage of the patient-group defined by x-axis, who presents with a symptom outlined on y-axis, at described time point. E.g., fever was reported by 78% of the overall patients in the acute phase, but only by 3% in the 6-month follow-up. Variables in the x-axis were selected based on clinical meaningfulness. Obese: BMI ≥30; at risk population: age >65 years old and/or at least one of the following: BMI ≥30, chronic kidney disease, diabetes, HIV infection, cardiovascular disease, chronic respiratory diseases, chronic liver disease, neurological disorder.

Fig. 2

Clusters of symptoms according to principal component analysis (PCA). The numbers near the arrows are the loadings (only loadings >0.4 are depicted). Component 1, 2, and 3 denote the obliquely transformed components.

Fig. 3

Comparison among distribution of gender, immune response (anti-S and anti-RBD titers) and SARs-CoV-2 variants by WHO definition, clinical phenotypes, and severity of post-COVID-19 syndrome. The numbers in brackets denote the number of patients.

Fig. 4

Severity of post-COVID-19 syndrome by clinical phenotypes and quality of life measured with SF-36 questionnaire. Chronic fatigue-like syndrome: fatigue, headache, and memory loss; respiratory syndrome: cough and dyspnoea; chronic pain: arthralgia and myalgia; and neurosensorial syndrome: altered taste and smell; SF-36: short form health survey 36.