Identification of Distinct Long COVID Clinical Phenotypes Through Cluster Analysis of Self-Reported Symptoms

Abstract

Background: We aimed to describe the clinical presentation of individuals presenting with prolonged recovery from coronavirus disease 2019 (COVID-19), known as long COVID.

Methods: This was an analysis within a multicenter, prospective cohort study of individuals with a confirmed diagnosis of COVID-19 and persistent symptoms >4 weeks from onset of acute symptoms. We performed a multiple correspondence analysis (MCA) on the most common self-reported symptoms and hierarchical clustering on the results of the MCA to identify symptom clusters.

Results: Two hundred thirty-three individuals were included in the analysis; the median age of the cohort was 43 (interquartile range [IQR], 36-54) years, 74% were women, and 77.3% reported a mild initial illness. MCA and hierarchical clustering revealed 3 clusters. Cluster 1 had predominantly pain symptoms with a higher proportion of joint pain, myalgia, and headache; cluster 2 had a preponderance of cardiovascular symptoms with prominent chest pain, shortness of breath, and palpitations; and cluster 3 had significantly fewer symptoms than the other clusters (2 [IQR, 2-3] symptoms per individual in cluster 3 vs 6 [IQR, 5-7] and 4 [IQR, 3-5] in clusters 1 and 2, respectively; P < .001). Clusters 1 and 2 had greater functional impairment, demonstrated by significantly longer work absence, higher dyspnea scores, and lower scores in SF-36 domains of general health, physical functioning, and role limitation due to physical functioning and social functioning.

Conclusions: Clusters of symptoms are evident in long COVID patients that are associated with functional impairments and may point to distinct underlying pathophysiologic mechanisms of disease.

Keywords: 2; 2 infection; CoV; SARS; long COVID; post–acute sequelae of SARS.

Figure 1.

Study cohort flowchart. Abbreviations: COVID-19, coronavirus disease 2019; PCR, polymerase chain reaction; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Figure 2.

Multiple correspondence analysis (MCA) and hierarchical clustering of symptoms in individuals presenting with prolonged recovery from coronavirus disease 2019 (long COVID). A, MCA factor map showing individual coordinates used to generate the dendrogram. B, Heatmap showing the symptoms present in individuals within clusters. Compared to cluster 3 (bottom bar), cluster 1 (top bar) demonstrates musculoskeletal and pain symptoms, and cluster 2 (middle bar) shows cardiorespiratory symptoms. Abbreviations: Dim1, dimension 1; Dim2, dimension 2.

Figure 3.

36-Item Short-Form Survey (SF-36) domain differences between clusters. Boxplots showing SF-36 scores between clusters. Center, median; box limits, first and third quartiles; whiskers, 1.5 × interquartile range; black dots, outliers. Significance determined by Wilcoxon rank-sum test: ∗P < .05; ∗∗P < .01; ∗∗∗P < .001. Abbreviations: EH, emotional health; En, energy; GH, general health; PF, physical functioning; REH, role limitations due to emotional health; RPF, role limitations due to physical functioning; SF, social functioning.