Post-acute sequelae of COVID-19 symptom phenotypes and therapeutic strategies: A prospective, observational study

by Jennifer A. Frontera, Lorna E. Thorpe, Naomi M. Simon, Adam de Havenon, Shadi Yaghi, Sakinah B. Sabadia, Dixon Yang, Ariane Lewis, Kara Melmed, Laura J. Balcer, Thomas Wisniewski, Steven L. Galetta

Post-acute sequelae of COVID-19 (PASC) includes a heterogeneous group of patients with variable symptomatology, who may respond to different therapeutic interventions. Identifying phenotypes of PASC and therapeutic strategies for different subgroups would be a major step forward in management.

In a prospective cohort study of patients hospitalized with COVID-19, 12-month symptoms and quantitative outcome metrics were collected. Unsupervised hierarchical cluster analyses were performed to identify patients with: (1) similar symptoms lasting ≥4 weeks after acute SARS-CoV-2 infection, and (2) similar therapeutic interventions. Logistic regression analyses were used to evaluate the association of these symptom and therapy clusters with quantitative 12-month outcome metrics (modified Rankin Scale, Barthel Index, NIH NeuroQoL).

Among 242 patients, 122 (50%) reported ≥1 PASC symptom (median 3, IQR 1–5) lasting a median of 12-months (range 1–15) post-COVID diagnosis. Cluster analysis generated three symptom groups: Cluster1 had few symptoms (most commonly headache); Cluster2 had many symptoms including high levels of anxiety and depression; and Cluster3 primarily included shortness of breath, headache and cognitive symptoms. Cluster1 received few therapeutic interventions (OR 2.6, 95% CI 1.1–5.9), Cluster2 received several interventions, including antidepressants, anti-anxiety medications and psychological therapy (OR 15.7, 95% CI 4.1–59.7) and Cluster3 primarily received physical and occupational therapy (OR 3.1, 95%CI 1.3–7.1). The most severely affected patients (Symptom Cluster 2) had higher rates of disability (worse modified Rankin scores), worse NeuroQoL measures of anxiety, depression, fatigue and sleep disorder, and a higher number of stressors (all P<0.05). 100% of those who received a treatment strategy that included psychiatric therapies reported symptom improvement, compared to 97% who received primarily physical/occupational therapy, and 83% who received few interventions (P = 0.042).

We identified three clinically relevant PASC symptom-based phenotypes, which received different therapeutic interventions with varying response rates. These data may be helpful in tailoring individual treatment programs.