Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach

@article{verfaillie2026postacute,
  title = {{Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach}},
  author = {Sander C. J. Verfaillie and Anouk Verveen and Denise Visser and Pythia Nieuwkerk and Brent Appelman and Ronald Boellaard and Caroline M. van Heugten and Janneke Horn and Hanneke E. Hulst and Menno D. de Jong and Tanja A. Kuut and Tessa van der Maaden and Yvonne M. G. van Os and Maria Prins and Johanna M. A. Visser-Meily and Michele van Vugt and Cees C. van den Wijngaard and Bart N. M. van Berckel and Jos A. Bosch and Nelleke Tolboom and Hans Knoop},
  journal = {PLOS One},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pone.0359844},
  url = {https://doi.org/10.1371/journal.pone.0359844},
  note = {CC BY 4.0},
}

TY  - JOUR
TI  - Post-acute sequelae of COVID-19 (PASC) are associated with distinct clinical phenotypes two years after SARS-CoV-2 infection: A data-driven approach
AU  - Sander C. J. Verfaillie
AU  - Anouk Verveen
AU  - Denise Visser
AU  - Pythia Nieuwkerk
AU  - Brent Appelman
AU  - Ronald Boellaard
AU  - Caroline M. van Heugten
AU  - Janneke Horn
AU  - Hanneke E. Hulst
AU  - Menno D. de Jong
AU  - Tanja A. Kuut
AU  - Tessa van der Maaden
AU  - Yvonne M. G. van Os
AU  - Maria Prins
AU  - Johanna M. A. Visser-Meily
AU  - Michele van Vugt
AU  - Cees C. van den Wijngaard
AU  - Bart N. M. van Berckel
AU  - Jos A. Bosch
AU  - Nelleke Tolboom
AU  - Hans Knoop
PY  - 2026
DA  - 2026/10/15
JO  - PLOS One
DO  - 10.1371/journal.pone.0359844
UR  - https://doi.org/10.1371/journal.pone.0359844
AB  - It is important to determine whether the persistent cognitive and fatigue complaints, as part of post-acute sequelae of COVID-19 (PASC), are associated with underlying patterns and specific symptoms clusters. Therefore, the aim of the present study was to investigate symptom clusters and clinical phenotypes in PASC. We included n = 153 individuals (53 years old, 66% female, 2 years post SARS-CoV-2 infection) categorized into groups with (n = 88) and without (n = 65) PASC, defined by severe fatigue and concentration problems using validated cut-offs. Symptom clusters (i.e., component loadings and component scores) were identified using principal component analyses (PCA, eigenvalue[EV]>1.0), using clinical, somatic, coping and sleep factors, symptom severity, neuropsychological and physical tests (totalling 19 tests and questionnaires). We then used logistic regression techniques on (participant-level) component scores (standardized) to investigate associations with PASC. Finally, K-means clustering methods to identify clinical phenotypes. Analyses were adjusted for age, sex, education, nationality and time since infection. PCA identified 5 components, explaining 70% of the variance. We labelled these components as follows: (1) PEM, ME/CFS and sleep symptoms, coping factors (EV = 7.0, 36.9% variance), (2) information-processing speed (EV = 2.5, 13.3%), (3) executive functioning (EV = 1.5, 8.0%, (4) physical performance (EV = 1.2, 6.5%), (5) somatic comorbidities and hospital admission (EV = 1.0, 5.5%). Logistic regression showed that only the first component scores (Odds ratio [95% confidence interval] = 97.1 [16.5–570.3], p < 0.001,), and none of the others (all p > 0.05), associated with PASC. Cluster analysis revealed two distinct clinical phenotypes among individuals with severe chronic fatigue: one marked by physical impairment and the other by diminished cognitive performance. Consistent with existing literature, we confirmed that PASC is a heterogeneous syndrome marked by extensive, interrelated symptoms. Notably, we identified specific cognitive and physical clinical phenotypes. These findings are important for future targeted diagnosis and treatment.
SN  - 1932-6203
ER  -