Immunopathology and therapeutic strategies for long COVID: mechanisms, manifestations, and clinical implications
Enaam M. Junainah 1, Azza H. Abd-El-Rahman 1, Amin A. Alamin 1, Khalid E. Hassan 1, Basem H. Elesawy 2, Ahmed H. Elrashidy 3, Amal A. Alhosary 4, Hammad Tufail-Chaudhary 1, Ayman E. EL-Kenawy 1, Amna F. Bashir 1, Ghaliah Obaid-Alnefaie 1, Dalal M. Nemenqani 1, Nihad A. El-Nashar 1, Mostafa Khairy 5, Nawaf A. Al-Thobaiti 1, Fawaz K. Alfahmi 1, Sama A. Taha 6
1 Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia; 2 Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia; Department of Pathology, Faculty of Medicine, Mansoura University, Mansoura, Egypt; 3 Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia;; Department of Pathology, Faculty of Medicine, Al-Azhar University, Assiut, Egypt; 4 Department of Pathology, College of Medicine, Taif University, Taif, Saudi Arabia;; Department of Clinical Pathology, Faculty of Medicine, Menoufia University, Shebin El-Kom, Egypt; 5 Department of Pathology, Assiut University, Assiut, Egypt; 6 Department of Microbiology, Taif University, Taif, Saudi Arabia
*Correspondence: Ahmed H. Elrashidy, Email not available
Abstract
Long coronavirus disease-19 (COVID-19) is a complex, multifactorial condition characterized by persistent symptoms lasting more than 12 weeks following acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The underlying mechanisms remain incompletely understood, but chronic inflammation, immune dysregulation, autoimmunity, and viral persistence are increasingly being implicated. This study investigated the immunopathological drivers of long COVID-19 and their associations with clinical manifestations and organ damage. A prospective, longitudinal cohort study was conducted on 200 COVID-19 survivors aged 18-65 years, in which immune markers, autoantibody profiles, lymphocyte dysfunction, and imaging findings were assessed over a 12-month period. Persistent inflammation was observed, with elevated interleukin-6 and tumor necrosis factor α ± levels correlated with lung fibrosis and cognitive impairment. Autoantibodies were detected in 40% of the participants, particularly those with cardiovascular and neurological symptoms. A significant reduction in CD8+ T-cell counts was associated with severe fatigue and cognitive dysfunction, whereas persistent SARS-CoV-2 RNA was identified in 10% of cases, primarily in individuals with gastrointestinal symptoms. Imaging studies revealed multiorgan involvement, with structural abnormalities in the lungs, heart, and brain. These findings highlight the interplay of immune dysfunction, chronic inflammation, and autoimmunity in long-term COVID-19, underscoring the need for targeted therapeutic strategies to address its longterm health impacts.
