José Pedro Cidade, Fabio Silvio Taccone, Luis Felipe Reyes, Laura Merson, Benjamin Lefevre, Barbara Wanjiru Citarella, Arie Zainul Fatoni, Pedro Póvoa, the ISARIC Characterization Group, Sabriya Abdalasalam, Alaa Abdalfattah Abdalhadi, Naana Reyam Abdalla, Almthani Hamza Abdalrheem, Saedah Abdeewi, Esraa Hassan Abdelgaum, Mohamed Abdelhalim, Mohammed Abdelkabir, Sheryl Ann Abdukahil, Lamees Adil Abdulbaqi, Nurul Najmee Abdulkadir, Eman Abdulwahed, Rawad Abdunabi, Ryuzo Abe, Laurent Abel, Ahmed Mohammed Abodina, Amal Abrous, Kamal Abu Jabal, Nashat Abu Salah, Abdurraouf Abusalama, Subhash Acharya, Andrew Acker, Safia Adem, Manuella Ademnou, Neill K. J. Adhikari, Samuel Yaw Adu, Anthony Afum-Adjei Awuah, Melvin Agbogbatey, Saleh Al Ageel, Musaab Mohammed Ahmed, Aya Mustafa Ahmed, Zainab Ahmed Alaraji, Abdulrahman Ahmed Elhefnawy Enan, R Khalil, Ali Abdelaziz, Kate Ainscough, Eka Airlangga, Tharwat Aisa, Ali Ait Hssain, Takako Akimoto, Ernita Akmal, Chika Akwani, Eman Al Qasim, Ahmed Alajeeli, Razi Alalqam, Zinah A. Alaraji, Safa Albatni, Angela Alberti, Tala Al-dabbous, Abdulkarim Aldoukali, Marta Alessi, Beatrice Alex, Kévin Alexandre, Abdulrahman Al-Fares, Asil Omar Saleh Alflite, Huda Alfoudri, Qamrah Alhadad, Hoda Salem Alhaddad, Maali Khalid Mohamed Abdalla Alhasan, Hasan Alhouri, Ahmad Nabil Alhouri, Maha TagElser Mohammed Ali, Imran Ali, Yomna Ali Abdelghafar, Kazali Enagnon Alidjnou, Mahmoud Aljadi, Sarah Aljamal, Mohammed Alkahlout, Akram Alkaseek, Qabas Alkhafajee, Clotilde Allavena, Nathalie Allou, Abdulrahman Almjersah, Walaa Alrfaea, Moayad Alrifaee, Yousef Al-Sabaa, Entisar Alshareea, João Melo Alves, João Melo Alves, Rita Vieira Alves, Joana Alves Cabrita, Maria Amaral, Amro Essam Amer, Nur Amira, Heidi Ammerlaan, Amos Amoako Adusei, John Amuasi, Roberto Andini, Claire Andrejak, Andrea Angheben, François Angoulvant
OBJECTIVE: Immune dysregulation plays a pivotal role in the pathophysiology of sepsis and COVID-19, with lymphopenia emerging as a consistent marker of severity and poor prognosis. However, most existing studies have assessed lymphocyte counts at isolated time points, limiting insights into their temporal behavior and prognostic value. The dynamics of lymphocyte recovery or persistence of lymphopenia remain largely unexplored in large populations, as well as the impact of adjunctive therapies such as corticosteroids. We hypothesized that the persistence or recovery of lymphopenia may be key to understanding disease progression and predicting outcomes. Using the multinational ISARIC cohort, we investigated longitudinal lymphocyte trajectories in hospitalized patients and the clinical determinants associated with their evolution over time. METHODS: We conducted a multinational prospective observational cohort study using data from the ISARIC-WHO Clinical Characterization Protocol. Patients with confirmed SARS-CoV-2 infection and at least four lymphocyte measurements during the first 28 days of hospitalization were included. We analyzed lymphocyte trajectories, Cox regression survival analyses and multivariable linear regression modelling. We also applied multistate models and joint modeling to assess the association between lymphocyte trajectories and 28-day mortality, incorporating corticosteroid use as a time-varying covariate. RESULTS: Of 945,317 screened patients, 231,933 hospitalized adults with confirmed COVID-19 and sufficient lymphocyte data were included, with 56.6% classified as lymphopenic. Lymphopenia was independently associated with higher rates of ICU admission, organ support, and in-hospital mortality (OR = 1.52, 95% CI 1.48-1.55), and lower absolute lymphocyte counts were strongly linked to worse survival in adjusted Cox models (HR = 1.33 per 1 × 10⁹ cells/L decrease, 95% CI 1.28-1.38). Multistate modeling revealed that lymphopenic patients had a significantly higher daily transition rate to death and a shorter duration in that immune state, while corticosteroid exposure was associated with an increased likelihood of entering and remaining in lymphopenia. Joint modeling identified age, sex, and corticosteroid use as significant predictors of lower lymphocyte trajectories over time, with distinct dynamics between survivors and non-survivors. CONCLUSION: Lymphopenia was common and strongly associated with worse outcomes in hospitalized COVID-19 patients, with impaired recovery particularly evident in those receiving corticosteroids. These findings highlight the value of lymphocyte monitoring to inform tailored immunomodulatory strategies in sepsis and severe viral infections.