Lymphopenia is Associated with Altered Pathogen Distribution and Increased Disease Severity in Viral Pneumonia: A Multicenter Retrospective Cohort Study.

BACKGROUND: Lymphopenia is common in viral pneumonia and has been associated with adverse outcomes. However, its relationship with pathogen distribution, mixed infections, and opportunistic infections across different immune statuses remains incompletely characterized. METHODS: We conducted a multicenter retrospective cohort study including 2363 adult patients hospitalized with viral pneumonia, of whom 690 were immunocompromised. Patients were stratified into four groups according to immune status and lymphocyte count on admission. Clinical characteristics, laboratory parameters, pathogen profiles, and clinical outcomes were compared across groups. Multivariable logistic regression analyses were performed to identify factors independently associated with in-hospital mortality. RESULTS: Patients with lymphopenia had more severe clinical presentations, higher inflammatory and coagulation markers, and increased severity scores than those without lymphopenia. Across both immune-status strata, patients with lymphopenia had higher observed rates of respiratory failure, invasive mechanical ventilation, ECMO, and in-hospital mortality than those without lymphopenia. Pathogen analyses demonstrated marked differences in pathogen distribution across groups. Immunocompromised patients with lymphopenia showed significantly higher proportions of bacterial co-infections, fungal infections, and mixed infections, particularly involving Aspergillus flavus, Pneumocystis jirovecii, Acinetobacter baumannii, and Pseudomonas aeruginosa. Viral co-infections with human herpesvirus-1 and cytomegalovirus were also more frequent in this group. In multivariable analyses, lymphopenia, advanced age, elevated D-dimer levels, bacterial co-infection, and pre-admission corticosteroid use were independently associated with in-hospital mortality. Overall in-hospital mortality in the cohort was 16.7%, with the highest mortality observed in immunocompromised patients with lymphopenia (27.4%) and the lowest in immunocompetent patients without lymphopenia (7.3%). CONCLUSION: Lymphopenia is associated with altered pathogen distribution, increased mixed and opportunistic infections, and worse clinical outcomes in viral pneumonia, independent of underlying immune status. Lymphocyte count represents a readily available clinical marker reflecting immune dysfunction and infection complexity, highlighting the need for heightened vigilance and comprehensive pathogen evaluation in patients with viral pneumonia and lymphopenia.