The global COVID-19 pandemic has caused significant morbidity and mortality. Understanding the mechanisms of severe disease in vulnerable patients is crucial for developing effective therapies. Analyzing the secretome is an effective method for identifying biomarkers and therapeutic targets. We studied the bronchoalveolar lavage fluid (BALF) secretome profiles of COVID-19 patients using bulk (RNA-Seq) and single-cell (scRNA-Seq) RNA sequencing, with a focus on ligand and receptor genes. High susceptibility patients (male, elderly, and high viral load) had differentially expressed ligand genes related to inflammation and immune response pathways. Low-susceptibility patients had 43 ligand genes with significantly lower expression levels than their negative controls. We found an association between the expression of lactoferrin ( LTF) and its receptor, LDL receptor related protein 11 ( LRP11), and susceptibility to severe COVID-19. LRP11 is predominantly expressed in human pulmonary epithelial cells, and its expression increases during SARS-CoV-2 infection in monkeys. Our study sheds light on the molecular mechanisms underlying susceptibility by analyzing gene expression of ligands and receptors in BALF. Additional investigations into targeted therapies that modulate LRP11 activity hold promise for improving patient outcomes and reducing the severity of COVID-19.