Bacterial pneumonia is an infectious disease with sever inflammatory condition of the lung. Parapneumonic effusion (PPE) is an accumulation of exudative pleural fluid associated with the pulmonary infection. PPEs are present in 20% to 40% of hospitalized patients with pneumonia and progressed from uncomplicated parapneumonic effusions (UPPE), complicated parapneumonic effusions (CPPE) to empyema. Pneumonia patients with late stage PPE have elevated mortality and a poor prognosis. To study the pathogenesis of PPE progression and identify the useful biomarkers for PPE diagnosis, we performed the transcriptomic and proteomic analyses to identify the biological pathways and networks in pneumonia patients with different stages of effusions. Comparative analysis of PPE transcriptome dataset allowed us to identify 1924 genes as differentially expressed genes; these included 331 upregulated and 1593 downregulated genes in CPPE compared to UPPE. The 331 up-regulated genes were enriched in pathways associated with respiratory burst, canonical glycolysis, and regulation of cell proliferation using gene set enrichment analysis. We also analyzed the secretome in pleural effusion using iTRAQ-based proteomic technology. About 760 proteins were identified in the pleural effusion and 50 proteins were defined as upregulated proteins in CPPE. The enrichment biological processes revealed that the up-regulated proteins were significantly involved in the innate immune response, defense response, and proteolysis. Integration of these two datasets validated several novel immune regulators as secreted proteins in pleural effusion. One of these secreted proteins was highly expressed in neutrophils and can be induced in Streptococcus pneumonia infected dHL60 cells. Also, the overexpression of this candidate protein was validated in CPPE patients using ELISA assay, western blot, and immunohistochemical staining. The area under curve of this candidate protein was 0.75 for distinguishing CPPE from UPPE. In conclusion, we identified one novel protein involved in the defense response to bacteria and were significantly associated with CPPE.