In polypathological patients an early diagnosis of respiratory failure is often difficult. Frequently, polypathology does not allow intubation and intensive care unit (ICU) treatment with invasive mechanical ventilation (IMV). Non-invasive ventilation (NIV) and admission to respiratory intermediate care unit (RICU) may be the only option in these cases. Presepsin, a new predictive marker of systemic infection, appears particularly usefull for early diagnosis, treatment and prognosis of sepsis. 1.2. Case A 73-year-old man with a previous history of ischemic heart disease undergoing coronary artery bypass grafting (CABG), residual constrictive pericarditis, previous multiple hospitalizations for heart failure (CHF), autoimmune hemolytic anemia on chronic steroid therapy and cognitive impairment arrived to the Emergency Department (ED) in acute global respiratory failure with severe acidosis; he was normothermic, radiological imaging showed aspecific diffuse parenchymal thickening and traditional inflammatory markers (white blood cell - WBC - count and serum level of C-reactive protein - CPR - and procalcitonin - PCT) were in normal range, but blood tests revealed a marked elevation in the value of presepsin. Intensivist’s evaluation concluded for a do-not intubate (DNI) status and the patient was admitted to RICU. The combined treatment with NIV, broad-spectrum antibiotics and dopamine resulted in a progressive improvement of the clinical, laboratoristic and radiological parameters and the subsequent discharge of the patient to home in satisfactory general condition. 1.3. Conclusions Elevated presepsin level was found to be an early predictor of severe sepsis, ofter preceding other laboratory or clinical signs of infection. NIV in RICU and medical therapy allowed the successful treatment of a severe global respiratory failure in a DNI patient.