*1.4. Severity Stages of COVID-19*

COVID-19 can have various stages of severity. Siddiqi et al. proposed three stages of COVID-19 severity [16] (Figure 1):

**Figure 1.** Classification of COVID-19 Disease States and Potential Therapeutic Targets. Legend: The figure shows three escalating phases of disease progression with COVID-19, with associated signs, symptoms and potential phase-specific therapies. ARDS = Acute respiratory distress syndrome; CRP = C-reactive protein; IL = Interleukin; JAK = Janus Kinase; LDH = Lactate Dehydrogenase; SIRS = Systemic inflammatory response syndrome. (From: Siddiqi HK, Mehra MR. COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal. *J Heart Lung Transplant*. 2020 [in press], DOI:https://doi.org/10.1016/j.healun.2020.03.012).

Stage I (early infection) can include mild constitutional symptoms—fever, dry cough, diarrhea, headache—with laboratory examination revealing lymphocytopenia, increased prothrombin time, increased D-dimer and mild Lactate Dehydrogenase (LDH) elevation.

Stage II (pulmonary phase) can be subdivided into IIa (without hypoxia) and IIb (with hypoxia, defined as a PaO2/FiO2 of < 300 mmHg). In Stage II disease, patients develop a viral pneumonia, with cough, fever and possibly hypoxia. Radiologic imaging shows bilateral infiltrates or ground-glass opacities. Laboratory tests reveal increasing lymphocytopenia, along with elevated transaminases. At this stage, most patients with COVID-19 should be hospitalized.

Stage III (systemic hyperinflammation) is characterized by Acute Respiratory Distress Syndrome (ARDS), Systemic Inflammatory Response Syndrome (SIRS)/shock, and/or cardiac failure. In the laboratory examination there are elevated inflammatory markers (C-reactive Protein, LDH, Interleukin-6, D-dimer, ferritin), and an elevation of troponin and N-Terminal-pro-Brain Natriuretic Peptide (NT-proBNP).
