*4.1. COVID-19 Severity: The Siddiqi Stages*

COVID-19 in most patients in our case series was classified as mild or moderate, according to the Siddiqi classification. The Siddiqi stages classify COVID-19 disease states and potential therapeutic targets [5]. This classification has three escalating phases. Stage I (early infection), characterized by a viral response phase, with clinical symptoms including mild constitutional symptoms, fever, a dry cough, and laboratory shows lymphopenia. In this phase, immunosuppression should be reduced, and excess systemic steroids be avoided. In Stage II (pulmonary phase), there is both a viral response phase and a host inflammatory response phase. Clinical symptoms include dyspnea without hypoxia (IIA) and with hypoxia (IIB), and chest imaging is abnormal (infiltrates), laboratory values showing elevated transaminases, and procalcitonin is generally low or normal. In this stage, mycophenolate should be reduced, according to the ISHLT guidance document [7]. In Stage III (hyperinflammation phase), there is solely a host inflammatory response, with acute respiratory distress syndrome (ARDS), systemic inflammatory response syndrome (SIRS) and cardiac failure, and laboratory values show elevated inflammatory markers (CRP, LDH, Interleukin-6, D-dimer, ferritin), troponin, and N-terminal pro-b-type natriuretic peptide (NT-proBNP). In Stage III, mycophenolate should also be discontinued [7]. Patients in Stage II and III are likely to be the patients that would benefit most of the continued use of calcineurin inhibitors, attenuating the hyperinflammation (cytokine storm).

## *4.2. SARS-CoV-2 Infection: Extrapulmonary Manifestations*

Although infection in the respiratory system is the most important manifestation of COVID-19, there are also important extrapulmonary disease manifestations. In our case series, the extrapulmonary manifestations were the predominant symptoms. Extrapulmonary COVID disease can result in gastrointestinal, cardiovascular, renal and neurological morbidity. Pathophysiologically, there is severe microvascular thrombosis and inflammation, resulting from vascular endothelial dysfunction [8,9]. Interestingly, endothelial dysfunction is also present in the high-risk population for severe COVID-19, in particular patients with hypertension, obesity and diabetes [8]. These comorbidities were also relevant in the patients in our case series, especially in the two patients with severe COVID-19 who did not survive. The patient in which autopsy was performed also showed extensive endothelial dysfunction, as has been described above.

In the literature, most COVID-19 fatalities in immunocompetent patients were observed in elderly men with the aforementioned comorbidities. Although the exact pathophysiology of endothelial dysfunction in COVID-19 needs further clarification, the scientific evidence suggests that COVID-19 targets endothelial cells [10].

### *4.3. SARS-CoV-2 Infection: Pulmonary Manifestations*

The autopsy report on our patient showed an important pulmonary component of COVID-19. Inflammation is a key component of SARS-CoV-2 infection. Research has shown that there are similarities between the acute respiratory distress syndrome (ARDS) and the acute radiation syndrome (ARS) [11]. The ARS, being a public health emergency, occurs after exposure to high doses of radiation and leads, as in ARDS, to a cytokine storm, with remarkably similar pathophysiology, including increased pro-inflammatory molecules and decreased other anti-inflammatory molecules [11]. Medical treatment strategies for ARS could be helpful in the clarification of the COVID-19 induced ARDS [11]. Among the medical countermeasures in ARS are growth factors, antioxidants, anti-inflammatory agents, anti-fibrotic drugs, RAS-targeted approaches, and treatment for vascular injury such as statins. These approaches are potentially of interest since treatment options for COVID-19 are still very limited and there is no cure for COVID-19. If all available treatment strategies fail to prevent post-COVID-19 lung fibrosis, lung transplantation may be the only curative option in selected severe cases without signs of improvement over weeks or months. Patients recovering from severe COVID-19, especially after ARDS, have a high risk of developing pulmonary fibrosis [12].
