*1.2. Morbidity and Mortality of Coronaviruses*

A dysregulated immune system, resulting in an overshooting inflammatory response, contributes to morbidity and mortality. Mortality rates in MERS, SARS and COVID-19 are around 35%, 9% and 5% of infected individuals, respectively. Nevertheless, the number of infected patients has never been so large as in the current COVID-19 pandemic. The total number of patients suffering from MERS was 2400, from SARS 8300, and from COVID-19 (so far) passes 17 million [7]. MERS spread to 27 countries, SARS to 30 countries and COVID-19 represents currently a global threat of increasing magnitude. Symptoms of these lethal coronaviruses differ.

MERS is a disease predominantly affecting the lower respiratory tract, which in most patients leads to pneumonia. Clinical manifestations are fever, malaise, chills, myalgia, cough, dyspnea, diarrhea, vomiting, and abdominal pain. In severely ill patients dyspnea is severe with acute respiratory failure, renal failure, and shock. As in SARS-CoV-2, there is a high incidence in older patients. Predictors of poor outcome include age above 60 years, male gender, diabetes mellitus, chronic lung disease and chronic renal disease, low albumin level and progressive lymphocytopenia [8]. MERS-CoV infections can be asymptomatic in 12.5–25% of patients [8].

SARS can present with hypoxia, cyanosis, fever, dyspnea and acute respiratory failure. The WHO case definition (2003) includes the following: (1) fever higher than 38 ◦C or history of such in the past 2 days, (2) radiological evidence of new infiltrates consistent with pneumonia, (3) chills, cough, malaise, myalgia, or known history of exposure, and (4) positive test for SARS-CoV by one or more assays.

In SARS patients, neutralizing antibodies are detected 2–3 weeks after the onset of disease, and 90% of patients recover without hospitalization [2]. About 10% of SARS patients develop severe respiratory failure after 5–7 days following infection, with interstitial pneumonia characterized by progressive diffuse alveolar damage.

In COVID-19, most frequent co-morbidities are hypertension, cardiovascular disease, diabetes, and obesity [9]. Age appears to be the strongest predictor of COVID-19 related death. Clinical manifestations of COVID-19 include fever, malaise, myalgia, non-productive cough, dyspnea, nausea, vomiting and diarrhea. Gastrointestinal symptoms can be the first manifestation of COVID-19, especially in patients with immunosuppressive drugs. Olfactory and/or gustatory dysfunctions have been reported in 64% to 80% of patients [10].

COVID-19 can progress to severe organ dysfunction of the heart, brain, lung, liver, kidney, and coagulation system [10], and can lead to myocarditis, cardiomyopathy, ventricular arrhythmias, and hemodynamic instability [10]. In severe infection, patients may develop acute cerebrovascular disease and encephalitis [10]. Hypercoagulopathy leading to both venous and arterial thromboembolic events occur in 10% to 25% in hospitalized patients, and in ICU patients with COVID-19 in 31–59% [10]. Approximately 72% of non-surviving COVID-19 patients had hypercoagulopathy [9].

SARS-CoV-2 also can induce vascular damage, and pre-existing endothelial dysfunction combined with the direct assault of SARS-CoV-2 on the vascular system may account for a high mortality of COVID-19 patients [9].

Hospitalized patients with COVID-19 need ICU treatment in approximately 17–35% of patients, most commonly due to hypoxemic respiratory failure requiring intubation and mechanical ventilation [10].

About 4–32% of patients are completely asymptomatic. However, it is unclear which of the following three scenarios are represented in these reports: (1) truly asymptomatic infection by individuals who never develop symptoms, (2) transmission by individuals with very mild symptoms, or (3) transmission by individuals who are asymptomatic at the time of transmission but subsequently develop symptoms [10].
