Clinical and Radiological Changes
Most COVID-19 patients exhibit mild to moderate symptoms, but approximately 15% progress to critical pneumonia and 5% eventually develop acute respiratory distress syndrome (ARDS), septic shock, multiple organ failure, and death (26, 108). Once the infection is installed, the spectrum of clinical presentations has been reported to range from asymptomatic infection to critical respiratory failure.
According to the severity of symptoms, patients can be classified as mild, severe, and critical. In general, the most commonly reported symptoms are fever, cough, myalgia, fatigue, pneumonia, dyspnea, as well as the loss of smell and taste, whereas less common reported symptoms include headache, diarrhea, hemoptysis, and a runny nose (108, 109). Most critically ill patients present progressive respiratory failure due to alveolar damage caused by hyper inflammation, which can result in lethal pneumonia (26).
A retrospective study conducted by Liu et al. (110) demonstrated that older patients with SARS-CoV-2 showed higher pneumonia severity index scores and had a higher chance of multiple lobe involvement compared with young patients. Elderly adults are more susceptible to SARS-CoV-2 and have a high risk of morbidity and mortality (111). This can be explained by factors such as physiological changes and multiple age-related comorbidities, in addition to associated polymedication (112).
Regarding the potential involvement of COVID-19 in the CNS, studies have investigated the neurological changes developed throughout the course of the disease. Nonspecific symptoms (dizziness, headache, and seizure) and specific symptoms (loss of smell or taste and stroke) were described (91, 113–115). Epidemiological studies have reported that some patients infected with SARS‐CoV‐2 did report headaches (8%), nausea, or vomiting (1%). A more recent study investigating 214 COVID‐19 patients found that about 88% of critically ill patients displayed neurologic manifestations, including acute cerebrovascular diseases and impaired consciousness (26, 116).
Among patients diagnosed with SARS-CoV-2, it has been reported that renal dysfunction is characterized by high levels of blood urea nitrogen, creatinine, uric acid, and D-dimer, associated with proteinuria and hematuria (90, 117–119). Recent studies have reported an incidence between 3-9% of acute kidney injury in COVID-19 patients, demonstrating renal abnormalities (94, 96, 111, 120). Cardiovascular complications are also associated with COVID-19 infection, including myocardial injury, myocarditis, acute myocardial infarction, heart failure, dysrhythmias, and venous thromboembolic events, being significant contributors to the mortality associated with this disease (121, 122).
Several studies found that CoVs can also affect other body regions, such as the gastrointestinal tract and ocular tissues (123, 124); some of them specifically investigated changes in the gastrointestinal tract and identified the presence of SARS-CoV-2 RNA in samples of anal/rectal swabs and feces of infected patients, establishing that the virus could be transmitted orally or fecally as well. Additionally, symptoms such as diarrhea, vomiting, and intestinal pain (125) have also been reported for SARS-CoV-2-positive patients, which can be associated with the expression of ACE2 in gastrointestinal epithelial cells, present especially in the small and large intestines, contributing to viral infection and replication in these cells (126).
Regarding ocular tissues, some studies have also identified the manifestation of conjunctivitis in patients with COVID-19 (<1%) (96), however, it is an underestimated number (127). Currently, it is still unclear how SARS-CoV-2 can cause conjunctivitis, but theories include: (i) conjunctiva can be a direct inoculation site for the virus, (ii) the virus can reach the upper respiratory tract through the nasolacrimal duct, or (iii) infection can occur via hematogenous through the lacrimal gland (123).
Histologically, biopsy samples of lungs reveal evident desquamation and hyaline membrane formation of pneumocytes, in addition to bilateral diffused alveolar damages along with cellular fibromyxoid exudate, indicating ARDS. In addition, the cytopathic effects found include multinucleated syncytial cells, increased atypical pneumocytes, and the presence of inflammatory infiltrates of mononuclear cells (26, 108).
More recently, reports on COVID-19 have included the occurrence of coagulation abnormalities in most critically ill patients (128–131). Tang et al. (132) reported the occurrence of disseminated intravascular coagulation in 71.4% of non-surviving COVID-19 patients and in only 0.6% of surviving patients, suggesting a high frequency in severe COVID-19 patients. Autopsies performed on patients with COVID-19 also demonstrated small fibrinous thrombi in pulmonary arterioles with endothelial tumefaction, the presence of megakaryocytes, and indications of coagulation cascade activation (133).
Although it is important to consider the direct procoagulant properties of SARS-CoV-2, the combination of immobility, systemic inflammation, platelet activation, endothelial dysfunction, and stasis of blood flow can lead to thrombotic complications that mimic systemic coagulopathies associated with severe infections, such as sepsis-induced coagulopathy (SIC), disseminated intravascular coagulation (DIC), and thrombotic microangiopathy (130). However, COVID-19 has some distinct features that may establish a new category of coagulopathy, denominated COVID-19 associated coagulopathy (CAC), whose main markers are higher D-dimer concentration and fibrinogen levels, a relatively lower platelet count, and longer prothrombin time (129). In COVID-19 patients, CAC has been associated with higher mortality (131).
Chest computed tomography (CT) in patients with COVID-19 has commonly demonstrated multifocal “ground-glass” opacity (GGO) in the lungs, which can occur concurrently with consolidation in posterior and peripheral areas, suggesting a pneumonia pattern in the organization of lung injury and indicating disease progression (134–136). Another important manifestation found through chest CTs is reticular pattern formation with interlobular septal thickening, which might be associated with interstitial lymphocyte infiltration and determine the disease course (108, 137, 138).
CT has highlighted many other alterations, including the “crazy-paving” pattern, which may result from the alveolar edema and interstitial inflammation in acute lung injury, and air bronchogram with a pattern of air-filled (low-attenuation) bronchi, but with gelatinous mucus and several airway changes, such as bronchiectasis and bronchial wall thickening resulting from the destruction of bronchial wall structure, proliferation of fibrous tissue, and fibrosis (137–140).