key: cord-342569-ja96xfns authors: Azer, Samy A. title: COVID-19: Pathophysiology, diagnosis, complications and Investigational therapeutics date: 2020-08-05 journal: New Microbes New Infect DOI: 10.1016/j.nmni.2020.100738 sha: doc_id: 342569 cord_uid: ja96xfns Abstract The novel coronavirus (COVID-19) outbreak started early in December 2019 in the Hubei province and its capital Wuhan of the People’s Republic of China and caused a global pandemic. The number of patients confined to this disease has exceeded nine million in more than 215 countries, and the number who died is over 480,600 (up to 25 June 2020). Coronaviruses were identified in the 1960s and recently identified to cause the Middle East Respiratory Syndrome (MERS-CoV) in 2012 and severe acute respiratory syndrome (SARS) in 2003. The current severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the most recently identified. Patients with COVID-19 may be asymptomatic. Typical symptoms including fever, dry cough, and shortness of breath. Gastrointestinal symptoms such as nausea, vomiting, abdominal pain and diarrhea, have been reported—neurologically related symptoms, particularly anosmia, hyposmia, and dysgeusia, have also been reported. Physical examination may reveal a fever in over 44% of patients (and could be documented in over 88% of patients after admission), increased respiratory rate, acute respiratory disease, and maybe decreased consciousness, agitation, and confusion. This article aims at presenting an up-to-date review on the pathogenesis, diagnosis and complications of COVID-19 infection. Currently, no therapeutics have been found to be effective. Investigational therapeutics are briefly discussed. On 31 December 2019, the Chinese authorities reported to the World Health Organisation (WHO) an emerging of a novice coronavirus, currently the virus is known as SARS-CoV-2 and the disease name is coronavirus-19 disease (COVID- 19) , that has emerged in patients from Wuhan city, Hubel Province [1] . This virus has a higher degree of lethality than other endemic viruses, and is more lethal to humans compared to earlier emerging outbreaks of single-stranded, positive-sense RNA genomes and it is roughly 80% identical with other coronaviruses at a nucleotide level. The virus closely related (share 90% of nucleotide structure) to SARS-CoV-2 is RaTG13-2013 which was identified in bats [2] . The complete genome of the severe acute respiratory syndrome coronavirus 2 isolated from Wuhan Hu-1 is available at (https://www.ncbi.nlm. nih.gov/nuccore/NC_045512). Genetic epidemiology of HCV-19 and submitted data since December 2019 are available from GISAID database (https ://www.gisaid.org/). The SARS-CoV-2 is composed of at least 11 ORFs (Open Reading Frames) with the full length of 29,903 bp. Four major structural protein-coding genes have been identified in the coronaviruses -Spike protein (S), Envelop protein (E), Membrane protein (M), and Nucleocapsid protein (N) [3] . The spike protein of SARS-CoV-2 utilizes angiotensin-converting enzyme (ACE2) as its cell surface receptor and utilization influences the tropism of the virus. The COVID-19 infects people of all ages. However, there are two main groups at a higher risk of developing severe disease including older people and people with underlying comorbidities such as diabetes mellitus, hypertension, cardiorespiratory disorders, chronic liver diseases, and renal failure. Patients with cancer and those on immunosuppressive medication as well as pregnant women are also be at a higher risk of developing severe disease when infected. [4] . The transmission of infection is mainly person-to-person through respiratory droplets. Fecal oral route is possible. The presence of the virus has been confirmed in sputum, pharyngeal swabs and feces [5] . Vertical transmission of SARS-CoV-2 has been reported [6] and confirmed by positive nasopharyngeal swab for COVID-19. The median incubation period of COVID-19 is 5.2 days (most patients will develop symptoms in 11.5 to 15.5 days). Therefore, it has been recommended to quarantine those exposed to infection (post-exposure) for 14 days. The SARS-Co-2 infection enters the host cells through the S spike protein by binding to ACE2 for internalisation, and aided by TMPRSS2 protease. The high infectivity of the virus is related to mutations in the receptor binding domain and acquisition of a furan cleavage site in the S spike protein. The virus interaction with ACE2 may down regulate the antiinflammatory function and heightened angiotensin II effects in predisposed patients [7] . With the challenge we face with COVID-19, there has been advocate for the use and the cessation of AT1R blockers and ACE inhibitors during the treatment of COVID-19 in hypertensive J o u r n a l P r e -p r o o f patients. Currently the recommendation of the Council on Hypertension of the European Society of Cardiology is that patients should continue their antihypertensive treatment with no changes because we do not have evidence supporting its cessation [8] . However, further research is needed to give more evidence to these questions. The invasion of the virus to the lung cells, myocytes and endothelial cells of the vascular system results in inflammatory changes including oedema, degeneration and necrotic changes. These changes are mainly related to pro-inflammatory cytokines including interleukins Il-6, IL-10, and TNF-oe, granulocyte colony stimulating factor, monocyte chemoattractant protein I, macrophage inflammatory protein 1 oe, and increased expression of programmed cell death marker-1 (PD-1) and T cell immunoglobulin and mucin domain 3 (Tim-3) [9] . These changes contribute to lung injury pathogenesis, hypoxia-related myocyte injury, body immune response, and increased damage of myocardial cells, intestinal and cardiopulmonary changes. Infection with SARS-CoV-2 has been also shown to cause hypoxaemia. These changes lead to the accumulation of oxygen free radicals, changes in intracellular pH, accumulation of lactic acid, electrolyte changes and further cellular damage. The respiratory system is the primary system affected in SARS-CoV-2, and multiple infiltrates of both lungs may be present. Real-time reverse transcription polymerase (RT-qPCR) amplification of SARS-CoV-2 virus nucleic acid of nasopharyngeal swabs or sputum is needed to confirm the diagnosis. However, the test may be negative in early days of presentation. Clinical picture, including shortness of breath, increased respiratory rate, decreased oxygen saturation, and raised C-reactive protein are non -specific. Other tests such as IgG and IgM antibodies against SARS-CoV-2, CD4+ and CD8+ should be ordered. Both J o u r n a l P r e -p r o o f CD4+ and CD8+ are substantially lowered in SARA-CoV-2. The pathology of the lungs shows microscopic bilateral diffuse alveolar damages, cellular fibromyxoid infiltrates, interstitial mononuclear inflammatory infiltrates with lymphocytes domination [10] . The cardiovascular system is usually involved in COVID-19 infection. Biomarkers such as elevated highly sensitive Troponin-T, natriuretic peptides and IL-6 are prognostic and their progressive rise are associated with poor outcomes. The inflammation of the vascular system results in these changes 1) Diffuse microangiopathic thrombi, 2) Inflammation of cardiac muscle (myocarditis), 3) Cardiac arrhythmias, heart failure, acute coronary syndrome. These cardiovascular complications may cause death [11, 12] . The lymphocytopenia observed during the infection, potentially involves the CD4+ and some CD8+ T cells. These changes disturb the innate and acquired immune responses causing delayed viral clearance, and hyperstimulated macrophages and neutrophils. The Notch signalling is known to be a major regulator of cardiovascular function and it is also implicated in several biological processes mediating viral infections. Recently it was debated that targeting the Notch signalling to prevent SARS-CoV-2 infection and interfering with the progression of COVID-19associated heart and lungs disease pathogenesis [13] . The reported gastrointestinal manifestations of COVID-19 include diarrhea, nausea, vomiting and abdominal pain. Studies indicated that SARS-CoV-2 RNA been isolated stool specimen and swabs taken from the anus/rectum [14] . The ACE2 has been found expressed in the epithelial cells of the gastrointestinal tract suggesting that the virus entry through the ACE2 receptors and its replication causing inflammatory changes and patient's symptoms. The SARS-CoV-2 also causes liver injury manifested by elevated serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) [15] . Mild elevation of serum bilirubin and J o u r n a l P r e -p r o o f gamma-glutamyl transpeptidase (GGT) have also been reported in some patients with COVID-19 infection [16] . In most cases the liver injury was transient and mild. However, severe liver dysfunction/injury has been reported in patients with severe disease. High levels of ALT of over 7500 U/L has been reported in a Chinese study [17] . Microscopically, microvesicular steatosis of the liver and mild lobular injury has been found in COVID-19 infected patents [16] . It is not clear whether the observed SARS-CoV-2-associated liver injury is cause by direct viral injury or related to hepatoxic drugs, coexisting systemic inflammatory changes, sepsis, respiratory distress syndrome-induced hypoxia, and multiple organ failure [18] . There is clinical evidence that the SARS-CoV-19 has potential neuropathic properties. Several neurologic related symptoms have been reported including headaches, dizziness, seizure, decreased level of consciousness, acute hemorrhagic necrotizing encephalopathy [19] , agitation, and confusion. In patients with type 2 diabetes mellitus who are infected with COVID-19, it is important to remember that two receptor proteins ACE-2 and dipeptidyl peptidase-4 (DPP-4) are test can detect IgM, and IgG antibodies against SARS-CoV-2 in the serum, plasma, and whole blood [23] . This test is a monoclonal antibody test against the SARS-CoV-2 nucleocapsid (N) protein. This protein is abnormally expressed in infected cells. Monoclonal antibodies specifically directed against N protein, and by using enzyme-linked immunosorbent assay (ELISA) it is possible to detect SARS-CoV-2. The test has a reported sensitivity of 84.1% and a specificity of 98.5%. No cross-reaction with human and animal coronaviruses in the assay were reported. There are no reports about applying this test yet on SARS-CoV-2 [24] . Ultrasonography Whole body point of care ultrasound has been used in patients with COVID-19. Ultrasound is considered an essential modality in the intensive care unit (ICU) and the wards in these patients to guide the treatment in patients with cardiorespiratory failure. The current recommendations are to extend its use to multisystem and the whole-body sonographythoracic, cardiac, abdomen, and deep venous thrombosis [25] . Earlier studies during the outbreak in China suggested that CT chest imaging together with clinical presentation, pneumonia patients with and without SARS-CoV-2 can be differentiated. The authors propose that radiological images and clinical features can form excellent diagnostic tools of COVID-19 [26] . Predictors of severe disease may include (i) high viral load, (ii) Elevated neutrophil lymphocyte ratio (NLR), (iii) CT chest changes and extend of lesion, (iv) patient age, and (v) presence of comorbidities [27] . Elevated age, and NLR are reported to be independent biomarkers for poor clinical outcomes [28] . The age and sex have been shown to affect the severity of complications of COVID-19. The rates of hospitalization and death are less than 0.1% in children and increased to 10% or more in older patients. Men are more likely to develop severe complications compared to women as a consequence of SARS-CoV-2 infection [29] . Patients with cancer and solid organ • Laryngeal oedema, and laryngitis in critically ill patients with COVID-19. • Necrotizing pneumonia as a result of superinfection caused by Panton Valentine leukocidin-secreting Staphylococcus aureus infection. This super infection is usually fatal [30] . • Cardiovascular complications including (i) Acute pericarditis, (ii) Left ventricular dysfunction, (iii) Acute myocardial injury (associated with increased serum troponin), and (iv) New or worsening arrhythmias, (v) New or worsening heart failure. • Acute respiratory failure. Approximately 5% of COVID-19 patients require to be admitted to intensive care unit because they develop severe disease complicated with acute respiratory distress syndrome [ARDS] [31] . • Sepsis, septic shock and multiple organ failure. • Patients with COVID-19 infection are at a higher risk of death, particularly (i) males with severe disease, (ii) presence of heart injury and cardiac complications, (iii) hyperglycemia, and (iv) patients on high dose of corticosteroids [32] . • Ventilation-associated pneumonia may occur in up to 30% of patients requiring intensive mechanical ventilation. • Massive pulmonary embolism complicated with acute right-sided heart failure [33] . complications [34] . Because of rapid spread of SARS-CoV-2, anti-HIV and anti-HCV medications have been tried in cases admitted to ICU with severe pneumonia. Table 1 summarized these drugs-possible mechanisms of action, side effects, precautions and recommendations. Also, shows ongoing registered clinical trials. 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The author declares no financial or relationships that can be considered a conflict of interest.J o u r n a l P r e -p r o o f