The clinical spectrum of COVID-19 varies from asymptomatic or paucisymptomatic forms to clinical conditions characterized by respiratory failure that necessitates mechanical ventilation and support in an ICU, to multiorgan and systemic manifestations in terms of sepsis, septic shock, and multiple organ dysfunction syndromes (MODS). In one of the first reports on the disease, Huang et al. illustrated that patients (n. 41) suffered from fever, malaise, dry cough, and dyspnea. Chest computerized tomography (CT) scans showed pneumonia with abnormal findings in all cases. About a third of those (13, 32%) required ICU care, and there were 6 (15%) fatal cases.[26] 

The case studies of Li et al. published in the New England Journal of Medicine (NEJM) on January 29, 2020, encapsulates the first 425 cases recorded in Wuhan.[12] Data indicate that the patients' median age was 59 years, with a range of 15 to 89 years. Thus, they reported no clinical cases in children below 15 years of age. There were no significant gender differences (56% male). On the contrary, in other reports, there is a lower prevalence in the female gender.

Clinical and epidemiological data from the Chinese CDC and regarding 72,314 case records (confirmed, suspected, diagnosed, and asymptomatic cases) were shared in the Journal of the American Medical Association (JAMA), providing the first important illustration of the epidemiologic curve of the Chinese outbreak.[27] There were 62% confirmed cases, including 1% of cases that were asymptomatic, but were laboratory-positive (viral nucleic acid test). Furthermore, the overall case-fatality rate (on confirmed cases) was 2.3%. Of note, the fatal cases were primarily elderly patients, in particular those aged ≥ 80 years (about 15%), and 70 to 79 years (8.0%). Approximately half (49.0%) of the critical patients and affected by preexisting comorbidities such as cardiovascular disease, diabetes, chronic respiratory disease, and oncological diseases, died. While 1% of patients were aged 9 years or younger, no fatal cases occurred in this group.

The authors of the Chinese CDC report divided the clinical manifestations of the disease by there severity:

• Mild disease: non-pneumonia and mild pneumonia; this occurred in 81% of cases.
• Severe disease: dyspnea, respiratory frequency ≥ 30/min, blood oxygen saturation (SpO2) ≤ 93%, PaO2/FiO2 ratio or P/F [the ratio between the blood pressure of the oxygen (partial pressure of oxygen, PaO2) and the percentage of oxygen supplied (fraction of inspired oxygen, FiO2)] < 300, and/or lung infiltrates > 50% within 24 to 48 hours; this occurred in 14% of cases.
• Critical disease: respiratory failure, septic shock, and/or multiple organ dysfunction (MOD) or failure (MOF); this occurred in 5% of cases.[27]

From the subsequent reports, it is estimated that in 70% of patients the disease is asymptomatic or with very mild symptoms, while in the remaining 30% there is a respiratory syndrome with high fever, cough until severe respiratory failure is reached who may require ICU admission. Thus, data obtainable from reports and directives provided by health policy agencies, allow dividing the clinical manifestations of the disease according to the severity of the clinical pictures. The COVID-19 may present with mild, moderate, or severe illness. Among the severe clinical manifestations, there are severe pneumonia, ARDS, as well as extrapulmonary manifestations and Systemic complications such as sepsis, and septic shock. The clinical course of the disease seems to predict a favorable trend in the majority of patients. In a percentage still to be defined of cases, after about a week there is a sudden worsening of clinical conditions with rapidly worsening respiratory failure and MOD/MOF. As a reference, the criteria of the severity of respiratory insufficiency and the diagnostic criteria of sepsis and septic shock can be used.[28]

Uncomplicated (mild) Illness

These patients usually present with symptoms of an upper respiratory tract viral infection, including mild fever, cough (dry), sore throat, nasal congestion, malaise, headache, muscle pain, or malaise. New loss of taste and/or smell, diarrhea, and vomiting are usually observed. Signs and symptoms of a more serious disease, such as dyspnea, are not present. 

Moderate Pneumonia

Respiratory symptoms such as cough and shortness of breath (or tachypnea in children) are present without signs of severe pneumonia. 

Severe Pneumonia

Fever is associated with severe dyspnea, respiratory distress, tachypnea (> 30 breaths/min), and hypoxia (SpO2 < 90% on room air). However, the fever symptom must be interpreted carefully as even in severe forms of the disease, it can be moderate or even absent. Cyanosis can occur in children. In this definition, the diagnosis is clinical, and radiologic imaging is used for excluding complications.

Acute Respiratory Distress Syndrome (ARDS)

The diagnosis requires clinical and ventilatory criteria. This syndrome is suggestive of a serious new-onset respiratory failure or for worsening of an already identified respiratory picture. Different forms of ARDS are distinguished based on the degree of hypoxia. The reference parameter is the PaO2/FiO2 or P/F ratio:

• Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg. In not-ventilated patients or in those managed through non-invasive ventilation (NIV) by using positive end-expiratorypressure (PEEP) or a continuous positive airway pressure (CPAP) ≥ 5 cmH2O.
• Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg.
• Severe ARDS: PaO2/FiO2 ≤ 100 mmHg. 

When PaO2 is not available, a ratio SpO2/FiO2 ≤ 315 is suggestive of ARDS.

Chest imaging utilized includes chest radiograph, CT scan, or lung ultrasound demonstrating bilateral opacities (lung infiltrates > 50%), not fully explained by effusions, lobar, or lung collapse. Although in some cases, the clinical scenario and ventilator data could be suggestive for pulmonary edema, the primary respiratory origin of the edema is proven after the exclusion of cardiac failure or other causes such as fluid overload. Echocardiography can be helpful for this purpose.

Extrapulmonary Manifestations and Systemic Complications

The involvement of other organs is an important aspect of the disease. For example, an understanding of pathophysiology and mechanisms of kidney damage and AKI is emerging in the context of critical forms of COVID-19, although further research is needed to identify patients at risk of AKI and guide management strategies. The clinical presentation ranges from mild proteinuria (>40% of patients have abnormal proteinuria at hospital admission[29]) to acute progressive renal injury (AKI) which represents a marker of MOD and disease severity and often requires renal replacement therapy (RRT) with the possible use of cytokine removal approaches[30]. Up to 20% of ICU patients with COVID-19 require RRT.[31]

Sepsis

According to the International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3), sepsis represents a life-threatening organ dysfunction caused by a dysregulated host response to suspected or proven infection, with organ dysfunction.[32] The clinical pictures of patients with COVID-19 and with sepsis are particularly serious, characterized by a wide range of signs and symptoms of multiorgan involvement. These signs and symptoms include respiratory manifestations such as severe dyspnea and hypoxemia, renal impairment with reduced urine output, tachycardia, altered mental status, and functional alterations of organs expressed as laboratory data of hyperbilirubinemia, acidosis, high lactate, coagulopathy, and thrombocytopenia. The reference for the evaluation of multiorgan damage and the related prognostic significance is the Sequential Organ Failure Assessment (SOFA) score, which predicts ICU mortality based on lab results and clinical data.[33] A pediatric version of the score has also received validation.[34] 

Septic Shock

In this scenario, which is associated with increased mortality, circulatory, and cellular/metabolic abnormalities such as serum lactate level greater than 2 mmol/L (18 mg/dL) are present. Because patients usually suffer from persisting hypotension despite volume resuscitation, the administration of vasopressors is required to maintain a mean arterial pressure (MAP) ≥ 65 mmHg. 

The Peculiar History of this New DiseaseIn some patients, the clinical history of this disease occurs with particular characteristics. It foresees that the patient manifests above all fever, which is not very responsive to antipyretics, and a state of malaise. A dry cough is often associated. After 5-7 days, older patients with already impaired lung function begin to experience shortness of breath and increased respiratory rate. In more fragile patients, however, dyspnea may already appear at the onset of symptoms. On the other hand, in younger subjects and in those who do not have basic respiratory impairments or other comorbidities, dyspnea may appear later. In these patients experiencing worsening inflammatory-induced lung injury, there is a decrease in oxygen saturation (<93%). This seems to be the crucial phase of the disease, from this point onwards, there may be a rapid deterioration of respiratory functions. The scenario is truly incredible because, for patients who are paucisymptomatic and slightly hypoxic, the first therapeutic approach is oxygen therapy. Although this strategy is effective, the worsening of respiratory failure may occur in some patients. With the drive preserved, the next step, according to logic, is the NIV. This therapy has a rapid success by increasing the P/F. In some patients, however, there is a sudden, unexpected worsening of clinical conditions. Patients collapse under the operator's eyes and require rapid intubation and invasive mechanical ventilation. However, after 24-48 hours the patient can have a rapid improvement with an increase in P/F. Operators are therefore tempted to proceed with weaning. But very often, after an initial success, there is a new worsening of respiratory conditions, such as to require a new invasive therapy. Therefore, mechanical ventilation has also been suggested for 1-2 weeks. 

Most countries are utilizing some type of clinical and epidemiologic information to determine who should have testing performed. In the US, criteria have been developed for persons under investigation (PUI) for COVID-19. According to the U.S. CDC, most patients with confirmed COVID-19 have developed fever and/or symptoms of acute respiratory illness (e.g., cough, difficulty breathing). If a person is a PUI, it is recommended that practitioners immediately put in place infection control and prevention measures. Initially, they recommend testing for all other sources of respiratory infection. Additionally, they recommend using epidemiologic factors to assist in decision making. There are epidemiologic factors that assist in the decision on who to test. This includes anyone who has had close contact with a patient with laboratory-confirmed COVID-19 within 14 days of symptom onset or a history of travel from affected geographic areas (presently China, Italy, Iran, Japan, and South Korea) within 14 days of symptom onset. 

Diagnosis

Molecular Test

The WHO recommends collecting specimens from both the upper respiratory tract (naso- and oropharyngeal samples) and lower respiratory tract such as expectorated sputum, endotracheal aspirate, or bronchoalveolar lavage. The collection of BAL samples should only be performed in mechanically ventilated patients as lower respiratory tract samples seem to remain positive for a more extended period. The samples require storage at four degrees celsius. In the laboratory, amplification of the genetic material extracted from the saliva or mucus sample is through a reverse polymerase chain reaction (RT-PCR), which involves the synthesis of a double-stranded DNA molecule from an RNA mold. Once the genetic material is sufficient, the search is for those portions of the genetic code of the CoV that are conserved. The probes used are based on the initial gene sequence released by the Shanghai Public Health Clinical Center & School of Public Health, Fudan University, Shanghai, China on Virological.org, and subsequent confirmatory evaluation by additional labs. If the test result is positive, it is recommended that the test is repeated for verification. In patients with confirmed COVID-19 diagnosis, the laboratory evaluation should be repeated to evaluate for viral clearance prior to being released from observation. The availability of testing will vary based on which country a person lives in with increasing availability occurring nearly daily.

Serology

Despite the numerous antibody tests designed, to date serologic diagnosis has limitations in both specificity and sensitivity. Again, results from different tests vary. A CDC research on a test developed by the US Vaccine Research Center at the National Institutes of Health is ongoing. Of note, this test seems to have a specificity higher than 99% with a sensitivity of 96%.

Research is providing us with a lot of data on the role of serology. For example, it has been shown that there is no cross-reactivity between autoantibodies collected from serum samples from patients with autoimmune disease and SARS-CoV-2 antibodies. Nevertheless, further research is needed for elucidating several aspects of the matter. In particular:

• If IgG antibodies will provide immunity from future SARS-CoV-2 infection.
• On the protective titer of antibodies.
• On the duration of the protection.

Serologic, however, can have an important role in broad-based surveillance.

Laboratory Examinations

Concerning laboratory examinations:

• In the early stage of the disease, a normal or decreased total white blood cell count (WBC) and a decreased lymphocyte count can be demonstrated. Interestingly, lymphopenia appears to be a negative prognostic factor.
• Increased values of liver enzymes, lactate dehydrogenase (LDH), muscle enzymes, and C-reactive protein can be detected.
• Unless a bacterial overlap, a normal procalcitonin value is found.
• The elevated neutrophil-to-lymphocyte ratio (NLR), derived NLR ratio (d-NLR) [neutrophil count divided by the result of WBC count minus neutrophil count], and platelet-to-lymphocyte ratio, can be the expression of the inflammatory storm.[35] The correction of these indices is an expression of a favorable trend.
• Increased  D-dimer
• In critical patients, D-dimer value is increased, blood lymphocytes decreased persistently, and laboratory alterations of multiorgan imbalance (high amylase, coagulation disorders, etc.) are found. 

Imaging

Chest X-ray Examination

Since the disease manifests itself as pneumonia, radiological imaging has a fundamental role in the diagnostic process, management, and follow-up. Standard radiographic examination (X-ray) of the chest has a low sensitivity in identifying early lung changes and in the initial stages of the disease. At this stage, it can be completely negative. In the more advanced stages of infection, the chest X-ray examination generally shows bilateral multifocal alveolar opacities, which tend to confluence up to the complete opacity of the lung. Pleural effusion can be associated.

Chest Computed Tomography

Given the high sensitivity of the method, chest computed tomography (CT), in particular high-resolution CT (HRCT), is the method of choice in the study of COVID-19 pneumonia, even in the initial stages. Several non-specific HRCT findings and patterns can be found. Most of these findings may also be observed in other lung infections, such as Influenza A (H1N1), CMV, SARS, MERS, streptococcus, and Chlamydia, Mycoplasma. The most common findings are multifocal bilateral "ground or ground glass" (GG) areas associated with consolidation areas with patchy distribution, mainly peripheral/subpleural and with greater involvement of the posterior regions and lower lobes. The "crazy paving" pattern can be also observed. This latter finding is characterized by the presence of GG areas with superimposed interlobular septal thickening and intralobular septal thickening. It is a non-specific finding that can be detected in different conditions. Other findings are the “reversed halo sign” which is a focal area of GG delimited by a peripheral ring with consolidation, and the finding of cavitations, calcifications, lymphadenopathies, and pleural effusion.

Lung Ultrasound

Ultrasound can allow evaluating the evolution of the disease, from a focal interstitial pattern up to "white lung" with evidence often of subpleural consolidations.It should be performed within the first 24 hours in the suspect and every 24/48 hours and can be useful for patient follow-up, choice of the setting of mechanical ventilation, and for the indication of prone positioning.The main sonographic features are:

• Pleural lines often thickened, irregular, and discontinuous until it almost appears discontinuous; subpleural lesions can be seen as small patchy consolidations or nodules.
• B lines. They are often motionless, coalescent, and cascade and can flow up to the square of "White lung".
• Thickenings. They are most evident in the posterior and bilateral fields especially in the lower fields; the dynamic air bronchogram within the consolidation is a manifestation of disease evolution.
• Perilesional pleural effusion

In summary, during the course of the disease, it is possible to identify the first phase with focal areas of fixed B lines, a phase of numerical increase of the lines B up to the white lung with small subpleural thickenings, and further progress until evidence of posterior consolidations.

There is no specific antiviral treatment recommended for COVID-19, and no vaccine is currently available. The treatment is symptomatic, and oxygen therapy represents the first step for addressing respiratory impairment. Non-invasive (NIV) and invasive mechanical ventilation (IMV) may be necessary in cases of respiratory failure refractory to oxygen therapy. Again, intensive care is needed to deal with complicated forms of the disease. 

Concerning ARDS treatment, accumulating knowledge on the pathophysiology of lung damage, have gradually induced clinicians to review strategies for dealing with respiratory failure. As Gattinoni et al. suggested, COVID-19-induced ARDS (CARDS) is not a "Typical" ARDS.[36] This aspect of the disease is of fundamental importance and has probably negatively affected the therapeutic approach in the early stages of the pandemic. Indeed, despite at beginning of the pandemic, early IMV was postulated as the better strategy for addressing CARDS, in COVID-19 pneumonia the typical ARDS respiratory mechanics featuring reduced lung compliance (i.e., ability to stretch and expand lungs) cannot be found. On the contrary, in CARDS, good pulmonary compliance can be demonstrated. As a consequence, and in contrast to what was initially believed, NIV can have a key role in CARDS therapy. 

O2 Fast Challenge

In a patient with a SpO2 < 93-94% (< 88-90% if COPD) or a respiratory rate > 28-30 / min, or dyspnoea, the administration of oxygen by a 40% Venturi mask must be performed. After a 5 to 10 minutes reassessment, if the clinical and instrumental picture has improved the patient continues the treatment and undergoes a re-evaluation within 6 hours. In case of failure improvement, or new worsening, the patient undergoes a non-invasive treatment, if not contraindicated.

HFNO and Non-invasive Ventilation 

In regards to HFNO or NIV, the experts' panel, points out that these approaches performed by systems with good interface fitting do not create widespread dispersion of exhaled air, and their use can be considered at low risk of airborne transmission.[37] 

HFNO

Because this procedure has a greater risk of aerosolization, it should be used in negative pressure rooms. 

Suggested ways to manage HFNO:

• Indication: when it is difficult to maintain SpO2 > 92% and/or not improved dyspnoea through standard oxygen.
• Setting: 30-40 L / min and FiO2 50-60%; adjust according to clinical response.
• Switch to NIV if the symptomatology is not improved after 1 hour with flow > 50 L / min and FiO2> 70%.
• HFNO can also be used for CPAP breaks (between CPAP cycles) and for assisted fibreoptic tracheal intubation in critically ill patients.[38]
• Contraindication to HFNO: hypercapnic patient.

Non-invasive ventilation and Continuous Positive Airway Pressure 

NIV/CPAP has a key role in managing COVID-19-associated respiratory failure. 

Suggested ways for performing NIV/CPAP:

• Interface: Helmet is preferred for minimizing the risk of aerosolization. In the case of NIV with face mask (full-face or oronasal), the use of expiratory valve integrated and non-tubes with exhalation port, and insert an antimicrobial filter on the expiratory valve is recommended.
• Setting: 
  • Continuous Positive Airway Pressure (CPAP): start with 8-10 cmH2O and FiO2 60%
  • NIV (e.g., Pressure support ventilation, PSV): start with PEEP 5 cmH2O checking the tolerance of the patient and bring to 8-10 cmH2O, FiO2 60%, PS 8-10 cmH2O 
• Management: do not make any changes in the first 24 hours; after at least 4-6 hours, if stabilized, detach for max 1 hour and allow the intake of small quantities of fluids; during the night, NIV continuously

Intubation and Protective Mechanical Ventilation

Special precautions are necessary during intubation. The procedure should be executed by an expert operator who uses personal protective equipment (PPE) such as FFP3 or N95 mask, protective goggles, disposable gown long sleeve raincoat, disposable double socks, and gloves. If possible, rapid sequence intubation (RSI) should be performed. Preoxygenation (100% O2 for 5 minutes) should be performed via the continuous positive airway pressure (CPAP) method. Heat and moisture exchanger (HME) must be positioned between the mask and the circuit of the fan or between the mask and the ventilation balloon.

Lung-protective ventilation. Mechanical ventilation should be with lower tidal volumes (4 to 6 ml/kg predicted body weight, PBW) and lower inspiratory pressures, reaching a plateau pressure (Pplat) < 28 to 30 cm H2O. PEEP must be as high as possible to maintain the driving pressure (Pplat-PEEP) as low as possible (< 14 cmH2O). Moreover, disconnections from the ventilator must be avoided for preventing loss of PEEP and atelectasis. Finally, the use of paralytics is not recommended unless PaO2/FiO2 < 150 mmHg. The prone ventilation for > 12 hours per day, and the use of a conservative fluid management strategy for ARDS patients without tissue hypoperfusion (strong recommendation) are emphasized. Lung-protective ventilation can also reduce the risk of new or worsening AKI by preventing ventilator-induced hemodynamic effects.

Other Therapies

Corticosteroids

Among other therapeutic strategies, although systemic corticosteroids for the treatment of viral pneumonia or acute respiratory distress syndrome (ARDS) were not recommended, in severe CARDS these drugs are usually used (e.g., methylprednisolone 1 mg/Kg/day). Of note, a recent large-size RCT (the RECOVERY trial) demonstrated that dexamethasone reduces deaths by one-third among critically ill COVID-19 patients. In the intervention group, 2,100 patients received dexamethasone (6 mg/day for 10 days) whereas in the control group patients (n=4,300) received standard care for the disease.[39]

Antiviral Agents

Although no antiviral treatments have been approved, several approaches have been proposed such as lopinavir/ritonavir (400/100 mg orally every 12 hours)[40]. Nevertheless, a recent randomized, controlled, open-label trial demonstrated no benefit with lopinavir/ritonavir treatment compared to standard care.[41] Preclinical studies suggested that remdesivir (GS5734) — an inhibitor of RNA polymerase with in vitro activity against multiple RNA viruses, including Ebola — could be effective for both prophylaxis and therapy of HCoVs infections.[42] This drug was positively tested in a rhesus macaque model of MERS-CoV infection[43] and recently in macaques infected with SARS-CoV-2[44]. Alpha-interferon (e.g., 5 million units by aerosol inhalation twice per day) was also used.

Several anti-flu drugs such as oseltamivir have been used for the treatment of COVID-19 patients[45]. Another anti-flu medication, favipiravir demonstrated a certain efficacy against SARS-CoV-2 in vitro. Again, a retrospective investigation showed that the broad-spectrum antiviral arbidol can improve the discharging rate and decrease the mortality rate of COVID-19 patients.[46]

Antiviral/Immunomodulatory Drugs

Chloroquine (500 mg every 12 hours), and hydroxychloroquine (200 mg every 12 hours) were proposed as immunomodulatory therapy. Of note, in a non-randomized trial, Gautret et al.[47] showed that hydroxychloroquine was significantly associated with viral load reduction until viral disappearance and this effect was enhanced by the macrolides azithromycin. In vitro and in vivo studies, indeed, have shown that macrolides may mitigate inflammation and modulate the immune system. In particular, these drugs may induce the downregulation of the adhesion molecules of the cell surface, reducing the production of proinflammatory cytokines, stimulating phagocytosis by alveolar macrophages, and inhibiting the activation and mobilization of neutrophils.[48] However, further studies are needed for recommending the use of azithromycin, alone or associated with other drugs such as hydroxychloroquine, outside of any bacterial overlaps. Again, attention must be paid with the concomitant use of hydroxychloroquine with azithromycin as the association can lead to a higher risk of QT interval prolongation and cardiac arrhythmias.[49] Chloroquine can also induce QT prolongation. 

Serotherapy

Antibodies taken from the blood of healed individuals represent a therapeutic option currently under study. It is calculated that the dose of antibodies necessary for the treatment of a single patient with SARS-CoV-2, requires the removal of antibodies carried out by at least three patients recovered from the SARS-CoV-2 infection. A clinical trial has been launched (June 11, 2020) for investigating an antibody cocktail for the prevention and treatment of COVID-19.

Anticoagulant

Because COVID-19 patients have a higher incidence of venous thromboembolism and anticoagulant therapy is associated with reduced ICU mortality, it is suggested that patients should receive thromboprophylaxis. Moreover, in the case of known thrombophilia or thrombosis, full therapeutic-intensity anticoagulation (e.g., enoxaparin 1 mg/kg twice daily) is indicated.[50]

Inflammation Inhibitors

In Italy, a great investigation led by the Istituto Nazionale Tumori, Fondazione Pascale di Napoli is focused on the use of tocilizumab in addition to standard therapies. It is a humanized IgG1 monoclonal antibody, directed against the IL-6 receptor and commonly used in the treatment of rheumatoid arthritis, juvenile arthritis, giant cell arthritis, Castleman’s syndrome, and for managing toxicity due to immune checkpoint inhibitors. Moreover, in the US, a Phase 2/3, randomized, double-blind, placebo-controlled study on sarilumab that is another anti-IL-6 receptor antibody, is ongoing.[51] Other similar strategies have been tested. Anakinra is a recombinant IL-1 receptor antagonist used to treat autoinflammatory disorders such as adult-onset Still's disease, systemic-onset juvenile idiopathic arthritis, and familial Mediterranean fever. The authors of a retrospective analysis showed that in patients with moderate-to-severe ARDS, and hyperinflammation (C-reactive protein ≥100 mg/L, ferritin ≥900 ng/mL, or both), the use of anakinra induced clinical improvement in 72% of patients[52].

Targeting excessive host inflammation can be also addressed in another way. Acalabrutinib is a selective Bruton tyrosine kinase inhibitor, which regulates macrophage signaling and activation. Roschewski et al.[53] tested this agent on 19 patients hospitalized with severe COVID-19 in a prospective off-label clinical study. The proved that the treatment improved oxygenation in a majority of patients, ameliorating measures of inflammation such as C-reactive protein and IL-6.  

Other Therapies

When the disease results in complex clinical pictures of MOD, organ function support in addition to respiratory support, is mandatory. Extracorporeal membrane oxygenation (ECMO) for patients with refractory hypoxemia despite lung-protective ventilation should merit consideration after a case-by-case analysis. It can be suggested for those with poor results to prone position ventilation.

Unselective or inappropriate administration of antibiotics should be avoided, although some centers recommend it.

Prevention

Preventive measures are the current strategy to limit the spread of cases. Because an epidemic will increase as long as R0 is greater than 1 (COVID-19 is 2.2), control measures must focus on reducing the value to less than 1. 

Preventive strategies are focused on the isolation of patients and careful infection control, including appropriate measures to be adopted during the diagnosis and the provision of clinical care to an infected patient. For instance, droplet, contact, and airborne precautions should be adopted during specimen collection, and sputum induction should be avoided.

The WHO and other organizations have issued the following general recommendations:

• Avoid close contact with subjects suffering from acute respiratory infections.
• Wash your hands frequently, especially after contact with infected people or their environment.
• Avoid unprotected contact with farm or wild animals.
• People with symptoms of acute airway infection should keep their distance, cover coughs or sneezes with disposable tissues or clothes and wash their hands.
• Strengthen, in particular, in emergency medicine departments, the application of strict hygiene measures for the prevention and control of infections.
• Individuals that are immunocompromised should avoid public gatherings.

The most important strategy is to frequently wash the hands and use portable hand sanitizer and avoid contact with their face and mouth after interacting with a possibly contaminated environment.

Isolation and contact tracing alone represent insufficient measures to control the spread of the disease. Nevertheless, their efficacy increases with the distancing. To this regard, a modeling study with data from over 40,000 participants in the UK, demonstrated that the combination of isolation and contact tracing with physical distancing measures can be effective for reducing the accounting of cases that would need to self-isolate and of contacts that would need to be traced, controlling in turn, the disease transmission. [54]

Healthcare workers caring for infected individuals should utilize contact and airborne precautions to include PPE such as N95 or FFP3 masks, eye protection, gowns, and gloves to prevent transmission of the pathogen.

The Vaccine

Meanwhile, scientific research is growing to develop a Sars-CoV-2 vaccine. There are more than 100 candidate vaccines in development worldwide, of those 8-10 under clinical investigation. In this 'vaccine gaming', Chinese researchers appear to be ahead, having completed a phase I investigation. Nevertheless, several studies are ongoing, especially in the US, and the UK.

First-in-Human Trial

The results of a phase I clinical trial carried out in a single center in Wuhan (China), designed to evaluate the safety, reactogenicity and immunogenicity of a recombinant adenovirus type-5 (Ad5) vectored COVID-19 vaccine expressing the spike glycoprotein have been published. Between 16 and 27 March 2020, 108 healthy adults aged 18-60 years were consecutively enrolled and assigned to one of the three study groups according to the dose of vaccine administered (intramuscular injection). The primary outcome was the evaluation of adverse events in the 7 days following vaccination. Safety was assessed over 28 days after vaccination. The specific antibodies were measured with the enzyme-linked immunosorbent assay (ELISA) method. Of the 108 enrolled subjects, 36 received a low dose, 36 a medium dose, and 36 a high dose of vaccine. Among participants, 87 (81%) reported at least one adverse reaction within the first 7 days of vaccination: 30 (83%) in the low-dose group, 30 (83%) in the medium-dose group and 27 (75%) in the low-dose group high dose group, with no significant difference in the overall number of adverse reactions between groups. The most common injection-site adverse reaction was pain, while the most commonly reported systemic adverse reactions were fever, fatigue, headache, and muscle pain. No serious adverse events were reported within 28 days. On the 7th day after vaccination, 9 participants (8%) had a mild to moderate increase in total bilirubin, 10 (9%) an increase in alanine aminotransferase, and 4 (4%) fasting hyperglycemia, but no cases were considered clinically significant. The specific antibody responses against SARS-CoV-2 peaked 28 days after the administration of the vaccine dose and the specific immune response of T lymphocytes was evident from the 14th day. The phase II trial (NCT04341389) currently ongoing will provide additional information on the safety and immunogenicity of this vaccine[55].

Other Ongoing Investigations

A Chinese phase II, randomized, double-blinded, placebo-controlled clinical trial was designed to evaluate the immunogenicity and safety of Ad5-CoV which encodes for a full-length spike protein of SARS-CoV-2. the estimated study completion date is January 31, 2021 (NCT04341389). In the US, a company study is aimed at evaluating the safety, tolerability, immunogenicity, and potential efficacy of up to 4 different SARS-CoV-2 RNA vaccine candidates against COVID-19. The spike sequence is included in two of the candidate vaccines, while the other two include the RBD. This Phase 1/2, randomized, placebo-controlled, observer-blind, dose-finding, study will end in March 2023 (NCT04368728). Another Phase I study was designed to assess the safety, tolerability, and immunological profile of a vaccine administered by intradermal injection followed by electroporation which is a technique used to facilitate the passage of drugs into the cell membrane, through the use of a specific device (NCT04336410). A study promoted by the National Institute of Allergy and Infectious Diseases (NIAID) divides the participants into three parallel arms based on the dose of a lipid nanoparticle (LNP)-encapsulated mRNA-based vaccine that encodes for the spike protein of SARS-CoV-2 (mRNA-1273). It is administered through an intramuscular injection on day 1 and day 29 and the subjects will be followed in follow-up for a period of 12 months after the second administration. The study completion date is scheduled for June 1, 2021 (NCT04283461). 

The symptoms of the early stages of the disease are nonspecific. Differential diagnosis should include the possibility of a wide range of infectious and non-infectious (e.g., vasculitis, dermatomyositis) common respiratory disorders. 

• Adenovirus
• Influenza
• Human metapneumovirus (HmPV)
• Parainfluenza
• Respiratory syncytial virus (RSV)
• Rhinovirus (common cold)

For suspected cases, rapid antigen detection, and other investigations should be adopted for evaluating common respiratory pathogens and non-infectious conditions.The Mayo Clinic proposed a COVID-19 self-assessment tool designed for establishing a potential candidate for a COVID-19 diagnostic test (https://www.mayoclinic.org/covid-19-self-assessment-tool).

Multiple studies globally are investigating the use of remdesivir, a broad-spectrum antiviral as well as immunomodulation strategies such as the IL-6-targeting therapies tocilizumab [NCT04317092], sarilumab [NCT04315298]

Preliminary data suggests the reported death rate ranges from 1% to 2% depending on the study and country. The majority of the fatalities have occurred in patients over 50 years of age. Young children appear to be mildly infected but may serve as a vector for additional transmission.

Long term complications among survivors of infection with SARS-CoV-2 having clinically significant COVID-19 disease are not yet available. The mortality rates for cases globally remain between 1% to 2%. Follow-up studies will clarify the extent of the sequelae on organ functions, such as respiratory, renal, cardiovascular, as well as psychological/psychiatric, and related to chronic pain problems [56]. 

Patients and families should receive instruction to:

• Maintaining good social distance is mandatory for preventing the spread of the disease.
• Strict personal hygiene measures (hands wash) are necessary for the prevention and control of this infection.
• Avoid close contact with subjects suffering from acute respiratory infections.
• People with symptoms of acute airway infection should keep their distance, cover coughs or sneezes with disposable tissues or clothes, and wash their hands.
• Immunocompromised patients should avoid public exposure and public gatherings. If an immunocompromised individual must be in a closed space with multiple individuals present, such as a meeting in a small room; masks, gloves, and personal hygiene with antiseptic soap should be undertaken by those in close contact with the individual. In addition, prior room cleaning with antiseptic agents should be undertaken and performed before exposure. However, considering the danger involved to these individuals, exposure should be avoided unless a meeting, group event, etc. is a true emergency.

The following pearls have been provided by health professionals in Italy, the UK, and the U.S. and are based on anecdotal experience.

• The disease is not a 'typical' adult respiratory distress syndrome (ARDS).
• Microvascular thrombosis in the pulmonary circulation can lead to an increased dead space. Early pulmonary fibrosis following the disease has been reported from Italy. This could be oxygen-related or inflammation-related. Pulmonary thrombosis has been associated with wedge-shaped infarcts in the lungs on imaging, without the evidence of deep vein thrombosis.
• In both NIV and MIV, prone positioning of the patient can be essential and should be done early. This procedure should be done more than once a day. Keep a lower threshold for proning even if the usual threshold is a PF ratio of 130. The benefit of proning lasts less than 4 hours in the early phase, but as the disease advances into ARDS, the beneficial effects become long-lasting. Prone positioning in MIV  should be followed by HNFO or NIV (preferably in the prone position) if the saturation is not maintained. There should be a low threshold for intubation if NIV fails for more than an hour. 
• Many centers use inhaled nitric oxide and prostacyclin with good effect. Tachyphylaxis with nitric oxide is usually seen after 4-5 days.
• Maintain euvolemia. There is a high risk of acute kidney injury with hypovolemia.
• Extubation should be delayed more than usual, especially if the inflammatory markers are remaining high. Always perform a leak test before extubation.

Since the first outbreak of coronavirus (COVID-19) in Wuhan, China, the disease is spreading worldwide. Individuals at the extreme of ages and those that are immunocompromised are at the most significant risk. All health care workers should understand the presentation of the disease, workup, and supportive care. Further, health professionals should be aware of the precautions necessary to avoid the contraction and spread of the disease. [Level 5]