3.3. Radiographic imaging
Radiological examinations are of great importance in the early detection and management of COVID-19. According to current experience, lung imaging manifests can be found earlier than clinical symptoms, so imaging examination is vital in preclinical screening (Sohrabi et al., 2020). Therefore, the suspected cases should undertake chest examination as soon as possible.
In the early stage, multiple small patchy shadows and interstitial changes were detected in the extrapulmonary zone. And then, it developed into multiple ground-glass infiltrations (Dawei Wang et al., 2020). In severe and critically cases, lung lesions usually involved most commonly 4-5 lobes in the bilateral lower and upper lobes. The first report of COVID-19 patients described that bilateral lung involvement was detected in 80% of patients, and consolidative pattern changes were always observed in most patients in an intensive care unit (ICU), but ground-glass pattern always showed in patients not in the ICU (Bernheim et al., 2020). Shi et al. analyzed the CT changes and found that most patients even the asymptomatic patients showed dynamic changes from focal unilateral to diffuse bilateral ground-glass opacities and then progressed to consolidations within 1-3 weeks (X. W. Xu et al., 2020). In general, combining assessment of imaging features with clinical and laboratory findings can facilitate the diagnosis of COVID-19 pneumonia and evaluate the severity of the disease.
4.Thepathological changes in COVID-19 patients
Pathological examination of patients with COVID-19 would confirm laboratory and radiological findings and contribute to further study and a better understanding of mechanisms of the disease (Z. Xu et al., 2020). A recent study reported the biopsy results from two patients who underwent surgery for malignancy and then were found to have been infected with SARS-CoV-2, which provided first opportunities to study the pathology of COVID-19. It revealed that the lungs of patients exhibited edema, proteinaceous exudate, focal reactive hyperplasia of pneumocytes with patchy inflammatory cellular infiltration, and multinucleated giant cells, but hyaline membranes were not prominent (Tian et al., 2020). This study may describe early phase changes of the lung pathology of COVID-19 pneumonia. After that pathologist from Huazhong University of Science and Technology, Wuhan, China performed autopsy from 12 dead patients and the results were released by the national health commission, China (Wang, Du, Yue, & Chen, 2020). The histopathological changes for different organs are summarized below:
Lung The lungs showed evident multi-pulmonary consolidation, acute interstitial inflammatory infiltrates and congestion in the alveolar septae. The lumina of alveoli and bronchioles were variably filled with protein-rich edema fluid, erythrocytes, cellular debris, and lymphocytes. Type II alveolar epithelial cells proliferated obviously with inclusion bodies inside. The blood vessel of the alveolar septum had congestion and edema, in which the infiltration of lymphocytes and monocytes, and intravascular hyaline thrombosis can be seen. Focal hemorrhage and necrosis of the lung tissue caused hemorrhagic infarction. Diffuse interstitial pulmonary fibrosis would be presented with the disease progress. Bronchial epithelial cells were degenerated, necrosis and fell off. Mucus plugs were visible in the bronchial lumen. Due to the over-inflation of the alveoli, a small number of the alveolar septum was broken, or the cysts were formed. SARS-CoV-2 particles could be observed in the cytoplasm of bronchial mucosal epitheliums and type II alveolar epithelial cells under an electron microscope. Immunohistochemical staining showed that some alveolar epitheliums and macrophages were positive for SARS-CoV-2 antigens. These tissue types also tested positive for nucleic acids on RT-PCR.
Immune systemThe volume of the spleen decreased significantly and the number of lymphocytes was significantly reduced. There were focal patchy hemorrhages, necrosis and proliferation, and phagocytosis of macrophages in the splenic tissue, with atrophy of white pulp lymphoid aggregates. The number of lymphocytes decreased obviously, and necrosis was visible in lymph nodes. Immunohistochemical staining showed that CD4 + T and CD8 + T cells were reduced in the spleen and lymph nodes. The number of three cell lines in the bone marrow was reduced.
Cardiovascular system There was notable degeneration and necrosis in the myocardial cells, and a few monocytes, lymphocytes and neutrophils infiltrated in the interstitium. Endothelial shedding, endovascular inflammation and thrombosis were visible in the blood vessel.
Liver and gallbladder The volume of the liver increased and its color was dark red. There were degeneration of hepatocytes, congestion of hepatic sinus, focal necrosis with neutrophil infiltration and microthrombosis, which feature the repeated interchange of these kinds of pathological course. The gallbladder was filled with bile.
Kidney There was proteinaceous exudate in the glomerular cavity and degeneration and necrosis in renal tubular epitheliums. Hyperemia, microthrombus and focal fibrosis can be observed in the renal interstitium.
Further, a cohort study conducted by Dominic Wichmann from Intensive Care Medicine University Medical Center Hamburg, demonstrated that 4 (4/12, 33.3%) patients died of pulmonary embolism, and 8 (8/12, 66.7%) exhibited substantial histomorphological diffuse alveolar damage. This study revealed that SARS–CoV-2 RNA could be detected at high concentrations in the lung of all the patients. And more than half of the patients demonstrated high viral RNA titers SARS–CoV-2 RNA was detected in the liver, kidney, or heart (Wichmann et al., 2020).
5. Treatment of COVID-19
Patients should be allocated to designated treatment areas according to the disease severity. Confirmed and suspected patients should be isolated in hospitals with applicable protective equipment and special conditions (e.g. negative pressure ward.). The confirmed cases can be admitted in the same ward, but the suspected cases would be better isolated in a single room to avoid transmission. Besides, critical cases should be treated in ICU as soon as possible (N. H. C. S. A. o. T. C. Medicine, 2020).
Until now, no medicine or anti-virus vaccine has yet been officially recommended for COVID-19 infection (J. Sun et al., 2020). In fact, many countries are focusing on investigating specific medicine to control the infections of SARS-CoV-2 such as vaccines, antibodies, and interferon, which may require a long time of clinical trial (Amanat & Krammer, 2020). Currently available treatment approaches include symptomatic and supportive therapies including supplementary oxygen, mechanical ventilation, glucocorticoids and infection prevention and control (Jin et al., 2020). Antibiotics have no role in treating COVID-19 patients, but they can be used in the case of a secondary bacterial infection. As for antiviral therapy, several agents previously used to treat SARS and Middle East Respiratory Syndrome (MERS) and HIV have been considered as the most potential candidates for COVID-19 patients in China firstly (Kang et al., 2020). With the spread of COVID-19, a large number of pre-clinical and clinical studies all over the world have been underway to investigate the potential agents for COVID-19.
Lopinavir/Ritonavir were the first two antivirals extensively applied for treatment of the COVID-19 in china. Though lopinavir/ritonavir have been used for the treatment of human immunodeficiency virus (HIV) infection with a generally good safety profile, clinical feasibility and safety require further investigation (Kaplan & Hicks, 2005). As has been pointed out, lopinavir/ritonavir usually has compromised interactions with many drugs commonly used in severe patients, which made it less promising for the treatment of COVID-19 patients. Nevertheless, this antivirus has been recommended by the available guidelines in many other countries including the US, Japan (Cao et al., 2020; Stower, 2020). Favilavir was another anti-virus drug that has been effective in relieving the symptoms COVID-19 patients in Japan and China (Abd El-Aziz & Stockand, 2020; Elfiky, 2020). However, this antivirus is not currently approved by the Food and Drug Administration (FDA) of the US (Guan et al., 2020; Li G Fau - De Clercq & De Clercq, 2020).
Remdesivir, a monophosphoramidate prodrug of an adenosine analogue, could inhibit viral replication through incorporating into nascent viral RNA chains resulting in pre-mature termination (M. Wang et al., 2020). A variety of studies have confirmed that remdesivir showed a significant antiviral activity against a broad variety of RNA viruses including SARS-CoV, MERS-CoV and Ebola virus in cultivated cells, mice and non-human primates (NHP) models (de Wit et al., 2020; Warren et al., 2020; Xie & Chen, 2020). Therefore, remdesivir has emerged as the most promising candidate based on the broad antiviral spectrum for the treatment of SARS-CoV-2 infection (Marto & Monteiro, 2020). Meanwhile, a large number of randomized clinical trials have been strictly conducted to investigated its antiviral and safety profile in patients with COVID-19 such as: NCT04252664 and NCT04257656 in many countries (Esposito, Noviello, & Pagliano, 2020; Y. Wang et al., 2020). Recently, a randomized, double-blind clinical trial conducted in China revealed that remdesivir could not improve the time to clinical cure and elimination of viruses, as well as the mortality in patients with COVID-19 (Y. Wang et al., 2020). However, the preliminary clinical study of compassionate use of remdesivir released in England Journal of Medicine came to diametrically opposed conclusions, which demonstrated that 68% (36/53) of patients showed significant clinical improvement with a mortality rate of 18% (Grein et al., 2020). Similarly, the National Institutes of Health of the US reported the findings from a randomized, placebo-controlled trial of remdesivir among 1,063 patients, which suggested that patients who received remdesivir tend to improve faster than patients without, and remdesivir could significantly reduce the mortality rates. Therefore, additional studies with the multicenter and large samples are required to evaluate the safety and efficiency of this antiviral agent.
Chloroquine (CQ) and hydroxychloroquine (HCQ), belonging to the class of aminoquinolines, have been approved for the treatment of malaria, chemoprophylaxis, and autoimmune diseases including lupus and rheumatoid arthritis (Jakhar & Kaur, 2020; Rempenault et al., 2020). In addition, these small-molecule agents have been identified as a promising broad-spectrum antiviral. Previous studies have shown that CQ and HCQ could inhibit the activity of RNA virus such as HIV, HCV, SARS, MERS, Ebola, Hendra viruses in vitro via targeting endosomal acidification as the major determinant of antiviral activity and affecting glycosylation of ACE2 receptor that are required for viral entry (Costanzo, De Giglio, & Roviello, 2020; Lentini, Cavalluzzi, & Habtemariam, 2020; Pereira, 2020; Savarino A Fau - Di Trani, Di Trani L Fau - Donatelli, Donatelli I Fau - Cauda, Cauda R Fau - Cassone, & Cassone, 2020). A recent study also supported the potent activity of CQ and HCQ against SARS-CoV-2, which suggesting the inhibiting effect of viral replication during the initial phases of viral infection. Therefore, they have been approved by the FDA and currently recommended for the treatment of COVID-19 patients. The China National Health Commission reported that CQ may be one of the three drugs with a promising profile for treatment of SARS-CoV-2, but not for infection prevention due to the frequent side effects including severe nausea, polymorphic ventricular tachycardia, digestive disorders, long QT syndrome, and increased risk for sudden death (Juurlink, 2020). A France study among 36 patients reported that single-agent HCQ or combination with azithromycin therapy holds the promise of shortening the clearance of SARS-CoV-2 RNA in the upper respiratory tract (CHEN Jun, 2020). Another report with a larger trial of 84 patients treated with hydroxychloroquine and 97 cases for control suggested that there was no evidence of improvement in patient outcomes between the two groups (Marto & Monteiro, 2020). According to the latest report released by European Medicines Agency (EMA) in April, CQ and HCQ should be only used in clinical trials or emergency use programs (Ferner & Aronson, 2020). Therefore, they are currently presented as an option for the treatment of hospitalized COVID-19 patients in several countries, including the United States, Portugal, Brazil, and France (Health., 2020; P. S. o. c. medicine, 2020; Wilson KC, 2020).
According to the previous reports, SARS-CoV-2 induced aberrant immune responses and excessive infection cytokine storm with increased plasma concentrations of interleukins IL-6, IL-2, IL-7, and IL-10 and tumor necrosis factor are believed to play major roles in disease severity (Yang et al., 2020). Zhou et al confirmed that the value of IL-6 was significantly elevated in patients with ARDS who died compared with patients who survived(Wu et al., 2020). Tocilizumab, a humanized IL-6-receptor (IL-6R) monoclonal antibody, has been experimentally administered in the treatment of COV-ID-19 patients with the severe form of the disease and elevated IL-6 levels in China and Italy (Commission., accessed 2020 Apr 12). In March, The Italian Medicines Agency (AIFA) announced the launch of the clinical phase 2 study named to evaluate the efficacy and safety of TCZ in the treatment of COVID-19 (Esposito et al., 2020). Up to now, many multicenter clinical trials have been registered and spanning the United States, Canada, China, and Europe. Therefore, the WHO has not given a positive response for the use of tocilizumab in COVID-19, due to insufficient evidence.
Convalescent plasma has been applied to treatment of infectious diseases for more than one century. Based on the initial successful experience in the treatment of SARS and MERS, convalescent plasma therapy may be another potentially promising option for COVID-19 patients by providing passive immunity against infectious agents (Cheng et al., 2020; van Griensven et al., 2020). Researches from China have demonstrated that convalescent plasma could significantly improve the symptoms and reduce the mortality rate (Duan et al., 2020; C. Shen et al., 2020). Recently, the FDA has approved convalescent plasma therapy for emergency use to treat COVID-19 patients especially patients with severe condition. Inevitably, convalescent plasma may increase the risks of blood-borne pathogen transmission such as HIV, HBV, HCV and so on (Bhimraj et al., 2020).
Corticosteroids have been previously used in SARS, MERS, H1N1 viral pneumonia with possible immunomodulatory properties (Arabi et al., 2020; Booth et al., 2020). However, reports have confirmed that instead of improving of the mortality among patients with SARS and MERS, corticosteroids increased risk of extended hospital lengths of stay, delayed viral clearance and secondary infections (Coondoo, Phiske, Verma, & Lahiri, 2014). One study among 31 patients from China showed that corticosteroid use did not influence the outcome of patients with mild COVID-19 (Zha et al., 2020). And systematic use of corticosteroids is even higher in critically ill patients with ARDS. However, a multicenter study of 213 patients from the University of Maryland Medical Center demonstrated that low-dose glucocorticoid treatment during the early stages of COVID-19 could significantly reduce the likelihood of being admitted to ICU, the requirement for mechanical ventilation and mortality. Therefore, the treatment of COVID-19 with glucocorticoids is rather controversial, and the WHO has recommended against routinely administering systemic corticosteroids to patients with COVID- 19.
6.The physical and mental health of medical staff
During the spread of the epidemic, COVID-19 prevention and control attracted considerable attention. The highly pathogenic and infectious COVID-19 undoubtedly poses a great challenge to the health of front-line medical staff who were testing for and treating patients with COVID-19 are at a higher risk of contracting it than the general publication (Magellan Health Insights, 2020). According to the existing study results, medical staffs were at high risk of infection during the MERS and SARS outbreaks, with 18.6% of MERS cases occurring in medical staff and 21% of SARS cases occurring in medical staff (Chan-Yeung, 2004; Kim et al., 2020). Due to insufficient understanding of the characteristics of pathogenic and insufficient and unequally-distributed medical resources at the beginning of the epidemic outbreak, a large number of medical staff were infected during the battle against COVID-19. According to the International Council of Nurses (ICN), there have been more than 90,000 health workers were infected, and 260 nurses died from this contagious disease (Nurses, 2020). Health care professionals, particularly those working in emergency units and resuscitation departments, were most often infected during the operation with high level of exposure levels such as endotracheal suction and intubation, nasogastric feed, cardiopulmonary resuscitation and high flow-rates of oxygen and so on (Gamage et al., 2005). In addition, many professionals may consistently experience a high intensity of work with the need of wearing Personal Protective Equipment (PPE), which usually cause physical discomfort and difficulty breathing (Huang, Han, Luo, Ren, & Zhou, 2020; Shigemura, Ursano, Morganstein, Kurosawa, & Benedek, 2020).
Apart from physical suffering, health professionals were suffered from great psychological pressure and other psychological-related problems. Frontline medical staff, especially those in the most severely affected city: New York, Madrid, London, are highly vulnerable to experiencing physical exhaustion, fear, emotion disturbance, sleep problem and concern for themselves, their families and colleagues (Kisely et al., 2020; Malta, Rimoin, & Strathdee, 2020). In one study of 1563 health medical staffs, 50.7% of the participants experienced serious depression symptoms, 44.7% anxiety, and 36.1% sleep disorders (Chersich et al., 2020). Another multicenter study conducted in Singapore and India demonstrated that 19.8% of healthcare workers exhibited varying degrees of psychological discomfort: moderate to very-severe depression, anxiety, psychological distress, and 32.3% always experienced with headache, panic (Cullen, Gulati, & Kelly, 2020). Early evidence indicates that medical staff especially the ones who participated in the treatment of SARS patients was more susceptible to psychological disorders. Therefore, healthcare organizations should adopt following key strategies urgently to protect the mental health of employees with their duty: enhanced decision making support to provide sufficient medical resources; the provision of time and space for clinicians to decompress; and staff working consistently in the same team (Kisely et al., 2020). At the same time, the National Health Commission of China (NHC) has integrated psychological crisis intervention into the general deployment of disease prevention, and released the clinical practice guideline of emergency psychological crisis interventions, psychological counseling for health staff. Recently, the platform for remote health counseling services has been established with psychological professionals in Wuhan, Macao and Rome,which made it easier and safer to provide mental health education for both patients and front-line medical staff (W. Li et al., 2020; Macau., 2020).
Therefore, we cannot ignore providing psychological counseling and crisis intervention training for medical staff. In addition, reasonable schedules, adequate sleep, and appropriate diet and exercise are also the keys to improving the body’s immunity and reducing the risks of suffering.