T‐cell responses and therapies against SARS‐CoV‐2 infection

Coronavirus disease 2019 (COVID‐19) is caused by SARS‐CoV‐2, a novel coronavirus strain. Some studies suggest that COVID‐19 could be an immune‐related disease, and failure of effective immune responses in initial stages of viral infection could contribute to systemic inflammation and tissue damage, leading to worse disease outcomes. T cells can act as a double‐edge sword with both pro‐ and anti‐roles in the progression of COVID‐19. Thus, better understanding of their roles in immune responses to SARS‐CoV‐2 infection is crucial. T cells primarily react to the spike protein on the coronavirus to initiate antiviral immunity; however, T‐cell responses can be suboptimal, impaired or excessive in severe COVID‐19 patients. This review focuses on the multifaceted roles of T cells in COVID‐19 pathogenesis and rationalizes their significance in eliciting appropriate antiviral immune responses in COVID‐19 patients and unexposed individuals. In addition, we summarize the potential therapeutic approaches related to T cells to treat COVID‐19 patients. These include adoptive T‐cell therapies, vaccines activating T‐cell responses, recombinant cytokines, Th1 activators and Th17 blockers, and potential utilization of immune checkpoint inhibitors alone or in combination with anti‐inflammatory drugs to improve antiviral T‐cell responses against SARS‐CoV‐2.     

Pathological post‐mortem findings in lungs infected with SARS‐CoV‐2

Italy was the first European nation to be massively infected by SARS‐CoV‐2. Up to the end of May 2020, more than 33,000 deaths had been recorded in Italy, with a large prevalence among males, those over 75 years of age, and in association with co‐morbidities. We describe the lung pathological and immunohistochemical post‐mortem findings at the autopsy of nine patients who died of SARS‐CoV‐2‐associated disease. We found in the lung tissues of all patients histological changes consistent with diffuse alveolar damage in various evolution phases ranging from acute exudative to acute proliferative to fibrotic phase. Alveolar damage was associated with prominent involvement of the vascular component in both the interstitial capillaries and the mid‐size vessels, with capillary fibrin micro‐thrombi, as well as organized thrombi even in medium‐sized arteries, in most cases not related to sources of embolism. Eosinophilic infiltrate was also seen, probably reactive to pharmacological treatment. Viral RNA of SARS‐CoV‐2 was detected from the lung tissues of all the nine patients. Immunohistochemistry for the receptor of the SARS‐CoV‐2, ACE2, and its priming activator TMPRSS2 revealed that both proteins co‐localize in airway cells. In particular, the ACE2 protein was expressed in both endothelial cells and alveolar type I and II pneumocytes in the areas of histological diffuse alveolar damage (DAD). Pneumocytes, but not endothelial cells, also expressed TMPRSS2. There are no distinctive histological features of SARS‐CoV‐2 infection with respect to SARS‐CoV‐1 and other DAD with different aetiology. The identification of the cause of death in the course of SARS‐CoV‐2 infection is more likely multi‐factorial. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

The clinical characteristics of pediatric inpatients with SARS‐CoV‐2 infection: A meta‐analysis and systematic review

Millions of people were infected with the coronavirus disease 2019 (COVID‐19) all over the world. Data on clinical symptoms of pediatric inpatients with COVID‐19 infection were unclear. The aim of study was to investigate the clinical features of pediatric inpatients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection. PubMed, EMBASE, and the Cochrane Library were searched to seek for studies providing details on pediatric inpatients with SARS‐CoV‐2 infection which were published from 1st January to 21st April 2020. Studies with more than five pediatric inpatients were included in our meta‐analysis.This study was registered in the PROSPERO database (CRD42020183550). As the results shown, fever (46%) and cough (42%) were the main clinical characters of pediatric inpatients with SARS‐CoV‐2 infection and the other clinical characters, such as diarrhea, vomiting, nasal congestion, and fatigue account for 10% in pediatric inpatients. The proportion of asymptomatic cases was 0.42 (95% confidence interval [CI]: 0.27‐0.59) and severe cases was 0.03 (95% CI: 0.01‐0.06). For the laboratory result, leukopenia (21%) and lymphocytosis (22%) were the mainly indicators for pediatric inpatients, followed by high aspartate aminotransferase (19%), lymphopenia (16%), high alanine aminotransferase (15%), high C‐reactive protein (17%), leukocytosis (13%), high D‐dimer (12%) and high creatine kinase‐MB (5%). Regard to chest imaging features, unilateral and bilateral accounts for 22% in pediatric inpatients, respectively. In conclusion, compared with adult inpatients with SARS‐CoV‐2 infection, the pediatric inpatients had mild clinical characters, lab test indicators, and chest imaging features. More clinical studies focus on the pediatric patients with SARS‐CoV‐2 infection in other countries should be conducted.     

The impact of the SARS‐CoV‐2 infection,with special reference to the hematological setting

Severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) is a disease known from a few months, caused by a recently arisen virus and, consequently, it is little known. The disease has a benign course in most infected subjects (children and young adults), is often symptomatic in adults over the age of 50 and often serious and life threatening in people with comorbidities and the elderly. The few data published on coronavirus disease‐2019 (COVID‐19) in the blood‐oncology field report a serious clinical presentation, a serious course of the disease, and a high mortality rate, as has also been reported for other cancer contexts. The current strategy for treating patients with SARS‐CoV‐2 includes antivirals that are effective against other viral infections and drugs that can moderate the cytokine storm. There is no specific vaccine and consequently all possible precautions must be taken to prevent SARS‐CoV‐2 infection in the areas of oncology, oncohematology, and bone marrow transplantation. In this reviewer's article, we report the information currently available on SARS‐CoV‐2 infection to help young doctors and hematologists to successfully manage patients with COVID‐19.     

Clinical exacerbation of SARS‐CoV2 infection after fingolimod withdrawal

The role of disease‐modifying therapies in patients with autoimmune disorders during severe acute respiratory syndrome coronavirus 2 (SARS‐CoV2) infection is controversial. Immunocompromised patients could have a more severe coronavirus disease‐2019 (COVID‐19) due to the absence of an adequate immune response against the SARS‐CoV‐2. However, therapies that act on immune response could play a protective role by dampening the cytokine‐release syndrome. Fingolimod is a drug used for immune therapy in patients with multiple sclerosis (MS) through the sequestration of activated lymphocytes in the lymph nodes. We report the case of a 57‐year‐old man with relapsing‐remitting MS treated with fingolimod that showed a reactivation of COVID‐19 with signs of hyperinflammation syndrome after fingolimod withdrawal. Our case suggests that discontinuation of fingolimod during COVID‐19 could imply a worsening of SARS‐CoV2 infection.     

Immune responses and pathogenesis of SARS‐CoV‐2 during an outbreak in Iran: Comparison with SARS and MERS

The beginning of 2020 has seen the emergence of COVID‐19, an outbreak caused by a novel coronavirus, SARS‐CoV‐2, an important pathogen for humans. There is an urgent need to better understand this new virus and to develop ways to control its spread. In Iran, the first case of the COVID‐19 was reported after spread from China and other countries. Fever, cough, and fatigue were the most common symptoms of this virus. In worldwide, the incubation period of COVID‐19 was 3 to 7 days and approximately 80% of infections are mild or asymptomatic, 15% are severe, requiring oxygen, and 5% are critical infections, requiring ventilation. To mount an antiviral response, the innate immune system recognizes molecular structures that are produced by the invasion of the virus. COVID‐19 infection induces IgG antibodies against N protein that can be detected by serum as early as day 4 after the onset of disease and with most patients seroconverting by day 14. Laboratory evidence of clinical patients showed that a specific T‐cell response against SARS‐CoV‐2 is important for the recognition and killing of infected cells, particularly in the lungs of infected individuals. At present, there is no specific antiviral therapy for COVID‐19 and the main treatments are supportive. In this review, we investigated the innate and acquired immune responses in patients who recovered from COVID‐19, which could inform the design of prophylactic vaccines and immunotherapy for the future.     

Diagnostic efficacy of anti‐SARS‐CoV‐2 IgG/IgM test for COVID‐19: A meta‐analysis

The serological testing of anti‐SARS‐CoV‐2 immunoglobulin G (IgG) and/or IgM is widely used in the diagnosis of COVID‐19. However, its diagnostic efficacy remains unclear. In this study, we searched for diagnostic studies from the Web of Science, PubMed, Embase, CNKI, and Wanfang databases to calculate the pooled diagnostic accuracy measures using bivariate random‐effects model meta‐analysis. As a result, 22 from a total of 1613 articles, including 2282 patients with SARS‐CoV‐2 and 1485 healthy persons or patients without SARS‐CoV‐2, were selected for a meta‐analysis. Pooled sensitivity, specificity, and area under curve of the summary receiver operator curve (SROC) were: (a) 0.85 (95% confidence interval [CI]: 0.79‐0.90), 0.99 (95% CI: 0.98‐1.00), and 0.99 (95% CI: 0.97‐0.99) for anti‐SARS‐CoV‐2 IgG and (b) 0.74 (95% CI: 0.65‐0.81), 0.99 (95% CI: 0.97‐1.00), and 0.95 (95% CI: 0.93‐0.97) for IgM. A subgroup analysis among detection methods indicated the sensitivity of IgG and IgM using enzyme‐linked immunosorbent assay were slightly lower than those using gold immunochromatography assay (GICA) and chemiluminescence immunoassay (P > .05). These results showed that the detection of anti‐SARS‐CoV‐2 IgG and IgM had high diagnostic efficiency to assist the diagnosis of SARS‐CoV‐2 infection. And, GICA might be used as the preferred method for its accuracy and simplicity.     

SARS‐CoV‐2 infection causes pulmonary shunt by vasodilatation

Patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) may present a significant hypoxemia. The exactly mechanism of such hypoxemia in patients with coronavirus disease 2019 (COVID‐19) is not well described. It has been suggested that microthrombosis contributes to this mechanism, increasing pulmonary dead space. However, dead spaces would not be sensible to oxygen supplementation, and also, enlargement of pulmonary vessels it has been evidenced. Shunt mechanism by vasodilatation, instead, could explain decubitus dependence in oxygenation by blood redistribution as observed in these patients, and moreover, would be more sensible to oxygen supplementation than dead spaces. We hypothesized that SARS‐CoV‐2 causes an intrapulmonary vascular dilatation (IPVD), determining a shunt mechanism by vasodilatation. We performed contrast‐enhanced transthoracic echocardiography to search IPVD shunt in patients with confirmed COVID‐19, hospitalized in an intensive care unit. Ten patients were recruited; one patient was excluded due to low quality of echocardiographic image, and nine patients were included. IPVD was found in seven (78%) patients, with different grades, including patient with normal compliance and the one without invasive ventilation. We demonstrated that shunt by IPVD is present among patients with COVID‐19, and this mechanism is probably implicated in significant hypoxemia observed.     

SARS‐CoV‐2 replicating in nonprimate mammalian cells probably have critical advantages for COVID‐19 vaccines due to anti‐Gal antibodies: A minireview and proposals

Glycoproteins of enveloped viruses replicating in nonprimate mammalian cells carry α‐1,3‐galactose (α‐Gal) glycans, and can bind to anti‐Gal antibodies which are abundant in humans. The antibodies have protected humans and their ancestors for millions of years, because they inhibit replication of many kinds of microbes carrying αGal glycans and aid complements and macrophages to destroy them. Therefore, severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) replicating in nonprimate mammalian cells (eg, PK‐15 cells) carry αGal glycans and could be employed as a live vaccine for corona virus 2019 (COVID‐19). The live vaccine safety could be further enhanced through intramuscular inoculation to bypass the fragile lungs, like the live unattenuated adenovirus vaccine safely used in US recruits for decades. Moreover, the immune complexes of SARS‐CoV‐2 and anti‐Gal antibodies could enhance the efficacy of COVID‐19 vaccines, live or inactivated, carrying α‐Gal glycans. Experiments are imperatively desired to examine these novel vaccine strategies which probably have the critical advantages for defeating the pandemic of COVID‐19 and preventing other viral infectious diseases.     

Duration of SARS‐CoV‐2 RNA shedding and factors associated with prolonged viral shedding in patients with COVID‐19

To investigate the factors associated with the duration of severe acute respiratory syndrome coronavirus 2 RNA shedding in patients with coronavirus disease 2019 (COVID‐19). A retrospective cohort of COVID‐19 patients admitted to a designated hospital in Beijing was analyzed to study the factors affecting the duration of viral shedding. The median duration of viral shedding was 11 days (IQR, 8‐14.3 days) as measured from illness onset. Univariate regression analysis showed that disease severity, corticosteroid therapy, fever (temperature>38.5°C), and time from onset to hospitalization were associated with prolonged duration of viral shedding (P < .05). Multivariate regression analysis showed that fever (temperature>38.5°C) (OR, 5.1, 95%CI: 1.5‐18.1), corticosteroid therapy (OR, 6.3, 95%CI: 1.5‐27.8), and time from onset to hospitalization (OR, 1.8, 95%CI: 1.19‐2.7) were associated with increased odds of prolonged duration of viral shedding. Corticosteroid treatment, fever (temperature>38.5°C), and longer time from onset to hospitalization were associated with prolonged viral shedding in COVID‐19 patients.     

Clinical characteristics and risk factors of mild‐to‐moderate COVID‐19 patients with false‐negative SARS‐CoV‐2 nucleic acid

This study investigates the clinical and imaging characteristics of coronavirus disease 2019 (COVID‐19) patients with false‐negative nucleic acids. Mild‐to‐moderate COVID‐19 patients, including 19 cases of nucleic acid false‐negative patients and 31 cases of nucleic acid positive patients, were enrolled. Their epidemiological, clinical, and laboratory examination data and imaging characteristics were analyzed. Risk factors for false negatives were discussed. Compared with the nucleic acid positive group, the false‐negative group had less epidemiological exposure (52.6% vs 83.9%; P = .025), less chest discomfort (5.3% vs 32.3%; P = .035), and faster recovery (10 [8, 13] vs 15 [11, 18.5] days; P = .005). The number of involved lung lobes was (2 [1, 2.5] vs 3 [2, 4] days; P = .004), and the lung damage severity score was (3 [2.5, 4.5] vs 5 [4, 9] days; P = .007), which was lighter in the nucleic acid false‐negative group. Thus, the absence of epidemiological exposure may be a potential risk factor for false‐negative nucleic acids. The false‐negative cases of COVID‐19 are worth noting because they have a risk of viral transmission without positive test results, lighter clinical manifestations, and less history of epidemiological exposure.     

An update on the origin of SARS‐CoV‐2: Despite closest identity,bat (RaTG13) and pangolin derived coronaviruses varied in the critical binding site and O‐linked glycan residues

The initial cases of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) occurred in Wuhan, China, in December 2019 and swept the world by 23 June 2020 with 8 993 659 active cases, 469 587 deaths across 216 countries, areas or territories. This strongly implies global transmission occurred before the lockdown of China. However, the initial source's transmission routes of SARS‐CoV‐2 remain obscure and controversial. Research data suggest bat (RaTG13) and pangolin carried CoV were the proximal source of SARS‐CoV‐2. In this study, we used systematic phylogenetic analysis of Coronavirinae subfamily along with wild type human SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2 strains. The key residues of the receptor‐binding domain (RBD) and O‐linked glycan were compared. SARS‐CoV‐2 strains were clustered with RaTG13 (97.41% identity), Pangolin‐CoV (92.22% identity) and Bat‐SL‐CoV (80.36% identity), forms a new clade‐2 in lineage B of beta‐CoV. The alignments of RBD contact residues to ACE2 justified? Those SARS‐CoV‐2 strains sequences were 100% identical by each other, significantly varied in RaTG13 and pangolin‐CoV. SARS‐CoV‐2 has a polybasic cleavage site with an inserted sequence of PRRA compared to RaTG13 and only PRR to pangolin. Only serine (Ser) in pangolin and both threonine (Thr) and serine (Ser) O‐linked glycans were seen in RaTG13, suggesting that a detailed study needed in pangolin (Manis javanica) and bat (Rhinolophus affinis) related CoV.     

Oromucosal immunomodulation as clinical spectrum mitigating factor in SARS‐CoV‐2 infection

Mounting evidence supports the importance of mucosal immunity in the immune response to SARS‐CoV‐2. Active virus replication in the upper respiratory tract for the first days of infection opens a new perspective in immunological strategies to counteract viral pathogenicity. An effective mucosal innate immune response to SARS‐CoV‐2 paves the way to an also effective adaptive immune response. A strong local immune response seems to be crucial in the initial contention of the virus by the organism and for triggering the production of the necessary neutralizing antibodies in sera and mucosal secretions. However, if the innate immune response fails to overcome the immune evasion mechanisms displayed by the virus, the infection will progress and the lack of an adaptive immune response will take the patient to an overreactive but ineffective innate immune response. To revert this scenario, an immune strategy based on enhancement of immunity in the first days of infection would be theoretically well come. But serious concerns about cytokine response syndrome prevent us to do so. Fortunately, it is possible to enhance immune system response without causing inflammation through immunomodulation. Immunomodulation of local immune response at the oropharyngeal mucosa could hypothetically activate our mucosal immunity, which could send an early an effective warning to the adaptive immune system. There are studies on immunotherapeutic management of upper respiratory tract infections in children that can place us in the right path to design an immune strategy able to mitigate COVID‐19 symptoms and reduce clinical progression.     

Laboratory testing of SARS‐CoV,MERS‐CoV,and SARS‐CoV‐2 (2019‐nCoV): Current status,challenges, and countermeasures

Emerging and reemerging infectious diseases are global public concerns. With the outbreak of unknown pneumonia in Wuhan, China in December 2019, a new coronavirus, SARS‐CoV‐2 has been attracting tremendous attention. Rapid and accurate laboratory testing of SARS‐CoV‐2 is essential for early discovery, early reporting, early quarantine, early treatment, and cutting off epidemic transmission. The genome structure, transmission, and pathogenesis of SARS‐CoV‐2 are basically similar to SARS‐CoV and MERS‐CoV, the other two beta‐CoVs of medical importance. During the SARS‐CoV and MERS‐CoV epidemics, a variety of molecular and serological diagnostic assays were established and should be referred to for SARS‐CoV‐2. In this review, by summarizing the articles and guidelines about specimen collection, nucleic acid tests (NAT) and serological tests for SARS‐CoV, MERS‐CoV, and SARS‐CoV‐2, several suggestions are put forward to improve the laboratory testing of SARS‐CoV‐2. In summary, for NAT: collecting stool and blood samples at later periods of illness to improve the positive rate if lower respiratory tract specimens are unavailable; increasing template volume to raise the sensitivity of detection; putting samples in reagents containing guanidine salt to inactivate virus as well as protect RNA; setting proper positive, negative and inhibition controls to ensure high‐quality results; simultaneously amplifying human RNase P gene to avoid false‐negative results. For antibody test, diverse assays targeting different antigens, and collecting paired samples are needed.     

YouTube as a source of patient information for Coronavirus Disease (COVID‐19): A content‐quality and audience engagement analysis

YouTube is the second most popular website in the world and is increasingly being used as a platform for disseminating health information. Our aim was to evaluate the content‐quality and audience engagement of YouTube videos pertaining to the SARS (severe acute respiratory syndrome)‐CoV‐2 virus which causes the Coronavirus Disease 2019 (COVID‐19), during the early phase of the pandemic. We chose the first 30 videos for seven different search phrases: “2019 nCoV,” “SARS CoV‐2,” “COVID‐19 virus,” “coronavirus treatment,” “coronavirus explained,” “what is the coronavirus” and “coronavirus information.” Video contents were evaluated by two independent medical students with more than 5 years of experience using the DISCERN instrument. Qualitative data, quantitative data and upload source for each video was noted for a quality and audience engagement analysis. Out of the total 210 videos, 137 met our inclusion criteria and were evaluated. The mean DISCERN score was 31.33 out of 75 possible points, which indicates that the quality of YouTube videos on COVID‐19 is currently poor. There was excellent reliability between the two raters (intraclass correlation coefficient = 0.96). 55% of the videos discussed prevention, 49% discussed symptoms and 46% discussed the spread of the virus. Most of the videos were uploaded by news channels (50%) and education channels (40%). The quality of YouTube videos on SARS‐CoV‐2 and COVID‐19 is poor, however, we have listed the top‐quality videos in our article as they may be effective tools for patient education during the pandemic.