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.     

Evaluation of sex‐related hormones and semen characteristics in reproductive‐aged male COVID‐19 patients

In the past several months, the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2)‐associated infection (coronavirus disease 2019 [COVID‐19]) developed rapidly and has turned into a global pandemic. Although SARS‐CoV‐2 mainly attacks respiratory systems, manifestations of multiple organs have been observed. A great concern was raised about whether COVID‐19 may affect male reproductive functions. In this study, we collected semen specimens from 12 male COVID‐19 patients for virus detection and semen characteristics analysis. No SARS‐CoV‐2 was found in semen specimens. Eight out of 12 patients had normal semen quality. We also compared the sex‐related hormone levels between 119 reproductive‐aged men with SARS‐CoV‐2 infection and 273 age‐matched control men. A higher serum luteinizing hormone (LH) and a lower ratio of testosterone (T) to LH were observed in the COVID‐19 group. Multiple regression analysis indicated that serum T: LH ratio was negatively associated with white blood cell counts and C‐reactive protein levels in COVID‐19 patients. It's the first report about semen assessment and sex‐hormone evaluation in reproductive‐aged male COVID‐19 patients. Although further study is needed to clarify the reasons and underlying mechanisms, our study presents an abnormal sex hormone secretion among COVID‐19 patients, suggesting that attention should be paid to reproductive function evaluation in the follow‐up.     

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.     

The “scar” of a pandemic: Cumulative incidence of COVID‐19 during the first trimester of pregnancy

Congenitally‐ or perinatally‐acquired viral infections can be harmful to the fetus but data are limited about prevalence and outcomes of coronavirus disease 2019 (COVID‐19) disease during the first trimester of pregnancy. We report epidemiologic data from a study investigating a cohort of women who became pregnant just before or during the COVID‐19 pandemic. We recruited 138 consecutive pregnant women attending for first trimester screening (11‐13 weeks of gestation) at Sant'Anna Hospital, Turin, Piedmont, Italy, during the plateau and the falling phase of the COVID‐19 epidemic curve. Patients were tested for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) immunoglobulin M/immunoglobulin G antibody levels and SARS‐CoV‐2 detection in sera and nasopharyngeal swab samples. COVID‐19 cumulative incidence during the first trimester was of 10.1% with high prevalence of asymptomatic patients (42.8%). Similar to the course of the disease in non pregnant adults, 80% to 90% of infections were not severe.The prevalence of reported symptoms was four‐fold higher in SARS‐CoV‐2 positive patients (57%) than in those negative (13%) (P < .001), suggesting that direct self‐testing should open doors to confirmatory testing for COVID‐19. Our findings support the need for COVID‐19 screening in early pregnancy in epidemic areas to plan materno‐fetal health surveillance programs.     

The cytokine storm and COVID‐19

Coronavirus disease 2019 (COVID‐19), which began in Wuhan, China, in December 2019, has caused a large global pandemic and poses a serious threat to public health. More than 4 million cases of COVID‐19, which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), have been confirmed as of 11 May 2020. SARS‐CoV‐2 is a highly pathogenic and transmissible coronavirus that primarily spreads through respiratory droplets and close contact. A growing body of clinical data suggests that a cytokine storm is associated with COVID‐19 severity and is also a crucial cause of death from COVID‐19. In the absence of antivirals and vaccines for COVID‐19, there is an urgent need to understand the cytokine storm in COVID‐19. Here, we have reviewed the current understanding of the features of SARS‐CoV‐2 and the pathological features, pathophysiological mechanisms, and treatments of the cytokine storm induced by COVID‐19. In addition, we suggest that the identification and treatment of the cytokine storm are important components for rescuing patients with severe COVID‐19.     

Immunopathology and immunotherapeutic strategies in severe acute respiratory syndrome coronavirus 2 infection

The outbreak of coronavirus disease 2019 (COVID‐19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID‐19 cases have been reported in 185 countries. Some patients with COVID‐19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS‐CoV‐2 infection as well as immunotherapeutic strategies for COVID‐19. Immune evasion by SARS‐CoV‐2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS‐CoV‐2 infection. Some potential immunotherapeutic strategies to control the progression of COVID‐19, such as passive antibody therapy and use of interferon αβ and IL‐6 receptor (IL‐6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID‐19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.     

Encephalitic syndrome and anosmia in COVID‐19: Do these clinical presentations really reflect SARS‐CoV‐2 neurotropism? A theory based on the review of 25 COVID‐19 cases

Since the discovery of coronavirus disease 2019 (COVID‐19), a disease caused by the new coronavirus severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), the pathology showed different faces. There is an increasing number of cases described as (meningo)encephalitis although evidence often lacks. Anosmia, another atypical form of COVID‐19, has been considered as testimony of the potential of neuroinvasiveness of SARS‐CoV‐2, though this hypothesis remains highly speculative. We did a review of the cases reported as brain injury caused by SARS‐CoV‐2. Over 98 papers found, 21 were analyzed. Only four publications provided evidence of the presence of SARS‐CoV‐2 within the central nervous system (CNS). When facing acute neurological abnormalities during an infectious episode it is often difficult to disentangle neurological symptoms induced by the brain infection and those due to the impact of host immune response on the CNS. Cytokines release can disturb neural cells functioning and can have in the most severe cases vascular and cytotoxic effects. An inappropriate immune response can lead to the production of auto‐antibodies directed toward CNS components. In the case of proven SARS‐CoV‐2 brain invasion, the main hypothesis found in the literature focus on a neural pathway, especially the direct route via the nasal cavity, although the virus is likely to reach the CNS using other routes. Our ability to come up with hypotheses about the mechanisms by which the virus might interact with the CNS may help to keep in mind that all neurological symptoms observed during COVID‐19 do not always rely on CNS viral invasion.     

A brief review of interplay between vitamin D and angiotensin‐converting enzyme 2: Implications for a potential treatment for COVID‐19

The novel coronavirus disease 2019 (COVID‐19) is rapidly expanding and causing many deaths all over the world with the World Health Organization (WHO) declaring a pandemic in March 2020. Current therapeutic options are limited and there is no registered and/or definite treatment or vaccine for this disease or the causative infection, severe acute respiratory coronavirus 2 syndrome (SARS‐CoV‐2). Angiotensin‐converting enzyme 2 (ACE2), a part of the renin‐angiotensin system (RAS), serves as the major entry point into cells for SARS‐CoV‐2 which attaches to human ACE2, thereby reducing the expression of ACE2 and causing lung injury and pneumonia. Vitamin D, a fat‐soluble‐vitamin, is a negative endocrine RAS modulator and inhibits renin expression and generation. It can induce ACE2/Ang‐(1‐7)/MasR axis activity and inhibits renin and the ACE/Ang II/AT1R axis, thereby increasing expression and concentration of ACE2, MasR and Ang‐(1‐7) and having a potential protective role against acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Therefore, targeting the unbalanced RAS and ACE2 down‐regulation with vitamin D in SARS‐CoV‐2 infection is a potential therapeutic approach to combat COVID‐19 and induced ARDS.     

Multisystem inflammatory syndrome in children related to COVID‐19: A New York City experience

In December 2019, the 2019, a novel coronavirus disease (COVID‐19) caused by severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) first emerged in Wuhan, China. This has now spread worldwide and was declared a pandemic by March 2020. Initially, the pediatric population was described as a low risk for severe COVID‐19. However, reports have emerged recently of cases of COVID‐19 in children with a systemic inflammatory disease, with features that overlap with Kawasaki disease (KD). We describe the first 15 cases with the multi‐systeminflammatory syndrome in children (MIS‐C), temporally related to COVID‐19, who presented for care to a tertiary pediatric referral center in New York City. We discuss the disproportionate burden of disease among Hispanic/Latino and Black/African American ancestry, the distinct cytokine signature across the disease spectrum (IL‐1/IL‐6), and the potential role and pathogenesis of SARS‐CoV‐2 in this new clinical entity.     

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.     

Angiotensin‐converting enzyme 2: The old door for new severe acute respiratory syndrome coronavirus 2 infection

Coronavirus (CoV) disease 2019 (COVID‐19) is an ongoing pandemic caused by severe acute respiratory syndrome CoV 2 (SARS‐CoV‐2). The highly contagious SARS‐CoV‐2 belongs to the genus Betacoronavirus, and it is phylogenetically closely related to SARS‐CoV, a human CoV that caused an outbreak back in 2002 to 2003. Both SARS‐CoV‐2 and SARS‐CoV enter human cells via the interactions between viral crown‐like spike protein and human angiotensin‐converting enzyme 2 (ACE2) receptor. Here, we aim to review the involvement of ACE2 in human CoV infections by discussing the roles of ACE2 in CoV evolution, cross‐species transmissibility, and COVID‐19 susceptibility. We also provide our perspectives on COVID‐19 treatment and prevention.     

Extrapulmonary complications of COVID‐19: A multisystem disease?

The outbreak of coronavirus disease 2019 (COVID‐19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), has been recently declared a pandemic by the World Health Organization. In addition to its acute respiratory manifestations, SARS‐CoV‐2 may also adversely affect other organ systems. To date, however, there is a very limited understanding of the extent and management of COVID‐19‐related conditions outside of the pulmonary system. This narrative review provides an overview of the current literature about the extrapulmonary manifestations of COVID‐19 that may affect the urinary, cardiovascular, gastrointestinal, hematological, hematopoietic, neurological, or reproductive systems. This review also describes the current understanding of the extrapulmonary complications caused by COVID‐19 to improve the management and prognosis of patients with COVID‐19.     

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.     

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.     

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.     

Neuropathogenic human coronaviruses: A review

Human Coronaviruses (HCoVs) have long been known as respiratory viruses. However, there are reports of neurological findings in HCoV infections, particularly in patients infected with the novel severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) amid Coronavirus disease 2019 (COVID‐19) pandemic. Therefore, it is essential to interpret the interaction of HCoVs and the nervous system and apply this understanding to the COVID‐19 pandemic. This review of the literature analyses how HCoVs, in general, and SARS‐CoV‐2, in particular, affect the nervous system, highlights the various underlying mechanisms, addresses the associated neurological and psychiatric manifestations, and identifies the neurological risk factors involved. This review of literature shows the magnitude of neurological conditions associated with HCoV infections, including SARS‐CoV‐2. This review emphasises, that, during HCoV outbreaks, such as COVID‐19, a focus on early detection of neurotropism, alertness for the resulting neurological complications, and the recognition of neurological risk factors are crucial to reduce the workload on hospitals, particularly intensive‐care units and neurological departments.     

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.