do individuals who recover from COVID-19 show sufficient immune response, including antibody levels and T-cell mediated immunity, to prevent re-infection?

Retest positive for SARS-CoV-2 RNA of "recovered" patients with COVID-19: Persistence, sampling issues, or re-infection?

"Retest Positive" for severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) from "recovered" coronavirus disease-19 (COVID-19) has been reported and raised several important questions for this novel coronavirus and COVID-19 disease. In this commentary, we discussed several questions: (a) Can SARS-CoV-2 re-infect the individuals who recovered from COVID-19? This question is also associated with other questions: whether or not SARS-CoV-2 infection induces protective reaction or neutralized antibody? Will SARS-CoV-2 vaccines work? (b) Why could some recovered patients with COVID-19 be re-tested positive for SARS-CoV-2 RNA? (c) Are some recovered pwith atients COVID-19 with re-testing positive for SARS-CoV-2 RNA infectious? and (d) How should the COVID-19 patients with retest positive for SARS-CoV-2 be managed?

Clinical recurrences of COVID-19 symptoms after recovery: viral relapse, reinfection or inflammatory rebound?

For the first 3 months of COVID-19 pandemic, COVID-19 was expected to be an immunizing non-relapsing disease. We report a national case series of 11 virologically-confirmed COVID-19 patients having experienced a second clinically- and virologically-confirmed acute COVID-19 episode. According to the clinical history, we discuss either re-infection or reactivation hypothesis. Larger studies including further virological, immunological and epidemiologic data are needed to understand the mechanisms of these recurrences.

Clinical characteristics of the recovered COVID-19 patients with re-detectable positive RNA test

Background It has been reported that several cases recovered from COVID-19 tested positive for SARS-CoV-2 after discharge (re-detectable positive, RP), however the clinical characteristics, significance and potential cause of RP patients remained elusive. Methods A total of 262 COVID-19 patients were discharged from January 23 to February 25, 2020, and were enrolled for analysis of their clinical parameters. The RP and non-RP (NRP) patients were grouped according to the disease severity during their hospitalization period. The clinical characterization at re-admission to the hospital was analyzed. SARS-CoV-2 RNA and plasma antibody levels were detected using high-sensitive detection methods. Findings Up to March 10, 2020, all of patients were followed up for at least 14 days, and 38/262 of RP patients (14.5%) were present. The RP patients were characterized by being less than 14-years old and having mild and moderate conditions as compared to NRP patients, while no severe patients became RP. Retrospectively, the RP patients displayed fewer symptoms, more sustained remission of CT imaging and earlier RNA negative-conversion but similar plasma antibody levels during their hospitalization period as compared to those NRP patients. When re-admitted to the hospital, these RP patients showed no obvious clinical symptoms or disease progression indicated by normal or improving CT imaging and inflammatory cytokine levels. All 21 close contacts of RP patients were tested negative for SARS-CoV-2 RNA, and no suspicious clinical symptoms were reported. However, 18/24 of RNA-negative samples detected by the commercial kit were tested to be positive for virus RNA using a hyper-sensitive method, suggesting the carrier status of virus possibly existed in patients recovered from COVID-19. Interpretation Our results showed that young and mild COVID-19 patients seem to be RP patients after discharge, who show no obviously clinical symptoms and disease progression upon re-admission. More sensitive RNA detection methods are required to monitor these patients during follow-up. Our findings provide empirical information and evidence for the effective management of COVID-19 patients during their convalescent phase.

Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing

COVID-19, caused by SARS-CoV-2, has recently affected over 1,200,000 people and killed more than 60,000. The key immune cell subsets change and their states during the course of COVID-19 remain unclear. We sought to comprehensively characterize the transcriptional changes in peripheral blood mononuclear cells during the recovery stage of COVID-19 by single-cell RNA sequencing technique. It was found that T cells decreased remarkably, whereas monocytes increased in patients in the early recovery stage (ERS) of COVID-19. There was an increased ratio of classical CD14(++) monocytes with high inflammatory gene expression as well as a greater abundance of CD14(++)IL1β(+) monocytes in the ERS. CD4(+) T cells and CD8(+) T cells decreased significantly and expressed high levels of inflammatory genes in the ERS. Among the B cells, the plasma cells increased remarkably, whereas the naïve B cells decreased. Several novel B cell-receptor (BCR) changes were identified, such as IGHV3-23 and IGHV3-7, and isotypes (IGHV3-15, IGHV3-30, and IGKV3-11) previously used for virus vaccine development were confirmed. The strongest pairing frequencies, IGHV3-23-IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity, which had not been reported yet. Furthermore, integrated analysis predicted that IL-1β and M-CSF may be novel candidate target genes for inflammatory storm and that TNFSF13, IL-18, IL-2, and IL-4 may be beneficial for the recovery of COVID-19 patients. Our study provides the first evidence of an inflammatory immune signature in the ERS, suggesting COVID-19 patients are still vulnerable after hospital discharge. Identification of novel BCR signaling may lead to the development of vaccines and antibodies for the treatment of COVID-19.

SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy

Most patients with COVID-19 lack antibody to SARS-CoV-2 in the first 10 days of illness while the virus drives disease pathogenesis. SARS-CoV-2 antibody deficiency in the setting of a tissue viral burden suggests that using an antibody as a therapeutic agent would augment the antiviral immune response. In this issue of the JCI, Wang and collaborators describe the kinetics of viral load and antibody responses of 23 individuals with COVID-19 with mild and severe disease. The researchers found: 1) individuals with mild and severe disease produced neutralizing IgG to SARS-CoV-2 10 days after disease onset; 2) SARS-CoV-2 persisted longer in those with severe disease; and 3) there was cross-reactivity between antibodies to SARS-CoV-1 and SARS-CoV-2, but only antibodies from patients with COVID-19 neutralized SARS-CoV-2. These observations provide important information on the serological response to SARS-CoV-2 of hospitalized patients with COVID-19 that can inform the use of convalescent plasma therapy.

SARS-CoV-2 viral load and antibody responses: the case for convalescent plasma therapy.

Is reinfection possible after recovery from COVID-19?

Protective immunity after COVID-19 has been questioned: What can we do without SARS-CoV-2-IgG detection?

Convergent antibody responses to SARS-CoV-2 in convalescent individuals.

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-21-5. Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal pseudovirus neutralizing titres: less than 1:50 in 33% and below 1:1,000 in 79%, while only 1% showed titres above 1:5,000. Antibody sequencing revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titres, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC50 values) as low as single digit nanograms per millitre. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Protective immunity after COVID-19 has been questioned: what can we do without SARS-CoV-2-IgG detection?

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a severe acute respiratory syndrome that is called COVID-19. Clinical manifestations of COVID-19 include diarrhea, pneumonia, lymphopenia, exhausted lymphocytes, and pro-inflammatory cytokine production. Immunology is part of the process of clinical evolution, but there are some questions around immunity-based protection: (1) why some infected people have only mild symptoms of the disease or are asymptomatic; (2) why delayed and weak antibody responses are associated with severe outcomes; and (3) why positivity in molecular tests does not represent protective antibody IgG. Perhaps T cell responses may be the key to solving those questions. SARS-CoV-2-specific memory T cells persist in peripheral blood and may be capable of providing effective information about protective immunity. The T cells studies can be helpful in elucidating the pathways for development of vaccines, therapies, and diagnostics for COVID-19 and for filling these immunology knowledge gaps.

Return to work for healthcare workers with confirmed COVID-19 infection

Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: anti-antibodies, immunoglobulins, and corticosteroids

Abstract The novel coronavirus, SARS-CoV2, can cause a potentially fatal disease, COVID-19, in humans. Here, we will provide an overview of therapeutic options for COVID-19. Plasma from patients recovered from COVID-19 that contains antibodies against SARS-CoV2 has shown promising results in patients with severe COVID-19. Also, IVIG, combined with moderate-dose of corticosteroids, might improve patient outcomes. Evidence links COVID-19 to variable degrees of inflammation. Studies show that the use of corticosteroids might accelerate recovery from COVID-19. There are, however, no controlled clinical trials that show whether the use of corticosteroids can reduce COVID-19-related death. Also, the pro-inflammatory cytokine IL6 is the best-documented cytokine in COVID-19 correlated with severity, criticality, viral load, and prognosis of patients with COVID-19. Tocilizumab, a monoclonal antibody against IL6, could confer clinical benefit in patients with high IL6 levels. Essential elements that process SARS-CoV2 cell entry and specific characteristics that allow SARS-CoV2 to escape the immune system have the potential as targets for COVID-19 therapy.

Convergent Antibody Responses to SARS-CoV-2 Infection in Convalescent Individuals

During the COVID-19 pandemic, SARS-CoV-2 infected millions of people and claimed hundreds of thousands of lives. Virus entry into cells depends on the receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S). Although there is no vaccine, it is likely that antibodies will be essential for protection. However, little is known about the human antibody response to SARS-CoV-2(1–5). Here we report on 149 COVID-19 convalescent individuals. Plasmas collected an average of 39 days after the onset of symptoms had variable half-maximal neutralizing titers ranging from undetectable in 33% to below 1:1000 in 79%, while only 1% showed titers >1:5000. Antibody cloning revealed expanded clones of RBD-specific memory B cells expressing closely related antibodies in different individuals. Despite low plasma titers, antibodies to three distinct epitopes on RBD neutralized at half-maximal inhibitory concentrations (IC(50)s) as low as single digit ng/mL. Thus, most convalescent plasmas obtained from individuals who recover from COVID-19 do not contain high levels of neutralizing activity. Nevertheless, rare but recurring RBD-specific antibodies with potent antiviral activity were found in all individuals tested, suggesting that a vaccine designed to elicit such antibodies could be broadly effective.

Willingness to Accept Tradeoffs among Covid-19 Cases, Social-Distancing Restrictions, and Economic Impact: A Nationwide US Study

We designed a discrete-choice experiment to quantify the extent to which US adults would accept greater risk of infection with SARS-CoV-2 in return for lifting social-distancing restrictions and diminishing the economic impact of the COVID-19 pandemic. 5953 adults representing all 50 states had 4 distinctly different preference patterns. About 37% were risk minimizers reluctant to accept any increases in risk of contracting the virus. Another group (26%) was primarily concerned about time required for economic recovery, accepting increases in COVID-19 risk levels up to 16% to shorten recovery from 3 to 2 years. The remaining two groups diverged on the relative importance of reopening nonessential businesses. The larger group (26%) strongly preferred delaying reopening while the smaller group (13%) would accept COVID-19 risks well beyond 20% to avoid a delay in reopening. Political affiliation, race, household income and employment status were predictive of group membership.

Towards treatment planning of COVID-19: Rationale and hypothesis for the use of multiple immunosuppressive agents: Anti-antibodies, immunoglobulins, and corticosteroids

Convergent antibody responses to SARS-CoV-2 in convalescent individuals

The Dynamic Changes of Antibodies against SARS-CoV-2 during the Infection and Recovery of COVID-19

Deciphering the dynamic changes of antibodies against SARS-CoV-2 is essential for understanding the immune response in COVID-19 patients. By comprehensively analyzing the laboratory findings of 1,850 patients, we describe the dynamic changes of the total antibody, spike protein (S)-, receptor-binding domain (RBD)-, and nucleoprotein (N)- specific IgM and IgG levels during SARS-CoV-2 infection and recovery. Our results indicate that the S-, RBD-, and N- specific IgG generation of severe/critical COVID-19 patients is one week later than mild/moderate cases, while the levels of these antibodies are 1.5-fold higher in severe/critical patients during hospitalization (P<0.01). The decrease of these IgG levels indicates the poor outcome of severe/critical patients. The RBD- and S-specific IgG levels are 2-fold higher in virus-free patients (P<0.05). Notably, we found that the patients who got re-infected had a low level of protective antibody on discharge. Therefore, our evidence proves that the dynamic changes of antibodies could provide an important reference for diagnosis, monitoring, and treatment, and shed new light on the precise management of COVID-19.

Innate immunity in COVID-19 patients mediated by NKG2A receptors, and potential treatment using Monalizumab, Cholroquine, and antiviral agents

Abstract Following the outbreak of a novel coronavirus (SARS-CoV-2), studies suggest that the resultant disease (COVID-19) is more severe in individuals with a weakened immune system. Cytotoxic T-cells (CTLs) and Natural Killer (NK) cells are required to generate an effective immune response against viruses, functional exhaustion of which enables disease progression. Patients with severe COVID-19 present significantly lower lymphocyte, and higher neutrophil, counts in blood. Specifically, CD8+ lymphocytes and NK cells were significantly reduced in cases of severe infection compared to patients with mild infection and healthy individuals. The NK group 2 member A (NKG2A) receptor transduces inhibitory signalling, suppressing NK cytokine secretion and cytotoxicity. Overexpression of NKG2A has been observed on CD8+ and NK cells of COVID-19 infected patients compared to healthy controls, while NKG2A overexpression also functionally exhausts CD8+ cells and NK cells, resulting in a severely compromised innate immune response. Blocking NKG2A on CD8+ cells and NK cells in cancers modulated tumor growth, restoring CD8+ T and NK cell function. A recently proposed mechanism via which SARS-CoV-2 overrides innate immune response of the host is by over-expressing NKG2A on CD+ T and NK cells, culminating in functional exhaustion of the immune response against the viral pathogen. Monalizumab is an inhibiting antibody against NKG2A which can restore the function of CD8 + T and NK cells in cancers, successfully ceasing tumor progression with no significant side effects in Phase 2 clinical trials. We hypothesize that patients with severe COVID-19 have a severely compromised innate immune response and could be treated via the use of Monalizumab, interferon α, chloroquine, and other antiviral agents.

Characterization of anti-viral immunity in recovered individuals infected by SARS-CoV-2

The WHO has declared SARS-CoV-2 outbreak a public health emergency of international concern. However, to date, there was hardly any study in characterizing the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. In this study, we collected blood from COVID-19 patients who have recently become virus-free and therefore were discharged, and analyzed their SARS-CoV-2-specific antibody and T cell responses. We observed SARS-CoV-2-specific humoral and cellular immunity in the patients. Both were detected in newly discharged patients, suggesting both participate in immune-mediated protection to viral infection. However, follow-up patients (2 weeks post discharge) exhibited high titers of IgG antibodies, but with low levels of virus-specific T cells, suggesting that they may enter a quiescent state. Our work has thus provided a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It has also implications in designing an effective vaccine to protect and treat SARS-CoV-2 infection.

No indications for overt innate immune suppression in critically ill COVID-19 patients

At the end of March 2020, there were in excess of 800.000 confirmed cases of coronavirus disease 2019 (COVID-19) worldwide. Several reports suggest that, in severe cases, COVID-19 may cause a hyperinflammatory 'cytokine storm'. However, unlike SARS-CoV infection, high levels of anti-inflammatory mediators have also been reported in COVID-19 patients. One study reported that 16% of COVID-19 patients who died developed secondary infection, which might indicate an immune-suppressed state. We explored kinetics of mHLA-DR expression, the most widely used marker of innate immune suppression in critically ill patients, in COVID-19 patients admitted to the ICU. Twenty-four confirmed COVID-19 patients were included, of which 75% was male and 79% had comorbidities. All patients were mechanically ventilated and exhibited large high levels of inflammatory parameters such as CRP and PCT. mHLA-DR expression levels were mostly within the normal range of 15000 - 45000 mAb/cell and showed no change over time. COVID-19 patients displayed notably higher mHLA-DR expression levels compared with bacterial septic shock patients. None of the COVID-19 patients developed a secondary infection. In conclusion, despite a pronounced inflammatory response, mHLA-DR expression kinetics indicate no overt innate immune suppression in COVID-19 patients. These data signify that innate immune suppression as a negative feedback mechanism following PAMP-induced inflammation appears not to be present in COVID-19.

Study of the lymphocyte change between COVID-19 and non-COVID-19 pneumonia cases suggesting other factors besides uncontrolled inflammation contributed to multi-organ injury

Background: The corona virus disease 2019 (COVID-19) shows unusually high transmission rate and unique clinical characteristics, with key pathological mechanism remaining unclear. Here, we analysed the laboratory data based on clinical samples from COVID-19 patients, in parallel comparison with non-COVID-19 pneumonia cases, in an attempt to elucidate the key pathological features of COVID-19 during its infection of the human body. Methods: We analysed biochemical indices and lymphocyte subpopulation in COVID-19 patients, and compare these data from non-COVID-19 pneumonia cases. Correlation analysis was performed between leukocyte subgroups count and biochemical indexes in COVID-19 patients. Results: The study enrolled 110 patients, comprising 88 COVID-19 patients and 22 non-COVID-19 pneumonia cases. We observed significant differences, including abnormal biochemical indices (CRP, LDH, AST, eGFR, and sodium ion concentration) and reduced lymphocyte subsets count, between the COVID-19 patients and non-COVID-19-caused pneumonia cases. Correlation analysis indicates that the count for lymphocyte subsets-but not that for neutrophils and monocytes-exhibits a significant negative correlation with biochemical indices relating to organ injury, in the COVID-19 infected patients. Conclusions: The study indicates significantly different clinical features between 2019 novel coronavirus (2019-nCoV)-caused and non-2019-nCoV-caused pneumonia, especially in terms of lymphocytopenia and organ injury. Notably, correlation analysis demonstrates that tissue damage in COVID-19 patients is attributed to virus infection itself rather than uncontrolled inflammatory responses ("cytokine storm"). These findings provide new insights for developing efficient therapeutic strategies against COVID-19 infection.

Long-term coexistence of SARS-CoV-2 with antibody response in COVID-19 patients

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection causing coronavirus disease 2019 (COVID-19) has spread worldwide. Whether antibodies are important for the adaptive immune responses against SARS-CoV-2 infection needs to be determined. Here, 26 cases of COVID-19 in Jinan, China, were examined and shown to be mild or with common clinical symptoms, and no case of severe symptoms was found among these patients. Strikingly, a subset of these patients had SARS-CoV-2 and virus-specific IgG coexist for an unexpectedly long time, with two cases for up to 50 days. One COVID-19 patient who did not produce any SARS-CoV-2-bound IgG successfully cleared SARS-CoV-2 after 46 days of illness, revealing that without antibody-mediated adaptive immunity, innate immunity alone may still be powerful enough to eliminate SARS-CoV-2. This report may provide a basis for further analysis of both innate and adaptive immunity in SARS-CoV-2 clearance, especially in nonsevere cases.

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.

Discontinuation of antiviral drugs may be the reason for recovered COVID-19 patients testing positive again

Identification of IgG antibody response to SARS-CoV-2 spike protein and its receptor binding domain does not predict rapid recovery from COVID-19

Diagnostic testing and evaluation of patient immunity against the novel severe acute respiratory syndrome (SARS) corona virus that emerged last year (SARS-CoV-2) are essential for health and economic crisis recovery of the world. It is suggested that potential acquired immunity against SARS-CoV-2 from prior exposure may be determined by detecting the presence of circulating IgG antibodies against viral antigens, such as the spike glycoprotein and its receptor binding domain (RBD). Testing our asymptomatic population for evidence of COVID-19 immunity would also offer valuable epidemiologic data to aid health care policies and health care management. Currently, there are over 100 antibody tests that are being used around the world without approval from the FDA or similar regulatory bodies, and they are mostly for rapid and qualitative assessment, with different degrees of error rates. ELISA-based testing for sensitive and rigorous quantitative assessment of SARS-CoV-2 antibodies can potentially offer mechanistic insights into the COVID-19 disease and aid communities uniquely challenged by limited financial resources and access to commercial testing products. Employing recombinant SARS-CoV-2 RBD and spike protein generated in the laboratory, we devised a quantitative ELISA for the detection of circulating serum antibodies. Serum from twenty SARS-CoV-2 RT-PCR confirmed COVID-19 hospitalized patients were used to detect circulating IgG titers against SARS-CoV-2 spike protein and RBD. Quantitative detection of IgG antibodies to the spike glycoprotein or the RBD in patient samples was not always associated with faster recovery, compared to patients with borderline antibody response to the RBD. One patient who did not develop antibodies to the RBD completely recovered from COVID-19. In surveying 99 healthy donor samples (procured between 2017-February 2020), we detected RBD antibodies in one donor from February 2020 collection with three others exhibiting antibodies to the spike protein but not the RBD. Collectively, our study suggests that more rigorous and quantitative analysis, employing large scale sample sets, is required to determine whether antibodies to SARS-CoV-2 spike protein or RBD is associated with protection from COVID-19 disease. It is also conceivable that humoral response to SARS-CoV-2 spike protein or RBD works in association with adaptive T cell response to determine clinical sequela and severity of COVID-19 disease.

Immune Cell Profiling of COVID-19 Patients in the Recovery Stage by Single-Cell Sequencing

COVID-19 caused by SARS-CoV-2 has recently affected over 200,000 people and killed more than 8000. Immune system dysregulation such as lymphopenia and inflammatory cytokine storm has been observed in COVID-19 patients, but it remains unclear for the change of key immune cell subsets and their states during COVID-19. Here, we applied single-cell technology to comprehensively characterize transcriptional changes of peripheral blood mononuclear cells in ten patients recovered from COVID-19. Compared with healthy control, COVID-19 induced a unique signature of immune cells in humans, especially in the early recovery stage (ERS). In ERS patients, T cells were decreased remarkably, while monocytes were increased. A detailed analysis of monocytes showed that there was an increased ratio of classical CD14++ monocytes with highly inflammatory genes expression, as well as a greater abundance of CD14++IL1B+ monocytes. For nature killer (NK) cells and T cells, CD4+ T cells were significantly decreased and expressed high level of inflammatory markers, while NK cells were increased. In addition, T cells were highly expanded clone, especially in CD4+ T memory cells and CD8+ T cells. Among B cells, plasma cells were increased remarkably, and naïve B cells were reduced. Our study also identified several novel B cell receptor (BCR) changes (such as IGHV1-8 and IGHV3-7), and confirmed isotypes (IGKV3-11 and IGHV3-21) previously used for virus vaccine development. The strongest pairing frequencies, IGHV3-23+IGHJ4, indicated a monoclonal state associated with SARS-CoV-2 specificity. Furthermore, integrated analysis predicated that IL-1B and M-CSF may be novel candidate target gene for inflammatory storm, and TNFSF13, IL-18 and IL-4 may be benefit for the recovery of COVID-19 patients. Our study provides the first evidence of inflammatory immune signature in early recovery stage, suggesting that the COVID-19 patients are still vulnerable after hospital discharge. Our identification of novel BCR signaling may lead to the development of vaccine and antibodies for the treatment of COVID-19.

C-reactive protein correlates with computed tomographic findings and predicts severe COVID-19 early

COVID-19 has developed into a worldwide pandemic; early identification of severe illness is critical for controlling it and improving the prognosis of patients with limited medical resources. The present study aimed to analyze the characteristics of severe COVID-19 and identify biomarkers for differential diagnosis and prognosis prediction. In total, 27 consecutive patients with COVID-19 and 75 patients with flu were retrospectively enrolled. Clinical parameters were collected from electronic medical records. The disease course was divided into four stages: initial, progression, peak, and recovery stages, according to computed tomography (CT) progress. to mild COVID-19, the lymphocytes in the severe COVID-19 progressively decreased at the progression and the peak stages, but rebound in the recovery stage. The levels of C-reactive protein (CRP) in the severe group at the initial and progression stages were higher than those in the mild group. Correlation analysis showed that CRP (R = .62; P < .01), erythrocyte sedimentation rate (R = .55; P < .01) and granulocyte/lymphocyte ratio (R = .49; P < .01) were positively associated with the CT severity scores. In contrast, the number of lymphocytes (R = -.37; P < .01) was negatively correlated with the CT severity scores. The receiver-operating characteristic analysis demonstrated that area under the curve of CRP on the first visit for predicting severe COVID-19 was 0.87 (95% CI 0.10-1.00) at 20.42 mg/L cut-off, with sensitivity and specificity 83% and 91%, respectively. CRP in severe COVID-19 patients increased significantly at the initial stage, before CT findings. Importantly, CRP, which was associated with disease development, predicted early severe COVID-19.

A systematic review of convalescent plasma treatment for COVID19

Background. Transfusion of convalescent immune plasma (CP) is commonly used in epidemics. Several articles now describe clinical report data of CP for treatment of SARS-CoV-2-induced COVID-19 disease. Methods. A systematic literature review was conducted using the NCBI curated COVID-19 related open-resource literature database LitCovid to identify studies using CP as treatment for COVID-19 patients. We retrieved and curated all COVID-19 related patient and treatment characteristics from previously reported studies. A Poisson model was developed to evaluate the association between age of the patients, older age being the most common risk factor for COVID-19 mortality, and recovery time since CP treatment using data extracted from the literature. Results. From 18,293 identified COVID-19 related articles, we included ten studies reporting results of CP treatment for COVID-19 from a total of 61 patients. Decreased symptoms of severe COVID-19 and clearance of SARS-CoV-2 RNA were the most direct observations. We found that patients over the age of sixty who received CP treatment for COVID-19 had a significantly prolonged recovery estimated by viral clearance (from 10 to 29 days since first dose of CP) compared to younger patients, who recovered from the infection in less than a week after receiving CP treatment. Conclusions. Limited published results on plasma transfusion treatment for COVID-19 disease with concomitant treatments suggest that CP therapy for COVID-19 is well tolerated and effective. First randomized clinical trial results, however, reveal no improvements in recovery time for elderly patients with severe COVID-19 between standard treatment alone and added with convalescent plasma. Accordingly, we argue that older patients may need a significantly longer time for recovery. Further randomized clinical trial data for COVID-19 with rigorous ethical standards is urgently needed.

SARS-CoV-2 environmental contamination associated with persistently infected COVID-19 patients

BACKGROUND: Severe COVID-19 patients typically test positive for SARS-CoV-2 RNA for extended periods of time, even after recovery from severe disease. Due to the timeframe involved, these patients may have developed humoral immunity to SARS-CoV-2 while still testing positive for viral RNA in swabs. Data are lacking on exposure risks in these situations. Here, we studied SARS-CoV-2 environmental contamination in an ICU and an isolation ward caring for such COVID-19 patients. METHODS: We collected air and surface samples in a hospital caring for critical and severe COVID-19 cases from common areas and areas proximal to patients. RESULTS: Of the 218 ICU samples, an air sample contained SARS-CoV-2 RNA. Of the 182 isolation ward samples, nine contained SARS-CoV-2 RNA. These were collected from a facemask, the floor, mobile phones, and the air in the patient room and bathroom. Serum antibodies against SARS-CoV-2 were detected in these patients at the beginning of the study. CONCLUSIONS: While there is a perception of increased risk in the ICU, our study demonstrates that isolation wards may pose greater risks to healthcare workers and exposure risks remain with clinically improved patients, weeks after their initial diagnoses. As these patients had serum antibodies, further studies may be warranted to study the utility of serum antibodies as a surrogate of viral clearance in allowing people to return to work. We recommend continued vigilance even with patients who appear to have recovered from COVID-19.

Discontinuation of antiviral drugs may be the reason for recovered COVID-19 patients testing positive again.

Serum-IgG responses to SARS-CoV-2 after mild and severe COVID-19 infection and analysis of IgG non-responders

Background: To accurately interpret COVID-19 seroprevalence surveys, knowledge of serum-IgG responses to SARS-CoV-2 with a better understanding of patients who do not seroconvert, is imperative. This study aimed to describe serum-IgG responses to SARS-CoV-2 in a cohort of patients with both severe and mild COVID-19, including extended studies of patients who remained seronegative more than 90 days post symptom onset. Results: Forty-seven patients (mean age 49 years, 38% female) were included. All (15/15) patients with severe symptoms and 29/32 (90.6%) patients with mild symptoms of COVID-19 developed SARS-CoV-2-specific IgG antibodies in serum. Time to seroconversion was significantly shorter (median 11 vs. 22 days, P=0.04) in patients with severe compared to mild symptoms. Of the three patients without detectable IgG-responses after >90 days, all had detectable virus-neutralizing antibodies and in two, spike-protein receptor binding domain-specific IgG was detected with an in-house assay. Antibody titers were preserved during follow-up and all patients who seroconverted, irrespective of the severity of symptoms, still had detectable IgG levels >75 days post symptom onset. Conclusions: Patients with severe COVID-19 both seroconvert earlier and develop higher concentrations of SARS-CoV-2-specific IgG than patients with mild symptoms. Of those patients who not develop detectable IgG antibodies, all have detectable virus-neutralizing antibodies, suggesting immunity. Our results showing that not all COVID-19 patients develop detectable IgG using two validated commercial clinical methods, even over time, are vital for the interpretation of COVID-19 seroprevalence surveys and for estimating the true infection prevalence in populations.

Retest positive for SARS‐CoV‐2 RNA of “recovered” patients with COVID‐19: Persistence, sampling issues, or re‐infection?

“Retest Positive” for severe acute respiratory syndrome‐related coronavirus‐2 (SARS‐CoV‐2) from “recovered” coronavirus disease‐19 (COVID‐19) has been reported and raised several important questions for this novel coronavirus and COVID‐19 disease. In this commentary, we discussed several questions: (a) Can SARS‐CoV‐2 re‐infect the individuals who recovered from COVID‐19? This question is also associated with other questions: whether or not SARS‐CoV‐2 infection induces protective reaction or neutralized antibody? Will SARS‐CoV‐2 vaccines work? (b) Why could some recovered patients with COVID‐19 be re‐tested positive for SARS‐CoV‐2 RNA? (c) Are some recovered pwith atients COVID‐19 with re‐testing positive for SARS‐CoV‐2 RNA infectious? and (d) How should the COVID‐19 patients with retest positive for SARS‐CoV‐2 be managed?

Coping with Covid-19.

The positive effects of covid-19.

COVID-19 Severity Correlates with Weaker T Cell Immunity, Hypercytokinemia and Lung Epithelium Injury

Neutralizing antibodies mediate virus-immune pathology of COVID-19.

SARS-CoV-2 is a novel beta-coronavirus causing over 200.000 lethal cases within six months of first infecting humans. SARS-CoV-2 causes COVID-19, a form of severe acute respiratory syndrome (SARS). COVID-19 is characterized by two phases: the first resembles the flu with pneumonia, but after about seven or eight days the disease suddenly worsens to a sepsis-like syndrome. It is difficult to explain this virus-immune-pathology sequence from virology or immunology only. This paper hypothesizes that host-produced anti-spike protein antibodies are responsible for immune-induced viral dissemination. Subsequently, systemic distribution of virus-antibodies complexes activates the immune pathology observed in severe COVID-19. This hypothesis may be counterintuitive to immunologist that consider many anti-spike antibodies to be virus-neutralizing antibodies. Although anti-spike antibodies may hinder infection of epithelial cells, antibody binding to the spike protein may facilitate virus infection of myeloid leukocytes. If myeloid leukocytes reenter the circulation, they could spread the virus from a locoregional infection to a systemic disease. Disseminated virus in combination with antibodies results in dispersed virus-antibody complexes that overstimulate the immune system. The hypothesis aligns with the sequences of virus, immune and pathological events in COVID-19. The delay in onset from both syndromes results from an immune system still naïve to the non-cross-reactive spike protein. Details of this hypothesis are in concordance with many clinical characteristics of COVID-19, including its predominant lethality for the elderly, and the mostly asymptomatic course of disease in children. It predicts putative detrimental effects of vaccines that induce virus-neutralizing antibodies against the spike protein, as has been shown for other coronaviruses. This hypothesis has consequences for treatment of patients, evaluation of personal and herd immunity and vaccine development. In patients, cellular immunity should be stimulated. Neutralizing antibodies might not be indicative for immunity. Vaccines should aim to stimulate cellular immunity COVID-19 and/or stimulate humoral immunity against viral proteins except for the immunodominant spike protein.

Tocilizumab treatment in COVID-19: A single center experience

Tocilizumab (TCZ), a monoclonal antibody against interleukin-6 (IL-6), emerged as an alternative treatment for COVID-19 patients with a risk of cytokine storms recently. In the present study, we aimed to discuss the treatment response of TCZ therapy in COVID-19 infected patients. The demographic, treatment, laboratory parameters of C-reactive protein (CRP) and IL-6 before and after TCZ therapy and clinical outcome in the 15 COVID-19 patients were retrospectively assessed. Totally 15 patients with COVID-19 were included in this study. Two of them were moderately ill, six were seriously ill and seven were critically ill. The TCZ was used in combination with methylprednisolone in eight patients. Five patients received the TCZ administration twice or more. Although TCZ treatment ameliorated the increased CRP in all patients rapidly, for the four critically ill patients who received an only single dose of TCZ, three of them (No. 1, 2, and 3) still dead and the CRP level in the rest one patient (No. 7) failed to return to normal range with a clinical outcome of disease aggravation. Serum IL-6 level tended to further spiked firstly and then decreased after TCZ therapy in 10 patients. A persistent and dramatic increase of IL-6 was observed in these four patients who failed treatment. TCZ appears to be an effective treatment option in COVID-19 patients with a risk of cytokine storms. And for these critically ill patients with elevated IL-6, the repeated dose of the TCZ is recommended.

Breadth of concomitant immune responses underpinning viral clearance and patient recovery in a non-severe case of COVID-19

We report the kinetics of the immune response in relation to clinical and virological features of a patient with mild-to-moderate coronavirus disease-19 (COVID-19) requiring hospitalisation. Increased antibody-secreting cells, follicular T-helper cells, activated CD4+ and CD8+ T-cells and IgM/IgG SARS-CoV-2-binding antibodies were detected in blood, prior to symptomatic recovery. These immunological changes persisted for at least 7 days following full resolution of symptoms, indicating substantial anti-viral immunity in this non-severe COVID-19.

Mesenchymal Stem Cells -Bridge Catalyst Between Innte And Adaptive Immunity In Covid 19

Majority of patients infected with the COVID 19 virus display a mild to moderate course of disease and spontaneously recover at 14 - 20 days,. However, about 15 % of patients progress to severe stages and 2.5% of these patients succumb to this illness. Most patients with severe disease belong to the elderly age group (< 65 years of age) and have multiple associated co-morbidities. The immune responses induced by the COVID 19 virus, during the incubation and non-severe stages, requires the early initiation of a specific adaptive immune response to eliminate the virus and prevent the progress to severe stages. In patients with a dysfunctional bridge adaptive immunity, the innate immune response becomes exaggerated due to the lack of feedback from the adaptive immune cells. The resultant cytokine storm is responsible for the severe lung injury leading to acute respiratory distress syndrome seen in COVID 19 patients. Mesenchymal stem cells are known to suppress overactive immune responses as well as bring about tissue regeneration and repair. This immuno-modulatory effect of MSCs could hold potential to manage a patient with severe symptoms of COVID 19 infection due to a dysfunctional adaptive immune system.

Neutralizing antibodies mediate virus-immune pathology of COVID-19

COVID-19 is milder in children possibly due to cross-immunity

Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN)

Patients with multiple myeloma (MM) seem to be at increased risk for more severe COVID-19 infection and associated complications due to their immunocompromised state, the older age and comorbidities. The European Myeloma Network has provided an expert consensus statement in order to guide therapeutic decisions in the era of the COVID-19 pandemic. Patient education for personal hygiene and social distancing measures, along with treatment individualization, telemedicine and continuous surveillance for early diagnosis of COVID-19 are essential. In countries or local communities where COVID-19 infection is widely spread, MM patients should have a PCR test of nasopharyngeal swab for SARS-CoV-2 before hospital admission, starting a new treatment line, cell apheresis or ASCT in order to avoid ward or community spread and infections. Oral agent-based regimens should be considered, especially for the elderly and frail patients with standard risk disease, whereas de-intensified regimens for dexamethasone, bortezomib, carfilzomib and daratumumab should be used based on patient risk and response. Treatment initiation should not be postponed for patients with end organ damage, myeloma emergencies and aggressive relapses. Autologous (and especially allogeneic) transplantation should be delayed and extended induction should be administered, especially in standard risk patients and those with adequate MM response to induction. Watchful waiting should be considered for standard risk relapsed patients with low tumor burden, and slow biochemical relapses. The conduction of clinical trials should continue with appropriate adaptations to the current circumstances. Patients with MM and symptomatic COVID-19 disease should interrupt anti-myeloma treatment until recovery. For patients with positive PCR test for SARS-CoV-2, but with no symptoms for COVID-19, a 14-day quarantine should be considered if myeloma-related events allow the delay of treatment. The need for surveillance for drug interactions due to polypharmacy is highlighted. The participation in international COVID-19 cancer registries is greatly encouraged.

Broad phenotypic alterations and potential dysfunctions of lymphocytes in COVID-19 recovered individuals

Background Lymphopenia is a typical symptom in the COVID-19 patients. While millions of patients are clinical recovered, little is known about the immune status of lymphocytes in these individuals. Methods A clinical recovered cohort (CR) of 55 COVID-19 individuals (discharged from hospital 4 to 11 weeks), and 55 age and sex matched healthy donors cohort (HD) were recruited. Detailed analysis on phenotype of the lymphocytes in peripheral blood mononuclear cells (PBMCs) was performed by flow cytometry. Findings Compared with cohort HD, the CD8+ T cells in cohort CR had higher Teff and Tem, but lower Tc1 (IFN-{gamma}+), Tc2 (IL-4+) and Tc17 (IL-17A+) frequencies. The CD4+ T cells of CR had decreased frequency, especially on the Tcm subset. Moreover, CD4+ T cells of CR expressed lower PD-1 and had lower frequencies of Th1 (IFN-{gamma}+), Th2 (IL-4+), Th17 (IL-17A+) as well as circulating Tfh (CXCR5+PD-1+). Accordingly, isotype-switched memory B cell (IgM-CD20hi) in CR had significantly lower proportion in B cells, though level of activation marker CD71 elevated. For CD3-HLA-DRlo lymphocytes of CR, besides levels of IFN-{gamma}, Granzyme B and T-bet were lower, the correlation between T-bet and IFN-{gamma} became irrelevant. In addition, taken into account of discharged days, all the lowered function associated phenotypes showed no recovery tendency within whole observation period. Interpretation The CR COVID-19 individuals still showed remarkable phenotypic alterations in lymphocytes after clinical recovery 4 to 11 weeks. This suggests SARS-CoV-2 infection imprints profoundly on lymphocytes and results in long-lasting potential dysfunctions.

Surviving the trauma of COVID-19

The first, holistic immunological model of COVID-19: Implications for prevention, diagnosis, and public health measures

The natural history of COVID-19 caused by SARS-CoV-2 is extremely variable, ranging from asymptomatic or mild infection, mainly in children, to multi-organ failure, eventually fatal, mainly in the eldest. We propose here the first model explaining how the outcome of first, crucial 10-15 days after infection, depends on the balance between the cumulative dose of viral exposure and the efficacy of the local innate immune response (natural IgA and IgM antibodies, mannose-binding lectin). If SARS-CoV-2 runs the blockade of this innate immunity and spreads from the upper airways to the alveoli in the early phases of the infections, it can replicate with no local resistance, causing pneumonia and releasing high amounts of antigens. The delayed and strong adaptive immune response (high-affinity IgM and IgG antibodies) that follows, causes severe inflammation and triggers mediator cascades (complement, coagulation, and cytokine storm), leading to complications often requiring intensive therapy and being, in some patients, fatal. Low-moderate physical activity can still be recommended. However, extreme physical activity and oral breathing with hyperventilation during the incubation days and early stages of COVID-19 facilitates re-inhalation and early direct penetration of high numbers of own virus particles in the lower airways and the alveoli, without impacting on the airway's mucosae covered by neutralizing antibodies ("viral auto-inhalation" phenomenon). This allows the virus to bypass the efficient immune barrier of the upper airway mucosa in already infected, young, and otherwise healthy athletes. In conclusion, whether the virus or the adaptive immune response reaches the lungs first is a crucial factor deciding the fate of the patient. This "quantitative and time-/sequence-dependent" model has several implications for prevention, diagnosis, and therapy of COVID-19 at all ages.

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1ß-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1ß-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.

Immunophenotyping of COVID-19 and influenza highlights the role of type I interferons in development of severe COVID-19.

Although most SARS-CoV-2-infected individuals experience mild coronavirus disease 2019 (COVID-19), some patients suffer from severe COVID-19, which is accompanied by acute respiratory distress syndrome and systemic inflammation. To identify factors driving severe progression of COVID-19, we performed single-cell RNA-seq using peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, patients with mild or severe COVID-19, and patients with severe influenza. Patients with COVID-19 exhibited hyper-inflammatory signatures across all types of cells among PBMCs, particularly up-regulation of the TNF/IL-1β-driven inflammatory response as compared to severe influenza. In classical monocytes from patients with severe COVID-19, type I IFN response co-existed with the TNF/IL-1β-driven inflammation, and this was not seen in patients with milder COVID-19. Interestingly, we documented type I IFN-driven inflammatory features in patients with severe influenza as well. Based on this, we propose that the type I IFN response plays a pivotal role in exacerbating inflammation in severe COVID-19.

COVID-19 Severity Correlates with Weaker T Cell Immunity, Hypercytokinemia and Lung Epithelium Injury.

Potential COVID-19 infection in patients with severe multiple sclerosis treated with alemtuzumab

BACKGROUND: Management of disease-modifying therapies in Multiple Sclerosis (MS) during the COVID-19 pandemic is a controversial issue. Alemtuzumab is an immunosuppressive drug that induces lymphocytes depletion. In this study, we aimed to evaluate the frequency and severity of COVID-19 in a case series of patients treated with alemtuzumab in our center. METHODS: Ten patients with a diagnosis of relapsing-remitting MS were phoned and asked about symptoms suggestive and COVID-19 using a semi-structured questionnaire. RESULTS: The mean age was 43.7 ± 9.65 years old, and 8 (80%) were females. The mean time since disease diagnosis was 17.30 ± 8.59 years, and all were patients with relapsing-remitting MS. Mean time from the last dose of Alemtuzumab was 9.80 ± 6.64 months, and last lymphocyte count was 760 ± 231 / μL. Two patients (20%) developed symptoms highly suggestive of COVID-19. Disease duration was 2 and 7 days. None patient required hospital admission. Patients with COVID-19 symptoms had longer clinical course of MS. Conversely, we did not find statistically significant differences regarding age, EDSS, last lymphocyte count, and months since the last dose of alemtuzumab administered between patients having or not symptoms of COVID-19. CONCLUSIONS: Our data suggest that patients receiving alemtuzumab showed very mild symptoms of COVID-19. We speculate that immune reconstitution induced by treatment may induce positive changes in the immune system in the defense against SARS-CoV2. Further research about alemtuzumab and their role in COVID-infection is necessary to confirm these preliminary findings.

Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study

Summary Background The outbreak of coronavirus-disease-2019 (COVID-19) has rapidly spread to many places outside Wuhan. Previous studies on COVID-19 mostly included older hospitalized-adults. Little information on infectivity among and characteristics of youngsters with COVID-19 is available. Methods A cluster of 22 close-contacts of a 22-year-old male (Patient-Index) including youngsters with laboratory-confirmed COVID-19 and hospitalized close-contacts testing negative for severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) in Anhui Province, China was prospectively-traced. Results Since January 23, 2020, we enrolled a cluster of eight youngsters with COVID-19 (median age [range], 22 [16–23] years; six males) originating from Patient-Index returning from Wuhan to Hefei on January 19. Patient-Index visited his 16-year-old female cousin in the evening on his return, and met 15 previous classmates in a get-together on January 21. He reported being totally asymptomatic and were described by all his contacts as healthy on January 19-21. His very first symptoms were itchy eyes and fever developed at noon and in the afternoon on January 22, respectively. Seven youngsters (his cousin and six classmates) became infected with COVID-19 after a-few-hour-contact with Patient-Index. None of the patients and contacts had visited Wuhan (except Patient-Index), or had any exposure to wet-markets, wild-animals, or medical-institutes within three months. For affected youngsters, the median incubation-period was 2 days (range, 1–4). The median serial-interval was 1 day (range, 0–4). Half or more of the eight COVID-19-infected youngsters had fever, cough, sputum production, nasal congestion, and fatigue on admission. All patients had mild conditions. Six patients developed pneumonia (all mild; one bilateral) on admission. As of February 20, four patients were discharged. Conclusions SARS-CoV-2-infection presented strong infectivity during the incubation-period with rapid transmission in this cluster of youngsters outside Wuhan. COVID-19 developed in these youngsters had fast onset and various nonspecific atypical manifestations, and were much milder than in older patients as previously reported.

Severe Covid-19.

BACKGROUND: Management of disease-modifying therapies in Multiple Sclerosis (MS) during the COVID-19 pandemic is a controversial issue. Alemtuzumab is an immunosuppressive drug that induces lymphocytes depletion. In this study, we aimed to evaluate the frequency and severity of COVID-19 in a case series of patients treated with alemtuzumab in our center. METHODS: Ten patients with a diagnosis of relapsing-remitting MS were phoned and asked about symptoms suggestive and COVID-19 using a semi-structured questionnaire. RESULTS: The mean age was 43.7 ± 9.65 years old, and 8 (80%) were females. The mean time since disease diagnosis was 17.30 ± 8.59 years, and all were patients with relapsing-remitting MS. Mean time from the last dose of Alemtuzumab was 9.80 ± 6.64 months, and last lymphocyte count was 760 ± 231 / µL. Two patients (20%) developed symptoms highly suggestive of COVID-19. Disease duration was 2 and 7 days. None patient required hospital admission. Patients with COVID-19 symptoms had longer clinical course of MS. Conversely, we did not find statistically significant differences regarding age, EDSS, last lymphocyte count, and months since the last dose of alemtuzumab administered between patients having or not symptoms of COVID-19. CONCLUSIONS: Our data suggest that patients receiving alemtuzumab showed very mild symptoms of COVID-19. We speculate that immune reconstitution induced by treatment may induce positive changes in the immune system in the defense against SARS-CoV2. Further research about alemtuzumab and their role in COVID-infection is necessary to confirm these preliminary findings.

Immune status could determine efficacy of COVID-19 therapies.

Proteome-wide analysis of differentially-expressed SARS-CoV-2 antibodies in early COVID-19 infection

Rapid and accurate tests that detect IgM and IgG antibodies to SARS-CoV-2 proteins are essential in slowing the spread of COVID-19 by identifying patients who are infected with COVID-19. Using a SARS-CoV-2 proteome microarray developed in our lab, we comprehensively profiled both IgM and IgG antibodies in forty patients with early-stage COVID-19, influenza, or non-influenza who had similar symptoms. The results revealed that the SARS-CoV-2 N protein is not an ideal biomarker for COVID-19 diagnosis because of its low immunogenicity, thus tests that rely on this marker alone will have a high false negative rate. Our data further suggest that the S protein subunit 1 receptor binding domain (S1-RBD) might be the optimal antigen for IgM antibody detection, while the S protein extracellular domain (S1+S2ECD) would be the optimal antigen for both IgM and IgG antibody detection. Notably, the combination of all IgM and IgG biomarkers can identify 87% and 73.3% COVID-19 patients, respectively. Finally, the COVID-19-specific antibodies are significantly correlated with the clinical indices of viral infection and acute myocardial injury (p≤0.05). Our data may help understand the function of anti-SARS-CoV-2 antibodies and improve serology tests for rapid COVID-19 screening.

Symptoms and immunoglobulin development in hospital staff exposed to a SARS-CoV-2 outbreak.

BACKGROUND Worldwide, the number of SARS-CoV-2 infections is increasing. Serological immunoglobulin tests may help to better understand the development of immune mechanisms against SARS-CoV-2 in COVID-19 cases and exposed but asymptomatic individuals. The aim of this study was to investigate exposure to SARS-CoV-2, symptoms and antibody responses in a large sample of health care workers following a COVID-19 outbreak. METHODS A COVID-19 outbreak among staff members of a major German children's and women's hospital was followed by massive RT-PCR SARS-CoV-2 tests and provided the opportunity to study symptoms, chains of infection and SARS-CoV-2 specific antibody responses (IgG and IgA) by ELISA. Study participants were classified as COVID-19 cases, and persons with close, moderate or no exposure to SARS-CoV-2 in the clinical setting, respectively. RESULTS Out of 201 study participants, 31 were COVID-19 cases. While most study participants experienced many symptoms indicative for SARS-CoV-2 infection, anosmia and coughing were remarkably more frequent in COVID-19 cases. Approximately 80% of COVID-19 cases developed some specific antibody response (IgA and IgG) approximately 3 weeks after onset of symptoms. Subjects in the non COVID-19 groups had also elevated IgG (1.8%) and IgA values (7.6%) irrespective of contact history with cases. CONCLUSION We found that a significant number of diseased did not develop relevant antibody responses three weeks after symptom onset. Our data also suggests that exposure to COVID-19 positive co-workers in a hospital setting is not leading to the development of measurable immune responses in a significant proportion of asymptomatic contact-persons.

Correlation between immune response and self-reported depression during convalescence from COVID-19

Self-reported depression has been observed in coronavirus disease-2019 (COVID-19) patients, infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), during discharge from the hospital. However, the cause of this self-reported depression during the convalescent period remains unclear. Here, we report the mental health status of 96 convalescent COVID-19 patients who were surveyed using an online questionnaire at the Shenzhen Samii Medical Center from March 2 to March 12, 2020 in Shenzhen, China. After obtaining their informed consent, we retrospectively analyzed the clinical characteristics of patients, including routine blood and biochemical data. The results suggested that patients with self-reported depression exhibited increased immune response, as indicated by increased white blood cell and neutrophil counts, as well as neutrophil-to-lymphocyte ratio. However, the mechanism linking self-reported depression to these cellular changes needs further study. In conclusion, self-reported depression occurred at an early stage in convalescent COVID-19 patients, and changes in immune function were apparent during short-term follow-up of these patients after discharge. Appropriate psychological interventions are necessary, and changes in immune function should be emphasized during long-term follow up of these patients.

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review

Importance: The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations: SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance: As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

Restoration of leukomonocyte counts is associated with viral clearance in COVID-19 hospitalized patients

Background: Viral clearance is one important indicator for the recovery of SARS-CoV-2 infected patients. Suboptimal T and B cell responses can delay viral clearance in MERS and SARS patients. The role of leukomonocytes in viral clearance of COVID-19 patients is not yet well defined.Methods: From January 26 to February 28, 2020, an observational study was launched at Zhongnan Hospital of Wuhan University, Wuhan, China. We enrolled 25 laboratory-confirmed COVID-19 patients, whose throat-swab specimens were tested positive for SARS-CoV-2 infection by qRT-PCR. We comprehensively analyzed clinical records, counts of lymphocyte subsets including CD3+, CD4+, CD8+ T cells, B cells and NK cells in the patients who successfully cleared SARS-CoV-2, and compared to those that failed to, after a standardized treatment of 8-14 days. Findings: In 25 enrolled COVID-19 patients, lymphopeniawas a common feature. After the treatment, 14 patients were tested negative for SARS-CoV-2. The patients that cleared the infection had restored the numbers of CD3+, CD4+, CD8+ T cellsand B cells as compared to the still viral RNA positive patients, while the recovered patients had a higher count of leukomonocytes. Conclusions: By comparison of leukomonocytes counts in COVID-19 patients at different stages of the disease, we found that CD3+, CD4+, CD8+ T cells and B cells appear to play important roles in viral clearance. The restoration of leukomonocytes counts from peripheral blood can be used as prognosis for the recovery of an COVID-19 infection. We propose that restoration of leukomonocytes counts can be added to the COVID-19 diagnostic guidanceas a criterion for releasing and discharging patients.

COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role?

BACKGROUND: Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19. METHODS: In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19. RESULTS: Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred. DISCUSSION: This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.

Why the immune system fails to mount an adaptive immune response to a COVID-19 infection

Can Stem Cells Beat COVID-19: Advancing Stem Cells and Extracellular Vesicles Toward Mainstream Medicine for Lung Injuries Associated With SARS-CoV-2 Infections

A number of medicines are currently under investigation for the treatment of COVID-19 disease including anti-viral, anti-malarial, and anti-inflammatory agents. While these treatments can improve patient's recovery and survival, these therapeutic strategies do not lead to unequivocal restoration of the lung damage inflicted by this disease. Stem cell therapies and, more recently, their secreted extracellular vesicles (EVs), are emerging as new promising treatments, which could attenuate inflammation but also regenerate the lung damage caused by COVID-19. Stem cells exert their immunomodulatory, anti-oxidant, and reparative therapeutic effects likely through their EVs, and therefore, could be beneficial, alone or in combination with other therapeutic agents, in people with COVID-19. In this review article, we outline the mechanisms of cytokine storm and lung damage caused by SARS-CoV-2 virus leading to COVID-19 disease and how mesenchymal stem cells (MSCs) and their secreted EVs can be utilized to tackle this damage by harnessing their regenerative properties, which gives them potential enhanced clinical utility compared to other investigated pharmacological treatments. There are currently 17 clinical trials evaluating the therapeutic potential of MSCs for the treatment of COVID-19, the majority of which are administered intravenously with only one clinical trial testing MSC-derived exosomes via inhalation route. While we wait for the outcomes from these trials to be reported, here we emphasize opportunities and risks associated with these therapies, as well as delineate the major roadblocks to progressing these promising curative therapies toward mainstream treatment for COVID-19.

Single-cell RNA-seq and V(D)J profiling of immune cells in COVID-19 patients

Coronavirus disease 2019 (COVID-19) has caused over 220,000 deaths so far and is still an ongoing global health problem. However, the immunopathological changes of key types of immune cells during and after virus infection remain unclear. Here, we enriched CD3+ and CD19+ lymphocytes from peripheral blood mononuclear cells of COVID-19 patients (severe patients and recovered patients at early or late stages) and healthy people (SARS-CoV-2 negative) and revealed transcriptional profiles and changes in these lymphocytes by comprehensive single-cell transcriptome and V(D)J recombination analyses. We found that although the T lymphocytes were decreased in the blood of patients with virus infection, the remaining T cells still highly expressed inflammatory genes and persisted for a while after recovery in patients. We also observed the potential transition from effector CD8 T cells to central memory T cells in recovered patients at the late stage. Among B lymphocytes, we analyzed the expansion trajectory of a subtype of plasma cells in severe COVID-19 patients and traced the source as atypical memory B cells (AMBCs). Additional BCR and TCR analyses revealed a high level of clonal expansion in patients with severe COVID-19, especially of B lymphocytes, and the clonally expanded B cells highly expressed genes related to inflammatory responses and lymphocyte activation. V-J gene usage and clonal types of higher frequency in COVID-19 patients were also summarized. Taken together, our results provide crucial insights into the immune response against patients with severe COVID-19 and recovered patients and valuable information for the development of vaccines and therapeutic strategies.

Clinical, immunological and virological characterization of COVID-19 patients that test re-positive for SARS-CoV-2 by RT-PCR

Background COVID-19 pandemic is underway. Some COVID-19 cases re-tested positive for SARS-CoV-2 RNA after discharge raising the public concern on their infectivity. Characterization of re-positive cases are urgently needed for designing intervention strategies. Methods Clinical data were obtained through Guangdong COVID-19 surveillance network. Neutralization antibody titre was determined using a microneutralization assay. Potential infectivity of clinical samples was evaluated after the cell inoculation. SARS-CoV-2 RNA was detected using three different RT-PCR kits and multiplex PCR with nanopore sequencing. Results Among 619 discharged COVID-19 cases, 87 were re-tested as SARS-CoV-2 positive in circumstance of social isolation. All re-positive cases had mild or moderate symptoms in initial diagnosis and a younger age distribution (mean, 30.4). Re-positive cases (n=59) exhibited similar neutralization antibodies (NAbs) titre distributions to other COVID-19 cases (n=150) parallel-tested in this study. No infective viral strain could be obtained by culture and none full-length viral genomes could be sequenced for all re-positive cases. Conclusions Re-positive SARS-CoV-2 was not caused by the secondary infection and was identified in around 14% of discharged cases. A robust Nabs response and a potential virus genome degradation were detected from nearly all re-positive cases suggesting a lower transmission risk, especially through a respiratory route.

Current studies of convalescent plasma therapy for COVID-19 may underestimate risk of antibody-dependent enhancement

Explanation for COVID-19 infection neurological damage and reactivations

Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review.

The need for proven disease-specific treatments for the novel pandemic coronavirus SARS-CoV-2 necessitates a worldwide search for therapeutic options. Since the SARS-CoV-2 virus shares extensive homology with SARS-CoV and MERS-CoV, effective therapies for SARS-CoV and MERS-CoV may also have therapeutic potential for the current COVID-19 outbreak. To identify therapeutics that might be repositioned for treatment of the SARS-CoV-2 disease COVID-19, we strategically reviewed the literature to identify existing therapeutics with evidence of efficacy for the treatment of the three coronaviruses that cause severe respiratory illness (SARS-CoV, MERS-CoV, and SARS-CoV-2). Mechanistic and in vitro analyses suggest multiple promising therapeutic options with potential for repurposing to treat patients with COVID-19. Therapeutics with particularly high potential efficacy for repurposing include camostat mesylate, remdesivir, favipiravir, tocilizumab, baricitinib, convalescent plasma, and humanized monoclonal antibodies. Camostat mesylate has shown therapeutic potential, likely by preventing viral entry into epithelial cells. In early research, the targeted antivirals remdesivir and favipiravir appear to benefit patients by decreasing viral replication; clinical trials suggest that remdesivir speeds recovery from COVID-19. Tocilizumab and baricitinib appear to improve mortality by preventing a severe cytokine storm. Convalescent plasma and humanized monoclonal antibodies offer passive immunity and decreased recovery time. This review highlights potential therapeutic options that may be repurposed to treat COVID-19 and suggests opportunities for further research.

Intrafamilial Exposure to SARS-CoV-2 Induces Cellular Immune Response without Seroconversion

Background. In the background of the current COVID-19 pandemic, serological tests are being used to assess past infection and immunity against SARS-CoV-2. This knowledge is paramount to determine the transmission dynamics of SARS-CoV-2 through the post pandemic period. Several individuals belonging to households with an index COVID-19 patient, reported symptoms of COVID-19 but discrepant serology results. Methods. Here we investigated the humoral and cellular immune responses against SARS-CoV-2 in seven families, including nine index patients and eight contacts, who had evidence of serological discordances within the households. Ten unexposed healthy donors were enrolled as controls. Results. All index patients recovered from a mild COVID-19. They all developed anti-SARS-CoV-2 antibodies and a significant T cell response detectable up to 69 days after symptom onset. Six of the eight contacts reported COVID-19 symptoms within 1 to 7 days after the index patients but all were SARS-CoV-2 seronegative. Six out of eight contacts developed a SARS-CoV-2-specific T cell response against structural and/or accessory proteins that lasts up to 80 days post symptom onset suggesting a past SARS-CoV-2 infection. Conclusion. Exposure to SARS-CoV-2 can induce virus-specific T cell responses without seroconversion. T cell responses may be more sensitive indicators of SARS-Co-V-2 exposure than antibodies. Our results indicate that epidemiological data relying only on the detection of SARS-CoV-2 antibodies may lead to a substantial underestimation of prior exposure to the virus

Systemically comparing host immunity between survived and deceased COVID-19 patients

Immune status could determine efficacy of COVID-19 therapies

Characterization of the Inflammatory Response to Severe COVID-19 Illness.

RATIONALE Coronavirus disease 2019 (COVID-19) is a global threat to health. Its inflammatory characteristics are incompletely understood. OBJECTIVES To define the cytokine profile of COVID-19, and to identify evidence of immunometabolic alterations in those with severe illness. METHODS Levels of interleukin (IL)-1β, IL-6, IL-8, IL-10 and soluble TNF receptor 1 (sTNFR1) were assessed in plasma from healthy volunteers, hospitalized-but-stable COVID-19 patients (COVIDstable), COVID-19 patients requiring intensive care unit (ICU) admission (COVIDICU) and individuals with severe community-acquired pneumonia requiring ICU support (CAPICU). Immunometabolic markers were measured in circulating neutrophils from patients with severe COVID-19. The acute phase response of alpha-1 antitrypsin (AAT) to COVID-19 was also evaluated. MAIN RESULTS IL-1β, IL-6, IL-8 and sTNFR1 were all increased in patients with COVID-19. COVIDICU patients could be clearly differentiated from COVIDstable, and demonstrated higher levels of IL-1β, IL-6 and sTNFR1 - but lower IL-10 - than CAPICU. COVID-19 neutrophils displayed altered immunometabolism, with increased cytosolic PKM2, phosphorylated PKM2, HIF-1α and lactate. The production and sialylation of AAT increased in COVID-19, but this anti-inflammatory response was overwhelmed in severe illness, with the IL-6:AAT ratio markedly higher in patients requiring ICU admission (P<0.0001). In critically unwell COVID-19 patients, increases in IL-6:AAT predicted prolonged ICU stay and mortality, while improvement in IL-6:AAT was associated with clinical resolution (P<0.0001). CONCLUSIONS The COVID-19 cytokinemia is distinct from that of other types of pneumonia leading to organ failure and ICU need. Neutrophils undergo immunometabolic reprogramming in severe COVID-19 illness. Cytokine ratios may predict outcomes in this population. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Targeted Immunosuppression Distinguishes COVID-19 from Influenza in Moderate and Severe Disease

Coronavirus disease 2019 (COVID-19) is characterized by a high incidence of acute respiratory failure. The underlying immunopathology of that failure and how it compares to other causes of severe respiratory distress, such as influenza virus infection, are not fully understood. Here we addressed this by developing a prospective observational cohort of COVID-19 and influenza subjects with varying degrees of disease severity and assessing the quality and magnitude of their immune responses at the cellular and protein level. Additionally, we performed single-cell RNA transcriptional profiling of peripheral blood mononuclear cells from select subjects. The cohort consists of 79 COVID-19 subjects, 26 influenza subjects, and 15 control subjects, including 35 COVID-19 and 7 influenza subjects with acute respiratory failure. While COVID-19 subjects exhibited largely equivalent or greater activated lymphocyte counts compared to influenza subjects, they had fewer monocytes and lower surface HLA-class II expression on monocytes compared to influenza subjects and controls. At least two distinct immune profiles were observed by cytokine levels in severe COVID-19 patients: 3 of 71 patients were characterized by extreme inflammation, with greater than or equal to ~50% of the 35 cytokines measured greater than 2 standard deviations from the mean level of other severe patients (both influenza and COVID-19); the other immune profile, which characterized 68 of 71 subjects, had a mixed inflammatory signature, where 28 of 35 cytokines in COVID-19 patients had lower mean cytokine levels, though not all were statistically significant. Only 2 cytokines were higher in COVID-19 subjects compared to influenza subjects (IL-6 and IL-8). Influenza and COVID-19 patients could be distinguished statistically based on cytokine module expression, particularly after controlling for the significant effects of age on cytokine expression, but again with lower levels of most cytokines in COVID-19 subjects. Further, high circulating levels of IL-1RA and IL-6 were associated with increased odds of intubation in the combined influenza and COVID-19 cohort [OR = 3.93 and 4.30, respectively] as well as among only COVID-19 patients. Single cell transcriptional profiling of COVID-19 and influenza subjects with respiratory failure identified profound suppression in type I and type II interferon signaling in COVID-19 patients across multiple clusters. In contrast, COVID-19 cell clusters were enriched for alterations in metabolic, stress, and apoptotic pathways. These alterations were consistent with an increased glucocorticoid response in COVID-19 patients compared to influenza. When considered across the spectrum of innate and adaptive immune profiles, the immune pathologies underlying severe influenza and COVID-19 are substantially distinct. The majority of COVID-19 patients with acute respiratory failure do not have a cytokine storm phenotype but instead exhibit profound type I and type II IFN immunosuppression when compared to patients with acute influenza. Upregulation of a small number of inflammatory mediators, including IL-6, predicts acute respiratory failure in both COVID-19 and influenza patients.

Clinical outcomes and immunologic characteristics of Covid-19 in people with HIV

We performed a retrospective study of Covid-19 in people with HIV (PWH). PWH with Covid-19 demonstrated severe lymphopenia and decreased CD4+ T cell counts. Levels of inflammatory markers, including C-reactive protein, fibrinogen, D-dimer, interleukin-6, interleukin-8, and TNF-alpha were commonly elevated. In all, 19/72 hospitalized individuals (26.4%) died and 53 (73.6%) recovered. PWH who died had higher levels of inflammatory markers and more severe lymphopenia than those who recovered. These findings suggest that PWH remain at risk for severe manifestations of Covid-19 despite ART and that those with increased markers of inflammation and immune dysregulation are at risk for worse outcomes.

Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review.

Importance The coronavirus disease 2019 (COVID-19) pandemic, due to the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a worldwide sudden and substantial increase in hospitalizations for pneumonia with multiorgan disease. This review discusses current evidence regarding the pathophysiology, transmission, diagnosis, and management of COVID-19. Observations SARS-CoV-2 is spread primarily via respiratory droplets during close face-to-face contact. Infection can be spread by asymptomatic, presymptomatic, and symptomatic carriers. The average time from exposure to symptom onset is 5 days, and 97.5% of people who develop symptoms do so within 11.5 days. The most common symptoms are fever, dry cough, and shortness of breath. Radiographic and laboratory abnormalities, such as lymphopenia and elevated lactate dehydrogenase, are common, but nonspecific. Diagnosis is made by detection of SARS-CoV-2 via reverse transcription polymerase chain reaction testing, although false-negative test results may occur in up to 20% to 67% of patients; however, this is dependent on the quality and timing of testing. Manifestations of COVID-19 include asymptomatic carriers and fulminant disease characterized by sepsis and acute respiratory failure. Approximately 5% of patients with COVID-19, and 20% of those hospitalized, experience severe symptoms necessitating intensive care. More than 75% of patients hospitalized with COVID-19 require supplemental oxygen. Treatment for individuals with COVID-19 includes best practices for supportive management of acute hypoxic respiratory failure. Emerging data indicate that dexamethasone therapy reduces 28-day mortality in patients requiring supplemental oxygen compared with usual care (21.6% vs 24.6%; age-adjusted rate ratio, 0.83 [95% CI, 0.74-0.92]) and that remdesivir improves time to recovery (hospital discharge or no supplemental oxygen requirement) from 15 to 11 days. In a randomized trial of 103 patients with COVID-19, convalescent plasma did not shorten time to recovery. Ongoing trials are testing antiviral therapies, immune modulators, and anticoagulants. The case-fatality rate for COVID-19 varies markedly by age, ranging from 0.3 deaths per 1000 cases among patients aged 5 to 17 years to 304.9 deaths per 1000 cases among patients aged 85 years or older in the US. Among patients hospitalized in the intensive care unit, the case fatality is up to 40%. At least 120 SARS-CoV-2 vaccines are under development. Until an effective vaccine is available, the primary methods to reduce spread are face masks, social distancing, and contact tracing. Monoclonal antibodies and hyperimmune globulin may provide additional preventive strategies. Conclusions and Relevance As of July 1, 2020, more than 10 million people worldwide had been infected with SARS-CoV-2. Many aspects of transmission, infection, and treatment remain unclear. Advances in prevention and effective management of COVID-19 will require basic and clinical investigation and public health and clinical interventions.

Convalescent plasma, an apheresis research project targeting and motivating the fully recovered COVID 19 patients: A rousing message of clinical benefit to both donors and recipients alike

This concise manuscript aims to make suggestions for a small step forward in both preventative and therapeutic measures against the Coronavirus disease 2019 (COVID 19) pandemic. This targeted strategy consists of using fully recovered COVID 19 Heroes, that is, brave volunteers, as the source of antibodies in plasma collected by plasmapheresis or affinity column- derived antibodies, both are sterilised and pathogen inactivated for substitution therapy for use in those populations in need of antibody. This include for use in critically ill COVID 19 patients and as a preventative measure, in those at potential risk of infection as no vaccine is yet available. This would be a small step forward, while we are waiting to produce an effective, validated vaccine and witnessing increasing demands for testing and self-isolation which are the two most effective current strategies. In line with this concept, some methodological aspects of the use of the UVC sterilization of FFP/ cryoprecipitate-depleted FFP or immunoglobulins containing neutralizing antibodies for clinical use against COVID-19 are highlighted. The plasmapheresis procedure is, of course, particularly targeted to male donors, who consist of about 75 % of the COVID-19 population and who are able to undergo multiple double, or even triple plasmapheresis procedures. Moreover, as some of these donors have already been in an induced-hypercoagulable state and prone to thrombosis and DVT, this strategy will be partially aimed at improving their health with the use of citrate based anticoagulants and removal of high molecular weight viscous components which contribute to the untoward clinical effects of DVT. Repeated targeted plasmapheresis or plasma exchange of selected COVID-19 positive individuals would undoubtedly lower their state of hypercoagulability and normalize their hypercoagulability. The recipients of such a derived FFP-product would benefit from the two to 3 doses of viral inactivated antibodies, which could neutralize the viral antigens even at very low concentration if present in the early stage. So, this practice would be a double-edged sword with benefits for both donors and recipients.

Convalescent Plasma, an Apheresis Research Project Targeting and Motivating the Fully Recovered COVID 19 Patients: A Rousing Message of Clinical Benefit To Both Donors and Recipients Alike

Immune Status of COVID-19 Patients with Reference to SARS and MERS

During this global pandemic of COVID-19 infection, it became well known that morbidity and mortality is especially high at the extreme of life especially in certain racial or ethnic groups like Americans and Africans This is presumed due to low immunity associated with other comorbid conditions like diabetes, hypertension, cardiovascular disease, obesity and metabolic syndrome But the information available on the immune status of COVID-19 patients is limited Attempts must be made to enhance our understanding of the immune status of COVID-19 patients by revisiting our knowledge on the immune mechanisms of already known coronaviruses such as SARS-CoV and MERS-CoV Early elevation of the serum levels of pro-inflammatory cytokines observed in SARS and MERS infection suggests a possible same type of cytokine storm-mediated lung damage in COVID-19 patients too Dysregulation of interferon-1 response and downstream cascade in initial innate immune response at virus entry point has been related to lethal pneumonia in COVID-19 patients Adaptive response of increased CD8+ levels in COVID-19 patients seems to be useful in mild cases where it causes deteriorating effects in progressed severe disease patients resulting in destruction of type 2 pneumocytes hence inability to regenerate the alveolar epithelium A phenomenon called cytokine storm activates violent immunological reactions in the lung tissue resulting in ARDS followed by multiple organ system damages in COVID-19 patients Several immune evading mechanisms are thought to be employed by severe respiratory syndrome virus-2 (SARS-CoV-2) that might have resulted in its extremely increased contagiousness probably related with its frequent RNA mutations Failure to develop adequate virus limiting immune reactions by some cured patients warrant monitoring of all recovered patients This rapid mini review is aimed to enhance our knowledge of the immune status of COVID-19 infected patients with reference to SARS-CoV and MERS-CoV

COVID-19 pandemic and health worker stress: The mediating effect of emotional regulation

Background/Introduction. Psychological and physical well-being of health personnel has been significantly affected by COVID-19. Work overload and continuous exposure to positive COVID-19 cases have caused them fatigue, stress, anxiety, insomnia and other detriments. This research aims: 1) to analyze whether the use of cognitive reevaluation and emotional suppression strategies decreases and increases, respectively, stress levels of health personnel, 2) to quantify the impact of contact with patients with COVID-19 on stress s level of medical staff. Method. Emotion regulation strategies and stress level were evaluated in 155 Dominican physicians by means of psychological tests with adequate levels of reliability. In addition, a questionnaire created by the researchers quantified the impact that contact with those infected had on their stress levels. Results. Contact with patients with COVID-19 predicts increased use of emotion suppression strategies, although is not associated with the use of cognitive reevaluation. These findings lead to an even greater increase in stress on health care providers. Conclusions. Contextual contingencies demand immediate responses and may not allow health personnel to use cognitive re-evaluation strategies, leaning more towards emotion suppression. However, findings regarding high levels of stress require the implementation of intervention programs focused on the promotion of more functional emotion regulation strategies. Such programs may reduce current stress and prevent post-traumatic symptoms.

Rapid asymptomatic transmission of COVID-19 during the incubation period demonstrating strong infectivity in a cluster of youngsters aged 16-23 years outside Wuhan and characteristics of young patients with COVID-19: A prospective contact-tracing study

BACKGROUND: The outbreak of coronavirus-disease-2019 (COVID-19) has rapidly spread to many places outside Wuhan. Previous studies on COVID-19 mostly included older hospitalized-adults. Little information on infectivity among and characteristics of youngsters with COVID-19 is available. METHODS: A cluster of 22 close-contacts of a 22-year-old male (Patient-Index) including youngsters with laboratory-confirmed COVID-19 and hospitalized close-contacts testing negative for severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2) in Anhui Province, China was prospectively-traced. RESULTS: Since January 23, 2020, we enrolled a cluster of eight youngsters with COVID-19 (median age [range], 22 [16-23] years; six males) originating from Patient-Index returning from Wuhan to Hefei on January 19. Patient-Index visited his 16-year-old female cousin in the evening on his return, and met 15 previous classmates in a get-together on January 21. He reported being totally asymptomatic and were described by all his contacts as healthy on January 19-21. His very first symptoms were itchy eyes and fever developed at noon and in the afternoon on January 22, respectively. Seven youngsters (his cousin and six classmates) became infected with COVID-19 after a-few-hour-contact with Patient-Index. None of the patients and contacts had visited Wuhan (except Patient-Index), or had any exposure to wet-markets, wild-animals, or medical-institutes within three months. For affected youngsters, the median incubation-period was 2 days (range, 1-4). The median serial-interval was 1 day (range, 0-4). Half or more of the eight COVID-19-infected youngsters had fever, cough, sputum production, nasal congestion, and fatigue on admission. All patients had mild conditions. Six patients developed pneumonia (all mild; one bilateral) on admission. As of February 20, four patients were discharged. CONCLUSIONS: SARS-CoV-2-infection presented strong infectivity during the incubation-period with rapid transmission in this cluster of youngsters outside Wuhan. COVID-19 developed in these youngsters had fast onset and various nonspecific atypical manifestations, and were much milder than in older patients as previously reported.

Surviving the trauma of COVID-19.

In-depth phenotyping of human peripheral blood mononuclear cells in convalescent COVID-19 patients following a mild versus severe disease course

Background: Covid-19, the disease caused by infection with SARS-CoV-2, has developed to a pandemic causing more than 239, 000 deaths worldwide as of 6th May according to the World Health Organization (WHO). It presents with a highly variable disease course ranging from a large proportion of asymptomatic cases to severe respiratory failure in 17-29% of cases even in the absence of apparent comorbidities 1, 2. This implies a diverse host immune response to SARS-CoV-2. The immunological characteristics underlying these divergent disease courses, however, still remain elusive. While insights into abrogations of innate immunity begin to emerge, adaptive immune responses towards SARS-CoV-2 are poorly investigated, although they serve as immune signatures of protection and vaccine responses. We therefore set out to characterize immune signatures of convalescent COVID-19 patients stratified according to their disease severity. Methods: We performed high-dimensional flow cytometric profiling of peripheral blood mononuclear cells of convalescent COVID-19 patients who we stratified according to their disease severity by a physician-assisted questionnaire based assessment of COVID-19 symptoms. Results: Surprisingly, we did not observe any difference in the relative proportions of any major immune cell type in convalescent patients presenting with different severity of COVID-19 disease except for a reduction in monocytes. The frequency of Tnaive T cells was significantly reduced in CD4+ and CD8+ T cells, whereas other T cell differentiations states (TCM, TEM, TEMRA) remained relatively unaffected by COVID-19 severity as assessed approximately two weeks after infection. Conclusions In our COVID-19 patient cohort, which is characterized by absence of comorbidities and therapeutic interventions other than symptomatic antipyretics, the immunophenotype is similar irrespective of a highly variable disease severity. Convalescence is therefore associated with a rather uniform immune signature. Abrogations, which were previously identified in the innate and adaptive immune compartment of COVID-19 patients should be scrutinized for direct associations with a preconditioned immune system shaped and made vulnerable for SARS-CoV-2 by preexisting comorbidities.

Expansion of SARS-CoV-2-specific Antibody-secreting Cells and Generation of Neutralizing Antibodies in Hospitalized COVID-19 Patients

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and has since become a global pandemic. Pathogen-specific antibodies are typically a major predictor of protective immunity, yet B cell and antibody responses during COVID-19 are not fully understood. Here, we analyzed antibody-secreting cell (ASC) and antibody responses in twenty hospitalized COVID-19 patients. The patients exhibited typical symptoms of COVID-19, and presented with reduced lymphocyte numbers and increased T cell and B cell activation. Importantly, we detected an expansion of SARS-CoV-2 nucleocapsid protein-specific ASCs in all twenty COVID-19 patients using a multicolor FluoroSpot assay. Out of the 20 patients, 16 had developed SARS-CoV-2-neutralizing antibodies by the time of inclusion in the study. SARS-CoV-2-specific IgA, IgG and IgM antibody levels positively correlated with SARS-CoV-2-neutralizing antibody titers, suggesting that SARS-CoV-2-specific antibody levels may reflect the titers of neutralizing antibodies in COVID-19 patients during the acute phase of infection. Lastly, we showed that interleukin 6 (IL-6) and C-reactive protein (CRP) concentrations were higher in serum of patients who were hospitalized for longer, supporting the recent observations that IL-6 and CRP could be used to predict COVID-19 severity. Altogether, this study constitutes a detailed description of clinical and immunological parameters in twenty COVID-19 patients, with a focus on B cell and antibody responses, and provides tools to study immune responses to SARS-CoV-2 infection and vaccination.

Symptoms and immunoglobulin development in hospital staff exposed to a SARS-CoV-2 outbreak

BACKGROUND: Worldwide, the number of SARS-CoV-2 infections is increasing. Serological immunoglobulin tests may help to better understand the development of immune mechanisms against SARS-CoV-2 in COVID-19 cases and exposed but asymptomatic individuals. The aim of this study was to investigate exposure to SARS-CoV-2, symptoms, and antibody responses in a large sample of healthcare workers following a COVID-19 outbreak. METHODS: A COVID-19 outbreak among staff members of a major German children's and women's hospital was followed by massive RT-PCR SARS-CoV-2 tests and provided the opportunity to study symptoms, chains of infection, and SARS-CoV-2-specific antibody responses (IgG and IgA) by ELISA. Study participants were classified as COVID-19 cases, and persons with close, moderate, or no exposure to SARS-CoV-2 in the clinical setting, respectively. RESULTS: Out of 201 study participants, 31 were COVID-19 cases. While most study participants experienced many symptoms indicative for SARS-CoV-2 infection, anosmia and coughing were remarkably more frequent in COVID-19 cases. Approximately 80% of COVID-19 cases developed some specific antibody response (IgA and IgG) approximately 3 weeks after onset of symptoms. Subjects in the non-COVID-19 groups had also elevated IgG (1.8%) and IgA values (7.6%) irrespective of contact history with cases. CONCLUSION: We found that a significant number of diseased did not develop relevant antibody responses three weeks after symptom onset. Our data also suggest that exposure to COVID-19 positive co-workers in a hospital setting is not leading to the development of measurable immune responses in a significant proportion of asymptomatic contact persons.

Differences in antibody kinetics and functionality between severe and mild SARS-CoV-2 infections.

We determined and compared the humoral immune response in severe, hospitalized and mild, non-hospitalized COVID-19 patients. Severe patients (n=38) develop a robust antibody response to SARS-CoV-2, including IgG and IgA antibodies. The geometric mean 50% virus neutralization titer is 1:240. SARS-CoV-2 infected hospital personnel (n=24), who developed mild symptoms necessitating leave of absence, self-isolation, but not hospitalization, 75 % develop antibodies, but with low/absent virus neutralization (60% < 1:20). While severe COVID-19 patients develop a strong antibody response, mild SARS-CoV-2 infections induce a modest antibody response. Long term monitoring will show whether these responses predict protection against future infections.

Thyroid function analysis in 50 patients with COVID-19: a retrospective study.

BACKGROUND Since the outbreak of the coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019, it has affected over 200 countries, areas, or territories in six continents. At present, whether COVID-19 has an effect on thyroid function is unclear. The aim of this study was to evaluate thyroid function in patients with COVID-19. METHODS Clinical manifestations, laboratory results, and chest computed tomography scans were retrospectively reviewed for 50 patients with laboratory-confirmed COVID-19 without a history of thyroid disease who underwent thyroid function testing during their course of COVID-19 infection and after recovery. They were admitted to the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China, between January and March 2020. Healthy participants who underwent routine physical checkups and non-COVID-19 pneumonia patients with a similar degree of severity during the same period were included in the study as the control group. Thyroid hormone and thyroid stimulating hormone (TSH) levels were analyzed and compared between the COVID-19 and control groups. RESULTS TSH lower than the normal range was present in 56% (28/50) of the patients with COVID-19. The levels of TSH and serum total triiodothyronine (TT3) of the patients with COVID-19 were significantly lower than those of the healthy control group and non-COVID-19 pneumonia patients. The more severe the COVID-19, the lower the TSH and TT3 levels were, with statistical significance (p < 0.001). The degree of the decreases in TSH and TT3 levels was positive correlated with the severity of the disease. The total thyroxine (TT4) level of the patients with COVID-19 was not significantly different from the control group. All the patients did not receive thyroid hormone replacement therapy. After recovery, no significant differences in TSH, TT3, TT4, free triiodothyronine (FT3), and free thyroxine (FT4) levels were found between the COVID-19 and control groups. CONCLUSIONS The changes in serum TSH and TT3 may be important manifestations of the courses of COVID-19.

Infection with SARS-CoV-2 causes abnormal laboratory results of multiple organs in patients

Aim: To evaluate the clinical value of abnormal laboratory results of multiple organs in patients with coronavirus disease 2019 (COVID-2019) and to help clinicians perform correct treatment. Results: Elevated neutrophil-to-LYM ratio (NLR), D-dimer(D-D), interleukin (IL)-6, IL-10, IL-2, interferon-Y, and age were significantly associated with the severity of illness. However, significant and sustained decreases were observed in the LYM subset (p<0.05). D-D, T cell counts, and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of mild cases. Second, D-D increased from 0.5 to 8, and the risk ratio increased from 2.75 to 55, eventually leading to disseminated intravascular coagulation. Moreover, the acute renal function damage occurred earlier than abnormal heart and liver functions (p<0.05). Conclusions: The degrees of lymphopenia and proinflammatory cytokine storm were higher in severe COVID-19 patients than in mild cases. The degree was associated with the disease severity. Advanced age, NLR, D-D, and cytokine levels may serve as useful prognostic factors for the early identification of severe COVID-19 cases. Methods: Peripheral blood samples were collected from 93 confirmed COVID-19 patients. The samples were examined for lymphocyte (LYM) subsets by flow cytometry and cytokine profiles by specific immunoassays. The receiver operating characteristic curve was applied to determine the best diagnostic thresholds for laboratory results, and principal component analysis was used to screen the major risk factors. The prognostic values were assessed using the Kaplan–Meier curve and univariate and multivariate COX regression models.

Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review

How do we decide to de-isolate COVID-19 patients?

AIM: To evaluate the clinical value of abnormal laboratory results of multiple organs in patients with coronavirus disease 2019 (COVID-2019) and to help clinicians perform correct treatment. RESULTS: Elevated neutrophil-to-LYM ratio (NLR), D-dimer(D-D), interleukin (IL)-6, IL-10, IL-2, interferon-Y, and age were significantly associated with the severity of illness. However, significant and sustained decreases were observed in the LYM subset (p<0.05). D-D, T cell counts, and cytokine levels in severe COVID-19 patients who survived the disease gradually recovered at later time points to levels that were comparable to those of mild cases. Second, D-D increased from 0.5 to 8, and the risk ratio increased from 2.75 to 55, eventually leading to disseminated intravascular coagulation. Moreover, the acute renal function damage occurred earlier than abnormal heart and liver functions (p<0.05). CONCLUSIONS: The degrees of lymphopenia and proinflammatory cytokine storm were higher in severe COVID-19 patients than in mild cases. The degree was associated with the disease severity. Advanced age, NLR, D-D, and cytokine levels may serve as useful prognostic factors for the early identification of severe COVID-19 cases. METHODS: Peripheral blood samples were collected from 93 confirmed COVID-19 patients. The samples were examined for lymphocyte (LYM) subsets by flow cytometry and cytokine profiles by specific immunoassays. The receiver operating characteristic curve was applied to determine the best diagnostic thresholds for laboratory results, and principal component analysis was used to screen the major risk factors. The prognostic values were assessed using the Kaplan-Meier curve and univariate and multivariate COX regression models.

COVID-19 with rheumatic diseases: a report of 5 cases

The coronavirus disease 2019 (COVID-19), the result of an infection with the new virus, SARS-CoV-2, is rapidly spreading worldwide. It is largely unknown whether the occurrence of COVID-19 in patients with rheumatic immune diseases has some specific manifestations, or makes them more prone to rapidly progress into severe COVID-19. In this case report, we describe the clinical features of 5 rheumatic immune disease patients with the concomitant presence of COVID-19. Amongst these patients, 4 had rheumatoid arthritis (RA) and 1 had systemic sclerosis (SSc). Two patients had a history of close contact with a COVID-19 patient. The age of the patients ranged between 51 and 79 years. Fever (80%), cough (80%), dyspnea (40%), and fatigue (20%) were the most common presenting symptoms. Laboratory investigations revealed leukopenia and lymphopenia in 2 patients. In all the patients, chest computerized tomography (CT) revealed patchy ground glass opacities in the lungs. During the hospital stay, the condition of two patients remained the same (i.e., mild COVID-19), two patients progressed to the severe COVID-19, and one patient worsened to the critically ill COVID-19. These patients were treated with antiviral agents for COVID-19, antibiotics for secondary bacterial infections, and immunomodulatory agents for rheumatic immune diseases. All the patients responded well, were cured of COVID-19, and subsequently discharged.

Real estimates of mortality following COVID-19 infection

Immunotherapies for COVID-19: Restoring the immunity could be the priority

Immunotherapies for COVID-19: restoring the immunity could be the priority

COVID-19 Is Distinct From SARS-CoV-2-Negative Community-Acquired Pneumonia

Background: Corona virus disease (COVID-19) is an infectious respiratory disease that has spread rapidly across the world. Many studies have already evaluated the clinical features of COVID-19, but how it compares with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-negative community-acquired pneumonia (SN-CAP) is still unclear. Moreover, COVID-19 mortality is correlated with disease severity, but indicators for severity grading have not been specified. We aimed to analyze the clinical characteristics of COVID-19 in comparison with SN-CAP and find indicators for disease severity in COVID-19. Methods: Patients diagnosed with COVID-19 and SN-CAP were enrolled. Clinical, radiological, and laboratory data were analyzed. Results: The numbers of COVID-19 and SN-CAP patients enrolled were 304 and 138, respectively. The age of the patients was not significantly different between the groups. Compared with SN-CAP, COVID-19 patients had more symptoms of fever and dyspnea; and showed significant difference in blood count results. Computed tomography (CT) imaging of COVID-19 patients showed patchy ground-glass opacities that correlated with disease severity, whereas the CT imaging of SN-CAP patients showed patchy high-density shadows. COVID-19 patients were classified into moderate, severe, and critically severe groups. The severe and critically severe groups had elevated levels of white blood cells (WBC), neutrophils, platelets, C-reaction protein (CRP), lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), troponin-I, creatinine, and blood urea nitrogen (BUN). However, they had decreased levels of lymphocytes, lymphocyte ratio, and albumin. Compared with the younger patients, the older COVID-19 individuals had more chronic diseases and significantly elevated levels of WBC, neutrophil, and CRP levels. Conclusion: SN-CAP showed more inflammatory reaction than COVID-19. Old people with chronic diseases are more susceptible to COVID-19 and have a high likelihood of developing severe and critically severe infection. Levels of WBC, lymphocytes, neutrophils, CRP, NLR, PLR, troponin-I, creatinine, and BUN are important indicators for severity grading in COVID-19.

Follow-up studies in COVID-19 recovered patients - is it mandatory?

Abstract The novel Coronavirus disease 2019 (COVID-19) is an illness caused due to Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The World Health Organization (WHO) has declared this outbreak a global health emergency and as on April 24, 2020, it has spread to 213 countries, with 25,91,015 confirmed cases and 742,855 cases have been recovered from COVID-19. In this dreadful situation our team has already published an article in the Science of the Total Environment, which elaborates the various aspects of the SARS-CoV-2 infection. In this situation, it is imperative to understand the possible outcome of COVID-19 recovered patients and determine if they have any other detrimental illnesses by longitudinal analysis to safeguard their life in future. It is necessary to follow-up these recovered patients and performs comprehensive assessments for detection and appropriate management towards their psychological, physical, and social realm. This urges us to suggest that it is highly important to provide counselling, moral support as well as a few recommended guidelines to the recovered patients and society to restore to normalcy. Epidemiological, clinical and immunological studies from COVID-19 recovered patients are particularly important to understand the disease and to prepare better for potential outbreaks in the future. Longitudinal studies on a larger cohort would help us to understand the in-depth prognosis as well as the pathogenesis of COVID-19. Also, follow-up studies will help us provide more information for the development of vaccines and drugs for these kinds of pandemics in the future. Hence, we recommend more studies are required to unravel the possible mechanism of COVID-19 infection and the after-effects of it to understand the characteristics of the virus and to develop the necessary precautionary measures to prevent it.

Do Not Minimize the Impact of Cellular Immunity in the Development of Vaccines and Therapeutics for COVID-19.

COVID-19 and the immune system

A close interaction between the virus SARS-CoV-2 and the immune system of an individual results in a diverse clinical manifestation of the COVID-19 disease While adaptive immune responses are essential for SARS-CoV-2 virus clearance, the innate immune cells, such as macrophages, may contribute, in some cases, to the disease progression Macrophages have shown a significant production of IL-6 suggesting they may contribute to the excessive inflammation in COVID-19 disease Macrophage Activation Syndrome may further explain the high serum levels of CRP, which are normally lacking in viral infections In adaptive immune responses, it has been revealed that cytotoxic CD8+ T cells exhibit functional exhaustion patterns, such as the expression of NKG2A, PD-1, and TIM-3 Since SARS-CoV-2 restrains antigen presentation by downregulating MHC class I and II molecules and, therefore, inhibits the T cell-mediated immune responses, humoral immune responses also play a substantial role Specific IgA response appears to be stronger and more persistent than IgM response Moreover, IgM and IgG antibodies show similar dynamics in COVID-19 disease

COVID-19 in a MS patient treated with ocrelizumab: does immunosuppression have a protective role?

Abstract Background Coronavirus disease 19 (COVID-19) is a novel disease entity that is spreading throughout the world. It has been speculated that patients with comorbidities and elderly patients could be at high risk for respiratory insufficiency and death. Immunosuppression could expose infected patients to even higher risks of disease complications due to dampened immune response. However, it has been speculated that overactive immune response could drive clinical deterioration and, based on this hypothesis, several immunosuppressants are currently being tested as potential treatment for COVID-19. Methods In this paper we report on a patient that has been treated with ocrelizumab (a B-cell depleting monoclonal antibody) for primary progressive multiple sclerosis who developed COVID-19. Results Despite complete B cell depletion, patient symptoms abated few days after hospitalization, and he was discharged to home-quarantine. Phone interview follow-up confirmed that, after 14 days, no new symptoms occurred. Discussion This report supports the putative role of immunosuppressive therapy in COVID-19 affected patients.

Detection of SARS-CoV-2-specific humoral and cellular immunity in COVID-19 convalescent individuals

Summary The World Health Organization has declared SARS-CoV-2 virus outbreak a world-wide pandemic. However, there is very limited understanding on the immune responses, especially adaptive immune responses to SARS-CoV-2 infection. Here, we collected blood from COVID-19 patients who have recently become virus-free and therefore were discharged, and detected SARS-CoV-2-specific humoral and cellular immunity in 8 newly discharged patients. Follow-up analysis on another cohort of 6 patients 2 weeks post discharge also revealed high titers of IgG antibodies. In all 14 patients tested, 13 displayed serum neutralizing activities in a pseudotype entry assay. Notably, there was a strong correlation between neutralization antibody titers and the numbers of virus-specific T cells. Our work provides a basis for further analysis of protective immunity to SARS-CoV-2, and understanding the pathogenesis of COVID-19, especially in the severe cases. It has also implications in developing an effective vaccine to SARS-CoV-2 infection.

A single-cell atlas of the peripheral immune response in patients with severe COVID-19.

There is an urgent need to better understand the pathophysiology of Coronavirus disease 2019 (COVID-19), the global pandemic caused by SARS-CoV-2, which has infected more than three million people worldwide1. Approximately 20% of patients with COVID-19 develop severe disease and 5% of patients require intensive care2. Severe disease has been associated with changes in peripheral immune activity, including increased levels of pro-inflammatory cytokines3,4 that may be produced by a subset of inflammatory monocytes5,6, lymphopenia7,8 and T cell exhaustion9,10. To elucidate pathways in peripheral immune cells that might lead to immunopathology or protective immunity in severe COVID-19, we applied single-cell RNA sequencing (scRNA-seq) to profile peripheral blood mononuclear cells (PBMCs) from seven patients hospitalized for COVID-19, four of whom had acute respiratory distress syndrome, and six healthy controls. We identify reconfiguration of peripheral immune cell phenotype in COVID-19, including a heterogeneous interferon-stimulated gene signature, HLA class II downregulation and a developing neutrophil population that appears closely related to plasmablasts appearing in patients with acute respiratory failure requiring mechanical ventilation. Importantly, we found that peripheral monocytes and lymphocytes do not express substantial amounts of pro-inflammatory cytokines. Collectively, we provide a cell atlas of the peripheral immune response to severe COVID-19.