Parallel Dysregulated Immune Response in Severe Forms of COVID-19 and Bacterial Sepsis via Single-Cell Transcriptome Sequencing.

Critically ill COVID-19 patients start developing single respiratory organ failure that often evolves into multiorgan failure. Understanding the immune mechanisms in severe forms of an infectious disease (either critical COVID-19 or bacterial septic shock) would help to achieve a better understanding of the patient's clinical trajectories and the success of potential therapies. We hypothesized that a dysregulated immune response manifested by the abnormal activation of innate and adaptive immunity might be present depending on the severity of the clinical presentation in both COVID-19 and bacterial sepsis. We found that critically ill COVID-19 patients demonstrated a different clinical endotype that resulted in an inflammatory dysregulation in mild forms of the disease. Mild cases (COVID-19 and bacterial non severe sepsis) showed significant differences in the expression levels of CD8 naïve T cells, CD4 naïve T cells, and CD4 memory T cells. On the other hand, in the severe forms of infection (critical COVID-19 and bacterial septic shock), patients shared immune patterns with upregulated single-cell transcriptome sequencing at the following levels: B cells, monocyte classical, CD4 and CD8 naïve T cells, and natural killers. In conclusion, we identified significant gene expression differences according to the etiology of the infection (COVID-19 or bacterial sepsis) in the mild forms; however, in the severe forms (critical COVID-19 and bacterial septic shock), patients tended to share some of the same immune profiles related to adaptive and innate immune response. Severe forms of the infections were similar independent of the etiology. Our findings might promote the implementation of co-adjuvant therapies and interventions to avoid the development of severe forms of disease that are associated with high mortality rates worldwide.

COVID-19 and renal involvement: a prospective cohort study assessing the impact of mild SARS-CoV-2 infection on the kidney function of young healthy males.

PURPOSE: COVID-19 frequently affects the kidneys with symptoms ranging from mild proteinuria to progressive acute kidney injury. This prospective study aimed to assess the short- and long-term impact of asymptomatic and mild COVID-19 on the renal function of healthy young adults, and to determine the correlation between viral load and kidney function among these patients. METHODS: This was a prospective cohort study conducted over a period of 6 months. Patients were followed-up at baseline, and then after 3 and 6 months, respectively. Real-time PCR cycle threshold (CT) was used to determine the viral load and disease activity. Patients were classified into two groups with either asymptomatic COVID-19 or mild pneumonia. The assessment parameters were variables that could directly or indirectly relate to the renal function. RESULTS: A total of 48 patients were included and evaluated. The majority of patients (62.5%) had asymptomatic COVID-19 disease. Patients with mild pneumonia had significantly higher serum creatinine (SCr) at the time of COVID-19 diagnosis (beta = 12.836, 95% CI = 2.405-23.268, P = 0.019), after 3 months (beta = 14.345, 95% CI = 1.149-27.542, P = 0.035), and after 6 months (beta = 14.100, 95% CI = 0.730-27.470, P = 0.040) compared to asymptomatic patients. Mild pneumonia was also significantly associated with lower serum albumin level at the time of COVID-19 diagnosis (beta = - 6.317, 95% CI = - 9.448-- 3.185, P < 0.001). CONCLUSION: Mild COVID-19 is associated with mild renal involvement without AKI. Changes in the renal function appear to be related to reduced creatinine clearance and possible albumin leakage in the acute phase of the disease. The reduction in creatinine clearance is not predicted by viral load, and it appears to be a long-term effect of the disease that can last for at least 6 months.

Role of Antiviral Drugs in Management of Mild and Moderate Coronavirus Disease-19: A Systematic Review

This study was conducted to determine the objective role of antiviral drugs such as arbidol, lopinavir/ritonavir, and others in improving clinical symptoms, decreasing duration of hospitalization, and decreasing duration of viral shedding in patients with mild and moderate COVID-19 infection. A systematic literature search was carried out on Google Scholar and PubMed databases, using the keywords "COVID-19”, "Antiviral”, "Treatment”, and "Symptomatic” in various combinations. Observational studies, cohort and case control studies, and clinical trials published in English with full-text available were included in the study. Data extraction was carried out from selected studies, and all statistical analysis for the study was carried out using Microsoft Excel. The key outcomes studied were time to negative PCR, duration of clinical stay, time to clinical improvement, and occurrence of adverse events. Seven studies were selected for final review after rigorous selection process. Data of total 4734 participants was analyzed, the majority of which were females (n=2810, 59.3%). The majority of participants had mild disease (n=4197, 88.65%). Average time for negative RT-PCR in the included treatment groups was 13.5 days, whereas the average duration of hospitalization was 14.9 days for the treatment groups. Adverse reactions such as ECG changes, gastrointestinal symptoms, secondary bacterial infections, and hepatic and renal dysfunction were scarcely reported in the included studies. There is no clear benefit in terms of duration of hospitalization and time to negative PCR with the use of various antiviral regimens in mild disease;however, these drugs did play a role in limiting disease progression in the participant population. Pending further evidence, the use of these drugs for the management of COVID-19 is not recommend in patients with mild disease. © 2022, The Running Line. All rights reserved.

Understanding the mechanisms for COVID-19 vaccine's protection against infection and severe disease.

INTRODUCTION: Multiple COVID-19 vaccines have been approved and employed in the fight against the pandemic. However, these vaccines have limited long-term effectiveness against severe cases and a decreased ability to prevent mild disease. AREAS COVERED: This review discusses the relevant factors influencing the efficacy of the vaccines against mild and severe infection, analyzes the possible underlying mechanisms contributing to the different outcomes in terms of vaccine function and disease progression, and proposes improvements for the next generation of vaccines. EXPERT OPINION: The reduced efficacy of the COVID-19 vaccine in the prevention of viral infection is closely related to the emergence of novel SARS-CoV-2 variants and their rapid transmission ability. Fundamentally, the immune responses induced by COVID-19 vaccines cannot effectively halt virus replication in the upper respiratory tract because only a limited number of specific antibodies reach these areas and decrease in concentration over time. However, the established immune response can provide sufficient protection against severe diseases by blocking viral infection of the lower respiratory tract or lung owing to sufficient antibody repertoires and memory responses. Considering this situation, future COVID-19 vaccines should have the potential to replenish the mucosal immune response in the respiratory tract to prevent viral infection.

Impact of asymptomatic and mild COVID-19 infection on fetal growth during pregnancy.

BACKGROUND: During pregnancy, certain viral infections are known to significantly affect fetal development. Data regarding the impact of COVID-19 viral infection in pregnancy, specifically in asymptomatic or mild cases, remains limited. This presents a challenge in providing prenatal counseling and antepartum surveillance in pregnancies complicated by COVID-19 infection. Placenta studies have demonstrated that vascular malperfusion patterns attributed to COVID-19 appear to depend on the timing of infection. Given these placental changes, we aim to evaluate the impact of COVID-19 on fetal growth in pregnant patients with asymptomatic or mild disease, stratified by trimester of infection. We hypothesize that COVID-19 infection, especially early in pregnancy, increases the risk of fetal growth restriction (FGR). STUDY DESIGN: This is a single institution, retrospective cohort study of patients ages 16-55 years old with a singleton delivery between December 10, 2020, and April 19, 2021 who had not received a COVID-19 vaccination prior to delivery. COVID-19 infection during pregnancy was defined as a positive SARS-CoV-2 RT-PCR test. FGR was defined as an estimated fetal weight less than the 10th percentile for gestational age or abdominal circumference less than the 10th percentile for gestational age. Maternal and fetal characteristics, including FGR, were compared between women with versus without COVID-19 infection during pregnancy. RESULTS: Among 1971 women with a singleton delivery, 208 (10.6 %) had a prior asymptomatic or mild COVID-19 infection during pregnancy. With the exception in the median prenatal BMI being significantly higher in the COVID-19 group (median, 27.5 vs 26.3, p = 0.04), there were no significant differences in demographics, baseline maternal comorbidities or gestational age between those with versus without COVID-19 infection during pregnancy, or in the proportion of their offspring with FGR (3.4 % (7/208) vs 4.8 % (84/1763), p = 0.36). When the 208 women were stratified by the timing of their COVID-19 infection, the proportion with an offspring with FGR was 8.7 % (2/23), 1.2 % (1/84), and 4.0 % (4/101), for those first diagnosed with COVID-19 during the 1st, 2nd, and 3rd trimesters, respectively (p = 0.72 Cochran-Armitage test for trend). CONCLUSION: Asymptomatic or mild COVID-19 infection in pregnancy, regardless of timing of infection, does not appear to be associated with FGR. Routine serial fetal growth assessment may not be warranted solely for history of COVID-19 infection.

Long-COVID in patients with a history of mild or asymptomatic SARS-CoV-2 infection: a Nationwide Cohort Study.

OBJECTIVE: Evaluating the prevalence of long-COVID symptoms in patients with a history of mild or asymptomatic infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and the factors associated with developing long-COVID. DESIGN: A nationwide cohort study. Using a centralized database, we have identified patients with and without a history of SARS-CoV-2 infection 1-6 months before data collection. Patients were asked to fill out an online questionnaire through text messages. SETTING: Israeli general practice. SUBJECTS: 2755 persons participated in the study in September 2021 (a response rate of 7.5%): 819 with and ,936 without a history of SARS-CoV-2 infection. MAIN OUTCOME MEASURES: We asked patients to provide details about their demographic status, medical history, COVID-related variables and the presence of long-COVID symptoms. RESULTS: Most prevalent long-COVID symptoms were decreased smell sensation (35.1% vs. 4.3%, p < 0.001), decreased taste sensation (25.2% vs. 3.2%, p < 0.001), memory disturbances (36.9% vs. 14.4%, p < 0.001), dyspnea (24.2% vs. 10.7%, p < 0.001) and arthralgia (33% vs. 16.3%, p < 0.001). Risk factors associated with long-COVID included female gender, symptomatic COVID-19, overweight or obesity and the presence of dyslipidemia. About 34.6% of participants reported not returning to their baseline health condition after the acute illness. CONCLUSION: Long-COVID is frequently seen following a mild symptomatic COVID-19 infection and, to a lesser extent, following an asymptomatic SARS-CoV-2 infection. Primary care physicians should be aware of these symptoms and consider this option in their differential diagnosis. Health policymakers should expect a significant impact of this syndrome on public health.Key PointsLong-COVID has emerged as a significant health problem with a serious impact on normal daily function• Long-COVID symptoms were evident in patients with mild symptomatic disease and in asymptomatic patients to a lesser extent.• Risk factors for having Long-COVID symptoms include female gender, symptomatic disease, increased BMI, and the presence of dyslipidemia.• Fatigue, dyspnea, weakness, decreased libido, weight changes, memory, and sleep disturbances were associated with not returning to the baseline health state.

The differential immune response in mild versus fatal SARS-CoV2 infection.

This study compared the immune response in mild versus fatal SARS-CoV2 infection. Forty nasopharyngeal swabs with either productive mild infection (n = 20) or negative for SARS-CoV2 (n = 20) were tested along with ten lung sections from people who died of COVID-19 which contained abundant SARS-CoV2 and ten controls. There was a 25-fold increase in the CD3+T cell numbers in the viral positive nasopharyngeal swabs compared to the controls (p < 0.001) and no change in the CD3+T cell count in the fatal COVID-19 lungs versus the controls. CD11b + and CD206+ macrophage counts were significantly higher in the mild versus fatal disease (p = 0.002). In situ analysis for SARS-CoV2 RNA found ten COVID-19 lung sections that had no/rare detectable virus and also lacked the microangiopathy typical of the viral positive sections. These viral negative lung tissues when compared to the viral positive lung samples showed a highly significant increase in CD3+ and CD8 T cells (p < 0.001), equivalent numbers of CD163+ cells, and significantly less PDL1, CD11b and CD206+ cells (p = 0.002). It is concluded that mild SARS-CoV2 infection is marked by a much stronger CD3/CD8 T cell, CD11b, and CD206 macrophage response than the fatal lung disease where viral RNA is abundant.

A SARS-CoV-2 Outbreak Among Nursing Home Residents Vaccinated with a Booster Dose of mRNA COVID-19 Vaccine.

This study describes a SARS-CoV-2 outbreak caused by the Delta (B.1.617.2) variant in a nursing home in Central Italy during October-November 2021. Trained interviewers collected data from residents, staff, and administration officers with an agreed informed consent procedure. Thirty-two (44.5%) out of 72 residents (median age 89 years) and six (26.1%) of 23 healthcare workers were found to be infected with SARS-CoV-2. Infections occurred more often among residents with a higher index of independence in daily living activities, suggesting an increased risk for those with more interactions. Twenty-five infected residents (78.1%) received the booster dose of mRNA anti-COVID-19 vaccine > 7 days before SARS-CoV-2 onset. Half of the infected residents had mild symptoms, and only three required hospitalisation, one of whom died from COVID-19 complications. The study underlines the effectiveness of a booster dose in providing a high protection against severe disease and hospitalisation even among vulnerable individuals infected with the Delta variant of concern.

Faster decay of neutralizing antibodies in never infected than previously infected healthcare workers three months after the second BNT162b2 mRNA COVID-19 vaccine dose.

OBJECTIVES: This study aimed to describe the longitudinal evolution of neutralizing antibody titres (NtAb) in three different cohorts of healthcare workers (HCWs), including vaccinated HCWs with and without a previous SARS-CoV-2 infection and previously infected unvaccinated HCWs. COVID-19 was mild or asymptomatic in those experiencing infection. METHODS: NtAb was tested before BNT162b2 mRNA COVID-19 vaccine (V0), 20±2 days after the first dose (V1_20), 20±3 days (V2_20) and 90±2 days (V2_90) after the second dose in vaccinated HCWs and after about 2 months (N_60), 10 months (N_300) and 13 months (N_390) from natural infection in unvaccinated HCWs. NtAb were measured by authentic virus neutralization with a SARS-CoV-2 B.1 isolate circulating in Italy at HCW enrolment. RESULTS: Sixty-two HCWs were enrolled. NtAb were comparable in infected HCWs with no or mild disease at all the study points. NtAb of uninfected HCWs were significantly lower with respect to those of previously infected HCWs at V1_20, V2_20 and V2_90. The median NtAb fold decrease from V2_20 to V2_90 was higher in the uninfected HCWs with respect to those with mild infection (6.26 vs 2.58, p=0.03) and to asymptomatic HCWs (6.26 vs 3.67, p=0.022). The median Nabt at N_390 was significantly lower than at N_60 (p=0.007). CONCLUSIONS: In uninfected HCWs completing the two-dose vaccine schedule, a third mRNA vaccine dose is a reasonable option to counteract the substantial NtAb decline occurring at a significantly higher rate compared with previously infected, vaccinated HCWs. Although low, Nabt were still at a detectable level after 13 months in two-thirds of previously infected and unvaccinated HCWs.

Pharmacological Treatment of Patients with Mild to Moderate COVID-19: A Comprehensive Review.

Mild to moderate COVID-19 can be found in about 80% of patients. Although mortality is low, mild to moderate COVID-19 may progress to severe or even critical stages in about one week. This poses a substantial burden on the health care system, and ultimately culminates in death or incapacitation and hospitalization. Therefore, pharmacological treatment is paramount for patients with this condition, especially those with recognized risk factors to disease progression. We conducted a comprehensive review in the medical literature searching for randomized studies carried out in patients with mild to moderate COVID-19. A total of 14 randomized studies were identified, enrolling a total of 6848 patients. Nine studies (64%) were randomized, placebo-controlled trials, whereas five were open-label randomized trials (35%). We observed that Bamlanivimab and nitazoxanide reduced viral load, whereas ivermectin may have shortened time to viral clearance; Interferon Beta-1 reduced time to viral clearance and vitamin D reduced viral load; Favirapir, peginterferon, and levamisole improved clinical symptoms, whereas fluvoxamine halted disease progression; inhaled budesonide reduced the number of hospitalizations and visits to emergency departments; colchicine reduced the number of deaths and hospitalizations. Collectively, therefore, these findings show that treatment of early COVID-19 may be associated with reduced viral load, thus potentially decreasing disease spread in the community. Moreover, treatment of patients with mild to moderate COVID-19 may also be associated with improved clinical symptoms, hospitalization, and disease progression. We suggest that colchicine, inhaled budesonide, and nitazoxanide, along with nonpharmacological measures, based on efficacy and costs, may be used to mitigate the effects of the COVID-19 pandemic in middle-income countries.

Submassive Pulmonary Embolism in Mild COVID-19 Without Lung Infiltrates.

A 66-year-old man who had been diagnosed with mild coronavirus 2019 (COVID-19) infection nine days prior presented to the emergency room with acute-onset chest pain and shortness of breath. Chest CT angiogram (CTA) revealed pulmonary emboli (PE) in the right and left pulmonary arteries with right heart strain; lung parenchyma showed no infiltrates. Although severe COVID-19 infection is associated with thrombotic complications, data regarding the occurrence of PE in mild cases of COVID-19 is scarce. However, even mild cases of COVID-19 are reported to have revealed lung infiltrates, particularly ground-glass opacities, on imaging. The possibility of the lungs being the primary source of COVID-19-associated coagulopathy has been raised. We report an uncommon case of submassive PE occurring in mild COVID-19, without any associated lung infiltrates. This case indicates that mild COVID-19, without significant lung parenchymal involvement, can also cause a hypercoagulable state, resulting in venous thromboembolism (VTE).

Validation of a combined ELISA to detect IgG, IgA and IgM antibody responses to SARS-CoV-2 in mild or moderate non-hospitalised patients.

BACKGROUND: Frequently SARS-CoV-2 results in mild or moderate disease with potentially lower concentrations of antibodies compared to those that are hospitalised. Here, we validated an ELISA using SARS-CoV-2 trimeric spike glycoprotein, with targeted detection of IgG, IgA and IgM (IgGAM) using serum and dried blood spots (DBS) from adults with mild or moderate disease. METHODS: Targeting the SARS-CoV-2 trimeric spike, a combined anti-IgG, IgA and IgM serology ELISA assay was developed using 62 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 624 COVID-19 negative samples. The assay was validated using 73 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 359 COVID-19 negative serum samples with an additional 81 DBSs. The assay was further validated in 226 PCR-confirmed non-hospitalised, mild or moderate COVID-19 samples, ≥14 days post symptom onset and 426 COVID-19 negative clinical samples. RESULTS: A sensitivity and specificity of 98.6% (95% CI, 92.6-100.0), 98.3% (95% CI, 96.4-99.4), respectively, was observed following validation of the SARS-CoV-2 ELISA. No cross-reactivities with endemic coronaviruses or other human viruses were observed, and no change in results were recorded for interfering substances. The assay was stable at temperature extremes and components were stable for 15 days once opened. A matrix comparison showed DBS to correlate with serum results. Clinical validation of the assay reported a sensitivity of 94.7% (95% CI, 90.9-97.2%) and a specificity of 98.4% (95% CI, 96.6-99.3%). CONCLUSIONS: The human anti-IgGAM SARS-CoV-2 ELISA provides accurate and sensitive detection of SARS-CoV-2 antibodies in non-hospitalised adults with mild or moderate disease. The use of dried blood spots makes the assay accessible to the wider community.

The diagnostic value of platelet distribution width in patients with mild COVID-19.

COVID-19 has a worldwide distribution; however, there is no effective diagnosis marker, especially for the mild-type COVID-19. The purpose of the current study was to identify parameters for mild-type COVID-19. We retrospectively analyzed a single-center data of patients with mild COVID-19. Forty patients diagnosed with COVID-19 were enrolled. Peripheral blood indices between the admission and discharge times were collected and analyzed. The platelet distribution width (PDW) was shown to be an indicator of significant change. The receiver operating characteristic curve for PDW was 0.7; the sensitivity and specificity for PDW were 82.5% and 55.0%, respectively. Therefore, a potential diagnostic value of PDW for mild-type COVID-19 was demonstrated.

Relationship between disease severity and serum IL-6 levels in COVID-19 anosmia.

BACKGROUND: An association between IL-6 levels and cytokine storm syndrome in COVID-19 patients has been suggested. Cases with higher IL-6 levels have more rapid progression and a higher complication rate. On the other hand, COVID-19 cases with anosmia have a milder course of the disease. OBJECTIVE: We aimed to investigate whether there is a relationship between serum IL-6 levels and presence of anosmia in COVID-19 patients. METHODS: Patients with a confirmed diagnosis of COVID-19 based on laboratory (PCR) were stratified into two groups based on presence of olfactory dysfunction (OD). In all cases with and without anosmia; psychophysical test (Sniffin' Sticks test) and a survey on olfactory symptoms were obtained. Threshold (t) - discrimination (d) - identification (i), and total (TDI) scores reflecting olfactory function were calculated. Clinical symptoms, serum IL-6 levels, other laboratory parameters, and chest computed tomography (CT) findings were recorded. RESULTS: A total of 59 patients were included, comprising 23 patients with anosmia and 36 patients without OD based on TDI scores. Patients with anosmia (41.39 ± 15.04) were significantly younger compared to cases without anosmia (52.19 ± 18.50). There was no significant difference between the groups in terms of comorbidities, smoking history, and symptoms including nasal congestion and rhinorrhea. Although serum IL-6 levels of all patients were above normal values (7 pg/mL), patients with anosmia had significantly lower serum IL-6 levels (16.72 ± 14.28 pg/mL) compared to patients without OD (60.95 ± 89.33 pg/mL) (p = 0.026). CONCLUSION: Patients with COVID-19 related anosmia tend to have significantly lower serum levels of IL-6 compared to patients without OD, and the lower IL-6 levels is related to milder course of the disease. With the effect of low cytokine storm and IL-6 level, it may be said that anosmic cases have a milder disease in COVID-19.

SARS-CoV-2 Virus Culture and Subgenomic RNA for Respiratory Specimens from Patients with Mild Coronavirus Disease.

We investigated 68 respiratory specimens from 35 coronavirus disease patients in Hong Kong, of whom 32 had mild disease. We found that severe acute respiratory syndrome coronavirus 2 and subgenomic RNA were rarely detectable beyond 8 days after onset of illness. However, virus RNA was detectable for many weeks by reverse transcription PCR.