Background To limit the spread of SARS-CoV-2, an evidence-based understanding of the symptoms is critical to inform guidelines for quarantining and testing. The most common features are purported to be fever and a new persistent cough, although the global prevalence of these symptoms remains unclear. The aim of this systematic review is to determine the prevalence of symptoms associated with COVID-19 worldwide. Methods We searched PubMed, Embase, CINAHL, AMED, medRxiv and bioRxiv on 5th April 2020 for studies of adults (>16 years) with laboratory test confirmed COVID-19. No language or publication status restrictions were applied. Data were independently extracted by two review authors into standardised forms. All datapoints were independently checked by three other review authors. A random-effects model for pooling of binomial data was applied to estimate the prevalence of symptoms, subgrouping estimates by country. I2 was used to assess inter-study heterogeneity. Results Of 851 unique citations, 148 articles were included which comprised 24,410 adults with confirmed COVID-19 from 9 countries. The most prevalent symptoms were fever (78% [95% CI 75%-81%]; 138 studies, 21,701 patients; I2 94%), a cough (57% [95% CI 54%-60%]; 138 studies, 21,682 patients; I2 94%) and fatigue (31% [95% CI 27%-35%]; 78 studies, 13,385 patients; I2 95%). Overall, 19% of hospitalised patients required non-invasive ventilation (44 studies, 6,513 patients), 17% required intensive care (33 studies, 7504 patients), 9% required invasive ventilation (45 studies, 6933 patients) and 2% required extra-corporeal membrane oxygenation (12 studies, 1,486 patients). The mortality rate was 7% (73 studies, 10,402 patients). Conclusions We confirm that fever and cough are the most prevalent symptoms of adults infected by SARS-CoV-2. However, there is a large proportion of infected adults which symptoms-alone do not identify.

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The Prevalence of Symptoms in 24,410 Adults Infected by the Novel Coronavirus (SARS-CoV-2;COVID-19): A Systematic Review and Meta-Analysis of 148 Studies from 9 Countries

Coronavirus disease 2019 (COVID-19), due to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has become an epidemiological threat and a worldwide concern. SARS-CoV-2 has spread to 210 countries worldwide and more than 6,500,000 confirmed cases and 384,643 deaths have been reported, while the number of both confirmed and fatal cases is continually increasing. COVID-19 is a viral disease that can affect every age group—from infants to the elderly—resulting in a wide spectrum of various clinical manifestations. COVID-19 might present different degrees of severity—from mild or even asymptomatic carriers, even to fatal cases. The most common complications include pneumonia and acute respiratory distress syndrome. Fever, dry cough, muscle weakness, and chest pain are the most prevalent and typical symptoms of COVID-19. However, patients might also present atypical symptoms that can occur alone, which might indicate the possible SARS-CoV-2 infection. The aim of this paper is to review and summarize all of the findings regarding clinical manifestations of COVID-19 patients, which include respiratory, neurological, olfactory and gustatory, gastrointestinal, ophthalmic, dermatological, cardiac, and rheumatologic manifestations, as well as specific symptoms in pediatric patients.

https://www.mdpi.com/2077-0383/9/6/1753/pdf

COVID-19: Specific and non-specific clinical manifestations and symptoms: The current state of knowledge

Summary Background Previous studies on the pneumonia outbreak caused by the 2019 novel coronavirus disease (COVID-19) were based on information from the general population. Limited data are available for pregnant women with COVID-19 pneumonia. This study aimed to evaluate the clinical characteristics of COVID-19 in pregnancy and the intrauterine vertical transmission potential of COVID-19 infection. Methods Clinical records, laboratory results, and chest CT scans were retrospectively reviewed for nine pregnant women with laboratory-confirmed COVID-19 pneumonia (ie, with maternal throat swab samples that were positive for severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) who were admitted to Zhongnan Hospital of Wuhan University, Wuhan, China, from Jan 20 to Jan 31, 2020. Evidence of intrauterine vertical transmission was assessed by testing for the presence of SARS-CoV-2 in amniotic fluid, cord blood, and neonatal throat swab samples. Breastmilk samples were also collected and tested from patients after the first lactation. Findings All nine patients had a caesarean section in their third trimester. Seven patients presented with a fever. Other symptoms, including cough (in four of nine patients), myalgia (in three), sore throat (in two), and malaise (in two), were also observed. Fetal distress was monitored in two cases. Five of nine patients had lymphopenia ( Interpretation The clinical characteristics of COVID-19 pneumonia in pregnant women were similar to those reported for non-pregnant adult patients who developed COVID-19 pneumonia. Findings from this small group of cases suggest that there is currently no evidence for intrauterine infection caused by vertical transmission in women who develop COVID-19 pneumonia in late pregnancy. Funding Hubei Science and Technology Plan, Wuhan University Medical Development Plan.

Clinical characteristics and intrauterine vertical transmission potential of COVID-19 infection in nine pregnant women: a retrospective review of medical records

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has had health implications of unprecedented magnitude. The infection can range from asymptomatic, mild to life threatening respiratory distress. It can affect almost every organ of the body. Ophthalmologists world over are reporting various manifestations of the infection in the eye. This review was undertaken to help ophthalmologists recognize the possible manifestations and the stage of the viral disease when they commonly appear. Literature search was performed for the publications on ophthalmic manifestations of coronavirus disease-19 (COVID-19) between January 1, 2020 and January 31, 2021. 46 case reports, 8 case series, 11 cross sectional/cohort observational studies, 5 prospective interventional studies, 3 animal models/autopsy studies and 6 reviews/meta-analysis were included. Conjunctivitis is the most common manifestation and can develop at any stage of the disease. Direct effect due to virus, immune mediated tissue damage, activation of the coagulation cascade and prothrombotic state induced by the viral infection, the associated comorbidities and drugs used in the management are responsible for the findings in the eye. The viral ribonucleic acid (RNA) has been isolated from ocular tissues but the role of eye as a route for infection is yet to be substantiated. Ophthalmic manifestations may be the presenting feature of COVID-19 infection or they may develop several weeks after recovery. Ophthalmologists should be aware of the possible associations of ocular diseases with SARS-CoV-2 in order to ask relevant history, look for specific signs, advise appropriate tests and thereby mitigate the spread of infection as well as diagnose and initiate early treatment for life and vision threatening complications.

COVID-19 and Eye: A Review of Ophthalmic Manifestations of COVID-19.

Since SARS-CoV-2 appeared in the human population, the scientific community has scrambled to gather as much information as possible to find good strategies for the containment and treatment of this pandemic virus. Here, we performed a systematic review of the current (pre)published SARS-CoV-2 literature with a focus on the evidence concerning SARS-CoV-2 distribution in human tissues and viral shedding in body fluids. In addition, this evidence is aligned with published ACE2 entry-receptor (single cell) expression data across the human body to construct a viral distribution and ACE2 receptor body map. We highlight the broad organotropism of SARS-CoV-2, as many studies identified viral components (RNA, proteins) in multiple organs, including the pharynx, trachea, lungs, blood, heart, vessels, intestines, brain, male genitals and kidneys. This also implicates the presence of viral components in various body fluids such as mucus, saliva, urine, cerebrospinal fluid, semen and breast milk. The main SARS-CoV-2 entry receptor, ACE2, is expressed at different levels in multiple tissues throughout the human body, but its expression levels do not always correspond with SARS-CoV-2 detection, indicating that there is a complex interplay between virus and host. Together, these data shed new light on the current view of SARS-CoV-2 pathogenesis and lay the foundation for better diagnosis and treatment of COVID-19 patients.

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On the whereabouts of SARS-CoV-2 in the human body: A systematic review.

Purpose To investigate the ocular manifestations and clinical characteristics of COVID-19 patients caused by SARS-CoV-2 in Wuhan, China. Methods A total of 535 COVID-19 patients were recruited at Mobile Cabin Hospital and Tongji Hospital. Information on demographic characteristics, exposure history, ocular symptoms, eye drop medication, eye protections, chronic eye diseases, systemic concomitant symptoms, radiologic findings and SARS-CoV-2 detection in nasopharyngeal swabs by real-time PCR was collected from questionnaires and electronic medical records. Results Of 535 patients, 27 patients (5.0%) presented with conjunctival congestion and 4 patients had conjunctival congestion as the initial symptom. The average duration of conjunctival congestion was 5.9 ± 4.5 days (mean [SD]). The other ocular symptoms, including increased conjunctival secretion, ocular pain, photophobia, dry eye and tearing, were also found in patients with conjunctival congestion. Notably, hand-eye contact was independently correlated with conjunctival congestion in COVID-19 patients. We also found that some COVID-19 patients had chronic eye diseases, including conjunctivitis (33, 6.2%), xerophthalmia (24, 4.5%) and keratitis (14, 2.6%). Similar to the published studies, the most common clinical symptoms were fever, cough and fatigue. A total of 343 patients (64.1%) had positive SARS-CoV-2 detection in nasopharyngeal swabs. Conclusions Conjunctival congestion is one of the COVID-19-related ocular symptoms, which could occur as the initial symptoms. Frequent hand-eye contact may be the risk factor for conjunctival congestion in COVID-19 patients. Screening of patients with conjunctival congestion by ophthalmologists is advocated during the outbreak of COVID-19. It is essential to provide eye-care equipment and strengthen education on eye protection.

https://www.medrxiv.org/content/medrxiv/early/2020/03/16/2020.03.12.20034678.full.pdf

Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China: a cross-sectional study.

Objective: The novel coronavirus disease (COVID-19) was first reported in Wuhan, China in December 2019 and is now pandemic all over the world. Previous study has reported several COVID-19 cases with conjunctivitis. However, the complete profiling of COVID-19 related ocular symptoms and diseases are still missing. We aim to investigate the ocular manifestations and clinical characteristics of COVID-19 patients.
Methods: A total of five hundred and thirty-four patients were recruited at Mobile Cabin Hospital and Tongji Hospital. We collected information on demographic characteristics, exposure history, ocular symptoms, systemic concomitant symptoms, eye drop medication, eye protections, radiologic findings, and SARS-CoV-2 detection in nasopharyngeal swabs by RT-PCR from questionnaires and electronic medical records.
Results: The median age of patients was 40 and 50 years at Mobile Cabin Hospital and Tongji Hospital, respectively. Of 534 COVID-19 patients, 25 patients (4.68%) presented with conjunctival congestion and 3 patients had conjunctival congestion as the initial symptom. The average duration of conjunctival congestion was 4.9 ± 2.6 days (mean [SD]), ranging from 2 to 10 days. Dry eye (112, 20.97%), blurred vision (68, 12.73%), and foreign body sensation (63, 11.80%) ranked as the top three COVID-19 related ocular symptoms. Notably, a total of 332 COVID-19 patients (62%) had a hand-eye contact history. We also found that some COVID-19 patients had a history of eye disease, including conjunctivitis (33, 6.18%), dry eye (24, 4.49%), keratitis (14, 2.62%), cataract (9, 1.69%), and diabetic retinopathy (5, 0.94%). In consistent with previous studies, the most common clinical symptoms were fever, cough, and fatigue. Patients, 60.5% in Mobile Cabin Hospital and 67.5% in Tongji Hospital, respectively were confirmed with positive SARS-CoV-2 detection.
Conclusions: Conjunctival congestion was one of the COVID-19 related ocular symptoms, which may have clinical diagnostic significance. It is essential to provide eye-care equipment and strengthen education on eye protection, as dirty hand-eye contact might be a high risk factor of COVID-19. Further detailed and comprehensive ophthalmological guidance is needed for COVID-19 control.

https://medrxiv.org/content/10.1101/2020.03.12.20034678v1.full.pdf

Ocular manifestations and clinical characteristics of 534 cases of COVID-19 in China: A cross-sectional study

Purpose Current treatments for diabetic retinopathy (DR) have considerable limitations, emphasizing the need for new therapeutic options. The effect of leukocyte cell-derived chemotaxin 2 (LECT2) on diabetes-induced blood–retinal barrier impairment and the possible underlying mechanism were investigated both in vivo and in vitro. Methods Twenty diabetic and 22 nondiabetic eyes were included in this study. Additionally, we established a streptozotocin-induced diabetic mouse model and observed vascular leakage in mice treated with or without recombinant LECT2 (rLECT2) intravitreal injection (40 µg/mL, 1 µL). The levels of LECT2 and interendothelial junction proteins (ZO1, VE-cadherin, and occludin) were analyzed by western blot and/or immunofluorescence. Endothelial junctions in mouse retinas were observed by transmission electron microscopy (TEM). Moreover, confluent human retinal microvascular endothelial cells (HRMECs) and human umbilical vein endothelial cells (HUVECs) were treated (0–72 hours) with glucose (0 or 30 mM) in the presence or absence of rLECT2 (40–360 ng/mL). After treatment, intact cell monolayers were monitored for permeability to 40-kD FITC-dextran. Interendothelial junction targets and Tie2/Akt/mTOR signaling pathway components were investigated by western blot. Results In diabetic human and mouse retinas and high-glucose (30 mM)–treated HRMECs and HUVECs, the levels of LECT2 and interendothelial junction proteins were decreased. rLECT2 treatment (80 ng/mL) significantly attenuated the hyperglycemia-induced reduction in endothelial cell barrier function and inhibited the migration and tube formation of HRMECs and HUVECs. In addition, rLECT2 increased the levels of interendothelial junction proteins via activation of the Tie2/Akt/mTOR signaling pathway. Furthermore, intravitreal rLECT2 injections increased the levels of interendothelial junction proteins and reversed diabetes-induced junction disruption. Conclusions rLECT2 can increase the levels of interendothelial tight junction proteins through activation of the Tie2/Akt/mTOR signaling pathway and can ameliorate inner blood–retinal barrier impairment secondary to diabetes. LECT2 might be a potential target to prevent the progression of DR.

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

Markers of the sympathetic, parasympathetic and sensory nervous system are altered in the human diabetic choroid.

Purpose The purpose of this study was to investigate the protective effect of low-dose trans-resveratrol (trans-RSV) on diabetes-induced retinal ganglion cell (RGC) degeneration and its possible mechanism. Methods A streptozotocin-induced diabetic mouse model was established and treated with or without trans-RSV intragastric administration (10 mg/kg body weight/day) for 12 weeks. Oscillatory potentials (Ops) of the dark-adapted electroretinogram (ERG) were recorded. The number of RGCs was detected by Tuj1 and TUNEL staining. The apoptosis markers in the retina were analyzed by Western blot. The cross sections of optic nerves were observed by transmission electron microscopy. In addition, mouse neuroblastoma N2a cells were injured by high-glucose (HG) treatment. Cell viability and apoptosis were measured with or without low-dose trans-RSV treatment. The intracellular localization of tyrosyl transfer-RNA synthetase (TyrRS) was observed in both mouse retinas and N2a cells. The effects of low-dose trans-RSV on the binding of TyrRS to the transcription factor c-Jun and the binding of c-Jun to pro-apoptotic genes were analyzed by co-IP and ChIP assays in HEK 293 cells. Results Trans-RSV relieved electrophysiological injury of retinas and inhibited RGC apoptosis in diabetic mice. It also protected N2a cells from HG-induced apoptosis. Additionally, it promoted TyrRS nuclear translocation in both diabetic mouse retinas and HG-treated N2a cells. Trans-RSV promoted TyrRS binding to c-Jun, inhibited the phosphorylation of Ser-63 of c-Jun, and downregulated pro-apoptotic gene transcription. Conclusions Low-dose trans-RSV can ameliorate diabetes-induced RGC degeneration via the TyrRS/c-Jun pathway. It can promote TyrRS nuclear translocation and bind to c-Jun, downregulating c-Jun phosphorylation and downstream pro-apoptotic genes.

Ke Xiao

Papers

Ocular manifestations and clinical characteristics of 535 cases of COVID-19 in Wuhan, China: a cross-sectional study.

Ocular manifestations and clinical characteristics of 534 cases of COVID-19 in China: A cross-sectional study

LECT2 Ameliorates Blood–Retinal Barrier Impairment Secondary to Diabetes Via Activation of the Tie2/Akt/mTOR Signaling Pathway

Markers of the sympathetic, parasympathetic and sensory nervous system are altered in the human diabetic choroid.

Low-Dose Trans-Resveratrol Ameliorates Diabetes-Induced Retinal Ganglion Cell Degeneration via TyrRS/c-Jun Pathway