• Adipose tissue
• RAS
• SARS-CoV-2
• Senescence

• Humans
• Aged
• COVID-19
• SARS-CoV-2
• Peptidyl-Dipeptidase A
• Angiotensin-Converting Enzyme 2
• Aging
• Obesity
• Adipose Tissue

• COVID-19
• Cognition
• GnRH
• Hypothalamus
• Infertility
• Neurodevelopment

• Humans
• Gonadotropin-Releasing Hormone/metabolism
• COVID-19/psychology
• COVID-19/metabolism
• Male
• Neurons/metabolism
• Cognitive Dysfunction/etiology
• Cognitive Dysfunction/metabolism
• SARS-CoV-2
• Aged
• Middle Aged
• Cell Death
• Hypothalamus/metabolism
• Testosterone/metabolism
• Testosterone/blood
• Aged, 80 and over
• Brain/metabolism
• Brain/pathology

• 810331 European Research Council

• SARS-CoV-2
• apgar scores
• gestational age
• placental pathology
• under-resourced patient population

• Female
• Humans
• Infant, Newborn
• Pregnancy
• Apgar Score
• COVID-19/epidemiology
• Infarction
• Mothers
• Placenta
• Pregnant Women
• SARS-CoV-2

• R16 GM145586 NIGMS NIH HHS
• R01 HD092533 NICHD NIH HHS

• COVID-19
• Infectivity
• Persistence
• Postmortem
• SARS-CoV-2

• Humans
• COVID-19
• SARS-CoV-2
• Oropharynx
• Nasopharynx
• Cadaver

• ace2, angiotensin-converting enzyme 2
• agm, african green monkey
• ali, acute lung injury
• ards, acute respiratory distress syndrome
• balf, bronchoalveolar lavage fluid
• cards, covid-19-associated acute respiratory distress syndrome
• dad, diffuse alveolar damage
• dpi, days postinfection
• ggo, ground glass opacities
• s, spike glycoprotein

• Autopsy and COVID19 deaths
• Autopsy findings in SARS-CoV-2 deaths
• COVID19 histopathology findings
• Forensic autopsy in COVID19 deaths

• Humans
• Autopsy
• COVID-19
• SARS-CoV-2
• Pandemics
• Biopsy

• COVID-19
• Cardiac sarcoidosis
• Giant cell myocarditis
• Heart failure

• Acute kidney damage
• Diffuse alveolar damage
• Immune response
• SARS-CoV-2

• Autopsy
• COVID-19
• Humans
• Lung/pathology
• Pandemics
• SARS-CoV-2

• 01KX2021 Bundesministerium für Bildung und Forschung
• ZMVI1-2520COR201 Bundesministerium für Gesundheit
• Universitätsklinikum RWTH Aachen (8915)

• COVID-19
• SARS-CoV-2
• diagnostic
• functional studies
• high content screening
• microscopy
• models
• super-resolution

• COVID-19
• COVID-19 Testing
• Humans
• Pandemics
• SARS-CoV-2

• University of the Witwatersrand, Johannesburg

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel virus that belongs to the Coronoviridae family, emerged in December 2019, causing the COVID-19 pandemic in March 2020. Unlike previous SARS and Middle East respiratory syndrome (MERS) outbreaks, this virus has a higher transmissibility rate, albeit a lower case fatality rate, which results in accumulation of a significant number of mutations and a faster evolution rate. Genomic studies on the mutation rate of the virus, as well as the identification of mutations that prevail and their impact on disease severity, are of great importance for pandemic surveillance and vaccine and drug development. Here, we aim to identify mutations on the SARS-CoV-2 viral genome and their effect on the proteins they are located in, in Greek patients infected in the first wave of the pandemic. To this end, we perform SARS-CoV-2 amplicon-based NGS sequencing on nasopharyngeal swab samples from Greek patients and bioinformatic analysis of the results. Although SARS-CoV-2 is considered genetically stable, we discover a variety of mutations on the viral genome. In detail, 18 mutations are detected in total on 10 SARS-CoV-2 isolates. The mutations are located on ORF1ab, S protein, M protein, ORF3a and ORF7a. Sixteen are also detected in patients from other regions around the world, and two are identified for the first time in the present study. Most of them result in amino acid substitutions. These substitutions are analyzed using computational tools, and the results indicate minor or major impact on the proteins’ structural stability, which could probably affect viral transmissibility and pathogenesis. The correlation of these variations with the viral load levels is examined, and their implication for disease severity and the biology of the virus are discussed.

• M protein
• ORF1ab
• ORF3a
• ORF7a
• S protein
• SARS-CoV-2
• mutations
• protein structure and stability

• SARS-CoV-2
• autopsy
• organ involvement
• qRT-PCR

Musculoskeletal (MSK) pain is being increasingly reported by patients as one of the most common persistent symptoms in post-COVID-19 syndrome or Long COVID. However, there is a lack of understanding of its prevalence, characteristics, and underlying pathophysiological mechanisms. The objective of this review is to identify and describe the features and characteristics of MSK pain in Long COVID patients.

The narrative review involved a literature search of the following online databases: MEDLINE (OVID), EMBASE (OVID), CINAHL, PsyclNFO, and Web of Science (December 2019 to February 2022). We included observational studies that investigated the prevalence, characteristics, risk factors and mechanisms of MSK pain in Long COVID. After screening and reviewing the initial literature search results, a total of 35 studies were included in this review.

The overall reported prevalence of MSK pain in Long COVID ranged widely from 0.3% to 65.2%. The pain has been reported to be localized to a particular region or generalized and widespread. No consistent pattern of progression of MSK pain symptoms over time was identified. Female gender and higher BMI could be potential risk factors for Long COVID MSK pain, but no clear association has been found with age and ethnicity. Different pathophysiological mechanisms have been hypothesized to contribute to MSK pain in Long COVID including increased production of proinflammatory cytokines, immune cell hyperactivation, direct viral entry of neurological and MSK system cells, and psychological factors.

MSK pain is one of the most common symptoms in Long COVID. Most of the current literature on Long COVID focuses on reporting the prevalence of persistent MSK pain. Studies describing the pain characteristics are scarce. The precise mechanism of MSK pain in Long COVID is yet to be investigated. Future research must explore the characteristics, risk factors, natural progression, and underlying mechanisms of MSK pain in Long COVID.

• chronic pain
• post-COVID-19 syndrome
• post-acute COVID-19

COVID-19 is a complex disease with short- and long-term respiratory, inflammatory and neurological symptoms that are triggered by the infection with SARS-CoV-2. Invasion of the brain by SARS-CoV-2 has been observed in humans and is postulated to be involved in post-COVID state. Brain infection is particularly pronounced in the K18-hACE2 mouse model of COVID-19. Prevention of brain infection in the acute phase of the disease might thus be of therapeutic relevance to prevent long-lasting symptoms of COVID-19. We previously showed that melatonin or two prescribed structural analogs, agomelatine and ramelteon delay the onset of severe clinical symptoms and improve survival of SARS-CoV-2-infected K18-hACE2 mice. Here, we show that treatment of K18-hACE2 mice with melatonin and two melatonin-derived marketed drugs, agomelatine and ramelteon, prevents SARS-CoV-2 entry in the brain, thereby reducing virus-induced damage of small cerebral vessels, immune cell infiltration and brain inflammation. Molecular modeling analyses complemented by experimental studies in cells showed that SARS-CoV-2 entry in endothelial cells is prevented by melatonin binding to an allosteric-binding site on human angiotensin-converting enzyme 2 (ACE2), thus interfering with ACE2 function as an entry receptor for SARS-CoV-2. Our findings open new perspectives for the repurposing of melatonergic drugs and its clinically used analogs in the prevention of brain infection by SARS-CoV-2 and COVID-19-related long-term neurological symptoms.

• Brain infection
• COVID-19
• Drug repurposing
• Melatonin
• Neuro-vasculature
• SARS-CoV-2

• Delta variant
• E484K
• SARS-CoV-2
• Targeted testing
• Variant identification
• Variant of concern
• Variant screening

• COVID-19/diagnosis
• High-Throughput Screening Assays
• Humans
• Pandemics
• SARS-CoV-2/genetics

• F30 MH116581 NIMH NIH HHS
• T32 GM007250 NIGMS NIH HHS
• TL1 TR002549 NCATS NIH HHS
• National Institutes of Health

Live-attenuated SARS-CoV-2 vaccines received relatively little attention during the COVID-19 pandemic. Despite this, several methods of obtaining attenuated coronaviruses are known. In this systematic review, the strategies of coronavirus attenuation, which may potentially be applied to SARS-CoV-2, were identified. PubMed, Scopus, Web of Science and Embase databases were searched to identify relevant articles describing attenuating mutations tested in vivo. In case of coronaviruses other than SARS-CoV-2, sequence alignment was used to exclude attenuating mutations that cannot be applied to SARS-CoV-2. Potential immunogenicity, safety and efficacy of the attenuated SARS-CoV-2 vaccine were discussed based on animal studies data. A total of 27 attenuation strategies, used to create 101 different coronaviruses, have been described in 56 eligible articles. The disruption of the furin cleavage site in the SARS-CoV-2 spike protein was identified as the most promising strategy. The replacement of core sequences of transcriptional regulatory signals, which prevents recombination with wild-type viruses, also appears particularly advantageous. Other important attenuating mutations encompassed mostly the prevention of evasion of innate immunity. Sufficiently attenuated coronaviruses typically caused no meaningful disease in susceptible animals and protected them from challenges with virulent virus. This indicates that attenuated COVID-19 vaccines may be considered as a potential strategy to fight the threat posed by SARS-CoV-2.

• Animals
• COVID-19/prevention & control
• COVID-19 Vaccines/immunology
• Humans
• SARS-CoV-2/genetics
• Spike Glycoprotein, Coronavirus/genetics
• Vaccine Development
• Vaccines, Attenuated/immunology

Whereas the COVID-19 disease pathophysiology is under investigation, it is important to identify the pathways of viral transmission and inflammation from the pre-illness to the disease-onset stages. We analyzed five lung lobes from a patient with COVID-19 who finally died after prolonged lung protective ventilation. Pathological examination revealed moderate inflammation in upper lung lobes and uneven yet severe inflammation and diffuse alveolar damage in lower lung lobes. SARS-CoV-2 was detected at higher levels not in severely, but rather moderately inflamed middle lung lobes, and immunohistochemistry and bulk RNA-sequencing results showed that immune cells were detected at higher levels in lower lung lobes. The mRNA expression of cytokine families varied. We found an increase in keratin 5- or aquaporin 3-expressing basal cells in the severely inflamed lower lung lobes, and the alveolar stromal tissues were filled with them. Thus, this analysis of lung samples from a patient helps to determine the COVID-19 pathophysiology at a specific time point, and the virus localization and inflammatory responses at each site of the lungs provide various important indications.

• AQP3
• COVID-19
• SARS-CoV-2
• basal cells
• immune cells

• ace2, angiotensin-converting enzyme 2
• pasc, post-acute sequelae of covid-19
• cvd, cardiovascular disease
• tnf, tumor necrosis factor
• pamp, pathogen associated molecular patterns
• damps, damage associated molecular patterns
• car-t, chimeric antigen receptor therapy
• dvt, deep venous thrombosis
• tf, tissue factor
• psgl, p-selectin glycoprotein ligand
• nets, neutrophil extracellular traps
• lv, left ventricular
• crp, c-reactive protein
• lge, late gadolinium enhancement
• cbv, coxsackie virus b
• b19v, parvovirus b12
• car, coxsackievirus and adenovirus receptor
• ns1, nonstructural protein 1
• ec, endothelial cells
• scrnaseq, single cell rna sequencing
• embx, endomyocardial biopsy
• tte, transthoracic echocardiograms
• rv, right ventricular
• gls, global longitudinal strain
• hscrp, high sensitivity c-reative protein
• vitt, vaccine-induced immune thrombotic thrombocytopenia
• dtap, diphtheria, tetanus, and polio
• vaers, vaccine adverse event reporting system

• In situ hybridization (ISH)
• Open reading frame (ORF1ab)
• Post-mortem lung samples
• Reverse transcription polymerase chain reaction (RT-PCR)
• SARS-CoV-2
• Spike(S)

• COVID-19/diagnosis
• Humans
• In Situ Hybridization/methods
• Lung
• RNA, Viral/genetics
• Reverse Transcriptase Polymerase Chain Reaction/methods
• SARS-CoV-2/genetics
• Sensitivity and Specificity

Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in late 2019, viral RNA has been detected in several different human tissues and organs. This study reports the detection of SARS-CoV-2 RNA in the bone marrow. Post-mortem samples were taken in a sterile manner during two forensic autopsies from the nasopharyngeal region, vitreous humor, cerebrospinal fluid, and bone marrow. SARS-CoV-2 was subsequently diagnosed via Genomtec^® SARS-CoV-2 EvaGreen^® RT-LAMP CE-IVD Duo Kit. In both postmortem patients, SARS-CoV-2 RNA was detected in bone marrow samples. However, both the vitreous humor and cerebrospinal fluid from the same patients gave negative results using the same test system. The evidence of viral RNA in the bone marrow, along with other reports supports the thesis that SARS-CoV-2 infections are systemic in nature, the consequences of which would profoundly influence both the testing and survival of patients.

• COVID-19
• FFPE
• SARS-CoV-2
• multi-organ dissemination
• multiplex real-time polymerase chain reaction
• viral load

• Aged
• Aged, 80 and over
• Autopsy
• COVID-19/pathology
• COVID-19/virology
• Female
• Humans
• Lung/pathology
• Lung/virology
• Male
• Middle Aged
• Multiple Organ Failure/pathology
• Multiple Organ Failure/virology
• RNA, Viral/genetics
• SARS-CoV-2/genetics
• SARS-CoV-2/isolation & purification
• SARS-CoV-2/metabolism
• SARS-CoV-2/pathogenicity
• Viral Load
• Viral Proteins/metabolism

• Coronavirus disease 2019
• Exosomes
• MIS-C
• Mesenchymal stem cell

• Animals
• COVID-19/complications
• COVID-19/genetics
• COVID-19/immunology
• COVID-19/therapy
• Humans
• Immunotherapy
• Mesenchymal Stem Cell Transplantation
• Mesenchymal Stem Cells/immunology
• Systemic Inflammatory Response Syndrome/genetics
• Systemic Inflammatory Response Syndrome/immunology
• Systemic Inflammatory Response Syndrome/therapy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in clinically significant multi-system disease including involvement in the kidney. The underlying histopathological processes were unknown at the start of the pandemic. As case reports and series have been published describing the underlying renal histopathology from kidney biopsies, we have started to gain an insight into the renal manifestations of this novel disease.

To provide an overview of the current literature on the renal histopathological features and mechanistic insights described in association with coronavirus disease 2019 (COVID-19) infection.

A systematic review was performed by conducting a literature search in the following websites-‘PubMed’, ‘Web of Science’, ‘Embase’ and ‘Medline-ProQuest’ with the following search terms-“COVID-19 AND kidney biopsy”, “COVID-19 AND renal biopsy”, “SARS-CoV-2 AND kidney biopsy” and “SARS-CoV-2 AND renal biopsy”. We have included published data up until February 15, 2021, which includes kidney biopsies (native, transplant and postmortem) from patients with COVID-19. Data on clinical presentation, histopathological features, management and outcome was extracted from the reported studies.

The total number of biopsies reported on here is 288, of which 189 are postmortem, 84 native and 15 transplants. The results are varied and show underlying pathologies ranging from collapsing glomerulopathy and acute tubular injury (ATI) to anti-nuclear cytoplasmic antibody associated vasculitis and pigment nephropathy. There was variation in the specific treatment used for the various renal conditions, which included steroids, hydroxychloroquine, eculizumab, convalescent plasma, rituximab, anakinra, cyclophosphamide and renal replacement therapy, amongst others. The pathological process which occurs in the kidney following COVID-19 infection and leads to the described biopsy findings has been hypothesized in some conditions but not others (for example, sepsis related hypoperfusion for ATI). It is important to note that this represents a very small minority of the total number of cases of COVID-19 related kidney disease, and as such there may be inherent selection bias in the results described. Further work will be required to determine the pathogenetic link, if any, between COVID-19 and the other renal pathologies.

This report has clinical relevance as certain renal pathologies have specific management, with the implication that kidney biopsy in the setting of renal disease and COVID-19 should be an early consideration, dependent upon the clinical presentation.

• COVID-19
• Histopathology
• Kidney biopsy
• Transplant
• SARS-CoV-2

• COVID-19
• Thrombosis
• gastrointestinal tract
• vasculitis

• R01 CA222064 NCI NIH HHS

• COVID-19
• interstitial nephritis
• podocyte
• proximal tubule
• pyelonephritis

• Animals
• Biopsy
• COVID-19/complications
• COVID-19/diagnosis
• COVID-19/mortality
• COVID-19/virology
• COVID-19 Testing
• Host-Pathogen Interactions
• Humans
• Kidney/virology
• Kidney Diseases/diagnosis
• Kidney Diseases/mortality
• Kidney Diseases/virology
• Predictive Value of Tests
• Prognosis
• Risk Assessment
• Risk Factors
• SARS-CoV-2/pathogenicity

• COVID-19
• Electron microscopy
• Fluorescence in situ hybridization
• Preanalytical phase
• Reverse transcriptase polymerase chain reaction

• Autopsy
• COVID-19
• Humans
• RNA, Viral
• SARS-CoV-2
• Sensitivity and Specificity

• covid-19
• acute kidney injury
• biology
• pathology
• pathophysiology
• glomerular disease
• acute tubular injury

• Acute Kidney Injury/pathology
• Acute Kidney Injury/physiopathology
• COVID-19/complications
• COVID-19/pathology
• Humans
• Kidney/pathology
• Kidney Tubular Necrosis, Acute/pathology
• SARS-CoV-2

• COVID-19
• SARS-CoV-2
• coronary microvascular dysfunction

• COVID-19/complications
• COVID-19/immunology
• COVID-19/physiopathology
• Cardiovascular Diseases/etiology
• Cardiovascular Diseases/physiopathology
• Coronary Vessels/physiopathology
• Disease Progression
• Endothelium, Vascular/physiopathology
• Female
• Humans
• Inflammation/physiopathology
• Male
• Microcirculation/physiology
• Models, Cardiovascular
• Renin-Angiotensin System/physiology
• Risk Factors
• SARS-CoV-2
• Thrombosis/etiology
• Thrombosis/physiopathology

• aav, adeno-associated virus
• ace2, angiotensin-converting enzyme 2
• ali, acute lung injury
• ards, acute respiratory distress syndrome
• covid-19, coronavirus disease 19
• dad, diffuse alveolar damage
• dpi, days postinfection
• dpp4, dipeptidyl peptidase 4
• hace2, human angiotensin-converting enzyme 2
• mace2, mouse angiotensin-converting enzyme 2
• mers, middle eastern respiratory syndrome
• mers-cov, middle eastern respiratory syndrome coronavirus
• sars, severe acute respiratory syndrome
• sars-cov, severe acute respiratory syndrome coronavirus
• sars-cov-2, severe acute respiratory syndrome coronavirus 2

• Animals
• COVID-19
• Disease Models, Animal
• Humans
• Lung
• Mice
• Pandemics
• SARS-CoV-2

• R01 AI157253 NIAID NIH HHS
• T32 AI007151 NIAID NIH HHS
• P30 CA016086 NCI NIH HHS
• U01 AI149644 NIAID NIH HHS
• U19 AI100625 NIAID NIH HHS
• UL1 TR002489 NCATS NIH HHS
• K01 OD026529 NIH HHS

• Asplenia
• Chronic liver disease
• IgM memory B cell
• Liver transplantation
• Transaminase

• COVID-19
• Humans
• Liver Diseases
• SARS-CoV-2
• Spleen

Current knowledge on histopathological changes occurring after COVID‐19 in transplanted kidneys is limited. Herein, we present renal allograft pathology findings in patients recovered from COVID‐19.

Six patients underwent indication biopsy, and one required allograft nephrectomy after acute COVID‐19. Demographic data, clinical characteristics, and laboratory findings were recorded. The histopathological analysis included light microscopy, immunostaining, and electron microscopy.

Five patients were hospitalized for acute COVID‐19, and all were diagnosed with imaging‐confirmed pneumonia, one requiring mechanical ventilation, and two requiring dialysis. Two patients had mild form. Histopathologic examination of renal allograft specimens revealed collapsing, perihilar, tip‐lesion and secondary FSGS in one patient each. One patient had borderline acute cellular rejection, and two had chronic antibody‐mediated rejection. Histopathologic changes of glomerular tufts were accompanied by acute tubular injury in four patients. None of our patients had signs of viral inclusions in kidney cells.

One patient died and one remained dialysis‐dependent after the good initial response to treatment. Patients with collapsing and perihilar FSGS had further progression of their chronic allograft nephropathy still without need for dialysis.

In conclusion, diverse kidney pathology may be found in SARS‐CoV‐2–infected renal transplant patients. It seems that viral infection may affect the immune system with triggering of glomerular diseases, while the acute tubular injury is of multifactorial etiology. Direct viral effect is less likely.

• COVID-19
• SARS-CoV-2
• biopsy
• histopathology
• renal transplantation

SARS-CoV-2 may produce intestinal symptoms that are generally mild, with a small percentage of patients developing more severe symptoms. The involvement of SARS-CoV-2 in the physiopathology of bowel damage is poorly known. Transmission electron microscopy (TEM) is a useful tool that provides an understanding of SARS-CoV-2 invasiveness, replication and dissemination in body cells but information outside the respiratory tract is very limited. We report two cases of severe intestinal complications (intestinal lymphoma and ischaemic colitis) in which the presence of SARS-CoV-2 in intestinal tissue was confirmed by TEM. These are the first two cases reported in the literature of persistence of SARS-CoV-2 demonstrated by TEM in intestinal tissue after COVID 19 recovery and SARS-CoV-2 nasopharyngeal clearance.

During the first pandemic peak (1st March–30th April 2020) 932 patients were admitted in Hospital Universitari Mútua Terrassa due to COVID-19, 41 (4.4%) required cross-sectional imaging techniques to assess severe abdominal pain and six of them (0.64%) required surgical resection. SARS-CoV-2 in bowel tissue was demonstrated by TEM in two of these patients. The first case presented as an ileocaecal inflammatory mass which turned to be a B-cell lymphoma. Viral particles were found in the cytoplasm of endothelial cells of damaged mucosa. In situ hybridization was negative in tumour cells, thus ruling out an oncogenic role for the virus. SARS-CoV-2 remained in intestinal tissue 6 months after nasopharyngeal clearance, suggesting latent infection. The second patient had a severe ischaemic colitis with perforation and SARS-CoV-2 was also identified in endothelial cells.

Severe intestinal complications associated with COVID-19 are uncommon. SARS-CoV-2 was identified by TEM in two cases, suggesting a causal role in bowel damage.

• COVID-19
• Case report
• Intestinal lymphoma
• Ischaemic colitis
• SARS-CoV-2
• Transmission electron microscopy

• COVID-19
• SARS-CoV-2
• geographical variants
• mutation
• strains