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sars, respiratory, clinical, cov, syndrome

Topic 17

sars respiratory clinical cov syndrome cat manifestation multisystem inflammatory pathogenesis shed viral mild severe acute

Virological assessment of hospitalized patients with COVID-2019

Coronavirus disease 2019 (COVID-19) is an acute respiratory tract infection that emerged in late 20191,2. Initial outbreaks in China involved 13.8% cases with severe, and 6.1% with critical courses3. This severe presentation corresponds to the usage of a virus receptor that is expressed predominantly in the lung2,4. By causing an early onset of severe symptoms, this same receptor tropism is thought to have determined pathogenicity, but also aided the control, of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of COVID-19 cases with mild upper respiratory tract symptoms, suggesting the potential for pre- or oligosymptomatic transmission6–8. There is an urgent need for information on body site-specific virus replication, immunity, and infectivity. Here we provide a detailed virological analysis of nine cases, providing proof of active virus replication in upper respiratory tract tissues. Pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4). Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Active replication in the throat was confirmed by viral replicative RNA intermediates in throat samples. Sequence-distinct virus populations were consistently detected in throat and lung samples from the same patient, proving independent replication. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (14 days in all), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild upper respiratory tract illness. Active virus replication in the upper respiratory tract puts the prospects of COVID-19 containment in perspective.
covid-19
infection
analysis
china
transmission
testing
hospitalization
symptom
infectious disease
viral load
virology
replication
rna
containment
sample
pathogen
cell, antibody, immune, cov-2-specific, epitope
sars, respiratory, clinical, cov, syndrome
Pediatric SARS-CoV-2: Clinical Presentation, Infectivity, and Immune Responses

ObjectivesAs schools plan for re-opening, understanding the potential role children play in the coronavirus infectious disease 2019 (COVID-19) pandemic and the factors that drive severe illness in children is critical.Study design: Children ages 0-22 years with suspected severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection presenting to urgent care clinics or being hospitalized for confirmed/suspected SARS-CoV-2 infection or multisystem inflammatory syndrome in children (MIS-C) at Massachusetts General Hospital (MGH) were offered enrollment in the MGH Pediatric COVID-19 Biorepository. Enrolled children provided nasopharyngeal, oropharyngeal, and/or blood specimens. SARS-CoV-2 viral load, ACE2 RNA levels, and serology for SARS-CoV-2 were quantified.ResultsA total of 192 children (mean age 10.2 +/- 7 years) were enrolled. Forty-nine children (26%) were diagnosed with acute SARS-CoV-2 infection; an additional 18 children (9%) met criteria for MIS-C. Only 25 (51%) of children with acute SARS-CoV-2 infection presented with fever; symptoms of SARS-CoV-2 infection, if present, were non-specific. Nasopharyngeal viral load was highest in children in the first 2 days of symptoms, significantly higher than hospitalized adults with severe disease (P = .002). Age did not impact viral load, but younger children had lower ACE2 expression (P=0.004). IgM and IgG to the receptor binding domain (RBD) of the SARS-CoV-2 spike protein were increased in severe MIS-C (P<0.001), with dysregulated humoral responses observed.ConclusionThis study reveals that children may be a potential source of contagion in the SARS-CoV-2 pandemic in spite of milder disease or lack of symptoms, and immune dysregulation is implicated in severe post-infectious MIS-C.
covid-19
transmission
epidemiology
immune response
children
contagion
symptom severity
spike protein
cell, antibody, immune, cov-2-specific, epitope
sars, respiratory, clinical, cov, syndrome
Characterization of Microbial Co-infections in the Respiratory Tract of hospitalized COVID-19 patients

Summary Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of Coronavirus disease 2019 (COVID-19). However, microbial composition of the respiratory tract and other infected tissues, as well as their possible pathogenic contributions to varying degrees of disease severity in COVID-19 patients remain unclear. Method Between January 27 and February 26, 2020, serial clinical specimens (sputum, nasal and throat swab, anal swab and feces) were collected from a cohort of hospitalized COVID-19 patients, including 8 mildly and 15 severely ill patients (requiring ICU admission and mechanical ventilation), in the Guangdong province, China. Total RNA was extracted and ultra-deep metatranscriptomic sequencing was performed in combination with laboratory diagnostic assays. Co-infection rates, the prevalence and abundance of microbial communities in these COVID-19 patients were determined. Findings Notably, respiratory microbial co-infections were exclusively found in 84.6% of severely ill patients (11/13), among which viral and bacterial co-infections were detected by sequencing in 30.8% (4/13) and 69.2% (9/13) of the patients, respectively. In addition, for 23.1% (3/13) of the patients, bacterial co-infections with Burkholderia cepacia complex (BCC) and Staphylococcus epidermidis were also confirmed by bacterial culture. Further, a time-dependent, secondary infection of B. cenocepacia with expressions of multiple virulence genes in one severely ill patient was demonstrated, which might be the primary cause of his disease deterioration and death one month after ICU admission. Interpretation Our findings identified distinct patterns of co-infections with SARS-CoV-2 and various respiratory pathogenic microbes in hospitalized COVID-19 patients in relation to disease severity. Detection and tracking of BCC-associated nosocomial infections are recommended to improve the pre-emptive treatment regimen and reduce fatal outcomes of hospitalized patients infected with SARS-CoV-2. Funding National Science and Technology Major Project of China, National Major Project for Control and Prevention of Infectious Disease in China, the emergency grants for prevention and control of SARS-CoV-2 of Ministry of Science and Technology and Guangdong province, Guangdong Provincial Key Laboratory of Genome Read and Write, Guangdong Provincial Academician Workstation of BGI Synthetic Genomics, and Shenzhen Engineering Laboratory for Innovative Molecular Diagnostics.
covid-19
tracking
comorbidity
epidemiology
research
contribution
detection
diagnostics
pattern
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome
Transplacental transmission of SARS-CoV-2 infection

SARS-CoV-2 outbreak is the first pandemic of the century. SARS-CoV-2 infection is transmitted through droplets; other transmission routes are hypothesized but not confirmed. So far, it is unclear whether and how SARS-CoV-2 can be transmitted from the mother to the fetus. We demonstrate the transplacental transmission of SARS-CoV-2 in a neonate born to a mother infected in the last trimester and presenting with neurological compromise. The transmission is confirmed by comprehensive virological and pathological investigations. In detail, SARS-CoV-2 causes: (1) maternal viremia, (2) placental infection demonstrated by immunohistochemistry and very high viral load; placental inflammation, as shown by histological examination and immunohistochemistry, and (3) neonatal viremia following placental infection. The neonate is studied clinically, through imaging, and followed up. The neonate presented with neurological manifestations, similar to those described in adult patients.
covid-19
transmission
symptom
virology
inflammation
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome
Comparative tropism, replication kinetics, and cell damage profiling of SARS-CoV-2 and SARS-CoV with implications for clinical manifestations, transmissibility, and laboratory studies of COVID-19: an observational study

BackgroundSevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was reported from China in January, 2020. SARS-CoV-2 is efficiently transmitted from person to person and, in 2 months, has caused more than 82 000 laboratory-confirmed cases of coronavirus disease 2019 (COVID-19) and 2800 deaths in 46 countries. The total number of cases and deaths has surpassed that of the 2003 severe acute respiratory syndrome coronavirus (SARS-CoV). Although both COVID-19 and severe acute respiratory syndrome (SARS) manifest as pneumonia, COVID-19 is associated with apparently more efficient transmission, fewer cases of diarrhoea, increased mental confusion, and a lower crude fatality rate. However, the underlying virus–host interactive characteristics conferring these observations on transmissibility and clinical manifestations of COVID-19 remain unknown.MethodsWe systematically investigated the cellular susceptibility, species tropism, replication kinetics, and cell damage of SARS-CoV-2 and compared findings with those for SARS-CoV. We compared SARS-CoV-2 and SARS-CoV replication in different cell lines with one-way ANOVA. For the area under the curve comparison between SARS-CoV-2 and SARS-CoV replication in Calu3 (pulmonary) and Caco2 (intestinal) cells, we used Student's t test. We analysed cell damage induced by SARS-CoV-2 and SARS-CoV with one-way ANOVA.FindingsSARS-CoV-2 infected and replicated to comparable levels in human Caco2 cells and Calu3 cells over a period of 120 h (p=0·52). By contrast, SARS-CoV infected and replicated more efficiently in Caco2 cells than in Calu3 cells under the same multiplicity of infection (p=0·0098). SARS-CoV-2, but not SARS-CoV, replicated modestly in U251 (neuronal) cells (p=0·036). For animal species cell tropism, both SARS-CoV and SARS-CoV-2 replicated in non-human primate, cat, rabbit, and pig cells. SARS-CoV, but not SARS-CoV-2, infected and replicated in Rhinolophus sinicus bat kidney cells. SARS-CoV-2 consistently induced significantly delayed and milder levels of cell damage than did SARS-CoV in non-human primate cells (VeroE6, p=0·016; FRhK4, p=0·0004).InterpretationAs far as we know, our study presents the first quantitative data for tropism, replication kinetics, and cell damage of SARS-CoV-2. These data provide novel insights into the lower incidence of diarrhoea, decreased disease severity, and reduced mortality in patients with COVID-19, with respect to the pathogenesis and high transmissibility of SARS-CoV-2 compared with SARS-CoV.
covid-19
transmission
epidemiology
symptom
mortality
observational study
severity
transmissibility
sars, respiratory, clinical, cov, syndrome
protein, spike, neutralize, ace2, design
Experimental infection of domestic dogs and cats with SARS-CoV-2: Pathogenesis, transmission, and response to reexposure in cats

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached nearly every country in the world with extraordinary person-to-person transmission. The most likely original source of the virus was spillover from an animal reservoir and subsequent adaptation to humans sometime during the winter of 2019 in Wuhan Province, China. Because of its genetic similarity to SARS-CoV-1, it is probable that this novel virus has a similar host range and receptor specificity. Due to concern for human–pet transmission, we investigated the susceptibility of domestic cats and dogs to infection and potential for infected cats to transmit to naive cats. We report that cats are highly susceptible to infection, with a prolonged period of oral and nasal viral shedding that is not accompanied by clinical signs, and are capable of direct contact transmission to other cats. These studies confirm that cats are susceptible to productive SARS-CoV-2 infection, but are unlikely to develop clinical disease. Further, we document that cats developed a robust neutralizing antibody response that prevented reinfection following a second viral challenge. Conversely, we found that dogs do not shed virus following infection but do seroconvert and mount an antiviral neutralizing antibody response. There is currently no evidence that cats or dogs play a significant role in human infection; however, reverse zoonosis is possible if infected owners expose their domestic pets to the virus during acute infection. Resistance to reinfection holds promise that a vaccine strategy may protect cats and, by extension, humans.
covid-19
infection
transmission
animal
immune response
cell, antibody, immune, cov-2-specific, epitope
sars, respiratory, clinical, cov, syndrome
Asymptomatic SARS-CoV-2 infection

The pandemic spread of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the cause of COVID-19, has placed lives and economies of many countries under unprecedented stress. Many countries have shut schools and workplaces and imposed physical distancing to reduce virus transmission, in an effort to prevent the number of COVID-19 cases from overwhelming health-care systems. Such measures, however, are not economically sustainable. Schools and workplaces will have to be reopened. An important challenge for returning to normality is the prevalence of asymptomatic infection and the question of whether such individuals could sustain community virus transmission.1Gandhi M Yokoe DS Havlir DV Asymptomatic transmission, the Achilles' heel of current strategies to control Covid-19.N Engl J Med. 2020; (published online April 24.)DOI:10.1056/NEJMe2009758Crossref Google Scholar As the health community debates and examines the epidemiological significance of asymptomatic individuals, such cases present unique opportunities to gain insight into COVID-19 pathogenesis.
covid-19
infection
outbreak
pathogenesis
asymptomatic
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome
Pathogenesis and transmission of SARS-CoV-2 in golden hamsters

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel coronavirus with high nucleotide identity to SARS-CoV and to SARS-related coronaviruses that have been detected in horseshoe bats, has spread across the world and had a global effect on healthcare systems and economies1,2. A suitable small animal model is needed to support the development of vaccines and therapies. Here we report the pathogenesis and transmissibility of SARS-CoV-2 in golden (Syrian) hamsters (Mesocricetus auratus). Immunohistochemistry assay demonstrated the presence of viral antigens in nasal mucosa, bronchial epithelial cells and areas of lung consolidation on days 2 and 5 after inoculation with SARS-CoV-2, followed by rapid viral clearance and pneumocyte hyperplasia at 7 days after inoculation. We also found viral antigens in epithelial cells of the duodenum, and detected viral RNA in faeces. Notably, SARS-CoV-2 was transmitted efficiently from inoculated hamsters to naive hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was not as efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally infected hamsters showed apparent weight loss on days 6–7 post-inoculation or post-contact; all hamsters returned to their original weight within 14 days and developed neutralizing antibodies. Our results suggest that features associated with SARS-CoV-2 infection in golden hamsters resemble those found in humans with mild SARS-CoV-2 infections.
covid-19
infection
transmission
symptom
animal
immune response
clinical outcome
pathogenesis
aerosol
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome
SARS-CoV-2, SARS-CoV-1 and MERS-CoV viral load dynamics, duration of viral shedding and infectiousness: a living systematic review and meta-analysis

Background Viral load kinetics and the duration of viral shedding are important determinants for disease transmission. We aim i) to characterise viral load dynamics, duration of viral RNA, and viable virus shedding of SARS-CoV-2 in various body fluids and ii) to compare SARS-CoV-2 viral dynamics with SARS-CoV-1 and MERS-CoV. Methods: Medline, EMBASE, Europe PMC, preprint servers and grey literature were searched to retrieve all articles reporting viral dynamics and duration of SARS-CoV-2, SARS-CoV-1 and MERS-CoV shedding. We excluded case reports and case series with < 5 patients, or studies that did not report shedding duration from symptom onset. PROSPERO registration: CRD42020181914. Findings: Seventy-nine studies on SARS-CoV-2, 8 on SARS-CoV-1, and 11 on MERS-CoV were included. Mean SARS-CoV-2 RNA shedding duration in upper respiratory tract, lower respiratory tract, stool and serum were 17.0, 14.6, 17.2 and 16.6 days, respectively. Maximum duration of SARS-CoV-2 RNA shedding reported in URT, LRT, stool and serum was 83, 59, 35 and 60 days, respectively. Pooled mean duration of SARS-CoV-2 RNA shedding was positively associated with age (p=0.002), but not gender (p = 0.277). No study to date has detected live virus beyond day nine of illness despite persistently high viral loads. SARS-CoV-2 viral load in the upper respiratory tract appears to peak in the first week of illness, while SARS-CoV-1 and MERS-CoV peak later. Conclusion: Although SARS-CoV-2 RNA shedding in respiratory and stool can be prolonged, duration of viable virus is relatively short-lived. Thus, detection of viral RNA cannot be used to infer infectiousness. High SARS-CoV-2 titres are detectable in the first week of illness with an early peak observed at symptom onset to day 5 of illness. This review underscores the importance of early case finding and isolation, as well as public education on the spectrum of illness. However, given potential delays in the isolation of patients, effective containment of SARS-CoV-2 may be challenging even with an early detection and isolation strategy. Funding: No funding was received.
covid-19
testing
infectiousness
dynamics
early stage
duration
viral load
systematic review
meta-analysis
detection
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome
Importance of precise data on SARS-CoV-2 transmission dynamics control

In December, 2019, COVID-19 was recognised as a novel respiratory disease in Wuhan, China,1Guan WJ Ni ZY Hu Y et al.Clinical characteristics of coronavirus disease 2019 in China.N Engl J Med. 2020; (published online Feb 28.)DOI:10.1056/NEJMoa2002032Google Scholar caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).2Zhu N Zhang D Wang W et al.A novel coronavirus from patients with pneumonia in China, 2019.N Engl J Med. 2020; 382: 727-733Google Scholar Accurate and reliable data on SARS-CoV-2 incubation time, secondary attack rate, and transmission dynamics are key to successful containment. In late January, 2020, infection with SARS-CoV-2 was detected in Germany for the first time. By rapid response, the public health authorities identified a business meeting in a Bavarian company as the primary transmission site and a participating Chinese employee who had travelled from Shanghai to Munich as the index patient.3Rothe C Schunk M Sothmann P et al.Transmission of 2019-nCoV Infection from an asymptomatic contact in Germany.N Engl J Med. 2020; 382: 970-971Google Scholar Subsequently, the rigorous investigation of contacts led to detection of 16 people infected with SARS-CoV-2 and to successful containment of this outbreak. This well defined event with limited extent of transmission enabled Merle Böhmer and colleagues to provide a meticulous description of SARS-CoV-2 transmission dynamics in an Article published in The Lancet Infectious Diseases.4Böhmer MM Buchholz U Corman VM et al.Investigation of a COVID-19 outbreak in Germany resulting from a single travel-associated primary case: a case series.Lancet Infect Dis. 2020; (published online May 15.)https://doi.org/10.1016/S1473-3099(20)30314-5Google Scholar The authors did standard and in-depth interviews with case patients and household members to determine the characteristics and the onset of symptoms. Data were used for calculation of SARS-CoV-2 secondary attack rates, defined as the probability that an infection occurs among susceptible people within the incubation period.5Liu Y Eggo RM Kucharski AJ Secondary attack rate and superspreading events for SARS-CoV-2.Lancet. 2020; 395: e47Google Scholar In addition, whole genome sequencing of virus isolates was done in 15 of the 16 cases. As a result, Böhmer and colleagues report a detailed transmission network of the outbreak, which is accurately displayed in the main figure of the Article
covid-19
germany
outbreak
infection control
symptom onset
transmission dynamics
transmission, cov-2, secondary, china, household
sars, respiratory, clinical, cov, syndrome