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1.
Sci Rep ; 11(1): 18120, 2021 09 13.
Article in English | MEDLINE | ID: covidwho-1406410

ABSTRACT

Isolation, contact tracing and restrictions on social movement are being globally implemented to prevent and control onward spread of SARS-CoV-2, even though the infection risk modelled on RNA detection by RT-qPCR remains biased as viral shedding and infectivity are not discerned. Thus, we aimed to develop a rapid viability RT-qPCR procedure to infer SARS-CoV-2 infectivity in clinical specimens and environmental samples. We screened monoazide dyes and platinum compounds as viability molecular markers on five SARS-CoV-2 RNA targets. A platinum chloride-based viability RT-qPCR was then optimized using genomic RNA, and inactivated SARS-CoV-2 particles inoculated in buffer, stool, and urine. Our results were finally validated in nasopharyngeal swabs from persons who tested positive for COVID-19 and in wastewater samples positive for SARS-CoV-2 RNA. We established a rapid viability RT-qPCR that selectively detects potentially infectious SARS-CoV-2 particles in complex matrices. In particular, the confirmed positivity of nasopharyngeal swabs following the viability procedure suggests their potential infectivity, while the complete prevention of amplification in wastewater indicated either non-infectious particles or free RNA. The viability RT-qPCR approach provides a more accurate ascertainment of the infectious viruses detection and it may complement analyses to foster risk-based investigations for the prevention and control of new or re-occurring outbreaks with a broad application spectrum.


Subject(s)
COVID-19/diagnosis , Platinum Compounds/pharmacology , RNA, Viral/genetics , Reverse Transcriptase Polymerase Chain Reaction/methods , SARS-CoV-2/genetics , COVID-19/epidemiology , COVID-19/virology , Contact Tracing/methods , Disease Outbreaks/prevention & control , Humans , SARS-CoV-2/physiology , Sensitivity and Specificity , Virus Shedding/drug effects
2.
Clin Dermatol ; 38(6): 750-756, 2020.
Article in English | MEDLINE | ID: covidwho-1385291

ABSTRACT

Pemphigus and its variants, viz., vulgaris, foliaceous, vegetans, Ig A pemphigus, paraneoplastic pemphigus and Senear-Usher syndrome are rare autoimmune blistering diseases of the skin and/or mucous membranes. The autoantibodies involved in the pathogenesis of pemphigus against desmoglein result in the breach of the skin and mucosal barrier, which acts as the first line of defence against pathogens. In this paper we underscore the importance of the integumentary system as a shield against the acquisition as well as transmission of SARS-CoV-2 virion. We have also made an attempt to delineate the various treatment modalities available and the viral-drug dynamics involved in choosing the optimum therapeutic modality.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/transmission , Pemphigus/drug therapy , Virus Shedding , Administration, Oral , Adrenal Cortex Hormones/adverse effects , COVID-19/complications , Feces/virology , Humans , Intestinal Mucosa/drug effects , Intestinal Mucosa/virology , Mouth Mucosa/virology , Pemphigus/complications , Risk Factors , SARS-CoV-2 , Virus Shedding/drug effects
3.
J Clin Lab Anal ; 35(9): e23923, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1353465

ABSTRACT

BACKGROUND: The dynamic alteration and comparative study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA shedding pattern during treatment are limited. This study explores the potential risk factors influencing prolonged viral shedding in COVID-19. METHODS: A total of 126 COVID-19 patients were enrolled in this retrospective longitudinal study. A multivariate logistic regression analysis was carried out to estimate the potential risk factors. RESULTS: 38.1% (48/126) cases presented prolonged respiratory tract viral shedding, and 30 (23.8%) cases presented prolonged rectal swab viral shedding. Obesity (OR, 3.31; 95% CI, 1.08-10.09), positive rectal swab (OR, 3.43; 95% CI, 1.53-7.7), treatment by lopinavir/ritonavir with chloroquine phosphate (OR, 2.5; 95% CI, 1.04-6.03), the interval from onset to antiviral treatment more than 7 days (OR, 2.26; 95% CI, 1.04-4.93), lower CD4+ T cell (OR, 0.92; 95% CI, 0.86-0.99) and higher NK cells (OR, 1.11; 95% CI, 1.02-1.20) were significantly associated with prolonged respiratory tract viral shedding. CD3-CD56+ NK cells (OR, 0.87; 95% CI, 0.76-0.99) were related with prolonged fecal shedding. CONCLUSIONS: Obesity, delayed antiviral treatment, and positive SARS-CoV-2 for stool were independent risk factors for prolonged SARS-CoV-2 RNA shedding of the respiratory tract. A combination of LPV/r and abidol as the initial antiviral regimen was effective in shortening the duration of viral shedding compared with LPV/r combined with chloroquine phosphate. CD4+ T cell and NK cells were significantly associated with prolonged viral shedding, and further studies are to be warranted to determine the mechanism of immunomodulatory response in virus clearance.


Subject(s)
COVID-19/virology , Feces/virology , SARS-CoV-2/physiology , Virus Shedding/physiology , Adult , Animals , Antiviral Agents/administration & dosage , CD4 Lymphocyte Count , COVID-19/epidemiology , Chloroquine/administration & dosage , Chloroquine/adverse effects , Chloroquine/analogs & derivatives , Female , Humans , Killer Cells, Natural , Longitudinal Studies , Lopinavir/administration & dosage , Lynx , Male , Obesity/epidemiology , Respiratory System/virology , Retrospective Studies , Risk Factors , Ritonavir/administration & dosage , Time Factors , Virus Shedding/drug effects
4.
Life Sci Alliance ; 4(10)2021 10.
Article in English | MEDLINE | ID: covidwho-1342114

ABSTRACT

The duration of viral shedding is determined by a balance between de novo infection and removal of infected cells. That is, if infection is completely blocked with antiviral drugs (100% inhibition), the duration of viral shedding is minimal and is determined by the length of virus production. However, some mathematical models predict that if infected individuals are treated with antiviral drugs with efficacy below 100%, viral shedding may last longer than without treatment because further de novo infections are driven by entry of the virus into partially protected, uninfected cells at a slower rate. Using a simple mathematical model, we quantified SARS-CoV-2 infection dynamics in non-human primates and characterized the kinetics of viral shedding. We counterintuitively found that treatments initiated early, such as 0.5 d after virus inoculation, with intermediate to relatively high efficacy (30-70% inhibition of virus replication) yield a prolonged duration of viral shedding (by about 6.0 d) compared with no treatment.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Virus Shedding/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Alanine/analogs & derivatives , Alanine/pharmacology , Animals , Lung/virology , Macaca mulatta , Models, Theoretical , Nose/virology , Pharynx/virology , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Time Factors , Viral Load/drug effects , Virus Replication/drug effects
5.
Lancet Respir Med ; 9(5): 498-510, 2021 05.
Article in English | MEDLINE | ID: covidwho-1301092

ABSTRACT

BACKGROUND: To date, only monoclonal antibodies have been shown to be effective for outpatients with COVID-19. Interferon lambda-1 is a type III interferon involved in innate antiviral responses with activity against respiratory pathogens. We aimed to investigate the safety and efficacy of peginterferon lambda in the treatment of outpatients with mild-to-moderate COVID-19. METHODS: In this double-blind, placebo-controlled trial, outpatients with laboratory-confirmed COVID-19 were randomly assigned to a single subcutaneous injection of peginterferon lambda 180 µg or placebo within 7 days of symptom onset or first positive swab if asymptomatic. Participants were randomly assigned (1:1) using a computer-generated randomisation list created with a randomisation schedule in blocks of four. At the time of administration, study nurses received a sealed opaque envelope with the treatment allocation number. The primary endpoint was the proportion of patients who were negative for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA on day 7 after the injection, analysed by a χ2 test following an intention-to-treat principle. Prespecified analysis of the primary endpoint, adjusted for baseline viral load, using bivariate logistic regression was done. The trial is now complete. This trial is registered with ClinicalTrials.gov, NCT04354259. FINDINGS: Between May 18, and Sept 4, 2020, we recruited 30 patients per group. The decline in SARS-CoV-2 RNA was greater in those treated with peginterferon lambda than placebo from day 3 onwards, with a difference of 2·42 log copies per mL at day 7 (p=0·0041). By day 7, 24 (80%) participants in the peginterferon lambda group had an undetectable viral load, compared with 19 (63%) in the placebo group (p=0·15). After controlling for baseline viral load, patients in the peginterferon lambda group were more likely to have undetectable virus by day 7 than were those in the placebo group (odds ratio [OR] 4·12 [95% CI 1·15-16·73; p=0·029). Of those with baseline viral load above 106 copies per mL, 15 (79%) of 19 patients in the peginterferon lambda group had undetectable virus on day 7, compared with six (38%) of 16 in the placebo group (OR 6·25 [95% CI 1·49-31·06]; p=0·012). Peginterferon lambda was well tolerated, and adverse events were similar between groups with mild and transient aminotransferase, concentration increases more frequently observed in the peginterferon lambda group. Two individuals met the threshold of grade 3 increase, one in each group, and no other grade 3 or 4 laboratory adverse events were reported. INTERPRETATION: Peginterferon lambda accelerated viral decline in outpatients with COVID-19, increasing the proportion of patients with viral clearance by day 7, particularly in those with high baseline viral load. Peginterferon lambda has potential to prevent clinical deterioration and shorten duration of viral shedding. FUNDING: The Toronto COVID-19 Action Initiative, University of Toronto, and the Ontario First COVID-19 Rapid Research Fund, Toronto General & Western Hospital Foundation.


Subject(s)
Ambulatory Care/methods , COVID-19 , Interleukins , Polyethylene Glycols , SARS-CoV-2 , Viral Load/drug effects , Virus Shedding/drug effects , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , COVID-19/diagnosis , COVID-19/drug therapy , COVID-19/immunology , Double-Blind Method , Drug Monitoring/methods , Female , Humans , Intention to Treat Analysis , Interleukins/administration & dosage , Interleukins/adverse effects , Male , Middle Aged , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/adverse effects , RNA, Viral/isolation & purification , SARS-CoV-2/isolation & purification , SARS-CoV-2/physiology , Severity of Illness Index , Treatment Outcome
6.
J Infect Dis ; 223(12): 2020-2028, 2021 06 15.
Article in English | MEDLINE | ID: covidwho-1246725

ABSTRACT

Effective clinical intervention strategies for coronavirus disease 2019 (COVID-19) are urgently needed. Although several clinical trials have evaluated use of convalescent plasma containing virus-neutralizing antibodies, levels of neutralizing antibodies are usually not assessed and the effectiveness has not been proven. We show that hamsters treated prophylactically with a 1:2560 titer of human convalescent plasma or a 1:5260 titer of monoclonal antibody were protected against weight loss, had a significant reduction of virus replication in the lungs, and showed reduced pneumonia. Interestingly, this protective effect was lost with a titer of 1:320 of convalescent plasma. These data highlight the importance of screening plasma donors for high levels of neutralizing antibodies. Our data show that prophylactic administration of high levels of neutralizing antibody, either monoclonal or from convalescent plasma, prevent severe SARS-CoV-2 pneumonia in a hamster model, and could be used as an alternative or complementary to other antiviral treatments for COVID-19.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antibodies, Neutralizing/therapeutic use , COVID-19/therapy , Lung/pathology , SARS-CoV-2/immunology , Virus Replication/drug effects , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Neutralizing/administration & dosage , COVID-19/immunology , Cricetinae , Disease Models, Animal , Humans , Immunization, Passive , Lung/drug effects , Virus Shedding/drug effects , Weight Loss/drug effects
7.
Viruses ; 13(5)2021 05 12.
Article in English | MEDLINE | ID: covidwho-1227067

ABSTRACT

SARS-CoV-2 nasopharyngeal shedding contributes to the spread of the COVID-19 epidemic. Among 3271 COVID-19 patients treated at the Hospital University Institute Méditerranée Infection, Marseille, France from 3 March to 27 April 2020, tested at least twice by qRT-PCR, the median SARS-CoV-2 nasopharyngeal shedding duration was 6 days (range 2-54 days). Compared with short shedders (qRT-PCR positivity < 10 days), 34 (1.04%) persistent shedders (qRT-PCR positivity ≥ 17 days; mean ± SD: 23.3 ± 3.8 days) were significantly older, with associated comorbidities, exhibiting lymphopenia, eosinopenia, increased D-dimer and increased troponin (p < 0.05), and were hospitalized in intensive care unit in 17.7% vs. 1.1% of cases (p < 0.0001). Viral culture was positive in six persistent shedders after day 10, including in one patient after day 17, and no viral co-pathogen was detected in 33 tested patients. Persistent shedders received azithromycin plus hydroxychloroquine ≥ 3 days in 26/34 (76.5%) patients, a figure significantly lower than in short shedders (86.6%) (p = 0.042). Accordingly, mortality was 14.7% vs. 0.5% (p < 0.0001). Persistent shedding was significantly associated with persistent dyspnea and anosmia/ageusia (p < 0.05). In the context of COVID-19 treatment, including treatment with azithromycin plus hydroxychloroquine, the persistence of SARS-CoV-2 nasopharyngeal shedding was a rare event, most frequently encountered in elderly patients with comorbidities and lacking azithromycin plus hydroxychloroquine treatment.


Subject(s)
COVID-19/metabolism , Hydroxychloroquine/pharmacology , Virus Shedding/drug effects , Adult , Aged , Azithromycin/metabolism , Azithromycin/pharmacology , COVID-19/drug therapy , Comorbidity , Drug Therapy, Combination , Female , France/epidemiology , Hospitalization , Humans , Hydroxychloroquine/metabolism , Male , Middle Aged , Nasopharynx , SARS-CoV-2/drug effects , SARS-CoV-2/metabolism , SARS-CoV-2/pathogenicity
8.
J Med Virol ; 93(1): 472-480, 2021 01.
Article in English | MEDLINE | ID: covidwho-1206789

ABSTRACT

During the early stages of the pandemic, some coronavirus disease (COVID-19) patients were misdiagnosed as having influenza, which aroused the concern that some deaths attributed to influenza were actually COVID-19-related. However, little is known about whether coinfection with influenza contributes to severity of COVID-19 pneumonia, and the optimal therapeutic strategy for these patients. We retrospectively studied 128 hospitalized patients with COVID-19 pneumonia. All patients were positive severe acute respiratory syndrome coronavirus 2 positive by nucleic acid detection. Sixty-four cases were coinfected with influenza A/B and the other 64 were influenza negative, matched by age, sex, and days from onset of symptoms. Among the 64 coinfected patients, 54 (84.4%) were coinfected with influenza A, and 10 (15.6%) with influenza B. The median duration of viral shedding time from admission was longer for patients with influenza coinfection (17.0 days) than for those without influenza coinfection (12.0 days) (P < .001). The multivariable Cox proportional hazards model showed that the hazards ratio of resolution in lung involvement was 1.878 (P = .020) for patients administered lopinavir/ritonavir, compared with those not administered lopinavir/ritonavir (95% confidence interval: 1.103-3.196). Among influenza coinfected patients, those treated with lopinavir/ritonavir exhibited faster pneumonia resolution within 2 weeks after symptom onset (37% vs 1%; P = .001). There was no difference in lung involvement between influenza coinfected and noninfected groups. Lopinavir/ritonavir eliminated the difference of lung involvement between influenza coinfected and noninfected groups, indicating that lopinavir/ritonavir is associated with pneumonia resolution in COVID-19.


Subject(s)
Antiviral Agents/therapeutic use , COVID-19/drug therapy , Coinfection/drug therapy , Influenza, Human/drug therapy , Lopinavir/therapeutic use , Pneumonia/drug therapy , Ritonavir/therapeutic use , Aged , COVID-19/virology , Case-Control Studies , Cohort Studies , Drug Therapy, Combination/methods , Female , Hospitalization , Humans , Influenza, Human/virology , Male , Middle Aged , Pandemics/prevention & control , Pneumonia/virology , Retrospective Studies , SARS-CoV-2/drug effects , Virus Shedding/drug effects
9.
J Med Virol ; 93(3): 1766-1769, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196474

ABSTRACT

Asymptomatic and convalescent coronavirus disease 2019 (COVID-19) subjects may carry severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for months in their upper respiratory ways. Desiring to permanently clean the mucosal surfaces, we investigated the chemical agents that fit to rapidly degrade the virus. Among these, hydrogen peroxide, initially tested by two of us for tolerability, showed both good performance and acceptable side effects (burning sensation for 15-20 s). We contacted circles of family physicians and the ATS Milano (Territorial Assistance and Prevention Service), and we tested this procedure on eight persistent carriers of SARS-CoV-2, performing swabs before the procedure and after it until the reappearance of the virus or until 14 days (the incubation period), keeping the surfaces clean with a hypertonic solution. Our patients had a median time from exposure or symptom onset of 111 days, and three had relapsed after being declared "cured" (two consecutive negative swabs after quarantine). One patient had a baseline negative swab and was excluded, and two successfully ended the 14 days' course, four suppressed viral elimination for 72 h, and one for 48 h, all rebounding to weak positive (cycle thresholds above 24). Although temporarily effective, such measures may have some place in the control of viral shedding to protect the most fragile subjects.


Subject(s)
COVID-19/drug therapy , Carrier State/drug therapy , Hydrogen Peroxide/therapeutic use , Oxidants/therapeutic use , SARS-CoV-2/drug effects , Adult , Antiviral Agents/therapeutic use , Carrier State/virology , Female , Humans , Male , Middle Aged , Nasopharynx/virology , SARS-CoV-2/isolation & purification , Treatment Outcome , Virus Shedding/drug effects
10.
J Med Virol ; 93(3): 1538-1547, 2021 03.
Article in English | MEDLINE | ID: covidwho-1196473

ABSTRACT

Steroids may play a critical role in the current pandemic of coronavirus disease-2019 (COVID-19), given the dearth of specific therapeutic options. This review was conducted to evaluate the impact of glucocorticoid therapy in patients with COVID-19 based on the publications reported to date. A comprehensive screening was conducted using electronic databases up to August 19, 2020. The randomized controlled trials (RCTs) and cohort studies evaluating the effectiveness and safety of steroids in patients with COVID-19 are included for the meta-analyses. Our search retrieved twelve studies, including two RCTs and 10 cohort studies, with a total of 15,754 patients. In patients with COVID-19, the use of systemic glucocorticoid neither reduce mortality (odds ratio [OR] = 1.94, 95% confidence interval [CI]: 1.11-3.4, I2 = 96%), nor the duration of hospital stay (mean difference [MD] = 1.18 days, 95% CI: -1.28 to 3.64, I2 = 93%) and period of viral shedding (MD = 1.42 days, 95% CI: -0.52 to 3.37, I2 = 0%). Systemic steroid therapy may not be effective for reducing mortality, duration of hospitalization, and period of viral shedding. Studies are mostly heterogeneous. Further RCTs are required.


Subject(s)
COVID-19/drug therapy , Glucocorticoids/therapeutic use , SARS-CoV-2/drug effects , COVID-19/mortality , Humans , Length of Stay , Treatment Outcome , Virus Shedding/drug effects
11.
Res Vet Sci ; 130: 222-229, 2020 Jun.
Article in English | MEDLINE | ID: covidwho-761807

ABSTRACT

Feline coronavirus (FCoV) is common among cats living indoors in groups. In about 10% of infected cats, a potentially lethal disease, feline infectious peritonitis (FIP) occurs. Virus transmission is faecal-oral. Mutian® Xraphconn (Mutian X) is a product marketed to treat cats with FIP but is also being used to stop virus shedding, although no clear guidelines exist for its use for this purpose. The aim of this study was to establish the minimum dose and treatment duration required to ensure viral clearance from the faeces of asymptomatic virus-shedding cats. In five multicat households, 29 cats naturally infected with FCoV and actively shedding virus in the faeces were given Mutian X pills. Virus shedding was monitored using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) controlled for faecal inhibitors to ensure sensitivity. Mutian X given orally cleared the virus in 29 cats; although four cats required a repeated course to finally stop virus shedding. A dose of 4 mg/kg q24 h for four days was found to be the optimal treatment protocol: 2 mg/kg cleared only 80% of cats. Post-treatment using a sensitive RT-qPCR test was essential to ensure that virus clearance had been achieved, since failure to clear even one cat can result in re-infection of the others. Records of virus shedding by cats before treatment provided a retrospective control: significantly more cats stopped shedding virus after Mutian X than recovered from infection during the control period (p < .00001). This is the first report of the successful elimination of faecal FCoV shedding in chronically infected cats.


Subject(s)
Antiviral Agents/therapeutic use , Coronavirus, Feline/drug effects , Feline Infectious Peritonitis/drug therapy , Virus Shedding/drug effects , Administration, Oral , Animals , Cats , Feces/virology , Retrospective Studies
12.
Nat Commun ; 12(1): 1967, 2021 03 30.
Article in English | MEDLINE | ID: covidwho-1159789

ABSTRACT

Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.


Subject(s)
Antiviral Agents/administration & dosage , COVID-19/drug therapy , Interleukins/administration & dosage , Polyethylene Glycols/administration & dosage , Adult , Aged , COVID-19/virology , Female , Humans , Injections, Subcutaneous , Male , Middle Aged , Outpatients , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Single-Blind Method , Treatment Failure , Virus Shedding/drug effects , Young Adult
13.
Clin Pharmacol Ther ; 110(2): 321-333, 2021 08.
Article in English | MEDLINE | ID: covidwho-1103289

ABSTRACT

Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) viral loads change rapidly following symptom onset, so to assess antivirals it is important to understand the natural history and patient factors influencing this. We undertook an individual patient-level meta-analysis of SARS-CoV-2 viral dynamics in humans to describe viral dynamics and estimate the effects of antivirals used to date. This systematic review identified case reports, case series, and clinical trial data from publications between January 1, 2020, and May 31, 2020, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A multivariable Cox proportional hazards (Cox-PH) regression model of time to viral clearance was fitted to respiratory and stool samples. A simplified four parameter nonlinear mixed-effects (NLME) model was fitted to viral load trajectories in all sampling sites and covariate modeling of respiratory viral dynamics was performed to quantify time-dependent drug effects. Patient-level data from 645 individuals (age 1 month to 100 years) with 6,316 viral loads were extracted. Model-based simulations of viral load trajectories in samples from the upper and lower respiratory tract, stool, blood, urine, ocular secretions, and breast milk were generated. Cox-PH modeling showed longer time to viral clearance in older patients, men, and those with more severe disease. Remdesivir was associated with faster viral clearance (adjusted hazard ratio (AHR) = 9.19, P < 0.001), as well as interferon, particularly when combined with ribavirin (AHR = 2.2, P = 0.015; AHR = 6.04, P = 0.006). Combination therapy should be further investigated. A viral dynamic dataset and NLME model for designing and analyzing antiviral trials has been established.


Subject(s)
Antiviral Agents/pharmacology , COVID-19/drug therapy , COVID-19/virology , Viral Load/drug effects , Adenosine Monophosphate/analogs & derivatives , Adenosine Monophosphate/pharmacology , Adult , Alanine/analogs & derivatives , Alanine/pharmacology , Clinical Trials as Topic , Drug Therapy, Combination , Female , Humans , Interferons/pharmacology , Male , Middle Aged , Proportional Hazards Models , SARS-CoV-2/pathogenicity , Virus Shedding/drug effects
14.
Curr Med Sci ; 41(1): 24-30, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-1082574

ABSTRACT

The role of corticosteroids in the treatment of Coronavirus disease 2019 (COVID-19) is controversial. In the present study, we evaluated the effects of adjuvant corticosteroids treatment on the outcome of patients with COVID-19 (n=966), using Propensity Score Matching to adjust for potential differences between the corticosteroids group (n=289) and the non-corticosteroids group (n=677). Analysis of data without adjusting differences in baseline characteristics indicated that the proportion of mechanical ventilation and the mortality was higher in the corticosteroids treatment group in total or severe/critical patients. The duration of viral shedding was longer in the non-corticosteroids treatment group in total or general/mild patients. After adjusting the difference between the corticosteroids and non-corticosteroids treatment group, the analysis revealed that the use of corticosteroids had no effect on the duration of viral shedding, in-hospital mortality or 28-day mortality.


Subject(s)
Adrenal Cortex Hormones/administration & dosage , COVID-19/drug therapy , SARS-CoV-2/physiology , Adrenal Cortex Hormones/therapeutic use , Aged , Chemotherapy, Adjuvant , Female , Hospital Mortality , Humans , Male , Middle Aged , Propensity Score , Retrospective Studies , SARS-CoV-2/drug effects , Virus Shedding/drug effects
15.
PLoS Comput Biol ; 17(1): e1008470, 2021 01.
Article in English | MEDLINE | ID: covidwho-1058291

ABSTRACT

Finding medications or vaccines that may decrease the infectious period of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) could potentially reduce transmission in the broader population. We developed a computational model of the U.S. simulating the spread of SARS-CoV-2 and the potential clinical and economic impact of reducing the infectious period duration. Simulation experiments found that reducing the average infectious period duration could avert a median of 442,852 [treating 25% of symptomatic cases, reducing by 0.5 days, reproductive number (R0) 3.5, and starting treatment when 15% of the population has been exposed] to 44.4 million SARS-CoV-2 cases (treating 75% of all infected cases, reducing by 3.5 days, R0 2.0). With R0 2.5, reducing the average infectious period duration by 0.5 days for 25% of symptomatic cases averted 1.4 million cases and 99,398 hospitalizations; increasing to 75% of symptomatic cases averted 2.8 million cases. At $500/person, treating 25% of symptomatic cases saved $209.5 billion (societal perspective). Further reducing the average infectious period duration by 3.5 days averted 7.4 million cases (treating 25% of symptomatic cases). Expanding treatment to 75% of all infected cases, including asymptomatic infections (R0 2.5), averted 35.9 million cases and 4 million hospitalizations, saving $48.8 billion (societal perspective and starting treatment after 5% of the population has been exposed). Our study quantifies the potential effects of reducing the SARS-CoV-2 infectious period duration.


Subject(s)
COVID-19/drug therapy , COVID-19/transmission , Models, Biological , Pandemics , SARS-CoV-2 , COVID-19/epidemiology , COVID-19 Vaccines/therapeutic use , Computational Biology , Computer Simulation , Humans , Pandemics/prevention & control , Pandemics/statistics & numerical data , SARS-CoV-2/drug effects , Time Factors , United States/epidemiology , Virus Shedding/drug effects
16.
Nat Commun ; 12(1): 81, 2021 01 04.
Article in English | MEDLINE | ID: covidwho-1007628

ABSTRACT

There is a vital need for authentic COVID-19 animal models to enable the pre-clinical evaluation of candidate vaccines and therapeutics. Here we report a dose titration study of SARS-CoV-2 in the ferret model. After a high (5 × 106 pfu) and medium (5 × 104 pfu) dose of virus is delivered, intranasally, viral RNA shedding in the upper respiratory tract (URT) is observed in 6/6 animals, however, only 1/6 ferrets show similar signs after low dose (5 × 102 pfu) challenge. Following sequential culls pathological signs of mild multifocal bronchopneumonia in approximately 5-15% of the lung is seen on day 3, in high and medium dosed groups. Ferrets re-challenged, after virus shedding ceased, are fully protected from acute lung pathology. The endpoints of URT viral RNA replication & distinct lung pathology are observed most consistently in the high dose group. This ferret model of SARS-CoV-2 infection presents a mild clinical disease.


Subject(s)
COVID-19/immunology , Disease Models, Animal , Ferrets/immunology , SARS-CoV-2/immunology , Animals , Antibodies, Viral/immunology , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , Dose-Response Relationship, Drug , Female , Lung/immunology , Lung/pathology , RNA, Viral/isolation & purification , SARS-CoV-2/genetics , Virus Replication/drug effects , Virus Replication/immunology , Virus Shedding/drug effects , Virus Shedding/immunology
17.
Front Immunol ; 11: 596761, 2020.
Article in English | MEDLINE | ID: covidwho-972668

ABSTRACT

The disease course of COVID-19 in patients with immunodeficiencies is unclear, as well as the optimal therapeutic strategy. We report a case of a 37-year old male with common variable immunodeficiency disorder and a severe SARS-CoV-2 infection. After administration of convalescent plasma, the patient's condition improved rapidly. Despite clinical recovery, viral RNA remained detectable up to 60 days after onset of symptoms. We propose that convalescent plasma might be considered as a treatment option in patients with CVID and severe COVID-19. In addition, in patients with immunodeficiencies, a different clinical course is possible, with prolonged viral shedding.


Subject(s)
Antibodies, Viral/administration & dosage , COVID-19/therapy , Common Variable Immunodeficiency , RNA, Viral , SARS-CoV-2 , Virus Shedding , Adult , COVID-19/blood , COVID-19/immunology , Common Variable Immunodeficiency/blood , Common Variable Immunodeficiency/immunology , Common Variable Immunodeficiency/therapy , Humans , Immunization, Passive , Male , RNA, Viral/blood , RNA, Viral/immunology , SARS-CoV-2/immunology , SARS-CoV-2/metabolism , Virus Shedding/drug effects , Virus Shedding/immunology
18.
Adv Drug Deliv Rev ; 169: 100-117, 2021 02.
Article in English | MEDLINE | ID: covidwho-966180

ABSTRACT

To address the COVID-19 pandemic, there has been an unprecedented global effort to advance potent neutralizing mAbs against SARS-CoV-2 as therapeutics. However, historical efforts to advance antiviral monoclonal antibodies (mAbs) for the treatment of other respiratory infections have been met with categorical failures in the clinic. By investigating the mechanism by which SARS-CoV-2 and similar viruses spread within the lung, along with available biodistribution data for systemically injected mAb, we highlight the challenges faced by current antiviral mAbs for COVID-19. We summarize some of the leading mAbs currently in development, and present the evidence supporting inhaled delivery of antiviral mAb as an early intervention against COVID-19 that could prevent important pulmonary morbidities associated with the infection.


Subject(s)
Antibodies, Monoclonal/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/therapy , Immunologic Factors/therapeutic use , SARS-CoV-2/drug effects , Angiotensin-Converting Enzyme 2/antagonists & inhibitors , Angiotensin-Converting Enzyme 2/metabolism , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/metabolism , Antiviral Agents/chemistry , Antiviral Agents/metabolism , COVID-19/diagnosis , COVID-19/metabolism , Humans , Immunization, Passive , Immunologic Factors/chemistry , Immunologic Factors/metabolism , Protein Structure, Secondary , Protein Structure, Tertiary , SARS-CoV-2/chemistry , SARS-CoV-2/metabolism , Virus Shedding/drug effects , Virus Shedding/physiology
19.
Chest ; 159(3): 1019-1040, 2021 03.
Article in English | MEDLINE | ID: covidwho-959674

ABSTRACT

BACKGROUND: Since its appearance in late 2019, infections caused by severe acute respiratory syndrome coronavirus 2 have created unprecedented challenges for health systems worldwide. Multiple therapeutic options have been explored, including corticosteroids. Preliminary results of corticosteroids in coronavirus disease 2019 (COVID-19) are encouraging; however, the role of corticosteroids remains controversial. RESEARCH QUESTION: What is the impact of corticosteroids in mortality, ICU admission, mechanical ventilation, and viral shedding in COVID-19 patients? STUDY DESIGN AND METHODS: We conducted a systematic review of literature on corticosteroids and COVID-19 in major databases (PubMed, MEDLINE, and EMBASE) of published literature through July 22, 2020, that report outcomes of interest in COVID-19 patients receiving corticosteroids with a comparative group. RESULTS: A total of 73 studies with 21,350 COVID-19 patients were identified. Corticosteroid use was reported widely in mechanically ventilated patients (35.3%), ICU patients (51.3%), and severe COVID-19 patients (40%). Corticosteroids showed mortality benefit in severelly ill COVID-19 patients (OR, 0.65; 95% CI, 0.51-0.83; P = .0006); however, no beneficial or harmful effects were noted among high-dose or low-dose corticosteroid regimens. Emerging evidence shows that low-dose corticosteroids do not have a significant impact in the duration of SARS-CoV-2 viral shedding. The analysis was limited by highly heterogeneous literature for high-dose and low-dose corticosteroids regimens. INTERPRETATION: Our results showed evidence of mortality benefit in severely ill COVID-19 patients treated with corticosteroids. Corticosteroids are used widely in COVID-19 patients worldwide, and a rapidly developing global pandemic warrants further high-quality clinical trials to define the most beneficial timing and dosing for corticosteroids.


Subject(s)
COVID-19 , Glucocorticoids/pharmacology , SARS-CoV-2/drug effects , COVID-19/drug therapy , COVID-19/epidemiology , Dose-Response Relationship, Drug , Humans , Mortality , SARS-CoV-2/physiology , Virus Shedding/drug effects
20.
J Med Chem ; 63(24): 15371-15388, 2020 12 24.
Article in English | MEDLINE | ID: covidwho-929526

ABSTRACT

Fatal infectious diseases caused by HIV-1, influenza A virus, Ebola virus, and currently pandemic coronavirus highlight the great need for the discovery of antiviral agents in mechanisms different from current viral replication-targeted approaches. Given the critical role of virus-host interactions in the viral life cycle, the development of entry or shedding inhibitors may expand the current repertoire of antiviral agents; the combination of antireplication inhibitors and entry or shedding inhibitors would create a multifaceted drug cocktail with a tandem antiviral mechanism. Therefore, we provide critical information about triterpenoids as potential antiviral agents targeting entry and release, focusing specifically on the emerging aspect of triterpenoid-mediated inhibition of a variety of virus-host membrane fusion mechanisms via a trimer-of-hairpin motif. These properties of triterpenoids supply their host an evolutionary advantage for chemical defense and may protect against an increasingly diverse array of viruses infecting mammals, providing a direction for antiviral drug discovery.


Subject(s)
Antiviral Agents/therapeutic use , RNA Viruses/drug effects , Triterpenes/therapeutic use , Virus Internalization/drug effects , Virus Release/drug effects , Animals , Cell Line, Tumor , Humans , Molecular Structure , SARS-CoV-2/drug effects , Structure-Activity Relationship , Virus Shedding/drug effects
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