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1.
Cell Chem Biol ; 2022 Jan 11.
Article in English | MEDLINE | ID: covidwho-1616412

ABSTRACT

The COVID-19 pandemic caused by SARS-CoV-2 has been socially and economically devastating. Despite an unprecedented research effort and available vaccines, effective therapeutics are still missing to limit severe disease and mortality. Using high-throughput screening, we identify acriflavine (ACF) as a potent papain-like protease (PLpro) inhibitor. NMR titrations and a co-crystal structure confirm that acriflavine blocks the PLpro catalytic pocket in an unexpected binding mode. We show that the drug inhibits viral replication at nanomolar concentration in cellular models, in vivo in mice and ex vivo in human airway epithelia, with broad range activity against SARS-CoV-2 and other betacoronaviruses. Considering that acriflavine is an inexpensive drug approved in some countries, it may be immediately tested in clinical trials and play an important role during the current pandemic and future outbreaks.

2.
Ann Intern Med ; 174(9): 1261-1269, 2021 09.
Article in English | MEDLINE | ID: covidwho-1547664

ABSTRACT

BACKGROUND: New treatment modalities are urgently needed for patients with COVID-19. The World Health Organization (WHO) Solidarity trial showed no effect of remdesivir or hydroxychloroquine (HCQ) on mortality, but the antiviral effects of these drugs are not known. OBJECTIVE: To evaluate the effects of remdesivir and HCQ on all-cause, in-hospital mortality; the degree of respiratory failure and inflammation; and viral clearance in the oropharynx. DESIGN: NOR-Solidarity is an independent, add-on, randomized controlled trial to the WHO Solidarity trial that included biobanking and 3 months of clinical follow-up (ClinicalTrials.gov: NCT04321616). SETTING: 23 hospitals in Norway. PATIENTS: Eligible patients were adults hospitalized with confirmed SARS-CoV-2 infection. INTERVENTION: Between 28 March and 4 October 2020, a total of 185 patients were randomly assigned and 181 were included in the full analysis set. Patients received remdesivir (n = 42), HCQ (n = 52), or standard of care (SoC) (n = 87). MEASUREMENTS: In addition to the primary end point of WHO Solidarity, study-specific outcomes were viral clearance in oropharyngeal specimens, the degree of respiratory failure, and inflammatory variables. RESULTS: No significant differences were seen between treatment groups in mortality during hospitalization. There was a marked decrease in SARS-CoV-2 load in the oropharynx during the first week overall, with similar decreases and 10-day viral loads among the remdesivir, HCQ, and SoC groups. Remdesivir and HCQ did not affect the degree of respiratory failure or inflammatory variables in plasma or serum. The lack of antiviral effect was not associated with symptom duration, level of viral load, degree of inflammation, or presence of antibodies against SARS-CoV-2 at hospital admittance. LIMITATION: The trial had no placebo group. CONCLUSION: Neither remdesivir nor HCQ affected viral clearance in hospitalized patients with COVID-19. PRIMARY FUNDING SOURCE: National Clinical Therapy Research in the Specialist Health Services, Norway.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/virology , Hydroxychloroquine/therapeutic use , Viral Load/drug effects , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Antibodies, Viral/blood , Biomarkers/blood , COVID-19/complications , COVID-19/mortality , Cause of Death , Female , Hospital Mortality , Humans , Inflammation/virology , Male , Middle Aged , Norway/epidemiology , Oropharynx/virology , Respiratory Insufficiency/virology , SARS-CoV-2/immunology , Severity of Illness Index , Standard of Care , Treatment Outcome
3.
Sci Rep ; 11(1): 23205, 2021 12 01.
Article in English | MEDLINE | ID: covidwho-1545647

ABSTRACT

The association between pulmonary sequelae and markers of disease severity, as well as pro-fibrotic mediators, were studied in 108 patients 3 months after hospital admission for COVID-19. The COPD assessment test (CAT-score), spirometry, diffusion capacity of the lungs (DLCO), and chest-CT were performed at 23 Norwegian hospitals included in the NOR-SOLIDARITY trial, an open-labelled, randomised clinical trial, investigating the efficacy of remdesivir and hydroxychloroquine (HCQ). Thirty-eight percent had a CAT-score ≥ 10. DLCO was below the lower limit of normal in 29.6%. Ground-glass opacities were present in 39.8% on chest-CT, parenchymal bands were found in 41.7%. At admission, low pO2/FiO2 ratio, ICU treatment, high viral load, and low antibody levels, were predictors of a poorer pulmonary outcome after 3 months. High levels of matrix metalloproteinase (MMP)-9 during hospitalisation and at 3 months were associated with persistent CT-findings. Except for a negative effect of remdesivir on CAT-score, we found no effect of remdesivir or HCQ on long-term pulmonary outcomes. Three months after hospital admission for COVID-19, a high prevalence of respiratory symptoms, reduced DLCO, and persistent CT-findings was observed. Low pO2/FiO2 ratio, ICU-admission, high viral load, low antibody levels, and high levels of MMP-9 were associated with a worse pulmonary outcome.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Hydroxychloroquine/adverse effects , Lung Diseases/pathology , Matrix Metalloproteinase 9/metabolism , SARS-CoV-2/drug effects , Viral Load , Adenosine Monophosphate/adverse effects , Aged , Alanine/adverse effects , Antibody Formation , Antimalarials/adverse effects , Antiviral Agents/adverse effects , Antiviral Agents/therapeutic use , COVID-19/virology , Female , Hospitalization , Humans , Lung Diseases/chemically induced , Lung Diseases/enzymology , Lung Diseases/virology , Male , Middle Aged , Severity of Illness Index
4.
Infect Dis (Lond) ; 54(2): 79-89, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1409418

ABSTRACT

BACKGROUND: COVID-19 patients are extensively treated with antibiotics despite few bacterial complications. We aimed to study antibiotic use in hospitalized COVID-19 patients compared to influenza patients in two consecutive years. Furthermore, we investigated changes in antibiotic use from the first to second pandemic wave. METHODS: This prospective study included both patients from two referral hospitals in Bergen, Norway, admitted with influenza (n = 215) during the 2018/2019 epidemic and with COVID-19 (n = 82) during spring/summer 2020, and national data on registered Norwegian COVID-19 hospital admissions from March 2020 to January 2021 (n = 2300). Patient characteristics were compared, and logistic regression analysis was used to identify risk factors for antibiotic use. RESULTS: National and local COVID-19 patients received significantly less antibiotics (53% and 49%) than influenza patients (69%, p < .001). Early antibiotics contributed to >90% of antibiotic prescriptions in the two local hospitals, and >70% of prescriptions nationally. When adjusted for age, comorbidities, symptom duration, chest X-ray infiltrates and oxygen treatment, local COVID-19 patients still had significantly lower odds of antibiotic prescription than influenza patients (aOR 0.21, 95%CI 0.09-0.50). At the national level, we observed a significant reduction in antibiotic prescription rates in the second pandemic wave compared to the first (aOR 0.35, 95% CI 0.29-0.43). CONCLUSION: Fewer COVID-19 patients received antibiotics compared to influenza patients admitted to the two local hospitals one year earlier. The antibiotic prescription rate was lower during the second pandemic wave, possibly due to increased clinical experience and published evidence refuting the efficacy of antibiotics in treating COVID-19 pneumonia.


Subject(s)
COVID-19 , Influenza, Human , Anti-Bacterial Agents/therapeutic use , Drug Prescriptions , Humans , Influenza, Human/drug therapy , Influenza, Human/epidemiology , Prospective Studies , SARS-CoV-2
5.
Nat Med ; 27(9): 1607-1613, 2021 09.
Article in English | MEDLINE | ID: covidwho-1290003

ABSTRACT

Long-term complications after coronavirus disease 2019 (COVID-19) are common in hospitalized patients, but the spectrum of symptoms in milder cases needs further investigation. We conducted a long-term follow-up in a prospective cohort study of 312 patients-247 home-isolated and 65 hospitalized-comprising 82% of total cases in Bergen during the first pandemic wave in Norway. At 6 months, 61% (189/312) of all patients had persistent symptoms, which were independently associated with severity of initial illness, increased convalescent antibody titers and pre-existing chronic lung disease. We found that 52% (32/61) of home-isolated young adults, aged 16-30 years, had symptoms at 6 months, including loss of taste and/or smell (28%, 17/61), fatigue (21%, 13/61), dyspnea (13%, 8/61), impaired concentration (13%, 8/61) and memory problems (11%, 7/61). Our findings that young, home-isolated adults with mild COVID-19 are at risk of long-lasting dyspnea and cognitive symptoms highlight the importance of infection control measures, such as vaccination.


Subject(s)
Antibodies, Viral/blood , COVID-19/complications , COVID-19/pathology , Cognitive Dysfunction/virology , Dyspnea/virology , Fatigue/virology , Adolescent , Adult , Ageusia/virology , Anosmia/virology , Child , Child, Preschool , Female , Humans , Infant , Male , Middle Aged , Norway , Patient Isolation , Prospective Studies , SARS-CoV-2 , Severity of Illness Index , Young Adult
6.
Lancet Reg Health Eur ; 3: 100014, 2021 Apr.
Article in English | MEDLINE | ID: covidwho-1157573

ABSTRACT

BACKGROUND: Households studies reflect the natural spread of SARS-CoV-2 in immunologically naive populations with limited preventive measures to control transmission.We hypothesise that seropositivity provides more accurate household attack rates than RT-PCR. Here, we investigated the importance of age in household transmission dynamics. METHODS: We enroled 112 households (291 participants) in a case-ascertained study in Bergen, Norway from 28th February to 4th April 2020, collecting demographic and clinical data from index patients and household members. SARS-CoV-2-specific antibodies were measured in sera collected 6-8 weeks after index patient nasopharyngeal testing to define household attack rates. FINDINGS: The overall attack rate was 45% (95% CI 38-53) assessed by serology, and 47% when also including seronegative RT-PCR positives. Serology identified a higher number of infected household members than RT-PCR. Attack rates were equally high in children (48%) and young adults (42%). The attack rate was 16% in asymptomatic household members and 42% in RT-PCR negative contacts. Older adults had higher antibody titres than younger adults. The risk of household transmission was higher when the index patient had fever (aOR 3.31 [95% CI 1.52-7.24]; p = 0.003) or dyspnoea (aOR 2.25 [95% CI 1.80-4.62]; p = 0.027) during acute illness. INTERPRETATION: Serological assays provide more sensitive and robust estimates of household attack rates than RT-PCR. Children are equally susceptible to infection as young adults. Negative RT-PCR or lack of symptoms are not sufficient to rule out infection in household members. FUNDING: Helse Vest (F-11628), Trond Mohn Foundation (TMS2020TMT05).

7.
J Infect Dis ; 223(4): 589-599, 2021 02 24.
Article in English | MEDLINE | ID: covidwho-1101849

ABSTRACT

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, many countries experienced infection in health care workers (HCW) due to overburdened health care systems. Whether infected HCW acquire protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. METHODS: In a Norwegian prospective cohort study, we enrolled 607 HCW before and after the first COVID-19 wave. Exposure history, COVID-19-like symptoms, and serum samples were collected. SARS-CoV-2-specific antibodies were characterized by spike-protein IgG/IgM/IgA enzyme-linked immunosorbent and live-virus neutralization assays. RESULTS: Spike-specific IgG/IgM/IgA antibodies increased after the first wave in HCW with, but not in HCW without, COVID-19 patient exposure. Thirty-two HCW (5.3%) had spike-specific antibodies (11 seroconverted with ≥4-fold increase, 21 were seropositive at baseline). Neutralizing antibodies were found in 11 HCW that seroconverted, of whom 4 (36.4%) were asymptomatic. Ninety-seven HCW were tested by reverse transcriptase polymerase chain reaction (RT-PCR) during follow-up; 8 were positive (7 seroconverted, 1 had undetectable antibodies). CONCLUSIONS: We found increases in SARS-CoV-2 neutralizing antibodies in infected HCW, especially after COVID-19 patient exposure. Our data show a low number of SARS-CoV-2-seropositive HCW in a low-prevalence setting; however, the proportion of seropositivity was higher than RT-PCR positivity, highlighting the importance of antibody testing.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19/immunology , Health Personnel/statistics & numerical data , SARS-CoV-2/immunology , Adult , Aged , Asymptomatic Infections , Female , Humans , Male , Middle Aged , Norway , Prospective Studies , Seroconversion , Spike Glycoprotein, Coronavirus/immunology , Young Adult
9.
BMJ Case Rep ; 14(1)2021 Jan 11.
Article in English | MEDLINE | ID: covidwho-1020900

ABSTRACT

Here we present the case of a 37-year-old previously healthy man who developed fever, headache and a unilateral, painful neck swelling while working offshore. He had no known contact with anyone with COVID-19; however, due to the ongoing pandemic, a nasopharyngeal swab was performed, which was positive for the virus. After transfer to hospital for assessment his condition rapidly deteriorated, requiring admission to intensive care for COVID-19 myocarditis. One week after discharge he re-presented with unilateral facial nerve palsy. Our case highlights an atypical presentation of COVID-19 and the multifaceted clinical course of this still poorly understood disease.


Subject(s)
Alkalosis, Respiratory/blood , Bell Palsy/physiopathology , COVID-19/physiopathology , Myocarditis/physiopathology , Adult , Alkalosis, Respiratory/etiology , Blood Gas Analysis , C-Reactive Protein/metabolism , COVID-19/blood , COVID-19/therapy , Echocardiography , Edema/etiology , Electrocardiography , Humans , Hypotension/etiology , Hypotension/physiopathology , Lymphadenitis/etiology , Lymphadenitis/physiopathology , Magnetic Resonance Imaging , Male , Myocarditis/blood , Myocarditis/diagnostic imaging , Myocarditis/therapy , Natriuretic Peptide, Brain/blood , Neck , Oxygen Inhalation Therapy , Peptide Fragments/blood , Procalcitonin/blood , Recovery of Function , SARS-CoV-2 , Troponin T/blood , Vasoconstrictor Agents/therapeutic use
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