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2.
Infection ; 50(1): 93-106, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1661756

ABSTRACT

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.


Subject(s)
COVID-19 , COVID-19/therapy , Hospitalization , Humans , Immunization, Passive , Practice Guidelines as Topic , SARS-CoV-2
3.
Internist (Berl) ; 63(1): 118-128, 2022 Jan.
Article in German | MEDLINE | ID: covidwho-1603180

ABSTRACT

Antiviral drugs inhibit viral replication by interaction with specific elements of the viral replication cycle. Directly acting antiviral agents have revolutionized the therapeutic options for chronic infections with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV). Pharmacological developments constantly improve therapeutic and prophylactic options for diseases caused by herpes viruses, which is of particular relevance for immunocompromised patients. While infections with persistent viruses, such as HIV, HBV or herpes viruses principally so far cannot be cured, complete elimination of viruses that cause acute infections is possible; however, acute infections, such as influenza or coronavirus disease 2019 (COVID-19) offer only a small therapeutic window for antiviral strategies due to their pathophysiological dynamics. The optimal time point for antiviral agents is immediately after exposure to the virus, which frequently limits its application in practice. An effective pre-exposure or postexposure prophylaxis has been established for infections with HIV and influenza A/B and also gains relevance for infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).


Subject(s)
COVID-19 , Antiviral Agents/therapeutic use , Hepacivirus , Humans , SARS-CoV-2
4.
Dtsch Arztebl Int ; 118(50): 865-871, 2021 12 17.
Article in English | MEDLINE | ID: covidwho-1594909

ABSTRACT

BACKGROUND: The mortality of COVID-19 patients who are admitted to a hospital because of the disease remains high. The implementation of evidence-based treatments can improve the quality of care. METHODS: The new clinical practice guideline is based on publications retrieved by a systematic search in the Medline databases via PubMed and in the Cochrane COVID-19 trial registry, followed by a structured consensus process leading to the adoption of graded recommendations. RESULTS: Therapeutic anticoagulation can be considered in patients who do not require intensive care and have an elevated risk of thromboembolism (for example, those with D-dimer levels ≥ 2 mg/L). For patients in intensive care, therapeutic anticoagulation has no benefit. For patients with hypoxemic respiratory insufficiency, prone positioning and an early therapy attempt with CPAP/noninvasive ventilation (CPAP, continuous positive airway pressure) or high-flow oxygen therapy is recommended. Patients with IgG-seronegativity and, at most, low-flow oxygen should be treated with SARS-CoV-2-specific monoclonal antibodies (at present, casirivimab and imdevimab). Patients needing no more than low-flow oxygen should additionally be treated with janus kinase (JAK) inhibitors. All patients who need oxygen (low-flow, high-flow, noninvasive ventilation/CPAP, invasive ventilation) should be given systemic corticosteroids. Tocilizumab should be given to patients with a high oxygen requirement and progressively severe COVID-19 disease, but not in combination with JAK inhibitors. CONCLUSION: Noninvasive ventilation, high-flow oxygen therapy, prone positioning, and invasive ventilation are important elements of the treatment of hypoxemic patients with COVID-19. A reduction of mortality has been demonstrated for the administration of monoclonal antibodies, JAK inhibitors, corticosteroids, tocilizumab, and therapeutic anticoagulation to specific groups of patients.


Subject(s)
COVID-19 , Antibodies, Monoclonal, Humanized , Hospitals , Humans , Practice Guidelines as Topic , SARS-CoV-2
7.
Infection ; 50(1): 93-106, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1296979

ABSTRACT

PURPOSE: This executive summary of a national living guideline aims to provide rapid evidence based recommendations on the role of drug interventions in the treatment of hospitalized patients with COVID-19. METHODS: The guideline makes use of a systematic assessment and decision process using an evidence to decision framework (GRADE) as recommended standard WHO (2021). Recommendations are consented by an interdisciplinary panel. Evidence analysis and interpretation is supported by the CEOsys project providing extensive literature searches and living (meta-) analyses. For this executive summary, selected key recommendations on drug therapy are presented including the quality of the evidence and rationale for the level of recommendation. RESULTS: The guideline contains 11 key recommendations for COVID-19 drug therapy, eight of which are based on systematic review and/or meta-analysis, while three recommendations represent consensus expert opinion. Based on current evidence, the panel makes strong recommendations for corticosteroids (WHO scale 5-9) and prophylactic anticoagulation (all hospitalized patients with COVID-19) as standard of care. Intensified anticoagulation may be considered for patients with additional risk factors for venous thromboembolisms (VTE) and a low bleeding risk. The IL-6 antagonist tocilizumab may be added in case of high supplemental oxygen requirement and progressive disease (WHO scale 5-6). Treatment with nMABs may be considered for selected inpatients with an early SARS-CoV-2 infection that are not hospitalized for COVID-19. Convalescent plasma, azithromycin, ivermectin or vitamin D3 should not be used in COVID-19 routine care. CONCLUSION: For COVID-19 drug therapy, there are several options that are sufficiently supported by evidence. The living guidance will be updated as new evidence emerges.


Subject(s)
COVID-19 , COVID-19/therapy , Hospitalization , Humans , Immunization, Passive , Practice Guidelines as Topic , SARS-CoV-2
8.
EMBO Mol Med ; 13(8): e14150, 2021 08 09.
Article in English | MEDLINE | ID: covidwho-1271067

ABSTRACT

Innate immunity triggers responsible for viral control or hyperinflammation in COVID-19 are largely unknown. Here we show that the SARS-CoV-2 spike protein (S-protein) primes inflammasome formation and release of mature interleukin-1ß (IL-1ß) in macrophages derived from COVID-19 patients but not in macrophages from healthy SARS-CoV-2 naïve individuals. Furthermore, longitudinal analyses reveal robust S-protein-driven inflammasome activation in macrophages isolated from convalescent COVID-19 patients, which correlates with distinct epigenetic and gene expression signatures suggesting innate immune memory after recovery from COVID-19. Importantly, we show that S-protein-driven IL-1ß secretion from patient-derived macrophages requires non-specific monocyte pre-activation in vivo to trigger NLRP3-inflammasome signaling. Our findings reveal that SARS-CoV-2 infection causes profound and long-lived reprogramming of macrophages resulting in augmented immunogenicity of the SARS-CoV-2 S-protein, a major vaccine antigen and potent driver of adaptive and innate immune signaling.


Subject(s)
COVID-19 , Spike Glycoprotein, Coronavirus , Humans , Immunity, Innate , Inflammasomes , Interleukin-1beta , Macrophages , NLR Family, Pyrin Domain-Containing 3 Protein/genetics , SARS-CoV-2
9.
Clin Microbiol Rev ; 34(1)2020 12 16.
Article in English | MEDLINE | ID: covidwho-962931

ABSTRACT

Patients and physicians worldwide are facing tremendous health care hazards that are caused by the ongoing severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) pandemic. Remdesivir (GS-5734) is the first approved treatment for severe coronavirus disease 2019 (COVID-19). It is a novel nucleoside analog with a broad antiviral activity spectrum among RNA viruses, including ebolavirus (EBOV) and the respiratory pathogens Middle East respiratory syndrome coronavirus (MERS-CoV), SARS-CoV, and SARS-CoV-2. First described in 2016, the drug was derived from an antiviral library of small molecules intended to target emerging pathogenic RNA viruses. In vivo, remdesivir showed therapeutic and prophylactic effects in animal models of EBOV, MERS-CoV, SARS-CoV, and SARS-CoV-2 infection. However, the substance failed in a clinical trial on ebolavirus disease (EVD), where it was inferior to investigational monoclonal antibodies in an interim analysis. As there was no placebo control in this study, no conclusions on its efficacy in EVD can be made. In contrast, data from a placebo-controlled trial show beneficial effects for patients with COVID-19. Remdesivir reduces the time to recovery of hospitalized patients who require supplemental oxygen and may have a positive impact on mortality outcomes while having a favorable safety profile. Although this is an important milestone in the fight against COVID-19, approval of this drug will not be sufficient to solve the public health issues caused by the ongoing pandemic. Further scientific efforts are needed to evaluate the full potential of nucleoside analogs as treatment or prophylaxis of viral respiratory infections and to develop effective antivirals that are orally bioavailable.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/pharmacology , Coronavirus Infections/drug therapy , Hemorrhagic Fever, Ebola/drug therapy , Pneumonia, Viral/drug therapy , Severe Acute Respiratory Syndrome/drug therapy , Adenosine Monophosphate/pharmacokinetics , Adenosine Monophosphate/pharmacology , Alanine/pharmacokinetics , Alanine/pharmacology , Antiviral Agents/pharmacokinetics , Betacoronavirus/drug effects , Betacoronavirus/growth & development , Betacoronavirus/pathogenicity , COVID-19 , Clinical Trials as Topic , Compassionate Use Trials/methods , Coronavirus Infections/mortality , Coronavirus Infections/pathology , Coronavirus Infections/virology , Drug Administration Schedule , Ebolavirus/drug effects , Ebolavirus/growth & development , Ebolavirus/pathogenicity , Hemorrhagic Fever, Ebola/mortality , Hemorrhagic Fever, Ebola/pathology , Hemorrhagic Fever, Ebola/virology , Humans , Middle East Respiratory Syndrome Coronavirus/drug effects , Middle East Respiratory Syndrome Coronavirus/growth & development , Middle East Respiratory Syndrome Coronavirus/pathogenicity , Pandemics , Patient Safety , Pneumonia, Viral/mortality , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , SARS Virus/drug effects , SARS Virus/growth & development , SARS Virus/pathogenicity , SARS-CoV-2 , Severe Acute Respiratory Syndrome/mortality , Severe Acute Respiratory Syndrome/pathology , Severe Acute Respiratory Syndrome/virology , Survival Analysis , Treatment Outcome
12.
EMBO Mol Med ; 13(1): e13105, 2021 01 11.
Article in English | MEDLINE | ID: covidwho-814824

ABSTRACT

The ongoing SARS-CoV-2 pandemic stresses the need for effective antiviral drugs that can quickly be applied in order to reduce morbidity, mortality, and ideally viral transmission. By repurposing of broadly active antiviral drugs and compounds that are known to inhibit viral replication of related viruses, several advances could be made in the development of treatment strategies against COVID-19. The nucleoside analog remdesivir, which is known for its potent in vitro activity against Ebolavirus and other RNA viruses, was recently shown to reduce the time to recovery in patients with severe COVID-19. It is to date the only approved antiviral for treating COVID-19. Here, we provide a mechanism and evidence-based comparative review of remdesivir and other repurposed drugs with proven in vitro activity against SARS-CoV-2.


Subject(s)
Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Drug Repositioning , SARS-CoV-2/drug effects , Adenosine Monophosphate/pharmacology , Adenosine Monophosphate/therapeutic use , Alanine/pharmacology , Alanine/therapeutic use , Amides/pharmacology , Amides/therapeutic use , Antiviral Agents/pharmacology , Benzamidines , Drug Repositioning/methods , Esters/pharmacology , Esters/therapeutic use , Guanidines/pharmacology , Guanidines/therapeutic use , Guanine/pharmacology , Guanine/therapeutic use , Humans , Indoles/pharmacology , Indoles/therapeutic use , Lopinavir/pharmacology , Lopinavir/therapeutic use , Protease Inhibitors/pharmacology , Protease Inhibitors/therapeutic use , Pyrazines/pharmacology , Pyrazines/therapeutic use , Ribavirin/pharmacology , Ribavirin/therapeutic use , Ritonavir/pharmacology , Ritonavir/therapeutic use , SARS-CoV-2/physiology , Virus Internalization/drug effects , Virus Replication/drug effects
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