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Objective: Develop evidence-based, rapid, living guidelines intended to support patients, clinicians, and other healthcare professionals in their decisions about treatment and management of patients with COVID-19.
Personnel Management N4 Pdf 89
Methods: In March 2020, the Infectious Diseases Society of America (IDSA) formed a multidisciplinary guideline panel of infectious disease clinicians, pharmacists, and methodologists with varied areas of expertise to regularly review the evidence and make recommendations about the treatment and management of persons with COVID-19. The process used a living guideline approach and followed a rapid recommendation development checklist. The panel prioritized questions and outcomes. A systematic review of the peer-reviewed and grey literature was conducted at regular intervals. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of evidence and make recommendations.
Results: Based on the most recent search conducted on May 31, 2022, the IDSA guideline panel has made 32 recommendations for the treatment and management of the following groups/populations: pre- and post-exposure prophylaxis, ambulatory with mild-to-moderate disease, hospitalized with mild-to-moderate, severe but not critical, and critical disease. As these are living guidelines, the most recent recommendations can be found online at:
Coronavirus disease 2019 (COVID-19) is a pandemic with a rapidly increasing incidence of infections and deaths. Many pharmacologic therapies are being used or considered for treatment. Given the rapidity of emerging literature, the Infectious Diseases Society of America (IDSA) identified the need to develop living, frequently updated evidence-based guidelines to support patients, clinicians and other health-care professionals in their decisions about treatment and management of patients with COVID-19. Please refer to the IDSA website for the latest version of the guidelines:
There has been an expanding number of studies rapidly published online and in academic journals; however, some of these may be of limited quality and are pre-published without sufficient peer-review. Critical appraisal of the existing studies is needed to determine if the existing evidence is sufficient to support currently proposed management strategies.
Lopinavir/ritonavir is a protease inhibitor that was U.S. Food and Drug Administration (FDA)-approved for the treatment of HIV in September 2000. Ritonavir is added to the combination as a pharmacokinetic enhancer due to its strong inhibition of cytochrome P450 3A4, a metabolic pathway for lopinavir metabolism. Lopinavir/ritonavir demonstrated in vitro inhibition of SARS-CoV-1 and MERS-CoV replication [62-64]. A trial of lopinavir/ritonavir and ribavirin versus historical controls in SARS-CoV-1 patients, showed a reduced rate of acute respiratory distress syndrome and mortality in those receiving lopinavir/ritonavir. This study had limitations including a control group from early in the outbreak when management strategies likely differed significantly [65]. During the MERS outbreak, case reports cited efficacy of lopinavir/ritonavir with interferon in the management of MERS patients [66, 67]. During the early phase of COVID-19, triple combination of interferon beta-1b, lopinavir/ritonavir, and ribavirin shortened the duration of viral shedding and hospital stay in patients with mild-to-moderate COVID-19 in an open-label, randomized, phase II trial [68].
In the early days of the SARS-CoV-2 pandemic, based on experience in both SARS and MERS, recommendations [73] cautioned against the use of systemic corticosteroids due to risk of worsening clinical status, delayed viral clearance, and adverse events [74-76]. Given the hyper-inflammatory state in COVID-19, immunomodulatory approaches, including steroids, continue to be evaluated to address both ARDS and systemic inflammation. ARDS stemming from dysregulated systemic inflammation may translate into prolonged ventilatory requirements and in-hospital mortality. In non-viral ARDS settings, there is increasing support for the role of steroids in the management of ARD [77]. A recent multicenter RCT in patients with moderate to severe ARDS demonstrated a reduced number of ventilatory days and reduction in mortality with use of a 10-day regimen of dexamethasone [78].
Systemic corticosteroids have become a mainstay of therapy for the management of systemic inflammation seen in patients with severe COVID-19 infection as a result of the mortality reduction demonstrated in the RECOVERY trial [95]. In addition to their anti-inflammatory properties, some corticosteroids have been shown to inhibit viral replication of coronaviruses including MERS-CoV. Specifically, ciclesonide has demonstrated the ability to block SARS-CoV-2 viral replication in vitro, where fluticasone and dexamethasone did not [96]. Therefore, ciclesonide, and potentially other corticosteroids, may offer both anti-inflammatory and antiviral activity for the management of SARS-CoV-2. The antiviral mechanism may be related to the action of corticosteroids on both angiotensin converting enzyme 2 (ACE2) and transmembrane protease serine 2 (TMPRSS2), which mediate SARS-CoV-2 viral attachment and entry into host cells. Preliminary data from a clinical cohort of patients taking inhaled corticosteroids suggest a lower expression of ACE2 and TMPRSS2 compared to those not taking inhaled corticosteroids and may suggest decreased susceptibility to SARS-CoV-2 in those taking inhaled corticosteroids [97].
Among hospitalized patients, tocilizumab showed a trend toward reduced mortality at 28 days compared to no tocilizumab treatment (RR: 0.91; 95% CI: 0.79, 1.04; moderate CoE). Tocilizumab demonstrated a lower relative risk of clinical deterioration, defined as death, need for mechanical ventilation, ECMO, or ICU admission, compared to placebo/usual care, RR: 0.83 (95% CI: 0.77, 0.89; moderate CoE). Four studies were not blinded, while in the remaining three trials healthcare personnel and outcome assessors were blinded. The panel noted that tocilizumab causes a decline in CRP levels, which if obtained would reveal the treatment arm designations of the patients, therefore introducing bias for the more subjectively measured outcomes of clinical deterioration and serious adverse events.
*Other options for treatment and management of ambulatory patients include nirmatrelvir/ritonavir, three-day treatment with remdesivir, and neutralizing monoclonal antibodies. Patient-specific factors (e.g., symptom duration, renal function, drug interactions) as well as product availability should drive decision-making regarding choice of agent. Data for combination treatment do not exist in this setting.
Baricitinib, a selective Janus kinase 1 and 2 (JAK1 and JAK2, respectively) inhibitor currently FDA-approved for the treatment of RA, is being investigated in multiple studies for treatment of COVID-19. The proposed benefits of baricitinib in the management of COVID-19 may be two-fold as it has both anti-inflammatory and potential antiviral activity [185]. Janus kinase (JAK) mediates cytokine signaling, which contributes to inflammation; JAK inhibitors, therefore, may decrease cytokine-mediated inflammation. Baricitinib inhibits host intracellular membrane proteins AP2-associated protein kinase 1 (AAK1) and also binds cyclin G-associated kinase (GAK), both thought to play a role in receptor mediated endocytosis of many viruses including Ebola, dengue, hepatitis C, and SARS-CoV-2 [186-188]. Baricitinib has been evaluated in people with COVID-19 in both randomized and non-randomized studies [189-193].
Our literature search identified one RCT that compared the use of tofacitinib 10 mg every 12 hours for up to 14 days or placebo [202]. Patients included were those who had laboratory-confirmed SARS-CoV-2 infection and evidence of COVID-19 pneumonia on imaging and who were hospitalized for less than 72 hours. Patients in this study could not be receiving non-invasive ventilation, mechanical ventilation, or ECMO at baseline. Additionally, patients with a history of or current thrombosis, personal or first-degree family history of blood clotting disorders, immunosuppression, any active cancer, or those with certain cytopenias were excluded from this trial. Patients who received other potent immunosuppressants, or other biologic agents were excluded, while the use of glucocorticoids for the management of COVID-19 was permitted. A composite outcome of death at day 28 or respiratory failure (defined as progression to NIAID ordinal scale 6, 7, or 8) was the primary outcome.
Among the RCTs, the risk of bias was high in two trials because of unsuccessful randomization into treatment and control groups. Hashim et al (2020) [214] inadequately randomized participants by allocating them to respective treatment arms on odd and even days, as well as assigning all critically ill patients to the ivermectin arm, and Podder et al (2020) [215] allocated participants based on odd or even registration numbers. In addition, across many RCTs, there were concerns due to lack of blinding of study personnel, which may lead to over- or under-estimates of treatment effects, particularly for subjective outcomes (e.g., symptom resolution, adverse events).
Fluvoxamine is a selective serotonin reuptake inhibitor (SSRI) which is currently FDA-approved for the treatment of obsessive-compulsive disorder. SSRIs have been shown to have affinity for Sigma-1 receptors, which have been demonstrated to modulate cytokine levels in animal models of septic shock [245]. Additionally, pharmacologic agents that act at Sigma-1 receptors have demonstrated in vitro activity against SARS-CoV-2 [246]. Amongst the SSRIs, fluvoxamine has been shown to have the high affinity for these receptors making it a potential repurposed drug option for the management of COVID-19 [247]. SSRIs like fluvoxamine may decrease uptake of serotonin from platelets during thrombosis, resulting in decreased neutrophil recruitment and platelet aggregation, which may be helpful in the early stages of COVID-19 [248, 249]. 2ff7e9595c
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