Anakinra is an interleukin-1 inhibitor that is approved in Europe for adults with COVID-19 pneumonia who require low- or high-flow supplemental oxygen and who are at risk of developing severe respiratory failure, as determined by blood soluble urokinase plasminogen activator receptor (suPAR) levels of at least 6 nanograms/mL. It is authorised under an emergency-use authorisation in the US for the same indication. Guidelines do not currently recommend anakinra for the treatment of COVID-19, as there is insufficient evidence to recommend either for or against its use. Systematic reviews and meta-analyses have found that anakinra may reduce mortality and the need for invasive mechanical ventilation in hospitalised patients, particularly those with C-reactive protein levels >100 mg/L, compared with standard care alone. However, a Cochrane review did not find evidence for an important beneficial clinical effect of interleukin-1 inhibitors , and the evidence is uncertain for several outcomes. Anakinra probably results in little or no improvement in symptoms at 28 days after treatment (moderate-certainty evidence). It is uncertain whether anakinra makes a difference to the number of deaths at 28 days after treatment (low-certainty evidence).
Colchicine is an anti-inflammatory agent that downregulates multiple pro-inflammatory pathways. Guidelines recommend against the use of colchicine for the treatment of COVID-19, except in the context of a clinical trial. A Cochrane review found that the use of colchicine probably has little to no influence on mortality or clinical progression in hospitalised patients with moderate to severe disease, compared with placebo or standard care alone (moderate-certainty evidence). Evidence for effect on all-cause mortality for people with asymptomatic or mild disease is uncertain; however, use probably results in a slight reduction in hospital admissions or 28-day mortality.
Granulocyte-macrophage colony-stimulating factor inhibitors
Investigational granulocyte-macrophage colony-stimulating factor (GM-CSF) inhibitors (e.g., lenzilumab, mavrilimumab, otilimab) may mitigate lung inflammation in severe and critical disease by minimising downstream production of numerous pro-inflammatory mediators. Guidelines do not currently recommend GM-CSF inhibitors for the treatment of COVID-19, as there is insufficient evidence to recommend either for or against their use. Randomised controlled trials have shown positive results for lenzilumab, but not mavrilimumab. A meta-analysis found that GM-CSF inhibitors may reduce the incidence of mechanical ventilation and decrease mortality, but evidence is limited and further studies are required.
High-titre convalescent plasma is a blood product that contains high titres of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from patients who have recovered. Guidelines recommend against the use of convalescent plasma for the treatment of hospitalised patients with COVID-19, except in the context of a clinical trial. Guideline recommendations in patients with non-severe disease are conflicting. Some guidelines recommend it in select patients (e.g., outpatients who are at high risk for progression to severe disease). Other guidelines recommend against its use in these patients. There is insufficient evidence to recommend either for or against the use of convalescent plasma for the treatment of hospitalised or non-hospitalised immunocompromised patients. Convalescent plasma collected prior to the emergence of the Omicron variant is not recommended. A Cochrane review found that convalescent plasma does not reduce mortality, and has little to no impact on measures of clinical improvement for the treatment of moderate to severe disease (high-certainty evidence). A living systematic review and network meta-analysis found that convalescent plasma may not confer any meaningful benefit in patients with any disease severity, but whether high-titre convalescent plasma confers any benefit remains uncertain. Evidence from meta-analyses is conflicting. While some meta-analyses found that treatment with convalescent plasma was not significantly associated with a decrease in all-cause mortality (or any benefit for other outcomes) compared with placebo or standard of care, others have found a reduction in mortality, especially when trials with low-titre convalescent plasma were removed from the analyses.
Intravenous immunoglobulin (IVIG) is a blood product prepared from serum pooled from healthy donors. It has an immunomodulatory effect that suppresses a hyperactive immune response. Guidelines do not currently recommend SARS-CoV-2-specific IVIG for the treatment of COVID-19, as there is insufficient evidence to recommend either for or against its use. Guidelines recommend against the use of non-SARS-CoV-2 specific IVIG for the treatment of COVID-19, except in the context of a clinical trial, unless otherwise indicated. A living systematic review and network meta-analysis found that IVIG may not confer any meaningful benefit in patients with any disease severity. However, another meta-analysis found that IVIG reduced mortality in patients with critical disease, although there was no significant difference between the severe and non-severe subgroups.
Stem cell therapy
Mesenchymal stem cells are an investigational product that have been studied for their immunomodulatory properties. Guidelines recommend against the use of mesenchymal stem cells for the treatment of COVID-19, except in the context of a clinical trial. Systematic reviews and meta-analyses have found that mesenchymal stem cells may reduce the incidence of adverse events and mortality in patients with severe or critical disease. However, evidence is limited.
Interferons are a family of cytokines with antiviral properties. Guidelines recommend against the use of interferons (alfa, beta, or lambda) for the treatment of COVID-19, except in the context of a clinical trial. The WHO Solidarity trial found that interferon beta appears to have little or no effect on hospitalised patients, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. A phase 2 trial found that peginterferon lambda reduced viral load and increased the number of participants with a negative nasopharyngeal swab at day 7 in outpatients with mild to moderate disease compared with placebo.
Ivermectin is a broad-spectrum antiparasitic agent that has shown to be effective against SARS-CoV-2 in vitro. Guidelines do not recommend ivermectin for the treatment of COVID-19, except in the context of a clinical trial. There is insufficient evidence to be clear to what extent ivermectin is helpful or harmful. For most key outcomes, including mortality, mechanical ventilation, hospital admission, duration of hospitalisation, and viral clearance, the evidence is of very low certainty. Data from meta-analyses are conflicting. A meta-analysis of 24 randomised controlled trials found that ivermectin provided a significant survival benefit (moderate-certainty evidence), and a likely clinical benefit in terms of improvement and deterioration (low-certainty evidence). Overall, the evidence suggested that early use may reduce morbidity and mortality. Other meta-analyses also support an improvement in clinical outcomes, although the quality of evidence was very low to low. However, there are other meta-analyses that have found that ivermectin does not reduce all-cause mortality or result in improvement in other clinical outcomes. A Cochrane review found no evidence to support the use of ivermectin for treating or preventing infection, but the evidence base was limited (as of 26 May 2021). The safety and efficacy of ivermectin was uncertain based on very low- to low-certainty evidence. Overall, the reliable evidence available does not support the use of ivermectin for treatment or prevention outside of well‐designed randomised trials.
Nitazoxanide is a broad-spectrum antiparasitic agent with in vitro activity against SARS-CoV-2. Guidelines recommend against the use of nitazoxanide for the treatment of COVID-19, except in the context of a clinical trial. A systematic review and meta-analysis found that nitazoxanide did not decrease viral load, frequency of polymerase chain reaction test positivity, or the risk for disease progression or death compared with placebo in patients with mild to moderate disease.
Fluvoxamine is a selective serotonin-reuptake inhibitor that has anti-inflammatory and possible antiviral effects. Guidelines recommend against the use of fluvoxamine for the treatment of COVID-19, as there is insufficient evidence to recommend either for or against its use. A meta-analysis of randomised controlled trials, including the TOGETHER trial, found that patients receiving fluvoxamine were less likely to experience clinical deterioration or hospitalisation compared with placebo, although analysis of hospitalisation-only data was not statistically significant.
Metformin is an antidiabetic agent that has been identified as a potential therapeutic due to its possible antiviral, anti-inflammatory, and antithrombotic properties. Guidelines recommend against the use of metformin for the treatment of COVID-19, except in the context of a clinical trial. Randomised controlled trials have not demonstrated benefit in reducing the risk of hospitalisation or death.
Sabizabulin is an investigational drug that binds to the microtubules in cells (similar to colchicine), thereby interfering with the lifecycle of the SARS-CoV-2 virus, and has antiviral and anti-inflammatory effects. The European Medicines Agency has started a review of the available data on the use of sabizabulin for the treatment of COVID-19. The US Food and Drug Administration voted against an emergency-use authorisation for use in hospitalised patients with moderate to severe infection. Interim results from a small phase 3 trial (204 patients) found that sabizabulin was associated with a reduction in mortality compared with placebo (45% versus 20%).
Vilobelimab is an investigational, first-in-class anti-C5a monoclonal antibody in development for the treatment of COVID-19 pneumonia. C5a plays a role in severe lung injury. A phase 3, double-blind, randomised placebo-controlled trial found that vilobelimab, in addition to standard of care, reduced mortality at 20 and 60 days in critically ill patients on invasive mechanical ventilation (absolute risk reduction of 11%) compared with placebo. The manufacturer has requested emergency-use authorisation from the US Food and Drug Administration for the treatment of critically ill patients.
Inhaled corticosteroids are thought to modulate the inflammatory pathways in the upper respiratory tract and circulation following infection. Guidelines do not recommend inhaled corticosteroids for the treatment of COVID-19 except in the context of a clinical trial, as there is insufficient evidence to recommend either for or against their use. A Cochrane review found that inhaled corticosteroids (budesonide and ciclesonide) probably reduced the combined end point of admission to hospital or death and increased the resolution of initial symptoms at day 14 in people with mild symptoms (moderate‐certainty evidence). However, inhaled corticosteroids make little to no difference in all‐cause 30-day mortality but may decrease duration to symptom resolution (low‐certainty evidence).
Aspirin (and other antiplatelet drugs) are not currently recommended by guidelines, and the evidence for their use is conflicting. The RECOVERY trial found that aspirin was not associated with a reduction in 28-day mortality or a reduced risk of progression to ventilation or death, and was associated with an increased risk of major bleeding events. Other randomised controlled trials also demonstrate no benefit with aspirin (alone or in combination with rivaroxaban). However, meta-analyses have found that aspirin may reduce mortality. Further randomised controlled trials are required.
Azithromycin and tetracycline have been investigated for the treatment of COVID-19. Guidelines recommend against the use of these antibiotics for the treatment of COVID-19 in the absence of another indication for their use. A Cochrane review found that azithromycin did not reduce 28-day all-cause mortality in hospitalised patients compared with standard care alone (high-certainty evidence). Hospitalised patients with moderate to severe disease did not benefit from azithromycin in terms of clinical worsening or improvement (moderate-certainty evidence). Azithromycin had no beneficial effect in the outpatient setting (low-certainty evidence). The UK PRINCIPLE trial found that doxycycline use was not associated with clinically meaningful reductions in time to recovery or hospital admissions or deaths in patients with suspected disease in the community who were at high risk of adverse outcomes.
Vitamins and minerals
Vitamin C, vitamin D, and zinc have shown promise in the treatment of viral respiratory tract infections. Guidelines do not currently recommend vitamin C, vitamin D, or zinc for the treatment of COVID-19 except as part of a clinical trial, as there is insufficient evidence to recommend either for or against their use. Meta-analyses found that high-dose vitamin C reduced the risk of severe disease and mortality. However, these findings are inconsistent with other meta-analyses and need to be substantiated by further large-scale studies. A Cochrane review found there is currently insufficient evidence to determine the benefits and harms of vitamin D supplementation, and the evidence is very uncertain. There was substantial clinical and methodological heterogeneity of included studies, mainly due to different supplementation strategies, formulations, vitamin D status of participants, and reported outcomes. Meta-analyses have found that vitamin D may be associated with improved clinical outcomes, including decreased risk of intensive care admission and mortality, and that there may be a potential role for vitamin D supplementation in reducing disease severity, but noted that additional evidence is required. The UK National Institute for Health and Care Excellence recommends vitamin D supplementation in adults (including pregnant and breastfeeding women), young people, and children over 4 years of age between October and early March (and at other times of the year depending on age and risk of vitamin D deficiency) to maintain bone and muscle health, but does not recommend supplementation to solely prevent or treat COVID-19, except as part of a clinical trial. A meta-analysis found that that zinc supplementation may be associated with a decreased risk of mortality.
Probiotics have been used in a variety of conditions, including respiratory infections. A systematic review and meta-analysis found that probiotics were associated with a 51% reduction in reported symptoms, with improvement noted in cough, headache, and diarrhoea. However, further research is required.
Melatonin has antioxidant, anti-inflammatory, immunomodulatory, and antiviral properties. Small studies have suggested an improvement in symptoms and clinical outcomes. However, further research is required.
Lung transplantation has been used as salvage therapy in patients with COVID-19–associated acute respiratory distress syndrome (ARDS) who do not recover despite maximum ventilatory support, extracorporeal membrane oxygenation, and optimal medical care. Between August 2020 and September 2021, 214 lung transplantations were performed in the US (7% of lung transplants nationally). The 3-month survival among these patients approached that among patients who underwent lung transplantation for reasons other than COVID-19. In a retrospective case series of 30 patients with COVID-19–associated ARDS who underwent lung transplantation, survival was 100% (median follow-up 351 days).
Various other treatments are in clinical trials around the world. International trials to identify treatments that may be beneficial, such as the World Health Organization’s Solidarity trial, and the UK’s randomised evaluation of COVID-19 therapy (RECOVERY) trial, are ongoing.
New drugs currently in clinical trials that show promise include narsoplimab (a monoclonal antibody targeting mannan-binding lectin-associated serine protease-2), ensitrelvir (a protease inhibitor approved for the treatment of COVID-19 in Japan), asunercept (a fusion protein), and nangibotide (a TREM-1 inhibitor peptide).
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