Nebulised heparin as a treatment for COVID-19: scientific rationale and a call for randomised evidence

Abstract

Nebulised unfractionated heparin (UFH) has a strong scientific and biological rationale and warrants urgent investigation of its therapeutic potential, for COVID-19-induced acute respiratory distress syndrome (ARDS). COVID-19 ARDS displays the typical features of diffuse alveolar damage with extensive pulmonary coagulation activation resulting in fibrin deposition in the microvasculature and formation of hyaline membranes in the air sacs. Patients infected with SARS-CoV-2 who manifest severe disease have high levels of inflammatory cytokines in plasma and bronchoalveolar lavage fluid and significant coagulopathy. There is a strong association between the extent of the coagulopathy and poor clinical outcomes. The anti-coagulant actions of nebulised UFH limit fibrin deposition and microvascular thrombosis. Trials in patients with acute lung injury and related conditions found inhaled UFH reduced pulmonary dead space, coagulation activation, microvascular thrombosis and clinical deterioration, resulting in increased time free of ventilatory support. In addition, UFH has anti-inflammatory, mucolytic and anti-viral properties and, specifically, has been shown to inactivate the SARS-CoV-2 virus and prevent its entry into mammalian cells, thereby inhibiting pulmonary infection by SARS-CoV-2. Furthermore, clinical studies have shown that inhaled UFH safely improves outcomes in other inflammatory respiratory diseases and also acts as an effective mucolytic in sputum-producing respiratory patients. UFH is widely available and inexpensive, which may make this treatment also accessible for low-and middle-income countries. These potentially important therapeutic properties of nebulised UFH underline the need for expedited large-scale clinical trials to test its potential to reduce mortality in COVID-19 patients.

Unfractionated heparin inhibits live wild type SARS‐CoV‐2 cell infectivity at therapeutically relevant concentrations

“…In the United Kingdom, Brazil and Australia, in addition to systemic heparin use, the novel approach of delivering UFH via nebulisation directly to lungs of COVID‐19 patients is undergoing evaluation in a clinical trial by the ACCORD clinical trials platform (https://accord-trial.org/)) (van Haren et al, 2020). This is to determine if there is a benefit from the additional known anti‐inflammatory activity of heparin and to provide high local anti‐coagulant effects on the alveolar region of patients with severe COVID‐19.…”

“…Independent from the systemic use of heparin in COVID‐19 patients, nebulised heparin has been proposed as a unique and potentially effective treatment for different stages of COVID‐19 disease (van Haren et al, 2020). In the United Kingdom, a clinical trial evaluating the effectiveness of nebulised UFH in hospitalised COVID‐19 patients is currently underway (https://accord-trial.org).…”

“…In the United Kingdom, a clinical trial evaluating the effectiveness of nebulised UFH in hospitalised COVID‐19 patients is currently underway (https://accord-trial.org). The strategy underpinning this treatment stems from positive observations made, based on anticoagulant and anti‐inflammatory activity, when running trials of nebulised heparin in patients with acute lung injury and other respiratory conditions (van Haren et al, 2020). The delivery of an aerosolised antiviral agent directly to the lungs where SARS‐CoV‐2 virus is known to be present (both upper and lower respiratory tract) (Schaefer et al, 2020) may help to treat the alveolar coagulopathy that is often a feature of COVID‐19, reduce the hyperinflammatory response and prevent patients from developing acute respiratory distress syndrome (ARDS) and pulmonary fibrosis (PF), the major complications of infection with SARS‐CoV‐2.…”

Nebulised heparin for patients on ventilation: implications for COVID-19 pneumonia

“…Pulmonary coagulopathy is once again receiving attention because pulmonary thrombosis is frequently seen in patients with COVID-19 pneumonia, 7 , 8 causing increased dead space and severe hypoxaemia. The promising findings of the CHARLI study 3 underline the importance of considering studies of nebulised heparin in patients with COVID-19 pneumonia, 9 and some studies have already been registered on ClinicalTrials.gov ( NCT04397510 , NCT04530578 ). The CHARLI study investigators discuss the need for future studies in more homogeneous populations and we could not agree more; the surges of COVID-19 pneumonia in many countries should trigger the scientific community to test nebulised heparin in these large, uniform populations.…”

Therapeutic modalities and novel approaches in regenerative medicine for COVID-19

“…showed that anticoagulation therapy using heparin, is presumably associated with a better prognosis in patients infected with COVID-19 ( 133 ). In addition, due to some critical features of unfractionated heparin (UFH), also called nebulized heparin, including anti-coagulant, anti-inflammatory and mucolytic effects, UFH may be a potentially effective treatment for COVID-19 ( 134 ).…”