Respiratory diseases, or lung diseases are pathological conditions affecting the organs and tissues that make gas exchange difficult in air-breathing animals. They include conditions of the respiratory tract including the trachea, bronchi, bronchioles, alveoli, pleurae, pleural cavity, the nerves and muscles of respiration. Respiratory diseases range from mild and self-limiting, such as the common cold, influenza, and pharyngitis to life-threatening diseases such as bacterial pneumonia, pulmonary embolism, tuberculosis, acute asthma, lung cancer, acute lung injury (ALI) and severe acute respiratory distress syndromes (ARDS).

• Respiratory disease affects one in five people and is the third biggest cause of death in England (after cancer and cardiovascular disease). Lung cancer, pneumonia and chronic obstructive pulmonary disease (COPD) are the biggest causes of death.

• Hospital admissions for lung disease have risen over the past seven years at three times the rate of all admissions generally.

• Respiratory diseases are a major factor in winter pressures faced by the NHS; most respiratory admissions are non-elective and during the winter period these double in number.

• The annual economic burden of asthma and COPD on the NHS in the UK is estimated as £3 billion and £1.9 billion respectively. In total, all lung conditions (including lung cancer) directly cost the NHS in the UK £11billion annually.

• Incidence and mortality rates from respiratory disease are higher in disadvantaged groups and areas of social deprivation, with the gap widening and leading to worse health outcomes. The most deprived communities have a higher incidence of smoking rates, exposure to higher levels of air pollution, poor housing conditions and exposure to occupational hazards.

Acute Lung Injury (ALI) and the more severe form Acute Respiratory Distress Syndrome (ARDS) represent a spectrum of progressive respiratory failure that can be initiated by multiple causes including smoke inhalation, drowning, trauma and infection. Currently there is no approved drug treatment available and generally patients are admitted to an intensive care unit (ICU) where they are given oxygen and/or placed on a low tidal volume, plateau pressure limited mechanical ventilator in an attempt to improve lung function/oxygen levels. Survival rates of ARDS 55%-75% when treatment is prompt.

Over recent years our founders have been involved in 50 clinical studies that have shown the efficacy and safety of the off-label use of nebulised Unfractionated Heparin in the treatment of respiratory disease. The strongest and most compelling data is provided in a soon to be published international meta-trial in 478 patients, conducted in 6 countries, which showed that inhaled nebulized UFH significantly reduces the rate of intubation and mortality in hospitalized non-intubated COVID-19 patients and provides convincing and undeniable evidence for the use of this product in the treatment of lung injury resulting from respiratory infections. It also showed that inhaled nebulized UFH is safe, with no pulmonary or systemic bleeding complications, and no clinically relevant effect on systemic coagulation parameters. However, despite the impressive clinical outcomes the use of the off-label UFH product was shown to be impractical for use in routine clinical practice currently, no approved inhaled UFH product exists.

Mechanism of action of Heparin

Some of the clinical benefit observed in patients with ALI, ARDS and other forms of lung injury is likely due to a local anti-coagulant effect of heparin in the airways influencing alveolar coagulation and subsequent development of hyaline membranes. It is unlikely that Inhaled heparin works via any systemic anti-coagulant effect as there was no change in markers of systemic anti-coagulation following inhaled heparin in these trials (despite many of the patients in these studies also receiving systemic heparin) .

UFH has been shown to possess broad spectrum anti-viral activity and is more active against SARS-CoV2 in vitro than low molecular weight heparins . This antimicrobial effect is not unique to SARS-CoV-2, as a large number of viral but also bacterial pathogens depend upon interactions with proteoglycan molecules such as heparan sulphate, which is expressed on a range of human tissue surfaces, for adhesion and invasion of host tissues. Heparin limits adhesion of a number of pathogens including Pseudomonas aeruginosa, Burkholderia cenocepacia, Burkholderia pseudomallei, Legionella pneumophila, Staph aureus, Strep pyogenes, Strep pneumonia, Respiratory syncytial virus and Influenza A. Human and animal studies suggest these actions may reduce the development of pneumonia and bacteraemia.

From an inflammatory perspective heparin has been shown to reduce the release of pro-inflammatory mediators such as elastase from neutrophils and other mediators from mast cells where the signaling pathways have been investigated showing that heparin can act as an IP3 antagonist intracellularly. Given the importance of neutrophils in the pathogenesis of acute lung injury, the ability of heparin to inhibit the release of pro-inflammatory mediators from this cell type in addition to its well-recognized effects of inhibiting the infiltration of inflammatory cells into the airways may well contribute to the clinical benefit observed with inhaled heparin in patients with lung injury such as caused by respiratory infections.

It has long been recognized that multiple cytokines, chemokines and growth factors have heparin binding domains in their structure which when bound to heparin reduces the action of the pro-inflammatory mediators. In addition, many other pro-inflammatory substances such as elastase when bound to heparin have reduced pro-inflammatory effects. Perhaps of greater importance is the recognition that many of the adhesion molecules expressed on inflammatory cells and endothelial cells have heparin binding domains which when bound to heparin prevent the adhesion molecule recognizing their counter ligand on adjacent cells. These effects, on both adhesion molecules and pro-inflammatory mediators, undoubtedly contribute to the overall ability to reduce the infiltration of inflammatory cells in the airways associated with the “cytokine storm” phenomena that can accompany severe respiratory infections, ARDS, and a range of other inflammatory conditions in the lung.

Another important target for heparin in the context of acute lung injury is the complement cascade and histones. It is also worth noting that these effects could be very significant in controlling exacerbations of patients with COPD along with the effects on inflammatory mediators (both action and release) and reduction of inflammatory cells. It is also worth repeating that many of these anti-inflammatory actions are independent of the anti-coagulant actions of heparin and therefore for future indications e.g. COPD or asthma, it would be preferable to use a heparin fraction lacking anti-coagulant activity.