Nebulized Heparin for the Treatment of COVID-19 Induced Lung Injury

COVID-19 is a novel coronavirus that can cause severe and potentially fatal respiratory
infections. COVID-19 has many similarities to previously seen coronaviruses, such as those
that caused the Middle Eastern Respiratory Syndrome (MERS) that emerged in 2011 and the
Severe Acute Respiratory Syndrome (SARS) in 2002-2003. Based on early reports, many patients
may present with mild to moderate respiratory symptoms, but approximately 20% developed
severe symptoms. These severe cases developed a multitude of life threatening complications,
like acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and shock.

An early investigation into the patients with severe presentations, revealed high levels of
inflammatory cytokines like interleukin 2 (IL-2), interleukin 6 (IL-6), tumor necrosis factor
alpha (TNF-α), and monocyte chemoattractant protein 1 (MCP-1). This upregulation of
inflammatory cytokines, also referred to as a cytokine storm, is similar to the innate immune
response triggered by the previous coronaviruses.5,6 The increased production of these
cytokines is the expected anti-viral response of the innate immune system, which is trigged
by viral RNA replication. Viral replication triggers downstream inflammatory signaling
cascades like NF-κB and IRF3 leading to increased neutrophil and monocyte-macrophages
infiltrating the tissue. While effective against viral infection, this process is also
believed to be responsible for the development of the significant respiratory complications
associated with COVID-19.

ALI and ARDS are not unique to COVID-19 and develop with many viral respiratory infections.
Several therapeutic strategies have been evaluated in ALI and ARDS and demonstrated benefit
outside of the current pandemic. Heparin, a commonly used anticoagulant, has been shown to
exhibit anti-inflammatory properties within the respiratory system. An in vitro study of
heparin in a pulmonary cell model of ALI found that heparin significantly inhibited the NF-κB
pathway. This inhibition led to a reduced levels of IL-6 and TNF-α in human alveolar
macrophages exposed to an E. coli lipopolysaccharide to simulate inflammatory ALI.
Additionally, heparin significantly reduced IL-6, TNF-α, and MCP-1 in human alveolar type II
cell models. No increases in necrosis or apoptosis were observed.

In addition to these immunomodulation effects, heparin is primarily an anticoagulant and
systemic administration carries a risk of bleeding. Due to this, several investigations were
conducted in animal models and in humans to determine if administering the heparin via
nebulization could take advantage of the immunomodulation, without increasing the risk of
bleeding. Nebulized heparin was studied in a rat model of ARDS and was observed to attenuate
ALI through reduction of pro-coagulant and pro-inflammatory pathways. Significant reductions
in IL-6 and TNF-α were observed. Additionally, reductions in the expression of NF-κB were
observed in the alveolar macrophages.

Several clinical investigations in humans with ARDS have also been completed. In a
randomized, placebo controlled study of 60 patients with severe ARDS, patients were
randomized to nebulized heparin, streptokinase and placebo. Patients in the heparin group
received 10,000 units via nebulizer every 4 hours and had significant improvements in their
ARDS by day 8. No effect on systemic coagulation markers like APTT and INR were observed.
Additionally, no major bleeding events or blood transfusions were observed. A second,
randomized placebo controlled trial of 50 patients requiring more than 48 hours of mechanical
ventilation was conducted to determine the possible benefit of nebulized heparin. Patients
with ALI that received nebulized heparin had a significant reduction in the time on the
ventilator as compared to placebo. Patients that received heparin had higher APTT values than
those that received placebo, but no significant bleeding events occurred. This study utilized
a heparin dose of 25,000 units every 4 hours, which may explain the difference between the
laboratory effects in the two human studies.

Heparin has demonstrated the ability to reduce the inflammatory cytokines believed to be
responsible for the development of ALI and ARDS in COVID-19 and it may prove to be beneficial
in this patient population. When administered via nebulization, no adverse effects were
observed in the previously conducted studies and may provide a safe therapeutic option to
improve the outcomes of patients with COVID-19 related ALI and ARDS.