Introduction

Overview of ARDS

Acute respiratory distress syndrome, also known as ARDS, is a systemic inflammatory disease characterised by acute respiratory failure due to severe lung inflammation and oedema, which is the swelling of your lungs resulting in a build-up of fluid into alveoli, damaging the membranes of alveoli thus negatively affecting gas exchange. 

ARDS usually occurs opportunistically and is more common in patients who already suffered from infections, diseases or injuries of other organs with widespread inflammation. For example, patients with sepsis, pneumonia, COVID-19, or any head, chest or other major injuries, with sepsis being the most common cause of ARDS, occurring when there is a severe infection in the lungs.¹

Symptoms of ARDS include: 

• severe shortness of breath
• fast heart rate
• extreme fatigue 
• blue or purplish colour of fingertips and lips due to low levels of oxygen
• shortness of breath

Although our knowledge of the causes and pathology of ARDS continues to expand, the mortality rate of ARDS remains high, coordinating with ageing as well as the severity level of illness. 

Current treatment landscape

There is no current treatment that cures ARDS. Oxygen therapy is the main approach that all patients of ARDS are supported with, whilst all the other treatments mainly aim at avoiding any complication of the syndrome and promoting lung recovery. 

Mechanical ventilation 

The recommendation for mechanical ventilation for all patients with ARDS is strong. There are different types of ventilation therapies including non-invasive; invasive; airway pressure release ventilation etc.² However experimental studies have shown that there is a possibility of ventilator-associated lung injuries with this approach. An ideal and protective mechanical ventilation strategy should be used with a low tidal volume and low inspiratory pressures to maintain oxygenation, further complemented with an optimised level of positive end-expiratory pressure (PEEP), amining to avoid oxygen toxicity plus any mechanical ventilation-associated secondary lung damage.³

Venoneous extracorporeal membranous oxygenation (ECMO) 

ECMO is an advanced type of life support that promotes the recovery of lungs and prevents further damage to alveoli by aiding your gas exchange. It differs from mechanical ventilation in that it removes blood from you for oxygenation and removes carbon dioxide from the blood before returning blood to your body, saving time for the lungs and allowing the lungs to heal. It is often used in complementation with mechanical ventilation to reduce the intensity of mechanical ventilation therapies, thus reducing ventilator-caused injury.⁴

Despite that no pharmacological therapies up to date have been approved to be beneficial in preventing or managing ARDS, the usage of certain drugs can still provide supportive effects, for example, neuromuscular blockers.

Neuromuscular blockers 

A pharmacological approach for supporting patients with ARDS. The purpose of neuromuscular blocking agents (NMBAs) includes reduction of inflammation, oxygen consumption plus facilitation of ventilatory synchrony. Currently, only nondepolarising NMBAS are being studied for ARDS as they tend to have a more prolonged effect than polarising NMBAs.⁵ NMBAs allow the relaxation of skeletal muscles by blocking the acetylcholine receptors at neuromuscular junctions, resulting in a decrease in oxygen consumption and fluid accumulation in alveoli.⁶ Current data regarding the use of NMBAs in patients with ARDS is limited, a few clinical trials obtained results showing beneficial effects to patients with early ARDS. However, this approach also comes with side effects including skin breakdown, myopathy, corneal abrasions, as well as risk of thromboembolism (VTE) if you are considered critically ill by your doctor.⁷ 

Novel Emerging Drug Therapies

Immunomodulatory therapies 

There are many emerging drugs with potential immunomodulatory effects for the treatment or prevention of ARDS in clinical trials.

Corticosteroids 

Studied for both early and late stages of COVID-19-associated ARDS, it is a synthetic drug that resembles a type of hormone secreted naturally by your adrenal glands named cortisol. Corticosteroids act as anti-inflammatory agents acting upon pro-inflammatory cytokine response and suppressing it. This is achieved by reducing the expression of proinflammatory cytokines in lung tissues (TNF-𝛼, IL-6, IL-1𝛼, IL-1𝛽, IL-12).⁸ However corticosteroid is not recommended as a routine therapy for treating ARDS. This is because not all trials have demonstrated their effectiveness, and treatment outcomes may vary depending on dosage and corticosteroid used. Moreover, corticosteroid use carries potential side effects, including immune suppression, which can pose significant risks.⁹ 

Antibiotics 

Antibiotics also demonstrate immunomodulatory effects beyond their antibiotic effects; certain antibiotic classes, for example, macrolides, have been under investigation as another potential immunomodulatory therapy to treat ARDS. Several preclinical studies have concluded that macrolides can inhibit the release of proinflammatory cytokines both in vitro and in vivo, as well as blocking the release of chemotactic factors thus inhibiting the recruitment of immune cells including neutrophils, fibroblasts and macrophages, thus leading to blockade of MAPK/ERK pathway that promotes inflammation.¹⁰

Developing cell-based therapy as drug products

Cell therapy works by introducing new cells that obtain specific characteristics or functions into the body to replace or repair damaged cells. In particular, mesenchymal stromal cells (MSCs) and their cellular products are potential for treating ARDS. MSCs are believed to exert their effects via diverse mechanisms, including regulation of neutrophils, macrophages and T cells; reduction of pulmonary permeability; and decrease in lung oedema, other than their tissue repairing effect.¹¹ There are more than 1000 clinical trials on MSCs registered at ClinicalTrials.gov, in general MSCs managed to show an acceptable safety profile in many phase I trials, furthermore, the low production cost compared with other stem cell candidates allowed MSCs to be the focus of development of cell-based therapies for ARDS.¹²

The latest positive news on cell-based therapy is an invariant natural killer T cell (iNKT) therapy that was originally designed for cancer patients, which happened to trigger an immune response in individuals diagnosed with ARDS caused by severe COVID-19 in the initial phase 1/2 clinical trial.¹³

Future directions and research needs

Despite promising preclinical data, the results from the majority of pharmacological therapy clinical trials remain disappointing. The attempt to apply the same drug products to all ARDS patients seems unfruitful, there seems to be a gap between clinical and heterogeneity of human ARDS that needs to be filled, thus precision medicine becomes the new hope that arises. 

Precision medicine, also known as personalised medicine, is a focused area at the frontier of treatment for many diseases and syndromes, including ARDS. Regarding the complexity of the pathophysiology of ARDS, pairing subtypes of patients with distinct biological features with therapies specifically designed for their conditions would be a suitable approach to maximise treatment outcomes and reduce mortality and morbidity in general. For example, the identification of elevated levels of a particular biomarker that is indicative of a dominant pathophysiologic mechanism.¹⁴ This approach requires a thorough understanding of underlying pathophysiological mechanisms as well as the heterogeneity of human ARDS. 

FAQs

What is the first-line treatment for ARDS?

Oxygen therapy such as mechanical ventilation, prone ventilation, non-invasive ventilation to restore blood oxygen level, and a machine or device will be suggested by your doctor to assist breathing. Other current available treatments are mainly aimed at preventing further complications and supporting the recovery of lungs.

What are the possible complications of ARDS?

• Ventilator-associated pneumonia
• Deep vein thrombosis (DVT)/ blood clots
• Multiple organ failure
• pneumothorax/ injured lungs due to usage of a ventilator
• Muscle weakness

What are the severity levels of ARDS?

Severity levels of ARDS are split into three categories: mild, moderate and severe. This is defined by the ratio of partial pressure of oxygen in a patient's arterial blood (PaO2) to the fraction of oxygen in the inhaled air (FiO2). The diagnosis of ARDS is defined by a ratio less than 200; if you are to be categorised as mild the ratio is between 200-300; for moderate level between 100-200; and less or equal to 100 to be considered severe.¹⁵

Summary

In summary, supportive therapies remain the mainstay as no definite drug reassures to treat ARDS. More sophisticated approaches are required for pharmacological therapies, with the aid of precision medicine to enhance therapeutic efficacy. Heterogeneity is one of the greatest challenges faced with ARDS drug development, in addition, the drug delivery system is also part of ongoing research fields, as it is considered attributed to a failure in many clinical trials, a more advanced approach allowing direct delivery of therapeutics to lungs is required, such as nanomedicine. Over the last decades, a range of drugs has been studied for different phases of the syndrome, with a variety of properties including repair of the alveolar membrane, reduction of inflammation and immune response, limitation of vascular permeability and such on, the investigation into potential pharmacological products continues, hopefully, the challenges can be overcome in short future with better designed clinical trials and more advanced understanding in phenotypic and biological heterogeneity associated with human ARDS.