Coronavirus ARDS (CARDS) - Healing a Broken Lung
Mary McElroy, PhD

Coronavirus ARDS (CARDS) - Healing a Broken Lung

What we are learning about the severe respiratory disease afflicting COVID-19 patients


In December 2019, a viral pneumonia of unknown cause was identified in the Wuhan province of China. Although the number of people infected was small, the pneumonia was of concern because of the high percentage of individuals with severe lung injury (WHO, Jan 12 2020). Subsequently, the causative agent was identified as a novel Coronavirus (SARS-CoV-2) and the disease caused by this virus known as COVID-19 (WHO). Since identification, COVID-19 has spread worldwide leading to infection of more than 4 million people with close to 280,000 confirmed deaths (WHO COVID-19 tracker, 12 May 2020). We are all susceptible to infection by SARS-CoV-2; however disease severity is greater in older individuals or individuals with underlying health problems such as cardiovascular disease or diabetes. There are no specific treatments for severe COVID-19 although there are on-going clinical trials for the safety and efficacy of vaccines, antivirals, anti-inflammatory and anti-coagulants (Reviewed by Tay et al., 2020; Sanders et al., 2020). However, there is still much to be learnt about the pathogenesis of COVID-19—particularly in relationship to the mechanisms that cause lung damage at the air-blood barrier.

Clinical Characteristics (Phenotypes) in COVID-19 Patients

SARS-CoV-2 infection causes a wide range of symptoms ranging from asymptomatic or mild to life-threatening respiratory distress requiring hospitalisation, oxygen support and mechanical ventilation. Rello and colleagues defined five possible phenotypes in COVID-19 and while these descriptors will become more refined with time they highlight the continual decline in lung function at each stage (low blood oxygen levels) leading ultimately to the diagnosis of ARDS (Rello et al., 2020). ARDS or Acute Respiratory Distress Syndrome defines a clinical condition of severe lung disease associated with pneumonia, sepsis and trauma. COVID-19-induced ARDS has a high mortality rate (estimate range from 50% to 80%), may be considered a sub-type of ARDS and has been referred to as CARDS (Marini et al., 2020).


Major clinical symptoms


Fever, headache, mild respiratory symptoms (cough/sore throat). Blood oxygen levels are normal.


Mild hypoxemia (low blood oxygen levels) evidence of pneumonia on chest X-rays.


Moderate to severe hypoxemia and rapid and shallow breathing.  High levels of inflammatory markers in blood (e.g. IL-6).


Severe hypoxemia requiring mechanical ventilation


Acute Respiratory Distress Syndrome (ARDS) – Protective ventilation (low tidal volumes to prevent additional physical damage to the lung). Serum markers associated with secondary infections

The clinical progression of COVID19 (adapted from Rello et al., 2020).

Rello and colleagues point out that patients in Stage 2 are at risk of rapid deterioration and recommend that blood oxygen levels and respiratory rate should be carefully monitored. This clinical description is mirrored by a recent article in the New York Times from an emergency doctor, Richard Levitan, who referred to Covid-19 as the ‘silent killer’ because in susceptible patients failing lung function will lead to dangerously low blood oxygen levels which are barely felt by the individual until almost too late for treatment and support (Levitan, 2020).

SARS-CoV-2 infection in the lung

The course of viral infection in the lungs has still be fully understood but a recent review by Robert Mason describes a possible sequence of events based on data from in vitro studies, preclinical animal models and histology data from patients with COVID-19. Inhaled SARS-CoV-2 gains entry into the lung by binding to the angiotensin-converting enzyme 2 (ACE2) in cells lining the nose—particularly goblet cells (Mason, 2020; Sungnak et al., 2020). This stage of the infection may be asymptomatic in part because the virus replicates in goblet cells and is released without cell damage (Sungnak et al., 2020). Disease progression is associated with dissemination of the virus to the lower gas-exchange region of the lung or alveoli. Once in this region the risk of severe acute lung injury becomes great because SARS-CoV-2 is able to infect and kill alveolar epithelial type II cells as these cells also express ACE2 (Mason, 2020; Sungnak et al., 2020; Tain et al., 2020; Yao et al 2020).

Alveolar epithelial II cells, along with alveolar type I cells, have many critical roles in the maintenance of an intact barrier air-blood barrier (reviewed by Guillot et al., 2013). Therefore, it is not hard to imagine that viral infection of alveolar type II cells has the potential to lead to a vicious circle of lung damage. For example, viral damage to alveolar type II cells will lead to flooding of airspaces because the water-tight air-blood barrier is broken. This damage may be exacerbated because alveolar type II cells also produce lung surfactant. Reduced lung surfactant will lead to collapsed alveoli and reduced surface area for gas exchange. Then following this viral damage, the lungs’ repair mechanisms will be triggered and include removal of excess fluid from the airspaces and replacement of the damaged alveolar epithelial cells. However, alveolar epithelial type II cells are also required for these repair processes – so hampering the healing process required to restore efficient gas exchange. Given what we know about SARS-CoV-2 infection, it would seem reasonable to suggest that the early hypoxia, as recognised by Rollo et al and Levitan, may be related to the extent of ongoing injury to alveolar type II cells.

In parallel to direct viral injury to the alveolar epithelium, indirect injury from an excessive inflammatory response is also considered a major component in the development severe lung damage in COVID-19 (reviewed by Tay et al., 2020). Damaged alveolar epithelial cells trigger pro-inflammatory responses leading to the generation of cytokines such as IL-6, IP-10, macrophage inflammatory protein 1 alpha and recruitment of inflammatory cells to the alveolar space to help reduce viral spread and restore the lung structure to normal (reviewed by Tay et al., 2020). However, a hyperactive immune response will lead to an excessive accumulation of inflammatory cells , such as macrophages and neutrophils, which further increases the fluid permeability of the air-blood barrier and cell damage (Mirad & Martin; 2020) . At this point in time it is unclear how the balance of direct vs. indirect injury to the alveolar epithelium affects the course of disease progression.

A final thought in this process is the role of alveolar epithelial type I cells in COVID-19. Alveolar type I cells constitute 95% of the lungs’ surface area and are the main epithelial barrier for gas exchange (along with capillary endothelial cells) (reviewed in Dobbs et al., 2010; McElroy & Kasper, 2004). Alveolar type I cells are difficult to study for two main reasons; first, they have a very thin cytoplasm which is difficult to observe by light microscopy and second, they have a highly complex three-dimensional structure which make them difficult to isolate from lung tissue for in vitro studies (Weibel, 2015). Nonetheless, careful investigations performed by Wong and Johnson demonstrated that alveolar type I cells can heighten the pro-inflammatory response during lung inflammation, in the presence of alveolar macrophages, while alveolar type II cells provide a counteracting anti-inflammatory response.These data emphasise the need to better understand cellular interactions at the air-blood barrier and raise the possibility that ATI cells may contribute in the hyper-immune response observed in COVID-19.


Much remains to be understood about the clinical course of COVID-19 and the molecular and cellular mechanisms associated with disease progression for effective treatments. However, progress has been made with US Food and Drug Administration (FDA) approval of the antiviral drug, Remdesivir, under Emergency Use Authorisation for severely ill hospitalised patients with confirmed COVID-19 (FDA).  Nonetheless it is likely that combination therapies including medicines that both modulate the immune response and protect the alveolar epithelium will also be required to limit air-blood damage and promote normal lung repair without scarring. Indeed lung surfactant replacement trials have been proposed and are currently recruiting as a possible treatment in COVID-19 (Chivukula  & Hardin, 2020;


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