How The Macrophage Trojan Horse Might Explain Happy Hypoxemia in COVID-19

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Eduardo Argaiz
Internal Medicine Resident – Aspiring Nephrologist – Crazy about POCUS, Venous Congestion and AKI. PhD: Molecular physiology of renal sodium and electrolyte handling

The Pre-brief

A recent publication in Nature has put forward an interesting hypothesis (1). The investigators collected BALs from 2 groups of mechanically ventilated patients (those with confirmed COVID-19 ARDS and those with alternate forms of ARDS) and used intensely detailed molecular methods (flow cytometry, bulk transcriptomic profiling and single-cell RNA-sequencing) to determine if key differences existed between the two populations. They then proposed a model for SARS-CoV-2 replication and propagation across the lung. I found it fascinating and wanted to share some thoughts on its clinical implications.  But first, the model…

In order to better understand it, let’s begin with a simplified model of alveolar viral replication in severe influenza pneumonia. Influenza A binds to sialic acid residues that are abundantly expressed in alveolar epithelial cells. This facilitates infection of a large number of cells leading to RAPID viral replication and widespread lung injury (2)

Video 1: Abundant sialic acid residues facilitate RAPID viral replication and widespread lung injury.

On the other hand, the proposed model of SARS-CoV-2 replication and spread looks fundamentally different. In contrast to sialic acid residues, only a small number of alveolar epithelial cells express ACE2 receptors (the commonly accepted ligand used by the virus to enter cells). Authors propose that viral replication in alveolar epithelial cells alone seems insufficient when explaining the significant spread of SARS-CoV-2 across the lung. Even with  viral replication occurring in alveolar macrophages (from phagocytosis of infected epithelial cells vs direct infection), the absence of macrophage activation would hinder viral spread.

Video 2: The small number of epithelial cells expressing the ACE2 receptor makes it hard for SARS-CoV-2 to spread across the lung.

The key insight brought on by this new model is that successful replication and spreading of SARS-CoV-2 depends on the unfortunate presence of pre-existing cross-reactive memory T-cells (CRM T-cells). CRM T-cells are normally present secondary to prior exposure to other common cold coronaviruses. These cells have been found in larger amounts in patients with severe compared to mild COVID-19. They are also found in greater numbers in elderly patients (3)

Figure1
Cross-Reactive Memory T-Cell: Created by prior exposure to common cold coronaviruses. These cells display lower avidity and reduced antiviral responses in response to stimulation with SARS-CoV-2.

CRM T-cells can interact with antigens presented by alveolar macrophages and become activated. This leads to the production of Interferon-γ (IFNγ), T-cell proliferation and recruitment of monocytes. These monocytes then become macrophages which can get infected by SARS-CoV-2, sustaining an inflammatory signaling loop which contributes to spread the infection into adjacent lung regions.

Video 3: Infected alveolar macrophages may act as a Trojan horse, transferring the virus to adjacent lung regions and SLOWLY propagating SARS-CoV-2 infection across the lung.

The beauty of this model is that it helps explain some of our clinical experience with COVID-19:  

1. It explains why it takes more time from symptom onset to the development of respiratory failure: While in Influenza A this can take as short as 2-4 days (4)(5) in SARS-CoV-2 this takes 6-12 days.

2. According to the model, SARS-CoV-2 pneumonia is a slowly-progressive, spatially-restricted infection. This can explain the localized areas of ground glass infiltrates in patients with COVID-19.

Could this model also explain why we are seeing so many patients with hypoxemia that are non or minimally symptomatic?

Because of the proposed nature of COVID-19 as a slowly progressive spatially-restricted infection, it is quite possible that we encounter a large number of patients with enough alveolar infiltrates to lower PaO2 but not enough to affect lung compliance. Because hypoxemia by itself does not constitute a potent mechanism to cause dyspnea (6)(7), these patients can present clinically with well tolerated hypoxemia. The reason some clinicians may not be as familiar with this presentation in other types of pneumonia might be that other pathologies progress faster and by the time patients seek medical attention, pulmonary mechanics are already screwed up (decreased lung compliance increases the work of breathing) (6)(7).

Furthermore, if you were to intubate these patients only for hypoxemia (that is without other signs or symptoms of respiratory distress), it is likely that you will measure a relatively preserved lung compliance. You might even be tempted to publish a small case series and make some bold claims about the pathophysiology of COVID-19 ARDS (8).

The hypercoagulability enigma

Finally, a recurrent topic in COVID-19 has been the increased prevalence of thrombosis. In an attempt to avoid adverse clinical outcomes, many resorted to therapeutic anticoagulation guided by some dubious biomarkers such as D-Dimer. It is now becoming clear that while prophylactic anticoagulation (standard of care) is a clear cornerstone in the management of these patients, routine use of therapeutic anticoagulation in severe COVID-19 might not work as well as we hoped (9). Cytokine and D-Dimer elevations seem to be similar between COVID-19 and other pneumonia etiologies (10)(11) which suggests complications such as clot formation could be the result of prolonged, rather than higher level of exposure to these inflammatory mediators.  In this regard it may be that we should change focus from routine therapeutic anticoagulation to early mobilization (12).

Insights regarding treatment strategies?

Based on this model,  could colchicine (Colcorona) be a real thing?. Colchicine directly inhibits microtubule formation and the deployment of inflammatory liposomes. You will never guess which cell lines are most directly affected by colchicine…macrophages and monocytes!

The Debrief

  • Influenza replication in alveolar epithelium is fast given the large amount of sialic acid residues expressed in these cells
  • ACE2 is less abundantly expressed in alveolar epithelial cells. This hinders SARS-CoV-2 replication and spread, accounting for slow propagation.
  • According to the Macrophage Trojan Horse model, cross-reactive memory T-cells initiate an inflammatory signaling loop that enhances SARS-CoV-2 replication in macrophages.
  • Macrophages can then propagate infection to adjacent lung regions creating a slowly-progressive, spatially-restricted infection.
  • This model can explain the longer duration from disease onset to respiratory failure and the longer duration of mechanical ventilation and ICU stay in COVID-19.
  • Slowly progressive infection can lead to a large number of patients with lower PaO2 but relatively preserved lung compliance. These patients can present with mild/moderate hypoxemia but no dyspnea = Happy Hypoxemia. 
  • The longer course of the disease might contribute to explain the hypercoagulable state in COVID-19.

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