Hypothesis
We hypothesize that COVID-19 that the first pulmonary pathogenic feature
in COVID-19 is non-cardiogenic pulmonary oedema ‘leaky lungs’ which
progresses to ‘cytokine storm’ and Adult Respiratory Distress Syndrome (
ARDS ).
During initial stages of COVID-19 infection, the most notable clinical
concern is often hypoxaemia. There are ten main causes for dyspnoea and
hypoxaemia in COVID-19.
- Non-cardiogenic pulmonary oedema ( both interstitial as well as intra
alveolar oedema ) confirmed on CT Scans demonstrating ground glass
opacification.
- Viral Pneumonia with consolidation confirmed with radiology.
- A mixed picture with varying levels of the viral pneumonia and
non-cardiogenic pulmonary oedema
- ‘Direct’ cardiac failure caused by SARS CoV2 cardiotoxicity (which has
been described as myocarditis or myocarditis-like entity associated
with cytokine storm) or worsening of pre-existing cardiac failure,
with raised pro-BNP and raised Troponin levels.
- Adult respiratory distress syndrome caused by alveolar epithelial cell
necrosis alveolar haemorrhage and consolidation.
- Takotsubo syndrome with (usually reversible) cardiac dysfunction and
only modest elevation of troponins for the degree of dysfunction.
- Pulmonary embolism
- Pleural Effusion
- Pericardial effusion
- Acute exacerbation of Chronic obstructive Pulmonary Disease or Asthma
The pathophysiology of the radiological findings of ground glass
opacification in COVID-19 is not well understood yet. This raises
questions as to whether in the initial phases of COVID-19, sudden
deteriorations in clinical condition may be secondary to non-cardiogenic
flash pulmonary oedema (high permeability pulmonary oedema). A recent
study on COVID-19 patients with ultrasound examinations of lungs has
shown evidence of pulmonary oedema as seen in patients previously
studied with cardiogenic pulmonary oedema ( 1,2,3).
Post-mortem studies following the 2003 SARS outbreak, described several
phases of diffuse alveolar damage from lung biopsies ( 4 ). In early
phases this was characterised by proteinaceous intra-alveolar oedema.
Macrophages were found mainly in the alveoli, and lymphocytes in the
interstitium. Solid intra-alveolar neutrophils and macrophage cell
infiltrates were found in secondary bacterial pneumonic consolidation of
areas of lungs. Diffuse alveolar damage (DAD) was the principal finding,
with early exudative DAD in some, intermediate inflammatory DAD in
others, and fibrosis as a late stage finding.
Aerated alveoli with evidence of lymphocytes within the alveolus, have
been reported in a histological study utilising transmission and
scanning electron microscopy in patients who died of SARS-CoV-2
infection ( 5 ).The entry of lymphocytes into the alveolus cannot occur
in isolation, and interstitial oedema with structurally deformed
capillaries was also noted, suggesting interstitial oedema which would
be associated with alveolar oedema as a key pathogenic process ( 5 ).
Radiological case series in COVID-19 infected patients showing ground
glass opacification was far commoner than consolidation in the first
week after onset of symptoms (6 ). CT chest reports of the presence of
ground-glass opacity (hazy areas of increased attenuation with
underlying blood vessels identifiable on imaging), would be in keeping
with transudative or exudative alveolar oedema ( 6 ).
This adds to the evidence that in the early stages, non-cardiogenic high
permeability pulmonary oedema is a principal feature of COVID-19
infection. Pulmonary oedema is thought to be a result of TNF receptor
related innate immunity (TRAIL) pathways. TRAIL pathways lead to reduced
water clearance from the alveoli, triggered by IFN- alpha activation of
macrophages ( 7 ).
Fluid reabsorption from alveoli is dependent on sodium-potassium ATPase
(Na-K-ATPase) activated pumps which reabsorb sodium against the
gradient. Influenza virus is known to down regulate Na-K-ATPase pumps (
8 ). Hypoxia per se can induce Reactive Oxygen species (ROS) which also
results in down regulation of the Na-K-ATPase pump. When this process is
amplified ARDS will occur instead of homeostatic resolution of pulmonary
oedema ( 9 ).
Endothelial dysfunction, possibly secondary to
impaired nitric
oxide synthesis, may also be an additional pathogenic factor for
excessive
pulmonary capillary
permeability and facilitate non-cardiogenic pulmonary oedema
formation. Part of the pathogenic process in COVID-19, is likely to
involve the disruption of barrier integrity due to apoptosis induced by
viral infection. As the disease progresses, with the onset of ARDS,
pulmonary oedema would worsen with additional critical alveolar barrier
cell damage leading to complete disruption of alveoli with necrosis,
haemorrhage and consolidation.