Statement of hypothesis
Though in several observational data, a significant proportion of
COVID-19 patients have presented with silent hypoxia with preserved
respiratory compliance, thus giving it a terminology of atypical ARDS
[1, 9], only a few have attempted to relate this phenomenon with
increased intrapulmonary shunt [1, 2, 3]. Despite this, based on
these observations, many researchers proceed to evoke a hypothesis of
bradykinin as a mediator for pulmonary vasoplegia and inflammation in
COVID-19. However, no study till date have demonstrated elevated
bradykinin levels in either serum or bronchoalveolar lavage fluid in
COVID-19 patients. Although, we agree with the Gattinoni et al. [1]
Reynolds et al. [2] and Brito-Azevedo et al. [3] findings of
increased intrapulmonary shunt in COVID-19 pneumonia but, we are
doubtful of their conclusion of pulmonary vasodilation as the
predominant phenomenon resulting in increased intrapulmonary shunt and
severe hypoxia. Instead, to explain the phenomenon of silent hypoxemia
in COVID-19 respiratory failure, we developed an alternate
pathophysiological model – Epithelial-Endothelial crosstalk hypothesis
– involving upregulation of ACE-Ang II- AT1R pathways producing a
mosaic pulmonary perfusion pattern of non-homogenous pulmonary
vasoconstriction with resultant intrapulmonary shunting and dead-space
[10, 11]. We base this on the following arguments:
First , blood flow through intrapulmonary arteriovenous
anastomoses has been demonstrated in approximately 30% of healthy adult
humans at rest, and in 100% of healthy adult humans during exercise and
inhalation of reduced oxygen gas mixtures [12]. Similarly,
pathological conditions such as high-altitude pulmonary edema,
bronchopulmonary dysplasia and congenital diaphragmatic hernia are
associated with intrapulmonary shunts as the predominant mechanism for
hypoxia [12]. In all these conditions raised pulmonary vascular
resistance (PVR) is a common denominator and non-homogenous pulmonary
vasoconstriction has been linked as the mechanism for the recruitment of
intrapulmonary arteriovenous anastomosis and increased shunt [13],
but not pulmonary vasodilation. Catecholamine infusions at rest, by
increasing cardiac output, can increase the shunt fraction by increasing
blood flow through these pathways and negatively impact pulmonary gas
exchange [12]. Notably, 66% patients in the Brito-Azevedo et al.
[3] study were on vasopressors while Reynolds et al. [2] did not
provide information about vasopressors in their study. Furthermore,
platypnea and orthodeoxia, the classical clinical features of
significant pulmonary vasodilation-induced shunts, as seen in
hepatopulmonary syndrome [14] (an entity closely compared to the
intrapulmonary shunt of COVID-19 pneumonia [2]), are not a part of
COVID-19 symptomatology.
Second , although TCD and TTSCE are well-known modalities to
determine intrapulmonary shunt, neither TCD nor TTSCE can determine the
pathophysiological process responsible of the development of shunt:
anatomical, vasodilation or non-homogenous pulmonary vasoconstriction.
Third , since COVID-19 lung compliance at the stage of silent
hypoxia is largely preserved and the areas of consolidation are minimal
[1, 3], the fraction of gasless tissue would be expected to be
minimal [1]. Thus, impaired hypoxic pulmonary vasoconstriction (HPV)
as a cause for severe hypoxia in early COVID-19 patients should not be
the sole mechanism. Studies based on in-silico [15] and mathematical
[16] modelling also reinforce that even complete loss of HPV could
not recreate severe hypoxia observed in COVID-19 pneumonia.
Fourth , the hypothesis of Ang II-induced downregulation of ACE
activity is not supported by translational research on
renin-angiotensinogen-angiotensin pathways. While increases in
bradykinin levels are possible secondary to angiotensin-type-2 receptor
(AT2R)-mediated Ang II action, this is often a
counterregulatory mechanism [17] and hence, should not predominate.
Previous studies on ARDS found a correlation between pulmonary capillary
endothelium bound ACE activity and severity of ARDS [18]. High ACE
levels in bronchoalveolar lavage (BAL) fluids have been observed in ARDS
despite a reduction in serum ACE levels [19]. Though, no study on
COVID-19 has actually measured the ACE levels in BAL fluid and ACE
protein expression in lungs, a recent study measuring the circulating
ACE levels in COVID-19 patients demonstrated decreased circulatory
levels of ACE in severe COVID-19 patients that normalizes during the
recovery phase [20]. This reduced serum ACE levels may reflect loss
of enzyme release from a damaged pulmonary vascular endothelium, but not
be the true representative of ACE activity in the lung compartment
[20] that may actually be increased [21]. High tissue ACE
activity increases degradation of bradykinin to inactive metabolites,
inhibiting vasodilator pathways in lungs. Similar mechanism can explain
the low incidence of rhinorrhea and nasal congestion in SARS-CoV-2,
unlike other viral upper respiratory tract infections wherein bradykinin
is considered to be the most important mediator. The presence of ACE in
the superficial lamina propria and the endothelium of superficial blood
vessels of human nasal mucosa also suggests the possible role of ACE in
limiting the inflammatory effects of bradykinin in nasal mucosa
[22]. A report of increased cerebrospinal fluid levels of ACE in two
patients with transient COVID-19 encephalitis (˂ 3 days) further
highlights the pathological role of local ACE upregulation in COVID-19
[23].
Fifth, and most important is to understand the normal
physiological and pathological roles of Ang II in humans. In health,
AT2R and masR, but not angiotensin-type-1 receptor
(AT1R), are the
only angiotensin receptor types expressed on pulmonary endothelium and
AT1R are expressed on the pulmonary vascular smooth cells and
mesenchymal cells located beneath the pulmonary endothelium [24].
Also, the locally produced Ang II in the vascular lumen could not
crosses the intact endothelium. Thus, in healthy alveolar capillaries,
AngII-AT2R and Ang(1-7)-masR induced nitric-oxide
(NO)-mediated vasodilatory effect is overactive and maintains low PVR,
explaining why Ang II infusions in physiological dose ranges failed to
increase PVR [25, 26]. However, with high-dose Ang II infusions
AT1R activity predominates and can produce intense
non-homogenous pulmonary vasoconstriction and ventilation-perfusion
mismatching akin to that produced by hypoxia [27, 28]. Ang II
infusion has also been demonstrated to produce non-cardiogenic acute
pulmonary edema [21]. Also, on one hand, the subpressor levels of
Ang II activate AMP-activated protein kinase (AMPK) and increases ACE2,
the high levels of Ang II (pathological state) inhibit AMPK, upregulates
ACE and downregulates ACE2 via the AT1R-ERK/p38 MAPK
pathway [29]. Thus, Ang II has beneficial as well as harmful
vascular effects depending upon the Ang II levels as well as effector
receptors expressions. Importantly, COVID-19 patients have high systemic
Ang II levels that are linked with disease severity [30] and
decrease in Ang II levels following human recombinant soluble ACE2
therapy correlated with the clinical improvement [31].