3c. Secondary pulmonary Infection.
Acute respiratory distress syndrome (ARDS) is a severe form of acute
lung injury with a high mortality rate and pneumonia; infections such as
COVID and sepsis are predisposing factors together with aspiration
(summarised in 17). Twenty years before COVID, it was suggested that the
RAS had a role in the pathogenesis of ARDS and demonstrated that
angiotensin converting enzyme insertion/deletion polymorphism was
associated with susceptibility and outcome in ARDS (49). This has been
shown in human data with COVID, mortality disproportionally affecting
Blacks who commonly have DD mutation. Even back in 2002 this team
suggested that that ACE inhibitors may lower the risk of developing ARDS
or reduce the severity of the disease. Subsequently in animal
experiments in acute lung injury angiotensin II is upregulated and
mediates acute lung failure by way of the AT1 receptor and that ACE2 and
the AT2 receptor are protective against this injury (16). Consistent
with theses findings Yan et al using influenza A H5N1 virus infection in
mice showed that the ARB losartan improved animal survival and
ameliorated acute lung injury (6).
Based on a retrospective cohort non COVID pneumonia study Mortensen et
al 2012 (50) examined the influence of statins and inhibitors of the RAS
on outcomes. They concluded that statins and to a lesser extent ACE
inhibitors and ARBs improved these outcomes. The potential benefits of
the pulmonary effects of ARBs aware seen, and he speculated that having
increased ACE2 expression with pre-existing ARB treatment may be of
benefit in the course of SARS-CoV-2 infection (13). In a similar fashion
in a recent review on COVID-19 (11) concluded that with patients with
lower respiratory tract infections ACEIs and ARBs may be associated with
improved outcomes. From a repurposing standpoint the prevailing view
would be that inhibitors of RAS may be of benefit in lower
respiratory tract infections.
3d . Intubation. Severe gas exchange problems requiring
mechanical ventilation can occur with COVID-19 disease. As indicated by
Kim et al 2017 acute respiratory distress syndrome (ARDS) is refractory
hypoxemic respiratory failure with a high mortality rates, which have
been reported to range from 30% to 70% (51). Animals studies of Jerng
et al 2006 have suggested a link between mechanically induced
proinflammatory responses and the RAS. In particular the observation
that mechanical ventilation can produce a proinflammatory response in
the lungs (52). Moreover, they demonstrated that RAS is involved in the
pathogenesis of the ventilator induced lung injury. Of particular
importance was the observation that pre-treatment with captopril or
concomitant infusion of losartan attenuated the lung injury and
inflammation (52). A role of Angiotensin 1-7 in improving key responses
in an experimental model of ARDS was described by Zambelli et al 2015
(53). They demonstrated that Angiotensin 1-7 reduced the severity of
lung injury and inflammation following pulmonary acid aspiration and
high stretch mechanical ventilation.
Subsequently Kim et al. (52) examined the medical records of patients
admitted to a medical intensive care unit for mechanical ventilation
support. They concluded that an ACE inhibitor or ARB may have beneficial
effect on ARDS patients. From the standpoint of repurposing what is
important is the observation that inhibition of RAS is implicated in
ventilation proinflammatory response in the lungs, that COVID-19 is a
disease of RAS dysregulation and that observational data with RAS
inhibitors suggests they may be beneficial.