ARDS causes diffuse alveolar damage in the lung.

There is hyaline
membrane formation in the alveoli in the acute stage, and this is
followed by interstitial widening and by oedema and then fibroblast
proliferation in the organising stage. COVID‐19 ARDS causes the
typical ARDS pathological changes of diffuse alveolar damage in the
lung.6, 7 As patients move through the course of their illness, the
longer term outcomes of ARDS are being reported, with lung fibrosis
appearing as part of COVID‐19 ARDS.8, 9 A study reported that 17% of
patients had fibrous stripes in chest CT scans,9 and considered that
the fibrous lesions may form during the healing of pulmonary chronic
inflammation or proliferative diseases, with gradual replacement of
cellular components by scar tissues.
COVID‐19 ARDS appears to have worse outcomes than ARDS from
other causes. The intensive care unit and hospital mortality from
typical ARDS are 35.3% (95% CI, 33.3–37.2%) and 40.0% (95% CI,
38.1–42.1%), respectively.3 For COVID‐19 ARDS, mortality ranged
between 26% and 61.5% if ever admitted into a critical care setting,
and in patients who received mechanical ventilation, the mortality can
range between 65.7% to 94%.4 Risk factors for poor outcomes include
older age; presence of comorbidities such as hypertension,
cardiovascular disease and diabetes mellitus; lower lymphocyte
counts; kidney injury; and raised D‐dimer levels. Death from COVID‐
19 ARDS is due to respiratory failure (53%), respiratory failure
combined with cardiac failure (33%), myocardial damage and
circulatory failure (7%), or death from an unknown cause.4
Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome
(ARDS): clinical features and differences from typical pre-COVID-19 ARDS.
Med J Aust. 2020 Jul;213(2):54-56.e1. doi: 10.5694/mja2.50674. Epub 2020
Jun 22. PMID: 32572965; PMCID: PMC7361309.

Pathogenesis and Pathology of COVID-19 and Typical ARDS

Pathogenesis and Pathology of ARDS

The pathogenesis of ARDS has not been known very well. It is widely believed that lung parenchyma
cell and several kinds of immune cells are involved in uncontrolled inflammatory response, which
leads to the development of ARDS. Several clinical disease or disorders can lead to ARDS, such as
sepsis, bacterial or viral pneumonia, trauma, aspiration pneumonia, shock and pancreatitis. On the
one hand, the above insults can directly cause damage to lung parenchymal cells; one the other
hand, the resident alveolar macrophages and dendritic cell are activated, leading to a robust release
of proinflammatory cytokines and chemokines that promote the accumulation of neutrophils and
monocytes in lung. Activated immune cells along with the injured epithelial and endothelial cells
induce a further injury to promote the sustaining inflammation and tissue injury. The resultant injury
leads to loss of barrier function, and accumulation of protein-rich edema fluid within the interstitium
and alveolus, finally cause respiratory failure (9, 10).

The typical pathological feature of ARDS was diffuse alveolar injury (DAD), including hyaline
membranes, edema, cell necrosis, or fibrosis, which was described by Katzenstein et al. in 1976 (11).
ARDS is not a single disease but a set of clinical syndromes caused by multiple etiologies. In
consequence, not all ARDS patients present typical DAD pathologically due to the different etiologies
and pathogenic mechanisms (9, 10).

Pathogenesis and Pathology of COVID-19

Contrast to the typical ARDS, the pathogen of COVID-19 is clear, caused by SARS-CoV-2, which is a
beta-coronavirus that bind the angiotensin-converting enzyme-related carboxypeptidase (ACE2)
receptor through the viral structural spike (S) protein to gain entry to cells. ACE2 receptor are widely
distributed in alveolar epithelial cells (II), bronchial epithelial cells, vascular endothelial cells, small
intestinal epithelial cells and several kinds of immune cells, including monocytes, macrophages and
dendritic cells (12, 13). It means that SARS-CoV-2 can directly result to lower respiratory infection
and induce inflammatory response by attacking immune cells in the lung.

Due to the abundance of blood vessels in lung tissues, SARS-CoV-2 infection can directly cause
extensive damage to pulmonary vascular endothelium, airway and alveolar epithelium also show
varying degrees of damage. The activation of stimulated endothelial cells further mediates the
rolling, adhesion, migration of inflammatory cells, and activates inflammatory cascades and
coagulation. Eventually, these processes will cause barrier damage, diffusion dysfunction and
coagulation activation.

The pathological manifestations of COVID-19 include pulmonary edema, fibrinous exudation and
inflammatory cell infiltration, alveolar septal vascular congestion, edema, vascular thrombi with
focal intraparenchymal hemorrhage, and hemorrhagic infarction (14). DAD was reported in 67% to
100% of these autopsy patients (15, 16), which are compatible with typical ARDS. However, due to
the serious damage to the endothelium, the COVID-19 patients showed distinctive vascular features,
such as microthrombosis and hyperplasia. Varga et al. (17) reported that SARS-CoV-2 infection
facilitates the induction of endotheliitis in several organs as a direct consequence of viral
involvement (as noted with presence of viral bodies) and of the host inflammatory response.
Ackermann and colleagues (15) also found that the lungs from patients who died of COVID-19
showed unique vascular characteristics. In addition to severe endothelial injury with the presence of
intracellular virus and disrupted cell membranes, the incidence of pulmonary capillary microthrombi
in COVID-19 patients was 9 times higher than that in influenza patients, accompanied by pulmonary
capillary hyperplasia through a mechanism of intussusceptive angiogenesis. In an autopsy study of
12 consecutive patients who died of COVID-19, the incidence of deep venous thrombosis was as high
as 58%, one third of the patients had a pulmonary embolism as the direct cause of death (16). Thus,
these data suggest that the predominant vascular changes including endothelial cell injury,
pulmonary capillary microthrombosis and hyperplasia are the main features of the patients with
COVID-19, which lead to a different pathophysiological process and different response to treatment
when compared with ARDS. Although most of the patients showed DAD, however, these data come
from autopsies of patients who died from COVID-19. DAD is probably a result of late stage of this
disease and not an early marker.

Lu Sen, Huang Xiaobo, Liu Rongan, Lan Yunping, Lei Yu, Zeng Fan, Tang Xuemei, He Hongli.
Comparison of COVID-19 Induced Respiratory Failure and Typical ARDS: Similarities and Differences
Frontiers in Medicine. Vol;9.2022.https://www.frontiersin.org/articles/10.3389/fmed.2022.829771
Doi.10.3389/fmed.2022.829771

Data indicate that 5%–12% of patients with SARS-CoV-2 infection

develop a severe illness requiring critical care, of whom 72%–81%
require invasive mechanical ventilation.
Standard UK intensive care practice is to consider tracheostomy after
7–10 days of invasive mechanical ventilation to aid weaning, facilitate
comfort and minimise complications relating to the prolonged
presence of an oral endotracheal tube.6–9 However, the role of
tracheostomy in mechanically ventilated patients with COVID-19
remains controversial. Guidance at the start of the pandemic, based
largely on expert opinion, recommended avoiding or delaying
tracheostomy until 14–21 days after intubation,10–12 and to only
proceed once the patient was COVID-19 reverse transcription (RT)-
PCR test negative.13–15 These measures aimed to prevent nosocomial
infection among healthcare professionals and to avoid futile
procedures in ventilated patients with COVID-19 who were predicted
not to survive or benefit from the procedure.16 17 These
recommendations have since been challenged as the risk of
transmission is now known to decline shortly after symptom onset
and the outcome of COVID-19 testing is believed not to correlate with
risk of infectivity later in the disease process
The PDT procedure is safe for both healthcare professionals and
COVID-19 patients. Early PDT procedures had a beneficial impact on
COVID ICU patients in terms of ICU LOS and time on MV in order to
both improve pulmonary performance and reduce the weaning
process.

During mechanical ventilation with the endotracheal tube (ETT) in the

ICU, all patients were sedated with drugs in continuous intravenous
infusion using propofol and remifentanil or, in case of an unstable
hemodynamic situation, using norepinephrine. In 10 cases,
continuously infused midazolam was used as an additional sedative
agent for less than 48 h. Likewise, curarization was used for less than
48 h. On day 7 after the PDT procedure, a significantly decreased dose
of continuous intravenous sedation and inotropic therapy was
observed (Figure 1 and Table 2).

No patients required surgical tracheostomy during the study period.

Percutaneous tracheotomy should be preferred over the surgical
technique in intensive care patients, as this recommendation has a
high level of evidence (GRADE 1+/strong agreement). In addition, PDT
is associated with a shorter operative time and a decreased incidence
of stoma infection, inflammation, and postprocedural major bleeding
[14].

One additional clinical benefit of PDT compared with ETT is the lack of
pharyngeal and laryngeal stimuli due to the ETT and a reduction in
tracheal stimuli. This allows a gradual reduction in the continuously
infused sedative agent and the dosages of the inotropic agent used to
counteract arterial hypotension. Furthermore, there was a statistically
significant improvement in ventilation support in terms of the
PaO2/FiO2 ratio, FiO2, and PEEP, all relevant parameters to increase
lung performance and achieve earlier recovery in ICU COVID-19
patients.

COVIDTrach collaborative. COVIDTrach: a prospective cohort study of mechanically

ventilated patients with COVID-19 undergoing tracheostomy in the UK. BMJ Surg Interv
Health Technol. 2021 Jul;3(1):e000077. doi: 10.1136/bmjsit-2020-000077. Epub 2021 Jul 8.
PMID: 34282409; PMCID: PMC8275367.
Questions might arise regarding the safety of a tracheostomy which
can cause hypoventilation, hypercarbia, hypoxemia and arterial
hypertension during the procedure especially when a patient is still on
cerebral resuscitation. In defence of that, Stocchetti et al. (12)
concluded that a translaryngeal tracheostomy is safe for the majority
of the patients. However, the risk of intracranial pressure (ICP) must
be taken into consideration and strict monitoring must include ICP, so
that the benefits of early tracheostomy are not outweighed by the
danger of intracranial decompensation.
An early tracheostomy is indicated for patients with severe TBIs in
order to reduce length of NHDU stays, the length of mechanical
ventilator use and to reduce rate of VAP.
Ismail MI, Idris Z, Abdullah JM, Rahman NAA, Nordin M. Comparing the Outcomes of Early
and Late Tracheostomy in Severe Traumatic Brain Injury Patient. Malays J Med Sci. 2021
Aug;28(4):63-70. doi: 10.21315/mjms2021.28.4.7. Epub 2021 Aug 26. PMID: 34512131;
PMCID: PMC8407789.

Tetaj N, Maritti M, Stazi G, Marini MC, Centanni D, Garotto G, Caravella I, Dantimi

C, Fusetti M, Santagata C, Macchione M, De Angelis G, Giansante F, Busso D, Di
Lorenzo R, Scarcia S, Carucci A, Cabas R, Gaviano I, Petrosillo N, Antinori A,
Palmieri F, D'Offizi G, Ianniello S, Campioni P, Pugliese F, Vaia F, Nicastri E,
Ippolito G, Marchioni L, Icu Covid-Study Group. Outcomes and Timing of Bedside
Percutaneous Tracheostomy of COVID-19 Patients over a Year in the Intensive Care
Unit. J Clin Med. 2021 Jul 28;10(15):3335. doi: 10.3390/jcm10153335. PMID:
34362118; PMCID: PMC8347124.