CHAPTER 2

Pathogenesis of COVID-19

Contents
1. Are there any special concerns on COVID-19 and its pathogenesis? 7
2. SARS-COV-2 infection and cardiac injury 8
3. Other injuries 9
4. What is the role of cytokine release storm triggered by pathogens in severe
and critical cases of COVID-19? 10
5. Invading organs and virus-induced infections 11

1. Are there any special concerns on COVID-19 and its

pathogenesis?
Combined with clinical manifestations and chest imaging features, such as
dry cough and abnormal coagulation function, chest imaging mainly
showed multiple small patches and interstitial changes at the early stage, with
obvious extravasation and less exudative lesions, which developed into mul-
tiple ground-glass opacity and infiltrating shadows in the lungs. In critically
ill patients receiving tracheal intubation, infiltration fluid is rare in the tra-
chea, which is different from influenza and avian influenza. We assume that
pathogenesis of COVID-19 lung injury could mainly be impairment of the
lung interstitium and vascular endothelium. Although ARDS can be found
in some patients, exudative lesions are relatively less.
To date, more than 10 studies of COVID-19 patients’ body anatomies
have been conducted at Wuhan Jin Yin Tan Hospital. Professor Liang Liu
from Tongji Medical College of Huazhong University of Science and Tech-
nology and academician Xiuwu Bian from the First Affiliated Hospital of the
Army Medical University have found that virus particles and inclusion bod-
ies can be seen in the lungs, and common features, such as secondary ARDS,
diffuse alveolar injury, and formation of hyaline membrane, are also present.
Interestingly, different from other viral pneumonia and bacterial infections,
fibrosis changes, with collapsing and occlusion of peripheral small airways as
well as macrophages and monocytes infiltration, are common in COVID-19
patients.

COVID-19 © 2021 Shanghai Jiao Tong University Press. Published by Elsevier Inc.
https://doi.org/10.1016/B978-0-12-824003-8.00002-4 All rights reserved. 7
8 COVID-19

In viral infection, the pathological change of fibrosis is similar to that of

secondary organic pneumonia (SOP). We have called this “quasi-SOP,”
because further screening and confirmation are required. In clinical practice,
similar organic manifestations are commonly seen, either in SARS or in
influenza virus infections. When will quasi-SOP occur? According to our
existing experience, it often developed in chest imaging at 7–10 days after
onset. We are able to hear a “burst sound” by auscultation, which is highly
consistent with interstitial lesions. Therefore, glucocorticoid may be helpful.
Meanwhile, we should also pay attention to the load of virus as well as the
state of humoral immunity. Measures have to be taken after comprehensive
consideration. There is no existing evidence from a well-designed RCT
study on how to choose the dosage of glucocorticoid. When a widespread
epidemic occurs, “ordered” things will be replaced by “disorder” or other
disturbing factors, which will affect strong research interpretation. Based on
previous experience, intravenous administration of 40–120 mg methylpred-
nisolone is recommended, either as a single dose or multiple doses, and dos-
age could be adjusted individually. Regarding the usage period, 3 days with a
high dose strategy, followed by gradual decrease is suggested by some expe-
rience. Currently, facing COVID-19, especially with SOP, the overall treat-
ment strategy remains to be determined with the help of viral load and
immune status.
Besides interstitial changes, other features can also be seen within the pul-
monary vessels. The description of the vascular endothelium requires further
observation by pathologists. However, thrombosis is common, especially
hyaline thrombus in the capillaries and pulmonary arterioles. This may be
related to the elevation of D-dimer. We are impressed by the thrombus
changes within blood vessels.

2. SARS-CoV-2 infection and cardiac injury

In addition to the direct effect on the lungs, the heart is another critical target
organ that requires more attention. The virus affects the myocardium as well
as the conduction system. This is why some patients experience arrhythmias
and other conductive changes. Continuous ECG, myocardial enzymes, and
BNP need to be monitored among those patients.
Preliminary studies show that BNP and hypersensitive cardiac troponin
are associated with the progress to critical illness. There are still many
unknown areas regarding SARS-CoV-2, but evidence has suggested that early
deaths occurred in some patients with fulminant myocarditis complicated
 Pathogenesis of COVID-19 9

with sepsis cardiomyopathy, while others suffered septic cardiomyopathy

only. The main feature of fulminant myocarditis was cardiomyocyte edema,
which required IABP and ECMO to maintain stability. Sepsis cardiomyop-
athy is a myocardial change of sepsis caused by bacterial infection, with
characteristics of left ventricular enlargement and EF downgrading.
A recent paper in Intensive Care Med revealed that the proportion of heart
failure caused by SARS-CoV-2 infection was as high as 40%. The period from
onset of symptoms to death in most patients is 12–24 days, which is not
consistent with the development of fulminant myocarditis. The long duration
of the disease and delayed treatment will increase the possibility of secondary
sepsis cardiomyopathy after mixed infection, which is different from influ-
enza. In some COVID-19 patients, myocardial hypertrophy and chronic
ischemic changes are found, which may be a manifestation of coronary heart
disease. The longer the duration of the disease, the longer the duration of
hypoxemia is maintained, and the more obvious the damage of chronic
myocardial ischemia will be. We have observed that most COVID-19 patients
died of increased hypersensitive troponin and BNP. In some cases, elevated
levels of hypersensitive troponin can be seen in all stages of the disease, ranging
from hundreds to thousands ng/ml. However, the relationship with prognosis
is still under investigation. Notably, COVID-19 patients can also have acute
cardiovascular events, such as acute coronary syndrome (ACS).

3. Other injuries
In addition to the lesions mentioned above, an elevated level of D-dimer can
be seen in a large proportion of COVID-19 patients. Several studies have
suggested that increased D-dimer is negatively correlated to prognosis. It
has a greater possibility to induce systemic inflammatory response. The issues
of hypercoagulability and fibrinolysis secondary to hypercoagulability often
occur in parallel.
Does DIC occur at the same time? If there is no decrease in fibrinogen
consumption and platelets, it should be mainly related to hypercoagulability
and fibrinolysis, thrombosis or in situ thrombosis formation, or venous
thromboembolism (VTE). The fall-off of deep vein thrombosis may lead
to blockage of pulmonary veins. It must be confirmed whether the level
of D-dimer is high. As learned from anatomical study of the bodies of
COVID-19 patients, thrombus can be seen in the middle cerebral artery
and pulmonary artery, as well as some hyaline thrombus in peripheral arte-
rioles and capillaries. Therefore, if there is no contraindication, we
10 COVID-19

recommend giving anticoagulation treatment while monitoring the adverse

effect of bleeding, especially in elderly patients. Moreover, for patients who
have received heparin it is necessary to observe platelet changes and pay
attention to the development of HIT.
In addition, acute kidney injury (AKI) has also been found in the anat-
omy of COVID-19 patients, mainly with renal tubule involvement. It is
necessary to monitor renal function in clinical situations.

4. What is the role of cytokine release storm triggered

by pathogens in severe and critical cases of COVID-19?
In addition to the presentation of viral infection, cytokine release storm
(CRS) induced by pathogens also plays a key role in aggravating clinical
symptoms. Recent studies reported that IL-6 and GM-CSF were signifi-
cantly associated with cytokine release storms. Large amounts of immune
cells and tissue fluid are infused within the lungs, demonstrating the exis-
tence of a CRS. We have analyzed the temporal curve, comparing the group
of surviving patients with deceased patients, and observed the dynamic
change of inflammatory mediators and cytokines over time, from no respi-
rator support (such as mask oxygen inhalation) required, to noninvasive ven-
tilation, to invasive mechanical ventilation, or even ECMO. We assume that
it would be helpful for us to have a more comprehensive understanding of
COVID-19 based on macroscopic and microscopic levels of pathology.
Cytokines involved in CRS induced by different viruses are not identi-
cal. H1N1 influenza A virus, H5N1 avian influenza virus, SARS coronavi-
rus, MERS coronavirus, and new SARS-CoV-2 virus are similar, but others
are not exactly the same. The proportions of elevated IL-6 and GM-CSF are
higher in COVID-19. Further studies on novel biomarkers indicating the
development from mild to severe ones, or severe to critical ones, are
required. We hope to provide some new targets for the treatment and inter-
vention of COVID-19, which will fundamentally help improve the prog-
nosis as well as reduce the mortality of critical cases.
Removal of cytokines from CRS can be a potential therapeutic target.
IL-6, as a major cytokine, plays a critical role in organ damage, and is a poten-
tial intervention target. The alternative way is to use an existing IL-6 receptor
inhibitor for the treatment of COVID-19. Whether cytokines can be
removed by CRRT remains controversial. We believe that with CRRT
implementation, the prognosis could be slightly improved. However,
whether it is directly related to the mortality rate needs to be studied further.
 Pathogenesis of COVID-19 11

5. Invading organs and virus-induced infections

The pathophysiological mechanism of COVID-19 is the systemic inflam-
matory reaction caused by viral pneumonia. We have seen many critically
ill patients suffering from shock. However, they actually have only the viral
infection instead of bacterial infection. As learned from anatomy studies, we
can see the invasion of multiple organs by the virus, presenting with particles
or inclusion bodies.
The characteristics of multiple organs involvement of SARS-CoV-2
include viral sepsis. No fever or normal temperature would be one of the
special manifestations of viral sepsis. Many severe and critically ill patients
in Wuhan showed no fever, which is consistent with viral sepsis. As is com-
monly known, a variety of viruses can lead to viral sepsis. Forty-two percent
of viral infections are mixed infection, such as respiratory syncytial virus,
influenza, parainfluenza virus, rhinovirus, and adenovirus. Recent reports
also suggested that SARS-CoV-2 was detected along with influenza virus.
On the other hand, a meta-analysis did not show the association between of
coinfection with aggressive clinical severity. A recent sampling study
showed that the proportion of HCMV coinfection is about one-third, that
of influenza virus is rare, with no other respiratory syncytial viruses, myco-
plasma, and legionella detectable. According to the experience from ICU
experts, there seems to be a certain possibility of herpes simplex virus coin-
fection, but conclusive studies are still in progress.