Review Article

J Nepal Health Res Counc 2020 Jul-Sep;18(48): 351-9

DOI: https://doi.org/10.33314/jnhrc.v18i3.3028

COVID-19:Current Understanding of Pathophysiology

Gentle S Shrestha,1 Sushil Khanal,2 Sachit Sharma,1 Gaurav Nepal3
1
Department of Anaesthesiology, Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal,
2
Department of Critical Care Medicine, Grande International Hospital, Kathmandu, Nepal, 3Department of
Internal Medicine, Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal.

ABSTRACT
ascular, renal, gastrointestinal and central nervous are not uncommon. In-depth understanding of the pathophysiological basis of organs and systems involve

INTRODUCTION have proven to be helpful in patients with COVID-19.

Only a few researches published are based on sound
The coronavirus disease 2019 (COVID-19) first emerged
pathophysiological basis and concrete evidences that
in China’s Hubei Province in December 2019. 1 It has
would guide management of patients with COVID-19 are
spread rapidly across the world as a pandemic,
lacking.4 Proper understanding of pathophysiology can
infecting individuals in several countries and causing
guide clinical management and form the basis for
significant morbidity and mortality. The virus that
future clinical research in developing potential
causes COVID-19 is severe acute respiratory
therapies.
syndrome coronavirus
2 (SARS-CoV-2), the beta coronavirus. 2 Efforts to METHODS
fight against the disease is limited by an incomplete
understanding of disease pathophysiology. Till date, For this narrative review, the following databases were
the approach to hospital management of COVID -19 reviewed for published studies before August 20, 2020:
is based on limited data. A better understanding of PubMed, Google Scholar, and SCOPUS. We also searched
disease transmission, pathophysiology and host immune pre-print servers including Research square, medRxiv,
response is essential for developing effective vaccines and SSRN. Boolean logic was used for conducting
and therapeutics. It is the highest priority at this hour database search and Boolean search operators “AND”
of crisis to develop validated and proven therapeutic and “OR” were used to link search terms. Search terms
measures to stop the explosive global spread of this “COVID-19”, “SARS-CoV-2”, and “novel coronavirus”
pandemic.3 In this review, we offer a comprehensive were combined with terms “pathophysiology” and
overview of the pathophysiology of COVID-19 on various “pathogenesis” and the name of each organ system.
organs and systems based on existing literature. The relevant articles were selected by the authors
Comprehensive review of the literatures was done to from the gallery of searched papers. This narrative
elicit the current understanding of pathophysiological review summarizes respiratory and non-respiratory
basis of various organ system involvement in patients manifestations of COVID-19 and their plausible
with COVID-19. Till date, only a few, if any therapies pathophysiology.
Correspondence: Dr Gentle S Shrestha, Department of Anaesthesiology,
Tribhuvan University Teaching Hospital, Maharajgunj, Kathmandu, Nepal.
Email: gentlesunder@hotmail.com, Phone: +9779841248584.
JNHRC Vol. 18 No. 3 Issue 48 Jul - Sep 2020 1
COVID-19: Current Understanding of
Pathophysiology
FINDING AND DISCUSSION positioning, and relatively high PEEP) may not show
beneficial effects in recruitable lungs. Type-H patients
Respiratory system have high lung elastance, higher lung weight, and
respond to high PEEP.16,17 However, this hypothesis is
SARS-CoV-2 gets access into human cells after binding based on a few case series and anecdotal
to Angiotensin-Converting Enzyme (ACE2) receptor observations. Further clinical studies are warranted to
present in the airway epithelium and lung parenchyma. better understand the COVID-19 ARDS and to explore
Direct injury to the lung tissue and the subsequent the optimal ventilator management strategies.
dysfunctional and excessive host response leads to
the pulmonary symptoms. Rapid viral replication and Hypoxia is noticed in about 14% of patients. 18 Some of
vigorous cytokine response lead to lung epithelial and the hypoxic patients do not have respiratory distress,
endothelial cell damage, eventually leading to referred to as silent hypoxemia.16 Patients experience
hypoxia.5 The degree of release of cytokines (tumor respiratory distress only when there is severe
necrosis factor [TNF], IL-6, and IL-1β) is directly hypoxemia or respiratory muscle fatigue. 19 In
related to the severity of symptoms.6 Several therapies spontaneously breathing hypoxic patient when there is
targeting cytokine response with anti-cytokine increased respiratory drive, the patient can develop
therapies or immunomodulators seem plausible in lung injury termed as patient self-inflicted lung
improving the outcome of COVID-19 patients. Alteration injury.16,20
of endogenous surfactant system has been noticed in
ARDS patients due to damage to type-2 epithelial cells Based upon the available data, similarities in terms of
and profound inflammation. 7 Clinical trials in ARDS have the clinical picture, pathophysiology and radiological
shown mixed results with exogenous surfactant use. 8-10 findings have been postulated between COVID-19
Surfactant protein has also been found to play an and high altitude pulmonary edema. Medications like
important role in treating viral pneumonia caused by acetazolamide, nifedipine and phosphodiesterase
Influenza A virus.11 inhibitors have been suggested as one of potential
treatment choices to abate hypoxemia in COVID-19. 21,22
Virus-induced downregulation of ACE2 may be one of Apart from standard respiratory and ventilator support
the proposed mechanisms for disease pathology. Loss of systems, alternative treatment strategies like
ACE2 expression results in enhanced vascular hyperbaric oxygen therapy (HBOT) has been
permeability, increased lung edema, neutrophil hypothesized to improve hypoxemia.23 Preliminary
accumulation and worsened lung function. 12 Blocking of evidence from the case report of patients with severe
the host target ACE2 receptor can be one of the to moderate ARDS treated with HBOT showed
potential therapeutic measures against SARS-COV-2. significant improvement in hypoxemia and lung
pathology without serious adverse events. 24,25 More
Microvascular thrombosis has been demonstrated in research should be conducted to explore the potential
lung tissue.13,14 Pauci-inflammatory septal capillary role of HBOT.
injury with significant mural and luminal fibrin
deposition and permeation of the interalveolar septa by Co-infection with other pathogens have been reported
neutrophils have been demonstrated in lung tissue of in patients with COVID-19 pneumonia. 26-28 Identification
COVID-19 patients.14 The underlying mechanism of of another pathogen may not rule out the presence of
pulmonary microvascular thrombosis may involve the novel coronavirus.26 Hospital-acquired pneumonia
hypercoagulability, direct endothelial injury and with resistant pathogens, was reported in 12% of
complement activation. Clinical trials need to explore intubated patients.27 More data on co-infections are
the therapeutic options for preventing and treating required to establish their importance in COVID-19
pulmonary microvascular thrombosis. pathophysiology, severity and mortality.

Acute Respiratory Distress Syndrome (ARDS) develops in Cardiovascular system

42% of patients presenting with COVID-19 pneumonia. 15
Gattinoni et al. described two patient subtypes: type-L Recent evidence have suggested that cardiovascular
and type-H according to the spectrum of ARDS. 16 In involvement is common in COVID-19. Raised cardiac
the type-L, patients present unique features with low biomarkers in the form of hs-cTnI (high sensitivity
lung elastance and low lung recruit ability but with cardiac Troponin I), LDH, CK-MB suggestive of
severe hypoxemia.17 Hypoxemia is likely due to loss of myocardial injury has been demonstrated. one study
hypoxic vasoconstriction and impairment of pulmonary demonstrated cardiac injury (elevated [hs-cTnI] or new
blood flow. Standard treatment for severe ARDS (prone ECG or echocardiographic abnormalities) in 7.2% of
 COVID-19: Current Understanding of
patients overall out of 138 hospitalized Pathophysiology
patients with COVID-19
 Corporeal
in Wuhan China,.29,30 Notably, hs-cTnI was above the
99th percentile of upper reference limit in 46% of non-
survivors as opposed to one percent of survivors.27

There may be several mechanisms responsible

for myocardial injury in patients with COVID-19.
Direct invasion of cardiomyocytes and
subsequent viral myocarditis is one of them.
Structurally, the SARS-CoV-2 particle has a domain to
bind to the ACE- 2 receptors in the human epithelial
cells.31 Through this receptor, the virus binds to and
invades human target cells. SARS-CoV-2 may also
activate the ACE-2 receptor and upregulate ACE-2
downstream signal transduction via the Ras-ERK–AP-1
pathway.32 This results in myocardial inflammation,
fibrosis and exacerbation of cardiac dysfunction.

Cytokine storm has been postulated as another possible

mechanism of myocardial injury in which there is
overwhelming production of pro-inflammatory
cytokines like interleukin-1β (IL-1β), IL-6, interferon-γ
(IFN-γ), IFNγ inducible protein-10 (IP-10), monocyte
chemo- attractant protein-1(MCP-1), granulocyte
colony- stimulating factor (G-CSF), macrophage
inflammatory protein-1α (MIP-1α) and tumor necrosis
factor-α (TNF-α) among many in response to infection.
significant elevation of these cytokines has also been
seen in COVID-19 and are associated with disease
progression.33 one study by Liu et al demonstrated high
amounts of inflammatory infiltrates in cardiac tissues
pointing out to the inflammatory nature of tissue
damage by SARS-CoV-2 infection.34

IL-6 is regarded as the most important among the

cytokines and is also responsible for stimulating the
production of other pro-inflammatory cytokines, the
cumulative effect of which is vascular leakage and
interstitial edema.35 Additional effects of IL-6 may be
papillary muscle contraction resulting in myocardial
dysfunction.36

Unbalanced myocardial oxygen supply & demand and

subsequent hypoxia is another mechanism of
myocardial injury in COVID-19 patients.37 The primary
target of SARS Cov-2 is the lungs which can lead to
hypoxia, hypotension and shock. Decreased oxygen
supply to various organs including the heart and
increased metabolic burden on cardiac tissues further
aggravates the myocardial injury.38 This effect may be
more prominent in patients with underlying
cardiovascular disease states.39

To conclude, overall management is mostly supportive

with concomitant use of antiviral medications, steroids,
intravenous immunoglobulins and ECMO (Extra
JNHRC Vol. 18 No. 3 Issue 48 Jul - Sep 2020 353
 coagulopathy, an endothelialopathy appears to
Membrane Oxygenation).40
contribute to the pathophysiology of microcirculatory
Hematological system changes in SARS- CoV-2 infections.50,51 Recent evidence
shows the presence of viral elements within
COVID-19 infection is associated endothelial cells and an accumulation of inflammatory
with significant thrombotic risks as cells, with evidence of endothelial and inflammatory
proven by numerous studies. cell death suggesting that SARS-CoV-2 infection
Infectious complications in facilitates the induction of endothelitis in several
critically ill patients can activate organs as a direct consequence of viral involvement
systemic coagulation pathways and of the host inflammatory response. 49 Therefore,
which can also lead to DIC.41 endothelial dysfunction acts as the principal
Microorganisms and their determinant of microvascular dysfunction by shifting
components can induce the the vascular equilibrium towards more vasoconstriction
expression of numerous products, with subsequent organ ischaemia, inflammation with
including tissue factor, by binding associated tissue oedema, and a procoagulant state.52
to pattern-recognizing receptors
In a meta-analysis by Xiong et al which included
on immune cells.42 Subsequent
1105 COVID-19 patients from nine studies,
generation of tissue factor can
coagulation parameters were assessed for mild and
induce host inflammatory reaction
and generate pro-inflammatory severe COVID-19.53 Pooled count, testing that can provide useful
cytokines. This can further results revealed that PT prognostic information. All confirmed
activate coagulation cascade and and D-dimer levels were or suspected COVID-19 patients
lead to consumptive coagulopathy. significantly higher in admitted to the hospital should be
All these responses act as an patients with severe COVID- treated with pharmacologic VTE
important link between humoral 19. Increasing values of D- prophylaxis, given the high
and cellular amplification dimer and PT support the inflammatory state, unless there are
pathways, a term also referred to notion that DIC, may be specific contraindications especially
as thrombo-inflammation or common in COVID-19 given reports of microvascular
immune-thrombosis.43,44 patients. thrombosis in early pathology
specimens or pulmonary emboli.54
Various components of In an analysis of 191 Early autopsy reports demonstrated
microorganisms can also activate patients, factors associated microvascular thrombosis as well as
the intrinsic coagulation pathway.45 with mortality included an marked inflammatory changes.55
Complement pathways can also elevated D-dimer, increased
contribute significantly in this PT, elevations in IL-6, and Renal system
process.46,47 Pathogen-associated other biomarkers of
molecular mechanisms (PAMPs) are inflammation elevated Emerging evidence has supported the
another essential aspect in this troponin levels, and co- development of kidney injury due to
interaction between the immune morbidities including older SARS CoV-2 infection. A sequential
response, coagulation pathway and age, hypertension, diabetes, investigation of 710 coronavirus
sepsis.42,48 Coagulopathy due to and coronary artery disease. positive subjects showed the presence
sepsis(SIC) can progress to DIC if All non-survivors met the of proteinuria in 44% and hematuria in
the etiology of sepsis remains definition of sepsis, and 50% 26.9% of patients. Raised plasma
unaddressed. had evidence of creatinine and blood urea nitrogen
coagulopathy. 27 were observed in 15.5% and 14.1% of
SARS-CoV-2 infects the host using their patients respectively.
the ACE2 receptor. ACE2 receptors Given this pro-thrombotic Furthermore, the acute renal injury
are also expressed by endothelial state hospitalized patients was found in 3.2% of infected
cells where viral replication occurs with confirmed or presumed individuals and was found to have a
causing inflammatory cell COVID-19 infection should greater risk for in-hospital mortality.56
infiltration, endothelial cell have coagulation testing
apoptosis, and microvascular performed on admission, Various mechanisms have been
prothrombotic effects.49 Consistent including D-dimer, PT, aPTT, postulated for the involvement of the
with vascular endothelial fibrinogen, and platelet kidney in COVID-19. Cytokine storm
dysfunction in sepsis-induced
354 JNHRC Vol. 18 No. 3 Issue 48 Jul - Sep
2020
can cause AKI as a and tubule specific subjective
result of intra-renal higher epithelial features and might
inflammation, alveolar- cells.61 have occurred due to
increased vascular capillary generalized illness and
permeability, permeabili Gastrointestinal system antibiotics use.
volume depletion ty and However, diarrhea is
and pulmonary A recent the objective
cardiomyopathy, haemorrha meta-analysis manifestation of viral
with subsequent ge.59 of 4,243 involvement in the
cardiorenal Rhabdomy COVID-19 gut. ACE2 is highly
syndrome.27 The olysis and patients expressed in the
syndrome includes raised found that esophagus and
systemic creatinine the pooled absorptive
endothelial injury, kinase prevalence of enterocytes from the
which manifests have been all ileum and colon.63
clinically as pleural observed gastrointestin Once infected by the
effusions, oedema, in few al symptoms virus, intestinal
intra-abdominal cases.60 was 17.6%, epithelial cells may
hypertension, third- Dehydratio which become highly
space fluid loss, n can have included permeable to foreign
intravascular fluid various anorexia,nau pathogens, leading to
depletion and consequen sea/ poor absorption and
hypotension. ces on the vomiting, diarrhea. Also, ACE2 is
Cytokine storms can kidney in diarrhea, and known to regulate
also lead to the form abdominal intestinal
hypoperfusion- of pain/discomf inflammation and may
related injury of the decreased ort.In the also cause
renal tubules.57,58 GFR or meta- diarrhea.64,65
Injured renal AKI. In analysis, the
tubular epithelium mild form, pooled A retrospective study
promotes the dehydratio prevalence of including 148 COVID-
upregulation of IL- n can be viral RNA 19 confirmed patients
6, and human and reversible positive in found that 55 patients
animal studies but if stool samples (37.2%) had an
increased IL-6 severe it was 48.1%. abnormal liver
serum may result Prolonged function at hospital
concentration in AKI in acute shedding of admission.66 It is due
were associated tubular viral RNA in to systemic
with necrosis. stool but not inflammation, hypoxia
Emerging in respiratory associated with
evidence samples was pneumonia, cytokine
suggests observed in storms, and drugs
the 70.3% of induced
possibility patients, hepatotoxicity. In the
of a direct which lasted aforementioned,
cytopathic as long as 33 patients with liver
effect of days after injury had a higher
SARS-CoV- onset of level of inflammatory
2 since disease.62 markers, namely CRP
ACE2 and procalcitonin.
receptor is Manifestation Besides, compared
highly s like nausea, with patients with
expressed vomiting, normal liver function,
on and anorexia patients with
podocytes are non- abnormal liver
JNHRC Vol. 18 No. 3 Issue 48 Jul - Sep 2020 355
 func COVID-19 immune response may be
Several assumptions
tion is found to severe neuronal inflammation,
support this
rece be leading to encephalitis and
manifestation of
ived associated myelitis.73,74
COVID-19. Through
a with
GBS along with its variants the ACE2 receptor of
signi myalgia,
have been reported to be the vascular
fica headache,
associated with COVID-19. GBS endothelium, the
ntly encephalo
is a post-infectious, acute viral invasion of the
high pathy and
inflammatory immune- endothelium may
er altered
mediated cause extensive
prop taste and
polyradiculoneuropathy endothelitis,
orti smell
presenting typically with increasing the risk of
on sensation.
paresthesia, neuralgia, thrombosis leading to
of However,
ascending motor weakness cerebrovascular
hep COVID-19
and dysautonomia. The events.49
atot can also
oxic present pathophysiology behind GBS
In a group of severe
drug with is molecular mimicry and
COVID-19 patients
s severe depending on its variants, the
with bilateral
lopi neurologic target of immune destruction
cerebral infarction,
navi al are myelin sheath, Schwann-
the levels of anti-
r/rit manifestat cell components and
phospholipid
ona ions such axolemma.75 The majority of
antibodies (including
vir as acute GBS patients have reported an
anti-cardiolipin and
afte ischemic antecedent respiratory or
anti-β-2 glycoprotein)
r stroke gastrointestinal illness in the 1
were elevated. This
adm (AIS), to 4 weeks before the
suggests that
issio intracerebr presentation of GBS.76 Mimicry
antiphospholipid
n.66 al between SARS-CoV-2
antibodies may play a
hemorrhag structural protein and nerve
role in the
Neurological system e, antigens are thought to be a
pathophysiology of
major driving
AIS in COVID-19
encephalomyelitis, exocytosis, could explain viral patients.79
and acute myelitis, migration into the brain.69-71
and Guillain- Barré Another possible route for the AIS may also arise
syndrome (GBS).67 entry of virus in the brain is secondary to cytokine
through the blood. Since the storm syndrome.73
Neurons and glial capillary endothelium The massive release
cella express ACE2 expresses ACE2 receptors, the of cytokines can
receptors, making slow movement of blood in cause severe
brain a potential the brain capillaries can endothelial damage,
target for COVID-19 promote viral interaction with disseminated
infection.68 However, endothelial ACE2 receptors. intravascular
the way the virus When in endothelium, the coagulation, and
enters the brain is virus can infect and destroy disrupted cerebral
still nebulous. One the endothelium and bud off auto-regulation, all
plausible route of into the brain parenchyma, of which increase the
entry is through the thereby promoting risk of ischemic
olfactory nerve. parenchymal infection.68,72 stroke.74 Besides,
Retrograde transfer Finally, it is well known that critically ill patients
into the axon SARS-CoV-2 can cause a with severe SARS-
whether through massive surge of cytokines, CoV-2 infection often
synapses, called a cytokine storm. The show elevated levels
endocytosis, or downstream effect of this of D-dimer. It serves

356 JNHRC Vol. 18 No. 3 Issue 48 Jul - Sep

2020
a m, with pathophys interim local policies,
s subseque iological awaiting stronger
a nt risk of basis of evidences. It can also
m AIS.60,80,81 disease help to plan well-
a may help designed future
r CONCLUSIONS to clinical trials.
k formulate
e In force behind the development of GBS in COVID-1977
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