Pathophysiology for nursing students

1. COVID 19
AETIOLOGY AND PATHOGENESIS
BY
DHARMESH CHATURVEDI
SNS (M.SC.NURSING)
SDRH RANAPRATAPNAGAR
AJMER DIVISION NWR
Aetiology

2. INTRODUCTION
• Corona virus was first identified as a cause of the
common cold in 1960. Until 2002, the virus was
considered a relatively simple, nonfatal virus.
• Coronavirus disease 2019 (COVID-19) is an
infectious disease mainly of respiratory system
caused by SARS-CoV-2.
• Started from “Wuhan City” of Hubei Province, China

4. • On January 30, 2020 WHO declared the 2019–20
coronavirus outbreak to be a Public HealthEmergency
of International Concern (PHEIC).
• COVID-19, named by WHO on Feb 11, 2020 and the
virus was named as SARS corona virus-2, belongs to
the family of coronavirus, the name to crown-like
spikes on their surface.
• In march 2020 WHO declared COVID 19 outbreak a
pandemic.

5. • The new coronavirus is called SARS-CoV2 because its
genetic sequence is very similar to that of SARS, another
coronavirus that appeared for first (and only) time in 2002

6. Aetiology
• Coronavirus tend to cause mild upper respiratory
diseases in humans. Of the 7 known species of CoV,
only 3 are known to cause severe infections in
humans, all within the betacoronavirus genus:
• An outbreak of severe acute respiratory syndrome
coronavirus (SARS-CoV) in 2003 in southern China
from civet cats, caused an eventual 8,098 confirmed
cases, resulting in 774 deaths reported in 17 countries
with fatality rate of 9.6%.

7. • In 2012, again another coronavirus Middle East
respiratory syndrome coronavirus (MERS-COV)
from dromedary camels caused an outbreak in Saudi
Arabia infected 2494 cases, resulting in 858 deaths
with fatality rate 36%.
• SARS-COV-2: emerged in November 2019 in China
from bats (still under investigation). The genome is
96.2% identical to bat coronavirus RaTG13. It has not
yet been determined whether the virus is transmitted
directly from bats or through an unknown
intermediate host

10. CORONA VIRUS
Corona virus look like a tennis ball with all these spikes
sticking out of it. Depending on the type of spikes, it
allows that virus to attach to certain places.

11. STRUCTURE OF CORONAVIRUS

12. • Coronaviruses (CoVs) are a family of enveloped,
positive-sense, single-stranded RNA viruses.
• The SARS-CoV-2 virion is approximately 125 nm in
diameter and its genome ranges from 26-32 kb, the
largest of all RNA viruses.
• It has 4 structural proteins: spike (S), envelope (E),
membrane (M), and nucleocapsid (N).
• S, E, and M proteins create the viral envelope.
• N protein forms a complex with RNA (nucleocapsid)
and aids in the regulation of viral RNA synthesis.

13. • M protein projects on the external surface of the
envelope, spans the envelope 3 times, and is important
in viral assembly.
• E protein has an unclear function, although it may aid
in viral release.
• S protein is a club-shaped surface projection, giving
the virus its characteristic crown-like appearance on
electron microscopy. It is responsible for receptor
binding and fusion with the host cell membrane.

15. • In January 2020, population genetic analysis
concluded that SARS-CoV-2 had evolved into 2
separate genotypes:
• L type: more aggressive and more prevalent
(approximately 70% of cases in the early stages of
outbreak; prevalence has since decreased)
• S type: evolutionary older, less common, and less
aggressive (approximately 30% of cases)

16. Mode of transmission
• Coronaviruses are zoonotic; transmitted to humans
through animals.
• It is hypothesized that horseshoe bats are the natural
reservoir of SARS-CoV-2, since the virus’s genome is
96.2% identical to that of a bat coronavirus.
• At this time, the intermediate host is still unknown
(may be a Pangolin)

17. • In humans the virus is transmitted when respiratory
droplets from coughing, sneezing, or talking of
infected individuals come into direct contact with the
mucous membranes of another individual, including
the eyes, nose, or mouth.
• In the air, larger droplets tend to drop toward the
ground, within 1 m (3 ft) of the infected person, while
smaller droplets can travel over 2 m (6 ft) and remain
viable in the air for up to 3 hours under certain
conditions

18. Other forms of transmission include the following:
• Direct transmission through hand-to-face contact from
infected surfaces.
• Fecal–oral transmission is also believed to occur
(SARS-CoV-2 RNA has been detected in stool
specimens, but fecal–oral transmission has not been
clinically described).
• Vertical transmission (mother-to-child) has not been
reported.
• COVID-19 is not considered to be airborne, as
coughing, sneezing, and talking do not generate
droplets small enough to behave as aerosols.
• However, certain medical procedures can generate
virus-laden aerosol clouds, which put healthcare
personnel at a higher risk of becoming infected

19. • The reproductive number (R0), or the number of
secondary infections generated from 1 infected
individual, is 2–2.5, higher than for influenza (0.9–
2.1).

20. COVID-19 is highly contagious for the
following reasons
• Production of high viral loads
• Efficient and prolonged shedding of virions from the
upper respiratory tract
• Asymptomatic individuals are also infectious, posing a
significant challenge for contagion prevention
• SARS-CoV-2 can remain infectious on surfaces
outside of a host from a few hours to a few days.

22. Risk Factors
• Chronic diseases:
– Chronic lung disease or moderate to severe asthma
– Cardiovascular disease
– Immunosuppression (from long-term steroid use,
cancer, AIDS/HIV infection, congenital
immunodeficiency, organ transplants,
immunosuppressants, etc.)
– Severe obesity (BMI > 30)
– Diabetes mellitus, chronic kidney disease
undergoing dialysis, cerebrovascular disease,
sickle cell disease and liver disease

23. • Age > 65 years
• Living in a nursing home or long-term care facility
• Children are at lower risk of developing severe or
critical infections, and complications appear to be
milder
• Pregnancy
– Risk of infection is the same as in non-pregnant
individuals.
– A higher risk of severe illness in pregnant
individuals is assumed due to the behavior of
similar respiratory infections, such as SARS and
influenza.

26. Patho-physiology
• It is believed that bat coronavirus had acquired the ability
to infect human, extending the host range (may be
Pangolin), by having a few mutations in the spike protein.
• The detail Pathogenesis of covid-19 is explained by
the following steps:
A. Virus Entry and Spread
B. Pathological Findings
C. Acute Respiratory Distress Syndrome (ARDS)
D. Cytokine Storm
E. Immune Dysfunction

27. A. Virus Entry and Spread
 SARS-CoV-2 is transmitted predominantly via
respiratory droplet, contact, and potential in fecal-
oral.
 Primary viral replication is presumed to occur in
mucosal epithelium of upper respiratory tract (nasal
cavity and pharynx), with further multiplication in
lower respiratory tract and gastrointestinal mucosa,
giving rise to a mild viremia.

28. • Few infections are controlled at this pointand
remain asymptomatic. Some patients have also
exhibited non- respiratory symptoms such as
acute liver and heart injury, kidney failure,
diarrhea, implying multiple organ involvement.

29. • SARS-CoV-2 attaches to the host cell by binding its S
protein to the receptor protein, angiotensin-
converting enzyme 2 (ACE2).
• ACE2 is expressed by epithelial cells of the intestine,
kidney, blood vessels, and, most abundantly, in type
II alveolar cells of the lungs.
• The human enzyme transmembrane protease, serine 2
(TMPRSS2), is also used by the virus for S protein
priming and to aid in membrane fusion. The virus
then enters the host cell via endocytosis.

30. Antibody-dependent enhancement (ADE); ACE2: angiotensin-converting enzyme 2;
RAS: renin-angiotensin system; ARDS: acute respiratory distress syndrome.
P o s t u l a t e d p a t h o g e n e s i s o f S A R S - C o V - 2 i n f e c t i o n .
NOTE: Red words in the chart represent the important turning points in SARS-CoV-2
infection.

31. B. Pathological Findings
 The first report of pathological findings from a severe
COVID-19 showed pulmonary bilateral diffuse
alveolar damage with cellular fibromyxoid exudates.
 The right lung showed evident desquamation of
pneumocytes and hyaline membrane formation,
indicating acute respiratory distress syndrome.
 The left lung tissue displayed pulmonary edema with
hyaline membrane formation, suggestive of early-
phase acute respiratory distress syndrome (ARDS).

32.  Interstitial mononuclear inflammatory infiltrates,
dominated by lymphocytes, could be observed in
both lungs.
 Multinucleated syncytial cells with atypical enlarged
pneumocytes characterized by large nuclei,
amphophilic granular cytoplasm, and prominent
nucleoli were identified in the intra-alveolar spaces,
indicating viral cytopathic-like changes.

33.  Moderate microvascular steatosis and mild lobular
and portal activity were observed in liver biopsy
specimens, which might be caused by either SARS-
CoV-2 infection or drug use.
 In addition, only a few interstitial mononuclear
inflammatory infiltrates were found in the heart
tissue, which means that SARS-CoV-2 might not
directly impair the heart.

34. C. Acute Respiratory Distress Syndrome
(ARDS)
• ARDS is a life-threatening lung condition that
prevents enough oxygen from getting to the lungs and
into the circulation, accounting for mortality of most
respiratory disorders and acute lung injury.
 Previous studies have found that genetic
susceptibility, and inflammatory cytokines were
closely related to the occurrence of ARDS.

36.  More than 40 candidate genes including ACE2,
interleukin 10 (IL-10), tumor necrosis factor (TNF),
and vascular endothelial growth factor (VEGF)
among others have been considered to be associated
with the development or outcome of ARDS.
 Increased levels of plasma IL-6 and IL-8 were also
demonstrated to be related to adverse outcomes of
ARDS.
 The above biomarkers suggest both a molecular
explanation for the severe ARDS and a possible
treatment for ARDS following SARS-CoV-2
infection.

38. D . C y t o k i n e S t o r m
 Rapid viral replication and cellular damage, virus-
induced ACE2 downregulation and shedding, and
antibody dependent enhancement (ADE) are are
responsible for aggressive inflammation caused by
SARS-CoV-2.
 SARS-CoV-2 hijacks the same entry receptor, ACE2,
as SARS-CoV for infection, suggesting the likelihood
of the same population of cells being targeted and
infected.

39.  The initial onset of rapid viral replication may cause
massive epithelial and endothelial cell death and
vascular leakage, triggering the production of
exuberant pro-inflammatory cytokines and
chemokines.
 Loss of pulmonary ACE2 function has been proposed
to be related to acute lung injury because ACE2
downregulation and shedding can lead to dysfunction
of the renin-angiotensin system (RAS), and further
enhance inflammation and cause vascular
permeability.

40.  A possible underlying mechanism of antibody-dependent
enhancement (ADE) has been proposed recently. ADE, a
well-known virology phenomenon, has been confirmed
in multiple viral infections.
 ADE can promote viral cellular uptake of infectious
virus–antibody complexes following their interaction
with Fc receptors (FcR), FcγR, or other receptors,
resulting in enhanced infection of target cells.
 The interaction of FcγR with the virus-anti-S protein-
neutralizing antibodies (anti-S-IgG) complex may
facilitate both inflammatory responses and persistent
viral replication in the lungs of patients

42. E . I m m u n e D y s f u n ct i o n
Peripheral CD4 and CD8 T cells showed reduction and
hyperactivation in a severe patient.
 High concentrations of proinflammatory CD4 T cells
and cytotoxic granules CD8 T cells were also determined,
suggesting antiviral immune responses and overactivation
of T cells.
Additionally, several studies have reported that
lymphopenia is a common feature of COVID-19,
suggestive of a critical factor accounting for severity and
mortality.

43. Stages of Infection
Stage 1 : Asymptomatic stage (initial 1-2 days of
infection)
 The inhaled virus SARS-CoV-2 likely binds to
epithelial cells in the nasal cavity and starts
replicating.
 ACE2 is the main receptor for both SARS-CoV2 and
SARS-CoV. ACE2 is broadly expressed in nasal
mucosa, bronchus, lung, heart, esophagus, kidney,
stomach, bladder, and ileum, and these human organs
are all vulnerable to SARS- CoV-2 .
 In vitro data with SARS-CoV indicate that the
ciliated cells are primary cells infected in the
conducting airways

44. • There is local propagation of the virus but a limited
innate immune response. At this stage the virus can
be detected by nasal swabs.
• Although the viral burden may be low, these
individuals are infectious. The RT-PCR value for the
viral RNA might be useful to predict the viral load
and the subsequent infectivity and clinical course

45. Stage 2 : Upper airway & conducting airway response
• The virus propagates and migrates down the
respiratory tract along the conducting airways, and a
more robust innate immune response is triggered.
• Nasal swabs or sputum should yield the virus (SARS-
CoV-2) as well as early markers of the innate immune
response. At this time, the disease COVID-19 is
clinically manifest.

46. • The level of CXCL10 (or some other innate response
cytokine) may be predictive of the subsequent clinical
course. Viral infected epithelial cells are a major
source of beta and lambda interferons.
• CXCL10 is an interferon responsive gene that has an
excellent signal to noise ratio in the alveolar type II
cell response to both SARS-CoV and influenza.
CXCL10 has also been reported to be useful as
disease marker in SARS.
• For about 80% of the infected patients, the disease
will be mild and mostly restricted to the upper and
conducting airways

47. Stage 3 : Hypoxia, ground glass infiltrates and
progression to ARDS
• Unfortunately, about 20% of the infected patients will
progress to stage 3 disease and will develop
pulmonary infiltrates and some of these will develop
very severe disease.
• The virus now reaches the gas exchange units of the
lung and infects alveolar type II cells. SARS-CoV
propagates within type II cells, large number of viral
particles are released, and the cells undergo apoptosis
and die. Suspect areas of the lung will likely lose
most of their type II cells, and secondary pathway for
epithelial regeneration will be triggered.

48. • The pathological result of SARS and COVID-19 is
diffuse alveolar damage with fibrin rich hyaline
membranes and a few multinucleated giant cells.
• The aberrant wound healing may lead to more severe
scarring and fibrosis than other forms of ARDS.
Recovery will require a vigorous innate and acquired
immune response and epithelial regeneration.

49. • Elderly individuals are particularly at risk because of
their diminished immune response and reduced
ability to repair the damaged epithelium.
• The elderly also have reduced mucociliary clearance,
and this may allow the virus to spread to the gas
exchange units of the lung more readily

51. Clinical Presentation
• The incubation period for COVID-19 ranges from 2–
14 days, with an average of 5 days.
• 80% of infections are mild or asymptomatic
• 15% of infections are severe (requiring oxygen
therapy)
• 5% of infections are critical (requiring intensive care
unit [ICU] admission and ventilation)
• The proportion of severe and critical-to-mild cases is
higher than in influenza infections

53. Asymptomatic cases:
• These individuals can transmit the virus.
• They represent > 50% of all infections (still under
investigation).
• They do not develop any noticeable symptoms.
• Anosmia, hyposmia, and dysgeusia have been
reported in many laboratory-confirmed cases of
patients who were otherwise asymptomatic.
• These individuals can present radiological and
laboratory findings characteristically found in
symptomatic COVID-19 patients

54. Mild cases:
• May present with dry cough and moderate fever
• Include common flu-like symptoms such as fatigue,
malaise, myalgia, runny nose, nasal congestion, and
sore throat
• Less frequently experience diarrhea, nausea,
vomiting, diffuse abdominal pain, productive cough,
headache, and muscle or joint pain
• Dermatologic symptoms have been reported,
including maculopapular, urticarial, and vesicular
eruptions, transient livedo reticularis, perniosis-like
red or purple tender nodules on the distal digits
(“COVID toes”)
• Have a recovery time of approximately 2 weeks

55. Severe cases and complications:
• Approximately 1 in 6 people with COVID-19 experience
clinical deterioration and/or develop a complication after
an average of 5–7 days.
• Median time from onset of symptoms to the onset of
critical care/ICU transfer is 8–9 days.
• Patients develop dyspnea, high fever, chest pain,
hemoptysis, anorexia, and/or respiratory crackles, which
indicates the development of pneumonia (most frequent
complication in severe cases).
• Respiratory failure from acute respiratory distress
syndrome (ARDS) is the most common finding in
critical cases.
• Recovery time is approximately 3–6 weeks.

57. Diagnosis
• Reverse transcription polymerase chain reaction (RT-
PCR) is currently the only test being used to confirm
cases of acute COVID-19 infection .
• A positive test for SARS-CoV-2 generally confirms
the diagnosis of COVID-19, regardless of the
patient’s clinical status

59. The specimens used for testing include the following:
• Nasopharyngeal (NP) or oropharyngeal (OP) swab
– NP is the first choice. OP swabs are acceptable
only if NP swabs are not available.
• Nasal mid-turbinate swab or swab of anterior nares
(nasal swab)
• Nasopharyngeal wash/aspirate or nasal wash/aspirate
specimen
• Sputum (for patients with productive cough; inducing
is not recommended)
• Bronchoalveolar lavage, tracheal aspirate, pleural
fluid, and lung biopsy (for patients with critical
infections receiving invasive mechanical ventilation)

60. • RT-PCR testing can be negative initially. If suspicion
of COVID-19 remains, the patient should be retested
every 2–3 days.
• In severe cases, swabs from the upper respiratory
tract may be negative, while specimens from the
lower respiratory tract are positive. RT-PCR tests can
also yield false negatives in 20%–30% of cases.

62. Other important investigations
• Patients with COVID-19 present with the following
laboratory and radiological findings. These are more
pronounced and common in severe and critical cases
but can also be present even in asymptomatic
infections:
• White blood cell count: leukopenia, leukocytosis, and
lymphopenia (most common)
• Inflammatory markers: ↑ LDH and ferritin
• Liver markers: ↑ AST and ALT

63. • Chest X-ray and computed tomography (CT):
– Not recommended for initial evaluation; reserved
for hospitalized patients or symptomatic patients
with specific clinical indications
– Common findings include ground-glass opacities
(GGOs), multiple areas of consolidation, “crazy
paving appearance” (GGOs + inter-/intralobular
septal thickening), and bronchovascular
thickening.
– Lesions usually have a bilateral, peripheral, and
lower lobe distribution.