Covid 19 pathogenesis

1. COVID-19
EPIDEMIOLOGY, CLINICAL
FEATURES, CASE DEFINITION,
TREATMENT AND PREVENTION
NPMCN UPDATE
JULY, 2022
H. Yusuph
1

2. Outline
• Introduction
• Historical Background
• Virology
1. Origin, Classification and Genome
2. Physicochemical Properties
3. Receptor Interactions and Cell Entry
4. Evolutionary Insights into the Ecology of SARS-CoV-2
5. Genomic Variation
• Epidemiology
– Geographic distribution
– Transmission
– Viral shedding
• Clinical features
• Diagnosis
• Case definition
• Treatment
• Complications
• Prevention 2

3. Introduction
• Coronavirus is a large family of viruses that cause
illnesses ranging from common cold to severe
pneumonia
• In Dec 2019, a novel β coronavirus was identified as
the cause of a cluster of pneumonia cases in Wuhan,
China.
• In February 2020, the WHO designated the disease
COVID-19.
• The causative virus is designated SARS-CoV-2;
previously, it was referred to as 2019-nCoV.
• Declared a world pandemic in March, 2020 (WHO)
3

4. Historical Background
• First described in 1931
• First coronavirus (HCoV-229E) isolated from
humans in 1965.
• Only two human coronaviruses (HCoV) were
known b4 2003– HCoV-229E and HCoV-
OC43
• Four new coronaviruses have been detected
later:
– SARS-coronavirus in 2003 (?Late 2002)
– Coronavirus NL63 in 2004
– Coronavirus HKU1 in 2005
– MERS-CoV in 2012.
4

5. Historical Background Contd.
Three antigenic groups:
–group 1 (HCoV-229E and HCoV-NL63)
–group 2 (HCoV-OC43 and HCoV-HKU1)
–group 3 (no human CoVs as yet).
SARS-CoV is an outlier to all three groups,
although some place it in group 2.
– Sub-families: α, β, γ and δ coronaviruses.
5

6. VIROLOGY
1. Origin, classification and Genome
Origin
• Linked to Huanan seafood wholesale
market in Wuhan city, where the virus is
thought to have originated.
• Genetic analysis has revealed that it
shares the highest level of genetic
similarity (96.3%) with CoV RaTG13
6

7. • Bats acted as the natural reservoir in both
SARS-CoV and MERS-CoV
• Differences between the bat coronavirus
and SARS-CoV-2 suggest that humans
were infected via an intermediate host.
• Masked palm civet for SARS-CoV
• Dromedary camels for MERS-CoV acting
as an intermediate host, with humans as
terminal hosts.
7
Origin

8. Origin
• On the basis of the
aforementioned, it seems likely
that the SARS-CoV-2 might have
been transmitted to humans via
currently unknown wild animal(s)
sold at the Huanan seafood
market.
8

9. • All human CoVs may be of zoonotic origin,
and bats are most likely the natural hosts for
all presently known CoVs.
• During the SARS pandemic in 2002 and
2003, the first hints pointed to a zoonotic
origin of the SARS-CoV, with civets as the
suspected natural source of human infection.
• Sequence identity between pangolin origin
CoVs and SARS-CoV-2 is 99%, indicating
that SARS-CoV-2 may be of pangolin
origin.
9
Evolutionary Insights into the
Ecology of SARS-CoV-2

10. 10

11. Classification
• SARS-CoV-2 is a betacoronavirus in
the same subgenus as the SARS
virus (as well as several bat
coronaviruses), but in a different
clade.
• The structure of the receptor-
binding gene region is very similar
to that of the SARS CoV. 11

12. Classification
• SARS-CoV-2 is a positive sense single
stranded RNA enveloped virus
• Genotypically and serologically
divided into four subfamilies - α, β, γ
and δ coronaviruses
• Human CoV infections are caused by
α- and β- CoVs
• SARS-CoV-2 shares 79.5% and 50%
sequence identity to SARS-CoV and
MERS-CoV, respectively.
12

13. Genome
• Genome size -29.9kb
• Possesses a nucleocapsid component
of genomic RNA and phosphorylated N
protein
• The helical nucleocapsid is surrounded
by a host-derived lipid bilayer and
covered by two different spike proteins
– S and HE
• M and E proteins are located among
the S proteins.
13

14. Crowns = Corona
14
S-protein

15. 15
Structure of CoV.

16. Genomic variation
• Initial 10 genomic sequences from 9
patients – extremely similar (˃99.98%
sequence)
• Mutation has developed recently – UK
• Due to the unstable nature of RNA
viruses, the continuous surveillance of
SARS-CoV-2 from humans is extremely
important for disease control
16

17. Genomic variation
• Phylogenetic analysis of SARS-CoV-2 from
China (Tang et al) – two different types of
SARS-CoV-2 were identified:
–Type L (accounting for 70 percent of the
strains)
–Type S (accounting for 30 percent)
• The L type predominated during the early
days of the epidemic in China, but accounted
for a lower proportion of strains outside of
Wuhan than in Wuhan. The clinical
implications of these findings are uncertain. 17

18. Physicochemical properties
• Diameter 60-100nm
• Sensitive to most disinfectants
• More stable on plastic and
stainless steal than on copper
and cardboard –viability up to
72hrs
18

19. Effect of Temperature, humidity and sunlight to
SARS-CoV-2 in saliva droplets on surfaces and
in the air
19
CONDITI
ON
TEMPERAT
URE
HUMIDITY SOLAR HALF LIFE
Surface 70-75oF 20% None 18 hours
Surface 70-75oF 80% None 6 hours
Surface 90oF 80% None 1 hour
Surface 70-75oF 80% Summer 2 minutes
Aerosol 70-75oF 20% None ~60 minutes
Aerosol 70-75oF 20% Summer ~1.5 minutes

20. EPIDEMIOLOGY
Geographic distribution
– Globally, > five hundred and sixty five million
confirmed cases have been reported by the end of
Friday 21st July 2022.
– Globally, there are 565,000,000 cases (22/7/22),
6.3M deaths
– In Africa, 9,181,118 cases confirmed (22/7/22)
– The first case in Nigeria was reported on 28
February, 2020 in an expatriate who returned
from Europe
– Total cases in Nigeria (up 22/7/22) =260,339 with
253, 566 discharged and 3,147 deaths 20

21. EPIDEMIOLOGY
–The cumulative incidence varies by country
and likely depends on a number of factors:
• Population density and demographics
• Extent of testing and reporting
• Timing of mitigation strategies.
• Outbreaks in long-term care facilities and
homeless shelters have emphasized the
risk of exposure and infection in
congregate settings
21

22. EPIDEMIOLOGY
Transmission
• **Understanding of the transmission risk is
incomplete.**
• Airborne precautions are universally
recommended when aerosol generating
procedures are performed.
• Epidemiologic investigation in Wuhan
identified an initial association with a seafood
market that sold live animals, where most
patients had worked or visited.
22

23. EPIDEMIOLOGY: Transmission contd.
• Person-to-person
– Route of person-to-person transmission — Direct
person-to-person transmission -primary means of
transmission.
Thought to occur through close-range contact, mainly via
respiratory droplets:
– Cough
– Sneezing
– Talking
– Touching an infected surface followed by touching
eyes, nose, or mouth. (Droplets typically do not
travel more than six feet (about two meters)).
Whether SARS-CoV-2 can be transmitted through the airborne
route under natural conditions has been a controversial issue 23

24. Transmission contd.
• SARS-CoV-2 has been detected in non-
respiratory specimens, including:
✓Stool –faeco-oral transmission not described
✓Blood –likelihood of blood transmission
appears very low
✓Ocular secretions – role uncertain
✓Semen – role uncertain
✓Urine – role uncertain
✓Skin - no evidence that transmission can
occur through contact with non-mucous
membrane sites
24

25. Risk factors for severe COVID-19
The following are underlying conditions that may
represent an increased risk of severe COVID-19:
• Chronic kidney disease
• COPD
• Immunocompromised state due to solid organ
transplant
• Obesity (BMI ≥30)
• Serious heart conditions (e.g. heart failure,
coronary artery disease, cardiomyopathies)
( Circulating ACE-2)
25

26. Risk factors for severe COVID-19
• Sickle cell disease
• Types 1 &2 diabetes mellitus
( Circulating ACE-2)
26

27. Risk factors for severe COVID-19
• Asthma (moderate to severe)
• Cerebrovascular disease
• Cystic fibrosis
• Immunocompromised state due to blood or
bone marrow transplant, immunodeficiencies,
HIV infection, corticosteroid use (or other
medications that weaken the immune system)
• Neurologic conditions (eg, dementia)
27

28. Risk factors for severe COVID-19
• Liver disease
• Pregnancy
• Pulmonary fibrosis
• Smoking
• Thalassemia
• Age >65years
• Living in a nursing home
• ??Male ( Circulating ACE-2)
28

29. Transmission contd.
Viral shedding and period of infectivity
• Duration of infectivity is uncertain.
• Transmission - prior to the development of
symptoms and throughout the course of
illness.
• Viral RNA levels from upper respiratory
specimens appear to be higher soon after
symptom onset compared with later in the
illness.
• Detection of viral RNA does not necessarily
indicate the presence of infectious virus, and
thus prolonged viral RNA detection following
the resolution of illness does not necessarily
indicate infectiousness. 29

30. Risk of transmission
• The risk of transmission varies by:
– Type and duration of exposure
– Use of preventive measures
– Likely individual factors (e.g. the amount of
virus in respiratory secretions)
• Most secondary infections have been
described among:
– Household contacts
– Congregate setting
– Health care setting (rates vary from 3-15%)
30

31. Risk of transmission Contd.
• The risk of transmission with more indirect
contact (e.g. passing someone with infection
on the street, handling items that were
previously handled by someone with infection)
is not well established and is likely low.
Environmental contamination
It is unknown how long SARS-CoV-2 can persist
on surfaces. However, other coronaviruses have
been tested and may survive on inanimate
surfaces for up to six to nine days without
disinfection.
31

32. Environmental contamination
• Duration of viral persistence on
surfaces also likely depends on:
–Ambient temperature
–Relative humidity
–The size of the initial inoculum
32

33. Animal contact
• No evidence suggesting animals (including
domesticated animals) are a major source
of infection in humans.
• Rare reports of animals with COVID-19
(including asymptomatic infections in dogs
and symptomatic infections in cats)
following close contact with infected
humans (The Tanzania Experience)
• No reports of domesticated animals
transmitting SARS-CoV-2 infection to
humans.
33

34. Immunity and risk of reinfection
• Data on protective immunity following COVID-19
are emerging
• Antibodies are induced in infected persons.
• Preliminary evidence suggests that some of these
antibodies are protective, but this remains to be
definitively established.
• It is unknown whether all infected patients mount
a protective immune response and how long any
protective effect will last.
• Animal studies have suggested that the immune
response to infection may offer some protection
against reinfection, at least in the short term 34

35. Clinical features
History
• Asymptomatic/mild symptoms to severe illness and mortality
– Asymptomatic – 81%
– Mild symptoms – 14%
– Severe symptoms – 5%
• Common symptoms - fever, cough, and shortness of breath.
• Other symptoms, such as malaise and respiratory distress, have
also been described
• Symptoms may develop 2 days to 2 weeks following exposure
• Mean incubation period – 5.1 days and 97.5% of individuals who
developed symptoms did so within 11.5 days of infection
35

36. Clinical features
The following symptoms may indicate COVID-19
– Fever or chills (98% -Huang, et al.)
– Cough (76% -Huang et al.)
– Shortness of breath or difficulty breathing (55% -
Huang, et al.)
– Fatigue
– Myalgia or body aches (44% -Huang, et al.)
– Headache
– Sore throat
36

37. Clinical features
• Anosmia (74%)
• Ageusia
• Nasal Congestion or runny nose
• Nausea or vomiting
• Diarrhoea
• Sputum production
• Malaise
• Respiratory distress
• Neurologic (e.g. headache, altered
consciousness) 37

38. Clinical features
• Severe COVID-19 and mortality, more
common in:
– Males
–Older individuals
–Individuals in poverty
–Black persons
–Patients with medical conditions such as
diabetes and severe asthma, among
others.
38

39. Clinical features
• Frailty is a greater predictor of mortality than age or co-
morbidities
– Age fatality rates differ and increase with age as shown below in data from the
USA.
• 80 years: 14.8%
• 70 - 79 years: 8%
• 60 - 69 years: 3.6%
• 50 - 59 years: 1.3%
• 40 - 49 years: 0.4%
• 10 - 39 years: 0.2%
• Type A blood has been suggested as a potential factor that
predisposes to severe COVID-19, specifically in terms of
increasing the risk of respiratory failure
• Blood type O appears to confer a protective effect
39

40. Diagnosis
• RT-PCR – recommended test
• Serology –antibody test
• Viral cultures – not recommended
• A nasopharyngeal (NP) swab and/or an
oropharyngeal (OP) swab or saliva are often
recommended for screening or diagnosis of early
infection
• A single NP swab has become the preferred swab -
tolerated better by the patient and is safer to the
operator. 40

41. Diagnosis
• NP swabs have an inherent quality control in that
they usually reach the correct area to be tested in
the nasal cavity.
• NP Vs OP (63% Vs 32% detection rate in 398 pts –
Wang et al.)
• BALF recommended in late detection and
monitoring
• Rectal swabs in advanced cases
• Self testing – emergency use authorization (EUA)
(FDA - Nov. 17, 2020)
41

42. 42
Diagnostic tests for detection of SARS-CoV-2 infection relative to time of symptom onset.
Adapted from Sethuraman N, Jeremiah S and Ryo A. Interpreting Diagnostic Tests for SARS-CoV-2;
JAMA. 2020;323(22):2249-2251. doi:10.1001/jama.2020.8259

43. Other Lab. investigations
• WBC may be normal or decreased
• Neutrophilia and mild thrombocytopaenia are seen in some patients
• Lymphopenia with absolute lymphocyte count <1.0x10 /L is seen in most
hospitalized patients
• Ferritin levels are also elevated in some patients.
• Elevated ALT and AST are seen in about a third of patients, but majority
of patients have low albumin levels.
• Increased prothrombin time/INR and 50% have elevated D-dimer.
Lactate dehydrogenase (LDH) and inflammatory markers such as IL2, IL7,
IL10,
• Elevated TNF-α
• Relevant investigations targeting comorbidities and complications such
as cardiac, renal, neurological, obesity and hypertension should be
conducted.
• Chest radiography commonly reveals consolidation and ground-glass
opacities which are often bilateral and distributed in the lower zone.
• Chest CT delineates these findings better. 43

44. Differential diagnosis
Other diseases that may mimic COVID-19 include:
❖ Community acquired pneumonia
❖ Common cold
❖ Influenza
❖ Avian influenzas (H7N9, H5N1)
❖ Aspiration pneumonia
❖ Pulmonary tuberculosis.
44

45. Complications
• ARDS – 20-41%
• Cardiac – 20% (arrhythmias, CV shock, heart attack)
• AKI – 36.6%
• Thyrotoxicosis
• Neurologic
• Thrombosis – venous: 21-31%, arterial : 2-5%
• Pneumonia – NCIP (26% of 138 pts in Wuhan needed
ICU Rx), mortality -4.3%
45

46. Prevention
• Limit contact
• Wash hands frequently -20 secs
• Hand sanitizers
• Don’t touch your face, nose, eyes and mouth when
hands are dirty
• Don’t go out when feeling sick or have any flu
symptoms
46

47. Prevention
• Physical distancing – 2meters
• Cover mouth with inside of elbow or tissue paper
when you sneeze or cough
• Clean any objects you touch a lot – disinfectants on
objects like phones, door knobs and soap and water
for utensils
• Mask
• VACCINES – being rolled out.
47

48. Case definition

49. NCDC CASE DEFINITIONS FOR COVID-19
(Version 4)
Suspected Case
Any person (including severely ill patients) presenting with fever,
cough or difficulty in breathing AND who within 14 days before
the onset of illness had any of the following exposures:
• History of travel to and more than 24 hours transit through
any high-risk country* with widespread community
transmission of SARS-CoV-2
OR
• Close contact with a confirmed case of COVID-19
OR
• Exposure to a healthcare facility where COVID-19 case(s) have
been reported

50. NCDC Case definition
A probable case
Any suspect case
• For whom testing for COVID-19 is Indeterminate test results
OR
• For whom testing was positive on a pan-coronavirus assay
OR
• Where samples were not collected before the demise of a
suspect case
A confirmed case
Any person with laboratory confirmation of SARS-CoV-2
infection with or without signs and symptoms.

51. Treatment
• Most COVID-19 treatment focuses on managing symptoms as
the virus runs its course
• Currently, there is no cure
• Some of the agents under investigation include:
– Remdesivir
– Convalescent plasma
– Monoclonal abs – banlanivimab, casirivimab, imdevimab
– Ivermectin
– Steroids
– Hydroxychloroquine
– NSAIDS
– Anticoagulants
– Vit. D, Vit C,
– Antiviral/retroviral medications
– Anti-arthritis drugs
– Mechanical ventilation
51

52. Remdesivir
• Remdesivir, is the only drug approved for
treatment of COVID-19 as of October 22, 2020.
• It is indicated for treatment of COVID-19 disease
in hospitalized adults and children aged 12 years
and older who weigh at least 40 kg.
• An emergency use authorization (EUA) remains in
place for treatment of paediatric patients
weighing 3.5 kg to less than 40 kg or children
younger than 12 years who weigh at least 3.5 kg.

53. Convalescent plasma
An EUA for convalescent plasma was announced on
August 23, 2020.

54. Monoclonal antibodies
• Emergency use authorization (EUA) for bamlanivimab on November 9,
2020.
• The EUA permits bamlanivimab for treatment of mild-to-moderate disease
in adults and paediatric patients who are 12 years and older weighing at
least 40 kg, and at high risk for progressing to severe COVID-19 and/or
hospitalization.
• Another EUA for casirivimab and imdevimab, was issued by the FDA on
November 21, 2020.
• Baricitinib was issued an EUA on November 19, 2020 for use, in
combination with remdesivir, for treatment of suspected or laboratory
confirmed cases in hospitalized patients aged 2 years and older who
require:
– Supplemental oxygen
– Invasive mechanical ventilation
– Extracorporeal membrane oxygenation (ECMO).

55. Ivermectin
• Inhibits COVID-19 causative virus (SARS-CoV-2) in-
vitro
• A single treatment able to effect ~5000-fold
reduction in virus at 48 h in cell culture
• Ivermectin is FDA-approved for parasitic
infections, and therefore has a potential for
repurposing
• The NIH COVID-19 Treatment Guidelines Panel
(the Panel) as at 21st Jan 2021 has determined
that currently there are insufficient data to
recommend either for or against the use of
ivermectin for the treatment of COVID-19.

56. Ivermectin
Most studies had incomplete information and
significant methodological limitations. The missing
information and limitations include the following:
• Small sample size of most of the trials
• Various doses and schedules of ivermectin were
used.
• Some of the RCTs were open-label studies in which
participants and the investigators were not
blinded to the treatment arms
• The severity of COVID-19 was not always well
described.

57. Ivermectin
• In addition to ivermectin or the comparator drug, patients
also received various concomitant medications (e.g.,
doxycycline, hydroxychloroquine, azithromycin, zinc,
corticosteroids), confounding assessment of the true efficacy
or safety of ivermectin.
• The study outcome measures were not always clearly
defined.
• Because of these limitations, the Panel cannot draw
definitive conclusions about the clinical efficacy or safety of
ivermectin for the treatment of COVID-19.
• Results from adequately powered, well-designed, and well-
conducted clinical trials are needed to provide more specific,
evidence-based guidance on the role of ivermectin for the
treatment of COVID-19.

58. Steroids
• A UK study found dexamethasone beneficial in
critical patients (RECOVERY) Study
• The WHO recommends use in severe or
critical cases
• WHO advises against use in mild cases
• Meta-analysis on clinical outcomes confirmed
a beneficial effect on short-term mortality and
a reduction in need for mech. vent. (Judith
Van Paassen and colleagues)

59. Chloroquine/Hydroxychloroquine
The WHO Had to stop HCQ in the SOLIDARITY trial
Ghazy RM et al in a SR and MA on CQ and HCQ as monotherapy
or combined wit AZM concluded that:
– Mortality was not decreased, in fact it was increased with
the addition of AZM
– Alone or in combination with AZM increased the duration
of hospital stay
– Overall virological cure rate not affected
– Addition of AZM did not show any benefit in terms of
virological cure
– Need for MV was not improved (alone or plus AZM)
– Duration of conversion to neg PCR not shortened
– Radiological progression unaffected
– Clinical worsening of disease not affected

60. Others
– NSAIDS
– Anticoagulants
– Zinc
– Vit. D, Vit C, selenium
– Antiviral/retroviral medications
– Anti-arthritis drugs
– Mechanical ventilation

61. CONCLUSION
• Not being pessimistic – COVID-19 has come to
stay!
• Information keeps evolving and our
understanding is improving
• Efforts at prevention should still be
emphasized
• Vaccines have generated so much controversy
• TAKE RESPONSIBILITY!!!
61

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