Covid-19 Timetable Relapse reactivation diagnosis treatment transmission infectivity viral shedding clinical picture incubation pathogenesis radiology vaccine

1. COVID-19 and Time

3.  Brain is time
 Heart is time
 Lung is time
 Kidney is time
 Liver is time

4. Infection is distance and TIME

7. Timetable of Deadliest Pandemics:

8. Timetable of 21st Century Emergent
Viruses

9. Timetable of HCoV Detection:

10. HCoV , Their Normal and Intermediate
Hosts:

12. SARS-CoV-2 virus genes:
96.2% similarity to bat CoV RaTG13
88% similarity to bat SARS-like CoVs
79% with SARS-CoV-1
50% with MERS-CoV
90% similarity to pangolin CoV
ACE2 receptors are present in animals other than pangolins

13. I didn't search PubMed for the last 12
hours, The data I present may be out of
date

14. Timetable of reasearch on COVID-19

15. Timetable for scientific papers publications :
Up to end of March 2020:
China had 37.3% of main investigators
North America 11.7%
Europe 22.6%
Middle East 3% mainly Iran

17. Timetable for scientific papers
publications (1):
It is too short
In NEJM a letter was published on 30-1-2020 while the
patient was tested on 28-1-2020
Journal of Royal Society of Open Science revise the
manuscripts in 24-48 hours
Paper on HCQ and azithromycin was applied on 16-3,
accepted on 17-3, published on 20-3-2020

18. Timetable for scientific papers
publications (2):
The rigorous peer-review standards and editorial practices
are the core to ensure high quality research and best way to
avoid the dissemination of erroneous, inaccurate or
inconclusive data

19. Timetable of Strain:

21. Timetable for pathogenesis:
Stage 1: Asymptomatic state (initial 1–2 days of infection)
The inhaled virus SARS-CoV-2 likely binds to epithelial cells
in the nasal cavity and starts replicating
Stage 2: Upper airway and conducting airway response
(next few days) The virus propagates and migrates down the
respiratory tract along the conducting airways, clinically
manifest
Stage 3: Hypoxia, ground glass infiltrates, and progression
to ARDS Unfortunately, about 20% of the infected patients will
progress to stage 3

23. SARS-CoV-2 Co-Pathogens:

24. Incubation Period

25. Incubatiion Period:
The mean incubation period is 5.2 days
3-9 days (range 0-24)

27. Mode of transmission

28. Transmission:
•Droplet
•Air-borne
•Fecal-Oral (Theoretical)
•Body fluids (vomits)
•Direct contact with surfaces
•No vertical
•Case reports of Breast milk
•Average R0 is 2.2
•Cummulative attack rate is 0-50 fold of flu

29. Yesterday, at last:

30.  The Maximum distance (till now) for transmission is 4
meters
 No significant difference between N-95 masks and surgical
mask as regard laboratory confirmed infection

31. Timetable of Symptoms and disease
course

32. No evidence of SARS-CoV-2 before the end of March
2020 in samples of patients with suspected CAP was
seen in Germany

34. Symptoms and Signs:
Fever (more early, may be at any time)
Cough (Early, may be prolonged)
Dyspnea (late, alarming)
Hypoxemia,(late, may be catastrophic)
Heart rate (mainly brady, may be tachy...)
Crackles (Alarming)
Fatigue (early, may be prolonged)
depressive mood and anxiety (prominent)

35. Fever in COVID-19 Patients In Shanghai

36. Low-grade fever during convalescence is an atypical
symptom of COVID-19. These cases are not rare, but the
mechanism and outcome of low-grade fever during
convalescence is not yet completely clear.

38.  ARDS in COVID-19 patients was related to, age more than
65, hypertension and DM
 The Median duration for onset of symptoms to ARDS is 9
days (5-12 days from symptoms)
 9.5-12 days to MODS

40. Timetable of anosmia improvement in
COVID-19 patients

43. Post COVID-19 symptoms (18% were
free, 44% worsened QOL) (Italy, 143
patients)

44. ABO group:
A: more disease
O: less
The mortality rate was similar across ABO phenotypes in all
race/ethnicity categories

45. CT of the Chest

46. Radiology and time:
In early stages (0-4 days), HRCT of chest is neagtive in 21%
of cases
At that stage, if CT is positive, the frequent finding is
Peripheral GGO in 76% of cases (terminal and respiratory
bronchiolitis and alveolitis)

47. Radiology and time:
In progressive stage (5-9 days), crazy paving, consolidation,
and linear opacities increase significantly (interstitial edema
and alveolar exudation)
These findings peak within 10-28 days and decrease
thereafter
Pleural effusion is rare, in late stages

48. Timetable of CT changes Differ:

49. Timetable of Serological tests

50. Timetable of Nabs and IgG in SARS
patients

51. Most Common Lab Results:

53. Causes of lymphopenia in COVID-19:
1- Lymphocyte infection without replication leading to cell
death
2- Release of inhibitory cytokines eg IL-10
3- Immune cell redistribution

54. Timetable of Cytokine Release,
Lymphocytes, Viral Load, According To
Disease Severity

55. D-Dimer and Prognosis:

57. Timetable for PCR, Serology and biomarkers in
COVID-19 patients

58. Timetable of serology:
IgM is the 1st line of defense
Then the adaptive, longlasting, high affinity IgG, represnting
immunological memmory
IgM is present in 5-7 days
IgG is present in 10-15 days and may persist for months or
years
At 9-1o days after symptoms onset, there is at least 4 folds
increase in Nabs and keep increasing to day 20
The level is higher in more severe disease
There is a correlation between level of Nabs and total level of
IgG

59. Validity of Rapid Test:

60. Diagnostic sensitivities and specificities
were above 93.8% and 85.9% (Iflash)

61. Timetable for viral shedding and
infectivity

62. Blood donation:
• No blood donation within 21 days of contact with a positive case
• No blood donation except after 4 weeks after recovery for patients with COVID-19
with completion of treatment

69. Infectivity:
Mainly in the 1st few days of symptoms
A significant percentage occur in 2-3 days before
symptoms
This is correlated with the highest level of viral load
About 88% stay undocumented, 55% of them were
contagious
although of positive PCR, scientist failed to grow it in
culture after 8 days
Samples with less than 106 copies per ml never grow an
isolate
Virus isolation from stool samples was never successful,
irrespective of viral RNA concentration, based on a total of 13
samples taken between days six to twelve from four patients

70. Reproduction Number:
 Ro for SARS-CoV-2 is 2.2-2.7 (5.7)
 Ro for SARS-CoV-1 is 3
 Ro for Flu is 1.3-1.8

71. Timetable of viral shedding:
Median duration of 53 days and maximum of 83 days in a
study of 36 patients
It is mostly about 20 days (8-37)
Asymptomatic and mild: 10 days (8-15)
Severe cases: upto 25 days
severe cases shed up to 60 folds viral load
Shortest duration of viral shedding is 4 days

72. Timetable of viral shedding:
Positive PCR does not mean infectivity
More in men than women
Viral shedding In COVID-19 peaked on or just before
symptom onset, and may probably occur before first
symptoms in the index case
The dynamics of viral shedding in asymptomatic patients are
similar to symptomatic patients

73. Timetable for infectivity in COVID-19

74. Timetable of RT-PCR conversion In a
Study In Shanghai (249 patients):

76. Is the Oxygen Cylinder a Source for
Infection:

77. Reinfection
It is unclear if convalescent patient can be reinfected
After recovery of experimentally infected monkies, They were
rechallnged with the same dose of same strain, and failed to
develop disease again for more 5 days thereafter
Hence, in short term, infection seems to give an immunity
against reinfection

78. Reinfection
Reinfection of HCoV-NL63 was reported in 28% of cases over
6 months period
Most of them were milder with lower viral titers
11% showed higher viral shedding than the previous attack

79. Cross Immunity:
The betacoronaviruses can induce immune responses
against one another: SARS-CoV-1 infection can generate
neutralizing antibodies against HCoV-OC43
HCoV-OC43 infection can generate cross-reactive
antibodies against SARS-CoV-1

80. Relapse/Reactivation:
9-20% of dischrged patients in small studies retest PCR
positive
The 2 discharge negative PCR may be falsely negative
In 10 re-test positive patients after being negative,
scientists failed to grow the virus in culture (low viral load or
dead virus)
In 13 re-test positive patients, none of their 104 close
family contacts developed disease

81. Relapse/Reactivation:
Causes of Relapse positive RT-PCR:
1.Still there is virus, esp in severe disease
2.Cross contamination with other betacoronaviruses
3.False positive results
4.Incorrect sample collection techniques

82. In Italy:

83. A Chinese Patient Who Tested +ve For
SARS-CoV-2 for 72 days (Throat).
CT scans showed that, Lung infiltrates almost disappeared
on day 54.

84. CDC Guidelines for Return-to-Work (1)

85. CDC Guidelines for Return-to-Work (2)

86. CDC Guidelines for Return-to-Work (3)

87. Last updates for Sick Leaves In Egypt:

88. Last updates for Sick Leaves In Egypt:

89. COVID-19 Treatment and Interventions

90. In Peru, Not in Egypt: Is it!

91. Early thearpy with antiviral shortens virus clearance time and
prevent rapid progression of COVID-19
Combined therapies with antiviral should be started at early
stages to prevent from mild to severe disease

93. HCQ:
400 mg twice 1st day then 200 mg twice daily up to 5-9 days
CQ 500 mg twice for the same period
HCQ elimination half-life is 40 days

94. Remdisivir:
Remdisivir was approved by FDA (EUA) according to a
study that reported 31% acceleration in recovery (from 15 to
11 days). It decreased mortality non-significantly (from 11% to
8%)
Remdisivir dose is 200 mg for 1st day IV followed by 100
mg daily for 9 days
5 days regimen is as effective as 10 days in non-MV
patients
Not recommended if estimated GFR less than 30 ml/min

95. In patients with severe Covid-19 not requiring mechanical
ventilation, No significant difference between a 5-day course and
a 10-day course of remdesivir.

96. Umifenovir (Arbidol):
Oral dose: 2 tab (Cap) 3 times daily for 14-20 days each
contain 100 mg

97. Lopinavir/ritonavir (Kaletra):
Doses of lopinavir (200mg) and ritonavir (50mg) every 12h
for 7-14 days. in patients with moderate and severe COVID-19
current data do not support lopinavir/ritonavir in COVID-19
treatment, although it was successful in some cases

98. Favipiravir (Avigan):
No sufficient information available to support the use of
favipiravir for COVID-19.
Favipiravir can cause hyperuricaemia, increase in
transaminases, decrease in the number of neutrophils,
diarrhea
1800 mg oral 1st days (may be up to 3000mg twice 1st day)
followed by 800 mg twice daily (may be 1200-1800) for
another 9 days
(Approved dose for flu in Japan is 1600 mg twice 1st day
then 600 mg twice for 4 days)

99. Tocilizumab injection:
4-8 mg per kg one dose can be
repeated in 12-24 hour to total of 800 mg

100. Recovery Study:
6 mg daily of dexamthasone decreased the mortality by 1/3 in
severe COVID-19 patients in need for MV

101. The FDA a criteria for CP In COVID-19:
• Laboratory confirmed COVID-19
• Severe or immediately life-threatening COVID-19.
_x0001_ Severe disease is defined as one or more of the folloing:
• Dysnea,
• Tacypnea ≥ 30/min,
• blood oxygen saturation ≤ 93%,
• PaO/FiO2 < 300,
• lung infiltrates >50% within 24-48 hours
_x0001_ The life-threatening disease is defined as one or more of the
following:
• respiratoy failure,
• septic shock
•MODS

102. FDA Criteria for CP Donors:
1.Recovered from COVID-19, blood donor tests weredone and
suitable for donation
2.Documented infection with PCR or Serologic IgG
3.Complete resolution of symptoms, at least 14 days before
donation
4.Male, Non-Pregnant females,

103. Coagulopathy and time:
SARS-CoV-2 causes a hypercogulable state
Incidence of thromboembolism among hospitalized patients
with COVID-19 ranged from 25 to 53%
Extended thromboprophylaxis for 2-6 weeks post discharge
should be considered

104. Coagulopathy and time:
LMWH is the drug of choice with fondaparinux is the second
choice
NOAC (out of licence) is easier to administer in the
community stting (rivaroxipan 10 mg daily or apixaban 2.5 mg
twice) with PPI to protect from GIT bleadimg
If chemoprophylaxis is contraindicated, use mechanicla
prophylaxis

105. IVIG:
Within 48 hours of hospital admission decresed need for
MV, ICU duration and 28-day mortality
Needs further study

106.  Higher duration of sunlight exposure was associated with
higher recovery rate
 Sunlight exposure does not prevent infection
 Sunlight boost the immune system

108. SARS-CoV-2 Vaccine

111. Vaccine and time:
Vaccine development is a lengthly and expensive process
In reality, 5 years to develop a novel vaccine is fast
In 2019, Vaccines approved (Dengue fever, Smallpox) were
under clinical trials for 15 years
Vaccines reach the public after the peak of epidemic wane
Ebola vaccine was approved 5 years after peak, MERS-CoV
and SARS-CoV are still in clinical deveolpment

112. Vaccine and Time:
Available vaccine does not equal uptake
The newer the vaccine, the higher the hesitancy
People trust slow vaccine
H1N1 vaccine , in 22 countries, was available but the
coverage rate was 0.4-59% only
The rate decreases also due to misinformation