2. INTRODUCTION
Coronaviruses are classified as a family within the Nidovirales order, viruses that
replicate using a nested set of mRNAs ("nido-" for "nest").
The coronavirus subfamily is further classified into four genera: alpha, beta,
gamma, and delta coronaviruses.
The human coronaviruses (HCoVs) are in two of these genera:
1) Alpha coronaviruses (HCoV-229E and HCoV-NL63)
2) Beta coronaviruses (HCoV-HKU1, HCoV-OC43, Middle East respiratory
syndrome coronavirus [MERS-CoV], and the severe acute respiratory
syndrome coronavirus [SARS-CoV])
3. VIRAL COMPOSITION
• Medium-sized enveloped positive stranded RNA viruses (characteristic crown-
like appearance in electron micrographs).
• Largest known viral RNA genomes, 27 to 32 kb.
• The host-derived membrane is studded with glycoprotein spikes and surrounds
the genome, which is encased in a nucleocapsid that is helical in its relaxed form
but assumes a roughly spherical shape in the virus particle.
• Replication of viral RNA- host cytoplasm (RNA polymerase binds to a leader
sequence and then detaches and reattaches at multiple locations, allowing for the
production of a nested set of mRNA molecules with common 3' ends )
5. Viral serotypes
• Coronaviruses are widespread among birds and mammals, with bats
being host to the largest variety of genotypes.
• There are SIX nonSARS coronavirus serotypes that have been associated
with disease in humans: HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-
HKU1, a novel coronavirus (MERS-CoV) that emerged in 2012 and
Novel coronavirus (COVID-19).
• , CoVs can rapidly mutate and recombine leading to novel CoVs
6. • SARS-CoV-2 is a positive-sense, single-stranded RNA virus
• genus Betacoronavirus
7.
8. EPIDEMIOLOGY
Seasonality —
• Northern Hemisphere, common circulating HCoVs between December
and May
• Southern Hemisphere between March and November with peaks in late
winter/early spring
• Infections can occur at any time of the year.
Routes of transmission —
• Respiratory coronaviruses probably spread in a fashion similar to that of
rhinoviruses, via direct contact with infected secretions or large aerosol
droplets.
9. Epidemiologic risk factors in children
• Common circulating HCoVs could isolated from 4% to 6% of
children hospitalized for acute respiratory tract infections
• m/c < 3 years with heart disease.
• Reinfections later in life are common despite the fact that most
individuals seroconvert to HCoVs.
• 11%–46% of cases, common circulating HCoVs are found as
coinfections with other respiratory viruses.
10. Transmission
• COVID 19: live -
• Steel 72 hrs
• Cardboard 24 hrs
• Copper 4 hrs
• Air 3hrs
NO evidence that food can transmit the virus
NO evidence that dogs can transmit the virus or become sick.
11. Basic Reproduction
Number R0
• Measure of infectiousness
(mean number of secondary
cases generated by one primary
case in susceptible)
• R0 COVID 19 about 2.5**
**Early dynamics of transmission and control of COVID-19: a
mathematical modelling study
12.
13. CFR
• Number of cumulative deaths divided by the number of cumulative
cases at a specific point in time.
Estimating Risk for Death from 2019 Novel Coronavirus Disease, China, January–February
2020
14. Duration of the infectious period
lasting for 10 days or more after the incubation period
Effect of seasons on transmission
With an R0 of 2–3, the warm months of summer might not
necessarily reduce transmission below the value of unity as they do
for influenza A, which typically has an R0 of around 1·1–1·5
15. Viral shedding
• Respiratory tract specimens: 1-2 days before the onset of symptoms, persist
for 7-12 days in moderate cases and up to 2 weeks in severe cases.
• In faeces, viral RNA has been detected from day 5 after onset and up to 4 to
5 weeks in moderate cases.
• Prolonged viral RNA shedding has been reported from nasopharyngeal
swabs, up to 37 days among adult patients and in faeces, for more than one
month after infection in paediatric patients.
• viral RNA shedding does not directly equate with infectivity.
16. Transmission in pre-symptomatic stage
• Around 48 – 62 %
• Based on a shorter serial interval of COVID-19 (4.0 to 4.6 days) than
the mean incubation period (five days).
• Peak viraemia seems to be at the end of the incubation period (trigger
transmission for 1–2 days before onset of symptoms).
17.
18. Simulations of a transmission model of COVID-19
https://www.washin
gtonpost.com/graphi
cs/2020/world/coron
a-simulator/
19. CLINICAL SYMPTOMS
• The illness is characterized primarily by fever, cough, dyspnea, and bilateral
infiltrates on chest imaging .
• Incubation period is about 1 to 14 days, and is supposed could be up to 24
days
• Although many of the reported infections are not severe, approximately 20
percent of confirmed patients have had critical illness (including respiratory
failure, septic shock, or other organ failure requiring intensive care).
• Most of the fatal cases have occurred in patients with underlying medical
comorbidities.
20. Symptoms in Pediatric Patients
SARS-CoV, MERS-CoV and COVID 19 seem to less commonly affect
children and to cause fewer symptoms and less severe disease
21. • Adults presents stereotypically with acute respiratory symptoms (acute
respiratory infection with fever, cough and/or shortness of breath, and
no other etiology that fully explains the clinical presentation)
• New findings: anosmia, hyposmia, and dysgeusia are associated with
COVID-19, and may be present before any other symptoms
• Children variable presentation.
• 65% having common respiratory symptoms fever (50%) and cough (38%),
26% only mild disease, and 9% as asymptomatic
• Old data gastrointestinal symptoms were considered rare
• New data- vomiting and diarrhea may presenting symptoms in adults
and in up to 10% of children.
22. COVID-19 AND THE INTESTINE
• Prolonged viral RNA shedding in faeces for more than one month after
infection.
• fecal oral transmission is being proposed as another route of spread
of infection*
• Reported symptoms nausea, vomiting, diarrhea and abdominal pain.
• Diarrhea 1 to 8 days after symptom onset (median time of 3.3 days)
Lu, et al. have reported that diarrhea and vomiting were observed in 15 (8.8%) and 11 (6.4%) in a cohort of 171 children. While
Jin, et al. reported that presence of GI symptoms in adults was associated with more severe illness, there is no similar report in
children.
23. ? Why Intestinal involvement
• Angiotensin converting enzyme 2 (ACE-2) receptor and
transmembrane serine protease 2 (TMPRSS2) are key proteins in the
cell entry process of the virus.
• Like alveolar type II cells in the lung, gland cells of the esophagus and
absorptive enterocytes in ileum and colon express them together.
• Also seems to alter the intestinal flora even when only the respiratory
mucosa is involved **through the common mucosal immune system
regulation called the gut-lung axis.
24. COVID-19 and IBD
• Most severe presentations of COVID-19 result from
hyperinflammatory cytokine responses in particularly dysregulated IL-
6-dependent acute phase responses.
• Thiopurine metabolites, 6- mercaptopurine and 6-thioguanine have
direct antiviral activity by inhibiting the papain-like protease of both
viruses as well as host proteins involved in antiviral response.
• Current literature: not indicate stopping these treatments or
modifying therapeutic regimes
• Seven children with IBD and COVID-19 have been reported... All cases
had a mild infection without the need for admission despite**
25. COVID-19 and Liver
• Mild rise in transaminases common
• Elevated liver enzymes and increased bilirubin are more common in
those with severe spectrum of the disease
• No evidence of active replication of the virus in hepatocytes
• Cause of Liver injury
• virus triggered auto reactive T cells and cytokine storm.
• Hypoxic injury from respiratory distress
• drug induced liver injury (Remdesivir, Tocilizumab)
26. • no evidence COVID-19 co-infection causes significant worsening in of
underlying chronic liver disease**
• Elevated transaminases in COVID-19 disease are not a contraindication
for antiviral therapy, with regular monitoring of liver function.
• COVID-19 +ive: continue calcineurin inhibitors and lower the dose of
mycophenolate or azathioprine. Patients on high dose steroids, should
have it reduced to a minimum dose
• Asymptomatic post-transplant patients: immunosuppression and
mycophenolate should not be reduced or stopped
• no recommendation for any antivirals or hydroxychloroquine
prophylaxis in post liver transplant children
27. Those at increased risk of severe disease
• older adults, with risk increasing by age (especially those > 60 years),
• infants under 12 months of age
• Individuals with serious chronic medical conditions such as cancer,
end-stage renal disease on dialysis, diabetes, poorly controlled
hypertension, coronary artery disease, heart failure, or pre-existing
chronic lung disease.
• children with liver disease on immunosuppression in Northern Italy
where only 3/700 were documented to have SARS-CoV-2 infection
and none with a severe course… despite treatment with
immunosuppressive medications
28. Risk during endoscopy
• During procedure: droplets aerosolized, more than 6 feet away..
• Risk not only with upper GI, colonic biopsy specimens and stool ..virus
isolated.
• SARS-CoV-2 remains stable in
• aerosols > 3 hours
• up to 72 hours on plastic and stainless steel
• copper up to 4 hours
• cardboard up to 24 hours.
29. Recommendations for gastroenterology
practices
• Classification of procedures into non-urgent/postpone and
urgent/perform may be useful
• Only endoscopic procedures conducted ex. life threatened (e.g.
significant acute bleeding).
• Pre-screen all patients for high risk exposure (history of fever or
respiratory symptoms, family members or close contacts with COVID-
suggestive symptoms, and any contact with a confirmed case of
COVID-19)
• Check body temperature of the patient
30. • Conservation of PPE is critical.
• Patients on immunosuppressive drugs should continue taking their
medications as we know that the risk of undertreated disease
outweighs the chance of contracting coronavirus.
31.
32. Investigations
• ground glass opacities of the lung, lymphopenia, and elevated C-
reactive protein (CRP)
• Lymphopenia and elevated CRP, ferritin and lactate dehydrogenase
levels are associated with a more severe course
• Increased levels of cytokines and chemokines, such as interleukin-6
(IL-6), have also been associated with increased disease severity.
• The ability to differentiate between mild and severe COVID-19-
highest specificity (93.3%) and sensitivity (96.4%) was with IL-6 and D-
Dimer tandem testing.
34. Case definition**
• Suspected or Probable case meets: two clinical criteria and one
epidemiologic criterion
• Clinical criteria:
• 1. Fever, fatigue, dry cough; some pediatric patients may have no fever
• 2. Patients with the following chest imaging findings: multiple small patchy
shadows and interstitial changes, mostly in the lung periphery, bilateral
multiple ground-galls opacity, infiltrating shadows, pulmonary
consolidation on chest radiography or ground-glass opacities, bilateral
segmental lung consolidation, especially in the periphery on chest CT
• 3. White blood cell counts are normal or decreased, or with decreased
lymphocyte count
35. Epidemiologic criteria:
1. Children with a travel or residence history in Wuhan City and neighboring
areas, or other areas with persistent local transmission within 14 d prior to
disease onset
2. Children with a history of contacting patients with fever or respiratory
symptoms who have a travel or residence history in Wuhan City and
neighboring areas, or in other areas with persistent local transmission within 14
d prior to disease onset
3. Children with a history of contacting confirmed or suspected cases infected
with SARS-CoV-2 within 14 d prior to disease onset
4. Children who are related with a cluster outbreak: in addition to this patient,
there are other patients with fever or respiratory symptoms, including suspected
or confirmed cases infected with SARS-CoV-2
5. Newborns delivered by suspected or confirmed SARS-CoV-2-infected mothers
36. • Confirmed case
• A person with laboratory confirmation of COVID-19 infection,
irrespective of clinical signs and symptoms.
1. Throat swab, sputum, stool or blood samples tested positive for
SARS-CoV-2 nucleic acid using RT-PCR
2. Genetic sequencing of throat swab, sputum, stool or blood
samples being highly homologous with the known SARS-CoV-2
3. SARS-CoV-2 granules being isolated by culture from throat swab,
sputum, stool or blood samples
37. Contact
• Definition of contact
• A contact is a person that is involved in any of the following: -
Providing direct care without proper personal protective equipment
(PPE)2 for COVID-19 patients
• - Staying in the same close environment of a COVID-19 patient
(including workplace, classroom, household, gatherings).
• - Traveling together in close proximity (1 m) with a COVID-19
patient in any kind of conveyance within a 14‐day period after the
onset of symptoms in the case under consideration.
40. Natural history of ARDS in COVID 19
• ARDS occurs as a result
of an acute systemic
inflammatory response
• Diffuse alveolar damage
with destruction of
epithelial (m/c) and
endothelial cells.
45. Hypoxemia in ARDS
• Oxygenation
• Ventilation-perfusion mismatch (V-Q mismatch)
• Shunt physiology
• CO2 clearance & dead space
• Work of breathing
Patients with COVID-19 often develop respiratory failure 8–
14 days after symptom onset, with ‘silent hypoxemia’ and a
high respiratory rate
46. Silent Hypoxemia
Refractory hypoxemia with a normal work of breathing can occur if all
of the following conditions are met:
• A right-to-left shunt is present.
• There isn’t excessive dead space.
• Compliance and resistance of the lungs are reasonably normal.
A high minute volume is worrying, and is a sign that
the patient is compensating for an increasing degree
of diffusion failure.
47. • SARS CoV2 potentially neuroinvasive
• Olfactory disturbances known (virus-induced neuronal damage in the
olfactory bulb)
• Retrograde axonal transport can then enable propagation of SARS-
CoV-2 toward the insula.
• Could also entry the CNS via an haematogenous route.
• Brain tissue highly express ACE2
• Hypothesized… Perception of laboured breathing involves the
activation of the insula, insular lesions are associated with blunted
perception of dyspnea.
CoVs are capable of rapid mutation and recombination leading to novel CoVs that can spread from animals to humans.
This occurred in China in 2002 when the novel CoV severe acute respiratory syndrome coronavirus (SARS-CoV) emerged, thought to have been transmitted from civet cats or bats to humans.22–25
Another novel CoVs emerged in Saudi Arabia in 2012, Middle East respiratory syndrome coronavirus (MERS-CoV), which is transmitted from dromedary camels to humans.26,27
The 2019 novel CoV (SARS-CoV-2), which originated in China and is currently causing outbreaks globally, is a novel Betacoronavirus belonging to the lineage B or subgenus sarbecovirus, which includes SARS-CoV.28
decline in Rt in late January, from 2·35 (95% CI 1·15–4·77) on January 16, 1 week before the restrictions, to 1·05 (0·41–2·39) on January 31.
speed of the initial spread of the epidemic, its doubling time, or the related serial interval (the mean time it takes for an infected person to pass on the infection to others), and the likely duration of the epidemic are determined by factors such as the length of time from infection to when a person is infectious to others and the mean duration of infectiousness.
Shortening the time from symptom onset to isolation is vital as it will reduce transmission and is likely to slow the epidemic.
Contact tracing is of high importance in the early stages to contain spread, and model-based estimates suggest, with an R0 value of 2·5, that about 70% of contacts will have to be successfully traced to control early spread.
CFR, during the course of an outbreak tends to be affected by right censoring and ascertainment bias (3–5). The phenomenon of right censoring is caused by the gap in illness onset to death between the vulnerable population and the healthy population, resulting in underestimation, whereas ascertainment bias is attributable to the unreported bulk of infected persons who have mild symptoms or asymptomatic infections, potentially leading to overestimation.
The death-to-case ratio is simply the number of cause-specific deaths that occurred during a specified time divided by the number of new cases of that disease that occurred during the same time.
The deaths included in the numerator of the death-to-case ratio are not restricted to the new cases in the denominator; in fact, for many diseases, the deaths are among persons whose onset of disease was years earlier.
In contrast, in the case-fatality rate, the deaths included in the numerator are restricted to the cases in the denominator.
serial interval of an infectious disease represents the duration between symptom onset of a primary case and symptom onset of its secondary cases
For reference, influenza A has a presymptomatic infectiousness of about 1–2 days, whereas SARS had little or no presymptomatic infectiousness.
baseline simulation with case isolation only (red); a simulation with social distancing in place throughout the epidemic, flattening the curve (green), and a simulation with more effective social distancing in place for a limited period only, typically followed by a resurgent epidemic when social distancing is halted (blue)
Corona viruses bind to their target cells through angiotensin-converting enzyme 2 (ACE2), which is expressed by epithelial cells of the lung, intestine, kidney, and blood vessels.4
The expression of ACE2 is substantially increased treated with ACE inhibitors and angiotensin II type-I receptor blockers (ARBs).4
ACE2 can also be increased by thiazolidinediones and ibuprofen and tobacco-use . These data suggest that ACE2 expression is increased in diabetes and treatment with ACE inhibitors and ARBs increases ACE2 expression. Consequently, the increased expression of ACE2 would facilitate infection with COVID-19. We therefore hypothesise that diabetes and hypertension treatment with ACE2-stimulating drugs increases the risk of developing severe and fatal COVID-19.
ability to differentiate between mild and severe COVID-19 was analyzed in 43 adult patients in China. 23 The highest specificity (93.3%) and sensitivity (96.4%) for the early prediction of severity in COVID patients was with IL-6 and D-Dimer tandem testing.
till date there is only report of the virus cultured from a single stool specimen.
Co-expression of these two proteins in the same cell is critical for viral entry.
After viral entry, virus-specific RNA and proteins are synthesized in the cytoplasm of these cells to assemble new virions, which are released to gastrointestinal tract. This gastrointestinal tropism explains the digestive symptoms and the viral shedding in stool.
findings explain why in addition to antiviral therapies, immunomodulatory therapies and passive immunisation strategies could potentially be considered to improve outcome in severely affected patients.. In light of the hyperinflammatory immune response seen in patients with COVID-19 it is highly relevant that blockade of IL-6R with tocilizumab resulted in clinical improvement
IBD-related immunosuppressive treatment has raised concerns regarding the management of COVID-19
233 PIBD children should had received scheduled infliximab infusions, of whom 66 (28%) had their infusions delayed because of the epidemic by 1-8 weeks (average length of delay 19.2±11.5 days) and 2 (0.9%) discontinued infusions temporarily. Among the 66 patients with delayed infusions, 14 (21%) experienced a disease exacerbation, of whom 10 (15%) required an admission
**treatment with immunosuppressive medications, steroids and/or biologics. The underlying IBD remained generally stable during the infection and the IBD-related medications were not held in any of the cases. Ibd patients do not have an increased risk of developing Covid-19 and should stay on IBD medications
**Children on treatment for chronic liver diseases like Wilson disease, autoimmune hepatitis, Hepatitis B and C should continue their treatment protocols.
11% of infants had severe or critical illness compared to 7% of children ages 1-5 years, 4% of those 6-10 years of age, 4% of those 11-15 years, and 3% of those 16 years and older
life threatened (e.g. significant acute bleeding), function of the organ may be at risk (e.g. liver biopsy for the diagnosis of autoimmune hepatitis), or the delay of the procedure could significantly change long-term prognosis (e.g. suspected cancer)
an effort to delay endoscopies due to abdominal pain, heartburn, diarrhea and other GI manifestations should be exercised, where the delay will not significantly impact long-term prognosis
In contrast, when a disease like inflammatory bowel disease is suspected and delay in diagnosis would be dangerous for the patient, and treatment is reliant on endoscopic evaluation
most severe presentations of COVID-19 result from hyperinflammatory cytokine responses in particularly dysregulated IL-6-dependent acute phase responses associated with a decrease in cytotoxic T cells and NK cells
**by the National Clinical Research Center for Child Health, Zhejiang University School of Medicine (adapted from Chen et al 72)
onset time of COVID-19-related ARDS was 8–12 days, which was inconsistent with ARDS Berlin criteria, which defined a 1-week onset limit. Some of these patients might have a relatively normal lung compliance. The severity was redefined into three stages according to its specificity: mild, mild-moderate, and moderate-severe.
Blood going to portions of the lung which are inadequately ventilated will be starved of oxygen. result is hypoxemia. Increasing the concentration of inhaled oxygen generally fixes this problem – because even poorly ventilated areas of the lung will now get enough oxygen.
Blood flows from the right ventricle to the left ventricle without ever coming into contact with oxygenated alveoli at all. Ex complete dysfunction of parts of the lung (e.g., mucus plugging of one lobe of the lung). A hallmark of shunt physiology is that it is poorly responsive to increased levels of oxygen (because blood isn’t coming anywhere close to ventilated alveoli).
CO2 clearance depends on the amount of gas entering and leaving the lungs every minute, which removes CO2 from the body.
work of breathing is most strongly affected by the drive to clear CO2. This is influenced by:
Dead space, Lung compliance, Airway resistance
hypoxia-driven tachypnoea accompanied by relatively preserved lung elasticity gives rise to a high minute volume with pronounced hypocapnia.
The pathophysiology is similar to that seen with hypobaric hypoxia at high altitude or in a low-pressure chamber (5). Hypoxia with accompanying hypocapnia generates no sensation of breathlessness
examples of patients going from being physiologically normal to decompensating just a few hours later.
Sensory afferent information arising from chemoreceptors (sensing pH,
PaO2, and PaCO2), upper airways stretch receptors (sensing inflation or deflation of
the lungs), and chest wall mechanoreceptors (sensing muscles tension and contraction)
reach the nucleus tractus solitarius (NTS) in the medulla oblongata. The NTS is the
main autonomic brain center involved in breathing control (master regulator); it
processes and projects the afferent signals to higher cortical centres, such as the insula,
and the sensory and motor cortices (integrated system)
![INTRODUCTION
Coronaviruses are classified as a family within the Nidovirales order, viruses that
replicate using a nested set of mRNAs ("nido-" for "nest").
The coronavirus subfamily is further classified into four genera: alpha, beta,
gamma, and delta coronaviruses.
The human coronaviruses (HCoVs) are in two of these genera:
1) Alpha coronaviruses (HCoV-229E and HCoV-NL63)
2) Beta coronaviruses (HCoV-HKU1, HCoV-OC43, Middle East respiratory
syndrome coronavirus [MERS-CoV], and the severe acute respiratory
syndrome coronavirus [SARS-CoV])](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)