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  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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