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covid-19

COVID-19 coronavirus (2019-nCoV / SARS-CoV-2)

Introduction

  • outbreak commenced in Dec 2019 originating in Wuhan (China) business operators at the Hua Nan Seafood Wholesale Market, who sold live animals such as poultry, bats, marmots, and wildlife parts
  • 80% of cases are “mild”, 14% severe and 5% were critical
    • in children, only 6% develop severe or critical illness - ie. 94% are “mild”
  • the pandemic created a multitude of issues:
    • large volumes of rapidly changing knowledge (see COVID-19 science) combined with changes in control phases (ability to quarantine cases vs management of community spread phase vs control phase of low numbers of new cases)
      • rapid, real time leadership and pandemic management decisions at state level as well as at hospital and patient management levels
      • communication of decisions and procedures to health care workers and the general public
      • managing disinformation and out-of-date information
      • managing poor health literacy and those guided by excessive fear, pseudo-science, wishful thinking or mystical ideation
      • managing complacency
    • unlike SARS virus, asymptomatic and pre-symptomatic transmission is high making control and case detection much more difficult
    • the required severe control measures need to be prolonged with incredibly high economic, health and social costs - see pandemic community lock down ramifications
    • failure to provide or comply with control measures results in very high hospitalisations and deaths, especially in those over 65yrs of age.

Transmission

  • in China, human to human transmission was mainly observed in healthcare facilities and among family members
  • appears to have a reproduction number (RO) of 2-2.6 however it is likely that some are super spreaders
  • more contagious than the seasonal flu
  • a patient is probably infectious from 1-3 days BEFORE onset of symptoms to 24hrs after resolution although viral particles appear to disappear from respiratory tract in mild cases by day 8 of symptoms
    • a Singapore study suggests people are infectious 1-3 days BEFORE they become symptomatic 1)
  • WHO are recommending isolation for positive cases for 2 weeks after they become symptom free 2)
  • the SARS-CoV-2 virus enters cells ONLY via ACE2 receptors on cells which also express TMPRSS2
  • transmission appears to be primarily via droplet spread from coughing or singing
    • pre-symptomatic patients seem to transmit virus from close proximity such as church-goers, mass singing or household contacts 6)
    • each droplet may contain thousands of viral particles and it seems you only need one viral particle to gain access to your upper airway mucosa to cause an infection
    • the droplets may either:
      • form an aerosol in the room which can be inhaled - these viable viral aerosols appear to remain for some 3hrs after they form7)
        • aerosols are solid or liquid particles that hang in the air, including fog, dust, and gas commonly used in medical procedures like ventilation and nebulizers
        • aerosols are also more likely to form if nebuliser therapy is used or during airway procedures such as intubation or airways suction and are more likely to form depending on heat and humidity
      • fall onto a person's face - hence the advice to stay at least 1.5m from other people (social distancing) and for people to use cough hygiene such as covering their mouths when coughing, and for infected people to wear surgical masks
        • a surgical mask on an infected person does not prevent transmission of virus from coughing at a distance of 8“ 8)
      • fall onto surfaces which other people then touch and then touch their faces
        • it seems that the virus can survive at least 3 days on most surfaces and is more stable on plastic and stainless steel (median half life of 6.8hrs and 5.6hrs respectively), than on copper and cardboard9)
        • hence the advice for regular hand hygiene and cleaning of surfaces

Minimizing risk of infection

general risk from a positive case

  • risk increases if either:
    • touch contaminated surfaces or objects and then touch your face (especially eyes or nose) before washing hands
      • virus half-life on most surfaces is about 5-6hrs and thus minimal viral load is present by 3 days or after cleansing surface with detergent or anti-viral solution
      • washing hands with detergent or alcohol based cleanser is effective in reducing viral load on hands
    • within 1.5m of a positive case who coughs without wearing a mask
    • no face mask or surgical mask and more than 15 minutes face to face with a positive case
    • no face mask or surgical mask and more than 2 hours in a room with a positive case who is more than 1.5m away
    • no PPE and being in a room within 3 hours of an aerosol generating event of a positive case

minimizing spread from positive cases

  • management of known positive cases:
    • quarantine for 14 days
    • use of PPE for those in contact including prior to commencing CPR
    • contact tracing and testing of contacts at risk
  • reduce risk of unknown positive cases spreading infection
    • manage high risk persons as per positive cases until proven negative
    • self-monitoring for infection - especially of healthcare workers
      • twice daily temp checks for fever
      • monitor for symptoms of Covid
    • self-isolation:
      • for 14 days if contact with a positive case or a person at high risk of infection
      • possible Covid symptoms even if Covid swab negative (high false negative rates) until asymptomatic and swab negative
    • health care workers should wear appropriate PPE for ALL patient contacts especially in high risk areas such as EDs:
      • surgical mask + goggles or face shield
      • short-sleeved scrubs to allow regular hand washing to elbows
      • consider hair protection if one does not want to wash hair after shift
    • decontaminate clothing and body after exposure (eg. end of shift for health care workers with any patient contacts)
      • scrubs should be removed at work, placed in bag or at least carried inside out, and laundered appropriately
      • shoes should not be worn into home but should be left outside preferably in the sun
      • have a shower on finishing shift or immediately on arrival home

Incubation period

  • from a Chinese study published March 10th 202010):
    • mean and median incubation periods are 5-6 days
    • < 2.5% were symptomatic within 2.2 days
    • 97.5% were symptomatic within 11.5 days
    • it is thought that only 1 per 10,000 would have longer than 14 days incubation

Diagnosis

  • in a small German study of patients with mild symptoms11):
    • viral loads were high in the throat for the 1st week only and this presumably contributes to its high infection rate
    • stool and sputum appear to retain PCR RNA positivity for at least 3 weeks
    • seroconversion appears to be attained by 50% on day 7 and perhaps all immune competent patients by 14 days
    • sequencing of viral genomes revealed distinct genomes in throat and sputum samples, suggesting independent viral replication in throat and lung
  • the gold standard at present is bronchoalveolar lavage (BAL) fluid or tracheal suction samples (for intubated patients)
  • for non-intubated patients, the gold standard is a nasopharyngeal swab left for 30 secs or sputum sample (sensitivity 72%)
    • however, concerns that such swabs may increase aerosolization risk has meant that many centres do a pharyngeal then nasal swab only but these appear to have lower sensitivity - nasal swabs detecting only 63% and pharyngeal swabs only detecting 32% (in comparison, fecal samples has 29% sensitivity) 12)
  • CXR is 59% sensitive (CT chest has sensitivity > 86% but takes CT scanner out of action for cleaning)
  • lung USS has better sensitivity than CXR but requires too close contact with patient
  • point of care finger prick 15 minute antibody test
  • Cepheid GeneXpert 45min PCR test

Clinical features

  • a Feb 2020 Chinese report suggests that nearly 90% of clinical infections occur in those aged 30-79yrs with a further 8% in those aged 20-29yrs - only 2% were aged under 20yrs! 13)
  • children
    • US study of 150,000 cases from Feb-Apr 2020 with only 1.7% were under 18yrs age and of these14):
      • median age was 11yrs; 73% had classic symptoms (cf 93% of adults);
      • hospitalization rate was 5.7% (cf 10% in 18-64 yr olds)
      • 23% had an underlying illness such as asthma
    • some asymptomatic children appear to develop “Covid fingers and toes” - pernio-like painful purple/red papules - esp. adolescents
    • rarely, some children may develop Kawasaki disease which in Italy had a 30x normal prevalence 15)
  • pregnant women
    • in a small study of 15 pregnant patients with mild disease, pregnancy did not appear to aggravate the clinical course16)
  • asymptomatic carriers
    • unclear as to the extent of spread via asymptomatic persons although it is thought 16-40% may spread it to others
    • a Chinese study of 1391 children tested for the virus showed 16% who tested positive were asymptomatic and had normal CXRs while a further 7% who tested positive were asymptomatic but had CXR features, thus a total of 23% were asymptomatic 17)
    • a New York study of universal screening of 215 women admitted for delivery Mar 22 to April 4 2020 showed 1.9% were positive with symptoms and 13.5% were positive without symptoms18)
  • mild illness
    • bothersome dry cough coming from the chest, low grade fevers (generally in late afternoon or evening) some may have sore throat or diarrhoea
    • some report loss of smell (anosmia) or taste
    • elderly or the immunocompromised may present with atypical symptoms
    • a NY report in April 2020 suggests it may cause a 7-fold increase risk of stroke in adults under aged 50yrs even with mild illness
    • 94% of symptomatic children and 80% of symptomatic adults have only mild symptoms
    • in contrast, influenza is more likely to have high fevers and more severe headache and myalgias
  • diarrhoeal illness
    • occurs in approx 20% who present to hospital with Covid-19 and although diarrhoea tends to be an early symptom, those with diarrhoea rather than respiratory symptoms typically have a more delayed presentation to hospitalization
    • tends to be more associated with elevated LFTs and impaired coagulation 19)
  • mild pneumonitis
    • as for mild illness but with SOB (particularly likely to be Covid-19 if this worsens after a week) and CXR changes
    • 20-40% may have no fever on admission to hospital
    • some have “silent hypoxia” with minimal cough or SOB and this is presumably due to a V/Q shunt issue
  • severe pneumonitis
    • as for mild pneumonia but with hypoxia in room air and/or tachypnoea (eg. RR > 30 in adults)
    • this occurs in 5% of symptomatic children and is more likely in infants under 1yr of age 20)
    • as for severe pneumonitis but with hypoxic respiratory failure and CXR or CT scan showing bilateral opacities consistent with pulmonary oedema which is not caused by a cardiac cause or fluid overload
    • patients usually develop SOB by Day 7 post-exposure, and then intubation by day 10-15 possibly followed by death at 2-3 weeks after symptoms begin with a mean time to death from onset of 18 days
    • median time to development of ARDS from hospital admission appears to be 2 days (IQR, 1–4 days)
    • this may be rapidly progressive over hours
    • this occurs in 0.6% of symptomatic children and is more likely in infants under 1yr of age 21)
    • endothelial cell infection and cardiovascular complications
      • of those admitted to ICU, apparently 30-70% develop DVTs and 25% develop PEs
    • sepsis occurs in a small minority of patients with severe illness
  • acquired immunity vs subsequent infections
    • it seems 3-10% may become positive again for Covid-19 after discharge from hospital and resolution of symptoms, it is not clear if these patients are a transmission risk
    • in April 2020, sampling suggests 20% of the NY city population had developed antibodies
  • long term effects
    • SARS virus patients tended to have impaired lipid metabolism lasting over 12 years after infection and this may be via programming of RAAS to chronically up-regulate ACE/Ang II at the expense of ACE2/Ang-(1-7) in otherwise healthy adolescents and young adults

Mortality rates and factors

  • cause of death is Acute Respiratory Distress Syndrome (ARDS) in the vast majority of patients who die from Covid-19
  • 94% of deaths are in people with underlying co-morbidities 22)
  • those aged over 64yrs with or without co-mordities were 2-3x more likely to need hospitalization or intensive care compared to 19-64yr olds23)
  • patients can have rapid deterioration over a few hours on day 5 to 11 on symptoms resulting in death if not immediately provided with ventilatory support
  • risk of pneumonitis and thus death is probably related to the degree of expression of ACE2 on pulmonary cells which is known to increase with:
    • age
    • diabetes
    • use of ACE inhibitors and angiotensin II receptor blockers (ARBs) both of which reduce the effect of Ang II on the AT1R which acts to reduce ACE2 expression via lysosomal internalization of ACE2
    • perhaps with genetic polymorphisms of ACE2
    • human influenza infection induces broader expression of ACE2 in upper airway epithelial cells
    • Covid-19 activated interferon alpha 24)
  • HOWEVER, the situation is complex and it may be that ACE2 and reduction of the activity of AT II is important in the resolution of lung injury and general over-activity of RAS (which may be due to viral binding of ACE2 reducing its actions), and thus there may even be a role for angiotensin II receptor blockers (ARBs) in the Mx of severe cases - research is investigating this
  • case fatality rate (CFR) is estimated to be around 3% overall, but 15% in those aged over 80yrs and 8% in those aged 70-79yrs while around half of those critically ill died and perhaps over 80% of those requiring mechanical ventilation had died within 28 days.
    • CFR was higher in those with premorbid conditions:
      • 10.5% CFR if cardiovascular disease
      • 7.3% CFR if diabetic
      • 6.3% CFR if chronic resp disease
      • 6% CFR if hypertension - it seems this may be related to up-regulation of the ACE2 receptor due to taking ACE inhibitors or angiotensin II receptor blockers (ARBs) in patients with certain ACE2 gene polymorphisms so a theoretical risk reduction strategy is to change to an alternate antihypertensive agent 25)
        • ARBs increase ACE2 receptor numbers by 3-5x
        • current advice is to continue these meds if they are being used to control congestive cardiac failure but as of 19th March 2020, the jury is still out on the risk-benefits of potential loss of BP control when changing to a different antihypertensive when used to Rx hypertension only, however, the main bodies are advising NOT to cease these meds at this stage. 26)27)
      • 5.6% CFR if cancer
    • Men are more likely to die than women
      • in China CFR for men was 2.8% cw 1.7% in women
      • in Italy 71% of deaths have been men
      • in Spain it appears men have died at twice the rate of women
    • vitamin D deficiency may be a risk factor28)
    • true fatality rate is thought to be around 0.7%

Prognostic factors

  • level of hypoxia
    • this is a marker of severity of pneumonitis and degree of lung function
  • pre-morbid factors and frailty score
    • mortality is higher in those with significant co-morbidities (including hypertension) as well as frailty and age > 64yrs
    • CRP > 50 appears to correlate with likelihood of hypoxaemia 29) and CRP > 100 with mortality risk 30)
    • this may also be elevated with secondary bacterial infection
  • procalcitonin
    • an elevated procalcitonin is a poor prognostic sign, possibly reflective of cytokine storm31)
    • this may also be elevated with secondary bacterial infection
    • raised troponin is a strong predictor of mortality. Among non-survivors, troponin tends to increase steadily from day 4 of illness through day 2232)
    • Overall, patients in a Chinese study with cardiac injury (raised hs-troponin) were more likely than those without cardiac injury to require noninvasive ventilation (46% vs. 4%) and invasive ventilation (22% vs. 4%). Cardiac-injury patients also had a higher mortality rate (51% vs. 5%). After adjustment for confounders, including acute respiratory distress syndrome, cardiac injury remained a significant predictor of mortality.33)
    • non-survivors had significantly higher levels of D-Dimer and prolonged prothrombin time
    • in one study, lymphopenia was present in 70% of hospitalized patients with Covid-19 pneumonia and progressive decline in the lymphocyte count and rise in the D-dimer over time were observed in nonsurvivors compared with more stable levels in survivors 34)
    • fibrinogen should be monitored as well as prothrombin time, D-Dimer and platelet count
    • non-survivors with severe illness have developed disseminated intravascular coagulation around day 4; significant worsening in these parameters at days 10 and 14 was also reported.35)
  • organ or coagulation dysfunction 36)
  • access to oxygen when needed
  • access to critical care and ventilators when needed

Clinical Mx of severe illness

  • see:
  • infection risk precautions
  • viral swabs / sputum culture as per local policy (may require rpt collections every 2-4 days to confirm viral clearance)
  • standard blood tests including blood cultures and perhaps blood gases
  • CXR
  • consider CT chest
  • general supportive care, avoiding fluid overload
  • supplemental low flow 100% oxygen as needed to no higher than 96% sats and lower for those with pre-existing COPD
  • self-proning appears to improve oxygen saturation 37)
  • avoid systemic corticosteroids unless a specific indication such as asthma
  • there is NO evidence to support ceasing ACE inhibitors or angiotensin II receptor blockers (ARBs) once a patient has Covid, and being on these whilst an inpatient may halve mortality in patients with hypertension 38)
  • assess patient's pre-morbid conditions and prognosis, tailor care as appropriate and discuss this with patient and family, particularly as intubation may be futile for many patients
  • high flow nasal oxygen and BiPAP NIV should be avoided as these create an aerosol dispersion of the virus and increases risk to all those in the room
  • monitor for and Rx Acute Respiratory Distress Syndrome (ARDS) and consider treating empirically for sepsis / septicaemia
  • consider VTE prophylaxis in the critically unwell cases
  • dexamethasone 6mg daily
    • the Recovery Trial published in June 2020 showed that 6mg dexamethasone daily for 10 days reduced deaths by 1/3rd for ventilated patients and by 20% for those on oxygen but without need for ventilator care39)
  • if intubation is deemed appropriate
    • preferably choose a negative pressure room
    • staff to wear appropriate PPE including N95 masks and eye wear as intubation creates aerosol risk in addition to droplet risk
    • minimize staff and family in the room and place signage to avoid unintended entrance to room
    • pre-oxygenate with 100% oxygen
    • minimize aerosol amount by:
      • avoiding NIV or high flow oxygen if possible (unless in a negative pressure room)
      • avoiding awake fibreoptic procedures
      • using two handed technique for better seal if bag mask ventilation is needed
      • utilizing the most experienced intubator to maximize probability of initial success
      • utilizing video laryngoscopy to increase chance of success
      • avoiding initial ventilations until cuff is inflated
      • avoiding disconnection of the circuit where possible and if needed keep it as brief as possible
      • use the airway circuit and ventilator that will be used in ICU to avoid having to change over circuits
      • using expiratory viral filters to maintain a closed circuit for the virus
    • ventilate as per Acute Respiratory Distress Syndrome (ARDS) although some feel the ARDS component is a later development and other strategies such as a less aggressive PEEP strategy and early prone ventilation may need to be considered early in the ventilation period.

Possible additional therapeutic options

    • very small study of 36 patients seemed to show a large benefit in viral clearance with 100% of hydroxychloroquine plus azithromycin treatment virologically cleared, and 70% of hydroxychloroquine only treated patients were virologically cleared comparing with 12.5% in the control group after 6 days (p= 0.001). Dose used: 200mg tds oral hydroxychloroquine sulfate for 10 days 40)
    • possible recommended dosage: 400 mg BID for the first day followed by 200 mg BID for the following four days.41)
    • unfortunately this benefit has NOT been replicated in later studies
  • potential future prophylaxis or treatment options
    • reduce viral access to cells or improve immune responses:
      • spike protein-based vaccine
      • inhibition of transmembrane protease serine 2 (TMPRSS2) activity
      • blocking ACE2 receptor site
      • delivering excessive soluble form of ACE2 to bind viral particles
      • role of BCG injection to increase general immune responses
      • proton pump inhibitors (PPIs) or disulfiram to inhibit the vacuolar proton ATPase which is involved in the endosomal pathway that the COVID19 virus, influenza A, and the anthrax toxin ride into the PEC cytoplasm.
      • ivermectin seems to kill the virus in 48hrs in cell cultures
    • medications to directly kill the virus
      • role of other known antivirals
        • remdesivir appears to improve outcome in patients requiring ventilation in a small study of 34 patients 42)
    • other possible Rx to reduce ARDS:
      • IL6 blockers
      • vitamin A
      • celebrex
      • pioglitazone
      • aspirin to prevent the increase in AMI and stroke in Covid infections which is presumably mediated by Covid activation of platelets
      • formoterol, a beta-2 agonist used in asthma, increases claudin-5 expression and strengthens tight junctions between PECs, limiting pulmonary edema
      • corticosteroids seem to have some beneficial effect in a Chinese study 44)
    • unusual and unlikely therapies:
      • ultraviolet blood irradiation (UBI)
        • apparently seemed to work for sepsis in the pre-antibiotic era and just needs 5-7% of blood to be irradiated - mechanism may be related to immune response or cytokines 45)

More Information

Pandemic timeline

  • China implemented extremely stringent quarantine measures for its people which has also allowed other countries time to prepare
    • as of Feb 28, 2020, 0.1% of the Hubei population had confirmed infections but there were only around 10-20 new Chinese cases each day outside of Hubei
  • 1st case in Italy on Feb 21st
  • early March - panic buying of goods such as toilet paper, pasta, rice, mince meat, paracetamol, scripts causing severe shortages
  • WHO declares it a pandemic on 11th March 2020
  • Italy averaging 340 deaths each day in mid-March with a 7-8% mortality rate due to an aged population and an overwhelmed health system - 87% were aged over 70yrs, 75% had hypertension
    • 50% of a northern Italian hospital's 1000 beds were occupied by Covid-19 cases and ED was seeing 60-90 suspect patients each day. Elective surgeries have been cancelled, semielective procedures postponed, and operating rooms turned into makeshift ICU. Contributing to the resource scarcity is the prolonged intubation many of these patients require as they recover from pneumonia — often 15 to 20 days of mechanical ventilation - in some hospitals the “cutoff age for intubation” was lowered further from 80yrs to 75yrs. Some staff as well as non-infected patients admitted with AMI became infected in hospital. “The rapidity of respiratory deterioration in the most severely affected patients, including some young ones, was striking and often unforeseeable.” 46)
  • global stock markets crash
  • Qantas announces cessation of international flights as of end of March 2020 and lays off 20,000 employees
  • 19th March, mass gatherings of more than 100 people indoors and 500 outdoors banned in Australia, resulting in sports being played without crowds, tourist destinations such as The Twelve Apostles Visitor Centre, the 1000 steps, Werribee mansion and Buchan Caves closed.
  • Australia bans entry of all non-residents as of 9pm 20th March 2020, residents will have to self-isolate for 14 days
  • 22nd March, Aust. PM announces further $66b stimulus package to assist small businesses and those stood down from jobs while the AFL suspends football season at least for several months, while in Italy daily death rates hit around 800 deaths!
  • WA, SA and NT close borders as of 24th March
  • Vic and NSW impose lock-down as of 24th March - only essential services open, while schools and non-essential retail, gyms, etc to close
  • Australia predicted to run out of ICU beds in the 1st week of April hence massive ramp up in ICU capacity planned as well as the substantive efforts to decrease R0
  • March 2020 modelling suggests possible NSW Covid peaks47):
    • without social distancing, peak hospitalisation in July with 16% infected, 35,000 in hospital and 11,800 ICU beds needed
    • with social distancing, peak hospitalisation in mid-Nov with 5% infected, 14,000 in hospital and 5,100 ICU beds needed (pre-Covid ICU bed capacity was 874 beds in NSW)
  • 3rd April: global confirmed cases pass 1 million; global deaths pass 50,000; UK passes 3000 deaths; Italy has almost 14,000deaths; Spain hits 950 in a day and over 10,000 deaths and over 6,000 in ICU; US at 5,300 deaths;
  • 10th April: 1.7m global cases confirmed with 100,000 deaths; US hits almost 0.5m confirmed and 16,000 deaths, nearly 6,000 in NY city alone; almost 19,000 deaths in Italy, 16,000 in Spain, 13,000 in France while UK is nearly 9,000 and over 900 per day;
  • 15th April: global confirmed cases hit 2 million, doubling in just 14 days, over 600,000 in US
  • 25th April: WHO warns that recovery from coronavirus might not protect a person from reinfection. Global cases exceed 2.86 million and death toll exceeds 200,000.
  • 1st May: study of 16,749 COVID patients in 166 UK hospitals between early February and mid-April48):
    • average age was 72yrs, and 35-40% of all admitted patients died from their infection
    • obesity or dementia increased mortality by nearly 40%
    • age over 80yrs were 14x more likely to die than those under 50yrs
  • 27th May: over 100,000 deaths in US with 1.7 million infected; Brazil now 2nd highest country overtaking Russia and UK;
  • 8th June: over 7 million infected and 400,000 deaths globally; 2 million in USA with 112,000 deaths; UK deaths now over 40,000 having the 2nd highest per capita death rate of the large countries (highest is Belgium); NZ is declared Covid-free;
  • 28th June: 10 millionth case 180 days after 1st reported case in Wuhan; Brazil, US, Sth Asia are the main areas with high rates of new cases.
  • latest data
  • epidemic calculators:
48)
Features of 16,749 hospitalised UK patients with COVID-19 using the ISARIC WHO Clinical Characterisation Protocol
covid-19.txt · Last modified: 2020/06/28 22:17 by gary1