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covid-19

COVID-19 coronavirus (2019-nCoV)

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
  • in China, human to human transmission was mainly observed in healthcare facilities and among family members
  • 80% of cases are “mild”, 14% severe and 5% were critical
    • in children, only 6% develop severe or critical illness - ie. 94% are “mild”
  • there have been reports of delayed onset of critical illness occurring some 1-2 weeks after initial mild symptoms
  • a Feb 2020 Chinese report suggests that nearly 90% of infections occur in those aged 30-79yrs with a further 8% in those aged 20-29yrs - only 2% were aged under 20yrs! 1)
  • median time to development of ARDS from hospital admission appears to be 2 days (IQR, 1–4 days)
  • 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 a small study of 15 pregnant patients with mild disease, pregnancy did not appear to aggravate the clinical course2)

Transmission

  • 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
  • it is presumed that a patient is infectious from onset of symptoms to 24hrs after resolution but this is still unclear as there have been reports of asymptomatic transmission
  • WHO are recommending isolation for positive cases for 2 weeks after they become symptom free 3)
  • the COVID-19 virus enters cells ONLY via ACE2 receptors on cells which also express TMPRSS2
    • the major target cells are type II pneumocytes and enterocytes 4)
    • binding of the coronavirus S (spike) protein to ACE2 triggers a conformational change in the S protein of the coronavirus, allowing for proteolytic digestion by host cell proteases (TMPRSS2)
    • Covid-19 has 10-20-fold higher affinity of ACE2 compared to SARS virus5)
    • the intracellular enzyme furin plays an important role in this viral life cycle of SARS-CoV-2 and this is distinctly different than SARS-CoV.6)
      • The furin cleavage site in the SARS-CoV-2S protein may provide an priming mechanism, and Alveolar type II cells were strongly positive for furin while transient secretory cells had an intermediate level of expression
  • transmission appears to be primarily via droplet spread from coughing
    • 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
      • 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 cardboard8)
        • hence the advice for regular hand hygiene and cleaning of surfaces

Incubation period

  • from a Chinese study published March 10th 20209):
    • 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

  • 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) 10)
  • 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

  • asymptomatic carriers
    • unclear as to the extent of spread via asymptomatic persons
    • 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 11)
  • 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
    • 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 12)
  • 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
  • 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 13)
    • 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
    • this occurs in 0.6% of symptomatic children and is more likely in infants under 1yr of age 14)
    • sepsis occurs in a small minority of patients with severe illness
  • 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
  • patients can have rapid deterioration over a few hours on day 5 to 8 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:
  • 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 15)
        • 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. 16)17)
      • 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
    • 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 18) and CRP > 100 with mortality risk 19)
    • this may also be elevated with secondary bacterial infection
  • procalcitonin
    • an elevated procalcitonin is a poor prognostic sign, possibly reflective of cytokine storm20)
    • 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 2221)
    • 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.22)
    • 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 23)
  • organ or coagulation dysfunction 24)
  • 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
  • avoid systemic corticosteroids unless a specific indication such as asthma
  • 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
  • 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

Possible additional therapeutic options

    • very small study of 36 patients seems 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 25)
    • possible recommended dosage: 400 mg BID for the first day followed by 200 mg BID for the following four days.26)
  • 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 tuberculin 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
    • other possible Rx to reduce ARDS:
      • vitamin A
      • vitamin D
      • 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 27)

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.” 28)
  • 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 peaks29):
    • 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;
  • latest data
  • epidemic calculators:
covid-19.txt · Last modified: 2020/04/05 11:39 by gary1