CORONA VIRUS


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Overview


Pathophysiology
Stages of Illness
Signs and Symptoms
Disease Progression
Special Investigations
Management
Prognosis


Pathophysiology


ARDS
•COVID-19 caused by Cov-SARS2 coronavirus, an a large envelope, positive strand RNA virus which can easily mutate •The primary pathology is ARDS, characterized by diffuse alveolar damage (e.g. including hyaline membranes). Pneumocytes with viral cytopathic effect are seen, implying direct virus damage (rather than a purely hyper-inflammatory injury. •Virus appears to attach to Angiotensin Converting Enzyme 2 in alveoli and respiratory tract, among other organs (also kidney, liver, GIT, vascular endothelium)



Cytokine storm
•Emerging evidence suggests that some patients may respond to COVID-19 with an exuberant “cytokine storm” reaction (with features of bacterial Sepsis or hemophagocytic lymphohistiocytosis). •Clinical markers of this may include elevations of C-reactive protein, LDH and ferritin, which appear to track with disease severity and mortality.


Stages of Illness


There seem to be different stages of illness that patients may move through
(1. Replicative stage – Viral replication occurs over a period of several days. An innate immune response occurs, but this response fails to contain the virus. Relatively mild symptoms may occur due to direct viral cytopathic effect and innate immune responses. It is unclear, but possible that carriers can disseminate the virus at this stage.



(2. Adaptive immunity stage – An adaptive immune response eventually kicks into gear. This leads to falling titres of virus. However, it may also increase levels of inflammatory cytokines and lead to tissue damage – causing clinical deterioration.



This progression may explain the clinical phenomenon wherein patients are relatively OK for several days, but then suddenly deteriorate when they enter the adaptive immunity stage.



This has potentially important clinical implications: •Initial clinical symptoms aren’t necessarily predictive of future deterioration •Anti-viral therapies might need to be deployed early to work optimally (during the replicative stage). •Anti-Cytokine therapies might be required later if massive cytokine release causes MOF.


Signs and Symptoms

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• Fever: present in 43-98%.
• Cough: present in 68-82%.
• Sputum production: present in 28-34% ( Hemoptysis in 1-3% ).
• Dyspnoea: present in 19-31%.
• Myalgia and Headache: present in 8-15%.
• Sore throat: present in 5-14%.
• Rhinorrhea: present in 4-6%.
• GI Symptoms: present in 5-10% – may precede fever.
• Silent Hypoxaemia: may occur without dyspnoea, esp. in elderly.


Disease Progression


At risk groups – Age > 60, Diabetes, Hypertension, Pre-existing respiratory conditions, Multiple co-morbidities.
Approx 81% mild disease, Management at home .
14% more severe disease, requiring Face-mask oxygen, manage on ward.
5% very severe, requiring Critical Care.
Severity predicted by increasing dyspnoea, CRP rise, worsening LFTs. Critical Care mortality 25-65%.
Usually single organ respiratory failure, with good compliance due to high degree of atelectasis.

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MOF rare, as is AKI, unless pre-existing CKD. GI symptoms including Diarrhoea not uncommon, virus may shed in stool for many days after respiratory secretions clear, but appears not to be active.
Secondary bacterial infection may present with rising PCT, increasing organ support requirement.
Co-infection with Influenza virus infrequent, 2-5%


Special Investigations


Radiology
•Typical Reticular / ground glass bilateral shadowing peripherally and basal, increase in segments and coalesce over time and with increased severity. Pleural effusions and hilar lymphadenopathy are unusual (<5%), as is cavitation.
•If CXR normal but high suspicion, can check for individual => coalescing ‘B’ lines on US, suggestive of interstitial edema.
•If ‘B’ lines present, PCR delay and early confirmation vital, could consider CT (88% sensitive but challenging to do safely).



Laboratory Investigations
CRP – initial 0-20, low likelihood of progression, 40-60 higher likelihood of progression, CRP tracks severity.
PCT – Usually v low (,0.5), any rise associated with secondary bacterial superinfection.
WCC – usually normal.
Lymphopaenia – present in up to 80%, Neut:Lcyte ratio > 3 also predictive.
Resp virology – should always be sent, but co-infection appears uncommon (<2%).



Evolving DIC and Thrombocytopaenia associated with worsening prognosis ØWorsening transaminitis associated with poor prognosis. ØFerritin and LDH – acute elevations associated with MOF and HLH-like syndrome with high mortality. ØPCR – sensitivity roughly 75%, as disease progresses, NPA samples less sensitive than resp tract / ETT secretions, so may require multiple tests to confirm both positivity and negativity. A single negative result may not exclude the diagnosis, and thus if Hi clinical suspicion, do not de-isolate. ØBAL – risks outweigh benefits and should not be done purely for confirmation of diagnosis, but may have a role if COVID-19 excluded as cause of resp. failure.


Management

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PPE and isolation – see separate documents – if patient suspected of COVID-19, ensure facemask is attached asap, PPE donned by anyone coming into contact, pt. is isolated and contact tracing set up.



Majority of pts who remain hypoxic on FM oxygen and HFNO will continue to deteriorate on NIV, so such hypoxemia necessitates early intubation for both patient and environmental safety. Cut off – FiO2 0.6 on HFNO.



Ventilation: •Usually lungs fairly compliant, high degree of atelectasis associated with small airway damage.
•Use low TV’s according to ideal body weight formulae (4-6ml/kg IBW).
•WHO recommends a high PEEP strategy using the HiPEEP ARDSnet table in relation to FiO2.
Consider early paralysis and early proning (if P/F < 150 after 12hrs conventional Ventilation), for 16-18 hr stints.
Early APRV has been used in other centres to aid alveolar recruitment, particularly if proning problematic. Initial settings : Hi – 35 cmH2O for 5 seconds, Low – 0 cmH2O for 0.5 seconds.



Recruitment manoeuvres appear to be out of favour in current ARDS literature following increased harm noted in recent trials.
Assess success of recruitment with prone positioning or APRV using before and after measurements of Driving Pressure, P/F ratio and Lung Compliance.
Prostacyclin nebs commonly used in US centres to improve V/Q matching.
Allow permissive hypercapnia down to pH 7.1 unless CVS instability develops, priority is lung protective Ventilation using low TVs.



ECMO Referral – usual criteria apply, refer to Papworth then GSTT then Harefield, with GSTT / Barts transferring. VV ECMO if hypoxaemia, VA ECMO if cardiorespiratory failure



Classical Septic Shock does not appear to be a common feature of this disease. Avoid volume loading, treat Hypotension with low dose vasopressors, ensure early enteric feed, give fluid only if end organ perfusion compromised ( rising lactate, falling urine output etc. , guided by cardiac output monitoring to minimise the fluid volumes administered ), aim even or negative fluid balance if possible.



Avoid NSAIDs, stop ACEI once intubated.
AKI / ARF – increased risk if pre-existing CKD, may benefit from early filtration to optimise fluid balance if urine output poor despite high dose diuretics. Extrapolating from SARS: “SARS causes renal failure in ~7% of patients. The pathology shows acute tubular necrosis, which appears to be a reflection of generalized multi-organ failure. In some cases Rhabdomyolysis may have contributed as well. Renal failure correlates with a poor overall prognosis (92% mortality with renal failure versus 9% without). In multi-variable analysis, renal failure was the strongest predictor of mortality (more-so even than ARDS)”.



CVS Instability – Associated myocarditis, may see elevated troponin on admission, with near normal LV function on Echo. However, may develop late Cardiomyopathy associated with sudden fall in ejection fraction associated with increased arrhythmias. Cardiomyopathy associated with 33% of deaths, rising troponin a poor prognostic indicator, but unclear whether due to primary cardiac damage or stress response. Cardiac output monitoring may help to clarify timing of introduction of inotropes. If pH < 7.2, trial of IV HCO3, aim serum HCO3 >28, check Ferritin / LDH and HLH diagnostic criteria, if positive, consider Tocoluzimab 1-2 doses.



Tracheostomy – if required, surgical approach on balance safer than percutaneous in this group of pts.


COVID-19 Specific Treatments


Antivirals under investigation include:
•Remdesivir – shows promise when administered under compassionate use programme in the US, undergoing trials but not commercially available yet
•Kaletra – lopinavir/ritonavir is a protease inhibitor which prevents viral replication. AntiHIV drug, easily available. Limited evidence of some benefit against MERS, but low volume low quality trials. RCTs ongoing in China currently
•Tocoluzimab – if massive cytokine release associated with haemophagocytosis and HLH-like syndrome. Associated with high mortality, evidence base lacks large numbers of pts to confirm
•Chloroquine – Interferes with ACE2 receptor and thus virus entry. An expert consensus group in China is recommending a treatment regimen of 500 mg PO twice daily for patients without contraindications, but this is not supported by any published clinical data yet.
•Steroids – Steroids do not appear to be generally used. “Steroids have not demonstrated benefit in prior SARS or MERS epidemics. Steroids may increase viral shedding. Nearly all articles recommend against the use of steroid”. However, if severe host response pneumonitis as judged from rising CRP / Ferritin late in disease, some centres in China using Methyl Prednisolone.
•Oseltamivir – Influenza still common, may be of use, like CAP antibiotics, until resp virology / sputum MC&S test results come back.



Criteria for de-isolation: •2 negative aspirates, 24hrs apart, sensitivity of PCR test proportional to quality of sample obtained, ETT aspirates more sensitive than NPA or Throat swabs.
•Because of the lack of PCR sensitivity (75%), if Hi clinical suspicion despite negative PCR, would recommend senior clinical review for final decision regarding de-isolation.


Prognosis

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(1) It remains unclear what fraction of patients are hospitalized.
There may be lots of patients with mild illness who don’t present to medical attention and aren’t counted.
The vast majority of infected patients (e.g. >80%) don’t get significantly ill and don’t require hospitalization.



(2) Among hospitalized patients:
10-20% of patients are admitted to ICU.
3-10% require intubation.
2-5% die.



(3) Longer term outcomes: Prolonged ventilator dependency ?
Patients who survive the initial phases of the illness may still require prolonged ventilator support (possibly developing some radiographic elements of fibrosis).
As the epidemic progresses, an issue which may arise is a large volume of patients unable to wean from mechanical Ventilation.


Preventive Measures


I.Maintain Hand Hygiene :- Wet your hands with clean, running water — either warm or cold.
II.Apply soap and lather well.
III.Rub your hands vigorously for at least 20 seconds. Remember to scrub all surfaces, including the backs of your hands, wrists, between your fingers and under your fingernails.
IV.Rinse well.
V.Dry your hands with a clean towel or air-dry them.