Coronavirus-2019 (COVID-19)

Orlando Debesa

updated: April 19, 2020

General

​In December of 2019, there was a cluster of pneumonia cases in China. Investigators discovered it was caused by the 2019 Coronavirus. Coronavirus is a large group of viruses, that like most viruses, consists of a core of genetic material enclosed in an envelope with protein spikes which gives it the appearance of a crown - "corona" in latin means crown. The different types of coronaviruses causes respiratory and intestinal symptoms. Respiratory symptoms range from the common cold to pneumonia but for the most part cause mild disease.

However, there are some coronaviruses that cause severe disease, such as:

  • SARS-CoV (identified in China in 2003)

  • MERS-CoV (identified in Saudi Arabia in 2012)

 

The 2019 Coronavirus was first identified in Wuhan, China among a group of people with pneumonia that were associated with a seafood and live animal market. 

Coronavirus has been known to circulate among a variety of animals (eg. camels, bats, civet cats) but sometimes these viruses can "spillover" from animals to humans simply from increase contact between humans and animals and/or mutations.  The animal that caused 2019 Coronavirus is not known yet.

 

  • caused by severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) and the clinical illness that it causes is called "COVID-19"

  • started as pneumonia outbreak in Wuhan city, capital of Hubei province in China

  • likely started as zoonotic transmission from Wuhan seafood market (pangolins?) BUT person-to-person transmission also occurs

  • median duration of hospitalization is 12 days 

  • mortality: 3 - 5.5% worldwide (varies between countries - Italy as high as 10%)

  • incubation time (time of transmission to infection): 3-15 days 

  • viral shedding: median 20 days (max 37 days)

  • R0: (reproductive number) - 2.2 (the number one infected person will infect on average) a number used to tell us how infectious an organism is

    • influenza - R0 = 3

    • small pox - R0 = 6 

    • measles - R0 = 9-18

Trajectory

 
COVID mortality age.PNG

Prognosis

  • age

  • comorbid conditions

    • diabetes mellitus​

    • COPD

    • cardiovascular disease

  • admission SOFA score

sneeze.PNG
 

Transmission

​Respiratory viruses are usually transmitted through droplets created when an infected person coughs or sneezes or through objects that have been contaminated by the virus. 

  • transmitted by:

    • contact​

    • fomites

    • droplets

  • viral particles enter the lungs via droplet nuclei

  • some articles cite the risk limited to 6 feet (1) while more recent sources studying turbulent gas cloud

  • dynamics have indicated up to 30 feet transmission by the "high-momentum cloud" (droplet nuclei)

  • and may stay suspended in air for hours (2)

  • N-95 and surgical masks are not tested for these potential characteristics of respiratory emissions (2)

References: (1) del Rio, JAMA, 2020 (2) Bourouiba, JAMA, 2020 (3) Zhu et al, NEJM, 2020

 

Signs/Symptoms

There are a number of symptoms ranging from mild to severe. "Flu-like symptoms " predominate but the presentation is extremely varied.  Most patients present with greater than one sign/symptoms on admission. The mean duration of symptoms before ICU admission was 1 week (13).

Clinical spectrum is very wide:

  • asymptomatic

  • mild upper respiratory tract illness

  • severe viral pneumonia with respiratory failure

  • death

Cough

  • the most common presenting symptom - 60-80%

Fever

  • 37.5C or higher axillary

  • only 50% of patients are febrile at admission which suggests the use of fever not useful criteria in determining the severity of illness and may delay diagnosis. Eventually 88.7% of patients developed fever after admission.  

Shock

  • large proportion of patients presented with shock that required vasopressor support

  • myocardial dysfunction on ECHOcardiogram was UNCOMMON

  • the lack of bacterial or viral co-infection suggests that the shock was due to COVID-19 (unlike seasonal influenza which is commonly associated with bacterial co-infection with pharyngeal microorganisms such as staphylococcus and streptococcus (16))

Acute Cardiac Injury

  • cardiac myoglobin

    • elevated predicts bad prognosis​

  • troponin

    • elevated predicts bad prognosis​

  • ECHOcardiogram abnormality

  • ECG abnormality

  • seen in patients with pneumonia

Cardiomyopathy

Heart Failure

  • seen in patients with pneumonia

Arrhythmia

  • seen in patients with pneumonia

Cardiac Arrest 

  • 3% of patient with pneumonia 

Silent Hypoxemia

Dyspnea - 20-40%

Acute Respiratory Distress Syndrome (ARDS)

  • characterized as diffuse alveolar damage

  • pneumocytes with viral cytopathic effect are seen, implying direct virus damage rather than hyper-inflammatory injury 

  • NOTE: some evidence to suggest that this is NOT ARDS in the early phase of the illness

  • lung "leak" not as prominent as in classic ARDS

Ventilator Associated Pneumonia

GI symptoms - 10%

  • uncommon

Liver Enzymes

  • elevated AST / ALT

Hypercoagulable

90% of inpatients with pneumonia had increased coagulation activity marked by increased d-dimer (25)

  • elevated d-dimer greater than 1 microgram/mL is associated with fatal outcome in COVID-19 patients (1)

  • ischemic limbs (eg. Nick Cordero, Broadway Canadian actor, had his right leg amputated. He had been on ECMO and its not sure how much of this contributed)

Renal Failure

Sepsis - 50%

Pharyngitis/Tonsil enlargement - 2%

References: (1) Zhou et al, Lancet, 2020, (2) Xu et al, Lancet, 2020, (3) Luo et al, Prognostic value of C-reactive protein in patients with COVID-19), (13) Guan et al, NEJM, 2020, (16) Chertow et al, JAMA, 2013,  (25) Milbrandt EB et al, Mol Med, 2009

 

Radiographs

  • CXR: hazy bilateral, peripheral opacities

  • CT scan:

    • ground glass opacity - 56.4%

    • bilateral patchy shadowing - 51.8%

    • crazy paving

    • rarely unilateral

 

Testing

  • real-time reverse-transcriptase-polymerase-chain-reaction - identifies the virus based on its genetic fingerprint

  • antibody testing

 

Risk Factors

Groups most at risk are those in close contact with animals, such as live animal market workers or those caring for those witrh infection such as family members or healthcare workers. 

Majority of patients have chronic illnesses before ICU admission:

  • diabetes mellitus

  • chronic kidney disease

Hypertension

Asthmatics

Risk factors for death

  • older age

  • d-dimer > 1 microgram/mL

  • high SOFA score on admission

Severe Illness

  • high IL-6

  • high cardiac troponin I

  • high lactate dehydrogenase

  • lymphocytopenia: was common on hospital admission (13) as it was in reports from China

References: (13) Guan et al, NEJM, 2020

 
corona structure.PNG

Pathophysiology

  • 30 kbp

  • enveloped

  • non-segmented, positive sense, single stranded RNA betacoronavirus (3)

  • lipid-bilayer

  • spike glycoprotein (S)

  • heagglutinin-acetylesterase glycoprotein (HE) (HAG)

  • M-protein

  • RNA and N protein

Replication Cycle

  1. receptor on virus binds to ACE receptor

  2. endocytosis occurs

  3. uncoating of ssRNA into cells cytoplasma 

  4. ssRNA uses cells ribosomes to make proteins: RNA polymerase, negative strand RNA

  5. negative strand RNA uses cells ribosomes to make another positive strand RNA and other small RNAs

  6. small RNAs use the cells endoplasmic reticulum to make structural components of the virus which will then get transferred to the golgi apparatus where it will get packaged up with the (+)ssRNA to make a new virus

  7. exocytosis occurs 

To complicate matters, COVID-19 is mutating and virulence and transmission

will shift over time in ways which will be difficult to predict - in this sense, there

is not just one type of COVID-19 but innumerable different viruses evolving over

time (2). There is new evidence to suggest that there are two different groups of

COVID-19 and explains why the initial reports from Wuhan described a higher

mortality than some recent case series (2):

  • L haplotype (blue)

  • S haplotype (red) - the ancient version of COVID 19

COVID-19 binds (via the "S" spike) to ACE-2 receptor found on (30-31): (same receptor used by SARS, hence the name SARS-CoV-2)

  • type-II alveolar cells (1) - surfactant producing 

  • intestinal epithelia (1)

  • myocytes

  • vascular endothelial cells

As the virus replicates within the alveolar cells, its damages them activating the inflammatory response causing the release of:

  • interferon and cytokines

    • acts in a paracrine fashion upon the surrounding cells preparing them to ward off the viral infection ​by activating macrophages

Macrophages cause the release of:

  • tumor necrosis factor-alpha (TNF-alpha)

  • IL-1

  • IL-6

  • IL-8

  • chemokines

It is these cytokines that stimulate the nerve endings near the alveoli responsible for the cough reflex. 

TNF-alpha / IL-1b

  • proinflammatory

  • cause vascular permeability which "floods" the alveoli causing pulmonary edema 

  • increase expression of adhesion molecules which recruit neutrophils and monocytes which will then enter the site of injury; in this case, the alveoli 

IL-6

IL-8

  • recruits neutrophils

Neutrophils

  • important in acute setting because engulf viruses

  • detrimental after awhile because it releases chemicals that damages the surrounding tissue 

 

The overall sequela of this inflammatory response causes alveoli to fill with fluid causing ARDS. However, we are hearing from different centers that this is not typical ARDS and the usual ARDS treatment strategies may not be sufficient to get patients through this complex disease. 

Unsure what role ACE-I/ARB play at this time - currently not recommended to discontinue 

Phases of COVID

Georges hospital cohorts patients according to what phase they are in. It involves more moving of patients but helps each team to focus on things more easily. 

  • early

  • late

  • extubation

  • tracheostomy

Cytokine Storm

  • seems to be more severe in some patients compared to others

  • features of bacterial sepsis or hemophagocytic lymphohistiocytosis (HLH)

  • CRP and ferritin are used as clinical markers and can track disease severity and mortality (3)

  • replenishment of C1-INH in refractory cases ??

 

Right Ventricle

Pathological findings are providing useful treatment direction and more often than

not "it's all about the right ventricle." For all of these ARDS patients, cardiovascular

dysfunction is centrally important and the right ventricle appears to be the main

culprit in the COVID-19 hemodynamically compromised patient. Autopsy series from

New Orleans reveals extreme right ventricular dilated right ventricle dilation with

straightening of the interventricular septum in all examined hearts.

Pulmonary Thrombotic Microangiopathy (microvascular thrombosis) (4)

  • this is prevalent 

  • causes an increase in dead space

  • without deep venous thrombosis

The New Orleans autopsies also reported this thrombosis which is restricted to the

lungs which is very unusual. 

Pulmonary Fibrosis

  • some evidence from Italy that this is occurring early

  • oxygen related ??

  • inflammation related ??

Pancreatic hypoperfusion

  • hyperglycemia

Disseminated Intravascular Coagulation (DIC)

  • purpura fulminans

 

Stages of Disease Course

 

Troponin Elevation

Transaminase elevation

Bacterial Superinfection

References: (1) Hamming, J Pathol, 2004, (2) Tang et al, National Science Review 2020, (3) Ruan, Intensive Care Medicine, 2020 (30) Gallagher, Am J Physiol Heart Circ Physiol, 2008, (4) Fox et al. Pulmonary and Cardiac Pathology in Covid-19: The First Autopsy Series from New Orleans. https://doi.org/10.1101/2020.04.06.20050575 , (31) Mendoza-Torres, Ther Adv Cardiovasc Dis, 2015

Screen Shot 2020-04-18 at 11.59.36 AM.pn
Haplotypes.PNG

Laboratory

WBC less than 10x10 9 - greater than 70%

  • leukopenia - 80%+

  • lymphocytopenia - 83.2% 

  • thrombocytopenia - 36.2% 

Ferritin

  • elevated predicts bad prognosis

Procalcitonin - below 0.25 nanograms/mL

  • tends to be low 

C-reactive protein (CRP)

  • most patients had elevated levels

  • > 100 is going to be a major red flag. (An admission CRP level above 100 mg/L was found to be associated with increased ICU and 30-day mortality by Luo et al, Prognostic value of C-reactive protein in patients with COVID-19)

D-Dimer

  • elevated predicts bad prognosis

Lactate Dehydrogenase

Creatine Kinase

IL-6 levels

  • 0-15 pg/mL (adult reference range)

 
 

Treatment

There are a number of standard hygiene practices that have been recommended to protect against infection and further spread of the virus. These include:

  • social distancing

    • ​6 feet apart 

  • covering mouth and nose during sneezing with medical mask or flexed elbow

  • prophylactically wearing mask in public

  • washing hands regularly with soap and water or alcohol-base hand rub

  • having the appropriate personal protection equipment (PPE) for healthcare workers

  • stay at home if sick but seek medical attention if symptoms worsen (eg. difficulty breathing, chest pain)

 

Sweden did NOT enforce this

Supportive

Right Ventricular Dysfunction

Right ventricular management plays a vital role in reducing the high mortality rate. Conventional hemodynamic measurements using volume responsiveness methods can not provide accurate guidance in the face of right ventricular dysfunction. These indirect methods are dependent on both normal heart-lung interaction and normal RV function. Such noninvasive monitors indicate the need for more fluid when in fact that may be the opposite if the right ventricle is overloaded (1).

Non-Invasive Mechanical Ventilation

  • high-flow nasal cannula

  • use CPAP for 1 hour and re-evaluate - if not effective, consider intubation (Martin notes)

Intubation

  • rapid sequence intubation

  • no bagging

  • avoid nebulizers

Invasive Mechanical Ventilation

High oxygen requirements were seen soon after initiation of mechanical ventilation. Plateau pressure 25 cm of water and driving pressure 12-13 cm of water. 

  • apparently early on, high PEEP is probably NOT the right strategy and may be harmful; this is not ARDS in the early phase of the illness (Martin notes)

  • avoid spontaneous ventilation early on because may be harmful (Martin notes)

  • ARDS 7P's:

    • protective lung ventilation

    • PEEP​

    • paralytics

    • proning 

    • prostacyclins (inhaled)

Extubation

  • the earliest occurred in 8 days which suggests that mechanical ventilation is prolonged (days to weeks) and the readiness for extubation is unlikely to occur early 

  • age range of extubated patients was 23-88 years which suggests that age may not be a sole indicator for successful extubation

  • wait longer than usual when extubating because of the high re-intubation rate; don't intubate if markers of inflammation are still high (Martin notes)

Re-intubation (Martin notes)

  • common

  • airway swelling, stridor 

    • important to do leak test because of the airway swelling​

splitting ventilators

Pulmonary microvascular thrombosis

  • anticoagulate? is this too risky?

  • LMWH being used because running out of pumps

Anticoagulation (Yajnik)

  • consider ASA 81 mg if there is significantly rising thrombocytosis

  • lovenox 40 mg daily, follow anti-Xa levels to ensure adequacy of ppx

  • systemic anticoagulation if D-dimer greater 1000 usually day 7-11

ECHOcardiography

  • increased right ventricular dysfunction without increased pulmonary pressures (Martin notes)

Bronchoscopy

Renal Failure / Fluid Balance

  • these patients are showing up severely dehydrated (eg. fevers, hyperventilation)

  • hypovolemia impedes gas exchange 

  • high rates of AKI / CVVHD from overzealous diuresis (Martin notes)

  • hypovolemia leads to poor pulmonary perfusion and increased dead space 

  • oliguria has improved by dropping the PEEP likely from the hypovolemia (Martin notes)

  • inferior vena cava ultrasonography might assist with this (Debesa)

  • CVVHD increases mortality 

    • circuits clot frequently ​- use aggressive systemic anticoagulation (Martin notes)

  • avoid HYPERvolemia

  • microthrombi in the kidney also probably contributing to AKI (Martin notes)

  • peritoneal dialysis being done because running out of CVVHD machines or use it like intermittent dialysis and sharing machines (Martin notes)

Acetazolamide (Diamox) 

  • for patients with L-phenotype (HAPE-like)

  • 250 mg q12h

  • reduces hypoxic pulmonary vasoconstriction

Ascorbic Acid (Vitamin C)

  • interferes with glucose oxidase assays in POCT and continuous glucose monitoring giving you a falsely elevated blood glucose 

  • also interferes with HbgA1c testing giving falsely elevated results 

Prone Position

  • essential and should be done early 

  • if P/F ratio remains < 150 on PEEP > 10 and FiO2 > 60%

  • proning patients on CPAP very effective (in most cases they can prone themselves)

  • many centres use a P/F ratio threshold of ???

  • early on in the disease, the benefits of proning lasts less than 4 hours when turned back to supine; as the disease progresses more into an ARDS picture, the effect is more long lasting 

Steroids

  • Asthmatic that had received systemic glucocorticoids within 1 week before ICU admission, as outpatients for presumed asthma exacerbation, had severe respiratory failure requiring mechanical ventilation. Previous studies of patients that received glucocorticoids for phylogenetically similar viruses (SARS-CoV 2003 and MERS-CoV) were associated with higher plasma viral load, longer duration of viremia and worse clinical outcomes (17-20). This is in contrast to recent studies that suggest glucocorticoids may be associated with improved outcomes in patients with COVID-19 and ARDS (21). 

inhaled Nitric Oxide

  • good results

  • tachyphylaxis after 4-5 days 

inhaled Prostacyclin

  • good results

  • seems to work early in the disease

Remdesivir

  • 200mg IV x 1, followed by 100mg q24h (max: 10 days)

  • insufficient information to report associated outcomes

  • prodrug metabolized by CYP3A4 (concomitant inhibitors of CYP3A4 should be avoided)

Hydroxychloroquine (Plaquenil)​

  • LD: 400mg PO bid x 1 day; MD: 200mg PO b id x 4 days

  • no adjustments with renal failure

  • zinc 50mg bid as a cofactor ???

  • G6PD, methemoglobinemia, especially with vitamin C and iNO 

  • obtain baseline ECG; avoid if QTC>500 msec

 

Chloroquine

Tocilizumab (Actemra)

  • 4mg/kg IV (upto 400mg); dose may be repeated once in 12-24 hours for suboptimal response)

  • IL-6 antagonist

  • don't give if IL-6 level is less than 6 picograms/mL

  • anecdotal accounts have good results with 2 doses (reduced second dose) 

  • cytokine release syndrome: 4-8mg/kg IV x 1; max: 400mg per dose (may repeat second dose)

  • check IL-6 level for response 

  • indications:

    • COVID-19 (+)​

    • moderate ARDS on mechanical ventilation

    • P/F < 200

Siltuximab

Lopinavir / Ritonavir

  • 400/100mg PO q12 x 14 days

  • no adjustments with renal failure

  • check HIV antibodies; if HIV+ would not use as monotherapy

  • consider adding Interferon-beta (0.25mg SC every other day for 14 days)

Sarilumab

Azithromycin

Herd Immunity

Convalescent plasma

  • antibody rich plasma from patients that have recovered from COVID-19

  • potential to lessen the severity or shorten the length of illness

  • Donate Covid-19 plasma website

  • every unit different because from different donors

Vaccine

  • in development 

ECMO

References: (1) Miller A, Mandeville J. Predicting and Measuring Fluid Responsiveness with Echocardiography. Echo Res Pract. 2016, https://doi.org/10.1530/erp-16-0008(17) Peiris et al, Lancet, 2003, (18) Lee et al, J Clin. Virol, 2004, (19) Arabi et al, Am J Respir Crit Care med, 2018 (20) Lansbury et al, Crit Care Med, 2019 (21) Wu et al, JAMA Intern Med, 2020

 

Logistics

  • "tactile commander" is essential to have on every shift who is not directly responsible

  • for patient care (Martin notes)

  • nursing ratio in most centres is 1:6 with high level of support workers (1 per patient) 

  • in the ICU (Martin notes)

  • training has fallen by the wayside - training on the job is occurring (Martin notes)

  • "flatten the curve" refers to hospitals exceeding their capacity

  • N95 re-sterilization process

  • having enough personal protection equipment (PPE)

  • iPhones inside the patients room that automatically answer in FaceTime mode 

  • makeshift ventilators with Ambu-bag

  • increase in unemployement rate for "nonessential" businesses 

... but I would more especially commend the clinician who, in acute diseases, by which the bulk of mankind are cutoff, conducts the treatment better than others.
 
Hippocrates, 400 BC