Definition

  • COVID-19 is new pandemic disease caused by SARS-2 Coronavirus (SARS-CoV-2)

  • Avoid stigma-generating terms such as “Wuhan virus” or "Chinese flu"

  • There are 4 conventional coronaviridae that cause a mild "common cold". These may be reported as "Coronavirus" in a standard Respiratory Viral Panel. 

  • There are 3 coronaviridae that cause severe respiratory illness: MERS-CoV, SARS-CoV, and SARS-CoV-2 (nCOV-19)

  • The virus is mutating at a relatively slow rate, with 2 - 3 nucleotide changes per month. The majority of these are not in open reading frames. Coding mutations have not significantly altered structural epitopes. These traits are advantageous for a broadly effective vaccine. A current viral phylogeny is available here

Virology & Transmission

  • ​Virus transmitted via four established routes:

    • Droplets (main route)

    • Aerosol (airborne, controversial)

    • Contact (fomite-to-face)

    • Fecal oral (rare)

  • The spike (S) protein binds to ACE2 and CD147 (Basagin) in lower respiratory tract and potentially gut epithelium. Host proteolytic processing at the cell surface is necessary for viral entry. 

  • Incubation period 4 – 6 days after contracting virus

Clinical Pathophysiology

 

Prototypical Illness "Script"

  • Some demonstrate a GI prodrome (10%). Chest CT may already abnormal at this point. 

  • Constitutional symptoms (asthenia), then cough (75%) and fever

  • Dysgeusia (altered taste), hyposmia/anosmia (decreased or absent smelll) in 40% of cases

  • Fever 

  • Dyspnea (50%), hypoxemia out of proportion to dyspnea. Upper respiratory symptoms are usually not prominent. Progressing to ARDS requiring MV within ~5 days of symptoms. Deterioration can be very rapid. 

 

Three stages  of infection with distinct pathobiologic themes

Stage 1: Early Infection (Prodromal Phase) 

  • Biology: Virus enters alveolar pneumocytes and begins early replication. Innate and cytotoxic immune responses are triggered but fail to eradicate the virus.  

  • Clinical: Constitutional symptoms, fever (50% on presentation, 90% eventually), asthenia, GI prodrome (10%, diarrhea and nausea)

  • Treatment Implications: Systemic glucocorticoids may exacerbate viral shedding in the early phase. Antiviral therapy is likely to be most effective. 

Stage 2: Lung Injury Phase

  • Biology: Direct viral cytopathic effect on alveolar epithelium lead to a diffuse viral pneumonia and ARDS. 

  • Clinical: 

    • Initially, hypoxemia may occur without attendant dyspnea (2 - 6 L/min required)

    • Next, hypoxemia worsens (HFNC or > 50% FM required). Increased respiratory secretions contribute to dyspnea and resistive work of breathing. 

    • Next, overt acute hypoxemic respiratory failure often requiring mechanical ventilation. Lung mechanics are often preserved (normal or slightly decreased compliance) despite profound intrapulmonary shunting (hypoxemia out of proportion to lung stiffness). Thick bronchorrhea is common.

    • Prolonged MV is to be expected. Many patients require salvage strategies (prone, inhaled pulmonary vasodilators, APRV*, ECMO). 

  • Treatment Implications: Early lung protection and recruitment may prevent further biotrauma. Glucocorticoids may have some benefit (avoid steroids with mineralocorticoid activity to prevent sodium-fluid retention). 

* An open lung approach should be considered as the primary strategy for severely injured lungs

Stage 3: Immune Dyscrasia Phase

  • Biology: Widespread and disorganized activation of immune responses with HLH-like features 

  • Clinical: This is the decisive phase of illness. Patients will proceed along two main trajectories:

    • Persistent organ inflammation and onset of multi-organ failure. Elevated acute  phase proteins (Ferritin, CRP, IL-6)

    • Slow improvement and resolution of hyperinflammatory state 

  • Treatment Implications: Immunomodulation with IL6R blocking antibodies and JAK inhibitors are promising

Other Complications

  • Renal – AKI common, 5% require RRT

  • CV – Acute Cardiac Injury – after honeymoon period of recovery from ARDS, sudden cardioplegia refractory to catecholamines; ventricular arrythmias and asystole.

  • Heme – DIC/HLH (< 2%) portends mortality

  • Liver – mild hepatocellular injury (AST, ALT 200 - 500) is seen in many cases

Epidemiology

  • Continues to displaying exponential spread in US (3/30/2020)

  • USA is leading epicenter of disease. Major hotspots include: New York, NY; Atlanta, GA; Miami, FL; Detroit, MI; Chicago, IL; New Orleans, LA

  • A live map of current cases can be viewed here .  

  • R0 ~ 2.7

    • R0 is a combination of viral contagiousness, human behavior, and immunity. For example, aggressive social distancing can halt the spread of a virus with very high attack rate. Models suggest that > 80% distancing can reduce R0 to 1. 

  • Case fatality ~ 3.4% (1 in 30)

  • Incubation ~ 4 – 18d

  • Surface longevity ~ 3d

  • Asymptomatic shedders are likely a large vector for spread. Shedding occurs for > 20 days

  • National emergency. The public health goal is to decelerate spread to keep hospitals below surge capacity. With each passing day, the window for containment closes. 

Diagnosis & Workup

 

Molecular Diagnosis

  • Isolate patient (place droplet mask and ideally relocated to negative pressure room if available)

  • Notify CDC for all COVID-19 PUIs and confirmed cases

  • Send confirmatory rRT-PCR from nasopharyngeal (NP) swab

    • A negative NP PCR does not preclude later development of COVID-19 disease

    • If a COVID-19 PUI is intubated, endotracheal aspirates have a higher positive predictive value

Imaging

  • Diffuse patches of ground glass and consolidative infiltrates. CXR often subtle.

  • Volume of lung tissue involved predicts illness severity

 

Other Studies

  • Acute cardiac injury is increasingly recognized as an important sequela of COVID-19. Myocardial dysfunction may be due to stress-induced cardiomyopathy, direct viral myocarditis, or RAAS (angiotensin-2) toxicity. 

  • A point-of-care echocardiogram performs reasonably well as a screening test 

Labs

  • Characteristic peipheral blood findings include: lymphopenia (75%) with approximately normal total WBC, AKI common, hepatocellular injury, elevated acute phase proteins (CRP, IL-6, ferritin – all predict severity)

  • Normal PCT unless bacterial co-infection

  • Some patient present with rapid kaliuresis due to RAAS activation, watch K+.

Avoid anchoring/framing bias. Thorough infectious workup even with positive SARS-CoV-2 PCR.​

Treatment

 

​See a detailed description of our ICU protocols here. See a list of ongoing clinical trials here

General principles

  • If intubating, place lines at same time to avoid repeated procedures/exposure/imaging

  • Consolidate care whenever possible (e.g. continuous IV drip instead of multiple push boluses)

  • Keep patients dry, conservative with fluids

  • Most patients get empiric antibiotics

  • Ulcer, DVT, VAP prophylaxis

  • Goals of care is a safety issue for HCWs and the community at large

    • CPR off vent – take time to secure excellent PPE, intubate. If BVM, use inline viral filter. 

    • CPR on vent – don’t break circuit. Switch to PS and give 30:2 rescue vent breaths.

Respiratory Failure

  • NC up to 6L → NRB, consider ‘intermediate’ HFNC at < 30L → early intubation and MV with ARDS strategy. Avoid NIPPV except for select circumstances (CHF, AECOPD). Poor outcomes with NIPPV. Possible aerosolization (open circuit)

  • Intubation – RSI by most experienced intubator with VL to minimize aerosolization and contact. Apneic oxygenation with PEEP valve.

 

Disease Modifiers

  • Antivirals

    • Chloroquine (HCQ, Plaquenil) – regimen of 400 mg q12 x 2 then 400 mg qd x 5d. When starting HCQ on intubated patient, consider enrollement into RDV clinical trial. Watch QTc prolongation, cardiomyopathy.

    • Remdesivir (RDV) – early data is promising. If possible, strive to enroll in NCT04280705. No longer offered for compassionate use. 

  • Immune Modulation

    • Sytemic Glucocorticoids

      • Avoid in early COVID-19 infection (Stage 1). May be useful for hyperinflammatory COVID-ARDS (high CRP). 

      • May be used for exacerbation of COPD, asthma, or refractory septic shock.

      • Dexamethasone (12 - 16 mg/day) is preferred due to lack of mineralocorticoid activity (less sodium-fluid retention)

    •  Anti-IL6R mAB

      • Tocilizumab and Sarilumab in clinical trials, initial data and anecdotal reports are promising

    • Janus Kinase Inhibitors – Baricitinib, Ruxolitinib
       

  • In Pipeline

    • Hyperimmune sera (survivors’ IgG) showed promising results in one uncontrolled case series (here)

Modern History & Prognosis

  • ​15 - 20% require hospitalization. Of these, 50% require MV. Of these, 33% will not survive.

  • Predictors of poor outcome

    • Demographic: age > 65, cardiovascular disease (esp. ischemic heart disease), smoking/COPD, diabetes

    • Clinical: N/L ratio > 3.1, D-dimer > 1 mcg/L, cardiac dysfunction, rising tempo of CRP elevation

Immunity

  • Clinical Vaccine Trials 

    • NIH/Moderna Study: An mRNA vaccine (recombinant full-length S protein) is being tested in a Phase 1 trial (Emory Vaccine Center, Atlanta, GA; Kaiser Permanente, Seattle, WA) ​

    • CanSino Study: An adenoviral vector-based recombinant protein vaccine (Ad5-nCoV) is being tested in a Phase 1 trial  (Tainjin, China)

    • Jenner Institute Study: An adenoviral vector-based recombinant protein vaccine (ChAd-OX1 nCoV-19( is being tested in a Phase 1/2 trial (Oxford, UK)

  • Other strategies still in preclinical testing include: oral recombinant antigen vaccines, self-amplifying RNA, DNA-based, and virus-like particles (VLPs)

Information presented on this website does not reflect the views or positions of the US Veterans Health Administration, Emory Healthcare, or its affiliated institutions. This is a rapidly evolving field. As such. the content on this site is being updated daily and protocols will be updated in real time.  The purpose of this site is to provide a centralized resource for ICU topics and protocols to promote the well-being of hospitalized or critically ill patients suffering from COVID-19.  Defer to your institutional guidelines for all clinical practice decisions.

 

© 2020  Victor Tseng, MD