Betacoronavirus pandemicum

Background

Microbiology

• Coronavirus related to SARS-CoV
• Virion consists of:
  • Spike glycoprotein (S), which appears to be an important virulence factor
    • Vaccines may target either the full protein or only its distal receptor binding domain
  • Membrane protein (M)
  • Nucleocapsid protein (N)
  • Hemagglutinin esterase (He)
  • Envelope protein (E)

Epidemiology

• Transmitted mostly by respiratory droplets, with some amount transmission via aerosols and little to no transmission via contact
• First cases detected Dec 2019 related to likely exposure in wet market in Wuhan, Hubei, China, and declared a pandemic in 2020
• Secondary household attack rate of 12-17%
• Possibility of animal reservoirs, including cats (possibly), dogs (unlikely), deer (probably)
  • Difficult to prove transmission to humans
  • Unlikely to contribute to household transmission, since human-to-human transmission is far more likely

Risk Factors for Mortality

• Greater age
• Male sex
• COPD
• Dyslipidemia
• Diabetes

Clinical Manifestations

• Incubation period 4 to 5 days (range 2 to 11 days), possibly as long as 14 days in some cases
• Common presenting symptoms were fever and cough, followed by myalgia, fatigue, headache, dyspnea
• Other symptoms include dyspnea, rhinorrhea, vomiting, diarrhea, anosmia/hyposmia
• Lymphopenia is common, as is hypoalbuminemia, elevated D-dimer, CRP, LDH, AST/ALT
• Viral load detectable before symptom onset and peaks around the time of symptom onset

Pregnancy

• Please refer to a living systematic review on the topic
• Slightly less reported fever and myalgias
• Slightly more ICU admissions and mechanical ventilation
  • Risk factors included age, obesity, hypertension, and diabetes
• With regards to the fetus, there were more preterm deliveries (6%) and more needed NICU admission (25%)

Bacterial Coinfection

• True coinfection with bacterial pneumonia is rare, detected in about 5% of patients at presentation, and complicates about 8% of cases as a secondary infection1
  • See https://www.tarrn.org/covid for a living systematic review
• Most commonly Mycoplasma pneumonia, Pseudomonas aeruginosa, and Haemophilus influenzae
• Also possibly need to consider Aspergillus fumigatus and even Pneumocystis jirovecii

Complications

• In critically ill patients:
  • ARDS (75%)
  • AKI (40%)
  • Thrombosis (10%)

Investigations

• Chest x-ray typically showed diffuse, bilateral mixed interstitial and airspace disease
• CT chest imaging may show:2
  • Typical appearance:, classic for COVID-19
    • Peripheral, bilateral ground-glass opacity with out without consolidation or visible intralobular lines (crazy paving)
    • Multifocal rounded GGO with or without consolidation or crazy paving
    • Reverse halo sign or other findings of organizing pneumonia (later finding)
  • Indeterminate appearance:
    • Multifocal, diffuse, perihilar, or unilateral GGO with or without consolidation lacking a specific distribution and are non-rounded or non-peripheral
    • Few very small GGO with a non-rounded and non-peripheral distribution
  • Atypical appearance, which suggests unlikely to be COVID-19:
    • Isolated lobar or segmental consolidation without GGO
    • Discrete small nodules (centrilobular, tree-in-bud)
    • Lung cavitation
    • Smooth interlobular septal thickening with pleural effusion

Diagnosis

• Rapid antigen testing from NP swab
  • Sensitivity depends on circulating variant
• PCR from NP swab
  • Highest sensitivity within 5 days of symptom onset, with decreasing sensitivity as the disease enters the immune-mediated phase
  • May be positive long after no longer infectious
• Diagnostic accuracy of PCR by sample site (below) has a lot of heterogeneity among the studies

	Sensitivity	Specificity
Upper Respiratory Samples
Oral	56	99
Nasal	76	100
NP	97	100
Nasal	95	100
Saliva	85	100
Mid-turbinate	100	100
Upper Versus Lower Tract
Upper respiratory tract	57	100
Lower respiratory tract	81	100
Single Versus Repeat Testing
Single test	71	100
Repeat testing	100	100

• Serology (IgM and IgG)
  • Total antibodies have poor sensitivity (51%) in first week, and increases to about 90% by week 3

Management

• Management differs by severity of disease

Severity	Definition
Mild	Signs or symptoms of COVID-19 and SpO2 greater than 92% at rest without oxygen (or no increase from baseline requirements)
Moderate	As above, but with clinical or radiographic evidence of lower respiratory tract infection
Severe	Require new supplemental low-flow oxygen to maintain SpO2 greater than 92%, or more oxygen supplementation than baseline
Critical	Require new respiratory support including high-flow nasal oxygen, non-invasive mechanical ventilation, or invasive mechanical ventilation and/or vasopressor support

Mild and Moderate Disease (No Supplemental Oxygen)

• For patients not requiring supplemental oxygen, the focus is on supportive care
• Patients who are high risk for progression to severe disease may benefit from prophylaxis with either 3 days of remdesivir or 5 days of nirmatrelvir-ritonavir
• Risk factors include age, vaccination status, and the following:
  • Obesity, with BMI ≥30
  • Diabetes
  • Heart disease, hypertension, or heart failure
  • Chronic respiratory disease, including cystic fibrosis
  • Cerebral palsy
  • Intellectual disability
  • Sickle cell disease
  • Chronic kidney disease with eGFR ≤60 mL/min
  • Liver disease with Child-Pugh class B or C

Risk for progression to severe disease

Age (years)	Vaccinations
	0 doses	1 or 2 doses	3+ doses
<20	higher risk if ≥3 risk factors	standard risk	standard risk
20 to 39	higher risk if ≥3 risk factors	higher risk if ≥3 risk factors	standard risk
40 to 69	higher risk if ≥1 risk factors	higher risk if ≥3 risk factors	standard risk
≥70	higher risk	higher risk if ≥1 risk factors	higher risk if ≥3 risk factors
Immunocompromised (regardless of age)	higher risk
pregnancy (regardless of age)	higher risk	standard risk	standard risk

• Nirmatrelvir-ritonavir for 5 days may be considered for patients at high risk of progressing to severe disease who are within 5 days of symptom onset
  • Nirmatrelvir-ritonavir 300 mg / 100 mg (3 tablets total) twice daily for 5 days
  • Needs dose adjustment in renal dysfunction
  • Management of drug-drug interactions is available at University of Michigan or University of Liverpool
• Remdesivir 200 mg IV once followed by 100 mg IV daily for 2 more days may be used within 7 days of symptom onset who have at least one risk factor for disease progression (age ≥60 years, obesity, or other medical conditions)3
• Consider of monoclonal antibodies, depending on the dominant variant and available monoclonals
• Can consider fluvoxamine or inhaled budesonide
  • Evidence for significant benefit is weak
  • Fluvoxamine 100 mg p.o. twice daily for 15 days, started within 7 days of symptom onset
  • Budesonide 800 mcg inhaled twice daily for 14 days

Severe Disease (Low-Flow Supplemental Oxygen)

• For patients requiring new or increased supplemental oxygen
• Dexamethasone 6 mg PO/IV daily for 10 days, which has a mortality benefit
• Remdesivir 200 mg IV once on day one followed by 100 mg IV daily for 4 more days
• If progressing to critical disease despite dexamethasone, add tocilizumab
  • If tocilizumab is unavailable, then baricitinib 4 mg p.o. daily for 14 days or until hospital discharge
• Consider monoclonal antibodies, depending on the dominant variant and available monoclonals
• Consider therapeutic anticoagulation with LMWH for 14 days (stopped at discharge or on transfer to ICU)
  • May decrease progression to invasive mechanical ventilation

Critical Disease (High-Flow or Mechanical Ventilation)

• Patients requiring ventilatory support, including high-flow nasal oxygen, non-invasive ventilation, invasive mechanical ventilation, or ECMO
• Dexamethasone 6 mg p.o./IV daily for 10 days
• Tocilizumab or baricitinib for patients on dexamethasone
• Do not treat with therapeutic anticoagulation, remdesivir, monoclonal antibodies, or nirmatrelvir-ritonavir

Strongyloidiasis

• Patients should be screened per CATMAT guidelines and treated if appropriate
• For steroid exposure, 10 days of dexamethasone +/- tocilizumab is considered substantial risk
• See also Ivermectin treatment for Strongyloides infection in patients with COVID-19 from the CCDR

Anti-SARS-CoV-2 Monoclonal Antibodies

• Effectiveness varies by specific antibody and current strain/lineage

Immunocompromised Patients With Persistent Infection

• A few case studies
  • 10.1093/cid/ciac847: 60M CLL, got Paxlovid x5 days; recurred, got remdesivir x10 days; recurred, got betelovimab; was on concurrent high-dose steroids essentially throughout for organizing pneumonia; finally remdesivir and Paxlovid combination to 20 days, with negative NP swab and clinical resolution
  • 10.1093/ofid/ofac382: 44 yo with GPA and hypogammaglobulinemia with 5 months of symptomatic infection treated with IVIG, convalescent plasma, and finally remdesivir to negative NP swab PCR, which took 30 days
  • 10.1093/infdi/jiaa446: 50M with CLL post-treatment had relapse twice after 10-day courses of remdesivir, finally resolved after infusion of convalescent plasma
  • 10.1136/bcr-2021-244768: child with PID eventually resolved with multiple courses of IVIG
  • 10.1093/infdis/jiaa666: lymphoma with 3 admissions over 4 months, treated with two courses of remdesivir and convlescent plasma
  • 10.1016/j.ijid.2020.12.050: follicular lymphoma post treatment with 2 months of COVID, got remdesivir twice (second time 10 days) as part of trials, as well as IVIG

Prevention

Infection Prevention and Control

Healthcare Workers

• Awaiting results
  • If symptomatic, HCWs should be off work
  • If asymptomatic, HCWs may return to work while awaiting results, depending on the reason for testing and the staffing needs
• Positive but asymptomatic: in exceptional circumstances, may return to work early

Clearance

• Non-test based (preferred)
  • Asymptomatic: isolate for 10 days from swab
  • Mild to moderate symptoms in immunocompetent person: 10 days from onset of symptoms, as long as afebrile (without antipyretics) and clinically improving
  • Severe (i.e. ICU-level care) or immunocompromised: 20 days from onset of symptoms, as long as afebrile (without antipyretics) and clinically improving
    • Immunocompromise includes chemotherapy, untreated HIV with CD4 <200, primary immunodeficiency, prednisone 20 mg/day for 14 days, and other immunosuppressing medication
• Test based (alternative): 2 negative swabs at least 24 hours apart (if still positive, repeat in 3 to 4 days), as long as afebrile and clinically improving

Further Reading

Review Articles

• Pathophysiology, Transmission, Diagnosis, and Treatment of Coronavirus Disease 2019 (COVID-19): A Review. JAMA. doi: 10.1001/jama.2020.12839

Canadian Guidelines

• AMMI Canada Practice Point: Treatments for adults with COVID-19 in 2021–2022. JAMMI. 2022;7(3):163-169. doi: 10.3138/jammi-2022-08-08
• Ontario Health COVID-19 Clinical Guidelines
• BC COVID-19 Therapeutics Committee (CTC) and COVID-19 Therapeutics Review and Advisory Working Group (CTRAWG) Clinical Practice Guidance