View source for Betacoronavirus pandemicum

{{DISPLAYTITLE:''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 [[Usual incubation period::4 to 5 days]] (range [[Incubation period range::2 to 11 days]]), possibly as long as 14 days in some cases
*Main 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 [https://doi.org/10.1136/bmj.m3320 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%)

===Severity===

*Mild: no oxygen
*Moderate: low-flow supplemental oxygen
*Severe: high-flow supplemental oxygen or non-invasive mechanical ventilation
*Critical: invasive mechanical ventilation

===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 infection[[CiteRef::lansbury2020co]]
**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 [[COVID-19-associated pulmonary aspergillosis|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:[[CiteRef::simpson2020ra]]
** 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

{| class="wikitable"
!
!Sensitivity
!Specificity
|-
! colspan="3" |Upper Respiratory Samples
|-
|Oral
|56
|99
|-
|Nasal
|76
|100
|-
|NP
|97
|100
|-
|Nasal
|95
|100
|-
|Saliva
|85
|100
|-
|Mid-turbinate
|100
|100
|-
! colspan="3" |Upper Versus Lower Tract
|-
|Upper respiratory tract
|57
|100
|-
|Lower respiratory tract
|81
|100
|-
! colspan="3" |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==

=== Mild 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 [[Paxlovid]]
*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 classification|Child-Pugh]] class B or C
{| class="wikitable"
|+Risk for progression to severe disease
! rowspan="2" |Age (years)
! colspan="3" |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)
| colspan="3" |higher risk
|-
|pregnancy (regardless of age)
|higher risk
|standard risk
|standard risk
|}

* [[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)[[CiteRef::gottlieb2021ea]]
*[[Paxlovid]] for 5 days may be considered for patients at high risk of progressing to severe disease, 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 [https://www.med.umich.edu/asp/pdf/outpatient_guidelines/Paxlovid-DDI.pdf University of Michigan] or [https://www.covid19-druginteractions.org/ University of Liverpool]
**[https://doi.org/10.47326/ocsat.2022.03.58.3.0 Ontario guidelines are available]
*Consider of monoclonal antibodies, depending on the variant
*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

=== Moderate Disease (Low-Flow Supplemental Oxygen) ===
*For patients requiring supplemental oxygen or with oxygen saturation less than 94%:
*[[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 PO daily for 5-10 days, which has not been shown to have a mortality benefit
*[[Tocilizumab]] indicated if progressing despite [[dexamethasone]], still requiring oxygen and CRP ≥75 mg/L, per RECOVERY trial
**ARR for 28-day mortality of about 4% in unvaccinated patients
**If tocilizumab is unavailable, then [[baricitinib]] 4 mg p.o. daily for 14 days or until hospital discharge
*Consider monoclonal antibodies, depending on the variant
*Consider therapeutic anticoagulation with [[LMWH]] for 14 days (stopped at discharge or on transfer to ICU)
**May decrease progression to invasive mechanical ventilation

=== Severe or 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
** Can consider 12 mg dosing in patients unable to receive IL-6 inhibitors
* [[Tocilizumab]] for patients on [[dexamethasone]]
* Do ''not'' treat with therapeutic anticoagulation, [[remdesivir]], monoclonal antibodies, or [[Paxlovid]]

=== 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 [https://www.canada.ca/en/public-health/services/reports-publications/canada-communicable-disease-report-ccdr/monthly-issue/2021-47/issue-7-8-july-august-2021/covid-19-treating-strongyloides-ivermectin-patients.html Ivermectin treatment for ''Strongyloides'' infection in patients with COVID-19] from the CCDR

=== Anti-SARS-CoV-2 Monoclonal Antibodies ===

* Effectiveness varies by strain/lineage
* Refer to https://www.covid19treatmentguidelines.nih.gov/tables/variants-and-susceptibility-to-mabs/ for up-to-date table of effectiveness

=== Immunocompromised Patients With Persistent Infection ===

* A few case studies
** [https://doi.org/10.1093/cid/ciac847 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
** [https://doi.org/10.1093/ofid/ofac382 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
** [https://doi.org/10.1093%2Finfdis%2Fjiaa446 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
** [https://doi.org/10.1136/bcr-2021-244768 10.1136/bcr-2021-244768]: child with [[Primary immunodeficiency|PID]] eventually resolved with multiple courses of [[IVIG]]
** [https://doi.org/10.1093/infdis/jiaa666 10.1093/infdis/jiaa666]: lymphoma with 3 admissions over 4 months, treated with two courses of [[remdesivir]] and convlescent plasma
** [https://doi.org/10.1016/j.ijid.2020.12.050 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: [https://doi.org/10.1001/jama.2020.12839 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: [https://doi.org/10.3138/jammi-2022-08-08 10.3138/jammi-2022-08-08]
*[https://doi.org/10.47326/ocsat.cpg.2022.11.0 Ontario Science Table Clinical Practice Guideline Summary: Recommended Drugs and Biologics in Adult Patients with COVID-19]
*[http://www.bccdc.ca/health-professionals/clinical-resources/covid-19-care/clinical-care/treatments BC COVID-19 Therapeutics Committee (CTC) and COVID-19 Therapeutics Review and Advisory Working Group (CTRAWG) Clinical Practice Guidance]

[[Category:Coronaviridae]]