COVID-19

Introduction

Introduction:

• information on this topic is continuously evolving, highlights below
• coronavirus first noted to have caused pneumonia in Wuhan City, China
• see SARS-CoV2 for information on COVID-19 variants

Etiology

• SARS-CoV2

Epidemiology

• see SARS Cov2 epidemiology

Pathology

• age & health of person & size of inoculum factors in severity of infection
  • susceptibility to SARS Cov2 associated with:
    • lower levels of interferon type 1 response in the nose
    • lower levels of HLA-DQA2 on antigen-presenting cells in both blood & nasal mucosa
• spike glycoprotein on SARS CoV-2 binds to human cell surface receptor ACE2 expressed on epithelial surfaces
  • nasal epithelium
    • ACE2 expression in nasal epithelium lowest in children < 10 years of age
  • salivary glands pharynx are major sources of coronavirus replication
  • lung alveolar epithelial cells (pneumocytes)
  • myofiber membrane of the diaphragm muscle
• the spike glycoprotein* requires a transmembrane serine protease TMPRSS2 expressed on type II pneumocytes as well as non-respiratory cells in order for the virus to enter a cell
• the TMPRSS2 cut exposes a run of hydrophobic amino acids that rapidly buries itself in the closest membrane, the host cell membrane
• the extended spike glycoprotien folds back onto itself, like a zipper, forcing the viral & cell membranes to fuse
• SARS-CoV2 then ejects its genome directly into the cell
• cathepsin-L provides an alternate route for the virus to enter a cell
• inside the cell, SARS-CoV2 is translated into non-structural proteins that suppress translation of host mRNA in favor of viral RNA
  • viral protein NSp1, one of the 1st translated viral proteins, recruits host ribonucleases to systematically cleave all cellular mRNAs without a viral tag
• SARS-Cov2 transforms the host cell endoplasmic reticulum into double membrane vesicles where viral replication occurs
  • T-cells block replication of SARS-CoV2 by disabling replication transcription complex, which facilitates viral replication
• double membrane vesicles fuse with Golgi &/or lysozymes & subsequently cell membrane
• host furin cleaves the spike glycoprotein at a site of 5 amino acids prior to cell membrane fusion & release from the cell facilitating the next entry of the virus into a new cell
• initial proline amino acid change (P681R) in the spike glycoprotein 5 amino acid sequence recognized by furin in the delta variant further enhances next cell infectivity
• as patients get sicker, SARS CoV-2 migrates from the nasopharynx to the oropharynx & into the lower respiratory tract
  • as it migrates down, it is unknown whether it leaves the nasopharynx
• coinfection with other respiratory pathogens common
  • 21% with rhinovirus/enterovirus &/or respiratory syncytial virus
• bacterial superinfection found in 21% of patients
  • use of dexamethasone & pulmonary infarction contribute
• endothelial injury, vascular thrombosis, microangiopathy, angiogenesis
  • endothelial dysfunction can lead to ischemic stroke & hemorrhagic stroke
  • activated neutrophils & platelets play roles in the immunologically mediated thrombosis associated with severe COVID-19
    • upregulation of neutrophil activation marker CD177 in severe COVID-19
    • intense formation of neutrophil extracellular traps, leading to occlusion of microvessels, especially in lung & in coronary arteries during STEMI
  • lupus anticoagulant associated with thrombosis (RR=4.4)
  • autopsies show little evidence of inflammation or direct viral cytopathology outside the respiratory tract
• SARS CoV2 directly infects atherosclerotic plaques in the coronary arteries, resulting in a persistent inflammatory response
• inflammatory cell infiltration of the nasal & olfactory mucosa
  • intracytoplasmic viral inclusion bodies in the olfactory bulb
  • olfactory bulb may show astrocytosis & microgliosis
• many patients have severe hypoxemia, but respiratory compliance - ability of the lung to expand with inhalation - frequently remains normal
• hypoxemia without dyspnea suggested due to ventilation-perfusion mismatch, a result of vascular pathology (pulmonary vessel dilatation & pulmonary capillary deformation)
• SARS CoV-2 found not only in upper & lower respiratory tract, but also in GI tract, heart, & on autopsy in liver, kidneys & brain
• SARS-CoV2 RNA found in human cornea
• COVID-19 may cause myocarditis & elevated serum troponin-I via SIRS
• SARS-CoV-2 commonly detected in brains of patients, but no evidence of damage caused directly by the virus but may result from thromboembolism
  • brain edema, astrocytosis & gliosis, micro infarcts not uncommon
  • microglial activation were most pronounced in the brainstem & meninges
  • megakaryocytes found in cortical capillaries of 5 people who died of COVID-19
  • no evidence of SARS-CoV-2 in the brain at the time of autopsy
  • altered gene expression in glial cells (innate immune cells of the brain) & cells of the choroid plexus involved in the blood-brain barrier
    • thus SARS-CoV2 may send signals through the blood-brain barrier to activate the brain's immune system
    • gene expression patterns similar to patterns in patients with dementias &/or schizophrenia
    • synaptic signaling impaired in excitatory neurons involved in cognition
  • complement-mediated antibody-activated cytotoxicity directed against endothelial cells initiates vascular leakage, platelet aggregation, neuroinflammation & neuronal injury
• the pattern of gene expression in the frontal cortex of younger patients with severe Covid-19 resembles gene expression in uninfected elderly
  • the genes expressed reflect a cellular response to DNA damage, inflammation, mitochondrial dysfunction, oxidative stress, & altered insulin signaling
• diffuse alveolar damage & SARS-CoV-2 persistence in the respiratory tract identified as the predominant histopathologic findings & leading cause of death
  • respiratory failure or heart failure most common cause of death
• in the innate immune repsonse of respiratory epithelial cells, ssRNA of SARS-CoV-2 is recognized by TLR7 within endosomes, leading to induction of cytokines & IFN
  • plasma levels of proinflammatory cytokines TNF, IL-6, & IL-8 less than with septic shock or ARDS in ICU patients with COVID-19
  • in most infections, the immate immune response is sufficient to clear the virus & prevent severe disease
  • if the innate immune response does not clear the virus, an overactive immune response may ensue & result in collateral inflammatory damage
• immune response may be less in asymptomtatic vs symtomatic patients
  • patients with more-severe COVID-19
    • mount stronger Ab responses to SARS-CoV2
    • mount weaker Ab responses to other common respiratory viruses (including common coronaviruses)
    • more likely to harbor cytomegalovirus & herpes simplex virus 1
• immunologic memory protects against severe disease & death
• memory T cells & memory B cells persist for at least 6-8 months after Covid-19 infection & continue to evolve & mature; this is not assessed by an antibody test
• spike protein-specific memory B cells higher at 4-6 months in most recovered patients, & continue to strengthen & mature for at least 12 months
  • quiescent spike protein-specific bone marrow plasma cells recovered 8 months after COVID-19 infection suggesting long-lived immunity
  • T-cell activity & immunity against SARS-CoV2 found in children with primary immune deficiencies after vaccination
• immunity after COVID-19 infection for at least 1 year strengthened by vaccination providing resistance to variants of concern including B.1.617.2 (delta)
• mutations in IFN-alpha pathway genes more common in patients with severe COVID-19
• auto-antibodies to IFN-alpha in 10% of patients with severe COVID-19
  • auto-antibodies to IFN type 1 account for both critical cases of COVID-19 in elderly > 80 years & total COVID-19 mortality
  • auto-antibodies to IFN type 1 are present in 0.18% of persons 18-69 years, 1.1% of persons 70-80 years & 3.4% of persons > 80 years
• women mount a stronger immune response to SARS-CoV-2 than men
  • women produce more T-cells than men in response to the virus
  • women produce less Ab response to SARS-CoV2 than men
  • older age associated with lower T-cell response in men but not women
• transplacental transfer of maternal antibodies to SARS-CoV-2 is inefficient
• minor lung inflammation may occur in many asymptomatic patients
• butyric acid-producing bacteria are decreased & lipopolysaccharide-producing bacteria are increased in Covid-19 patients
  • during recovery, 47 lipids, including sphingomyelin & monoglyceride are depleted, 122 lipids, including phosphatidylcholine, phosphatidylethanolamine & diglyceride are enriched in oral cavity
• gut microbiota composition reflects disease severity & dysfunctional immune response
  • Faecalibacterium prausnitzii & Eubacterium rectale diminished in COVID-19
• SARS-CoV-2 infects human adipose tissue & elicits an inflammatory response
• inhibition or knockout of GRP78 suppresses SARS-Cov2 replication & infectivity

* 3D structure of spike glycoprotein

Genetics

viral genetic factors

• see SARS-CoV2

human genetic factors

• apo e4 allele confers risk for COVID-19 (RR=2.3-2.4)
• 3p21.31 gene cluster is a genetic susceptibility locus for Covid-19 respiratory failure
  • locus 3p21.31 region contains LZTFL1 gene that may regulate epithelial-mesenchymal transition in pulmonary epithelial cells in COVID-19
  • linked to the ABO blood group system
  • the receptor binding domain (RBD) of SARS-CoV2 bears sequence & overall ABO blood binding similarity with human galectins
  • SARS-CoV2 preferentially infects blood group A cells, linking expression of blood group A expression with increased risk of infection
  • persons with blood type A or blood type B may be more susceptible to COVID-19 than persons with blood type O
  • compared with type O blood, type A is not associated with increased SARS-CoV2 infection, hospitalization, or ICU admission
  • types B & AB are not associated with worse outcomes than type O
  • the SARS-CoV2 receptor binding domain preferentially recognizes blood group A antigen expressed on respiratory epithelial cells
  • persons with blood type O or Rh-negative blood may be slightly less susceotible to COViD-19
• ability to taste bitterness via T2R38 associated with enhanced innate immunity to SARS-Cov2
• putative loss-of-function variants of X-chromosomal TLR7 associated with impaired IFN response identified in young men with severe COVID-19
• mutations in IFN-alpha genes in 3,5% of patients with severe COVID-19
• mutations in IFN-alpha pathway genes more common in patients with severe COVID-19
• Can SARS CoV2 RNA genes insert into human DNA? (see SARS-CoV2)

Clinical manifestations

• median incubation period is 4-5 days; range: 2-12 days, 2-7 days
• symptom rebound occurs in 26% of patients a median of 11 days after symptom onset
  • rebound lasts 1 day in 89%, 5% are hospitalized
  • virologic rebound
    • occurs in ~20% of patients who receive Paxlovid vs < 2% in those who do not
    • occurs in 27% of paxlovid treated vs. 7% of untreated patients
  • no relationship between previous treatment with antiviral & Covid-19 rebound
• most people with the Omicron variant (56%) are unaware that they have it
• most common symptoms
  • sore throat is becoming a dominant symptom in the Omicron period
  • anosmia & dysgeusia may be early signs of COVID-19
    • anosmia may occur in > 60%; generally resolves within weeks [91
  • fever* (40%-90%), chills
    • median duration of fever in all patients with fever is 10 days (95% CI* 8-11 days) after onset of symptoms
    • ICU patients with significantly longer duration of fever (31 days vs 9 days) after onset of symptoms
  • cough*, dyspnea*, sputum production (30%)
  • myalgia, fatigue, anorexia
  • sore throat 58%, headache* 49%, cough without phlegm 40%, nasal congestion 40% rhinitis 40%, cough with phlegm 37%, hoarse voice 35%, sneezing 32% are the most common symptoms reported during Omicron predominance in 2022 & 2023
• can present as common cold
  • runny nose, sore throat
• night sweats associated with Omicron infection, especially BA.5
• in children, anosmia/ageusia, nausea/vomiting, headache & fever most common
  • ~2/3 of children who test positive report symptoms
• children < 5 years infected with Omicron variant may present with symptoms of croup with barking cough
• pulmonary symptoms may include chest pain or pressure
  • bronchospasm is uncommon & generally due to pre-existing pathology
  • dyspnea is most common end-of-life symptom
• GI symptoms in 12%
  • anorexia, diarrhea (7%), nausea/vomiting (5%) & abdominal pain (4%)
  • fever common with GI symptoms, cough less common
• neurological symptoms in older sicker patients
  • headache (tension headache vs migraine) predicts clinical course
    • headache associated with shorter symptomatic period
  • acute cerebrovascular disease, impaired consciousness, encephalophy
  • COVID-19 may present as breakthrough seizure(s) in patients with epilepsy
  • new onset confusion, altered mental status [CDPH]
  • brain fog, new-onset anxiety, depression, psychosis
• confusion/delirium may be presenting symptom in elderly patients
• cyanosis of lips &/or face [CDPH]
• chilblain-like lesions on toes (COVID toes) seen largely in younger patients including children with benign clinical course)
  • heterogeneity of skin lesions may or may not be due to SARS CoV2
• ocular manifestations (epiphora, conjunctival congestion, chemosis) occur in < 1/3 of patients. most commonly in patients with more severe disease
• elderly may present with atypical signs/symptoms
• hyperglycemia on hospital admission predicts severity & mortality (RR=2)
• symptom recurrence common after 2 consecutive symptom-free days

* CI: confidence interval

* fever, cough & dyspnea 3 most common signs/symptoms

* headache among inpatients may be a marker of enhanced survival

Laboratory

• see SARS Cov2 laboratory

Diagnostic procedures

• bedside lung ultrasound
  • right ventricular hypertrophy may result from pulmonary artery hypertension due to pulmonary artery thrombosis
  • may be useful in determining which patients need hospitalization
• echocardiogram
  • right ventricular dilation & left ventricular diastolic dysfunction are the most common fundings
• electrocardiogram
• bronchoalveolar lavage might minimize empirical broad-spectrum antibiotics
• dogs can sniff out Covid-19 (see screening for Covid-19)
• olfactory testing (see screening for Covid-19)

Radiology

• indications:
  • imaging (chest X-ray vs CT of lungs) recommended for patients with moderate-severe symptoms & for patients whose symptoms progress.
  • imaging findings can be used for triage when testing is unavailable or unreliable, or when results may be delayed by several hours or days
  • imaging is not recommended for patients with mild symptoms, unless high likelihood of disease & risk factors for disease progression
• bilateral pulmonary infiltrates on chest X-ray
• CT of lungs:
  • ground-glass opacification
  • mixed ground-glass opacification & consolidation
  • extensive multifocal involvement
  • abnormalities bilateral in 86% of cases
  • lesions particularly evident in lower lobes, posterior lung fields, & peripheral lung zones
  • consolidation generally occurs later than ground glass opacities
  • pleural effusion uncommon (8%)
  • useless for COVID-19 diagnosis
  • CT imaging findings may persist at 3 months & 1 year after Covid-19
    • ground-glass opacities & curvilinear bands most common
    • no correlation of long Covid-19 symptoms & persistent imaging findings
• brain MRI:
  • encephalopathy, corticospinal tract signs, & frontotemporal hypoperfusion commonly observed in the absence of detectable virus in CSF
• high-resolutution MRI shows microvascular brain injury in deceased COVID-19 patients with thinning & leaky brain blood vessels without signs of SARS-CoV2 brain tissue infection
• echocardiography abnomralities in 1/2 of Covid-19 patients

Complications

• acute respiratory distress syndrome (ARDS) (30% of symptomatic cases)
  • extreme air hunger may ocuur in mechanically ventilated patients
  • 20% of patients show evidence of early bacterial pneumonia
    • < 50% of patients develop ventilator-associated pneumonia
    • ventilator-associated pneumonia in patients with Covid-19 higher than other causes of ARDS
      • frequently associated with treatment failure, recurrences, abscesses, empyema
  • pulmonary fibrosis
• cardiomyopathy
  • acute cardiac injury (12% of symptomatic cases)
  • ST segment elevation myocardial infarction (STEMI)
  • ICU admission associated with increased risk of cardiac arrest (RR=4.7)
  • 60% with cardiac inflammation by MRI 7 days after positive test
  • few cases of inflammatory heart disease after COVID-19 detected in professional athletes, thus safe to return to play
  • post COVID-19 heart failure predicted by editorialist
• QTc prolongation in hospitalized patients
• large vessel stroke reported in patients < 50 years
• higher incidence of autoimmune inflammatory rheumatic diseases among patients with a history of COVID-19
• secondary infection (10% of symptomatic cases)
  • mortality of hospitalized patients with comorbid COVID-19 & fungal infection is 48% vs 12% for Covid-19 alone
  • aspergillosis, invasive candidiasis, mucormycosis, other mycoses linked to most fungal infection-associated deaths
  • ~15% of patients with COVID-19 hospitalized in an ICU develop Aspergillosis
• hospitalized patients with increased risk for myocardial infarction (RR=10), stroke (RR=18), atrial fibrillation (RR=15), heart failure (RR=22), pericarditis (RR=14) within 5 months
  • risks highest in 1st 30 days
• risks for death & adverse medical &/or mental health sequelae after hospitalization for COVID-19 are <= risks after hospitalizations for influenza or sepsis
  • exception: Covid-19 confers excess risk for venous thromboembolic disease

COVID-19 deaths

• 3rd leading cause of death in the U.S. in 2020 & 2021 (CDC)
  • deaths attributed to COVID-19 accounted for 72.4% of US excess deaths
• 30 day mortality for hospitalized veterans with COVID-19 vs influenza: RR=6.6
• COVID-19 death estimates variable (15%); 2.2%
  • may be < 1% of symptomatic cases
  • overall COVID-19 infection fatality rate 0.5-1%
  • COVID-19 fatality is 0.26% among noninstitutionalized persons >= 12 years
  • COVID-19 fatality is 5 times that of seasonal influenza
  • COVID-19 fatality is age & race-dependent
    • COVID-19 fatality is 1.71% among those >= 60 years
      • vs fatality of 0.8% among those >= 65 years for seasonal influenza
    • COVID-19 fatality is 0.59% among non-whites
  • Up to 90% mortality in intubated patients in New York City
  • 1/3 of hospitalized COVID-19 patients may die (early estimate)
  • 30 mortality after hospitalization for Covid-19 Oct 1, 2022 to Jan 31, 2023, 6.0% vs 3.8% for influenza
  • median time from disease onset to death is 16 days
  • deceased patients, compared with patients who recovered, were older (age, 68 vs 51), more likely to be male (73% vs 55%), & more likely to have chronic hypertension & cardiovascular disease (48% vs 14%)
  • frailty is a risk factor for Covid-19 mortality (RR=1.9)
  • dementia is a risk factor for Covid-19 mortality
  • deceased patients were more likely to have leukocytosis (50% vs 4%) & lymphopenia (91% vs 47%)
  • LFTs, serum creatinine, serum lactate dehydrogenase, serum troponin-I, serum N-terminal pro-BNP. plasma d-dimer, & systemic inflammatory marker levels were much higher in deceased patients than in those who recovered
  • ARDS (100%), sepsis (100%), acute cardiac injury (77%), heart failure (49%), acute kidney injury (25%), & encephalopathy (20%) were much more common in deceased patients
  • high vs low physical activity reduces risk of death 42%
  • even moderate exercise (> 150 minutes/week) reduces risk of death 21%
• increased risk of death within 5 months
  • RR=10 non-hospitalized, RR-118 hospitalized
• US reported 370,298 deaths due to Covid-19 (112/100,000) during the Delta & Omicron waves (61/100,000 Delta wave) & (51/100,000 Omicron wave) exceeding death rates in 20 peer countries
  • the 10 states with most-vaccinated persons had excess all-cause mortality <= to Denmark, Germany, the Netherlands, Austria, Italy, & Finland
• 6% of adults >=50 years progress to severe, critical or fatal disease
  • risk varies minimally with age & gender, but increases with comorbidities, & decreases with vaccination, more so with Covid-19 vaccine booster

* Online tool estimates COVID-19 mortality risk

Major adverse cardiac events including Cardiopulmonary arrest

• acute & chronic risk of major adverse cardiovascular events
  • few COVID-19 survivors of in-hospital cardiac arrest
    • none in one study, 7% with normal to mildly impaired neurologic function in larger study
    • non-shockable rhythms common, usually pulseless electrical activity
  • return of spontaneous circulation in out-pf-hospital cardiac arrest lower during the COVID-19 pandemic
• risk of myocardial infarction & stroke elevated post-hospitalization for 3 years (RR=3.8) particularly in non-O blood types

Coagulopathy & hyperviscosity

• Coagulopathy with arterial thromboemolism & venous thromboembolism
  • coagulopathy & antiphospholipid Ab in older man in China with a history of hypertension, diabetes, & stroke
  • 29.4% of ICU patients with thrombosis
    • 13.6% venous thrombosis, 18.6% arterial thrombosis
  • 11.5% of non ICU hospitalized patient with thrombosis
    • 3.6% venous thrombosis, 8.4% arterial thrombosis
  • venous thromboembolism: 4.8% overall, 7.6% in critically ill patients & 3.1% in non-critically ill patients
  • arterial thromboembolism: 2.8% overall, 5.6% in critically ill patients 7 1.2% non-critically ill patients
  • Thrombosis predicted by elevated D-dimer level at admission (>2500 ng/mL)
  • major bleeding: 2.3% overall, 5.6% in critically ill patients
  • deep vein thrombosis discovered in 58% of COVID-19 autopsies & in 79% of ICU patients
  • disseminated intravascular coagulation on day 4 with worseninng days 10-14
  • obstruction of pulmonary arteries by thrombosis (macroscopic & microscopic) in > 90% of patients (on autopsy) despite anticoagulation frequently associated with pulmonary infarction & bronchopneumonia
  • venous thromboembolism risk not increased in outpatients with COVID-19
  • venous thromboembolism risk is increased in ambulatory patients with COVID-19
    • 60 vs 2.4 per 1000 person-years with 30 days (RR=21)
    • risk attenuated in fully vaccinated with breakthrough infection (RR=6)
    • older age, male sex, & obesity associated with higher risk
  • risk of cerebral venous thrombosis 100 fold greater than normal, several fold higher than post Covid-19 vaccination or following influenza
  • excess risk for venous thromboembolism persists for months after Covid-19
    • risk greater for hospitalized patients
• high arterial blood viscosity is associated with ~60% increased risk for mortality among patients hospitalized with COVID-19
  • link between hyperviscosity & immune-mediated thrombosis of COVID-19
• increased risks for venous thromboembolism within 5 months
  • RR=2 for non-hospitalized, RR=28 for hospitalized
• venous thromboembolism recurrence rate (5/100 patient-years) after discontinuation of anticoagulation (no deaths observed)

Neuropsychiatric complications

• neurologic complications common
  • 42% at onset, 63% at hospital admission, 82% at any time of illness
  • most common manifestations: myalgias, headaches, encephalopathy, dizziness, dysgeusia, anosmia
  • seizures, ischemic stroke & encephalopathy in severely ill patients
• toxic metabolic encephalopathy is common & often lethal in hospitalized patients with COVID-19
• neurological manifestations found in ~80% of hospitalized COVID-19 patients
  • most common self-reported symptoms: headache (37%), anosmia or ageusia (26%)
  • most common neurological signs &/or syndromes: acute encephalopathy (49%), coma (17%). & stroke (6%)
• long-term neuropsychiatric complications common after hospitalization
  • 39% of hospitalized patients, 50% after ICU admission
  • cognitive deficits, hyposmia, & postural tremor most common
  • intracranial hemorrhage; ischemic stroke; parkinsonism; Guillain-Barre syndrome; nerve, nerve root & plexus disorders; myoneural junction & muscle disease; encephalitis; dementia; psychotic, mood, & anxiety disorders; insomnia.
• altered mental status
  • stroke in 2% of patients admitted to ICU
    • hemorrhagic stroke was linked to higher mortality
    • ischemic stroke was not
      • ischemic stroke often severe with poor outcome
  • disorders of consciousness (20% of elderly with severe disease)
  • encephalopathy or encephalitis often in younger patients
  • cognitive dysfunction in sustained attention domain
    • delirium median duration 3 days
      • frailty is a risk factor for delirium
    • use of benzodiazepines during mechanical ventilation independently associated with increased risk for delirium
    • friend or family visitation (in person or virtual) reduces risk of delirium
  • 82% of ICU patients comatose for median of 10 days
• Guillain-Barre syndrome (1 case); no association
  • 1 in 5 cases of Guillain-Barre syndrome with prior Covid-19
• acute myopathic quadriplegia in ICU patients
• acute necrotizing hemorrhagic encephalopathy (case report)
• stroke in 2% of patients admitted to ICU
  • hemorrhagic stroke was linked to higher mortality
  • ischemic stroke was not
  • stroke risk highest in first 3 days after infection
• demyelination may occur
• peripheral nerve injury associated with severe Covid-19

Other complications

• acute kidney injury in 34-50% of hospitalized patients, dialysis in 14%
  • risk factors include mechanical ventilation, vasopressors, diuretics, elevations in inflammatory markers
  • parenchymal infection of tubular epithelial cells & podocytes with acute tubular injury & RBC aggregation occurs in lethal COVID-19
• gastrointestinal complications
  • mesenteric ischemia, ileus
• pediatric multisystem inflammatory syndrome
  • inflammation may involve the skin, eyes, blood vessels & heart.
  • thought to be a post-infectious immune response
  • 80% of children admitted to ICU with underlying condition, most commonly immunodeficiency or cancer
  • bears some resemblance to Kawasaki disease
• Strongyloides hyperinfection syndrome in patients receiving dexamethasone with unrecognized underlying chronic infection with Strongyloides
• 3 cases of myasthenia gravis following SARS-CoV-2 infection in elderly
• thyroiditis
• postinfectious, immune-mediated myopathy
  • inflammation of skeletal muscles associated with duration of illness
    • more pronounced than cardiac inflammation
    • rhabdomyolysis
• Covid-19 is associated with an increased risk for a composite outcome of maternal mortality or serious morbidity from obstetric complications
• burnout among healthcare workers
• risk for postoperative complications remains elevated for 8 weeks after Covid-19
• increased risk for diabetes mellitus within 90 days of Covid-19 (RR=2.35)
  • Covid-19 vaccine reduces risk
• progression to diabetes mellitus type 1 accelerated after Covid-19
• increased risk of diabetes mellitus type 2

Risk factors for poor outcomes

• Risk factors for symptomatic & severe disease (SARS) & death
  • older age (> 65 years)*
  • male
  • COPD* & moderate-to-severe asthma
  • obstructive sleep apnea
  • cardiovascular disease
    • heart failure 12%; coronary artery disease
  • immunodeficiency from solid organ transplantation
  • hematopoietic stem cell transplantation (HSCT)
  • cancer immunotherapy (~3-fold risk)
  • HIV1 infection
  • systemic glucocorticoids not autoimmune disease a risk factor for poor outcomes
  • obesity*, (30%) & overweight, BMI > 23 mg/kg2
    • weight loss through bariatic surgery associated with improved outcomes in Covid-19
  • diabetes mellitus type 2, 20%
    • ~10% of COVID-19 patients with type 2 diabetes die within 7 days of hospital admission
    • sitagliptin treatment at the time of hospitalization is associated with reduced mortality in patients with diabetes mellitus type-2 & COVID-19
  • diabetes mellitus type 1
  • chronic kidney disease
    • end-stage renal disease: excess death for renal dialysis 2-3 fold higher than for renal transplantation
  • sickle cell disease
  • proton pump inhibitors (RR=2-4 for infection)
  • other comorbidities;
    • hypertension* most common comorbidity at Northern California Kaiser Permanente ; 26%
    • cerebrovascular disease, stroke
    • asthma does not seem to predict severe disease
      • CDC says people with moderate to severe asthma may be at higher risk of getting very sick from COVID-19
      • eosinophilia in asthma is protective against severe COVID-19
    • smoking*; vaping; hospitalization 80% more likely for smokers
    • cystic fibrosis
    • other immunodeficiency (immunosuppressive agents, leukemia etc)
      • HIV1 infection does not appear to influence risk of COVID-19 or outcomes in thosed infected with HIV1 (see HIV1/COVID-19 coinfection)
    • dementia & other neurologic conditions
      • presentation with altered mental status
      • neurological disability in multiple sclerosis
      • nursing home residents with moderate-severe cognitive impairment
      • Alzheimer's disease (RR=2)
      • intellectual disabilities
    • liver disease
    • pregnancy
      • pregnant women with COVID-19 face higher rates of adverse outcomes, including maternal mortality, preeclampsia, & preterm birth
      • in women hospitalized for delivery, COVID-19 increased risk for preterm labor, preeclampsia, venous thromboembolism & mortality
      • obesity, pregestational diabetes & hypertension increase risk of severe COVID-19
      • maternal SARS-CoV2 infection in pregnancy may be associated with small increases in some neonatal morbidities
    • diabetes mellitus type 1
    • thalassemia
  • psychiatric diagnosis for patients hospitalized with COVID-19 is linked to increase mortality
  • substance abuse
  • elective surgery during the incubation period of COVID-19 largely due to pulmonary complications
• independent risk factors of severe disease
  • abnormal chest imaging
  • hemoptysis
  • dyspnea
  • unconsciousness
  • number of comorbidities
  • cancer history
    • leukemia, non-Hodgkin lymphoma, & lung cancer greatest risk
    • CD20-targeting agents such as rituximab (Rituxan) & obinutuzumab (Gazyva) associated with severe COVID-19 in lymphoma patients
    • active cancer chemotherapy may not be a risk factor for severe COVID-19
    • androgen-deprivation therapy does not reduce severity of Covid-19
  • neutrophil/lymphocyte ratio
  • serum lactate dehydrogenase
  • bilirubin conjugated in serum
• inflammation through serum IL-6 & thromboses through plasma D-dimer predict death in ICU patients
• vitamin D deficiency associated with increased Covid-19 severity & mortality
• may reduce Covid-19 ICU admission/mortality (RR=0.32-0.41) when administered after diagnosis (dose, duration, & mode of administration unknown)
• vitamin D supplementation may reduce risk of Covid-19 infection (RR=0.40-0.59)
• risk stratification score for predicting in hospital mortality
  • uses age, sex, comorbidities, respiratory rate, SaO2, Glasgow Coma Scale, serum urea, & serum C-reactive protein
• COVID-19 fatality ratio is 1.15% of all infected people in high-income nations & 0.23% in low-income nations
• risk factors in children & adolescents
  • diabetes mellitus type 1, congenital heart disease, obesity

Risk factors in Nursing Home Residents

• risk of hospitalization
  • increased BMI, male sex, Black, Hispanic, Asian
  • impaired functional status
  • increased comorbidities: kidney disease, diabetes mellitus
• risk of mortality
  • increased age. cognitive impairment, dementia, functional impairment

Not risk factors?

* Obesity, black race, bispanic ethnicity, COPD, hypertension, & smoking not associated with mortality in a Veterans Admniminstration study

Persistent symptoms & late complications - long COVID-19

• Persistent symptoms after COVID-19 common (see long Covid-19)
  • 90% of discharged COVID-19 patients report persistent symptoms 2 months later: Fatigue, dyspnea, arthralgia, & chest pain most common
  • 75% have >= 1 persistent symptom 6 months after hospitalization
    • fatigue or muscle weakness (63%)
    • sleep disorder (26%)
    • anxiety or depression (23%)
• during a mean 140 days after hospitalization for Covid-19
  • 29% of patients were readmitted & 12% died

Epidemiology

• patients age 60-69 years most common age group hospitalized (25%) & admitted to ICU (27%) at Northern California Kaiser Permanente; proportion of younger adults hospitalized similar to proportion of older adults hospitalized

Survival among the very old

* Even very old people (supercentenarians) can survive COVID-19

reducing risk of complications

• high vs low physical activity reduces risk of complications
  • 34% lower risk for hospitalization
  • 41% lower risk for ICU admission
  • 45% lower risk for requiring mechanical ventilation
  • 42% lower risk for death
• even moderate exercise (> 150 minutes per week) reduces risk of complications
  • 13% lower risk for hospitalization
  • 20% lower risk for ICU admission
  • 27% lower risk for requiring mechanical ventilation
  • 21% lower risk for death
• physical activity before COVID-19 infection is associated with less severe outcomes
• higher cardiorespiratory fitness favorably impacts survival, hospitalization, & need for endotracheal intubation regardless of age, body mass index, or comorbidities

• disease interaction(s) of prostate cancer with Covid-19
• disease interaction(s) of Covid-19 with STEMI
• disease interaction(s) of multiple sclerosis with COVID-19
• disease interaction(s) of HIV1 with COVID-19
• disease interaction(s) of Covid-19 with Alzheimer's disease

Differential diagnosis

• see common cold vs influenza vs Covid-19

Management

• see COVID-19 management
• prevention:
  • see COVID-19 vaccine
  • prevention after high-risk exposure: see casirivimab
  • prevention with Paxlovid
    • only thromboembolic events seem to be reduced by Paxlovid
    • Paxlovid reduces incidence of long Covid-19 (absolute risk reduction = 4.5%)
    • molnupiravir treatment for COVID-19 slightly lowers risk of long Covid-19
  • prevention with diet
    • high adherence to Mediterranean diet is a protective factor against COVID-19,
      • unclear benefits against COVID-19 symptoms & severity

Comparative biology

• experiments in mice:
  • candidate vaccine delivered via microneedle arrays elicited an immune response to SARS-CoV-2 in mice
• nasal spray that blocks absorption of SARS CoV2 completely protects ferrets from COVID-19 in a small study
  • the nasal spray attaches to cells in the nose & lungs & lasts about 24 hours
  • the spray contains a lipopeptide that exactly matches a stretch of amino acids in the spike protein of the virus, which SARS CoV2 uses to attach to human airways
  • before SARS CoV2 can inject its RNA into a cell, the spike protein must effectively unzip, exposing two peptides (amino acid chains), in order to fuse to the cell wall.
  • before the spike protein is able to zip back up to complete the process, the lipopeptide in the spray inserts itself, latching on to one of the spike protein peptide chains preventing zipping the zipper & attachment of SARS CoV2
• minks can transmit SARS-CoV-2 to humans
• gorillas at the San Diego Zoo Safari Park have tested positive for SARS-CoV2
  • asymptomatic staff member may have transmitted the virus to the gorillas
• SARS-CoV2 induces brain inflammation in Rhesus macaques & African green monkeys

Notes

• allocation of resources may be affected by the COVID-19 pandemic
• discussed in updated references
  • CDC discusses COVID-19 & long-term care facilities
  • CDC discusses therapeutic options & potential therapies
• asymptomatic critical infrastructure workers who have been exposed to SARS-CoV-2 may continue to work provided they remain asymptomatic & wear a face mask for 14 days since the last exposure (CDC)
• virus surveillance & intermittent social distancing may have to continue until 2022 if treatment, vaccine, or contact tracing & quarantine are not effective
• following SARS CoV-2 in sewage may provide population prevalence of virus in watershed of sewage drainage
• Amabie - A Japanese Symbol of the COVID-19 Pandemic

More general terms

• viral infection
• respiratory tract infection

More specific terms

• Covid-19 reinfection

Additional terms

• common cold vs influenza vs Covid-19
• COVID-19: multisystem inflammatory syndrome (MIS-C, MIS-A)
• ICD10 codes associated with Covid-19
• long Covid-19; post-acute sequelae of COVID-19 (PASC); post-Covid syndrome
• screening for COVID-19; screening for SARS-CoV2
• severe acute respiratory syndrome coronavirus 2; SARS-CoV2; Wuhan coronavirus

Patient information

COVID-19 patient information