Infectious Diseases
COVID-19: Background, Pathophysiology, and Diagnostics
Background
- Definition
- Formerly 2019-nCOV
- Novel coronavirus (betacoronavirus) first identified in Wuhan, Hubei Province, China (View image)
- The virus has been called Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV 2)
- CDC named disease: Coronavirus Disease 2019 (COVID-19)
- Synopsis
- Outbreak of pneumonia of unknown etiology in Wuhan City initially reported to WHO on December 31, 2019
- Hundreds of confirmed cases and reports of cases rapidly rising worldwide
- Supportive
- Vaccines available
- Health care providers
- Obtain detailed travel history if patient evaluated with fever and acute respiratory illness
- As of November 29, 2024
- Variants of interest (VOIs)
- Variants under monitoring (VUMs)
Pathophysiology
- Mechanism
- Structure and cell entry
- Coronavirus entry into host cells is mediated by the transmembrane spike (S) glycoprotein (homotrimers protruding from viral surface)
- S comprises 2 functional subunits:
- Binding to host cell receptor (S1 subunit)
- Fusion of viral and cellular membranes (S2 subunit)
- For many CoVs, S is cleaved at boundary between S1 and S2 subunits (remain non-covalently bound in prefusion conformation)
- The distal S1 subunit comprises the receptor-binding domain(s)
- Contributes to stabilization of prefusion state of membrane-anchored S2 subunit (contains the fusion machinery)
- For all CoVs, S is further cleaved by host proteases at so-called S2′ site (immediately upstream of fusion peptide)
- This cleavage has been proposed to activate protein for membrane fusion via extensive irreversible conformational changes
- The Receptor binding domain is highly variable and may possibly account for the high mutagenicity of the virus
- There is some evidence that SARS-CoV 2 glycoproteins also bind to heme groups in RBCs, leading to O2 dissociation (i.e., hypoxia without dyspnea)
- Possible targets for treatment
- SARS-CoV and several SARS-related coronaviruses (SARSr-CoV) interact directly with angiotensin-converting enzyme 2 (ACE2) to enter target cells
- The SARS-CoV-2 SB engages human ACE2 (hACE2) with comparable affinity to SARS-CoV SB from viral isolates (i.e., binding with high affinity to hACE2)
- Tight binding to hACE2 could partially explain the efficient transmission of SARS-CoV-2 in humans
- SARS-CoV recognizes its entry receptor hACE2 at surface of type II pneumocytes using SB
- ∼75% overall amino acid sequence identity with SARS-CoV-2 SB and 50% identity within their receptor-binding motifs (RBMs)
- SARS-CoV S-elicited polyclonal antibody responses potently neutralize SARS-CoV-2 S-mediated entry into cells
- Previous studies also showed host proteases cathepsin L and TMPRSS2 prime SARS-CoV S for membrane fusion through cleavage at S1/S2 and at the S2′ sites
- The coronavirus S glycoprotein is surface-exposed and mediates entry into host cells (main target of neutralizing antibodies (Abs) upon infection/focus of therapeutic and vaccine design)
- S trimers are extensively decorated with N-linked glycans
- Important for proper folding and for modulating accessibility to host proteases and neutralizing Abs
- Furin cleavage site at S1/S2 boundary of SARS-CoV-2 S (cleaved during biosynthesis) - a novel feature setting this virus apart from SARS-CoV and SARSr-CoVs
- Furin-like proteases may expand SARS-CoV-2 cell and tissue tropism compared with SARS-CoV
- It may also increase its transmissibility and/or alter its pathogenicity
- Incubation: up to 2 weeks
- Symptoms may develop 3-10 days
- Disease course may take 2-3 weeks
- Transmission: respiratory droplets and body fluids
- Some evidence shows virus can be viable in the environment for hours
- Studies seem to indicate virus is stable at cooler temperatures (40°F [4°C])
- Viral shedding can occur from 8-37 days from time of symptom onset
- For more genetic information: GISAID Initiative (https://www.gisaid.org/)
- Etiology/Risk Factors
- Novel beta-coronavirus
- Highly pathogenic zoonotic pathogens: SARS-CoV, MERS-CoV, and SARS-CoV-2, all belonging to the β-coronavirus genus
- Low-pathogenic coronaviruses endemic in humans: HCoV-OC43, HCoV-HKU1, HCoV-NL63, HCoV-229E
- Both SARS-CoV and SARS-CoV-2 are closely related
- Originated in bats (most likely reservoir host for these two viruses)
- Palm civets and racoon dogs are intermediate hosts for zoonotic transmission of SARS-CoV between bats and humans
- However, SARS-CoV-2 intermediate host remains unknown
- SARS-CoV-2 is most closely related to the bat SARSr-CoV RaTG13, with which it forms a distinct lineage from other SARSr-CoVs, and that their S glycoproteins share 97% amino acid sequence identity
- There are recurrent spillovers of coronaviruses in humans along with detection of numerous coronaviruses in bats, including many SARS-related coronaviruses (SARSr-CoVs)
- Suggests that future zoonotic transmission events may continue
- Travel to endemic areas (Wuhan City, Hubei Province) within the last few weeks/months
- Thailand and Japan have confirmed additional cases in travelers from Wuhan, China
- Modes of transmission
- Close-range contact via respiratory particles
- Coughing
- Sneezing
- Talking
- Inhaled/makes direct contact with mucous membranes
- Epidemiology
- Incidence/Prevalence
- Emerging disease
- WHO: Presumed to have originated in Wuhan, China
- First case in USA announced January 21, 2020
- > 770,000,000 confirmed cases worldwide
- Mortality/Morbidity
- > 6,900,000 deaths worldwide
- USA
- 6,502,997 hospitalizations
- 1,155,145 deaths
- 2023 USA
- 916,300 people hospitalized
- 75,5000 deaths
- Higher risk of mortality amongst older adults, especially with underlying illnesses/immunocompromised (e.g., DM, cardiovascular disease, etc.)
- Pneumonia is a significant risk for mortality
- See the MuLBSTA Score
- Specific for Viral pneumonia similar to COVID-19 induced, but may not yet be valid for COVID-19 patients (use with caution)
Diagnostics
- History/Symptoms
- Most common
- Fever/chills
- Cough
- SOB, dyspnea
- Fatigue
- Muscle, body aches
- Headache
- Sore throat
- New loss of taste or smell
- Congestion or runny nose
- Nausea or vomiting
- Diarrhea
- Emergency warning symptoms
- Shortness of breath
- Persistent pain or pressure in the chest
- New confusion or inability to arouse
- Bluish lips or face
- Physical Exam/Signs
- Asymptomatic Infections
- May still have objective clinical abnormalities (e.g., typical ground-glass opacities, patchy shadowing, atypical imaging abnormalities)
- Mild Illness
- In uncomplicated upper respiratory tract viral infection
- May have no signs during early infection
- Rarely: diarrhea, nausea, and vomiting
- No or mild pneumonia
- Elderly and immunosuppressed may present with atypical signs/symptoms
- Signs/Symptoms due to physiologic adaptations of pregnancy or adverse pregnancy events (e.g. dyspnea, fever, GI-symptoms, or fatigue) may overlap with COVID-19 signs/symptoms
- Pneumonia
- Adult
- Imaging indicating pneumonia but no signs of severe pneumonia AND NO need for supplemental oxygen
- Children
- Non-severe pneumonia in a child with cough/difficulty breathing AND tachypnea
- RR- < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40
- NO signs of severe pneumonia
- Severe pneumonia
- Adolescents or adults- fever or suspected respiratory infection in plus one of the following:
- Respiratory rate > 30 breaths/min
- Severe respiratory distress OR SpO2 ≤ 93% on room air
- Children- cough or difficulty in breathing, plus at least one of the following:
- Central cyanosis or SpO2 < 90%
- Severe respiratory distress (e.g. grunting, very severe chest indrawing)
- Signs of pneumonia with a general danger sign: inability to breastfeed or drink, lethargy or unconsciousness, or convulsions
- Other signs: chest indrawing, tachypnea (in breaths/min): < 2 months: ≥ 60; 2–11 months: ≥ 50; 1–5 years: ≥ 40
- While the diagnosis is made by clinical means, chest imaging can help identify/exclude pulmonary complications
- Acute Respiratory Distress Syndrome
- Onset: within 1 week of a known clinical insult or new/worsening respiratory symptoms
- Chest imaging (radiograph, CT scan, or lung ultrasound): bilateral opacities, lobar or lung collapse, nodules
- Origin of pulmonary infiltrates and respiratory failure should not completely be explained by cardiac failure or fluid overload
- Oxygenation impairment in adults:
- Mild ARDS: 200 mmHg < PaO2/FiO2 ≤ 300 mmHg (with PEEP or CPAP ≥ 5 cmH2O, or non-ventilated)
- Moderate ARDS: 100 mmHg < PaO2/FiO2 ≤ 200 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated)
- Severe ARDS: PaO2/FiO2 ≤ 100 mmHg (with PEEP ≥ 5 cmH2O, or non-ventilated)
- When PaO2 is not available, SpO2/FiO2 ≤ 315 suggests ARDS (including in non-ventilated patients)
- Oxygenation impairment in children:
- NOTE: OI = Oxygenation Index and OSI = Oxygenation Index using SpO2
- Use PaO2-based metric when available
- If PaO2 not available, wean FiO2 to maintain SpO2 ≤ 97% to calculate OSI or SpO2/FiO2 ratio:
- Bilevel (NIV or CPAP) ≥ 5 cmH2O via full face mask: PaO2/FiO2 ≤ 300 mmHg or SpO2/FiO2 ≤ 264
- Mild ARDS (invasively ventilated): 4 ≤ OI < 8 or 5 ≤ OSI < 7.5
- Moderate ARDS (invasively ventilated): 8 ≤ OI < 16 or 7.5 ≤ OSI < 12.3
- Severe ARDS (invasively ventilated): OI ≥ 16 or OSI ≥ 12.3
- Sepsis
- Adults
- Life-threatening multi-organ dysfunction due to proven infection:
- Altered mental status
- Difficult/fast breathing
- Low oxygen saturation
- Reduced urine output
- Tachycardia, hypotension, weak pulse, cold extremities, skin mottling, or laboratory evidence of coagulopathy
- Thrombocytopenia
- Acidosis, high lactate, or hyperbilirubinemia
- Children
- Suspected/proven infection AND
- ≥ 2 aged based systemic inflammatory response syndrome criteria, of which one must be abnormal temperature or white blood cell count
- Septic shock
- Adults
- Persistent hypotension despite volume resuscitation,
- Need of vasopressors to maintain MAP ≥ 65 mmHg and
serum lactate level > 2 mmol/
- Children
- Any hypotension OR two or three of the following:
- Altered mental state
- Tachycardia or bradycardia (HR < 90 bpm or > 160 bpm in infants and HR < 70 bpm or > 150 bpm in children)
- Prolonged capillary refill (> 2 sec) or weak pulse tachypnea
- Mottled or cool skin or petechial or purpuric rash;
- Increased lactate
- Oliguria
- Hyperthermia or hypothermia
- Labs/Tests
- There may be available FDA-approved bedside tests
- Common labs/tests profile for severe cases/poor outcomes (may be anecdotal from multiple sources)
- May be hypoxic +/- dyspnea
- May have late onset (> 5 days) cytokine storm leading to ARDS in severe cases (ARDS is leading cause of mortality); the following are elevated
- IL-6, IL-2, IL-7
- Granulocyte-colony stimulating factor
- Interferon-γ inducible protein 10
- Monocyte chemoattractant protein 1
- Macrophage inflammatory protein 1-α
- Tumor necrosis factor-α
- Secondary hemophagocytic lymphohistiocytosis (sHLH)
- Fulminant and fatal hypercytokinemia with multiorgan failure
- Unremitting fever, cytopenias, hyperferritinemia, and elevated CRP
- Elevated LFT, CPK, LDH, D-dimer
- ANC:Absolute lymphocyte count > 3.5 may predict poor outcome
- See the HScore calculator
- Testing Criteria
- Consider COVID-19 testing if
- New onset fever and/or respiratory tract symptoms (e.g., cough, dyspnea)
- Severe lower respiratory tract illness without clear etiology
- Other symptoms: myalgias, diarrhea, and smell or taste changes etc.
- May present with atypical signs/symptoms (clinical judgement)
- Significant likelihood of COVID-19 if
- Resides/travels to endemic areas with widespread transmission or
- Close contact with confirmed/suspected COVID-19 patient within 14 days
- Close contact defined as
- Being within approximately 6 ft [2 m], or
- Within the room/care area for a prolonged period of time without recommended personal protective equipment (PPE)
- Close contact can include:
- Caring for, living with, visiting, or sharing a healthcare waiting area or room with confirmed infected patient, or
- Having direct contact with infectious secretions while not wearing recommended PPE
- Non-emergent suspected COVID-19 should call their PCP before going to a health care facility
- Guidance for Testing Priority (due to limitations of test availability)
- CDC Guidance
- PRIORITY 1
- Ensure optimal care options for hospitalized patients, decrease risk for nosocomial spread, maintain integrity of healthcare system
- Health care facility workers, workers in crowded living settings, and first responders with symptoms
- Residents in long-term care facilities or other crowded living conditions with symptoms (e.g., prisons and shelters)
- Individuals identified/contacted via public health cluster and selected contact investigations
- PRIORITY 2: Persons identified by public health officials or clinicians as high priority
- Symptoms of potential COVID-19
- Fever, cough, shortness of breath, chills, myalgia, new loss of taste/smell, vomiting/diarrhea and/or sore throat
- Without symptoms who are from racial and ethnic minority groups disproportionately affected by adverse COVID-19 outcomes
- African Americans
- Hispanics and Latinos
- Some American Indian tribes (e.g., Navajo Nation)
- Without symptoms but prioritized by health departments or clinicians, including but not limited to:
- Public health monitoring
- Sentinel surveillance
- Comorbidity or disability
- Residency in a congregate housing setting (e.g., homeless shelter or long-term care facility)
- Screening of other asymptomatic individuals according to state and local plans
- IDSA Guidance
- SARS-CoV-2 NAAT recommended in symptomatic individuals suspected of having COVID-19
- Strong recommendation, moderate certainty evidence
- Symptomatic individuals suspected of having COVID-19
- Suggest collecting and testing swab specimens from either
- Nasopharynx, anterior nares, oropharynx, or mid-turbinate regions; saliva or mouth gargle
- Conditional recommendation, low certainty evidence
- Symptomatic individuals suspected of having COVID-19
- Anterior nasal (AN) and MT swab specimens may be collected for SARS-CoV-2 RNA testing by
- Either patients or healthcare providers
- Conditional recommendation, moderate certainty evidence
- Use of either rapid or standard lab-based NAATs in symptomatic individuals suspected of
- Having COVID-19
- Conditional recommendation, moderate certainty of evidence
- Performing a single NAAT and not repeating testing routinely in symptomatic or
- Asymptomatic individuals suspected of having COVID-19 whose initial NAAT result is negative
- Conditional recommendation, very low certainty of evidence
- For individuals who have clinical or epidemiologic reasons that might make testing desirable
- Suggests SARS-CoV-2 RNA testing in asymptomatic individuals
- Who are either known or suspected to have been exposed to COVID-19
- Conditional recommendation, moderate certainty evidence
- Suggests using either rapid or standard laboratory-based NAATs in asymptomatic individuals with known exposure to SARS-CoV-2 infection
- SARS-CoV-2 NAAT is not suggested for routine use in
- Asymptomatic individuals w/o known exposure to COVID-19
- Who are being hospitalized
- Conditional recommendation, very low certainty evidence
- Who are undergoing a medical or surgical procedure
- Conditional recommendation, very low certainty evidence
- NAAT is suggested not to be repeated for pts w/ COVID-19 to guide release from isolation
- Conditional Recommendation, very low certainty evidence
- Suggests neither for nor against home testing for SARS-CoV-2
- Microbiologic Testing
- Imaging
- ACR Recommends Chest Xray and CT for suspected COVID-19 Infection
- Chest CT has a high sensitivity for diagnosis of COVID-19 (consider as primary tool for the current COVID-19 detection)
- Sensitivity: 97% (95%CI, 95-98%, 580/601 patients) based on positive RT-PCR results
- Negative RT-PCR results: 75% (308/413) had positive chest CT findings
- Of 308, 48% were considered as highly likely cases, with 33% as probable cases
- Chest X-ray (View image)
- May be normal or pneumonia-like (e.g., infiltrates, airspace opacities, lobar/lobular consolidation, etc.)
- CXR of 35 yo male with positive COVID-19 (View image)
- Patient illness day 10, hospital day 6
- Image shows stable streaky opacities in lung bases (likely atypical pneumonia)
- Opacities steadily increased in density over time on serial CXR
- CT (View image)
- 75% of cases have presented with bilateral pneumonia
- Typical findings:
- Ground-glass opacities in all hospitalized patients
- Inter-/intra-lobular septal thickening
- Air space consolidation
- Vascular enlargement in the lesion
- Traction bronchiectasis
- Atypical findings:
- Mediastinal lymphadenopathy
- Pleural effusions
- May occur as a complication of COVID-19
- Multiple tiny pulmonary nodules
- Unlike many other viral pneumonias
- Progression CT: 29 yo male positive for COVID-19 with fever for 6 days (View image)
- (A) normal chest CT: axial and coronal planes at onset
- (B) chest CT: axial and coronal planes- minimal ground-glass opacities in bilateral lower lung lobes
- (C) chest CT: axial and coronal planes- increased ground-glass opacities
- (D) chest CT: axial and coronal planes- progression of pneumonia with mixed ground-glass opacities and linear opacities in subpleural area
- (E) chest CT: axial and coronal planes- absorption of both ground-glass opacities and organizing pneumonia
- Electron microscopy (View image)
- Allows gross visualization of the virus
- Color electron microscopy (View image)
- Other Tests/Criteria
- CDC has developed a real time Reverse Transcription-Polymerase Chain Reaction (rRT-PCR) test that can diagnose 2019-nCoV
- Criteria to Guide Evaluation
- Fever AND symptoms of lower respiratory illness and in the last 14 days before symptom onset
- History of travel from Wuhan City, China, or
- Close contact with an ill person under investigation for COVID-19
- Fever or symptoms of lower respiratory illness and in the last 14 days before symptom onset
- Close contact with an ill lab-confirmed COVID-19 patient
- Fever may not be present (i.e., very young, elderly, immunosuppressed, or taking certain fever-lowering medications)
- Clinical judgment should be used to guide testing of patients in such situations
- Close contact with a person who is under investigation for COVID-19
- Close contact is defined as
- Being within approximately 6 ft [2 m], or
- Within the room or care area for a prolonged period of time while not wearing recommended personal protective equipment (PPE)
- For example: gowns, gloves, NIOSH-certified disposable N95 respirator, eye protection
- Close contact can include:
- Caring for, living with, visiting, or sharing a healthcare waiting area or room with confirmed infected patient, or
- Having direct contact with infectious secretions while not wearing recommended PPE (e.g., being coughed on)
- Multisystem inflammatory syndrome in children (MIS-C) criteria:
- Hospitalization, fever > 24 hrs
- Lab evidence of inflammation, signs of > 2 organs involved, or epidemiologic association with SARS-COV-2 infection
- Features of Kawasaki disease or Toxic shock syndrome
- Postinfectious inflammatory syndrome (fever, tachycardia, and gastrointestinal symptoms with systemic inflammatory signs)
- Report to CDC
- COVID-19 breath test
- InspectIR COVID-19 Breathalyzer test
- Provides COVID result in 3 minutes
- 91.2% sensitivity and 99.3% specificity
- Negative predictive value 99.6%
- Uses has chromatography gas mass-spectrometry (GC-MS0 to separate and identify
- Chemical admixtures and rapidly detect 5 Volatile Organic Compounds (VOCs)
- Assoc/ w/ SARS-CoV-2 infection in exhaled breath
- Differential Diagnosis
Related Topics
References
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Contributor(s)
- Wedro, Benjamin, MD
- Ho, Nghia, MD
- Cherian, Geo, MD
- Singh, Ajaydeep, MD
Updated/Reviewed: November 2024