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Basic Information ⬇

AUTHORS: Frank Sanchez, MD, MBA, and Glenn G. Fort, MD, MPH

Definition

COVID-19 disease is a human respiratory illness, transmitted person-to-person primarily via respiratory droplets (Fig. 1) as well as contact with contaminated surfaces, caused by a novel coronavirus, SARS-CoV-2, that emerged in December 2019 in Wuhan, China. By March 2020 it was declared a worldwide pandemic by the World Health Organization. Over time, like many viruses, mutations occurred that significantly changed the clinical course of the disease. These variants are labeled by distinct phylogenetic classification systems or by the Greek alphabet as per the WHO: Alpha, Beta, Gamma, Delta, and Omicron, etc.

Figure 1 Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) from Person to Person

The major mode of transmission is by droplets (>5 μm diameter), generated by coughing, sneezing, or talking, consistent with the known presence of virus in the upper respiratory tract. Aerosol transmission has been strongly suggested by certain spreading events, in which small particles (<5 μm) can spread more than 6 feet and remain suspended. Fomite transmission, by touching surfaces and spreading virus to the face, happens but appears to be a minor mode of transmission.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Synonym

SARS-CoV-2

COVID-19

ICD-10CM CODES
U07.1Confirmed diagnosis
U07.1andJ12.89COVID-19 with pneumonia, other viral pneumonia
U07.1andJ80COVID-19 with ARDS, acute respiratory distress syndrome
U07.1andJ98.8COVID-19 with lower respiratory infection, other specified respiratory disorder
Epidemiology & Demographics
Incidence

After originating in China, the worst countries/areas affected worldwide include the United States, Europe, Brazil, India, and Russia. Most current information on incidence: www.coronavirus.jhu.edu.

Peak Incidence

The pandemic started in the winter of 2019. With the advent of vaccines directed toward COVID-19, the incidence has steadily decreased.

Prevalence

At the time this chapter was written, the COVID-19 pandemic has claimed an estimated 15 million lives, including more than 1 million in the U.S. alone.1

Predominant Sex & Age

Men are more at risk for worse outcomes and death, independent of age, with COVID-19. Whereas males and females have the same prevalence of COVID-19, male patients have a higher mortality rate. Children also get infected but have milder disease, much better outcomes, and a lower mortality rate of about 0.1% in the United States.

Genetics

Variations in the DNA sequences of the ACE2 and TMPRSS2 genes in humans may affect susceptibility to the infection by altering how the virus attaches to the receptor on human cells.

Risk Factors
Age

  • Most reported cases are in adults of middle age or older, but pediatric infections in adolescents and children also occur.
  • Risk of severe disease increases with age; in the United States, 94% of deaths occur in people older than 50 yr.
Sex

  • Overall, where sex or gender data are available, it appears that females are more often affected, but disease is more severe in males.

Other Risk Factors/Associations:

Various underlying medical conditions have been associated with increased risk for severe disease, especially if they are not well controlled:

  • Chronic kidney disease
  • Chronic obstructive pulmonary disease
  • Immunosuppression because of previous solid organ transplant
  • Malignancy
  • Obesity (body mass index [BMI] of 30 or higher)
  • Serious cardiac conditions (e.g., heart failure, coronary artery disease, cardiomyopathy)
  • Sickle cell disease
  • Diabetes type 2

Conditions That May Be Associated With Higher Risk for Severe Disease:

  • Asthma (moderate to severe)
  • Cerebrovascular disease
  • Cystic fibrosis
  • Hypertension
  • Immunodeficiency from various other causes (e.g., bone marrow or hematopoietic stem cell transplant, primary immunodeficiencies, HIV disease, chronic treatment with corticosteroids or other agents with immunosuppressive effects)
  • Neurologic dysfunction
  • Chronic liver disease
  • Pregnancy
  • Pulmonary fibrosis
  • Smoking
  • Thalassemia
  • Diabetes type 1
  • Children with medically complex conditions (e.g., neurologic, metabolic, genetic, cardiac) are also at higher risk for severe disease.
  • Residents of nursing homes and long-term care facilities are at high risk for acquiring infection and for severe disease, probably owing to a combination of heightened transmission in a close-quarters community and prevalence of compromised health status.
Physical Findings & Clinical Presentation (Fig. E1

Figure E1 Clinical manifestations of COVID-19.

Neurologic manifestations are present in 36% to 57% of patients, with the most common findings of dizziness, headache, and impaired consciousness. The most common ocular manifestation is conjunctivitis. Disorders of taste and smell are very common ear, nose, and throat (ENT) manifestations, affecting as many as 89% of patients. Cough (45% to 80%) and dyspnea (20% to 55%) are common respiratory manifestations. Arrhythmias affect 7% to 17% of patients, and myocarditis is a cardiac manifestation described in several case reports. Gastrointestinal manifestations are less common (7% to 9% in metaanalyses), but they may be the only symptoms in some patients. Elevated D-dimer levels are a common hematologic disorder and likely confer an increased risk for thromboembolism. Rash may present as a dermatologic feature in up to 20% of patients with COVID-19, and these rashes may appear as erythema, urticaria, or vesicles. Fever, myalgias, and fatigue are common systematic symptoms in the influenza-like illness characteristic of COVID-19.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

  • Incubation period: Within 14 days of exposure but most patients exhibit symptoms by day 4 to 5 after exposure (Fig. 3)
  • Spectrum of disease (Fig. 4):
    1. Asymptomatic disease: May be as high as 30% to 40%
    2. Mild disease: No or mild pneumonia-about 80% of symptomatic cases
    3. Severe disease: Dyspnea, hypoxia, or >50% lung involvement within 24 to 48 hours-less than 10% with new variants
    4. Critical disease: Respiratory failure, shock, or multiorgan failure-less than 5% with new variants
    5. Overall case fatality rate is less than 2%
  • Initial presentation: Pneumonia manifested by fever, cough, dyspnea, and bilateral infiltrates on chest imaging is the most serious presentation of the infection; however, in a study of 370,00 confirmed cases in the United States, a variety of symptoms were associated with COVID-19 infection:
    1. Cough: 50%
    2. Fever: Subjective or >100.4° F: 43%
    3. Myalgia: 36%
    4. Headache: 34%
    5. Dyspnea: 29%
    6. Sore throat: 20%
    7. Diarrhea: 19%
    8. Nausea/vomiting: 12%
    9. Loss of smell or taste, abdominal pain, and rhinorrhea: Less than 10% each
  • Available data suggest that as least one third of SARS-CoV-2 infections are asymptomatic.2
  • In some patients, gastrointestinal manifestations (nausea and diarrhea) may be how the infection presents.
  • Clinicians should be particularly attuned to pulmonary and hemodynamic indicators of severe disease:
    1. Patients with severe disease may appear quite ill, with tachypnea and labored respirations.
    2. Patients in apparent distress require immediate assessment of airway, breathing, and circulation (e.g., pulses, blood pressure, O2Sat).
    3. Clinicians should be aware of the COVID-19-related phenomenon of silent (or “happy”) hypoxemia; absence of signs of respiratory distress may be misleading.
    4. Oxygenation should be assessed promptly by peripheral saturation (e.g., pulse oximetry).
  • Fever is typical, occasionally exceeding 39° C. Patients in the extremes of age or with immunodeficiency may not develop fever.
  • Conjunctival secretions, injection, and chemosis have been reported.
  • A variety of skin changes have been described, including erythematous rashes, purpura, petechiae, and vesicles; Pernio (chilblain)-like acral lesions (COVID Toes) or Janeway lesions have been seen, particularly in young patients.
  • Hypotension, tachycardia, and cool/clammy extremities suggest shock.
  • In children, hypotension plus two or more of the following criteria may be indicative of COVID-19-associated multisystem inflammatory syndrome:
    1. Altered mental status
    2. Tachycardia (heart rate more than 160 beats per minute in infants or 150 in older children) or bradycardia (heart rate less than 90 in infants or 70 in older children)
    3. Prolonged capillary refill (more than 2 seconds) or warm vasodilation and bounding pulses
    4. Tachypnea
    5. Mottled skin, petechiae, or purpura
    6. Oliguria
    7. Hyperthermia or hypothermia

Figure 4 The phases of COVID-19 infection.

Many patients are infected but are totally asymptomatic. In some patients, the disease progresses in a variable course through several overlapping phases, with changes in symptoms, laboratory findings, and therapy requirements.

From Kryger M et al: Principles and practice of sleep medicine, ed 7, Philadelphia, 2023, Elsevier.

Figure 3 Clinical course of COVID-19.

The presymptomatic incubation period may last a median of 5 days. During the first week of illness, symptoms tend to be flu-like, with the added symptoms of losses of taste and smell. Severe disease may develop in the second week, with dyspnea and the need for intensive care unit (ICU) treatment. Many patients remain asymptomatic during their illness.

From Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Complications

  • Respiratory failure:
    1. High-flow nasal cannula (HFNC) is recommended over noninvasive positive pressure ventilation (NIPPV).
    2. If hypoxemia persists and intubation is not indicated, it is recommended to use a trial of awake prone positioning to improve oxygenation.
    3. If patient requires intubation, use a higher positive end expiratory pressure (PEEP) strategy over a lower PEEP strategy.
    4. If still hypoxemic despite intubation, prone ventilation for 12 to 16 hours a day is recommended.
  • Cardiac and cardiovascular complications:
    1. Acute coronary syndrome (ACS): There has been an increased coronary artery thrombus burden in patients with COVID-19 and an increased risk of developing a STEMI. This is likely related to the hypercoagulable state produced by COVID-19. The ability to reperfuse the patient with PCI or fibrinolysis will depend on how ill the patient is.
    2. Myocarditis is a known complication and likely results from a combination of direct viral injury and cardiac damage due to the host’s immune response. Clinical findings include changes in electrocardiogram or cardiac biomarkers and impaired cardiac function. Cardiac magnetic resonance imaging or cardiac computed tomography (CT) with angiography may help in the diagnosis.
    3. Arrhythmias, congestive heart failure, and cardiac shock can also occur.
  • Thromboembolic complications: Severe COVID-19 illness is associated with intense inflammation, leading to high rates of thrombotic complications that lead to higher morbidity and mortality rates. One study showed a 25% incidence of deep vein thrombosis (DVT) in severe COVID-19, and another study found a combined incidence of 31% for DVT, pulmonary embolus, and arterial embolism.
    1. Histopathologic studies show diffuse alveolar damage with profound inflammation, thrombosis, and thrombotic microangiopathy of small vessels and capillaries of the lung.
    2. Measurement of D-dimer, fibrinogen, prothrombin time, INR, and APTT should be obtained every 48 hours.
    3. Prophylaxis against DVT is recommended for all patients with COVID-19 in the hospital using low-molecular-weight heparin, unfractionated heparin for those in renal failure, or fondaparinux for those with heparin-induced thrombocytopenia, as long as platelet count is above 25 × 109/L.
    4. Patients with a D-dimer level of 3.0 μg/ml or higher should undergo screening with point-of-care ultrasound to rule out DVT and receive more intensive prophylaxis.
      1. Elevated levels of D-dimer on presentation are associated with more severe disease.
      2. Levels of 0.5 μg/ml or higher were found in 59.6% of patients with severe disease.
      3. Higher levels correlate with the need for intensive care and increased risk of death.
  • Other complications: Stroke
    1. Encephalopathy with agitated delirium (common in the intensive care unit [ICU] setting)
    2. Acute kidney injury
    3. Multisystem inflammatory syndrome seen in children
    4. Stroke
Etiology

  • The SARS-CoV-2 is a coronavirus, an enveloped positive stranded RNA virus. It is in the same subgenus as the severe acute respiratory virus (SARS) as well as several bat coronaviruses. It is not known if there was direct transmission from bats or some other intermediary host.
  • The name coronavirus comes from the Latin word meaning “crown” or “halo” because on two-dimensional electron microscopy the virus has a “crown-like” appearance caused by club-shaped spike peplomers covering the surface.
  • The virus enters cells through an endocytosis pathway, using surface spike (S) proteins to bind to angiotensin-converting enzyme 2 (ACE-2) and dipeptidyl peptidase 4 (DPP4) receptors on the ciliated bronchial epithelial cells and type II pneumocytes. Once the virus enters a host cell, viral RNA is exposed and replication occurs.
  • COVID-19 Variants
    1. Alpha Variant (B.1.1.7 lineage): First seen in the UK in December 2020 and felt to be 50% to 75% more transmissible than previous circulating strain.
    2. Beta Variant (B.1.351 lineage): Identified in South Africa in late 2020.
    3. Delta (B.1.617.2 lineage): First identified in India in December 2020 and had become the most prevalent variant in India, United Kingdom, and the U.S. by summer of 2021. It is felt to be much more transmissible than previous variants, and it appears current vaccines are less efficacious against this variant.
    4. Omicron: First identified in Africa in fall 2021, became most prevalent strain by winter 2021-2022. A much higher transmission rate than prior strains but with milder symptoms.
    5. The CDC now houses a collection of Variants of Concern (VOC) and Variants of Interest (VOI) on their website to keep track of emerging variants that may lead to another pandemic and can be found at: https://www.cdc.gov/coronavirus/2019-ncov/variants/.

Diagnosis ⬆ ⬇

Differential Diagnosis

  • Early stages:
    1. Viral: Influenza, parainfluenza, adenovirus, respiratory syncytial virus, human metapneumovirus, other coronaviruses
    2. Streptococcus pneumoniae pneumonia
    3. Haemophilus pneumoniae pneumonia
    4. Moraxella catarrhalis pneumonia
    5. Atypical bacterial pneumonia: Legionella or Mycoplasma pneumoniae
  • Severe acute respiratory syndrome (SARS)
  • Middle East respiratory syndrome (MERS)
  • Noninfectious: Heart failure, pulmonary embolism, salicylate poisoning, toxic shock
Workup

  • Consists of a combination of laboratory tests, viral diagnostic tests, radiology, and a compatible clinical course. The Centers for Disease Control and Prevention (CDC) has the following guidelines for COVID-19 diagnostic testing:
    1. High priority:
      1. Hospitalized patients with symptoms
      2. Health care facility workers, workers in congregate settings, and first responders with symptoms
      3. Residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms
  • Priority:
      1. Persons with symptoms of potential COVID-19 infection, including fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat
      2. Persons without symptoms who are prioritized by health departments or clinicians, for any reason, including but not limited to public health monitoring, sentinel surveillance, or screening of other asymptomatic individuals according to state or local plans
Laboratory Tests

Virologic testing for SARS-CoV-2 infection uses a molecular diagnostic nucleic acid amplification test (NAAT) or antigen test. Initial tests used a reverse transcriptase polymerase chain reaction (PCR) platform that is still also widely used in hospital settings; however, more recent tests use additional platforms such as the antigen rapid tests, including one on saliva and tests that take 15 min that can be done in home setting.

  • The CDC recommends nasopharynx swab samples, but nasal swabs or oropharyngeal swabs are acceptable alternatives.
  • NAAT tests are the most reliable according to the CDC and can detect viral genetic material for up to 90 days, and these tests should not be used if an individual was positive for COVID-19 within 90 days, even if the individual has a significant COVID-19 exposure.
  • Antigen tests are rapid tests that produce results in 15 to 30 minutes but are less reliable than NAATs, especially for individuals who are asymptomatic. A single negative test does not rule out infection, and a repeat antigen test should be performed within 48 hr of the negative test to best detect if an infection is present; this can sometimes be followed up with a NAAT.
  • Although lower respiratory tract samples have a higher yield than upper tract samples, they are often not done because of concerns of aerosolization of virus during sample collection procedures.
  • Serology testing is not useful in early diagnosis (Fig. 5) because it may take 21 days to develop IgM/IgG antibodies, plus there is variability in terms of sensitivity and specificity of these tests. In areas of low prevalence of infection, false positives may be quite high.
  • It is not recommended to use serology tests to see if a patient is still immune because it is currently unknown how long antibodies persist following infection and whether the presence of antibody confers immunity against future infection.
Figure 5 Time Course of Viral Exposure, Clinical Infection, and the Results of Clinical Assays for Severe Acute Respiratory Syndrome Coronavirus 2 and the Immune Response to It

Given the high virus counts, the patient may be most contagious in the few days before and after symptoms begin (see virus in airways, blue line). During the first week of symptoms, when virus is abundant, the nucleic acid tests are most reliable. With the onset of an immune response, virus numbers start to decline. By the second week, the immune system has been activated and, from 7 to 10 days after symptoms, the antibody test may be useful in detecting infection. Interestingly, both tests may be unreliable between the first and second weeks.

From UK Research and Innovation. What is the purpose of testing for COVID-19? 2020. https://coronavirusexplained.ukri.org/en/article/vdt0006/, In Broaddus VC et al: Murray & Nadel’s textbook of respiratory medicine, ed 7, Philadelphia, 2022, Elsevier.

Other Laboratory Tests

Laboratory tests associated with worse outcomes include the following:

  • Lymphopenia
  • Thrombocytopenia
  • Elevated liver function tests
  • Elevated lactate dehydrogenase (LDH)
  • Elevated inflammatory markers: C-reactive protein (CRP), ferritin
  • Elevated D-dimer: >1 μg/ml
  • Elevated prothrombin time (PT)
  • Elevated troponin
  • Elevated creatine phosphokinase (CPK)
  • Elevated creatinine
  • Elevated interleukin-6 (IL-6) levels
  • Procalcitonin level initially normal but may become elevated in critically ill patients
Imaging Studies

  • Radiologic findings of SARS-CoV-2 pneumonia are variable.
  • More than 75% of patients present with bilateral lung involvement, and multilobe involvement is also common (over 70%).
  • On CT, ground-glass opacity (GGO) is the most common finding in over 80% of patients, with one third of patients presenting GGO in the periphery; consolidation is also present in 30% of patients.
  • Nodules, cavitation, pleural effusions, and lymphadenopathy are not seen on CT.
  • Due to the hypercoagulable state of COVID-19, pulmonary embolism (PE) or DVT is not uncommon, and a high D-dimer should prompt consideration for workup with CT.
  • CT angiography is used to rule out PE.

Treatment ⬆ ⬇

Nonpharmacologic Therapy

COVID Convalescent plasma (CCP): Plasma from donors who have recovered from COVID-19 may contain antibodies to SARS-CoV-2 that may help suppress the virus and modify the inflammatory response. Randomized trials have shown that the administration of COVID-19 convalescent plasma to high-risk outpatients within 1 wk after the onset of symptoms of COVID-19 did not prevent disease progression. In addition, the COVID-19 Treatment Guidelines Panel, of the Department of the National Institute of Health, recommends against the use of CCP that was collected prior to the emergence of the Omicron variant and recommends against the use of CCP for the treatment of COVID-19 in hospitalized, immunocompetent patients. However, there is insufficient evidence for the Panel to recommend either for or against the use of high-titer CCP that was collected after the emergence of Omicron for the treatment of immunocompromised patients and nonhospitalized, immunocompetent patients with COVID-19.

Vaccines

Two mRNA vaccines (BioNTECH/Pfizer and Moderna) were approved under Emergency Use Authorization (EUA) use in late 2020 and are now both Food and Drug Administration (FDA) approved in adults for prevention of COVID-19 illness as well as children. In adults, both vaccines require two shots: Pfizer 21 to 28 days after the first and Moderna 28 days after the first. In children, BioNTECH/Pfizer is a 3-dose primary series for individuals 6 mo through 4 yr of age and a 2-dose primary series for individuals 5 yr of age and older. Moderna is a 2-dose primary series for individuals 6 mo of age and older. Two other vaccines (Johnson & Johnson/Janssen and Novavax) are approved under EUA for prevention of COVID-19 in adults age 18 yr and older. Janssen is a single primary vaccination dose for individuals who may otherwise not receive a second dose (noncompliant patients), and a booster can be given 2 mo after the primary dose. Novavax is a 2-dose primary series given 3 wk apart.

  • Messenger RNA (mRNA)-based vaccines: Moderna (mRNA-1273) and BioNTECH//Pfizer (BNT162a1). mRNA is the intermediate step between the translation of DNA and production of proteins in the cytoplasm, and both vaccines use mRNA to encode for the spike protein of the virus.
  • Viral vector vaccines use adenovirus as the vector. A gene from the SARS-CoV-2 is inserted into the adenovirus. Johnson & Johnson/Janssen vaccine uses replication-defective human adenovirus 26 vector and was approved by EUA in 2021 as a single dose only. The AstraZeneca/University of Oxford uses a replication-defective simian adenovirus vector that was approved in the UK and elsewhere but not the U.S.
  • Protein subunit vaccines: Janssen and Novavax introduce protein subunits of the outer coating spike protein of the COVID-19, which trigger a systemic immunological response.
  • Booster doses of the BioNTECH/Pfizer and Moderna vaccine are recommended, especially for immunocompromised patients, patients with comorbid conditions, and adults older than 50.
Acute General Rx
Pharmacologic Therapy Currently In Use

  • Oral antiviral agents for outpatient use in mild-to-moderate COVID-19 include nirmatrelvir/ritonavir (Paxlovid, Pfizer) 300 mg/100 mg BID for 5 days or Molnupiravir (Lagevrio, Merck) 800 mg PO BID for 5 days. Both agents have shown reduced rates of hospitalization and mortality when administered at early stages of COVID-19 infections in individuals older than 50 yr and those at higher risk with underlying health conditions. Paxlovid and Molnupiravir have been associated with viral rebound and recurrence of COVID-19 symptoms of which the clinical implications are not yet known and no data exists on efficacy of longer treatment durations. Molnupiravir should not be used in sexually active individuals due to the risk of fetal toxicity associated with this drug. Nirmatrelvir/ritonavir has a renally adjusted dose version for CrCl <or equal to 60.
  • Corticosteroids: A large randomized open label trial (RECOVERY trial) in the UK showed that oral or IV dexamethasone at 6 mg/day for 7 to 10 days reduced mortality rates among hospitalized patients.
    1. Overall relative reduction for all patients was 17%.
    2. Relative reduction in mortality in patients intubated or on extracorporeal membrane oxygenation (ECMO) was 35%.
    3. For patients on noninvasive oxygen therapy, relative reduction was 18%.
    4. There was no benefit in patients who either did not require oxygen or were intubated.
    5. Other glucocorticosteroids at equivalent doses: Hydrocortisone (150 mg total daily dose), methylprednisolone (32 mg), or prednisone (40 mg) can also be used.
  • Monoclonal antibodies: Target the spike protein and prevent viral cell entry. Currently there are several anti-SARS-CoV-2 MAb products that have received EUA from the FDA: Bamlanivimab plus etesevimab, bebtelovimab, casirivimab plus imdevimab, and sotrovimab. Anti-SARS-CoV-2 MAb products have received EUA for treatment of high-risk individuals recently diagnosed with mild to moderate COVID-19 with high-risk of progression who are 12 yr of age or older, BMI>25, diabetic, pregnant, immunocompromised, have CKD, sickle cell, cardiovascular disease or hypertension, neurodevelopmental disorders, or chronic lung disease. The drugs are infused over 1 h in the outpatient setting, and there are rare infusion-related events, including fever, chills, and urticaria. It can also be given SQ.
  • Baricitinib and Janus kinase (JAK) inhibitors (tofacitinib) have demonstrated a survival benefit in both the RECOVERY and STOP-COVID trial. For patients requiring high flow oxygen but are progressing to higher levels of ventilatory support despite corticosteroids and/or remdesivir, either Baricitinib: 4 mg po daily for up to 14 days or Tofacitinib 10 mg BID for 14 days or until hospital discharge, whichever is earlier.
  • IL-1 pathway inhibitors (Canakinumab): Also, a component of the inflammatory cytokine cascade, currently it is not recommended for use in COVID-19 infection as there is not enough evidence for or against its use.
  • IL-6 pathway inhibitors (tocilizumab and sarilumab): Interleukin-6 is part of the inflammatory cytokine cascade and thus blockers may prevent disease progression to prevent intubation or for patients who are intubated or on ECMO. Tocilizumab (Actemra) at a dose of 8 mg/kg IV (maximum dose: 800 mg) is an option for patients on high flow oxygen and who could still progress toward intubation within 24 to 48 h and have elevated inflammatory markers (D-dimer, CRP, ferritin, IL-6 levels). Patients should also be on dexamethasone. Side effects include anaphylaxis and significant infections due to bacteria, mycobacteria, and fungal or viral pathogens. Other side effects include neutropenia and thrombocytopenia. Other IL-6 inhibitors include sarilumab. Siltuximab is not recommended for use against COVID-19.
  • Other antiviral medications:
    1. Remdesivir is an antiviral therapy that prevents RNA replication. It was issued EUA by the FDA in 2020 for patients with severe COVID-19 illness with signs of hypoxia requiring supplemental oxygen, mechanical ventilation, or mechanical circulatory support requirements. It should be avoided in patients with an eGFR <30 ml/min. Clinical trials have produced mixed results. The drug has been shown to shorten the time to recovery in hospitalized adults but little to no mortality difference. It appears to be most beneficial when given earlier in the illness.
    2. Colchicine is an antiinflammatory drug commonly used in gout and acts by inhibition of neutrophil chemotaxis and decreasing inflammatory cytokine production and can theoretically help mitigate the effects of COVID-19. Colchicine is not approved for treatment of COVID-19. There are still research trials investigating its effectiveness.
    3. IVIG non-SARS-COV2 specific: Unclear if these products exhibit neutralizing antibodies and is currently not recommended for treatment in COVID-19.
    4. GM-CSF: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a myelopoietic growth factor and pro-inflammatory cytokine that plays a central role in a broad range of immune-mediated diseases. Evidence is lacking to support or reject its use in COVID-19; because of this, it is currently not recommended for treatment of COVID-19.
    5. Chloroquine and hydroxychloroquine prevent entry of SARS-CoV-2 into cells. Initial studies suggested clinical benefit. However, multiple subsequent studies showed no evident clinical benefit of hydroxychloroquine (with or without azithromycin) as well as potential increased risk of harm from side effects. Thus these agents are not recommended for use in patients with severe COVID-19 illness.
    6. Fluvoxamine: A selective serotonin reuptake inhibitor (SSRI) that is approved by the FDA for the treatment of obsessive-compulsive disorder and is used for other conditions, including depression. In mouse models, it demonstrated immunomodulatory effects by decreasing cytokine production by binding to the sigma-1 receptor on immune cells in mice models. Evidence is lacking to recommend for or against its use in COVID-19. Studies currently are ongoing. A recent randomized study showed fluvoxamine did not prevent hypoxia, ER visits, hospitalization, or deaths.
    7. Ivermectin: Its use is not supported by high quality data. In vitro data uses doses that are not comparable to what can be given safely PO. A recent randomized study showed ivermectin did not prevent hypoxia, ER visits, hospitalizations, or deaths.
    8. Metformin: A recent randomized study also showed metformin did not prevent hypoxia, ER visits, hospitalizations, or deaths.
    9. Mesenchymal stem cells: Hypothesized that these stem cells could reduce the acute lung injury and cell mediated inflammation caused by COVID-19 infection; it is advised against using in treatment of COVID-19 infection.
    10. Vitamins and zinc: No high-quality data exists that supplementing vitamin D or zinc reduces the severity of COVID-19.
Disposition

Long-term data is lacking, and patients can have a mixed prognosis depending on severity of disease and comorbid conditions. “Long COVID” has been identified in some populations where patients have debilitating sequelae. However, it should be noted that the vast majority of patients recover and return to their baseline.

Referral

Infectious diseases, pulmonary, and intensivist, if patient requires ICU level of care, should be consulted for hospitalized patients.

Pearls & Considerations ⬆ ⬇

Multisystem Inflammatory Syndrome in Children (Mis-C) Associated with Covid-19

The clinical presentation includes fever, severe illness, and the involvement of two or more organ systems, in combination with laboratory evidence of inflammation and laboratory or epidemiologic evidence of COVID-19 infection. It appears to be a rare complication with an incidence of 2 per 100,000.

  • Organ system involvement can be cardiac, renal, respiratory, dermatologic, hematologic, gastrointestinal, or neurologic.
  • Lab evidence: Elevated CRP, erythrocyte sedimentation rate, fibrinogen, procalcitonin, D-dimer, ferritin, LDH, or IL-6; elevated neutrophils or reduced lymphocytes; low albumin.
  • Positive SARS-CoV-2 testing by RT-PCR, serology, or antigen or COVID-19 exposure within 4 wk before onset of symptoms. There appears to be a lag of several weeks between the peak of COVID-19 cases within a community and the rise of MIS-C cases.
  • It appears that the pathogenesis involves a postinfectious immune dysfunction similar to what is seen in Kawasaki disease.
  • Treatment options include intravenous immunoglobulin (IVIG), aspirin, and corticosteroids (Solu-Medrol). Anakinra (IL-1 blocker) or tocilizumab (IL-6 blocker) for refractory disease. Infliximab is also a standalone treatment for refractory disease.
Infection Control

  • Patients undergoing aerosol-generating procedures should be placed in a negative pressure room. Otherwise patients can go into a well-ventilated single-occupancy room with a closed door and dedicated bathroom. Two COVID-19-positive patients can be placed in a room if necessary.
  • Quarantine guidelines are changing frequently as more information is learned about transmissibility and incubation of the disease. The CDC website has the most recent guidelines.
  • Personal protective equipment (PPE): Gowns and gloves and eye protection should be worn.
    1. On COVID-19 units gowns do not need to be routinely changed between patients.
    2. The CDC recommends an N-95 respirator or KN-95 mask for patient care but acknowledges that a medical mask is acceptable when supplies of respirators are limited.
Prevention

  • Preventive measures are of utmost importance to combat the COVID-19 pandemic and reduce the spread of disease. Widespread vaccination of the general population and following basic safety protocols such as maintaining social distancing (no longer 6 ft but recommend increasing distance from ill individuals and large crowds), practicing proper hand hygiene, quarantining if symptomatic, and wearing masks in public are strongly recommended.
  • Proper mask use reduces the transmission of respiratory viruses, including SARS-CoV-2, by about 40% (fitted filtration efficiency [FFE] 38% to 72%). N95 masks are more effective than surgical masks (FFE >95%) and are preferred for prevention of respiratory infection. The CDC recommends use of N95 respirators while caring for patients with confirmed or suspected COVID-19 (especially during aerosol-generating procedures such as intubation).
Patient & Family Education

  • Social distancing: Increase space and distance from large crowds or ill individuals.
  • Cover cough or sneeze.
  • Hand washing: Especially after touching surfaces in public. Use soap and water for 30 seconds or hand sanitizer of at least 60% alcohol.
  • Avoid touching the face, especially eyes, nose, and mouth.
  • Wearing masks in the community: The CDC recommends the use of a nonmedical cloth mask in public settings with high rates of transmission and where social distancing may be more difficult. It is thought that this will contain secretions of and prevent transmission from individuals with infection, including those who are asymptomatic or presymptomatic.
  • Individuals who develop any of the symptoms of COVID-19 should self-isolate at home away from other people or, if they need to be around others, wear a mask until they can be tested and results known.
Reinfection

  • In most cases of persons who became reinfected several months after an initial episode of COVID-19, genetic material of the virus analyzed from each episode suggested that patients had two distinct viral infections of the COVID-19 virus.
  • Reinfection has become more frequent as most of the vaccines only provide 6 months or less of protection thus requiring boosters, and some boosters are less effective against new variants. Persons who are not boosted are more likely to get reinfected
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Suggested Readings ⬆ ⬇

  1. Baden L.R. : Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccineN Engl J Med. ;384:403-416, 2021.
  2. Beigel : Remdesivir for the treatment of COVID-9 - final reportN Engl J Med. ;383:1813-1826, 2020.
  3. Berlin D.A. : Severe COVID-19N Engl J Med. ;383:2451-2460, 2020.
  4. Cheng : Diagnostic testing for severe acute respiratory syndrome-related coronavirus 2: a narrative reviewAnn Intern Med. ;172:726-734, 2020.
  5. Chih-Cheng L et al: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and coronavirus disease-2019 (COVID-19): the epidemic and the challenges. https://doi.org/10.1016/j.ijantimicag.2020.105924.
  6. https://www.cdc.gov/coronavirus/2019-ncov/symptoms-testing/.
  7. https://www.cdc.gov/coronavirus/2019-ncov/variants/.
  8. https://www.covid19treatmentguidelines.nih.gov/therapies/anti-sars-cov-2-antibody-products/.
  9. https://www.fda.gov/emergency-preparedness-and-response/coronavirus-disease-2019-covid-19/.
  10. https://www.panoramictrial.org/.
  11. Jayk Bernal A. : Molnupiravir for oral treatment of COVID-19 in nonhospitalized patientsThe New England Journal of Medicine. ;386(6):509-520, 2021.
  12. Lauer S.A. : The incubation period of coronavirus disease 2019 (COVID-19) from publicly reported confirmed cases: estimation and Application Epub 2020 Mar 10 Ann Intern Med. ;172(9):577-582, 2020.
  13. Mahase E. : Covid-19: Pfizer's paxlovid is 89% effective in patients at risk of serious illness, company reportsBMJ. ;375, 2021.
  14. Mucha S.R. : Coagulopathy in COVID-19: manifestations and treatmentCCJM. ;87:461-468, 2020.
  15. Nakra N. : Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection: review of the clinical presentation, hypothetical pathogenesis, and proposed managementChildren (Basel). ;7(7), 2020.
  16. O’Callaghan K. : Developing a SARS-CoV-2 vaccine at warp speedJAMA. ;324:437-438, 2020.
  17. Parasher A. : COVID-19: current understanding of its pathophysiology, clinical presentation and treatmentPostgraduate Medical Journal. ;97:312-320, 2021.
  18. Pau A.K. : Convalescent plasma for the treatment of COVID-19: perspectives of the National Institutes of Health COVID-19 treatment guidelines panelAnn Intern Med. ;174:93-95, 2021.
  19. Stokes E.K. : Coronavirus Disease 2019 Case Surveillance - United States, January 22-May 30, 2020MMWR Morb Mortal Wkly Rep. ;69(24):759-765, 2020.
  20. Dexamethasone in hospitalized patients with COVID-19-preliminary report , 2020.doi:10.1056/NEJMoa2021436
  21. Weinreich D.M. : REGN-COV2, a neutralizing antibody cocktail, in outpatients with COVID-19N Engl J Med. ;384:238-251, 2021.
  22. Xu H. : High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa PMID: 32094336; PMCID: PMC7039956 Int J Oral Sci. ;12(1), 2020.doi:10.1038/s41368-020-0074-x
  23. Yadav R. : Thoracic imaging in COVID-19CCJM. ;87:469-476, 2020.

Related Content ⬆

    1. Barouch DH : Covid-19 vaccines - immunity, variants, boostersN Engl J Med. ;387(11):1011-1020, 2022.
    2. Oran DP, Topol EJ : The proportion of SARS-CoV-2 infections that are asymptomatic: a systematic reviewAnn Intern Med. ;174(5):655-662, 2021.