Severe COVID-19 Symptoms, Diagnosis, and Treatment – NEJM Guide

The following text is from the world's leading scientific medical journal, New England Journal of Medicine (NEJM), which published on December 17 the article Severe Covid-19 , translated here.

Case example

A previously healthy 50-year-old man with 2 days of dyspnea (respiratory distress) presents to the emergency department. He has had fever, cough, and fatigue for 1 week before presentation. His body temperature is 39.5, heart rate is 110 beats per minute, respiratory rate is 24 per minute, and blood pressure is 130/60 mmHg. His oxygen saturation while breathing room air is 87%. His white-cell count is 7300 per microliter, with lymphopenia. Chest radiography shows irregular bilateral opacities (ground-glass appearance) in the lung parenchyma. A reverse-transcriptase polymerase chain reaction (rt-PCR) test on a nasopharyngeal swab for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detects the presence of RNA; in other words, the COVID-19 test is positive. How should this case be evaluated and treated?

Key points in the evaluation and management of serious / severe Covid-19

• Patients with severe Covid-19 may become “critically ill” because of ARDS, which typically begins approximately 1 week after symptoms.
• For a patient with severe Covid-19, deciding when endotracheal intubation should be performed is a fundamental component of care.
• After intubation, patients should receive lung-protective ventilation with a plateau pressure of 30 cm water or less and tidal volumes based on the patient's height.
• Prone positioning (lying face down) is a potential treatment strategy for refractory hypoxemia.
• Thrombosis and kidney failure are well-known complications of severe Covid-19.
• Dexamethasone has been shown to reduce mortality in hospitalized Covid-19 patients who require oxygen, particularly those receiving mechanical ventilation.
• For hospitalized Covid-19 patients, remdesivir use was recently approved, on the basis of randomized trials showing that the drug shortens time to clinical recovery, by the United States Food and Drug Administration (FDA), but more data are needed to establish its role in patients with severe Covid-19.

What are the symptoms of severe Covid-19, and how is it defined?

The most common initial symptoms of Covid-19 are cough, fever, fatigue, headache, muscle pain, and diarrhea. Severe illness begins approximately 1 week after symptom onset. Dyspnea is the most common symptom of severe Covid-19 and is often accompanied by hypoxemia (Figure-1)

Many patients with severe COVID-19 develop progressive respiratory failure shortly after dyspnea and hypoxemia appear. These patients generally meet the criteria for Acute Respiratory Distress Syndrome (ARDS). ARDS (Acute Respiratory Distress Syndrome) is defined as pulmonary edema with severe hypoxemia and acute-onset ground-glass appearances in both lungs that cannot be explained by heart failure or fluid overload. A large proportion of patients with severe Covid-19 have lymphopenia, and some have central and peripheral nervous system disorders as well as thromboembolic complications. Severe Covid-19 can also cause acute heart, kidney, and liver injury, in addition to cardiac arrhythmias, rhabdomyolysis, coagulopathy, and shock. These organ failures can be associated with clinical and laboratory signs of inflammation: high fever, thrombocytopenia, hyperferritinemia, and elevations in C-reactive protein (CRP) and interleukin-6 (IL-6).

Covid-19 can be diagnosed on the basis of a suggestive clinical history and detection of SARS-CoV-2 RNA in respiratory secretions. Thoracic imaging (most commonly HRCT) should be performed; it generally shows bilateral consolidations and ground-glass opacities (Figure-2).

What are the diagnostic criteria for severe Covid-19?

Severe Covid-19 can be defined by:

• Dyspnea,
• A respiratory rate of 30 or more per minute,
• Blood oxygen saturation of 93% or less,
• A ratio of arterial partial oxygen pressure to inspired oxygen fraction (PO2: FiO2) below 300 mmHg, or
• Infiltration of more than 50% of the lung area.

In a large cohort (study group) of symptomatic Covid-19 patients described early in the pandemic, 81% had mild disease, 14% had severe disease, and 5% with organ failure became critically ill; mortality in the critically ill group was 49%.

Healthy people of any age can become critically ill with Covid-19. However, “age” is the most important risk factor for death or critical illness, and risk increases with each additional 10 years. Cardiovascular disease, diabetes mellitus, immunosuppression, and obesity are chronic health conditions associated with a greater likelihood of becoming critically ill from Covid-19. Severe disease is more common in men than women. Risk is also increased among some racial and ethnic groups, such as Black and Hispanic people living in the United States. Social determinants of health (socioeconomic status and health insurance) probably have a strong influence on severe disease risk.

A distinctive feature of the Covid-19 pandemic is the sudden appearance of unprecedented numbers of critically ill patients within a small geographic area. This may strain local healthcare resources, resulting in shortages of trained staff, ventilators, dialysis, and intensive care unit beds.

How should severe Covid-19 be treated?

Initial step   

Patients with severe Covid-19 should be hospitalized for close monitoring. Strict infection-control procedures are always needed because the risk of hospital (nosocomial) spread is high. Patients should wear surgical masks to prevent the dispersal of infectious droplets. Clinicians should wear appropriate personal protective equipment as defined in local infection-prevention programs, taking particular care during procedures that may increase the generation or dispersal of infectious aerosols. These procedures include endotracheal intubation, extubation, bronchoscopy, airway suctioning, medication nebulization, high-flow nasal cannula use, non-invasive ventilation, and manual ventilation with an Ambu bag. Current guidelines recommend that clinicians wear at least a gown, gloves, an N95 mask, and eye protection, and that patients be placed in negative-pressure rooms whenever possible during aerosol-generating procedures.

Patients with severe Covid-19 are at substantial risk of prolonged critical illness and death. At the earliest opportunity, clinicians should therefore collaborate with patients by reviewing advanced guidance and establishing appropriate goals of care. Because infection-control measures during the pandemic may prevent families from visiting seriously ill patients, care teams should develop plans to communicate with patients' families or proxies.

Fundamentals of respiratory care

Patients should be monitored carefully by direct observation and pulse oximetry. Oxygen should be administered through a Venturi mask or nasal cannula to maintain hemoglobin oxygen saturation between 90-96%. Deciding whether to intubate is a critical aspect of caring for patients with severe Covid-19.

Clinicians must weigh the risks of early intubation against those of sudden respiratory arrest and chaotic emergency intubation, which exposes staff to greater infection risk. Excessive breathing effort, hypoxemia refractory to supplemental oxygen, and encephalopathy signal impending respiratory arrest and the need for emergency endotracheal intubation and mechanical ventilation. No single number or algorithm determines the need for intubation, and clinicians should consider various factors (Figure-3A)

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If patients do not require intubation but remain hypoxic, a high-flow nasal cannula may improve oxygenation and prevent intubation in selected patients.

Non-invasive positive-pressure ventilation should be restricted to Covid-19 patients with respiratory failure due to chronic obstructive pulmonary disease, cardiogenic pulmonary edema, or obstructive sleep apnea rather than ARDS.

Patients treated with a high-flow nasal cannula or non-invasive ventilation require careful monitoring for deterioration that would indicate a need for invasive mechanical ventilation.

Turning patients prone while they breathe high concentrations of supplemental oxygen may improve oxygenation in severe Covid-19. This approach is supported by data from prospective cohorts describing its use in non-intubated patients with severe hypoxemia. However, it is unclear whether prone positioning prevents intubation in severe Covid-19. Because rescue ventilation is difficult in prone patients, this position should be avoided in patients whose condition is deteriorating rapidly.

Endotracheal intubation

Endotracheal intubation in patients with severe Covid-19 should be performed by a skilled operator. Unfamiliar personal protective equipment, infection risk to staff, and severe hypoxemia in patients make intubation more difficult. If possible, intubation should follow preoxygenation, rapid-sequence induction of sedation, and neuromuscular blockade. An antiviral filter should always be placed in the airway circuit. Video laryngoscopy may provide a good view of the airway from a distance. However, operators should choose the technique with which they are most likely to succeed on the first attempt. Continuous-wave capnography is the best method of confirming tracheal intubation. Patients with severe Covid-19 often become hypotensive immediately after intubation because of positive-pressure ventilation and systemic vasodilation from sedatives. Intravenous fluids and vasopressors should therefore be immediately available during intubation, and careful hemodynamic monitoring is required.

Ventilator management

It is uncertain whether Covid-19 is associated with a distinct form of ARDS that would benefit from a new mechanical ventilation strategy. However, many autopsies in severe Covid-19 reveal diffuse alveolar damage, the hallmark of ARDS. Moreover, respiratory-system compliance and gas exchange in patients with respiratory failure due to severe Covid-19 are similar to those in populations included in earlier ARDS treatment trials. Clinicians should therefore follow the treatment paradigm developed for ARDS over the last 20 years (Figure-3B) This strategy aims to prevent ventilator-induced lung injury by avoiding cyclical alveolar collapse, hyperoxia, and alveolar overdistension.

To prevent alveolar overdistension (excessive stretching), clinicians should limit both the tidal volume (breath volume) delivered by the ventilator and maximum alveolar pressure at the end of inspiration. Clinicians should set the ventilator to deliver a tidal volume of 6 ml per kilogram of ideal body weight, an approach called “lung-protective ventilation”. If patients become distressed and try to take larger tidal volumes, tidal volumes up to 8 ml per kilogram of ideal body weight are permitted. Several times daily, clinicians should initiate a half-second end-inspiratory pause, allowing pressure in the airway circuit to equilibrate between the patient and ventilator. At the end of the pause, airway-circuit pressure, the “plateau pressure”, approximates alveolar pressure (relative to atmospheric pressure). To avoid alveolar overdistension, plateau pressure should be limited to 30 cm water and should not exceed that value. In patients with central obesity or a non-compliant chest wall, higher plateau pressures may be possible without ventilator-induced lung injury. In Covid-19-associated ARDS, setting adequate positive end-expiratory pressure (PEEP) on the ventilator may prevent alveolar collapse and facilitate improvement of unstable lung regions. PEEP may consequently improve respiratory-system compliance and allow a decrease in FiO2. However, PEEP may reduce venous return to the heart and cause hemodynamic instability. Excessive PEEP may also cause alveolar overdistension and reduce respiratory-system compliance. No particular method for determining the appropriate PEEP level has been shown superior to others.

Sedatives and analgesics should aim to prevent pain, dyspnea, and distress. They can also blunt the patient's respiratory drive, improving patient synchrony with mechanical ventilation. Sedation is particularly important in febrile patients with high metabolic rates treated with lung-protective ventilation. Neuromuscular blocking agents may be used in deeply sedated patients who continue using accessory respiratory muscles and have refractory hypoxemia. These agents can reduce the work of breathing, reducing oxygen consumption and carbon dioxide production. Sedatives and neuromuscular blocking agents also help reduce the risk of lung injury that may occur when patients make vigorous spontaneous breathing efforts.

Refractory hypoxemia

Clinicians should consider prone positioning during mechanical ventilation in patients with refractory hypoxemia (PaO2: Fi02 < 150 mmHg during breathing and FiO2= 0.6 despite appropriate PEEP).

In randomized trials involving intubated patients with ARDS unrelated to Covid-19, keeping patients prone for 16 hours daily improved oxygenation and reduced mortality. However, prone positioning requires a team of at least three trained clinicians wearing full KKE (personal protective equipment). Inhaled pulmonary vasodilators (e.g., an inhaled pulmonary vasodilator) may improve oxygenation in refractory respiratory failure, although they do not improve survival in ARDS unrelated to Covid-19.

Extracorporeal membrane oxygenation (ECMO) is a potential rescue strategy in patients with refractory respiratory failure. Clinicians should carefully balance potential benefits against risks (such as bleeding) and resources available during the pandemic.

Medical treatment

A large randomized clinical trial involving more than 6400 patients hospitalized for Covid 19 showed that dexamethasone use significantly reduced 30-day mortality (17%); benefits were limited to patients requiring supplemental oxygen and were greater in those receiving mechanical ventilation. Consequently, dexamethasone (or other potential corticosteroids) is now accepted for patients with severe Covid-19 as standard care in current practice.

Data from a randomized, placebo-controlled trial involving more than 1000 patients with severe Covid-19 showed that the antiviral agent remdesivir shortened time to clinical recovery, with the greatest benefit in patients receiving supplemental oxygen but not intubated. In this study, 29-day mortality was 11.4% with remdesivir and 15.2% with placebo (hazard ratio for death, 0.73; confidence interval 95%; 0.52 to 1.03). These data led the United States Food and Drug Administration (FDA) to approve remdesivir in October 2020 for patients hospitalized because of Covid-19 (see the related approval article). Recent preliminary results from a large, multinational, open-label randomized trial did not show a reduction in in-hospital mortality with remdesivir. Clinical use of dexamethasone combined with remdesivir has increased, but its benefits have not been demonstrated in randomized clinical trials. An Interleukin-6 inhibitor, tocilizumab, did not significantly reduce disease progression or deaths in small randomized trials involving patients with severe Covid-19.

Supportive treatments

Covid-19 patients often present with volume depletion and receive isotonic-fluid resuscitation. Volume replacement helps maintain blood pressure and cardiac output during intubation and positive-pressure ventilation. After the first few days of mechanical ventilation, avoiding hypovolemia should be the main goal. Fever and tachypnea often increase insensible water loss in severe Covid-19, so water balance requires attention. If the patient is hypotensive, the vasopressor dose may be adjusted to maintain mean arterial pressure between 60 and 65 mmHg. The preferred vasopressor is norepinephrine. Unexplained hemodynamic instability should suggest myocardial ischemia, myocarditis, or pulmonary embolism.

In case series, 5% of patients with severe Covid-19 received renal replacement therapy (dialysis). The pathophysiology of kidney failure is currently uncertain but probably multifactorial. Because blood clotting in the circulation is common in severe Covid-19, the effectiveness of continuous renal replacement therapy is uncertain.

Abnormalities of the coagulation cascade, such as thrombocytopenia or elevated D-dimer levels, are common in severe Covid-19 and associated with increased mortality. Unless contraindicated, patients should receive standard thromboprophylaxis (such as subcutaneous low-molecular-weight heparin). Some case series in severe Covid-19 have shown clinically important thrombosis despite thromboprophylaxis. However, the benefits and risks of routinely using more intensive prophylactic anticoagulation are unknown.

Patients hospitalized with severe Covid-19 are often treated empirically with antibiotics. However, bacterial coinfection is uncommon in immunocompetent patients when they first present to hospital. Antibiotics may be discontinued after a short period if there are no signs of bacterial coinfection, such as leukocytosis and focal pulmonary infiltrates. Although Covid-19 itself can cause prolonged fever, clinicians should remain alert to hospital (nosocomial) infections.

Cardiopulmonary resuscitation in Covid-19 patients can expose healthcare workers to infectious droplets and aerosols. All members of the resuscitation team should therefore wear appropriate personal protective equipment before rescue ventilation, chest compressions, or defibrillation.

Mechanically ventilated Covid-19 patients should receive appropriate nutrition and care to prevent constipation and skin and corneal injuries. If patients are stable, clinicians should try to interrupt continuous sedation daily. Daily awakening can be difficult because increased breathing and loss of synchrony with mechanical ventilation can cause distress and hypoxemia.

The large increase in hospital presentations during the Covid-19 pandemic may temporarily require allocation of healthcare resources. Local guidelines and medical ethics consultation can help clinicians make these difficult decisions with patients and families.

Areas of uncertainty

Although the FDA has approved remdesivir for hospitalized Covid-19 patients, more data are needed to establish this drug's role in severe Covid-19. Numerous randomized trials of many other candidate treatments, including antivirals, antibodies, and immunomodulatory agents, are ongoing (Table-1).

Table 1. Selected Candidate Treatments for Coronavirus Disease 2019 (Covid-19)

ARDS denotes acute respiratory distress syndrome; BTK, Bruton tyrosine kinase; FDA, Food and Drug Administration; HIV, human immunodeficiency virus; IND, investigational new drug; JAK, Janus kinase; MERS, Middle East respiratory syndrome; SARS, severe acute respiratory syndrome; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Despite observational studies suggesting benefits of Interleukin-6 inhibitors, small randomized clinical trials have not shown consistent benefit. Other immunomodulatory agents being evaluated for severe Covid-19 include convalescent plasma, monoclonal antibodies, immunoglobulins, and passive immunotherapy with Interleukin-1 pathway inhibitors.

While final results of randomized trials are awaited, the risks and benefits of these approaches remain unknown. Candidate Covid-19 treatments require separate evaluation in patients with severe illness and those with milder illness to determine whether they reduce the risk of progression to severe disease.

Guidelines

The recommendations in this article are broadly consistent with severe Covid-19 guidelines from the American Thoracic Society, Infectious Diseases Society of America, National Institutes of Health, and Surviving Sepsis Campaign.

Conclusion and recommendations

An important aspect of care for the patient described at the beginning of the article is careful monitoring of respiratory status to decide whether endotracheal intubation is appropriate. If mechanical ventilation is initiated, the clinician should follow a lung-protective ventilation strategy by limiting plateau pressure and tidal volumes. If refractory hypoxemia develops, deep sedation with neuromuscular blocking agents and prone positioning should be considered. Prophylactic anticoagulants should be administered to prevent thrombosis. Because data from a randomized clinical trial showed reduced mortality, dexamethasone treatment should be started. Both remdesivir and dexamethasone require more data to establish the benefits of combined treatment; nevertheless, given its antiviral mechanism and data from randomized clinical trials showing shorter time to clinical recovery, remdesivir should also be given.

Meticulous adherence to infection-control measures is always important. Given the high risk of complications from severe Covid-19, clinicians should work with patients and families as early as possible to establish appropriate goals of care.

Given the uncertainties about effective treatment, clinicians should discuss available clinical trials with their patients. Clinicians should also discuss the value of autopsies with the families of patients who have died.

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Important development: DSÖ, NIH, and IDSA updated COVID-19 treatment guidelines

In December, guidelines from the World Health Organization (DSÖ), United States National Institutes of Health (NIH), and Infectious Diseases Society of America (IDSA) opposed chloroquine, hydroxychloroquine, lopinavir/ritonavir, and azithromycin use.

All guidelines recommend dexamethasone 6 mg/day in severe patients but do not recommend it in those who do not require oxygen, even if hospitalized. IDSA and NIH do not recommend tocilizumab, bamlanivimab, or convalescent plasma. Remdesivir for 5 days is recommended for those receiving supplemental oxygen, while it is not recommended for those receiving mechanical ventilation. NIH recommends remdesivir and corticosteroids together in severe disease, whereas DSÖ opposes remdesivir.

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