Treatment and management of COVID-19

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There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID‑19), the disease caused by the SARS-CoV-2 virus.[1][needs update][2] One year into the pandemic, highly effective vaccines have now been introduced and are beginning to slow the spread of SARS-CoV-2; however, for those awaiting vaccination, as well as for the estimated millions of immunocompromised persons who are unlikely to respond robustly to vaccination, treatment remains important.[3] Thus, the lack of progress developing effective treatments means that the cornerstone of management of COVID‑19 has been supportive care, which includes treatment to relieve symptoms, fluid therapy, oxygen support and prone positioning as needed, and medications or devices to support other affected vital organs.[4][5][6]

Most cases of COVID‑19 are mild. In these, supportive care includes medication such as paracetamol or NSAIDs to relieve symptoms (fever, body aches, cough), proper intake of fluids, rest, and nasal breathing.[7][2][8][9] Good personal hygiene and a healthy diet are also recommended.[10] The U.S. Centers for Disease Control and Prevention (CDC) recommend that those who suspect they are carrying the virus isolate themselves at home and wear a face mask.[11]

People with more severe cases may need treatment in hospital. In those with low oxygen levels, use of the glucocorticoid dexamethasone is strongly recommended, as it can reduce the risk of death.[12][13][14] Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing.[15] Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.[16][17] Some of the cases of severe disease course are caused by systemic hyper-inflammation, the so-called cytokine storm.[18]

Several experimental treatments are being actively studied in clinical trials.[1] These include fluvoxamine, a cheap and widely available antidepressant;[19] and the antivirals molnupiravir (developed by Merck),[20] and nirmatrelvir (developed by Pfizer).[21] Others were thought to be promising early in the pandemic, such as hydroxychloroquine and lopinavir/ritonavir, but later research found them to be ineffective or even harmful.[1][22][23] Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment.[22][23] Nevertheless, in the United States, two monoclonal antibody-based therapies are available for early use in cases thought to be at high risk of progression to severe disease.[23] The antiviral remdesivir is available in the U.S., Canada, Australia, and several other countries, with varying restrictions; however, it is not recommended for people needing mechanical ventilation, and is discouraged altogether by the World Health Organization (WHO),[24] due to limited evidence of its efficacy.[1] In November 2021, the UK approved the use of molnupiravir as a COVID treatment for vulnerable patients recently diagnosed with the disease.[25]

Some people may experience persistent symptoms or disability after recovery from the infection; this is known as long COVID. There is still limited information on the best management and rehabilitation for this condition.[15]

The WHO, the Chinese National Health Commission, the UK National Institute for Health and Care Excellence, and the United States' National Institutes of Health, among other bodies and agencies worldwide, have all published recommendations and guidelines for taking care of people with COVID‑19.[26][27][15][28] Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.[29][30]

Medications

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See also: COVID-19 drug repurposing research and COVID-19 drug development
File:Covid-19 San Salvatore 09.jpg
An exhausted anesthesiologist physician in Pesaro, Italy, March 2020

A large number of drugs have been considered for treating COVID‑19 patients.[31] As of February 2021, in the United States, remdesivir has FDA approval for certain COVID‑19 patients, so far the first only drug to achieve that permission.[32] There are Emergency Use Authorizations for baricitinib, bamlanivimab, bamlanivimab/etesevimab, and casirivimab/imdevimab.[33] On 16 April 2021, the FDA revoked the emergency use authorization (EUA) that allowed for the investigational monoclonal antibody therapy bamlanivimab, when administered alone, to be used for the treatment of mild-to-moderate COVID‑19 in adults and certain pediatric patients.[34] In the European Union, the use of dexamethasone is endorsed, and remdesivir has a conditional marketing authorisation.[35] Despite being controversial at the beginning of the pandemic,[36] corticosteroids like dexamethasone have ultimately showed clinical benefit in treating COVID‑19, once randomized controlled trials were performed on them.[37][38] Specifically, there is moderate‐certainty evidence suggesting that dexamethasone, and systemic corticosteroids in general, probably cause a slight reduction in all‐cause mortality in hospitalised patients suffering COVID‐19.[39] Early research suggested a benefit of remdesivir in preventing death and shortening illness duration, but this was not borne out by subsequent trials.[1] Other drugs such as budesonide and tocilizumab have shown promising results in some patients but remain under investigation.[40][41][42]

In the early months of the pandemic, many ICU doctors faced with the deadly nature of the virus ventured to prescribe conjectured treatments because of the unprecedented circumstances.[43] However, the standard of care for most intractable illnesses is that, as it develops over years, doctors build a body of research that tests various theories, compares and contrasts dosages, and measures one drug's power against another.[43]

Several antiviral drugs are under investigation for COVID‑19, though none has yet been shown to be clearly effective on mortality in published randomized controlled trials.[44] Convalescent plasma, plasma from persons who have recovered from SARS-CoV-2 infection, as a treatment option was frequently implemented during 2020, with preliminary reports at the time indicating that it was well tolerated and with low risk of adverse events.[45] Convalescent plasma even received Emergency Use Authorization in the US in August 2020. Further trial studies found convalescent plasma to be ineffective.[46][47] Other trials are investigating whether existing medications can be used effectively against the body's immune reaction to SARS-CoV-2 infection.[44][48] Research into potential treatments started in January 2020,[49] and several antiviral drugs are in clinical trials.[50][51] Although new medications may take until 2021 to develop,[52] several of the medications being tested are already approved for other uses or are already in advanced testing.[53] Antiviral medication may be tried in people with severe disease.[4] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[54]

The monoclonal antibody therapies bamlanivimab/etesevimab and casirivimab/imdevimab have been found to reduce the number of hospitalizations, emergency room visits, and deaths.[55][56] Both combination drugs have emergency use authorization by the US Food and Drug Administration (FDA).[55][56]

Taking over-the-counter drugs such as paracetamol or ibuprofen, drinking fluids, and resting may help alleviate symptoms.[2][57][58] Depending on the severity, oxygen therapy and intravenous fluids may be required.[59]

Several potentially disease-modifying treatments have been investigated and found to be ineffective or unsafe, and are thus not recommended for use; these include baloxavir marboxil, lopinavir/ritonavir, ruxolitinib, chloroquine, hydroxychloroquine, interferon β-1a, and colchicine.[14] Favipiravir and nafamostat have shown mixed results but are still in clinical trials in some countries.[60][61][62]

A retrospective case-control study performed by Hungarian clinicians of Uzsoki Hospital (Budapest) found that 20 mg fluoxetine as an adjuvant therapy was associated with reduced mortality from COVID‑19.[63][64]

Respiratory support

File:Respiradores da USP utilizados do Incor (50119127303).jpg
A critically ill patient receiving invasive ventilation in the intensive care unit of the Heart Institute, University of São Paulo, during the COVID‑19 pandemic in Brazil. Due to a shortage of mechanical ventilators, a bridge ventilator is being used to automatically actuate a bag valve mask.

Mechanical ventilation

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See also: Shortages related to the COVID-19 pandemic § Mechanical ventilation

Most cases of COVID‑19 are not severe enough to require mechanical ventilation or alternatives, but a percentage of cases are.[65][66] The type of respiratory support for individuals with COVID‑19 related respiratory failure is being actively studied for people in the hospital, with some evidence that intubation can be avoided with a high flow nasal cannula or bi-level positive airway pressure.[67] Whether either of these two leads to the same benefit for people who are critically ill is not known.[68] Some doctors prefer staying with invasive mechanical ventilation when available because this technique limits the spread of aerosol particles compared to a high flow nasal cannula.[65]

Mechanical ventilation had been performed in 79% of critically ill people in hospital including 62% who previously received other treatment. Of these 41% died, according to one study in the United States.[69]

Severe cases are most common in older adults (those older than 60 years,[65] and especially those older than 80 years).[70] Many developed countries do not have enough hospital beds per capita, which limits a health system's capacity to handle a sudden spike in the number of COVID‑19 cases severe enough to require hospitalisation.[71] This limited capacity is a significant driver behind calls to flatten the curve.[71] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.[16] In China, approximately 30% of people in hospital with COVID‑19 are eventually admitted to ICU.[72]

The administration of inhaled nitric oxide to people being ventilated is not recommended, and evidence around this practice is weak.[73]

Acute respiratory distress syndrome

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Main article: Acute respiratory distress syndrome

Mechanical ventilation becomes more complex as acute respiratory distress syndrome (ARDS) develops in COVID‑19 and oxygenation becomes increasingly difficult.[74] Ventilators capable of pressure control modes and high PEEP[75] are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax.[76]

Extracorporeal membrane oxygenation

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Main article: Extracorporeal membrane oxygenation

Extracorporeal membrane oxygenation (ECMO) is an artificial lung technology that has been used since the 1980s to treat respiratory failure and acute respiratory distress syndrome when conventional mechanical ventilation fails. In this complex procedure, blood is removed from the body via large cannulae, moved through a membrane oxygenator that performs the lung functions of oxygen delivery and carbon dioxide removal, and then returned to the body. The Extracorporeal Life Support Organization (ELSO) maintains a registry of outcomes for this technology, and it has been used in >120,000 patients over 435 ECMO centers worldwide with 40% mortality for adult respiratory patients.[77]

Initial use of ECMO in COVID‑19 patients from China early in the pandemic suggested poor outcomes, with >90% mortality.[78] In March 2020, the ELSO registry began collecting data on the worldwide use of ECMO for patients with COVID‑19 and reporting this data on the ELSO website in real time. In September 2020, the outcomes of 1,035 COVID‑19 patients supported with ECMO from 213 experienced centers in 36 different countries were published in The Lancet, and demonstrated 38% mortality, which is similar to many other respiratory diseases treated with ECMO. The mortality is also similar to the 35% mortality seen in the EOLIA trial, the largest randomized controlled trial for ECMO in ARDS.[79] This registry based, multi-center, multi-country data provide provisional support for the use of ECMO for COVID‑19 associated acute hypoxemic respiratory failure. Given that this is a complex technology that can be resource intense, guidelines exist for the use of ECMO during the COVID‑19 pandemic.[80][81][82]

Prevention of onward transmission

File:DonningCDC2020.jpg
The U.S. Centers for Disease Control and Prevention (CDC) recommends four steps to putting on PPE.[83]

Self-isolation has been recommended for people with mild cases of COVID‑19 or who suspect they have been infected, even those with nonspecific symptoms, to prevent onward transmission of the virus and help reduce the burden on health care facilities.[2] In many jurisdictions, such as the United Kingdom, this is required by law.[84] Guidelines on self-isolation vary by country; the U.S. CDC and UK National Health Service have issued specific instructions, as have other local authorities.[85][84]

Adequate ventilation, cleaning and disinfection, and waste disposal are also essential to prevent further spread of infection.[57]

Personal protective equipment

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See also: Shortages related to the COVID-19 pandemic

Precautions must be taken to minimise the risk of virus transmission, especially in healthcare settings when performing procedures that can generate aerosols, such as intubation or hand ventilation.[86] For healthcare professionals caring for people with COVID‑19, the CDC recommends placing the person in an Airborne Infection Isolation Room (AIIR) in addition to using standard precautions, contact precautions, and airborne precautions.[87]

The CDC outlines the guidelines for the use of personal protective equipment (PPE) during the pandemic. The recommended gear is a PPE gown, respirator or facemask, eye protection, and medical gloves.[88][89]

When available, respirators (instead of face masks) are preferred.[90] CDC recommends mask use in public places, when not able to social distance, and while interacting with people outside of those that the person lives with.[91] N95 respirators are approved for industrial settings but the FDA has authorized the masks for use under an emergency use authorization (EUA). They are designed to protect from airborne particles like dust but effectiveness against a specific biological agent is not guaranteed for off-label uses.[92] When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.[93]

Psychological support

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See also: Mental health during the COVID-19 pandemic

Individuals may experience distress from quarantine, travel restrictions, side effects of treatment, or fear of the infection itself. To address these concerns, the National Health Commission of China published a national guideline for psychological crisis intervention on 27 January 2020.[94][95]

The Lancet published a 14-page call for action focusing on the UK and stated conditions were such that a range of mental health issues was likely to become more common. BBC quoted Rory O'Connor in saying, "Increased social isolation, loneliness, health anxiety, stress, and an economic downturn are a perfect storm to harm people's mental health and wellbeing."[96][97]

Special populations

Concurrent treatment of other conditions

Early in the pandemic, theoretical concerns were raised about ACE inhibitors and angiotensin receptor blockers. However, later research found no evidence to justify stopping these medications in people who take them for conditions such as high blood pressure.[15][98][99][100] One study from 22 April found that people with COVID‑19 and hypertension had lower all-cause mortality when on these medications.[101] Similar concerns were raised about non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen; these were likewise not borne out, and NSAIDs may both be used to relieve symptoms of COVID‑19 and continue to be used by people who take them for other conditions.[102]

People who use topical or systemic corticosteroids for respiratory conditions such as asthma or chronic obstructive pulmonary disease should continue taking them as prescribed even if they contract COVID‑19.[37]

During pregnancy

To date, most SARS-CoV-2-related clinical trials have excluded, or included only a few, pregnant or lactating women. This limitation makes it difficult to make evidence-based therapy recommendations in these patients and potentially limits their COVID‑19 treatment options. The US CDC recommends shared decision-making between the patient and the clinical team when treating pregnant women with investigational medication.[103]

References

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External links

Treatment guidelines

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