Treatment and management of COVID-19

There is no specific, effective treatment or cure for coronavirus disease 2019 (COVID-19), the disease caused by the SARS-CoV-2 virus.[1][2] Thus, the cornerstone of management of COVID-19 is 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.[3][4][5]

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.[6][2][7][8] Good personal hygiene and a healthy diet are also recommended.[9] 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.[10]

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.[11][12][13] Noninvasive ventilation and, ultimately, admission to an intensive care unit for mechanical ventilation may be required to support breathing.[14] Extracorporeal membrane oxygenation (ECMO) has been used to address the issue of respiratory failure, but its benefits are still under consideration.[15][16]

Several experimental treatments are being actively studied in clinical trials.[1] 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][17][18] Despite ongoing research, there is still not enough high-quality evidence to recommend so-called early treatment.[17][18] 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.[18] 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),[19] due to limited evidence of its efficacy.[1]

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.[14]

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.[20][21][14][22] Intensivists and pulmonologists in the U.S. have compiled treatment recommendations from various agencies into a free resource, the IBCC.[23][24]

Medications
See also: COVID-19 drug repurposing research and COVID-19 drug development
An exhausted anesthesiologist physician in Pesaro, Italy, March 2020

As of January 2021, dexamethasone is the only medication with proven clinical benefit in treating COVID-19, as determined in randomized controlled trials, with some low-certainty evidence to support remdesivir.[1][25][26] Early research suggested a benefit of remdesivir in preventing death and shortening illness duration, but this was not borne out by subsequent trials.[1]

Taking over-the-counter drugs such as paracetamol or ibuprofen, drinking fluids, and resting may help alleviate symptoms.[2][27][28] Depending on the severity, oxygen therapy and intravenous fluids may be required.[29]

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, favipiravir, lopinavir/ritonavir, ruxolitinib, chloroquine, hydroxychloroquine, interferon β-1a, and colchicine.[13]

Systemic corticosteroids

Dexamethasone may be used, but is only helpful in people requiring supplemental oxygen. Following an analysis of seven randomized trials,[30] the WHO recommends the use of systemic corticosteroids in guidelines for treatment of people with severe or critical illness, and that they not be used in people that do not meet the criteria for severe illness.[31]

The use of corticosteroids can cause a severe and deadly "hyperinfection" syndrome for people with strongyloidiasis, which may be an underlying condition in populations exposed to the parasite Strongyloides stercoralis. This risk can be mitigated by the presumptive use of ivermectin before steroid treatment.[32]

Remdesivir

Emergency use authorization for remdesivir was granted in the U.S. on May 2020 for people hospitalized with severe COVID-19.[33][34] The interim authorization was granted considering the lack of other specific treatments, and that its potential benefits appeared to outweigh the potential risks.[33][35][36] In September 2020, following a review of later research, the WHO recommended that remdesivir not be used for any cases of COVID-19, as there was no good evidence of benefit.[11]

In November 2020, the FDA issued a further emergency use authorization (EUA) for the combination of remdesivir with baricitinib (see below) for the treatment of suspected or laboratory confirmed COVID-19 in hospitalized people two years of age or older requiring supplemental oxygen, invasive mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).[37] The data supporting the EUA for baricitinib combined with remdesivir were based on a randomized, double-blind, placebo-controlled clinical trial (ACTT-2), which was conducted by the National Institute of Allergy and Infectious Diseases (NIAID).[37]

Immunomodulation

In January 2021 in the United Kingdom, the National Health Service issued guidance that the immune modulating drugs tocilizumab and sarilumab were beneficial when given promptly to people with COVID-19 admitted to intensive care, following research which found a reduction in the risk of death by 24%.[38]

The oral JAK inhibitor baricitinib is also being studied for COVID-19 treatment.[39] In November 2020, the FDA granted emergency use authorization for baricitinib to be given to certain people hospitalized with suspected or confirmed COVID-19 (specifically, adults and children two years of age or older requiring supplemental oxygen, mechanical ventilation, or ECMO), but only in conjunction with remdesivir.[40] In a single clinical trial, this combination therapy was shown to have a small, but statistically significant effect on patient outcomes compared to administration of remdesivir alone.[41]

Other disease-modifying treatments

Medications to prevent blood clotting have been suggested for treatment, and anticoagulant therapy with low molecular weight heparin appears to be associated with better outcomes in severe COVID‐19 showing signs of coagulopathy (elevated D-dimer).[42]

In November 2020, the U.S. Food and Drug Administration issued emergency use authorizations (EUAs) for the investigational monoclonal antibody therapies bamlanivimab[43] and casirivimab/imdevimab for the treatment of mild to moderate COVID-19 in outpatients.[44] Nevertheless, the NIH Treatment Guidelines state that there is still insufficient evidence to recommend either for or against the use of bamlanivimab and casirivimab?imdevimab.[14]

Respiratory support
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
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.[45][46] 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.[47] Whether either of these two leads to the same benefit for people who are critically ill is not known.[48] 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.[45]

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.[49]

Severe cases are most common in older adults (those older than 60 years,[45] and especially those older than 80 years).[50] 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.[51] This limited capacity is a significant driver behind calls to flatten the curve.[51] One study in China found 5% were admitted to intensive care units, 2.3% needed mechanical support of ventilation, and 1.4% died.[15] In China, approximately 30% of people in hospital with COVID‑19 are eventually admitted to ICU.[52]

The administration of inhaled nitric oxide to people being ventilated is not recommended, and evidence around this practice is weak.[53]

Acute respiratory distress syndrome
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.[54] Ventilators capable of pressure control modes and high PEEP[55] are needed to maximise oxygen delivery while minimising the risk of ventilator-associated lung injury and pneumothorax.[56]

Extracorporeal membrane oxygenation
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.[57]

Initial use of ECMO in COVID-19 patients from China early in the pandemic suggested poor outcomes, with >90% mortality.[58] 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.[59] 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.[60][61][62]

Prevention of onward transmission
The U.S. Centers for Disease Control and Prevention (CDC) recommends four steps to putting on PPE.[63]

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.[64] 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.[65][64]

Adequate ventilation, cleaning and disinfection, and waste disposal are also essential to prevent further spread of infection.[27]

Personal protective equipment
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.[66] 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.[67]

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.[68][69]

When available, respirators (instead of face masks) are preferred.[70] 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.[71] 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.[72] When masks are not available, the CDC recommends using face shields or, as a last resort, homemade masks.[73]

Psychological support
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.[74][75]

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."[76][77]

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.[14][78][79][80] One study from 22 April found that people with COVID‑19 and hypertension had lower all-cause mortality when on these medications.[81] 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.[82]

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.[25]

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.[83]

Clinical research and experimental treatments
See also: Coronavirus disease 2019 § Research, COVID-19 drug repurposing research, and COVID-19 drug development

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.[84] The safety and effectiveness of convalescent plasma as a treatment option requires further research.[85] Other trials are investigating whether existing medications can be used effectively against the body's immune reaction to SARS-CoV-2 infection.[84][86]

Antiviral medications

Research into potential treatments started in January 2020,[87] and several antiviral drugs are in clinical trials.[88][89] Although new medications may take until 2021 to develop,[90] several of the medications being tested are already approved for other uses or are already in advanced testing.[91] Antiviral medication may be tried in people with severe disease.[3] The WHO recommended volunteers take part in trials of the effectiveness and safety of potential treatments.[92]

Passive immunization
Convalescent plasma collected at a blood donor center during the COVID-19 pandemic.

Passive immunization with convalescent plasma or hyperimmune serum has been proposed as a potential treatment for COVID-19.[93]

In the United States, the FDA has granted temporary authorization to convalescent plasma (plasma from the blood of people who have recovered from COVID-19, which thus contains antibodies against SARS-CoV-2) as an experimental treatment in cases where the person's life is seriously or immediately threatened.[94] However, convalescent plasma treatment has not undergone the randomized controlled or non-randomized clinical studies needed to determine if is safe and effective for treating people with COVID-19.[93][95][96]

Argentina, Brazil, Costa Rica, and Mexico have pursued development of antisera.[97] Brazil began development of an equine hyperimmune serum, obtained by inoculating horses with recombinant SARS-CoV-2 spike protein, in mid-2020. A consortium of Instituto Vital Brazil, UFRJ, the Oswaldo Cruz Foundation and the D’Or Institute for Research and Education in Rio de Janeiro began preclinical trials in May 2020,[98] while Instituto Butantan in São Paulo completed animal testing in September.[97] In December 2020, Argentina granted emergency authorization to CoviFab, a locally developed formulation of equine hyperimmune serum, for use in cases of moderate to severe COVID-19, based on the initial results of a single phase 2/3 trial which suggested reductions in mortality, ICU admission, and mechanical ventilation requirements in patients who received the serum.[99][100] This was harshly criticized by the Argentine Intensive Care Society, which stated that the trial failed to achieve its primary or secondary endpoints and did not demonstrate any statistically significant differences between the serum and placebo groups.[100]

Vitamin D

There has been particular interest given the significant overlap in the risk factors for severe COVID-19 and vitamin D deficiency, including obesity, older age, and Black or Asian ethnic origin, noting that vitamin D deficiency is common in Europe and the United States particularly within these groups.[101] The general recommendation to take vitamin D supplements, particularly given the levels of vitamin D deficiency in Western populations, has been repeated.[102]

There are a number of clinical trials being undertaken to examine any specific role for vitamin D in COVID-19 prevention and management.[103] Emerging results indicate a link between vitamin D deficiency and the severity of the disease. A systematic review and meta-analysis of 27 publications found that, although vitamin D deficiency was not associated with a higher probability of becoming infected with COVID-19, there were significant associations between vitamin D deficiency and the severity of the disease, including relative increases in hospitalization and mortality rates of about 80%.[104] As of October 2020 there has been no advisory recommendation to use vitamin D or its metabolites specifically for COVID-19 therapy.[102]

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Treatment guidelines
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