Approach —
The optimal approach to treatment of COVID-19 is uncertain. Trial data suggest a mortality benefit with dexamethasone and a possible clinical benefit with remdesivir, but no other therapies have clearly proven effective. Based on the pathogenesis of COVID-19, approaches that target the virus itself (eg, antivirals, passive immunity, interferons) are more likely to work early in the course of infection, whereas approaches that modulate the immune response may have more impact later in the disease course.
Thus, in addition to dexamethasone and/or remdesivir for eligible patients, we strongly recommend enrollment into a well-controlled clinical trial, when available. Our approach is consistent with recommendations from expert groups in the United States, which also endorse clinical trial enrollment. The IDSA additionally recommends that certain therapies (including convalescent plasma, lopinavir-ritonavir, tocilizumab, and famotidine) only be administered in the context of a clinical trial because of a greater level of uncertainty or potential for toxicity [32]. Similarly, the NIH COVID-19 Treatment Guidelines Panel specifically recommends against using certain therapies (including IL-6 pathway inhibitors, HIV protease inhibitors, ivermectin, interferons, and kinase inhibitors) outside the context of a clinical trial [4].
A registry of international clinical trials can be found at covid-trials.org, as well as on the WHO website and at clinicaltrials.gov.
We use a risk-based approach to try to enroll those patients who may be most likely to benefit. The approach is dependent on local availability of clinical trials and may not be universally applicable. Clinicians should consult their own local protocols for management.
Defining disease severity — Mild disease is characterized by fever, malaise, cough, upper respiratory symptoms, and/or less common features of COVID-19, in the absence of dyspnea. Most of these patients do not need hospitalization.
If patients develop dyspnea, that raises concern that they have at least moderate severity disease, and these patients often warrant hospitalization. Patients can have infiltrates on chest imaging and still be considered to have moderate disease, but the presence of any of the following features indicates severe disease:
●Hypoxia (oxygen saturation ≤94 percent on room air)
●Need for oxygenation or ventilatory support
This definition is consistent with the definition used by the US Food and Drug Administration [138]. Some studies have used other features in addition to hypoxia to characterize severe disease, such as tachypnea, respiratory distress, and >50 percent involvement of the lung parenchyma on chest imaging [139].
Thresholds for oxygen supplementation are discussed in detail elsewhere. (See "Coronavirus disease 2019 (COVID-19): Critical care and airway management issues", section on 'Respiratory care of the nonintubated patient'.)
Nonsevere disease — For most hospitalized patients with nonsevere disease, we suggest supportive care only, with close monitoring for clinical worsening. If they develop features of severe disease (eg, hypoxia or oxygen requirement (see 'Defining disease severity' above)), we treat them as described below. (See 'Severe (including critical) disease' below.)
Some patients with nonsevere disease have laboratory abnormalities that are associated with progression to severe disease (table 1). We prioritize these patients for clinical trials for treatment of nonsevere disease in addition to monitoring them closely for progression. A registry of international clinical trials can be found at covid-trials.org. In the United States, EUAs have been granted for convalescent plasma and for remdesivir for hospitalized patients with COVID-19, regardless of severity. We do not use convalescent plasma outside clinical trials for patients with nonsevere disease. However, plasma obtained through the EUA may be a reasonable option for such patients in locations where access to clinical trials is limited, with the caveat that the benefit remains uncertain. We also do not routinely use remdesivir for patients with nonsevere disease, as studies suggest only a modest benefit of uncertain clinical significance in this population, availability may be limited, and we prioritize it for patients on low-flow oxygen at baseline. (See 'Convalescent plasma and other antibody-based therapies' above and 'Remdesivir' above.)
We recommend not using dexamethasone in patients with nonsevere disease. (See 'Dexamethasone and other glucocorticoids' above.)
Severe (including critical) disease — We prioritize COVID-19-specific therapy for hospitalized patients who have severe disease. The approach depends on the oxygen or ventilatory requirement:
●Patients with severe disease (ie, with hypoxia) but without oxygen requirement – For these patients, we suggest remdesivir; however, if supplies are limited, we prioritize remdesivir for patients on low-flow oxygen supplementation at baseline, as below. We suggest not using dexamethasone in such patients. Trial data in this population suggest that remdesivir may improve time to recovery and that dexamethasone does not confer a mortality benefit and may cause harm.
●Patients with severe disease who are receiving supplemental oxygen – For patients on supplemental oxygen (including those who are on high-flow oxygen and noninvasive ventilation), we suggest low-dose dexamethasone. Trial data suggest that dexamethasone improves mortality in patients who are on noninvasive oxygen supplementation; it is uncertain if there are particular patients in this relatively heterogeneous group who would benefit more than others.
For patients who are on low-flow supplemental oxygen only, we also suggest remdesivir. Subgroup analysis of trial data suggests that remdesivir improves mortality in patients who are on low-flow supplemental oxygen, but clinical benefit is less certain in patients who need higher levels of noninvasive support (eg, high-flow oxygenation and noninvasive ventilation). We also suggest remdesivir in patients with higher levels of noninvasive support, but prioritize it for patients on low-flow supplemental oxygen.
●Patients with severe disease who require mechanical ventilation or ECMO – For such patients, we recommend low-dose dexamethasone as trial data suggest that dexamethasone improves mortality in this population. Because the clinical benefit of remdesivir is less certain for this population, we only suggest remdesivir in patients who have been intubated for a short period of time (eg, 24 to 48 hours). If the supply is limited, we prioritize remdesivir for patients who are on low-flow supplemental oxygen, as above.
Remdesivir and dexamethasone have not been systematically evaluated in combination, however, based on their pharmacokinetic characteristics, a clinically significant drug interaction is not anticipated [140]. If dexamethasone is not available, other glucocorticoids at equivalent doses are reasonable alternatives. Remdesivir is approved or available for emergency use in some countries but is not universally available [141-143]. Furthermore, some guidelines panels suggest not using remdesivir because of a lack of clear reduction in mortality [34,43]. Details on administration of remdesivir and dexamethasone and the evidence supporting their use are found elsewhere. (See 'Remdesivir' above and 'Dexamethasone and other glucocorticoids' above.)
In addition to these therapies, we often refer patients to clinical trials of other therapies, if they allow concurrent use of remdesivir and/or dexamethasone. Other therapies being evaluated in trials include additional antiviral agents, convalescent plasma, and immunomodulatory agents (including cytokine inhibitors and kinase inhibitors). A registry of international clinical trials can be found at covid-trials.org. Detailed discussion of these agents is found elsewhere. (See 'Specific treatments under evaluation' above.)
We do not routinely use convalescent plasma outside clinical trials because a clear clinical benefit has not been demonstrated. In the United States, convalescent plasma is available through EUA, and other clinicians may choose to use it as additional therapy for patients with severe disease. If used, the potential benefit appears most likely with administration early in the course of severe disease, when virus replication appears to be greatest (ie, prior to the need for intubation). (See 'Convalescent plasma and other antibody-based therapies' above.)
Although baricitinib has also been granted EUA to be used in combination with remdesivir for patients on oxygen or ventilatory support, we await additional data on the effect of baricitinib before using it with remdesivir in such patients. (See 'Remdesivir' above and 'Others' above.)
We generally suggest against off-label use of other agents. Although repurposed use of agents available for other medical indications has been described, for most of these agents there are insufficient data to know whether they have any role in treatment of COVID-19; thus, we recommend that such agents only be used in the setting of a clinical trial.
In particular, we suggest not using hydroxychloroquine or chloroquine in hospitalized patients; available data do not suggest a clear benefit and do suggest the potential for toxicity. We also suggest not using lopinavir-ritonavir in hospitalized patients.
Originally Posted by Nephrology
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