Treatment of COVID-19 in Adults
Nikolaus Jilg
Adil Yunis
Christopher Newton-Cheh
Rajesh T. Gandhi
INTRODUCTION
COVID-19, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), emerged in late 2019 and rapidly evolved into a global pandemic. Basic, translational, and clinical research have informed the development of novel drugs for the treatment of COVID-19. In addition, agents already in clinical use for other indications were studied for their potential role in treating COVID-19. In this chapter, we provide an overview of the evolving pharmacologic management of COVID-19. As therapeutic recommendations for COVID-19 change frequently, it is important to consult the latest guidelines when caring for patients. Here, we provide a framework for understanding the role of different therapeutic options and summarize the development of current management strategies.
THERAPEUTIC RESEARCH DURING A PANDEMIC
Development of successful therapies for COVID-19 happened at an unprecedented speed and required herculean efforts by clinical scientists, study participants, research organizations, foundations, the pharmaceutical industry, and governments. In the early months of the pandemic, there were massive obstacles to conducting clinical trials, including supply chain disruptions that hindered or prevented SARS-CoV-2 testing and led to shortages of personal protective equipment for healthcare workers and researchers; limitations on movement of study participants and investigators; and immense clinical needs requiring academic medical centers and clinicians (including clinical scientists) to focus on clinical care in overcrowded hospitals. Conversely, there was a single-minded focus on
COVID-19 research given the magnitude of the problem, with streamlining and acceleration of research to a pace that exceeded any previous era.
COVID-19 research given the magnitude of the problem, with streamlining and acceleration of research to a pace that exceeded any previous era.
The urgent need to address the COVID-19 crisis and public pressure on politicians, clinicians, researchers, health officials, and others also resulted in early or misguided therapeutic decisions that were based on preliminary and incomplete data or invalid extrapolation of data. For instance, many people, including patients and their relatives, caregivers, and public figures, were vocal about potential benefits in COVID-19 of drugs that had been approved for other indications. Examples of medications that were recommended in the absence of sufficient evidence are the human immunodeficiency virus (HIV) medication lopinavir/ritonavir, the antiparasitic treatment ivermectin, and the antidepressant fluvoxamine. Other medications that temporarily became standard of care for the treatment of COVID-19 in some areas were azithromycin and hydroxychloroquine. All these medications were later found to be ineffective for COVID-19 in large randomized clinical trials. Use of drugs with insufficiently proven efficacy against COVID-19 not only exposes patients to the risk of adverse events but also has the potential to impede clinical research. Emergency use authorization (EUA) of hydroxychloroquine for the treatment of COVID-19, which was eventually withdrawn, may have dissuaded patients from participation in placebo-controlled trials. Moreover, supply shortages of hydroxychloroquine limited access for patients with rheumatologic illness and some in the public ingested high doses of ivermectin from supplies unintended for human consumption.
It was only when well-conducted, randomized controlled trials started yielding results in May 2020 that progress was made. In the United States, the Adaptive COVID-19 Treatment Trial (ACTT) evaluated the use of remdesivir, an intravenous antiviral originally developed for Ebola, in hospitalized patients with COVID-19 pneumonia. Preliminary results demonstrated that remdesivir significantly shortened the time to recovery, which, in the absence of any other therapeutic options, led to swift EUA by the U.S. Food and Drug Administration (FDA), and recommendations to use remdesivir to treat hospitalized patients with severe COVID-19 followed almost instantaneously. Soon thereafter, the RECOVERY trial in the United Kingdom demonstrated that dexamethasone, which decreases inflammation, reduced mortality in hospitalized patients requiring oxygen supplementation. These two early randomized studies set the stage for future trials of novel and repurposed agents.
Ultimately, the lesson of COVID-19 therapeutics is a reminder of what we learned during the early days of HIV and, more recently, during Ebola. Not only can randomized clinical trials be performed during a pandemic, they must be done during a pandemic.1,2 For in the face of a new infectious threat, we do not know what does and does not work, and randomized trials are the most definitive method for answering critical therapeutic questions.
CLINICAL MANAGEMENT OF COVID-19
Management of COVID-19 has evolved considerably since the illness was first recognized in late 2019.3 Various medical organizations have published guidelines for the management of individuals with COVID-19. Given the rapid changes in clinical management, it is important to consult the latest guidelines when caring for patients.4
Most people with COVID-19 experience mild-to-moderate disease that does not require hospitalization. However, moderate disease, defined as clinical or radiographic evidence of lower respiratory tract infection in the absence of hypoxemia, requires close monitoring because of the risk of progression, as does severe disease, which is characterized by dyspnea, hypoxemia, or infiltrates involving more than 50% of the lungs. In severe COVID-19, hospitalization is typically indicated (Table 15.1).
TABLE 15.1 Clinical spectrum of COVID-19 and staging by severity | ||||||||||||||
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Initial Considerations
Identifying patients who are at high risk for progression to severe COVID-19 is a priority, and research on predictors, including identifying biomarkers, is ongoing. Known risk factors for severe COVID-19 include older age, male sex, obesity, many forms of immunosuppression (including immunosuppressive medications), and chronic medical conditions like lung disease, cardiovascular disease, chronic kidney or liver disease, diabetes mellitus, and cancer.5, 6, 7, 8 and 9 Patients with these and other
high-risk conditions should be closely monitored for signs and symptoms of progression, such as shortness of breath, hypoxemia, confusion, chest pain, or other unexplained symptoms, and if these conditions develop, additional expeditious evaluation is warranted.
high-risk conditions should be closely monitored for signs and symptoms of progression, such as shortness of breath, hypoxemia, confusion, chest pain, or other unexplained symptoms, and if these conditions develop, additional expeditious evaluation is warranted.
There is a correlation between increasing age and risk for severe COVID-19, and younger children are at lower risk for most complications than older children and adults. Children, however, may develop complications such as multisystem inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection. As the pandemic progresses, the correlation between age and complications may change as individual and population immunity evolve and new viral variants emerge. The correlation between age and risk for complications is different for other respiratory diseases like respiratory syncytial virus (RSV) or influenza in which, for example, neonates have a higher risk for severe complications than older children.
People who have had a known exposure to COVID-19 or who have symptoms compatible with COVID-19 should be prioritized for SARS-CoV-2 testing and evaluated for possible treatment. Distinguishing COVID-19 from other acute respiratory and febrile illnesses is important as there are differences in specific therapies. Of note, patients can have concomitant or subsequently other viral or bacterial infections, which may require additional treatment. Depending on the risk for other infections, additional testing (eg, for influenza, RSV, and other circulating respiratory viruses, or for bacterial or fungal pneumonia) should be performed if the findings will change clinical management.
Management of Acute COVID-19
Development and evaluation of new therapeutic strategies for acute COVID-19 are ongoing. The goals of treatment in the initial stages of COVID-19 are to reduce symptoms, hasten clinical recovery, and prevent complications, including progression to severe COVID-19 and postacute sequelae of SARS-CoV-2 infection (PASC). There is a continuing need for more efficacious medications against COVID-19. Moreover, host and viral determinants are in flux and may necessitate adjustments of therapeutic strategies in the future. For example, the immune status of individuals and the population at large continues to change because of prior infection with SARS-CoV-2 and vaccination. In addition, SARS-CoV-2 continues to evolve with emergence of variants with pronounced differences in transmissibility, immune evasion, and, possibly, virulence. As individual and population immunity changes and as new viral variants develop, therapeutic strategies will continue to evolve to meet the goals of hastening recovery and preventing complications.
Supportive Care
Supportive care focuses on reducing symptoms and generally includes the use of antipyretic and analgesic medications, for example, nonsteroidal anti-inflammatory drugs (NSAIDs) or acetaminophen, and antitussives to control cough, as well as rest and adequate hydration. Although there was initial
speculation about the detrimental effects that NSAIDs may have on the course of COVID-19, this concern was subsequently not confirmed.10,11 Hence, medications like NSAIDs and acetaminophen are regarded as safe options for symptom relief in people with COVID-19.
speculation about the detrimental effects that NSAIDs may have on the course of COVID-19, this concern was subsequently not confirmed.10,11 Hence, medications like NSAIDs and acetaminophen are regarded as safe options for symptom relief in people with COVID-19.
For hospitalized patients with hypoxemia, therapy consists of pharmacologic agents along with respiratory and, at times, circulatory support and renal replacement therapy. Respiratory support may include provision of conventional oxygen, high-flow nasal cannula oxygen, noninvasive ventilation, mechanical ventilation, or extracorporeal membrane oxygenation (ECMO).
COVID-19 Pathogenesis and Therapeutic Options
Therapies for COVID-19 have advanced in line with our understanding of COVID-19 pathogenesis (Figure 15.1).12,13 Initial symptoms and signs of COVID-19 are likely related to viral replication in the upper respiratory tract. Accordingly, patients with early COVID-19 usually have high levels of SARS-CoV-2 RNA in the nasopharynx; it is in this phase of the infection that antiviral therapies are thought to be most effective. By contrast, during the phase of severe COVID-19 when people are hospitalized, viral levels in the upper respiratory tract may be declining, but there is evidence for pneumonia and systemic inflammation, which may trigger hypercoagulability and dysfunction of multiple organs. During severe and critical COVID-19, anti-inflammatory/immunomodulatory medications and, in some individuals, anticoagulants are the mainstays of therapy. There is certainly overlap between phases, such that people who are early in their hospitalization course or who have high levels of circulating SARS-CoV-2 may still benefit from the use of specific antiviral agents, such as remdesivir.
 FIGURE 15.1 Pathogenesis and treatment across the COVID-19 spectrum. COVID-19, coronavirus disease 2019; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. (Adapted from Gandhi RT. The multidimensional challenge of treating coronavirus disease 2019 (COVID-19): remdesivir is a foot in the door. Clin Infect Dis. 2021;73:e4175-e4178; Gandhi RT, Lynch JB, Del Rio C. Mild or moderate Covid-19. N Engl J Med. 2020;383:1757-1766.) |
Pharmacologic Treatment Options for Nonhospitalized Patients With COVID-19
Specific antiviral therapies for mild-to-moderate COVID-19, typically in nonhospitalized patients, are in clinical use. As of January 2023, these include ritonavir-boosted nirmatrelvir (orally for 5 days), remdesivir (intravenously for 3 days) and, if those are not available or feasible to use, molnupiravir (orally for 5 days).
These medications are currently reserved for patients at high risk for progression to severe disease who have recently developed signs and symptoms of COVID-19.14 However, the criteria for treatment are likely to evolve as additional research informs use of these and other medications. Not all patients qualify for the same medications (depending on regulatory agency authorization), and some individuals have contraindications to certain therapies, for example, those who must receive concomitant medications that have significant interactions with the ritonavir component of ritonavir-boosted nirmatrelvir.
The National Institutes of Health (NIH) COVID-19 Treatment Guideline Panel has prioritized different risk groups to facilitate allocation of treatments to patients who are most likely to benefit and to inform triage decisions when drug supplies or ability to administer agents is limited (Table 15.2). The tiers and risk factors may be revised with changing virology and epidemiology of COVID-19 and further understanding of risk factors. For example, underlying medical conditions that are considered to be associated with higher risk for severe COVID-19 have changed over time, hence it is recommended to refer to up-to-date, current information like the one provided by the Centers for Disease Control and Prevention in the United States.14
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