Treatment Approach, Pharmacological Agents and Vaccines

Introduction

The goal of this chapter is to inform the neurologist of the disease-specific treatments that exist and are recommended for the patient with COVID-19. The proposed approach to management is tiered according to the severity of illness and encompasses medications that are recommended by several notable organizations, such as the National Institute of Health (NIH) and the Society of Critical Care Medicine (SCCM), according to their most recent guidelines. Treatment of severe COVID-19 is complex and requires expertise in critical care medicine including hemodynamic and ventilatory support, topics that are beyond the scope of this book. An appendix grouping several medications related to the care of patients with COVID-19 is provided at the end of this book (Appendix: Medication). We also present a summary table of the various treatments with a particular mention of the neurological complications and considerations for each one of them ( Table 12.1 ).

Treatment Approach for Patients With COVID-19

The approach more commonly adopted to caring for the hospitalized patient with COVID-19 depends on the degree of severity of the illness. Therefore defining severity in COVID-19 is important and one of the first steps in managing such patients. Dyspnea is the key in categorizing patients with suspected or confirmed COVID-19. Patients with no dyspnea but with other symptoms such as fever, chills, cough, malaise, anosmia, headaches, and upper respiratory symptoms are considered nonsevere and rarely require hospitalization. Once dyspnea is observed and the patient requires supplemental oxygen, the patient’s condition is deemed severe. The Surviving Sepsis Campaign Guidelines on the Management of Adults with Coronavirus Disease 2019 (COVID-19) in the ICU , for instance, further differentiates severe from critical disease. Severe disease concerns patients with clinical signs of pneumonia (e.g., tachypnea, dyspnea, fever, and cough) and one of the following: respiratory rate greater than 30 breaths per minute, severe respiratory distress, or oxygen saturation of less than 90% on room air. Critical disease identifies patients with acute respiratory distress syndrome (ARDS) or respiratory distress requiring mechanical ventilation, sepsis, or septic shock. The NIH Panel on COVID-19 Treatment Guidelines published a pharmacological management based on disease severity, which can be found in Fig. 12.1 .

In general terms:

• 1.

  Only supportive treatment and monitoring is recommended for patients with nonsevere disease.

• 2.

  Anti-SARS-CoV-2 monoclonal antibody combinations, such as bamlanivimab plus etesevimab, or casirivimab plus imdevimab, should be considered for nonhospitalized patients or patients with mild COVID-19 hospitalized for reasons other than COVID-19 who are at high risk of disease progression.

• 3.

  Dexamethasone is strongly recommended in patients who require any amount of supplemental oxygen and/or mechanical ventilation or extracorporeal membrane oxygenation (ECMO).

• 4.

  Remdesivir is the only FDA-approved medication for the treatment of COVID-19. It is recommended in patients on supplemental oxygen but not in patients who present to the hospital needing mechanical ventilation or ECMO, since their condition is considered too advanced to derive any significant benefit from the antiviral. The combination dexamethasone/remdesivir has not been studied in patients requiring mechanical ventilation.

• 5.

  Interleukin-6 antagonists, such as tocilizumab, can be added to dexamethasone in patients who display evidence of systemic inflammation or whose respiratory condition rapidly decompensates, requiring escalating levels of oxygen, increasing settings on noninvasive ventilation, or mechanical ventilation.

Importantly, several societies and organizations now recommend against the use of hydroxychloroquine or chloroquine (with or without azithromycin), for either hospitalized or nonhospitalized patients with COVID-19. Also, due to poor-quality data, insufficient data, or lack of benefit, the use of convalescent plasma or intravenous immunoglobulin (IVIG) is not authorized for use in nonhospitalized patients. The NIH Panel on COVID-19 Treatment Guidelines recommends against its use in patients with severe disease who are mechanically ventilated, or those who are hospitalized but not on mechanical ventilation, except in the context of a clinical trial. It is however authorized under the EAU for use in hospitalized patients with immune deficiencies. Additionally, due to lack of evidence, the guidelines recommend neither for nor against the routine use of therapeutic anticoagulation for hospitalized patients with COVID-19 who do not have confirmed venous thromboembolic disease.

Special Considerations for COVID-19-Specific Treatments in Patients With Neurological Conditions

In this section, we provide information about the neurological considerations of drugs used for the specific treatment of COVID-19. These drugs and a summary of their neurotoxicities can be found in Table 12.1 . We hope that neurologists consulting on hospitalized patients with COVID-19 will find this data relevant and useful.

Corticosteroids . Corticosteroids can have a plethora of complications depending on their route of administration, dose, and duration of use. In addition to hyperglycemia which can worsen encephalopathy, delay wound healing and independently worsen outcomes in patients with stroke or cerebral edema, these drugs have other more direct effects on central and peripheral nervous systems. Mood disturbances are the most pervasive and can occur with a few days of treatment, usually causing early euphoria and anxiety. Depression can set in with more prolonged therapy. Memory impairment also occurs with more protracted treatment and usually happens with increased frequency and more rapidly in elderly patients (3 months as opposed to 1 year). Psychosis also tends to happen with prolonged therapy and is therefore not expected in steroid therapy used for COVID-19 infection. Delirium, sleep disturbances, and akathisia (psychomotor restlessness) are typical central nervous side effects of corticosteroids. In addition to their central complications, steroids can lead to ICU-acquired weakness, ICUAW (also known as critical care myopathy and neuropathy), especially when coadministered with neuromuscular blocking agents, a combination that is commonly used for the treatment of severe ARDS in patients with COVID-19. The association between steroids and ICUAW is almost twofold. Other important risk factors for ICUAW are mechanical ventilation, prolonged ICU stay, and sepsis and septic shock. Finally, although a ubiquitous treatment for it, steroids can initially worsen a myasthenic crisis and need to be started or increased with caution in patients with a confirmed or suspected diagnosis of MG. IVIG or plasmapheresis may be needed as a bridge to steroids when the symptoms get worse with treatment.

Hydroxychloroquine/chloroquine . The antimalarial drugs are associated with a high risk of retinopathy which is dose and duration dependent (7.5%). Ototoxicity in the form of sensorineural hearing loss, tinnitus, and imbalance can happen with both chloroquine and hydroxychloroquine and tends to happen more abruptly with the former and more insidiously with the latter. The ototoxicity risk at the doses used in COVID-19 infection is however not known. Furthermore, these drugs can also prolong the QT interval, making the choice of antipsychotics in delirious patients with COVID-19 more challenging. They have been linked to several psychiatric manifestations such as mania, depression, and psychosis as well as central nervous side effects like insomnia, dizziness, and headache in 4%–6% of patients. Although seizure is listed in the package insert for both drugs, it is a very rare occurrence and data is limited to case reports and case series, without any causal relationship firmly established.

Immunoglobulins . Thromboembolic events after IVIG can occur within hours to days of treatment for arterial clots and days to weeks for venous ones. They can lead to acute coronary syndromes, transient ischemic attacks (TIA) and stroke, cerebral venous sinus thrombosis, pulmonary embolism, and deep venous thrombosis (DVT). Adequate hydration, slowing down the rate or breaking down the infusion into several smaller doses can help prevent this complication. Discontinuing the treatment is likely the safest approach in cases of thromboembolic events. Aseptic meningitis is another neurological complication of IVIG. It occurs in about 1% of patients and its pathophysiology is poorly understood. It is a self-limiting condition and resolves by slowing down the rate of infusion along with symptomatic care including use of proper hydration, analgesics, antipyretics, and antihistamines.

Ivermectin . The anthelmintic is not used or recommended for use in COVID-19 outside of clinical trials in the United States. It is used in countries like India, South Africa, Zimbabwe, or Mexico. This drug is known to cause dizziness (2.8%), vertigo, tremor, and lethargy (< 1%). Although coma and encephalopathy were reported in patients treated with ivermectin for Onchocerciasis volvulus in Africa, many of these cases were thought to be due to concomitant infection with Loa loa (loiasis). Cotreatment with drugs that inhibit the CYP3A4 enzyme can also predispose to higher neurotoxicity from ivermectin.

Tocilizumab. Headaches (7%) and dizziness (3%) are the most commonly reported nervous side effects of tocilizumab. A case of multifocal cerebral microangiopathy arising shortly after a single infusion of the medication in a patient with rheumatoid arthritis was reported and was believed to be an immune-mediated vasculitic process. Additionally, two cases of leukoencephalopathy in patients with rheumatoid arthritis treated with tocilizumab were reported. One of them was associated with limbic encephalitis and both cases showed symptoms several months following treatment with the IL-6 antagonist. These are believed to be exceedingly rare occurrences.

Introduction

Due to the rapid spread and devastating effects caused by SARS-CoV-2 on the human loss of life and livelihood, the need for vaccine development has been an unrivaled priority. Publication of the viral genome in January 2020 enabled many pharmaceutical companies around the world to start developing a variety of vaccines against the pathogen.

Vaccines have to go through a rigorous series of steps before being approved for marketing. After research, discovery, and development, the vaccine is tested in animals (preclinical stage). In all, 77 COVID-19 vaccines are currently undergoing animal trials. If the vaccine passes this first checkpoint, it proceeds to phase 1 clinical trials. In this phase, the safety of the vaccine using various doses is determined by testing it in a small group of healthy volunteers (20–100 subjects). There are currently 49 COVID-19 vaccines in phase 1 trials. Phase 2 trials are randomized, controlled, and recruit hundreds of patients at risk for developing the condition. The goal is to measure the vaccine’s immunogenicity (i.e., the ability of the vaccine to elicit an immune response) and determine its tolerability and safety. A total of 37 COVID-19 vaccines are currently in phase 2 trials. Phase 3 aims at gathering more information on the effectiveness of the vaccine and detecting less common side effects by recruiting a much larger cohort of subjects (usually, thousands) and randomizing them to vaccine or placebo arm. For vaccine approval, the United States FDA generally recommends that there be at least a 50% reduction in the primary endpoint of the phase 3 trial, which is usually effective in vaccine development. In all, 27 COVID-19 vaccines are presently in this third stage of the study. In the United States, three vaccines (BNT162b2, mRNA-1273, and Ad26.COV2·S) have received authorization for emergency use by the FDA but are not yet fully approved. Four vaccine trials were ultimately abandoned due to lack of effectiveness.

Further complicating the matter are the naturally occurring sporadic mutations of the virus leading to regional variants that are more transmissible, evade the traditional detection assays, and make vaccine development more challenging. Among the many SARS-CoV-2 virus mutants present across the world, five are of specific concern in the United States because they lead to more severe disease, greater transmissibility, and decreased neutralization by antibodies acquired via infection or vaccination: the United Kingdom, the South African, the Brazilian, and the two California variants.

Of note, none of these vaccines has been studied in human pregnancy or children, although some trials are currently underway in these populations. Long-term effects are still not known due to a lack of data but are presumed to be few. All currently used vaccines are in the form of intramuscular injection although there are several nasal mist vaccines in development.

At the time of writing, at the end of the first week of May 2021, approximately 257 million vaccines have been administered in the United States, with 34% of the population being fully vaccinated and 46% having received at least one dose. Pfizer-BioNTech’s vaccine leads in the number of doses administered followed closely by Moderna’s mRNA-1273. Johnson & Johnson/Janssen’s Ad26.COV2·S vaccine trails behind others due to the later issuance of emergency use authorization by the FDA.

Types of SARS-CoV-2 Vaccines

Most human antibodies produced in response to SARS-CoV-2 are in the form of neutralizing antibodies directed against the receptor-binding domain of the spike protein, which is located on the surface of the viral envelope and acts as the portal of viral entry into the host cells ( Chapter 2 ). Variants of SARS-CoV-2 generally carry a mutation in the receptor-binding domain of the spike protein. Although most mutations make the virus less infectious, some of them, like D614G present in all the variants of interest mentioned above, have been shown to increase the virus’ affinity to the ACE2 receptor, evade the host’s neutralizing antibodies, and jeopardize vaccine effectiveness since the vast majority of vaccines target the spike protein.

Vaccines currently developed for COVID-19 come in different flavors, such as mRNA, adenoviral vector, protein subunit, DNA, or inactivated viruses. Each vaccine type is associated with a different mechanism of action, delivery method, advantages, and disadvantages. Here, we give a brief overview of the various types along with a description of a few pharmaceutical products in use around the world for each category. Table 12.2 gives a summary of the efficacy, regimen, and neurological complications of some of the marketed vaccines in use around the world.