Introduction
During the early days of the pandemic there was no known early effective treatment for outpatients with COVID-19. Initial treatment was symptomatic care with antipyretics, analgesics, antitussives, bronchodilators, and antibiotics.1–3 Patients were advised to go to the emergency room if they could not breathe or they noticed their “lips to turn blue.”1,4 This approach led to patients present late in their disease during the pulmonary phase of the disease.3,5 During the pulmonary phase of the disease a large proportion of patients require oxygen and many deteriorate requiring intensive care admission thus overwhelming hospital resources.3,5–7 Antiviral therapy with Remdesivir is less effective during this phase which is characterized by severe inflammation and thrombosis.3,6,8 With the exception of monoclonal antibody therapy for high-risk patients, in the majority of western developed countries such as the United States, United Kingdom, France, and Germany, public health authorities (national institutes of health (NIH), national health service (NHS), food and drug administration (FDA)) offer no effective outpatient management protocols.1,9–14 In terms of outpatient therapies, there remains a paucity of large randomized, double-blinded placebo-controlled trial. Studies evaluating potential candidate agents for outpatient therapy have included investigator-led studies, observational, small placebo-controlled trials, and open label studies. This approach has been criticized by evidence-based medicine (EBM) purists as being small, underpowered, and containing significant bias.2,3,6,12,14/ Meta-analysis performed by different groups have yielded conflicting reports. Although application of the principles of EBM is the gold standard approach to care, this may not be feasible or appropriate during a pandemic.3,6 It is the opinion of the authors that the reliance on large trials by “the Ivory Tower” evidence-based purists has led to some degree of therapeutic nihilism.
Many clinicians caring for patients afflicted with COVID-19 have based their treatment decisions based on what we have learned about the virology, the clinical phases, and the pathophysiology of disease to devise early treatment protocols.3,6,8 COVID-19 disease progression can be characterized by an asymptomatic viremic phase, a symptomatic viremic phase, an early inflammatory pulmonary phase, and a late pulmonary phase.3,6,8,15 As the disease progresses viral-induced injury decreases, and a hyperinflammatory coagulopathic state ensues. Using this approach, timing of treatment has been based on knowledge of the phases of disease employing antivirals, immunomodulatory, anti-inflammatory, and antithrombotic agents.6,8,15 Proponents of early outpatient multifaceted treatment such as McCullough, Zelenko, Marik, the Front line critical care consortium (FLCCC), and others have devised early multifaceted protocols that have the potential to decrease the severity and burden of disease.3,6,15–17 The current therapeutic arsenal for outpatient therapy includes nutraceuticals, repurposed agents that have shown potential as antiviral and anti-inflammatory agents. This chapter will review the principles of early treatment based on the phases of the disease. It is important to note that this chapter covering early outpatient treatment includes nutraceuticals, repurposed medications, and agents that have demonstrated basic science evidence of potential benefit or low-level evidence of benefit. Many of these protocols have not undergone the thorough, evidence-based scrutiny in large, randomized placebo-controlled trials which in the current crisis is difficult to perform. In contrast to western developed nations, many countries’ health authorities have developed outpatient protocols.
We briefly discuss potential agents and timing of therapy in outpatients. For a more detailed discussion on therapeutic agents, we refer you to Chapter 12.
Paradigm of Early Treatment: The Phases of Disease and Treatment
Infection with SARS-CoV-2 results in COVID-19 disease, which generally progresses through at least three distinct phases during the clinical course of disease, and therapy should be directed with this understanding.6,8,15,18 The early viremic phase progresses from an asymptomatic to a symptomatic phase and is associated with rapid viral replication followed by activation of the innate and adaptive immunity (approximately day 1–7).8,15,18 An appropriate immune response results in viral clearance and resolution of symptoms.15,18 However, in a proportion of patients even as viral load decreases, dead viral particles, viral proteins, and pseudovirions generate a dysregulated immune response, and an exaggerated increase in proinflammatory macrophages and cytokines (Fig. 18.1). The net result is an organizing pneumonia and in some patients progressive hypoxemia respiratory failure and the cytokine storm.8,18,19
Risk Stratification and Early Therapy
In approximately 80% of patients SARS-CoV-2 infection is either asymptomatic or self-limited.3,5,20,21 However, in the remaining 20% of individuals disease progress is severe, with a high risk of morbidity and mortality.1 Therefore, patients likely to derive the greatest benefit of early treatment are those with comorbidities, age 60 or greater, those with underlying comorbidities regardless of age, and moderately ill patients regardless of age-displaying dyspnea.
Home Monitoring
Patients diagnosed with COVID-19 should be instructed on frequent home pulse-oximetry monitoring. Patient monitoring can be performed using telehealth.22–24 Although the field of home pulse oximetry is complex and is beyond the scope of this chapter, suffice to say that inexpensive nonmedical use pulse oximeters have been compared to those approved for medical use and have demonstrated reasonable accuracy in arterial oxygen saturations between 90 and 99%.22–24 Smart phone pulse oximeters have been found to lack accuracy for home monitoring and the use of these devices is discouraged. Hospital or urgent care evaluation is advised when saturation falls below 94. At this level early identification helps those patients who are at high risk for clinical decompensation and require in-person evaluation.22–24 Initially it was thought that pulse oximetry in individuals of brown or black color would be inaccurate; however, this is usually when oxygen saturations fall below 80% which is way below the threshold that would raise alarm in the outpatient management of COVID-19.22–24 Measurement should be taken using the index finger. There should be no nail polish on the persons nail. After allowing approximately 1 minute to allow for a clear pulse signal recording, proceed with obtaining readings. Only readings associated with a strong pulse signal should be recorded. Measurement should be observed over 1 minute and the average reading should be recorded. Reading should be obtained indoors with individual at rest; however, if patients’ clinical course dictates readings can be measured with walking or increased activity.22–24
It is pertinent to note that in western developed nations patients are usually hospitalized when oxygen therapy is required; it is not unfeasible to utilize all noninvasive oxygenation methods in the outpatient settings in areas where hospital resources are limited or overburdened.
Phases of Disease and Treatment
Viremic Phase
Monoclonal Antibody Therapy
Monoclonal neutralizing antibodies directed against SARS-CoV-2 have been implemented in clinical trials and have obtained emergency use agreement (EUA) for the treatment of high-risk patients with COVID-19.9,11,25,26 Combination monoclonal antibody therapy seems to be more effective than monotherapy.27 A Cochrane review of monoclonal therapy revealed that outpatient therapy with bamlanivimab/etesevimab compared to placebo decreased hospitalization by day 29.28 Casirivimab/imdevimab compared to placebo was found to reduce hospital admissions or death.10,11 We recommend early implementation of these agents in patients who are at high risk for hospitalization, worsening disease, or death.
Oral Antiviral Agents
Hydroxychloroquine (HCQ) and Chloroquine (CQ)
Chloroquine and hydroxychloroquine due to in vitro antiviral effects and immunomodulatory effects were one of the first medications repurposed for the management of COVID-19.29,30 Both agents are zinc ionophores facilitating zinc uptake into the intracellular compartment where zinc can exert antiviral activity.31,32 In Wuhan, China, initial reports by Gao demonstrated that CQ improved the clinical course of COVID-19 pneumonia and shortened duration of disease; however, this study to date has not released datasets.33
Hydroxychloroquine given along with zinc and azithromycin initially demonstrated clinical benefits in terms of symptom resolution, decreased hospitalization, and mortality in multiple retrospective and large observational studies.34–39 However, prospective randomized controlled trials and Cochrane group meta-analysis demonstrated no clinical benefit.30,40–43 Observational and retrospective data on early outpatient therapy employing HCQ have demonstrated improved clinical symptoms and decrease hospitalization rates.34–39 There have been very little prospective randomized trials employing HCQ. Many of these trials have been stopped prematurely for futility and unknown reasons.40,41,44 Schwartz et al, in a randomized double-blind study that did not reach enrollment goals and terminated early, enrolled patients with up to 12 days of symptoms, demonstrated no clinical benefit in the HCQ group.41 The Together trial was a randomized trial comparing HCQ, lopinavir/ritonavir against placebo. This trial found no difference in resolution. The trial was terminated early due to futility and it is unclear if this trial is representative of early therapy.40 Skipper et al performed a randomized double-blind trial evaluating HCQ versus placebo and demonstrated no clinical benefit of HCQ.44 It is pertinent to note that the placebo employed in this trial did not use inert substance and there was PCR confirmed cases in only 58% of patients.44 Thus there remains controversy regarding HCQ; regardless it is still incorporated in some outpatient early protocols. If HCQ or CQ is used in protocols for outpatient therapy, it is prudent to monitor for QTc interval prolongation and drug–drug interactions.
Interferon
Type 1 interferons (IFNs) are a group of cytokines which are one of the bodies’ innate immune response defenses against viral infection.45,46 They possess antiviral properties and are known to inhibit viral proteases.47,48 In patients with advancing age, comorbidities, and a subset of patients at high risk for progression, there may be a blunted IFN response to SARS-CoV-2 infection. In addition SARS-CoV-2 proteins particularly open reading frame (ORF) 3b, ORF 6, and nucleocapsid are known to inhibit expression of IFNs.46 From a pathophysiological standpoint, Mosaddeghi et al demonstrated that individuals with an initial decreased expression of IFN during the early stages of infection had a higher risk of mortality.46,49 The investigators proposed early therapy with IFN.46 Thus, there has been a significant interest in employing IFN therapy in patients with infection. In a meta-analysis, Nakhlband and colleagues demonstrated that the administration of subcutaneous IFN-β1 in conjunction with antiviral therapy improved hospital length of stay and mortality in hospitalized patients with COVID-19.47 In a randomized, outpatient, placebo-controlled trial comparing IFN-λ1 versus placebo, Feld et al demonstrated an accelerated viral clearance particularly in those with high viral loads.50 Idelsis et al in a randomized controlled trial of intramuscular injection of IFN-α2b and IFN-γ demonstrated improved viral clearance and improved symptoms in patients with COVID-19.51 In a large retrospective study with over 1,400 patients, inhalational therapy with 5 million units bid of IFN-α2b therapy observed that early treatment within 0 to 2 days of symptom onset resulted in decreased need for mechanical ventilation and mortality.52 In those patients where treatment was initiated 3 to 5 days later from symptom onset, clinical outcomes were noted to be poor.52
Favipiravir (FAV) is an orally administered antiviral agent that has demonstrated a broad-spectrum in vitro and in vivo antiviral activity against many negative-stranded RNA viruses.53 Similar to Remdesivir it is an inhibitor of RNA polymerase.53 In hospitalized patients there has been encouraging results in improved rates of recovery, viral shedding, and trend in decreasing rates of the need for mechanical ventilation.53–55 The ability of oral administration makes FAV an attractive agent for early outpatient protocols. Based on the interim results of a Russian phase II/III demonstrating improved viral clearance and resolution of symptoms in patients with moderate COVID-19, the agent has been approved for outpatient and inpatient use by Russian health authorities.56 FAV is also approved for the treatment of COVID-19 by Indian health authorities.57 It is important to note that the dosages employed for COVID-19 1,600 to 2,000 mg bid day 1 followed by 600 to 800 mg bid for up to 14 days may result in side effects such as hyperuricemia elevated transaminases and significant gastrointestinal side effect.58,59 Furthermore, FAV is teratogenic, and appropriate contraceptive measures should be employed.58 There are some pertinent drug–drug interactions such as sulfonylurea toxicity-associated hypoglycemia.59
Antibiotics
Azithromycin (AZA) and Doxycycline (DOXY)
Although AZA and DOXY have demonstrated antiviral properties and have been employed in outpatient treatment protocols,60 it is the opinion of the authors that there is no benefit in adding these patients to outpatient protocols unless there is a suspicion of an underlying secondary infection.
Nitazoxanide (NTZ), an oral antiprotozoal agent, has demonstrated in-vitro and in-vivo antiviral activity and has been employed in small clinical trials against a variety of viruses.61,62 In a small, double-blind randomized placebo-controlled trial involving 50 hospitalized patients, NTZ 600 mg bid started within 3 days of symptoms and 36 hours of admission, investigators demonstrated a significant reduction in hospital length of stay, greater resolution to SARS-CoV-2 PCR negativity, and a reduction in inflammatory markers.63 In a randomized clinical trial employing 500 mg of NTZ, treatment with NTZ resulted in a greater reduction of viral load compared with placebo. The study demonstrated no difference in clinical outcomes.64 Cadegiani et al in a prospective observational trial, the Pre-Andro trial, observed that early treatment with azithromycin combined with either HCQ, ivermectin, or NTZ was associated with a marked reduction in viral shedding, hospitalizations, respiratory compromise, need for mechanical ventilation, and the development of post-COVID complications.65 Historically, the agent has demonstrated reasonable safety and tolerability profile.
Ivermectin
Interest in ivermectin (IVM), an antiparasitic agent, with known in-vitro and in-vivo antiviral activity as a potential therapeutic agent against SARS-Cov-2 began when Caly et al demonstrated marked in-vitro anti-SARS-CoV-2 activity.66 In addition IVM possesses anti-inflammatory and immune-modulating properties mainly acting in the NFK-β pathway of inflammation.67–69 Since the initial antiviral in-vitro discovery by Caly et al, there have been numerous clinical studies performed, and for reasons unknown, there has been a significant amount of controversies.70–72 There has been conflicting evidence regarding IVM and improved clinical outcomes. However, in at least two meta-analysis which included over 28 randomized controlled trials, 78% improvement was noted in important clinical outcomes.70–72 A website analysis of 63 studies on the use of IVM for COVID-19 treatment found that early treatment was associated with a 61% improvement in lowering hospitalizations, a 66% improvement in clinical recovery, a 68% improvement in viral clearance, and a 37% decrease in mortality.73 In contrast, the Cochrane database and the study by Roman et al, which evaluated fewer studies, found no statistically significant differences in important clinical outcomes or mortality.74 Currently, there are several clinical trials in progress.
Symptomatic Phase
Fluvoxamine
Fluvoxamine (FLUV), although not an antiviral agent per se, exerts antiviral effects by inhibiting endolysosomal viral trafficking. Studies have demonstrated that early therapy with FLUV may prevent clinical deterioration in COVID-19 patients.75,76 Lenz et al in a double-blind placebo-controlled trial involving outpatients demonstrated that 100 mg of FLUV given three times a day prevented clinical deterioration and lower hospitalization rates when compared to placebo.77 Similarly, Boulware et al in a prospective trial observed lower need for hospitalization in patients receiving early treatment with FLUV.78 FLUV has many pleiotropic effects that make it an important agent in the early outpatient management of COVID-19.75,79 These include antiviral effects via inhibition of lysosomal trafficking, functionally inhibiting sphingomyelinase preventing viral entry, anti-inflammatory effects, inhibition of mast cell degranulation and antithrombotic effects by inhibiting platelet aggregation. Together these effects suggest that FLUV may be effective in all stages of the disease and have the potential to mitigate the cytokine storm.75,77
Budesonide
In an open-label randomized controlled phase 2 early treatment trial comparing inhaled budesonide 400 µg two puffs two times a day to usual care started within 7 days of onset of mild treatment demonstrated that early treatment with inhaled budesonide decreased duration of symptoms, need for urgent care visits, and need for hospitalization.80 The study was terminated early due to superiority of budesonide treatment. The Principal trial, a much larger study that enrolled patients age 65 or greater with symptoms for 14 days or less and at high risk for adverse outcomes, randomized 692 patients to inhaled budesonide 800 µg two times a day for 14 days versus 968 patients to usual care.81 Patients randomized to budesonide treatment demonstrated a statistically significant difference in improved time to recovery.81,82 There was a trend toward decreased hospitalizations and mortality in the treatment group; however, this did not meet Bayesian analysis superiority threshold.81 Thus, budesonide is an ideal candidate for use in outpatient COVID-19 treatment protocols, although an inhaled corticosteroid can be utilized in the symptomatic and pulmonary phases of the disease.81,82
Antithrombotic Agents
The pathophysiologic hallmark of COVID-19 disease is its inflammatory, thrombotic, and coagulopathic nature. Aspirin possesses both anti-inflammatory and antithrombotic properties. There is observational evidence that aspirin has the potential to improve clinical outcomes.83 In two large propensity matched retrospective analysis, the investigators observed that use of aspirin pre-COVID-19 diagnosis was associated with a marked decrease in mortality.84,85 Chow et al observe that aspirin use within 7 days of diagnosis and 24 hours of admission was associated with a decreased risk of need for mechanical ventilation, ICU admission, and hospital mortality.84 To date, there are no prospective trials involving aspirin use in outpatients. The authors feel that if there is no contraindication in the initiation of aspirin, it should be included as an agent in early outpatient treatment protocols. In patients already on aspirin pre-COVID-19 diagnosis, aspirin should not be discontinued unless there is a clear-cut indication for discontinuation.
Heparin, an anticoagulation and antithrombotic prophylaxis, has proven to improve clinical outcomes in hospitalized patients.86–90 However, although most likely it has not been employed as outpatient therapy in western developed nations, it is not inconceivable for its incorporation in outpatient protocols in areas with scarce hospital resources.
Epidemiological data has demonstrated that male sex is a risk factor for adverse outcomes, and interest in antiandrogen treatment as a therapeutic agent has been explored. Early trials with differing agents such as dutasteride, spironolactone, and proxalutamide have demonstrated promise as repurposed agents that can be employed in decreasing hospitalization, decreasing inflammatory markers, and improving radiographic abnormalities.91–94 In an observational study of an electronic health record database involving over 6 million individuals, a sample of 3,057 COVID-19 patients receiving androgen deprivation therapy appeared to have less severity of disease.95 An outpatient double-blind placebo-controlled trial demonstrated that proxalutamide decrease hospitalization in COVID-19 patients compared to standard of care.96 Thus, androgen deprivation is a potential agent that can be employed in a multimodal outpatient management protocol in COVID-19.
Although used clinically to lower low density lipoprotein (LDL) cholesterol, statins possess antithrombotic, anti-inflammatory, and immunomodulatory properties.97–99 In silico molecular docking has demonstrated that statins bind effectively to SARS-CoV-2 major protease and have potential antiviral properties.97 In addition by decreasing cell membrane cholesterol they may inhibit viral cellular penetration. An in vitro experiment demonstrated simvastatin was able to inhibit SARS-CoV-2 nucleocapsid protein-induced endothelial cell activation and monocyte adhesion to activated endothelium.98,100 Several observational studies have demonstrated that statin use within 30 days of hospital admission for COVID-19 decreased mortality.99,101–103 A propensity matched retrospective study during the height of the pandemic in China involving over 13,000 patients of which 1,219 received statins, investigators observed that statin use was significantly associated with a markedly lower risk of death.103
In vitro data has demonstrated that fenofibrate stimulates ACE2 dimerization and inhibits receptor-binding domain (RBD) and ACE2 binding, exerting an antiviral effect.104,105 Fenofibrate increased the glycosphingolipid sulfatide which inhibits viral entry through the cell membrane.105
Nutraceuticals
Many nutraceuticals possess adaptogenic, antioxidant, anti-inflammatory, and immunomodulating properties that make them ideal agent to employ in early outpatient therapeutic regimens.106 Nutraceuticals of interest include vitamin D, ascorbic acid, bioflavonoids, and small molecules such as melatonin and quercetin.106 Extensive review of these agents is beyond the scope of this chapter; however, we will discuss the major agents employed.
Vitamin D
Observational studies have demonstrated that individuals who live in northern latitudes where vitamin D deficiency is prevalent have worse clinical outcomes when they develop SARS-CoV-2 infection and COVID-19 disease.107–110 Prior to the pandemic, there was evidence mounting that low vitamin D levels in critically ill persons was associated with a higher risk of developing acute respiratory distress syndrome (ARDS).111 Low vitamin D levels are highly correlated with increased risk of SARS-CoV-2 infection and adverse outcomes.109,110,112,113 Vitamin D has many pleiotropic effects involving the immune system, including modulating expression of antiviral defensins which inhibit viral entry and replication, immunomodulatory effects on professional antigen-presenting cells, and anti-inflammatory effects reducing levels of proinflammatory cytokines.107,109,113–115 In addition, vitamin D via its action on inducing the anti-inflammatory, antiproliferative, antifibrotic, antiapoptotic and vasodilatory ACE2/Ang 1-7/MasR arm of the renin angiotensin system (RAS) downregulating the vasoconstrictive arm of pulmonary renin angiotensin system.107,109,113,115 Vitamin D deficiency may result in an increase in the activation of the vasoconstrictive, proliferative, proinflammatory, profibrotic arm of pulmonary angiotensin system mediated by Ang 2.107,109,113,115 Thus vitamin D may prevent or ameliorate the severe lung injury which occurs in patients with severe COVID-19. In a meta-analysis involving over 10,000 patients, supplementation with vitamin D decreased the risk of respiratory infections. Many observational studies have demonstrated that low vitamin D level in patients with COVID-19 is associated with poor clinical outcomes.109,110,112,113 In a small clinical study high-dose vitamin D supplementation for 7 days resulted in significant conversions of SARS-CoV-2 RT-PCR to negative status, thus suggesting that vitamin D supplementation resulted in decreased viral clearance.116 Castillo et al in a small randomized trial involving hospitalized patients demonstrated that administration of 25-OH vitamin D (calcifediol) administered for 3 to 7 days when added to a regimen of HCQ and azithromycin significantly reduced severity of disease and need for ICU admission when compared to HCQ and azithromycin treatment alone.117 Lakkireddy et al performed an open-label randomized trial involving mild to moderately ill hospitalized patients with COVID-19 and demonstrated that administration of high-dose vitamin D for up to 10 days reduced inflammatory markers.118
Thus, due to its relatively short-term nontoxic effects, immune-modulating properties, and anti-inflammatory and antiviral effects, vitamin D is ideal for potentially preventing infection and severity of disease and should be incorporated in early and prophylactic treatment protocols against COVID-19.
Quercetin
Flavonoids such as quercetin possess immunomodulatory, anti-inflammatory, and antioxidant properties. In addition, there is mounting in vitro evidence that quercetin possesses the ability to inhibit polymerases, proteases, and many other enzymes necessary for viral replication.119–124 In addition, studies have demonstrated that quercetin can bind to viral capsid proteins, thus potentially preventing viral assembly.122,124–126 A recent open-label randomized controlled trial of nonhospitalized patients demonstrated that quercetin added to standard care led to a reduction in the length of hospital stay need for increased noninvasive oxygen delivery and ICU admission.127 In a small open-label randomized controlled trial involving 42 consecutive patients with COVID-19, Quercetin Phytosome added to standard care revealed a significant amelioration of symptoms, decreased inflammatory markers, and increased viral clearance in the treatment group compared to standard care.119 In the clinical trials to date quercetin demonstrates very low toxicity, intolerance, and appears safe to use. Coadministration with ascorbic acid seems to potentiate the antiviral, anti-inflammatory effects of both agents.120 Due to ease of use and safety profile, quercetin is an ideal agent for early outpatient treatment protocols.
Ascorbic Acid
There is both in vitro and in vivo evidence that ascorbic acid (AA) possesses antiviral, anti-inflammatory, antioxidant, and immune-modulating properties.128–131 Humans lack the enzymatic machinery to synthesize AA and require supplementation to have adequate levels. Hypovitaminosis of AA is common in critical illness.130 Several studies in patients with pneumonia and sepsis demonstrate that AA levels are depleted.130,132,133 In addition, AA acts synergistically with and is able to recycle quercitin.120 AA is necessary cofactor in the synthesis of catecholamines, enhances the synthesis of IFN production, limits proinflammatory cytokine end organ injury, and inhibits the activation of the NLRP3 inflammasome.132,134–141 COVID-19 infection leads to intracellular disruption via its viroporin proteins activating immune-signaling inflammasome NLRP3.142,143 Activation of NLRP inflammasome plays a critical role in the increased production of inflammatory cytokines resulting in the cytokine storm.142 Experimental evidence supports that AA inhibits the activation of NLRP by scavenging mitochondrial reactive oxygen species (ROS).142,143 Two large meta-analyses involving critically ill patients demonstrated that intravenous vitamin C administration showed no adverse reactions, reduced the need for fluids and vasopressor support, and reduced intubation time.144,145 In summary, due to the pleiotropic effects of AA on important physiologic functions, its properties as powerful antioxidant/ROS scavenger, and previous successful clinical use as a pharmacologic agent in the treatment of hyperinflammatory conditions, AA should be considered in the outpatient management of COVID-19.
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