Introduction
The so-called common cold is a respiratory viral illness that has afflicted mankind for all of recorded history. Hippocrates described the “cough of Perinthus” 2,500 years ago.1 The Chinese have been treating “wind-cold” with traditional herb remedies to relieve symptoms for thousands of years.2 In our era, cold sufferers are offered symptomatic treatments for nasal congestion and rhinorrhea, sore throat, headache, muscle aches, and cough for the duration of the viral illness, typically several days until the body’s immune system suppresses viral replication. There are well over 200 viruses that cause cold symptoms. The cold viruses have a seasonal incidence, usually surfacing when cold weather encourages people to congregate indoors, promoting person-to-person transmission, resulting in unpleasant epidemics, which usually subside without residual damage.
However, there are cold viruses that have provoked frequent epidemics of life-threatening severe illness. The influenza of 1918 was a grievous event causing death of about 50 million people worldwide.3 Although not as catastrophic, every year there is a death toll from influenza. In the 1940s, the first inactivated influenza vaccines were developed to stimulate protective immune reactions.4 The influenza viruses mutate rapidly, requiring annual development of new vaccines to immunize the population. The vaccinations are moderately effective, yielding reductions of influenza infections of 40 to 60% varying from year to year.5 Several chemical agents have been used effectively to combat influenza viral replication, including amantadine, oseltamivir, peramivir, zanamivir, baloxavir, and umfenovir.6–8 These agents are only effective if administered early in the first few days of the influenza infection during the period of active viral replication or when used as prophylaxis among contacts of infected individuals.
The causative agent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is an RNA virus with high sequence similarity to other betacoronaviruses, which are responsible for perhaps 20% of common colds. The spread of COVID-19 was rapid as is typical for seasonal upper respiratory infections. The majority of individuals display no symptoms or have trifling coldlike manifestations, during a 7- to 10-day period of viral replication and immunologic response.9 However, in up to 20% of patients, even as the viral load falls, a reactive inflammatory phase ensues characterized by rising cytokine levels and susceptibility to coagulopathy.10–12 Clinically, this usually manifests as an organizing pneumonia with additional systemic complications. Oxygenation fails, and in perhaps 5% of patients, intubation ensues, with incipient death.10 As of May 15, 2021, there have been 162,177,376 documented cases of COVID-19 worldwide recorded by the World Health Organization (WHO) and 3,364,178 deaths, giving a crude mortality estimate of 3.4%.13 Given the high incidence of asymptomatic disease, this estimate is much greater than the true infection fatality ratio, but this illness has clearly changed the world. Griffin et al have called attention to the stages of COVID-19 and the necessity to provide treatment suited to each stage of the illness14 (Fig. 12.1). The stages of COVID-19 so defined include: (1) the incubation stage during which virus replicates but is not yet detectable; (2) the detectable viral replication period; (3) the symptomatic stage; (4) the inflammatory stage; (5) the secondary infection stage; (6) the hyperinflammatory stage; and (7) the chronic stage, which sometimes involves a lengthy convalescence. There is significant overlap of the phases, but what is clear is that direct viral damage declines as immunologic events take hold (Fig. 12.1). By 10 days postinfection, viral load has dropped to near undetectable levels in most patients. Yet, this happens typically when the inflammatory phase accelerates in patients destined to severe disease. In hospitalized patients, the 28-day death rate has consistently been about 20%, although it has been as low as 6% in some centers.15
Fig. 12.1 Time course of SARS-CoV-2 evolution. The phases of COVID-19 so defined include: (1) the incubation phase during which virus replicates but is not yet detectable; (2) the detectable viral replication period; (3) the viral symptom phase; (4) the early inflammatory phase; (5) the secondary infection phase; (6) the hyperinflammatory phase; and (7) the tail phase.
In China, strict control of personal interactions with isolation of all diagnosed cases was successful in limiting spread and eventually extinguishing SARS-CoV-2 transmission. Attempts were made to treat empirically with antiviral agents such as umifenovir, lopinavir/ritonavir (LPV/R), and interferons. In western developed countries, the focus of therapeutics was directed at hospitalized patients in the late stages of COVID-19. The emphasis was to carry out randomized controlled inpatient trials to prove benefit. Patients with early disease were counseled to self-isolate for a period of 14 days until the illness ran its course. The vast majority of patients recovered but those who entered an inflammatory phase with hypoxia were then hospitalized with treatment delivered only at that late stage.
Late-Stage Therapy for Hospitalized Patients
Very few pharmacotherapeutics have proven beneficial to treat the disease in hospitalized patients, most of whom are in the inflammatory phase with significant hypoxia. Prior to COVID-19, glucocorticoids had long shown benefit to treat acute respiratory distress syndrome.16 The RECOVERY trial confirmed a mortality reduction in hospitalized COVID-19 patients treated with glucocorticoid.17 In this trial, randomized patients were to receive dexamethasone versus standard of care. Patient survival was greater in those individuals randomized to dexamethasone. There was a statistically significant decrease in 28-day mortality when compared to usual care. The benefit was seen predominantly in those patients requiring supplemental oxygen.
Other studies of different glucocorticoids have shown similar benefit.18 Investigations have demonstrated that combination therapy with interleukin inhibition and glucocorticoid has yielded improved 90-day survival.19,20
In the RECOVERY trial, patients allocated to tocilizumab and standard of care compared to standard of care including glucocorticoids demonstrated a statistically significant survival benefit.
Antiviral Agents in Hospitalized Patients
Given that patients sick enough to be hospitalized with COVID-19 are typically at the late stage in the course of the inflammatory process with declining viral replication, antiviral treatment has been less effective at that stage of the disease.
Remdesivir
The RNA polymerase inhibitor remdesivir is an antiviral drug. It is administered intravenously for 5 days and thus it must be used only in hospitalized patients. In a preliminary double-blind, randomized trial, there was no advantage in terms of viral clearance or survival advantage.21 In a double-blind, randomized, placebo-controlled trial of remdesivir involving moderately to severely ill patients, remdesivir-treated patients had a statistically significant median recovery time of 10 days versus 15 days in the placebo arm.22 By 29 days following randomization, the estimates of mortality demonstrated a non–statistically significant favorable trend in mortality with remdesivir versus placebo. In a recent trial evaluating the benefits of extended therapy with remdesivir, a 5-day course of therapy demonstrated clinical improvement by day 11. However, there was no statistically significant benefit in extending therapy for 10 days.23 The addition of baricitinib, a janus kinase inhibitor used to treat rheumatoid arthritis, to remdesivir has shown a small improvement in time to improvement in clinical status compared to remdesivir alone.24 For the remdesivir studies conducted in the United States, no data on virus clearance have been reported.
The WHO Solidarity trial assessed four distinct therapeutic regimens involving large numbers of hospitalized patients worldwide. The agents included: (1) remdesivir; (2) LPV/R; (3) LPV/R plus interferon β-1a; and (4) hydroxychloroquine (HCQ) and chloroquine.25 The study found no effect of remdesivir on 28-day mortality, need for mechanical ventilation, or duration of hospitalization. Nor was there any benefit shown for any of the other agents. Similarly, the RECOVERY trial has shown no benefit for hospitalized patients in trials of agents with possible antiviral activity including LPV/R,26 HCQ,27 and convalescent plasma.28 It is pertinent to note that the median duration of symptomatology for patients randomized in the RECOVERY trial was 8 to 9 days. Therefore, one would expect that the period of viral replication would be waning, reducing anticipated benefit of antiviral medication.
Interferon
There has been a positive study reported for inhaled interferon β in hospitalized patients.29 In that trial, 51 patients receiving interferon β had greater odds of improvement on the Ordinal scale for clinical improvement (OSCI)scale on day 15 or 16 and were more likely than 50 patients receiving placebo to recover to an OSCI score of 1 (no limitation of activities) during treatment. Interferon is a standard treatment in Cuba for COVID-19, where it was demonstrated that a dual therapy with interferon α-2b and interferon γ in patients receiving antiviral therapy with LPV/R and chloroquine was successful in achieving viral clearance compared to patients receiving interferon α-2b alone.30 Interferon is also the recommended treatment in Hong Kong.31
Favipiravir
This is an RNA polymerase inhibitor like remdesivir but is administered orally. There were two positive randomized, active-control clinical trials of favipiravir (FVP).32,33 In a trial comparing patients on FVP to those on umifenovir, the 7-day clinical recovery rate was 15% greater in the FVP group.33 A preliminary study of FVP in hospitalized patients demonstrated a reduction in viral shedding, resulting in FVP approval as a therapeutic agent in several Russian hospitals.34 In a follow-up phase 3 study, they reported 27% clinical improvement at day 10 compared to 15% for standard care, with 98% clearance of SARS-CoV-2 compared to 79%.35 In India, a study involving mild-to-moderate COVID-19 patients demonstrated a statistically significant difference in median time to clinical cure of 3 days for FVP versus 5 days for control.36
Molnupiravir is another oral RNA polymerase inhibitor. It is currently undergoing studies in outpatients after it proved ineffective in inpatient hospital studies.
Neutralizing Antibodies
Although convalescent plasma treatment is not successful as viremia wanes and the inflammatory phase of COVID-19 takes hold, early use in hospitalized patients proved beneficial.37 Bamlanivimab, a synthetic monoclonal antibody to the SARS-CoV-2 spike protein, was not successful when administered to hospitalized patients, and inpatient studies were stopped.38 However, studies have shown that in ambulatory patients, presumably still in the viral replication phase, bamlanivimab helps in improving the course of the illness and avoiding hospitalization in 60 to 70% of diagnosed patients.39,40 The RECOVERY trial has recently reported that the casirivimab and imdevimab antibody cocktail lowered 28-day mortality from 30 to 24% in 3,153 seronegative patients but not in the entire cohort of 9,785 patients.41 These antibody preparations are approved and in use for COVID-19 patients diagnosed at the early stage of viral replication.
Hydroxychloroquine
HCQ was widely used to treat COVID-19 and is still used in many countries. HCQ has an in vitro effectiveness by inhibiting viral endosomal entry due to its its action as a zinc ionophore. In addition, HCQ possesses anti-inflammatory and immune-modulating effects on the inflammatory dysregulation commonly observed in COVID-19. HCQ has a long period to reach its equilibrium drug level, making it unlikely to be of value in the acute therapy of individuals with severe disease. Certainly, the use of HCQ in hospitalized patients has not been successful. There are few studies in outpatients. In a small randomized control Spanish study with 136 HCQ-treated patients and 157 patients in the control arm, the risk of hospitalization (7.1% for control vs. 5.9% for HCQ; relative risk, 0.75 [0.32–1.77]) nor the time to complete resolution of symptoms (12 days for control vs. 10 days for HCQ; p = 0.38) reached significance.42 The recent publication of a series of 10,429 patients by the Institut Hospitalo-Universitaire Méditerranée Infection group in Marseille supports combination treatment with HCQ and azithromycin (AZM). In this very large series, treatment with HCQ and AZM resulted in an infection fatality ratio of only 0.06%. Compared to other regimens received by their outpatients, treatment with HCQ+AZM was associated with a lower risk of death (0.17 [0.06–0.48]).43
Ivermectin
This agent is universally used for its antiparasitic properties and has a safety profile well established up to 10 times the usual antiparasitic dose. A study in Australia showed that it suppressed SARS-CoV-2 replication 5,000-fold in cell culture at a concentration thought to be 100-fold higher than typical serum levels attained at typical human dosage.44 However, ivermectin is taken up and concentrated in tissues including respiratory epithelium. The effect of ivermectin is broad spectrum on RNA viruses through inhibition of nuclear transport of viral components by the IMPα/β1 importer protein.45 In clinical use, there have been many studies, including 28 randomized controlled studies, summarized in two major meta-analyses suggesting benefit of ivermectin treatment in COVID-19.46,47 In particular, there has been evidence of 78% improvement in early treatment studies, 84% improvement in prophylaxis studies, and a 74% reduction in mortality. Almost all the ivermectin studies have occurred outside the United States and Europe. One retrospective study of hospitalized patients in the United States showed lower mortality in the ivermectin group (15 vs. 25.2%; odds ratio, 0.52; 95% confidence interval [CI], 0.29–0.96; p = 0.03).48 Although results are highly positive for ivermectin early treatment and prophylaxis, there has been no urgency to begin major trials in the United States nor in Europe. In fact, the FDA and the WHO have argued against use of ivermectin to treat COVID-19 outside of randomized controlled trials.
Topical Antiviral Therapy
Several studies have shown that mouth rinses with povidone-iodine inactivate SARS-CoV-2.49,50 In a study in Singapore among dormitory-housed migrant laborers, a povidone mouth rinse reduced the frequency of polymerase chain reaction (PCR)–positive COVID-19 diagnoses, while a single dose of ivermectin substantially decreased symptomatic COVID-19 disease.51 There is considerable interest in the development of a slow-release nitric oxide solution from a company called SaNOtize. The solution is useable as a nasal spray, gargle, and inhaled spray. It has shown a 99% reduction in swabbed viral load. It has been granted emergency approval in Israel and New Zealand.
Outpatient Anti-Inflammatory Treatment
There is an overlapping transition between the phase of viral replication and the inception of the immune-mediated inflammatory phase of COVID-19.
Inhaled Glucocorticoid
There has been reluctance to use glucocorticoid treatment early due to concern of increased viral load and decreased viral clearance. However, clinical trials suggest that early immune suppression is beneficial. In a small trial in 146 patients in the United Kingdom, inhaled budesonide decreased the frequency of immediate care visits and hospitalizations by 91% (p < 0.004).52 The mean time to recovery was 8 days in the budesonide group and 12 days in the standard care group. There was no difference in viral load at various intervals in budesonide-treated patients and controls. In a much larger trial, there were 59/692 (8.5%) COVID-19-related hospitalizations/deaths in the budesonide group versus 100/968 (10.3%) in the usual care group (estimated percentage benefit, 2.1% [95% CI, 0.7–4.8]; probability of superiority 0.928).53
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