Respiratory Immune Support

Respiratory Immune Support

Last updated: 11/24/2020

Reviewers: Dr. Gary Gonzalez, MD; Dr. Shayna Sandhaus, PhD., Chemistry; Julia Dosik, MPH; Andrew Roberts Jr., MPH in Global Health; Dr. Maureen Williams, ND

1 Background

Over the last few decades, several new viruses have emerged as threats to human health around the globe. The most recent example is the 2019‒2020 novel coronavirus.

The virus itself is called SARS-CoV-2, and the disease it causes is called COVID-19 (short for Coronavirus Disease 2019).

SARS-CoV-2 came to the attention of health authorities in late 2019 when it was identified as the cause of a cluster of pneumonia cases in the city of Wuhan in Hubei province, China.1 Since then, COVID-19 has spread globally and was declared a pandemic by the World Health Organization on March 11th, 2020.2,3

Coronaviruses are a large group of related viruses that cause many common human and animal infections.4 In humans, coronaviruses typically cause mild respiratory infections. Responsible for an estimated 10–30% of all upper respiratory tract infections, coronaviruses are among the most frequent causes of the common cold.5 Over the last decade, new coronaviruses that cause potentially lethal respiratory diseases have emerged. These include severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS) coronaviruses in addition to SARS-CoV-2.6

The SARS pandemic in the early 2000s, which lasted about nine months in 2002–2003, affected over 8,000 people in 29 world regions and caused fatality in almost 10% of cases. MERS, on the other hand, has been smoldering mainly on the Arabian Peninsula since 2012, infecting approximately 2,400 people and having a case fatality rate of nearly 35%.7,8 Current estimates of the infection-fatality rate for COVID-19 range from about 0.5% to 1%, with some researchers reporting higher rates for older individuals.9,10

For perspective, the fatality rate of typical influenza viruses is much lower, reaching a maximum of about 0.2% in people over 75 years old; however, because of its high incidence, the number of deaths attributable to the flu worldwide averages between 291,000 and 646,000 annually.11

2 Symptoms and Manifestations

One of the major challenges in suppressing the spread of COVID-19 has been that many cases are asymptomatic; that is, some people are infected but do not exhibit any symptoms or have only very mild symptoms and may not realize they are capable of infecting others. Estimates of the proportion of cases that are asymptomatic vary widely. Recent population-based screening studies have suggested that around 40% of people who test positive do not have symptoms at the time of diagnostic testing, though they may develop symptoms later.10,12,13

Among infections that do become symptomatic, the first symptoms typically manifest within about five days after exposure.10 The most common presentation of COVID-19 is fever and dry cough accompanied by flu-like symptoms. Loss of sense of smell and taste are common symptoms of COVID-19 as well. Although loss of sense of smell and taste sometimes occurs with other viral respiratory diseases such as the common cold or influenza, these manifestations appear to be much more common in COVID-19.14,15 Some patients may experience early ocular symptoms, such as conjunctivitis (pink eye) and eye discharge.16 Emerging evidence also suggests some people may experience gastrointestinal symptoms such as loss of appetite or diarrhea in addition to—or in rare cases instead of—initial respiratory symptoms.17,18 Acute kidney injury is relatively common in COVID-19 patients as well.19,20

In many cases, early symptoms of COVID-19 do not clearly distinguish it from other viral respiratory infections. However, shortness of breath that develops within a week of initial symptom onset may be suggestive of COVID-19.10

A marked increase in blood clotting and vascular complications throughout the body are prominent features of severe COVID-19.21-24 Importantly, infection with SARS-CoV-2 appears to cause excessive clotting in the tiny capillaries in the lungs where gas exchange takes place, impairing the lungs’ ability to oxygenate the blood.25,26 This excessive clotting tendency also underlies a pronounced incidence of ischemic strokes in younger people with COVID-19 who do not have traditional stroke risk factors.27 Other complications attributable to blood clots are also common in severe cases, including deep vein thrombosis and pulmonary embolism.28 Accordingly, anti-coagulation therapy has become a standard of care recommended by most expert panels.29 Some early evidence suggests that, compared with lower-dose (prophylactic) anticoagulation, more aggressive (therapeutic) anticoagulation may improve outcomes in hospitalized patients with severe COVID-19 requiring mechanical ventilation.30

The pathophysiology of low blood oxygen levels (hypoxemia) in COVID-19 is somewhat unique and differs from that of low blood oxygen levels in other forms of acute respiratory distress syndrome (ARDS). Patients with COVID-19 often develop low blood oxygen levels without apparent signs of respiratory distress. This phenomenon has been referred to as “happy hypoxemia” because patients may seem relatively comfortable but exhibit alarmingly low blood oxygen levels. Low blood oxygen levels may portend disease progression. Several factors contribute to the lungs’ inability to properly oxygenate the blood in COVID-19, such as altered vasoconstriction-vasodilation dynamics in the pulmonary blood vessels, small blood clots in the lungs, and the inability of sections of lung tissue to properly oxygenate blood due to collapsing alveoli.31,32 As physicians have learned more about the complex pathophysiology of COVID-19 ARDS, management has improved and timely use of anti-clotting medications, prone-positioning (having patients lie on the stomach instead of their back), and timely use of supplemental oxygen and mechanical ventilation in appropriately selected patients have improved outcomes.31

Skin manifestations such as rashes, plaque-like lesions, and painful red or purple lesions on the fingers or toes, called chilblains, have been reported in the context of COVID-19. It is not entirely clear whether these manifestations represent inflammatory effects of the SARS-CoV-2 virus, or arise secondarily to coagulation and clotting problems that damage the delicate blood vessels supplying the skin.33,34 Some doctors think both factors are at play given the wide variety of skin manifestations being reported in COVID-19 patients. Further research will be necessary to determine if certain skin manifestations may predict clinical outcomes or help guide treatment decisions. If you notice a new or unusual rash or skin problems, you should mention these concerns to your healthcare provider, especially if the skin issues arise along with other potential COVID-19 symptoms.

Rapid progression to ARDS and death is more likely to occur in older individuals and those with pre-existing conditions that increase their risk such as obesity, diabetes, or hypertension.7,35,36

Reports of lingering illness and complications lasting weeks or months after the initial course of COVID-19 began to gain attention in May and June 2020. Preliminary reports have suggested SARS-CoV-2 can infect a variety of tissues and organs such as pancreatic beta cells,37 liver cells, sweat glands, and others.38 Damage inflicted at these non-respiratory sites may have lasting consequences that researchers do not yet understand. Some COVID-19 patients are requiring rehab for extended periods after infection, and research is needed to better understand the post-infection consequences.39 Imaging studies have also suggested that some patients may experience lasting cardiac effects after clinical recovery from COVID-19.40 Adverse cardiac effects may arise even in young, healthy individuals following COVID-19. In a preliminary study of 26 collegiate athletes, MRI findings were suggestive of possible cardiac pathology following recovery from mild COVID-19,41 although larger studies are needed to confirm these findings. Other evidence suggests that SARS-CoV-2 has neuro-invasive capacity,42 which may account for reports of lingering cognitive impairment after apparent recovery from COVID-19.43 A review article published in August estimated that, overall, about 10% of people experience prolonged illness after COVID-19.44

NOTE: At the first signs of a respiratory tract infection (eg, sneezing, coughing, feeling unwell, mild fever), contact your doctor and immediately initiate the interventions described in the Integrative Approaches section of this protocol. The interventions described in this Protocol, though not necessarily validated as effective specifically for COVID-19, are nevertheless advisable upon onset of symptoms of respiratory tract infections.

3 Risk Factors for Severe Disease

As the pandemic unfolded around the world, researchers and clinicians identified several risk factors that predispose to more severe disease and worse outcomes in COVID-19 patients. The presence of pre-existing comorbid conditions is a strong predictor of worse outcomes, so people with any of the conditions mentioned in this section should take extra precaution to avoid infection. One analysis of 355 deaths attributed to COVID-19 found that the average (mean) number of pre-existing conditions in these cases was 2.7, and only three deaths occurred in individuals who did not have any pre-existing conditions.45

The more well-established risk factors for severe disease, as well as those that are emerging but less-well established, are summarized below.

Established Risk Factors for Severe Disease

Obesity. Obesity and greater body mass index (BMI) have emerged as predictors of poor outcomes in COVID-19 patients.10 A systematic review published in July 2020 pooled data from 24 retrospective cohort studies and assessed the association of obesity and increasing BMI with poor outcomes in COVID-19 patients.46 The meta-analysis showed that obesity significantly increased the odds of being admitted to the intensive care unit (ICU) and of needing mechanical ventilation. The authors also evaluated outcomes across BMI strata and remarked that “…we found that a higher BMI always carries a higher risk.” However, it should be noted that a paper published in late September described a rigorous analysis of data from over 10,000 U.S. veterans who had tested positive for COVID-19, which found that obesity was not significantly associated with mortality.47 Further studies may help clarify the degree to which obesity alone, in the absence of other confounding risk factors, contributes to poor outcomes in COVID-19.

High blood pressure. High blood pressure has been observed to be among the most common comorbid conditions in COVID-19 patients.48 In many cases, high blood pressure co-occurs with elevated glucose and obesity, forming a constellation of illness described as “metabolic syndrome.” One study found that the presence of metabolic syndrome increased death risk among black COVID-19 patients more than the presence of hypertension alone.49 Some evidence suggests that the increased risk of severe COVID-19 associated with high blood pressure may be more pronounced in males.50

Dyslipidemia. A systematic literature review published in August 2020 found that dyslipidemia (ie, elevated cholesterol and/or triglycerides) is associated with increased risk of severe outcomes among COVID-19 cases.51 Interestingly, a meta-analysis of four studies including nearly 9,000 COVID-19 patients found that use of statin drugs was associated with a 30% reduction in fatal or severe disease in COVID-19 patients. However, these findings represent preliminary evidence and need to be corroborated in a randomized controlled trial before conclusions can be drawn as to the potential utility of statins in reducing COVID-19 severity.52

Diabetes. An elevated case-fatality rate has been documented among COVID-19 patients with diabetes.10,53 Some evidence suggests elevated glucose levels may increase the expression of the angiotensin converting enzyme 2 (ACE2) receptor in lung tissue, facilitating more efficient SARS-CoV-2 infection. Experts recommend safe but stringent control of blood glucose, blood pressure, and lipids among people with diabetes as measures that could potentially decrease severity of COVID-19 illness should SARS-CoV-2 infection occur.54

Older age and immune senescence. Older age (generally, 65 years or older) is associated with worse outcomes in COVID-19. This increased vulnerability of older individuals is due in part to immune senescence—the general decline in the immune system’s function during aging. Older individuals may have trouble mounting coordinated antibody-mediated and T-cell-mediated responses to SARS-CoV-2 infection due to immune senescence, and this may contribute to the worse outcomes that occur more frequently in aging populations.55-57

Cardiovascular disease. An analysis of over 70,000 COVID-19 cases in China showed that pre-existing cardiovascular disease was associated with a 10.5% case-fatality rate, significantly higher than the case-fatality rate among otherwise healthy individuals.53

Chronic kidney disease. Chronic kidney disease (CKD) is associated with immunologic changes that predispose patients to many types of infections. In COVID-19 specifically, the risk of severe disease has been reported to be three-fold greater in people with CKD than in those without. Also, CKD is a common comorbidity among COVID-19 patients admitted to the ICU.58

Chronic respiratory/lung disease. Chronic respiratory disease, such as chronic obstructive pulmonary disease (COPD), increases risk of severe disease and death among COVID-19 patients.10,53,59 Asthma has also been linked to more severe disease.60

Smoking. Smoking has been associated with worse COVID-19 outcomes and greater need for mechanical ventilation support in COVID-19 patients.59,61

Cancer. Cancer patients have an increased risk of poor outcomes from COVID-19. This is due in part to immune system compromise caused either by cancer itself or cancer therapies.53

Emerging or Potential Risk Factors for Severe Disease

Proton pump inhibitors. Results of a preliminary online survey of over 53,000 participants published in early July suggested proton pump inhibitor (PPI) use was associated with increased odds of a positive COVID-19 test.62 PPIs are drugs used to reduce stomach acid to relieve symptoms of gastroesophageal reflux disease (GERD) and other gastroesophageal problems. These drugs are associated with increased risk of some enteric infections, which is thought to be because reduced stomach acidity allows some pathogens to survive. The findings of this recent survey suggest reduced stomach acidity may increase susceptibility to SARS-CoV-2 infection, but more rigorous studies are needed to confirm this possibility. Of note, in this same survey, use of histamine-2 receptor antagonists, which also reduce stomach acidity but are less potent than PPIs, was not associated with increased odds of a positive COVID-19 test.

Table 1: Laboratory Features Possibly Associated with Severe COVID-19*# Illness10

Parameter

Values Possibly Associated with Severe COVID-19

Normal Value

D-Dimer

>1,000 ng/mL

<500 ng/mL

C-Reactive Protein (CRP), quantitative ( not high-sensitivity [hs-CRP])

>100 mg/L

<8 mg/L

LDH

>245 units/L

110–210 units/L

Troponin

>2x the upper limit of normal

Troponin T High-sensitivity

  • Females: 0–9 ng/L
  • Males: 0–14 ng/L

Ferritin

>500 mcg/L

Females: 10–200 mcg/L

Males: 30–300 mcg/L

CPK

>2x the upper limit of normal

40–150 units/L

Absolute lymphocyte count

<800 per microL

1,800–7,700 per microL

*Values may vary between laboratories. Consult with a qualified clinician for interpretation of lab values in the context of COVID-19.

#These parameters have not yet been rigorously established to have prognostic value. Research is ongoing to more firmly establish laboratory prognosticators in COVID-19. These factors are presented here to inform readers as to the parameters that clinicians treating COVID-19 may monitor.

4 Spread

Coronaviruses are highly adaptable and known to undergo host-switching. Several established human coronaviruses have evolved from bird or mammalian coronavirus origins.63 For example, the human coronavirus associated with MERS is likely to have come from camels, though its origins may have been a bat coronavirus; the SARS coronavirus also appears to have originated in bats and was possibly transmitted by an intermediate mammalian host called a civet.36,64 Although distinct from all other known coronaviruses, SARS-CoV-2 also appears to be closely related to a bat coronavirus.65

Once adapted to the human host, coronaviruses can become transmissible between humans. There are four possible routes of transmission: respiratory droplet, contact, aerosol, and oral-fecal.66

  • Respiratory droplet. Respiratory droplets are an important route of SARS-CoV-2 transmission. In this kind of viral transmission, the virus is suspended in droplets emitted from the respiratory tract of an infected individual through a sneeze or cough, which are then inhaled by nearby uninfected individuals. Because respiratory droplets play such an important role in transmission of SARS-CoV-2, it is imperative that everyone practices social distancing whenever possible.
     
    Another possibility is that droplets may land on or near uninfected individuals, be picked up on hands, and transferred to the respiratory tract through touching the nose, mouth, or eyes.64 However, the CDC stated in mid-May 2020 that infection via contaminated surfaces is not likely to be a major route of transmission for SARS-CoV-2.
     
    Setting and activity likely influence the risk of infection and the degree to which infectious droplets are dispersed into the atmosphere. For example, risk is thought to be lower in well-ventilated, low-occupancy settings, and risk rises as occupancy increases and ventilation decreases, which is why outdoor settings are thought to have the lowest risk, while crowded indoor settings with poor ventilation have the highest risk. Similarly, risk is thought to be higher among groups of people singing or shouting than those who are speaking normally because shouting or singing likely increases the dispersion of infectious droplets from infected individuals.67
  • Aerosol. The aerosol route of transmission involves inhalation of very small, airborne viral particles, possibly at some distance from the infected person.68,69 These particles are smaller than those described as respiratory droplets. Aerosol transmission is an especially important concern in healthcare settings.68 SARS-CoV-2 aerosols are detectable for up to three hours.70
     
    A critical issue related to aerosol transmission of SARS-CoV-2 is that loose-fitting surgical facemasks or cloth facemasks are unlikely to effectively prevent the transmission of aerosolized viral particles. It is imperative that the public understand that cloth or surgical facemasks do not provide protection to the wearer from aerosolized viral particles. Rather, these masks are intended to help capture some respiratory droplets expelled by already-infected individuals.71
  • Contact. Direct person-to-person contact is another mode of transmission for coronaviruses such as those associated with SARS, MERS, and the current COVID-19 outbreak.8 In these cases, the virus is transferred when an uninfected individual comes into direct contact with an infected person who is actively shedding virus. A study published in early October found that SARS-CoV-2 may be able to survive as long as nine hours on human skin. However, this study also showed that the virus could be inactivated within 15 seconds with topical alcohol (ethanol) application.72
  • Oral-fecal. The oral-fecal route involves viruses being shed through the feces (usually in people with diarrhea), contaminating surfaces and ultimately hands that can then introduce the virus to the respiratory tract. This is an uncommon but documented route of transmission for coronaviruses such as the SARS virus.64

5 Protective Measures

Below are some basic measures to consider in order to reduce your risk of contracting COVID-19 and other viral illnesses.

  1. Social distancing. Avoiding contact with infected individuals is the most effective strategy to protect yourself from COVID-19. Because SARS-CoV-2 has become pervasive throughout the world, you should assume the people you come in contact with may be infected and stay at least six feet away from them. The Centers for Disease Control and Prevention (CDC) and other health authorities worldwide strongly advise that citizens—especially those at increased risk—living in communities experiencing community spread of COVID-19 "[remain] out of congregate settings, avoid mass gatherings, and maintain distance (approximately 6 feet or 2 meters) from others when possible".73 In places where the virus has become more widespread, more stringent measures have been taken such as closing public parks, limiting activity outside the home to "essential" tasks, and urging people to remain at home as much as possible. Such strict measures can help further limit the spread of infection. When it is impossible to avoid coming into close proximity to other people, taking steps to minimize exposure should be encouraged. These include limiting the duration of exposure to others, wearing a mask, staying outdoors or in well-ventilated indoor areas, and keeping as much distance as possible form others.74
  2. Avoid non-essential travel. Avoiding travel to areas with known community spread is advisable.75 In addition, all air travel is associated with exposure to people and the infectious agents they carry. Outbreaks of infectious illnesses, including measles, influenza, SARS, and many others, aboard commercial flights have been documented.76,77 Therefore, avoiding air travel is a reasonable precaution for reducing your risk of viral infections in general, particularly if you have other vulnerabilities.
  3. Wash your hands. Frequent hand washing is an important strategy for protecting against all types of infectious diseases. Studies in office and healthcare settings have further demonstrated strategic use of alcohol-based surface disinfectants and hand sanitizers can reduce viral spread by 85–94%.78,79
  4. Strengthen immunity. Optimal functioning of the immune system is vital for defending against all types of infections, from mild colds to dangerous influenza and life-threatening pneumonia. A nutrient-dense diet, regular exercise, adequate sleep, and stress management can all contribute to healthy immune function.80 Other strategies for strengthening immunity and reducing risk of viral infections in general can be found in Life Extension’s Influenza, Pneumonia, and Immune Senescence protocols.
  5. Disinfect surfaces. A study published in March 2020 by scientists from the U.S. National Institutes of Health (NIH) and CDC along with UCLA and Princeton University researchers found that SARS-CoV-2 was detectable on cardboard for up to 24 hours and for up to three days on plastic and stainless steel.81 A study published in October 2020 in the Virology Journal assessed SARS-CoV-2 viability on several surfaces in the dark at 68ºF, 86°F, and 104°F. The half-life ranged between 1.7 and 2.7 days at 68º, but was reduced to a few hours at 104º. Viable virus was detected for up to 28 days at 68° on surfaces such as glass, stainless steel, paper, and polymer banknotes.82
     
    Fortunately, coronaviruses can be inactivated with proper cleaning and disinfecting agents. Therefore, keeping surfaces clean and properly disinfected is important to limit the spread of infectious diseases caused by coronaviruses. A study published in February 2020 found that coronaviruses on inanimate surfaces can be inactivated within one minute through disinfection with 62‒71% ethanol, 0.5% hydrogen peroxide, or 0.1% sodium hypochlorite (eg, bleach).70
     
    The United States Environmental Protection Agency (EPA) provides a list of EPA-registered disinfectant products for use against the SARS-CoV-2 virus.83 The list is available on the EPA’s webpage: https://www.epa.gov/pesticide-registration/list-n-disinfectants-use-against-sars-cov-2.

Should You Wear a Facemask?

Yes, you should wear a facemask when in public.

Beginning in early April 2020, the CDC and other health authorities recommended that everyone use cloth face coverings in public. N95 respirator masks should be reserved for healthcare workers.84 Importantly, wearing a mask is not a substitute for social distancing.

The recommendation for widespread cloth facemask use is to help reduce the spread of COVID-19 in the population by reducing the spread of respiratory droplets in the environment. This is critical because many people infected with SARS-CoV-2 show no or mild symptoms and may not realize they have it.86-89 In addition, recent evidence has shown that cloth facemasks have almost the same blocking efficiency as surgical masks.226 Whether or not cloth facemasks can reduce transmission of aerosolized SARS-CoV-2 is not known currently, but they have been previously shown to reduce transmission of other respiratory viruses that are aerosolized.227

When an infected person breathes, they release contaminated air into their surroundings—the volume of the contaminated air “cloud” is even larger when the person is talking or coughing. According to a study published in October 2020, the volume of air clouds produced by coughs without a mask is about 7 and 23 times larger than the cough-clouds produced when wearing a surgical mask and N95 mask, respectively.228 This study also found that the duration of the cloud lasts between 5 and 8 seconds, irrespective of a mask.

The CDC provides instructions on making homemade facemasks.

The U.S. Surgeon General has a video demonstrating how to make a homemade cloth face covering.

6 Video: Foundations for Immune Health

Our Director of Education, Dr. Michael Smith, discusses strategies to support immune health and build strong defenses against respiratory viruses.

7 Testing and Diagnosis

In general, there are two testing priorities that both the public and private sectors are working to optimize in the United States:

  1. Establish widespread availability of accurate, rapid point-of-care diagnostic tests for COVID-19; and
  2. Establish widespread and accurate serological (blood serum) tests to determine who has been exposed and subsequently recovered, possibly establishing immunity. Importantly, it is not yet clear whether the presence of antibodies against SARS-CoV-2 confers long-term immunity against COVID-19; research is ongoing to clarify this crucial question.90

If you have symptoms such as fever, dry cough, fatigue, lack of appetite, and muscle pain and think you might have COVID-19, but do not have urgent symptoms such as shortness of breath, you should call your doctor or local health department for further guidance. Do not go to the doctor’s office or hospital for testing unless you feel your condition is severe and/or rapidly worsening. Because there is currently no effective treatment for COVID-19, and interacting with other people risks transmitting the infection, people with mild symptoms should rest at home.

Diagnostic Testing

Diagnostic testing for SARS-CoV-2 consists primarily of a type of test called a nucleic acid amplification test (NAAT). These tests typically use a procedure called reverse-transcription polymerase chain reaction (RT-PCR) to replicate large quantities of certain parts of SARS-CoV-2 genetic material.91 This step is necessary because the absolute amount of viral genetic material in a diagnostic swab sample is generally very small, especially soon after infection.

Accuracy and reliability of some available diagnostic tests remain a concern. SARS-CoV-2 testing remains plagued by false-negative results, which occur when a test result is negative but the person being tested actually is infected with the virus. False-negative rates have been reported to be as high as 40% for some tests.91,92

Therefore, initial test results should ideally be repeated and confirmed with additional testing conducted by a healthcare professional trained in proper sample collection techniques; this is especially important if a symptomatic person tests negative or an asymptomatic person tests positive.

Results of SARS-CoV-2 testing may take several days, depending on the testing methodology.

Serology (Antibody) Testing

Serology testing to detect antibodies to SARS-CoV-2 is a different type of testing and is used for a different purpose. Antibody tests are not used to diagnose a current SARS-CoV-2 infection. These tests are used to identify individuals who have been exposed to SARS-CoV-2 in the past, and whose immune system has fought off the infection in part by producing antibodies, which persist for some time in the blood.91 SARS-CoV-2 serology tests typically detect IgG antibodies.

Unfortunately, several issues with serology (antibody) testing persist. The accuracy of many of the tests (sensitivity and specificity) are questionable and there are the important issues of cross-reactivity to other common coronaviruses that are not COVID-19. The rate of false-positive results (when an uninfected person tests positive) may be up to 15% in some cases.93 Moreover, serology tests must be interpreted with caution in areas with a low prevalence of infection in the population. This is due to the effect of diminishing positive predictive value with diminishing prevalence. In other words, positive serology test results in an area with low prevalence of infection have an increasing tendency to reflect false-positive results rather than true positive results.91

The implications of the presence of IgG antibodies to SARS-CoV-2 are not yet fully understood. As of mid-October, it is not clear to what extent antibodies to SARS-CoV-2 confer immune protection against a future re-infection or infection with a different strain of the virus. More research is underway to clarify these critical questions.

Serological antibody testing is now available from patient service centers with a physician’s order. LabCorp and Quest Diagnostics both offer qualitative IgG antibody tests under Emergency Use Authorization (EUA) at their patient service centers. In addition, LabCorp and Quest Diagnostics now offer direct-to-consumer tests for the COVID-19 antibody IgG test. Please see their dedicated websites for details and limitations of the test:

8 Medications and Treatment Approaches

Overall State of COVID-19 Treatments

As of mid-fall 2020, there is no medication or therapeutic agent that is broadly effective in preventing or treating COVID-19.94-96

Of the treatments under investigation, none have proven to be efficacious in non-severe disease. Doctors will not generally prescribe any investigational therapies for people with mild COVID-19 outside of clinical trials.96

For hospitalized patients, anticoagulation therapy and general respiratory support (eg, prone positioning, medical management of ARDS) are standard. The choice of COVID-19-specific therapy depends on disease severity and whether the patient requires supplemental oxygen. Remdesivir is generally recommended for hospitalized patients, although clinical trials suggest that its overall benefits are likely modest. For those requiring supplemental oxygen, dexamethasone is generally recommended. Other investigational agents are generally not recommended outside of clinical trials.95

The following sections describe the status of several investigational COVID-19-specific therapies.

Dexamethasone

On June 16th, researchers at the University of Oxford announced preliminary results from the RECOVERY trial, a large randomized open-label controlled trial, which showed that the common glucocorticoid steroid drug dexamethasone reduced mortality in COVID-19 patients requiring supplemental oxygen or mechanical ventilation. The results were subsequently summarized and published in the New England Journal of Medicine on July 17th.97

The trial randomized 2,104 patients to receive standard of care plus 6 mg dexamethasone daily (orally or via intravenous infusion) and 4,321 patients to receive standard care alone. Among patients receiving invasive mechanical ventilator support, dexamethasone reduced deaths by 36%, while the death rate was reduced by 18% in those who did not need a ventilator but needed supplemental oxygen. There was no mortality benefit among patients who did not need any respiratory support or supplemental oxygen.

The researchers remarked, “Based on these results, 1 death would be prevented by treatment of around 8 ventilated patients or around 25 patients requiring oxygen alone.”

The researchers went on to state, “Dexamethasone is the first drug to be shown to improve survival in COVID-19. This is an extremely welcome result. The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become standard of care in these patients. Dexamethasone is inexpensive, on the shelf, and can be used immediately to save lives worldwide.”

Additional trials and meta-analyses accumulated into the fall, and by early October dexamethasone had become standard care for severely ill COVID-19 patients. Other systemic corticosteroids (eg, hydrocortisone, methylprednisolone, or prednisone) are sometimes used if dexamethasone is not available, although evidence supporting their use is not as robust as that supporting the use of dexamethasone specifically.95 A meta-analysis published in September by a World Health Organization working group included data from seven randomized trials and over 1,700 critically ill COVID-19 patients. The analysis found that systemic corticosteroids were associated with reduced all-cause mortality 28 days after randomization compared with placebo or standard care.98

An observational study published in late July suggested that levels of C-reactive protein (CRP) may help identify patients more likely to benefit from glucocorticoid therapy.99 The study found that hospitalized COVID-19 patients whose CRP level was >20 mg/dL had significantly decreased odds of needing mechanical ventilation or dying when they were treated with glucocorticoids within 48 hours of hospital admission. In contrast, patients whose CRP level was <10 mg/dL were more likely to need mechanical ventilation or die when treated with glucocorticoids. These results derive from a retrospective observational study, which does not have the ability to prove causality. Therefore, prospective studies are needed to fully elucidate the potential of using CRP level to guide glucocorticoid treatment decisions.

Remdesivir

Remdesivir is an antiviral drug that showed promise against SARS-CoV-2 in preliminary studies. It is a prodrug of an adenosine analog that has potent antiviral activity against many RNA virus families.100 In late April, 2020, data began to emerge from controlled clinical trials testing the efficacy of remdesivir in the United States and elsewhere around the world.

In late May, results of a large randomized controlled trial (called ACTT-1) conducted by the U.S. National Institute of Allergy and Infectious Disease (NIAID) were published in The New England Journal of Medicine. The trial randomly assigned 1,059 COVID-19 patients to a 10-day course of remdesivir plus standard of care or standard of care plus placebo. The time to clinical recovery improved with remdesivir treatment: those who took remdesivir recovered in a median of 11 days, whereas those who received a placebo recovered in a median of 15 days. There was a suggestion of reduced mortality with remdesivir in the trends in the data, but there was no statistically significant reduction in mortality with remdesivir.101

Although remdesivir improved time to recovery in the ACTT-1 trial, overall mortality remained high. The researchers remarked, “… given high mortality despite the use of remdesivir, it is clear that treatment with an antiviral drug alone is not likely to be sufficient. Future strategies should evaluate antiviral agents in combination with other therapeutic approaches or combinations of antiviral agents to continue to improve patient outcomes in Covid-19.

Importantly, not all remdesivir trials have shown clear benefit. Interim results from the large SOLIDARITY trial, run by the World Health Organization, were published in mid-October. This large trial found that remdesivir provided little benefit in hospitalized COVID-19 patients.94 Similarly, a smaller clinical trial conducted in China did not find a statistically significant effect of remdesivir on time to clinical recovery.102

Research is ongoing and will help clarify which patients may benefit most from remdesivir, and with which other drugs remdesivir should be co-administered.

Convalescent Plasma

When a person is exposed to viruses like SARS-CoV-2, their immune system responds by producing antibodies, which facilitate the recognition and elimination of the virus. After the patient recovers, antibodies typically remain in their blood and can help the immune system respond again if the patient is re-exposed to the virus in the future.

Researchers are currently investigating whether administering the antibody-rich blood plasma of people who have recovered from COVID-19 to patients who become ill with SARS-CoV-2 infection can improve their outcomes. This antibody-rich blood plasma is called convalescent plasma and may help the immune system of people with active COVID-19 respond to the virus. This approach has been used for many decades to combat infectious diseases—similar approaches were even used during the 1918 influenza pandemic.103,104

A randomized controlled trial published in early June found that convalescent plasma did not improve time to clinical improvement within 28 days overall. However, the trial did find that patients with severe (but not critical) disease experienced more frequent and faster clinical improvement compared with controls. This trial was limited by early termination, and the benefit in severe patients was derived from a secondary outcome analysis, so further trials are needed. Nevertheless, this preliminary evidence suggests that convalescent plasma administered earlier in the course of the disease may provide more benefit than if administered later when the patient is already in critical condition.105

Interim results of another study published in August provided additional support for the notion that convalescent plasma may provide a mortality benefit if administered early in the course of COVID-19 illness (ie, within 72 hours of hospital admission).106

The Food and Drug Administration (FDA) has granted EUAs and expanded access programs for convalescent plasma.107

If you have recovered from confirmed COVID-19 and are interested in potentially donating plasma, you can contact a local hospital or visit the American Red Cross website.

Exogenous Interferon Treatment

Interferons (IFNs) are a class of cytokines released by cells, including immune cells, in response to viral infection. They induce an antiviral response and help activate and regulate antiviral immune activity.108 There are three main groups of interferons: types I, II, and III. Type I IFNs, mainly IFN-alpha [α] and IFN-beta [β], are crucial during early viral infection because they stimulate many key steps in the immune response against viral pathogens.109,110 A grossly inadequate type I IFN response to infection with SARS-CoV-2 has been observed in severe and critical patients, accompanied by persistent viral load and an exaggerated cytokine response.111

Evidence published in early 2020 showed that SARS-CoV-2 was susceptible to in vitro inhibition by treatment with recombinant type I IFNs α and β.112 An open-label trial in China in medical staff exposed to SARS-CoV-2 infection yielded some preliminary evidence that IFN-α nasal drops may be effective as a preventive therapy.113 Previous in vitro evidence suggested that the original SARS coronavirus is susceptible to treatment with IFN-β.114,115 Several studies have examined using type I IFN-based therapies, and particularly IFN-β-based targeting of SARS-CoV-2 in the hope that it can become a clinically effective treatment for COVID-19.116-120

In late July 2020, Synairgen, a UK-based biotech company, announced positive preliminary results from an early-stage clinical trial of a nebulized (inhaled into the lungs) IFN-β drug, SNG001.121,122 Results have not yet been published in a peer-reviewed journal, only announced via press release, so they should be interpreted with caution. Nevertheless, the company reported that treatment with SNG001 reduced the odds of developing severe disease by 79% compared with placebo treatment (although the 95% confidence interval was very broad: 0.04–0.97). Moreover, the study found that patients treated with SNG001 were more than twice as likely to recover during treatment than those given placebo. (Recovery was defined as “no limitation of activities" or "no clinical or virological evidence of infection.")

The study of SNG001 also found that the IFN-β-based treatment significantly reduced a measure of breathlessness compared with placebo. Median time to hospital discharge was six days among those treated with SNG001 and nine days for those who received a placebo. Patients treated with SNG001 also had nearly 4-fold greater odds of having recovered by day 28 compared with placebo-treated patients.

A trial published in August evaluated the efficacy of interferon-β-1a (IFN-β-1a) in patients with severe COVID-19.123 Forty-two subjects received IFN-β-1a in addition to standard care, while 39 patients received standard care only. The study’s primary outcome was time to clinical response, and that metric did not differ significantly between the IFN-β-1a and control subjects. However, 28-day mortality, a secondary outcome measure, was significantly lower in the IFN-β-1a group than in the control group. Moreover, early administration of IFN-β-1a was associated with significantly reduced mortality, consistent with the role of IFN in establishing a robust immune response to viral pathogens soon after infection. Importantly, the mortality reductions observed in this study were secondary outcome measures, so these results should be interpreted cautiously.

On the other hand, interim results of the WHO’s SOLIDARITY trial published in October found that interferon-based regimens provided little benefit in hospitalized COVID-19 patients.94

The completion of larger ongoing trials of IFN-based therapies is needed to bolster confidence in this treatment approach.

Immunotherapies and “Cytokine Storm” in COVID-19

As the COVID-19 pandemic unfolded around the globe, doctors and scientists suggested that an exaggerated immune response could play an important role in the pathology of severe and fatal SARS-CoV-2 infections. Subsequently, research was undertaken to investigate whether therapies targeting certain inflammatory mediators could mitigate the excessive immune response and improve the clinical course of advanced COVID-19.

When a person’s airways become infected with SARS-CoV-2, the body must mount a robust innate immune response to prevent rapid viral replication and prevent the infection from spreading to other organs and tissues. In some cases, however, the immune response to the virus may spiral out of control and do more harm than good. Evidence suggests that if the immune system does not detect SARS-CoV-2 infection early, it may respond instead in an exaggerated fashion once the virus has begun replicating in the body and the viral load is high.124 Too many immune cells infiltrate tissues where the virus is replicating and release too many pro-inflammatory signals called cytokines. These cytokines recruit even more immune cells, and the cycle propagates throughout the body. Ultimately, multiple organs and tissues become damaged or impaired due to the buildup of immune cells and their inflammatory detritus. This phenomenon is referred to as a “cytokine storm”—a fitting metaphor given the ominous and rapid clinical decline that typically accompanies this immunopathology.125

Previous studies have documented clinical manifestations of ARDS cytokine storm that resemble the progression seen in some COVID-19 cases. As of Fall 2020, the role of cytokine storm in COVID-19 is not entirely understood. Research has revealed differences in the inflammatory milieu between advanced COVID-19 and ARDS due to some other causes. One inflammatory mediator thought to contribute to cytokine storm is interleukin-6 (IL-6).126 Unfortunately, data available as of early fall have suggested that targeting IL-6 may not be as effective as initially hoped.

Drugs that block IL-6 signaling received considerable attention for several months following the initial revelations that advanced COVID-19 patients experiencing cytokine storms typically had very elevated levels of this cytokine. Two drugs that target IL-6 signaling, tocilizumab (Actemra) and sarilumab (Kevzara), both of which target the IL-6 receptor, underwent extensive testing but unfortunately did not show benefit in randomized controlled trials despite promising results in early observational studies.

On July 29th, Roche, the pharmaceutical company that makes Actemra, announced preliminary results of a large phase 3 randomized controlled trial that showed that the drug failed to improve clinical status or reduce mortality in patients hospitalized with severe COVID-19 pneumonia.127 Similarly, Roche announced in September that tocilizumab did not reduce overall mortality in COVID-19 patient populations that are often underrepresented in clinical studies (ie, the vast majority of participants were from racial and ethnic minority groups).128 In addition, a separate randomized clinical trial published in October found that, compared with standard care, tocilizumab offered no benefit in terms of disease progression in hospitalized patients with COVID-19 pneumonia.230

Research on sarilumab has been similarly disappointing. A large clinical trial first showed in April that sarilumab did not benefit patients with severe (but not critical) COVID-19.129 That same trial was continued in patients with more severe disease until early July, when it was halted due to lack of efficacy. On July 2nd, Regeneron and Sanofi, the pharmaceutical companies sponsoring the study, announced that sarilumab did not significantly improve clinical status in patients with severe COVID-19 requiring mechanical ventilation.130 Other trials of sarilumab are ongoing.

The initial enthusiasm for these IL-6-targeted drugs early in the pandemic on the basis of observational studies was not borne out in more rigorous randomized controlled trials. These circumstances represent an important lesson in the context of COVID-19 and medicine in general: it is critical not to become over-enthusiastic about potential therapies on the basis of early studies with weak methodological quality. Observational studies cannot establish a causal link between an intervention and an outcome. They only establish correlations or associations. Randomized controlled trials, on the other hand, can establish causality, but they take longer to complete. As we continue to move forward through the pandemic, the medical community and the public in general must remember that good quality scientific studies take time and that we need reliable data to inform treatment decisions.

Hydroxychloroquine

The antimalarial drugs chloroquine and hydroxychloroquine received attention early in the pandemic when anecdotal reports and preclinical evidence suggested these drugs might benefit COVID-19 patients. However, as higher-quality evidence accumulated through the summer and into the fall, enthusiasm waned and concern about side effects and lack of efficacy mounted.

On June 3rd, the first rigorous study testing whether hydroxychloroquine could prevent development of COVID-19 was published in The New England Journal of Medicine. The 821 trial participants were randomly assigned to either hydroxychloroquine or placebo and took their first dose within four days after exposure to someone known to have COVID-19. There was no statistically significant difference in incidence of COVID-19 illness in the two groups. Side effects were more common among those who took hydroxychloroquine, but there were no serious adverse reactions reported.131 Subsequent studies found that hydroxychloroquine is not effective for prevention of COVID-19 when used preventively,132 and does not improve outcomes in hospitalized133,134 or non-hospitalized COVID-19 patients.135

On June 15th, the U.S. FDA revoked the EUA it had earlier issued for hydroxychloroquine and chloroquine. The agency stated that “The totality of scientific evidence currently available indicate a lack of benefit,” and that “...in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”136

Colchicine

Colchicine, an older anti-inflammatory drug normally used to treat gout and inflammation of the tissue surrounding the heart, piqued the interest of doctors and scientists working in inflammation research after a 2019 study showed that, in low doses, it reduced the risk of cardiovascular events in people who had recently had a heart attack.137 Then, preliminary evidence published in late June 2020 suggested that colchicine may improve time to clinical deterioration in hospitalized COVID-19 patients.138

Evidence suggests that SARS-CoV-2 infection may trigger inflammation in cardiac tissue. The virus is thought to damage the heart by other mechanisms as well, such as triggering endothelial dysfunction, promoting blood clotting, and impairing the lung’s ability to supply the oxygen demanded by the hard-working cardiac tissue. Some researchers think these events may be triggered in part by activation of inflammatory pathways that colchicine can inhibit, namely the NLRP3 inflammasome.139-141

A prospective open-label trial published in June 2020 found that colchicine improved time to clinical deterioration in 105 hospitalized COVID-19 patients.138 However, this was a preliminary trial and should be interpreted with caution. Other trial are ongoing.142

Although colchicine is generally well tolerated, it may cause problems in people with kidney impairment. This is important in the context of COVID-19 because SARS-CoV-2 infection has been shown to cause kidney damage in some cases. This is a potential safety concern that will be clarified in the ongoing trials.

Camostat Mesylate

An enzyme called TMPRSS2 facilitates a necessary step in the process by which SARS-CoV-2 and other coronaviruses enter cells.143 Therefore, inhibitors of this enzyme have been suggested as potential modalities to limit the pathogenicity of SARS-CoV-2. Some preclinical evidence suggests the drug camostat mesylate, a TMPRSS2 inhibitor developed in Japan in the 1980s, blocks viral entry of SARS-CoV-2 and might be a viable therapeutic option.144,145

As of early May, at least three clinical trials are recruiting subjects with confirmed COVID-19 to test whether camostat mesylate can improve clinical status or time to recovery. Camostat mesylate is approved in Japan for the treatment of chronic pancreatitis and postoperative gastric reflux. It is generally well tolerated, but there have been rare reports of serious side effects.146

Antibody-Based Therapies

Antibody-based therapies were highlighted as a potential intervention early in the pandemic.147 During SARS-CoV-2 infection, effective neutralizing antibody production by the immune system may be helpful for avoiding a severe disease course. Antibodies produced by the immune system can help prevent viral particles from infecting cells.148 However, the role of the antibody response in the effective control of SARS-CoV-2 infection is somewhat unclear because T cells are thought to play a crucial role as well. Some studies have shown that the magnitude of antibody response correlates with disease severity.149

Antibody-based therapies deliver synthetic antibodies to COVID-19 patients, ideally early after SARS-CoV-2 infection, in hopes of complementing the body’s own immune response and neutralizing viral particles to prevent severe illness. These therapies are delivered via intravenous infusion. Several antibody-based therapies are in development.

By Fall 2020, antibody-based therapies developed by Regeneron and Eli Lilly and Company had gained attention. In late September, Regeneron announced preliminary results indicating that their antibody cocktail, REGN-COV2, reduced viral levels and improved symptoms in non-hospitalized COVID-19 patients who did not have evidence of having yet produced their own antibodies to SARS-CoV-2 (ie, seronegative individuals).150 The Regeneron antibody cocktail received considerable attention in the media after President Donald Trump received the experimental therapy after becoming infected with SARS-CoV-2 in early October.

Eli Lilly and Company announced similar results with its antibody therapy, LY-CoV555, in September as well. In early analysis of data from a preliminary trial, patients with mild-to-moderate COVID-19 were less likely to progress to needing hospitalization if they were treated with LY-CoV555 than if they had been given placebo.151

As of mid-October, data available on the utility of antibody-based therapies remains preliminary, and trials are ongoing.

Other Medications

Because there are no proven medical treatments for COVID-19 or other human coronaviruses, scientists are looking to both old and new antiviral drugs in search of effective therapies. Several drugs are currently being evaluated in preliminary research. These include antiviral drugs used to treat human immunodeficiency virus (HIV) and hepatitis B and C, such as ribavirin (Ribasphere), lopinavir-ritonavir (Kaletra), and interferon beta-1b (Betaseron).152-154 An early-stage open-label clinical trial published in the New England Journal of Medicine on March 18th, 2020 failed to show benefit with lopinavir-ritonavir in patients with severe COVID-19.155 Similarly, a randomized controlled trial published in The Lancet in October found that lopinavir-ritonavir did not reduce 28-day mortality, hospital stay duration, or risk of progressing to mechanical ventilation.156

Another antiviral drug, favipiravir (Avigan), is also undergoing studies to determine if it is efficacious in COVID-19 patients.157,158 Preliminary results from a phase 3 trial conducted in India showed that favipiravir led to faster viral clearance and offered more clinical benefit for patients compared with standard of care. Moreover, subjects who deteriorated clinically despite taking favipiravir did not need oxygen support as soon as those not receiving favipiravir.159 However, some safety concerns have arisen related to potential for the drug to cause birth defects.160

Ivermectin, an antiparasitic medication, has been proposed as a potentially helpful medication in the context of COVID-19. It has demonstrated antiviral properties against SARS-CoV-2 in vitro.161 However, the concentrations of the drug that achieved viral inhibition of SARS-CoV-2 in vitro far exceed those safely achievable in vivo.95,162,163 Nevertheless, some preliminary evidence suggests ivermectin may benefit COVID-19 patients. Unpublished, early results from a trial on 400 COVID-19 patients in Bangladesh found that ivermectin plus the antibiotic doxycycline may have improved time to clinical recovery compared with placebo.164 Numerous additional clinical trials are underway as of October to assess the potential utility of ivermectin in patients with COVID-19.165

Heparin, an anticoagulant medication, has become a mainstay of therapy in COVID-19 patients because the disease causes a dramatic increase in blood clotting tendency. Heparin, normally administered via subcutaneous injection or intravenous infusion, has several interesting properties aside from its anti-clotting effects—it exerts mucolytic, anti-inflammatory, and antiviral actions as well.156,166 Therefore, a few clinical trials are evaluating nebulized heparin in patients with COVID-19.167 The results of these ongoing trials will help determine if this novel application of heparin can help mitigate the lung pathology characteristic of COVID-19.166

Recombinant human granulocyte-colony stimulating factor (rhG-CSF) is a growth factor that increases leukocyte and lymphocyte cell counts. Because lymphopenia is common in patients ill with SARS-CoV-2 infection and correlates with severe disease, rhG-CSF has drawn attention for its potential to ameliorate this aspect of COVID-19. A randomized open-label trial published in September found that rhG-CSF did not improve the time to clinical improvement compared with usual care. However, some improvements in secondary endpoints were intriguing: rhG-CSF rapidly improved subjects’ lymphocyte and NK cell counts and appeared to decrease the frequency of progression to severe illness or death.168 These findings should be interpreted with caution because they derive from secondary endpoint analyses. Moreover, this study excluded patients with comorbidities, so it is not clear whether these findings are relevant to populations who tend to be the most vulnerable to poor outcomes in COVID-19. Additional studies are needed to clarify whether rhG-CSF may be a useful therapy for COVID-19.

Drugs that inhibit bradykinin pathway signaling, such as icatibant (Firazyr), have gained some attention as potential therapeutics in COVID-19 as well. An emerging hypothesis suggests that dysregulation of the renin-angiotensin-aldosterone system (RAAS), which is involved in blood pressure regulation and fluid balance, may contribute to several aspects of pathology associated with SARS-CoV-2 infection. In particular, excessive bradykinin signaling has been suggested to contribute to fluid accumulation in the lungs of COVID-19 patients and heightened inflammatory signaling. This theory has been dubbed the “bradykinin storm” hypothesis.169-172

A preliminary, single-center, retrospective case-control study found that the bradykinin receptor antagonist icatibant may have reduced the need for supplemental oxygen in eight of nine COVID-19 patients treated with the drug.173 However, in three patients who initially exhibited a reduction in the need for supplemental oxygen, the need for supplemental oxygen later resurged. Additional studies are needed to evaluate the potential benefits of targeting the bradykinin signaling pathway in patients with COVID-19.

Some preliminary evidence has suggested that use of statin drugs correlates with lower risk of progressing to severe disease in patients with COVID-19.174,175 A preclinical study published in October has shed some light on a potential mechanism through which statins may mitigate COVID-19 severity.176

A gene, CH25H, is upregulated by interferons released as part of the early immune response to some viral infections.177 The CH25H gene encodes an enzyme that modifies cholesterol into a form called 25-hydroxycholesterol (25HC). This modified form of cholesterol then activates further cellular signaling that ultimately results in depletion of cholesterol from the cellular membrane. Researchers found that treating human lung cells with 25HC reduced the ability of SARS-CoV-2 to infect the cells. The researchers suggested that cholesterol in cellular membranes may be necessary for the infection of cells by SARS-CoV-2, and thus depletion of membrane cholesterol by 25HC may be one of the body’s defenses against the virus. Because statins lower cholesterol levels in the blood and in turn in cellular membranes, they may also undermine the ability of SARS-CoV-2 and other viruses to infect cells.176,178

Ongoing studies will help determine if statins offer therapeutic benefit in COVID-19. However, because they are generally safe, some experts have suggested that statins should at least be continued in COVID-19 patients who had been taking them before diagnosis.95

Aspirin is of interest for its potential utility in the context of COVID-19. Excessive clotting and coagulopathy are pronounced features of severe COVID-19. Because aspirin is a well-tolerated anti-platelet agent with anti-inflammatory activities, it is considered a potentially useful therapy in the context of COVID-19, and ongoing research is evaluating whether aspirin therapy can improve outcomes in COVID-19 patients.231

The Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial is evaluating several different treatments for COVID-19 across 176 hospital sites throughout the United Kingdom. The trial has recruited an estimated 20,000 patients as of early November 2020.232 On November 6th, 2020, aspirin was added to the list of treatments being investigated.233 At least 2,000 patients are expected to be randomly allocated to receive aspirin (150 mg/day) plus standard-of-care and will be compared with patients receiving standard-of-care alone. The primary outcome is all-cause mortality after 28 days; secondary outcomes are duration of hospital stay, and a composite of death and the need for mechanical ventilation.

Additionally, an observational study found that aspirin use (median of 81 mg), within seven days prior to or 24 hours after hospital admission for SARS-CoV-2 infection, was associated with decreased mechanical ventilation, ICU admission, and in-hospital mortality. Randomized-controlled trials on low-dose aspirin are needed to establish whether this relationship is causal.234

Prone Positioning in Awake, Non-Intubated COVID-19 Patients

Although mechanical ventilation can be lifesaving in some COVID-19 patients suffering with ARDS, it is not a pleasant experience and most patients would prefer to avoid intubation if possible. One strategy that may delay or avert the need for mechanical ventilation in some COVID-19 patients is as simple as adjusting the position in which they lie on their hospital bed.

For some hospitalized but non-critical COVID-19 patients, switching from lying on their back to lying on their stomach may help their lungs absorb more oxygen and keep their blood oxygen saturation at sufficient levels to avoid intubation. The strategy calls for patients to lie on their stomachs for several hours daily while receiving supplemental oxygen via a nasal cannula. Patients lying on their stomach are said to be in the “prone position,” and those lying on their back are in the “supine position.”

Although rigorous evidence is not yet available to clarify to what extent awake prone positioning can help avert deterioration in COVID-19 patients, many hospitals now implement proning in COVID-19 patients. Early, anecdotal reports179 and observational data in ARDS due to other causes180 are encouraging. Several clinical trials are underway to formally evaluate the potential benefit of prone positioning plus supplemental oxygen in non-intubated patients with COVID-19.181

Some preliminary evidence suggests that COVID-19 patients may be susceptible to peripheral nerve injury during prone positioning, possibly due to mechanical factors combined with the heightened inflammatory milieu common in those ill due to SARS-CoV-2 infection.182

Angiotensin-II Receptor Blockers (ARBs), ACE inhibitors, and COVID-19

The SARS-CoV-2 virus enters the human body by interacting with a receptor on the outside surface of cells called angiotensin converting enzyme 2 (ACE2). ACE2 is a component of the renin-angiotensin system, which plays a critical role in maintaining homeostasis. Popular blood pressure medications—angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs)—modulate this system to control blood pressure. Examples of ACE inhibitors are lisinopril (Prinivil, Zestril) and enalapril (Vasotec); ARBs include losartan (Cozaar) and telmisartan (Micardis).

When it became widely reported that ACE2 served as the receptor site for SARS-CoV-2, many people taking ACE inhibitors or ARBs grew concerned that these drugs could increase their risk of COVID-19. However, cardiology societies around the world have issued statements urging patients not to discontinue their blood pressure medications, and stating that there is no compelling evidence that these drugs increase risk of COVID-19.183,184 It is important to keep in mind that stopping a blood pressure medication does have known risks and is not advised.

A systematic review published on May 15th, 2020 found that observational and retrospective data available as of mid-May did not suggest that ACE inhibitors or ARBs were associated with increased risk of infection with SARS-CoV-2 or more severe COVID-19.185 The analysis included data from two retrospective cohort studies, one case-control study, and 14 observational studies. The researchers concluded that “High-certainty evidence suggests that ACE inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients.”

Results of the BRACE-CORONA trial helped clarify whether ACE inhibitors and ARBs should be discontinued at the time of hospitalization in patients with COVID-19. The findings, presented in early September 2020 at the European Society of Cardiology annual meeting, were derived from the first high-quality randomized data to address this question. The trial showed that temporarily discontinuing ACE inhibitors and ARBs did not alter the clinical course of illness in patients hospitalized with COVID-19. The study’s principal investigator remarked, “Because these data indicate that there is no clinical benefit from routinely interrupting these medications in hospitalized patients with mild to moderate COVID-19, they should generally be continued for those with an indication.”186,187


 

NSAIDs (eg, Ibuprofen) and COVID-19

In mid-March, questions arose as to whether non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen would be helpful or harmful in the context of COVID-19. Most experts agreed that evidence is too limited to make a conclusive recommendation for or against NSAIDs, but that there is little evidence that NSAIDs would worsen outcomes in most cases.188 Nevertheless, some physicians and health authorities recommend acetaminophen (Tylenol, known as paracetamol in Europe) rather than ibuprofen or other NSAIDs in the context of COVID-19.

The concern with NSAIDs in the context of COVID-19 is that the drugs may mask the early symptoms of COVID-19, or possibly suppress the immune response to the virus, worsening outcomes. However, these concerns are theoretical. As of late June, there is no evidence that taking NSAIDs increases risk of infection with SARS-CoV-2 or of developing COVID-19.189

9 SARS-CoV-2/COVID-19 Vaccine Development

The development of a SARS-CoV-2 vaccine is among the most pressing issues facing the medical and scientific communities during the COVID-19 pandemic. Many experts believe that COVID-19 will remain a global health concern until a safe and effective vaccine has been developed and administered to much of the world’s human population. Given the urgency and magnitude of the situation, global research collaborations have initiated unprecedented efforts to develop a safe and effective vaccine against SARS-CoV-2. However, the process of developing a vaccine is inherently time consuming and, critically, safety and efficacy trials must be long enough to allow thorough outcome and safety assessment.

There are several general types of vaccines being developed for SARS-CoV-2/COVID-19, some of which utilize tried and true technologies, while others are building upon unproven novel technologies. The kinds of vaccines being studied include:

  • Live attenuated or inactivated virus vaccines
    • These kinds of vaccines aim to use modified variants of the SARS-CoV-2 virus that do not cause disease but can nevertheless cause the human immune system to mount a defense against future SARS-CoV-2 exposures. Many traditional familiar vaccines such as those for influenza and measles are of this type.190,191
  • Viral vector vaccines
    • Viral vector vaccines would incorporate SARS-CoV-2 genes into a different, non-pathogenic virus. When the non-pathogenic virus containing SARS-CoV-2 genes is administered in a vaccine, it does not cause illness but arms the immune system to be able to mount a defense against SARS-CoV-2 upon future exposure.
  • Subunit vaccines
    • Subunit vaccines are meant to deliver specific proteins or antigens unique to the SARS-CoV-2 virus that can prime the immune system to respond against a future SARS-CoV-2 infection. Familiar vaccines of this type include hepatitis B and whooping cough.191
  • Nucleic acid vaccines
    • This is a new kind of vaccine technology that delivers the genetic material (DNA and/or RNA) that codes for the viral antigens. The vaccine recipient’s own cells then use the genetic material to manufacture the antigens, alerting the immune system to be on the lookout for future exposure to SARS-CoV-2. No vaccines of this type have been approved as of mid-June 2020.

As of early October, 11 vaccine candidates were in phase 3 trials, with dozens more in earlier stages of development. Some Chinese and Russian vaccines had already been granted limited approval in those countries, although many in the scientific community criticized the early approvals due to insufficient safety and efficacy data.192

Vaccines must have an outstanding safety and efficacy profile given that they are administered to, ideally, most of the population. This differs from therapeutic drugs, which are given to far fewer individuals. Any risks associated with vaccines are amplified because they are generally administered to large numbers of healthy people. Therefore, long-term clinical trials are essential to ensure that any vaccine candidate is not only effective in preventing its target disease, but also safe.

Phase 3 vaccine trials take a long time because vaccinated trial subjects must be followed-up for many months so researchers can determine whether they become sick upon exposure to the virus circulating in the population. It is also important that phase 3 trials follow subjects for a long time to help determine how long the immunity granted by the vaccine lasts, which will inform vaccination schedules in such matters as if and how often booster shots are needed.

Aside from the medical and scientific challenges that SARS-CoV-2 vaccine developers must overcome, there are tremendous logistical and manufacturing hurdles that will influence the availability of shots once one or more are approved.193 In theory, most people on Earth should be vaccinated, which means distributing and administering over seven billion doses of vaccine.

These are just some of the substantial hurdles standing in the way of rapid vaccine development for SARS-CoV-2. One potential difficulty is that vaccines shown to work in younger individuals may not confer the same degree of immunity to older adults. Another is that the track record of vaccine development suggests that success is not common: less than 10% of vaccines make it through clinical trials. Not least, the problem of trying to compress what is ordinarily a very lengthy process into a shorter time period creates multiple potential scientific, medical, and logistical challenges. Still, many experts are optimistic that the urgent and global nature of the current situation, along with the many remarkable recent innovations in multiple scientific disciplines, will allow successful vaccine development on a shorter-than-usual timeline.194-197

Most experts expect that the first vaccine(s) will become generally available in mid-2021 at the earliest, with ongoing efforts to vaccinate the world population extending beyond 2021.198

10 Integrative Approaches

There are many integrative therapies with well-established antiviral and immune-modulating properties. Details regarding these therapies can be found in Life Extension’s Influenza, Pneumonia, and Immune Senescence protocols. The interventions described in these protocols, though not necessarily validated as effective specifically for severe viral illness resulting in ARDS or SARS, are nevertheless reasonable upon onset of signs and symptoms of respiratory tract infections to provide optimal support for the respiratory tract and/or immune system.

For respiratory tract health and immune support, Life Extension has long recommended swift action to help mitigate the likelihood of an evolution of respiratory tract infection to a more serious course. During the initial signs and symptoms of respiratory illness, contact your personal healthcare provider as soon as possible, and strongly consider the following options to support your respiratory health and the health of your immune system:

  1. Zinc Lozenges: Completely dissolve in mouth one lozenge containing 18.75 mg of zinc acetate every two waking hours. Do not exceed 8 lozenges daily, and do not use for more than three consecutive days.
  2. Garlic: Take 9,000‒18,000 mg of high-allicin garlic each day until symptoms subside. Take with food to minimize stomach irritation.
  3. Vitamin D: If you do not already maintain a blood level of 25-hydroxyvitamin D over 50 ng/mL, then take 50,000 IU of vitamin D the first day and continue for three more days and slowly reduce the dose to around 5,000 IU of vitamin D each day. If you already take around 5,000 IU of vitamin D daily, then you probably do not need to increase your intake.
  4. Cimetidine: Take 800‒1,200 mg a day in divided doses. Cimetidine is a heartburn drug that has potent immune support properties. (It is sold in pharmacies over-the-counter.)
  5. Melatonin: Take 3‒50 mg at bedtime.

Avoid delay. Once microbes (eg, bacteria, viruses) that cause respiratory infections are allowed to multiply, they can replicate rapidly and strategies like zinc lozenges may not be effective. Interventions should be initiated as soon as signs and symptoms manifest. Although this regimen has not been studied specifically in the context of severe viral illness resulting in ARDS or SARS, implementation of this strategy along with contacting a qualified healthcare provider as soon as possible after onset of upper respiratory tract infection symptoms is advisable.

Several additional integrative interventions to help provide functional support for the health of the respiratory tract and immune system in the context of viral upper respiratory tract infections are provided below.

  • Vitamin C. Several studies have shown that vitamin C, both before and soon after the onset of symptoms of upper respiratory tract infections, may help ease symptom burden and reduce the duration of illness.199-201 However, available evidence does not consistently support the notion that vitamin C can reduce the risk of acquiring upper respiratory tract infections.202,203 Importantly, studies to date have not focused specifically on coronavirus infections but on upper respiratory tract infections in general such as those caused by rhinoviruses, enteroviruses, and influenza viruses.
     
    A 2017 case report suggested that high-dose intravenous vitamin C may have contributed to the recovery of a 20-year-old patient with ARDS due to a viral respiratory tract infection.204 On April 1st, 2020, the American Association of Naturopathic Physicians issued a recommendation in favor of the use of intravenous vitamin C as supportive care for patients with severe, SARS-type viral respiratory illness. Their recommended dosing regimen is 100 mg/kg as a 24-hour continuous infusion for general supportive care, and 200 mg/kg (24-hour continuous infusion) for patients with severe SARS-type viral respiratory illness also experiencing a profound inflammatory immune response known as “cytokine storm.”205
  • N-acetylcysteine (NAC). N-acetylcysteine (NAC) is an amino acid derivative with mucolytic properties often used in the context of respiratory illnesses.206-208 A meta-analysis published in 2017 found that treatment with NAC led to shorter duration of ICU stay compared with control among patients with ARDS.209 Based upon some positive observational data during late 2019 and early 2020, some institutions have initiated using NAC as part of the standard management of patients in the hospital setting,210 although clinical trials are needed to specifically assess outcomes in patients with severe, viral respiratory illness treated with NAC. Some researchers have suggested NAC could provide valuable functional support for the health of mucous-producing cells lining the respiratory tract in some types of patients suffering from SARS-type viral respiratory illness on the basis of its potent antioxidant and mucolytic properties.211
  • Lactoferrin. Lactoferrin, a glycoprotein involved in immune response and several other functions,212 is found in secreted fluids and is abundant in milk (breast and cow). Lactoferrin has well-documented antibacterial, antiviral, and antifungal properties.213-215 It appears to exert antiviral effects by activating the antiviral cytokines interferon (IFN)-α/β and boosting natural killer (NK) cell activity and Th1 cytokine responses.214 Some studies suggest lactoferrin administration may reduce the incidence and severity of common respiratory tract viral infections, like colds and flu.214,216
     
    In 2005, researchers reported that the gene encoding lactoferrin was highly upregulated in patients affected during the SARS epidemic that emerged in 2003, suggesting that it plays a role in the innate immune response to the infection.217 A follow-up study suggested that lactoferrin interfered with the ability of the 2003 SARS virus from breaching the functional and structural integrity of host cells.218
  • Selenium. Selenium has important antioxidant, anti-inflammatory, and antiviral activities in the body, and deficiency is associated with increased risk of viral infection.219 In patients with HIV infection, poor selenium status is correlated with increased mortality, and selenium has been reported to slow progression of immune dysfunction and reduce hospital admissions.219,220 Some researchers have proposed that lack of selenium in regional soils may have contributed to weakened immunity and the associated SARS outbreak in 2003.221
  • Probiotics. A growing body of evidence shows Bifidobacterium and Lactobacillus species can support the health of the host’s immune response and may reduce the occurrence, severity, and duration of viral respiratory tract infections such as influenza.222,223
  • Epigallocatechin gallate (EGCG). EGCG is a polyphenol from green tea. Because of its broad immune-benefiting effects, EGCG has been proposed as a promising agent for supporting the host’s immune response in the context of viral infections such as SARS and MERS.224,225

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This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the therapies discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.

The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. Life Extension has not performed independent verification of the data contained in the referenced materials, and expressly disclaims responsibility for any error in the literature.

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