Respiratory Immune Support

Respiratory Immune Support

Last updated: 4/8/2021

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 Nutrients to Support Respiratory Immune Health

  • Vitamin D. Numerous studies around the world have found correlations between low vitamin D status and increased risk of respiratory viral infections and poor outcomes.
  • Zinc. Zinc has demonstrated antiviral effects against several respiratory viruses, promoting their clearance from the airway surfaces, preventing their entry into cells, and suppressing viral replication.
  • Lactoferrin (as apolactoferrin). Lactoferrin is an immune modulator, capable of enhancing antimicrobial immune activity while reducing inflammation, and has exhibited a broad spectrum of activity against bacteria, fungi, protozoa, and viruses.
  • Omega-3 Fatty Acids. Omega-3 fatty acids may help ease inflammatory processes in critically ill individuals, including those with acute respiratory distress.
  • Curcumin. Numerous preclinical studies indicate curcumin may activate antiviral immunity, and it has demonstrated antiviral effects against a range of respiratory viruses.
  • Melatonin. Preclinical research has shown that melatonin can reduce expression of cell receptors used by a highly infectious respiratory virus and inhibit a critical viral enzyme. Some researchers have suggested that those at high risk for severe illness associated with respiratory infections, such as the elderly, may benefit from 3–10 mg of melatonin at bedtime.
  • N-Acetylcysteine (NAC). NAC inhibits cellular entry and replication of some respiratory viruses, assists in clearing thickened mucous from the airways, and suppresses inflammatory signaling.
  • Vitamin E. Supplementing with vitamin E has been found to improve immune defenses and reduce the risk of respiratory infections, especially in the elderly.
  • Vitamin C. When initiated soon after symptom onset, vitamin C may reduce the duration of influenza-like respiratory illness symptoms such as fever, chills, and body pain.
  • Selenium. Selenium has been shown to reduce infectivity, replication, and virulence of several respiratory viruses.
  • Probiotics. Multiple randomized controlled trials and several meta-analyses have shown probiotics reduce the risk of acute respiratory tract infections.
  • Licorice. Active constituents of licorice have demonstrated antiviral effects against human respiratory viruses and may help suppress cytokine signaling involved in cytokine storm.
  • Vitamin A. Vitamin A can modulate innate and adaptive immunity as well as help mitigate inflammation and support tissue repair in the respiratory tract.
  • Vitamin K1 and K2. Low levels of circulating vitamin K (indicated by high levels of uncarboxylated proteins) may increase the risk of severe viral respiratory infection and predict poorer outcomes.
  • Thiamine. Thiamine (vitamin B1) is rapidly depleted during times of metabolic stress.
  • Garlic. Garlic compounds have demonstrated antiviral activity against respiratory viruses such as rhinoviruses, influenza viruses, and others, and various garlic extracts have been shown in randomized controlled trials to help prevent and treat common viral respiratory illness.
  • Quercetin. Quercetin may inhibit replication and infectivity of cold-causing viruses and a highly infectious respiratory virus as well as reduce inflammation induced by viral infection.
  • Andrographis. Andrographis and its active components enhance the antiviral immune response while suppressing inflammatory signaling and potentially interrupting progression to a hyper-inflammatory state.
  • Green Tea. Green tea polyphenols may help mitigate hyper-inflammation and prevent lung fibrosis in patients with severe acute viral respiratory illness.

2 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

3 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.

4 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.

5 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

6 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.

7 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.

8 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. Establishing widespread availability of accurate, rapid, point-of-care or at-home diagnostic tests for COVID-19288 ; and
  2. Establishing 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.289

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 generally effective treatment for COVID-19, and interacting with other people risks transmitting the infection, people with mild symptoms should rest at home.

Diagnostic Testing

Current diagnostic technologies for COVID-19 include molecular tests, chest imaging tests, viral antigen tests, and host antibody tests.

Molecular tests. Molecular tests are used to detect viral genetic material. The preferred initial diagnostic test for SARS-CoV-2 is a nucleic acid amplification test (NAAT). This type of test most commonly uses a procedure called reverse transcription polymerase chain reaction (RT-PCR).91 RT-PCR technology allows targeted regions of the SARS-CoV-2 genome from samples collected from the upper respiratory tract (nasal passages or throat), the lower respiratory tract, or saliva to be replicated many times, increasing the number of copies exponentially during each of multiple heating and cooling cycles. This amplification process is needed for virus detection because the absolute amount of viral genetic material in a diagnostic swab sample is generally very small, especially soon after infection.290,291 There are several types of RT-PCR, as well as other methods of gene amplification, currently being used around the world. Most tests target three genes of the SARS-CoV-2 virus to increase the likelihood of detection.290,292

While a positive test is generally sufficient for diagnosis of COVID-19, it may be important to confirm a negative test result in certain cases, particularly in patients with symptoms that cannot otherwise be explained and those for whom infection control is a concern (eg, a resident in a long-term care facility).91 Additional testing, conducted by a healthcare professional trained in proper sample collection techniques, substantially improves the likelihood of identifying infected individuals.293,294 Molecular SARS-CoV-2 testing generally takes several hours, but because of its reliance on healthcare personnel and laboratory equipment, results may not be available for days.288,290 Some newer point-of-care tests can provide results in less than an hour.288

  • Accuracy. NAATs are highly accurate in an ideal setting, but their ability to detect SARS-CoV-2 in real life conditions is variable and depends in part on proper specimen timing, collection, handling, and processing.91,290 The most frequent problem with RT-PCR tests is a false-negative result, which occurs when a test result is negative but the person being tested actually is infected with the virus. A comprehensive review of 34 studies reporting on clinically observed false-negative rates associated with RT-PCR testing calculated an overall false-negative rate of 13%; however, false-negative rates across studies varied widely (1.8–58%) for unknown reasons.295 The rate of false-positives (when an uninfected person tests positive) is significantly lower, with real-world estimates ranging from 0.8–4%. Both false-negative and false-positive diagnostic errors pose societal and personal costs that increase as COVID-19 prevalence rises.296,297
     
    Although errors in testing practices can lead to false-negative results, the timing of testing in relation to symptom onset is thought to be a major contributor to false-negative results.293,298 The probability of a false-negative result is higher during the very early and very late stages of infection, when the rate of viral shedding is low, while the lowest chance of a false-negative result is three days after the onset of symptoms.298,299 Findings from several large studies indicate false-negative results are more common in the days preceding or within one to two days after symptom onset, but most true positive cases can be identified through repeat testing one to two days later.294,299,300
     
    Samples from nasopharyngeal swabs (from the upper throat behind the nose), oropharyngeal swabs (from the lower throat behind the mouth), and saliva, when properly collected, have the potential to yield similarly accurate test results. Findings from studies using self-collected saliva suggest it may be superior to nasopharyngeal swab for accurate detection early in the course of the infection; nevertheless, the nasopharyngeal swab method has demonstrated better reliability in some studies and is currently the preferred screening method in most cases.91,293,298
     
  • Emerging technologies. Recent evidence suggests the false-negative rate of NAATs can be reduced by using a technology called droplet digital PCR (ddPCR) instead of RT-PCR. 301-303 In ddPCR, the sample is partitioned into thousands of nanodroplets, each of which then undergoes nucleic acid amplification. Unfortunately, despite its better performance, ddPCR takes approximately twice as long as RT-PCR testing, is more expensive, and requires specialized equipment.302,303
     
    Another method of nucleic acid amplification being explored is isothermal amplification. This technique targets six viral genes, increasing its potential specificity for SARS-CoV-2. Unlike RT-PCR, which requires multiple heating and cooling cycles, isothermal amplification is done at one temperature. Although still in the preliminary stages of development, isothermal amplification technology could potentially be a faster and less expensive testing option.292
     
    CRISPR technology, which is used to alter genetic sequences, is the basis of another new SARS-CoV-2 testing method. One CRISPR-based diagnostic test under investigation isothermally amplifies viral genetic material, excises target sequences, and tags them with a fluorescing probe that is easily detectable, possibly even by a cellphone camera.304 In another test that uses CRISPR technology, the amplification step is not needed and actual viral presence can be quantified.305 These and other CRISPR-based tests use samples from saliva or nasal secretions that are relatively easy to obtain and have so far demonstrated similarly high specificity (few false-positives) plus higher sensitivity (fewer false-negatives, even with low viral presence) than RT-PCR. In addition, they are inexpensive, portable, and able to provide results in minutes. 304-307 Several CRISPR-based tests have been approved for emergency use by the US Food and Drug Administration. If approved for broad use, CRISPR-based tests could help accurate COVID-19 testing to become widely accessible.303

Antigen tests. SARS-CoV-2 antigen tests detect the presence of SARS-CoV-2 viral proteins in upper or lower respiratory fluid samples. These are rapid tests, generally performed at the point of care, but test reliability depends on proper collection and volume of samples.298 Antigen tests are typically prone to more false-negatives than NAATs, but are inexpensive and offer turnaround times of less than one hour.1 Because of their advantages, antigen tests may be the preferred diagnostic tests in clinical situations that require a rapid diagnosis, during outbreaks when contacts are being tested frequently, or in cases when NAATs are not available.91,298

In December 2020, the FDA approved the first fully at-home COVID-19 diagnostic test, which uses a simple antigen-detecting technology known as lateral flow assay (LFA). The test, called Ellume, is available without a prescription. The sample is collected using a mid-turbinate nasal swab (deep in the nasal passage but not as far back as the throat) and can provide results in as little as 20 minutes via an application on a smartphone. The Ellume COVID-19 Home Test is reported to have a 4–9% rate of false-negatives and 0–4% rate of false-positives.308

If COVID-19 is suspected in a symptomatic individual who tests negative on any antigen test, the result should be confirmed by another test. In addition, an individual who tests positive but who has no symptoms should self-isolate and consult with their healthcare provider to determine whether further testing is warranted.91

Chest imaging . Chest computed tomography (CT) and chest ultrasound can identify COVID-19-related changes in the lungs and are sometimes recommended as an alternative to, or in conjunction with, routine tests for COVID-19 diagnosis.309,310 Chest imaging may be most useful in patients who have tested negative with RT-PCR tests but who are older, have been symptomatic for more than five days, have fever and shortness of breath, and/or have chronic health problems.311,312 Chest imaging is not recommended as a screening test for asymptomatic individuals.309

Serology (Antibody) Testing

Serology tests are blood tests that detect antibodies produced by the immune system in response to SARS-CoV-2 infection. Antibody tests (sometimes called assays) are primarily used to identify individuals who were exposed to SARS-CoV-2 in the past, whether or not they experienced symptomatic illness.91,298 These tests could therefore play a role in assessing vaccine- or infection-induced immunity across populations. Antibody tests may also be helpful in identifying active SARS-CoV-2 infection in patients who have been symptomatic for three to four weeks and have diminished levels of viral shedding. In most patients, measurable levels of IgG antibodies to SARS-CoV-2 can be detected 14 days after symptom onset.298 However, it is important to note that not all COVID-19 patients produce detectable levels of SARS-CoV-2 antibodies, and the presence of antibodies does not necessarily indicate protection against further infection.298,313,314 In addition, levels of specific antibodies have been noted to change over time in those who have had COVID-19, and the implications of their persistence or disappearance is still a topic of exploration.289,315

Most antibody tests currently in use rely on enzyme-linked immunosorbent assay (ELISA) technology, but interest in LFA-based tests has recently grown due to their low cost and ease of use.298 The sensitivity of antibody tests varies. Assays that test for IgG or total antibodies have been reported to produce fewer false-negative results than those that test for IgM or IgA antibodies.91,313 There have been reports of cross-reactivity to other common coronaviruses, resulting in lower specificity for some antibody tests.316,317 False-positive results from antibody tests are especially likely to occur in regions where infection prevalence is low.91

An emerging type of antibody test that appears to be more sensitive and specific, known as the two-step ELISA test, detects the presence of either two IgG or two IgM antibodies to two related but distinct viral proteins; another promising assay is the surrogate virus neutralization test, which identifies the presence of antibodies that inhibit interactions between viral proteins and receptors on cells. These and other innovative serology tests have the potential to provide highly accurate and reliable results.298,317,318

A number of laboratories, including LabCorp (https://www.labcorp.com/antibody-testing) and Quest Diagnostics (https://questdirect.questdiagnostics.com/), offer serological SARS-CoV-2 antibody testing at their patient service centers with a physician’s order. The details and limitations of their tests are described on their websites. Some antibody tests are also available directly to the consumer, but because many are not accurate, the FDA maintains a list of tests that should not be used.319

9 Treatment

Overall State of COVID-19 Treatments

For most who develop non-severe COVID-19 illness, the recommended approach continues to be at-home rest and basic self-care, including use of over-the-counter pain relievers and fever medications as needed. However, for those with mild-to-moderate COVID-19 who are at high risk of developing severe illness or needing hospitalization due to COVID-19, certain medical therapies may be appropriate.329

In general, the standard of care for COVID-19 continues to evolve as evidence emerges. At present, for hospitalized patients, anticoagulation therapy to prevent blood clots and general respiratory support (eg, prone positioning and medical management of ARDS) are standard. The addition of COVID-19-specific therapies depends on disease severity and prognosis. Remdesivir is generally recommended for hospitalized patients, and clinical trials suggest it may have a small positive impact on duration of illness. For those requiring supplemental oxygen, dexamethasone, with or without remdesivir, is generally recommended. In the most severe cases requiring invasive mechanical ventilation or cardiorespiratory life support, only dexamethasone alone has been shown to be helpful.329

Other agents for preventing and treating COVID-19 at any stage of illness remain investigational and are only recommended in the context of clinical trials at this time. As of early 2021, no medications have proven to be broadly effective in preventing or treating COVID-19.329

In the context of an unsuccessful search for effective treatment, an urgent call to curb the pandemic, and society’s unprecedented access to both accurate and inaccurate information, a daunting and confusing body of anecdotal and observational evidence has grown, while meaningful findings accumulate slowly. As you read the information below, bear in mind the highest quality of evidence comes from double-blind, randomized, controlled trials that include large numbers of participants in multiple venues. Findings from observational studies and anecdotal reports (in the form of case reports) in general lend support for better research to be undertaken and do not form the basis for best medical practice.

The US Food and Drug Administration (FDA) issues emergency use authorizations (EUAs) for drugs that show promise in preliminary research, facilitating access to these medications for further investigation. With sufficient evidence, the National Institutes of Health (NIH) recommends for or against specific therapies, but in the absence of conclusive evidence, the NIH does not offer a recommendation. Medications without a positive or negative recommendation remain investigational.

Recommended Therapies

Dexamethasone. The NIH recommends use of dexamethasone (Decadron), a common and inexpensive corticosteroid, in COVID-19 patients requiring increasing amounts of supplemental oxygen, as well as those requiring ventilation support; however, the NIH recommends against its use in patients with mild-to-moderate illness who do not need oxygen.329 The RECOVERY trial, published in July 2020, was the first randomized controlled trial to demonstrate clear benefits with dexamethasone. In the trial, 2,104 patients received standard care plus dexamethasone (orally or intravenously) and 4,321 patients received standard care alone. In patients needing invasive mechanical ventilator support, dexamethasone reduced deaths by 36%, and in those needing supplemental oxygen but not ventilator support, dexamethasone reduced deaths by 18%. There was no reduction in mortality in patients who did not need either respiratory support or supplemental oxygen.330

Numerous additional trials, many of which have used other corticosteroids such as methylprednisolone, are confirming the importance of corticosteroid therapy in severely ill COVID-19 patients.331,332 A meta-analysis published in September 2020 by a World Health Organization working group included data from seven randomized trials and 1,703 critically ill COVID-19 patients. The analysis found corticosteroid therapy reduced 28-day mortality compared with placebo or standard care.333 A systematic review and meta-analysis published in December 2020 included data from 44 randomized controlled trials and observational studies in which the effectiveness and safety of corticosteroid drugs in hospitalized COVID-19 patients were examined. The analysis found corticosteroid use reduced mortality, as well as the need for mechanical ventilation, in those with compromised respiratory function.332

In addition to illness severity, certain biomarkers may be helpful in identifying COVID-19 patients most likely to benefit from corticosteroid therapy. Various inflammatory markers have been linked to progression to more severe illness and may be indicators of the need for corticosteroid treatment.334 One observational study found hospitalized COVID-19 patients with CRP levels >20 mg/dL had an improved clinical course when treated with corticosteroids, but those with CRP levels <10 mg/dL had a worse clinical course.99 Another observational study found higher levels of the inflammatory cytokine interferon gamma-inducible protein 10 (IP-10) correlated with poorer prognosis in hospitalized COVID-19 patients, and IP-10 levels decreased with corticosteroid treatment.335

Remdesivir . Remdesivir (Veklury), an antiviral drug that inhibits viral replication,331 is the only FDA-approved drug for use in treating COVID-19, and current NIH treatment guidelines recommend its use in hospitalized patients who require supplemental oxygen, but not mechanical ventilation.329 Nevertheless, its benefits are somewhat uncertain and likely to be modest. The most important supportive evidence comes from a randomized, double-blind, placebo-controlled trial that included 1,062 patients hospitalized for COVID-19, 85% of whom had severe illness and 15% who had mild-to-moderate illness. In addition to standard care, participants were treated with either intravenous remdesivir or placebo for up to 10 days. Overall, the clinical status of the remdesivir group at day 15 was significantly better than the placebo group. The median time to recovery in those given remdesivir was 10 days versus 15 days with placebo. Although reduced mortality was also seen with remdesivir compared with placebo, this difference was not statistically significant.336

An open-label controlled trial included 584 participants hospitalized with moderate COVID-19 randomly assigned to receive standard care plus either five days of remdesivir, 10 days of remdesivir, or placebo. On day 11, those given remdesivir for five days were more likely to have better clinical status than those given placebo, but those given remdesivir for 10 days were not. Because the trial was not blinded, the importance of these findings is unclear.337 A placebo-controlled trial in 237 patients with severe COVID-19 found a 10-day course of remdesivir did not improve clinical outcomes except in a subgroup of participants with symptom duration of 10 days or less, although this did not reach statistical significance.102

Interim results from the ongoing SOLIDARITY trial, funded by the World Health Organization, were published in December 2020. The report included data from 11,330 patients hospitalized with COVID-19 and randomly assigned to one of four investigational drugs or no investigational drugs. Remdesivir, as one of the drugs being tested, was found to have no impact on duration of hospitalization, need for mechanical ventilation, or mortality. A meta-analysis of findings from other trials was included in the report and suggested remdesivir may have a small positive effect on mortality.338

Remdesivir can cause mild-to-serious adverse side effects, including digestive upset, increased levels of liver enzymes indicating liver inflammation, increased time needed to form blood clots, and allergic reactions.329

Therapies with Emergency Use Authorization

Convalescent plasma . Researchers are currently investigating whether convalescent plasma, the antibody-rich blood plasma of people who have recovered from COVID-19, is helpful in treating SARS-CoV-2 infection.329 Convalescent plasma may contain antibodies that can improve antiviral defenses and modify inflammatory response. This approach to infection treatment was discovered more than a century ago and has been used for many infectious diseases, especially prior to the emergence of antibiotics.339 Convalescent plasma was granted EUA in August 2020 for use in hospitalized COVID-19 patients.329

A number of clinical trials included in systematic reviews and meta-analyses concluded convalescent plasma may promote more rapid viral clearance, increase likelihood of clinical improvement, decrease likelihood of death in COVID-19 patients, and may be more effective when used early in those with severe illness.340-342 However, randomized controlled trials to date have failed to show convalescent plasma therapy has clear clinical benefits. A randomized, open-label, controlled trial that enrolled 103 patients with severe or life-threatening COVID-19 found adding convalescent plasma to standard care did not increase the odds of clinical improvement within 28 days compared with standard care alone; however, results indicated convalescent plasma treatment may have been effective in a subgroup of patients with severe (but not life-threatening) illness.105 Another randomized, open-label, controlled trial in 464 patients with moderate COVID-19 found convalescent plasma therapy did not reduce disease progression or mortality; however, antibody levels in the convalescent plasma used in this trial were not measured.343 A randomized placebo-controlled trial in 333 hospitalized patients with severe COVID-19 found convalescent plasma had no effect on clinical status or mortality at day 30.238

There is growing interest in the possibility that convalescent plasma may be particularly beneficial in COVID-19 patients with compromised immune function. This includes individuals with primary and acquired immunodeficiencies, cancer, and recipients of organ or stem cell transplants.344

Convalescent plasma therapy infrequently causes adverse side effects, most of which are related to the inherent risks of transfusions. They include allergic and anaphylactic transfusion reactions, transfusion-transmitted infections, transfusion-related acute lung injury, transfusion-associated circulatory overload, hemolytic reactions (in which red blood cells rupture), and non-hemolytic fevers.329

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 or the FDA’s Donate COVID-19 Plasma website.

Bamlanivimab and etesevimab. Bamlanivimab is a human antibody that targets the SARS-CoV-2 spike protein and may block the virus’ ability to enter cells. In November 2020, the FDA authorized bamlanivimab for emergency use in non-hospitalized COVID-19 patients at high risk of progression to severe illness and hospitalization, including329:

  • Those with metabolic disease or impaired immune function
  • Those aged 55 years and older with high blood pressure or chronic respiratory or cardiovascular disease
  • Those aged 65 years and older

Etesevimab is another human antibody against SARS-CoV-2. Because it targets a different part of the viral spike protein than bamlanivimab, it is thought that using these antibodies together may increase effectiveness and reduce risk of resistance.345 Importantly, the EUA for bamlanivimab does not currently include co-treatment with etesevimab.

The first report from an ongoing, randomized, double-blind, placebo-controlled trial examining the effects of bamlanivimab in outpatients with mild-to-moderate COVID-19 included data from 452 participants. They were treated with one of three doses (700, 2,800, or 7,000 mg) of intravenous bamlanivimab or placebo, administered as a single infusion within three days of having a positive SARS-CoV-2 test result and a median of four days after symptom onset. Those who received the middle dose of bamlanivimab had a greater reduction in nasopharyngeal viral presence compared with placebo 11 days after treatment. Bamlanivimab was also associated with fewer emergency room visits and hospitalizations within 28 days, particularly in a subgroup of participants at high risk of hospitalization; however, the number of these outcomes was too small overall to draw firm conclusions. There were no deaths among participants.346 A second report from the same trial included data from 577 participants treated with bamlanivimab, bamlanivimab plus etesevimab, or placebo, and found only the combination of bamlanivimab plus etesevimab reduced viral load within 11 days compared with placebo. Once again, numbers of emergency room visits and hospitalizations were low but appeared to indicate a protective effect of bamlanivimab, alone and in combination with etesevimab.345 Bamlanivimab has not demonstrated positive effects in hospitalized COVID-19 patients being treated with remdesivir, and research in this population has been halted.347

Bamlanivimab and etesevimab appear to be safe, with no serious drug-related adverse side effects having been reported to date. Because they are delivered intravenously, infusion reactions can occur.329

Casirivimab and imdevimab, Casirivimab and imdevimab are unique human antibodies that bind to the spike protein of SARS-CoV-2 and inhibit viral attachment and entry. This antibody combination of casirivimab and imdevimab together was granted EUA in November 2020, allowing research into its use in non-hospitalized COVID-19 patients with mild-to-moderate illness and high risk of progression to severe illness and hospitalization. This is the same population for which bamlanivimab is authorized for emergency use, and includes329:

  • Those with metabolic disease or impaired immune function
  • Those aged 55 years and older with high blood pressure or chronic respiratory or cardiovascular disease
  • Those aged 65 years and older

A report from an ongoing, randomized, double-blind, placebo-controlled trial included data from 275 participants who received a single intravenous infusion of casirivimab plus imdevimab or placebo within three days of a positive SARS-CoV-2 test result and no more than eight days after symptoms onset. Data showed participants receiving the antibody combination had a greater reduction in viral load seven days after treatment and were less likely to require medical attention during 29 days of monitoring. Results also showed the effect was stronger in those with a high baseline viral load and those with a negative SARS-CoV-2 antibody test prior to treatment.348

The antibody combination casirivimab plus imdevimab has demonstrated relative safety, and most adverse side effects reported have been related to allergic and infusion reactions.348

Baricitinib. Baricitinib (Olumiant), an oral anti-inflammatory drug that interferes with cytokine signaling, is approved for treatment of moderate-to-severe rheumatoid arthritis and has demonstrated clinical benefits for other inflammatory conditions. In November 2020, the FDA granted EUA for baricitinib in combination with remdesiver for the treatment of COVID-19 in hospitalized patients requiring supplemental oxygen, invasive mechanical ventilation, or life support.329 This authorization was based on the results of a randomized, double-blind, placebo-controlled trial in 1,033 hospitalized COVID-19 patients with moderate or severe illness treated with standard care and remdesivir plus either baricitinib or placebo. Those receiving remdesivir plus baricitinib had a slightly greater likelihood of not having worsened on day 29 compared with remdesivir plus placebo. In addition, combination treatment led to higher odds of clinical improvement at day 15 and a one-day reduction in median time to recovery (seven vs. eight days). The greatest benefit was seen in those needing high-flow oxygen or non-invasive ventilation at the beginning of the trial. The baricitinib/remdesivir group also experienced fewer serious adverse side effects.349

Findings from a small trial that included 37 hospitalized COVID-19 patients with moderate-to-severe illness suggest a loading dose of baricitinib may improve its effectiveness. In the trial, participants who received a high dose of baricitinib for one day followed by usual doses for the remainder of two weeks had better clinical outcomes than those who received usual doses for the full two weeks.350

Importantly, baricitinib has not been studied as a stand-alone therapy for COVID-19. Baricitinib may produce immunosuppressive effects during acute viral infection, which could delay viral clearance and increase vulnerability to secondary infections. Corticosteroids, which also suppress immune function, may not be safe in combination with baricitinib; however, this combination has not been well studied. Ongoing research will help determine which patients are most suited for treatment with baricitinib and what other drugs can safely and effectively be used with baricitinib.351

Chloroquine and Hydroxychloroquine—Revoked EUA

The antimalarial drugs chloroquine (Aralen) and hydroxychloroquine (Plaquenil) received EUA in March 2020 based on preliminary evidence suggesting these drugs might benefit COVID-19 patients; however, this authorization was revoked in June 2020 after accumulating evidence showed potential dangers associated with their use outweighed their possible benefits.136

As of early 2021, the US NIH recommends against use of chloroquine and hydroxychloroquine for prevention and treatment of COVID-19.329

A randomized, double-blind, placebo-controlled trial in 479 hospitalized COVID-19 patients found no difference in 14-day clinical status, 28-day mortality, or any other outcome between those treated with hydroxychloroquine and those given placebo.352 In a randomized, open-label, controlled trial that compared outcomes in 1,561 hospitalized COVID-19 patients treated with hydroxychloroquine to outcomes in 3,155 patients given standard care, no difference in 28-day mortality was found. In fact, those given hydroxychloroquine had longer hospitalization times and, among those not needing mechanical ventilation at the start of treatment, hydroxychloroquine was associated with increased risk of progression of illness and death.353

A large systematic review of 35 observational studies and randomized controlled trials found hospitalized COVID-19 patients treated with hydroxychloroquine had no reduction in risk of death or time to recovery, and longer hospital stays compared with those receiving standard care. Furthermore, the addition of the antibiotic azithromycin (Zithromax) to hydroxychloroquine therapy did not improve outcomes and appeared to increase mortality.354 Other large meta-analyses have also found hydroxychloroquine, with or without azithromycin, had no beneficial effects in COVID-19 patients and may cause more adverse side effects, including abnormal heart rhythms.355,356

Hydroxychloroquine has also been promoted as a preventive against COVID-19; however, a meta-analysis of four randomized controlled trials with a combined total of 4,921 participants showed the drug did not reduce incidence of SARS-CoV-2 infection, hospitalization, or death, and increased risk of adverse side effects.357

Other Investigational Treatments

Antiviral drugs. Numerous studies have explored the use of antiviral drugs, alone and in combination, in COVID-19 treatment and prevention. Based on in vitro evidence of its efficacy against SARS-CoV-2, lopinavir-ritonavir (Kaletra) gained attention as an antiviral option in severe cases of COVID-19. Clinical trials, however, have yielded disappointing results. Interim results from the World Health Organization’s ongoing SOLIDARITY trial, which included 1,399 COVID-19 patients randomly assigned to receive lopinavir-ritonavir and compared their outcomes to those of 1,372 controls, indicated lopinavir-ritonavir had little or no effect on COVID-19 outcomes or mortality.338 A randomized, open-label, controlled trial with 199 participants found lopinavir-ritonavir did not reduce 28-day mortality, hospital stay duration, or risk of progressing to mechanical ventilation in patients with severe COVID-19.358 Because lopinavir-ritonavir frequently causes digestive upset, interacts with many other medications, and can cause serious adverse side effects such as abnormal heart rhythm and liver toxicity, it is unclear whether its potential benefits outweigh its potential harm.329

Favipiravir (Avigan), another drug that interferes with viral replication, was originally developed as an anti-influenza drug but is now being investigated for potential effects against SARS-CoV-2.359 A randomized, open-label, controlled trial in 60 hospitalized patients with COVID-19 pneumonia found favipiravir-treated participants had faster viral clearance: four days after starting treatment, 62.5% of those receiving favipiravir and 30% of those receiving standard care tested negative for SARS-CoV-2.360 Similarly, in a non-randomized controlled trial in 80 COVID-19 patients, those treated with favipiravir had a shorter time to viral clearance and had more improvement on chest imaging after 14 days than those treated with lopinavir-ritonavir.157 However, not all findings have found favipiravir to be effective. Several randomized controlled trials have failed to show favipiravir, alone or in combination with other experimental treatments, is beneficial in treatment of COVID-19.361,362 Favipiravir can cause diarrhea and has been found to raise uric acid and liver enzyme levels. Importantly, favipiravir is not safe in pregnancy because it may cause birth defects.359

Ivermectin (Stromectol) is an antiparasitic medication that has demonstrated antiviral properties against SARS-CoV-2 in vitro. Although a meta-analysis of observational studies and randomized controlled trials concluded ivermectin was not able to reduce COVID-19 mortality,363 some evidence suggests ivermectin may be helpful in reducing the risk of SARS-CoV-2 infection and severe COVID-19 illness. A small, randomized, double-blind, placebo-controlled trial compared the effect of a single dose of ivermectin, administered within 72 hours of symptom onset, to placebo in 24 outpatients with non-severe COVID-19 and a low risk of complications. Although viral loads decreased more in the ivermectin group on days four and seven post-treatment, the difference was not statistically significant. Interestingly, those treated with ivermectin were more likely to recover their full sense of smell compared with placebo.364 A randomized, open-label, controlled trial enrolled 304 close contacts of COVID-19 patients: 203 were treated with two doses of ivermectin, two days apart, and 101 were not. After 14 days, 7.4% of those treated with ivermectin and 58.4% of those not treated tested positive for SARS-CoV-2, and the effect was more pronounced in those under 60 years of age.365 An observational study comparing 481 outpatients with COVID-19 who were treated with a combination of ivermectin, azithromycin (an antibiotic), montelukast (Singulair) (a leukotriene receptor blocker), and aspirin to 287 other COVID-19 outpatients who received other therapies found those who received the test combination had a higher rate of recovery, were less likely to need hospitalization, and had lower mortality during 14 days of monitoring.366

As research continues, widespread reports of ivermectin’s preventive effects, combined with its accessibility and low cost, have led to its mass and indiscriminate use by healthy populations in some countries. According to one report, countries where ivermectin is routinely administered prophylactically have lower incidences of COVID-19.367 Although short-term ivermectin has been shown to be generally safe, its long-term safety is unknown.368

Camostat mesylate (Foipan), a drug used to treat chronic pancreatitis and post-operative gastroesophageal reflux, has recently been shown to inhibit an enzyme needed by SARS-CoV-2 to gain entry into cells.369,370 A case series reported on the outcomes of 11 critically ill COVID-19 patients, six of whom were treated with camostat mesylate and five with hydroxychloroquine. During eight days of monitoring, clinical status improved only in those treated with camostat mesylate.371 Camostat mesylate has been associated with adverse side effects such as rash, abdominal discomfort, and elevation of liver enzyme levels.370

Immune activators. Interferons (IFNs) are a class of cytokines released by cells, including immune cells, in response to viral infection. They help activate and regulate antiviral immune activity. IFN-α and IFN-β in particular are crucial players in the early response to viral infection. IFN therapy is used to treat viral hepatitis B and hepatitis C (IFN-α) and multiple sclerosis (IFN-β), but has not been shown to be helpful in treating coronavirus infections such as SARS and MERS. Furthermore, therapeutic use of IFNs causes significant side effects and is contraindicated in COVID-19 patients with severe or critical illness.329,372

A randomized, double-blind, placebo-controlled trial that included 98 patients hospitalized with presumed or confirmed COVID-19 found those treated with inhaled nebulized IFN-β1a daily for 14 days were more likely to improve and had more rapid recovery during 28 days of monitoring. In fact, patients treated with IFN-β1a were twice as likely to have recovered at the end of the trial compared with placebo.373 In another randomized controlled trial, 42 patients hospitalized with severe COVID-19 received IFN-β1a (administered by subcutaneous injection three times weekly for two weeks) in addition to standard care, while 39 similar patients received only standard care. Although participants treated with IFN-β1a did not improve more quickly than those given placebo, they were more likely to be discharged from the hospital by day 14 and less likely to die by day 28. The strongest benefit on mortality appeared to occur in those who received treatment early in their illness.123 However, a report from an ongoing study sponsored by the World Health Organization found no differences in outcomes in 2,063 participants treated with IFN-β1a compared with 4,088 who received no experimental treatment.338

In a randomized, open-label, controlled trial that included 66 participants with severe COVID-19, the addition of IFN-β1b, initiated within 48 hours of hospital admission and administered subcutaneously every other day for two weeks, to standard care shortened time to recovery and reduced risk of progression to critical illness compared with standard care alone.374 In another randomized, open-label, controlled trial that included 127 COVID-19 patients being treated with lopinavir-ritonavir, those who also received a combination of IFN-β1b plus the antiviral medication ribavirin had a shortened time to recovery.375

One observational study examined data from 446 COVID-19 patients and determined treatment with IFN-α2b within five days of hospital admission was associated with reduced mortality, but when IFN-α2b was started more than five days after hospital admission, it was associated with increased mortality.376 Another observational study with 2,037 participants compared outcomes of COVID-19 patients treated with ribavirin, IFN-α, ribavirin plus IFN-α, or neither medication within 48 hours of hospital admission. None of the treatments were found to correlate with progression to more severe illness or 30-day mortality.377

Although available evidence is inconclusive, it suggests type 1 IFNs may have a role in treatment of COVID-19 when used in conjunction with antiviral therapies and initiated soon after infection. It is important to recognize that IFN therapy causes systemic side effects, such as flu-like symptoms, nausea, fatigue, blood toxicities, elevated liver enzyme levels, and depression; IFN-β may cause fewer side effects than IFN-α.329 Although some evidence suggests inhalation of nebulized IFNs may be more tolerable and effective than subcutaneous injections, inhaled forms are not widely available in the United States.378

Granulocyte-colony stimulating factor (G-CSF) (Neupogen, Filgrastim) is a blood protein and growth factor that stimulates bone marrow to produce more white blood cells. Because patients with COVID-19 often have low numbers of white blood cells, which are critical for mounting an effective antiviral immune response, the medical use of G-CSF has drawn attention as a potential strategy to combat COVID-19.379 A randomized, open-label, controlled trial compared G-CSF to standard care in 200 COVID-19 patients with pneumonia and low blood lymphocyte (a type of white blood cell) counts who had no chronic health problems. While G-CSF raised white blood cell numbers more rapidly than standard care, it did not improve time to clinical improvement. Those who received G-CSF were less likely to progress to severe illness or death; however, these effects did not reach statistical significance.168 It is important to recognize that, while G-CSF may help some COVID-19 patients, it may increase the risk of inflammatory complications such as ARDS by stimulating immune activity in others. In fact, some treatment options being explored include antibodies that inhibit G-CSF. More research is needed to elucidate the patient characteristics associated with likelihood of benefit from G-CSF treatment.380,381

Cytokine inhibitors. Interleukin-1 (IL-1) and interleukin-6 (IL-6) inhibitors are drugs that interfere with inflammatory cytokine signaling and may interrupt the hyper-inflammatory cascade believed to cause life-threatening complications in critically ill patients with COVID-19.382

Tocilizumab (Actemra) is a monoclonal antibody that targets IL-6 receptors, interrupting highly inflammatory IL-6 signaling. While mainly used to treat rheumatoid arthritis, tocilizumab is also approved for use in an acute inflammatory condition called cytokine release syndrome. Based on promising reports from observational studies suggesting tocilizumab prevented progression and death in those with COVID-19-related hyper-inflammation and ARDS, several randomized controlled trials were undertaken.382

In a randomized, double-blind, placebo-controlled trial in 243 COVID-19 patients with evidence of respiratory distress and hyper-inflammation, a single dose of intravenous tocilizumab was not found to improve outcomes over placebo when added to standard care.383 Another randomized, double-blind, placebo-controlled trial included 389 COVID-19 patients, most of whom (87.3%) were of racial or ethnic minority backgrounds. All participants had pneumonia but were not receiving mechanical ventilation. Those treated with two doses of intravenous tocilizumab were less likely to worsen in clinical status; however, tocilizumab did not reduce 28-day mortality compared with placebo.384 In an open-label trial with 129 COVID-19 patients with elevated inflammatory marker levels, an alarmingly higher mortality rate was noted in those receiving tocilizumab plus standard care (17%) than those receiving standard care alone (3%) after 15 days.385 Other randomized, open-label, controlled trials have also found that, compared with standard care, tocilizumab offered no benefit in terms of disease progression or mortality in hospitalized patients with COVID-19 pneumonia.230,386 A meta-analysis of six randomized controlled trials concluded that, although tocilizumab appears to reduce progression of illness in patients with COVID-19, it does not lower overall mortality.387

Nevertheless, some evidence indicates select patients who experience worsening respiratory and inflammatory status despite standard therapy may benefit from tocilizumab.388,389 A randomized, open-label, controlled trial with 4,116 COVID-19 patients, most of whom were receiving invasive or non-invasive ventilation support and 82% of whom were being treated with corticosteroids, found those receiving tocilizumab plus standard care were more likely to survive at 28 days than those receiving standard care alone. In addition, those given tocilizumab who did not require invasive mechanical ventilation at baseline were less likely to progress to needing invasive mechanical ventilation than those provided standard care alone.390

Sarilumab (Kevzara), like tocilizumab, is an IL-6 receptor blocker, and is currently used to treat rheumatoid arthritis. Research on short-term use of sarilumab in COVID-19 treatment has been disappointing, showing no benefit in those with severe or critical illness. Ultimately, the pharmaceutical companies sponsoring sarilumab research announced their findings do not support a clinical benefit of sarilumab for any of the disease severity subgroups or dosing strategies studied.130

Siltuximab (Sylvant) is a monoclonal antibody that binds to IL-6 (rather than the IL-6 receptor) and thereby disrupts inflammatory signaling. As of early 2021, only unpublished observational evidence exists suggesting siltuximab may reduce mortality in COVID-19 patients requiring ventilation support.391

Anakinra (Kineret) is an IL-1 inhibitor used in treating moderate-to-severe rheumatoid arthritis that has not responded to other therapies. Findings from observational studies indicate COVID-19 patients treated with intravenous anakinra may have better clinical outcomes than comparable patients treated with standard care.392-395 However, in a randomized, open-label, controlled trial with 116 participants, anakinra did not improve outcomes in hospitalized patients with mild-to-moderate COVID-19.396

Repurposing Anti-Inflammatory Drugs

Colchicine (Colcrys) is an older anti-inflammatory drug normally used to treat gout and prevent pericarditis (inflammation of the tissue surrounding the heart). Colchicine appears to decrease inflammation mainly by stabilizing inflammasomes—intracellular protein complexes that, when activated, trigger inflammatory cytokine signaling. Inflammasomes play a substantial role in the progression of COVID-19 to cytokine storm and resulting complications; through inhibiting the activation of inflammasomes, and possibly other anti-inflammatory mechanisms, colchicine may reduce the risk of COVID-19 progression and mortality.397,398

Observational evidence suggests treatment with colchicine may improve outcomes and reduce mortality in patients with moderate-to-severe COVID-19.399-401 A randomized, open-label, controlled trial included 105 hospitalized COVID-19 patients treated with standard care plus oral colchicine or standard care alone and found the time between treatment initiation and a clinical event was slightly longer in colchicine-treated participants.138 In a randomized, double-blind, placebo-controlled trial that included 72 patients with moderate-to-severe COVID-19, treatment with colchicine was found to reduce the length of time supplemental oxygen was needed and length of hospital stay. Seven days after starting treatment, supplemental oxygen was still needed by 42% of those receiving standard care and 9% of those receiving colchicine. The trial was too small to detect differences in mortality between the two treatment regimes.402

Although colchicine is generally well tolerated, it can cause digestive upset. In addition, it is prone to drug-drug interactions, and can cause problems in people with kidney impairment.398

Icatibant (Firazyr), a drug that inhibits bradykinin signaling by blocking bradykinin receptors, is used to treat hereditary angioedema, a condition characterized by recurring bouts of severe swelling. Excessive bradykinin signaling has been suggested to contribute to fluid accumulation in the lungs and heightened inflammatory signaling in COVID-19 patients.403 An observational study found icatibant may have reduced the need for supplemental oxygen in eight of nine COVID-19 patients; however, three patients whose need for supplemental oxygen was initially reduced had a resurgence in oxygen need later.173

Aspirin may benefit COVID-19 patients through both its anti-inflammatory and anti-thrombotic properties since heightened inflammatory signaling and excessive clotting are pronounced features of severe COVID-19 and its life-threatening complications.404,405 Several observational studies have noted regular use of low-dose aspirin (75‒100 mg per day) for cardiovascular protection was associated with decreased COVID-19 infection and mortality,234,406-408 but other studies have observed no relationship between aspirin use and COVID-19 outcomes.409,410

Adjunctive Therapies

Heparin. SARS-CoV-2 infection is well known to activate inflammatory and thrombogenic (blood clot-inducing) pathways, both of which contribute to the onset of respiratory distress.411 In addition, increased clotting in those with severe COVID-19 leads to complications such as pulmonary embolism, heart attack, and stroke.411,412 Anticoagulant therapy, usually with low-dose heparin, is widely accepted to be beneficial as an adjunct to other treatments in order to counter these effects in COVID-19 patients.411,413 Some evidence further suggests heparin may have anti-inflammatory and antiviral effects.413 A subset of hospitalized COVID-19 patients given prophylactic heparin were found to have reduced mortality compared with those not given heparin in one observational study.414

The NIH recommends use of low-dose heparin for hospitalized patients not already using long-term anticoagulants to manage a chronic condition and for whom there is no other contraindication. Drug-drug interactions are common with heparin, as with other anticoagulants, and should be considered before initiating treatment. The most serious adverse events associated with heparin use are related to an increased bleeding risk.329,413 Tests assessing coagulation markers, such as platelets, prothrombin, fibrinogen, and D-dimer may help identify those most at risk of complications associated with an increased tendency to form blood clots.412

Statins. A growing body of observational evidence suggests people taking statin drugs to lower high cholesterol levels have a lower risk of severe COVID-19 and better COVID-19 outcomes.415-417 It is thought that statins may reduce inflammation by inhibiting cytokine signaling. This effect may reduce the risk of a cytokine storm, which may precipitate COVID-19 complications like ARDS and cardiovascular events.418 Statins may also have antiviral, vascular-protective, and blood clot-inhibiting effects.419 The use of statins in prevention or treatment of COVID-19 in people with normal cholesterol levels has not yet been explored. Guidelines generally note that routine-use statins should not be discontinued in patients who present with COVID-19.420

Prone positioning. 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. The strategy calls for patients to lie on their stomach (in prone position) for several hours daily while awake and receive supplemental oxygen via a nasal cannula. Prone positioning appears to help the lungs absorb more oxygen and keep blood oxygen saturation at sufficient levels to avoid the need for mechanical ventilation.421 It has previously been shown to substantially reduce mortality in patients with ARDS due to other causes.422,423 Observational data suggest prone positioning can improve oxygenation, reduce the likelihood of needing mechanical ventilation, shorten hospital stays, and reduce mortality in patients with COVID-19 needing supplemental oxygen (but not ventilation).421,424-427 The most common adverse effect of prone positioning is peripheral nerve injury; this may be preventable with careful positioning to protect vulnerable body regions, such as the elbow, upper arm, and shoulder.428

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

The SARS-CoV-2 virus attaches to cells by interacting with cell surface receptors called angiotensin converting enzyme 2 (ACE2) receptors. ACE2 receptors are part of the renin-angiotensin system, which plays a critical role in regulating blood pressure, fluid, and electrolyte balance. Two widely used classes of blood pressure-lowering medications—angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs)—work by modulating this system. Examples of ACE inhibitors include lisinopril (Prinivil, Zestril) and enalapril (Vasotec); ARBs include losartan (Cozaar) and telmisartan (Micardis).

Because long-term use of ACEIs and ARBs has been reported to increase expression of ACE2 receptors, some researchers suggested early in the pandemic that people using these medications may be at higher risk of SARS-CoV-2 infection and more severe illness. On the other hand, these medications reduce levels of a peptide hormone called angiotensin II that has been associated with worsening of acute pneumonia, leading others to propose ACEIs and ARBs may help protect those with COVID-19 from lung injury.429,430

A number of systematic reviews and meta-analyses of data from observational studies have indicated ACEI and ARB use is not associated with COVID-19 severity, and may be correlated with reduced mortality.431-434 One meta-analysis of findings from 14 studies with a total of 73,073 hospitalized COVID-19 patients with high blood pressure found those taking ACEIs or ARBs were 35% less likely to die than those not taking ACEIs or ARBs.435 Furthermore, an observational study noted hospital stays were longer in COVID-19 patients who switched from ACEIs or ARBs to other anti-hypertensives than those who stayed on ACEIs or ARBs.436

Cardiology societies around the world have issued statements urging patients not to discontinue their blood pressure medications based on lack of compelling evidence that these drugs increase risk associated with COVID-19. It is important to keep in mind that stopping blood pressure medications has well established risks and is not advised.


NSAIDs and COVID-19

Non-steroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Advil) and naproxen (Naprosyn) work by altering the production of prostaglandins that regulate immune system signaling. Preclinical evidence suggests NSAIDs have the potential to exert both harmful and beneficial effects during SARS-CoV-2 infection, since they decrease the antiviral immune response, yet also reduce inflammatory cytokine signaling.437 Questions about whether NSAID use increases the risk and severity of COVID-19 or protects against COVID-19 complications related to cytokine storm have not been definitively answered; however, observational studies have so far found no association between NSAID use and worse COVID-19 outcomes.438-440 One research group compared COVID-19 mortality in 536,423 current users of NSAIDs to 1,927,284 non-users in the general population and found no difference. In a separate study of data from 1,708,781 individuals with osteoarthritis or rheumatoid arthritis, the same researchers found current NSAID users were 22% less likely to die from COVID-19 than non-NSAID users.441 In the absence of conclusive evidence of an effect on the course of COVID-19, decisions about NSAID use should be based on other potential clinical benefits and risks.

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

The development and distribution of a SARS-CoV-2 vaccine have been 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 administered to much of the world’s human population.

There are several general types of vaccines for SARS-CoV-2/COVID-19 that have moved beyond their initial safety and immunogenicity studies.239 Some of these utilize tried and true technologies, while others are building upon 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
  • 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
  • Viral vector vaccines
    • Viral vector vaccines incorporate SARS-CoV-2 genes into a different, non-pathogenic virus. When the non-pathogenic virus containing SARS-CoV-2 genes is administered as 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. Treatments that utilize viral vectors have been approved for use in some genetic diseases, however no vaccine has previously been approved based on this technology.240
  • 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 FDA approved for humans prior to the COVID-19 pandemic.

As of mid-January, 20 vaccine candidates are in phase 3 trials, with dozens more in earlier stages of development.192,269 Two nucleic acid vaccines, one produced by Moderna and one produced by Pfizer in collaboration with BioNTech, have been approved for EUA in the United States and other countries, and have been granted full approval in Canada. On December 31, the World Health Organization granted emergency validation to the Pfizer/BioNTech vaccine, which may help expedite the approval process in other countries.270

A third viral vector vaccine, produced by AstraZeneca in collaboration with the University of Oxford, has been approved for emergency use in Britain, India, Mexico, and other countries.192,271

On December 10th, the interim analysis of Pfizer’s phase 2/3 trial was published in the New England Journal of Medicine; its primary endpoints were laboratory-confirmed COVID-19 and adverse event incidence over a median of two months. The results showed that the vaccine was 95% effective at preventing COVID-19.242 Common reactions in the vaccine group included fatigue and headaches, although these reactions were also reported in the placebo group. Less common reactions were fever and chills, primarily in the vaccine group. These reactions were observed within the first 1 to 2 days after vaccination and resolved shortly thereafter.

The primary endpoint for vaccine efficacy in Moderna’s phase 3 trial was prevention of symptomatic COVID-19.241 The interim results, released as part of the emergency use approval process, showed 94.5% efficacy at reaching this primary endpoint.272 In participants who only received one dose of the vaccine, this efficacy was reduced to 80.2%, although the majority of COVID-19 cases occurred within 28 days of the first dose. The most commonly reported side effects were injection site pain, headache, muscle pain, and chills. As of mid-January, details of Moderna’s interim analysis have yet to be formally published in a peer-reviewed journal.

Both vaccines contain mRNA for the SARS-CoV-2 spike protein. The mRNA in the vaccine is used by the vaccine recipient’s cells to manufacture parts of the SARS-CoV-2 spike protein, which are then recognized by the immune system, prompting an antibody response. In both vaccines, mRNAs are encapsulated in lipid nanoparticles to prevent degradation and ensure they are efficiently transported inside cells.

Although the two vaccines are similar, there are subtle but important technical differences in how they are manufactured and how they elicit an immune response against the SARS-CoV-2 spike protein.239 Importantly, Moderna reports that its vaccine needs to be stored at temperatures between -13° and 5° F, but remains stable at standard refrigeration temperatures (36‒46° F) for up to 30 days, whereas Pfizer/BioNTech have stated their vaccine must be chilled to -94° F, but may be kept for up to five days at standard refrigeration temperatures once ready for use.241-243 Additionally, it has been reported that Moderna’s vaccine does not require dilution whereas Pfizer’s does, which may make Moderna’s more efficient to use.244,245 Both vaccines require a prime shot followed by a booster a few weeks later; Pfizer requires the two doses to be at least 3 weeks apart, whereas Moderna requires them to be at least 4 weeks apart.246,247 There is a 4-day grace period for boosters administered earlier than recommended, so boosters administered as early as days 17 and 24 for the Pfizer and Moderna vaccines, respectively, are still considered valid.273

One concern that has been raised with vaccines is that they may not be as efficacious in older individuals due to immune senescence.262 Fortunately, results from the Pfizer/BioNTech and Moderna trials have demonstrated efficacy and safety across age groups.263-265,272

On December 2nd, the UK accepted an EUA for the Pfizer vaccine, making it the first Western country to authorize a vaccine against COVID-19.251 The first vaccine was administered on December 8th. In the United States, EUAs were requested by Pfizer on November 20th and Moderna on November 30th. On December 10th, the FDA Vaccines and Related Biological Products Advisory Committee voted to recommend that the FDA authorize use of the Pfizer vaccine, and on December 11th the FDA officially announced its EUA.248,268 The first vaccines were given on December 14th. On December 17th, the same committee reviewed the data for the Moderna vaccine, which was granted EUA on December 18th.274

Results from an interim analysis of the Oxford-AstraZeneca clinical trials, another frontrunner to provide a safe and effective vaccine, were published December 8th.275 The primary endpoint for this analysis, which included 11,636 participants from four pooled clinical trials, was a negative nucleic acid amplification swab test 14 days after receiving the booster shot. The vaccine efficacy rate was 62% for participants who received the full prime dose and then the booster; however, for those that received a low prime dose followed by the standard dose, the efficacy increased to 90%.252 No one who received the low-dose primer was over age 55. Twenty-one days after the first dose, there were 10 participants hospitalized for COVID-19, all in the control group; two were classified as severe COVID-19, including one death.

In a secondary analysis, the Oxford-AstraZeneca vaccine was also examined for its ability to prevent asymptomatic spread of SARS-CoV-2. In participants who received the low-dose prime shot, the vaccine was 58.9% effective at preventing asymptomatic SARS-CoV-2 infection.275 The Moderna and Pfizer/BioNTech vaccine trials did not report efficacy against asymptomatic infection with SARS-CoV-2, but researchers do emphasize the importance of continued infection control measures, including hand washing, mask wearing, and social distancing.274,276

Oxford-AstraZeneca’s vaccine differs in formulation from those produced by Pfizer/BioNTech and Moderna because it is a viral vector vaccine. It utilizes a modified chimpanzee adenovirus that cannot replicate, but which expresses the spike protein for SARS-CoV-2, causing the immune system to produce antibodies against SARS-CoV-2.253 A potential advantage to using this vaccine is that it may be able to last for at least six months at temperatures between 36‒46° F.254

As of mid-January, AstraZeneca has not applied for EUA in the United States, although EUA is expected in April, according to the chief advisor for the United States COVID-19 vaccine program.277 On December 30th, the United Kingdom authorized emergency supply of the Oxford-AstraZeneca vaccine, now called COVID-19 Vaccine AstraZeneca, for individuals 18 years of age or older.278 Vaccination with COVID-19 Vaccine AstraZeneca began on January 4th in the United Kingdom. The same day, the vaccine was authorized for use in Mexico, India, and Argentina.269

In China and Russia, some vaccines have already been granted limited approval, although many in the scientific community criticized the early approvals due to insufficient safety and efficacy data.192 The vaccines distributed in China and Russia have not been validated in large-scale, rigorous clinical trials before their initial distribution.

Safe and efficacious vaccines usually take many years to produce. However, technology has advanced significantly since the origination of traditional vaccines (live attenuated or inactivated vaccines). Historically, the bulk of the time needed to produce a safe and efficacious traditional vaccine has been in the development phase. With newer technologies—nucleic acid and viral vector type vaccines—once the genome of the target virus is sequenced, vaccine development is more efficient. Once developed, it can be quickly evaluated in preclinical/animal models, and, if successful, be immediately moved to phase 1 or phase 1/2 safety/efficacy clinical trials. 255,256 Although a nucleic acid vaccine and a viral vector vaccine have not received approval for other diseases, they have been explored by researchers in preclinical and clinical stages for decades. 257,258 Some people have raised concerns about these vaccines due to the speed at which they have been developed. However, it is important to understand that the development of these SARS-CoV-2 vaccines was supported by unprecedented resource allocation and existing research for related viruses, including the original SARS-CoV-1 and Middle Eastern Respiratory Syndrome (MERS)-CoV. The safety and efficacy trials for these vaccines received far greater scrutiny than typical given the global urgency of the situation.

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 for the general population.193 Although the exact number remains unclear, experts believe that in order to reach herd immunity, at least 75% of a population would need to be vaccinated.279 Although polls suggest Americans are growing less reluctant to vaccination, current figures suggest this may be difficult to achieve, with only 71% of respondents from a late-November/early-December poll indicating they would get a COVID-19 vaccine.280 Additionally, actual vaccination rates have lagged significantly behind the amount of vaccine distributed across the country.281

In the United States, vaccine rollout began in mid-December, with priority given to high-risk essential workers (eg, healthcare workers) and residents of long-term care facilities, followed by adults 75 years of age or older and other frontline essential workers. The CDC recommends a phased rollout for vaccination, although they have not provided a concrete estimate for availability to the general public.266,267,282,283 The Pfizer/BioNTech vaccine has been approved for individuals 16 years of age or older, and the Moderna vaccine is currently approved for adults 18 or older. Both companies are currently completing clinical trials to examine the safety and efficacy in adolescents 12 years or older.284,285 Pregnant or breastfeeding women are encouraged to talk to their doctor before vaccination.

With the rollout of COVID-19 vaccines, there have been reports of rare but severe allergic reactions after receipt of the vaccines. According to the CDC, 21 cases of severe anaphylactic reactions were reported among 1,893,360 Pfizer first doses administered.286 Most of these serious reactions occurred within 13 minutes of vaccine receipt, which is why the CDC recommends all people who receive a COVID-19 vaccine be monitored on-site for at least 15 minutes. For those with a history of allergic reactions to vaccines or injectable therapy, monitoring for at least 30 minutes is recommended. Vaccination is not recommended for individuals with a history of severe allergic reactions to any of the mRNA vaccine components. Those with a history of allergic reactions to other types of vaccines should ask their doctors about whether they should receive a COVID-19 vaccine. People with other types of allergies (eg, food, pets) should get vaccinated.287

Pfizer/BioNTech and Moderna Vaccines Do Not Contain Controversial Preservatives

Some vaccine preservatives or adjuvants, such as thimerosal, aluminum, and formaldehyde, have generated controversy in the past. It is important to be aware that these ingredients are not present in leading mRNA-based COVID-19 vaccines currently being distributed (ie, those produced by Pfizer/BioNTech and Moderna).

The excerpts below are taken directly from the product labeling information for the Pfizer/BioNTech and Moderna COVID-19 vaccines.

Pfizer/BioNTech

The Pfizer-BioNTech COVID-19 Vaccine Multiple Dose Vial contains a volume of 0.45 mL, supplied as a frozen suspension that does not contain preservative.”320

Moderna

The Moderna COVID-19 Vaccine multiple-dose vial contains a frozen suspension that does not contain a preservative and must be thawed prior to administration.”321

11 Nutrients

Many nutrients have well-documented antiviral and immune-modulating properties. Details regarding these therapies can be found in Life Extension’s Common Cold, Influenza, Pneumonia, and Immune Senescence protocols. The interventions described in these protocols, although 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 nutritional support for the respiratory tract and 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. Vitamin D: If you do not already maintain a blood level of 25-hydroxyvitamin D over 50 ng/mL, then take 250 mcg (10,000 IU) vitamin D the first day and continue for three more days; then reduce the dose to 50–125 mcg (2,000–5,000 IU) vitamin D each day. If you already take 2,000–5,000 IU vitamin D daily, then you probably do not need to increase your intake.
  2. Zinc Lozenges: Completely dissolve in mouth one lozenge containing 18.75 mg of zinc, in the form of zinc gluconate, oxide, or acetate, every 2‒3 waking hours, up to five times per day acutely.
  3. Lactoferrin: Take 150–300 mg of bovine apolactoferrin daily.
  4. Omega-3 Fatty Acids: Take EPA plus DHA or fish oil providing 2,000–3,000 mg of combined omega-3 fatty acids per day.
  5. Curcumin (providing curcuminoids): Take 160–400 mg of curcuminoids daily.
  6. Melatonin: Take 3‒50 mg at bedtime.

Avoid delay. Once the bacteria or 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.

Vitamin D

The active form of vitamin D (1,25-[OH]2-D3) is an immunomodulatory hormone that influences antiviral defenses by increasing production of antiviral compounds in the respiratory mucosa, as well as cytokines that regulate the immune response to infection. At the same time, vitamin D inhibits excessive inflammatory signaling and is thought to be vital to suppressing the potentially fatal cytokine storm that can accompany some types of severe viral respiratory illness.442,443

Numerous studies around the world have found correlations between low and deficient vitamin D status and increased risk of respiratory viral infection, severe infection, and poor outcomes.444-447 In one study that examined records from more than 987,000 patients during the time of a viral respiratory infection outbreak, the chance of testing positive for the presence of the highly infectious respiratory virus was 4.6 times higher in those with vitamin D deficiency.448 Another study that included data from 204 participants with pneumonia related to the same highly infectious virus found only 12.3% of participants were vitamin D sufficient, while 46% had vitamin D insufficiency and 41.7% had vitamin D deficiency.449

Several observational studies have found regular users of vitamin D supplements had a lower risk of contracting a highly transmissible respiratory virus.450,451 Other observational studies indicate an association between treatment with high doses of vitamin D (500–1,250 mcg [20,000–50,000 IU] per week or a single 2,000 mcg [80,000 IU] bolus) soon after being diagnosed with a viral respiratory infection and lower odds of severe complications or death.452-454 However, some researchers have questioned whether high-dose bolus vitamin D would be as effective in the context of acute viral respiratory illness as continual lower-dose daily vitamin D supplementation.455 As of early 2021, available research does not clearly support the superiority of one dosing strategy over the other. Clinical trials are needed to clarify potential differences between these dosing regimens on outcomes among people with acute viral respiratory illness.

In a randomized controlled trial, 40 participants with vitamin D deficiency and asymptomatic or mildly symptomatic viral respiratory infection were given either 1,500 mcg (60,000 IU) vitamin D3 daily or placebo for seven days; 62.5% of those given vitamin D tested negative for the virus by day 21 versus 20.8% of those given placebo.456 In another randomized, double-blind, placebo-controlled trial that included 240 hospitalized patients with a severe acute viral respiratory illness, those given a single oral dose of 5,000 mcg (200,000 IU) vitamin D3 had improved vitamin D status but no improvement in the course of their illness, even when only those with baseline vitamin D deficiency were considered.457 The effect of calcifediol (25-hydroxyvitamin D3), a vitamin D3 metabolite, was tested in a randomized controlled trial in 76 patients hospitalized with a severe viral respiratory infection. Only 2% of those given calcifediol at a dose of 21,280 IU on day one and 10,640 IU on days three and seven required intensive care versus 50% of those who received placebo.458 More randomized controlled trials using vitamin D3 and calcifediol in patients with severe respiratory viral infections are underway at this time.459

Zinc

Zinc, the second most abundant trace metal in the body, following iron, affects the function of every organ, tissue, and cell; however, as much as one-third of the world’s population is estimated to have inadequate zinc status, which is especially prevalent among the elderly and those with chronic health problems.460-463 Zinc deficiency results in compromised immune function, increased susceptibility to infection, and longer duration of infectious illness.464,465 Zinc has demonstrated antiviral effects against respiratory viruses such as influenza viruses, rhinoviruses (the most frequent cause of common colds), and others, promoting their clearance from the airway surfaces, preventing their entry into cells, and suppressing viral replication.462,464 In addition, zinc modulates the immune response to viral infection, reduces oxidative stress, and helps regulate inflammatory signaling, and has been shown to mitigate infection-induced cytokine storm in laboratory models. In fact, some estimates suggest zinc deficiency contributes to the occurrence of 16% of lower respiratory infections.462

Some evidence indicates zinc levels decrease during acute infectious illness and may not recover for several weeks.466 Recent studies have noted patients with severe acute viral respiratory infections had lower zinc levels than healthy matched controls, and low zinc levels were correlated with increased risk of complications including ARDS, longer hospital stays, and higher mortality.467-469 Findings from one study suggest the simultaneous occurrence of low zinc and low selenium levels may be an especially strong predictor of mortality in older patients with acute viral respiratory illness.470-473

Zinc supplementation, using doses of 80–92 mg daily and beginning soon after symptom onset, has been found to shorten symptom duration in those with viral respiratory illness and reduce mortality in those with severe pneumonia.467-469 A retrospective study analyzed outcomes in 411 patients hospitalized with an acute viral respiratory infection who were treated with 440 mg of zinc sulfate (providing 100 mg of elemental zinc) daily for five days in addition to hydroxychloroquine and azithromycin. When these patients’ outcomes were compared with those of 521 similar patients who received the same treatment but without zinc, those who received zinc were more likely to have been discharged home and, among those who did not require intensive care, the individuals given zinc were less likely to die or be transferred to hospice care than those who received no zinc.474 However, another retrospective analysis based on data from 242 patients hospitalized with the same viral infection found the addition of 100 mg elemental zinc (from zinc sulfate) per day to standard treatment (which varied dramatically) was not correlated with significantly lower mortality.475 In addition, a randomized, open-label, controlled trial of patients initially receiving outpatient care for the same viral infection found the addition of 50 mg zinc (from zinc gluconate) per day for 10 days to standard treatment did not improve outcomes in 116 patients compared with 98 similar patients who did not receive zinc.476

Interestingly, some researchers have proposed low zinc status may contribute to the loss of smell that sometimes accompanies respiratory viral infections477; while one study found no significant relationship between zinc status and loss of smell in 134 patients with a viral respiratory infection, it did note those who received 50 mg elemental zinc twice daily recovered their sense of smell more quickly than those who received no zinc.478

Lactoferrin

Lactoferrin is an iron-binding protein made by cells such as those in secretory glands and activated neutrophils (a type of immune cell). It is found in most bodily fluids, including tears and breast milk, and lactoferrin derived from bovine whey is frequently used in supplements.479,480 Lactoferrin is an immune modulator, capable of enhancing antimicrobial immune activity while reducing inflammation, and has exhibited a broad spectrum of activity against bacteria, fungi, protozoa, and viruses.479,480 Laboratory research also suggested lactoferrin may inhibit entry of a highly infectious respiratory virus into cells by blocking its interactions with cell membrane components.481,482 Other research showed lactoferrin may induce immune activity targeting this virus.483

Lactoferrin may slow pathogen multiplication through its iron binding capacity. While iron is required for DNA replication and energy production, the presence of excess iron increases free radical generation, stimulates inflammatory processes, and exacerbates viral infection by promoting increased viral replication.484,485 Furthermore, patients with a severe acute viral respiratory infection have been found to have elevated levels of ferritin, and these levels correlated with increased risk of death.486,487 In its iron-free state (apolactoferrin), lactoferrin can sequester pro-oxidant free iron, lowering oxidative stress and suppressing the growth of pathogens, and possibly mitigating the serious complications of infection.481,485

In a pilot trial, 75 patients who tested positive for an acute viral respiratory tract infection were treated at home with a liposomal preparation of a combination of 32 mg bovine lactoferrin with 12 mg vitamin C, with or without 10 mg liposomal zinc, four to six times daily for 10 days. In addition, lactoferrin nasal drops, mouth spray, and aerosol were used as needed by participants with headaches, loss of sense of smell and taste, nasal congestion, dry cough, or difficulty breathing. After 48 hours, all symptoms had diminished except loss of smell and taste, and by day five, all infected participants recovered from their illness with only loss of smell and taste remaining as residual symptoms.488

Omega-3 Fatty Acids

The omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) modulate inflammatory processes in the body through a variety of mechanisms.489,490 Severe acute viral respiratory infections can sometimes trigger cytokine storm, in which excessive production of inflammatory cytokines leads to uncontrolled systemic inflammation and life-threatening tissue and organ damage. Another phenomenon, called eicosanoid storm, has also been proposed to contribute to widespread inflammation, tissue damage, and organ failure. Eicosanoid storm is characterized by excessive production of pro-inflammatory and procoagulant eicosanoids made from arachidonic acid, an omega-6 fatty acid synthesized in the body and obtained from dietary animal fat.490,491 By competing with arachidonic acid for metabolic enzymes, EPA and DHA decrease the production of pro-inflammatory and procoagulant eicosanoids and increase production of specialized inflammation-resolving compounds.490-492

Accumulating evidence shows omega-3 fatty acids, administered orally or intravenously, may help control inflammation and improve outcomes in critically ill patients, including those with ARDS.489 A meta-analysis of 12 randomized controlled trials with a total of 1,280 critically ill patients with ARDS found supplementation with omega-3 fatty acids, in combination with gamma-linolenic acid (a less-inflammatory omega-6 fatty acid) and antioxidants, improved markers of lung function; however, only hourly administration, rather than large bolus intravenous dosing, was associated with reduced mortality. Although reductions in mechanical ventilation and length of stay in intensive care were seen, these effects did not reach statistical significance.493

An observational study in 100 patients hospitalized with a severe acute viral respiratory illness found higher levels of EPA plus DHA were associated with lower mortality, though the effect was not statistically significant, possibly due to the small number of participants.494 During an outbreak of a severe viral respiratory infection, another study found countries with the highest intake of omega-3 fatty acids from marine sources had lower mortality rates than other regions of the world.495 The same research group used computer modeling to show how omega-3 fatty acids might bind to the highly infectious virus and interfere with its ability to enter cells.495

Curcumin

Curcumin, a yellow carotenoid from turmeric, is well known for its anti-inflammatory and free radical-scavenging effects. It has also demonstrated antiviral effects against a range of respiratory viruses, including influenza A virus and others.496 Computer models suggest curcumin may interfere with viral entry into cells as well as viral replication inside cells.497-501 Numerous preclinical studies indicate curcumin may activate antiviral immunity; at the same time, curcumin appears to inhibit infection-induced inflammatory signaling and promote anti-inflammatory processes, reducing the potential for a cytokine storm and ARDS and protecting other organ systems.496,502,503 By suppressing inflammation, curcumin has the potential to help mitigate complications and sequelae of severe acute viral respiratory infections.504,505

In an open-label trial, 21 patients hospitalized with mild-to-moderate illness due to a highly infectious respiratory virus were treated with a nano-curcumin preparation providing 80 mg curcuminoids (curcumin and its related compounds) twice daily for two weeks in conjunction with standard therapies; their progress was compared with 20 similar patients treated with standard therapies alone. Those who received curcumin had better oxygenation status beginning on day two of treatment, as well as faster resolution of most symptoms, faster normalization of immune cell numbers, less likelihood of worsening of their clinical status, shorter time requiring supplemental oxygen, and shorter hospital stays.506

In a double-blind placebo-controlled trial of 40 participants with a viral respiratory illness, those who received 160 mg nano-curcumin per day for 14 days along with standard therapy had greater reductions in some inflammatory cytokines, including IL-6. They also experienced significant improvement in more symptoms and had a lower fatality rate than those receiving placebo.507 The same research group conducted another double-blind placebo-controlled trial in hospitalized patients with the same virulent respiratory virus, 40 with severe illness receiving intensive care and 40 with mild illness; half of the participants in each group received 160 mg nano-curcumin per day for 14 days and the other half received placebo. Curcumin-treated patients had lower numbers and activity of immune cells known to be involved in cytokine storm and hyper-inflammation. They also had greater improvement in fever, cough, and shortness of breath, and had lower mortality rates (0% vs. 5% in those with mild illness and 5% vs. 25% in those with severe illness [p<.0001 for both mild and severe cases]) than those who received placebo.508

Melatonin

Melatonin is released by the brain’s pineal gland in response to nighttime darkness and is a key regulator of circadian synchrony. It also exerts strong anti-inflammatory and oxidative stress-reducing actions, and is an important modulator of mitochondrial function.509 Melatonin has been found to reduce expression of cell receptors used by a highly infectious respiratory virus and inhibit a critical viral enzyme in the laboratory.510 Production of melatonin diminishes with age, contributing to immune dysfunction and increasing oxidative stress, inflammation, and infection susceptibility.511 In addition, infectious viruses can suppress melatonin production, disrupting circadian controls and impairing immune function.509

Melatonin supplementation may reduce the risk of acute viral respiratory infections, help mitigate some chronic health problems that increase infection vulnerability, and protect against neurological and cardiovascular complications of viral respiratory infections.511,512 Based on melatonin’s therapeutic potential and well-established safety profile, it has been suggested those at higher risk for severe illness and complications from viral respiratory infection, including the elderly and those with chronic medical conditions, may benefit most from regular use of 3–10 mg melatonin at bedtime.511 And some researchers have suggested high doses of melatonin, ranging from 50 to 200 mg twice daily, might help treat patients hospitalized for severe acute respiratory illness.511

In an observational study that followed 11,672 individuals, melatonin use was associated with a reduced risk of testing positive for a common, highly infectious respiratory virus.513 Another study looked at data from 791 patients intubated for respiratory support during an outbreak of a severe acute viral respiratory illness and 2,981 patients needing the same level of respiratory support for other reasons. The use of melatonin, most often for sleep issues, during the intubation period was associated with significantly improved outcomes in both groups and increased the likelihood of survival in virus-infected patients who required mechanical ventilation.514 A number of clinical trials to investigate the effects of melatonin in individuals with a severe viral respiratory infection are currently underway.515-518

N-acetylcysteine

N-acetylcysteine (NAC) is a source of the amino acid cysteine that is needed for production of the important free radical scavenger glutathione and provides sulfur for the generation of hydrogen sulfide, a major source of intracellular antioxidant compounds known as sulfane sulfur species.519 NAC inhibits cellular entry and replication of some respiratory viruses, assists in clearing thickened mucous from the airways, suppresses inflammatory signaling, and may help mitigate viral infection-induced cytokine storm.520-522

NAC may help reduce the risk of viral respiratory infections.523 A randomized controlled trial that included 262 frail older adults found taking 1,200 mg NAC per day for six months reduced the incidence of influenza-like viral respiratory illness: 29% of those receiving NAC versus 51% of those receiving placebo became ill. Interestingly, viral testing revealed the infection rate was similar in both groups, but most of those treated with NAC remained asymptomatic. In addition, the severity of symptoms was lower in the NAC group.524

High-dose intravenous NAC has been proposed to have a therapeutic benefit in those with acute lung injury and ARDS.523 In a controlled trial that included 27 patients with ARDS, those who received intravenous NAC (150 mg/kg body weight on day one and 50 mg/kg body weight on days two through four) had a more rapid increase in blood oxygenation; in addition, only 5 of 14 (35.7%) patients in the NAC group versus 10 of 13 (76.9%) in the placebo group died while in the hospital.525 Another trial in 61 patients with mild-to-moderate acute lung injury found treatment with intravenous NAC, at 40 mg/kg body weight, for three days improved oxygenation and reduced the need for mechanical ventilation, but did not significantly reduce progression to ARDS or mortality.526

More recently, a set of 10 case reports described reductions in inflammatory marker levels following the addition of intravenous NAC to treatment in patients hospitalized with a severe acute viral respiratory illness. In several cases, inflammatory marker levels rebounded upon discontinuation of NAC therapy.527 However, in a randomized, double-blind, placebo-controlled trial in 135 patients with severe acute respiratory syndrome related to a viral infection, intravenous NAC, at approximately 300 mg/kg body weight administered over a 20-hour period, in addition to standard treatment did not alter the clinical course compared with placebo.528

As of early 2021, several clinical trials are underway to assess the efficacy of NAC in the context of highly infectious respiratory viral infections.529

Vitamin E

Vitamin E, a fat-soluble antioxidant, plays a critical role in healthy immune function. Supplementing with vitamin E has been found to improve immune defenses and reduce the risk of respiratory infections, especially in the elderly.530,531 Severe infections trigger the production of free radicals that damage tissue and set inflammatory processes in motion. Rising oxidative stress in acute respiratory infections promotes progression of symptoms and contributes to the onset of severe complications, including ARDS. Increasing antioxidant intake may help restore oxidation-reduction balance and interrupt the inflammatory cycle that contributes to poor outcomes.532,533

In addition to its free radical scavenging effects, vitamin E has been shown to stimulate interferons, cytokines that activate antiviral immune function, and reduce the production of highly inflammatory cytokines like IL-6.531 Clinical trials in elderly subjects have shown vitamin E, in doses of 50–800 mg (about 56–889 IU) of dl-alpha[α]-tocopherol per day, can improve immune cell function.534,535 In a small placebo-controlled trial, 10 patients with ARDS who received 600 IU vitamin E (form not specified) per day by intramuscular injection had greater improvement in clinical status than 10 patients who received saline injections (placebo) during seven days of monitoring.536

Vitamin C

Vitamin C is a free radical scavenger that may improve the course of acute respiratory infections by lowering oxidative stress and inflammation, supporting normal tissue repair, and enhancing anti-infection immune function.537,538 Studies have found critically ill patients with pneumonia and ARDS were more likely to have low or deficient vitamin C status than healthy individuals.539,540 In one study, 17 of 18 participants with ARDS had undetectable levels of vitamin C.540

Meta-analyses have found regular use of vitamin C can lower the risk and shorten the duration of common colds.541-543 When initiated soon after symptom onset, vitamin C may reduce the duration of influenza-like respiratory illness symptoms such as fever, chills, and body pain.544 In a randomized controlled trial in elderly patients hospitalized for bronchitis or pneumonia, 200 mg vitamin C daily led to improved outcomes compared with placebo, and the benefits were greater in those with the most severe illness.545 Another randomized controlled trial compared intravenous vitamin C (50 mg/kg body weight) with placebo in 167 critically ill patients with sepsis (infection in the blood) and ARDS; while vitamin C therapy did not appear to affect markers of organ dysfunction, vascular injury, or inflammation, it was associated with a dramatic 81% reduction in mortality during four days of treatment.546,547 A meta-analysis found intravenous vitamin C therapy reduced the need for and duration of mechanical ventilation in ARDS patients, although it did not significantly reduce mortality.548 However, in a randomized controlled trial, 2,000 mg intravenous vitamin C (in combination with 200 mg vitamin B1) daily was not effective in ARDS patients with sepsis.549

An open-label controlled trial in 60 hospitalized patients with a severe acute viral respiratory illness found the addition of intravenous vitamin C, at 6 grams per day, to treatment with antiviral medications for five days did not impact outcomes.550 In another randomized, open-label, controlled trial, 48 patients hospitalized with the same acute viral infection received 8,000 mg oral vitamin C (taken in divided doses) per day in addition to standard treatment for 10 days; compared with 50 similar patients who received standard care alone, there were no differences in outcomes.476 More clinical trials are underway to determine whether vitamin C has a role in treating acute viral respiratory illness.551

Selenium

Selenium plays a role in immune cell function and activation through its incorporation into enzymes and other proteins. It also reduces infectivity, replication, and virulence of several respiratory viruses.552,553 Sodium selenite, a form often used in supplements, has been found to block an infectious respiratory virus from entering cells by interacting with its spike protein in the laboratory.554 Selenium works closely with vitamin E and cysteine to regulate oxidation and reduction balance and neutralize free radicals, and can help reduce inflammatory signaling by controlling oxidative stress.552,555 Human and animal studies indicate poor selenium status is associated with increased risk of viral respiratory infections and increases the virulence of various viruses by allowing their rapid mutation in the body.555,556 Poor selenium status may also increase the likelihood of induction of excess inflammation due to cytokine storm.553,557

The soil concentration of selenium varies geographically around the world, affecting selenium status and resulting in endemic insufficiency and deficiency.555 One observational study found selenium levels were lower in 30 individuals with non-severe illness compared with 30 healthy individuals during an outbreak of a common viral respiratory infection.558 Another study found, among 50 patients hospitalized with a severe acute viral respiratory illness, 42% were selenium deficient.559 A study comparing acute viral respiratory infection survival to regional selenium status during a major outbreak in China found survival was more likely in high-selenium regions.560 A study done during an outbreak in Germany found higher selenium and selenium-containing protein levels in acute viral respiratory infection survivors versus non-survivors.561

Blood selenium levels have been noted to diminish in patients with critical illness, and lower levels are correlated with more severe illness and lower chance of survival.562 A meta-analysis of 19 randomized controlled trials found intravenous selenium supplementation in critically ill patients reduced total mortality (but not 28-day mortality) and shortened the length of hospital (but not intensive care unit) stay.563 In a randomized controlled trial in 40 patients with ARDS, those who received sodium selenite intravenously for 10 days had increased glutathione levels, decreased inflammatory cytokine levels, and improved lung function compared with those who received saline (placebo). However, there were no differences in survival or intensive care unit stay.564

Probiotics

Probiotics are living non-pathogenic microorganisms that, when administered in adequate amounts, can have a positive impact on health. Bacteria in theLactobacillus and Bifidobacterium genera, as well as Streptococcus thermophiles and Saccharomyces boulardii, are examples of common probiotics.565,566 Probiotic supplements are often used to restore balanced microbial signaling in the intestines, affecting homeostasis throughout the body. The growing volume of research that shows their ability to strengthen anti-infection immune activity while dampening inflammatory processes make probiotics a potential therapeutic for limiting acute viral respiratory infection spread and reducing the risk of severe illness and multi-organ complications.567-569 Some evidence even suggests certain probiotic species may inhibit respiratory viruses from gaining access to cells by altering expression of some receptors.569,570 B. lactis, B. infantis, L. reuteri, L. rhamnosus, L. paracasei, L. casei, and L. fermentum are among the many probiotic species shown to increase resistance to viral respiratory infections.567

The gut microbiome (the collective activity, composition, and microenvironment of the microorganisms living in the intestines) has a profound impact not only on digestion, but also immune function. Factors that alter the microbiome, including poor diet, alcohol intake, stress, aging, antibiotic use, and chronic disease, can disrupt interactions between gut microbes and the body’s regulatory systems and increase the risk of acute infections and myriad other health problems.571,572 At the same time, acute viral respiratory infections can negatively impact the composition of the gut microbiome due to interactions between the gut and lung microbial communities.569,570,572 A disrupted gut microbiome (dysbiosis) can damage the barrier function of the intestinal lining, potentially resulting in a condition known as leaky gut that may contribute to accelerated inflammatory signaling and increased susceptibility to severe infections and complications.573-575

Respiratory viruses may affect gut microbiome composition differently, but overall diversity (a marker of microbiome health) was found to be decreased in patients with respiratory infections due to influenza virus and other respiratory viruses.576 A study in which stool tests were conducted in 100 patients with an acute viral respiratory illness during an outbreak found several gut bacterial species known to be important modulators of immune function were underrepresented during illness and for up to 30 days after recovery. Furthermore, the degree of dysbiosis, and in particular the diminished presence of Faecalibacterium prausnitzii and B. bifidum, was correlated with severity of illness and levels of inflammatory markers.577

Other researchers have noted decreased presence of beneficial bacteria and increased presence of pathogenic bacteria and opportunistic fungi in stool samples from patients with the same viral respiratory infection.576,578-580 In addition, stool analyses have shown this respiratory virus to be present in the digestive tracts of some patients with the acute respiratory illness, and that it may persist in the gut longer than in the airways, sometimes causing digestive symptoms.581 Widespread and often inappropriate use of antibiotics in hospitalized virus-infected patients may further contribute to the problem of dysbiosis and increase vulnerability to poor outcomes.574

Multiple randomized controlled trials and several meta-analyses have shown probiotics reduce the risk of acute respiratory tract infections (eg, colds and flu).568,582-584 Recently, several peer-reviewed reports of clinical experiences, preclinical studies, small, open clinical trials, case series, and clinical hypotheses have suggested that certain immune-modulating probiotic strains, such as L. rhamnosus CRL-1505,585-588 Streptococcus salivarius K12,589-591 L. plantarum LP01,592 and B. lactis BS01,593 may confer protection against respiratory viral infections and/or subsequent inflammatory sequela. Numerous clinical trials to investigate the usefulness of probiotics in treating severe acute viral respiratory infections have been registered since early 2020, and many are currently underway.594

Licorice

Licorice (Glycyrrhiza glabra) is a plant that is widely used in traditional herbal medicine systems. Licorice extract contains the active compounds glycyrrhizic and glycyrrhetinic acids, which are known to have antioxidant, anti-inflammatory, and immune-modulating properties.595 They have also demonstrated antiviral effects against human respiratory viruses such as influenza viruses and others, and the ability to suppress cytokine signaling involved in cytokine storm.595 Computer models have found compounds from licorice have the potential to reduce the virulence of a highly infectious respiratory virus by binding to a protein needed for entry into cells and inhibiting an enzyme needed for viral replication.596-598

A case was reported in which a patient with a severe acute viral respiratory illness presented for medical care at the beginning of what became a widespread outbreak of the illness. The cause of the condition was unknown at the time, but later confirmed by an antibody test. The patient received standard antibiotic and antiviral therapies with no improvement. The patient was then given 150 mg diammonium glycyrrhizinate (a glycyrrhizic acid derivative) along with 200 mg vitamin C three times per day. Symptoms abated within 12 hours, and the illness was completely resolved by day 8 of this therapy.599

Vitamin A

Vitamin A is known to modulate innate and adaptive immunity as well as help mitigate inflammation and support tissue repair in the respiratory tract. Interestingly, some researchers have proposed that vitamin A deficiency may develop in the context of severe viral respiratory infections due to depletion of vitamin A stores as a result of inflammation and kidney impairment. Moreover, preclinical research suggested vitamin A and some other retinoids may bind to the viral-entry protein of a highly infectious respiratory virus, locking it into the closed conformation and preventing interaction with host receptor cells. Thus, vitamin A has been proposed as a potential therapeutic against severe viral respiratory infection.600-603 However, it is unclear whether vitamin A supplementation in a person with adequate vitamin A status at baseline will lead to these beneficial effects or whether these benefits primarily arise in the context of correcting vitamin A deficiency.

As of the first quarter of 2021, a few clinical trials are underway to test the effects of various nutrient combinations that include vitamin A in people with highly infectious viral respiratory disease.604

Vitamin K

Vitamin K, a group of fat-soluble vitamins, fall into two major structural categories: K1 and K2. Despite their structural differences, vitamins K1 and K2 are both involved in biochemical processes known as carboxylation reactions.605 Vitamin K1 is preferentially stored in the liver for use in clotting pathways while K2, which is more widely distributed in the body, helps regulate calcium metabolism in bone, blood vessels, and other tissues. Vitamin K is therefore vital for normal blood coagulation, mineralization of bone, and inhibition of calcification of cardiovascular, pulmonary, and other tissues.605,606 In addition, vitamin K appears to reduce oxidative stress, modulate inflammatory signaling, and support mitochondrial function and cellular energy production, and may have other as yet unidentified functions.605,607

Recent observational evidence suggests low levels of circulating vitamin K (indicated by high levels of uncarboxylated proteins) may increase the risk of severe viral respiratory infection and predict poorer outcomes.606,608 In addition, use of vitamin K antagonists was correlated with increased mortality in frail elderly patients with severe acute respiratory infection,609 although a study that included a wider age group found vitamin K antagonist use was associated with better outcomes.610 Vitamin K antagonists are anticoagulants that work by interfering with vitamin K recycling, inducing vitamin K deficiency, and are commonly prescribed for patients with an increased blood clot risk.605 Other findings suggest vitamin K deficiency may contribute to precipitation of cytokine storm and, paradoxically, thrombotic complications associated with ARDS.607,611

Thiamine

Thiamine (vitamin B1), a water-soluble B-complex vitamin, is rapidly depleted during times of metabolic stress, including severe illness. Thiamine deficiency is common in hospitalized patients, especially those with critical illness.612 Thiamine is needed for cellular energy production and helps regulate reduction-oxidation balance, immune function, nervous system function, and vascular function.612,613 Thiamine, at 200 mg twice daily, reduced mortality in patients with septic shock and thiamine deficiency, and laboratory research suggests it may inhibit the hyper-inflammatory immune response that accompanies cytokine storm.613,614 It is a key therapeutic in the MATH+ protocol (methylprednisolone, ascorbic acid [vitamin C], thiamine, and heparin, plus other supportive nutrients and medications), a treatment strategy proposed for managing advanced stages of severe acute viral respiratory illness.612,613 Although high-quality clinical evidence is lacking, two US hospitals implementing the MATH+ protocol in patients with a severe acute viral respiratory illness reported mortality rates that were approximately one-quarter of those reported from other US hospitals using standard care.613,615

Garlic

Garlic has been used historically as an herbal remedy for colds, flu, and other infections. In addition to strong antimicrobial effects, garlic and its active sulfur-containing compounds have been found to lower high blood glucose levels, reduce high blood pressure, inhibit blood clot formation, modulate the immune response, and support colonies of beneficial intestinal bacteria.616 Garlic has been shown to enhance antiviral immune function.617 Garlic compounds have demonstrated antiviral activity against respiratory viruses such as rhinoviruses, influenza viruses, and others, and various garlic extracts have been shown in randomized controlled trials to help prevent and treat common viral respiratory illness.618 Computer modeling suggests sulfur compounds from garlic may also interfere with viral entry into cells and inhibit an enzyme needed for viral replication.616

Quercetin

Quercetin, a flavonoid with anti-inflammatory, antioxidant, and antiviral properties, is naturally found in foods such as apples, grapes, broccoli, kale, red onions, tea, and wine.619 Research suggests quercetin may decrease infection risk, prevent histamine release, and support balanced immune cell activity.620,621 Quercetin may inhibit replication and infectivity of cold-causing viruses and a highly infectious respiratory virus as well as reduce inflammation induced by viral infection.622,623 However, some experts have questioned whether quercetin’s antiviral activity observed in vitro will translate to in vivo applications, due in part to the rapid metabolism of quercetin.624

A few clinical trials have found quercetin supplementation may reduce incidence of some mild viral respiratory infections, particularly among otherwise healthy individuals.625,626 Several clinical trials to assess the utility of quercetin in the context of more severe viral respiratory disease are underway as of the first quarter of 2021.627

Andrographis

Andrographis (Andrographis paniculata) has a long history of use in treating upper respiratory infections and influenza as part of traditional Chinese and Ayurvedic herbal medicine systems. Andrographis and its active components enhance the antiviral immune response while suppressing inflammatory signaling and potentially interrupting progression to a hyper-inflammatory state.628 Laboratory research and computer modeling suggest compounds from andrographis can bind to and inhibit the activity of an enzyme needed for replication of a virus that causes a severe acute respiratory illness.501,629-632 Other andrographis extracts have been noted in computer modeling studies to bind to structural proteins of the same virus, reducing its ability to attach to and enter cells.630 Multiple clinical trials have shown andrographis can relieve symptoms and shorten the duration of acute respiratory tract infections such as colds and influenza.633-635

Green Tea

The strong oxidative stress-reducing and anti-inflammatory effects of green tea catechins, including epigallocatechin gallate (EGCG), have been well established. A solution of green tea catechins was found to inactivate a highly infectious respiratory virus in the laboratory.636 Other laboratory and computer models suggest tea catechins may inhibit viral infectivity and growth.637-640 It has been proposed that EGCG, due to its immune-modulating effect, could have a role in suppressing hyper-inflammation and preventing lung fibrosis in patients with severe acute viral respiratory illness.641

Disclaimer and Safety Information

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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