Respiratory Immune Support

1) Background

Over the last few decades, several new viruses have emerged as threats to human health around the globe. The most recent example is the 2019 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 small number 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.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 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.⁹

Although the characteristics of COVID-19 illness are still being elucidated, those most likely to contract the disease are people in close proximity to other infected individuals. Importantly, healthcare workers are at increased risk of developing and transmitting coronavirus infections.^10,11

2) Symptoms and Manifestations

The most common presentation of COVID-19 is fever and dry cough accompanied by flu-like symptoms. Some reports indicate that patients may experience early ocular symptoms, such as conjunctivitis (pink eye) and eye discharge.¹² Emerging evidence suggests that 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.^13,14 Loss of sense of smell and taste appear to be 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 are thought to be much more common in COVID-19.^15,16

A prominent feature of severe COVID-19 appears to be a marked increase in blood clotting and vascular complications throughout the body.^17-20 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.^21,22 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.²³ Accordingly, anti-coagulation therapy has become a standard of care recommended by most expert panels.²⁴

Skin manifestations such as rashes, plaque-like lesions, and painful red or purple lesions on the fingers or toes, called chilblains, are increasingly being recognized in the context of COVID-19. It is not entirely clear whether these manifestations represent inflammatory effects of the SARS-CoV-2 virus, or if they arise secondarily to coagulation and clotting problems that damage the delicate blood vessels supplying the skin.^130,131 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 acute respiratory distress syndrome (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.^7,25,26 Commonly reported estimates of the case-fatality rate range from about 1% to 3%; however, the potential for mild cases to go undetected means that the actual fatality rate may be much lower.^27,28

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

3) Spread

Coronaviruses are highly adaptable and known to undergo host-switching. Several established human coronaviruses have evolved from bird or mammalian coronavirus origins.²⁹ 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.^26,30 Although distinct from all other known coronaviruses, SARS-CoV-2 also appears to be closely related to a bat coronavirus.³¹

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.³²

• Respiratory droplet. Respiratory droplets are thought to be 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.³⁰ 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.
• 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.
• Aerosol. The aerosol route of transmission involves inhalation of airborne viral particles, possibly at some distance from the infected person.^10,33 Aerosol transmission appears to be an especially important concern in healthcare settings.¹⁰ SARS-CoV-2 aerosols are detectable for up to three hours.³⁴
• 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.³⁰

4) 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“.³⁵ In some 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.
2. Avoid non-essential travel. Avoiding travel to areas with known community spread is advisable.³⁶ 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.^37,38 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%.^39,40
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.⁴¹ Other strategies for strengthening immunity and reducing risk of viral infections can be found in Life Extension’s Influenza, Pneumonia, and Immune Senescence protocols.

5. Disinfect surfaces. A study published on March 17th, 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 aerosols were detectable for up to three hours. The virus was detectable on cardboard for up to 24 hours and for up to three days on plastic and stainless steel.⁴²

Should You Wear a Facemask?

Yes, you should wear a facemask when in public.

As of early-April, 2020, the CDC and other health authorities recommended that everyone use cloth face coverings in public. Surgical masks and N95 respirator masks should be reserved for healthcare workers.⁴⁴

The recommendation for widespread cloth facemask use is to help reduce the spread of COVID-19 in the population. Cloth facemasks offer very limited protection against infection with SARS-CoV-2 and are not a substitute for social distancing. However, they may help prevent the spread of infection by infected individuals by reducing the dispersion of respiratory droplets into the environment.⁴⁵ This is critical because many people infected with SARS-CoV-2 show no or mild symptoms and may not realize they have it.^46-49

Cloth facemasks made of high-quality, high-thread-count woven cotton are preferred.

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.

5) Know the Facts Video

Our Director of Education Dr. Michael Smith debunks common misperceptions about COVID-19 and offers guidance for staying well.

6) Testing and Diagnosis

Testing for COVID-19 has been inefficiently rolled out in the United States and many other countries. As of early-May, 2020, there are two testing priorities that both the public and private sectors are working to optimize in the United States:

1. Establish widespread availability of accurate, rapid point-of-care diagnostic tests for COVID-19; and
2. Establish widespread and accurate serological (blood serum) tests to determine who has been exposed and subsequently recovered, possibly establishing immunity. Importantly, it is not yet clear whether the presence of antibodies against SARS-CoV-2 confers long-term immunity against COVID-19; research is ongoing to clarify this crucial question.⁵⁰

As of early May, testing capacity in the United States was insufficient to test all potentially infected individuals and to engage in population screening. Therefore, testing has been prioritized for hospitalized patients, the highly vulnerable, healthcare workers, and first responders. The decision to order a test has been left up to individual clinicians. The CDC provided the following diagnostic testing priority guidelines in early May⁵¹:

High Priority

•  Hospitalized patients with symptoms
•  Healthcare facility workers, workers in congregate living settings, and first responders with symptoms
•  Residents in long-term care facilities or other congregate living settings, including prisons and shelters, with symptoms

Priority

•  Persons with symptoms of potential COVID-19 infection, including: fever, cough, shortness of breath, chills, muscle pain, new loss of taste or smell, vomiting or diarrhea, and/or sore throat.
•  Persons without symptoms who are prioritized by health departments or clinicians, for any reason, including but not limited to: public health monitoring, sentinel surveillance, or screening of other asymptomatic individuals according to state and local plans.

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

Diagnostic Testing

Unfortunately, there is a lot of misinformation circulating as to the availability of testing in the United States. As of early May, the accuracy and reliability of the tests that are available is a major concern. SARS-CoV-2 testing remains plagued by false-negative results, which occur when a test result is negative but the person being tested actually is infected with the virus. False-negative rates have been reported to be as high as 30% for some tests.⁵²

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

At-home collection kits are not yet widely available for the general public. LabCorp offers an at-home collection kit for a PCR molecular test (you mail the collected sample back to the lab) intended only for healthcare workers and COVID-19 first-responders with mild symptoms and suspected exposure. It is the only at-home collection kit with FDA Emergency Use Authorization as of May 6^th, 2020. (Note: an Emergency Use Authorization does not mean it is officially “approved” by the FDA.)

Other available and authorized tests require a clinician to order and collect the sample to be sent to a qualified lab for analysis. Results may take several days, depending on the testing methodology.

Serology (Antibody) Testing

Unfortunately, several issues with serology (antibody) testing persist. The accuracy of many of the tests (sensitivity and specificity) are questionable and there are the important issues of cross-reactivity to other common coronaviruses that are not COVID-19. The rate of false-positive results (when an uninfected person tests positive) may be up to 15% in some cases.⁵³

Roche Diagnostics recently launched an antibody immunoassay with in vitro qualitative detection of antibodies (including IgG) in human serum and plasma. Based on the measurement of a total of 5,272 samples, Roche Diagnostics claims the Elecsys^® Anti-SARS-CoV-2 assay has 99.81% specificity (with no cross-reactivity to four human coronaviruses known to cause common colds) and 100% sensitivity in samples taken 14 days after a PCR-confirmed infection.⁵⁴ Those levels of specificity and sensitivity are a significant improvement in serology testing. This test is starting to be used as of early May.

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

•  LabCorp: https://www.labcorp.com/antibody-testing
•  Quest Diagnostics: https://questdirect.questdiagnostics.com/

Interpreting SARS-CoV-2 serology (antibody) testing results. The detection of IgG antibodies to SARS-CoV-2 suggests that a person was likely exposed to the virus at some point in the past. But the probability that the test is accurate depends on its sensitivity, specificity, and prevalence of disease in the population, to name a few major confounding factors that influence accuracy.

The implications of the presence of IgG antibodies to SARS-CoV-2 are not yet fully understood. As of early May, it is unknown if having the antibodies to SARS-CoV-2 confers immune protection. More research is underway to clarify this critical question.

7) Medications and Treatment Approaches

Dexamethasone

On June 16th, researchers at the University of Oxford announced preliminary results from the RECOVERY trial, a large randomized open-label controlled trial, which showed that the common steroid drug dexamethasone reduced mortality in COVID-19 patients requiring supplemental oxygen or mechanical ventilation.¹⁴⁷ Although the results have yet to be peer-reviewed and published in a medical journal, and thus the study conclusions are subject to change, the news is nonetheless encouraging.

The trial randomized 2,104 patients to receive standard of care plus 6 mg dexamethasone daily (orally or via intravenous infusion) and 4,321 patients to receive standard care alone. Among patients receiving mechanical ventilator support, dexamethasone reduced deaths by 35%, while the death rate was reduced by 20% in those who did not need a ventilator but needed supplemental oxygen. There was no mortality benefit among patients who did not need any respiratory support or supplemental oxygen.

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

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

Remdesivir

Remdesivir is an antiviral drug that showed promise against SARS-CoV-2 in preliminary studies. It is a prodrug of an adenosine analog that has potent antiviral activity against many RNA virus families.⁵⁵ In late April, 2020, data began to emerge from controlled clinical trials testing the efficacy of remdesivir in the United States and elsewhere around the world.

In late May, results of a large randomized controlled trial (called ACTT-1) conducted by the U.S. National Institute of Allergy and Infectious Disease (NIAID) were published in The New England Journal of Medicine. The trial randomly assigned 1,059 COVID-19 patients to a 10-day course of remdesivir plus standard of care or standard of care plus placebo. The time to clinical recovery improved with remdesivir treatment: those who took remdesivir recovered in a median of 11 days, whereas those who received a placebo recovered in a median of 15 days. There was a suggestion of reduced mortality with remdesivir in the trends in the data, but there was no statistically significant reduction in mortality with remdesivir.¹³⁴

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

Importantly, not all remdesivir trials have shown clear benefit. For instance, a smaller clinical trial conducted in China did not find a statistically significant effect of remdesivir on time to clinical recovery.⁵⁷

At the same time the preliminary results from the ACTT-1 trial were announced via NIAID press release on April 29^th, Gilead Sciences, Inc., the maker of remdesivir, announced the results of a trial that suggested a 5-day treatment course may deliver similar results as a 10-day treatment course in patients with severe COVID-19.⁵⁸

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

Immunotherapies and Cytokine Storm in COVID-19

As the COVID-19 pandemic has unfolded around the globe, doctors and scientists have increasingly reported that an exaggerated immune response likely plays an important role in the pathology of many severe and fatal SARS-CoV-2 infections.

When a person becomes infected with SARS-CoV-2, the body must mount a robust innate immune response soon after infection to prevent rapid viral replication and full-blown infection.

In some cases, the immune response to the virus rages out of control and does more harm than good. Too many immune cells infiltrate tissues where the virus is replicating and release too many pro-inflammatory signals called cytokines. These cytokines recruit even more immune cells, and the cycle propagates throughout the body. This phenomenon is referred to as a “cytokine storm”—a fitting metaphor given the ominous and rapid clinical decline that typically accompanies this immunopathology.^20,59

Previous studies have documented clinical manifestations of ARDS cytokine storm that resemble the progression seen in some COVID-19 cases.⁵⁹ Ultimately, multiple organs and tissues become damaged or impaired due to the buildup of immune cells and their inflammatory detritus.

The irony of cytokine storm is that the very aspect of our biology meant to protect us from viral infections—our immune system—becomes a source of harm and destruction in some cases of severe COVID-19. But there is some promising news.

Researchers know quite a lot about the immune system. They have been studying it for a long time, and they have identified ways to manipulate the signaling pathways involved in the exacerbation of inflammatory processes. One area receiving a lot of attention in the context of COVID-19 involves using existing drugs to block one of these pathways. That pathway is interleukin-6 (IL-6) signaling, and one of the drugs being tested is tocilizumab (Actemra).⁶⁰ This drug binds receptors for IL-6 and prevents the IL-6 cytokine signal from being transmitted.

Early research with tocilizumab in COVID-19 has been intriguing. It appears this drug may help slow the runaway immune response that often portends demise in those with severe COVID-19. Rigorous clinical trials are underway; their results will help clarify the utility of tocilizumab in treating COVID-19-related cytokine storm.

One of the key open questions is when to start treatment with tocilizumab. Some researchers worry that starting the drug too early might impair the immune system’s ability to mount a proper response to a SARS-CoV-2 infection in the first place. Indeed, preclinical studies have shown that IL-6 signaling is necessary for the early immune response to certain kinds of viral infections.⁶¹

Ongoing trials will help clarify which COVID-19 patients are the best candidates for tocilizumab treatment, and at what point in their course of illness they should receive the drug. Research is also underway to investigate the utility of a related drug, sarilumab (Kevzara).

Hydroxychloroquine

The antimalarial drugs chloroquine and hydroxychloroquine received attention early in the pandemic when anecdotal reports and preclinical evidence suggested these drugs might benefit COVID-19 patients.^62,63 However, as evidence continued to accumulate through May and June, enthusiasm waned and concern about side effects and lack of efficacy mounted.

On June 3rd, the first rigorous study testing whether hydroxychloroquine could prevent development of COVID-19 was published in The New England Journal of Medicine. The 821 trial participants were randomly assigned to either hydroxychloroquine or placebo and took their first dose within four days after exposure to someone known to have COVID-19. There was no statistically significant difference in incidence of COVID-19 illness in the two groups. In addition, among subjects in either group who chose to take vitamin C or zinc supplements after their exposure to someone infected with SARS-CoV-2, there was an increased risk of developing COVID-19 illness.¹³⁸ Side effects were more common among those who took hydroxychloroquine, but there were no serious adverse reactions reported.¹³⁵

On June 15th, the U.S. FDA revoked the emergency use authorization (EUA) it had earlier issued for hydroxychloroquine and chloroquine. The agency stated that “The totality of scientific evidence currently available indicate a lack of benefit,” and that “…in light of ongoing serious cardiac adverse events and other potential serious side effects, the known and potential benefits of chloroquine and hydroxychloroquine no longer outweigh the known and potential risks for the authorized use.”¹⁴⁶

Colchicine

As of early May, 2020, a study sponsored by the Montreal Heart Institute is enrolling patients at centers in New York, San Francisco, Montreal, and Spain in a clinical trial to test whether an older anti-inflammatory drug can suppress the excessive immune response that ravages some COVID-19 patients.⁷²

The drug, colchicine, is normally used to treat gout and inflammation of the tissue surrounding the heart. However, it piqued the interest of doctors and scientists working in other areas of inflammation research after a 2019 study showed that, in low doses, it reduced the risk of cardiovascular events in people who had recently had a heart attack.⁷³

Preliminary evidence suggests that SARS-CoV-2 infection may trigger inflammation in cardiac tissue. The virus is thought to damage the heart by other mechanisms as well, such as triggering endothelial dysfunction, promoting blood clotting, and impairing the lung’s ability to supply the oxygen demanded by the hard-working cardiac tissue. Some researchers think these events may be triggered in part by activation of inflammatory pathways that colchicine can inhibit, namely the NLRP3 inflammasome.^74-76

At least three other clinical trials, in addition to the one being undertaken by the Montreal Heart Institute, are enrolling patients as of early May to test the effects of colchicine in COVID-19.⁷⁴

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

Camostat Mesylate

An enzyme called TMPRSS2 facilitates a necessary step in the process by which SARS-CoV-2 and other coronaviruses enter cells.⁷⁷ Therefore, inhibitors of this enzyme have been suggested as potential modalities to limit the pathogenicity of SARS-CoV-2. Some preclinical evidence suggests the drug camostat mesylate, a TMPRSS2 inhibitor developed in Japan in the 1980s, blocks viral entry of SARS-CoV-2 and might be a viable therapeutic option.^78,79

As of early May, at least three clinical trials are recruiting subjects with confirmed COVID-19 to test whether camostat mesylate can improve clinical status or time to recovery. Camostat mesylate is approved in Japan for the treatment of chronic pancreatitis and postoperative gastric reflux. It is generally well tolerated, but there have been rare reports of serious side effects.⁸⁰

Other Medications

Because there are no proven medical treatments for COVID-19 or other human coronaviruses, scientists are looking to both old and new antiviral drugs in search of effective therapies. Several drugs are currently being evaluated in preliminary research. These include antiviral drugs used to treat human immunodeficiency virus (HIV) and hepatitis B and C, such as ribavirin (Ribasphere), lopinavir-ritonavir (Kaletra), and interferon beta-1b (Betaseron).^62,81,82 An early-stage open-label clinical trial published in the New England Journal of Medicine on March 18th, 2020 failed to show benefit with lopinavir-ritonavir in patients with severe COVID-19.⁸³ Another antiviral drug, favipiravir (Avigan), is also undergoing studies to determine if it is efficacious in COVID-19 patients.^84,85 However, some safety concerns have arisen related to potential for the drug to cause birth defects.⁸⁶

Convalescent Plasma

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

Researchers are currently investigating whether administering the antibody-rich blood plasma of people who have recovered from COVID-19 to patients who become ill with SARS-CoV-2 infection can improve their outcomes. This antibody-rich blood plasma is called convalescent plasma and may help the immune system of people with active COVID-19 respond to the virus. This approach has been used for many decades to combat infectious diseases—similar approaches were even used during the 1918 influenza pandemic.^87,88

The FDA has granted emergency use authorizations and expanded access programs for convalescent plasma.⁸⁹ Research is ongoing to determine whether convalescent plasma can improve COVID-19 outcomes and to identify which patients should receive the treatment and at what point during the illness it is most helpful.^90,91

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

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

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

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

Although rigorous evidence is not yet available to clarify to what extent awake prone positioning can help avert deterioration in COVID-19 patients, some hospitals have begun to implement proning in COVID-19 patients. Early, anecdotal reports⁹² and observational data in ARDS due to other causes⁹³ are encouraging. At least one clinical trial is underway to formally evaluate the potential benefit of prone positioning with high-flow nasal cannula in moderate-to-severe COVID-19 patients.⁹⁴

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

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

When it became widely reported that ACE2 served as the receptor site for SARS-CoV-2, many people taking ACE inhibitors or ARBs grew concerned that these drugs could increase their risk of COVID-19. However, cardiology societies around the world have issued statements urging patients not to discontinue their blood pressure medications, and stating that there is no compelling evidence that these drugs increase risk of COVID-19.^95,96 It is important to keep in mind that stopping a blood pressure medication does have known risks and is not advised.

A systematic review published on May 15th, 2020 found that observational and retrospective data available as of mid-May did not suggest that ACE inhibitors or ARBs were associated with increased risk of infection with SARS-CoV-2 or more severe COVID-19.¹³² The analysis included data from two retrospective cohort studies, one case-control study, and 14 observational studies. The researchers concluded that “High-certainty evidence suggests that ACE inhibitor or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients.”

Emerging, preliminary evidence suggests ARBs may actually be linked with improved outcomes in COVID-19. While it is crucial to acknowledge that these findings are preliminary, a retrospective study presented (pre-peer review) in late March suggested that people who had been taking ARBs prior to developing COVID-19 were less likely to develop severe disease than people who had not been taking ARBs.⁹⁷Other preclinical and preliminary evidence supports the potential beneficial effects of ARBs in COVID-19 as well.⁹⁸ As of mid-May, at least four randomized controlled trials are planned to evaluate the use of ACE inhibitors or ARBs in the treatment of COVID-19.¹³²

NSAIDs (eg, Ibuprofen) and COVID-19

In mid-March, questions arose as to whether non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen would be helpful or harmful in the context of COVID-19. Most experts have agreed that evidence is too limited to make a conclusive recommendation for or against NSAIDs, but that there is little evidence that NSAIDs would worsen outcomes in most cases.¹⁰¹ Nevertheless, some physicians and health authorities recommend acetaminophen (Tylenol, known as paracetamol in Europe) rather than ibuprofen or other NSAIDs in the context of COVID-19.

The concern with NSAIDs in the context of COVID-19 is that the drugs may mask the early symptoms of COVID-19, or possibly suppress the immune response to the virus, worsening outcomes. However, these concerns are theoretical. As of this writing, there is no evidence that taking NSAIDs increases risk of infection with SARS-CoV-2 or of developing COVID-19.¹⁰²

8) SARS-CoV-2/COVID-19 Vaccine Development

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

There are several general types of vaccines being developed for SARS-CoV-2/COVID-19, some of which utilize tried and true technologies, while others are building upon unproven novel technologies.^139,140 The kinds of vaccines being studied as of mid-June 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.^139,141
• Viral vector vaccines
  • Viral vector vaccines would incorporate SARS-CoV-2 genes into a different, non-pathogenic virus. When the non-pathogenic virus containing SARS-CoV-2 genes is administered in a vaccine, it does not cause illness but arms the immune system to be able to mount a defense against SARS-CoV-2 upon future exposure.
• Subunit vaccines
  • Subunit vaccines are meant to deliver specific proteins or antigens unique to the SARS-CoV-2 virus that can prime the immune system to respond against a future SARS-CoV-2 infection. Familiar vaccines of this type include hepatitis B and whooping cough.¹⁴¹
• 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 exposures to SARS-CoV-2. No vaccines of this type have been approved as of mid-June 2020.

In mid-June, public-private partnerships to conduct large phase 3 trials of at least three vaccine candidates were reported.¹⁴² The trials are set to start during the summer and into the early fall of 2020 and will test vaccine candidates being developed by Moderna, AstraZeneca, and Johnson & Johnson. AstraZeneca and the University of Oxford have already begun a phase 3 trial in 10,000 participants in the United Kingdom.¹⁴³ Other biotech firms are launching phase 3 trials of vaccine candidates during the summer months as well, including a private partnership between Pfizer and BioNTech SE. As of mid-May, there were over 160 vaccine candidates in various stages of development.¹⁴⁰

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

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

Aside from the medical and scientific challenges that SARS-CoV-2 vaccine developers must overcome, there are tremendous logistical and manufacturing hurdles that will influence the availability of shots once one or more are approved.¹⁴⁴ In theory, most people on Earth should be vaccinated, which means distributing and administering over seven billion doses of vaccine.

These are just some of the substantial hurdles standing in the way of rapid vaccine development for SARS-CoV-2. One potential difficulty is that vaccines that are shown to work in younger individuals may not confer the same degree of immunity to older adults. Another is that the track record of vaccine development suggests that success is not common: less than 10% of vaccines make it through clinical trials. Not least, the problem of trying to compress what is ordinarily a very lengthy process into a shorter time period creates multiple potential scientific, medical, and logistical challenges. Still, many experts are optimistic that the urgent and global nature of the current situation, along with the many remarkable recent innovations in multiple scientific disciplines, will allow successful vaccine development on a shorter-than-usual timeline.^{140,142,143,145}

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

9) Integrative Approaches

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

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

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

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

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

• Vitamin C. Several studies have shown that vitamin C, both before and soon after the onset of symptoms of upper respiratory tract infections, may help ease symptom burden and reduce the duration of illness.^103-105 However, available evidence does not consistently support the notion that vitamin C can reduce the risk of acquiring upper respiratory tract infections.^106,107 Importantly, studies to date have not focused specifically on coronavirus infections but on upper respiratory tract infections in general such as those caused by rhinoviruses, enteroviruses, and influenza viruses.
• N-acetylcysteine (NAC). N-acetylcysteine (NAC) is an amino acid derivative with mucolytic properties often used in the context of respiratory illnesses.^111-113 A meta-analysis published in 2017 found that treatment with NAC led to shorter duration of intensive care unit (ICU) stay compared with control among patients with ARDS.¹¹⁴ Based upon some positive observational data during late 2019 and early 2020, some Chinese institutions have initiated using NAC as part of the standard management of patients in the hospital setting,⁷⁰ although clinical trials are needed to specifically assess outcomes in patients with severe, viral respiratory illness treated with NAC. Some researchers have suggested NAC could provide valuable functional support for the health of mucous-producing cells lining the respiratory tract in some types of patients suffering from SARS-type viral respiratory illness on the basis of its potent antioxidant and mucolytic properties.¹¹⁵
• Lactoferrin. Lactoferrin, a glycoprotein involved in immune response and several other functions,¹¹⁶ is found in secreted fluids and is abundant in milk (breast and cow). Lactoferrin has well-documented antibacterial, antiviral, and antifungal properties.^117-119 It appears to exert antiviral effects by activating the antiviral cytokines interferon (IFN)-α/β and boosting natural killer (NK) cell activity and Th1 cytokine responses.¹¹⁸ Some studies suggest lactoferrin administration may reduce the incidence and severity of common respiratory tract viral infections, like colds and flu.^118,120
• Selenium. Selenium has important antioxidant, anti-inflammatory, and antiviral activities in the body, and deficiency is associated with increased risk of viral infection.¹²³ In patients with HIV infection, poor selenium status is correlated with increased mortality, and selenium has been reported to slow progression of immune dysfunction and reduce hospital admissions.^123,124 Some researchers have proposed that lack of selenium in regional soils may have contributed to weakened immunity and the associated SARS outbreak in 2003.¹²⁵
• Probiotics. A growing body of evidence shows Bifidobacterium and Lactobacillus species can support the health of the host’s immune response and may reduce the occurrence, severity, and duration of viral respiratory tract infections such as influenza.^126,127
• Epigallocatechin gallate (EGCG). EGCG is a polyphenol from green tea. Because of its broad immune-benefiting effects, EGCG has been proposed as a promising agent for supporting the host’s immune response in the context of viral infections such as SARS and MERS.^128,129

Obtaining Reliable Situation Updates

The CDC regularly updates their COVID-19 information portal. This is a reliable and trustworthy source of information about SARS-CoV-2 and COVID-19. The URL is: https://www.cdc.gov/coronavirus/2019-ncov/summary.html

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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This blog is reposted from: https://www.lifeextension.com/protocols/infections/respiratory-immune-support – All credit belong to www.lifeextension.com and the respective author(s).