There are three interesting facts about sleep deprivation and immunity that are based on scientific study.

Lack of quality sleep is associated with a higher likelihood of getting sick after being exposed to a virus.

Lack of quality sleep negatively impacts how fast you recover if you do get sick.

Long-term poor-quality sleep increases the risk of specific diseases that in and of themselves are risk factors for an increased risk of infection and those are cardiovascular disease, diabetes and obesity.

The goal for adults should be to obtain 7 to 9 hours of uninterrupted sleep per night. For teens the ideal range is 8 to 10 hours per night. Raise your hand if you hit your target.

Why does sleep deprivation equate with truncated immune functioning?

The governing concept is that sleep is believed to support the initiation of an adaptive immune system response. So, a good night sleep on a regular basis supports the following: if exposed to an invading antigen the human immune system takes up that antigen with antigen presenting cells and presents fragments of the antigen to cells called T helper cells. The T helper cells release a cytokine called IL-12 and that calls in the squad known as a T helper cell 1 response which supports the work of antigen-specific T cells and starts the production of antibodies by another type of cell called B cells. It’s this antigen/antibody response that initiates long lasting immunity. Sleep helps foster this adaptive immune response in lymph nodes. Disrupting sleep, disrupts the adaptive immune system response [1].

Of course the first question you should ask if you are experiencing a major deviation from the recommending amount of sleep is are there any medical reasons behind your poor-quality sleep that need to be addressed?

The following can interfere with quality sleep.

•	Gastrointestinal problems such as reflux

•	Neurological conditions such as Parkinson's disease

•	Prescription medications – birth control, cold and flu medicines, drugs for asthma, hypertension medication, thyroid medication, etc. There are many prescription medications that can interfere with sleep. Please talk to your doctor about any concerns.

•	Restless leg syndrome – a neurological condition causing discomfort and the need to move one’s legs, strongly linked to iron deficiency anemia.

•	Sleep apnea – (main types are obstructive, central and complex).

Let’s hypothesize that’s all covered. What about prescription sleep medications?

As I mentioned on a previous podcast, “I’ve spoken with many sleep experts over the years and none of them believe these drugs are sleep saviors. On the contrary they do not believe a human obtains true restorative sleep on these medications.” I also stated, “All of these aforementioned prescription drugs and OTC medications have a risk of side effects including but not limited to drug tolerance, rebound insomnia, headaches, dizziness, nausea, difficulty swallowing or breathing, worsening depression, suicidal ideation and even a potential link to dementia and increased mortality.” Please listen to that episode for more info. While there are many physicians that recommend these medications, I’m certain none would recommend them for chronic use every single night for the rest of your life.

Address stress in the best way that works for you – meditation, exercise, cognitive behavioral therapy, psychotherapy, etc.

Do not consume caffeine late in the day. Some people are so sensitive that any more than one cup in the morning disrupts their sleep and for others they are fine having more, including late in the day. Learn your tolerance and stick with it.

Napping too late in the day can disrupt sleep in the evening.

Exposure to artificial light late in the evening, or prior to sleep. It disrupts normal neurological signaling required for sleep from taking place, such as the formation and release of melatonin, and the upregulation of excitatory neurotransmitters.

Adjust room temperature – too warm of a temperature can have negative affect on sleep

Alcohol is a sedative. It can make you fall asleep initially but may disrupt your sleep later in the night.

Nicotine from vaping or smoking – it’s a stimulant and disrupts sleep. Nicotine is a neurotoxin. Seek help to stop if you use it.

Eating too close to bed is a problem as well, keeping you up digesting instead of sleeping.

Consider trying something natural. I’m always asked about melatonin. So, let me explain that for a moment before I tell you what I personally take every night before bed.

Melatonin elicits its effects on the suprachiasmatic nucleus (SCN), an area of the brain the controls our circadian timing system, via at least two high-affinity melatonin receptors, MT1/MT1a and MT2/MT1b. Two distinct functional roles for melatonin on SCN physiology have been identified. Firstly, melatonin acts to promote sleep through the acute inhibition of SCN neuronal firing, a mechanism mediated by MT1/MT1a receptors. Secondly, melatonin has a phase-shifting effect which entrains the circadian rhythms within the environment and is mediated in part by MT2/MT1b receptors. The impact of these efforts are initiating sleep.

Unfortunately, many people experience negative side effects from melatonin, even at the standard lowest over the counter dose. In my early days in practice I successfully found a dose that had 500mcg, which is exactly half of the standard 1mg dose. Currently, I see 3mg to 5mg as a starting dose and I couldn’t imagine taking those. The feeling I had was akin to others reporting side effects such as a groggy feeling the next day, something I called a “melatonin hangover.” While we all know melatonin plays a crucial role in sleep, I always desired the tiniest dose possible. I also believe in a multifactorial approach to assisting sleep. As a dad, I absolutely need something. I cannot just turn off my brain at night and sleep. Every night I take an over the counter supplement called 

, that contains nine ingredients to help foster sleep. I co-authored a paper on each of these ingredients with Dr. Jennifer Newson, a PhD in neuroscience from Oxford. I have found it to be a game changer.

There are three interesting facts about sleep deprivation and immunity that are based on scientific study. 

Poor Sleep Quality and Immunity

Studies have indicated that certain cardiovascular maladies, including cardiomyopathy, myocarditis (Inflammation of the middle layer of the heart wall), arrhythmias, and premature atherosclerosis, are more prevalent in individuals with celiac disease as compared to their non-celiac disease counterparts.

Historically it is important to note the first few published studies on celiac disease and cardiovascular disease were in published in the 1970s. There was a decent body of published peer-reviewed literature around 2015 to clearly see the connection.

Impact of Celiac Disease on the Cardiovascular System

There are negative changes that appear to the arteries, veins, serology, physical structure of the heart, electrical changes of the heart, and increase the risk of myocardial infarction (heart attack).

One area of focus for celiac disease and cardiovascular disease is arterial function. As many will know arteries carry blood away from the heart and other than the pulmonary artery blood flow, arterial blood is oxygenated. The arterial system is the high-pressure portion of the circulatory system and many people are aware of this when they have their blood pressure checked. The upper number of a blood pressure reading, known as the systolic pressure is the peak arterial pressure during heart contraction. And the bottom number, which is called the diastolic pressure represents the minimum arterial pressure between contractions, when the heart expands and refills. The main artery of the body is the aorta. It connects to the upper left ventricle of the heart and at that connection is the aortic valve. So blood pumps through the valve to the aorta to the body.

The following can transpire as a result of celiac disease:

In undiagnosed celiac disease, aortic function can deteriorate, and this deterioration is predictive of subclinical atherosclerosis and future cardiovascular events.

Aortic stiffness index is significantly higher, in untreated CD patients vs controls. Celiac disease patients are at increased risk for coronary artery disease.

Occlusion of the brachiocephalic trunk and right and left common carotid artery has been noted in celiac disease.

Spontaneous coronary artery dissections have been observed as a cause of acute myocardial infarction in celiac disease patients. This is when a tear forms in an artery inside the heart and results in blood pooling in the area between the layers. This can result in a hematoma (blood clot).

Important note: even after a gluten free diet, the lack of a significant reduction in aortic elastic properties suggests that some risk of cardiovascular disease may persist.

Carotid intima-media thickness values are significantly higher in patients with diabetes and celiac disease as compared to those patients with diabetes or celiac disease alone. The carotid intima-media thickness test (CIMT) is a test to measure carotid atherosclerotic vascular disease. The test measures the thickness of the intima and media of the carotid artery.

Celiac disease in the youth has been associated with increased risk of developing early atherosclerosis (a disease of the arteries characterized by the deposition of plaques of fatty material on their inner walls).

Mesenteric ischemia risk is increased by celiac disease. It occurs when damaged, narrowed or blocked arteries restrict blood flow to your small intestine with the strong potentially to permanently damage the small intestine separate from celiac disease.

Veins are blood vessels low oxygenated blood from the body back to the heart for reoxygenation. We also need to keep in mind that while cardiovascular diseases make us think of the heart, it encompasses circulation and that includes conditions that transpire in other parts of the body such as venous thrombosis which is a blood clot in the veins that can lead to a pulmonary embolism (when a clot blocks a blood vessel in the lungs. It is life threatening). There are other complications of thrombosis.

Celiac disease is linked to venous thrombosis in the clinical literature and the main connection is inflammation and nutrient deficiencies.

Celiac Disease and Cardio Specific Serology

In an adult celiac disease patient there can be the presence of:

Abnormal homocysteine (Homocysteine is an amino acid that is made endogenously in error in the presence of a deficiency of B vitamins, particularly folate and B12, but also B6). It may increase the risk of heart disease and stroke if level elevated.

Erythrocyte sedimentation rate is the measurement of erythrocytes (red blood cells) settling at the bottom of a test tube. Normally, red blood cells settle relatively slowly. A faster-than-normal rate may indicate inflammation in the body. Erythrocyte sedimentation rate may provide evidence of coronary heart disease.

C-reactive protein (C-reactive protein (CRP is a blood test marker for inflammation in the body) or high-sensitivity C-reactive protein (hs-CRP) test, which is more sensitive than a standard CRP test, can be used to evaluate the risk of developing coronary artery disease.

Elevated insulin levels may, along with inflammation markers above, contribute to arterial stiffening.

Other nutritional factors, such as low B12, folate, omega 3 fatty acids, magnesium, selenium, etc., may contribute to cardiovascular disease.

Celiac Disease and the Physical Structure of the Heart

There are some key structural changes of the heart that can transpire as a complication of celiac disease. I will list the most common ones below.

1. Pericardial effusion occurs more frequently in celiac disease. A pericardial effusion is when there is an excess buildup of fluid between the heart and the sac surrounding the heart, known as the pericardium.

Risk factors for pericardial effusion in celiac disease include:

Vessel dysfunction in the presence of high antibody titer (celiac disease antibodies).

Selenium and or iron deficiency (caused by celiac disease).

Viral infection due to reduced immune system functioning (higher risk in celiac disease).

Diminished ability to eliminate toxic free radicals.

2. Celiac disease patients have a higher risk of dilated cardiomyopathy, idiopathic cardiomyopathy and ischemic or valvular cardiomyopathy

Dilated cardiomyopathy (DCM) is a condition in which there is an enlargement of the left ventricle of the heart. This enlargement reduces the heart's ability to pump blood.

Idiopathic cardiomyopathy is a condition the presents with an enlarged left ventricle that is stretched and weakened, losing the ability to contract efficiently.

Ischemic cardiomyopathy (CM) is a type of dilated cardiomyopathy. The main characteristic is the blocking of an artery to the heart, typically post heart attack, preventing oxygen rich blood from entering the heart resulting in a dilated heart muscle.

3. Autoimmune myocarditis may be a complication of celiac disease and presents with inflammation of the heart muscle.

4. Celiac disease patients are more prone to have atrial septal defect as compared to controls. In an atrial septal defect there is a hole in the wall that separates the top two chambers of the heart (the atrium).

Celiac Disease and Heart Attack or Stroke

1. Celiac disease patients may be at risk for acute myocardial infarction with ST-elevation and spontaneous coronary artery dissection. This is a very serious type of heart attack. An ST-segment elevation is an abnormality detected on an electrocardiogram.

However, chronic hypocalcemia (low calcium) in untreated celiac disease patients due to poor absorption of the mineral can result in electrocardiographic changes that mimic acute myocardial infarction. This echoes my podcast where I constantly refer to the importance of measuring nutrient status of the celiac disease patient, and suspected celiac disease patient.

2. There is a higher prevalence of atrial fibrillation among celiac disease patients because in celiac disease there is a higher risk of having a slower atrial electrical conduction, which may also increase the risk of atrial fibrillation. In atrial fibrillation the atrium (upper chambers of the heart) beats out of coordination with the ventricles (lower chambers of the heart). Atrial fibrillation is associated with an increased risk of ischemic stroke and heart failure.

3. Celiac disease also presents with an increased general risk for stroke. It is such a strong connection that researchers believe celiac disease should be considered as a possible etiology for stroke cases of unknown cause, particularly in the young, whether gastrointestinal manifestations are evident or not. The reasons can be a clinical B12 deficiency and hyperhomocysteinemia (high homocysteine), which can be secondary to a folate deficiency.

How can a gluten free diet help those with celiac disease induced cardiovascular disease?

A healthy gluten free diet enables a reduction in inflammation, oxidative stress, and insulin resistance. Each of these are linked to increased risk of cardiovascular disease if not managed.

How long after being diagnosed with celiac disease can it take to heal some cardiovascular disease risk factors?

Cardiovascular dysfunction can be reverted in less than one year in diagnosed celiac disease patients adopting a healthy, whole foods, gluten free diet.

However, there are some caveats to the gluten free diet that can compound problems. There is the strong potential to over consume simple carbohydrates, highly processed fatty acids and sugars on a gluten free diet. Markets are replete with such products and overconsumption can result in elevated triglycerides and insulin resistance, which are risk factors on the path toward cardiovascular disease.

Why is it important for someone with cardiovascular disease get tested for celiac disease?

Incredibly, the treatment of celiac disease patients with a healthy, whole foods, gluten free diet can reverse some, but not all of the cardiovascular involvement associated with the disease. Therefore, it is essential to act quickly in obtaining a diagnosis and start treatment in cases of cardiovascular disease.

Have a full cardiovascular work up if you were recently diagnosed with celiac disease. Include all standard lipid panels and fractionated lipid panels and speak with your physician about the following:

Carotid intima-media thickness test (CIMT)

Coronary artery calcium test (CAC) which measures the amount of calcium in the walls of the arteries.

Test for as many nutrients as possible, but at least: folate, B12, B6, magnesium, calcium, selenium, percent of omega 3 fatty acids.

Studies have indicated that certain cardiovascular maladies, including cardiomyopathy, myocarditis (Inflammation of the middle layer of the heart wall), arrhythmias, and premature atherosclerosis, are more prevalent in individuals with celiac disease as compared to their non-celiac disease counterparts. 

Celiac Disease and Cardiovascular Disease

Refractory celiac disease is identical to celiac disease except that in refractory celiac disease the patient is unresponsive to at least 1 year of treatment with a strict gluten free diet and they receive the diagnosis only after a thorough examination.

It is my opinion that it must be evaluated as part of the diagnostic process, so I guess you could say in my view it is diagnosed by the process of elimination and a thorough medical examination.

First, you need to review the original diagnosis of celiac disease, going back as far as you can to in the medical records, including the original biopsy, serology, DNA, etc., and then you must have confirmation that the patient was following a strict GF diet for at least 1 year but still has symptoms and villi damage. You want to be certain there is no gluten contamination because that could rule out RCD quickly.

Next, you double down on identifying any other condition that can negatively impact the villi including cancers such as intestinal lymphoma, inflammatory bowel disease such as Crohn’s disease, microscopic colitis, hypogammaglobulinemia (is an immune system abnormality that results in reduced antibody production making enough antibodies called immunoglobulins) and believe it or not, even small intestinal bacterial overgrowth – if severe enough, over use of NSAIDS or reaction to NSAIDS, etc.

Then, an endoscopy and colonoscopy must be performed, with biopsies taken at both sites.

In a perfect world I like a capsule endoscopy which is basically swallowing a camera in a pill format. You can obtain excellent images and identify some inflammation and ulceration.

Also, it may warranted to have a CT scan (computerized tomography) and MRE (Magnetic resonance enterography) as well as a barium x-ray (A barium X-ray is a radiographic (X-ray) examination of the gastrointestinal (GI) tract. Barium absorbs x-rays and appears white on the images. These tests should be done particularly if there is any suspicion of lymphoma. There may be multiple diagnoses during the search for the cause behind suspected refractory celiac disease.

Finally, fecal fat and pancreatic tests should be completed as well.

There are two types. Type 1 which has a better prognosis than type 2 which is very high risk for lymphoma. Type 1 is characterized by normal intestinal epithelial lymphocytes and type 2 with abnormal or premalignant lymphocytes (they are immature and precancerous). In type 2 malnutrition risk is extremely high. Some data indicates 85% of refractory celiac disease patients have type 1. So type 2 is the minority by far.

What is the prevalence of refractory celiac disease within the celiac disease population?

Currently it is 1 to 2% of diagnosed celiac disease patients. Interestingly enough, the individuals that present with this rare type of celiac disease are typically over 50 years of age.

The challenge for even the knowledgeable physician is that the symptoms are virtually identical to celiac disease except they are typically more severe.

Is there any physical difference between refractory celiac disease and celiac disease?

In some refractory celiac disease patients there have been reports of ulceration of the middle part of the small intestine called the jejunum which is called ulcerative jejunitis. This is quite serious because if this is present there is a high risk of what is known as enteropathy associated T cell lymphoma.

What are the causes of refractory celiac disease?

Sadly, we are not sure. We know what goes wrong. In celiac disease the T cells that are so aggressive against gliadin and that are involved in the pathology become inactive on a strict GF diet. In refractory celiac disease the intestinal T cells are still active even with gluten elimination, resulting in continued destruction of the villi and microvilli. 

Other evidence suggests that in refractory celiac disease the cytokine interleukin 15, which is a proinflammatory cytokine, stimulates the production of interferon-gamma that may increase the attack of the intraepithelial lymphocytes against the intestinal lining in the small intestine. So, in summary it’s the T cell stimulation that doesn’t stop, that pushes interleukin 15 production, that results in the secretion of interferon gamma, which drives the intraepithelial lymphocytes against the intestine. That is actually a recipe for intestinal lymphoma.

What is the treatment for refractory celiac disease?

Steroid therapy is the current main treatment, along with a gluten free diet of course.

Some patients have been put on immunosuppressive drugs and even chemotherapy with cladribine has been used in a research setting.

Some patients have been put on what is called an elemental diet which is a liquid diet that requires no digestion. It is nutrient rich with vitamins, minerals, triglycerides, amino acids. It is used to bypass all digestion and hopefully treat and or prevent malnutrition in extreme cases

Total parental nutrition has been used as well. TPN is nutritional supplementation entirely by intravenous or non-gastrointestinal route.

I’m in favor of identifying secondary intolerances, sensitivities and or true allergies that are most likely happening in concert. Please note this is my strong opinion as a celiac and scientist. This sadly is not the path practitioners take to address true refractory celiac disease, but it is the path I take with wonderful results.

Arriving soon is anti-interleukin-15 monoclonal antibody which may help tame interleukin-15 for a calming impact on the immune system. 



Refractory Celiac Disease

A biopsy of the small intestine is invasive and potentially costly depending on insurance coverage for the individual. However, here in the United states, it currently remains the gold standard for diagnosing celiac disease. 

I do believe that will change in my life time and even the top gastroenterologists that believe in biopsy-based diagnosis, would love to reach a point when it is not necessary. Therefore, it is essential to have solid clinical evidence to refer a patient for a biopsy. 

One excellent piece of evidence lies in what are known as antibodies toward an enzyme that can be specific in celiac disease known as anti-tissue transglutaminase antibodies (and they can be IgA and IgG).

Tissue transglutaminase (also referred to as transglutaminase 2 or TTG2) is an enzyme that requires calcium for the transamidation of proteins, particularly in its association with celiac disease. In organic chemistry transamidation is the transfer of an amide group from one compound to another. The amide group is COHN2.

TTG2 is the member of a family of enzymes known as the protein-glutamine gamma-glutamyltransferases. The enzymes in this family catalyze modifications of proteins at specific side chains, crosslink lysine residues and are involved in deamidation, which in in biochemistry is the conversion of amino acid residues of glutamine and asparagine to glutamic acid or aspartic acid (other amino acids) and in organic chemistry deamidation is the conversion of an amide to a carboxylic acid (side note carboxylic acid is any organic compound with the group COOH such as fatty acids and amino acids). All these activities can result in or leave protein structures that are highly resistant to proteolysis (enzymatic protein breakdown).

Please note TTG2 is a ubiquitous enzyme and not just linked to celiac disease, but it is a crucial link in celiac disease progression. Meaning this enzyme is involved in everything from apoptotic mechanisms of cells, to cancer, to neurodegenerative diseases. It’s even found in heart muscle tissue.

When a patient with celiac disease consumes gluten, it enters the submucosa in the duodenum resulting in a production of autoantibodies to tissue transglutaminase prior to the disassociation of tissue transglutaminase from the gluten molecule [1]. This changes the charge and form of the gluten molecule, promoting an autoimmune attack and fostering the binding of gluten to HLA-DQ2 and DQ8 receptors [1]. Proinflammatory cytokines including interferon-gamma are secreted into the location, along with a lymphocyte presence and gliadin specific CD 4+T cells, resulting in atrophy of the duodenal villi and microvilli

In celiac disease there are two roles that are extremely important for TTG2. 1) acting as a deamindating enzyme that upregulates an immunostimulatory impact of gluten and 2) as a target autoantigen for the immune response. Keep in mind gliadin (the most toxic component of gluten for celiac disease patients is so glutamine rich) and that makes it an excellent substrate for tissue transglutaminase which results in the deamidated negatively charged peptides that will have a higher affinity for the HLA molecules (DQ2 and DQ8). Therefore, the action of TTG2 is considered a main step in celiac disease.

In the path toward diagnosis, anti-tissue transglutaminase IgA has the sensitivity and specificity over 90% in children and adults. In children the sensitivity ranges from 93.1 to 95.7% and thespecificity ranges from96.3 to 99% in adults the range for sensitivity is 90 to 95% and the specificity is 95.3 to 98.3%. Remember that the sensitivity is the ability to identify those with the disease (we call this the true positive rate) and specificity is the ability to identify those without the disease. We call this the true negative rate (vs. false negative). With that data in mind one can see why the tissue transglutaminse IgA is the cornerstone for celiac diagnosis.

The most common is TTG IgA. I prefer to either start with sIgA or run an sIgA in addition to the TTG IgA so that we do not miss any chance for IgA insufficiency (there is a 15-fold increase risk for sIgA deficiency in celiac disease). In the case of a selective IgA deficiency, we need to run TTG IgG and Gliadin deamidated antibody IgG (known as a DGGL blood test).

Now if the sIgA is below age-matched values then we run the TTG IGA and IGG along with DGLDN (gliadin deamidated antibodies IgG and IgA.

If the sIgA is completely normal or elevated, then we simple look at the TTG IgA results and see where they land on a scale. Using the Mayo Clinic scale as a reference, if TTG IgA is between 4.0 U/mL and 10 U/mL I do like a follow up that includes DAGL (gliadin deamidated antibody IgA) and Endomysial antibody IgA.

If the TTG igA is greater than 10 U/mL that patient should be referred directly to a biopsy.

Tissue Transglutaminase

Please let me be clear that COVID-19 treatment is a fast-moving target and what I am about to write will definitely change in the near future. As for now (May 8th, 2020) there is no FDA or CDC recommended approved treatment for COVID-19. Patients are receiving lifesaving therapy and many doctors are using all they have at their disposal to save lives. I applaud them daily.

Having said that, please note there are multiple research endeavors transpiring at the same time right now. At the time of this writing there are many trials completed, planned, recruiting, or underway. I have a spreadsheet of 1,159 as of this writing. Here is just some of the current research.

There is the aggressive analysis for repurposing small molecule drugs to treat COVID-19. That means scientists are using drugs that have already been approved for other conditions and are currently being studied for a new use, to combat COVID-19 in different ways:

 is believed to inhibit the action of RNA polymerase and has been in a COVID-19 trial, with more planned. The delivery is intravenous. 

What we understand at this point in time is that the RNA-Dependent RNA Polymerase (RdRp also called nsp12) is the central replication and transcription component of the novel coronavirus responsible for COVID-19, which is why drugs that are inhibitors or binders of RdRp are are part of clinical trials. Both inhibition and binding of RdRp may truncate transcription and replication of the novel coronavirus. Early studies may indicate Remdesivir potentially having both characteristics.

Based on short term favorable outcomes in shortening the duration of COVID-19 in study participants, the drug has been issued an Emergency Use Authorization (EUA) in the U.S. However, this is far from the full story. We still do not have enough information about the safety and efficacy of using remdeisvir to treat people with COVID-19. Please note receiving EUA is not the same as receiving FDA approval. The FDA needed to evaluate the current state of limited evidence and way the risk versus benefits and made the EUA decision.

 is a monoclonal microbial drug that acts as an anti-inflammatory agent. The drug is taken orally. Rutgers University is leading the Phase 1b clinical trial right now on COVID-19 patients. In preclinical models, the novel monoclonal microbial drug EDP1815 has been found to exert a positive influence on cytokines that have been implicated in the cytokine storm of certain COVID-19 patients. Addressing such hyperinflammation while attacking the replication pathways of this novel coronavirus may expedite recovery.

 is a viral RNA-polymerase binder. It is in trial right now. The delivery is oral and intravenous.

is a transmembrane protease serine 2 inhibitor. It is in trial right now. It is an oral medication. Viral host cell entry requires serine proteases that activate what are called viral spike glycoproteins. Transmembrane protease serine 2 known as TMPRSS2 is a potential target in COVID-19 treatment. Drugs that act as transmembrane protease serine 2 inhibitors, like Camostat (but there is also Trasylol and Flumadine) have potential to stop the novel coronavirus from cell entry and subsequent spread.

is a selective viral RNA-polymerase inhibitor. It is in trial and the route is oral.

 are two HIV drugs that have been studied in a clinical environment. These are oral medications. At this time there is lack of evidence to support their use for COVID-19.

, which is a sphingosine 1-phosphate receptor modulator, is an oral medication in phase 2 clinical trial right now, with an estimated primary completion date of July 1, 2020. It is in a class of drugs used as immunomodulators. These medications are used in conditions such as multiple sclerosis. This drug is being used in an attempt to truncate the immune response to acute respiratory distress syndrome caused by the cytokine storm associated with COVID-19.

 better known as hydroxychloroquine, was part of a clinical trial because it is possible that it may inhibit the terminal glycosylation of ACE2 of this virus. A study just published in the New England Journal of Medicine did not conclude any benefit of using this drug for COVID-19 patients. In fact, over 800 patients that took the medication were more ill than those that did not. However, this is the first observational study in the US and the recommendation is further study. Currently, the FDA is cautioning against the use of this medication for COVID-19 outside of a hospital environment due to the high risk of heart rhythm abnormalities (such as Long QT or QT prolongation).

There are at least 7 more drugs and remember these are the repurposed medications. That doesn’t include the new drugs that are currently in development. The repurposed medications would receive a fast approval due to the fact that they have a track record and a dataset of safety vs. risks for other conditions.

Additionally, there is research ongoing to address some of the symptom complexes of COVID-19 that would allow other medications to work more rapidly or with higher efficacy. Interestingly, NYU is conducting a trial on hyperbaric oxygen therapy (HBOT) on COVID-19 patients and is currently recruiting patients as of April 2nd, 2020.

There is interesting data on addressing the cytokine storm by blocking specific receptors. One such receptor is the cell surface receptor GPR55. This receptor can signal an immune response that results in a cytokine expression. I’m working with researchers on these efforts.

The CDC recently provided recommendations for investigational COVID-19 convalescent plasma. It is important to note that convalescent plasma has not yet been approved for use by FDA as a treatment, but it is encouraged as part of the research to find a treatment. The reasoning for studying convalescent plasma is sound scientifically because it has successfully been used in SARS, MERS and the 2009 N1H1. It is considered classic adaptive immunotherapy. The plasma is donated from patients who have completely recovered from COVID-19 with a high titer of neutralizing antibodies and delivered intravenously into those battling the infection. In a very small study of 10 patients, seven recovered after receiving the donor plasma. Larger studies are needed and are underway.

The following paragraph may be antiquated by the time of publication but at the time of this writing there are at least 23 pharmaceutical companies and universities involved in the race for a vaccine for the novel coronavirus. For example, there is a vaccine trial underway at the University of Oxford with the first two subjects receiving the test vaccine as an injection in late April. The goal is to reach over 1000 participants with half receiving the potential vaccine and the other half a placebo. It will take months for the data to come to fruition.

While waiting for an approved treatment and or vaccine, the current method of care in an emergency room / hospital environment is supportive care and managing any comorbidities/illnesses, along with the discretionary use of the aforementioned EUA status drug Remdesivir and other treatments as warranted.

For more information on the coronavirus and COVID-19, you can listen to my podcast 

 and read my previous article on COVID-19 & Cytokine Storms 

As for now (May 8th, 2020) there is no FDA or CDC recommended approved treatment for COVID-19. Patients are receiving lifesaving therapy and many doctors are using all they have at their disposal to save lives. This article presents just some of the treatment research for COVID-19 being pursued now. 

2020-05-08-an-overview-of-treatment-research-for-covid-19.jpg

An Overview of Treatment Research for COVID-19

COVID-19 is not just a problem for the elderly population - young and healthy individuals can also end up hospitalized, or even on a ventilator, depending on their genetics.

There are reports of marathon runners under the age of 50 almost dying from COVID-19. I personally am aware of a case of a woman in her early 20s on a ventilator from COVID-19 complications. What is the reason why healthy people in addition to the elderly can succumb to COVID-19?

The term “cytokine storm” encompasses a multi-factorial hyperinflammation associated with increased expression of different cytokines including but not limited to interleukins (IL), chemokines, granulocyte colony-stimulating stimulating factors (G-CSF), and tumor necrosis factor-1a (TNF).

Cytokines are small proteins secreted by cells that have a major impact on the normal communication system between cells. Cytokines is a blanket term. There are many different cytokines, including named after the cells that secrete them such as monokines, the type of cytokines released by a type of white blood cell called monocytes.

I am aware of at least 14 different cytokines that have been reported to be significantly elevated in COVID-19 patients. This number will vary and change. Regardless, it is concerning.
According to recent published studies the body of available evidence suggests that a subgroup of patients with severe COVID-19 might have a cytokine storm syndrome. The culmination of this “storm” is a massive immune system response that actually ends up negatively impacting normal pulmonary function, in some cases leading to death.


Different cell types such as B cells (which create antibodies to help our immune system remember enemies and threats), T cells, macrophages, eosinophils and basophils work in concert, communicating with each other using the language of cytokines. 

For example, the phagocytes macrophages will use specific cytokines to create specific responses by B and T cells, and so on. This broad communication network uses many “dialects” of the language of cytokines. Meaning, many different cytokines are stimulated resulting in a chronic, always on alert immune system response.

Immunologically, the lungs are highly dependent on a vigilant immune system and inflammatory response because of their constant exposure to a wide variety of infectious agents, particulates and gases as per the process of respiration. In classic immunology we learn that as part of homeostasis living in a modern world the lungs mount a protective service by deploying cytokines that regulate host defense mechanisms.

One could say cytokines play a crucial role in immune homeostasis in the lungs. There is a law to cytokines in the lungs. First, they need to categorize friend from foe. Second, cytokines help the immune system ignore or attack. Third, cytokines must act as a conductor of a fine orchestra, and govern or regulate the symphony of that decision - to activate an all out immune attack, or calm the immune response, considering tolerance instead, and cease the attack once the battle is being won.

In cases of COVID-19 cytokines in the lungs react in an all-out war, first against the coronavirus that is behind the COVID-19 symptomatology and secondly against healthy lung tissue due to an exaggerated immune response. This infection is linked to cells in the lungs committing suicide (a process known as apoptosis) as part of the defense mechanism to prevent the spread of this virus. 

Additionally, there is solid evidence of a pro-inflammatory response that leads to capillary leakage and the stimulation of lymphocytes, neutrophils and macrophages that secrete cytokines targeting the vascular endothelial cells in the lungs, reducing the ability to breathe. That’s just one pathway in a highly complex process that can lead to the urgent need for a ventilator.

Clinical studies on treatments to address the cytokine storm include drugs such as Fingolimod, which is a sphingosine 1-phosphate receptor modulator. It is in a class of drugs used as immunomodulators. Other medications that directly address the cytokine storm include the anti-inflammatory medications sarilumab, anakinra, emapalumab and tocilizumab. 

These medications offer a calming influence on the immune system. Combining immunomodulators and or anti-inflammatory medications with antiviral medications and other palliative care methodologies are logical treatment paths to taming the storm and granting recovery.

I cover such research in my article titled An Overview of Treatment Research for COVID-19.

You can find my podcast covering some key aspects of COVID-19 here - 

https://drrobertpastore.com/podcasts/058-coronavirus-covid19

What is the reason why healthy people in addition to the elderly can succumb to COVID-19? One key reason is cytokine storm. The culmination of this “storm” is a massive immune system response that actually ends up negatively impacting normal pulmonary function, in some cases leading to death.  


COVID-19 and Cytokine Storms

Lactose intolerance is not the same as an allergy to milk. Lactose intolerance differs from a milk allergy in that a milk allergy is an immune system reaction and true lactose intolerance is due to a deficiency of the enzyme lactase that digests the milk sugar lactose that does not cause an immune system reaction. Lack of this enzyme can cause some disturbing symptoms including but not limited to bloating, gas and diarrhea. 

It is estimated that 68% of the world’s population have lactose intolerance, which is also referred to as lactose malabsorption. The 68% of the population with lactose intolerance also has a majority demographic in Africa and Asia, while in northern Europe, some people carry a gene where the C allele indicates lactase nonpersistence (they do not produce the enzyme lactase) and the T allele indicates lactase persistence (they do produce the enzyme lactase).

In the general US population high risk groups include: African Americans, Indigenous peoples of the Americas, Asian Americans, Hispanics/Latinos. 

How is lactose intolerance diagnosed traditionally?

Doctors use a hydrogen breath test to make a diagnosis because typically there is a small amount of hydrogen (a gas) in our breath, but if you suffer from lactose intolerance and cannot digest the milk sugar lactose, hydrogen levels become very elevated and it is easy to capture with this test. The test itself is not fun for the lactose intolerant individual. You drink a liquid that contains a set quantity of lactose and every 30 minutes over a few hours you must breathe into a balloon type container that calculates the amount of hydrogen in your breath. Additionally, your symptoms will be monitored. The combination of increased hydrogen and symptoms results in a diagnosis.

There also is data indicating that a simple genetic test is as sensitive and specific as an H2 test, without the side effects for those who are positive on the breath test. The gene MCM6 rs4988235 is associated with the risk of lactose intolerance. A CC allele is strong evidence of lactose intolerance.

There are three important points to mention with regard to celiac disease. First, celiac disease patients have a high prevalence of a positive H2-lactose breath test compared to healthy controls and a high prevalence of celiac disease was observed in patients with a positive H2-lactose breath test compared to healthy controls. 

In layman’s terms, those with celiac disease are at a much higher risk of also having a lactose intolerance. In a study by Ojetti in the journal Digestion back in 2005, 24% of subjects with lactase deficiency tested positive for celiac disease and lactose intolerance was the ONLY symptom manifestation of celiac disease. The study authors went on to suggest serologic screening for celiac disease in all patients with a positive H2-lactose breath test before beginning a milk-exclusion diet.

If you have been diagnosed with lactose intolerance, you should also be tested for celiac disease. My previous article 

“What do you do if you think you may have celiac disease?”

 outlines the proper steps for diagnosis. 

The second point is that many doctors believe celiac disease patients experience “secondary lactose intolerance”. Meaning even if they have normal H2 breath tests and are not CC genotype for MCM6, they simply lack the ability to digest lactose due to the fact that celiac disease shrinks or obliterates villi in the small intestine and the smaller hair like projections called microvilli (also known as the brush border) in the intestines is the location of where we would normally have lactase, the enzyme that breaks down lactose. 

Damage to these structures decreases or eliminates the ability to have the enzyme present and therefore creates lactose intolerance. After six months of a strict GF diet to allow the villi to heal, this may normalize and you may no longer have a lactose intolerance.

Third, it is important to distinguish between primary lactose intolerance and secondary causes of maldigestion of lactose, including the aforementioned celiac disease, AND also infectious enteritis, or Crohn’s disease, which have distinct pathogenic paths and treatments.

If you were diagnosed with lactose intolerance and consume gluten, it would be wise to discuss with your doctor about being tested for celiac disease and vice versa.

Those with celiac disease are at a much higher risk of also having a lactose intolerance. In a study by Ojetti in the journal Digestion back in 2005, 24% of subjects with lactase deficiency tested positive for celiac disease and lactose intolerance was the only symptom manifestation of celiac disease.

Lactose Intolerance and Celiac Disease

Receiving continuing proper medical care after the diagnosis of celiac disease is critical. I call the process of medical follow up for the celiac disease patient the 3 or 6 and 12 month post diagnosis process (just remember 3 or 6 and 12). 

Around 3 to 6 months after your diagnosis see your physician for a follow up appointment. I prefer 3 months, but there is one test that actually requires 6 months to become normal on a strict GF diet, I’ll explain in a moment. The reason I prefer a medical follow up at 3 months post diagnosis versus 6 is to follow up on or discover any nutritional deficiencies that are linked to celiac disease. Quoting Green and Cellier as I did in a previous blog post , “after the diagnosis of celiac disease has been established, the patient should be assessed for deficiencies of vitamins and minerals, including folic acid, B12, fat-soluble vitamins, iron, and calcium, and any such deficiencies should be treated. It is important to identify deficiencies and track the normalization of any essential nutrient. I prefer to not wait half a year to see how the patient is progressing or for the first time uncover a deficiency post diagnosis. 

At your appointment, discuss with your doctor the blood tests that were part of your path to diagnosis. Were you IgA deficient and then had a subsequent “alternative” path to serology that led you to a biopsy, and the diagnosis of celiac disease? If that’s the case, your doctor should be monitoring your sIgA level and make sure that is normal or at the very least, normalizing. My point is it is important to repeat any abnormal blood tests that were part of your path to diagnosis along with the standard blood test that is most frequently used in celiac disease diagnostics. For example, your doctor needs to check you for the traditional tissue transglutaminase IgA (TTGIgA) and the blood test that led to the biopsy or the additional test that led to your biopsy. Expanding on that thought for clarification, if you had a non-TTGIgA path to biopsy, such as an endomysial antibody test, that should be repeated along with a TTGIgA needs to be monitored at each check up with your physician. Why? It is crucial to determine if a) your immune system is normalizing and if b) you are still producing antibodies to gluten. Please keep in mind a TTGIgA is typically negative around 6 months after diagnosis. So, do not be discouraged if you see your doctor earlier as I recommend and only see a downward trend of this marker. That’s ok.

Be your own health care advocate and make a list of any abnormal blood tests, or diagnostic tests that you had prior to your diagnosis and be sure they are monitored (repeated at the correct time interval). For example, if an abnormal DEXA scan revealed early onset osteoporosis (a symptom of celiac disease) it should be repeated in due course. Any aforementioned deficiencies identified should be checked and become part of the routine follow up going forward in your life. This is extremely important because celiac disease has one treatment and that treatment is a militant gluten free diet. Gluten exposure is a common problem for people with celiac disease and such exposure exacerbates anything and everything – from the original symptoms and deficiency states that could have led to your diagnosis, to new problems. So, it is our job to be health care advocates for ourselves and make sure we are being followed up appropriately.

At 12 months post diagnosis you should have another follow up with your doctor and once again measure TTGIgA and any other prior abnormal serology and standard serology. At this point it would be wise to have an additional blood test that checks for hepatitis B titers, to see if the vaccination response is present for those that were vaccinated. In multiple clinical studies, researchers tested known celiac patients who had been vaccinated for hepatitis B and found that the rate of non-response was significantly higher in the celiac patients when compared to controls. It seems that only patients with active and untreated celiac disease are at risk for not responding to the hepatitis B vaccine.

From a nutritional care perspective, of course it is essential for the diagnosed celiac disease patient to have routine follow ups with a nutrition professional who is knowledgeable in celiac disease such as a Certified Nutrition Specialist (CNS) or Registered Dietician to discuss your diet and dietary challenges. It may also be necessary to have psychological support. Seek help if you need it.

Receiving continuing proper medical care after the diagnosis of celiac disease is critical. I call the process of medical follow up for the celiac disease patient the 3 or 6 and 12 month post diagnosis process (just remember 3 or 6 and 12).

What is the proper medical follow up for a celiac patient?

As a celiac disease expert, one question I am asked most often is “what if you have celiac disease and are exposed to gluten?” Unfortunately there are no magic bullets. There is no cure for this disease. Sadly, many celiac disease organizations estimate over 75% of celiac disease patients confirm exposure to gluten over a short period of time. It is important to state what I hope is obvious, but it is critical to communicate that you have celiac disease to whomever is preparing your food. Regardless, sometimes things do not go as planned. If you, like me, have celiac disease, you may have experienced that dining out doesn’t always go as planned regardless of how much planning you do, or orate the seriousness of the disease. So, when exposure happens, this is what I believe is a logical course of action.

Call your doctor’s office (preferably the office that diagnosed you or at least is knowledgeable of your condition) and let them know what transpired and the symptoms you are experiencing. Take their advice.

Hydrate! If diarrhea is a primary symptom of celiac disease prior to diagnosis, or you have been strictly gluten free for a period of time and have been exposed to gluten, diarrhea may be your main symptom. Drinking plenty of water can help prevent diarrhea induced

Do your best to get plenty of rest. Sometimes gluten exposure in the celiac disease patient can cause sleepiness and in others cause insomnia. My advice is if it is at all possible to get some rest, do it and that includes taking a nap during the day.

Build your post gluten exposure meals on a foundation of healthy food that is more on the bland, plain side of the flavor palette. This is not the time for a super spicy chicken dinner following your gluten spiked lunch. Homemade chicken soup is a better option.

Speaking personally and professionally, speak with your doctor about keeping pharmaceutical grade L-glutamine powder in your home for emergency exposure to gluten. I have used this tactic and based my opinion on multiple studies on the role of glutamine in intestinal diseases. The findings suggest that glutamine supplementation may be beneficial for individuals with impaired gut permeability by enhancing the expression of tight junction proteins. A wonderful scientific review that includes the mention of celiac disease is by Kim and Kim in the international journal of molecular sciences from back in 2017 titled “The Roles of Glutamine in the Intestine and Its implication in Intestinal Diseases.

 I have taken as much as one tablespoon dissolved in water as part of my healing process.

Extrapolating from a study of celiac disease patients with IBS and from my experience in clinical practice, probiotics may be of benefit. In a randomized study of 109 celiac disease patients strictly adhering to a gluten free diet but with irritable bowel syndrome (IBS) symptoms by Francavilla and colleagues published in the journal of clinical gastroenterology back in March of 2019, enrolled patients were randomized to probiotics (a mixture of five strains of lactic acid bacteria and bifidobacteria: Lactobacillus casei LMG 101/37 P-17504 (5 Å~109 CFU/sachet), Lactobacillus plantarum CECT 4528 (5 Å~109 CFU/sachet), Bifidobacterium animalis subsp. lactis Bi1 LMG P-17502 (3.4 Å~109 CFU/sachet), Bifidobacterium breveBbr8 LMG P-17501 (3.4 Å~109 CFU/sachet), Bifidobacterium breve Bl10 LMG P-17500 (3.4 Å~109 CFU/sachet)), or placebo for six weeks, and then followed up for six more weeks. The results revealed that the probiotics were efficacious in ameliorating the severity of IBS symptoms measured by IBS severity score (IBS-SS) 

I discuss this topic mone in-depth during my podcast “On Gluten Exposure Recovery for Celiacs” which can be found on 

What should you do if you have celiac disease and consumed gluten? I share my recommendations on the logical course of action and two different supplementations that may be helpful post-exposure.

What if you have celiac disease and consumed gluten?

A paper published last year by Simons and colleagues identified a direct link between celiac disease and pneumococcal infection.

 While the incidence was higher in hospitalized patients versus the general population, the data has been building for years in the general population. The main cause of action for this increased risk involves the spleen.


Individuals with celiac disease have a higher risk of pneumococcal infection due to the higher incidence of hyposplenism in the celiac disease population. Those with celiac disease should consider pneumococcal vaccination. 

Dr. Robert Pastore, PhD, CNS

Poor Sleep Quality and Immunity

Celiac Disease and Cardiovascular Disease

Refractory Celiac Disease

Tissue Transglutaminase

An Overview of Treatment Research for COVID-19

Search Archive

List of Topics