Asthma: Up-To-Date Review 17.10.2020

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Asthma: Up-To-Date Review 17.10.2020

Postby doogles on December 5th, 2020, 5:26 am 

I've posted Personal Hypotheses before in this Health and Nutrition Section. The first was on the major importance of vitamin K in moderating or preventing end organ degenerative diseases, including atherosclerosis, osteoarthritis, cardiovascular disease, dementia, stroke, and many others. I've seen nothing since then except more recent literature supporting that dissertation. It attracted a few supportive comments.

I posted a second one on Old and New Evidence relating to Hypertension. It did not attract any comments, even though most of us oldies would have been diagnosed with the condition.

I've had cause recently to re-evaluate the literature on asthma because I've been affected by wheezing respiration since my wife and I conducted the demolition of a bathroom and en-suite some 8 months ago prior to renovations. I had been affected by asthma since I was 14 years of age and also had been diagnosed with Chronic Obstructive Respiratory Disease (COPD) on the basis of chest Xrays 20 and 10 years ago. I assumed that my recent months of wheezing was due to an exacerbation of COPD caused by the dust arising in the bathroom demolitions.

After six months of imperfect control of my wheezing by asthma inhalants, my request for a chest Xray suggested that the COPD was NOT a major issue.

This left the possibility that my problem was one of chronic asthma.

So I decided to review the literature on asthma.

The results are shown in the attachment.

My breathing is now 'normal' in a non-exercise state.

As you read the attachment, you may recall a thread we had on 'leaky gut' and zonulin a few years back.
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Postby doogles on December 5th, 2020, 5:59 am 

The attachment opened in the preview, but not the final 'Submit'.

Ill have to copy and paste it. I hope it is not too long:


When I was a child, the cause of asthma was believed to be an allergy to certain inhaled proteins. The analogy was nettle rash, wherein a small amount of protein produced exaggerated skin weals, and it was postulated that such a hypersensitivity also occurred in the lungs. It was the general belief that allergic reactions resulted in the release of histamines, causing constriction of the bronchioles and dilation of capillaries (congestion). At the age of 14, I had a few sporadic bouts of dyspnoea, accompanied by a hoarse cough that resulted in bed rest for several days. It was misdiagnosed as bronchitis. The treatment consisted of sulphonamide tablets, and a cough medicine containing potassium iodide and liquorice extract as far as I know. During these bouts, my dyspnoea was so bad that my chest muscles would ache from forced breathing. I sometimes thought I would die during the night. After a few days, the congestion began to break and I would cough up yellowish mucus containing specks of blood. My breathing would return to normal until the next bout. Adrenaline injections were available for treatment, but they seemed to be available only in hospitals and some emergencies.

During the next couple of years I used to get some relief from an over-the-counter medication called 'Mendaco'. It contained ephedrine, a drug in the same class as benzadrine, dexadrine, and the now illicit drug methyl-amphetamine. This family of drugs blocked the normal metabolic breakdown of a patient's adrenaline, so that blood concentrations of adrenaline remained higher for longer. Adrenaline, of course, constricts congested blood vessels and relaxes constricted bronchiolar smooth muscles. I never did get an adrenaline injection, but when I was 17, and having great trouble breathing, I had a chance to try a new treatment called 'Aspaxadrene'. A Melbourne chemist, named Crundall, had developed a technique for keeping adrenaline in a stable solution and for administering it as an aerosol. He developed a hand held glass nebuliser consisting of a rubber bulb which you squeezed in order to force air past a capillary tube containing the stabilised adrenaline and you breathed it in. The first time I used it, I had a miraculous reversal of symptoms and was able to run up and down our street within minutes of fighting for every breath. I used it until I was into my early 50s, when the disease was still regarded as an allergy.

There is so much literature now that inflammatory processes are involved in asthma, that it seems safe to conclude that it is an inflammatory, rather than allergic, disease, at least in some cases. --

Kraft et al (1996; ... .5.8912772) Alveolar tissue inflammation in asthma. " ... These findings suggest that eosinophils and macrophages accumulate to a greater extent in the alveolar tissue and these changes contribute more to the variation in lung function compared with inflammation in the more proximal tissue."

Louis et al (1998; ... .1.9802048) The Relationship between Airways Inflammation and Asthma Severity. " ... This study points to persistent, disease severity–related airways inflammation in asthma, involving eosinophils, mast cells, and neutrophils, which is evident despite treatment with corticosteroids. ... "

Murdoch and Lloyd (2010; ... 0709002826) Chronic inflammation and asthma. "Allergic asthma is a complex and chronic inflammatory disorder which is associated with airway hyper-responsiveness and tissue remodelling of the airway structure. Although originally thought to be a Th2-driven inflammatory response to inhaled innocuous allergen, the immune response in asthma is now considered highly heterogeneous. ... " This author still used the word 'allergic'.

Fahy (2015; Type 2 inflammation in asthma — present in most, absent in many. " ... I consider how dichotomizing asthma according to levels of type 2 inflammation — into 'T helper 2 (TH2)-high' and 'TH2-low' subtypes (endotypes) — has shaped our thinking about the pathobiology of asthma and has generated new interest in understanding the mechanisms of disease that are independent of type 2 inflammation."

The old notion that it was an over-reaction (allergy) to ranges of airborne proteins probably holds to some extent, but there are gaps in rationalising the process. This hypothesis requires the unlikely premise that masses of immunoglobulins are normally lining the airways surface of alveolar or brochiolar endothelia. If the membranes lining the respiratory system remained intact, then immunoglobulins would not be in abundance within the airways, and airborne proteins would not be able to penetrate the membranes to react with the immunoglobulins underneath those membranes.

There has been a developing novel hypothesis over the last decades involving the notion that membrane interfaces (epithelium, endothelial and mucous) between animal tissues and the outside world can become weak and actually 'leak'. In terms of surface area, the alimentary canal has an even bigger interface with the outside environment than the skin. The respiratory tracts also have cell linings separating airways from underlying tissues. Theoretically, these membranous linings should stay intact and prevent undigested environmental proteins from gaining access to underlying animal tissues. If entire proteins manage to penetrate these membranes, the immune systems react to them as 'foreign' matter and produce inflammatory chemicals such as histamines and cytokines. The result is a broncho-constriction, vasodilation, and a build-up of fluids in alveoli and sub-membrane tissues, all of which compromise breathing.

As far as gut function is concerned, during digestion and absorption of food materials, bacteria and enzymes in the gut are supposed to break down complex carbohydrates and proteins into much smaller particles such as monosaccharides or glycerophosphates and amino acids. These in turn have to be absorbed into the cells lining the gut and transported across these cells to the interstitial fluid and small blood vessels on the other side of the cells. The only way that undigested products can get into the blood stream is if they bypass transport through the cells lining the gut, and enter between the cells of the gut.

After decades of study of coeliac disease, research now shows that the junctions between these cells are normally kept tight as a result of the action of a number of proteins working in concert, but that they can be negated by a protein called 'zonulin'. The literature also suggests that certain bacterial enzymes and wheat proteins (gliadins and glutenins) can actually activate this zonulin, resulting in a breakdown of the bonding between neighbouring cells. As I said, this allows whole proteins (undigested) to leak though the gut lining where they are regarded as 'foreign' material by the immune system, setting up degrees of inflammation. If this inflammation occurs at the surface of the gut, it produces coeliac disease. This 'leaky gut' hypothesis seems to be now well-established as far as coeliac disease is concerned, but researchers are now suspecting that leaky membranes may also be a pre-disposing feature of asthma.

Hodgson et al (1976; ... 367693155X) ATOPIC DISORDERS AND ADULT CŒLIAC DISEASE "A history of asthma, hay fever, and flexural eczema was significantly more common in patients with adult cœliac disease (A.C.D.) than in normal controls. Autoantibodies were also more common in A.C.D. First-degree relatives of A.C.D. patients were more likely than controls to have atopic disorders."

Bernard et al (1996; ... 4996701811) Increased intestinal permeability in bronchial asthma " ... Our results support the hypothesis that a general defect of the whole mucosal system is present as a cause or a consequence of bronchial asthma."
Ludwigsson et al (2011; Coeliac disease confirms a 1.6 fold increased risk of asthma: A Nation-wide population-based cohort study "
... Most earlier research has indicated a positive relationship between CD and asthma or airflow obstruction, but relative risk estimates have varied widely from 1.0 to 7.26, and studies have generally suffered from small numbers.

Farshchi et al (2016; ... 7216682169) A Viewpoint on the Leaky Gut Syndrome to Treat Allergic Asthma: A Novel Opinion " ... Due to several mechanisms that have been mentioned in the protective effects of plant gums and plantain family seeds on the intestinal epithelium, we can propose an effective management for leaky gut syndrome to treat asthma."

Salameh et al (2019; ... /sji.12855) The role of gut microbiota in atopic asthma and allergy, implications in the understanding of disease pathogenesis " ... This review provides insight into the role of dysbiosis in asthma, and an understanding that is required to establish clinical trials which aim to modulate the gut microbiota as a means of preventing and treating asthma."

One particular method of checking for 'leaky gut' is to dispense an oral dose of radioactive-labelled chromium EDTA and to measure the kidney output. It can be shown that people with asthma have a significantly higher output than those with COPD and healthy controls.

Bernard et al ( 1996; ... 4996701811) Increased intestinal permeability in bronchial asthma " ... Our results support the hypothesis that a general defect of the whole mucosal system is present as a cause or a consequence of bronchial asthma. "

The missing link for asthma is whether the zonulin concentrations in the blood also control the tightness of the junctions of cells lining the respiratory system. Leaky respiratory membranes would explain why foreign airborne proteins can make contact with so much immunoglobulin to produce widespread lung reactions. There is some low to moderate evidence supporting this.

Fasano (2011; ... 00003.2008) Zonulin and Its Regulation of Intestinal Barrier Function: The Biological Door to Inflammation, Autoimmunity, and Cancer " ... We have generated preliminary data suggesting that serum zonulin levels are high in a subset of subjects affected by asthma and that ∼40% of asthmatic patients have an increased intestinal permeability (C. Blaisdell and A. Fasano, personal communication). This preliminary observation suggests that, beside inhalation, an alternative route for the presentation of specific antigens or irritants may occur through the gastrointestinal mucosal immune system following their paracellular passage (normally prevented by the intercellular TJ)." Fasano did not mention the possibility that the increased zonulin associated with gut permeability may also result in leaky respiratory membranes, thus predisposing to reactions from inhaled proteins.

Sturgeon and Fasano (2016; ... 16.1251384) in Zonulin, a regulator of epithelial and endothelial barrier functions, and its involvement in chronic inflammatory diseases This paper contains the results of high quality research on the origins and actions of zonulin.

Zonulin may not be the sole cause of breakdown of tight junctions in asthmatics. This article suggests a separate possibility.

Sugita et al (2018; ... 4917305729) Type 2 innate lymphoid cells disrupt bronchial epithelial barrier integrity by targeting tight junctions through IL-13 in asthmatic patients. I looked up Interleukin-13 here. According to Wikipedia, Interleukin 13 (IL-13) is a protein that in humans is encoded by the IL13 gene. "... Interleukin-13 is a central regulator in IgE synthesis, goblet cell hyperplasia, mucus hypersecretion, airway hyperresponsiveness, fibrosis and chitinase up-regulation" -- The authors concluded that "These data highlight an essential mechanism in asthma pathogenesis by demonstrating that ILC2s are responsible for bronchial epithelial TJ barrier leakiness through IL-13." This paper also suggests that asthma is an inflammatory disease."

Managements now being suggested

1. Gluten-free Diet. The obvious first and major choice is now a gluten-free diet. I've been on this for 8 weeks now, and the wheezing I've manifested for over 6 months has stopped completely. I'm now back to using my Oxis and Pulmocort only twice a day, not to treat an attack, but to prevent one. I haven't use Spiriva as a back-up for 2 weeks. My forced expiratory volume in one second has increased by about 50 mL.

2. Symptomatics. These are the mainstay of asthma management these days. Whereas the gluten-free diet is removing a basic cause of asthma, the formoterol in Oxis causes bronchodilation (relaxation of the constricted smooth muscles of the bronchioles); this simply reverses or reduces an effect of the disease (a symptom). Drugs that do this are called symptomatics. The Pulmicort of course delivers budesonide, a corticosteroid, which reduces the amount of fluid buildup associated with inflammation. It is also just a symptomatic. The tiotropium in Spiriva is also just a symptomatic in that, like the formoterol in Oxis, it produces brochodilation.

The rest of these suggested management tools should be considered as maybe helpful.

3. High-fibre Diet (and some Fatty Acids). A couple of interesting pieces of research now report that high fibre in the diet reduces even refractory asthma. As you can see, the suggestion is that gut bacteria convert fibre into short chain fatty acids, which in turn may have a beneficial effect on asthma.

Saeed et al (2020; ... 1910-776OC) Association of Dietary Fiber on Asthma, Respiratory Symptoms, and Inflammation in the Adult National Health and Nutrition Examination Survey Population "High-fiber diet may mediate an inflammatory response and decrease odds of having asthma, especially for women and specific racial groups, cough, wheeze, and phlegm production when compared with low-fiber diet."

Trompette et al (2014; Gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis " ... Mice fed a high-fiber diet had increased circulating levels of short chain fatty acids (SCFAs) and were protected against allergic inflammation in the lung, whereas a low-fiber diet decreased levels of SCFAs and increased allergic airway disease. ... Our results show that dietary fermentable fiber and SCFAs can shape the immunological environment in the lung and influence the severity of allergic inflammation."

Anushiravani et al (2020; ... 3319300442) The effect of Plantago major seed and almond gum on refractory asthma: A proof of concept study "Conditions like refractory asthma (RA) have led to a renewed interest in non-conventional approaches to managing asthma such as those used in Traditional Persian medicine (TPM). The aim of this trial was to test a TPM formulation including Plantago major seed and Almond gum powder for asthma. ... The results demonstrate that a combination of Plantago major seed and Almond gum is well-tolerated and potentially beneficial for patients with RA."

These appear to be early stage reports, but it may be interesting to note that in my case at least, a gluten-free diet has resulted in more fibre in the form of fruits and vegetables instead of bread and pasta (see Charts in ... -Chart.pdf). I'm not sure about the effects of short chain fatty acids. Here's some literature:

Yoon et al (2020; https://www.worldallergyorganizationjou ... 39-4551(20)30107-1/fulltext) Effects of respiratory short-chain fatty acids on bronchial inflammation in asthma "SCFA (sodium acetate, proprionate and butyrate) -treated mice showed a significant decrease in total inflammatory cell counts and eosinophil counts in bronchioalveolare lavage (BAL) fluid and lung histology. Airway hyperresponsiveness was significantly attenuated in the sodium proprionate-administrated group. OVA (ova-albumin) -specific IgE level and the expression of IL-1 beta, inflammasome cytokine, were also significantly decreased with administration of SCFA. Moreover, SCFA attenuated the synthesis of interleukin (IL) -1 beta in HDM treated BEAS-2B cells." Just a comment that the above are sodium salts of short-chain fatty acids. The short chain fatty acids are acetic, proprionic and butyric acids.

Schubert et al (2009; Effect of n–3 Polyunsaturated Fatty Acids in Asthma after Low-Dose Allergen Challenge "Our results provide evidence that dietary supplementation with n–3 PUFA is able to reduce bronchial inflammation even after low-dose allergen challenge." As far as I can tell, this is fish oil Omega 3 fatty acid.

Thien et al (2000; Dietary marine fatty acids (fish oil) for asthma in adults and children "There was no consistent effect on any of the analysable outcomes: FEV1, peak flow rate, asthma symptoms, asthma medication use or bronchial hyper reactivity. One of the studies performed in children which combined dietary manipulation with fish oil supplementation showed improved peak flow and reduced asthma medication use. There were no adverse events associated with fish oil supplements." The results were inconclusive.

Stoodley et al (2019; Higher Omega-3 Index Is Associated with Better Asthma Control and Lower Medication Dose: A Cross-Sectional Study " ... Subjects with a high O3I (≥8%) had a lower maintenance dose of inhaled corticosteroids (ICS) compared to those with a low O3I (<8%) (1000 μg (400–1000) versus 1000 μg (500–2000) p = 0.019). This study demonstrates that a higher O3I is associated with better asthma control and with lower ICS dose, suggesting that a higher erythrocyte n-3 PUFA level may have a role in asthma management."

4. Adequate Vitamin B6

Vitamin B6 is readily available over the counter and is cheap. It usually comes as 100 mg tablets or capsules, but the maximum daily recommended dose is 25 mg. So it should be taken at that dose maybe once a week. It appears to have anti-inflammation effects.

Yanaka et al (2005; ... .16.6.1071) Vitamin B6 suppresses NF-kB activation in LPS-stimulated mouse macrophages " ... These observations suggest that the anti-inflammatory effect of vitamin B6 is mediated by suppression of NF-κB activation."

Zhang et al (2016; Vitamin B6 Prevents IL-1β Protein Production by Inhibiting NLRP3 Inflammasome Activation " ... Collectively, these findings reveal novel anti-inflammatory activities for vitamin B6 and suggest its potential for preventing inflammatory diseases driven by the NLRP3 inflammasome."

Ueland et al (2017; ... 9716300395) Inflammation, vitamin B6 and related pathways "The active form of vitamin B6, pyridoxal 5′-phosphate (PLP), serves as a co-factor in more than 150 enzymatic reactions. Plasma PLP has consistently been shown to be low in inflammatory conditions ... "

Du et al (2020; ... jcmm.15917) Vitamin B6 prevents excessive inflammation by reducing accumulation of sphingosine‐1‐phosphate in a sphingosine‐1‐phosphate lyase–dependent manner " Vitamin B6 is necessary to maintain normal metabolism and immune response, especially the anti‐inflammatory immune response. ... "

5. Dupilumab
A new class of drug that blocks the effects of inflammation products such as the interleukins, is currently being assessed. Currently it looks as if it involves an injection every 2 weeks, as an 'add-on' to current medication. It's efficacy confirms to some extent that asthma is an inflammation.

Vatrella et al (2014; ... rticle-JAA) Dupilumab: a novel treatment for asthma " ... A recent trial showed that in patients with difficult-to-control asthma, dupilumab can markedly decrease asthma exacerbations and improve respiratory symptoms and lung function; these effects were paralleled by significant reductions in T-helper 2-associated inflammatory biomarkers. However, further larger and longer trials are required to extend and validate these preliminary results, and also to carefully study the safety and tolerability profile of dupilumab."

Corren et al (2020; ... 13219819307755) Dupilumab Efficacy in Patients with Uncontrolled, Moderate-to-Severe Allergic Asthma " Dupilumab reduced severe exacerbation rates, improved FEV1 and asthma control, and suppressed type 2 inflammatory biomarkers in patients with uncontrolled, moderate-to-severe asthma with or without evidence of allergic asthma, highlighting the key role of IL-4 and IL-13 in airway inflammation."

Agache et al (2020; ... /all.14235) Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma; A systematic review for the EAACI Guidelines - Recommendations on the use of biologicals in severe asthma This is a severe review with many provisions on findings. All of the research so far has been funded by Industry and the authors mention the possibility of bias in findings. This finding is part of the Discussion "The current systematic review of efficacy showed with high certainty that benralizumab, dupilumab and omalizumabas add-on to standard care reduce the exacerbation rates for patients with allergic asthma older than 12 years (adolescent/adults). Similarly, for children 6-11 years old with allergic asthma, omalizumab as add-on treatment significantly reduces the exacerbation rates."

What I'm personally doing about it.

I started having a small tin of fish plus a banana, orange and mandarine or equivalent for lunch instead of sandwiches, and my wife, Christine, utilises mainly meat, eggs and vegetables for dinner in the form of fries, mornays and stir fries or stews.

My staple medication is Oxis plus Pulmicort, but I forgot to take it on a couple of occasions because I was not wheezing any more.

Eating more fruit and vegetables than wheat flour products of course supplies more fibre and therefore apparently more short chain fatty acids.

I used some vitamin B6 a few weeks ago when I started on the gluten-free diet.
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