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ADAPTIVE IMMUNITY and PRECISION MEDICINE
ASTHMA, ARDS, & CoVID-19 – Is There a Role for Testosterone and Anabolic Steroids in Autoimmune Disease?

Potential Role of Androgenic-Anabolic Steroids, Estrogen Receptor-beta, proinflammatory cytokines in CoVID-19 in Autoimmune Disease

Edward M. Lichten, M.D., F.A.C.O.G., F.A.C.S.

Fellow, American College of Obstetricians and Gynecologists

Fellow, American College of Surgeons

600 West Brown Street Suite #202

Birmingham, MI 48009

Office phone: (248) 593.9999  

Cellular Phone: (248) 420.8726   

Fax: (248) 593.9037

Email: edwardlichten@gmail.com

Dr. Lichten’s focus for forty years has been the treatment of autoimmune and chronic diseases with natural, bio-identical androgenic anabolic steroids derived from testosterone.

FOREWORD

The most important benefits to be realized by the future practice of medicine from living through CoVID-19 is more than the sheer logistics of providing health care for 50 million1 dying nor the technology to create a miRNA-based vaccination2 but, rather the awareness that ignorance of augmenting the host’s adaptive-to-innate immunity is responsible for half the loss3 of life and continuing morbidity post-infection. Our direction is to do what the CDC did not: believe that health comes from within the host’s natural immunity where there is an inherent ability to ‘heal itself.’  The creation of the first-in-the-world in-vitro laboratory allows the research and treating physician to look in at the building block of the immune system.  Survival depends every day on proper immune (humoral) adaptation to those external forces that would weaken and destroy.

The CoVID-19 pandemic is the war fought in the trenches of mankind’s immune system. This is not the “war” against CoVID-19: it is our body being in the cross-hairs of SARS-2/ ARDS Adult Respiratory Distress Syndrome and our own body’s autoimmune Cytokine Storm (CS) killing our normal cells deep within.

Our immune system cannot get into balance:

homeostasis.

Without being able to turn off the Cytokine Storm, death and morbidity follow.

NEED TO FIND THE CYTOKINE STORM “OFF-SWITCH.”

Because the components of the CoVID-19 viral infection are unique and unrelated to previous coronavirus infections, the older host’s slow-to-respond adaptive immunity is the predetermining factor affecting survival: turning off Cytokine Storm.  Unable to generate a robust response, the older host is ravaged by the disease: morbidity and mortality. This energy void occurs when the body cannot control the ravaging self-generated inflammation from its own proinflammatory cytokines.

.

“IN-VITRO” LAB SHOWS HOW TO SHUT DOWN CYTOKINE STORM

The laboratory shows which pro-inflammatory cytokine, macrophages, ICL2, CD4+/ CD8+ and Th2 systems are activated causing the autoimmune inflammation. This is Personal Medicine unique for the individual and Precision Medicine in determining the individual best choice of intervention. Interactive drug-therapy is determined in the test tube.  Potential benefits are determined by the drug-therapy that quantitatively reduces pro-inflammatory cytokines/ inflammation, without harming the host. by decreasing anti-inflammatory cytokines, and causing cytotoxicity and early immune cell death.

 

WITH DRUG THERAPY THAT BLOCKS INFLAMMATION of CYTOKINES

Many physicians, researchers and media focus on the low levels of bioavailable testosterone (Bio-T) in those who suffer CoVID-19 deaths.4-7 Low levels of bioavailable testosterone (Bio-T) and naturally occurring androgenic-anabolic steroid (AAS) are of critical importance but, nowhere has any CoVID-19 patient been treated. Why not?

EVERY SYSTEM INCLUDING IMMUNE SYSTEM DEPEND ON ENERGY BIO-T

That is the epiphany presented herein. Living is all about augmenting the host’s natural immune system.   Men and women need the energy supplied by androgenic-anabolic steroids (AAS) just like an automobile needs gasoline to power their ATP engines for all aspects of life including immune health.  Suppression of Bio-T shifts homeostatic Testosterone Dominance to a state of inflammation and Estrogen Dominance.  Inflammation is the basis of disease and the proinflammatory cytokine is the integral biomarker of inflammation. The in-vitro laboratory quantitates the host’s responses to drug-therapies:  pro-inflammatory, anti-inflammatory cytokines, and cytotoxicity. This is Precision Medicine determined in-vitro what drug-therapy(s) may be most specifically beneficial in-vivo.

PERSONAL MEDICINE: The goal of treatment is to find the best medical treatment to induce remission for the one individual. This is called Personal Medicine. The inflammation is autoimmune and systemic. This is best achieved when both the innate response of vaccination and the adaptive, humoral response promoted by androgenic-anabolic steroids are needed to completely treat the affliction.  The proinflammatory cytokines of the T-lymphocytes are the basic building blocks of inflammation. Every T-lymphocyte cell in the host’s body responds the same way. Remission of disease follows reduction of these proinflammatory cytokines by precise, drug-therapies in head-to-head comparison.  Failure to achieve homeostasis may result in unrestrained inflammation. In CoVID-19 this may be result in fatal Cytokine Storm (CS).

HYPOTHESIS:

The hypothesis in disease is clear:

  1. Loss of Bio-T. The stressed host is found to have Hypothalamic-Pituitary-Gonadal Axis (HPG) suppression. The serum/ hormonal biomarker of disease is Bio-T (bioavailable testosterone). It is testosterone unbound to sex hormone binding globulin (SHBG). Hotz in 1981 established this fact in Crohn’s Disease although Selye included similar general observations 20 years previously.
  2. Loss of Estrogen Receptor-beta homeostasis. The loss of homeostatic levels of Bio-T and Testosterone Dominance results in dysregulation of the Estrogen Receptor-beta (ERβ). ERβ is the nuclear membrane hormone receptor biomarker of disease.
  3. Release of proinflammatory cytokines. In most diseases Il-6 and Il-1 activate and propagate additional pro-inflammatory They activate and propagate additional pro-inflammatory cytokines.  Remission only occurs with reversal of this process of unconstrained inflammation. TABLE I. IN CoVID-19 CHAPTER ONE.

Life depends on reestablishment of homeostasis: the balance between the pro-inflammatory invader and anti-inflammatory cytokines of the immune competent host.

In viral infections of CoVID-19, the virus is ever-changing and mutating. The host must adapt and generate a new immune response. The innate immunity of the vaccine is already old-news to the virus. In Star Trek 400-years in the future they do not have a cure for the common cold, either.  Rather, CoVID-19 is today’s new “cold-plus” that encompasses the majority of “upper respiratory tract infections.1” (URI) While influenza H1N1 and H5N2 took 34,200 live in the 2018 – 2019 season, the U.S. deaths from CoVID-19 today exceed the 1918-1920 pandemic.   CoVID-19 is the worse pandemic and it is not under any control: it is getting worse, the delta variant is mutating, and attempts at vaccination have as of today failed to achieve herd immunity, even though 83.3% of the population show antibodies. [Jones JW, at.al. Estimated US Infection-and Vaccine- Induced SARS2-CoV-2 Seroprevalence. JAMA. 2021; 326:14): doi; 10.1001/jama/2021.15161].

In lieu of the absence of significant reporting of influenza deaths, the true direction of CoVID-19 from Columbia (1.B.621) will become apparent.  The case fatality ratio (CFR) approached 10% in the spring 2020; today, it is slightly over 1 percent in 2021. The annual U.S. CoVID-19 deaths in 2020 were 350,000 while the first half of 2021 saw the total CoVID-19 deaths increase by one-thirds to approximate 350,000 over the first 8-months. when the delta variant changed the total death trajectory.  Before CovID-19, there were 70,000 influenza deaths in 2017. CoVID-19 has become mankind’s new “influenza,” albeit more so based on saturating in-hospital bed space and all-overall at this time more fatal.

DISCUSSION:

The researcher, physician and health professionals acknowledge that the host’s adaptive-innate immunity is key to CoVID-19 survival.  The extreme measures of medical expertise with ECMO, (life support), intravenous corticosteroids and intravenous magnesium are now routine in the ICU. Unrecognized worldwide, there is a pressing need to refocus our medical efforts on augmenting the adaptive-innate immune response. The disappearing testosterone levels in CoVID-19 men’s ICU predict deaths4-7, yet the world is misdirected away from replacement. Why?

 

IN-VITRO LABORATORY: DIAGNOSING & TREATING UNKNOWN DISEASE

The in-vitro laboratory establishes a unique role in determining what drug-therapy is most appropriate for the PRECISE MEDICINE treatment of unexplained inflammation.

The only disease to treat is inflammation.

The only way to do this is to reduce the

quantity of proinflammatory cytokines.

 

HYPOTHESIS: THE  PRECISE STEPS – THE FUTURE EVALUATION PROTOCOL

  1. Bio-T augmentation: corrects the low serum hormone levels. Use the drug-therapies determine in the in-vitro laboratory.
  2. Estrogen Receptors: Immunology System is reset toward homeostasis.
  3. Proinflammatory Cytokines are reduced in remission: reduced inflammation moves host’s immune response toward homeostatic levels.
  4. Remission potentially achieved, i.e., recovery.

Testosterone Dominance is established as the normal state of homeostasis. Testosterone Dominance is the state of remission that occurs when drug-therapies reduce inflammation. Androgenic-anabolic steroids (AAS) do this by turning off proinflammatory cytokines and activate anti-inflammatory cytokines. This in-vitro laboratory offers a precise process of determining the correct drug-therapy. The goal of naturally improving the host’s immune system is so the body must “Heal Itself.”

ADVANCES IN MEDICAL THERAPY:

The ultimate and long-term benefit to the practice of medicine after the CoVID-19 pandemic is being able to quantitate and separate the building blocks of inflammation, proinflammatory cytokines.  Then, the in-vitro laboratory determines drug-therapies that are host specific and precise. Precision laboratory findings and treatment of inflammation provide the physician with scientific direction.  The lab determines which drug therapy reduces cytokine inflammation and which drug therapy(s) are effective.

CONCLUSION:

THE IN-VITRO LABORATORY ALLOWS for DETERMINATION OF DRUG-THERAPY TREATMENTS EVEN WITHOUT A PRESUME DIAGNOSIS or UNDERSTANDING OF IMMUNE DYSFUCTION.

Ultimately, in-vivo clinical response will determine if drug-therapy is effective. Decrease mortality and morbidity is expected: it should correlate with decrease quantification of host in-vitro and in-vivo proinflammatory cytokines and inflammation.

Establishing the Hypothesis as Theorem:

APPLYING HYPOTHESIS TO AUTOIMMUNE DISEASES.

Previous publications have documented remission in autoimmune diseases such as Crohn’s and Lupus Erythematosus when the hypothesis is applied. In CoVID-19 and inflammatory bowel disease, the plethora of identified proinflammatory cytokines is exactly the same 91 of 92 biomarkers, except CoVID-19 showed greater viral INF-gamma (INF-γ) levels. TABLE II-III. CoVID-19 CHAPTER ONE.

The Hypothesis states that all chronic autoimmune humoral responses in all individuals are potential similar if not the same. The body has only one disease: inflammation. The pro-inflammatory cytokine pathway is ubiquitous. We propose that the in-vitro cytokine and hormone receptor analysis be considered as a diagnostic test when the underlying disease process in unknown. The drug-therapies determined in-vitro may prove to be the drug-therapy to evaluate in-vivo.  Success in the difficult asthma case is proof of concept.

EPIPHANY:

Our facility may offer a unique directive in bringing a Precision Medicine direction to disease states of unknown causation and profound illness.

REFERENCE:

  1. CDC: https://www.cdc.gov/flu/about/burden/2018-2019.html
  2. JAMA: https://jamanetwork.com/journals/jama/fullarticle/2783644
  3. GoodRx: https://www.goodrx.com/blog/flu-vs-coronavirus-mortality-and-death-rates-by-year
  4. Schroeder M, Schaumburg B, Mueller Z, Parplys A, Jarczak D, Roedl K, Nierhaus A, Heer G, Grensemann J, Schneider B, Stoll F, Bai T, Jacobsen H, Zickler M, Stanelle-Bertram S, Klaetschke K, Renné T, Meinhardt A, Aberle J, Hiller J, Peine S, Kreienbrock L, Klingel K, Kluge S, Gabriel G. High estradiol and low testosterone levels are associated with critical illness in male but not in female COVID-19 patients: a retrospective cohort study. Emerg Microbes Infect. 2021 Aug 17:1-32. doi: 10.1080/22221751.2021.1969869. Epub ahead of print. PMID: 34402750.
  5. Çayan S, Uğuz M, Saylam B, Akbay E. Effect of serum total testosterone and its relationship with other laboratory parameters on the prognosis of coronavirus disease 2019 (COVID-19) in SARS-CoV-2 infected male patients: a cohort study. Aging Male. 2020 Dec;23(5):1493-1503. doi: 10.1080/13685538.2020.1807930. Epub 2020 Sep 3. PMID: 32883151.
  6. Salonia A, Pontillo M, Capogrosso P, Gregori S, Tassara M, Boeri L, Carenzi C, Abbate C, Cignoli D, Ferrara AM, Cazzaniga W, Rowe I, Ramirez GA, Tresoldi C, Mushtaq J, Locatelli M, Santoleri L, Castagna A, Zangrillo A, De Cobelli F, Tresoldi M, Landoni G, Rovere-Querini P, Ciceri F, Montorsi F. Severely low testosterone in males with COVID-19: A case-control study. Andrology. 2021 Jul;9(4):1043-1052. doi: 10.1111/andr.12993. Epub 2021 Mar 9. PMID: 33635589
  7. Straight J . For men, low testosterone means high risk of severe COVID-19. Washington University. May 21, 2021. https://medicine.wustl.edu/news/for-men-low-testosterone-means-high-risk-of-severe-covid-19/

ASTHMA

ABSTRACT:

Asthma is a long-term autoimmune systemic disease affecting 250 million people worldwide while causing 42,000 annual deaths in the U.S. Lung symptoms present with varying and reversible obstruction to airflow. Symptoms include bronchospasm, wheezing, and shortness of breath ranging from a few times per day to a few times per week.  Forced expiratory volume (FEV1) and spirometry of peak expiratory flow rate are the diagnostic tests.  Atophy refers to a type-1 hypersensitivity and over-reaction to environmental trigger.  Half of children will outgrow asthma in 10-years. The disease varies from intermittent to severely persistent and to the extremes of life-threatening.

Numbers of asthma patients have increased by 400 percent since 1960 with half being children. It is an epigenetic disease: (epi-) refers to an environmental trigger such as drug inhalant, chemicals, aspirin, etc. and genetics refer to those inherited factors that predispose 25 percent. Caesarian section deliveries increase the incidence for future asthma attacks as does remaining indoors.

There is no cure for asthma but, avoidance of triggers and addition of a number of naturally occurring vitamins and minerals including zinc, magnesium, glutathione, and ascorbic acid are often effective in preventing and minimizing symptoms. Schrader3 shows a 200-cubic centimeter increase in FEV1 in those with acute and chronic asthma on a protocol of intravenous ascorbic acid and magnesium. Intramuscular vitamin D3, glutathione (oral, parenteral and inhaled), and intravenous and inhaled ozone offer simple and statistically effective symptomatic treatments.

Acute bronchial inflammation is treated with corticosteroids by oral, inhalation and in emergency situations, intravenous. Long-term corticosteroids can be detrimental: Cushing’s syndrome, osteoporosis, central obesity, diabetes, kidney, and heart disease.  Preferred long-term drug-therapies for the symptoms of bronchoconstriction are beta-2 agonists (salmeterol). anticholinergics (ipratropium) and theophylline: Long-Acting Bronchial inhalers (LABA) are the most often prescribed asthma drug choice. Subsequent drug-therapies incorporate blockade of cysteinyl-leukotriene type 1 receptors. In summary, there are no benefits for most asthma sufferers in use of the biologics.4

Leukotriene type 1 receptors reduce eosinophil counts and block smooth muscle bronchospasm.  They have anti-inflammatory properties. [reserved for standard medication failures]

New Pharmaceutical Drug Therapy Targets Innate and Adaptive Immunity:

Since 1997, pharmaceutical research has shifted direction to blocking proinflammatory cytokines.  These drug-therapies are termed “biologics.” They may directly block the cytokine or inactivate it by being an antagonist to the cytokine receptor.

Although there is certainly an important component of adaptive immunity in these models there is also a much more pronounced innate immune cell influx in the airways.  In patients with severe asthma with no exacerbation, basophils and mast cells were found he most predominant producers of IL-4 and IL-13 in the airways, and not ILC2. Asthma research targets now the individual cytokine or receptor. There are now at least four immune pathways involved in asthma.  Multiple proinflammatory derangements of the immune system follow.

MAST CELLS: RERESENT A SEPARATE IMMUNE RESPONSIVE BRONCHIAL CHANNEL 

The innate immune response by epithelial cells promotes the release within minutes to hours of the cytokines IL-33, thymic stromal lymphopoietin (TSLP), IL-25, granulocyte-macrophage colony stimulating factor (GM-CSF), macrophage colony stimulating factor (M-CSF), transforming growth factor-β (TGF-β), and IL-1α.

  1. The unique immune component is the Mast cell It activates the pro-Inflammatory cytokine L-4 which branches out to activate the T-lymphocyte (IL-5), B-cell, various chemokines, etc.
  2. Eosinophil stabilizing drug therapies Macrolide antibiotics (azithromycin has recently been added by GINA for both eosinophilic and non-eosinophilic refractory asthma.
  3. Monoclonal antibodies directed against Il-5 or its receptor IL-5R (mepolizumab) is an expensive and borderline effective addition to the standard of asthma care.
  4. Th2-cell-associated cytokines: ICL2.

TABLE I lists the specific cytokine, the drug-therapy ingredient/ brand name, receptor, and drug effectiveness or ineffectiveness. Unfortunately, the Cochrane database reports these expensive drug therapies are not more effective than standard.4

METHOD/ RESULTS:

The method for collecting venous blood and transportation to the international in-vitro laboratory has been described herein.

Case Report: EB was a 48-year-old Caucasian male of Middle East decent. A non-smoker, his asthma was so severe that even with four medications, repeated allergy testing/ injections and daily corticosteroids he needed emergency relief inhalants almost daily. His allergist strongly urged EB to move to the southwestern states. His spirometry showed severe restriction even at rest and his FEV1 was 400cc.

Laboratory testing showed his total testosterone to be 146ng/dl; 25% of expected and his SHBG was 58nmol/l triple expected for his age. Bio-T was calculated to be 13%. His 17β estradiol 42 pg/ml and all inflammatory makers including C-Reactive Protein, fasting insulin, antinuclear antibody, platelets, and ferritin were slightly elevated. He showed some central obesity and metabolic syndrome. HgB A1c 6.4, i.e., prediabetes.

The Schrader protocol was begun 3-times per week. At 6-weeks his increased FEV1 was greater than 600 c/sec. He resumed playing tennis with an acute inhalant pre-game. 

Treatment was MAAS (mixed androgenic-anabolic steroids) with 200mg of testosterone, 40mg of nandrolone and 15mg of stanozolol intramuscularly weekly. His need for asthma medications, montelukast and salbuterol, were reduced. Testosterone 671 ng/dl, SHBG 25 nmol/l and his calculated Bio-T was 93%. For the next 5-years he played tennis and only a few times was unable to play due to asthma. He never moved out of state.

DISCUSSION:

Asthma is a much more complex syndrome with various pathophysiological mechanisms, or endotypes, driving various clinical presentation forms and requiring specific therapy.1 It is currently estimated that only about half of asthma patients have evidence of Type 2 immunity.  Standard therapy with these pharmaceutical biologic anti-monoclonal antibodies are not more effective than standard therapy reports the Cochrane Review.  Definitely, a new direction is in order.

With multiple immune pathways to inflammation, it is most difficult to judge the importance and contribution from each pathway: 1) Mast cell/ Th-2 IL-4 and IL-5, 2) HPG dysregulation: IL- m IL-6, IL-10 and 3) ILC2.

HYPOTHESIS TWO:

Hypothesis-2: Laboratory measurements of venous blood proinflammatory cytokine and hormonal receptors can be utilized to determine precise drug-therapies.  Blood in Phase I   constitutes initial analysis. Phage II follow when single FDA drug-therapy aliquots are admixed with T-lymphocytes. Quantitative changes in individual pro-inflammatory, anti-inflammatory cytokines, hormonal receptors, and evaluation for toxicity discern how to best reduce “inflammation” disease. Combination drug-therapies can be further analyzed to define a single ‘best’ drug-therapy for in-vivo use.

The difficult asthma patient with fully 50 percent in some instability of control, may provide beneficial drug-therapies.  Hypothesis-2 offers a combination in-vitro analysis to reverse inflammation. While androgen receptors play an active role in asthma, estrogen receptor play an active role in autoimmune diseases.  Much information will be gathered as these patients’ blood is analyzed in-vitro.

HYPOTHESIS: COMPONENTS

  1. Low Bio-Testosterone7 in asthma
  • Testosterone seems to suppress asthma, and dehydroepiandrosterone (DHEA), a less virilizing androgen, may be effective for treating asthma8
  • Low blood testosterone was found mainly in the patients with severe (37.76%) and moderate (40.00%) form of the disease9
  • Heller and her team demonstrated that the primary female sex hormone, estrogen, was a potent activator of a key cell type in the lungs and processes known to drive lung inflammation.10
  1. Estrogen Receptor-beta: no contributing data in the asthma literature 9
  2. Proinflammatory cytokines (IL-17, IL-6, IL-18 and IL-12) and Th cytokines (IFN-γ, IL-4, IL-10 and IL-13) in patients with allergic asthma. I-1, IL-2, IL-4.12

 

 

IN-VITRO CYTOKINE LABORATORY

The in-vitro laboratory offers for the first time to he ability to measure the number of pro-inflammatory, anti-inflammatory cytokines and hormone receptors. Phase I. In Phase II, FDA approved drug-therapies and other products are admixed with T-lymphocyte and incubated for 72 hours.   The drug-therapy can have no effect, reduce the number of pro-inflammatory cytokines, or increasing them. The focus is on reducing inflammation which only occurs when there is reduction in the pro-inflammatory cytokine count.  This head-to-head comparison identifies the ‘best’ drug-therapy for in-vivo treatment.  The in-vitro cytokine laboratory can determine treatment protocols without knowledge of the disease, the cause, previously failed drug-therapies, propped therapies, and degree of inflammation.  Inflammation is measured as the quantitation of pro-inflammatory cytokines—and nothing else.

CONCLUSION:

Asthma is another autoimmune disease that is predilected by HPG suppression. These standard serum laboratory testing are readily available and replacement of testosterone with either weekly injections or 3-month testosterone implants are effective. Topical testosterone is aromatized to 17β estradiol which negates the shift back toward Testosterone Dominance.  Stanozolol lowers SHBG by 70%, quadrupling unbound testosterone. Nandrolone, the most anti-inflammatory substance in the body, displaces testosterone but, also add benefits to the quality of life.

Addressing asthma’s hormonal-autoimmune causation first, inflammation is reduced and symptoms may be mitigated.  The in-vitro research shows the nuclear membrane estrogen receptor-beta to be the intermediary that needs to remain homeostatic and supported by the host’s AAS to prevent loss of signaling to IL-6, Il-1 and other pro-inflammatory cytokines. Loss of signaling initiates the release and propagation of pre-inflammatory cytokines: inflammation.4

 

 

This does not preclude use of Androgenic-Anabolic Steroid concurrent with man-made pharmaceutical drugs — Why not try?

REFERENCES:

  1. Lambrecht BN, Hammad H, Fahy JV. The Cytokines of Asthma. Immunity. 2019 Apr 16;50(4):975-991. doi: 10.1016/j.immuni.2019.03.018. PMID: 30995510.
  2. Menzella F, Lusuardi M, Galeone C, Taddei S, Facciolongo N, Zucchi L. Mepolizumab for severe refractory eosinophilic asthma: evidence to date and clinical potential. Ther Adv Chronic Dis. 2016 Nov;7(6):260-277. doi: 10.1177/2040622316659863. PMID: 27803792; PMCID: PMC5076744.
  3. Shrader, W.A. Short and long-term treatment of asthma with intravenous nutrients.Nutr J 3, 6 (2004). https://doi.org/10.1186/1475-2891-3-6
  4. Agache I, Beltran J, Akdis C, Akdis M, Canelo-Aybar C, Canonica GW, Casale T, Chivato T, Corren J, Del Giacco S, Eiwegger T, Firinu D, Gern JE, Hamelmann E, Hanania N, Mäkelä M, Hernández-Martín I, Nair P, O’Mahony L, Papadopoulos NG, Papi A, Park HS, Pérez de Llano L, Posso M, Rocha C, Quirce S, Sastre J, Shamji M, Song Y, Steiner C, Schwarze J, Alonso-Coello P, Palomares O, Jutel M. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab, mepolizumab, omalizumab and reslizumab) for severe eosinophilic asthma. A systematic review for the EAACI Guidelines – recommendations on the use of biologicals in severe asthma. Allergy. 2020 May;75(5):1023-1042. doi: 10.1111/all.14221. PMID: 32034960.
  5. Humbert M, Taillé C, Mala L, Le Gros V, Just J, Molimard M; STELLAIR investigators. Omalizumab effectiveness in patients with severe allergic asthma according to blood eosinophil count: the STELLAIR study. Eur Respir J. 2018 May 10;51(5):1702523. doi: 10.1183/13993003.02523-2017. PMID: 29545284.
  6. Farne HA, Wilson A, Powell C, et.al. Anti-IL5 therapies for asthma. Cochrane Database Syst Rev. 2017 Sep 21;9(9):CD010834. doi: 10.1002/14651858. CD010834.pub3. PMID: 28933516; PMCID: PMC6483800.
  7. Canguven O, Albayrak S. Do low testosterone levels contribute to the pathogenesis of asthma? Med Hypotheses. 2011 Apr;76(4):585-8. doi: 10.1016/j.mehy.2011.01.006.. PMID: 21282014.
  8. Choi IS. Gender-specific asthma treatment. Allergy Asthma Immunol Res. 2011 Apr;3(2):74-80. doi: 10.4168/aair.2011.3.2.74. PMID: 21461245.
  9. Mileva Zh, Maleeva A. Serumno testosteronovo nivo pri bolni ot bronkhialna astma, lekuvani i nelekuvani s kortikosteroidi [The serum testosterone level of patients with bronchial asthma treated with corticosteroids and untreated]. Vutr Boles. 1988;27(4):29-32. Bulgarian. PMID: 3213021.
  10. https://www.hopkinsmedicine.org/news/newsroom/news-releases/male-sex-hormones-have-a-role-in-asthma
  11. Pierdominici M, Maselli A, Varano B, Barbati C, Cesaro P, Spada C, Zullo A, Lorenzetti R, Rosati M, Rainaldi G, Limiti MR, Guidi L, Conti L, Gessani S. Linking estrogen receptor β expression with inflammatory bowel disease activity. 2015 Dec 1;6(38):40443-51. doi: 10.18632/oncotarget.6217. PMID: 26497217; PMCID: PMC4747344
  12. https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln_archive.pdf. National Asthma and Prevention Program.

ASTHMA TABLE I

Cytokine

Drug-therapy Name

Action=direct or receptor

FDA YEAR

USEFUL

Il-4

Dupilumab/ 

inhibits IL-4 & IL-13

2017

Suppress type-2

IL-13

Duplixent® mono-clonal antibody

signaling

inflammation

Il-5

Omalizumab /Xolair®

Mast cells stabilizers.   Antagonist IL-5

2003

>40% reduce eosinophils5,6

IL-5R

Reslizumab/ Ciqair® monoclonal antibody

IL-5 receptor antagonist

2016

IL-5R

Mepolizumab/ Nucala®

“mepolizumab did not

2015

anti-interleukin IgE antibody

 inhibit airway bronchoconstrictor of aerosolized allergens”

IL-5R

Benralizumab/ anti-interleukin IgE antibody

IL-5 receptor antagonist

2017

Il-1

Il-6

The effect of inhaled beclomethasone dipropionate

Anti-inflammatory corticosteroid

The cytokine production by Th17 cells is notoriously resistant to inhibition by steroids,

IL-9,

IL-13

tralokinumab are antibodies targeting IL-13

IL-4Ra

Dupilumab: human cytotoxic monoclonal antibodies

Il-7R

Tezepelumab/ AMG-1

Il-17

Il-33ST-2

  • “None reach the minimal important difference4

Schrader Protocol

Welman A Shrader Jr .  Short and long-term treatment of asthma with intravenous nutrients. Nutrition Journal volume 3: 6 (2004)

Abstract

Background

Asthma is an increasing problem in this country and others. Although medications for the treatment of asthma abound and are improving, there are inherent risks and side effects with all of them. Intravenous magnesium has been employed in the treatment of acute asthma, but its use has not become universal, nor has it been studied for the treatment of chronic asthma. It is known to be a safe drug with minimal side effects. In this study, the author investigates the use of magnesium and other nutrients in the treatment of both acute and chronic asthma.

Methods

In this non-blinded outcome study, following informed consent, forty-three (43) randomly selected volunteer patients with both acute and chronic asthma were treated with IV infusions described herein. All patients were observed with spirometry 10 minutes post-infusion; two sub-groups of patients were also observed after multiple infusions over a short period of time (less than one month) and a longer period of time (average 5.8 months). Pulmonary function was analyzed by spirometric testing with pre- and post-infusion spirometric measurements with the pre/post group. For longer term (Trend) patients, baseline spirometry measurements were compared to spirometry measurements after patients had received multiple infusions over a period of time. Eight (8) patients were measured for both pre/post and Trend data.

Results

The 38 pre-infusion/post-infusion patients with acute and chronic asthma demonstrated an overall average improvement (percentage improvement in percent predicted) of 45%. The 13 patients measured for improvement over time (Trend data, average duration 5.82 months), demonstrated an overall average improvement (percentage improvement in percent predicted) of 57%. Of the 13 patients in the multiple infusion group, 9 patients who received longer-term therapy (average duration of 12.58 months) for chronic asthma demonstrated an overall average improvement of 95% (percentage improvement in percent predicted).

Conclusion

The use of intravenous treatment with multiple nutrients, including magnesium, for acute and chronic asthma may be of considerable benefit. Pulmonary function improved progressively the longer patients received treatment.

Background

Asthma has been a major focus for physicians in recent years because both the incidence and the mortality appear to be increasing, especially within certain ethnic or geopolitical groups [13]. This increase has been blamed variously on different types of inhalers used for asthma, [4] chemical environmental pollution, mostly of the air, [5] increased reporting incidences and many other factors. No matter what the cause, the incidence of asthma has appeared to increase and to worsen over the years, even if it may appear to be more stable recently [67].

In addition, asthma has become increasingly more difficult to treat. Several studies indicate the mortality of asthma is higher and that the incidence of status asthmaticus patients seen in emergency rooms has increased [8]. Despite many newer drugs for asthma, people are dying more frequently from this illness.

In view of these rather grim realizations and statistics, the author has undertaken research of a modality in an attempt to mitigate the effects of asthma. A most promising treatment appears to be intravenous therapy with magnesium and other nutrients, both for the acute and chronic illness.

The use of IV parenteral nutrient therapy for asthma was begun in the author’s office in the late 1980’s, soon after the first papers appeared in the literature involving the use of IV magnesium for the treatment of acute asthma [9]. Many papers have followed since then, but they have concentrated primarily on intravenous magnesium, usually in the sulfated form [1035]. Most of these authors have found that magnesium sulfate, via IV infusion, is beneficial for the treatment of asthma, and often extremely so. However, not all study results have been positive. This may have been due to the way the infusions were administered, the dose employed, or other factors such as severity of disease.

The author’s IV protocols were expanded based on studies of the theoretical and known effects of various other nutrients on both acute and chronic asthma, as a result of previous work with general parenteral nutrients. Dr. Jonathan Wright’s work with molybdenum [36] for the treatment of chronic asthma, as well as his and others’ work with vitamin B-12, [3738] further influenced this study. Based on the early studies with magnesium and the work with molybdenum and B-12, the author undertook to employ other added nutrients to test the combined clinical efficacy.

The Trend group was further divided into “Short Term” and “Long Term” groups. The Short Term group consisted of those patients who had “trend” data measured for one month or less, while those in the Long Term group were treated for up to 19 months. There were 4 patients in the Short Term group, 3 females and 1 male, average age 62, with an average duration of therapy of 0.43 mos. and 3.25 infusions per patient. There were 9 patients in the Long Term group, 6 females and 3 males, average age 53, with an average duration of therapy 12.58 mos. and 9.25 infusions per patient.

The average length of treatment periods for combined Trend patients was 5.82 months, with the shortest being 0.2 months. Intravenous therapy were given anywhere from twice weekly to once every few months, with an average of 6.77 IV’s per patient, or 1.16 IV’s per patient per month.

Parameters monitored in all patients were Total Forced Vital Capacity (FVC), Forced Expiratory Flow in 1 second (FVC 1.0), Peak Expiratory Flow (PEF), Forced Expiratory Flow through 25% to 75% of exhalation (FEF 25–75%) and Forced Expiratory Flow through 75% to 85% of exhalation (FEF 75–85%).

Preservative-free nutrients were used without exception, and there were no serious systemic and no local reactions at any time during therapy. Early in the study some patients experienced lightheadedness, nausea or near fainting with rapid IV infusions. This was secondary to magnesium-induced hypotension, and this problem was recognized early in the study and avoided.

Results

Results were measured as percentage improvement of the percentage predicted on the Knudsen scale. For example, if the result of a parameter of the pre-infusion pulmonary function test was calculated as 50% of predicted normal, and IV treatment resulted in a value of 75% of predicted normal for that same parameter, the percentage improvement for that particular parameter would be entered as 50%.

The 38 pre-infusion/post-infusion patients demonstrated an average improvement of 28% in FVC, 44% in FEV 1, 44% in PEF, 54% in FEF 25–75 and 38% in FEF 75–85, with an overall average improvement of 45% (Tables 2,3).

Of the 13 patient multiple infusion group, 4 patients who received Short Term therapy (infusions for an average duration of a month or less) for chronic asthma demonstrated an average improvement of 40% in FVC, 43% in FEV 1, 45% in PEF, 36% in FEF 25–75 and 6% in FEF 75–85, with an overall average improvement of 34% (Table 6). Nine (9) patients who received Long Term therapy (infusions for an average duration of 12.58 months) for chronic asthma demonstrated an average improvement of 59% in FVC, 87% in FEV 1, 88% in PEF, 128% in FEF 25–75 and 113% in FEF 75–85, with an overall average improvement of 95%

Discussion

Although there were no age-matched control patients in this outcome study, and certainly uncontrolled variables, considerable improvement was observed after parenteral infusion therapy with multiple nutrients, both for pre/post treatment and treatment over time. There was more pronounced improvement after longer-term treatment. Patients who received treatment for longer than a month fared considerably better than those who stopped therapy within a month or less.

Patients experienced rapid clinical relief during – or at some time after – most infusions, depending on their degree of distress, and as the data demonstrates, pulmonary function improved overall during the sequential infusion study. It would also appear that the effectiveness of this type of therapy might be cumulative, as patients appeared to require treatment less often as time passed. Drug usage was decreased in all patients, and discontinued or reduced to intermittent use in over half of the patients studied.

The primary reason mixed nutrients were employed in this study is that prior to this study the author had observed that the effect of a combination of nutrients was consistently more beneficial than the infusion of IV magnesium sulfate alone. Patients given magnesium (sulfate) alone also seemed to develop a more rapidly increasing tolerance for (or resistance to) magnesium, and pulmonary function did not improve nearly as significantly as were those of patients who were given the complete protocols. Therefore, infusions of magnesium sulfate alone, without other nutrients added, was not employed in this study.

It has been demonstrated previously that intravenous infusions with magnesium sulfate appear to be more effective that nebulized albuterol alone [26], and it has also been demonstrated that intravenous magnesium may be successful when all other more “traditional” interventions, including corticosteroids, have failed [28]. Considering this, the results of this study came as no surprise to the author.

There are numerous metabolic and biochemical explanations as to why each of the specific nutrients added might indeed provide more benefit for asthmatics than magnesium sulfate alone. For example, Vitamin C is known to have a general antihistaminic effect [39], it decreases bronchial responsiveness overall [40] and bronchial responsiveness to histamine in patients with allergic rhinitis [41]. Vitamin C is also a potent free radical scavenger, and free radicals are known to play a role in the cause of airway obstruction attendant with asthma [42].

Trace minerals also mitigate the inflammatory response [43], perhaps because they play a major role in the anti-oxidation of free radicals [44]. Further, manganese has been found deficient in bronchial biopsies of asthmatic patients, indication manganese replenishment could aid in the treatment of asthma. [45].

Lastly, zinc is an essential trace mineral for most immune mechanisms in the body to function, including lymphocyte (T-cell) function [46].

This reasoning could partly explain why the patients in this study who received longer-term therapy with infusions fared best. Molybdenum, as Wright’s study demonstrated [36], may be a significant part of the long-term benefit. Indeed, those patients who received an average of less than one infusion monthly for over a year fared almost three times as well as those who received infusions for a month or less.

Over the period of this study, the author observed that 6 of 44 asthmatic patients appeared to fail with this particular type of infusion therapy. These 6 patients, however, were judged as failures prior to any patient having received three IV treatments. Since this study was undertaken, the author has found that it sometimes takes 3 to 5 infusions for patients to observe a substantial clinical benefit. Therefore, actual failure may be in question.

Shortly after this study was first begun, it became clear that patients who received weekly or more frequent therapy with these parenteral nutrients for a period of 1 1/2 to 3 months improved more rapidly and distinctly than patients who received only occasional infusions. It also became evident that this group of patients was able to extend the interval between treatments to 8–14 days and then longer. Several patients were able to extend their intervals out as far as 4–6 months with little apparent loss of efficacy.

This led the author to reach the preliminary conclusion that there may be some type of “loading” period, or dose accumulation, of one or more of these nutrients employed here. Dr. Wright, working with intravenous molybdenum for asthma, discovered this same phenomenon [36].

It was also often observed that patients with acute asthma sometimes did not improve immediately, or even appeared to worsen immediately after an infusion. This is very likely secondary to the acute bronchodilatation resulting from this treatment, with resultant mucous production (release) and coughing. Studies have shown that optimal pulmonary function is likely to occur considerably later than 10 minutes after an infusion of magnesium, even out to perhaps 80–110 minutes [10]. The author’s experience supports this observation and it is likely that the post-infusion measurements in this study were usually taken before the maximum benefit occurred.

As a more important note, the author observed that the Infusion protocol, when given as the initial treatment, whether for a patient with acute or chronic asthma, could cause considerable worsening of symptoms several hours after the infusion. Early in the study, three patients who were given the Infusion as their first treatment experienced increased respiratory distress later in the day, two of which required emergency treatment. The author postulates that the infusion administration of either the molybdenum or the trace minerals (containing molybdenum) prior to “priming” a patient with at least one IV that does not contain minerals can cause an adverse reaction. Although the mechanism of this reaction is not yet clear, the author speculates this response may be secondary to an acute sulfite detoxification response to molybdenum.

Considering this, the author advises that neither trace minerals nor molybdenum be included in any rapidly infused IV or in any IV to be administered for acute asthma.

The author would conclude that parenteral infusion therapy with the nutrients used in this study might have considerable benefit. Infusions of these particular parental nutrients very often made the difference for patients who otherwise were responding poorly to other modalities of treatment.

As a result of this study, the author is of the opinion that this type of therapy adds a dimension to the treatment of chronic asthma not attainable with conventional therapy using bronchodilators and corticosteroids, especially in the acute situation.

In a time when multiple factors appear to be coalescing to increase both the incidence and morbidity of asthma around the world, it would seem that any therapy that adds a measure of exclusion from these statistics should be considered whenever possible.

References

  1. 1.Sly RM, O’Donnell R: Stabilization of asthma mortality. Comment in Ann Allergy Asthma Immunol. 1997, 78 (4): 347-54. Ann. Aller. Asthma & Immunol. 1997;78 (4): 347-54.
  2. 2.Lang DM: Trends in US asthma mortality: good news and bad news. Comment on: Ann Allergy Asthma Immunol. 1997, 78 (4): 333-7. Ann. Aller. Asthma Immunol. 1997;78(4): 333-7.
  3. 3.Lieberman JS, Kane GC: Asthma mortality: the worldwide response. J R Soc Med. 1997, 90 (5): 265-7.
  4. 4.Beasley R, Nishima S, Pearce N, Crane J: Beta-agonist therapy and asthma mortality in Japan [letter]. Lancet. 1998, 351 (9113): 1406-7.
  5. 5.Keistinen T, Saynajakangas O, Tuuponen T, Kivela S, Ostro B, Chestnut L: Assessing the health benefits of reducing particulate matter air pollution in the United States. Environ Research. 1998, 76 (2): 94-106. 10.1006/enrs.1997.3799.
  6. 6.Ertle A, London M: Insights into asthma prevalence in Oregon. J Asthma. 1998, 35 (3): 281-9.
  7. 7.Mannino DM, Homa DM, Pertowski CA, Ashizawa A, Nixon LL, Johnson CA, Ball LB, Jack E, Kang DS: Surveillance for asthma – United States 1960–1995. MMWR CDC Surveill Summ. 1998, 47 (1): 1-27.
  8. 8.Nakazawsa T, Kawakami Y, Sudo M, Kobayashi S, Suetsugu S, Nakajima S, Yamakido M, Nagano H: [Trends of asthma death among adults in Japan 1992–1994. Analysis of 313 cases reported questionnaires sent to hospitals with more than 100 beds]. Arerugi – Jap J Allergology. 1998, 47 (1): 41-7.
  9. 9.Okayama H, Aikawa T, Okayama M, Sasaki H, Mue S, Takishima T: Bronchodilating effect of intravenous magnesium sulfate in bronchial asthma. JAMA. 1987, 257 (8): 1076-78. 10.1001/jama.257.8.1076.
  10. 10.Rolla G, Bucca C, Caria E, Arossa W, Bugiani M, Cesano L, Caropreso A: Acute effect of intravenous magnesium sulfate on airway obstruction of asthmatic patients. Ann Allerg. 1988, 61 (5): 388-91.
  11. 11.McNamara R, Spivey W, Skobeloff E, Jacubowitz S: Intravenous magnesium sulfate in the management of acute respiratory failure complicating asthma. Ann Emerg Med. 1989, 18 (2): 197-9.
  12. 12.Bone R, Burch S: Management of status asthmaticus. Ann Allerg. 1991, 67 (5): 461-9.
  13. 13.Noppen M, Vanmaele L, Impens N, Schandevyl W: Bronchodilating effect of intravenous magnesium sulfate in acute severe bronchial asthma. Chest. 1990, 97 (2): 373-6.
  14. 14.Kuitert L, Kletchko S: Intravenous magnesium sulfate in acute, life-threatening asthma. Ann Emerg Med. 1991, 20 (11): 1243-5. [published erratum appears in Ann. Emerg. Med. 1992 Oct, 21(10): 1272].
  15. 15.Green SM, Rothrock SG: Intravenous magnesium for acute asthma: failure to decrease emergency treatment duration or need for hospitalization [see comments]. Ann Emerg Med. 1992, 260-5.
  16. 16.Tiffany B, Berk W, Todd I, White S: Magnesium bolus or infusion fails to improve expiratory flow in acute asthma exacerbations. Chest. 1993, 104 (3): 831-4.
  17. 17.Rolla G, Bucca C, Brussino L, Colagrande P: Effect of intravenous magnesium infusion on salbutamol-induced bronchodilatation in patients with asthma. Magnesium Research. 1994, 7 (2): 129-33.
  18. 18.Lemesle FG: High-dose intravenous magnesium sulfate in the management of life-threatening status asthmaticus. Intensive Care Med. 1995, 21 (1): 94-5.
  19. 19.Sydow M, Crozier T, Zielmann S, Radke J, Burchardi H: High-dose intravenous magnesium sulfate in the management of life-threatening status asthmaticus. Intensive Care Med. 1993, 19 (8): 467-71.
  20. 20.Schiermeyer R, Finkelstein J: Rapid infusion of magnesium sulfate obviates need for intubation in status asthmaticus. Amer J Emer Med. 1994, 12 (2): 164-6. 10.1016/0735-6757(94)90238-0.
  21. 21.Bloch H, Silverman R, Mancherje N, Grant S, Jagminas L, Scharf S: Intravenous magnesium sulfate as an adjunct in the treatment of acute asthma [see comments]. Chest. 1995, 07 (6): 1576-8. Chest 1995;07(6):1576-81.
  22. 22.Keen J: Intravenous magnesium sulfate for acute asthma. J Emerg Nurs. 1995, 21 (1): 44-6.
  23. 23.Hill J, Britton J: Effect of intravenous magnesium sulpfate on airway calibre and airway reactivity to histamine in asthmatic subjects. Br J Clin Pharmacol. 1996, 42 (5): 629-31.
  24. 24.Downey P, Cox R: Update on the management of status asthmaticus. Curr Opin Pediatr. 1996, 8 (3): 226-33.
  25. 25.Ciarallo L, Sauer A, Shannon M: Intravenous magnesium therapy for moderate to severe pediatric asthma: results of a randomized, placebo-controlled trial [see comments]. J Ped. 1996, 129 (6): 809-14. J. Ped. 1996;129(6): 809-14.
  26. 26.Devi PR, Kumar L, Singhi S, Prasad R, Singh M: Intravenous magnesiumsulfate in acute severe asthma not responding to conventional therapy. Indian Pediatr. 1997, 34 (5): 389-97.
  27. 27.Frakes MA, Richardson LE: 2nd. Magnesium sulfate therapy in certain emergency conditions. Am J of Emerg Med. 1997, 15 (2): 182-7.
  28. 28.Mills R, Leadbeater M, Ravalia A: Intravenous magnesium sulphate in the management of refractory bronchospasm in a ventilated asthmatic. Anaesthesia. 1997, 52 (8): 782-5. 10.1111/j.1365-2044.1997.176-az0312.x.
  29. 29.Gurkan F, Haspolat K, Bosnak M, Dikici B, Derman O, Ece A: Intravenous magnesium sulphate in the management of moderate to severe acute asthmatic children non-responding to conventional therapy. Eur J Emerg Med. 1999, 6 (3): 201-5.
  30. 30.Swain R, Kaplan-Machlis B: Magnesium for the next millennium. South Med J. 1999, 92 (11): 1040-7.
  31. 31.Alter H, Koepsell T, Hilty WM: Intravenous magnesium as an adjuvant in acute bronchospasm: a meta-analysis. Ann Emerg Med. 2000, 36 (3): 191-7. 10.1067/mem.2000.109170. Comment in: Ann Emerg Med. 2000;36(3):234-6.
  32. 32.Ciarallo L, Brousseau D, Reinert S: Higher-dose intravenous magnesium therapy for children with moderate to severe acute asthma. Arch Pediatr Adolesc Med. 2000, 154 (10): 979-83.
  33. 33.Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA: Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. Cochrane Database Syst Rev. 2000, CD001490-2
  34. 34.Schenk P, Vonbank K, Schnack B, Haber P, Lehr S, Smetana R: Intravenous magnesium sulfate for bronchial hyperreactivity: a randomized, controlled, double-blind study. Clin Pharmacol Ther. 2001, 69 (5): 365-71. 10.1067/mcp.2001.114926.
  35. 35.Silverman RA, Osborn H, Runge J, Gallagher EJ, Chiang W, Feldman J, Gaeta T, Freeman K, Levin B, Mancherje N, Scharf S: IV magnesium sulfate in the treatment of acute severe asthma: a multicenter randomized controlled trial. Chest. 2002, 122 (2): 489-97. 10.1378/chest.122.2.489. Erratum in: Chest 2002;122(5):1870. Comment in: Chest. 2002;122(2):396-8
  36. 36.Wright J., Littleton K: Defects in sulfur metabolism. Internatl Clin Nut Rev. 1989, 9 (3): 118-19
  37. 37.Wright J: Vitamin B-12: Powerful protection against childhood asthma. Internatl Clin Nutr Rev. 1989, 9 (4): 185-8
  38. 38.Anibarro B: Asthma with sulfite intolerance in children: a blocking study with cyanocobalamin. J Allerg Clin Immunol. 1992, 90: 103-9
  39. 39.Johnston C: Antihistamine effect of supplemental ascorbic acid in neutrophil chemotaxis. J Am Coll Nutr. 1992, 11 (2): 172-6.
  40. 40.Bucca C: Effect of Vitamin C on transient increase of bronchial responsiveness in conditions affecting the upper respiratory airways. Beyond Deficiency: New Views on the Function and Health Effects of Vitamins, New York Academy of Sciences. 1992, 9-12. Abstract 16
  41. 41.Bucca C: Effect of vitamin C on histamine bronchial responsiveness of patients with allergic rhinitis. Ann Allergy. 1990, 65: 311-14
  42. 42.Kanazawa H: The role of free radicals in airway obstruction in asthmatic patients. Chest. 1991, 100: 1319-22.
  43. 43.McClain C: Minerals and inflammatory response. J Am Coll Nutr. 1992, 11 (5): 598 Abstract 4-
  44. 44.Zidenberg-Cherr S: Essential trace elements in antioxidant processes. Trace Elements, Micronutrients and Free Radicals. 1992, 107-27.
  45. 45.Campbell M: Low levels of manganese in bronchial biopsies from asthmatic subjects. J Aller Clin Immunol. 1992, 89 (1, Part II): 332-749
  46. 46.Prasad A: Zinc and lymphocyte immune function. J Am Coll Nutr. 1992, 11 (5): 567 Abstract 3-

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