the etiologies, pathophysiology, and alternative ......underlying pathophysiology of asthma is...

Alternative Medicine Review ◆ Volume 6, Number 1 ◆ 2001

IntroductionAsthma is a chronic inflammatory disorder of the respiratory airways, characterized by

increased mucus production and airway hyper-responsiveness resulting in decreased air flow,and marked by recurrent episodes of wheezing, coughing, and shortness of breath. It is a multi-factorial disease process associated with genetic, allergic, environmental, infectious, emotional,and nutritional components. Because of their symptomatology the majority of individuals withasthma experience a significant number of missed work or school days. This can create a severe

The Etiologies, Pathophysiology, andAlternative/Complementary Treatment of

AsthmaAlan L. Miller, ND

AbstractA chronic inflammatory disorder of the respiratory airways, asthma is characterized bybronchial airway inflammation resulting in increased mucus production and airway hyper-responsiveness. The resultant symptomatology includes episodes of wheezing,coughing, and shortness of breath. Asthma is a multifactorial disease process withgenetic, allergic, environmental, infectious, emotional, and nutritional components. Theunderlying pathophysiology of asthma is airway inflammation. The underlying processdriving and maintaining the asthmatic inflammatory process appears to be an abnormalor inadequately regulated CD4+ T-cell immune response. The T-helper 2 (Th2) subsetproduces cytokines including interleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13, whichstimulate the growth, differentiation, and recruitment of mast cells, basophils, eosinophils,and B-cells, all of which are involved in humoral immunity, inflammation, and the allergicresponse. In asthma, this arm of the immune response is overactive, while Th1 activity,generally corresponding more to cell-mediated immunity, is dampened. It is not yetknown why asthmatics have this out-of-balance immune activity, but genetics, viruses,fungi, heavy metals, nutrition, and pollution all can be contributors. A plant lipidpreparation containing sterols and sterolins has been shown to dampen Th2 activity.Antioxidant nutrients, especially vitamins C and E, selenium, and zinc appear to benecessary in asthma treatment. Vitamins B6 and B12 also may be helpful. Omega-3fatty acids from fish, the flavonoid quercetin, and botanicals Tylophora asthmatica,Boswellia serrata, and Petasites hybridus address the inflammatory component. Physicalmodalities, including yoga, massage, biofeedback, acupuncture, and chiropractic canalso be of help.Altern Med Rev 2001;6(1):20-47.

Alan L. Miller, ND – Technical Advisor, Thorne Research, Inc; Senior Editor, Alternative Medicine Review.Correspondence address: PO Box 25, Dover, ID 83825. E-mail: [email protected]

Copyright©2001 Thorne Research, Inc. All Rights Reserved. No Reprints Without Written Permission

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Alternative Medicine Review ◆ Volume 6, Number 1 ◆ 2001 1

disruption in quality of life, often leading todepressive episodes. It also disrupts the livesof caregivers and family members of the af-fected individual. Asthma patients who haveincreased symptomatology at night (a signifi-cant portion) also tend to have disturbed sleeppatterns and impaired daytime attention, con-centration, and memory.1

In 1998 it was estimated that asthmaaffected 17.3 million individuals in the UnitedStates and 150 million worldwide. From 1980-1995 the incidence of asthma in children un-der age 18 increased five percent per year, re-sulting in an increase of more than 100 per-cent in that time period, according to the Na-tional Health Interview Survey (NHIS), themechanism the U.S. government uses to gatherdata regarding asthma prevalence and mortal-ity. The current overall prevalence in childrenis estimated at 6.0-7.5 percent, with a total ofover five million children affected. Asthma isthe fourth-leading cause of disability in chil-dren, and one of the most common reasonsfor school absenteeism. The prevalence inadults is approximately five percent. Asthmaprevalence among African-Americans is con-siderably higher than Caucasians or Hispan-ics, with black children having a 26-percentgreater incidence than white children in 1995-1996.

Approximately 5,000 people die eachyear due to asthma. Across racial and socio-economic groups, the death rate from asthmamirrors the incidence, with African-Americanshaving the highest mortality from this disease.The death rates for asthma are higher in theinner city and in lower socioeconomic groups.The exact cause of these differences might bedue to genetic, socioeconomic, and/or accessto health care issues. Direct costs (doctors’visits, hospitalization, drugs, etc.) and indirectcosts (work and school absenteeism, etc.) ofasthma vary, depending on the reference, butare estimated to be approximately $6 billionper year.

Why the ever-increasing incidence ofasthma in the last three decades? Some blamenew home construction in the 1970s, whenhigher fuel costs prompted the construction ofmore airtight homes. Newer houses are moreinsulated and have less air exchange than olderhomes. Wall-to-wall carpet is much more com-mon, as is central heating. Synthetic buildingmaterials laden with chemicals also enjoygreater utilization by builders. These “im-provements” in construction make for a moreclosed micro-environment that has insufficientfresh air and is more conducive to the growthof microorganisms.

Other researchers point the finger atenvironmental pollutants. Industrialization ofcountries and the use of fossil fuels have par-alleled the incidence of respiratory disease.There is good evidence that the increases inozone, nitrogen dioxide, sulfur dioxide, andparticulates in the atmosphere have exacer-bated allergic diseases, including asthma, dueto irritant effects of these substances causingchronic inflammation, as well as interactionswith allergens and amplification of allergicreactions.2,3

Changes in diet – including an in-creased intake of omega-6 fatty acids and adecreased intake of nutrients such as magne-sium – and altered intestinal microflora are alsohypothesized as contributors to the increasedincidence of asthma.2,4,5

There is also the possibility that thepractice of vaccinating children has contrib-uted to this increase in asthma incidence, al-though presently this theory has not been stud-ied thoroughly. Investigators in New Zealand,which has one of the highest rates of asthmain the world, found that 23 children who hadnot been immunized with the diptheria/teta-nus/pertussis (DPT) and polio vaccines had noepisodes of, or physician consultations for,asthma, whereas a group of immunized chil-dren had a 23-percent incidence of asthma.6

Researchers in England note similar results ina survey of 446 children. In a group of 203



children who had not been im-munized for pertussis, two per-cent had a diagnosis of asthmaat eight years of age, comparedto 11 percent of 243 who hadbeen vaccinated for pertussis(p=0.0005).7 However, Swedishresearchers did not find this con-nection in a study of 9,000 chil-dren given either DPT or only theDT components.8

The Role ofInflammation in Asthma

The underlying patho-physiology of asthma, regardlessof allergic components ortriggering mechanisms, is airwayinflammation. At the center of this improperinflammatory reaction is the T-cell. There isincreasing evidence that theunderlying process driving andmaintaining the asthmaticinflammatory process is anabnormal or inadequatelyregulated CD4+ T-cell immuneresponse to otherwise harmlessenvironmental antigens. Themajor CD4+ T-cell subsetinvolved in this process is theCD4+ Th2 subset, whichproduces a series of cytokines(secondary messagingmolecules), includinginterleukin-4 (IL-4), IL-5, IL-6, IL-9, IL-10, and IL-13(Table 1). These cytokinesstimulate the growth,differentiation, and recruitmentof mast cells, basophils,eosinophils, and B-cells, all ofwhich are involved in humoralimmunity and the allergic response. The othersubset of CD4+ cells is the Th1 cell, which isresponsible for production of interferon

gamma (IFN-γ) and interleukin-2 (IL-2), which are involvedin delayed hypersensitivityresponses and cellular immuneresponses to intracellularparasites and viruses. It is notyet known precisely whyindividuals with asthma havethis overriding Th2 activity. Itmay be that genetics, viruses,fungi, heavy metals, nutrition,and pollution all contribute tothis debilitating and sometimesdeadly disease process (Table2).

Antigen-specific IgE ispartly responsible for initiation

of an allergic response in asthma. Antigenscross-link with IgE on mast cells, which thenspill their contents (histamine, leukotrienes)

and further amplify theinflammatory response bydamaging local tissue andattracting other lymphocytes.The regulation of IgEproduction involvesinteractions between antigen-presenting cells, and B and Tlymphocytes. Antigen-presenting cells such asmacrophages and dendriticcells present an antigen toCD4+ Th2 cells, which secretecytokines that magnify theimmune response. IL-4produced by Th2 cellsstimulates IgE production inB-cells, while IL-5 stimulateseosinophil differentiation andmobilization to inflammatorysites (Figure 1). IL-10enhances the growth and

differentiation of mast cells and – veryimportantly – inhibits the production of IFN-γ. It appears the presence of excess IL-4 canalso “switch” cytotoxic CD8+ cells from their

Table 1: CytokinesProduced by Th1 andTh2 Cells.

Th1

TNF - αIFN - γIL - 1IL - 2

Th2

IL - 3IL - 4IL - 5IL - 6IL - 9IL - 10IL - 13

Table 2: Inducers ofTh2 Activity.

GeneticsMicroorganisms

RSVYeast/FungiChlamydia?

Pertussis vaccination?Heavy Metals

LeadMercury

Zinc deficiencyPollution


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normal production of IFN-γ (which promotesantiviral and antitumor activity) to productionof IL-4 and IL-5, further augmentinginflammatory activity.9-18

The inflammatory process is also pro-moted when histamine and leukotrienes arereleased by mast cells. Histamine acts veryquickly and stimulates bronchoconstrictionand excess mucus production. After the initialrelease of histamine, mast cells and other leu-kocytes manufacture and release leukotrienes,eicosanoid molecules that also enhance theinflammatory response. In this late-phase re-sponse, leukotrienes – lipid-based moleculescreated by the action of the enzyme 5-lipoxygenase on arachidonic acid in cell mem-branes – exacerbate the broncho-constrictionbrought on by histamine. Leukotriene B4(LTB

4) is a very potent mediator of

bronchoconstriction and chemotaxis. Thecysteinyl leukotrienes – leukotrienes bound tothe amino acid cysteine – which include LTC

4,

LTD4, and LTE

4, also at-

tract leukocytes, in additionto their involvement inbroncho-constriction andmucus production. The endresult of these complex in-teractions is a cascadingimmune and inflammatoryresponse characterized byairway eosinophilia, mucushypersecretion, and airwayhyper-responsiveness – thehallmarks of asthma.

Etiologic Factors inAsthmaAllergies

Although asthma isa multifactorial condition,the strongest risk factor inthe etiology of asthma isatopy (allergies, atopic der-

matitis, allergic rhinitis). An atopic individualhas a significantly greater probability of de-veloping asthma, and persons with a familyhistory of atopic disease are at greatest risk. Itis accepted that an immunological responseto various allergenic stimuli, including petdander, dust mites, cockroaches, fungi, andfoods is a major triggering factor in asthmasymptomatology.

Estimates of the number of people withasthma who also have allergic rhinitis are ashigh as 80 percent.19 Some practitioners sug-gest they are the same malady, only in differ-ent areas of the respiratory tract and should betreated similarly.19 In one study, 79 percent ofindividuals with asthma also had chronicrhinosinusitis.20

Dust mitesIndoor allergens are numerous; how-

ever, dust mites (Dermatophagoidespteronyssinus) contribute greatly to the over-all antigenic load in asthmatic individuals. The

Figure 1: Interactions of Th2 Cells with Other Cells.

IL-3, IL-5

IL-4IL-3,IL-4,IL-10

IL-3,IL-5

IgEIL-4,IL-5

Mast cell/basophil

B-Cell

Eosinophil

Th2 Cell

IL-4, IL-5,IL-10, IL-13



average home provides optimal temperature,humidity, and other environmental conditionsfor dust mite growth and reproduction, al-though dust mites appear in greater numbersin warm, humid climates. Dust mite feces arethe major antigenic component, containing atleast 10 antigens. A number of epidemiologi-cal studies have shown a correlation betweendust mite exposure and asthma symptoms.21-24

A Swedish study found significantly greaterrisk for asthma symptomatology in homes withhigher levels of dust mites.25 A U.S. study ofinner-city children with asthma discovered ahigh proportion of these children had both asignificant exposure and an immunologicalsensitization to dust mites and cockroaches.26

Dust mite allergenicity could be at leastpartly due to enzymes in dust mite feces, whichwhen inhaled can interrupt tight junctions be-tween epithelial cells in the lungs. This dis-ruption of the normal epithelial barrier cansubsequently enhance the presentation of an-tigens (dust mite and others) to dendritic cellsresiding beneath the airway epithelium andfacilitate immune response to those antigens.Such a mechanism would to some extent ex-plain commonly-occurring allergenic re-sponses to other inhalant antigens in individu-als exposed and sensitized to dust mites.27

The allergic response to dust mites in-volves an immediate hypersensitivity response,including increases in specific IgE antibodiesand T-cells of the Th2 phenotype. Inhalationchallenge of the allergic individual with dustmite antigen produces airway hyper-reactiv-ity and bronchospasm, along with an eosino-phil-dominated inflammatory response.

Preventive hygienic measures to re-duce dust mite exposure include washing bed-ding in hot water, eliminating carpet wherepossible, and encasing mattresses and pillowsin occlusive covers. The use of high efficiencyparticulate air (HEPA) filters in heating, ven-tilation, and air conditioning systems is alsohelpful, as is the use of a vacuum cleaner with

an on-board HEPA filter to clean floors andupholstery.28

CockroachesAs with dust mites, cockroaches can

be a very significant allergen source in the al-lergic asthmatic. It is thought that cockroachantigens (from the body and feces) pose a sig-nificant threat to individuals with asthma, andmay be partially responsible for the greatlyincreased morbidity and mortality from asthmain inner-city residents. Results of The NationalCooperative Inner-City Asthma Study(NCICAS) demonstrate the degree of expo-sure to cockroach antigen, measured in bed-room dust, is directly correlated with a sensi-tized child’s risk of hospitalization.29

Dog and Cat DanderDogs and cats are another significant

source of antigenic stimuli in the home, andcan initiate or aggravate airway inflammationand asthma symptoms.30 Cat dander tends tobe more antigenic, as the allergen (which de-rives from salivary and sebaceous glands) isquite small, and thus can stay airborne for longperiods of time. Conversely, dog allergen islarger and tends not to be airborne as much ascat allergen, making it more likely cat aller-gen will be inhaled.31

In a study involving 787 asthmatics,the presence of domestic animals in the homewas one of the most significant predictors ofasthma morbidity;32 other studies have con-firmed these results.33-35 An interesting studywas conducted in Los Alamos, New Mexico,which is at 7,200 feet elevation. At this alti-tude, household dust does not contain highlevels of dust mite antigens. Among schoolchildren in this community with asthma,(n=57) sensitization to cat and dog allergenswas strongly associated with bronchial reac-tivity and asthma symptoms, while mites,cockroaches, and pollens were not signifi-cantly associated with asthma symptoms.36


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Unfortunately, strict avoidance of ani-mal allergens is practically impossible, be-cause even if domestic animals are not in thehome there is still a possibility of significantexposure due to transfer of animal dander inpublic places. Studies of cat and dog allergensin Swedish schools discovered high concen-trations of these allergens in school dust.37,38

Perzanowski et al found allergen levels higherthan those found in homes without pets andnoted, “The schools appear to be a major siteof exposure to cat and dog allergens.”38 Sig-nificant levels of cat and dog allergens werealso found in public waiting areas of a Britishhospital, although vacuuming three times perweek decreased allergen levels in upholsteredchairs.39 Bathing animals can also be helpfulin reducing the amount of allergen transfer.According to a recent British study, washingthe pet dog twice per week can decrease air-borne canine allergen 84 percent.40

It is vital to reduce total allergenic load,if possible. If a pet lives in the house, maxi-mizing the time the animal spends outdoors isa must. Animals must not be allowed into thebedroom, which should be considered a “cleanroom” that has as few allergens as possible.This provides the asthmatic an environmentthat is as free as possible from allergens for atleast eight hours out of 24. HEPA filters are ahelpful adjunct in reducing the allergenic loadfrom animal dander in the home.41

Food AllergyAsthma can also be caused or exacer-

bated by food allergy. It is probably not asimportant a causative factor as inhalant aller-gies, but nevertheless contributes to the over-all allergenic load of the asthmatic. Some es-timates are that 5-8 percent of people withasthma have a food allergy that can be con-firmed via a double-blind, placebo-controlledfood challenge.42-46 Patient estimates of foodallergy in asthma are much higher, rangingfrom 20-60 percent.45,46 Many who make di-etary modifications to avoid foods they believe

are causing asthmatic symptoms feel thosemodifications help their asthma, including 79percent of asthma patients in one study.45

Atopic individuals produce specificIgE antibodies to food proteins, which bindprimarily to mast cells and basophils. Whenthe person comes in contact with the allergicfood, histamine is released by these cells,stimulating an inflammatory response in thelungs, and asthma symptoms ensue. This re-action, or the involvement of non-IgE-medi-ated reactions, can be immediate or may takehours or days to manifest. This might be onereason why estimates of food allergy in asthmapatients are low, as researchers often look forsymptoms to appear quickly following chal-lenge; whereas, with a delayed reaction tofoods, it is more difficult to assess the causeof the symptoms.

Gastrointestinal symptoms occur morefrequently in children with asthma and atopicdermatitis; 47 and abnormal gastrointestinalpermeability is found in a greater percentageof asthmatics compared to non-asthmatic con-trols.48 It is possible there is a common defectin the respiratory and gastrointestinal mucosa,either caused by the asthma or as a possiblecause of asthma. Increased gastrointestinalpermeability can allow large antigenic mol-ecules to be absorbed through the mucosa,causing sensitization to foods. Possibly theincreased permeability in the lungs caused bydust mite antigen causes a similar increase intransfer of antigenic material across the respi-ratory epithelium.27

Although the role of food allergies asa causative factor in asthma remains ambigu-ous, it seems some individuals do benefit fromavoidance of identified problem foods. Thisoption should not be overlooked in dealingwith asthma.

Yeast/FungiFungi are known to be causative factors

that induce asthmatic symptoms. Outdoorairborne fungi, including Cladosporium,



Alternaria, Penicillium, and Aspergillus aresignificant triggers of IgE formation, as arethe indoor fungi Aspergillus, Neurospora, andEurotium. In addition, some practitionersbelieve there is a strong fungal/yeastcomponent in the lung and/or gut microflorain individuals with asthma.31,49,50 Ridding thehome or work environment of these organismsand utilizing antifungal treatments asappropriate has been reported to improveasthma symptomatology.

Subjective symptoms and peak expi-ratory flow (PEF) in 74 children with asthmawere followed for 16 weeks, and correlatedwith the amount of bacterial endotoxin andfungal 1,3-beta glucan levels present in housedust. After adjusting for pet presence, type offloor cover, and dust mite allergen levels, yeastlevels were positively correlated with PEFvariability in these children.51

Sensitivity to fungal allergens has alsobeen found to be a risk factor for severe life-threatening asthma. A New Zealand study ofpatients admitted to a hospital intensive careunit (ICU) revealed that patients admitted tothe ICU had a significantly greater incidenceof reactivity to Alternaria tenuis, Cladospo-rium cladosporoides, Helminthosporiummaydis, or Epicoccum nigrum (54% vs 30%for other groups not admitted to the ICU ornot hospitalized for asthma).52

Fungal cultures were performed frombronchial secretions of 13 asthma patients andfrom the skin of 91 patients with atopicdermatitis. The predominant yeast speciespresent on the skin were Candida andRhodotorula species, while Candida specieswere the most prominent species isolated frombronchial secretions.53 Candida albicans maywell be a prominent allergen for people withasthma. The cell wall constituent, mannan, andacid protease – an enzyme secreted by C.albicans – are both highly allergenic, andserum IgE antibodies are often increased inatopic individuals.54,55

Animal and in vitro studies suggest ifthere is an imbalanced Th1/Th2 ratio of im-mune activity, Candida infection is more likelyto occur.56-60 There has been little investiga-tion to date as to whether asthmatics are morelikely to have Candida infections because ofTh2-dominance, or whether Candida infectionpredisposes an individual to experience asthmasymptoms. What data there is suggests bothmay be true.49,50,61,62 Regardless, these data sug-gest that environmental fungi and/or coloni-zation with Candida or other organisms prob-ably contribute to asthma severity. Environ-mental eradication of fungi, as well as inter-nal antifungal agents, should be considered inthose testing positive for reactivity to theseorganisms.

A Probable Connection to PersistentViruses and Chlamydia

The search for etiologic agents in bron-chial asthma has brought some researchers tobelieve viruses or other organisms might bepartly responsible for some asthma cases. In-fections with common cold viruses and influ-enza frequently precipitate symptoms in thosewith established asthma. The chief mechanismfor these exacerbations appears to be viral rep-lication in respiratory epithelial cells trigger-ing cytokine release, inflammation, and mu-cus production. These processes are necessaryto clear the viral infection; but superimposedover a pre-existing inflammatory condition inthe airways they can trigger symptomatology.

There is evidence that some virusesmay, in the presence of IL-4 (produced in ex-cess by Th2 cells in asthmatics) cause CD8+

cells to drastically reduce their usual secretionof IFN-γ and switch to production of IL-4 andIL-5. This switch to greater Th2 activity canslow the immune system’s clearance of thevirus, cause pulmonary eosinophil infiltration,and exacerbate asthma inflammation.18

Marin et al reported that 39 of 50(78%) presently asymptomatic asthmatic


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children harbored adenovirus DNA in theirnasopharynx, detected from nasal swabs, whilethe virus was found in only one of 20 controls(5%). Rhinovirus was found in 16 asthmapatients (32%), and none of the controls. Theauthors believe the presence of these virusesin patients, but not controls, might reveal apossible connection between viral infectionsand asthma.63

It also has been hypothesized thatChlamydia pneumoniae infection might pre-dispose individuals to asthma. A recent reviewon this subject examined papers over a 15-yearperiod; epidemiological studies and case re-ports were included. The authors found sig-nificant epidemiological associations betweenChlamydia infection and asthma, as well asreports of clinical improvement following an-tibiotic treatment for this organism.64 A studyof children and young adults with asthmafound the opposite – higher IgG titers forChlamydia were correlated with a reduced riskof asthma.65 Another study related high IgGand IgA titers with lower FEV1 (Forced Ex-piratory Volume in One Second – an objectivemeasurement of airflow); i.e., higher titers ofantibodies to Chlamydia were associated withincreasing severity of asthma in adults.66 Thereis possibly a difference in how Chlamydiamight affect children compared to adults,which might explain the disparity in these re-sults.

Another virus with a possible link toasthma symptoms is respiratory syncytial virus(RSV). Wheezing is a cardinal sign of acuteRSV infection in infancy, and may persistchronically for years after an acute infection.In a 10-year follow-up of children hospitalizeddue to RSV infection, 40 percent reportedwheezing at five years (11 percent in controls),and 22 percent reported wheezing at 10 years(10 percent in controls).67 A Brazilian studyconfirms these findings, demonstrating asignificantly increased risk for wheezing at agesix in children who had RSV before age three.The risk for wheezing decreased with

increasing age, becoming insignificant by age13.68 These studies show that, while RSVinfection in a young child is a significant riskfactor for wheezing until ages 10-13, it doesnot pose a significant risk for asthmasymptoms in adults. It has been proposed thatRSV infection stimulates an over-active Th2cytokine response69,70 which, as noted above,predisposes toward eosinophilia and hyper-reactive airways (Table 2).

Indoor and Outdoor Air PollutionAn increase in inhaled particulate mat-

ter, whether from cigarette smoking, environ-mental tobacco smoke, fossil fuels, or woodburning stoves can exacerbate asthma symp-toms. Recent animal research reveals second-hand smoke up-regulates the Th2 immune re-sponse. This mechanism might partially ex-plain epidemiological evidence linking sec-ond-hand smoke with asthma prevalence.71

Use of gas appliances in the home can increasethe concentration of nitrogen dioxide in in-spired air, correspondingly reducing lung func-tion. Volatile organic compounds and formal-dehyde in the indoor environment, from off-gassing of paints, adhesives, furnishings, andbuilding materials can also increase the riskof asthma attacks. An excellent review of thesubject of asthma and the home environmentcan be found in Jones’ recent article in theJournal of Asthma.31

Does Heavy Metal Toxicity PromoteInflammation in Asthma?

Lead and mercury toxicity has beenshown in animal studies to inhibit Th1 cellsand stimulate a Th2 immune response and, insome animals, promote autoimmune dis-eases.11,72 In humans, if heavy metals wereproven to cause an imbalance in the normalTh1:Th2 ratio, it would explain practitionerreports of improvements in asthma symptomsafter heavy metal detoxification.



Gastroesophageal Reflux: a PossibleConnection

Another possible contributor to the eti-ology of asthma is gastroesophageal reflux(GER). An increased incidence of GER hasbeen noted in asthma patients;73,74 however, itis not fully understood if these conditions sim-ply overlap, if GER causes or exacerbatesasthma, or if asthma causes GER. In his 2000review, Sontag74 estimates that approximately75 percent of asthmatic patients experienceGER symptoms, 80 percent have abnormalacid reflux, 60 percent have a hiatal hernia,and 40 percent have esophageal damage (ero-sions or ulcerations). Two mechanisms havebeen proposed to explain how GER mightcause asthma symptoms: (1) a vagal-mediatedreflex from the irritated esophagus to the lung,causing reflex bronchoconstriction, or (2)microaspiration of gastric acid, causing pul-monary irritation, injury, and subsequent over-production of mucus.

Proponents of the vagal reflex theorynote that the esophagus and lungs share thesame embryonic tissue and innervation. Anirritated esophagus could, therefore, initiate avagal reflex, resulting in increased bronchialreactivity.74-79 Animal and human studies haveshown increased pulmonary airway resistancewith esophageal acid infusion. Thisbronchoconstriction was reversed with antacidtherapy80 or surgical interruption of the vagusnerves.74 In a small study of pediatric asthma(n=9), acid was infused into the esophagusduring sleep, causing bronchoconstriction onlyin the four children with previously diagnosedesophagitis (positive Bernstein test). Theseresults led the researchers to comment thatreflux, an irritated esophagus, and a low noc-turnal threshold to bronchoconstrictive stimuliwere all necessary for reflux to causebronchoconstriction. It is interesting to notethat, in this study, acid did not causebronchoconstriction during a midnight infu-sion, but did in the 4-5 a.m. infusion.78 In a

study of 47 adults (20 asthmatics with reflux,7 without, 10 participants with GER, and 10controls) esophageal acid infusion caused asignificant decrease in PEF in all participants;however, the group of asthma patients withreflux had a greater decrease in PEF, as wellas further deterioration after the acid wascleared with normal saline. The authors statedthat since there was no microaspiration of acid,a vagally mediated reflex must be involved.77

Subsequent studies found increased vagal re-sponsiveness in patients with asthma and GER;this was blocked by atropine, which inhibitsvagal stimulation.81,82

Animal and human studies have pro-vided evidence for the microaspiration theoryof GER, although overall the evidence looksless convincing than the “reflex theory.” Inha-lation of a dilute acid solution in cats causedsignificantly greater bronchoconstriction thaninfusion of acid into the esophagus.83 Ambu-latory esophageal pH monitoring and scinti-graphic technetium monitoring have provideddocumentation of esophageal acid reflux andmicroaspiration of gastric acid in humans.84,85

It might be that asthma related to GER is amultifactorial problem, with components ofmicroaspiration and gastroesophageal reflux.

If indeed GER causes asthma or exac-erbates hypersensitive respiratory tissue, thetrue test should be that anti-reflux or antacidtherapy significantly improves asthma symp-toms. However, antacid therapy, which hasconsisted mostly of H2 blockers (cimetidine,ranitidine) or a proton pump inhibitor(omeprazole), has not been consistently effec-tive, showing mixed results.74

A small study (n=5) of asthma patientswith nocturnal symptoms and GER determinedthat treating asthma with ephedrine improvedasthma symptoms as well as reflux symptoms.The authors stated the bronchodilation pro-vided by the ephedrine and the subsequentimprovement in GER symptoms suggests GERmight be a result of asthma symptomatology,not the opposite.86


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The most common GER therapy is apharmacological reduction in gastric acid out-put. However, Wright found a substantial num-ber of children with asthma actually have areduction in gastric acid output. He theorizesthat reduced gastric output results in inad-equate protein digestion and an increase inallergenicity of foods, as well as a reductionin nutrient absorption. Treatment with hydro-chloric acid supplementation is part of his in-tegrated treatment protocol, and is claimed toprovide symptomatic improvement.87,88

The Possible Role of Dehydration inAsthma

It is important to ensure the asthmapatient is well hydrated; however, good datadoes not exist showing a firm association be-tween dehydration and asthma, except in ex-ercise-induced asthma (EIA). In EIA, dehy-dration of airway epithelial cells may contrib-ute to epithelial damage, edema, and hyper-responsiveness.89-93 This does not rule out thepossibility that chronic sub-clinical dehydra-tion may contribute to asthma-related symp-toms; in fact, it lends credibility to the theory.

Aspirin-induced AsthmaticExacerbation

A subset of individuals with asthmaexperience symptoms after ingestion of aspi-rin or other similar non-steroidal anti-inflam-matory drugs (NSAIDs). Since most NSAIDsblock the enzyme cyclooxygenase, it is thoughtthis leaves more arachidonic acid to react withthe other arm of the eicosanoid pathway, regu-lated by activity of lipoxygenase. Downstreammetabolites of this pathway include theleukotrienes, very potent stimulators of inflam-mation and bronchial constriction. Avoidanceof NSAIDs is imperative in these individuals.Some asthmatics also react to sulfites presentin some foods and wines. This reaction is morecommon in people who experience symptomsfollowing ingestion of NSAIDs.95

The Emotional ConnectionIt is often said that asthma can be trig-

gered by emotional stress. In fact, traditionalChinese medicine refers to the lungs in con-nection with grief and sorrow. Asthma patientshave been noted to have a more negative af-fect, and emotional upheavals have been linkedto asthma symptom exacerbations. In a recentstudy, Cetanni et al95 examined 80 patients withasthma, 40 patients with either hepatitis B orC, and 40 healthy controls. Significantlygreater anxiety and depression were found inasthma patients compared to hepatitis patientsand controls. In a study of 230 patients withasthma, 45 percent scored high enough ondepression ratings scales to be considered de-pressed. Those with more depressive symp-toms reported worse health-related quality oflife than asthma patients without depression.96

This begs the question, do a significant num-ber of asthma patients have anxiety and de-pression because of their asthma, or do thesepsychological diagnoses predispose one toasthma symptoms? It may be a combinationof both. No doubt it is an anxiety-producingfeeling when one cannot get enough air. Con-versely, intense emotions can bring aboutasthma symptoms. Increased respiratory resis-tance, airway reactivity, shortness of breath,and decreased peak expiratory flow rate havebeen reported after an emotional challenge.97-99

Nutrients and AsthmaVitamin C

There is reason to believe oxygen radi-cals are involved in the pathophysiology ofbronchial asthma. Inflammatory cells gener-ate and release reactive oxygen species,100 andinflammatory cells from asthma patients pro-duce more reactive oxygen species than non-asthmatics.101,102 Significantly decreased lev-els of vitamin C and vitamin E were found inlung lining fluid of asthmatics in a recent study,even though plasma levels were normal.103

Fourteen children with asthma were found to



have significantly decreased serum levels ofvitamin E, beta-carotene, and ascorbic acidduring an asymptomatic period, with elevatedlevels of lipid peroxidation products during anasthma attack.104 To combat the increased oxi-dant burden in asthmatics, the attainment andmaintenance of optimal levels of antioxidantnutrients might be essential

Epidemiological studies of vitamin Cintake and asthma symptoms and respiratoryfunction note a beneficial overall effect of vi-tamin C. Generally, as vitamin C intake rises,FEV1 and FVC (forced vital capacity) in-crease.105-108 Yet the effect of vitamin C onasthma remains controversial, as studies onvitamin C supplementation in asthma patientshave yielded contradictory results. For ex-ample, asthma patients subjected to methacho-line challenge testing alone and after ascorbicacid supplementation (1 g one hour prior tochallenge) were able to withstand greater dosesof methacholine after vitamin C dosing.109 Inthis test, methacholine, a bronchoconstrictingdrug, is inhaled. In those with hyper-reactiveairways, there will be a greater constriction ofpulmonary smooth muscle and loss of lungfunction. However, short-term dosing withascorbic acid failed to improve bronchialhyper-reactivity with inhaled histamine chal-lenge.110 Schachter and Schlesinger studied theeffect of ascorbic acid on exercise-inducedasthma, and concluded that ascorbic acid hasa mild bronchodilatory effect in exercise-in-duced bronchospasm, seen as a protective ef-fect on FEV1 and FVC compared to placebo.111

Reviews regarding vitamin C andasthma point to the fact that the studies per-formed to date, whether showing positive ornegative effects, utilized short-term vitamin Cdosing, as if they were attempting to assess animmediate effect of vitamin C only, and notthe effects of long-term optimal blood and tis-sue levels of this nutrient.112,113 Long-termsupplementation studies of vitamin C, asthmasymptomatology, and pulmonary function

need to be conducted to further elucidate vita-min C’s role in asthma treatment.

Vitamin B6Pyridoxal 5’-phosphate (PLP), the ac-

tive form of vitamin B6 in the body, is involvedin numerous biochemical processes, and hasbeen found in lower concentrations in asthmapatients.114 However, investigations of thetherapeutic efficacy of B6 supplementationhave resulted in mixed results. Treatment ofasthma with pyridoxine (50 mg twice daily)resulted in improvements in a reduction ofasthma exacerbations and wheezing episodesin adults. 114 In 76 children with asthma, B6supplementation (100 mg pyridoxine HCltwice daily) resulted in fewerbronchoconstrictive attacks; less wheezing,cough, and chest tightness; and less use ofbronchodilators and steroid medications.115 Adouble-blind trial of B6 (300 mg/day pyridox-ine HCl) in steroid-dependent asthma patientsresulted in no change in lung function.116

Asthma patients treated with the bron-chodilator theophylline have lower blood lev-els of PLP, possibly due to PLP depletion sec-ondary to its use in theophylline metabolism.Theophylline is not used as much as it oncewas, mostly due to side effects and its narrowtherapeutic range;117,118 however, monitoring ofvitamin B6 levels and supplementation if war-ranted should be considered for individualsusing this drug.

Vitamin B12It has been reported that children with

asthma may be B12 deficient, although thereis no peer-reviewed literature to corroboratesuch a statement. Jonathan Wright, MD, andAlan Gaby, MD, relate that asthmatic childrenrespond well to B12 supplementation, particu-larly if they are sulfite-sensitive. Daily dosesof 1000-3000 mcg may be needed.119


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MagnesiumMagnesium is a cofactor in over 300

biochemical processes in the body, and is es-pecially vital to the contraction/relaxation stateof smooth muscle. Magnesium and calciumwork in concert to regulate the contraction andrelaxation of smooth muscle. Low magnesiumenhances the contraction activity of calcium,while higher magnesium levels inhibit calciumand promote relaxation. Hypomagnesemia iscommon in asthmatics,120-123 and worsens inmore severe cases.120,121

Serum levels are often used to assessmagnesium status; however, serum magne-sium can be normal while intracellular mag-nesium is deficient. Intracellular assessmentutilizing erythrocytes or leukocytes is recom-mended for an accurate depiction of magne-sium status. Intracellular magnesium was as-sessed in 22 asthma patients and comparedwith 38 controls with allergic rhinitis. Mag-nesium levels were significantly lower in in-dividuals with asthma versus controls. Lowerintracellular magnesium was correlated withincreased airway hyper-reactivity via themethacholine challenge test. Magnesium lev-els did not significantly affect FEV1.122 Simi-lar findings were recently reported byHashimoto et al.121 While low magnesium sta-tus is a consistent finding, the role of magne-sium supplementation is more ambiguous.

A large British study of dietarymagnesium intake and asthma symptoms in2,633 people found individuals who had agreater dietary intake of magnesium had asignificantly higher FEV1 and significantlydecreased airway hyper-reactivity.124 In arandomized, double-blind, placebo-controlledcrossover study, Hill et al reported significantlyfewer asthma symptoms and reducedsubjective bronchial hyper-reactivity inpatients given 400 mg magnesium per day asa dietary supplement. However, objectivemeasurements of pulmonary function were notsignificantly better in the three-week study, anduse of short-acting beta agonist inhaler

medications was not decreased.125 It might bethat a three-week trial, while seeming toimprove aspects of patient subjectivesymptomatology, is not long enough to have along-term stabilizing effect on pulmonaryfunction. An investigation on the effects oflong-term magnesium supplementation tocorrect tissue levels of this mineral seemswarranted.

Intravenous magnesium sulfate is acritical treatment component for severe asthmaseen in the emergency department in manyhospitals. Intravenous magnesium often re-lieves symptoms soon after infusion is be-gun,126 and can decrease the need for intuba-tion in status asthmaticus127 and respiratoryfailure.128 In recent pediatric studies, additionof magnesium sulfate IV to standard emer-gency care initiated faster improvement in PEFand oxygen saturation in patients not respon-sive to conventional treatments.129,130

Another pediatric study of 30 patientswith an acute asthma exacerbation used a high-dose protocol of 40 mg/kg magnesium sulfateinfused over a 20-minute period. Significantimprovement was noted at 20 minutes, and amuch greater improvement was noted at 110minutes: PEF had improved 26 percent (vs.2% in saline controls), FEV1 24 percent (2%),and FVC 27 percent (3%). All results werehighly significant (p<0.001).131

Acute administration of intravenousmagnesium has been studied as a stand-alonetherapy, as well as an adjuvant to conventionalbeta-adrenergic, methyl xanthine, and steroidtreatment. Results have been mixed, with somestudies finding statistically significant im-provements in lung function130-134 and othersdetermining that IV magnesium sulfate is nothelpful.135,136 In two recent reviews of the sub-ject, IV magnesium sulfate was found in onereview to be of significant benefit to patientswith severe asthma,137 and found not to affecttreatment outcomes in a meta-analysis.138

It is unknown why these various in-vestigations resulted in diverse outcomes.



Some intravenous trials used 1-2 g magnesiumsulfate alone, while others used a similar doseas an initial bolus, followed by slower dripsover the next few hours. There does not seemto be a pattern of results following a specifictype of protocol. Regardless of the inconsis-tent results seen with IV magnesium sulfate,asthmatics do tend to have lower intracellularlevels of magnesium, and supplementation tocorrect those levels seems warranted.

ZincThere is little direct evidence of zinc

deficiency causing asthma symptoms, butasthma patients have been shown to have lowerplasma zinc than healthy controls.139 Serumand hair zinc were significantly lower in indi-viduals with asthma and atopic dermatitis.140

Similar results were reported by Di Toro et alin asthmatics versus controls.141

It has been proposed that a zinc defi-ciency switches the Th1 immune response to-ward a Th2-type response, which, as men-tioned earlier, is a hallmark of asthma patho-physiology.142,143 Prasad et al studied how mildzinc deficiency affects the immune system.Zinc deficiency caused an imbalance betweenTh1 and Th2 functions, with a subsequent in-creased production of IL-4, IL-6, and IL-10,and decreased production of IL-2, IFN-γ, andtumor necrosis factor alpha. They also noteddecreased NK-cell activity and decreased num-bers of cytotoxic CD8+ T-cell precursor cells.144

In two other studies of zinc and immunity, in-dividuals deficient in zinc exhibited dimin-ished Th1 activity, but unaffected Th2 activ-ity, creating a relative Th1 deficiency.145,146

Even without the benefit of definitiveresearch on long-term zinc supplementationin asthma patients, this author believes it isvitally important to ensure proper zinc nutri-ture in asthma patients to avoid a potentialzinc-deficiency-induced exacerbation ofasthma symptoms due to increased Th2 im-mune activity.

SeleniumGlutathione is a vital component of the

body’s antioxidant system. Glutathione peroxi-dase (GSH-Px) is the selenium-containingenzyme that uses glutathione as a cofactor tometabolize hydrogen peroxide, and can thusprotect against oxidative damage. Individualswith asthma tend to have increased oxidativeactivity, lowered selenium status, and decreasedactivity of glutathione peroxidase.147-150

Only one study has been conducted onselenium supplementation to combat the in-creased pulmonary oxidative burden in asth-matics. Hasselmark et al performed a double-blind, placebo-controlled study in whichasthma patients were given 100 mcg sodiumselenite (containing 46 mcg elemental sele-nium) for 14 weeks. Significant increases wereseen in serum and platelet selenium and GSH-Px activity, and improvements were seen insubjective symptomatology. However, objec-tive measurements of lung function were notchanged.151 It may be that the supplementaldosage given was too low and that a supple-mental dose of 200-250 mcg might be morebeneficial. More study is warranted in thisimportant arena.

Omega-3 Fatty AcidsIntermediate and end-products of fatty

acid metabolism are known to have potent ef-fects on the inflammatory process. Prostaglan-dins and leukotrienes from arachidonic acidmetabolism are highly inflammatory mol-ecules, and play an important role in the patho-physiology of asthma. Arachidonic acid is re-leased from cell membrane phospholipids ofactivated immune cells (via activity of the en-zyme phospholipase A

2) in response to vari-

ous immunological stimuli. Prostaglandins andleukotrienes resulting from arachidonic acidmetabolism are pro-inflammatory molecules.Leukotriene B

4 (LTB

4) is involved in

bronchoconstriction and leukocyte chemot-axis, while the cysteinyl leukotrienes – LTC

4,


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LTD4, and LTE

4 – are far more potent

promotors of smooth muscle constriction andmucus production. An overabundance of theseleukotrienes is implicated in the pathophysi-ology of asthma.

Research into the effects ofleukotrienes has spurred the development ofnew drugs that block the activity of these po-tent substances. These drugs appear to be ofbenefit in some asthma patients, particularlythose with more severe disease. Steroid medi-cations, either inhaled or systemic via oral orparenteral dosing, have been the mainstay ofanti-inflammatory asthma drug therapy. Incontrast to the new leukotriene-inhibitingdrugs, corticosteroids strongly inhibit the re-lease of arachidonic acid from cell membranes

by blocking the activity of phospholipase A2,

resulting in a greatly diminished amount ofprostaglandins and leukotrienes. Two LTD

4receptor antagonists, zafirlukast andmontelukast, have been approved for use inasthma and provide moderate improvementsin objective lung function tests, as well as lessreliance on inhaled steroid medications. A 5-lipoxygenase inhibitor, zileuton, has demon-strated similar results.152,153 Cromolyn sodium,used prophylactically in asthma, has beenshown to inhibit LTE

4-induced

bronchoconstriction, probably by inhibitingmast cell degranulation.154

Cold-water fatty fish contain relativelylarge amounts of the omega-3 fatty acidseicosapentaenoic acid (EPA) and

Figure 2: Fatty Acids and Inflammation.

Eicosapentaenoic Acid (EPA)

Docosahexaenoic Acid (DHA)

Cyclooxygenase 5-Lipoxygenase

Arachidonic Acid

4-seriesLeukotrienes

5-seriesLeukotrienes

3-seriesProstaglandins

2-seriesProstaglandins

Cyclooxygenase

INFLAMMATIONBRONCHOCONSTRICTION

5-Lipoxygenase



docosahexaenoic acid (DHA). When these fishare eaten, or when oil derived from them istaken as a supplement, EPA and DHA displacearachidonic acid from cell membranes. Whenthese cells are stimulated they subsequentlyrelease relatively higher concentrations of fish-derived oils. The resultant downline metabo-lites of EPA and DHA differ from arachidonicacid metabolites. EPA and DHA are convertedby cyclooxygenase into 3-series prostaglan-dins, and by lipoxygenase to 5-seriesleukotrienes, both categories of which are farless potent inflammatory mediators than the2-series prostaglandins and 4-seriesleukotrienes arising from arachidonic acidmetabolism155,156 (Figure 2). Because of thisshift toward less inflammatory eicosanoids,one would expect to see less inflammatoryactivity in the lungs, and a subsequent im-provement in asthma symptoms and lung func-tion. Epidemiological studies of dietary fishintake and risk of asthma show an inverse cor-relation; i.e., more fish consumed equals lessrisk of asthma.157,158 However, the clinical datais equivocal, with well-designed studies show-ing both positive and negative results fromomega-3 fatty acid supplementation.

A group (n=7) of individuals with sea-sonal asthma were supplemented with 3 g/dof a fish oil concentrate containing approxi-mately 1,300 mg each of EPA and DHA, re-sulting in decreased residual volume (whichis usually increased in asthma patients) anddecreased bronchial reactivity.159

Broughton et al studied 26 asthmapatients after a one-month regimen of low- orhigh-dose omega-3 fatty acid intake. Patients’dietary intake of fish was evaluated, thensupplementation was individualized for eachpatient so they ingested omega-3 and omega-6 fatty acids in a ratio of 0.1:1 or 0.5:1. Thisprovided either 0.7 grams EPA/DHA or 3.3grams EPA/DHA, respectively (the ratio ofEPA to DHA in this study was not given). Thehigh-dose protocol stimulated an improvementin bronchial reaction to methacholine

challenge in 40 percent of subjects, comparedto a reduction in lung function in the low-dosegroup. Leukotriene B

5 was increased in the

high-dose group and was predictive of lungfunction.160 This seems to indicate a role forfish oil supplementation in asthma treatment.

In a separate study, after 10 weeks ofsupplementation with 3.2 g EPA and 2.2 gDHA per day, 12 subjects underwent histaminechallenge, exercise challenge, and neutrophilstudies to assess the efficacy of fish supple-mentation in asthma. Although there was a sig-nificant increase in omega-3 fatty acid con-tent of neutrophils and a 50-percent inhibitionof LTB

4 synthesis, there was no detectable

change in the clinical outcome; e.g., no sig-nificant change in histamine response, exer-cise response, FEV1, or symptom score.161

Hodge et al reported similar results in theirstudy of asthmatic children. After six months’supplementation with 1.2 g/d of omega-3 fattyacids, a five-fold increase in plasma EPA anda decrease in peripheral blood eosinophils wasseen, but there was no change in symptom se-verity.158 The reason for these mixed findingsis not known.

Botanicals and AsthmaFor botanicals to be effective in asthma

treatment they should provide some symptom-atic relief and optimally should have a signifi-cant effect on the pathophysiology of the dis-ease; e.g., excess histamine release, leukotrienesynthesis, imbalanced Th1/Th2 immune activ-ity. A number of botanical medicines indicatedfor asthma are listed in various herbal com-pendiums. Expectorants such as Lobelia, San-guinaria, and Grindelia are often used by herb-alists, naturopaths, etc., and are reported tohave some symptomatic benefit; however, noresearch on these plants with respect to effi-cacy in the treatment of asthma is available.Those botanicals and botanically-derived sub-stances with some research explaining theirmechanism and/or efficacy in asthma are dis-cussed below.


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Tylophora asthmaticaOne botanical that has undergone clini-

cal scrutiny and shown success in treatingasthma is an Indian plant called Tylophoraasthmatica (also known as Tylophora indicaor Indian ipecac). The leaves of the plant areused in Ayurvedic medicine for the treatmentof asthma, bronchitis, and arthritis. It can havean irritant effect on the gastrointestinal mu-cosa, and in large doses will act as an emetic.In smaller doses, however, it acts as an expec-torant, anti-inflammatory, and may providebenefit in asthma cases.

Alkaloids from this plant have beenisolated and identified as tylophorine andtylophorinine. These alkaloids are believed tobe responsible for the plant’s therapeutic effi-cacy. In a rat study, tylophorine inhibited sys-temic anaphylaxis, adjuvant-induced arthritis,and mast cell degranulation.162 It is suggestedthat Tylophora might have a direct effect onthe adrenal glands, thus increasing endogenoussteroid production and anti-inflammatory ac-tivity.163

Ingestion of Tylophora leaf in asthmapatients resulted in decreased nocturnal symp-toms, as well as significant improvements inlung function indices compared to placebo ina double-blind, crossover study. These im-provements continued for weeks beyond theshort-term (7-day) trial period.164 Similar long-lasting results were reported in a study of 110asthmatics. These patients chewed and swal-lowed one Tylophora leaf per day for six days.At one week, 62 percent of individuals takingTylophora had moderate to complete symp-tom relief, which lasted for weeks after thetrial. A significant percentage of subjects com-plained of nausea, although there tended to bea positive correlation between nausea and de-gree of symptomatic improvement.165 To date,no nutrient or other botanical has demonstrateda similar long-lasting effect after short-termdosing.

Boswellia serrataThe gum resin of Boswellia serrata,

also known as frankincense, has been used inAyurvedic medicine for centuries, and is alsoknown in that system of medicine as Salaiguggul. Leukotrienes are elevated in asthmaand are a major component of inflammationand bronchoconstriction. The 4-seriesleukotrienes (LTB

4, LTC

4, LTD

4, LTE

4) are

derived from arachidonic acid in cell mem-branes via activity of the enzyme 5-lipoxygenase. Components of Boswellia calledboswellic acids have been found to specificallyinhibit 5-lipoxygenase.166 In animal studies,Boswellia not only inhibited LTB

4 produc-

tion,167 but also prevented leukocyte migrationto inflammatory sites.168

Due to 5-lipoxygenase inhibition,Boswellia should be a beneficial componentof asthma therapy. A double-blind, placebo-controlled study of Boswellia in asthma lookedat just this issue. Forty patients were treatedfor six weeks with a Boswellia extract (300mg three times daily). Symptomatic improve-ment (dyspnea, wheezing) was seen in 70 per-cent of patients, as were objective measure-ments of lung function (FEV1, FVC, PEF). Areduction of eosinophilia was also noted.Twenty-seven percent of participants in theplacebo group showed improvement.169 Thisis a very promising study, showing both sub-jective and objective improvement in asthma.The new anti-leukotriene medications blockleukotriene receptors, whereas Boswelliablocks the formation of leukotrienes. Eitherway, the end result should be a decrease inleukotriene-induced inflammation andbronchoconstriction.

QuercetinQuercetin is one of the most widely

occurring flavonoids ingested in food byhumans. It has been demonstrated to havepotent anticarcinogenic, anti-inflammatory,and antioxidant capacity. In experimental



study, quercetin reduced the concentration ofprostaglandin E

2 and LTB

4 in pleural exudate

of rats given carrageenan intrapleurally.170 Thispoints to a possible inhibition of eitherphospholipase A2 – the enzyme involved inrelease of arachidonic acid from cellmembranes – or inhibition of cyclooxygenaseand lipoxygenase. Quercetin also inhibits mastcell degranulation and subsequent release ofhistamine.171,172 Clinical studies of quercetinuse in asthma are lacking; however, thisflavonoid is probably useful in the overalltreatment due to its antihistaminic activity. Dueto the poor bioavailability of quercetin,173 thisauthor utilizes a water-soluble quercetinanalogue – quercetin chalcone.

Plant Sterols and SterolinsOne of the basic biochemical dysfunc-

tions in asthma is an increase in IgE and spe-cific T-cell activity. The overactivity of Th2cells produces increased IgE antibody forma-tion, chemotaxis of neutrophils, eosinophilia,and a subsequent improper immune and in-flammatory response.

One of the most intriguing and prom-ising adjuncts in the treatment of asthma areplant sterols and sterolins (sterol glycosides).A proprietary blend of these plant lipids (in aratio of 100:1) has been shown in vitro and invivo to increase Th1 activity while dampen-ing Th2. This has been studied in animals andhumans in chronic viral infections, tuberculo-sis, and HIV. Clinical studies are ongoing withthis compound on rheumatoid arthritis, HIV,hepatitis C, human papilloma virus, andasthma/allergic rhinitis.174-177 While the mecha-nism of action of plant sterols and sterolins isintriguing, and while anecdotal reports of thiscompound’s efficacy in asthma treatment areencouraging, research-based evidence is cur-rently lacking.

Petasites hybridusPetasites hybridus, also known as

butterbur, was used historically by the Greeks

in the treatment of asthma, and most recentlyin clinical studies for migraines.178 Cell cul-ture studies have shown an extract of this plantinhibits leukotriene synthesis, possibly by in-hibition of 5-lipoxygenase.179,180 A recent studyon guinea pig trachea tissue revealed a con-centration-dependent inhibition of histamineand leukotriene-induced contraction in this tis-sue upon introduction of this compound.181 Inan open study of 70 asthma and chronic bron-chitis patients, a single dose of Petasites (600mg powdered rhizome) resulted in significantimprovements in FEV1 and bronchial reactiv-ity on methacholine challenge (both p<0.05).182

Further clinical studies on Petasites and itseffects on patients with asthma are warranted.

Hands-On and Mind-BodyMedicine’s Contribution to AsthmaTreatmentAcupuncture

A number of studies have been con-ducted on the effect of acupuncture on asthmasymptoms. Unfortunately, many suffer frompoor methodology and/or poor data reporting,making it difficult to draw accurate conclu-sions regarding the therapeutic efficacy of acu-puncture in asthma. Another challenge in acu-puncture studies is the use of “sham” acupunc-ture or placebo acupuncture performed by non-acupuncturists. While these methodologicalflaws do exist, the overall trend in acupunc-ture research indicates that acupuncture canbe a beneficial adjunctive therapy in the treat-ment of asthma.183-187 Jobst provides an excel-lent analysis of this issue.188

Non-Acupuncture InjectionTherapy – The Infraspinatus Reflex

Harry Philibert, MD, of Metairie, Loui-siana, has pioneered a non-acupuncture tech-nique involving injection of a small amountof a saline-lidocaine solution into the in-fraspinatus muscle bilaterally. Dr Philibert usesthis technique on all asthma patients and


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claims an astounding “total remission” rate of84 percent. He began using this technique be-cause he found the majority of asthma patientshad extremely painful infraspinatus musclesto palpation. Upon injecting these tender pointswith a saline-lidocaine-hydrocortisone solu-tion (2 mL of a 25 mg/mL hydrocortisone ac-etate solution added to a 50 mL bottle of 0.5%lidocaine HCl – inject 0.5 mL into belly ofinfraspinatus and 0.5 mL into the infrascapularfossa bilaterally) he found the tender pointsresolved, and in those patients with asthma,so did their asthma symptoms.189-191 This tech-nique is simple and usually involves one setof injections (Figure 3). Dr. Philibert now usesonly the lidocaine-saline solution.192

BiofeedbackBiofeedback training appears to be a

helpful adjunct in asthma treatment protocols.Biofeedback emphasizing relaxation and/or

beneficial slow, deep, diaphrag-matic breathing was noted todecrease symptom severity, de-crease medication usage, de-crease emergency room visits,and increase lung function val-ues.193,194 Transcendental medi-tation training yielded similarresults.195

Yoga BreathingYoga, which has a

strong emphasis on breathingtechniques, has been demon-strated to benefit asthma pa-tients. Yoga training programsenrolling a total of 715 patientsdemonstrated significant im-provement in asthma symp-toms, medication usage, peakflow rate, and exercise toler-ance.196-199 It appears the breath-ing techniques utilized are re-sponsible for the beneficial ef-fects seen in asthma, not the

yoga postures alone.

MassageAsthma patients can also benefit from

regular massage therapy. Massage relaxes themusculature and reduces anxiety. A study ofchildren with asthma who received massagedaily for 30 days demonstrated increased peakairflow and FEV1 during the course of thestudy.200

Chiropractic/OsteopathicManipulation

Many osteopathic and chiropracticphysicians perform spinal adjustments on pa-tients with asthma, and symptomatic improve-ments are often noted.201 This is an area thatneeds further well-designed trials to ascertainwhether symptomatic or lasting benefit is de-rived from this type of therapy. Studies to date

Figure 3: Infraspinatus Reflex Injection Technique.

Scapular spine

Infraspinatusmuscle



have not confirmed objective benefit from theuse of manual manipulation in asthma.202-204

While spinal adjustments certainly can helpan individual breathe better if there is a struc-tural and neurological element making it dif-ficult to breathe, they cannot be expected toalter the underlying immunological and bio-chemical dysfunctions of the asthmatic.

ConclusionsAsthma is at best an annoying condi-

tion, and at worst a debilitating, even deadlydisease. Research in the last decade has of-fered significant insight into the pathophysi-ology of asthma; however, there is still muchunknown about the prevention, pathophysiol-ogy, and treatment of this increasingly preva-lent disease. Many studies of single nutrientor botanical approaches to asthma treatmenthave yielded subjective improvements only, oreven contradictory results. Since asthma is amulti-factorial health problem, it is not sur-prising that single therapies often work in somepatients, but not others. To obtain a true repre-sentation of the usefulness of natural therapiesin asthma, researchers need to study multipleinterventions. This can still be done in a con-trolled manner that can produce meaningfuldata.

The incidence of asthma, especially inchildren, is escalating at an alarming rate –more than 100 percent over the last 20 years.There are now over 17 million individuals inthe United States suffering with asthma – 5,000of them will die from asthma this year. Thegenetic component of atopy remains the stron-gest risk factor for the incidence of asthma.But human genetics have not changed thatmuch in the last 20 years. Therefore, there mustbe a multi-factorial process that is triggering agenetic predisposition, or causing many new,non-heritable cases of asthma.

New, more airtight home construction,indoor and outdoor environmental pollutants,nutritional deficiencies, viral and fungal

infections, gastroesophageal reflux, andvaccinations have each been implicated in therising incidence of asthma.

Inflammation and airway hyper-reac-tivity are at the core of asthma pathophysiol-ogy, with an out-of-balance immune processat the center of both problems. The immunesystem in asthmatic individuals tends to havean overabundance of CD4+ Th2 cellular activ-ity, resulting in production of cytokines thatpromote and enhance the inflammatory cas-cade. Numerous nutritional, environmental,and immunological insults also push the im-mune system toward Th2 activity, includingviral and chlamydial infection, tobacco smoke,heavy metal toxicity, and zinc deficiency.

Conventional asthma treatment is cur-rently aimed at inflammation (inhaled steroidsare the mainstay of treatment) and airwayhyper-responsiveness (short-acting broncho-dilators are often used here). The use of newanti-leukotriene drugs is also increasing.

Natural approaches toward the treat-ment of asthma overlap conventional treatmentin a few areas. First, it is essential for asthmapatients to monitor their lung function dailywith a peak flow meter. They are relativelyinexpensive, and can give the individual anobjective measurement of how the treatmentis working. Another essential component is asymptom diary, which enables the patient tomonitor how different treatments and dosageregimens are working, as well as providinginsight into potential food or environmentaltriggers. Efforts to improve the patient’s homeand working environment are also important,especially in toxicity or allergy-related asthma.Maintaining a clean bedroom space is essen-tial. HEPA filters and mattress and pillow cov-ers can also be helpful.

There are several natural treatmentsthat can have an impact on the immuneimbalance in asthma. Plant sterols and sterolinsare a promising treatment, as they have a re-balancing effect on Th1:Th2 ratios. Moreclinical studies are needed, and are currently


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underway. Zinc deficiency can cause animproper Th1:Th2 ratio, and studies suggestproper zinc intake may affect this immuneimbalance positively.

It is also important to address the anti-oxidant/oxidant balance in the body. Since in-flammation promotes the formation of reac-tive oxygen species, and asthmatics have anincreased oxidant burden, nutrients such asvitamins C and E, zinc, and selenium are im-portant to consider. Symptomatic improvementwas seen after selenium supplementation –even though a small amount was used (46 mcg/day). The vitamin C literature does not pro-vide an unequivocal answer regarding its use;however, the negative studies seem to be look-ing for an immediate response to supplemen-tation. The positive studies showed increasesin lung function with long-term increases invitamin C intake.

Intracellular magnesium is lower inasthma patients, and it is essential to supple-ment these individuals with magnesium. Themagnesium literature is also fraught with con-tradictory information regarding intravenoususe for severe asthma attacks. But the bottomline is – these people are deficient. VitaminsB6 and B12 may also be helpful, as the litera-ture and anecdotal reports suggest they are bothdeficient in some asthma patients and supple-mentation lessens asthma symptomatology.

Other natural therapies seek to addressthe inflammatory problem. Quercetin reduceshistamine degranulation and the subsequentrelease of histamine and inflammatoryleukotrienes. To date, Boswellia is the onlyknown specific 5-lipoxygenase inhibitor in theplant kingdom, and has been shown to decreaseasthma symptomatology, both subjectively andobjectively. Butterbur extract might have asimilar mode of action, but more clinical in-formation would be helpful for the asthmapatient. The mechanism of action of Tylophorais unknown, but clinically it can provide a greatdeal of relief to the asthmatic. Relatively long

lasting symptomatic and objective relief wasshown with short-term dosing in two clinicalstudies.

Omega-3 fatty acids should be in-cluded in the diet or supplemented on a long-term basis. It is unknown why some fish oilstudies are positive and some are negative, asthey are proven to lower 4-series leukotrienes.Possibly these oils need to be consumed overa longer period than these studies allowed, andperhaps more attention needs to be paid to theoverall fatty acid ratio in the diet, as well assupplementing with omega-3 oils. Long-termepidemiological studies show lower incidenceof inflammatory conditions, including asthma,with increased fish intake.

Addressing toxicity may also be animportant factor. Yeast/fungi in the patient’senvironment can be a potent allergen. Intesti-nal yeast overgrowth after antibiotic treatment,which can be a common occurrence in theasthma patient, is another consideration.Heavy metals increase the toxic burden andshould be investigated.

Physical medicine modalities appear tobe an effective adjunct to the other therapiesmentioned above. Massage, biofeedback, acu-puncture, yoga, and spinal manipulation allhave shown symptomatic – and in some casesobjective – improvement.

Treating the asthma patient can be amost difficult and frustrating endeavor.However, non-invasive environmentalmodifications, dietary suggestions, andsupplements can help reduce the overallimmunological and biochemical burden on theindividual with asthma. In some cases, theycan prevent the patient from having to use beta-agonist bronchodilators or steroids, or they canbe used as an adjunct to these allopathicmedications, to allow less usage or lowerdosing. However they are used, it is imperativefor the practitioner to investigate the patient’sreactivity to substances in their environmentand promote avoidance of those substances,as well as encouraging proper nutrition and



lifestyle characteristics that will reduce theoverall toxic burden of these individuals.

I would like to thank my daughterSophie (who has asthma) for teaching me anextraordinary amount about this disease, andfor allowing me to see first-hand what this dis-ease is about from a very personal perspec-tive.

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