Alternative Medicine Review 2001 (Feb); 6 (1): 20–47 ~ FULL TEXT
Alan L. Miller, ND
Introduction
Asthma 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 multifactorial disease process
associated with genetic, allergic, environmental, infectious, emotional,
and nutritional components. Because of their symptomatology the majority
of individuals with asthma experience a significant number of missed work
or school days. This can create a severe disruption in quality of life,
often leading to depressive episodes. It also disrupts the lives of caregivers
and family members of the affected individual. Asthma patients who have
increased symptomatology at night (a significant portion) also tend to
have disturbed sleep patterns and impaired daytime attention, concentration,
and memory. [ 1 ]
In 1998 it was estimated that asthma affected 17.3 million individuals
in the United States and 150 million worldwide. From 1980-1995 the incidence
of asthma in children under age 18 increased five percent per year, resulting
in an increase of more than 100 percent in that time period, according
to the National Health Interview Survey (NHIS), the mechanism the U.S.
government uses to gather data regarding asthma prevalence and mortality.
The current overall prevalence in children is estimated at 6.0-7.5 percent,
with a total of over five million children affected. Asthma is the fourth-leading
cause of disability in children, and one of the most common reasons for
school absenteeism. The prevalence in adults is approximately five percent.
Asthma prevalence among African-Americans is considerably higher than Caucasians
or Hispanics, with black children having a 26-percent greater incidence
than white children in 1995-1996.
Approximately 5,000 people die each year due to asthma. Across racial
and socioeconomic groups, the death rate from asthma mirrors the incidence,
with African-Americans having the highest mortality from this disease.
The death rates for asthma are higher in the inner city and in lower socioeconomic
groups. The exact cause of these differences might be due to genetic, socioeconomic,
and/or access to health care issues. Direct costs (doctors' visits, hospitalization,
drugs, etc.) and indirect costs (work and school absenteeism, etc.) of
asthma vary, depending on the reference, but are estimated to be approximately
$6 billion per year.
Why the ever-increasing incidence of asthma in the last three decades?
Some blame new home construction in the 1970s, when higher fuel costs prompted
the construction of more airtight homes. Newer houses are more insulated
and have less air exchange than older homes. Wall-to-wall carpet is much
more common, as is central heating. Synthetic building materials laden
with chemicals also enjoy greater utilization by builders. These "improvements"
in construction make for a more closed micro-environment that has insufficient
fresh air and is more conducive to the growth of microorganisms.
Other researchers point the finger at environmental pollutants. Industrialization
of countries and the use of fossil fuels have paralleled the incidence
of respiratory disease. There is good evidence that the increases in ozone,
nitrogen dioxide, sulfur dioxide, and particulates in the atmosphere have
exacerbated allergic diseases, including asthma, due to irritant effects
of these substances causing chronic inflammation, as well as interactions
with allergens and amplification of allergic reactions. [ 2,3 ]
Changes in diet including an increased intake of omega-6 fatty
acids and a decreased intake of nutrients such as magnesium and altered
intestinal microflora are also hypothesized as contributors to the increased
incidence of asthma. [ 2,4,5 ]
There is also the possibility that the practice of vaccinating children
has contributed to this increase in asthma incidence, although presently
this theory has not been studied thoroughly. Investigators in New Zealand,
which has one of the highest rates of asthma in the world, found that 23
children who had not been immunized with the diptheria/tetanus/pertussis
(DPT) and polio vaccines had no episodes of, or physician consultations
for, asthma, whereas a group of immunized children had a 23-percent incidence
of asthma. [ 6 ] Researchers in England note
similar results in a survey of 446 children. In a group of 203 children
who had not been immunized for pertussis, two percent had a diagnosis of
asthma at eight years of age, compared to 11 percent of 243 who had been
vaccinated for pertussis (p=0.0005). [ 7 ] However,
Swedish researchers did not find this connection in a study of 9,000 children
given either DPT or only the DT components. [ 8 ]
The Role of Inflammation in Asthma
The underlying patho-physiology of asthma, regardless of allergic components
or triggering mechanisms, is airway inflammation. At the center of this
improper inflammatory reaction is the T-cell. There is increasing evidence
that the underlying process driving and maintaining the asthmatic inflammatory
process is an abnormal or inadequately regulated CD4+ T-cell immune response
to otherwise harmless environmental antigens. The major CD4+ T-cell subset
involved in this process is the CD4+ Th2 subset, which produces a series
of cytokines (secondary messaging molecules), including interleukin-4 (IL-4),
IL-5, IL-6, IL-9, IL-10, and IL-13 (Table 1). These cytokines stimulate the growth, differentiation, and recruitment
of mast cells, basophils, eosinophils, and B-cells, all of which are involved
in humoral immunity and the allergic response. The other subset of CD4+
cells is the Th1 cell, which is responsible for production of interferon
gamma (IFN-g) and interleukin-2 (IL-2), which are involved in delayed hypersensitivity
responses and cellular immune responses to intracellular parasites and
viruses. It is not yet known precisely why individuals with asthma have
this overriding Th2 activity. It may be that genetics, viruses, fungi,
heavy metals, nutrition, and pollution all contribute to this debilitating
and sometimes deadly disease process (Table 2).
Antigen-specific IgE is partly responsible for initiation of an allergic
response in asthma. Antigens cross-link with IgE on mast cells, which then
spill their contents (histamine, leukotrienes) and further amplify the
inflammatory response by damaging local tissue and attracting other lymphocytes.
The regulation of IgE production involves interactions between antigen-presenting
cells, and B and T lymphocytes. Antigen-presenting cells such as macrophages
and dendritic cells present an antigen to CD4+ Th2 cells, which secrete
cytokines that magnify the immune response. IL-4 produced by Th2 cells
stimulates IgE production in B-cells, while IL-5 stimulates eosinophil
differentiation and mobilization to inflammatory sites (Figure1). IL-10 enhances the growth and differentiation of mast cells and
very importantly inhibits the production of IFN-g. It appears
the presence of excess IL-4 can also "switch" cytotoxic CD8+
cells from their normal production of IFN-g (which promotes antiviral and
antitumor activity) to production of IL-4 and IL-5, further augmenting
inflammatory activity. [ 9-18 ]
The inflammatory process is also promoted when histamine and leukotrienes
are released by mast cells. Histamine acts very quickly and stimulates
bronchoconstriction and excess mucus production. After the initial release
of histamine, mast cells and other leukocytes manufacture and release leukotrienes,
eicosanoid molecules that also enhance the inflammatory response. In this
late-phase response, leukotrienes lipid-based molecules created by
the action of the enzyme 5-lipoxygenase on arachidonic acid in cell membranes
exacerbate the broncho-constriction brought on by histamine. Leukotriene
B4 (LTB4) is a very potent mediator of bronchoconstriction and chemotaxis.
The cysteinyl leukotrienes leukotrienes bound to the amino acid cysteine
which include LTC4, LTD4, and LTE4, also attract leukocytes, in addition
to their involvement in broncho-constriction and mucus production. The
end result of these complex interactions is a cascading immune and inflammatory
response characterized by airway eosinophilia, mucus hypersecretion, and
airway hyper-responsiveness the hallmarks of asthma.
Nutrients and Asthma
Vitamin C
There is reason to believe oxygen radicals are involved in the pathophysiology
of bronchial asthma. Inflammatory cells generate and release reactive oxygen
species, [ 100 ] and inflammatory cells from
asthma patients produce more reactive oxygen species than non-asthmatics. [ 101,102 ]
Significantly decreased levels of vitamin C and vitamin E were found in
lung 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 of vitamin
E, beta-carotene, and ascorbic acid during an asymptomatic period, with
elevated levels of lipid peroxidation products during an asthma attack. [ 104 ]
To combat the increased oxidant burden in asthmatics, the attainment and
maintenance of optimal levels of antioxidant nutrients might be essential.
Epidemiological studies of vitamin C intake and asthma symptoms and
respiratory function note a beneficial overall effect of vitamin C. Generally,
as vitamin C intake rises, FEV1 and FVC (forced vital capacity) increase. [ 105,108 ]
Yet the effect of vitamin C on asthma remains controversial, as studies
on vitamin C supplementation in asthma patients have yielded contradictory
results. For example, asthma patients subjected to methacholine challenge
testing alone and after ascorbic acid supplementation (1 g one hour prior
to challenge) were able to withstand greater doses of methacholine after
vitamin C dosing. [ 109 ] In this test, methacholine,
a bronchoconstricting drug, is inhaled. In those with hyper-reactive airways,
there will be a greater constriction of pulmonary smooth muscle and loss
of lung function. However, short-term dosing with ascorbic acid failed
to improve bronchial hyper-reactivity with inhaled histamine challenge. [ 110 ]
Schachter and Schlesinger studied the effect of ascorbic acid on exercise-induced
asthma, and concluded that ascorbic acid has a mild bronchodilatory effect
in exercise-induced bronchospasm, seen as a protective effect on FEV1 and
FVC compared to placebo. [ 111 ]
Reviews regarding vitamin C and asthma point to the fact that the studies
performed to date, whether showing positive or negative effects, utilized
short-term vitamin C dosing, as if they were attempting to assess an immediate
effect of vitamin C only, and not the effects of long-term optimal blood
and tissue levels of this nutrient. [ 112,113 ]
Long-term supplementation studies of vitamin C, asthma symptomatology,
and pulmonary function need to be conducted to further elucidate vitamin
C's role in asthma treatment.
Vitamin B6
Pyridoxal 5'-phosphate (PLP), the active form of vitamin B6 in the body,
is involved in numerous biochemical processes, and has been found in lower
concentrations in asthma patients. [ 114 ] However,
investigations of the therapeutic efficacy of B6 supplementation have resulted
in mixed results. Treatment of asthma with pyridoxine (50 mg twice daily)
resulted in improvements in a reduction of asthma exacerbations and wheezing
episodes in adults. [ 114 ] In 76 children with
asthma, B6 supplementation (100 mg pyridoxine HCl twice daily) resulted
in fewer bronchoconstrictive attacks; less wheezing, cough, and chest tightness;
and less use of bronchodilators and steroid medications. [ 115 ]
A double-blind trial of B6 (300 mg/day pyridoxine HCl) in steroid-dependent
asthma patients resulted in no change in lung function. [ 116 ]
Asthma patients treated with the bronchodilator theophylline have lower
blood levels of PLP, possibly due to PLP depletion secondary to its use
in theophylline metabolism. Theophylline is not used as much as it once
was, mostly due to side effects and its narrow therapeutic range; [ 117,118
] however, monitoring of vitamin B6 levels and supplementation
if warranted should be considered for individuals using this drug.
Vitamin B12
It has been reported that children with asthma may be B12 deficient,
although there is no peer-reviewed literature to corroborate such a statement.
Jonathan Wright, MD, and Alan Gaby, MD, relate that asthmatic children
respond well to B12 supplementation, particularly if they are sulfite-sensitive.
Daily doses of 1000-3000 mcg may be needed. [ 119 ]
Magnesium
Magnesiumis a cofactor in over 300 biochemical processes in the body,
and is especially vital to the contraction/relaxation state of smooth muscle.
Magnesium and calcium work in concert to regulate the contraction and relaxation
of smooth muscle. Low magnesium enhances the contraction activity of calcium,
while higher magnesium levels inhibit calcium and promote relaxation. Hypomagnesemia
is common in asthmatics, [ 120-123 ] and worsens
in more severe cases. [ 120,121 ]
Serum levels are often used to assess magnesium status; however, serum
magnesium can be normal while intracellular magnesium is deficient. Intracellular
assessment utilizing erythrocytes or leukocytes is recommended for an accurate
depiction of magnesium status. Intracellular magnesium was assessed in
22 asthma patients and compared with 38 controls with allergic rhinitis.
Magnesium levels were significantly lower in individuals with asthma versus
controls. Lower intracellular magnesium was correlated with increased airway
hyper-reactivity via the methacholine challenge test. Magnesium levels
did not significantly affect FEV1. [ 122 ] Similar
findings were recently reported by Hashimoto et al. [ 121 ]
While low magnesium status is a consistent finding, the role of magnesium
supplementation is more ambiguous.
A large British study of dietary magnesium intake and asthma symptoms
in 2,633 people found individuals who had a greater dietary intake of magnesium
had a significantly higher FEV1 and significantly decreased airway hyper-reactivity. [ 124 ]
In a randomized, double-blind, placebo-controlled crossover study, Hill
et al reported significantly fewer asthma symptoms and reduced subjective
bronchial hyper-reactivity in patients given 400 mg magnesium per day as
a dietary supplement. However, objective measurements of pulmonary function
were not significantly better in the three-week study, and use of short-acting
beta agonist inhaler medications was not decreased. [ 125 ]
It might be that a three-week trial, while seeming to improve aspects of
patient subjective symptomatology, is not long enough to have a long-term
stabilizing effect on pulmonary function. An investigation on the effects
of long-term magnesium supplementation to correct tissue levels of this
mineral seems warranted.
Intravenous magnesium sulfate is a critical treatment component for
severe asthma seen in the emergency department in many hospitals. Intravenous
magnesium often relieves symptoms soon after infusion is begun, [ 126 ]
and can decrease the need for intubation in status asthmaticus [ 127 ]
and respiratory failure. [ 128 ] In recent pediatric
studies, addition of magnesium sulfate IV to standard emergency care initiated
faster improvement in PEF and oxygen saturation in patients not responsive
to conventional treatments. [ 129,130 ]
Another pediatric study of 30 patients with an acute asthma exacerbation
used a high-dose protocol of 40 mg/kg magnesium sulfate infused over a
20-minute period. Significant improvement was noted at 20 minutes, and
a much greater improvement was noted at 110 minutes: PEF had improved 26
percent (vs. 2% in saline controls), FEV1 24 percent (2%), and FVC 27 percent
(3%). All results were highly significant (p<0.001). [ 131 ]
Acute administration of intravenous magnesium has been studied as a
stand-alone therapy, as well as an adjuvant to conventional beta-adrenergic,
methyl xanthine, and steroid treatment. Results have been mixed, with some
studies finding statistically significant improvements in lung function [ 130-134 ]
and others determining that IV magnesium sulfate is not helpful. [ 135-136 ]
In two recent reviews of the subject, IV magnesium sulfate was found in
one review to be of significant benefit to patients with severe asthma, [ 137 ]
and found not to affect treatment outcomes in a meta-analysis. [ 138 ]
It is unknown why these various investigations resulted in diverse outcomes.
Some intravenous trials used 1-2 g magnesium sulfate alone, while others
used a similar dose as an initial bolus, followed by slower drips over
the next few hours. There does not seem to be a pattern of results following
a specific type of protocol. Regardless of the inconsistent results seen
with IV magnesium sulfate, asthmatics do tend to have lower intracellular
levels of magnesium, and supplementation to correct those levels seems
warranted.
Zinc
There is little direct evidence of zinc deficiency causing asthma symptoms,
but asthma patients have been shown to have lower plasma zinc than healthy
controls. [ 139 ] Serum and hair zinc were significantly
lower in individuals with asthma and atopic dermatitis. [ 140 ]
Similar results were reported by Di Toro et al in asthmatics versus controls. [ 141 ]
It has been proposed that a zinc deficiency switches the Th1 immune
response toward a Th2-type response, which, as mentioned earlier, is a
hallmark of asthma pathophysiology. [ 142,143 ]
Prasad et al studied how mild zinc deficiency affects the immune system.
Zinc deficiency caused an imbalance between Th1 and Th2 functions, with
a subsequent increased production of IL-4, IL-6, and IL-10, and decreased
production of IL-2, IFN-g, and tumor necrosis factor alpha. They also noted
decreased NK-cell activity and decreased numbers of cytotoxic CD8+ T-cell
precursor cells. [ 144 ] In two other studies
of zinc and immunity, individuals deficient in zinc exhibited diminished
Th1 activity, but unaffected Th2 activity, creating a relative Th1 deficiency. [ 145,146 ]
Even without the benefit of definitive research on long-term zinc supplementation
in asthma patients, this author believes it is vitally important to ensure
proper zinc nutriture in asthma patients to avoid a potential zinc-deficiency-induced
exacerbation of asthma symptoms due to increased Th2 immune activity.
Selenium
Glutathione is a vital component of the body's antioxidant system. Glutathione
peroxidase (GSH-Px) is the selenium-containing enzyme that uses glutathione
as a cofactor to metabolize hydrogen peroxide, and can thus protect against
oxidative damage. Individuals with asthma tend to have increased oxidative
activity, lowered selenium status, and decreased activity of glutathione
peroxidase. [ 147-150 ]
Only one study has been conducted on selenium supplementation to combat
the increased pulmonary oxidative burden in asthmatics. Hasselmark et al
performed a double-blind, placebo-controlled study in which asthma patients
were given 100 mcg sodium selenite (containing 46 mcg elemental selenium)
for 14 weeks. Significant increases were seen in serum and platelet selenium
and GSH-Px activity, and improvements were seen in subjective symptomatology.
However, objective measurements of lung function were not changed. [ 151 ]
It may be that the supplemental dosage given was too low and that a supplemental
dose of 200-250 mcg might be more beneficial. More study is warranted in
this important arena.
Omega-3 Fatty Acids
Intermediate and end-products of fatty acid metabolism are known to
have potent effects on the inflammatory process. Prostaglandins and leukotrienes
from arachidonic acid metabolism are highly inflammatory molecules, and
play an important role in the pathophysiology of asthma. Arachidonic acid
is released from cell membrane phospholipids of activated immune cells
(via activity of the enzyme phospholipase A2) in response to various immunological
stimuli. Prostaglandins and leukotrienes resulting from arachidonic acid
metabolism are pro-inflammatory molecules. Leukotriene B4 (LTB4) is involved
in bronchoconstriction and leukocyte chemotaxis, while the cysteinyl leukotrienes
LTC4, LTD4, and LTE4 are far more potent promotors of smooth
muscle constriction and mucus production. An overabundance of these leukotrienes
is implicated in the pathophysiology of asthma.
Research into the effects of leukotrienes has spurred the development
of new drugs that block the activity of these potent substances. These
drugs appear to be of benefit in some asthma patients, particularly those
with more severe disease. Steroid medications, either inhaled or systemic
via oral or parenteral dosing, have been the mainstay of anti-inflammatory
asthma drug therapy. In contrast to the new leukotriene-inhibiting drugs,
corticosteroids strongly inhibit the release of arachidonic acid from cell
membranes by blocking the activity of phospholipase A2, resulting in a
greatly diminished amount of prostaglandins and leukotrienes. Two LTD4
receptor antagonists, zafirlukast and montelukast, have been approved for
use in asthma and provide moderate improvements in objective lung function
tests, as well as less reliance on inhaled steroid medications. A 5-lipoxygenase
inhibitor, zileuton, has demonstrated similar results. [ 152,153 ]
Cromolyn sodium, used prophylactically in asthma, has been shown to inhibit
LTE4-induced bronchoconstriction, probably by inhibiting mast cell degranulation. [ 154 ]
Cold-water fatty fish contain relatively large amounts of the omega-3
fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).
When these fish are eaten, or when oil derived from them is taken as a
supplement, EPA and DHA displace arachidonic acid from cell membranes.
When these cells are stimulated they subsequently release relatively higher
concentrations of fish-derived oils. The resultant downline metabolites
of EPA and DHA differ from arachidonic acid metabolites. EPA and DHA are
converted by cyclooxygenase into 3-series prostaglandins, and by lipoxygenase
to 5-series leukotrienes, both categories of which are far less potent
inflammatory mediators than the 2-series prostaglandins and 4-series leukotrienes
arising from arachidonic acid metabolism [ 155,156 ]
(Figure 2). Because of this shift toward
less inflammatory eicosanoids, one would expect to see less inflammatory
activity in the lungs, and a subsequent improvement in asthma symptoms
and lung function. Epidemiological studies of dietary fish intake and risk
of asthma show an inverse correlation; i.e., more fish consumed equals
less risk of asthma. [ 157,158 ] However, the
clinical data is equivocal, with well-designed studies showing both positive
and negative results from omega-3 fatty acid supplementation.
A group (n=7) of individuals with seasonal asthma were supplemented
with 3 g/d of a fish oil concentrate containing approximately 1,300 mg
each of EPA and DHA, resulting in decreased residual volume (which is usually
increased in asthma patients) and decreased bronchial reactivity. [ 159 ]
Broughton et al studied 26 asthma patients after a one-month regimen
of low- or high-dose omega-3 fatty acid intake. Patients' dietary intake
of fish was evaluated, then supplementation was individualized for each
patient so they ingested omega-3 and omega-6 fatty acids in a ratio of
0.1:1 or 0.5:1. This provided either 0.7 grams EPA/DHA or 3.3 grams EPA/DHA,
respectively (the ratio of EPA to DHA in this study was not given). The
high-dose protocol stimulated an improvement in bronchial reaction to methacholine
challenge in 40 percent of subjects, compared to a reduction in lung function
in the low-dose group. Leukotriene B5 was increased in the high-dose group
and was predictive of lung function. [ 160 ]
This seems to indicate a role for fish oil supplementation in asthma treatment.
In a separate study, after 10 weeks of supplementation with 3.2 g EPA
and 2.2 g DHA per day, 12 subjects underwent histamine challenge, exercise
challenge, and neutrophil studies to assess the efficacy of fish supplementation
in asthma. Although there was a significant increase in omega-3 fatty acid
content of neutrophils and a 50-percent inhibition of LTB4 synthesis, there
was no detectable change in the clinical outcome; e.g., no significant
change in histamine response, exercise response, FEV1, or symptom score. [ 161 ]
Hodge et al reported similar results in their study of asthmatic children.
After six months' supplementation with 1.2 g/d of omega-3 fatty acids,
a five-fold increase in plasma EPA and a decrease in peripheral blood eosinophils
was seen, but there was no change in symptom severity. [ 158 ]
The reason for these mixed findings is not known.
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