The most potent chemical mediators in asthma are the lipoxygenase products (i.e., leukotrienes) (Figure 147-1). The leukotrienes composing SRS-A (LTC₄, LTD₄, LTE₄) are 1000 times more potent as stimulators of bronchial constriction than histamine. Researchers have observed that asthmatics have an imbalance in arachidonic acid metabolism, leading to a relative increase in lipoxygenase products.¹¹ Platelets from asthmatic patients show a 40% decrease in cyclooxygenase-derived metabolites and a 70% increase in lipoxygenase products. This pathophysiologic alteration is further aggravated in “aspirin-induced asthma.” Aspirin and other nonsteroidal anti-inflammatory drugs (e.g., indomethacin, phenylbutazone) inhibit cyclooxygenase while promoting lipoxygenase.^12,¹³ The net result is a shunting of arachidonic acid toward the lipoxygenase pathway and the production of excessive levels of leukotrienes.

FIGURE 147-1 Arachidonic acid metabolism.

Tartrazine (yellow dye no. 5) is also a cyclooxygenase inhibitor and known inducer of asthma, particularly in children.¹² Tartrazine is ubiquitous in processed foods and can even be found in vitamin preparations and antiasthmatic prescription drugs (e.g., aminophylline). Tartrazine may also indirectly support the asthmatic process via its role as an antimetabolite of vitamin B₆ (see later discussion of tryptophan).

Autonomic Nervous System

The relationship between the autonomic nervous system and bronchial asthma represents an interaction between parasympathetic and sympathetic innervation and beta₂ adrenergic receptors (which are localized in lung tissue and react to circulating catecholamines).¹⁴ Stimulation of the parasympathetic vagus nerve results in airway constriction. This vagal mechanism involves the following: release of acetylcholine at the synapse, subsequent binding to its receptor on smooth muscle tissue, and subsequent formation of cyclic guanosine monophosphate (cGMP). Accumulation of cGMP or a relative deficiency in cyclic adenosine monophosphate (cAMP), or both, result in constriction of the airway smooth muscle, as well as degranulation of mast cells and basophils. Decreased sympathetic activity or diminished beta₂ receptor numbers or sensitivity also promote the cyclic nucleotide imbalance. Some of the mediators discussed earlier block beta₂ receptors and elevate cGMP levels both directly and indirectly.

Adrenal Gland

The activity of the adrenal gland is important in asthma owing to its hormones cortisol and epinephrine. Cortisol is an effective prime activator of beta receptors and epinephrine is considered to be the prime stimulator of beta receptors. It has been suggested that during asthmatic attacks there is a relative deficiency of cortisol and epinephrine (which stimulates beta₂ receptors to catalyze the formation of cAMP from AMP). This leads to a decrease in the cAMP:cGMP ratio, resulting in bronchial constriction.

Pertussis Vaccine

An evaluation of health criteria among 448 children and adolescents in Britain who had received only breast milk for the first 6 months of life and in particular on the first day after birth produced some interesting findings. All of the children were weaned after 1 year of age and were older than 4 years at the time the parents responded. The mean age was 7.87 years. In response to the question “Has your child ever been diagnosed as asthmatic?” there were 30 positive answers (6.72%). The surprise came when the researchers classified the respondents according to whether or not they had received the pertussis vaccine.¹⁵

Among the 243 immunized children, 26 were diagnosed as having asthma (10.69%). In contrast, of the 203 children who had not been immunized, only 4 had asthma (1.97%). The relative risk of developing asthma from the pertussis vaccine was 5.43 in this study. The significance of this finding was at the P = 0.0005 level.

Even though all of the children who received the pertussis vaccine received other vaccinations, the researchers suspected that the statistical evidence focused on pertussis. Among the children who did not receive the pertussis vaccine, most had received some other vaccination. Of the 91 subjects of the study who received no vaccines, only 1 had asthma, compared with 3 with asthma in the 112 who had other vaccinations. Therefore, the relative risk of developing asthma is about 1% in children receiving no immunizations, 3% in those receiving vaccinations other than pertussis, and 11% in those receiving pertussis vaccine. Another finding to weigh in the group not immunized to pertussis is that 16 developed whooping cough compared with only 1 in the immunized group.

Influenza Vaccine

One evaluation of more than 9600 children was employed to determine the safety of cold-adapted trivalent intranasal influenza virus vaccine in children. Although this relatively new vaccination was deemed safe for children and adolescents, a significantly increased relative risk of 4.06 was observed in children 18 to 35 months of age for asthma and associated reactive airways disease.¹⁶

Therapeutic Considerations

As with many complex diseases, the initial cause or causes of asthma (e.g., hypochlorhydria) may initiate a sequence of events that becomes self-propagating (e.g., hypochlorhydria-induced food allergies leading to increased intestinal permeability and then to increased susceptibility to food allergy). Effective treatment requires control of both the initiating cause or causes and the induced physiologic abnormalities.

General

Hypochlorhydria

Fractional gastric analyses in 200 asthmatic children by Bray in 1931 showed that 80% of them had gastric acid secretions below normal levels.¹⁷ This high occurrence suggests that decreased gastric acid output may predispose these children to food allergies and has a major impact on the success of rotation or elimination diets or both and, if not corrected, on the development of additional food allergies.

Increased Intestinal Permeability

The presence of food allergies is thought to be responsible for asthmatics having been shown to have “leaky guts.”¹⁸ As a result of increased gut permeability, there an is increased antigen load on the immune system. This subsequently overwhelms the immune system, increasing the likelihood of developing additional allergies as well as increasing bronchoconstrictive compounds in the circulation. It is essential to identify offending foods as soon as possible so as to avoid the development of further allergies.

Candida Albicans

An overgrowth of the common yeast Candida albicans in the gastrointestinal tract has been implicated as a causative factor in allergic conditions including asthma. Apparently the acid protease produced by C. albicans is the responsible allergen.¹⁹ Appropriate anticandidal therapy may result in significant clinical improvement of asthma in many cases.

Food Additives

Vitally important in the control of asthma is the elimination of food additives.²⁰ Artificial dyes and preservatives are widely used in foods, beverages, and drugs. The most common coloring agents are azo dyes—tartrazine (orange), sunset yellow, amaranth, and coccine (red)—and the nonazo dye pate blue. The most commonly used preservatives in food are sodium benzoate, 4-hydroxybenzoate esters, and sulfur dioxide. Various sulfites are commonly used in prepared foods.

Tartrazine, benzoates, sulfur dioxide, and sulfites in particular have been reported to cause asthma attacks in susceptible individuals.^20,²¹ It is estimated that 2 to 3 mg of sulfites are consumed each day by the average U.S. citizen, while an additional 5 to 10 mg are ingested by wine and beer drinkers.²¹ The largest sources are the salads, vegetables (particularly potatoes), and avocado dip served in restaurants. A customer can ingest 25 to 100 mg of metabisulfite in as little as one restaurant meal. It has been postulated that a molybdenum deficiency may be responsible for sulfite sensitivity.²² Sulfite oxidase, the enzyme responsible for neutralizing sulfites, is molybdenum dependent.

Salt

Strong evidence indicates that an increased intake of salt increases bronchial reactivity and mortality from asthma.^23,²⁴ The degree of bronchial reactivity to histamine is positively correlated with the 24-hour urinary sodium excretion and rises with increased dietary sodium. Because the severity of asthma correlates with the degree of bronchial reactivity, the severity of asthma can clearly be influenced by alterations in dietary sodium consumption.

Estrogen and Progesterone

For female patients who experience severe asthma symptoms, it may be useful to consider therapeutic regimens that encourage a decrease in hormonal fluctuations. Some studies find estrogen withdrawal to increase lung contractility.²⁵ However, other studies find little relationship between estrogen use and asthmatic symptoms.²⁶^–²⁸ Estrogen²⁹ and progesterone are both known to act as smooth muscle relaxants. It may be that the airways of premenopausal and postmenopausal women may respond differently to exogenous hormone replacement and therefore need to be assessed independently with this intervention.

One interesting review of more than 90 papers published from 1966 to 2001 found that during the premenstrual and menstrual phases, when hormone levels are low, asthmatic women have been found to experience increased asthma exacerbations, increased hospitalizations for asthma, and decreased pulmonary function. Additionally, women who experienced decreased fluctuations in hormone levels either by becoming pregnant or by starting oral contraceptive therapy tended to have improvements in pulmonary function and fewer requirements for medication.²⁵ Natural hormone replacement may offer a safer approach than synthetic hormones, although no studies to verify the safety or efficacy of these natural forms of female sex hormones have been conducted. In the longer term, natural therapeutics designed to balance estrogen and progesterone, along with specific recommendations from this chapter, may offer the most risk-free relief for those premenopausal and postmenopausal women who suffer from asthmatic exacerbations (see Chapter 188 and 202).

Dehydroepiandrosterone

Decreased levels of dehydroepiandrosterone (DHEA) have been shown to be common in postmenopausal women with asthma compared with matched controls.³⁰ One study of 55 asthmatic and 20 healthy postmenopausal women aged 48 to 60 before hormone replacement therapy and after 6 months of transdermal 17b-estradiol (E2) and medroxyprogesterone acetate treatment demonstrated a significant increase in serum DHEA levels in the asthmatic group, with no change in the control group.³¹ Whether DHEA itself produces any therapeutic benefit in asthma remains to be demonstrated; however, given its important role in proper immune function, an ability to produce positive effects is certainly possible.

Melatonin

There is some concern regarding elevated melatonin levels contributing to increased airway inflammation in patients with nocturnal asthmatic exacerbations ^32,³³ as well as proinflammatory reactions in rheumatoid arthritis.³⁴ In the study of people with nocturnal asthma, peak measured serum melatonin level was significantly and inversely correlated with overnight change in FEV₁ in subjects with nocturnal asthma but not in those with non-nocturnal asthma or healthy controls. An interesting note is that this study observed a delayed release of melatonin in the patients with nocturnal asthma. Therefore it is theoretically possible that supplementation combined with an earlier sleep regimen may help regulate this late peaking of melatonin and possibly mitigate symptoms. Nevertheless, the practitioner may want to avoid giving this supplement to patients with asthma, especially the nocturnal type, until more studies are conducted regarding melatonin’s immunotherapeutic effect.

Diet

Beneficial Foods

A number of publications corroborate the notion that people who have a diet rich in fruits and vegetables have a lower risk of poor respiratory health.³⁵^–³⁷ This effect is most likely due to the increased levels of antioxidants in such foods. One epidemiologic review³⁸ found that among children, consumption of fresh fruit, particularly fruit high in vitamin C, has been related to a lower prevalence of asthma symptoms and better lung function. This effect was observed even at low levels of fruit consumption (one or two servings per week vs. fewer than one serving per week), which suggests that a small increase in fruit intake could be beneficial. This same review discussed consumption of fish as also being related to lower airway hyperreactivity among children and better lung function in adults.

A study of Scottish adults also found a dose-response relationship between fruit consumption and pulmonary function, whereby increased fruit consumption led to decreases in phlegm and better pulmonary function.³⁹ In addition, a “reasonable” intake of fruit (>180 g/day), whole grains (>45 g/day), and moderate alcohol consumption (one to three glasses a day) was associated with a 139-mL higher FEV₁ and a 50% lower prevalence of chronic obstructive pulmonary disease versus diets that did not meet these intake requirements.³⁵ Finally, one study of 607 asthma patients and 864 controls highlighted apples and moderate red wine consumption as sources of antioxidants that decreased asthma severity.⁴⁰

Dietary intake of soy foods may be helpful, as the soy isoflavone genistein is associated with reduced severity of asthma. Although this effect may be due to some antioxidant action, studies have also shown that genistein is able to block eosinophil leukotriene C(4) synthesis and inhibit the pathway of NF-κB and TNF-α in asthma patients.⁴¹^–⁴³

Food Allergy

Many studies have indicated that food allergies play an important role in asthma (see Chapter 15.)⁴⁴^–⁴⁸ Adverse reactions to food may be immediate or delayed. Double-blind food challenges in children have shown that immediate-onset sensitivities are usually due (in decreasing order of frequency) to egg, fish, shellfish, nuts, and peanuts, while foods most commonly associated with delayed onset include (in decreasing order of frequency) milk, chocolate, wheat, citrus, and food colorings.⁴⁶ Elimination diets have been successful in identifying allergens and treating asthma and are a particularly valuable diagnostic and therapeutic tool in infants.⁴⁹ Elimination of common allergens during infancy (first 2 years) has been shown to reduce allergic tendencies in high-risk children (e.g., strong familial history).⁵⁰

Breastfeeding

Many studies have demonstrated the protective effect of breastfeeding in the prevention of asthma. One study examined the association of breastfeeding and the presence of chronic respiratory symptoms among 5182 Brazilian schoolchildren 7 to 14 years of age. Ninety percent of the mothers in this population had breastfed their infants. After adjusting for potential confounding factors, these researchers revealed that children who had not been breastfed were more likely to have a medical diagnosis of asthma.⁵¹ One Iraqi study additionally showed that the vitamin C content of breast milk was significantly correlated with the maternal intake of vitamin C: low vitamin C intake by mother translates to low intake by the child, thus leaving him or her more susceptible to oxidative stress.⁵²

The Canadian Asthma Primary Prevention study collected 2 years of data in which researchers chose 545 infants who were considered at high risk for asthma on the basis of a history of familial atopy. These children were broken down into control and intervention groups. The interventions included (1) measures to control house dust; (2) recommendations for avoidance of pets, environmental tobacco smoke, and day care during the first year; and (3) only breastfeeding or use of partially hydrolyzed whey formula until at least the age of 4 months. At 1 year of age, risk of asthma was significantly reduced by 34%. At 2 years of age, significantly fewer children had asthma in the intervention group than in the control group (16.3% vs. 23%) and 60% fewer of those in the intervention group had persistent asthma. A 90% reduction in recurrent wheeze was seen in the intervention group compared with the control group.⁵³ Multifactorial studies like these are quite useful in order to elucidate the multitude of changes necessary to affect multifactorial diseases like asthma in an effective manner.

Antibiotics, Probiotics, and Mucosal IgA

In a combined analysis of seven studies involving more than 12,000 youngsters, researchers at the University of British Columbia found that those prescribed antibiotics before their first birthday were more than twice as likely as untreated kids to develop asthma.⁵⁴ And, if they had multiple courses of antibiotics it bumped up the risk even higher—16% for every course of the drugs taken before age 1. There are a couple of explanations for this association between antibiotic use and asthma. One is that antibiotics contribute to a state of “excess hygiene,” leading to a reduced exposure to microbes. This, in turn, creates an oversensitive immune system, mounting an over-the-top allergic reaction to pollen and dust mites and ultimately resulting in asthma. The second explanation is that antibiotics have a negative effect on the normal flora of the gastrointestinal tract and respiratory passages. Some studies have shown that giving probiotics (active cultures of Lactobacillus and Bifidobacterium species) lowers the risk of atopic allergic diseases like asthma and eczema. Some of this protective effect may be mediated by mucosal IgA, which participates in antigen elimination. In a cohort of 237 allergy-prone infants given a combination of four probiotic strains or placebo, it was shown that supplementation with probiotics increased fecal IgA and calprotectin while reducing inflammatory markers (e.g., α₁-antitrypsin and tumor necrosis factor alpha).⁵⁵ In infants with high fecal IgA concentration at the age of 6 months, the risk of having any allergic disease or any IgE-associated (atopic) disease before the age of 2 years was cut by nearly 50%. High intestinal IgA in early life is associated with minimal intestinal inflammation and indicates a reduced risk for IgE-associated allergic diseases.

Vegan Diet

A long-term trial of a vegan diet (elimination of all animal products) provided significant improvement in 92% of the 25 treated patients who completed the study (9 dropped out).⁵⁶ Improvement was determined by a number of clinical variables including vital capacity, FEV₁, and physical working capacity as well as by biochemical indices such as haptoglobin, IgM, IgE, cholesterol, and triglyceride levels in the blood. The researchers also found a reduction in the vulnerability to infection. Importantly, however, although 71% of the patients responded within 4 months, 1 year of therapy was required before the 92% level was reached.

The diet excluded all meat, fish, eggs, and dairy products. Drinking water was limited to spring water (chlorinated tap water was specifically prohibited), and coffee, ordinary tea, chocolate, sugar, and salt were excluded. Herbal spices were allowed, and water and herbal teas were allowed up to 1.5 L/day. Vegetables eaten freely were lettuce, carrots, beets, onions, celery, cabbage, cauliflower, broccoli, nettles, cucumber, radishes, Jerusalem artichokes, and all beans except soybeans and green peas. Potatoes were allowed in restricted amounts. A number of fruits were also eaten freely: blueberries, cloudberries, raspberries, strawberries, black currants, gooseberries, plums, and pears. Apples and citrus fruits were not allowed, and grains were either restricted or eliminated.

The beneficial effects of this dietary regimen are probably related to three areas: