Chapter 7 Asthma
OVERVIEW AND AETIOLOGY
Asthma is a chronic inflammatory disorder of the airways and may be classed as atopic (extrinsic) or intrinsic.1 It is marked by recurrent attacks of paroxysmal dyspnoea with wheeze, due to spasmodic contraction of the bronchi.1,2 Key indicative symptoms include wheeze, cough, shortness of breath, chest tightness and sputum production.3 The signs and symptoms of asthma may be subtle, and some children present with atypical features such as recurrent respiratory tract infections, seasonal asthma and night-time cough. Often symptoms will present or worsen in relation to certain triggers.3
The most common theory of asthma development proposes that the condition is the result of multicellular inflammation driven by airway hyperresponsiveness, with airway remodelling and potentially permanent bronchial obstruction.4,5 This inflammation is due to the recruitment and activation of mast cells, macrophages, dendritic cells, neutrophils and eosinophils with resultant cellular infiltration and airway inflammation.4,5 With the activation of such cells, preformed and generated cytokines and growth factors are released, resulting in the remodelling of the airways with amplified goblet cell
production, smooth muscle hypertrophy and deposition of extracellular proteins.6 The inflammatory mediators also induce changes in the noradrenergic and parasympathetic nervous systems that may lead to bronchial hyperresponsiveness.5
It is postulated that allergen exposure in genetically predisposed individuals leads to T helper type 2 (Th2) proliferation. Th2 cells stimulate B-lymphocytes to produce specific IgE antibodies, which then activate an inflammatory cascade upon subsequent exposure to the allergen (see Figure 7.1).7
In general, infants are born with a disposition towards pro-allergic and pro-inflammatory Th2 immune responses, but early childhood exposure to infections and endotoxins shifts the body towards a predominance of Th1 responses, which suppress Th2 cells and induce tolerance.8 The hygiene hypothesis suggests that in developed countries, the trend towards smaller families,9 cleaner environments10 and early use of vaccinations and antibiotics may deprive children of these Th2-suppressing, tolerance-inducing exposures, partly explaining the continuous increase in asthma prevalence in developed countries.8 It should be noted that, in contrast to this hypothesis, certain studies have identified a pathogenic role for viral respiratory infection in the development of asthma in atopic infants.11
In exercise-induced (intrinsic) asthma, bronchoconstriction seems to be stimulated by moisture loss from the respiratory tract and increased airway cooling due to an increase in ventilation.12 However, despite the lack of identifiable allergenic triggers, immune dysregulation, in the form of inappropriate IgE production and activated T-cells, still seems to be a feature.13
RISK FACTORS
Familial, genetic and environmental factors
Having first-degree relatives with a history of asthma, or a personal or family history of atopy, is a risk factor for the condition.1 Atopic responsiveness is inherited, and genes have been identified that influence bronchial hyperresponsiveness, even in the absence of allergies.14,15
The environment also affects asthma development, particularly during early childhood. Breastfeeding during the neonatal period seems to prevent the development of atopy, perhaps as a desensitisation response to continual oral intake of the allergen.16,17 However, antigen exposure later in infancy seems to promote atopic responses.14 This may partially explain why the early introduction of formula seems to lead to an increase in child body mass index (BMI) and early asthma and atopy.18 Childhood exposure to air pollution has been found to be associated with the development of persistent wheeze and atopy in children living in urban environments.19 Paracetamol use in infancy has also been associated with an increased risk of current wheeze in young children.20
Digestive and dietary factors
Gastrointestinal symptoms appear to be common in children with asthma;21 and an increased prevalence of increased intestinal permeability and cytokines in patients with asthma may support naturopathic theory that leaky gut is associated with the condition.22,23
Gastro-oesophageal reflux has been recognised as a common trigger of asthma,24 via oesophageal acid-induced reflex bronchoconstriction, or microaspiration of acid. A connection has also been made between hypochlorhydria and bronchial asthma.25 This correlation may be the result of inadequate protein digestion,26 increasing atopic allergic reactions. It may also cause poorer nutrient absorption in general,26 affecting the development of atopy and/or bronchial hyperresponsiveness through various deficiencies.
Dietary intake also plays a role in atopic asthma. Nutrient deficiencies, in particular of vitamins D and E, magnesium, potassium, vitamin C and fatty acids, are associated with asthma.27–29 Poor maternal diet has been correlated with a rise in asthma at the ages of 2 and 5 years.28 Asthma is also known to have a number of dietary triggers such as specific ‘allergenic’ foods or food additives.30,31 Hen’s eggs, cow’s milk, soy, wheat, tree nuts, peanuts, fish and shellfish, monosodium glutamate (MSG), tartrazine and sulfites have all been implicated.29
Antibiotic use in the first year of life is associated with an increased risk of wheeze in New Zealand children,20 suggesting that dysbiosis may be a risk factor. This theory is supported by evidence showing that atopic infants have higher levels of i-caproic acid (a marker of Clostridium difficile) and lower populations of lactobacilli, bifidobacteria and Bacteroides than non-atopic children.32
Stress
Stress is a well-known asthma trigger, but it may also play a role in pathogenesis.2,3,33 Parental divorce or separation, exposure to violence and severe disease of a family member all increase the risk of developing atopic conditions.34 Lower socioeconomic status is associated with elevated levels of stress and threat perception, as well as heightened production of IL-5 and IL-13 and higher eosinophil counts in children with asthma.35 Children from this background are more likely to develop asthma, and exhibit poorer health outcomes.36,37 Anxiety disorders and asthma are also common comorbidities, but the exact relationship is unclear.38
Metabolic syndrome
Abdominal obesity and hypertension are both components of metabolic syndrome that increase the risk of asthma-like symptoms.39 Epidemiological studies show that, generally, people with asthma tend to be heavier than those without—a relationship that is more consistent in adults than children.32 Additionally, the risk of asthma seems to increase as body mass index (BMI) rises.40 As both obesity and asthma begin in early life, some researchers have proposed common predisposing factors including genetics, early life weight gain, low physical activity, prenatal diet and nutrition, altered intestinal microflora and adipocytokines.32
CONVENTIONAL TREATMENT
There is a lack of international consensus on conventional diagnosis and treatment, with a significant number of children continuing to suffer symptoms despite current treatment.41 Patient attitudes towards medical professionals and asthma treatment have been found to predict the degree of asthma control a patient is likely to achieve with conventional therapies.42
The National Asthma Education and Prevention Program (NAEPP) proposes a stepwise approach to the management of asthma, based upon severity.3 Medications fall into two categories: short-acting agents designed to relieve airway obstruction in an acute exacerbation, and longer-term prevention therapy:40
| STAGE | ASTHMA SYMPTOMS | RECOMMENDATION |
|---|---|---|
| 1 | Mild, intermittent |
KEY TREATMENT PROTOCOLS
A symptom diary and elimination diet are useful tools to identify trigger factors (see Chapter 5 on food intolerance and allergy). Once known, these should be avoided wherever possible. With time, and naturopathic treatment (including digestive repair and immune support), the patient may be well enough that certain factors cease to be problematic. As the underlying mechanism of airway obstruction is inflammation, a key priority is to manage the inflammatory response with anti-inflammatory, antiallergic and immune-modulating substances, and reduce airway hypersensitivity. On a symptomatic level, respiration will be most efficient and uncomplicated when the bronchioles are clear. Bronchodilation and expectoration are central actions to open the airways and promote symptom-free ventilation. Given the sizeable role of digestive dysfunction in the aetiogenesis of asthma, once symptoms are stabilised, better control and prevention may then be established by redressing intestinal permeability and dysbiosis.
Dampen the inflammatory cascade
Reducing pulmonary inflammation in asthma will improve symptoms and assist in moderating disease progression. A number of herbal agents demonstrate anti-inflammatory actions specific to asthma. Boswellia serrata inhibits 5-lipoxygenase,43 a key cytokine implicated in asthmatic inflammation. Seventy per cent of patients treated with B. serrata showed improvement in their asthma symptoms, as opposed to 27% of controls.44 The anti-inflammatory, antioxidant and antiviral activity of curcumin in Curcuma longa has been effective in treating airway hyperresponsiveness in allergic inflammatory diseases.45,46 The oil of this botanical is also significantly active in removing sputum, relieving cough and preventing asthma,47 and phytochemicals derived from C. longa may interrupt the action of NF-κB (which induces inflammation) and diminish Th2 responses, with a concurrent reduction in asthmatic symptoms.48 Zingiber officinale may also inhibit the release of prostaglandins,49 suppress Th2-mediated immune responses50 and inhibit airway contraction, possibly via blockade of plasma membrane Ca2+ channels.51
Dietary supplementation with omega-3 fatty acids, zinc and vitamin C significantly improved asthma control, pulmonary function tests and pulmonary inflammatory markers in children with moderately persistent bronchial asthma.52 Benefits from essential fatty acids may be derived as far back as fetal development, with research showing that adequate maternal intake corresponds with lower rates of asthma in offspring (see Figure 7.2).53 The ingestion of 2.7 g of omega-3 polyunsaturated fatty acids for the last 10 weeks of pregnancy was shown to have a significant protective effect against the development of asthma in offspring by the age of 16 years.54
Omega-3 fatty acids may also be beneficial in direct treatment, as 3.2 g EPA and 2.2 g DHA daily for 3 to 10 weeks reduces inflammatory markers, pulmonary compromise (fall in FEV1) by nearly 80% and bronchodilator use by up to 20% in exercise-induced asthma.55,56
In the airways of asthmatics, inflammation is often associated with increased generation of reactive oxygen species and free radical damage.57 Thus the antioxidants vitamins A, C and E may be useful. By reducing the effect of the reactive oxygen species produced in the inflammatory process, these modulate the development of asthma and the impairment of pulmonary function.57 Vitamin C supplementation demonstrates a protective effect against exercise-induced airway narrowing in asthmatic subjects.58 Serum levels of the antioxidants alpha and beta carotene have also been positively correlated to lung function and FEV1 and FVC in epidemiological studies.59,60
Quercetin has the ability to inhibit inflammatory cytokine and chemokine production in acute and chronic inflammatory conditions.61,62 High levels of this flavonoid are found in onions, apples, blueberries, curly kale, hot peppers, green and black tea and broccoli.63,64
In asthma, platelet activating factor (PAF) is released in response to exposure to allergens and induces an inflammatory airway response.65 It is a potent bronchoconstrictor,66 and elicits pulmonary and bronchial oedema, leading to airway obstruction and difficulty breathing.67 While pharmaceutical PAF antagonists have not displayed absolute therapeutical efficacy alone, they may be a useful part of a combined treatment strategy.68
Ginkgo biloba is best known for its well-demonstrated neurological effects.69,70 However, it has also shown activity as a PAF antagonist, exerting an anti-inflammatory action and reducing airway hyperresponsiveness and bronchospasm.71 The most active constituents appear to be quercetin and the ginkgolides, in particular ginkgolide B.72 Some researchers also suggest that G. biloba may modulate lymphocyte activation in asthma,73 and in murine models of asthma the herb appears to impede the disease progress by alleviating all established chronic histological changes of lung except smooth muscle thickness.74 Glycyrrhizae from Glycyrrhiza glabra has also demonstrated ability to inhibit PAF production by human neutrophils in a dose-dependent manner.75 Allium cepa exerts antiasthmatic and anti-PAF effects through its thiosulfinate content. In one study, allergen-induced asthma attacks were almost completely inhibited by an A. cepa extract.76 Thus, there may be potential for garlic, onions and shallots to be included in dietary management of asthma.
Immune regulation
Immune dysregulation is a key feature of atopic asthma (and perhaps intrinsic asthma – see above). Strengthening immune resistance generally, rebalancing T-cell levels and restoring immune homeostasis in the lung may decrease sensitisation to allergens and triggers.7 In addition, viral infections are known to worsen asthma symptoms,3 and immune enhancement will help to prevent these.
Herbal immune modulators such as Echinacea angustifolia may be beneficial in supporting the body’s natural resistance to infection and is particularly efficacious in prophylaxis/treatment of upper respiratory tract infections.77 In addition to its significant immune enhancing properties,78 Andrographis paniculata may also be anti-inflammatory via inhibition of the NF-κB pathway.79 Astragalus membranaceus has good traditional evidence as an immune-enhancing herb, and may potentially play a specific role in treating allergic asthma.80 Also useful is Picorrhiza kurroa, which helps to prevent allergen- and PAF-induced bronchial obstruction.76 General immune supportive nutrients are vitamin C, vitamin A, zinc and selenium (for further immune modulators, refer to Chapter 6 on infectious respiratory disease).
Allergy management
Albizzia lebbeck stabilises mast cell membranes in murine models, suggesting that it may inhibit histamine release in allergenic asthma.81 This herb appears to deliver best results in asthma of less than 2 years’ duration.82 Scutellaria baicalensis contains various flavonoids that suppress eotaxin—a chemokine associated with recruitment of eosinophils to sites of allergic inflammation—indicating a theoretical mechanism for its traditional use in asthma.83 The flavonoid baicalin was associated with significant reductions in inflammatory mediators in patients with bronchial asthma and was five to 10 times more potent than the antiallergic drug azalestine.84
In severe cases, the practitioner may consider immunosuppressive herbs, such as Tylophora indica or Hemidesmus indicus, but caution is urged with regard to dosage, and the patient should be monitored closely. (For protocol on using these herbs, see Chapter 28 on autoimmunity.) Four small, early studies using T. indica for short periods indicate beneficial effects (such as increased peak expiratory flow rate and ventilatory capacity).85–87
In addition to an anti-inflammatory role, quercetin is useful for its anti-allergic qualities. In animal models it reduced the production of IL-4 (a Th2 cytokine) and increased the production of IFN-γ (a Th1 cytokine), potentially indicating a T-cell regulatory effect.88 Dietary intake of antioxidant nutrients such as vitamin A, C, E and selenium may also help to regulate this balance. Supplementation of vitamin E and selenium are reported to promote Th1 differentiation.89–93
Enhance brochodilation
Adhatoda vasica is considered a specific for asthma, and is generally thought to be safe for long-term treatment.94 The alkaloids in A. vasica have been compared to theophylline for their bronchodilator and antiasthmatic actions,95 as they exhibit pronounced protection against allergen-induced bronchial obstruction.76 Euphorbia spp. are also considered a reliable antiasthmatic, particularly in spasmodic forms of the condition. These promote expectoration, allay cough96 and have antiproliferative properties.97
Forskolin from Coleus forskohlii has been shown to increase the levels of cAMP in cells, making it a natural bronchodilator.98 In a model using guinea pig trachea, it showed efficacy in reducing antigen-induced constriction;99 and in early trials it improved forced expiratory volume and decreased airway resistance in male asthmatics.100 Other useful bronchospasmolytics and bronchodilators with traditional evidence are Grindelia camporum and Glycyrrhiza glabra.101,102
Magnesium is also a renowned bronchodilator. It antagonises the movement of calcium across cell membranes, decreasing the uptake and release of the mineral in bronchial smooth muscle, and leading to relaxation and dilation of the airways.103 In acute situations, magnesium sulfate administered intravenously or via a nebuliser appears to be effective in improving the pulmonary function of asthmatics.104,105 In a short-term trial, 400 mg of magnesium was added to a low-magnesium diet for 3 weeks, producing an improvement in symptom scores.106 In asthmatic children, 300 mg/day for 2 months produced reduced bronchial and skin hyperreactivity to known antigens, in addition to fewer asthma exacerbations and less medication use.107
Tea, yerba maté and coffee108 are all agents that may be useful in bronchodilation. The pharmaceutical agent theophylline was derived from tea, and the caffeine that these agents contain may improve lung function for up to 4 hours in people with asthma.109
Digestive connection
The development of asthma has been variously linked to increased digestive permeability,23 oesophageal reflux110 and dysbiosis,111,112 making these the key areas to address.
Inflammation may be attenuated, and the healing of the mucosal lining facilitated, by interventions including vitamin A,113 glutamine114,115 and Aloe vera.116 Improving overall digestive capacity involves the use of herbal bitters such as Gentiana lutea or Peumus boldus and warming digestives such as Zingiber officinale or Cinnamomum cassia in association with enzyme therapy.96,117–119
