A
eviation: PEF, peak expiratory flow.
Ha
ison's Principles of Internal Medicine, 20e
Chapter 281: Asthma
Peter J. Barnes
INTRODUCTION
Asthma is a syndrome characterized by airflow obstruction that varies markedly, both spontaneously and with treatment. Asthmatics ha
or a special
type of inflammation in the airways that makes them more responsive than nonasthmatics to a wide range of triggers, leading to excessive na
owing
with consequent reduced airflow and symptomatic wheezing and dyspnea. Na
owing of the airways is usually reversible, but in some patients with
chronic asthma there may be an element of i
eversible airflow obstruction. Asthma is a heterogeneous disease with several phenotypes recognized,
ut thus far these do not co
espond well to specific pathogenic mechanisms (endotypes) or responses to therapy. The increasing global prevalence of
asthma, the large burden it now imposes on patients, and the high health care costs have led to extensive research into its mechanisms and treatment.
PREVALENCE
Asthma is one of the most common chronic diseases globally and cu
ently affects ~300 million people worldwide, with ~250,000 deaths annually. The
prevalence of asthma has risen in affluent countries over the last 30 years but now appears to have stabilized, with ~10–12% of adults and 15% of
children affected by the disease. In developing countries where the prevalence of asthma had been much lower, there is a rising prevalence, which is
associated with increased u
anization. The prevalence of atopy and other allergic diseases has also increased over the same time, suggesting that the
easons for the increase are likely to be systemic rather than confined to the lungs. Most patients with asthma in affluent countries are atopic, with
allergic sensitization to the house dust mite Dermatophagoides pteronyssinus and other environmental allergens, such as animal fur and pollens.
Asthma can present at any age, with a peak age of 3 years. In childhood, twice as many males as females are asthmatic, but by adulthood the sex ratio
has equalized. Long-term studies that have followed children until they reach the age of 40 years suggest that many with asthma become asymptomatic
during adolescence but that asthma returns in some during adult life, particularly in those with persistent symptoms and severe asthma. Adults with
asthma, including those with onset during adulthood, rarely become permanently asymptomatic. The severity of asthma does not vary significantly
within a given patient; those with mild asthma rarely progress to more severe disease, whereas those with severe asthma usually have severe disease at
the onset.
Deaths from asthma are relatively uncommon, and in many affluent countries have been steadily declining over the last decade. A rise in asthma
mortality seen in several countries during the 1960s was associated with increased use of short-acting inhaled β2-adrenergic agonists (as rescue
therapy), but there is now compelling evidence that the more widespread use of inhaled corticosteroids (ICS) in patients with persistent asthma is
esponsible for the decrease in mortality in recent years. Major risk factors for asthma deaths are poorly controlled disease with frequent use of
onchodilator inhalers, lack of or poor compliance with ICS therapy, and previous admissions to hospital with near-fatal asthma.
It has proved difficult to agree on a definition of asthma, but there is good agreement on the description of the clinical syndrome and disease
pathology. Until the etiologic mechanisms of the disease are better understood, it will be difficult to provide an accurate definition.
RISK FACTORS AND TRIGGERS
Asthma is a heterogeneous disease with interplay between genetic and environmental factors. Several risk factors that predispose to asthma have
een identified (Table XXXXXXXXXXThese should be distinguished from triggers, which are environmental factors that worsen asthma in a patient with
established asthma.
TABLE 281-1
Risk Factors and Triggers Involved in Asthma
ENDOGENOUS FACTORS ENVIRONMENTAL FACTORS
Genetic predisposition
Atopy
Airway hype
esponsiveness
Gende
Ethnicity
Obesity
Early viral infections
Indoor allergens
Outdoor allergens
Occupational sensitizers
Passive smoking
Respiratory infections
Air pollution (diesel particulates, nitrogen oxides)
Diet
Dampness and mold exposure
Acetaminophen (paracetamol)
Triggers
Allergens
Upper respiratory tract viral infections
Exercise and hyperventilation
Cold ai
Sulfur dioxide and i
itant gases
Drugs (β-blockers, aspirin)
Stress
I
itants (household sprays, paint fumes)
Atopy
Atopy is the major risk factor for asthma, and non-atopic individuals have a very low risk of developing asthma. Patients with asthma commonly suffe
from other atopic diseases, particularly allergic rhinitis, which may be found in >80% of asthmatic patients, and atopic dermatitis (eczema). Atopy may
e found in 40–50% of the population in affluent countries, but only a proportion of atopic individuals becoming asthmatic. This observation suggests
that some other environmental or genetic factor(s) predispose to the development of asthma in atopic individuals. The allergens that lead to
sensitization are usually proteins that have protease activity, and the most common allergens are derived from house dust mites, cat and dog fur,
cockroaches (in inner cities), grass and tree pollens, and rodents (in laboratory workers). Atopy is due to the genetically determined production of
specific IgE antibody, with many patients showing a family history of allergic diseases.
Genetic Predisposition
The familial association of asthma and a high degree of concordance for asthma in identical twins indicate a genetic predisposition to the disease;
however, whether or not the genes predisposing to asthma are similar or in addition to those predisposing to atopy is not yet clear. It now seems likely
that different genes may also contribute to asthma specifically, and there is increasing evidence that the severity of asthma is also genetically
determined. Genetic screens with classical linkage analysis and single-nucleotide polymorphisms of various candidate genes indicate that asthma is
polygenic, with each gene identified having a small effect that is often not replicated in different populations. This observation suggests that the
interaction of many genes is important, and these may differ in different populations. The most consistent findings have been associations with
polymorphisms of genes on chromosome 5q, including the T helper 2 (TH2) cells interleukin (IL)-4, IL-5, IL-9, and IL-13, which are associated with atopy.
There is increasing evidence for a complex interaction between genetic polymorphisms and environmental factors that will require very large
population studies to unravel. Novel genes that have been associated with asthma, including ADAM-33, DPP-10, and ORMDL3, have also been identified
y positional cloning, but their function in disease pathogenesis is not yet clear. Recent genome-wide association studies have identified further novel
genes, such as ORMDL3, although their functional role is not yet clear. Genetic polymorphisms may also be important in determining the response to
asthma therapy. For example, the Arg-Gly-16 variant in the β2-receptor has been associated with reduced response to β2-agonists, and repeats of an
Sp1 recognition sequence in the promoter region of 5-lipoxygenase may affect the response to antileukotrienes. However, these effects are small and
inconsistent and do not yet have any implications for asthma therapy.
It is likely that environmental factors in early life determine which atopic individuals become asthmatic. The increasing prevalence of asthma,
particularly in developing countries, over the last few decades also indicates the importance of environmental mechanisms interacting with a genetic
predisposition.
Epigenetic Mechanisms
There is increasing evidence that epigenetic mechanisms may be important, particularly in the early development of asthma. DNA methylation and
histone modification patterns may be influenced by diet, cigarette smoke exposure, and air pollution, and may affect genes involved in the
pathogenesis of asthma. These epigenetic changes may occur in the fetus as a result of maternal environmental exposure.
Infections
Although viral infections (especially Rhinovirus) are common as triggers of asthma exace
ations, it is uncertain whether they play a role in etiology.
There is some association between respiratory syncytial virus infection in infancy and the development of asthma, but the specific pathogenesis is
difficult to elucidate, as this infection is very common in children. Atypical bacteria, such as Mycoplasma and Chlamydophila, have been implicated in
the mechanism of severe asthma, but thus far, the evidence is not very convincing of a true association. Living in damp houses with exposure to mold
spores is now recognized to be a risk factor, and removal of these factors may improve asthma.
The observation that allergic sensitization and asthma were less common in children with older siblings first suggested that lower levels of infection
may be a factor in affluent societies that increase the risks of asthma. This “hygiene hypothesis” proposes that lack of infections in early childhood
preserves the TH2 cell bias at birth, whereas exposure to infections and endotoxin results in a shift toward a predominant protective TH1 immune
esponse. Children
ought up on farms who are exposed to a high level of endotoxin are less likely to develop allergic sensitization than children
aised on dairy farms. Intestinal parasite infection, such as hookworm, may also be associated with a reduced risk of asthma. While there is
considerable epidemiologic support for the hygiene hypothesis, it cannot account for the parallel increase in TH1-driven diseases such as diabetes
mellitus over the same period.
Diet
The role of dietary factors is controversial. Observational studies have shown that diets low in antioxidants such as vitamin C and vitamin A,
magnesium, selenium, and omega-3 polyunsaturated fats (fish oil) or high in sodium and omega-6 polyunsaturates are associated with an increased
isk of asthma. Vitamin D deficiency may also predispose to the development of asthma. However, interventional studies with supplementary diets
have not supported an important role for these dietary factors. Obesity is also an independent risk factor for asthma, particularly in women, but the
mechanisms are not yet clear.
Air Pollution
Air pollutants such as sulfur dioxide, ozone, and diesel particulates may trigger asthma symptoms, but the role of different air pollutants in the etiology
of the disease is not yet clear. Asthma had a much lower prevalence in East Germany compared to West Germany despite a much higher level of ai
pollution, but since reunification these differences have decreased as Eastern Germany has become more affluent. There is increasing evidence that
exposure to road traffic pollution is associated with increased asthma symptoms, with the main culprits being diesel particulates and nitrogen dioxide.
Indoor air pollution is also important with exposure to nitrogen oxides from cooking stoves and exposure to passive cigarette smoke. There is some
evidence that maternal smoking is a risk factor for asthma, but it is difficult to dissociate this association from an increased risk of respiratory
infections.
Allergens
Inhaled allergens are common triggers of asthma symptoms and have also been implicated in allergic sensitization. Exposure to house dust mites in
early childhood is a risk factor for allergic sensitization and asthma, but rigorous allergen avoidance has not shown any evidence for a reduced risk of
developing asthma. The increase in house dust mites in centrally heated poorly ventilated homes with fitted carpets has been implicated in the
increasing prevalence of asthma in affluent countries. Domestic pets, particularly cats, have also been associated with allergic sensitization, but early
exposure to cats in the home may be protective through the induction of tolerance.
Occupational Exposure
Occupational asthma is relatively common and may affect up to 10% of young adults