ETIOLOGY

Although the fundamental causes of asthma are not completely understood, there is strong evidence that the development of asthma includes a combination of genetic predisposition and environmental exposure to ingested or inhaled substances that could provoke allergic reactions or irritate the airways as well as to infectious agents.

Genetic Contributions

Asthma runs in families, and if one identical twin has asthma, the other twin is likely to have it. Observations such as these demonstrate that the tendency to develop asthma is inherited. Over 100 different genes are thought to be linked to asthma, and through linkage studies (i.e., gene “hunting” and genetic testing), the following novel genes for asthma have been identified:

• ADAM33: A gene that influences lung function in early life and affects how people inhale and exhale
• VDR: Provides instruction for making vitamin D receptors, allowing the body to respond to vitamin D, low levels of which are linked to increased risk of asthma attacks
• DPP10: A rare mutation associated with asthma that encodes a protein that binds specific voltage-gated potassium channels that play a significant role in cytokine production and airway smooth muscle cell and goblet cell function
• PHF11: A regulator of human atopic disease
• HLA: Genes involved in the regulation of immune-specific responses to common allergens
• GPR154: Increased expression of this gene in ciliated cells of the respiratory epithelium and in bronchial smooth muscle cells
• BPFIB1: A key component for clearance of mucus containing inhaled particles and pathogens from the airway
  (Donoghue et al., 2020; Weiss, 2020)

Lung Microbiome

The notion that the lungs are sterile has been abandoned now that evidence has been found of bacterial populations (microbiome) in the lung and that intestinal microbiota provide these bacteria. Each person has their own unique microbiota, and when microbial populations are disturbed, a negative impact occurs known as dysbiosis. A higher microbial abundance and species variation are observed in chronic disease states of the respiratory tract, including asthma.

It has been reported that several fungi associated with intestinal dysbiosis could enhance the severity of asthma since intestines and lungs communicate and work in tandem. Specific types of proteobacteria are pronounced in asthma and are usually associated with uncontrolled asthma. In addition, Firmicutes with the genus Lactobacillus have been isolated in asthmatic patients as well as the genus Clostridium in children with airway allergies (Stavropoulou et al., 2021).

Environmental Contributions

In a person with asthma, substances in the environment can trigger an episode of bronchoconstriction, and it appears that exposure to some of the same substances can also initiate the disease.

TOBACCO PRODUCTS

Tobacco smoke irritates the lining of the airways and is a powerful trigger of asthma symptoms. This is true for adults, but especially so for children. Tobacco smoke harms the smoker and people exposed to secondhand smoke by:

• Damaging the cilia that sweep particles and mucus out of the airways
• Causing an increase in mucus, which together with the damaged cilia, leads to mucus and other irritating substances building up in the airways
• Introducing many cancer-causing substances into the lungs

Secondhand smoke is a combination of smoke from a burning tobacco product and smoke that has been exhaled by a smoker. Inhaling secondhand smoke may be even more harmful than actually smoking the product because the smoke that burns off the end of a cigar or cigarette contains more harmful substances (tar, carbon monoxide, nicotine, and others) than the smoke inhaled by the smoker.

Adults and children who live with a smoker are more likely to develop respiratory illnesses such as asthma. Children with asthma are especially sensitive to secondhand smoke. They are more likely to develop asthma symptoms and more likely to develop lung and sinus infections, which can make asthma symptoms worse and more difficult to control.

Use of tobacco products, including cigarette smoking, smokeless tobacco, and electronic cigarettes, is harmful to both mothers and unborn children, as nicotine and other substances cross the placenta and go directly to the fetus. Smoking in pregnancy causes structural changes in the placenta and impaired oxygen delivery to the fetus. Children of mothers who smoked during pregnancy are more likely to have respiratory problems and are ten times more likely to develop asthma (Cleveland Clinic, 2021a; Rodriguez, 2021).

For those who live in multi-unit housing, such as an apartment, duplex, or condo, secondhand smoke from another resident’s indoor smoking can trigger asthma symptoms. Secondhand smoke can migrate from other units and common areas and travel through doorways, cracks in walls, along electrical lines, via plumbing, and through ventilation systems (ALA, 2020b).

AIR POLLUTION

Poor air quality due to an increase in the amount of carbon dioxide emitted into the atmosphere can trigger asthma symptoms. Carbon dioxide is created by the burning of fossil fuels like coal and oil. Increases in global atmospheric CO₂ concentration stimulates earlier and greater production of pollen allergens and airborne fungal spores, both known aggravators of asthma (Sims et al., 2020).

Increased temperatures lead to increased ground-level ozone, which causes airway inflammation and damages lung tissue. Ground-level ozone can be the most harmful for people living with asthma. It is created by a chemical reaction between nitrogen oxide and organic compounds when exposed to sunlight. These compounds can include emissions from industrial facilities, motor vehicle exhaust, and gasoline fumes. Ground-level ozone is very likely to reach unhealthy levels on hot sunny days in urban environments and is a major component of urban smog.

The populations most vulnerable to ground-level ozone are children, older adults, people with lung disease, or people who spend a great deal of time outdoors. Children are at the greatest risk and are more likely than adults to have asthma. Unhealthy rises in ground-level ozone pollution correspond with increases in emergency room visits and hospitalizations for people with asthma (AAFA, 2021e).

Each year wildfires occurring across the country have a significant effect on air quality. Smoke is made up of a complex mixture of gases and fine particles produced when wood and other organic materials burn. The biggest threat from smoke is from fine particles that can penetrate deep into the lungs. Children and those with respiratory disease like asthma are at high risk for asthma episodes when the air quality is poor. Wildfires not only affect those in the immediate fire area; smoke can blow and impact people hundreds of miles away (EPA, 2021a; AAFA, 2020).

INDOOR AIR POLLUTION

Many reports and studies have found that the following populations may be disproportionately impacted by indoor asthma triggers:

• Children
• Older adults
• Low-income individuals
• Minority populations

Indoor air quality can be up to five times more polluted than outdoor air. Sources of indoor air pollution include:

• Fuel-burning combustion appliances
• Tobacco products
• Dust, pet dander, molds
• Cockroach allergens
• Building materials, furnishings, upholstery, carpets
• Household cleaning and maintenance products
• Personal care products
• Hobby supplies
• Central heating and cooling systems
• Humidifiers (high humidity can lead to higher dust mite levels)
• Excess moisture
• Outdoor sources such as radon, pesticides, air pollution (especially for low-income and communities of color who are far more likely to live in areas with heavy pollution)
• Inadequate ventilation
• Cooking (oil and fat particulates)

If too little fresh air enters indoors, pollutants can accumulate to levels that can pose health and comfort problems. If clean outdoor air does not replace indoor air often, then allergens and pollutants may stay in the home and recirculate. The indoor air in newer, more energy-efficient homes may become more polluted because these homes do not have the same gaps and cracks as older homes to allow air circulation (EPA, 2021b).

WEATHER

Thunderstorm asthma results when a potent mix of pollen and weather conditions trigger severe asthma symptoms in a large number of people over a short period of time. Epidemic thunderstorm asthma (ETSA) outbreaks have occurred globally over the last four decades. Thunderstorm asthma has been reported in the United Kingdom, Australia, Canada, Italy, and the United States. Australia has been particularly susceptible, with nearly half of all episodes reported internationally.

Pollen grains from grasses are large and normally unable to enter the bronchial tree. However, in storms these grains get swept up in the wind and carried for long distances. Some burst open and release tiny particles that are concentrated in the wind just before the storm. These particles are small enough to go deep into the lungs, making it difficult to breathe. This can become very severe, very quickly and may be life-threatening (GINA, 2021; Thien et al., 2020).

DIETARY FACTORS

Several food and food groups have been found to influence the development and course of asthma.

• High fat/low fiber intake: A high-fat and low-fiber diet results in increased airway hyperresponsiveness via enhanced cytokine production in the lungs.
• Dairy products: Frequent dairy consumption has been found to increase the odds of developing childhood asthma. The mechanism is unclear but may include responses to milk protein or milk lipids.
• Plant-based diet: Diets emphasizing fruits, vegetables, and whole grains, while placing less emphasis on high-fat meats and dairy products, have been associated with reduced asthma risk in children and a reduced risk of lifetime diagnosis of asthma.
• Vitamin E deficiency: Vitamin E interrupts lipid peroxidation to inhibit oxidant-induced damage in human tissue. An isoform of vitamin E scavenges reactive nitrogen species, which can become elevated with acute neutrophilic inflammation. Children born to mothers with vitamin E deficiency are more likely to develop symptoms of asthma requiring medication.
• Vitamin D deficiency and insufficiency: Both deficiency and insufficiency in vitamin D levels are significantly higher in asthma patients. Children who are vitamin D deficient have been found to be five times as likely to have asthma, and those who are vitamin D insufficient were three times as likely. Vitamin D insufficiency has also been associated with increased risk of hospitalization or emergency department visits. Low maternal vitamin D intake during pregnancy is associated with an increased risk of children developing asthma in the first 10 years of life.
  (Alwarith et al., 2020)

RESPIRATORY INFECTIONS

Respiratory infections are common and can affect lungs, nose, sinuses, and throat, especially in children and adults with preexisting asthma.

Respiratory tract infections are a main asthma trigger and can result in severe asthma symptoms. A respiratory tract infection causes inflammation, and asthma is an inflammatory condition. Together they deliver an inflammatory onslaught that triggers an asthma attack. People with asthma can have a more severe illness and take longer to recover from respiratory infections (Cleveland Clinic, 2020).

Viral Infections

There is a large body of evidence that demonstrates a link between early viral infections and asthma inception and exacerbation. Viral respiratory tract infections are the most common cause of wheezing illnesses and asthma exacerbations in both children and adults. Respiratory viruses can induce symptoms of acute bronchiolitis, croup, and recurrent wheezing in young children (Mikhail & Grayson, 2019; Kakumanu, 2021).

Respiratory viruses infect and cause cytopathic damage to airway epithelium. This damage then induces the release of proinflammatory agents, which then propagate eosinophilia and stimulate the release of cytokines that promote asthma and atopic disease. Some viruses may not damage the epithelium directly but rather interact with macrophages, T cells, or mast cells to stimulate allergic airway inflammation and modulate the host’s response to allergens and irritants in the environment (Kakumanu, 2021).

Specific viruses associated with the development of asthma include:

• Respiratory syncytial virus (RSV) in children under 2 years of age is the most common cause of wheezing and is an important risk factor for intrinsic asthma, with severe infections conferring greater risk.
• Rhinovirus (RV) (the common cold) is a more important risk factor for the development of extrinsic asthma, likely through T-helper 2-biased inflammation. Rhinovirus is more significant in adults and children older than 2 years, causing increased symptomatology in patients with preexisting asthma.
• Parainfluenza can cause lower respiratory tract infections and is most likely to affect infants, young children, the older adult, those with chronic diseases such as asthma, and those with compromised immune systems, causing new onset asthma and also acting as an asthma trigger.
• Human metapneumovirus (hMPV) presents similar to RSV and is a common cause of upper and lower respiratory tract infections in infants and children. It also affects adults, particularly older adults, and those with weakened immune systems. Lower airway infections have been shown to trigger asthma attacks in those with existing asthma.
• Coronavirus (CoV) infections can range from a mild common cold to more severe disease such as COVID-19, which can be fatal.
• Adenovirus (AdV) has been found to initiate chronic, more persistent, and severe asthma. How AdV affects asthmatic patients, however, remains unclear.
  (Kakumanu, 2021; Jarrti et al., 2020)

Bacterial Infections

Similar to viruses, airway bacteria have also been suggested as early-life risk factors for later development of asthma. Also, the gut microbiome, considered to be a risk factor for later development of asthma, might influence the susceptibility to viral infections in the airway.

In addition, there is substantial evidence of an interaction between bacteria and viruses in the airways. Rhinovirus has been found to be associated with increased bacterial pathogens, and Moraxella catarrhalis and Streptococcus pneumoniae seem to contribute to the severity of respiratory tract illness and asthma.

Several mechanisms are involved in which viral infections can increase the risk of bacterial infections, including immune suppression, epithelial damage, and changes in the local lung environment, altering the growth conditions for pathogenic bacteria and viruses (Jartti et al., 2020).

CESAREAN SECTION

Children born by cesarean section have a higher risk of asthma than those born by vaginal delivery, particularly children of parents with allergies. There are two possible causes that have been hypothesized:

• Lack of contact by the infant with the mother’s bacteria. Neonates born by vaginal delivery acquire most of their intestinal flora by being exposed to their mother’s vulvovaginal/bowel flora during birth, which influences early immune modulation (Litonjua & Weiss, 2020b).
• Infants delivered by cesarean section have less contact with stress hormones and chest pressure that normally occurs during vaginal delivery, which has a negative effect on lung function because these mechanisms are associated with the reabsorption of amniotic fluid from the lungs (Darabi et al., 2019).

Neonates who are born following a planned cesarean section without labor do not experience labor-related stress and immune modulation and are at increased risk of asthma up to the age of 12 years.

In an attempt to restore normal neonatal colonization of cesarean-born neonates, vaginal seeding has been suggested; however, both the safety and effectiveness of this practice is unproven and is only recommended in research trials (Norwitz, 2021).

Comorbid Factors

OBESITY

Obesity is a risk factor for asthma, particularly in adult women, and the greater the body mass index (BMI), the greater the risk of asthma. An increased prevalence of asthma also occurs in children with obesity. Among adults with severe asthma, nearly 60% are obese. This is related to a complex interplay of biologic, physiologic, and environmental factors. Asthma in patients who are obese is often severe and difficult to control.

In some people, obesity precedes asthma, and obesity is a risk factor for later development of asthma. In others, asthma precedes obesity, suggesting that asthma may be a risk factor for the development of obesity.

Obesity results in mechanical changes. It increases the collapsibility of the peripheral airways and parenchyma, especially among people with late-onset asthma. Excessive accumulation of fat in the thoracic and abdominal cavities leads to lung compression and an attendant reduction in lung volume. Other factors that are likely contributors to the increased risk and severity of asthma in obese individuals include:

• Genetics, evidenced by twin studies suggesting 8% of genetic component is shared with asthma
• Air pollution and parental smoking, which are independent risk factors for both obesity and asthma
• Dietary factors, including high sugar or saturated fat intake or low antioxidant or fiber intake
• Lung growth in children (e.g., increased lung volume relative to airway caliber)
• Adipose tissue proinflammatory mediators
• Immune cell function alterations (e.g., suppression of T-helper lymphocyte function or lymphoid cell response to intrinsic damage)
• Increased oxidative stress with late-onset asthma
  (Dixon & Nyenhuis, 2021)

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Chronic obstructive pulmonary disease (COPD) has been found in a significant proportion of patients who present with symptoms of chronic airway disease. These patients have features of both asthma and COPD, which is referred to as asthma-COPD overlap (ACO), although specific features that can be used to make a diagnosis of ACO have yet to be agreed upon.

Despite the lack of a well-accepted definition, there are a range of features that support the diagnosis of ACO, including:

• Age 40 years or older
• Persistent respiratory symptoms, but variability in symptoms may be prominent
• Airflow limitation that is not fully reversible
• History of doctor-diagnosed asthma at some point
• History of atopy or allergies
• Exposure to a risk factor such as tobacco smoking or equivalent indoor/outdoor pollution

Research efforts are needed to better understand asthma and COPD phenotypes and what types of biomarkers (physiologic, radiologic, or biologic) help to distinguish those patients with ACO who are most responsive to specific therapies (Han & Wenzell, 2020).

GASTROESOPHAGEAL REFLUX DISORDER

Studies have shown that gastroesophageal reflux disorder (GERD) can trigger asthma symptoms. In addition, GERD is more common in people with asthma than in the general population, and anyone—including infants, children, and teens—can develop GERD. Individuals with asthma that is especially difficult to treat appear more susceptible to GERD than other affected persons. GERD is thought to cause asthma symptoms in one of two ways:

• Stomach acid that enters the esophagus irritates nerve endings, and the brain responds with impulses to the lungs stimulating muscle and mucus production in the airways, which then constrict, resulting in asthma symptoms.
• Refluxed stomach contents are aspirated into the lungs, irritating the airways and causing the symptoms of asthma to occur.

It is also believed by some that asthma may trigger GERD. Either breathing difficulties or certain asthma medications cause the esophageal sphincter muscle to relax and allow stomach contents to reflux, which then causes asthma symptoms, completing a cycle. GERD may also be related to eating specific foods or, rarely, to food allergies (AAFA, 2021f).