#90484: Asthma: Diagnosis and Management

In response to irritation and immune response, muscles on the outer layer of the bronchi contract, causing a bronchospasm. Tightened muscles restrict the movement of air. Depending on the degree of airway narrowing, which differs for each patient and with the severity of the attack, the characteristic breathing difficulty, chest tightness, wheezing, and coughing will follow [13].

Inflammation can produce excess mucus as a protective mechanism. During an asthma attack, glands secrete excessive amounts of thick mucus to compensate for the increased amount of irritants or allergens. The excess mucus clumps together in the airways, further narrowing the bronchial tubes by partially blocking the passageway and hindering breathing. This increased amount of mucus can also form plugs that clog very small airways. During an asthma episode, some patients attempt to clear their airways by coughing up what seems to be a mucus plug. However, patients may produce many plugs; consequently, they may have a continuous, irritating hacking cough. If left untreated, mucus plugs can prolong asthma episodes and increase the risk of infection [13].

When secretions become too thick for cilia to handle, the system responds by coughing to remove the unwanted substance. Dry coughs in patients with asthma are generally the product of extra-thick mucus plugs or bronchioles so blocked that the mucus cannot be removed or moved through. Nasal and sinus drainage, a common symptom of allergies, may also irritate airways and produce a nagging, unproductive cough [13]. If a patient has been mouth breathing, the airways may become dry and have decreased elasticity, making it more difficult to clear them. If this is the case, the patient should be encouraged to take frequent sips of water or isotonic fluids (e.g., electrolyte replacement drinks).

Wheezing is considered to be a trademark of asthma, but it is not a definite indicator. The wheezing sound associated with asthma results from a forceful rush of air pushing through narrowed, constricted airway lumens. The surge of air causes vibrations that make the wheezing sound. In some cases, airways can be so constricted that the air flowing past a blockage is not sufficient to produce a wheeze. In very severe attacks, the absence of wheezing is a worrisome sign.

It is important to note that patients with severe asthma have acute airway inflammation during an episode, and as stated previously, patients with chronic asthma have continuous symptoms of airway inflammation, which can eventually destroy airway tissue and alter lung function. Prolonged inflammation may result in permanent obstruction as a result of alteration of the bronchial walls. Unfortunately, after this change occurs, the airways may not respond to common treatment as quickly or at all. This is why it is important to use medication to reduce airway inflammation, subsequently preventing permanent obstruction [13].

Breathing with asthma can fatigue the body. As exhalation is blocked and air is trapped in the lungs, more force is required to maintain adequate oxygen supply. To aid in exhalation, accessory muscles become involved, which can deplete the body of energy. Untreated asthma can produce severe degrees of fatigue for the patient, and this can become a critical situation warranting immediate intervention [13]. Lethargy, decreased response time, and weakness are all late signs of fatigue.

A spirometer is a simple machine used to determine both the total amount of air that can be forcefully exhaled after maximum inspiration, referred to as forced vital capacity (FVC), and how fully air can be expelled from the lungs, measured by the amount of air forced from the lungs in one second, which is expressed as FEV₁[9,21]. The spirometer is generally used in diagnosis to establish airflow obstruction and reversibility. Obstruction may be ascertained if the FEV₁ is less than 80% of the predicted value or if FEV₁ divided by FVC is less than 65%. Normally, the FEV₁ should account for more than 75% of the FVC; anything less than 75% indicates a possible obstruction and 65% or less may indicate a diagnosis of asthma [9,10,21].

A peak flow meter measures the speed of exhalation. The highest speed or best flow is PEF or peak flow. The peak flow meter is less sophisticated than a spirometer, which provides a more thorough assessment of lung function. However, the meter has the advantages of being less expensive, portable, and easy to use. The severity of a patient's asthma can be determined by careful and consistent monitoring of peak flow and comparison to a patient's best peak flow and to standard measurements. Studies confirm that short-term peak flow measurements assist healthcare providers in assessing asthma severity [8,9,21].

Studies have shown that measuring exhaled nitric oxide (FeNO) is helpful in evaluating and diagnosing asthma, particularly in cases of an uncertain diagnosis of asthma using history, clinical course, clinical findings, and spirometry (including bronchodilator responsiveness testing) or when spirometry cannot be performed [9,10,13]. Nitric oxide is a mediator for the inflammation that occurs during an asthma episode; the amount of nitric oxide measured during exhalation will directly correlate with the inflammation in the bronchial tubes. In general, higher concentrations of nitric oxide are a sign of more severe forms of asthma. However, the NAEPP notes that increased FeNO levels can be caused by allergic rhinitis and atopy, which can be present in individuals with and without asthma; taking these factors into consideration is important for accurate interpretation of FeNO test results [9,10].

Monitoring the concentration of nitric oxide in expired breath may allow healthcare providers to confirm the reversible nature of the inflammation and assess the effectiveness and adherence to the prescribed therapeutic treatment. It is not recommended, however, that asthma treatment be routinely tailored based on exhaled nitric oxide levels alone [9,10,13].

Differential diagnosis for children presenting with wheezing and recurrent lower respiratory infections should include cystic fibrosis, bronchopulmonary dysplasia (prevalent in premature infants), dysmotile cilia syndrome, alpha-1-antitrypsin deficiency, and immunodeficiencies [9,31].

Cystic Fibrosis

Cystic fibrosis is the leading cause of chronic debilitating pulmonary disease and pancreatic exocrine deficiency in the first three decades of life. The median age at diagnosis is 6 to 8 months; more than 75% of patients are diagnosed by 2 years of age. It occurs most often in White children, and it is estimated that 1 in every 20 White Americans is a carrier of the cystic fibrosis mutation. Among Black individuals, the incidence is approximately 1 in 16,000, and in Asian Americans, it is 1 in 31,000 [31,32]. Although cystic fibrosis can be a multisystem disorder, the respiratory system is almost always involved and tends to dominate the clinical picture. Common respiratory complications include air trapping and wheezing, chronic cough and sputum production, retractions, tachypnea, and recurrent or chronic pneumonia. However, the earliest signs of cystic fibrosis can be gastrointestinal and pancreatic, not respiratory. Signs of cystic fibrosis include radiograph abnormalities such as bronchiectasis, atelectasis, infiltrates, and hyperinflation. Therefore, a chest x-ray or computed tomography scan may be useful in determining the correct diagnosis, especially in children [9,31].

GERD

Excessive mucosal secretion secondary to GERD or gastrointestinal malformation may cause wheezing in both children and adults and should be considered during evaluation. It is reported that 34% of patients with GERD experience chronic cough and/or wheezing as part of their symptomatology. Additionally, bronchiole irritation resulting from repeated exposure to gastric acid may trigger asthma symptoms. Generally, asthma-like symptoms that stem from GERD can be controlled with initiation of reflux medications and lifestyle modification [9,31].

Structural Issues

If respiratory difficulties are suspected to be more of a structural issue, a bronchoscopy may be performed. This is especially important if congenital abnormality, such as laryngomalacia or tracheobronchomalacia, or tumors or growths are suspected. It can also rule out foreign body aspiration. Samples of tissue and sputum to be used in additional testing may be taken during the procedure, if necessary [9,31].

In adults, CHF and other cardiac conditions, such as mitral valve disease, should be considered in the differential diagnosis of asthma. Establishing an asthma diagnosis is difficult for patients older than 55 years of age due to the increased incidence of CHF and respiratory difficulties resulting from cardiac problems, or "cardiac asthma." Conversely, asthma can aggravate heart disease when oxygen supplied by the lungs is inadequate for the reduced blood supply to the heart. Any diseases or conditions that may cause dyspnea should be considered when determining a differential diagnosis of asthma [9,33].

A particular form of an infection-plus-allergy condition known as allergic bronchopulmonary aspergillosis, often shortened to aspergillosis or ABPA, should also be considered. The condition initiates with the introduction of the fungus Aspergillus fumigatus, a mold that is abundant in damp straw, compost heaps, birdcages, and any decomposing material. A. fumigatus does not usually have an adverse effect on those with normal immune systems. However, in individuals with asthma or immunocompromise, the spores from this mold may begin to grow in the lung tissue. An allergic reaction may then occur in response to the fungus. This is an important consideration for those who work in agricultural occupations and is one example of the usefulness of a thorough history and lifestyle questionnaire in the diagnosis and management of asthma [9,33].

ABPA may present comorbid with asthma or the similar symptoms may result in a false asthma diagnosis. The signs and symptoms of ABPA include rubbery plugs of golden-brown or green sputum; a fever apparent only when the asthma symptoms are severe; worsening symptoms despite treatment; dependence on steroid medications; and very high levels of serum IgE. ABPA is normally treated with steroids to control the allergic reaction and with physiotherapy to clear the mucus from the lungs [9,33].

There are also certain medications that may induce asthma-like symptoms. Specifically, there are two conditions, aspirin-sensitive triad and nonallergic rhinitis with eosinophilia syndrome (NARES), known for their similar presentation to asthma. The diagnosis of aspirin-sensitive triad is based on three distinct symptoms: perennial rhinitis, nasal polyps, and asthma. Patients with an aspirin-sensitive triad diagnosis tend to collect all three symptoms gradually, in no particular order, over a period of years or decades. Although it is not known how common nonsteroidal anti-inflammatory drug (NSAID) sensitivity is for adult patients with asthma, various reports site frequencies from 3% to approximately 40%. It is far less common in pediatric patients with asthma; women in their third decade are most commonly affected [9,33].

Quite often, aspirin-sensitie patients with asthma have other related respiratory conditions, including sinusitis, severe rhinitis, and nasal polyps. Nasal polyps are benign inflammatory growths that begin in the sinuses but protrude into the nostril. However, the absence of sinusitis and nasal polyps does not automatically rule out the presence of aspirin sensitivity. Aspirin sensitivity can develop suddenly and produce a reaction similar to anaphylaxis, but it usually builds over many years. Patients with asthma found to have a sensitivity, usually by an aspirin challenge test, are advised to avoid all NSAIDs even if they have not reacted to these medications in the past. Also, patients with aspirin-sensitive triad will often have cross intolerances with sulfides, particularly wine and other alcoholic beverages containing sulfides, and naturally occurring salicylates, which are found in citrus fruit, nuts, and grapes. Food additives may also be problematic [9,33].

NARES is caused by the invasion of eosinophils into the nasal passages, resulting in severe inflammation. Nasal secretions testing positive for the presence of eosinophils (usually greater than 20% of the cells on nasal smears) are used to confirm a positive diagnosis of NARES. NARES may develop as part of aspirin-sensitive triad or completely separately from any aspirin sensitivities. The cause of the eosinophil infiltration is not clear [9,33].

In general, a diagnosis of asthma may be reached if a patient has a strong family history, has repeated episodes of wheezing or other breathing difficulties, and responds to bronchodilators. However, because a wide spectrum of diseases and disorders have strikingly similar symptomatology, it is vital that those avenues are exhausted prior to establishing an asthma diagnosis [9,33].

Asthma medications may be inhaled, taken orally in pill, granule, or liquid form, or in emergency situations, injected intravenously.

Inhalers

There are several types of inhalers available including aerosol, dry powder, and nebulizers. Metered-dose inhalers (MDIs) rely on a mixture of medication, preservatives, and liquid propellant gas to deliver medicine into the lungs in aerosol form. As of 2008, inhalers that contain chlorofluorocarbon propellants are no longer permitted to be sold [34].

Some short-acting inhaled medications begin to reverse airway constriction within five minutes; however, long-acting medications have been developed in inhalant form as well. Inhaled medications have advantages over oral administration because the medication is able to enter directly into the lungs rather than through the circulatory system. Some MDIs discharge medication after a trigger is pressed, but newer versions are breath activated. For patients with poor coordination or impaired hand function, such as those with arthritis or with a history of stroke, breath-activated devices may improve medication delivery. The drawback of the breath-activated inhalers is that, during a severe attack, a lack of air may make device triggering difficult [9,11].

Some patients require the assistance of a spacer when using an inhaler. A spacer is a plastic tube that attaches to an MDI; its function is to momentarily trap medication as it exits the inhaler, allowing the medication to be inhaled more easily and preventing it from being lost. Spacers may benefit patients who find it difficult to squeeze the trigger and inhale at the same moment, such as young children or older adults. As medicine deposited in the mouth area can produce side effects, spacers can help limit this and ensure that more medication reaches the lungs instead of the tongue or back of the throat [9,11].

A major problem with MDIs is knowing when they are empty. Usually, a patient cannot see, hear, or taste when a canister is empty or delivering less medication than intended; in fact, at times, inhalers may feel heavy enough to hold medication but only contain propellant and preservatives. In some cases, empty inhalers may leave a strange taste or heavier spray in the patient's mouth [9,11].

Each inhaler should have a label that indicates how many measured metered doses the canister holds. For regularly scheduled medications, it is best to calculate the number of usable doses before a new inhaler is needed. Patients may mark calendars or the canister to remind themselves when to reorder another inhaler. In the past, some patients have used the so-called "float test" to determine the amount of medication remaining in the canister. This has been proven to be inaccurate and should not be recommended. Some canisters may require cleaning to prevent the accumulation of bacteria [9,11].

Breath-activated dry powder inhalers incorporate the same benefits as other breath-activated inhalers; patients are not required to coordinate inhaling with releasing medication. Some dry powder inhalers have a different delivery system involving the insertion of a capsule with medicated, fine powder into the canister. In general, each capsule contains a single dose that equals two sprays of medication (although double doses are available). One disadvantage of the dry powder is the amount of coordination needed to load the capsule into some inhalers. This can be a problem for the young or elderly or for people with arthritis, Parkinson disease, or other diseases affecting coordination or dexterity. Furthermore, depending upon the patient's ability to breathe in deeply, variable amounts of medication may be inhaled. Another concern involves the effect of humidity on dry powder, which may influence dose strength [9,11].

The nebulizer is a form of inhaler that acts as a vaporizer or humidifier, delivering microdroplets of asthma medication in spray form and allowing a patient to breathe it in through a mouthpiece or face mask. Larger doses from nebulizers may increase the risk of side effects, and studies have shown MDIs to be as effective as nebulizers in delivering medication to the lungs. Nebulizers are used frequently in children as they are easier to administer and provide more accurate dosing. In the past, hospitals frequently provided medication in nebulizers to treat emergency asthma episodes, but now many facilities have converted to the use of MDIs [9,11].

Oral Administration

In addition to inhalers, many asthma medications are manufactured as pills, granules, or liquids to be ingested orally. Oral medications benefit patients by reaching the small bronchial tubes that most inhaled medication cannot reach. Newer developments in longer-acting, timed-release oral medications adapt to the needs and lifestyles of many patients. However, the amount of medication absorbed over a given time period can vary. Some medications may take up to six times longer than others to reach peak concentrations, which means each patient may require a different dose and frequency of administration to reverse breathing problems [11,13].

The disadvantage associated with oral medications is the systemic distribution. If negative or unpleasant side effects occur, they last the entire time the medication is active in the body. Depending upon the form and dose, oral medication may be more difficult for the system to balance throughout a 12- or 24-hour period than inhaled formulations [11,13].

Bronchodilators are used to address the acute symptoms of an asthma attack. They act by relaxing the muscles surrounding airways, thereby dilating bronchial tubes. The primary categories of bronchodilators are beta₂ agonists, theophylline derivatives, and anticholinergics. Most often, bronchodilators are prescribed in inhaler or aerosol form. They are also available in liquid, tablet, and capsule forms, but these are generally not used due to gastrointestinal side effects. The bronchodilator inhaler is usually the first line of defense in an asthma attack [11,13].

Epinephrine

The first oral medication to become available for the relief of an acute asthma episode was epinephrine, a hormone produced by the sympathetic nervous system. Epinephrine was once the first choice for treating acute asthma, but it has proved to be a weak bronchodilator with quickly diminished action. Moreover, epinephrine has very potent systemic effects, causing tachycardia, high blood pressure, nervousness, headache, and in some cases, panic attacks. However, this medication may still be used intravenously or subcutaneously in severe asthma emergencies. Epinephrine can be described as nonselective; that is, the medication acts on both the lungs and the heart [9,13].

Despite its limitations, epinephrine remains the treatment of choice for severe asthma and airway constriction related to allergy. There is agreement that self-injectable epinephrine should be prescribed for patients who have had a previous allergic reaction involving the respiratory or cardiovascular system. The patient, as well as caregivers and all members of the family, should be instructed in how to administer the injection. Parents of children who have been prescribed self-injectable epinephrine should inform school personnel about the allergy and the availability of the medication. Instructions regarding the proper use of self-injectable epinephrine should be repeated frequently to ensure proper use during emergency situations [9,31].

Beta₂ Agonists

Bronchodilators that selectively act on the lungs have largely replaced the routine use of epinephrine. These drugs are called beta₂ agonists. Beta₂ agonists stimulate the sympathetic nervous system, similar to epinephrine. However, they only act on receptors located in nerve endings inside the lungs. These medications provoke specific beta₂ receptors in the muscles encasing the bronchial tubes to reverse; when the drug stimulates these receptors, bronchial muscles relax and bronchial tubes dilate. Beta₂ agonists last longer in the body than epinephrine and result in less risk of cardiovascular side effects, making them the drugs of choice for safe, short-acting bronchodilation [9,11,35].

Beta₂ agonists may cause negative side effects, especially if fast-acting forms are taken too frequently for too long. Overuse can lead to poor asthma control and possibly desensitization. Inhaling more than one canister a month indicates an excessive reliance on bronchodilators to improve asthma. Patients with severe asthma may prefer a beta₂ agonist for quicker action than anti-inflammatory medications, which take days to act. However, patients may then expose themselves to potentially fatal attacks due to decreased beta₂ agonist effectiveness if the asthma flares out of control [9,11].

Inhaled beta₂ agonist medications are associated with fewer major side effects than orally administered preparations. However, patients who use inhalers may report problems as well. The most common complaint is shakiness; other noticeable side effects may include tachycardia, heart palpitations, headache, dizziness, and increased serum glucose [35]. These side effects tend to diminish over time. Patients using oral beta₂ agonists have reported tremors, nervousness, tachycardia, muscle cramps, and sleeplessness [9,11].

There are several beta₂ agonists approved by the U.S. Food and Drug Administration (FDA) for use as bronchodilators. Beta₂ agonists come in every administration form, which can assist in individualizing treatment. Injections may work quickly in case of emergency, although the effect lasts only about 20 minutes. Two to four puffs of an inhaled beta₂ agonist taken before exercise or travel in cold air can block wheezing for up to four hours [11,35]. Long-acting beta₂ agonists are usually taken twice a day and last up to 12 hours. Their longer action can help prevent interruptions from night-time symptoms and/or allow patients to engage in activities that they would otherwise be advised to avoid.

However, even longer-acting beta₂ agonists cannot control unstable asthma. These medications are unable to reverse the chronic airway inflammation found in patients with asthma, necessitating the additional use of an anti-inflammatory drug to prevent symptoms in the long-term. And, as discussed, overuse of these medications can lead to poor asthma control, possible desensitization, and even death. FDA analyses of clinical trials have shown that use of long-acting beta₂ agonists without concurrent use of an inhaled corticosteroid is associated with an increased risk of severe worsening of asthma symptoms, leading to hospitalization and death in some patients with asthma, including children [9,36,37].

Theophylline Derivatives

Before inhalers became widely available, methylxanthines were the leading asthma medications. They could be administered intravenously or orally. Theophylline was formerly the most widely prescribed bronchodilator in the methylxanthine category and a keystone of asthma treatment in the United States. Theophylline reduces airway responsiveness to histamine, adenosine, methacholine, and allergens, and also relaxes airway muscles and pulmonary blood vessels, allowing the tubes to open and airflow to continue [35]. However, controversies over the medication's benefits and action, and higher efficacy of newer drugs have led to a decline in use [11,35].

Theophylline provides both a short- and a long-term alternative for patients who cannot tolerate beta₂ agonists. The drug reduces mucus buildup and blocks night-time symptoms in mild-to-moderate asthma. Its long-term benefits for preventing symptoms are well documented for up to 12 hours, although theophylline is generally less effective than beta₂ agonists. It should be noted that caffeine is considered a methylxanthine drug, so patients should be advised to monitor coffee, tea, and chocolate intake while using this medication. Many factors may affect the metabolism or serum concentration of theophylline, including diet, viral infections, hypoxia, age, some antibiotics, and smoking [11,35]. In addition, studies have shown that theophylline for asthma management is not as effective in patients with obesity [20].

Anticholinergics

Anticholinergics such as ipratropium bromide, atropine, and tiotropium are shown to be effective in relieving breathing disorders, including asthma. When used for asthma, these medications are not usually the first line of defense but rather are used to supplement beta₂ agonists. Anticholinergics act on different nerves than beta₂ agonists, although both block nerve pathways to the lung and alter muscle tone in the bronchial wall. Anticholinergics affect specific lung nervous system receptors, or cholinergics, in the vagus nerve; this nerve branches into the smooth muscles responsible for airway opening and the mucous glands that discharge thick secretions. The result is reduced inflammation and relaxed bronchial muscles. Throughout the respiratory tract, the drug stimulates nerve activity in other reactive cells to decrease mouth and lung secretions [9,11].

In 2007, a panel of experts, under the guidance of the NAEPP, noted that the critical role of airway inflammation in asthma has been further substantiated since the 1990s, when this inflammatory role was first acknowledged and treatment was shifted away from calming acute flare-ups to engaging in preventative measures. The NAEPP also noted that bronchodilators work best for acute asthma situations and for preventative treatment before exertion or exercise, but it emphasized anti-inflammatory medications as the foundation for long-term treatment of asthma; this was reaffirmed in the NAEPP 2020 Focused Updates to the Asthma Management Guidelines and in the 2024 GINA guidelines. This approach relies on daily medication to maintain healthy lungs. Patients who require regularly administered bronchodilators should switch to longer-acting drugs designed to reduce airway inflammation [8,9,10].

Anti-inflammatory medications block production of substances from cells involved in inflammation, such as mast cells; this action reduces or reverses the swelling that causes asthma symptoms. Equally important, these medications lessen airway sensitivity, which prevents edema. If asthma symptoms appear more than once or twice a week and less powerful options cannot control them, anti-inflammatory medication is indicated. Before newer drugs were developed, the only anti-inflammatory asthma medication available was an oral corticosteroid, such as prednisone. Long-term treatment with oral corticosteroids is associated with serious side effects, including stunted growth in children, hyperlipidemia, thinning skin, and immune system impairment, making patient compliance difficult. As a result, several inhaled anti-inflammatory drugs were developed, which greatly reduced negative reactions. The four primary types of anti-inflammatory drugs are corticosteroids, mast cell stabilizers, antiallergic medications, and antileukotriene medications [9,11,13].

Corticosteroids

The most common group of anti-inflammatory medications is oral corticosteroids. Oral corticosteroids are powerful anti-inflammatory medications. They are easy to administer and offer dramatic reversal of symptoms during life-threatening asthma situations. Although some corticosteroids take a few hours to work, their protection is long-lasting. Oral corticosteroids can be used for a brief period to gain control of asthma before moving to other long-term treatments that have fewer side effects, such as inhaled corticosteroids. Although reports about side effects from steroids may concern some patients with asthma, oral or inhaled corticosteroids can be a promising remedy for severe, uncontrolled asthma [9,11]. Patients and/or parents may require reassurance that these are not the same class of steroids used illegally by athletes.

Corticosteroids used in the treatment of asthma are adrenal hormones. Oral corticosteroid medications are absorbed into the circulatory system and are distributed throughout the body. In the lungs, they prevent the development of airway edema. Significant amounts of corticosteroids for prolonged periods can adversely affect other organ systems, such as bones and skin [9,11].

Severe asthma may require higher doses for longer periods, which may then be tapered off over a period of one to three weeks. Patients should be reminded that it is dangerous to abruptly discontinue oral corticosteroids. Corticosteroids are usually taken upon awakening, mimicking the body's natural steroid production schedule. Night-time symptoms may be managed with split doses taken in the morning and at night [9,35].

A major disadvantage of oral corticosteroids is the array of negative side effects associated with taking large doses over long periods of time. Because these medications enter the circulatory system, there is potential for damage to other organs. If taken for severe asthma, patients should be diligent about identifying and reporting any side effects [9,11].

Inhaled corticosteroids are the most consistently effective long-term control medication for both children and adults with persistent asthma, and the NAEPP recommends the use of inhaled corticosteroids, either alone or in combination, for most individuals with persistent asthma [9,10]. Inhaled corticosteroid therapy concentrates on reducing airway edema and improves results obtained from bronchodilators while eliminating extraneous effects to other systems. A beta₂ agonist may be prescribed in conjunction with an inhaled corticosteroid; the beta₂ agonist is used first to unblock airways so the corticosteroid can penetrate deeper. Common inhaled corticosteroids include beclomethasone, flunisolide, triamcinolone, and budesonide (available in a dry powder inhaler) [11]. Corticosteroids are often combined with formoterol in a single inhaler for ease of use and better asthma control [9]. In 2023, the FDA approved an albuterol/budesonide combination inhaler; this is the first inhaler combining both a corticosteroid and a beta₂ agonist [53].

In 2010, the FDA required a boxed warning for drugs that include both a long-acting beta₂ agonist and inhaled corticosteroid due to an increased risk of severe exacerbation of asthma symptoms that led to hospitalization and death in some patients using these drugs for the treatment of asthma. In 2011, the FDA required post-market safety trials for these drugs [36]. In 2017, clinical trials were concluded, and it was determined that there was no significant increase of serious risks in patients taking beta₂ agonists in conjunction with an inhaled corticosteroid; however, it was noted that taking a long-acting beta₂ agonist alone to treat asthma without an inhaled corticosteroid to treat lung inflammation increases the risk of asthma-related death. The boxed warning, therefore, only pertains to single-ingredient long-acting beta₂ agonists [37].

Patients who take inhaled corticosteroids may complain about the lack of immediate symptom relief and cite it as a reason for not taking the medication. It is important to stress the long-term benefits when discussing this therapy with patients. Although risks of corticosteroid side effects are greatly reduced with inhalers, they do exist; prolonged use of high doses can increase chances for the same types of unpleasant symptoms attributed to the oral or injected forms [9,11].

The doses of the inhaled corticosteroid must be very high to equal the risk of side effects associated with oral corticosteroids. Two more common adverse reactions to inhaled corticosteroids are throat irritation and candidiasis. Candidiasis can develop when a patient is taking antibiotic medications in addition to the corticosteroid inhaler or if other medical problems, such as diabetes, exist. To prevent candidiasis, advise patients to rinse their mouths after each inhaler treatment and to gargle with warm water to remove any medication left in the throat. The use of a spacer may also be advisable, as it should ensure that medicine particles are delivered to the lungs rather than to the mouth and throat [9,11].

Mast Cell Stabilizers

Mast cell stabilizers or inhibitors are considered mild-to-moderate anti-inflammatory agents and are most effective in the treatment and prevention of exercise- or allergen-induced asthma. Mast cell stabilizers interfere with the inflammatory process by stabilizing mast cell membranes and inhibiting the activation and release of mediators such as histamine and leukotrienes. They may also restrain the development of early and late bronchoconstriction responses to inhaled antigens. Mast cell stabilizers used to treat asthma are generally administered by inhalation, but eye and nasal drops are also available. One mast cell inhibitor available for the long-term management of asthma is cromolyn. However, this medication is considered less effective than inhaled steroids in the treatment of moderate-to-severe persistent asthma in adults and children and is not effective for immediate relief of acute asthma attacks [11,35]. The NAEPP recommends that they may be considered for treatment of persistent asthma for patients of all ages, but their use is not preferred [9,10].

Other Antiallergic Medications

Similar to mast cell stabilizers, the concept of antiallergic medications as a separate category is under intense study. The idea behind antiallergic drugs is simple—eliminate the allergic reaction so allergic asthma symptoms are greatly reduced. Particularly, some studies have been undertaken to research the effectiveness of antihistamine medications on the long-term control of asthma symptoms. However, research generally shows that the effect of antihistamines for the control of asthma is modest, especially if the patient is receiving the recommended treatment with corticosteroids. If the patient also has allergic rhinitis, as many patients with asthma do, antihistamine medications may help to control the rhinitis with secondary benefits to asthma symptoms. While second-generation antihistamines (e.g., loratadine, cetirizine) have been reported to decrease emergency department visits, the NAEPP recommends against their routine use for home management of asthma, as patient delays in seeking treatment have been associated with home use of antihistamines. Data on the use of second-generation antihistamines suggest that they are safe for use during pregnancy [9,10]. There are also some preliminary data that suggest that asthma and allergies may provide protection against adult malignant gliomas; however, it was also found that the long-term use of immune mediators such as antihistamine medications may be a cancer risk for developing gliomas [38,39,40]. Research is ongoing to determine the link between antihistamine response and cancer.

Antileukotrienes

Antileukotriene medications, introduced in 1996, were the first new class of asthma medications released in decades. Leukotrienes act as a communication system for the inflammation process. Antileukotrienes disrupt this communication process, reducing the effects of hyper-responsiveness in patients with asthma. There are two types of antileukotriene drugs: leukotriene synthesis inhibitors, which prevent these chemicals from being generated, and leukotriene receptor antagonists, which prevent the chemicals from delivering their messages by blocking their receptors [9,11].

Antileukotrienes are strong and very effective in preventing exercise-induced asthma; they can also prevent the development of bronchospasm caused by aspirin and may be useful in milder forms of asthma. These medications may be useful in the management of moderate-to-severe asthma when combined with an inhaled corticosteroid but may not be as effective as other approaches.

Common antileukotriene medications approved in the United States include montelukast, zafirlukast, and zileuton. Compared to other anti-inflammatory drugs, antileukotrienes may produce more serious side effects, including reversible liver problems, headache, and nausea. Healthcare providers should caution pregnant women against taking these medications. For patients receiving antileukotrienes, serum levels of the agent(s) should be checked regularly to monitor for potential liver problems. The use of antileukotrienes has been associated with the rare condition Churg-Strauss syndrome. This condition usually occurs in adult patients with asthma, with an initial presentation of flu-like symptoms and blood vessel inflammation. Other signs include eosinophilic rash, nasal polyps, and pulmonary infiltrates. Left untreated, Churg-Strauss syndrome can result in major organ damage and even death. The FDA issued a boxed warning for montelukast in 2020 [9,10,35].

Mucolytics may be prescribed to patients with asthma to destroy or dissolve mucus buildup in airways; expectorants may be used to thin and loosen mucus. With mucus thinned, coughing and clearing the airways should become easier. However, the value of mucolytics and expectorants for patients with asthma is the subject of debate, as they do not halt the production of excess mucus or treat the underlying causal factors [9,11].

Antibiotics are useful for combating bacterial infections throughout the respiratory system; most respiratory infections, however, are viral, and antibiotics would not be useful in these cases. In general, antibiotics do not eliminate common asthma triggers, nor do they contribute to shorter hospital stays after severe attacks [9,11]. The NAEPP and GINA recommend against the routine use of antibiotics for asthma [8,9].

Decongestants are found in over-the-counter cold remedies and can produce side effects of nervousness, nausea, and headache; these side effects increase when compounded with asthma medications with similar side effect profiles. Decongestants are usually not recommended for patients who have cardiac or prostate problems and should be carefully monitored if taken in conjunction with other asthma medications [11]. Research continues for new, improved decongestants.

For some patients, particularly those with allergy-induced asthma, immunotherapy may result in a reduction of airway sensitivity, which should help prevent asthma attacks. With immunotherapy, small amounts of diluted allergen are injected, causing the patient's immune system to produce the antibodies associated with an allergic reaction. This process is repeated once or twice a week for three to four months, sensitizing the patient with gradually higher concentrations of allergen, until the body is able to tolerate the trigger without reaction. The frequency of injections may be reduced, but the allergen dose may be increased for up to three to five years. Successful immunotherapy results in fewer symptoms and decreased need for medication to control allergies and allergy-related asthma. Immunotherapy is generally more successful in children than adults. Studies report that this preventive treatment is effective in reducing symptoms of allergic asthma if the allergies involve animal dander, house dust mites, pollen, or fungi; to date, research has not confirmed that the positive effects are lasting. Also, immunotherapy may be costly and time-consuming and may not result in a complete cure. Even without cure, lessening an allergic reaction can result in better control of asthma and asthma-like symptoms. It may also provide additional time for medical interventions in cases of severe asthmatic reactions [8,9,13].

Several biologics for moderate-to-severe allergic and/or eosinophilic asthma are currently approved by the FDA. Omalizumab has become a widely used option for patients with persistent allergic asthma not adequately controlled with inhaled corticosteroids, either alone or in combination with inhaled long-acting beta₂ agonist bronchodilators. Omalizumab is a humanized monoclonal antibody that binds circulating IgE antibody, which leads to a decrease in the release of mediators in response to allergen exposure. It is approved for the treatment of adults and children older than 12 years of age in conjunction with inhaled corticosteroids and long-acting beta₂ agonists. The agent is administered subcutaneously every two or four weeks (depending on the dosage schedule), and the dose used is based on pretreatment IgE serum levels and body weight. Possible adverse effects of omalizumab use include injection site pain and bruising, viral infection, headache, and sinusitis. Allergic reactions (e.g., urticaria, anaphylaxis) occur in 0.1% to 0.2% of patients [9,35,41].

Several other biologics have been approved to treat moderate-to-severe allergic and moderate-to-severe asthma with levels of blood eosinophils (i.e., eosinophilic asthma). These therapies include three monoclonal antibodies that treat eosinophilic asthma by targeting IL-5 pathways (mepolizumab, reslizumab, and benralizumab), and one that treats both eosinophilic and allergic asthma by targeting IL-4/IL-13 pathways (dipilumab). Patients with eosinophilic asthma should have their blood eosinophils tested several times per year, as studies have shown that eosinophil count may shift over time into a range that may warrant immunotherapy [11,35,42].

Another novel monoclonal antibody (tezepelumab-ekko) binds to human thymic stromal lymphopoietin (TSLP) and blocks the interaction with the TSLP receptor. The interaction reduces the biomarkers and cytokines associated with inflammation, including blood eosinophils, airway submucosal eosinophils, IgE, IL-5, and IL-13. Tezepelumab-ekko is the first biologic approved for all types of severe asthma [35,43]

Mepolizumab was approved in 2015 for use in patients 12 years of age and older. Patients with uncontrolled asthma who are receiving NAEPP step 5 or 6 treatment, with an initial blood eosinophil count of ≥150 cells/mcL and at least two asthma exacerbations requiring systemic corticosteroids in the past year are good candidates for therapy ]. Mepolizumab is administered as a subcutaneous injection every four weeks at a fixed dose of 100 mg [9,35,42].

Reslizumab is approved for patients 18 years of age and older. Patients with severe eosinophilic asthma (initial blood eosinophil count of ≥400 cells/mcL) that is not controlled with high-dose corticosteroids and inhalers and who have a history of exacerbations may be good candidates. Reslizumab is administered as an IV infusion every four weeks at a dose of 3 mg/kg [35,42].

Benralizumab is approved for patients 12 years of age and older as add-on maintenance treatment for uncontrolled severe eosinophilic asthma (recommended for blood eosinophil count of ≥300 cells/mcL). Benralizumab is administered at a dose of 30 mg subcutaneous every four weeks for the first three doses and then once every eight weeks [35,42].

Dupilumab is also approved for patients 12 years of age and older as an add-on maintenance treatment for moderate-to-severe allergic and/or eosinophilic asthma. Indications for use include NAEPP steps 5–6, inflammation characterized by increased blood eosinophils and/or elevated FeNO. Dupilumab is initially administered as two 200-mg (total: 400 mg) or two 300-mg (total: 600 mg) subcutaneous injections, followed by one 200-mg or 300-mg injection (depending on initial dose) every other week [35,42].

Tezepelumab-ekko was approved in 2021 for patients 12 years of age and older as an add-on maintenance treatment for patients with severe asthma (with or without inflammatory markers) and a history of severe exacerbations. Tezepeluab-ekko may be used for any type of asthma and is administered subcutaneously at a dose of 210 mg once every four weeks [35,43]

There are many alternative or complementary therapies available to patients with asthma. In general, these therapies should be regarded as adjuncts, not replacements, to conventional treatment. The most common complementary therapies used in the management of asthma include breathing exercises, acupuncture, yoga, postural drainage, massage therapy, homeopathy, and herbal medications. There has been relatively little research into the effectiveness of complementary treatments in the management of asthma. However, some inconclusive, small trials support the further investigation of these treatment modalities. For example, studies focusing on magnesium's role in lung function have found that the element appears to block chemicals that inflame the lungs by stabilizing mast cells and T cells released during exposure to allergens. The results are relaxed airway muscles and open bronchioles, which contribute to improved lung function and a reduction in wheezing and other allergy-induced asthma symptoms. Magnesium is often used in the emergency department, but it is not recommended in the management of chronic asthma. Patients and/or their caregivers should be cautioned not to self-prescribe these and other agents without consent or supervision by a qualified healthcare provider [8,11].

Patient J is a boy, 5 years of age, residing in Southwest Michigan. One March evening, Patient J was home with a conscientious babysitter. He had experienced several coughing episodes during the previous days and began to cough while playing hide-and-seek with the babysitter. She noticed that the coughing was continuing and that the more he coughed, the more he cried. She was not able to calm the patient and telephoned his parents at a nearby restaurant. Within 20 minutes, the parents returned home and found Patient J upset, crying, and coughing. They could hear audible wheezing on exhalation and could see the young boy's chest retract on inspiration. A physician was called immediately, and the parents were instructed to meet the pediatrician at his office located next to the area's hospital; they arrived within 30 minutes. The pediatrician administered a nebulizer treatment with albuterol in a 0.083% solution for inhalation, which seemed to resolve the cough, wheeze, and labored breathing after 15 to 20 minutes.

The patient's history was reviewed. According to his parents and office records, Patient J's first few years of life were essentially medically uneventful with the exception of occasional benign rashes, several that were specifically found to be related to a wood sensitivity. By 4 years of age, Patient J had experienced a number of cold viruses and allergies, with severe bouts of nasal and chest congestion. He had no history of medical emergencies related to labored breathing or otherwise.

As a precaution, the physician was prepared to recommend hospital admission to provide intensive respiratory tent therapy in the event that the symptoms did not improve. However, the symptoms seemed to resolve completely, and Patient J was sent home with his parents and placed on a 10-day period of antibiotic therapy and an albuterol aerosol inhaler, one or two inhalations every four to six hours as needed. It was also recommended that a nebulizer be kept at home, for faster results in case of sudden onset of moderate-to-severe coughing, chest congestion, wheezing, and/or tightness in the chest.

Patient J was subsequently diagnosed with an extrinsic, mild-intermittent asthma, triggered by several sensitivities, specifically to wood, dust, pollen, and cold weather. Recommendations for control of the patient's asthma symptoms were made to the patient and his family in an effort to manage the condition. He was encouraged to sleep with his head propped up with pillows about 30 degrees. Outdoor play and activities at home or at school were evaluated for appropriate participation based on severe weather, particularly when accompanied by wind. On very cold days or days with high mold or pollen counts, Patient J was instructed to wear a mask. Spring and fall proved to be difficult times for outdoor activities. His lungs became sensitive to the smoke from burning leaves and the mold-infested fallen leaves in autumn.

At home, Patient J's room was evaluated for sources of asthma triggers. Stuffed animals, carpeting, and heavy draperies were kept to a minimum. He had no feather-filled pillows, and his bedding was washed weekly in hot water. He slept with a room air purifier. When his asthma flared up, the patient was given his prescribed medications and warm liquids. A soothing bath or shower allowed him to be in an area of humidified, misty air, which often relaxed and dilated the bronchial airways.

One decade later, Patient J's asthma remains in control. At 15 years of age, he continues to take his medication and stays aware of his asthma triggers. The frequency and severity of asthma episodes have gradually lessened over time. He and his family, however, are aware that the condition is capable of changing or worsening at any time and may return with increased frequency and severity in later years. For now, Patient J is living a normal, healthy, active adolescent life.

Pollen is likely the most difficult allergen to avoid. To a great degree, this is because pollen release occurs at different times of day for different plants. For example, most grasses release pollen from about 7:30 a.m. throughout the day; however, if the ground is damp, the release will be delayed until the moisture has evaporated. A few species of grass and other plants delay pollen release until afternoon hours, so pollen may be entering the air all day. All types of plants generally favor warm, sunny days for releasing pollen and avoid rainy, wet weather. Rain also washes residual pollen out of the air. So, days of rain may be a relief to pollen-sensitive individuals with asthma. However, on cloudy and/or wetter days, there is a pollen buildup, which results in a massive release of pollen on the next day of good weather. These pollen release patterns may correspond with incidences of asthma symptoms in sensitive patients [8,47,48].

For certain patients with asthma, it may be useful to realize that pollen settles quickly in rural areas, reaching ground level between 8:00 p.m. and 10:00 p.m. In the city, hot pavements and buildings keep upward air currents going and pollen stays aloft longer. As most pollen lands in the city between roughly midnight and 2:00 a.m., it may contribute to night-time symptom aggravation in urban patients with asthma. If a patient with asthma has a noticeable response to a specific type of pollen, staying indoors or avoiding heavily wooded areas at release times may help alleviate symptoms. A daily pollution index figure should be available from a regional office of your state's Department of Environmental Conservation [8,47,48]. Many local and online weather stations include pollen counts in their daily reports as well.

The verdict regarding the effects of outdoor pollution on the condition of asthma remains controversial. Consider two main types of outdoor pollution: industrial smog (such as sulfur dioxide) and photochemical smog (a combination of ozone and nitrogen oxides). Physicians and scientists are cautious about implicating these and other environmental pollutants as asthma triggers. But the findings of several studies confirm a relationship between pollutants and asthma, particularly when nitrogen oxide, acid aerosols, and ozone are involved [8,47,48].

Air pollution plays a variety of roles in asthma and allergy. Some pollutants irritate the nose, airways, and/or skin, making them more sensitive to allergens. Specifically, ozone can increase the effects of allergens and may take 4 to 24 hours to produce its effects on the lungs and airways. Such pollutants can worsen existing asthma symptoms and may even promote development of allergies and/or asthma, particularly in children, whose airway membranes are more permeable. Other chemical pollutants may affect the immune system directly, which would tend to increase any existing tendency to allergic reactions [8,47,48].

In many regions, air quality is also reported. A government-backed program, AIRNow, is available online to monitor the air quality in various areas around the United States [49]. This information can be used to determine when indoor activities should be encouraged. Local air quality monitoring services may also be available.

One of the worst irritants in indoor air, and perhaps the most obvious, is tobacco smoke. Cigarette, cigar, or pipe smoke can trigger asthma attacks in the short term and generally worsen asthma symptoms in the long term. Passive, or second-hand, smoking may also adversely affect the immune system. Smoking should not be permitted around a patient with asthma or in rooms an individual with asthma uses. Patients who smoke should be advised to stop smoking. Patients should also be advised of the many techniques available to assist in smoking cessation, including the various nicotine replacement agents [8,47,48].

Smoking during pregnancy significantly increases the risk of the infant developing allergies and asthma. In addition, research also reveals that, for those who had asthma as children for whom symptoms have resolved, cigarette smoking greatly increases the chance of the asthma returning. Generally, pediatric patients with asthma who have one or more parents who smoke indoors tend to have more severe and frequent asthma symptoms. It has been found that teenagers can be just as affected by passive smoking as young children [8,50]. Smoking has many distressing effects on patient health, and smoking cessation should be integrated into all care plans and general assessments.

In addition to tobacco smoke, other air pollutants can irritate the lungs of patients with asthma. Such pollutants can worsen existing allergic symptoms and may promote development of allergies in pediatric patients. Common household soaps, detergents, and cleaners may be very irritating for a patient with asthma; contact with strong odors and sprays should be reduced. The use of natural cleaning products can be helpful; however, even the safest products and thorough cleaning may still leave an environment with airborne pollutants. Other chemical contaminants may affect the immune system directly, which would tend to increase any existing tendency to allergic reactions [8,47,48].

Traffic pollution, most often characterized by the presence of nitrogen oxide, has long been considered a trigger or cause of asthma symptoms; yet, some research reveals the link between traffic pollution and asthma to be, for the most part, tenuous. However, there have been several studies confirming the negative impact of exposure to freeway traffic on lung development in children and on respiratory infections, allergy, and asthma [8,47,48]. The exact mechanism responsible for this association is still being investigated.

Cooking with a gas stove generates a significant amount of nitrogen dioxide, the same pollutants emitted from motor-vehicle traffic. But, peak levels of nitrogen dioxide in kitchens with gas stoves are often ten times the average level on city streets, frequently exceeding standards for outdoor air set by the WHO. Other sources of nitrogen dioxide include cigarettes, gas fireplaces, and kerosene heaters. If a patient has a nitrogen oxide sensitivity, he or she should be encouraged to use electric stoves and heaters as often as possible and to always use a ventilation fan or open windows when cooking with a natural gas appliance [8,47,48].

Patients with asthma seem to have more frequent symptoms if exposed to high formaldehyde levels. Formaldehyde is common in both gas and liquid forms; the vapors expelled by the compound may irritate the lining of the eyes, nose, and lungs when inhaled. A formaldehyde solution is often used as a preservative in laundry detergents, air fresheners, shampoos, dish soaps, medications, cosmetics, cigarettes, and some processed foods. Additionally, it may be found in manufacturing plastics, wrinkle-free clothes, and some building materials, such as particle board, plywood, pressed board fiberboard, carpet backing, glues, and foam insulation. The frequent use of formaldehyde in the production of so many different items makes it a very commonly encountered irritant. Materials that produce formaldehyde should be eliminated from the environment of patients with asthma as much as possible. If a manufactured product contains formaldehyde, it should be noted that the emissions generally decrease as the item ages. Formaldehyde is also created by the combustion of wood and natural gas. Flues for wood burning fireplaces and stoves must be clear; if smoke can be smelled, there is formaldehyde present in the air. When a natural gas appliance is used, adequate ventilation, preferably with a powered vent, is necessary [8,48,51].

Cleaning products, furniture polish, and even deodorant were never intended to enter the nasal airways, but substances sprayed from aerosols do just that and can trigger asthma attacks. Patients with asthma should be advised to avoid the use of aerosols as much as possible. Additionally, air fresheners and perfumes with strong odors can trigger asthma attacks in sensitive individuals. Avoidance of strong fragrances may help alleviate symptoms [8,47].

The FDA estimates that 1 out of every 100 people is sulfite-sensitive and that 5% of those who have asthma are at risk of experiencing an adverse reaction to the substance. Patients with asthma should be aware of instructions and ingredients listed on all usable or edible products. It is important not only to be knowledgeable as to what is in the product but also as to what gases may be given off when used. One such example is sulfur and sulfur dioxide gas. "Sulfuric," "sulfate," or "sulfite" in a list of ingredients should serve as a warning for a patient with asthma; the product may give off sulfur dioxide gas [8,52].

In 1986, the federal government established guidelines for sulfites, and a partial ban on sulfites was enacted for restaurant and market fresh salad bars. Regulations also require labels to indicate if sulfites have been added to prepared products. Many medications and processed foods, including some wines, juices, and shellfish, contain sulfites. Due to the fact that inhaled asthma medications may include sulfur-based preservatives, care should be taken when prescribing or administering medications to patients with sulfite sensitivity [8,9,52].

For a patient with asthma, bleach and other chlorine-based cleaning products, such as toilet cleaner and scouring powder, should be used sparingly and with plenty of ventilation. These products release chlorine gas, which, in large amounts, can irritate air passages. Bleach and toilet cleaner should not be mixed with any other products, as chemical reactions may exacerbate the amount of chlorine gas expelled. Patients should be instructed to be careful when using any manufactured good containing hypochlorite, chloramines, ammonia, acids, morpholine, or chemicals used for swimming pool water, as all of these agents have the ability to trigger asthma attacks [8,47,48].

The possible harmful effects of paint for people with asthma are mainly due to the presence of solvents; these solvents can act as irritants to nasal air passages. Areas where paint is being used should be well ventilated. Solvent-free, odorless paints are also available and may be useful for patients who are unable to avoid paint fumes as part of their occupation or daily lives [8,47,48].

One of the most powerful asthmagens is isocyanate. "Instant foam" kits sold for do-it-yourself insulation can provoke asthma in those who were previously not asthmatic. This is due to two different substances that are mixed to create the polyurethane foam, one of which is unreacted isocyanate. The combination of these substances results in the release of isocyanate at potentially harmful levels[ [8,48]. The most common incidences of isocyanate asthma occur in patients who have high exposures in their occupation. The National Institute for Occupational Safety and Health has published an alert regarding the risks to U.S. workers exposed to diisocyanate [54]. Although IgE antibodies against isocyanate may be detected by a RAST, this test is positive in only a minority of cases of isocyanate asthma.

Any job may present a worker with some environmental hazards. For a patient with asthma, this risk is heightened as a result of the many harmful agents that may be released into the environment and inhaled into the lungs. Some of the most potent irritants are hard metal dusts, such as silica, asbestos, and talc, used in mining and refineries. Fumes from fluorocarbon propellants and oxide of such metals as copper, zinc, manganese, and iron are also on a long list of agents that provoke lung diseases and disorders, including asthma. Other work-related agents that can cause asthma include animal proteins, enzymes, wheat flour, and certain reactive chemicals [8,55].

Since the healthcare industry has required personnel to wear protective gloves, more healthcare professionals have discovered that latex allergies trigger airway sensitivity. Healthcare providers who have known sensitivities should also be aware of contact with irritants such as disinfectants, formaldehyde, sulfathiazole, chloramine, and psyllium [8,55].

Office workers in insulated office buildings with central air conditioning systems may never find the source of their symptoms; fewer than 40% of those who feel sick on the job ever discover exactly which pollutant to avoid. Common office triggers include paper dust, perfumes or colognes, industrial cleaners, and mold. Additional and ongoing research continues to provide information about irritants and occupational asthma [8,55].

Many consider upper respiratory tract infection or rhinoviruses to be the most important (and for many patients, the most significant) asthma trigger other than allergy. Viral infections such as these, also referred to as "the common cold," are known to cause complications for many (30% to 40%) patients with asthma. For those without asthma, these infections are usually single nuisances characterized by spontaneously resolving symptoms typically lasting about 7 to 10 days. Symptoms include nasal congestion and drip, postnasal drainage, sore throat, edematous glands, and at times, fatigue. In some instances, the lower respiratory tract may also be involved, and individuals without asthma can develop bronchitis with cough; these symptoms can be confused with allergic reactions in atopic patients. There are more than 200 viruses capable of causing what is generally recognized as a cold. It may be worth noting that colds, especially versions produced by RSV, are often the event that precipitates the onset of asthma in children and adults. In fact, these infections not only often precipitate acute events, but they seem to alter the immune system response to initiate the development of allergy or asthma [8,47,56].

Asthma episodes that are the result of viruses may be severe and sudden in onset; lower respiratory tract symptoms of coughing, wheezing, and shortness of breath can occur within 24 hours after the onset of upper respiratory tract viral symptoms, such as nasal congestion. Occasionally, wheezing may occur without any premonitory upper respiratory tract warning, so the patient with asthma should be alert to the earliest onset of chest symptoms as well as the premonitory upper respiratory tract symptoms that usually precede them. It is known that early treatment, especially with oral corticosteroids, may prevent the often serious asthmatic consequences of a viral infection. It is imperative, therefore, that patients are able to recognize early warning signals. Vaccination for typical respiratory viruses, such as influenza, measles, varicella (chicken pox), and pertussis, should be considered as a preventive measure, especially in children. The CDC Advisory Committee on Immunization Practices and GINA recommend that people with asthma receive either the Moderna or Pfizer-BioNTech COVID-19 vaccine series [8,57].

Some patients with asthma will indicate that they are able to predict weather because they notice their symptoms worsen or disappear with fluctuating barometric pressures and sudden, extreme temperature shifts. Symptoms such as chest tightening and excess mucus production may warn of high humidity, thunderstorms, snowstorms, or freezing temperatures [8,47,48].

Cold air, which usually does not limit airflow with other lung diseases, is a major trigger for many individuals with asthma. Bronchial muscles constrict in cool, dry air, and muscles may not relax until temperatures rise. Even ingesting cold foods or drinks can cause muscle constriction. Exercise during cold weather increases the risk of bronchial constriction by forcing inhalation of cold air [8,47,48].

An anti-asthma diet is generally neither an avoidance diet nor a diagnostic diet, but rather a health-promoting diet, designed to protect against asthma and asthma symptoms. However, if specific food allergies or triggers are identified, they should be avoided as much as possible. Patients with asthma with food sensitivities and/or those who care for them should be made aware of potentially allergenic-specific food ingredients (Appendix).

Because overweight and obesity have been linked to an increased risk for asthma, some patients may benefit from weight loss and limiting their calorie intake to lose weight. Dieting patients with asthma should be taught that some packaged goods, including some recommended by several diet plans, contain sugar substitutes, food coloring, and preservatives, all of which have been associated with exacerbation of asthma symptoms in sensitive individuals [8,19,47].

Before any dietary treatment, investigation, or recommendation is initiated, a physician or healthcare provider should be aware of assessed risks; referral to a dietician or nutritionist may also be necessary.

Hormone Changes

The relationship between hormonal changes and asthma is unclear. However, there are types of asthma that are triggered by changes in hormone levels. The number of girls who develop asthma at puberty, when large amounts of estrogen are produced, is growing. A higher incidence of asthma among women, as compared to men, continues through reproductive years [8,18].

Many women have reported that their asthma worsens when they menstruate. Indeed, research suggests that the decreased levels of progesterone and estrogen during menstruation alter the body's water and salt balance and may negatively affect bronchial muscles and smooth muscles. A few studies concur that premenstrual hormone changes stimulate airway constriction [8,47,18].

Contraceptive pills and hormone replacement therapy (HRT) during menopause are being studied as possible asthma stimulants. A Harvard research team surveyed 23,035 women in the Nurses' Health Study and revealed that asthma was twice as prevalent among women who took hormones for 10 years or more, during and after menopause, compared to those women who did not take HRT [58]. However, more research is necessary to discover how and when hormonal changes during the menstrual cycle or menopause affect lungs and asthma symptoms.

Stress

There was once a theory that asthma was the body's way of communicating emotions. The current understanding of asthma is that emotions and mental disorders do not cause asthma in otherwise healthy patients. However, there is evidence that strong emotions may arouse symptoms in individuals with asthma; extreme bouts of laughter or fear can cause bronchial lumens to narrow abruptly. Also, any activity that stresses the respiratory system, including crying or shouting, can stimulate nerves to constrict bronchial lumens. If asthma seems worse during particularly stressful times, specific activities and medications may be used to reduce asthma symptoms [8,9,47]. Referral to a counselor, psychologist, or support group may be helpful for patients whose stress is prompting asthma symptoms.

Exercise

Exercise is a proven asthmagen in some individuals. Exercise-induced asthma (EIA) refers to airway changes following activity, which distinguish it from chronic asthma. In patients with chronic asthma, symptoms surface any time, in response to one or more triggers. With EIA, the trigger is more obvious, as symptoms appear when the patient is engaged in exercise and can persist for several hours after activity ends. It is estimated that between 80% and 90% of patients with chronic asthma experience symptoms from exercise at some time [8,9,59].

It is very important to realize that any burst of exercise or sustained exercise can trigger asthma flare-ups; reactions can be immediate or delayed, in some cases occurring several hours later. The exact cause of EIA is unknown. One theory focuses on the loss of warmth and moisture from the airways during exercise. After the activity concludes, patients with asthma warm their airways four times faster than those without asthma; some researchers believe that this warming is a sign of edematous airways. Exercise-related airflow problems result in coughing, wheezing, and shortness of breath. The earliest symptoms, such as wheezing, may not be apparent at first because exercise stimulates the increased production of epinephrine, which can mask the symptoms associated with the onset of an attack. Patients with EIA usually begin to have difficulties about 10 minutes into strenuous activity or within 5 to 20 minutes of ending the activity [8,9,59].

Another theory suggests that the major cause of EIA is hyperventilation. In fact, the bronchial constriction that occurs during exercise in those with EIA may also be induced by hyperventilation, even in the absence of vigorous physical activity [59].

Some exercises are more likely than others to cause asthma. Team sports that require short bursts of energy (e.g., baseball, football) are less likely to cause symptoms than sports such as soccer or long-distance running that require ongoing activity. Cold weather activities (e.g., cross-country skiing, ice hockey) also tend to make symptoms worse. Swimmers are exposed to warm, moist air, which does not tend to trigger asthma symptoms. Walking, leisure biking, and hiking also are good activities for individuals with EIA [8,9,59].

Generally, patients with EIA would be categorized as having mild intermittent asthma and their treatment plans would reflect this categorization. Practitioners should discourage any patients known to experience EIA from engaging in high-risk activities without access to fast-acting medications. This is not to say patients with asthma should not be active. On the contrary, the majority of individuals with asthma benefit greatly from daily exercise, as better physical conditioning generally results in decreased asthma symptoms. The trick is to map out a routine and group of exercises that work best for the patient.

Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)

It is important to realize, as mentioned before, that at least some patients with asthma are particularly sensitive to NSAIDs, which are used to treat pain and inflammation. Several of these medications, such as aspirin, naproxen, ibuprofen, and ketoprofen, are available over the counter. NSAIDs available by prescription only include [35,60]:

Known NSAID sensitivity should be noted in a patient's record, as prescribing any of these medications may be extremely hazardous. Other medications, such as paracetamol, may be prescribed instead.

Beta Blockers

The beta-adrenergic system includes the neurologic system, which relaxes the smooth muscle of the bronchial tree and stimulates the heart. Blockage of this system can calm the heart but may also constrict the muscles of the bronchi. This bronchoconstrictive tendency can occur in an exaggerated form in patients with asthma. Beta blockers are used in treating a number of conditions, including hypertension, cardiac arrhythmias, glaucoma (as ophthalmic drops), and migraines. Medications within this category include propranolol, labetalol, atenolol, and timolol [35,60].

Patients with asthma should be educated regarding the risks of beta blockers and instructed on the appropriate steps to take if they begin to experience asthma symptoms after taking these agents.

Pets

The number of household pets is on the rise; surveys indicate that there are 62 million dog-owning households in the United States and 37 million cat-owning households [61]. These domestic animals, as well as mice, guinea pigs, and even horses and sheep, give off saliva, fur, and dander as they live their normal lives—rubbing against or licking their owners or other individuals. Exposure to any of these elements may trigger asthma symptoms in sensitive individuals.

Certain breeds of dogs and most cats shed clumps of fur throughout the year; saliva holds and spreads dander and fur throughout a house. Further, animals that explore outdoors bring pollen and mold spores indoors on their fur, another potential problem for those with asthma[8,47].

For very sensitive patients, even the slightest exposure to dander can result in airway constriction. The situation can become dangerous for a child with allergies who keeps rodents in a bedroom or sleeps with a dog or cat. In fact, those with asthma may react whether or not the animal is in the room because dander and/or other allergens may remain in the air for long periods of time [8,47].

Cat dander is one of the smallest allergens; most of the particles are less than 2.5 microns and the smallest may be only 0.5 micron. A sensitive individual would require a very good dust mask or high efficiency particulate air (HEPA) filter to eliminate these particles in a contaminated indoor area. It should be noted that, in many cases, dander can linger in house dust for approximately six months after a pet has been removed from the environment [8,47,48]].

Other, less common pets may produce allergens through shedding of fur or dander. For example, horses are known to produce very powerful allergens. In the case of small mammals, such as mice or guinea pigs, urine is usually the main cause of allergic and asthmatic reactions. Proteins in the urine become airborne and are carried throughout the environment. Allergic reactions to reptiles and amphibians are extremely rare; however, cases of reactions have been documented [62]. With pet insects and snakes, lizards, and other reptiles, the allergens are found in tiny skin particles that float in the air. In addition, live grasshoppers and other insects used to feed reptiles may cause allergic reactions. Because reptiles and amphibians are known to carry Salmonella, which can cause life-threatening infection in young children, the CDC recommends against keeping them in homes with children younger than 5 years of age [8,47,48].

Dust Mites, Cockroaches, and Rodents

Allergy research reveals that dust mites play an important role in the development of asthma symptoms. The dust mite allergen provokes immune cells, and after an allergy to dust mites has developed, other allergies become more likely.

It should also be noted that researchers have demonstrated that 18% of children in urban areas in the United States have an allergic reaction to mice, and this can surely contribute to asthma. Cockroaches are another significant cause of asthma symptoms in urban environments. Meticulous cleaning to combat cockroach allergen is advisable, as even slightly reducing exposure can be of great benefit to individuals with asthma. One study of children with asthma who were allergic to cockroaches concluded that the levels of the allergen in the homes were directly related to the severity of the asthma symptoms; children exposed to the highest levels of cockroach allergen were more likely to be hospitalized for asthma, miss more school due to asthma, and have sleepless, wheezy nights [8,47,63].

As noted, the NAEPP updated guidelines include recommendations for the assessment of environmental factors during any stage of asthma management, to provide applicable patient education and manage comorbidities. For example, [9,10]:

Mold

Except in very dry climates, mold spores are the predominant particulate in the air. In the United Kingdom, a relatively damp country where molds flourish, the record count is more than 160,000 spores/m3, compared to a record pollen count of only 2,800 grains/m3. The size of most mold spores is between 2 and 10 microns, but a few species have spores that are smaller than 2 microns[8,47,64].

Molds and fungi reproduce through the release of spores. Often, healthcare providers will refer to mold allergies singularly, because molds are the most common offenders, but layer fungi, including mushrooms and toadstools, also produce allergenic spores. There are different species of mold in different environments, and these species can grow in a very wide range of situations, including indoors. A sensitive individual may have cross-reactions between some molds, meaning that a sensitive individual will react to a variety of mold species [8,47,64].

One mold allergy in particular has a risk of severe reaction. During the spore-producing season, healthcare professionals should consider increasing the dose of preventive inhaler medications for individuals with asthma who also have allergy to the mold Alternaria. Research shows that severe, near-fatal asthma attacks often occur during the Alternaria spore season among those allergic to this mold. These individuals may also be referred to a local pollen/spore monitoring service. Alternaria spore release usually occurs in the summer or fall, although timing varies from one part of the world to another. Alternaria may colonize outdoors, in soil, seeds, or plants, or indoors, in window frames, carpets, or textiles [8,47,64].

Mold-sensitive individuals with asthma should be advised to avoid the following places as much as possible; if avoidance is not possible, the use of HEPA facemasks is recommended when patients are in these environments [8,47,64]:

Healthcare professionals should note that mold-sensitive individuals, just as those with pollen allergy or sensitivity, often experience more frequent or intense asthma symptoms during certain times of the year. Increased symptoms during late summer and autumn, when molds flourish outdoors, or following the first frost, which prompts spore release by fungi living in the soil, may indicate a mold allergy. Patients with asthma should be advised to avoid disturbing compost piles, damp straw or hay, piles of grass clippings, or heaps of fallen leaves, all of which are likely to be full of molds. These same patients should not collect fallen leaves or fruit, remove dead leaves or flowers from plants, or water gardens because mold spores are released when water hits dry soil [8,47,64].

Indoor molds and the indoor conditions that promote mold growth can be difficult to endure for mold-sensitive patients. Sensitive patients should be advised to avoid the following places, wear a mask while in these areas, or correct the problem areas at their source [8,47,64]:

Asthma symptoms can be influenced by the time of the day. Often, asthma worsens at night, especially between 2:00 a.m. and 4:00 a.m., or in the early morning prior to or upon awakening. Many patients with asthma awaken with a choking cough, wheezing, breathlessness, or chest tightness; symptoms may last a short period or may persist for minutes or hours. For patients with persistent nocturnal asthma, symptoms disrupt sleep and may affect ability to function normally during waking hours. Nocturnal asthma not only leads to sleep loss but also usually indicates uncontrolled asthma [8,13,65]. There are many possible causes of nocturnal asthma.

In sensitive individuals, increased amounts of dust mites and other allergens, such as fungal spores, embedded in bedding may trigger allergic asthma. This would, of course, only affect those patients with specific sensitivities. Levels of the hormones epinephrine and cortisol, which play an important role in keeping bronchial airways open, reach their lowest point between midnight and 6:00 a.m. Additionally, histamine levels, which may worsen asthma symptoms, peak at night. Reduced adrenal gland function at night may also be responsible for the decreased amounts of epinephrine and corticosteroids in the blood [8,13,65].

The cold night air may lower bronchial airway temperatures, inducing lumen constriction and triggering asthma symptoms. Furthermore, about half of individuals with asthma notice that their symptoms intensify 4 to 12 hours after the first reaction, suggesting that a nocturnal attack may result from a trigger encountered earlier in the day. Lastly, a reclining sleep position may increase the likelihood of gastric reflux symptoms, which may exacerbate or mimic an asthma episode [8,13,65].