Managing patients with high-risk asthma

Patients with highly variable lung function, marked bronchial hyperreactivity, and poor perception of breathlessness are at high risk for fatal or near-fatal asthma. Respiratory arrest may occur minutes after the onset of asthma symptoms.

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Patients with high-risk asthma are those more likely to require hospitalization, emergency department (ED) visits, or to experience fatal or near-fatal episodes of asthma. High-risk asthma is characterized by

• Low resting pulmonary function
• Wide variations in pulmonary function
• Marked bronchial hyperreactivity
• Poor perception of one's own pulmonary status
• Severe mold sensitivity
• Past hospitalizations and ED visits for asthma, particularly if intensive care with intubation was required.

Patients classified as having severe persistent asthma, who need chronic corticosteroid treatment, are likely to be in this high-risk group. Pregnant women who require corticosteroid treatment are often included because of the danger to themselves and the fetus. Patients with significant comorbid conditions are also at high risk. Although the elderly are frequently placed in this category as well, many of the patients who experience unexpected, profound bronchospasm with the potential to proceed quickly to respiratory arrest and death are younger than 25. Children 10 to 14 years old are particularly susceptible to fatal and near-fatal asthma. Factors that may increase the risk in children include

• Poor adherence to treatment
• Inappropriate use of metered-dose inhalers (MDIs)
• Poor self-management skills (denial of the disease)
• Increased atopic sensitivity.

Inhabitants of the inner city, particularly people of lower socioeconomic status, continue to experience the greatest burden of morbidity and mortality from asthma. Various factors have been suggested to explain this association, including increased exposure to cockroach allergen, exhaust fumes, and cigarette smoke; poorer access to health care; lower educational status; and possibly a more severe expression of the disease in African Americans. The rate of ED visits for asthma among African Americans during the period from 1992 to 1999 was more than 3 times the rate for whites.²

A fatal or near-fatal asthma attack is usually a prolonged episode lasting days or weeks and marked by a slow, steady decline in pulmonary function. A fulminant form, sometimes called sudden asphyxic asthma (SAA), may also occur. Respiratory arrest may occur 30 to 60 minutes after the onset of symptoms in a patient with SAA. Many patients with SAA have recently been discharged from the hospital or ED after treatment for asthma.

ASSESSMENT OF RISK STATUS

The physical examination and history are always important parts of the patient evaluation. The diagnosis of asthma, assessment of its severity, and determination of the patient's risk category are based on pulmonary function studies or spirometry, however.

History and physical examination

A history of previous respiratory arrest or sudden attacks of severe bronchospasm leading to asphyxia places patients at increased risk of another, similar episode. The occurrence of a seizure during an asthma attack is a particularly ominous sign. Determining the patient's stress level may be helpful because distressing events may precipitate SAA in some patients. In assessing risk status, ask how often the patient has had daytime symptoms during the past week and how often nighttime symptoms have occurred in the previous month. Asthma is an episodic disease in which lung function can vary significantly within a short period of time. Severity is categorized according to frequency of symptoms as well as lung function (see "Stepwise approach to asthma in adults and children aged 5 years and older"). Asthma severity is often underestimated because assessments are not based on objective lung function testing and the frequency with which patients use bronchodilators. Frequency of bronchodilator use, a good measure of symptom frequency, was associated with near-fatal asthma in a recent case-control study.³ Indices of asthma severity should be reassessed frequently in patients with asthma.

 

GUIDELINE
Stepwise approach to asthma in adults and children aged 5 years and older
Classify severity: Clinical features before treatment or adequate control		Medications required to maintain long-term control
	Symptoms by day Symptoms by night	PEFR or FEV1 PEFR variability	Daily medications
Step 4 Severe persistent	Continual ___________ Frequent	<60% _____ >30%	Preferred treatment High-dose inhaled corticosteroids AND Long-acting inhaled beta2-agonists AND, if needed,
			Corticosteroid tablets or syrup long term (2 mg/kg/d, generally do not exceed 60 mg/d). Make repeat attempts to reduce systemic corticosteroids and maintain control with high-dose inhaled corticosteroids.
Step 3 Moderate persistent	Daily __________ >1 night/wk	>60% to <80% ___________ >30%	Preferred treatment Long to medium dose inhaled corticosteroids and long-acting inhaled beta2-agonists.
			Alternative treatments (listed alphabetically) Increase inhaled corticosteroids within medium-dose range OR Low to medium dose inhaled corticosteroids and either leukotriene modifier or theophylline
Step 2 Mild persistent	>2/wk but <1/d ___________ >2 nights/mo	>80% ________ 20%-30%	Preferred treatment Low-dose inhaled corticosteroids
			Alternative treatments (listed alphabetically) Cromolyn, leukotriene modifier, nedocromil OR Sustained-release theophylline to serum concentration of 5-15 mcg/mL
Step 1 Mild intermittent	<2d/wk ___________ <2 nights/mo	>80% ______ <20%	No daily medication needed
			Severe exacerbations may occur, separated by long periods of normal lung function and no symptoms. A course of systemic corticosteroids is recommended.
All patients	Short-acting bronchodilator: 2-4 puffs short-acting inhaled beta2-agonists as needed for symptoms. Intensity of treatment depends on severity of exacerbation; up to 3 treatments at 20-minute intervals or a single nebulizer treatment as needed. Course of systemic corticosteroids may be needed. Use of short-acting inhaled beta2-agonists on a daily basis, or increasing use, indicates the need to initiate or increase long-term control therapy.
Step down Review treatment every 1 to 6 months; a gradual stepwise reduction in treatment may be possible. Step up If control is not maintained, consider step up. First, review patient medication technique, adherence, and environmental control.		Note: The stepwise approach is meant to assist, not replace, the clinical decision-making process required to meet individual patient needs. Classify severity: assign patient to most severe step in which any feature occurs (PEFR is percent of personal best; FEV1 is percent predicted). Gain control as quickly as possible (consider a short course of systemic corticosteroids); then step down to the least medication necessary to maintain control. Provide education on self-management and controlling environmental factors that worsen asthma (eg, allergens and irritants). Refer to an asthma specialist if there are difficulties controlling asthma or if step-4 care is required. Referral may be considered if step-3 care is required.
Key: FEV1 forced expiratory volume in 1 sec; PEFR, peak expiratory flow rate. Source: National Asthma Education and Prevention Program Expert Panel. The Executive Summary of the NAEPP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002. NIH publication 02-5075. Available at: http://www.nhlbi.nih.gov/guidelines/index.htm . Accessed November 15, 2002.

The physical examination rarely holds clues to the possibility of SAA. The fast onset of symptoms in SAA does not correlate with measures such as respiratory rate, pulse rate, BP, use of accessory muscles of respiration, lung hyperinflation on chest radiography, or ECG findings such as cardiac arrhythmias.¹

Pulmonary function testing

An objective measure of lung function should be obtained at the initial evaluation, with any change in patient status, and at least annually. Patients may not perceive the severity of their disorder for several reasons. First, someone who has never experienced good asthma control may become accustomed to even very severe symptoms. A patient with lung function that is only 60% of the predicted value may rate his symptoms as a 10 on a 10-point scale, indicating excellent symptom control. In addition, a small percentage of patients have a specific inability to perceive their own breathlessness.

The primary purpose of spirometry is to detect reductions in percent predicted of forced expiratory volume in 1 second (FEV₁). Using the percent predicted value corrects for the patient's age, height, weight, gender, and race. An FEV₁ that is 80% or more of the predicted value is considered normal. Additional data obtained from spirometry include the forced vital capacity (FVC) and the ratio of FEV₁ to FVC. A reduced FEV₁ to FVC ratio indicates obstructive lung disease, which occurs most commonly with asthma or emphysema. The severity of disease is determined from the FEV₁ level. A low value for resting pulmonary function, an FEV₁ of less than 60% of predicted for example, is associated with a high risk for hospitalization. If the FEV₁ is less than 30% of predicted in a patient with asthma, immediate hospitalization is recommended. A pattern of highly variable or gradually deteriorating pulmonary function is also associated with an increased risk of death from asthma.

If spirometry is unavailable, the peak expiratory flow rate (PEFR) should be obtained at each visit. This measure is effort-dependent, however, and its routine use has not been demonstrated to improve outcome. The major benefit of the peak flow meter is in-home use, especially for patients who find it difficult to accurately assess the severity of their symptoms. A wide diurnal variation in PEFR, which is related to altered perception of breathlessness, has been consistently associated with risk of a life-threatening episode of SAA.¹

MANAGEMENT OF THE ACUTE EPISODE

Episodes of severe bronchospasm with rapidly progressive dyspnea often proceed from relatively asymptomatic to full respiratory arrest in a matter of minutes. The patient may not have an opportunity to summon help. Sudden mucus plugging and overwhelming allergen exposure are possible mechanisms by which these attacks occur. Acute stress has also been proposed as a possible precipitating factor. Attacks frequently occur in the early morning, as do most asthma-related ED visits and hospital admissions. The diurnal variation of severe asthma attacks may occur because of lowered serum levels of endogenous epinephrine and cortisol in the early morning hours and increased responsiveness to inhaled allergens and histamine at night.¹

It is not possible to determine when the patient presents whether a severe asthma attack will become a fatal or near-fatal episode. Patients at high risk for SAA may have a higher incidence of silent chest on auscultation than those with a slower onset of symptoms. In this situation, a silent chest is caused by severe bronchospasm and poor air movement.

Patients undergoing rapid decompensation from SAA must be brought immediately to the ED. Initial management includes oxygen administration, IM epinephrine (the treatment of choice), mechanical ventilation (if indicated), IV corticosteroids, and nebulized beta₂-agonists. Antibiotics are recommended in acute asthma exacerbations only for patients with fever and purulent sputum, evidence of pneumonia, or suspected bacterial sinusitis.⁴

MANAGEMENT OF CHRONIC DISEASE

Patients who are subject to near-fatal asthma attacks should be seen by a physician at least monthly. They should also have periodic consultations with a pulmonologist or allergist so that their medical program can be reviewed and additional education provided. Chronic management of the high-risk asthma patient requires combination therapy with rescue and controller medication (see Table 1).

 

GUIDELINE
TABLE 1 Long-term control medications: Usual adult dosages
Medication	Dosage form	Dosage
SYSTEMIC CORTICOSTEROIDS
Methylprednisolone	2-, 4-, 8-, 16-, 32-mg tablets	7.5-60 mg/d in a single dose in the morning or qod as needed for control
Prednisolone	5-mg tablets, 5 mg/5 mL, 15 mg/5 mL
Prednisone	1-, 2.5-, 5-, 10-, 20-, 50-mg tablets; 5 mg/mL, 15 mg/mL	Short-course burst to achieve control: 40-60 mg/d in a single dose or 2 divided doses for 3-10 d
CROMOLYN, NEDOCROMIL
Cromolyn	MDI, 1 mg/puff	2-4 puffs tid-qid
	Nebulizer, 20 mg/ampule	1 ampule tid-qid
Nedocromil	MDI, 1.75 mg/puff	2-4 puffs bid-qid
INHALED LONG-ACTING BETA2-AGONISTS*
Formoterol	DPI, 12 mcg/single-use capsule	1 capsule q12h
Salmeterol	MDI, 21 mcg/puff	2 puffs q12h
	DPI, 50 mcg/blister	1 blister q12h
COMBINATION MEDICATION
Fluticasone/salmeterol	DPI, 100, 250, or 500 mcg/50 mcg	1 inhalation bid; dosage depends on asthma severity
LEUKOTRIENE MODIFIERS
Montelukast	4- or 5-mg chewable tablet; 10-mg tablet	10 mg qhs
Zafirlukast	10- or 20-mg tablet	40 mg/d in 2 divided doses
Zileuton	300- or 600-mg tablet	2400 mg/d (give tablets qid)
METHYLXANTHINE†
Theophylline	Liquids, sustained-release tablets, and capsules	Starting dosage, 10 mg/kg/d up to 300 mg max; usual max, 800 mg/d
Key: DPI, dry powder inhaler; MDI, metered-dose inhaler. Note: See Table 2, for estimated high dosages for inhaled corticosteroids. *Not used for symptom relief, exacerbations, or without inhaled corticosteroids. †Monitor to maintain serum concentrations at 5-15 mcg/mL. Source: National Asthma Education and Prevention Program Expert Panel. The Executive Summary of the NAEPP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002. NIH publication 02-5075. Available at: http://www.nhlbi.nih.gov . Accessed November 15, 2002.

Rescue treatment

Rapid-acting beta₂-agonist bronchodilators such as albuterol, used as needed to provide immediate relief from an attack, are the mainstay of rescue treatment for asthma. Bronchodilation occurs within about 5 minutes of use. Of the 4 categories of asthma severity, only patients with intermittent asthma can be treated with a beta₂-agonist bronchodilator alone.

Patients who have experienced previous SAA attacks or with risk factors for SAA should be trained in emergency measures in the event of a severe bronchospastic episode. These patients should wear a medical alert bracelet and carry an epinephrine kit.

Controller medication

Patients with mild persistent, moderate persistent, and severe persistent asthma require a controller medication, usually an inhaled corticosteroid. Only patients with mild intermittent asthma are exempt from the need for controller medications.

Corticosteroids In assessing the need for controller medication, the most effective of which are inhaled corticosteroids, think of the "rule of 2s": If a patient has asthma symptoms or needs to use a beta₂-agonist bronchodilator more than twice a week in the daytime or more than twice a month at night, he or she should be using a controller medication. The available evidence from studies comparing inhaled corticosteroids to other controller medications show that none are as effective as inhaled corticosteroids in improving asthma outcome. Another way of gauging the need for controller medications is by the length of time a beta-agonist inhaler lasts. In general, an inhaler should last 10 to 12 months; any patient who requires more than 2 such inhalers within 1 year should be using controller medication. Patients who fulfill these criteria and are already taking a controller medication should be using the combination of a long-acting bronchodilator and inhaled corticosteroid. An alternative regimen consists of a leukotriene antagonist and an inhaled corticosteroid.

Inhaled corticosteroids may be delivered through an MDI, popularly called a puffer, a dry powder inhaler (DPI), or a nebulizer. Used properly, MDIs are as effective as nebulizers, are less expensive to use, and are easier to transport. The learning curve associated with MDIs is steep, however. Patients must be taught how to use MDIs properly and how to determine when the container is empty (shaking an empty MDI can produce misleading sounds). The specific inhaled corticosteroid that is prescribed often depends on the formulary of the patient's insurance plan. The dosages of the available products are notably variable, however (see Table 2). In general, the complications of inhaled corticosteroids are minimal and are related to the dosage and duration of use.

TABLE 2 Estimated high dosages for inhaled corticosteroids
Drug	High dosage (adult)	High dosage (children)
Beclomethasone CFC (42 or 84 mcg/puff) Beclomethasone HFA (40 or 80 mcg/puff) Budesonide DPI (200 mcg/inhalation) Flunisolide (250 mcg/puff) Fluticasone MDI (44, 110, or 220 mcg/puff) Fluticasone DPI with salmeterol (50, 100, 250, or 500 mcg/inhalation) Triamcinolone acetonide (100 mcg/puff)	>840 mcg >640 mcg >1200 mcg >2000 mcg >660 mcg >600 mcg >2000 mcg	>672 mcg >320 mcg >800 mcg >1250 mcg >440 mcg >400 mcg >1200 mcg
Key: CFC, chlorofluorocarbon; DPI, dry powder inhaler; HFA, hydrofluoroalkane; MDI, metered-dose inhaler. Note: Dosages are daily cumulative dosages and are usually administered as 2 divided dosages. Children are defined as patients aged 12 years and younger. Source: National Asthma Education and Prevention Program Expert Panel. The Executive Summary of the NAEPP Expert Panel Report: Guidelines for the Diagnosis and Management of Asthma—Update on Selected Topics 2002. Bethesda, Md: National Heart, Lung, and Blood Institute; 2002. NIH publication 02-5075. Available at: http://www.nhlbi.nih.gov . Accessed November 15, 2002.

Patients whose asthma falls in the severe-persistent category may require an oral corticosteroid for several weeks to stabilize pulmonary function, along with the combination of a long-acting bronchodilator plus an inhaled corticosteroid, or high doses of an inhaled corticosteroid. In particular, patients with wide variability in PEFR that is unaffected by aggressive therapy with high-dose inhaled corticosteroids plus a long-acting bronchodilator are candidates for oral corticosteroids. These patients are best referred for treatment by a specialist, who should make every effort to reduce dosages of the oral agents and, eventually, maintain control with inhaled agents. IV corticosteroids are rarely used for chronic management but may be employed in hospitalized patients.

Other controller medications Long-acting beta₂-agonists such as salmeterol and formoterol may be used to prevent asthma-induced or exercise-induced bronchospasm; their prolonged onset of action precludes their use as rescue medication. Long-acting beta₂-agonists do not treat the underlying disease, however, and should not be used as the sole controller medication. Instead, they are prescribed as add-on therapy for patients already using an inhaled corticosteroid.

Leukotriene-modifying drugs are alternative controller medications. Although they have not been shown to be as effective as corticosteroids, they may be used as corticosteroid-sparing agents, particularly for patients with exercise-induced bronchoconstriction. The available agents include montelukast, zafirlukast, and zileuton.

The mast cell stabilizers cromolyn and nedocromil are most useful in children when there is concern regarding inhibition of long bone growth from inhaled corticosteroids. Although these agents are not as effective as inhaled corticosteroids, they may be an alternative for children with mild asthma.

Skin testing and immunotherapy

Because the majority of patients with asthma are atopic, it is reasonable to refer patients to an allergist for assessment of environmental triggers (which may include skin testing) and education about allergen avoidance. There is evidence, too, that patients with a widely variable PEFR, who are at increased risk of life-threatening episodes, have a greater degree of atopy than other asthma patients.⁵ Immunotherapy has a demonstrated benefit in patients with allergic rhinitis and asthma with allergic triggers. It has also been shown to help prevent sensitization to new allergens and reduce the risk of developing asthma among patients with allergic rhinitis. Even if immunotherapy is not indicated, patients will benefit from knowing what allergens they react to and learning how to avoid those substances.

Control of associated diseases

A large percentage of patients with asthma are atopic; that is, they have a genetic predisposition to develop an IgE-mediated response to aeroallergens. These patients are likely to have allergic rhinitis as well as asthma. Although they may not request treatment for their nasal symptoms, therapy for this condition may improve asthma symptoms.⁶ Rescue treatment for allergic rhinitis consists of antihistamines (with or without decongestants), and controller treatment is provided by nasal corticosteroids. Control of sinus disease is also important because a chronic sinus infection can worsen asthma.

PRODUCED BY MARY DESMOND PINKOWISH

REFERENCES

1. Mannino DM, Homa DM, Akinbami U, et al. Surveillance for asthma--United States, 1980-1999. MMWR Morb Mortal Wkly Rep. 2002;51:1-13. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/ss5101a1.htm . Accessed November 15, 2002.

2. O'Hollaren MT. Warning signs that an asthmatic may be prone to a fatal or near-fatal attack. Paper presented at: 58th Annual Meeting of the American Academy of Allergy, Asthma & Immunology; March 5, 2002; New York, NY.

3. Mitchell I, Tough SC, Semple LK, et al. Near-fatal asthma: a population-based study of risk factors. Chest. 2002;121:1407-1413.

4. National Heart, Lung and Blood Institute. NAEPP Expert Panel Report. Guidelines for the Diagnosis and Management of Asthma--Update on selected topics 2002. Available at: http://www.nhlbi.nih.gov . Accessed November 15, 2002.

5. Miles J, Cayton R, Ayres J. Atopic status in patients with brittle and nonbrittle asthma: a case-control study. Clin Exp Allergy. 1995;25:1074-1082.

6. Corren J. Allergic rhinitis and asthma: how important is the link? J Allergy Clin Immunol. 1997;99:S78l-S786.

SUGGESTED READING

Allergic Disorders Task Force Members and Organizations. The Allergy Report: Science­Based Findings on the Diagnosis & Treatment of Allergic Disorders. Available at: http://www.theallergyreport.org . Accessed November 15, 2002.

Haby MM, Peat JK, Marks GB, et al. Asthma in preschool children: prevalence and risk factors. Thorax. 2001;56:589-595.

Lipworth BJ. Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis. Arch Intern Med. 1999;159:941-955.

Marik PE, Varon J. Oral vs inhaled corticosteroids following emergency department discharge of patients with acute asthma. Chest. 2002;121:1735-1736.

MARK O'HOLLAREN, MD, Director, The Allergy Clinic, and Clinical Professor of Medicine, Oregon Health and Science University, Portland.

TINA HARTERT, MD, MPH, Assistant Professor of Medicine, Division of Allergy, Pulmonary, and Critical Care Medicine, Center for Health Services Research, Vanderbilt University, Nashville, Tenn.

 

Managing patients with high-risk asthma. Patient Care 2003;1:14-38.