Accepted Manuscript

Acute Asthma, Prognosis and Treatment

Jennifer E. Fergeson, DO, Shiven Patel, MD, Richard F. Lockey, MD
PII:

S0091-6749(16)30800-4

DOI:

10.1016/j.jaci.2016.06.054

Reference:

YMAI 12290

To appear in:

Journal of Allergy and Clinical Immunology

Received Date: 5 April 2016

Accepted Date: 14 June 2016

Please cite this article as: Fergeson JE, Patel S, Lockey RF, Acute Asthma, Prognosis and Treatment,
Journal of Allergy and Clinical Immunology (2016), doi: 10.1016/j.jaci.2016.06.054.
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Jennifer E. Fergeson, DOa

Authors:

Shiven Patel, MDa

Richard F. Lockey, MDa

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Affiliations:

Department of Internal Medicine

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Acute Asthma, Prognosis and Treatment

Division of Allergy and Immunology

University of South Florida

Tampa, Florida, United States

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Jennifer E. Fergeson DO

13000 Bruce B. Downs Blvd (111D)

Tampa, FL 33612
Phone (813) 972 -7631; Fax (813) 910-4041

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Corresponding author:

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Email - jfergeso@health.usf.edu

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Abstract

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Asthma affects about 300 million people globally and accounts for 1 in every 250 deaths

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in the world. Approximately 12 million people in the United States each year experience

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an acute exacerbation of their asthma, a quarter of which require hospitalization. Acute

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asthma should be differentiated from poor asthma control. In acute asthma, patients will

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exhibit increasing shortness of breath, chest tightness, coughing, and/or wheezing. In

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contrast, poor asthma control typically presents with a diurnal variability in airflow and is

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a characteristic that is usually not seen during an acute exacerbation. The history should

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include a review of comorbidities, adherence with medications, previous episodes of

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near-fatal asthma, and whether the patient has experienced multiple emergency room

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visits or hospitalizations, particularly those requiring admission to an intensive care unit,

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involving respiratory failure, intubation and mechanical ventilation. Patient education is

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important to ensure that the patient understands that asthma is mostly a chronic disease

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and necessitates the avoidance of allergens, prevention of infections, adherence with

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routine vaccinations, management of comorbid conditions and adherence to treatment

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regimens. This article is a structured review of the available literature regarding the

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diagnosis and management of acute asthma.

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Key word: Asthma flare; Acute asthma; Asthma attack; Wheezing; Acute asthma

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diagnosis; Acute asthma management

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Abbreviations:

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EPR 3 - The Expert Panel Report 3

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OCS - Oral corticosteroids

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ICS Inhaled corticosteroids

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GERD - Gastroesophageal reflux disease

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OSA - Obstructive sleep apnea

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COPD - Chronic obstructive pulmonary disease

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PEF - Peak expiratory flow

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MDI - Metered dose inhaler

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SABA - Short acting beta agonist

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AE Adverse events

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SCS- systemic corticosteroids

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FVC- Forced vital capacity

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Introduction

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Asthma exacerbations are avoidable with appropriate, regular therapy and patient

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education. Despite this, asthma affects about 300 million people globally, and accounts

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for 1 in every 250 deaths [1]. In the United States alone, approximately 12 million people

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each year experience an acute exacerbation of their asthma, a quarter of which require

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hospitalization [2]. In Europe, approximately 30 million people have asthma, and 15,000

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people die yearly from this disease [4]. This manuscript is about acute asthma, its

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diagnosis, prognosis, and treatment.

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Various clinical symptoms and signs may assist the clinician in determining the severity

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of acute asthma (Figure 1) [2,10]. To prevent severe exacerbations of asthma, the goals

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for the physician managing subjects with asthma include:

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1. Recognition of patients who are at a greater risk for near-fatal or fatal asthma.

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2. Education of the patient to recognize deterioration in their disease.

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3. Provision of an individual action plan for the patient to manage the exacerbation and to

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know when to seek professional help

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4. Management of comorbidities such as rhinitis, sinusitis, obesity, gastroesophageal

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reflux disease (GERD), obstructive sleep apnea (OSA), chronic obstructive respiratory

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disease (COPD), vocal cord dysfunction (VCD) and atopic dermatitis [3, 6-9].

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Physical examination

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Clinical estimates of severity based on an interview and a physical examination can result

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in an inaccurate estimation of disease severity; audible wheezing is usually a sign of

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moderate asthma, whereas no wheezing can be a sign of severe airflow obstruction.

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Symptoms of severe asthma include chest tightness, cough (with or without sputum),

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sensation of air hunger, inability to lie flat, insomnia and severe fatigue. The signs of

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severe asthma include use of accessory muscles of respiration, hyperinflation of the chest,

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tachypnea, tachycardia, diaphoresis, obtundation, apprehensive appearance, wheezing,

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inability to complete sentences and difficulty in lying down. Altered mental status, with

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or without cyanosis, is an ominous sign and immediate emergency care and

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hospitalization are required. A detailed examination should include examining for signs

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and symptoms of pneumonia, pneumothorax or a pneumomediastinum, the latter of

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which can be investigated by palpation for subcutaneous crepitations, particularly in the

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supraclavicular areas of the chest wall. Special attention should be paid to the patient's

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blood pressure, pulse and respiratory rate. Tachycardia and tachypnea may be suggestive

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of a moderate to severe exacerbation, while bradycardia may indicate impending

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respiratory arrest. Pulsus paradoxus is often present and may correlate with the severity

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of exacerbation (Figure 1) [2-5].

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Differential diagnosis of acute asthma

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The differential diagnosis of acute asthma includes COPD, VCD, bronchitis,

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bronchiectasis, epiglottitis, foreign body, extra-or intra-thoracic tracheal obstruction,

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cardiogenic pulmonary edema, non-cardiogenic pulmonary edema, pneumonia,

pulmonary embolus, chemical pneumonitis, and hyperventilation syndrome [3-4].

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Acute asthma triggers

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Risk factors for asthma exacerbations can be identified from the clinical history. The

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patient interview should include questions about recent events including [2,5]:

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1.

Upper or lower respiratory tract infections

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2.

Cessation or reduction of medication

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3.

Concomitant medication, e.g., non-selective -blockers

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4.

Allergen or pollutant exposure

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Predictors of fatal or near-fatal asthma

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Major risk factors for near-fatal and fatal asthma are recognized, and their presence

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makes early recognition and treatment of an asthma exacerbation essential. The history

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should include a review of previous episodes of near-fatal asthma and whether the patient

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has experienced multiple emergency room visits or hospitalizations, particularly those

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requiring admission to an intensive care unit, involving respiratory failure, intubation and

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mechanical ventilation. A history of allergic asthma and other known or suspected

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allergic symptoms should be obtained. For example, Nelson et al. identified a trigger for

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severe asthma is allergy to the mold Alternaria and several dust mite species [5,10].

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Adherence with medical treatments should be reviewed; poor adherence with prescribed

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therapies is a major risk factor. Inadequate therapy may include excessive use of 2-

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agonists, concomitant use of -blockers, and failure to prescribe or use inhaled

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corticosteroids (ICS) as a primary therapy. Recent withdrawal of oral corticosteroids

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(OCS) suggests that the patient is at greater risk for a severe exacerbation. Lack of a

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written asthma action plan is another risk factor. Limited access of the patient to

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appropriate health care and lack of education about appropriate management strategies

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are additional risk factors. Socioeconomic factors associated with severe asthma

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exacerbations include the non-adherent adolescent or elderly asthmatics living in inner

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city environments. Certain ethnic groups within a population may have a higher

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incidence of severe asthma, such as Americans of African or Spanish inheritance.

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Comorbidities, such as chronic lung, psychiatric, and cardiovascular diseases are other

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risk factors [5,12].

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Physiological and laboratory parameters

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Serial measurements of lung function facilitate quantification of the severity of airflow

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obstruction and response to therapy. A peak expiratory flow (PEF) rate provides a simple,

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quick, and cost-effective assessment of the severity of airflow obstruction. Patients can be

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supplied with an inexpensive PEF meter and taught to perform measurements at home to

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detect deterioration of their asthma. An individual management plan will be based upon

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the personal best PEF value. Predetermined PEF values can be set at which time the

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patient is alerted to the degree of severity of symptoms and can institute appropriate

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therapy and/or consult their physician (Figure 2). In non-acute settings, assessment of

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PEF and spirometry before and after administration of a bronchodilator can indicate the

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likely degree of improvement in lung function which can be achieved by adequate

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therapy. PEF values of 50-79% of predicted or personal best signify the need for

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immediate treatment with an inhaled short acting beta agonist (SABA). Values below

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50% indicate the need for immediate medical care. Values below 35% indicate a possible

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severe life threatening episode. This treatment should be administered with a SABA via

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nebulizer or metered dose inhaler (MDI). SABA dose, response, and further

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management is depicted in Figure 2 [2, 12-15].

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The forced expiratory volume in one second (FEV1) is measured by spirometry to assess

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the volume of air exhaled over one second and is the most sensitive test for airflow

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obstruction. The FEV1 is less variable than PEF and is independent of effort once a

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moderate effort has been made by the patient. Post bronchodilator reversibility should be

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assessed and an increase in FEV1 > 12% and > 200 ml is diagnostic of asthma [2, 12].

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Most patients do not require laboratory testing for the diagnosis of acute asthma. If

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laboratory studies are obtained, they must not delay asthma treatment. Laboratory studies

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may assist in detecting other comorbid conditions that complicate asthma treatment, such

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as infection, cardiovascular disease, or diabetes. A measurement of brain natriuretic

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peptide (BNP) and a 2-D transthoracic echocardiogram aid in the diagnosis of congestive

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heart failure. For patients taking diuretics who have co-morbid cardiovascular disease,

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serum electrolytes may be useful as frequent SABA administration can cause transient

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decreases in serum potassium, magnesium, and phosphate. A baseline electrocardiogram

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and monitoring of cardiac rhythm are appropriate in patients older than 50 years of age

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and in those with comorbid cardiovascular disease or COPD. A complete blood cell

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count (CBC) may be useful in patients with fever or purulent sputum; however, modest

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leukocytosis is common in asthmatics, and patients using corticosteroids may have a

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corticosteroid-induced neutrophil leukocytosis. Serum theophylline levels are essential

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for patients taking theophylline due to its narrow therapeutic window [12].

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Chest radiographs are not usually necessary for the diagnosis of acute asthma if the

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examination of the chest reveals no abnormal findings other than the expected clinical

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signs and symptoms associated with an acute exacerbation. If a complication is

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suspected, such as pneumonia, pneumothorax, pneumomediastinum, congestive heart

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failure, or atelectasis secondary to mucous plugging, a chest X-ray should be obtained

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[12].

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Arterial blood gas (ABG) analysis should be considered in patients who are critically ill

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and have oxygen saturations of < 92% or an FEV1 < 30% who do not respond to

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intensive conventional treatment. Proper interpretation of the pH, PaO2, and PaCO2 may

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help further assess the severity of an acute exacerbation of asthma (Figure 1). For

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example, a breathless asthmatic presenting with a PaCO2 > 45 mmHg indicates a life

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threatening attack and the need for transfer to a medical intensive care unit for further

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care. Less than 10% of asthmatic patients presenting to the emergency department have

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arterial oxygen values < 50 mmHg and carbon dioxide levels > 45 mmHg [11, 15]. Lactic

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acidosis is common in severe acute asthma. However, elevated lactic acid levels are also

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associated with high doses of inhaled 2-agonist treatment [16].

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Venous blood gases (VBG) have been evaluated as a substitute for arterial measurements

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since venous blood is easier to obtain. However, The Expert Panel Report 3 (EPR3) does

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not recommend substituting venous PCO2 (PvCO2) for ABG. Arteriovenous correlation

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for PCO2 is poor, and therefore PvCO2 cannot be relied upon as an absolute

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representation of PaCO2. However, a normal PvCO2 has a good negative predictive value

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for a normal PaCO2. Therefore, it may be used as a screening test to exclude hypercapneic

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respiratory distress [12,17].

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Treatment

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Treatment is based not only on assessment of lung function parameters but on clinical

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findings and the efficacy of previous treatment. A seasonal exacerbation of asthma in a

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pollen-sensitive patient is more easily treatable than an exacerbation triggered by a viral

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infection. Allergic asthma is more likely to respond immediately to an inhaled 2-agonist

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and to an adjustment in ICS, whereas the infected patient is more likely to require a

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systemic corticosteroid (SCS) [4]. A patient who is over-using short acting 2-agonists

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may be refractory to nebulized 2-agonists and will usually require a SCS. Physician

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knowledge of an individual patient will suggest whether a SCS is required or whether an

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exacerbation can be managed on high doses of ICS [4,12,18].

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There are various national and international guidelines available for the diagnosis and

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management of acute asthma. In particular, the EPR3 guidelines are referenced in this

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manuscript as it is centered upon a systematic review of the published scientific literature

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and provides the best evidence for clinical practice guidelines. EPR3 recommended

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treatment choices in order of introduction in the acute setting are listed below and

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depicted in Figure 3. Treatment options and their recommended doses are listed in Figure

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4.

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Primary treatment choices include:

1. SABA; inhaled by MDI or by nebulization

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2. Anticholinergics; inhaled by MDI or nebulization

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3. Corticosteroids; parenteral, oral or inhaled

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4. Oxygen

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Some patients may not respond to primary treatment and show signs of worsening

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asthma. Other treatments are sometimes used in these patients and may include:

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1. Epinephrine; intramuscular (IM) or subcutaneous (SQ)

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2. Magnesium sulfate; parenteral

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3. Heliox driven albuterol nebulization

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4. Intubation and mechanical ventilation

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5. Noninvasive positive pressure ventilation

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Short-acting 2-agonists

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EPR 3 guidelines recommend the use of only selective SABAs in high doses (i.e.

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albuterol, levalbuterol) due to the risk of cardiotoxicity, especially in elderly asthmatic

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patients. Initial treatment should begin with albuterol, either administered by MDI with a

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spacer device or mask (children < 4 years of age) or nebulizer.

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Treatment should be continued until the patient has stabilized or a decision to hospitalize

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is made. Studies show that the use of either MDI or nebulizer for delivery of inhaled

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SABAs produces similar outcomes. Nebulizer treatment may be preferred in patients

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who are unable to cooperate using an MDI because of the severity of acute asthma, age or

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agitation. Additionally, continuous nebulization should be considered in very severe

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asthma based on evidence of reduced admissions and improved pulmonary function [12,

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19-21].

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Levalbuterol (R-albuterol) nebulizer solution can be given in a similar fashion. Notably,

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levalbuterol administered at one-half the mg dose of albuterol is found to deliver

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comparable efficacy and safety. However, the efficacy of continuous nebulization has

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not been evaluated. Continuous administration of albuterol via large volume nebulizers

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may be more efficacious when compared to intermittent administration in patients with

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severe asthma [12].

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For patients unable or unwilling to use an MDI/spacer or nebulizer, epinephrine may be

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utilized, injected subcutaneously or intramuscularly, as long as the patient is carefully

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monitored for signs of adrenergic toxicity. At this time, there is no proven advantage of

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use of epinephrine over SABA. If there is no immediate response to epinephrine,

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treatment should be discontinued and the patient hospitalized [12].

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Ipratropium bromide

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Ipratropium bromide is a quaternary derivative of atropine sulfate available as a nebulizer

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solution. It provides competitive inhibition of acetylcholine at the muscarinic cholinergic

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receptor, thus relaxing smooth muscle in large central airways. It is not a first-line

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therapy but can be added in severe asthma particularly when albuterol is not optimally

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beneficial. It can be given with albuterol or levalbuterol and may be used for up to 3

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hours in the initial management of acute asthma. There is increasing support for adding

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ipratropium bromide to 2-agonist therapy in more severe asthma exacerbations in

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children. Studies indicate that combined therapy reduces the risk of hospital admission

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by 25% [12, 21-22].

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Corticosteroids: Treatment in the ambulatory setting

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High-dose ICS may be initiated in selected patients. Evidence suggests equivalence in

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treatment of mild asthma exacerbations with OCS. However, due to limited data, high-

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dose ICS should be reserved for patients with mild asthma and those who refuse or

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cannot tolerate OCS, e.g., have brittle diabetes or experience major side effects from

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SCS. Guidelines recommend at least quadrupling the recommended dose of ICS. For

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example, a top recommended maintenance dose of fluticasone can be increased from 220

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g, 2 puffs 2x/day to 220 g, 4 puffs 4x/day for exacerbations. Beclomethasone can be

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increased from 160 mcg, 2 puffs, 2x/day to 160 mcg, 4 puffs, 4x/day [2]. Treatment

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should be started before the patient becomes too ill to manage their disease at home.

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Inhaled therapy reduces the risk of unwanted side effects associated with SCS treatment

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e.g., insomnia, increased appetite, hyperactivity, psychosis, and effects on bone

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metabolism and other organ systems. ICS are less likely to be effective in patients with

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upper respiratory tract infections or those who are over-utilizing 2-agonists. OCS, with

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instructions for its use, should be prescribed as a backup treatment regimen and the

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patient and/or family understand when to start it. They should also have immediate access

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to a physician and/or other healthcare professional until the asthma exacerbation is

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resolved [23-25]. When an ICS is prescribed for mild asthma and is not effective, OCS

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are indicated, regardless of their potential side effects. Glucocorticoid-induced

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psychosis, hypertension, and other side effects should be concomitantly treated until the

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OCS is tapered and no longer necessary for treatment.

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Short courses of OCS are effective to establish control of flare-ups of asthma or during a

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period of gradual deterioration of asthma not responding to increased doses of an ICS.

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Treatment should be continued until the patient is well or achieves a PEF of 80% of

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personal predicted best. Improvement may be seen between 5 to 14 days, although

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patients whose asthma is corticosteroid-resistant may take several weeks to respond. It is

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not necessary to taper OCS after three weeks or less of treatment, but when used for

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longer than 3 weeks, it is advisable to taper the medication over one to two weeks to

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decrease withdrawal side effects such as fatigue, myalgias, nausea/vomiting, abdominal

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pain, decreased appetite and joint pain [12,25].

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Corticosteroids: Treatment in the acute setting

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There are no substantial data to indicate that SCS are immediately helpful in the acute

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asthma setting because the onset of action does not occur for hours after administration.

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However, SCS are the best medications available to reduce airway inflammation and

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should be used immediately until the attack has abated as evidenced based on their

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clinical response or by the PEF and FEV1 returning to near baseline levels [12].

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Intramuscular (IM) or intravenous (IV) corticosteroids may be used in the initial

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treatment of acute asthma; however, there is no evidence that these routes have a more

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rapid onset of action or are more effective than is oral administration [12].

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Corticosteroids: Treatment after discharge from the hospital

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After discharge from the hospital, approximately 10-20% of patients treated for acute

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asthma will relapse within 2 weeks. This may be due to unresolved inflammation

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associated with asthma. As a result, EPR3 encourages treatment with OCS following

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emergency room discharge. ICS therapy should be resumed or short/long term ICS

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therapy initiated to reduce the chances of a relapse. When the patients asthma is stable,

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the ICS should be incrementally reduced to maintain an asymptomatic state and a PEF at

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a personal best level. A combination of long acting 2-agonist and an ICS can be

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considered in order to achieve the lowest ICS dose possible [12,27-29].

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Magnesium sulfate

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Magnesium sulfate has both immediate bronchodilator and mild anti-inflammatory

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effects. IV magnesium is a safe and effective treatment and may be considered in

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patients presenting with severe life-threatening asthma exacerbations (FEV1 < 25%

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predicted) and those who remain in the severe category after 1 hour of intensive

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conventional treatment [2,12].

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Heliox driven albuterol

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The role of heliox - driven albuterol in the treatment of acute exacerbations is

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controversial. Despite these uncertainties, heliox driven albuterol may be considered in

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both children and adults who exhibit severe life-threatening exacerbations and those who

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remain in the severe category after one hour of intensive conventional therapy [12,26].

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Hospitalization

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Failure to respond to treatment necessitates hospitalization. The patients fluid status

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should be assessed and oral or intravenous hydration therapy administered as indicated.

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Hydration in young infants and children may be essential as these patients are at

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increased risk for dehydration due to poor oral intake and an increased respiratory rate.

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Oxygen may be administered at 2 to 4 L/min via a nasal cannula or mask, whichever is

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better tolerated to maintain a SaO2 > 90%. In pregnant patients and those with underlying

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cardiac disease, a SaO2 > 95% is recommended. The patient should be monitored

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continuously with pulse oximetry and telemetry. Blood gases should be obtained until

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the patient is stable. The patient should be treated with continuous nebulized albuterol or

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levalbuterol, with or without ipratropium bromide, and a corticosteroid. Viral respiratory

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tract infections are more common in acute asthma exacerbation and therefore antibiotics

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should be reserved for patients who present with evidence of a co-existing bacterial

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infection, i.e., pneumonia, bronchitis, and sinusitis. EPR3 does not recommend the use of

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methylxanthines, mucolytics, sedation or chest physiotherapy for treatment of acute

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asthma [2, 12,27].

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Impending respiratory failure

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The use of non-invasive positive pressure ventilation (NPPV) in the treatment of severe

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acute asthma can be tried in patients who are at increased risk of respiratory failure, can

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safely cooperate with NPPV treatment, and do not require emergent intubation [12]. A

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review article by the Cochrane Reviews Group carried out a search of randomized

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controlled trials of adults with severe acute asthma that presented to the emergency

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department or were admitted to the hospital. Studies in the article were included if the

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intervention was usual medical care for the management of severe acute asthma plus

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NPPV compared to usual medical care alone. All six studies that were reviewed

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concluded that NPPV may be beneficial. The results did not show a clear benefit for

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NPPV use for its primary outcomes, i.e. mortality rate and tracheal intubation. However,

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NPPV use did show favorable outcomes in many secondary objectives, such as number

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of hospital admissions, length of ICU stay, length of hospital stay, and improvement in

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lung function parameters (PEF, FVC, FEV1, and FEF25-75). Study quality of the evidence

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was an issue in this review as all six studies included had at least one identifiable source

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of unclear or high risk of bias. As only six studies were reviewed by the Cochrane

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Reviews Group, no guidelines or implications for current practice can be made.

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Randomized controlled trials with a large sample size, good methodological design, and

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minimizing the risk of bias are needed to answer the question of the use of NPPV in acute

345

asthma [30].

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The EPR3 recommends that intubation should not be delayed in a patient once it is

347

deemed necessary. Patients that present with apnea or coma should be intubated

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immediately. Persistent or increasing hypercapnia, exhaustion, and mental status changes

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strongly suggest the need for mechanical ventilation. Intubation is difficult in patients

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with acute asthma and should be performed, where possible, by a physician who has

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extensive experience in airway management. Ventilator management by a physician

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expert is important because ventilation of patients with severe acute asthma is

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complicated. Two important issues to consider at the time of intubation include

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intravascular volume, which must be maintained or replaced, because hypotension

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commonly accompanies the introduction of positive pressure ventilation. In addition,

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high ventilator pressures should be avoided where possible, due to their associated risks

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of barotrauma. Permissive hypercapnia or controlled hypoventilation is the preferred

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ventilator strategy because this provides adequate oxygenation and ventilation without

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the risks of barotrauma associated with high ventilator pressures. SABA should be

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continued in ventilated patients, although no randomized controlled trials provide

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evidence to support its use.

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Conclusion

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Asthma affects approximately 300 million people in the world and accounts for 1 in

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every 250 deaths. The World Health Organization recognizes asthma as a major global

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health issue affecting all age groups in all countries. All patients presenting with an

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asthma exacerbation should be triaged and evaluated immediately. Treatment should be

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based on recognition of a moderate, severe, or life-threatening exacerbation. Clinicians

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should recognize the symptoms, signs, and risk factors (including comorbidities) for

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severe and life-threatening exacerbations. Primary treatment includes oxygen

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administration, SABA, and SCS. If the patient cannot tolerate SCS, high dose ICS may

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be initiated in selected patients. For patients that do not respond to primary treatment and

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show worsening signs of ventilation, secondary treatment options may be utilized. These

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include epinephrine, magnesium sulfate, heliox driven albuterol, intubation and

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mechanical ventilation, and noninvasive positive pressure ventilation.

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At the time of discharge, education on self-management of asthma may reduce the

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frequency of ED visits. Physicians and other healthcare professionals should assess

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inhaler techniques for all prescribed medications and reinforce correct technique. Patients

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should be referred for a follow-up appointment with a primary care physician or asthma

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specialist within 1-4 weeks.

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Asthma exacerbations are avoidable with appropriate therapy and

patient education.
Asthma remains a global health issue with significant morbidity and
mortality.
The primary treatment for acute asthma includes SABA, SCS and
oxygen administration
For patients unresponsive to primary treatment, secondary measures
such as epinephrine, magnesium sulfate, heliox driven albuterol,
noninvasive positive pressure ventilation, and intubation may be
considered.
After discharge, education on self-management of asthma should be
prioritized to reduce the frequency of exacerbations. Patients should be
referred to a primary care provider or asthma specialist upon being
discharged.

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Key points

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Figure 1: Acute asthma severity: clinical signs and symptoms. Originally published

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as Figure 5-3 in the Expert Panel Report 3.

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Definition of abbreviations: PaO2 = arterial oxygen pressure; PCO2 = partial pressure of

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carbon dioxide; PEF = peak expiratory flow

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Figure 2: Management of Asthma Exacerbations: Home Treatment Predicted.

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Originally published as Figure 5-4 in the Expert Panel Report 3.

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Figure 3. Acute Asthma Management: Emergency Department and Hospital-Based

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Care. Originally published as Figure 5-6 in the Expert Panel Report 3.

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FEV1 = forced expiratory volume in 1 second; ICS = inhaled corticosteroid; MDI =

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metered dose inhaler; PCO2 = partial pressure of carbon dioxide; PEF = peak expiratory

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flow; SABA = short-acting beta2-agonist; SaO2 = oxygen saturation

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Figure 4 a,b. Dosages of Drugs for Asthma Exacerbations. Originally published as

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Figure 5-5 in the Expert Panel Report 3.

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*Children < 12 years of age

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ED = emergency department; MDI = metered-dose inhaler; PEF = peak expiratory flow;

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VHC = valved holding chamber

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Notes:

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There is no known advantage for higher doses of corticosteroids in severe asthma

exacerbations, nor is there any advantage for intravenous administration over oral

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therapy provided gastrointestinal transit time or absorption is not impaired.

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The total course of systemic corticosteroids for an asthma exacerbation requiring

an ED visit of hospitalization may last from 3 to 10 days. For corticosteroid

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courses of less than 1 week, there is no need to taper the dose. For slightly longer

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courses (e.g. up to 10 days), there is probably no need to taper, especially if

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patients are concurrently taking ICSs.

ICSs can be started at any point in the treatment of an asthma exacerbation.

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1. Masoli, M. (2004, February 1). The global burden of asthma: Executive summary
of the GINA Dissemination Committee Report. Allergy, 469-478.
2. Camargo, C.A., Rowe, B.H. Asthma Exacerbations. Barnes, P.J., Drazen, J.,
Rennard, S., Thomson, N. (Eds.), Asthma and COPD: Basic Mechanisms and
Clinical Management, 2nd ed. San Diego, CA: Elsevier Ltd; 2009. p. 775-791.
3. Lockey RF, Ledford DK, in collaboration with the World Allergy Organization
(eds): Asthma, Comorbidities, Co-Existing Conditions, and Differential
Diagnoses. Oxford University Press, New York, NY, 2014, p, 231-367.
4. The Journal of Allergy and Clinical Immunology: In Practice. Asthma Phenotypes.
November - December 2014; 2(6): 645-826.
5. Global Initiative For Asthma (GINA) Website. http://www.ginasthma.com/.
(Accessed on 3/15/15)
6. Holguin F, Bleecker E, Busse W, Calhoun W, et al. Obesity and asthma: An
association modified by age of asthma onset. J Allergy Clin Immunol 2011;
127(6): 1486-1493.e2.
7. Ledford DK, Lockey RF. Asthma and comorbidities. Curr Opi Allergy Clin
Immunol 2013; 13: 78-86.
8. Blake K, Teague WG. Gastroesophageal reflux disease and childhood asthma.
Curr Opin Pulm Med 2013; 19:24-9.
9. Gibson PG, Henry RL, Coughlan JL. Gastro-oesophageal reflux treatment for
asthma in adults and children. Cochrane Database Syst Rev 2003; 1: Art. No.:
CD001496.
10. Nelson R, DiNicolo R, Fernndez-Caldas E, Seleznik MJ, Lockey RF, Good R.
Allergen-specific IgE levels and mite allergen exposure in children with acute
asthma first seen in an emergency department and in nonasthmatic control
subjects. J Allergy Clin Immunol 1996; 98: 258-263.
11. Patel M, Pilcher J, Reddel H, Qi V. Predictors of severe exacerbations, poor
asthma control, and Beta-agonist overuse for patients with asthma. J Allergy Clin
Immunol 2014; 2(6); 751-758.e1.
12. Camargo, C.A., Rachelefsky, G., and Schatz, M. Managing Asthma
Exacerbations in the Emergency Department: Summary of the National Asthma
Education and Prevention Program Expert Panel Report 3 Guidelines for the
Management of Asthma Exacerbations. Proceedings of the American Thoracic
Society 2009; Vol 6, No 4: 357-366.
13. Hasegawa K, Sullivan A, Tsugawa Y, Turner, S. Comparison of US emergency
department acute asthma care quality: 1997-2001 and 2011-2012. J Allergy Clin
Immunol 2014; 135(1): 73-80.e7.
14. Waseem M, Leber M, Wasserman E, Sullivan A, et al. Factors associated with
concordance with the non-level-A guideline recommendations for emergency
department patients with acute asthma. J Allergy Clin Immunol 2015; 3(4): 618620.e2.
15. British Thoracic Society, Scottish Intercollegiate Guidelines Network. British
guideline on the management of asthma. Thorax 2014; 69 Suppl1:1.
16. GJ, R. Elevated plasma lactate level associated with high dose inhaled albuterol
therapy in acute severe asthma. Emergency Med 2005; 404-408.

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References

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17. Bloom BM, Grundlingh J, Bestwick JP, Harris T. The role of venous blood gas in
the emergency department: a systematic review and meta-analysis. Eur J Emerg
Med 2014; 21:81.
18. Goodacre S, Braburn M, Cohen J, et al. Prediction of unsuccessful treatment in
patients with severe asthma. Emerg Med J 2014; 31: e40.
19. Camargo CA Jr., Spooner CH, Rowe BH. Continuous versus intermittent betaagonists for acute asthma. Cochrane Database Syst Rev (4): CD0011115, 2003.
20. Cates CJ, Crilly JA, Rowe BH. Holding chambers (spacers) versus nebulizers for
beta-agonist treatment of acute asthma. Cochrane Database System Rev(2):
CD000052, 2006.
21. Hasagawa K, Sullivan H, Hirashima E, et al. A multicenter observational study of
US adults with acute asthma: Who are the frequent users of the emergency
department. J Allergy Clin Immunol 2014; 2(6): 733-740.e3.
22. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children
and adults with acute asthma: a systematic review with meta-analysis. Thorax
2005; 60:740.
23. Oborne J, Mortimer K, Hubbard RB, et al. Quadrupling the dose of inhaled
corticosteroid to prevent asthma exacerbations: a randomized, double-blind,
placebo-controlled, parallel-group clinical trial. Am J Respir Crit Care Med 2009;
180:598.
24. Beckhaus AA, Riutort MC, Castro-Rodriguez JA. Inhaled versus systemic
corticosteroids for acute asthma in children. A systematic review. Pediatr
Pulmonol 2014; 49: 326-34.
25. Krishnan J, Nowak R, Davis S, Schatz M. Anti-inflammatory treatment after
discharge home from the emergency department in adults with acute asthma. J
Allergy Clin Immunol 2009; 124(2): S29-S34
26. Chaudry RQ, Weinstein ME, Petrova A. Efficacy of inhaled compared to oral
corticosteroids for acute asthma exacerbation in children. J Allergy Clin Immunol.
2010: 125 (2); AB69.
27. Thomas AO, Lemanske RF Jr, Jackson DJ. Infections and their role in childhood
asthma inception. Pediatr Allergy Immunol 2014; 25: 122-8.
28. Gibson PG, Powell H, Coughlan J, Wilson AJ, Abramson M, Haywood P,
Bauman A, Hensley MJ, Walters EH. (2003). Self management education and
regular practitioner review for adults with asthma. The Cochrane Library 1:
CD001117.
29. Kang MG, Kim JY, Jung JW, Song JW, Cho SH, Min KU, et al. Lost to follow
up in asthmatics does not mean treatment failure: causes and clinical outcomes of
non-adherence to outpatient treatment in adult asthma. Allergy Asthma Immunol
Res 2013; 5:357-64.
30. Lim WJ, Mohammed Akram R, Carson KV, Mysore S, Labiszewski NA,
Wedzicha JA, Rowe BH, Smith BJ. Non-invasive positive pressure ventilation for
treatment of respiratory failure due to severe acute exacerbations of asthma.
Cochrane Database of Systematic Reviews 2012, Issue 12. Art. No.: CD004360.
DOI: 10.1002/14651858.CD004360.pub4.

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Windows is either a registered trademark or a trademark of Microsoft Corporation in the United States and/or other countries. Mac is a trademark
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Journal of Allergy and Clinical Immunology Manuscript Review

In order to be eligible to receive CME credit for your review, you must read the following
information.

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Educational Learning Objectives

1. To update knowledge of the current literature through literature searches conducted for
critique of manuscripts
2. To glean new information and understanding of specific areas of study that can impact
the reviewers' research or practice
3. To exercise and expand use of critical analytical skills
4. To develop teaching skills by advising authors on study design, scientific method and
analysis, and scientific writing
5. To contribute to expansion of the body of knowledge in allergy/ immunology

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Accreditation Statement
This activity has been planned and implemented in accordance with the Essential Areas and
Policies of the Accreditation Council for Continuing Medical Education (ACCME) by the
American Academy of Allergy, Asthma and Immunology (AAAAI). The AAAAI is accredited
by the ACCME to provide continuing medical education for physicians.

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Designation Statement
The American Academy of Allergy, Asthma and Immunology designates this educational
activity for 3.0 AMA PRA Category 1 Credits per review, with a maximum of 15.0 credits per
calendar year. Physicians should only claim credit commensurate with the extent of their
participation in the activity.

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Target Audience
This activity is intended for board-certified physicians and researchers in the fields of allergy and
immunology.

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Overall Purpose/Goal
The purpose of this activity is to affirm or modify knowledge, competence, or performance as a
result of reading the manuscript.
DESIGN COMMITTEE:

Cezmi Akdis, MD FAAAAI (Co-Editor-in-Chief): Employer: Swiss Institute of Allergy and

Asthma Research B) University of Zurich, Switzerland Title: A) Director (SIAF) B) Medical
Faculty (University of Zurich) Competing Relationships: Advisory Board: Circassia (United
Kingdom), Allergopharma (Germany), Novartis (Basel, Switzerland), Teva (Amsterdam, the
Netherlands), Anergis (Lausanne, Switzerland); Board Member and Shareholder (Ongoing):
Alimentary Health Pharma (Davos, Switzerland); Advisory Board Member and Shareholder
(Ongoing): Davos Diagnostics (Davos, Switzerland Organizational Interests: CK-CARE
Christine Khne - Center for Allergy Research and Education (Ongoing): Directorium Member

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and Speaker; GA2LEN, Global Allergy And Asthma European Network (Ongoing): Ex-com
Member World Immune Regulation Meetings (Ongoing): Chair, Organizer.

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Andrea Apter, MD MA MSc FAAAAI: Employer: University of Pennsylvania (Professor of

Medicine) Competing Relationships: NHLBI: RC1 (funded-now complete) - PI, NHLBI
(Ongoing): R18, PCORI (Ongoing): PI. Organizational Interests: American College of
Asthma Allergy & Immunology (Ongoing): Fellow, American College of Physicians (Ongoing):
Fellow, American Thoracic Society (Ongoing): Behavioral Science Assembly program
committee, Associate Editor (Ongoing): Journal of Allergy & Clinical Immunology, Consultant
(Ongoing): UPTODATE. Conflict Resolution: The research grant from Bristol-Myers Squibb
and AstraZeneca is paid directly to my institution, and 2.5% of my salary is supported by these
grant funds. The research focuses on a diabetes drug, and is not related to any of their respiratory
products.

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Leonard Bacharier, MD FAAAAI: Employer: Washington University (Professor of

Pediatrics) Competing Relationships: AstraZeneca China (Ongoing): Honoraria for lectures,
DBV Technologies (Ongoing): Consultant, Novartis (Ongoing): Honoraria for lectures, Teva
(Ongoing): Honoraria for lectures, consultant, Sanofi (Ongoing): Advisory Board attendance,
NIH/NHLBI/NIAID (Ongoing): Investigator: AsthmaNet, Severe Asthma Research Program,
Inner City Asthma Consortium. Organizational Interests: AAAAI (Ongoing): Fellow, Editorial
Boards of JACI and JACI: In practice, AMPC Member (Ongoing). Conflict Resolution: Will
present data from a variety of published peer-reviewed studies.

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Claus Bachert, MD PhD: Employer: Universitair Ziekenhuis Gent (Professor, Chief of

Clinics) Competing Relationships: ALK (Ongoing): speaker, Allergopharma: speaker, board,
Bionorica (Ongoing): speaker, board, Genentech: board, Meda (Ongoing): speaker, board, MSD
(Ongoing): speaker, Novartis (Ongoing): board, Stallergenes (Ongoing): speaker, Uriach
(Ongoing): speaker, board. Organizational Interests: DGAKI (Ongoing): Vice President, WAO
(Ongoing): Executive Board. Conflict Resolution: Spread of bias over many companies, no
direct influence in any presentations.

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Zuhair K. Ballas, MD FAAAAI: Employer: University of Iowa Health Care (Professor of

Medicine) Competing Relationships: Honorarium/Gift: Up-To-Date, Immune Deficiency
Foundation, NIH (Ongoing): Received grant, Veterans Administration (Ongoing): Received
Merit grant. Organizational Interests: Clinical Immunology Society (Ongoing): Member of
Nominating committee, Immune Deficiency Foundation (Ongoing): immunodeficiency
consultant, Medical Advisory Council.
Joshua A. Boyce, MD FAAAAI: Employer: Brigham and Women's Hospital (Albert L. Sheffer
Prof of Medicine; Director, Inflammation and Allergic Disease Research Section)
Organizational Interests: Consultant: Calcimedica, LPath, Inc. (Ongoing).
Robert K. Bush, MD FAAAAI: Employer: Retired; Competing Relationships:
Honorarium/Gift: Section editor Current Opinion in Allergy&Clinical Immunology and Current
Allergy Reports, Honorarium/Gift: Section editor Allergy & Immunology Reports

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Javier Chinen, MD PhD FAAAAI: Employer: Baylor College of Medicine (Associate

Professor) Nothing to disclose.
Raif S. Geha, MD FAAAAI: Employer: Children's Hospital of Boston (Chief, Div. Imm., Prof.
Ped.) Nothing to disclose.

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Kenji Kabashima, MD PhD: Employer: Kyoto University (Associate Professor) Competing

Relationships: A*Star (Senior Principal Investigator) Competing Relationships: Advisory
Board: Chugai, Janssen, Ono Pharmaceutical (Ongoing), Daiichi Sakyo, Polo Pharma, Kao Co.
Carole Ober, PhD: Employer: University of Chicago (Professor) Nothing to disclose.

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David B. Peden, MD MS FAAAAI: Employer: University NC School Medicine (Andrews

Distinguished Professor of Pediatrics, Medicine and Microbiology/Immunology) Nothing to
disclose.

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Harald E. Renz, MD FAAAAI: Employer: Philipps University Marburg (Professor and

Director) Organizational Interests: Deutsche Gelsellschaft fur Klinische Chemie und
Laboratoriumsmedizin (DGKL) (Ongoing): Chairman Working Group Autoimmune Diagnostics
Deutsche Gesellschast fur Allergologie and Klinische Immunologie (DGAKI) (Ongoing):
President.

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Marc E. Rothenberg, MD PhD FAAAAI: Employer: Cincinnati Children's Hospital Medical

Center (Director of the Division of Allergy and Immunology) Competing Relationships:
Consultant: Novartis, NKT Therapeutics, Celsus Pharmaceuticals (Ongoing), Immune
Pharmacueticals (Ongoing), Receptos. Organizational Interests: American Partnership for
Eosinophilic Disorders (Ongoing): Member, Medical Advisory Board
CEGIR (Consortium of Eosinophilic Gastrointestinal Disease Researchers) (Ongoing): Principal
Investigator, International Eosinophil Society (Ongoing): Steering Committee TIGERS
(Ongoing): Steering Committee. Conflict Resolution: I present unbiased information in my
activities for the AAAAI, and I am not currently studying any product produced by these
companies.

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Hirohisa Saito, MD PhD FAAAAI: Employer: National Research Institute for Child Health &
Development (Deputy Director of the Research Institute) Competing Relationships: Speaker:
Teijin Pharma Ltd, Shiseido Co.,Ltd., MSD (Merck Sharp and Dohme) K.K., Ono
Pharmaceutical Co., Ltd., GlaxoSmithKline K.K., Pfizer Japan Inc., Kyowa Hakko Kirin, Kyorin
Pharmaceutical, Daiichi Sankyo.
Stanley Szefler, MD FAAAI: Employer: University of Colorado Denver School of Medicine
(Professor of Pediatrics; Head, Pediatric Asthma Research) Competing Relationships: Advisory
Board: Aerocrine, Boehringer-Ingelheim, Novartis, Roche, Glaxo Smith Kline. NIH:NHLBI
(Ongoing): Research Grant: AsthmaNet, NIH:NIEHS/EPA (Ongoing): Research Grant:
Childhood Health and Environmental Center Grant, Colorado Public Health Department
(Ongoing): Research Grant, NIH:NIAID (Ongoing): Research Grant: Inner City Asthma
Consortium. Organizational Interests: AAAAI (Ongoing): Fellow; Deputy Editor For Journal

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of Allergy and Clinical Immunology, ACAAI (Ongoing): Fellow, American Academy of

Pediatrics (Ongoing): Fellow, American Thoracic Society (Ongoing): Member, Colorado
Allergy and Asthma Society (Ongoing): Member. Conflict Resolution: I disclose my potential
conflicts at all meetings and lectures. I focus my working relationships on research and providing
advice on drug development, as well as overseeing research studies. I do not provide lectures that
serve as marketing formats for specific drugs. I also disclose all of my financial relationships to
National Jewish Health for ongoing review.

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Robert A. Wood, MD FAAAAI: Employer: Johns Hopkins University School Medicine

(Professor of Pediatrics) Competing Relationships: Advisory Board: Sanofi, Stallergenes. DBV
Technologies (Ongoing): Research Support. Up To Date (Ongoing): Royalties. Organizational
Interests: American Board of Allergy and Immunology (Ongoing): Liaison to the ABP
The American Board of Pediatrics (Ongoing): Liaison from the ABAI.

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FACULTY DISCLOSURES
Please refer to the opening pages of the assigned manuscript for the authors relevant funding and
employment information.