INTRODUCTION — Assessing patient risk for a future fatal asthma exacerbation is important because many, if not most, asthma-related deaths are preventable if risk factors are recognized and addressed early [1].
The epidemiology and risk factors for fatal asthma are reviewed here. The evaluation and management of severe asthma are discussed separately. (See "Evaluation of severe asthma in adolescents and adults" and "Treatment of severe asthma in adolescents and adults".)
MORTALITY STATISTICS — Asthma mortality varies among and within countries [2-6]. Based on World Health Organization (WHO) data, age standardized death rates per 100,000 range from 40.79 in Kiribati, 11.35 in India, 1.72 in China, 1.06 in Russia, 1.06 in the United Kingdom, 0.96 in France, 0.95 in the United States, 0.39 in the Netherlands, and 0.34 in Italy [2].
In an analysis of the WHO database using a locally weighted scatter plot smoother (LOESS) curve for the 5 to 34-year age group weighted by the individual country population, asthma mortality was essentially unchanged from 2006 to 2012, after decreasing substantially from 1993 to 2006 [4]. The analysis included the 46 countries for which data were available. The decline in death rates from 1993 to 2006 is largely attributable to the widespread use of inhaled glucocorticoids for persistent asthma and avoidance of highly potent, poorly selective beta-agonists such as isoprenaline forte and fenoterol [4].
Similar to international trends, asthma mortality in the United States has declined since reaching a peak in the 1990s (figure 1) [7]. From 2001 to 2015, United States deaths due to asthma decreased from 15 deaths per million population to 10.3 deaths per million population [8,9]. Among individuals with asthma, the rate of asthma deaths decreased from 2.1 per 10,000 persons in 2001 to 1.4 per 10,000 persons in 2009 [8].
In contrast, asthma deaths increased by 33 percent in the decade from 2008 to 2018 in England and Wales [10]. A review deemed that two-thirds of asthma deaths could have been prevented by basic asthma care to ensure regular review of asthma care, proper inhaler use, and a written asthma action plan.
DEMOGRAPHICS — Patients who have frequent and severe asthma symptoms and evidence of airflow limitation are at greatest risk; however, cluster analysis has identified significant patient heterogeneity [11]. Fatal and near-fatal asthma exacerbations can occur sporadically and inexplicably in a minority of asthmatics whether the baseline level of disease activity is mild, moderate, or severe [12,13]. Therefore, any acute exacerbation of asthma may be a potentially fatal attack. (See "Acute exacerbations of asthma in adults: Home and office management".)
Group-based trajectory analysis has suggested three distinct clinical trajectories for patients with severe and/or difficult to control asthma [14]. In this study, 58 percent of patients with asthma had infrequent severe exacerbations during five-year follow-up, 32 percent improved, having fewer exacerbations in subsequent years, and 10 percent had persistently frequent exacerbations. Near-fatal asthma events occurred in all three trajectories but were significantly more frequent for patients in the trajectory with persistently frequent exacerbations.
In the United States, fatalities from asthma most commonly occur in lower income urban populations [8,9,15]. In 2019, the reported death rate from asthma per million population in the United States was 24 for non-Hispanic Black Americans, 10 for non-Hispanic White Americans, and 6 for Hispanic Americans, although data identifying Hispanic origin may not be strictly comparable [9]. Disparities in income, education, and access to health care are widely recognized as important contributors to differences in mortality rates among different sociodemographic groups. In this regard, an analysis showed that the higher risk of death in African American patients compared with White patients is not explained by race differences in deaths occurring in hospital and are therefore likely due to differences that precede hospitalization, such as differences in management at home or during transportation to the emergency department [16].
Even in the modern treatment era with an emphasis on inhaled glucocorticoids, mortality among asthmatic patients is mainly due to asthma. In a retrospective Australian study conducted from 2005 to 2009, 85 percent of 283 asthma-associated deaths were specifically due to asthma rather than to other comorbidities [17]. Notably, 70 percent of the deaths due to asthma had preventable or modifiable risk factors present.
TEMPORAL PATTERNS OF FATAL ASTHMA — The pathology of acute severe asthma is complex and variable, possibly reflecting what may be different subtypes of the disease: slow onset and rapid onset (table 1) [18,19]. Deaths from status asthmaticus are ultimately due to the consequences of severe airway obstruction, but the cause of the obstruction varies.
Slow onset fatal asthma — Based on clinical and pathologic observations, it has been estimated that approximately 80 to 85 percent of patients who die of asthma have a history of progressive symptoms for more than 12 hours and often for one to three weeks. At autopsy, the airways of patients who die of this "slow-onset" asthma typically feature an eosinophilic inflammation and obstruction of airway lumens by tenacious mucus and desquamated epithelium [20-22]. These changes probably develop over days to weeks. This suggests that most of these patients would have had sufficient time to seek medical attention for worsening shortness of breath [23,24].
Rapid onset fatal asthma — In a minority of patients with fatal or near-fatal exacerbations of asthma, possibly up to 20 percent (8 to 14 percent of asthma exacerbations in general), death occurs less than 2 to 6 hours after symptom onset [25-27]. The airways of these patients with "rapid-onset" fatal asthma do not have eosinophil-predominant inflammation or widespread mucus plugging typical of status asthmaticus. Instead, severe airway obstruction appears to be mainly due to smooth muscle bronchospasm and neutrophils are the predominant inflammatory cell in the airway mucosa [28,29].
Unfortunately, specific characteristics that would help the clinician predict which patients are predisposed to rapid-onset asthma attacks have not been identified. Neither the severity of baseline asthma symptoms, years of asthma, smoking habits, asthma medication use, nor history of hospitalization for asthma help in identifying these patients. However, patients with rapid onset asthma exacerbations may more commonly report sensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) [27]. Rapid-onset asthma exacerbations do not appear to be due to anaphylaxis, although that diagnosis must be considered given the rapidity of the deterioration [27,30]. (See "Fatal anaphylaxis".)
IDENTIFYING HIGH-RISK PATIENTS — A number of potential risk factors for fatal or near-fatal asthma exacerbations have been identified.
Major risk factors — Two elements of the clinical history are most useful in assessing risk for a future fatal or near-fatal asthma exacerbation in an individual patient (algorithm 1).
●Recent history of poorly controlled asthma – Recent history of poor or only partial control of asthma symptoms indicates increased risk. While no single symptom is predictive of an impending severe attack, increases in dyspnea and wheezing, frequency of nocturnal awakenings, use of short-acting, beta-adrenergic agonist rescue medications, and increased diurnal variability in peak expiratory flow rate (PEFR) all indicate a pattern of poor or partial control of asthma [23,31,32]. Hospitalization or emergency care visits in the past year, current or recent use of oral glucocorticoids, and lack of treatment with inhaled glucocorticoids are all indicative of poorly controlled asthma and should alert the physician to increased risk of asthma-related death [33,34].
●Prior history of near-fatal asthma – Any past history of a prior near-fatal asthma exacerbation requiring endotracheal intubation and mechanical ventilation or a history of a prior intensive care unit admission for asthma should alert the clinician to the patient's propensity and high risk for near-fatal or fatal asthma exacerbations [24,35-37].
In a population-based case-control study, 71 percent of patients with a near-fatal asthma attack reported a prior history of intubation or cardiopulmonary resuscitation compared to only 6 and 2 percent in emergency department and community control subjects with asthma, respectively [36]. In a prospective case-control study, univariate analysis showed that the odds ratio for a second near-fatal attack was 28 among patients with a history of previous mechanical ventilation and 10 if there was a history of a prior admission to an intensive care unit [24]. A study of patients discharged after mechanical ventilation for near-fatal asthma showed a mortality rate of 10 percent at one year, 14 percent at three years, and 23 percent at six years [37].
Although a previous history of mechanical ventilation is high among patients being evaluated for near-fatal or fatal attacks, the lack of such prior history in an individual patient does not rule out the possibility of a potentially fatal attack and should not be reassuring to the clinician assessing risk [23].
Minor risk factors — Other clinical features also have been linked to near-fatal or fatal asthma, but the associations are not as strong as the factors noted above (algorithm 1).
●Sensitivity to aeroallergens – After adjusting for age and lung function (FEV1), patients with non-allergic asthma have a higher risk of mortality than patients with allergic asthma (relative risk 1.9) [38]. However, aeroallergen exposure, particularly due to pet ownership, is associated with episodes of near fatal and fatal asthma in sensitized individuals [39,40].
●Food allergy – A history of food allergy in a patient with asthma may be a significant risk factor for asthma-related death. Importantly, deaths can occur in patients with a history of only mild prior reactions to a specific food [41-43]. (See "Food intolerance and food allergy in adults: An overview".)
●Aspirin exacerbated respiratory disease (AERD) – For patients with AERD, exposure to aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase (COX)-1 can result in severe and potentially fatal asthma exacerbations (table 2) [44]. Patients with AERD should avoid aspirin and NSAIDs (table 3), unless they have been desensitized to aspirin. (See "Aspirin-exacerbated respiratory disease".)
●Exercise – Exercise is an uncommon cause of fatal asthma but certain features have been observed in association with fatal events. In an eight year period in the United States, 61 episodes of fatal asthma were identified that were precipitated by exercise [45]. Most subjects were White males between the ages of 10 and 14. Basketball and track were the most common sports associated with fatal asthma. The level of asthma control of these individuals prior to participation in exercise was not reported. (See "Exercise-induced bronchoconstriction".)
●Illicit drug use – Cocaine and heroin usage is a frequent trigger for severe acute asthma exacerbations: both are associated with a higher rate of intubation, and cocaine use is associated with a longer ICU length of stay [46,47]. In a retrospective study of hospital admissions for asthma in patients age 16 and older, 27.6 percent were cocaine users and 30.9 percent were heroin users [46]. Intubation and ICU admission were over 10 times more frequent among users compared with nonusers, even after controlling for cigarette smoking.
Several mechanisms contribute to the adverse effect that cocaine and heroin have on asthma: direct thermal injury from smoking the drugs, IgE mediated allergy to cocaine, direct bronchoconstriction by cocaine, and an irritant effect on respiratory epithelium from cocaine or insufflated heroin [46,47].
●Menstruation – An increased frequency of near-fatal asthma episodes at the time of menstruation has been reported [48].
●Respiratory virus infection – In one series, evidence of respiratory viral infection, particularly picornavirus and adenovirus, was found in 59 percent of patients presenting to a hospital with near fatal asthma exacerbations [49]. However, it is notable that SARS-CoV-2 (COVID-19) pneumonia requiring hospitalization did not appear to induce severe exacerbations in patients with a history of asthma [50].
●Smoking and vaping – Current smoke exposure is predictive of acute care need for asthma, and both in-hospital and post-hospital mortality are increased in smokers who require mechanical ventilation for asthma [37,40,51,52]. Use of electronic nicotine delivery systems for vaping has not been definitively linked to fatal or near-fatal exacerbations of asthma per se, but asthmatics may represent a population especially vulnerable to the adverse effects of vaping [53,54]. Vaping has been associated with an increased number of days absent from school for asthma symptoms among high school students in South Korea, and second hand exposure to vaping aerosols was associated with increased self-reported asthma attacks in the 2016 Florida Youth Tobacco Survey [55,56].
●Other factors – Other features associated with fatal and near fatal asthma, particularly slow onset fatal asthma, include: long duration of asthma, systemic glucocorticoid dependence, non-adherence to therapy, poor asthma control, psychosocial problems and less adaptive personality, delay in obtaining medical care, older age, and comorbid conditions [37,44,57-61]. Noncompliance with inhaled glucocorticoids was high among patients who required mechanical ventilation for asthma (57 percent), but this was not different from other patients seen in the emergency department for acute asthma [35].
Objective measures — Several studies have observed that a low forced expiratory volume in one second (FEV1) is associated with an increased risk of asthma exacerbations and the lower the FEV1, the greater the risk [40,62-65]. In addition, air trapping and hyperinflation are associated with an increased frequency of serious asthma exacerbations [66,67]. As an example, in a prospective study of severe or difficult to control asthma, postbronchodilator forced vital capacity (FVC) less than 70 percent was a predictor of asthma related emergency department visits and hospitalization [66].
Despite these associations, patients with subsequent fatal or near fatal asthma may have entirely normal baseline spirometry.
Poor perception of dyspnea — Other clinical or physiological features that have been noted in some asthmatics with a history of near-fatal asthma are reduced chemosensitivity to hypoxia, a poor perception of airway obstruction, a blunted perception of dyspnea, and difficulty communicating symptoms [68-72]. These phenomena could be important in explaining, at least in part, the apparent delays these patients sometimes have in seeking medical attention during an asthma exacerbation. While no specific aspects of the medical history can identify a patient with such a blunted sense of dyspnea, Borg scale scoring of dyspnea during resistive loading, exercise, and breath-holding maneuvers hold promise for better identification of these patients in the future [73-75]. (See "Cardiac rehabilitation programs", section on 'Rating of perceived exertion (Borg scale)'.)
PREVENTION — Only one-third of asthma mortalities in the United States in the year 2000 occurred in hospitalized patients, suggesting that many patients who ultimately die from asthma must either fail to seek medical attention during the hours or days of increased symptoms, or have a course of deterioration that is too rapid to reach hospital care in time, or are not appropriately hospitalized upon presentation [16]. Therefore, efforts to decrease mortality from asthma have focused on educating patients to recognize the symptoms of an attack early and to follow an appropriate action plan that includes prompt medical evaluation [76,77]. For patients who are at high risk of fatal asthma (algorithm 1), we prescribe prednisone (or equivalent) for the patient to keep on hand and start as advised by a prednisone-based action plan. (See "Asthma education and self-management".)
Efforts to modify risk factors for fatal and near fatal asthma include: avoidance of asthma triggers such as aeroallergens, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs); consideration of aspirin desensitization in aspirin sensitive patients; adherence to use of inhaled glucocorticoids; smoking and vaping cessation; appropriate treatment of exercise-induced bronchoconstriction; and avoidance of illicit drugs (table 3). Patients with severe asthma should undergo evaluation for therapy with a biologic agent to reduce exacerbations. (See "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)
While patients do better than clinicians in assessing the severity of an asthma attack, subjective assessments of the severity of airway obstruction, by either patients or clinicians, are widely recognized as poor and insensitive. Use of objective measures such as peak expiratory flow rate, forced expiratory volume in one second (FEV1), and forced vital capacity (FVC) can be an important component of assessing asthma control and the severity of an acute exacerbation. (See "Acute exacerbations of asthma in adults: Home and office management".)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Severe asthma in adolescents and adults" and "Society guideline links: Asthma in adolescents and adults".)
SUMMARY AND RECOMMENDATIONS
●Near-fatal and fatal asthma exacerbations may occur in patients with mild, moderate, or severe asthma and the course may be either slow or rapid in onset (table 1). (See 'Demographics' above.)
●In the United States, fatalities from asthma most commonly occur in lower income, urban populations. (See 'Demographics' above.)
●Recent history suggestive of poor asthma control or any prior history of endotracheal intubation and mechanical ventilation for asthma should alert the asthma care provider that the patient is at high-risk for fatal or near-fatal asthma exacerbations (algorithm 1). (See 'Temporal patterns of fatal asthma' above.)
●Other clinical features, alone or in combination, may also suggest a high-risk patient: long duration of asthma, poor adherence to medical therapy, systemic glucocorticoid dependence, psychosocial problems, older age, aspirin/NSAID sensitivity, cigarette smoke exposure, prior hospitalization for asthma, and aeroallergen exposure in sensitized individuals. (See 'Identifying high-risk patients' above.)
●Objective measures of airflow obstruction, such as spirometry or peak expiratory flow rate, obtained at the time of office visits may help predict which patients are at increased risk for future emergency department visits and hospitalization. (See 'Objective measures' above.)
●Poor perception of dyspnea has been noted in survivors of near-fatal asthma and likely contributes to delays in seeking medical care. (See 'Poor perception of dyspnea' above.)
●Identifying patients prone to severe exacerbations is important because education of the patient and provision of a detailed action plan for these patients can reduce the risk of fatal or near-fatal asthma (table 3). (See 'Prevention' above.)
