Progression and timeline of acute exacerbation of asthma to CAS 

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... and difficult decisions must be made quickly to protect the patient (e.g., oxygen, pharmacotherapy, endotracheal intubation, mechanical ventilation). Published guidelines including the National Asthma Education and Prevention Program (NAEPP) Expert Panel Report-3 (EPR-3) [1] and the World Health Organization (WHO) Global Initiative for Asthma (GINA) [2] present stepwise evaluation and treatment recommendations for chronic persistent asthma management, but do not emphasize as well a coherent plan for this urgent if not critical setting. While management strategies for asthma in the ED and intensive care unit (ICU) setting have been proposed, these state- ments lack the rigor of the NAEPP guidelines and fail to define the role of other providers caring for the patient in question. In this vein, we propose the umbrella term "critical asthma syndrome" (CAS) to define a severe and sudden respiratory condition that, although needing aggressive and urgent treatment, has not progressed to irreversible hypoxia and cardiopulmonary arrest (Fig. 1). CAS includes all sub-acutely to acutely decompensating asthmatics where common but non- specific signs and symptoms predominate, primarily shortness of breath, progressive respiratory fatigue (paradoxical breathing), and lightheadedness. These CAS patients are very un- stable and require close monitoring of vital signs and their response or lack thereof to treatments. In every case, CAS begins with what appears to be an ordinary asthma exacerbation. In this and succeeding manuscripts, the authors address many aspects of critical asthma situations, including the immediate treatment of CAS, and pitfalls in hospital management that must be avoided or acted upon quickly, and secondary prevention of future CAS. Asthma itself is a very common complex syndrome, rather than a single disease. Approximately 26 million people in the United States and a significant percentage are at risk for critical events, particularly those with poor access to care, poor self-management skills, and a personal history of past critical asthma episodes. Approximately 2 million ED visits are attributed to acute asthma exacerbations annually in the United States. It is projected that 500,000 will be hospitalized (25 % of visits), 25,000 will be intubated (5 % of hospitalizations), and between 10 % and 25 % of patients will die primarily from consequences of anoxia and cardiopulmonary arrest [3]. Approximately 3,000 deaths occur annually, but the majority of these deaths occur outside the hospital. A recent study of the effect of age on asthma mortality showed that age >55 years conferred a 5-fold increased risk of death from asthma com- pared to younger adults and children [4]. Overall the risk of death from asthma in the ED or hospital in this large inpatient database study was 0.06 %. Asthmatic patients gain a modicum of understanding of their disease from their doctors, but also from their family and friends, the Internet, and the lay press. Much of the information that patients procure informs them that asthma is a disease that requires regular attention and treatment, but also that it is intermittent and inherently controllable. Instead, we believe it is important to emphasize to patients, physicians, caregivers, and all healthcare providers that not all asthma is equal and that perception of acute dyspnea is highly variable among patients. Besides age, the highest rates of asthma death are in African Americans, Puerto Rican Americans, Cuban Americans and women over age 55 years. Approximately 1 % to 7 % of people with severe asthma will die of their disease each year, and perhaps 17 % of those who survive near-fatal attacks will eventually succumb to asthma [5]. Asthma deaths are very uncommon (approximately nine deaths occur daily in the United States), especially among children and young adults, but they remain a target of costly education and pre- ventive efforts to avoid asthma-related deaths [6]. Early treatment of exacerbations, better control of asthma symptoms, and special attention to patients who are at high risk of asthma-related death are key clinical activities. Predictors of fatal asthma include three or more ED visits for asthma in the past year, an asthma hospitalization or ED visit in the past month, overuse of short-acting beta 2 agonist, a history of intubation or ICU stay for asthma, difficulty perceiving asthma symptoms, lack of a written asthma action plan, certain patient characteristics (e.g., low socioeconomic status, female, nonwhite, current smoker, or major psychosocial problems), and the presence of other medical conditions such as heart disease. Death from asthma or CAS continues to decline and is down between 25 % and 30 % since 1996. A total of 4,269 deaths from asthma were reported in 2001, whereas 3,388 deaths were recorded in 2009 [7]. Many CAS cases occur because chronic asthma is not well controlled, raising the risk and frequency for acute exacerbations (Fig. 2), and there is plenty of evidence to support this. For example, in one study up to 77 % of patients in the United States have moderate to severe persistent disease [8]. The Real-world Evaluation of Asthma Control and Treatment (REACT) study found that 55 % of 1,812 patients assessed using an Internet- based survey had uncontrolled asthma using the Asthma Control Test (ACT) TM to stratify cohorts [9]. Such patients with "con- tinuous asthma exacerbations" are at higher risk for CAS and therefore ED visits and hospitalization. They often have persistent expiratory airflow obstruction (FEV1 <68 % predicted) despite high medication use [10]. Critical asthma is not severe asthma. The former is an acute clinical syndrome conceptually similar to stroke or acute coronary syndrome, whereas the latter describes a specific chronic asthma phenotype notable for poor asthma control, despite the use of multiple controller medications, that is coincidentally at high risk of acute exacerbation. Critical asthma episodes will occur at times to patients who fit the severe asthma framework, but those with mild asthma may suffer such events also. Other historical terms have been used to frame the spectrum of critical asthma, which we will explore and compare, such as status asthmaticus, brittle asthma, refractory asthma, and near-fatal asthma. The definition of severe asthma is probably most important to discuss as a comparator to our definition of CAS. Our understanding of severe asthma has improved considerably with the advent of consensus definitions from the American Thoracic Society (ATS) [11] and the WHO [12], and further updates on severe asthma management from the ATS/ European Respiratory Society (ERS) are expected in the next 1 – 2 years. Severe asthma includes any or all of the following asthma characteristics: the failure to achieve asthma control despite confirmed adherence to treatment with inhaled corticosteroids (ICS), the repeated need for emergency health-care services for asthma exacerbations, the need for chronic daily oral corticosteroid therapy, and reduced lung function. The most commonly applied definition of severe asthma was developed as part of an ATS workshop and has been adopted by the 10- year-old Severe Asthma Research Program (SARP) [11] funded by the National Institutes of Health (NIH) [13]. Severe asthma is defined by at least one major criterion and two minor criteria. The major criteria are as follows: (1) requirement for treatment with high-dose ICS (>800 μ g/d fluticasone or equivalent); and (2) treatment with oral corticosteroids for >50 % of the year. Minor criteria are as follows: (a) requirement for additional daily preferred controller treatments (long-acting beta 2 agonists [LABA], theophylline, omalizumab, leukotriene receptor antagonists [LTRA]); and (b) asthma symptoms requiring albuterol on a daily basis; (c) persistent airway obstruction (FEV 1 <80 %, peak expiratory flow rate [PEFR] >20 %); (d) one or more urgent care visits per year; (e) three or more oral corticosteroid bursts per year; and (f) near-fatal asthma event in the past [11]. The NIH-funded SARP consortium investigators have invested heavily in phenotyping research with the hope of ultimately targeting potential treatments to certain subgroups of patients. An important study by Wenzel and colleagues [14] defined two populations of severe asthma based on the pattern of inflammatory cells found in endobronchial biopsy samples. Patients referred to the investigators' clinic who required ≥ 10 mg of prednisone during >75 % of the year underwent evaluation with bronchoscopy. In 14 patients with severe asthma, biopsy samples yielded solely neutrophils, while 20 patients had both eosinophils and neutrophils. Mem- bers of the latter group had significantly more episodes of respiratory failure requiring intubation and ventilatory support and a lower ratio of FVC to slow vital capacity. More recently, Woodruff and colleagues outlined "Th2-high" and "Th2-low" groups. The T helper type 2 (Th2) lymphocytes are defined by the cytokines, namely IL-4, IL-5, and IL-13, all of which are important in the development and persistence of eosinophilic airway inflammation [15]. In this 8-week study in subjects with mild to moderate asthma, Th2-high subjects had an average increase of 300 ml in FEV 1 with ICS treatment and this was significantly greater than the increase in either the Th2-low or the placebo-control group. This study was one of the first to show clear responses to therapy tailored to the specific molecular phenotype of asthma. Many more research studies outside of the US have promoted phenotyping efforts and directions, mostly in more symptomatic adult asthmatics [16, 17] with the eventual hope of developing a personalized- medicine treatment approach. More broadly, the SARP investigators have proposed a "clustering" paradigm for severe asthma patients based on baseline FEV 1 , max FEV 1 (the maximum FEV 1 effort ...

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... CAS cases occur because chronic asthma is not well controlled, raising the risk and frequency for acute exacerbations Fig. 1 Critical asthma syndrome (CAS) is an umbrella term that repre- sents many other terms historically and currently used to describe acute and severe life-threatening exacerbations ( Fig. 2), and there is plenty of evidence to support this. For example, in one study up to 77 % of patients in the United States have moderate to severe persistent disease [8]. The Real-world Evaluation of Asthma Control and Treatment (REACT) study found that 55 % of 1,812 patients assessed using an Internet- based survey had uncontrolled ...