acute asthma case study

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Acute Severe Asthma in Adolescent and Adult Patients: Current Perspectives on Assessment and Management

Eirini kostakou.

1 ICU, 1st Department of Pulmonary Medicine, “Sotiria” Hospital, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece

Evangelos Kaniaris

Effrosyni filiou, ioannis vasileiadis, paraskevi katsaounou.

2 1st ICU, Evangelismos Hospital, Athens School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece

Eleni Tzortzaki

3 Respiratory Outpatient Clinic, 71305 Heraklion, Greece

Nikolaos Koulouris

Antonia koutsoukou, nikoletta rovina.

Asthma is a chronic airway inflammatory disease that is associated with variable expiratory flow, variable respiratory symptoms, and exacerbations which sometimes require hospitalization or may be fatal. It is not only patients with severe and poorly controlled asthma that are at risk for an acute severe exacerbation, but this has also been observed in patients with otherwise mild or moderate asthma. This review discusses current aspects on the pathogenesis and pathophysiology of acute severe asthma exacerbations and provides the current perspectives on the management of acute severe asthma attacks in the emergency department and the intensive care unit.

1. Introduction

Asthma is a chronic inflammatory disorder of the airways, a common and potentially serious chronic disease that is associated with variable expiratory flow, airway wall thickening, respiratory symptoms, and exacerbations (flare-ups), which sometimes require hospitalization and may be fatal [ 1 ]. In reference to asthma, an exacerbation is defined as an event characterized by change from the patient’s previous status, including a progressive increase in relevant symptoms and a decrease in respiratory function. The latter can be quantified by respiratory function measurements such as peak expiratory flow (PEF), and forced expiratory volume in 1 s (FEV 1 ), which when compared with the patient’s previous or predicted values, reflect the deterioration in expiratory airflow, the prominent pathophysiological effect of an asthma attack.

The most common causes of these exacerbations are exposure to external agents, such as indoor and outdoor allergens [ 2 , 3 , 4 ], air pollutants [ 5 ], and respiratory tract infections (primarily viral mainly human rhinovirus (HRV) [ 6 , 7 ]. The mechanisms by which these environmental stimuli and viruses initiate asthma or cause worsening of the disease are under research.

Asthma exacerbations may also be triggered by exercise [ 8 ], weather changes [ 9 ], foods [ 10 , 11 ], additives, drugs [ 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ], and extreme emotional expressions [ 15 , 16 ]. The physiological hallmarks of asthma are airway inflammation, airway remodeling and bronchial hyperresponsiveness (BHR) [ 17 ]. Exposure to the above-mentioned external stimuli and specifically to inhaled allergens is capable of inducing an inflammatory response in sensitized individuals and as a result to lead to exacerbations [ 18 , 19 ]. A hypothesis explaining this fact is that the inflammatory response resulting from inhaled allergen may drive BHR directly, or induce structural changes in the airway leading to persistent BHR [ 17 , 20 ]. Experimental mouse models of asthma have shown that allergen exposure protocols induce immune-mediated airway inflammation defined by: elevated levels of asthma biomarkers (IgE, the T-helper cell 2 (Th2) cytokines, interleukins (IL)-4, -5 and -13, and eosinophils), induction of airway remodeling (increases in airway smooth muscle, collagen deposition and goblet cell hyperplasia), and BHR that is sustained after the resolution of eosinophilic inflammation [ 21 , 22 , 23 ].

Other factors that may cause exacerbations are rhinitis [ 24 ] or sinusitis [ 25 ], polyposis [ 26 ], gastroesophageal reflux [ 27 ], menstruation [ 28 , 29 ], or even pregnancy [ 30 , 31 ]. They can happen either to patients with known asthma of any level of severity, or less frequently as a first presentation. Exacerbations vary in severity, as well as in response to therapy. This has led to an effort of categorize the severity of these exacerbations. The most frequently proposed categories include elements of the clinical presentation of the asthma patient, as well as a measurement of their respiratory function at the time of the exacerbation. It is of paramount importance for the clinician to distinguish the severe exacerbations, because these are the ones that correlate with worse consequences.

2. Definition of Acute Severe Asthma

The Global Initiative for Asthma guidelines refers to a severe asthma exacerbation describing a patient who talks in words, leans forward, is agitated, uses accessory respiratory muscles, has a respiratory rate > 30/min, heart rate > 120/min, O 2 saturation on air < 90% and PEF ≤ 50% of their best or predicted value [ 1 ]. According to the 2014 British Guidelines for Asthma, acute severe asthma is defined as the asthma exacerbation that presents with any of the following: PEF 33–50% best or predicted, respiratory rate ≥ 25/min, heart rate ≥ 110/min and inability to complete sentences in one breath [ 32 ]. The ATS/ERS task force defines a severe asthma exacerbation by the fact that they require urgent action in order to prevent a serious outcome, such as hospitalization or death from asthma [ 33 ]. This task force recommends that the definition of a severe asthma exacerbation for clinical trials should include at least one of the following: (a) use of systemic corticosteroids (tablets, suspension, or injection), or an increase from a stable maintenance dose, for at least three days; and (b) a hospitalization or emergency department visit because of asthma, requiring systemic corticosteroids. Although these definitions are not identical, the point remains that identifying this condition is important as it is correlated with worse outcomes and greater risk of needing mechanical ventilation.

There are other entities similar but not identical to that of acute severe asthma that also require precise definitions. Kenyon et al. proposed the term Critical Asthma Syndromes (CAS) to identify any child or adult who is at risk of fatal asthma [ 34 ]. This term includes acute severe asthma, refractory asthma, status asthmaticus, and near fatal asthma, all of them conditions that can lead to respiratory exhaustion and arrest. Refractory asthma is, according to a definition set by the Unbiased Biomarkers for the Prediction of Respiratory Disease Outcomes (U-BIOPRED) consortium in 2011, patients with asthma in whom after excluding any alternative diagnoses, after treating comorbidities and removing trigger factors cannot maintain good asthma control, despite high-intensity treatment and confirmed compliance with treatment. These patients have frequent severe exacerbations (≥2 per year), or can only be well when receiving systemic corticosteroids [ 35 ]. Near fatal asthma (NFA) is defined as an asthma exacerbation resulting in respiratory arrest requiring mechanical ventilation or a pCO 2 ≥ 45 mm Hg. Some writers tend to recognize status asthmaticus and acute severe asthma as the same condition and define it mainly by its response to treatment, thus referring to it as an exacerbation that does not respond to repeated courses of β2-agonist therapy [ 36 ].

3. Epidemiology

According to the Global Asthma Report, approximately 334 million people in the world suffer from asthma, thus being the most prevalent chronic respiratory disease, with chronic obstructive pulmonary disease (COPD) affecting only half of the aforementioned number of people [ 37 ]. However, according to Eurostat [ 38 ], in most European countries age standardized asthma admission rates declined from 2001–2005 to 2011–2015, with an over two-fold reduction in some countries. ( Figure 1 ) The latest World Health Organization (WHO) estimates, released in December 2016, present that there were 383,000 deaths due to asthma in 2015. There has been a decrease of almost 26% in the asthma deaths, when comparing 2015 to 1990 [ 37 ]. However, international mortality statistics for asthma are limited to those countries reporting detailed causes of death. Figure 2 depicts the age-standardized mortality rates for asthma among countries reporting asthma separately in two recent five-year periods (2001–2005 and 2011–2015) [ 38 ].

Age-standardized admission rates for asthma (all ages) in 30 European countries in two time periods: 2001–2005 and 2011–2015. Source: Eurostat updated from ec.europa.eu/Eurostat/web/health/health-care/data/database (version dated November 2017).

Age-standardized mortality rates for asthma (all ages) by country in two time periods: 2001–2005 and 2011–2015. Source: Eurostat updated from ec.europa.eu/Eurostat/web/health/health-care/data/database (version dated November 2017).

Although asthma is a disease not only of low- and lower-middle-income countries, most asthma-related deaths occur in those areas [ 38 ]. There is an established connection between asthma deaths and the Socio-Demographic Index (SDI), but interestingly not with SDI and asthma prevalence. A recent study in Brazil demonstrated that urbanization has affected public health, resulting in higher asthma related morbidity and mortality, despite the fact that the urbanized population now has improved access to the health system [ 39 ]. There are no accurate figures describing the rate of acute severe asthma, but there are sufficient data regarding the asthma related hospitalizations and asthma related mortality. Recent studies estimate the risk of death of the patients who are hospitalized as a result of asthma exacerbation as less than 0.5% [ 40 , 41 ]. That risk is greater when the patient requires intubation and mechanical ventilation, which underlines the importance of identifying and promptly treating acute severe asthma. Four percent of asthma related hospitalizations result in mechanical ventilation. There is a substantial economic burden associated with asthma hospitalizations, and it has been demonstrated that in the US in 2012 the overall cost was more than 2 billion dollars, which is a significant percentage (more than 1/3) of the annual asthma related expenditure [ 41 ]. Middle aged women are more likely to get hospitalized with asthma related morbidities [ 41 ].

With regards to the identified phenotypes of asthma, data from a recent cluster analysis from Japan revealed a wide heterogeneity among asthma patients who presented and were admitted with severe and life-threatening asthma in 17 institutions across the country [ 42 ]. Another recent group-based trajectory analysis on patients with problematic and uncontrolled asthma, showed that near fatal events were noted in all groups, but were more frequent in patients with persistent frequent exacerbations [ 43 ]. It is not only patients with severe and poorly controlled asthma who are at risk for having an acute severe asthma exacerbation, but this has been observed as well in patients with otherwise mild or moderate asthma. The current literature describes two distinct clinico-pathophysiological entities of acute severe asthma attacks that present at the emergency department: the slow onset, late arrival and the sudden onset fatal asthma. It has been estimated that the majority (80–85%) of asthma-related fatalities belong to the slow onset group. These patients may have symptoms and uncontrolled disease for several days prior to the presentation with acute severe asthma. Sudden onset has been defined as severe airflow obstruction established after 1–3 h of symptom presentation. Barr et al. reported that patients presenting with sudden onset asthma, were more likely to have been exposed to an exacerbation trigger such as a respiratory allergen, exercise and psychosocial stress and less often respiratory infection and had greater improvement when compared with the slow onset cohort [ 44 ]. A retrospective cohort study in the United States demonstrated evidence that the sudden-onset patients were older, were more likely to present during the night and early morning hours at the emergency department, more often required intubation and mechanical ventilation, and had higher rate of ICU admission, but, on the other hand, had shorter hospital stay [ 45 ]. In this study the sudden onset cohort was only 6% of 1260 patients in 30 hospitals.

4. Risk Factors for Asthma Exacerbations

Many factors have been studied regarding their correlation with acute severe asthma and asthma related death ( Table 1 ). In adults, asthma exacerbations are more often in females [ 46 , 47 ]. This is difficult to be explained since female asthmatics have lower levels of total serum IgE [ 48 ] and the incidence of atopy is actually lower in comparison to males [ 49 ]. A possible explanation could have to do with the connection between asthma worsening and the menses, which is a recognized contributing factor of asthma worsening [ 50 ]. Furthermore, pregnancy in asthmatic women is a condition that requires special considerations, considering the effect of the disease, as well as the medication on the mother and the fetus. Pregnancy is not always correlated with worse asthma control, although there seems to be a correlation between asthma severity and morbidities and exacerbations during pregnancy [ 51 ]. There has been reported a cluster of obese females with late-onset corticosteroid asthma with frequent exacerbations although they preserve a relatively good baseline lung function [ 52 ].

Risk factors for fatal asthma exacerbations.

SABA, short acting beta agonist. Adapted from Global Initiative for Asthma (GINA) guidelines 2018 [ 1 ].

Obesity per se has also been correlated with worse asthma control, as well as more frequent and severe exacerbations. This correlation is strengthened by the apparent effect of weight loss and bariatric surgery on better control and less exacerbations and hospitalizations [ 53 ].

Ethnicity and socioeconomic status [ 54 , 55 ] are robust determinants of asthma exacerbation rates. African Americans have 4.2- and 2.8-fold higher rates of emergency room visits and hospitalizations for asthma exacerbation, respectively, compared to Caucasians, followed by Hispanics [ 39 ]. A possible explanation for these differences could be the poorer adherence to treatment [ 56 ] and the poorer quality of healthcare in ethnic minorities [ 57 ]. A significant genetic component might also contribute, since an increased risk of exacerbations has been documented in males with African ancestry [ 58 ].

Severe exacerbations may occur in patients with mild or well controlled asthma [ 59 , 60 ]. However, poor asthma control is an independent risk factor for future acute exacerbations [ 61 , 62 , 63 , 64 , 65 ]. A history of a recent exacerbation is the strongest predictor of future exacerbations in children and adults with asthma [ 66 , 67 , 68 , 69 ]. A small percentage of asthmatics exhibit severe disease exacerbations, despite the fact that they are already under treatment with high doses of inhaled and/or systemic corticosteroids [ 70 , 71 ]. These patients suffering from severe asthma (SA) that is poorly controlled and in some cases life-threatening [ 34 , 35 ], although comprising a small percentage of the total asthma population (5–10%), they denote 50% of total healthcare costs, rendering SA a substantial health and socio-economic burden [ 36 , 37 ].

Finally, poor perception of airflow limitation may affect patients with a history of near-fatal asthma and appears to be more common in males [ 72 , 73 ]. On the other hand, regular or overuse of short acting beta agonists (SABA) causes down regulation of beta receptors and leads to lack of response, leading in turn to overuse [ 74 ]. Overuse may also be habitual. Dispensing ≥3 SABA canisters/year (average 1.5 puffs/day or more) is associated with increased risk of emergency department visits or hospitalizations no matter what the severity of asthma is [ 75 ], while dispensing ≥12 canisters/year (1/month) increases the risk of death [ 76 ]. Incorrect inhaler technique (seen in up to 80% of asthma patients) [ 77 ], as well as suboptimal adherence to treatment (seen in up to 75% of patients) are important modifiable factors contributing to symptoms and exacerbations [ 77 ].

There has been a lot of interest regarding the effect of psychological factors on the risk for fatal or near fatal asthma, this however has not been established, as shown in a 2007 systematic review by Alvarez et al. [ 78 ]. Anxiety, depression and socio-economic problems are very common in patients with difficult to treat asthma and contribute to poor symptom control, poor adherence to treatment and impaired quality of life [ 79 ].

Obesity and other comorbidities other than the psychiatric conditions already mentioned that contribute to persistent symptoms, exacerbations and poor quality of life include chronic rhinosinusistis [ 80 ], inducible laryngeal obstruction (often referred as vocal cord dysfunction, VCD), gastroesophageal regurgitation disorder (GERD), chronic obstructive pulmonary disease (COPD), obstructive sleep apnea, bronchiectasis, cardiac disease, and kyphosis due to osteoporosis (followed by corticosteroid overuse) [ 80 ].

5. Factors that Trigger Asthma Exacerbations

Severe exacerbations usually occur in response to a variety of external agents (e.g., respiratory pathogens, allergens, air pollutants, smoke, and cold or dry air).

5.1. Respiratory Pathogens

Viral respiratory infections are the most common triggers for a severe asthma exacerbation, comprising up to 76–80% of the causes of an acute asthma exacerbation in adults [ 81 ]. Human rhinovirus (RV) (types A and C), influenza virus (types A and B), para-influenza virus, and respiratory syncytial virus (RSV) are frequent causes of an acute exacerbation and hospitalization [ 56 , 82 ]. Coronaviruses, meta-pneumoviruses, bocaviruses, and adenoviruses may also trigger a severe acute exacerbation, however to a lesser extent [ 57 ]. During the 2009 H1N1 influenza A pandemic, mortality and admissions to the ICU with H1N1 infections were frequently associated with asthma [ 82 , 83 ]. In contrast to other respiratory viruses (i.e., RSV and Influenza Virus), RV does not exert a definite cytopathic effect [ 84 ]; instead, it compromises the function of the epithelial barrier through the release of reactive oxygen species during viral replication [ 85 ]. During this process, the induction of immune and adaptive immune response activates the synthesis and early secretion of IFNs and other pro-inflammatory cytokines (i.e., IL-10, IL-6, IL-8, RANTES, and ENA-78) [ 86 ], which play a significant role in the protective mechanisms against viral infection [ 87 , 88 ]. There is evidence that in asthmatic patients there is dysregulated immune response against RV [ 89 ]. Several studies have demonstrated the implication of interferons in the susceptibility to asthma exacerbations in children and adults in the context of a viral respiratory infection. Miller et al. [ 90 ] showed that RV was related to asthma exacerbation with the implication of IFN III. Similarly, Jones et al. [ 91 ] documented an increased susceptibility to severe respiratory viral infections during the first years of life through dysregulated type III IFN responses, while recent studies [ 92 , 93 ] document a varying susceptibility to asthma exacerbations depending on the type and level of expression of cytokines and IFNs upon viral infection. Finally, Fedele et al. [ 94 ] documented that RV infection more frequently induces a Th2-mediated immune response than RSV infection, justifying the higher incidence of asthma prevalence after RV infections.

Bacterial infections may also trigger acute exacerbations, usually on the basis of impaired anti-bacterial defense after a viral respiratory infection [ 95 ]. There are bidirectional interactions between viruses and bacteria that seem to have an impact on the severity of asthma as well as the likelihood of an acute exacerbation. Viral infections facilitate the disruption of airway epithelial layers and the expression of airway receptors that bacteria use in order to invade [ 96 ]. Furthermore, in the presence of co-infection, an increased release of inflammatory cytokines and mediators is induced, heightening the burden of inflammation and predisposing to a higher risk of exacerbations [ 97 ]. Specifically, co-infections of respiratory viruses and Moraxella catarrhalis , Hemophilus influenza , and/or Streptococcus pneumonia have a greater impact on the risk for more severe acute asthma exacerbations [ 97 ]. The clarification of the mechanisms implicate the case of co-infections on inter-relationship for providing evidence for potential novel therapeutic targets that may prevent acute asthma exacerbations.

5.2. Allergen Sensitization and Viral Infections

Evidence support the theory that allergic sensitization increases the susceptibility for viral infections and probably their ability to provoke further inflammation [ 98 ].

For example, it has been shown that the combination of RV infection and direct exposure to allergens cause epithelial cell production of IL-25 and IL-33 in the airways, mediators involved in Th2 type inflammation and remodeling [ 99 , 100 ]. Moreover, in a murine model of asthma RV infection acquired in early life stages in mice induced an IL-13- and IL-25-mediated Th2 immune response with parallel suppression of IFN-γ, IL-12, and TNF-α [ 101 ], with detrimental changes in airway homeostasis, consisting of innate lymphoid cell expansion, mucous hypersecretion, and airway responsiveness. Furthermore, recurrent RV infections stimulate airway remodeling by upregulating molecules such as VEGF and TGF-β, as well as chemoattractants for airway smooth muscles (i.e., CCL5, CXCL8, and CXCL10) [ 102 , 103 ].

Other data show that the occupancy of the IgE membrane receptors inhibits antiviral induction of interferon-a from plasmacytoid dendritic cells leading to subsequent increased susceptibility to viral infections and asthma exacerbations. It is noteworthy that an inverse correlation between interferon levels and airway eosinophilia, IL-4 levels, and total serum IgE was observed [ 104 ].

5.3. Allergen Exposure, Tobacco Smoke, and Environmental Pollutants

Indoor or outdoor exposure to allergens may lead to poor asthma control and severe asthma exacerbations in sensitized patients [ 105 , 106 , 107 , 108 , 109 ]. Allergens activate mast cells to release histamine, prostaglandin D2, and cysteinyl leukotrienes. These induce inflammatory responses, airway smooth muscle constriction, increased microvascular permeability, and mucus secretion, diminishing at the same time the innate immune responses and subsequently increasing the susceptibility to viral infections [ 106 , 107 ]. Of great importance is the mold sensitization, which has been associated with the phenotype of severe asthma and with severe asthma attacks. High airborne concentrations of mold have been associated with increased emergency visits for asthma exacerbations [ 108 ]. Specifically, Alternaria is associated with highly increased risk (almost 200-fold) of severe exacerbations and need for ICU admittance in both children and adults [ 109 ]. Furthermore, cockroach and mouse antigens are associated with early wheeze and atopy in an inner-city birth cohort [ 110 ].

Exposure to multiple allergens has been documented as being a common feature in several studies of indoor exposure [ 111 , 112 ]. Salo et al. [ 112 ] showed that more than 50% of subjects were sensitized at least to six detectable allergens, while 45% were sensitized at least to three allergens. In a study from China, Kim et al. [ 111 ] showed sensitization to one or more allergens in almost 50% of the subjects with most common sensitizers being shellfish, dust mites, and cockroaches. However, less than 1% of these subjects had clinically important food allergy or asthma.

Indoor exposure to endotoxin and pollutants (such as particulate matter and nitrogen dioxide) has also been found to increase the risk of severe exacerbations in children with asthma and the use of particulate filters seem effective in reducing exposure levels and therefore, asthma control [ 113 , 114 ]. Differences in allergic sensitizations by race and genetic ancestry have also been documented [ 115 ], and along with the location of residence seem to be more important predictors of allergic sensitization than genetic ancestry. This fact points out the hypothesis that disparities in allergic sensitization by race may be observed as an effect of environmental rather than genetic factors.

Tobacco smoke remains one of the most significant triggers of disease, despite increased public awareness of the detrimental effects of smoking. Asthma patients who smoke have more frequent emergency department visits and hospitalizations for an exacerbation than asthma patients who do not smoke [ 116 ]. Several studies of patients with allergic rhinitis have shown the significant effect of smoking on the development of asthma. Polosa et al. [ 117 ] showed that in a 10-year period smoking had a dose-related effect on the development of asthma in allergic rhinitic patients resulting in an odds ratio of 2.05 for incident asthma for smoking 10 pack-years, and 3.7 and 5.05 for 11–20 and >20 pack-years, respectively.

Second-hand smoke is also associated with deteriorated lung function, poor treatment response, and frequent emergency department visits for asthma [ 118 , 119 , 120 ]. The measurement and monitoring of cotinine levels in serum, urine, and saliva have become a useful tool in determining passive smoke exposure as well as in evaluating uncontrolled asthma. Hassanzad et al. demonstrated that higher cotinine levels were associated with a higher risk for severe asthma. [ 121 ]. Increasing interest has also raised on the potential hazards of third-hand smoke (THS) in children. THS is residual nicotine and other chemical pollutants remaining in the indoor environment and on household surfaces for weeks to months after active tobacco smoking has stopped. It seems that young children may be more susceptible to the adverse effects of THS exposure since they crawl and tend to ingest several items from the surrounding [ 122 ]. However, more research is needed to assess the real extent of the hazards arising from THS.

Environmental pollutants, such as particulate matter, ozone, sulfur dioxide, nitrogen dioxide, and diesel exhaust, may act synergistically with viral infections to cause asthma exacerbations [ 123 ] The effects of air pollution on severe asthma exacerbations may be affected by other exposures, such as stress, vitamin D insufficiency, and seasonality [ 4 , 5 ]. This was demonstrated in a study of children aged 0–18 years in California, where particulate matter (size, 2.5 mm; PM 2.5 ) and ozone were associated with severe asthma exacerbations in the warm season, while in the cool season exacerbations were associated with articulate matter of PM 2.5 , carbon monoxide, and NOx (NO 1 NO 2 ) [ 124 , 125 ].

6. Genetic Associations with Asthma Exacerbations

Genome-wide association studies of asthma in children and adults have identified polymorphisms for IL33, IL1RL1/IL18R1, HLA-DQ, SMAD3, and IL2RB9 and the locus on chromosome 17q21 including the genes ZPBP2, GSDMB, and ORMDL3 that are implicated in epithelial barrier function and innate and adaptive immune responses in asthma [ 126 , 127 ]. Genetic variants in the class I major histocompatibility complex-restricted T cell-associated molecule gene (CRTAM) was associated with an increased rate of asthma exacerbations in children with low circulating vitamin D levels [ 128 ]. One of the most well replicated genetic regions affecting asthma risk is the 17q12–21 locus, which includes ORMDL3 and GSDMB. The TT allele at rs7216389 is associated with an odds ratio of 1.6 of having an asthma exacerbation when compared with the CC allele [ 129 ].

Furthermore, polymorphisms for FCER2 have been associated with decreased FCER2 gene expression, increased serum IgE levels and risk of severe exacerbations [ 130 ]. Association was also found between variants in chitinase 3-like 1 (CHI3L1; YKL-40) and asthma exacerbations and hospitalizations [ 131 , 132 ]. Specifically, studies in murine models of asthma implicate YKL-40 in IgE induction, antigen sensitization, dendritic cell accumulation and activation, and alternative macrophage activation [ 133 ], while purified YKL-40 induces interleukin-8 secretion in bronchial epithelial cells [ 134 ].

7. Pathogenesis-Immunobiology

Asthma is a heterogeneous condition with complex observable characteristics (phenotype) and their underlying mechanisms (endotype), resulting from complex host–environment interactions ( Figure 3 ). Usually, inflammatory cells are present and activated in the airways of severe asthmatics and persist despite treatment, but their relevance to lack of control and disease severity is largely unknown. These cells include not only eosinophils and neutrophils, but also T-lymphocytes, mast cells, macrophages and airway structural cells which are also crucially involved in the inflammatory reaction and remodeling in asthma. Although it is well accepted that asthma is characterized by eosinophilic infiltration, inflammatory phenotypes of severe asthma can be characterized by persistence of eosinophilic or neutrophilic infiltration, as well as by absence of inflammatory infiltration (paucigranulocytic) [ 135 , 136 ]. Depending on the type of immune cell responses implicated in disease pathogenesis, asthma endotypes are categorized as type 2 asthma, characterized predominantly by T helper type 2 (Th2) cell-mediated inflammation and non-type 2 asthma, associated with Th1 and/or Th17 cell inflammation [ 137 , 138 ]. Eosinophilic, Th2 airway inflammation is present in around 50% of adults with asthma, and is estimated to be higher in the absence of corticosteroids [ 139 ].

Pathogenesis of acute exacerbations in asthma.

Th2 mediated airway inflammation plays a central role in the pathophysiology of allergic eosinophilic asthma. The allergic sensitization of dendritic cells (DCs) in the presence of thymic stromal lymphopoietin (TSLP), induces Th2 lymphocytes to produce cytokines such as interleukins IL-4, IL-5, and IL-13 [ 140 ]. Chemokines such as eotaxin 1, 2, 3 (CCL11, CCL24 and CCL26, respectively) induce through their receptors (chemokine receptor 3, CCR3) [ 141 ] and other chemoattractant agents, such as mast cell derived prostaglandin D2 (PGD2) eosinophil recruitment in the mucosa. Furthermore, IL-4 and IL-13 activate B lymphocytes to produce allergen specific IgE, which binds to the high affinity mast cell receptors, leading to their activation [ 140 ].

In non-allergic eosinophilic asthma, airway epithelial damage caused by pollution and pathogens leads to IL-5 and IL-13 production by innate lymphoid cells (ILC2s), in response to PGD2, TSLP, IL-25 and IL-33 [ 142 ]. ILC2s and Th2 cells are a significant source of type 2 cytokines and play a role in eosinophilic inflammatory response, allergy and remodeling in asthma [ 143 , 144 ]. Increased circulating and sputum IL-5 and IL-13-producing ILC2s were detected in severe asthma compared to mild asthma patients [ 145 ]. Furthermore, increased numbers of IL-5 + and IL-13 + ILC2s were found in sputum after allergen challenge in asthma patients [ 146 ]. IL-13-expressing ILC2 and Th2 cells are also responsible for bronchial epithelial tight junction barrier leakiness in asthma patients [ 147 , 148 ].

Chronic inflammation that characterizes severe asthma leads to tissue remodeling, fixed airway obstruction, and no response to bronchodilatory treatment [ 149 ]. It seems that chronic persistent inflammation and the release of a plethora of cytokines (IL-5, IL-9, IL-13, osteopontin, and activin-A9), chemokines (CCR3 dependent) and growth factors (TGF-β1 and VEGF) from inflammatory and epithelial cells play a central role in the establishment of airway remodeling [ 150 ].

Physiologically, airway inflammation is counteracted by inhibitory molecules and suppressor cells including CD4 + regulatory T cells (Tregs) [ 151 , 152 ] which becomes visible upon Treg depletion which causes spontaneous asthma-like airway pathology [ 153 ]. Patients suffering from allergic asthma have reduced numbers of Tregs that furthermore show impaired suppressive capacity [ 154 , 155 , 156 , 157 ]. Some currently applied therapies aim at enhancing Treg cell number and function [ 154 , 158 ], whereas adoptive transfer of Tregs can suppress both the priming and the effector phase of allergic airway inflammation in experimental models of murine asthma [ 159 , 160 , 161 ].

Mixed eosinophilic and neutrophilic inflammation of the airways are commonly found in severe asthma [ 162 ] and this mixed inflammatory pattern can be a biomarker of the most severe types of the disease [ 163 ]. Elevated sputum neutrophil counts were found to be associated with more severe asthma phenotypes and with poor response to treatment with steroids in a cluster analysis from the Severe Asthma Research Program (SARP) [ 164 ]. Airway neutrophilia has been associated with persistent airflow obstruction in patients with refractory asthma and a progressive loss of lung function [ 165 ] Furthermore, it is associated with higher bronchial hyperresponsiveness independent of eosinophilia [ 166 ].

It is suggested that increased neutrophil counts in peripheral blood and sputum could be secondary to the treatment with corticosteroids, since the anti-apoptotic effect of corticosteroids on neutrophils is well established [ 167 ]. However, neutrophilic inflammation may be observed regardless of corticosteroid treatment in patients with refractory asthma or in patients experiencing acute severe exacerbations [ 168 , 169 , 170 ].

Neutrophil recruitment and activation into the airways have been associated with stimulation of toll-like receptors (TLR) signaling and activation of innate immunity, causing a shift toward Th1 and Th17 responses. This process leads to increased production of interleukin (IL)-8, IL-17A, neutrophil elastase, and matrix metalloproteinase 9 [ 171 ]. Neutrophils are triggered by IL-8 to produce enzymes and other factors that contribute to eosinophil activity [ 171 ]. Evidence suggests that neutrophil subsets may mediate differential effects on immune surveillance and microbial killing. A variety of epithelial insults (ozone, bacteria, and viruses) induce secretion of chemokines and cytokines that promote neutrophil trafficking. Neutrophils primarily traffic to inflamed sites and then secrete granular enzymes, reactive oxygen species, and proteins to eliminate invading bacteria, fungal elements, and viruses. Undoubtedly, neutrophils play pivotal roles in innate immunity [ 172 ]. During asthma exacerbations, the presence of chemokines and cytokines (IL-8 and IL-17A) prolongs neutrophils’ lifespan thus enabling them to migrate from tissue to the systemic circulation or to lymph nodes to modulate adaptive immune responses, Figure 4 . The combined functions of these cytokines and activated enzymes promote airway structures to contribute to the lower FEV 1 , remodeling and fixed airway obstruction seen in adult patients with severe neutrophilic asthma [ 173 ].

The role of the neutrophil in modulating local inflammatory responses.

8. Biomarkers Correlating with Risk of Asthma Exacerbations

The better understanding of the pathophysiology of asthma has led to the recognition of biomarkers with a potential to predict severe exacerbations. Among T2-high asthma biomarkers sputum and blood eosinophil count, serum IgE, serum periostin levels, and levels of nitric oxide in exhaled breath (FeNO) seem to associate with the severity of asthma and the rate and severity of exacerbations.

Sputum eosinophils have been correlated with increased asthma severity and airway responsiveness. Increased sputum eosinophil counts have been used as a measure of better response to corticosteroid treatment, in terms of reducing exacerbations. In the systematic review by Petsky et al. [ 174 ] it was demonstrated that asthma treatment guided by sputum eosinophil counts led to a significant reduction in the exacerbation rate. In children, elevated blood eosinophil count is associated with persistent asthma symptoms, and responsiveness to treatment can be predicted by the number of eosinophils without having set though a validated cut-off point [ 175 ]

Baseline blood eosinophil count is being used as a biomarker that predicts the clinical efficacy of anti-IL5 therapy in patients with severe eosinophilic asthma with a history of exacerbations [ 176 , 177 , 178 ], with eosinophil cut-offs set to ≥150 to ≥300 cells/μL [ 179 ] in mepolizumab trials. It has been demonstrated, however, that higher eosinophil counts than these cut-offs are associated with poor asthma control and more severe exacerbations [ 180 ]. In the study of Zieger et al. [ 181 ], a blood eosinophil count > 400 cells/μL was found to be an independent risk factor for exacerbations, emergency department visits or hospitalizations for asthma. Although blood eosinophil count levels predict the rate of exacerbations, this is not the case with sputum eosinophil count [ 179 , 182 ].

Total serum IgE level is a biomarker used in severe allergic asthma for the treatment with anti-IgE antibody (omalizumab). In association with elevated levels of fractional exhaled nitric oxide (FENO) (>19.5 parts per billion) and blood eosinophil count (>260/μL), it significantly predicts which patients with severe allergic asthma will respond to omalizumab, reducing the exacerbation rate [ 183 ].

The production of nitric oxide in the airways indicates Th2 type inflammation [ 184 , 185 ] and FeNO is a noninvasive biomarker of eosinophilic airway inflammation. There are contradictory data on whether FeNO has the ability to classify asthma severity [ 186 , 187 , 188 ]. Studies have shown that FeNO can predict accelerated decline of lung function [ 189 ], asthma relapse after corticosteroid treatment discontinuation [ 184 ], and degree of airway inflammation [ 190 ]. However, its ability to be used as a biomarker to predict exacerbations seems to be limited, even when combined with clinical features [ 191 ]. In the study by van der Valk et al. [ 192 ], repeated measurements of FENO predicted moderate asthma exacerbations (not requiring systemic corticosteroids or hospitalizations) but not severe asthma exacerbations.

Exhaled breath condensate (EBC) has been used in assessing exacerbations. Low EBC pH, various cytokines, chemokines, NO-related products, leukotrienes, and volatile organic compounds, better in combination, have been used as biomarkers associated with clinical characteristics and exacerbations [ 193 ].

Serum periostin is a biomarker of allergic eosinophilic asthma and has been used in the identification of patients who will respond to Th2-directed therapies [ 194 ]. However, limited data suggest that the serum periostin level predicts asthma exacerbations [ 195 ]. Sputum periostin, on the other hand, is associated with persistent airflow limitation, eosinophilic asthma refractory to ICS [ 196 ], while it is a potential marker for airway remodeling, as well [ 197 , 198 ].

There is an increasing need for developing biomarkers that will guide clinicians in the management of asthma, in terms of better and easier phenotyping asthma, predicting exacerbations, and treatment response.

9. Pathophysiology

Acute severe asthma commonly presents with abnormal arterial gas exchange. Arterial hypoxemia is largely attributed to ventilation/perfusion mismatch (V/Q mismatch). Hypercapnia, on the other hand, is not only present due to V/Q mismatch, but also due to respiratory muscle fatigue leading to alveolar hypoventilation. Trying to assess the exact profile of the V/Q mismatch that characterizes acute severe asthma, studies have demonstrated that although in asthma patients there is a wide spectrum of V/Q abnormalities, the most common in acute severe asthma (ASA) patients is having increased blood flow, in the context of high cardiac output, distributed in alveolar spaces with low ventilation and remarkably low V/Q ratios [ 199 ]. The pattern of ventilation-perfusion is bimodal in acute severe asthma, ranging from normally perfused areas to areas of hypoxic pulmonary vasoconstriction.

With regards to the mechanics of the respiratory system, acute asthma exacerbation is characterized by reversible bronchoconstriction and increased airway resistance, followed by low flow rates, premature small airway closure, decreased elastic recoil, pulmonary hyperinflation and increased work of breathing. There is a substantial decrease in the FEV 1 and the PEF of the patients, whereas the residual volume may increase as much as 400% of the normal and the functional residual capacity may even reach double the normal values [ 199 ]. In severe asthma exacerbations, total lung capacity (TLC) is also increasing. These changes in lung volumes help constricted airways remain open. During passive expiration of the lungs, the driving forces of the respiratory system are the elastic forces. The lower the elastic forces are, or the higher the resistive forces, the longer will the time needed to full expiration of the inspired tidal volume be, characteristic that may be quantified by a long expiratory time constant of the respiratory system. Incomplete exhalation of delivered tidal volume makes inspiration begin at a volume at which respiratory system exhibits a positive recoil pressure. The presence of flow at the end of the expiration is due to the presence of positive alveolar pressure at the end of expiration. This process is called dynamic hyperinflation and the positive end-expiratory alveolus pressure associated with higher relaxation volume is called intrinsic (auto) Positive End Expiratory Pressure (PEEP) [ 200 ] ( Figure 5 ). Dynamic hyperinflation depends on the expiratory time constant, expiratory flow limitation, expiratory time, inspiratory muscle activity during exhalation, tidal volume, and external flow resistance [ 201 ]. Although this initially may act in favor of the patient, by reducing the resistive work of breathing, the thorax and lungs increase in volume, length–tension relationships of the respiratory muscles shorten and the strength of contraction eventually diminishes. As the severe exacerbation remains unresponsive, expiratory and accessory muscles become active, the work of breathing increases and fatigue is a serious and potentially fatal possibility, as it further compromises respiratory function and deteriorates respiratory failure. Bronchospasm and increased resistance, mucous and compression of the peripheral airways from auto-PEEP, lead to significant heterogeneity of the lung. Normal lung units coexist with pathological lung units creating a variety of many different time constants across the lung.

Dynamic hyperinflation during exacerbation.

Hemodynamic compromise is another important feature of a severe asthma attack that leads to significant dynamic hyperinflation. The development of positive intrathoracic pressures lead to decrease of the right heart output by decreasing right heart preload (venous return and end–diastolic volume of the right heart) and increasing right heart afterload (vascular pulmonary resistance). The decreased right heart output in parallel with the diastolic dysfunction of the left heart (caused by shifting the intraventricular septum towards the left ventricle) and its incomplete filling, lead to a significant reduction of the arterial systolic pressure in inspiration and the presence of pulsus paradoxus sign [ 202 ] ( Figure 6 ).

Pathophysiological changes due to dynamic hyperinflation.

Thus, due to uncontrolled or difficult to treat dynamic hyperinflation, a patient with asthma can be drowsy, confused or agitated, or may present with paradoxical thoracic-abdominal movement, with absent of wheeze in lung auscultation, bradycardia or with pulsus paradoxus. This patient is near respiratory arrest status and endotracheal intubation. Mechanical ventilation and admission to an ICU may be imminent [ 203 ].

10. Clinical Assessment

Identification of severe asthma exacerbations is of outmost importance, as they are related with worse outcomes and require close observation and aggressive management. A brief interview with the patient is necessary to determine certain features in the patient’s history that need to be looked into closely, because current literature identifies them as factors that increase asthma-related death. Hospital and Intensive Care Unit (ICU) admission, as well as mechanical ventilation due to an asthma exacerbation has been shown to significantly increase the risk for a new episode of near fatal and fatal asthma [ 204 ]. It is also very important to obtain a detailed description of the patient’s medication history. Medications that play a significant role in the prediction of asthma related morbidities and death are inhaled and systematic corticosteroids, as well as the use of beta agonists. In this context, not currently using inhaled corticosteroids (ICS), currently using or having recently discontinued treatment with oral corticosteroids (OCS), as well as documented overuse of short acting β agonists (SABAs) are all factors related with an increased risk for asthma associated morbidity and mortality [ 205 , 206 ]. Elements from the medication history may also conceal clues that may suggest inadequate treatment, or even poor adherence to a prescribed treatment plan. The lack of a written asthma plan and socioeconomic factors are also associated with a greater risk for a severe exacerbation [ 207 ].

Patients suffering from an asthma exacerbation may present with a variety of signs and symptoms [ 208 ] ( Figure 7 ). Dyspnea, chest tightness, cough and wheezing are few of those, but there is wide heterogeneity in the asthmatic patient presentation. Features that characterize acute severe asthma are agitation, drowsiness or signs of confusion, significant breathlessness at rest, with the patient talking in words, tachypnea of more than 30 breaths per minute, use of accessory respiratory muscles, tachycardia of >120 beats per minute and pulsus paradoxus. Moreover, it is crucial to identify signs that indicate an imminent respiratory arrest, such as paradoxical thoraco-abdominal movement, silent chest with absence of wheeze, bradycardia, while the absence of pulsus paradoxus might imply muscle fatigue [ 208 ]. Upon examining the patient with acute severe asthma, apart from recognizing the signs that indicate severity, it is imperative to diagnose any pathology that might attenuate the exacerbation and requires specific treatment. Such entities are pneumothorax and pneumo-mediastinum, and pneumonia. At the same time, the clinician needs to exclude conditions that may mimic the symptoms of an asthma attack, such as cardiogenic pulmonary edema, exacerbation of chronic obstructive disease, airway obstruction caused by a foreign body or an intraluminal mass, pulmonary embolism, hyperventilation syndrome and vocal cord dysfunction [ 209 , 210 , 211 ].

Global Initiative for Asthma (GINA) recommendations for the management of asthma exacerbations in acute care facility. PEF: Peak expiratory flow; FEV 1 : Forced expiratory volume in one second; SABA, short acting beta 2 agonists; ICU, Intensive Care Unit.

Although lung function measurements are less sensitive than the history of symptoms, during an asthma exacerbation, serial PEF and FEV 1 measurements are more objective and reliable indicators of severity and should remain part of the initial assessment of an asthma patient presenting to the emergency department according to current guidelines [ 1 , 2 ]. Regarding PEF, the cut-off value of 50% of the patient’s best or predicted value is within the definition of an acute severe asthma episode, and requires greater attention and action. Moreover, a value of less than 33% of their best or predicted value is an indicator of life-threatening asthma. Serial monitoring of PEF may also assist the decision of either discharging the patient, should this be accompanied with a clinical improvement, or for ICU referral if the values are continuously deteriorating despite initial appropriate treatment. There is certainly a concern regarding the safety of this test in the setting of an acute exacerbation in the emergency department, and it should be performed with caution and continuous observation of the patient.

Further laboratory testing is not necessary for every patient that presents to the emergency department with an exacerbation. Chest radiographs are advised when the clinician needs to exclude conditions such as pneumonia, pneumothorax or atelectasis, but not for all patients. Arterial blood gas analysis should be performed on all patients that are critically ill, and/or are desaturating less than 92% despite treatment [ 212 ]. By performing arterial blood gas analysis, the clinician will be able to assess not only hypoxemia and the trend of PaCO 2 , but also acid base disturbances, such as respiratory acidosis and lactic acidosis which are common on acute severe asthma [ 213 ]. Further investigations may include total white blood cell count, to evaluate the potential of infection, levels of brain natriuretic peptide to exclude the presence of congestive heart failure and electrolyte level measurement.

11. Pharmacological and Non-Pharmacological Management

Most current guidelines regarding asthma exacerbations highlight the necessity of supplying the asthma patient with a written plan of action appropriate for their level of control, which will lead to early recognition and management of their exacerbations [ 1 , 2 ]. It is of outmost importance that the patients become educated on when to seek help, during the event of an acute exacerbation. In primary care and further in the emergency department or the hospital ward, a severe asthma attack needs to be identified within a short time period in order for the correct action to be taken. A severe exacerbation of asthma is a life-threatening medical emergency, thus being crucial to transfer the patient to an acute care facility, once such a condition is identified, ensuring the patient’s safety. During the transfer, it is required to provide controlled oxygen therapy, inhaled SABA, ipratropium bromide, and systemic corticosteroids. In the emergency department the pharmacological therapy of acute severe asthma should consist of SABA, ipratropium bromide, systemic corticosteroids (oral or iv), controlled oxygen therapy, and the clinician should consider the use of iv magnesium sulfate and high dose ICS [ 1 ]. ( Figure 7 , Table 2 )

Pharmacological management of patients with acute severe exacerbation in the emergency department.

iv, intravenous; sc, subcutaneous.

11.1. β2-Adrenergic Receptor Agonists

The cornerstones of acute asthma medication are bronchodilators and especially short acting beta agonists (SABA). It is recommended that in acute severe asthma SABAs are administered repetitively or continuously. These substances activate the β2 adrenoreceptors (β2ARs), which are located mainly on the smooth airway muscle cells, but are also found on other airway cells even on the inflammatory cells. Their very important characteristic is that they have a rapid onset of action, while at the same time being well tolerated, despite high doses. Although the β2 AR agonists are substances known for centuries, the great challenge remains improving their selectivity, in order to benefit from their desired effect, while at the same time reducing their adverse effects. All current asthma guidelines introduce short acting β2 agonists (SABAs), as the first line treatment for acute severe asthma. In the first steps of escalating therapy during an exacerbation, the patient is advised to increase their use “as needed”. That is also the recommendation for the primary care setting, as well as for the emergency department, where repeated inhaled administration of SABA is advised. Studies on the efficacy of nebulizers vs. metered dose inhalers (MDIs) have not proven superiority of nebulized administration. In a recent review, nebulized delivery did not improve hospital admission, length of stay in the emergency department or pulmonary function [ 214 ]. According to GINA 2018, the preferred method of administration is with strong evidence (Evidence A) pMDI with a spacer [ 1 ]. This evidence becomes less strong when referring to severe and near fatal asthma. Although continuous nebulization of SABAs was initially a very promising perspective, several studies and meta-analyses have failed to clearly demonstrate strong evidence on favor of continuous nebulized SABAs for acute asthma. Rodrigo et al. in 2002 performed a systematic review and meta-analysis that showed no difference in respiratory function measured in the first hours of administration or on the rate of hospital admissions [ 215 ]. A Cochrane systematic review on the subject, including few more studies, showed significant difference on both respiratory function and hospital admissions, in favor of the continuous use of SABA, while at the same time demonstrating a good tolerance from the patients who did not present more adverse effects with this method of administration [ 216 ]. The most commonly used SABA is salbutamol or albuterol as named in the United States, which has an onset of action of less than 10 min and duration of approximately 6 h. Lebalbuterol is a recent addition to the choices of SABAs, with its benefit of a lower than salbutamol dose that provides similar effect. There is currently evidence about its efficacy in acute severe asthma as an intermittent regimen, but not as a continuous nebulization strategy [ 217 , 218 ]. Continuous intravenous infusion of β2 agonists has also been proposed as a therapy, especially in patients who did not respond to intensive bronchodilation. There is no evidence to support the use of intravenous β2 agonists [ 219 , 220 ] or the method of continuous, subcutaneous infusions of terbutaline [ 221 ]. Epinephrine has been studied, as a nebulized, subcutaneous, intramuscular and intravenous administration, but, in current guidelines, its use is restricted for acute asthma related with anaphylaxis and angioedema [ 1 , 222 , 223 ].

11.2. Anticholinergics

Anticholinergic agents act as inhibitors of acetylcholine at the muscarinic cholinergic receptor. Therefore, they inhibit parasympathetic nerve impulses and they produce a beneficial effect in acute asthma, by causing airway smooth muscle relaxation. Furthermore, they enhance β2-agonist-induced bronchodilation via intracellular processes and they prolong their bronchodilator effect [ 61 , 224 ]. The anticholinergic agent used primarily is ipratropium bromide due to its selectivity for airway smooth muscle receptors, which reduces the systemic adverse effects. Their use is included in current guidelines for moderate to severe acute and life-threatening asthma, as well as for patients who show poor response to initial SABA therapy [ 1 , 2 ]. It is not recommended to use anticholinergics as a single therapy for acute asthma. It has been demonstrated that the addition of inhaled ipratropium bromide to therapy with SABAs improve hospitalization rates, relapse rates and are associated with lung function improvement [ 62 , 63 , 64 ]. This combination therapy benefit is greater for the patients who present with acute severe asthma and are at a higher risk of hospitalization. There is an increased rate of adverse effects, which are of mild nature, such as mouth dryness and tremor.

11.3. Corticosteroids

Within the asthma setting, it has been well established that inhaled corticosteroids reduce the rates of hospitalization and mortality for patients with asthma [ 65 , 225 ]. In the event of acute exacerbation, there is a different approach of their use. Current recommendations suggest that high dose ICS given within the first hour of the patient’s presentation in the emergency department, reduce the rate of hospital admissions, for patients who are not on systemic corticosteroid therapy [ 1 ]. Recent evidence however seems to be conflicting regarding their performance without the use of systemic corticosteroids, when rate of hospital admissions or changes in lung function has been studied [ 226 , 227 ].

Systemic corticosteroids, due to their significant anti-inflammatory properties, have a fundamental role in the management of acute asthma, and particularly for patients who present with exacerbation while receiving oral corticosteroids (OCS), or have previous history of exacerbation that required use of OCS. They are also recommended for patients who did not respond to initial SABA therapy with a prolonged effect. Apart from their role against asthma associated inflammation, they seem to increase the number and sensitivity of β-adrenergic receptors, and also restrain the migration and function of eosinophils and other inflammatory cells. On the other hand, their lack of bronchodilatory effects prohibits their use for acute asthma as a monotherapy [ 74 ]. A recent multi-center study showed that there is a significant percentage of patients who get admitted to hospital with acute asthma and do not receive systemic corticosteroids, despite the clear suggestion of current guidelines [ 228 ]. With regards to the root of administration, intravenous administration seems to not provide additional efficacy to the use of oral therapy [ 229 , 230 ]. Intramuscular regimens seem to be as effective as oral in reducing the risk for relapse [ 231 ]. The oral route is better tolerated and preferred, because it is quicker and less expensive. Identifying groups of patients where intravenous administration could be more beneficial is a recent field of study, and guidelines support that they should be considered for patients who may be unable to swallow due to breathlessness, or may not absorb efficiently the medication due to gastro-enteral disturbances, such as vomiting [ 1 ]. There is a lack of robust evidence to clarify the superiority of longer or higher dose OCS, thus the literature suggests a 5–7-day regimen of 50 mg prednisolone as a single dose, or 200 mg hydrocortisone in divided doses [ 1 , 2 , 232 ].

11.4. Magnesium Sulfate

Magnesium has been proven to be an important co-factor in enzymatic reactions and changes of its concentrations may result in different response from the smooth muscles. Hypomagnesemia may cause contraction, whereas hypermagnesemia causes relaxation of the smooth muscles and bronchodilation, possibly through inhibition of calcium influx into the muscles.

Recent recommendations include magnesium sulfate, at dose of 2 g infused over 20 min, as a second line intervention for acute severe asthma exacerbation [ 1 , 233 ]. It has been shown to reduce the rate of hospitalization in adults with FEV 1 of 25–30% at presentation and those who are unresponsive to initial treatment, and have persistent hypoxemia, and correlates with improvement in lung function [ 234 , 235 ]. Its infusion has not been correlated with severe adverse events; it is however contra-indicated for patients with renal insufficiency, hypermagnesemia and myasthenia Gravis. Magnesium has also been tried in its nebulized form for asthma exacerbation, with very few data to support it. A recent systematic review, which examined the efficacy and safety of inhaled administration of magnesium, concluded that, although safe, it has not shown significant benefits when compared with the first line inhaled agents, thus it is not routinely recommended [ 236 ]. The current literature is reluctant to fully support the use of magnesium, mainly because of the heterogeneity of the severity of asthma attacks it has been used on in trials, especially in the context of optimized first line treatment with β2-agonists and corticosteroids [ 237 ]. A 2014 randomized controlled trial failed to show any evidence of clear benefit in the use of either intravenous or inhaled magnesium [ 238 ]. Further prospective trials are necessary to provide accurate evidence on this treatment option.

11.5. Methylxanthines

On the ground of their anti-inflammatory properties, methylxanthines (aminophylline and theophylline) used to be included in the primary treatment for acute asthma. Their poor safety profile, which includes significant side effects, in combination with the inability to provide evidence of improved outcomes, such as improved pulmonary function or rate of hospitalization when given for severe acute asthma, has excluded them from current guidelines [ 1 , 239 ]. A more recent review and meta-analysis, however, has supplied some evidence of aminophylline’s efficacy, when combined with other bronchodilators, but more data are needed on this direction [ 240 ].

11.6. Leukotriene Modulators

Although leukotriene receptor antagonists (LTRAs) are included as a controller agent in the asthma management, there are limited data on the efficacy of intravenous or oral antileukotriene drugs in acute asthma. Montelukast and zafirlukast were studied on patients with acute asthma and demonstrated some evidence of lung function improvement [ 241 , 242 ]. A review of the literature, however failed to provide robust evidence of the effectiveness of this medication category on lung function or on the outcomes of the patients [ 243 ].

11.7. Oxygen Supply

Although asthma exacerbations are not usually accompanied with severe hypoxemia, acute severe asthma often presents with arterial PO 2 derangements, due to extensive V / Q mismatch as explained above. Oxygen should be administered via nasal cannula or mask, with a target of arterial oxygen saturation of 93–95%, or to those patients where saturation monitoring is not available [ 1 ]. Although not all guidelines agree on the level of the desirable target saturation, studies have shown that, in severe acute asthma, oxygen therapy with controlled low flow administration, with a target SpO 2 , is correlated with better outcomes than the use of per se high flow 100% oxygen delivery, as it has been shown to correlate with increases in PaCO 2 , as well as with decreased values of PEF [ 244 , 245 ]. There is also some evidence about the use of oxygen driven nebulization with SABAs, because of the pulmonary vasodilation caused by the β2-agonist, which results in increasing perfusion of poorly ventilated areas, thus resulting in deterioration of the V/Q abnormalities [ 246 ].

11.8. Heliox

Heliox is a mixture of helium (70–80%) with oxygen (20–30%). Heliox can be used for severe asthma exacerbations that are unresponsive to standard therapy or in patients having an upper airway obstruction component. Heliox, with density less than air, leads to lower Reynolds number, thus decreasing resistance to airflow under conditions of turbulent flow, as are prominent in the central airways and at the branch points. This effect can potentially decrease the work of breathing and improve ventilation. On the contrary, airflow in smaller airways, which are mainly affected during an asthma exacerbation, will not improve with heliox, as it is typically laminar, depending on gas viscosity rather than density.

Despite the theoretical benefits of heliox, and while a few case series have suggested a beneficial effect in acute asthma, no studies in adults have demonstrated an advantage of heliox above and beyond standard oxygen therapy. In asthma exacerbation either without or with intubation, heliox has not demonstrated consistent benefit [ 247 , 248 ].

Heliox has demonstrated greatest benefit for improving symptoms when used as a nebulizing gas for a beta-2 agonist medication. Benefit is generally seen within minutes after the initiation of therapy [ 247 ]. Another study has shown that using heliox as a carrier gas increase gas delivery up to 50% in a mechanical model for both MDIs and nebulizers [ 249 ]. Given that its effect is based on the percentage of helium, it should not be administrated to patients requiring FiO 2 > 40%.

11.9. Ketamine

Ketamine is well known drug that has been in use since circa 1960. It is a dissociative anesthetic drug that has the potential to have different actions, depending on the dose used. It may work as a potent analgesic and as an anesthetic agent, but may also have secondary effects as a bronchodilator, while at the same time preserving airway reflexes and sympathetic nervous system tone, with no effects on the cardiovascular system. A dose of 1–2 mg/kg dose has been described as an inductive agent in rapid sequence intubation (RSI) of asthma patients [ 250 ]. In doses lower than this it does not have sedative effects, whereas in higher doses it can cause laryngospasm and apnea. Its psychoactive effects make it even less popular for use. In the context of asthma, there are no large randomized trials to examine its effect. There is some evidence of its bronchodilatory effect, especially in mild and moderate asthma exacerbations, and in doses lower than 1 mg/kg, but larger trials would be necessary to establish its role for asthma [ 251 , 252 ].

11.10. Antibiotics

There is no evidence supporting the use of antibiotics per se for severe acute asthma, unless the patient’s history and clinical assessment indicate the presence of infection. In a recent retrospective cohort study, it has been demonstrated that, in patients hospitalized with acute asthma and receiving OCS, antibiotic use was associated with longer hospital length of stay and hospital cost, whereas it held similar risk of treatment failure [ 253 ]. In a previous study in the US, 60% of the patients who were admitted to hospital with asthma exacerbation, received antibiotics, with no clear indication accompanying this decision [ 254 ]. Current guidelines suggest against their use and that they should be considered after optimizing other treatment options and when there is clear evidence of infection [ 1 ].

11.11. Non-Invasive Mechanical Ventilation

Although the benefits of non-invasive mechanical ventilation (NIMV) are well recognized in the acute exacerbation of chronic obstructive pulmonary disease and pulmonary edema, its usage for asthma exacerbation remains controversial. Despite the lack of supporting evidence, NIMV is commonly used in patients with severe asthma exacerbation as a mean to obviate the need for intubation and mechanical ventilation and its detrimental effects.

In the absence of clinical guidelines that recommend the use of NIMV for the management of acute asthma, evidence suggests that a trial of NIMV (for one or two hours) may be beneficial for a low risk group of patients [ 255 ], particularly those unresponsive to medical therapy. Prolonged trials of NIMV are not recommended. Suggested criteria for an NIMV trial include RR > 25 breaths per minute, heart rate > 110 beats per minute, hypoxemia with PaO 2 /FiO 2 ratio greater than 200, hypercapnia with PaCO 2 < 60 mmHg, FEV 1 < 50% less than predicted and use of accessory respiratory muscles. A trial of NIMV should not be undertaken if there is any absolute criterion for endotracheal intubation (respiratory arrest, hemodynamic instability or shock, GSC < 8), excessive respiratory secretions and risk of aspiration, severe agitation and poor patient collaboration and any cause that precludes the right mask fitting (facial surgery) [ 256 ].

In a trial of 30 patients who presented to the emergency department with a severe asthma exacerbation that was not responding to inhaled bronchodilator therapy, NIMV was associated with reduction in the rate of hospitalization and increased lung function. Improvements in respiratory rate and dyspnea appear to be influenced by the amount of pressure support above expiratory positive airway pressure (EPAP) provided. The use of NIMV has been associated with reduction in endotracheal intubation, improvement in oxygenation, decrease in carbon dioxide retention, and improvement in airflow obstruction. Studies are controversial regarding the mortality and ICU length stay [ 86 ]. NIMV can also be used in the asthmatic patients who are at risk for intubation, following extubation [ 257 ].

11.12. Invasive Mechanical Ventilation

The decision to intubate and mechanically ventilate a near-fatal asthma patient is considered a challenging task and should be based primary on a series of clinical evaluations. Major indications for initiation of invasive mechanical ventilation (IMV) are: (1) cardiac arrest; (2) respiratory arrest or bradypnea; (3) respiratory insufficiency with PaO 2 < 60 mmHg on 100% FiO 2 and PaCO 2 > 50 mmHg; (4) physical exhaustion; and (5) compromised level of consciousness. Relative indications for IMV are: (1) hypercapnia PaCO 2 > 50 mmHg or PaCO 2 increased by 5 mmHg per hour; (2) worsening respiratory acidosis;, (3) inability to treat patient appropriately; (4) failure to improve with proper therapy; and (5) clinical signs of deterioration and respiratory fatigue such as tachypnoea of >40 breaths per minute, severe hypoxemic respiratory insufficiency, hemodynamic instability, paradoxical thoracic movement, and silent chest [ 258 ].

The decision to intubate and mechanically ventilate a patient with acute asthma exacerbation is a clinical one and may be made urgently. When the clinician decides that respiratory failure is progressing, and is unlikely to be reversed by further pharmacologic therapy, intubation should be performed as quickly as possible by a skilled intensivist or anesthesiologist, who has extensive experience in intubation and airway management, using rapid sequence intubation (RSI) protocol suitable for asthmatic patients (good preparation, sufficient pre-oxygenation, suitable induction to anesthesia agents suitable for asthma, and placement of the endotracheal tube) [ 259 ]. Regarding the preferred method of intubation, oral endotracheal intubation is preferred, although the literature also includes awake nasotracheal intubation, which may be complicated by the fact that many asthmatic patients also have nasal polyps [ 203 ]. Additionally, oral intubation allows the use of an endotracheal tube of a larger diameter, facilitating secretion removal and bronchoscopy, if needed, while at the same time decreasing inspiratory airway resistance. It should be noted that unlike other conditions in which intubation and mechanical ventilation can solve problems, the dynamic hyperinflation that mechanical ventilation can create or even exacerbate can have devastating consequences for a severe asthmatic patient, such as cardiovascular collapse and/or barotrauma and ventilator induced lung injury. Therefore, there are certain considerations to be made before and during RSI. During RSI in such patients one should anticipate rapid oxygen desaturation despite maximal effort at pre-oxygenation especially in those patients who do not achieve a SpO 2 above 93%, so adequate pre-oxygenation is advised. Bag mask ventilation should be done using small tidal volume and high inspiratory flow rate with a prolonged expiratory phase, attempting with this way to mimic the approach used during mechanical ventilation. Excessive mag mask ventilation should be avoided because of the risk of pneumothorax [ 260 , 261 ]. Manipulation of the airway can cause laryngospasm and worsening of bronchoconstriction, so one could consider the use of atropine to attenuate vagal reflexes [ 203 ]. The literature suggests the bolus use of intravenous ketamine for RSI taking advantage of its bronchodilatory effect, while propofol is also considered a safe approach. Opiates and barbiturates should be avoided due to the risk of histamine release that can exacerbate bronchoconstriction [ 262 ]. If muscle relaxants are needed, non-depolarizing muscle relaxants (except maybe atracurium and mivacurium) and succinylcholine are suitable in asthmatic patients [ 263 ].

11.13. Goals of Mechanical Ventilation

Near fatal asthma is characterized by severe dynamic hyperinflation of the lung with severe respiratory and circulatory consequences. The aim of mechanical ventilation is to maintain adequate oxygenation, to reduce the work of breathing and to prevent and confront further hyperinflation without any circulatory compromise or ventilator induced lung injury [ 264 ]. The intubation and post-intubation period is often complicated with severe cardio-respiratory derangement. Hypotension, the most common post-intubation complication, may be caused due to dynamic hyperinflation and auto-PEEP, and can be aggravated by dehydration, sedatives and neuromuscular blocking agents. Arrhythmias, barotraumas, laryngospasm or even seizures have also characterized the post-intubation period [ 265 , 266 ]. Phenomena such as hypercapnia, hypoxemia and acidemia, as well as ventilatory lung injury and life threatening pneumotrauma (pneumothorax and pneumo-mediastinum), may also complicate the post-intubation period. Reasons for the aforementioned may be the severity and non-responsiveness of the disease, but may also be the result of inadequate sedation or patient–ventilator desynchrony. Wrong and harmful initial ventilator settings may also result in providing too little or too excessive minute ventilation, potentially deteriorating the already very fragile asthmatic patient [ 267 ].

Management of the asthmatic patient post intubation starts with ensuring adequate sedation in order to achieve the desirable patient–ventilator synchronization. Sedation and analgesia will also decrease the metabolic rate, oxygen consumption and carbon dioxide production. Dexmedetominide, propofol and remifentanyl are the appropriate drugs for sedation and analgesia. Their usage has been associated with shorter length of ICU stay, shorter duration of mechanical ventilation and improved long term neurocognitive outcomes when compared to benzodiazepines [ 266 , 268 ]. It is important to use agents that accomplish deep sedation, while at the same time allow rapid awakening, should the patient improve quickly, which is common in the asthma cases ( Table 3 ).

Sedation, analgesia and paralysis in patients with acute severe asthma exacerbation requiring intubation.

Patients with severe asthma with persistently dangerous levels of hypercapnia and arterial hypoxemia, and extreme patient–ventilatory asynchrony may require paralysis in addition to sedation. The preferred paralytic, non-depolarizing agent is cis-atracurium, as it is eliminated by esterase degradation and spontaneous breakdown in the serum. Paralytic agents can be administered either intermittently through bolus injections, or by continuous intravascular infusion. Its duration must be as short as possible, because concomitant use of intravascular corticosteroids and paralytic neuromuscular agents increases the incidence of critical illness myopathy [ 269 , 270 ].

To avoid the hemodynamic effects of dynamic hyperinflation, once the patient is intubated, it is advised to perform a brief discontinuation (60–90 s) from the ventilation (apnea test), a slowly bagged ventilation and to administer fluids (1–2 L or more) and vasopressors. Although there is no clear evidence to support the volume-preset over the pressure-preset modes, the preferred ventilator modes for the asthmatic patient are the volume-limited ones [ 263 ]. Barotrauma seems to occur regardless of the mode of ventilation. Volume-limited modes of ventilation are usually used for near death asthmatic patients at their entrance in the ICU. It is essential to closely monitor the Peak inspiratory and Plateau pressures, to early detect any change in resistance and compliance, and this is easily achievable when using volume modes ( Figure 8 ). Although high inspiratory flow rates of 80 L/min up to 100 L/min and square waveforms shorten inspiratory time and increase expiration time, thus reducing hyperinflation, it has been shown that this may not have a significant impact to the degree of hyperinflation once the minute ventilation has been limited by high peak inspiratory pressure [ 271 ]. Minute ventilation should be set at a level of less than 115 mL/kg/min (less than 10 L/min) with a respiratory rate of 10–12 breaths/min and a prolonged expiratory time by decreasing I:E ratio (1:3 or 1:4 up to 1:5) [ 263 , 266 ]. Tuxen and Lane showed a remarkable increase in hyperinflation when using higher levels of minute ventilation [ 120 ]. The fraction of inspired oxygen (FIO 2 ) should be titrated to maintain the pulse oxygen saturation (SpO 2 ) above 90% (up to 94%) or the arterial oxygen tension (PaO 2 ) above 60 mmHg. One should avoid SpO 2 > 96% due to oxygen toxicity ( Table 4 ).

Flow time tracing of a patient with persistence of flow at the end of expiration which indicates dynamic hyperinflation and pressure time tracing with a slope increase indicative of over-distension.

Initial ventilator settings in intubated patients with acute severe asthma exacerbation.

SaO 2 : Oxygen saturation; Peep: positive end expiratory pressure.

Limited data exist about the use of external PEEP when ventilating a patient with severe asthma. The use of progressively higher external PEEP from 5 to 15 cmH 2 O has been shown to have a deteriorating effect both in respiratory (deterioration of the end-inspiratory volume, the functional residual capacity and plateau pressure) and circulatory system (decrease of systolic arterial pressure and cardiac output) [ 271 ]. In one prospective study of patients undergoing control mode of ventilation, external PEEP worsened hyperinflation and had serious hemodynamic effects by worsening gas trapping [ 272 ]. On the other hand, other studies have shown that the application of external PEEP, may produce a paradoxical lung deflation by reducing lung volumes and airway pressures and increasing lung homogeneity [ 273 ]. In the case of assist mode of mechanical ventilation, the application of external PEEP at a value less than 80% of the intrinsic PEEP, or 5 cm H 2 O if intrinsic PEEP is <10 cm H 2 O can counterbalance the endogenous peep and reduce the work of breathing [ 274 ]. A trial of stepwise increase in PEEP can be used and terminated when indications of worsening of dynamic hyperinflation it is shown.

11.14. Permissive Hypercapnia

Hypercapnia is a common fact during mechanical ventilation of asthmatic patients. PaCO 2 levels up to 60 mmHg and pH values less than 7.20 are common on the first day of mechanical ventilation even with increased minute ventilation. The term permissive hypercapnia is a ventilating strategy that can be applied to mechanically ventilated asthma patients, that emphasizes on giving priority to the reduction of hyperinflation rather than normal minute ventilation. The reduction of minute ventilation through reduction of tidal volume and respiratory rate is used to decrease pulmonary hyperinflation. PaCO 2 levels should rise gradually during mechanical ventilation rather than rapidly, preferably at a rate of <10 mmHg per hour or even slower if the PaCO 2 exceeds 80 mmHg. Generally, a pH level of 7.20–7.25 is accepted, but the literature has failed to demonstrate a benefit from using alcalotic agents, such as bicarbonate infusion to accomplish that [ 274 ].

11.15. Additional and Unconventional Therapies for Acute Severe Asthma

11.15.1. oxygen delivery by high flow nasal canula.

Oxygen delivery via high flow nasal canula (HFNC) can be used to hypoxemic patients who are not expected to respond to conventional therapies. HFNC with flow up to 60 L/min of warmed and humidified oxygen, decreases inspiratory resistance, as well as the work of breathing, can wash out carbon dioxide, thus decreasing the anatomic dead space and may also produce a positive end expiratory pressure (up to 5 mmHg) by increasing the end expiratory lung volume. The role of HFNC in asthmatic adults is unknown. Studies in children have shown that its use reduces respiratory distress in moderate and severe asthma exacerbations and also reduces the need for intubation [ 275 , 276 ].

11.15.2. Extracorporeal Life Support (ECLS)

Extracorporeal membrane oxygenation (ECMO) is an invasive therapy, in which oxygenation and carbon dioxide removal are performed through an artificial membrane. Although evidence based on clinical trials for the use of ECMO in asthmatic patients is lacking [ 277 , 278 ], there is growing evidence on the subject, supporting the use of ECLS for patients receiving mechanical ventilation due to an asthmatic exacerbation. A 2009 review by Mikkelsen et al. has demonstrated that, when ECLS is used for status asthmaticus, it correlates with better outcomes in comparison to its use for other causes of respiratory failure [ 279 ]. In this study, they used data from the multicenter Extracorporeal Life Support Organization (ELSO), but included only a small number of patients. In 2017, there was another review of the same database, confirming that the use of ECMO is an acceptable option, and resulted in acceptable survival rates, although it is necessary to understand and reduce the ECMO related complications [ 280 ]. Di Lascio et al., using ECMO for asthmatic patients receiving IMV, showed that it could provide adjunctive pulmonary support for patients who remain severely acidotic and hypercapnic despite aggressive conventional therapy [ 281 ]. The writers conclude that ECMO should be considered as an early treatment in patients with status asthmaticus whose gas exchange is not satisfactory despite using conventional therapy, aiming to provide adequate gas change and to prevent ventilator induced lung injury.

A modified ECMO technique such as extracorporeal carbon dioxide removal (ECCO 2 R) may also play an important role in severe asthmatic patient in mechanical ventilation. In a difficult to safely ventilate asthmatic patient, due to extremely high airway pressures, hypoventilation and persistent severe respiratory acidemia are common issues. The usage of ECCO 2 R, considering the reversibility of the pathophysiology of asthma, provide the opportunity for more protective ventilation and more time for the bronchodilator agents to act and reverse inflammation and hyperinflation. There is no sufficient evidence to support a clear role of this technique in asthmatic patients, but there seems to be a growing interest on the subject [ 282 , 283 ]. Schneider et al. even presented a case where ECCO 2 R was used in an “awake” patient with a near fatal asthma attack, refractory to the use of pharmacological intervention and NIMV, resulting in avoidance of intubation [ 284 ]. However, more data are needed to establish an indication for this intervention in the context of an acute severe asthma exacerbation.

11.15.3. Anesthetic Agents

Some inhalational anesthetic agents such as halothane, isoflurane and sevoflurane act as bronchodilators, probably not only through a direct relaxation effect on airway smooth muscles but also by attenuating cholinergic tone [ 285 , 286 ]. This characteristic may have favorable effects in patients with refractory to conventional and optimized bronchodilatory therapy. Case report studies have indicated a positive effectiveness with halothane, but also with isoflurane and sevoflurane but with several limitations. Hypotension, myocardial depression, increased ventricular irritability especially in the presence of acidosis, beta-agonists and theophylline have been reported [ 287 , 288 , 289 ]. In addition, factors such as the expense of inhalational treatment, the need of a bedside anesthesiologist, the practical issues concerning the equipment for delivering the inhalational agents, the short time of duration of bronchodilation (immediate return of bronchoconstriction after discontinuation), and, finally, the absence of randomized trials to evaluate and confirm their efficacy in near-death adult asthmatic patients make the usage of anesthetic agents a last resort as a non- conventional bronchodilatory therapy for refractory near death asthma exacerbations [ 290 , 291 ].

11.15.4. Enoximone

Enoximone is an intravenous bronchodilatory agent that can be used in severe asthma exacerbation in adults. Enoximone, a selective phosphodiasterase inhibitor III, was tested in a study by Beute et al. on eight patients with status asthmaticus, six of whom had a respiratory arrest or hypercapnia [ 292 ]. The bronchodilatory effect was immediate. Even if the intravenous administration bypasses inhalation incapability in severe asthma, and no side-effects were observed in this study, phosphodiesterase inhibitors in general are associated with ventricular and atrial arrhythmias, hypotension, and hepatotoxicity. Further studies are needed to confirm enoximone efficacy and safety in patients with acute exacerbations of asthma that are refractory to conventional therapies.

12. Prognosis

Asthmatic patients who require mechanical ventilation, not only have increased hospital mortality (7%), but also long-term mortality [ 40 , 293 ]. Most of the long-term mortality is attributed to recurrent asthma [ 294 ]. Psychological disturbances such as depression and denial are also common features of asthmatic patients who survived a near fatal episode. Anxiety seems to be more common among close family members than the patients themselves [ 295 ]. Smoking cessation is one of the recognized factors that improves survival [ 151 ].

13. Prevention and Risk Reduction

GINA recommends that all adults and adolescents with asthma should receive ICS-containing controller treatment, either as-needed (in mild asthma) or daily, in order to reduce their risk of serious exacerbations and to control symptoms, [ 1 ] ( Figure 9 ). Asthma treatment should be optimized in patients continuing having poor symptom control and/or exacerbations, even though Step 4 and Step 5 treatments and contributing factors should be assessed, in order to treat modifiable risk factors that compromise disease stability (smoking, environmental exposures, allergen exposure (if sensitized on skin prick testing or specific IgE), and medications such as beta-blockers and NSAIDs) ( Table 5 ). It is imperative to optimize the inhaler technique and adherence to treatment, as well as overuse of SABAs, and medication side effects. Furthermore, comorbidities should be assessed including obesity, GERD, chronic rhinosinusitis, obstructive sleep apnea, anxiety, depression, and social difficulties. Non-pharmacological interventions (e.g., smoking cessation, exercise, weight loss, mucus clearance, and influenza vaccination) should also be recommended where indicated.

Personalized management for adults and adolescents to control symptoms and minimize future risk [ 1 ].

Modifiable risk factors that have to be treated in order to reduce exacerbations.

FEV 1 , forced expiratory volume in 1 s; HDM, house dust mite; ICS, inhaled corticosteroids; OCS, oral corticosteroids; SLIT, sublingual immunotherapy.

If the problems continue after having optimized all the above parameters, patients should refer to a specialist center for phenotypic assessment and consideration of add-on therapy including biologics ( Figure 10 ). The prevalence of severe, refractory asthma is generally estimated to be 5–10% of the total asthma population [ 77 , 151 ]. It is important to distinguish between asthma that is difficult to control and asthma that is truly severe. Severe asthma is defined by the joint European Respiratory Society/American Thoracic Society (ERS/ATS) guidelines according to the following criteria [ 151 ]:

• Requirement for treatment with high-dose inhaled corticosteroids (ICS) and a second controller (and/or systemic corticosteroids) to maintain control.
• Refractory to the treatment mentioned above.
• Incomplete management of comorbidities such as severe sinus disease or obesity.

Criteria for the choice of biologic as add on treatment in Th2 driven severe asthma.

The GINA 2019 guidelines for adolescents and adults with difficult-to-treat and severe asthma [ 77 ] recommend that assessment of the severe asthma phenotype should be done during high dose ICS treatment (or lowest possible dose of OCS), and biological treatment should be chosen accordingly ( Figure 8 ). Where relevant, test for parasitic infection should precede and be treated if present, before commencing Type 2 targeted treatment. The currently approved add-on biological treatments for severe asthma include anti-IgE treatment for severe allergic asthma (omalizumab), anti-IL5 or anti-IL5R for severe eosinophilic (mepolizumab, benralizumab, and reslizumab), and anti-IL4R for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS asthma (dupilumab) ( Table 6 ).

Currently available biologics: indications and adverse effects.

14. Conclusions

Severe asthma exacerbations are a major cause of disease morbidity, functional impairment, increased healthcare costs, and increased risk of mortality. Asthma patients experience exacerbations irrespective of underlying disease severity, phenotype, or despite optimal guideline-directed treatment, as a result of the ongoing inflammatory processes and loss of the disease control. Patients with frequent emergency department visits, patients requiring hospitalization, and, more importantly, patients intubated for an asthma exacerbation are at significantly increased risk for future severe exacerbations. It is evident that prevention of exacerbations remains a major unmet need in asthma management. The identification of patients at risk to have severe exacerbations is of paramount importance. Patient education and written plans of management, control of triggering/risk factors and co-morbid conditions, monitoring of asthma control and pulmonary function as well as optimal pharmacotherapy are needed to prevent and/or decrease exacerbations. A better understanding of the pathogenesis of asthma exacerbations will ultimately lead to better strategies and the development of novel treatments in the pursuit of preventing and treating severe asthma exacerbations.

Author Contributions

Conceptualization: N.R.; Literature search and data extraction: E.K. (Eirini Kostakou), E.K. (Evangelos Kaniaris), and N.R.; Writing—Original Draft Preparation: I.K., E.K. (Evangelos Kaniaris), and N.R.; Writing, Review and Editing: E.K. (Eirini Kostakou), E.K. (Evangelos Kaniaris), E.F., P.K., E.T., I.V., and N.R.; and Supervision: A.K., N.K, and N.R.

Conflicts of Interest

The authors declare no conflict of interest.

Case of Acute Severe Asthma

Kane guthrie.

• Dec 2, 2022

A 25-year-old lady Miss. Poor Compliance is rushed into your Emergency Department as a Priority 1. She is a brittle asthmatic and has been given 3x 5mg salbutamol nebs, and 0.5mg of adrenaline IM prehospital. On arrival Miss PC is sitting forward in the tripod position , using her accessory muscles to breath. She is tachypnoeic, agitated and unable to talk.

Vital signs: Pulse 143, BP 138/95, RR 42, Sp02 91% on neb, GCS 14/15.

Past Medical and Medication History

• Smoker. Severe asthmatic. Intubated twice in past 2 years
• Currently taking seritide 250/50mg, salbutamol MDI PRN and prednisolone 50mg PRN

Asthma Epidemiology

• Over 2.2 million Australians have currently diagnosed asthma
• 406 deaths attributed to asthma in 2006
• Highest risk of dying from asthma is in the elderly over 70
• The emergency clinician’s goal in treating acute severe asthma is preventing intubation
• Severe/Critical asthma is a life threatening condition

Asthma Pathophysiology

• Asthma is a chronic inflammatory disorder of the airways in which many cells and cellular elements play a role, in particular, mast cells, eosinophils, T lymphocytes, macrophages, neutrophils, and epithelial cells.
• Smooth muscle hypertrophy and hyperplasia
• Inflammatory cell infiltration and oedema
• Goblet cell and mucous gland hyperplasia with mucous hypersecretion
• Protein deposition including collagen
• Epithelial desquamation
• Most common, responsible for 80-85% of all fatal events is characterised by eosinophilic inflammation associated with gradual deterioration over days-weeks occurring in patients with severe or poorly controlled asthma, and is slow to respond to therapy.
• The second phenotype, with neutrophilic inflammation, has both rapid onset and response to therapy.

Markers of severe asthma:

• Inability to speak in full sentences
• Use of accessory muscles or tracheal tugging
• Cyanosis and sweating
• Pulsus paradoxus (>15mmHg decreased with inspiration). With severe muscle fatigue might be absent
• Quiet chest on auscultation (The “Silent Chest”)
• Confusion or decreased level of consciousness
• Hypotension or bradycardia
• FEV 1<40% predicted
• PEF <40% of predicted or best (<25% in life threatening asthma)
• Oxygen saturation <90-92%
• PaO2 <60mmHg
• PaCO2 >45mmHg

Complications of Asthma :

• Pneumothorax, Pneumomediastinum, Pneumopericardium and Pneumoretroperitoneum
• Cardiac Arrhythmias, Myocardial ischaemia or infarction
• Electrolyte disturbances (hypokalaemia, hypomagnesaemia, hypophosphataemia)
• Lactic Acidosis
• Hyperglycaemia

Conditions that may mimic acute asthma:

• Upper airway obstruction
• Foreign-body aspiration
• Vocal cord dysfunction syndrome
• Pulmonary oedema
• Acute exacerbations of COPD
• Hysterical conversion reaction
• Munchausen syndrome

Diagnostic Test:

• Hyperinflation 5-10%
• Infiltrate 5%
• Pneumothorax <1%
• Pneumomediastinum <1%
• Respiratory alkalosis typical
• Inaccurate predictor of outcome
• Will seldom alter your treatment plan
• An objective measure of lung function
• Useful to assess response to treatment
• Impossible to obtain in the dying patient
• <25% Severe
• 25-50% Moderate
• 50-70% Mild
• >70% Discharge Goal
• Simple, and less painful than ABG
• Provides continuous oxygenation measurements
• Needs to placed on well-perfused site, difficult to obtain readings if global hypoperfusion or peripheral vasoconstriction present.
• Aim to keep sp02 >92%

Management of Acute Severe Asthma

• Hypoxia is the main cause of death in asthma
• Oxygen should be given to keep Sp02 above 92%
• A slight Pco2 rise may occur with oxygen therapy but this is of no clinical significance.

Beta-agonists:

• Rapid acting inhaled beta-agonists (bronchodilators) are the first line therapy for acute asthma.
• Nebulisers should generally be used in acute severe asthma, as provide easier delivery of medication to patient, multi dose inhalers have a role in mild to moderate asthma.
• IV salbutamol gives you the advantage of hitting the beta 2 receptors from the back door, while continuing nebulizer treatment, and should be trialed in patients not responding to nebulisers.
• Continuous nebuliser therapy appears to be more effective than intermittent nebulisers for delivering beta-agonist drugs to relieve airway spasm in acute severe asthma.  (Cochrane Review, 2009)
• Salbutamol toxicity can caused a lactic acidosis which is often unrecognized in asthma patients, the lactic acidosis has been hypothesized to adversely affect ventilation by increasing ventilatory demand, increasing dead space ventilation, worsening dynamic hyperinflation and intrinsic PEEP. Management is to discontinue salbutamol at the earliest opportunity.
• Dose:  Salbutamol Nebuliser Ampoule 5mg
• Dose: Salbutamol IV 5mg in 500mL of 0.9% sodium chloride or 5% dextrose start at 30mL/hr titrating up to 120mL/hr

Anticholinergics:

• Anticholinergics agents block muscarinic receptors in airway smooth muscles, inhibit vagal cholinergic tone and result in bronchodilation.
• Dose: Ipratropium bromide (Atrovent) 500ug to second dose of salbutamol via neb, can be repeated every 4hours
• Use of corticosteroids within 1 hour of presentation to an ED significantly reduces the need for hospital admission in patients with acute asthma. Benefits appear greatest in patients with more severe asthma, and those not currently receiving steroids
• Dose: Prednisolone 50mg PO
• Dose: IV Hydrocortisone 100-200mg
• Note: Parenteral route is indicated in ventilated patient or patient unable to swallow, eg. Vomiting

Adrenaline:

• Can be give either intravenously or via nebulizer
• Bronchoconstriction is the major pathology in asthma; airway oedema might also make a significant contribution. Both the a-agonist and B-agonist effects of adrenaline might be beneficial, with the alpha effect decreasing oedema and the beta effect responsible for bronchodilation.
• Dose:  IV 6mg in 100mls 5% dextrose start at 1-15mLs/hour
• Dose: Nebulizer 1mg in 3ml normal saline

Aminophylline:

• The popularity of aminophylline in asthma exacerbations has diminished in recent years.
• Systematic reviews have shown that IV aminophylline in severe acute asthma does not produce additional bronchodilation above that achieved with beta-agonist and corticosteroids.
• Side effects; cardiac arrhythmia’s, vomiting, toxicity.
• Dose : 5mg/kg over 20min followed by infusion of 500mg aminophyline n 500mL of 5% dextrose at 0.5mg/kg per hour

Magnesium Sulphate:

• Magnesium potential role is asthma may involve a combination of smooth muscle relaxation, inhibition of histamine release and acetylcholine release from nerve endings.
• Most evidence to support the use of magnesium in asthma is in the acute severe asthmatic were it has been shown to be safe and beneficial.
• Dose : IV 2-4g over 30-60mins
• Heliox Mixture 80% helium/20% oxygen
• There is evidence that helium and oxygen mixtures (heliox) may provide additional benefits to patients with acute asthma.
• Heliox mixtures have the potential to decrease airway resistance, and therefore decrease the work of breathing for the severe acute asthma patient.

Antibiotics:

• Antibiotics are not indicated in the management of severe acute asthma.
• Antibiotics should only be used in the setting of an underlying pneumonia, respiratory tract infection or to aid in the prevention of ventilator-associated pneumonia in ICU.

Airway Management

Non-Invasive Positive Pressure Ventilation:

Good quality evidence and trails to support the use of NPPV in asthma are lacking, however it is worth trying when intubation is not immediately indicated. Remember the goal of the emergency clinician’s in treating asthma is to prevent intubation.

• Positive pressure is generally less than 15cmH2O
• Benefit between CPAP vs BiPAP is unknown
• Tachypnea caused by severe asthma can make it difficult for the patient to coordinate they’re breathing with machine making BiPAP uncomfortable
• Need a large randomised control trial to determine the effectives properly of NIV, in acute severe asthma.

“Asthmatic on BiPAP before being Intubated”

Mechanical Ventilation:

1-3% of acute severe asthma requires intubation. Prevention of intubation and mechanical ventilation are the goals of managing acute severe asthma, this can be achieved by maximising pre-intubation therapy, however you don’t want to wait too long or let the severe asthmatic tire before trying to intubate them. Once an asthmatic is intubated and ventilated their morbidity and mortality increasing dramatically, and it can be difficult to wean from the ventilator.

Criteria for Intubation:

• Cardiac or Respiratory arrest
• Altered mental status
• Progressive exhaustion
• Severe hypoxia despite maximal oxygen delivery
• Failure to reverse severe respiratory acidosis despite intensive therapy
• pH <7.2, carbon dioxide pressure increasing by more than 5mmHg/hr or greater than 55 to 70mm/Hg, or oxygen pressure of less than 60mm/Hg.

Challenges:

• Effective pre-oxygenation impossible
• No margin for error or delay
• Need to be intubated by most experienced person available
• High intrathoracic pressure after RSI

Recommendations:

• Fluid bolus before intubation if possible
• RSI preferred
• Ketamine for bronchodilator effects
• Permissive hypercapnea essential

Initial Ventilator settings in paralysed patients:

• FiO2 1.0, then titrate to keep SpO2 >94%
• Tidal Volume 5-6ml/kg
• Ventilator rate 6-8 breaths/min
• Long expiratory time (I:E ratio >1:2)
• Minimal PEEP < 5cmH2O
• Limit peak inspiratory pressure to <40cmH2O
• Target plateau pressure <20cmH2O
• Ensure effective humidification

• Brenner, B. Corbridge, T. & Kazzi, A. (2009). Intubation and mechanical ventilation of the asthmatic patient in respiratory failure. The Journal of Emergency Medicine. 37(2s), s23-s34.
• Camargo, C. Rachelefsky, G. & Schatz, M. (2009). Managing Asthma Exacerbation in the Emergency Department: Summary of the National Asthma Education and Prevention Program Expert Panel Report 3 Guidelines for the Management of Asthma Exacerbation.The Journal of Emergency Medicine. 37 (2S), S6-S17.
• Camargo, C. Spooner, C. & Rowe, B. (2009). Continuous versus intermittent beta-agonist for acute asthma (Review). http://www.thecochranelibrary.com.
• Chua, F. & Lai, D. (2007). Acute severe asthma: Triage, treatment and thereafter. Current Anaesthesia & Critical Care. 18, 61-68.
• Creagh-Brown, B. & Ball, J. (2007). An under-recognized complication of treatment of acute severe asthma. American Journal of Emergency Medicine. 26, 513-515.
• Hodder, R. et al. (2009). Management of acute asthma in adults in the emergency department: nonventilatory management.  CMAJ. 182(2), E55-E67.
• Holley, A. & Boots, R.(2009). Review article: Management of acute severe and near-fatal asthma. Emergency Medicine Australasia, (21) 259-268.
• Jones, L. & Goodacre, S. (2009). Magnesium sulphate in the treatment of acute asthma: evaluation of current practice in adult emergency departments. Emergency Medicine Journal. 26, 783-785.
• Melnick, E. & Cottral, J. (2010). Current Guidelines for Management of Asthma in the Emergency Department.  http://www.ebmedicine.net. 2(2). 1-13.
• Morris, F. & Fletcher, A. (Ed). (2009). ABC of Emergency Differential Diagnosis. Oxford: Blackwell Publishing
• National Asthma Council of Australia. Asthma management handbook: 2006. Accessed http://www.nationalasthma.org.au/cms/images/stories/amh2006_web_5.pdf, 12/02/2010
• Nowak, R. Corbridge, T. & Brenner, B. (2009). Noninvasive Ventilation. The Journal of Emergency Medicine. 37(2S), S18-S22.
• Peters, S. (2007). Continuous Bronchodilator Therapy. Chest. 131(1),1-5.
• Phipps, P. & Garrard, C. (2003). The pulmonary physician in critical care. 12: Acute severe asthma in the intensive care unit. Thorax. 58, 81-88.
• Ram, F. Wellington, S. Rowe, B. & Wedzicha, J. (2009). Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma (Review)
• Rodrigo, G. Pollack, C. Rodrigo, C. Rowe, B. (2010). Heliox for non-intubated acute asthma patents (Review).
• Rowe, B. Spooner, C. Ducharme, F. Bretzlaff, J. Bota, G. (2008). Early emergency department treatment of acute asthma with systemic corticosteroids (Review). http://www.thecochranelibrary.com.
• Rowe, B. et al. (2009). Magnesium sulfate for treating exacerbations of acute asthma in the emergency department (Review). http://www.thecochranelibrary.com.

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• Case report
• Open access
• Published: 21 February 2018

Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment

• Virginia Mirra 1 ,
• Silvia Montella 1 &
• Francesca Santamaria 1  

BMC Pediatrics volume  18 , Article number:  73 ( 2018 ) Cite this article

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The primary goal of asthma management is to achieve disease control for reducing the risk of future exacerbations and progressive loss of lung function. Asthma not responding to treatment may result in significant morbidity. In many children with uncontrolled symptoms, the diagnosis of asthma may be wrong or adherence to treatment may be poor. It is then crucial to distinguish these cases from the truly “severe therapy-resistant” asthmatics by a proper filtering process. Herein we report on four cases diagnosed as difficult asthma, detail the workup that resulted in the ultimate diagnosis, and provide the process that led to the prescription of omalizumab.

Case presentation

All children had been initially referred because of asthma not responding to long-term treatment with high-dose inhaled steroids, long-acting β 2 -agonists and leukotriene receptor antagonists. Definitive diagnosis was severe asthma. Three out four patients were treated with omalizumab, which improved asthma control and patients’ quality of life. We reviewed the current literature on the diagnostic approach to the disease and on the comorbidities associated with difficult asthma and presented the perspectives on omalizumab treatment in children and adolescents. Based on the evidence from the literature review, we also proposed an algorithm for the diagnosis of pediatric difficult-to-treat and severe asthma.

Conclusions

The management of asthma is becoming much more patient-specific, as more and more is learned about the biology behind the development and progression of asthma. The addition of omalizumab, the first targeted biological treatment approved for asthma, has led to renewed optimism in the management of children and adolescents with atopic severe asthma.

Peer Review reports

Children with poor asthma control have an increased risk of severe exacerbations and progressive loss of lung function, which results in the relevant use of health resources and impaired quality of life (QoL) [ 1 ]. Therefore, the primary goal of asthma management at all ages is to achieve disease control [ 2 , 3 , 4 ].

According to recent international guidelines, patients with uncontrolled asthma require a prolonged maintenance treatment with high-dose inhaled corticosteroids (ICS) in association with a long-acting β 2 -agonist (LABA) plus oral leukotriene receptor antagonist (LTRA) (Table  1 ) [ 5 ].

Nevertheless, in the presence of persistent lack of control, reversible factors such as adherence to treatment or inhalation technique should be first checked for, and diseases that can masquerade as asthma should be promptly excluded. Finally, additional strategies, in particular anti-immunoglobulin E (anti-IgE) treatment (omalizumab), are suggested for patients with moderate or severe allergic asthma that remains uncontrolled in Step 4 [ 5 ].

Herein, we reviewed the demographics, clinical presentation and treatment of four patients with uncontrolled severe asthma from our institution in order to explain why we decided to prescribe omalizumab. We also provided a review of the current literature that focuses on recent advances in the diagnosis of pediatric difficult asthma and the associated comorbidities, and summarizes the perspectives on anti-IgE treatment in children and adolescents.

Case presentations

Table  2 summarizes the clinical characteristics and the triggers/comorbidities of the cases at referral to our Institution. Unfortunately, data on psychological factors, sleep apnea, and hyperventilation syndrome were not available in any case. Clinical, lung function and airway inflammation findings at baseline and after 12 months of follow-up are reported in Table  3 . In the description of our cases, we used the terminology recommended by the ERS/ATS guidelines on severe asthma [ 6 ].

A full-term male had severe preschool wheezing and, since age 3, recurrent, severe asthma exacerbations with frequent hospital admissions. At age 11, severe asthma was diagnosed. Sensitization to multiple inhalant allergens (i.e., house dust mites, dog dander, Graminaceae pollen mix, and Parietaria judaica ) and high serum IgE levels (1548 KU/l) were found. Body mass index (BMI) was within normal range. Combined treatment with increasing doses of ICS (fluticasone, up to 1000 μg/day) in association with LABA (salmeterol, 100 μg/day) plus LTRA (montelukast, 5 mg/day) has been administered over 2 years. Nevertheless, persistent symptoms and monthly hospital admissions due to asthma exacerbations despite correct inhaler technique and good adherence were reported. Parents refused to perform any test to exclude gastroesophageal reflux (GER) as comorbidity [ 6 ]. However, an ex-juvantibus 2-month-course with omeprazole was added to asthma treatment [ 7 ], but poor control persisted. Anterior rhinoscopy revealed rhinosinusitis that was treated with nasal steroids for six months [ 8 ], but asthma symptoms were unmodified. Treatment with omalizumab was added at age 12. Reduced hospital admissions for asthma exacerbations, no further need for systemic steroids, and improved QoL score (from 2.0 up to 6.7 out of a maximum of 7 points) were documented over the following months. Unfortunately, after one year of treatment, adherence to omalizumab decreased because of family complaints, and eventually parents withdrew their informed consent and discontinued omalizumab. Currently, by age 17, treatment includes inhaled salmeterol/fluticasone (100 μg/500 μg∙day -1 , respectively) plus oral montelukast (10 mg/day). Satisfactory symptom control is reported, with no asthma exacerbations.

A full-term male, who had a recurrent severe preschool wheezing, at 6 years of age developed exercise-induced asthma. At age 10, severe asthma was diagnosed. High serum IgE levels (1300 KU/l) and skin prick tests positive to house dust mites were found. Despite a 3-year treatment with progressively increasing doses of inhaled fluticasone (up to 1000 μg/day) combined with salmeterol (100 μg/day) and oral montelukast (5 mg/day), monthly hospital admissions with systemic steroids use were reported. At age 13, a 24-h esophageal impedance/pH study demonstrated the presence of acid and non-acid GER [ 7 ]. Esomeprazole was added to asthma medications, but with an incomplete clinical benefit for respiratory symptoms. Esomeprazole was withdrawn after 3 months, and parents refused to re-test for GER. As respiratory symptoms persisted uncontrolled despite treatment, severe asthma was definitively diagnosed [ 6 ]. BMI was within the normal range and anterior rhinoscopy excluded rhinosinusitis. Inhaler technique and adherence were good; thus we considered the anti-IgE treatment option [ 9 ]. Subcutaneous omalizumab was started, with fast improvement of both symptoms and QoL score (from 3.9 up to 6.5). Seventeen months later, the dose of ICS had been gradually tapered and oral montelukast definitely discontinued. Currently, at age 14, treatment includes the combined administration of bimonthly subcutaneous omalizumab and of daily inhaled salmeterol/fluticasone (50 μg/100 μg∙day - 1 , respectively). Asthma control is satisfactory and no side effects are reported. Omalizumab has been continuously administered for 2.6 years and is still ongoing.

A full-term male had severe preschool wheezing and, since age 3, recurrent, severe asthma exacerbations with acute respiratory failure that frequently required intensive care unit (ICU) admission. At age 6, sensitization to multiple perennial inhalant (i.e., house dust mites, dog and cat danders, Alternaria alternata , Graminaceae pollen mix, Artemisia vulgaris , Parietaria judaica , and Olea europaea pollen) and food allergens (i.e., egg, milk, and peanut) was diagnosed. Serum IgE levels were 2219 KU/l. Weight and height were appropriate for age and sex. The patient has been treated over 3 years with a combined scheme of high-dose inhaled fluticasone (up to 1000 μg/day) plus salmeterol (100 μg/day) and oral montelukast (5 mg/day), with correct inhaler technique and good adherence. Despite this, monthly hospital admissions with systemic steroids use were recorded. Rhinosinusitis and GER were excluded on the basis of appropriate testing; thus treatment with omalizumab was started when the patient was 9 years old. At age 11, adherence to treatment is satisfactory, with no side effects. More importantly, reduced hospital admissions for asthma exacerbations, no further need for systemic steroids, and improved QoL score (from 6.4 to 6.8) were reported. Finally, progressive step-down of anti-asthma treatment was started, and at present (by 11.5 years) inhaled fluticasone (200 μg/day) plus bimonthly subcutaneous omalizumab provide good control of symptoms. Omalizumab has been continuously administered for 2.6 years and is still ongoing.

A full-term male had severe preschool wheezing and, since age 4, recurrent, severe asthma exacerbations with frequent hospital admissions. At age 8, multiple perennial inhalants and food sensitization (i.e., house dust mites, dog dander, Graminaceae pollen mix, Olea europaea pollen, tomatoes, beans, shrimps, and peas) and high serum IgE levels (1166 KU/l) were found. The patient has been treated over 5 years with inhaled fluticasone (up to 1000 μg/day) in association with salmeterol (100 μg/day) and oral montelukast (5 mg/day). Despite this, monthly hospital admissions with systemic steroids need were recorded. After checking the inhaler technique and adherence to treatment, comorbidities including obesity, rhinosinusitis and GER were excluded. Omalizumab was proposed, but parents refused it. By 13.6 years, despite a treatment including the association of inhaled salmeterol/fluticasone (100 μg/1000 μg∙day − 1 , respectively) plus oral montelukast (10 mg/day), monthly exacerbations requiring systemic steroids are reported.

Discussion and conclusions

Most children and adolescents with asthma respond well to inhaled short-acting beta 2 -agonists (SABA) on demand if symptoms are intermittent, or to low dose controller drugs plus as-needed SABA if the risk of exacerbations increases [ 1 ]. Nevertheless, a proportion of patients is referred to specialists because this strategy is not working and asthma is persistently uncontrolled [ 4 ]. For these children, assessment is primarily aimed at investigating the reasons for poor control. Indeed, when the child is initially referred, before the label of “severe, therapy-resistant asthma” (i.e., not responding to treatment even when factors as exposure to allergens and tobacco smoke have been considered) is assigned, three main categories need to be identified: 1) “not asthma at all”, in which response to treatment is suboptimal because the diagnosis is wrong; 2) “asthma plus ”, when asthma is mild but exacerbated by one or more comorbidities; and 3) “difficult-to-treat asthma”, when asthma is uncontrolled because of potentially reversible factors [ 10 ].

The reported cases highlight some aspects of the disease process that may expand the diagnosis and improve patients’ care. At our institution, the severe asthma program includes a multidisciplinary approach with consultations by gastroenterologists as well as ear, nose and throat experts. Recently, sleep medicine experts joined this multidisciplinary team; thus, unfortunately, sleep-disordered breathing (SDB) could not be excluded at the time of our patients’ assessment. Inhalation technique is periodically evaluated by nurses or doctors in each patient. Unfortunately, in Italy an individual prescription database is not available and thus we cannot assess patients’ use of medication. In two cases, the filtering process eventually identified GER and rhinosinusitis, but poor control of asthma persisted even after comorbidities were treated. In all subjects, inhaler skills, treatment adherence, and environmental exposure to indoor/outdoor allergens as well as to second- and third-hand smoke were excluded as cause of lack of control. Eventually, three out of four patients started anti-IgE treatment; asthma control was obtained and maintenance drugs were progressively reduced. In the case that refused omalizumab therapy, pulmonary function, clinical features and controller treatment including high-dose ICS were unchanged.

Previous studies have highlighted an association between increasing asthma severity in children and reduced QoL [ 11 , 12 , 13 ]. Uncontrolled asthma symptoms not only affect children physically, but can impair them socially, emotionally, and educationally [ 13 ]. In line with previous observations, 3 out 4 of our cases had poor QoL, assessed by a standardized questionnaire [ 14 ]. It is well known that improving QoL in difficult asthma is not an easy task, despite a variety of treatments aimed at achieving control [ 12 ], and much more remains to be done to address the problem. Nevertheless, 2 of our 3 cases showed a remarkable improvement of QoL after one year of treatment with omalizumab.

Reduction in forced expiratory volume in the first second (FEV 1 ) is often used to define childhood asthma severity in treatment guidelines and clinical studies [ 5 , 11 , 15 ]. Nevertheless, children with severe asthma often have a normal FEV 1 that does not improve after bronchodilators, indicating that spirometry may be a poor predictor of asthma severity in childhood [ 6 , 16 , 17 ]. Actually, children with a normal FEV 1 , both before and after β 2 -agonist, may show a bronchodilator response in terms of forced expiratory flow between 25% and 75% (FEF 25–75 ) [ 18 ]. However, the utility of FEF 25–75 in the assessment or treatment of severe asthma is currently unknown. Interestingly, all the reported cases showed normal or slightly reduced values of FEV 1 but severe impairment of FEF 25–75 . Two cases showed a bronchodilator response in terms of FEV 1 (subjects 3 and 4), while 3 patients had a significant increase of FEF 25–75 (cases 1, 3 and 4). Unfortunately, we could not provide the results of bronchodilator response during or after the treatment with omalizumab in any case.

Available literature on the diagnostic approach to difficult asthma in children offers a number of reviews which basically summarize the steps needed to fill the gap between a generic diagnosis of “difficult asthma” and more specific labels (i.e., “severe” asthma, “difficult-to-treat” asthma, or even different diagnoses) [ 3 , 5 , 6 , 8 , 10 , 19 , 20 , 21 ]. So far, few original articles and case reports have been published, probably due to the peculiarity of the issue, which makes retrospective discussion of cases easier than the design of a prospective clinical study [ 4 , 22 , 23 , 24 , 25 , 26 ]. Available knowledge mainly derives from the experience of specialized centers.

The evaluation of a child referred for uncontrolled asthma should start with a careful history focused on typical respiratory symptoms and on the definition of possible triggers. In the “severe asthma” process, it is crucial for clinicians to maintain a high degree of skepticism about the ultimate diagnosis, particularly in the presence of relevant discrepancies between history, physical features and lung function, as many conditions may be misdiagnosed as asthma. In order to simplify this process, herein we propose an algorithm for the diagnosis of difficult-to-treat and severe asthma (Fig.  1 ). Confirmation of the diagnosis through a detailed clinical and laboratory re-evaluation is important because in 12–50% of cases assumed to have severe asthma this might not be the correct diagnosis [ 10 ]. Several documents have indicated the main steps of the process that should be followed in children with uncontrolled asthma [ 3 , 8 , 10 ]. The translation of these procedures into real life practice may deeply change from one subject to another due to the variability of individual patients’ history and clinical features, which will often lead the diagnostic investigations towards the most likely reason for uncontrolled asthma. For children with apparently severe asthma, the first step is to confirm the diagnosis and, before proceeding to broader investigations, to verify that the poor control is not simply determined by poor adherence to treatment, inadequate inhaler skills and/or environmental exposure to triggers. A nurse-led assessment, including a home visit, despite not being applicable in all settings, may be useful for identifying potentially modifiable factors in uncontrolled pediatric asthma [ 27 ].

A practical algorithm for the diagnosis of difficult-to-treat and severe asthma. ICS, inhaled corticosteroids; OCS, oral corticosteroids

A number of comorbidities have been increasingly recognized as factors that may impact asthma clinical expression and control in childhood [ 10 , 28 ]. Children with uncontrolled disease should be investigated for GER, rhinosinusitis, dysfunctional breathing and/or vocal cord dysfunction, obstructive sleep apnea, obesity, psychological factors, smoke exposure, hormonal influences, and ongoing drugs [ 3 , 6 , 8 , 20 ]. Indeed, the exact role played by comorbidities in pediatric asthma control is still debated [ 28 ]. The most impressive example is GER. Several pediatric documents recommend assessing for GER because reflux may be a contributing factor to problematic or difficult asthma [ 7 , 29 ]. Nevertheless, GER treatment might not be effective for severe asthma [ 30 , 31 ], as confirmed by current cases 1 and 2. There is an established evidence that chronic rhinosinusitis is associated with more severe asthma in children [ 32 , 33 , 34 ]. Therefore, examination of upper airways and ad hoc treatment if rhinosinusitis is evident are recommended in children with severe asthma [ 3 , 8 , 35 ]. However, intranasal steroids for rhinitis resulted in a small reduction of asthma risk in school-aged children [ 36 ], and actual placebo-controlled studies on the effect of treatment of rhinosinusitis on asthma control in children are lacking [ 10 , 37 ].

Dysfunctional breathing, including hyperventilation and vocal cord dysfunction, is associated with poorer asthma control in children [ 8 , 10 , 38 , 39 ]. Unfortunately, there is scarce literature on the effect of its treatment on the control of severe asthma in children [ 40 ]. SDB ranging from primary snoring to obstructive sleep apnea syndrome is very common in children [ 41 ], and an increased prevalence of SDB together with increasing asthma severity has been reported [ 42 ]. Interestingly, GER may also be worsened by recurrent episodes of upper airway obstruction associated with SDB, and this may further trigger bronchial obstruction. Asthma guidelines recommend the assessment of SDB through nocturnal polysomnography in poorly controlled asthmatics, particularly if they are also obese [ 5 ]. There are no studies examining whether pediatric asthma improves after SDB has been treated, for example, with nasal steroids, adenotonsillectomy, continuous positive airway pressure or weight reduction if the child is also obese [ 43 ]. The parallel increase in obesity and asthma suggests that the two conditions are linked and that they can aggravate each other [ 44 , 45 ], even though the exact mechanisms that underlie this association remain unclear [ 46 ]. Indeed, other coexisting comorbidities such as SDB or GER may play a confounding role in the development of the interactions between obesity and the airways [ 47 , 48 ]. Obesity is associated with increased markers of inflammation in serum and adipose tissue and yet decreased airway inflammation in obese people with asthma [ 49 ]. Several interventions, including behavioral and weight reduction programs or bariatric surgery, may result in improved asthma control, quality of life and lung function in adult obese asthmatics [ 50 ]. Although reports of adolescent bariatric surgery demonstrate a significant body weight decrease, this approach is not widely available and there are no published reports on its effect on pediatric severe asthma control [ 51 ]. Finally, although it is still unclear whether food allergy is causative or shares a common pathway with difficult asthma, it might explain the loss of asthma control at least in some children and thus be considered as a comorbid condition [ 10 , 16 , 52 ].

In conclusion, establishing the impact of comorbidities on asthma control may be cumbersome, and an ex-juvantibus treatment is sometimes necessary to assess their role. Comorbid conditions can also worsen each other, and symptoms arising from some of them may mimic asthma [ 6 ]. Although the ability to improve pediatric severe asthma by treating comorbidities remains unconfirmed, they should be treated appropriately [ 9 ].

The vast majority of asthmatic children exhibit a mild or at most a moderate disease that can be fully controlled with low-to-medium dose ICS associated or not with other controllers [ 5 , 6 ]. However, a subset of asthmatics remains difficult-to-treat [ 5 , 6 ]. With the advent of biologics, these severe steroid-dependent asthmatics have alternative options for treatment, as steroid-related adverse events are common in severe asthma [ 53 ]. Omalizumab, an anti-IgE monoclonal antibody, is the only biologic therapy recommended in children with moderate-to-severe asthma by the recent guidelines [ 5 , 6 ]. In Italy, this treatment is fully covered by the National Health System. Therefore, there is no influence by any funding on treatment decisions. It was approved by the US (Food and Drug Administration) in 2003 and by the European Union (European Medicines Agency) in 2005 as an add-on treatment for patients aged > 12 years with severe persistent allergic asthma and who have a positive skin test or in-vitro reactivity to a perennial aeroallergen, FEV 1  < 80% predicted, frequent daytime symptoms or nighttime awakenings, and multiple documented severe asthma exacerbations despite daily ICS plus a LABA [ 54 , 55 ]. In 2009, it also received approval in Europe for treating patients aged 6–12 years. Figure  2 illustrates current indications for treatment with omalizumab in children and adolescents with severe asthma.

Indications for omalizumab in children and adolescents with severe asthma

IgE antibodies, Th 2 -derived cytokines and eosinophils play a major role in the development of chronic airway inflammation in asthmatic subjects [ 56 ]. Once released from plasma cells, IgE binds principally to the high-affinity IgE receptor (FcεRI) on mast cells, triggering different effector responses, including the release of mediators leading to allergic inflammatory reactions [ 56 ]. The activation of the allergic cascade by IgE, under constant allergen stimulation, leads to the establishment of chronic allergic inflammation in the airways of asthmatic patients, with IgE being a key element of the vicious circle that maintains it. Cytokines produced during the late phase and subsequent chronic inflammation stage have been directly associated with the induction of airway remodelling, indirectly implicating IgE in the process [ 56 ]. At present, omalizumab is the only commercially available recombinant humanized anti-IgE monoclonal antibody that specifically binds serum free IgE at its CH 3 domain, in the proximity of the binding site for FcεRI, thus preventing IgE from interacting with its receptor on mast cells, basophils, antigen-presenting cells and other inflammatory cells [ 57 ]. The rapid reduction of free IgE levels leads to a downregulation of the FcεRI expression on inflammatory cells and an interruption of the allergic cascade, which results in the reduction of peripheral and bronchial tissue eosinophilia and of levels of granulocyte macrophage colony stimulating factor, interleukin (IL)-2, IL-4, IL-5, and IL-13 [ 58 ]. Moreover, basophils have a relevant role in the initiation and progression of allergic inflammation, suggesting that they may represent a viable therapeutic target. Indeed, in children with severe asthma, it has been reported that omalizumab therapy is associated with a significant reduction in circulating basophil numbers, a finding that is concurrent with improved clinical outcomes [ 59 ]. This finding supports a mechanistic link between IgE levels and circulating basophil populations, and may provide new insights into one mechanism by which omalizumab improves asthma symptoms.

Several clinical controlled and real-life studies of adults with severe, inadequately controlled allergic asthma have demonstrated the efficacy and safety of omalizumab in reducing asthma-related symptoms, corticosteroid use, exacerbation rates, and healthcare resource utilization, and in improving QoL and lung function [ 60 , 61 , 62 , 63 ]. Fewer studies have been published in children. In two double-blind, randomized, placebo-controlled trials (RCTs) of children aged 6 to 12 years with moderate-to-severe allergic asthma, treatment with omalizumab reduced the requirement for ICS and protected against disease exacerbations, but there was little change in asthma symptom scores or spirometry [ 9 , 64 ]. These findings were confirmed and extended in older children [ 65 , 66 , 67 ].

The results of the ICATA study, a multicenter RCT of 419 inner-city children, adolescents and young adults with persistent allergic asthma, showed that, compared to placebo, omalizumab reduces the number of days with asthma symptoms and the proportion of participants with at least one exacerbation by approximately 25% and 19%, respectively ( p  < 0.001), thus reducing the need for asthmatic symptom controllers [ 68 ]. Another multicenter RCT of inner-city children and adolescents showed that the addition of omalizumab to ongoing guidelines-based care before patients return to school reduces fall asthma exacerbations (odds ratio, 0.48), particularly in subjects with a recent exacerbation [ 69 ]. Moreover, in a real-life study of 104 children and adolescents with severe allergic refractory asthma followed over 1 year, treatment with omalizumab resulted in good asthma control in 67% of the cases ( p  < 0.001), while FEV 1 improved by 4.9% ( p  = 0.02) and exacerbation rates and healthcare utilisation decreased approximately by 30% ( p  < 0.001) [ 70 ]. The same authors also showed that, after two years of treatment, exacerbation rate and healthcare utilisation were further decreased by 83% and 100%, respectively, while level of asthma control, steroid use and lung function remained unchanged [ 71 ].

A systematic review of pediatric RCTs pooled the data of 1381 children and adolescents with moderate-to-severe allergic asthma in order to establish the efficacy of omalizumab as an add-on therapy [ 72 ]. During the stable-steroid phase, omalizumab decreased the number of patients with at least one exacerbation (risk ratio, 0.69; p  < 0.001), the mean number of asthma exacerbations per patient (risk ratio, 0.35; p  < 0.001), and the asthma symptom score (mean difference, 0.12; p  = 0.005) when compared to placebo. During the steroid reduction phase, omalizumab further reduced the number of patients with at least one exacerbation (risk ratio, 0.48; p  < 0.001) and the mean number of asthma exacerbations per patient (mean difference, 0.12; p  < 0.05).

Given the cost of omalizumab, many authors have argued for the importance of identifying specific asthma populations who will have significant benefit from it [ 68 , 73 , 74 ]. In the ICATA study, baseline predictors of good response to treatment were sensitization and exposure to cockroach allergen, sensitization to house dust mite allergens, a serum IgE level of more than 100 IU per milliliter, a BMI of 25 or more, and a history of at least one unscheduled medical visit in the previous year [ 68 ].

Several studies have assessed the long-term safety of omalizumab in children and adults. A pooled analysis of 67 RCTs conducted over 2 decades on 4254 children and adults treated with omalizumab showed no association between omalizumab treatment and risk of malignancy [ 75 ]. In an RCT evaluating 225 school-aged children, omalizumab was well tolerated, there were no serious adverse events, and the frequency and types of all adverse events were similar to the placebo group [ 9 ]. These results have been further confirmed by a recent systematic review of RCTs that concluded that treatment with omalizumab does not result in increased risk of malignancy or hypersensitivity reactions [ 72 ].

While the rationale for long-term treatment with omalizumab is supported by pharmacokinetic-pharmacodynamic models [ 76 ], the duration of treatment is still under discussion. Results from published studies suggest that omalizumab should be continued for > 1 year [ 77 , 78 ]. In a retrospective study of adults and children with uncontrolled severe asthma treated with omalizumab, the response to treatment was ‘excellent’ in 52.5% of patients, particularly in the subgroup of children aged 6 to 11 years [ 77 ]. After the discontinuation of treatment, loss of asthma control was documented in 69.2% of the patients who had received omalizumab for < 1 year, 59.1% of the subjects treated for 1–2 years, and 46.1% of the cases treated for > 2 years. Time to loss of control was shorter in younger children and longer in patients with an ‘excellent’ response compared with patients with a ‘good’ response. No early loss of control (within 6 months) was observed among patients with > 3.5 years of continuous treatment with omalizumab. Finally, 20% of patients in whom omalizumab was re-prescribed because of loss of control did not respond to the treatment anymore [ 77 ]. Despite these encouraging findings, the impact of omalizumab on the natural history of severe asthma in children deserves to be further investigated by long-term studies that will also define the criteria and timing for discontinuing the treatment.

It is well known that asthma pharmacotherapy is effective in controlling symptoms and bronchial inflammation, but cannot affect the underlying immune response, thus leading to the possibility of symptom reappearance after its discontinuation [ 79 ]. In this scenario, allergen-specific immunotherapy (AIT) has been proposed as the only therapeutic method that can modulate the underlying immune pathophysiology in allergic asthma [ 80 ].

AIT is currently indicated in children and adults with mild-moderate allergic asthma that is completely or partially controlled by pharmacotherapy and with the evidence of a clear relationship between symptoms and exposure to a specific allergen [ 81 , 82 , 83 , 84 ]. However, according to recent guidelines, the efficacy of AIT in asthmatic subjects is limited, and its potential benefits must be weighed against the risk of side effects and the inconvenience and costs of the prolonged therapy [ 5 ]. Moreover, severe or uncontrolled asthma (regardless of its severity) is a major independent risk factor for non-fatal or even fatal adverse reactions, thus representing a contraindication for AIT [ 85 , 86 , 87 ]. Finally, children with severe asthma are often sensitized to multiple allergens, thus making AIT prescription even more complicated [ 88 ].

In subjects with uncontrolled and/or severe allergic asthma, a combination of omalizumab and AIT has been proposed [ 88 ]. Surprisingly, only a few studies have addressed this issue [ 89 , 90 , 91 , 92 ]. However, pre-treatment with omalizumab seems to improve the efficacy and tolerability of subcutaneous AIT in children and adults with severe allergic asthma both during omalizumab treatment and after its discontinuation [ 89 , 91 , 92 ]. Omalizumab has also been successfully used as a supplementary treatment to AIT in order to improve asthma control in children ≥6 years with severe persistent allergic asthma [ 90 ]. Given the scarcity of studies on AIT plus omalizumab in children with severe allergic asthma, further research is warranted to assess risks and benefits of the combined treatment.

Children with severe asthma require a detailed and individualized approach including re-assessment for differential diagnoses, comorbidities and contributory factors, environmental triggers, lung function and inflammation, adherence and response to therapy, and QoL. Treatment of pediatric severe asthma still relies on the maximal optimal use of corticosteroids, bronchodilators and other controllers recommended for moderate-to-severe disease. However, the management of asthma is becoming much more patient-specific, as more and more is learned about the biology behind the development and progression of asthma.

In the current paper, we described the characteristics of four children with severe asthma in whom omalizumab was prescribed. A review of the relevant literature on the topic was also performed. Finally, we provided an algorithm for the diagnosis of difficult-to-treat and severe asthma in children and adolescents, based on the evidence from the literature review. As all algorithms, it is not meant to replace clinical judgment, but it should drive physicians to adopt a systematic approach towards difficult and severe asthma and provide a useful guide to the clinician.

The addition of omalizumab, the first targeted biological treatment approved for asthma, has led to renewed optimism of outcome improvements in patients with allergic severe asthma. As severe asthma is a heterogeneous condition consisting of different phenotypes, the future of asthma management will likely involve phenotypic and potentially even genotypic characterization in selected cases in order to determine appropriate therapy and thus to provide the highest possible benefit, especially if specific responder phenotypes can be identified and selected for this highly specific treatment.

Abbreviations

Anti-immunoglobulin E

Body mass index

IgE receptor

Forced expiratory flow between 25% and 75%

Forced expiratory volume in the first second

Gastroesophageal reflux

Inhaled corticosteroids

Intensive care unit

Interleukin

Long-acting β 2 -agonist

Oral leukotriene receptor antagonist

Quality of life

Randomized controlled trials

Short-acting β 2 -agonists

Sleep-disordered breathing

O'Byrne PM, Pedersen S, Schatz M, Thoren A, Ekholm E, Carlsson LG, et al. The poorly explored impact of uncontrolled asthma. Chest. 2013;143:511–3.

Article   PubMed   Google Scholar  

National Asthma Education and Prevention Program. Expert panel report 3 (EPR-3): guidelines for the diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol. 2007;120:S94–8.

Article   Google Scholar  

Hedlin G. Management of severe asthma in childhood-state of the art and novel perspectives. Pediatr Allergy Immunol. 2014;25:111–21.

Konradsen JR, Nordlund B, Lidegran M, Pedroletti C, Grönlund H, van Hage M, et al. Problematic severe asthma: a proposed approach to identifying children who are severely resistant to therapy. Pediatr Allergy Immunol. 2011;22:9–18.

Global Initiative for Asthma Report. Global strategy for asthma management and prevention (updated 2016). https://www.ginasthma.org . Accessed 07 June 2017.

Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J. 2014;43:343–53.

Article   CAS   PubMed   Google Scholar  

Vandenplas Y, Rudolph CD, Di Lorenzo C, Hassall E, Liptak G, Mazur L, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the north American Society for Pediatric Gastroenterology, Hepatology, and nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49:498–507.

Lødrup Carlsen KC, Hedlin G, Bush A, Wennergren G, de Benedictis FM, De Jongste JC, et al. Assessment of problematic severe asthma in children. Eur Respir J. 2011;37:432–40.

Milgrom H, Berger W, Nayak A, Gupta N, Pollard S, McAlary M, et al. Treatment of childhood asthma with anti-immunoglobulin E antibody (omalizumab). Pediatrics. 2001;108:E36.

Bush A, Saglani S. Management of severe asthma in children. Lancet. 2010;376:814–5.

Article   CAS   PubMed   PubMed Central   Google Scholar  

Lang A, Mowinckel P, Sachs-Olsen C, Riiser A, Lunde J, Carlsen KH, et al. Asthma severity in childhood, untangling clinical phenotypes. Pediatr Allergy Immunol. 2010;21:945–53.

Nordlund B, Konradsen JR, Pedroletti C, Kull I, Hedlin G. The clinical benefit of evaluating health-related quality-of-life in children with problematic severe asthma. Acta Paediatr. 2011;100:1454–60.

Dean BB, Calimlim BC, Sacco P, Aguilar D, Maykut R, Tinkelman D. Uncontrolled asthma: assessing quality of life and productivity of children and their caregivers using a cross-sectional internet-based survey. Health Qual Life Outcomes. 2010;8:6.

Juniper EF, Guyatt GH, Feeny DH, Ferrie PJ, Griffith LE, Townsend M. Measuring quality of life in children with asthma. Qual Life Res. 1996;5:35–46.

British Thoracic Society. Scottish Intercollegiate Guidelines Network. British guideline on the management of asthma, 2014. https://www.brit-thoracic.org.uk/guidelines-and-quality-standards/asthma-guideline . Accessed 13 Apr 2016.

Montella S, Baraldi E, Cazzato S, Aralla R, Berardi M, Brunetti LM, et al. Severe asthma features in children: a case-control online survey. Ital J Pediatr. 2016;42:9.

Article   PubMed   PubMed Central   Google Scholar  

Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG, National Institutes of Health/National Heart, Lung, and Blood Institute Severe Asthma Research Program. Features of severe asthma in school-age children: Atopy and increased exhaled nitric oxide. J Allergy Clin Immunol. 2006;118:1218–25.

Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ, et al. Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol. 2010;126:527–34.

Hedlin G, Bush A, Lødrup Carlsen K, Wennergren G, De Benedictis FM, Melén E, et al. Problematic severe asthma in children, not one problem but many: a GA2LEN initiative. Eur Respir J. 2010;36:196–201.

Fitzpatrick AM, Teague WG. Severe asthma in children: insights from the National Heart, Lung, and Blood Institute's severe asthma research program. Pediatr Allergy Immunol Pulmonol. 2010;23:131–8.

Konradsen JR, Caffrey Osvald E, Hedlin G. Update on the current methods for the diagnosis and treatment of severe childhood asthma. Expert Rev Respir Med. 2015;9:769–77.

Lang AM, Konradsen J, Carlsen KH, Sachs-Olsen C, Mowinckel P, Hedlin G, et al. Identifying problematic severe asthma in the individual child—does lung function matter? Acta Paediatr. 2010;99:404–10.

Rao DR, Gaffin JM, Baxi SN, Sheehan WJ, Hoffman EB, Phipatanakul WJ. The utility of forced expiratory flow between 25% and 75% of vital capacity in predicting childhood asthma morbidity and severity. Asthma. 2012;49:586–92.

Eid N, Yandell B, Howell L, Eddy M, Sheikh S. Can peak expiratory flow predict airflow obstruction in children with asthma? Pediatrics. 2000;105:354–8.

Cicutto LC, Chapman KR, Chamberlain D, Downey GP. Difficult asthma: consider all of the possibilities. Can Respir J. 2000;7:415–8.

Wener RR, Bel EH. Severe refractory asthma: an update. Eur Respir Rev. 2013;22:227–35.

Bracken M, Fleming L, Hall P, et al. The importance of nurse-led home visits in the assessment of children with problematic asthma. Arch Dis Child. 2009;94:780–4.

De Groot EP, Kreggemeijer WJ, Brand PL. Getting the basics right resolves most cases of uncontrolled and problematic asthma. Acta Paediatr. 2015;104:916–21.

Grimaldi-Bensouda L, Zureik M, Aubier M, Humbert M, Levy J, Benichou J, et al. Does omalizumab make a difference to the real-life treatment of asthma exacerbations? Results from a large cohort of patients with severe uncontrolled asthma. Chest. 2013;143:398–405.

American Lung Association Asthma Clinical Research Centers, Mastronarde JG, Anthonisen NR, Castro M, Holbrook JT, Leone FT, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med. 2009;360:1487–9.

Article   PubMed Central   Google Scholar  

Writing Committee for the American Lung Association Asthma Clinical Research Centers, Holbrook JT, Wise RA, Gold BD, Blake K, Brown ED, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. JAMA 2012;307:373-381.

Wright AL, Holberg CJ, Martinez FD, Halonen M, Morgan W, Taussig LM. Epidemiology of physician-diagnosed allergic rhinitis in childhood. Pediatrics. 1994;94:895–901.

CAS   PubMed   Google Scholar  

De Groot EP, Nijkamp A, Duiverman EJ, Brand PL. Allergic rhinitis is associated with poor asthma control in children with asthma. Thorax. 2012;67:582–7.

Rotiroti G, Roberts G, Scadding GK. Rhinitis in children: common clinical presentations and differential diagnoses. Pediatr Allergy Immunol. 2015;26:103–10.

Bousquet J, Khaltaev N, Cruz AA, Denburg J, Fokkens WJ, Togias A, et al. Allergic rhinitis and its impact on asthma (ARIA). 2008 update (in collaboration with the World Health Organization, GA(2)LEN and AllerGen). Allergy. 2008;63:S8–160.

Deliu M, Belgrave D, Simpson A, Murray CS, Kerry G, Custovic A. Impact of rhinitis on asthma severity in school-age children. Allergy. 2014;69:1515–21.

Brozek JL, Bousquet J, Baena-Cagnani CE, Bonini S, Canonica GW, Casale TB, et al. Allergic rhinitis and its impact on asthma (ARIA) guidelines: 2010 revision. J Allergy Clin Immunol. 2010;126:466–76.

Weinberger M, Abu-Hasan M. Pseudo-asthma: when cough, wheezing, and dyspnea are not asthma. Pediatrics. 2007;120:855–64.

De Groot EP, Duiverman EJ, Brand PL. Dysfunctional breathing in children with asthma: a rare but relevant comorbidity. Eur Respir J. 2013;41:1068–73.

Barker NJ, Jones M, O'Connell NE, Everard ML. Breathing exercises for dysfunctional breathing/hyperventilation syndrome in children. Cochrane Database Syst Rev. 2013;12:CD010376.

Google Scholar  

Section on Pediatric Pulmonology, Subcommittee on Obstructive Sleep Apnea Syndrome, American Academy of Pediatrics. Clinical practice guideline: diagnosis and management of childhood obstructive sleep apnea syndrome. Pediatrics. 2002;109:704–12.

Goldstein NA, Aronin C, Kantrowitz B, Hershcopf R, Fishkin S, Lee H, Weaver DE, et al. The prevalence of sleep-disordered breathing in children with asthma and its behavioral effects. Pediatr Pulmonol. 2015;50:1128–36.

Ross KR, Storfer-Isser A, Hart MA, Kibler AM, Rueschman M, Rosen CL, et al. Sleep-disordered breathing is associated with asthma severity in children. J Pediatr. 2012;160:736–42.

Santamaria F, Montella S, Greco L, Valerio G, Franzese A, Maniscalco M, et al. Obesity duration is associated to pulmonary function impairment in obese subjects. Obesity (Silver Spring). 2011;19:1623–8.

Sivapalan P, Diamant Z, Ulrik CS. Obesity and asthma: current knowledge and future needs. Curr Opin Pulm Med. 2015;21:80–5.

Rasmussen F, Hancox RJ. Mechanisms of obesity in asthma. Curr Opin Allergy Clin Immunol. 2014;14:35–43.

Santamaria F, Montella S, Pietrobelli A. Obesity and pulmonary disease: unanswered questions. Obes Rev. 2012;13:822–33.

Lang JE, Hossain J, Holbrook JT, Teague WG, Gold BD, Wise RA, et al. Gastro-oesophageal reflux and worse asthma control in obese children: a case of symptom misattribution? Thorax. 2016;71:238–46.

Santamaria F, Montella S, De Stefano S, Sperlì F, Barbarano F, Valerio G. Relationship between exhaled nitric oxide and body mass index in children and adolescents. J Allergy Clin Immunol. 2005;116:1163–4.

Van Huisstede A, Rudolphus A, Castro Cabezas M, Biter LU, van de Geijn GJ, Taube C, et al. Effect of bariatric surgery on asthma control, lung function and bronchial and systemic inflammation in morbidly obese subjects with asthma. Thorax. 2015;70:659–67.

Katzmarzyk PT, Bouchard C. Where is the beef? Waist circumference is more highly correlated with BMI and total body fat than with abdominal visceral fat in children. Int J Obes. 2014;38:753–4.

Article   CAS   Google Scholar  

De Groot EP, Duiverman EJ, Brand PL. Comorbidities of asthma during childhood: possibly important, yet poorly studied. Eur Respir J. 2010;36:671–8.

Sweeney J, Patterson CC, Menzies-Gow A, Niven RM, Mansur AH, Bucknall C, et al. Comorbidity in severe asthma requiring systemic corticosteroid therapy: cross-sectional data from the optimum patient care research database and the British thoracic difficult asthma registry. Thorax. 2016; https://doi.org/10.1136/thoraxjnl-2015-207630 .

Federal Drug Administration Advisory for Omalizumab. Available at: https://wayback.archive-it.org/7993/20170111075347/ . http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/default.htm . Accessed 4 Feb 2018.

European Medicines Agency: assessment report for Xolair. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000606/human_med_001162.jsp&mid=WC0b01ac058001d124 . Accessed 7 June 2017.

Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet. 2015;386:1086–96.

Jensen RK, Plum M, Tjerrild L, Jakob T, Spillner E, Andersen GR. Structure of the omalizumab Fab. Acta Crystallogr F Struct Biol Commun. 2015;71:419–26.

Holgate S, Smith N, Massanari M, Jimenez P. Effects of omalizumab on markers of inflammation in patients with allergic asthma. Allergy. 2009;64:1728–36.

Hill DA, Siracusa MC, Ruymann KR, Tait Wojno ED, Artis D, Spergel JM. Omalizumab therapy is associated with reduced circulating basophil populations in asthmatic children. Allergy. 2014;69:674–7.

Humbert M, Beasley R, Ayres J, Slavin R, Hébert J, Bousquet J, et al. Benefits of omalizumab as add-on therapy in patients with severe persistent asthma who are inadequately controlled despite best available therapy (GINA 2002 step 4 treatment): INNOVATE. Allergy. 2005;60:309–16.

Normansell R, Walker S, Milan SJ, Walters EH, Nair P. Omalizumab for asthma in adults and children. Cochrane Database Syst Rev. 2014;1:CD003559.

Lai T, Wang S, Xu Z, Zhang C, Zhao Y, Hu Y, Cao C, et al. Long-term efficacy and safety of omalizumab in patients with persistent uncontrolled allergic asthma: a systematic review and meta-analysis. Sci Rep. 2015;5:8191.

Abraham I, Alhossan A, Lee CS, Kutbi H, MacDonald K. “real-life” effectiveness studies of omalizumab in adult patients with severe allergic asthma: systematic review. Allergy. 2015; https://doi.org/10.1111/all.12815 .

Lanier B, Bridges T, Kulus M, Taylor AF, Berhane I, Vidaurre CF. Omalizumab for the treatment of exacerbations in children with inadequately controlled allergic (IgE-mediated) asthma. J Allergy Clin Immunol. 2009;124:1210–6.

Solèr M, Matz J, Townley R, Buhl R, O'Brien J, Fox H, et al. The anti-IgE antibody omalizumab reduces exacerbations and steroid requirement in allergic asthmatics. Eur Respir J. 2001;18:254–61.

Holgate ST. Cytokine and anti-cytokine therapy for the treatment of asthma and allergic disease. Cytokine. 2004;28:152–7.

Odajima H, Ebisawa M, Nagakura T, Fujisawa T, Akasawa A, Ito K, et al. Omalizumab in Japanese children with severe allergic asthma uncontrolled with standard therapy. Allergol Int. 2015;64:364–70.

Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al. Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl J Med. 2011;364:1005–15.

Teach SJ, Gill MA, Togias A, Sorkness CA, Arbes SJ Jr, Calatroni A, et al. Preseasonal treatment with either omalizumab or an inhaled corticosteroid boost to prevent fall asthma exacerbations. J Allergy Clin Immunol. 2015;136:1476–85.

Deschildre A, Marguet C, Salleron J, Pin I, Rittié JL, Derelle J, et al. Add-on omalizumab in children with severe allergic asthma: a 1-year real life survey. Eur Respir J. 2013;42:1224–33.

Deschildre A, Marguet C, Langlois C, Pin I, Rittié JL, Derelle J, et al. Real-life long-term omalizumab therapy in children with severe allergic asthma. Eur Respir J. 2015;46:856–9.

Rodrigo GJ, Neffen H. Systematic review on the use of omalizumab for the treatment of asthmatic children and adolescents. Pediatr Allergy Immunol. 2015;26:551–6.

Oba Y, Salzman GA. Cost-effectiveness analysis of omalizumab in adults and adolescents with moderate-to-severe allergic asthma. J Allergy Clin Immunol. 2004;114:265–9.

Campbell JD, Spackman DE, Sullivan SD. The costs and consequences of omalizumab in uncontrolled asthma from a USA payer perspective. Allergy. 2010;65:1141–8.

Busse W, Buhl R, Fernandez Vidaurre C, Blogg M, Zhu J, Eisner MD, et al. Omalizumab and the risk of malignancy: results from a pooled analysis. J Allergy Clin Immunol. 2012;129:983–9.

Lowe PJ, Renard D. Omalizumab decreases IgE production in patients with allergic (IgE-mediated) asthma; PKPD analysis of a biomarker, total IgE. Br J Clin Pharmacol. 2011;72:306–10.

Molimard M, Mala L, Bourdeix I, Le Gros V. Observational study in severe asthmatic patients after discontinuation of omalizumab for good asthma control. Respir Med. 2014;108:571–6.

Busse WW, Trzaskoma B, Omachi TA, Canvin J, Rosen K, Chipps BE, et al. Evaluating Xolair persistency of response after long-term therapy (XPORT). Am J Respir Crit Care Med. 2014;189:A6576.

Guilbert TW, Morgan WJ, Zeiger RS, Mauger DT, Boehmer SJ, Szefler SJ, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. N Engl J Med. 2006;354:1985–97.

Akdis CA. Therapies for allergic inflammation: refining strategies to induce tolerance. Nat Med. 2012;18:736–49.

National Heart, Lung, and Blood Institute. Expert panel report 3: Guidelines for the diagnosis and management of asthma—full report 2007. Available at: https://www.nhlbi.nih.gov/files/docs/guidelines/asthgdln.pdf . Accessed 4 Feb 2018.

Joint Task Force on Practice Parameters, American Academy of Allergy, Asthma and Immunology, American College of Allergy, Asthma and Immunology, Joint Council of Allergy, Asthma and Immunolgy. Allergen immunotherapy: a practice parameter second update. J Allergy Clin Immunol. 2007;120:S25–85.

Zuberbier T, Bachert C, Bousquet PJ, Passalacqua G, Walter Canonica G, Merk H, et al. GA(2) LEN/EAACI pocket guide for allergen-specific immunotherapy for allergic rhinitis and asthma. Allergy. 2010;65:1525–30.

Pajno GB, Bernardini R, Peroni D, Arasi S, Martelli A, Landi M, et al. Clinical practice recommendations for allergen-specific immunotherapy in children: the Italian consensus report. Ital J Pediatr. 2017;43:13.

Pitsios C, Demoly P, Bilo MB, Gerth van Wijk R, Pfaar O, Sturm GJ, et al. Clinical contraindications to allergen immunotherapy: an EAACI position paper. Allergy. 2015;70:897–909.

Tsabouri S, Mavroudi A, Feketea G, Guibas GV. Subcutaneous and sublingual immunotherapy in allergic asthma in children. Front Pediatr. 2017;5:82.

Jutel M, Agache I, Bonini S, Burks AW, Calderon M, Canonica W, et al. International consensus on allergy immunotherapy. J Allergy Clin Immunol. 2015;136:556–68.

Hedlin G, van Hage M. The role of immunotherapy in the management of childhood asthma. Ther Adv Respir Dis. 2012;6:137–46.

Lambert N, Guiddir T, Amat F, Just J. Pre-treatment by omalizumab allows allergen immunotherapy in children and young adults with severe allergic asthma. Pediatr Allergy Immunol. 2014;25:829–32.

Kopp MV, Hamelmann E, Zielen S, Kamin W, Bergmann K-C, Sieder C. Combination of omalizumab and specific immunotherapy is superior to immunotherapy in patients with seasonal allergic rhinoconjunctivitis and co-morbid seasonal allergic asthma. Clin Exp Allergy. 2009;39:271–9.

Massanari M, Nelson H, Casale T, Busse W, Kianifard F, Geba GP. Effect of pretreatment with omalizumab on the tolerability of specific immunotherapy in allergic asthma. J Allergy Clin Immunol. 2010;125:383–9.

Stelmach I, Kaczmarek-Woźniak J, Majak P, Olszowiec-Chlebna M, Jerzynska J. Efficacy and safety of high-doses sublingual immunotherapy in ultra-rush scheme in children allergic to grass pollen. Clin Exp Allergy. 2009;39:401–8.

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Acknowledgements

The authors gratefully thank Dr. Marco Maglione for his contribution in the clinical assessment of the described cases. Medical writing assistance was provided by Stephen Walters on behalf of City Hills Proofreading.

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VM, SM and FS, authors of the current manuscript, declare that they have participated sufficiently in the work to take public responsibility for appropriate portions of the content. VM and SM carried out the initial investigations, drafted the initial manuscript, revised the manuscript, and approved the final manuscript as submitted. FS conceptualized and designed the study, and critically reviewed and approved the final manuscript as submitted. All authors read and approved the final manuscript.

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Correspondence to Francesca Santamaria .

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Mirra, V., Montella, S. & Santamaria, F. Pediatric severe asthma: a case series report and perspectives on anti-IgE treatment. BMC Pediatr 18 , 73 (2018). https://doi.org/10.1186/s12887-018-1019-9

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Received : 24 May 2016

Accepted : 29 January 2018

Published : 21 February 2018

DOI : https://doi.org/10.1186/s12887-018-1019-9

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