case study 106 asthma

• 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

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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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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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• Published: 16 October 2014

A woman with asthma: a whole systems approach to supporting self-management

• Hilary Pinnock 1 ,
• Elisabeth Ehrlich 1 ,
• Gaylor Hoskins 2 &
• Ron Tomlins 3  

npj Primary Care Respiratory Medicine volume  24 , Article number:  14063 ( 2014 ) Cite this article

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A 35-year-old lady attends for review of her asthma following an acute exacerbation. There is an extensive evidence base for supported self-management for people living with asthma, and international and national guidelines emphasise the importance of providing a written asthma action plan. Effective implementation of this recommendation for the lady in this case study is considered from the perspective of a patient, healthcare professional, and the organisation. The patient emphasises the importance of developing a partnership based on honesty and trust, the need for adherence to monitoring and regular treatment, and involvement of family support. The professional considers the provision of asthma self-management in the context of a structured review, with a focus on a self-management discussion which elicits the patient’s goals and preferences. The organisation has a crucial role in promoting, enabling and providing resources to support professionals to provide self-management. The patient’s asthma control was assessed and management optimised in two structured reviews. Her goal was to avoid disruption to her work and her personalised action plan focused on achieving that goal.

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A 35-year-old sales representative attends the practice for an asthma review. Her medical record notes that she has had asthma since childhood, and although for many months of the year her asthma is well controlled (when she often reduces or stops her inhaled steroids), she experiences one or two exacerbations a year requiring oral steroids. These are usually triggered by a viral upper respiratory infection, though last summer when the pollen count was particularly high she became tight chested and wheezy for a couple of weeks.

Her regular prescription is for fluticasone 100 mcg twice a day, and salbutamol as required. She has a young family and a busy lifestyle so does not often manage to find time to attend the asthma clinic. A few weeks previously, an asthma attack had interfered with some important work-related travel, and she has attended the clinic on this occasion to ask about how this can be managed better in the future. There is no record of her having been given an asthma action plan.

What do we know about asthma self-management? The academic perspective

Supported self-management reduces asthma morbidity.

The lady in this case study is struggling to maintain control of her asthma within the context of her busy professional and domestic life. The recent unfortunate experience which triggered this consultation offers a rare opportunity to engage with her and discuss how she can manage her asthma better. It behoves the clinician whom she is seeing (regardless of whether this is in a dedicated asthma clinic or an appointment in a routine general practice surgery) to grasp the opportunity and discuss self-management and provide her with a (written) personalised asthma action plan (PAAP).

The healthcare professional advising the lady is likely to be aware that international and national guidelines emphasise the importance of supporting self-management. 1 – 4 There is an extensive evidence base for asthma self-management: a recent synthesis identified 22 systematic reviews summarising data from 260 randomised controlled trials encompassing a broad range of demographic, clinical and healthcare contexts, which concluded that asthma self-management reduces emergency use of healthcare resources, including emergency department visits, hospital admissions and unscheduled consultations and improves markers of asthma control, including reduced symptoms and days off work, and improves quality of life. 1 , 2 , 5 – 12 Health economic analysis suggests that it is not only clinically effective, but also a cost-effective intervention. 13

Personalised asthma action plans

Key features of effective self-management approaches are:

Self-management education should be reinforced by provision of a (written) PAAP which reminds patients of their regular treatment, how to monitor and recognise that control is deteriorating and the action they should take. 14 – 16 As an adult, our patient can choose whether she wishes to monitor her control with symptoms or by recording peak flows (or a combination of both). 6 , 8 , 9 , 14 Symptom-based monitoring is generally better in children. 15 , 16

Plans should have between two and three action points including emergency doses of reliever medication; increasing low dose (or recommencing) inhaled steroids; or starting a course of oral steroids according to severity of the exacerbation. 14

Personalisation of the action plan is crucial. Focussing specifically on what actions she could take to prevent a repetition of the recent attack is likely to engage her interest. Not all patients will wish to start oral steroids without advice from a healthcare professional, though with her busy lifestyle and travel our patient is likely to be keen to have an emergency supply of prednisolone. Mobile technology has the potential to support self-management, 17 , 18 though a recent systematic review concluded that none of the currently available smart phone ‘apps’ were fit for purpose. 19

Identification and avoidance of her triggers is important. As pollen seems to be a trigger, management of allergic rhinitis needs to be discussed (and included in her action plan): she may benefit from regular use of a nasal steroid spray during the season. 20

Self-management as recommended by guidelines, 1 , 2 focuses narrowly on adherence to medication/monitoring and the early recognition/remediation of exacerbations, summarised in (written) PAAPs. Patients, however, may want to discuss how to reduce the impact of asthma on their life more generally, 21 including non-pharmacological approaches.

Supported self-management

The impact is greater if self-management education is delivered within a comprehensive programme of accessible, proactive asthma care, 22 and needs to be supported by ongoing regular review. 6 With her busy lifestyle, our patient may be reluctant to attend follow-up appointments, and once her asthma is controlled it may be possible to make convenient arrangements for professional review perhaps by telephone, 23 , 24 or e-mail. Flexible access to professional advice (e.g., utilising diverse modes of consultation) is an important component of supporting self-management. 25

The challenge of implementation

Implementation of self-management, however, remains poor in routine clinical practice. A recent Asthma UK web-survey estimated that only 24% of people with asthma in the UK currently have a PAAP, 26 with similar figures from Sweden 27 and Australia. 28 The general practitioner may feel that they do not have time to discuss self-management in a routine surgery appointment, or may not have a supply of paper-based PAAPs readily available. 29 However, as our patient rarely finds time to attend the practice, inviting her to make an appointment for a future clinic is likely to be unsuccessful and the opportunity to provide the help she needs will be missed.

The solution will need a whole systems approach

A systematic meta-review of implementing supported self-management in long-term conditions (including asthma) concluded that effective implementation was multifaceted and multidisciplinary; engaging patients, training and motivating professionals within the context of an organisation which actively supported self-management. 5 This whole systems approach considers that although patient education, professional training and organisational support are all essential components of successful support, they are rarely effective in isolation. 30 A systematic review of interventions that promote provision/use of PAAPs highlighted the importance of organisational systems (e.g., sending blank PAAPs with recall reminders). 31 A patient offers her perspective ( Box 1 ), a healthcare professional considers the clinical challenge, and the challenges are discussed from an organisational perspective.

Box 1: What self-management help should this lady expect from her general practitioner or asthma nurse? The patient’s perspective

The first priority is that the patient is reassured that her condition can be managed successfully both in the short and the long term. A good working relationship with the health professional is essential to achieve this outcome. Developing trust between patient and healthcare professional is more likely to lead to the patient following the PAAP on a long-term basis.

A review of all medication and possible alternative treatments should be discussed. The patient needs to understand why any changes are being made and when she can expect to see improvements in her condition. Be honest, as sometimes it will be necessary to adjust dosages before benefits are experienced. Be positive. ‘There are a number of things we can do to try to reduce the impact of asthma on your daily life’. ‘Preventer treatment can protect against the effect of pollen in the hay fever season’. If possible, the same healthcare professional should see the patient at all follow-up appointments as this builds trust and a feeling of working together to achieve the aim of better self-management.

Is the healthcare professional sure that the patient knows how to take her medication and that it is taken at the same time each day? The patient needs to understand the benefit of such a routine. Medication taken regularly at the same time each day is part of any self-management regime. If the patient is unused to taking medication at the same time each day then keeping a record on paper or with an electronic device could help. Possibly the patient could be encouraged to set up a system of reminders by text or smartphone.

Some people find having a peak flow meter useful. Knowing one's usual reading means that any fall can act as an early warning to put the PAAP into action. Patients need to be proactive here and take responsibility.

Ongoing support is essential for this patient to ensure that she takes her medication appropriately. Someone needs to be available to answer questions and provide encouragement. This could be a doctor or a nurse or a pharmacist. Again, this is an example of the partnership needed to achieve good asthma control.

It would also be useful at a future appointment to discuss the patient’s lifestyle and work with her to reduce her stress. Feeling better would allow her to take simple steps such as taking exercise. It would also be helpful if all members of her family understood how to help her. Even young children can do this.

From personal experience some people know how beneficial it is to feel they are in a partnership with their local practice and pharmacy. Being proactive produces dividends in asthma control.

What are the clinical challenges for the healthcare professional in providing self-management support?

Due to the variable nature of asthma, a long-standing history may mean that the frequency and severity of symptoms, as well as what triggers them, may have changed over time. 32 Exacerbations requiring oral steroids, interrupting periods of ‘stability’, indicate the need for re-assessment of the patient’s clinical as well as educational needs. The patient’s perception of stability may be at odds with the clinical definition 1 , 33 —a check on the number of short-acting bronchodilator inhalers the patient has used over a specific period of time is a good indication of control. 34 Assessment of asthma control should be carried out using objective tools such as the Asthma Control Test or the Royal College of Physicians three questions. 35 , 36 However, it is important to remember that these assessment tools are not an end in themselves but should be a springboard for further discussion on the nature and pattern of symptoms. Balancing work with family can often make it difficult to find the time to attend a review of asthma particularly when the patient feels well. The practice should consider utilising other means of communication to maintain contact with patients, encouraging them to come in when a problem is highlighted. 37 , 38 Asthma guidelines advocate a structured approach to ensure the patient is reviewed regularly and recommend a detailed assessment to enable development of an appropriate patient-centred (self)management strategy. 1 – 4

Although self-management plans have been shown to be successful for reducing the impact of asthma, 21 , 39 the complexity of managing such a fluctuating disease on a day-to-day basis is challenging. During an asthma review, there is an opportunity to work with the patient to try to identify what triggers their symptoms and any actions that may help improve or maintain control. 38 An integral part of personalised self-management education is the written PAAP, which gives the patient the knowledge to respond to the changes in symptoms and ensures they maintain control of their asthma within predetermined parameters. 9 , 40 The PAAP should include details on how to monitor asthma, recognise symptoms, how to alter medication and what to do if the symptoms do not improve. The plan should include details on the treatment to be taken when asthma is well controlled, and how to adjust it when the symptoms are mild, moderate or severe. These action plans need to be developed between the doctor, nurse or asthma educator and the patient during the review and should be frequently reviewed and updated in partnership (see Box 1). Patient preference as well as clinical features such as whether she under- or over-perceives her symptoms should be taken into account when deciding whether the action plan is peak flow or symptom-driven. Our patient has a lot to gain from having an action plan. She has poorly controlled asthma and her lifestyle means that she will probably see different doctors (depending who is available) when she needs help. Being empowered to self-manage could make a big difference to her asthma control and the impact it has on her life.

The practice should have protocols in place, underpinned by specific training to support asthma self-management. As well as ensuring that healthcare professionals have appropriate skills, this should include training for reception staff so that they know what action to take if a patient telephones to say they are having an asthma attack.

However, focusing solely on symptom management strategies (actions) to follow in the presence of deteriorating symptoms fails to incorporate the patients’ wider views of asthma, its management within the context of her/his life, and their personal asthma management strategies. 41 This may result in a failure to use plans to maximise their health potential. 21 , 42 A self-management strategy leading to improved outcomes requires a high level of patient self-efficacy, 43 a meaningful partnership between the patient and the supporting health professional, 42 , 44 and a focused self-management discussion. 14

Central to both the effectiveness and personalisation of action plans, 43 , 45 in particular the likelihood that the plan will lead to changes in patients’ day-to-day self-management behaviours, 45 is the identification of goals. Goals are more likely to be achieved when they are specific, important to patients, collaboratively set and there is a belief that these can be achieved. Success depends on motivation 44 , 46 to engage in a specific behaviour to achieve a valued outcome (goal) and the ability to translate the behavioural intention into action. 47 Action and coping planning increases the likelihood that patient behaviour will actually change. 44 , 46 , 47 Our patient has a goal: she wants to avoid having her work disrupted by her asthma. Her personalised action plan needs to explicitly focus on achieving that goal.

As providers of self-management support, health professionals must work with patients to identify goals (valued outcomes) that are important to patients, that may be achievable and with which they can engage. The identification of specific, personalised goals and associated feasible behaviours is a prerequisite for the creation of asthma self-management plans. Divergent perceptions of asthma and how to manage it, and a mismatch between what patients want/need from these plans and what is provided by professionals are barriers to success. 41 , 42

What are the challenges for the healthcare organisation in providing self-management support?

A number of studies have demonstrated the challenges for primary care physicians in providing ongoing support for people with asthma. 31 , 48 , 49 In some countries, nurses and other allied health professionals have been trained as asthma educators and monitor people with stable asthma. These resources are not always available. In addition, some primary care services are delivered in constrained systems where only a few minutes are available to the practitioner in a consultation, or where only a limited range of asthma medicines are available or affordable. 50

There is recognition that the delivery of quality care depends on the competence of the doctor (and supporting health professionals), the relationship between the care providers and care recipients, and the quality of the environment in which care is delivered. 51 This includes societal expectations, health literacy and financial drivers.

In 2001, the Australian Government adopted a programme developed by the General Practitioner Asthma Group of the National Asthma Council Australia that provided a structured approach to the implementation of asthma management guidelines in a primary care setting. 52 Patients with moderate-to-severe asthma were eligible to participate. The 3+ visit plan required confirmation of asthma diagnosis, spirometry if appropriate, assessment of trigger factors, consideration of medication and patient self-management education including provision of a written PAAP. These elements, including regular medical review, were delivered over three visits. Evaluation demonstrated that the programme was beneficial but that it was difficult to complete the third visit in the programme. 53 – 55 Accordingly, the programme, renamed the Asthma Cycle of Care, was modified to incorporate two visits. 56 Financial incentives are provided to practices for each patient who receives this service each year.

Concurrently, other programmes were implemented which support practice-based care. Since 2002, the National Asthma Council has provided best-practice asthma and respiratory management education to health professionals, 57 and this programme will be continuing to 2017. The general practitioner and allied health professional trainers travel the country to provide asthma and COPD updates to groups of doctors, nurses and community pharmacists. A number of online modules are also provided. The PACE (Physician Asthma Care Education) programme developed by Noreen Clark has also been adapted to the Australian healthcare system. 58 In addition, a pharmacy-based intervention has been trialled and implemented. 59

To support these programmes, the National Asthma Council ( www.nationalasthma.org.au ) has developed resources for use in practices. A strong emphasis has been on the availability of a range of PAAPs (including plans for using adjustable maintenance dosing with ICS/LABA combination inhalers), plans for indigenous Australians, paediatric plans and plans translated into nine languages. PAAPs embedded in practice computer systems are readily available in consultations, and there are easily accessible online paediatric PAAPs ( http://digitalmedia.sahealth.sa.gov.au/public/asthma/ ). A software package, developed in the UK, can be downloaded and used to generate a pictorial PAAP within the consultation. 60

One of the strongest drivers towards the provision of written asthma action plans in Australia has been the Asthma Friendly Schools programme. 61 , 62 Established with Australian Government funding and the co-operation of Education Departments of each state, the Asthma Friendly Schools programme engages schools to address and satisfy a set of criteria that establishes an asthma-friendly environment. As part of accreditation, the school requires that each child with asthma should have a written PAAP prepared by their doctor to assist (trained) staff in managing a child with asthma at school.

The case study continues...

The initial presentation some weeks ago was during an exacerbation of asthma, which may not be the best time to educate a patient. It is, however, a splendid time to build on their motivation to feel better. She agreed to return after her asthma had settled to look more closely at her asthma control, and an appointment was made for a routine review.

At this follow-up consultation, the patient’s diagnosis was reviewed and confirmed and her trigger factors discussed. For this lady, respiratory tract infections are the usual trigger but allergic factors during times of high pollen count may also be relevant. Assessment of her nasal airway suggested that she would benefit from better control of allergic rhinitis. Other factors were discussed, as many patients are unaware that changes in air temperature, exercise and pets can also trigger asthma exacerbations. In addition, use of the Asthma Control Test was useful as an objective assessment of control as well as helping her realise what her life could be like! Many people with long-term asthma live their life within the constraints of their illness, accepting that is all that they can do.

After assessing the level of asthma control, a discussion about management options—trigger avoidance, exercise and medicines—led to the development of a written PAAP. Asthma can affect the whole family, and ways were explored that could help her family understand why it is important that she finds time in the busy domestic schedules to take her regular medication. Family and friends can also help by understanding what triggers her asthma so that they can avoid exposing her to perfumes, pollens or pets that risk triggering her symptoms. Information from the national patient organisation was provided to reinforce the messages.

The patient agreed to return in a couple of weeks, and a recall reminder was set up. At the second consultation, the level of control since the last visit will be explored including repeat spirometry, if appropriate. Further education about the pathophysiology of asthma and how to recognise early warning signs of loss of control can be given. Device use will be reassessed and the PAAP reviewed. Our patient’s goal is to avoid disruption to her work and her PAAP will focus on achieving that goal. Finally, agreement will be reached with the patient about future routine reviews, which, now that she has a written PAAP, could be scheduled by telephone if all is well, or face-to-face if a change in her clinical condition necessitates a more comprehensive review.

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Pinnock, H., Ehrlich, E., Hoskins, G. et al. A woman with asthma: a whole systems approach to supporting self-management. npj Prim Care Resp Med 24 , 14063 (2014). https://doi.org/10.1038/npjpcrm.2014.63

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DOI : https://doi.org/10.1038/npjpcrm.2014.63

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A 29-year-old man with mild persistent asthma presented to an outpatient office for a follow-up visit.  He was originally referred 6 months ago by his primary care provider after having an asthma exacerbation which required treatment in an emergency room.

At his initial visit, he reported wheeze and cough 4 days a week and nocturnal symptoms three times a month.   Spirometry revealed forced vital capacity (FVC) 85% predicted, forced expiratory volume in 1 second (FEV 1 ) 75% predicted, FEV 1 /FVC 65%, and an increase in FEV 1 of 220 ml or 14% following an inhaled short-acting bronchodilator.   He was placed on a low-dose inhaled corticosteroid twice a day and a short-acting inhaled beta-agonist as needed.  He returned 4 weeks later improved, but with continued daytime symptoms 2 days a week.  He also had symptoms of rhinitis; therefore he was referred to an allergist for evaluation. Skin testing was positive for trees, ragweed, dust mites, and cats, and he was prescribed a nasal steroid spray and nonsedating oral antihistamine.   He presents today and reports no asthma exacerbations since his last visit.  Furthermore, during the past 4 weeks, he has not been awakened by his asthma, experienced morning breathing symptoms, missed work, had any limitations in activities due to asthma, or required the use of rescue albuterol.  He currently denies shortness of breath or wheezing.  He performs aerobic exercise 4 days a week for 45 minutes per session without symptoms, provided he premedicates with a short-acting inhaled beta-agonist.  His review of symptoms is otherwise unremarkable.  His current medications include low-dose inhaled corticosteroid, 1 puff twice a day ; steroid nasal spray, 2 puffs each nostril daily; a nonsedating antihistamine, 1 tablet daily; and inhaled beta-agonist, 2 puffs as needed.    His past medical history is significant for intermittent asthma diagnosed at age 13 and frequent “colds.”  He has never required hospitalization for an asthma exacerbation .  He works as a hospital microbiologist and does not smoke, drink alcohol, or use illicit drugs.  He recently moved to a pet-free apartment complex and instituted dust mite protective barriers for his bedding .  His family history is noncontributory.

Physical Exam

The goal of asthma therapy is to minimize risk and maintain asthma control with the least amount of medication (1).   In patients with mild persistent asthma, recent studies have demonstrated several options for "step-down therapy."  The American Lung Association Asthma Clinical Research Centers network study found that patients who stepped down from twice daily low-dose fluticasone to once daily combination therapy with fluticasone/salmeterol had equivalent asthma control scores, FEV 1 , and frequency of exacerbations compared with continued therapy with twice daily fluticasone (2).  Once-daily montelukast demonstrated a slightly higher treatment failure compared with either of the regimens containing inhaled steroids.   Despite the slight increase in treatment failure with montelukast, each of the treatment groups had equivalent symptom-free days and rates of clinically significant asthma exacerbations.   Thus, while either regimen would be appropriate, stepping down to once-daily combination therapy with fluticasone/salmeterol appears to be more beneficial.

Recent studies also suggest that those with mild persistent asthma taking inhaled corticosteroids in combination with either a long-acting beta-agonist or a short-acting beta-agonist when symptomatic, had no increase in adverse outcomes compared with those taking scheduled daily inhaled doses.   Boushey et al. (3) compared patients with mild persistent asthma using twice-daily budesonide versus twice-daily zafirlukast verses placebo. All three groups used budesonide as-needed following a symptom-based action plan. The study found that in comparison with patients on a daily controller (budesonide or zafikulast), participants using only as-needed budesonide had no significant difference in morning peak expiratory flow, postbronchodilator FEV 1 , quality of life, or frequency of asthma exacerbations. Results of this study raise the possibility of treating mild persistent asthmatics with as-needed inhaled corticosteroids.   More recently, Papi et al. (4) found as-needed use of an inhaler containing both beclomethasone and albuterol for symptom relief was associated with fewer exacerbations and higher morning peak flow readings than using an inhaler with albuterol alone.   The morning peak flow readings in the as-needed combination beclomethasone/albuterol group was equivalent to those taking scheduled daily doses of beclomethasone alone, or scheduled daily doses of beclomethasone/albuterol combined.   The combination of an inhaled steroid and a short-acting beta-agonist in a single inhaler is not currently available in the United States.

In the mild persistent asthmatic there is now strong evidence to support multiple treatment approaches which provide good asthma control.   Matching the drug regimen with the patient’s preferences, lifestyle, comorbidities, and financial limitations will help ensure drug adherence and maintain asthma control.

When spirometry is used to diagnose or confirm asthma, testing must include pre- and post-bronchodilator readings (1).   A change in FEV 1 of >200 ml and ≥ 12% from the baseline measure following the administration of a short-acting bronchodilator is indicative of significant airway reversibility which has been shown to correlate with airway inflammation (7).  

The Expert Panel (1) classifies asthma severity by FEV 1 , FEV 1 /FVC, short-acting beta-agonist use, or frequency of asthma symptoms.    Parameters are measured at baseline with asthma severity determined by the worse parameter, e.g., daily symptoms with normal FEV 1 is classified as moderate persistent asthma.   Correct identification of asthma severity guides the provider in choosing the appropriate type and amount of therapy.  

Asthma symptoms should be assessed at each office visit to determine asthma control.   Validated self-assessment tools such as the Asthma Control Test (ACT), Asthma Therapy Assessment Questionnaire (ATAQ), or Asthma Control Questionnaire (ACQ) can facilitate consistent measurement and documentation of asthma symptoms during office visits (1, 8).   All asthmatics are at risk for a severe asthma attack regardless of their asthma classification; therefore, providers are encouraged to teach patients to recognize symptoms of inadequate asthma control and provide them with specific instructions for adjusting their medications or seeking medical care (1).  

When studied, only approximately 25% of patients are able to properly demonstrate use of a meter dose inhaler when asked.   The remaining 75% improved with specific instruction and practice which reinforces the need to incorporate proper inhaler use during the office visit (9,10).   The use of a spacer significantly improves accuracy and dose delivery, particularly in patients with poor coordination skills (9,10).

Assessing patient adherence is best approached with a nonjudgmental attitude.   Adherence to inhaled corticosteroids is estimated at < 50% (11).   Causes of nonadherence are multifactorial but may be improved by providing asthma education, encouraging self management through use of an asthma action plan, and facilitating open communication (11).   Financial barriers often transcend all other efforts to improve adherence and must be taken into account when prescribing asthma therapy (11).

Methacholine challenge testing is useful to demonstrate airway hyperresponsiveness in those with normal spirometry and a suspicion of asthma, but is not recommended as a serial procedure.   Biomarkers for inflammation such as eosinophils or nitric oxide are being investigated in clinical trials but currently have no indication in routine asthma care (1).   Peak flow monitoring is useful for long-term home assessment of asthma control and medication response, but is not indicated for regular office assessment or diagnostic purposes (1).

• Expert Panel Report 3 (EPR 3). Guidelines for the Diagnosis and Management of Asthma. Bethesda, Md: National Institutes of Health; 2007. NIH Publication No. 08-4051.
• The American Lung Association Asthma Clinical Research Centers. Randomized comparison of strategies for reducing treatment in mild persistent asthma. N Engl J Med 2007;356:2027-2039.
• Boushey HA, Sorkness CA, King TS, et al. Daily versus as-needed corticosteroids for mild persistent asthma. N Engl J Med 2005;352:1519-1528.
• Papi A, Giorgio GW, Maestrelli P, et al. Rescue use of beclomethasone and albuterol in a single inhaler for mild asthma. N Engl J Med 2007;356:2040-2052.
• Gibson PG, Powell H. Written action plans for asthma: an evidence-based review of the key components. Thorax 2007;59:94-99.
• Miller MR, Hankinson J, Brusasco V, et al. Series ATS/ERS Task Force: Standardization of lung function testing. Eur Respir J 2005;26:319-338.
• Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. N Engl J Med 2005;26:948-968.
• Global Initiative for Asthma. Pocket guide for asthma management and prevention. Bethesda, Md: National Institutes of Health; 2006.
• Giraud V, Roche N. Misuse of corticosteroid metered-dose inhaler is associated with decreased asthma stability. Eur Respir J 2002;19(2):246-251.
• Johnson DH, Robart P. Inhaler technique of outpatients in the home. Respir Care 2000;45(10):1182-1187.
• Elliott RA. Poor adherence to anti-inflammatory medication in asthma reasons, challenges, and strategies for improved disease management. Dis Manage Health Outcomes 2006;14(4):223-233.

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Case Study: Managing Severe Asthma in an Adult

—he follows his treatment plan, but this 40-year-old male athlete has asthma that is not well-controlled. what’s the next step.

By Kirstin Bass, MD, PhD Reviewed by Michael E. Wechsler, MD, MMSc

This case presents a patient with poorly controlled asthma that remains refractory to treatment despite use of standard-of-care therapeutic options. For patients such as this, one needs to embark on an extensive work-up to confirm the diagnosis, assess for comorbidities, and finally, to consider different therapeutic options.

Case presentation and patient history

Mr. T is a 40-year-old recreational athlete with a medical history significant for asthma, for which he has been using an albuterol rescue inhaler approximately 3 times per week for the past year. During this time, he has also been waking up with asthma symptoms approximately twice a month, and has had three unscheduled asthma visits for mild flares. Based on the  National Asthma Education and Prevention Program guidelines , Mr. T has asthma that is not well controlled. 1

As a result of these symptoms, spirometry was performed revealing a forced expiratory volume in the first second (FEV1) of 78% predicted. Mr. T then was prescribed treatment with a low-dose corticosteroid, fluticasone 44 mcg at two puffs twice per day. However, he remained symptomatic and continued to use his rescue inhaler 3 times per week. Therefore, he was switched to a combination inhaled steroid and long-acting beta-agonist (LABA) (fluticasone propionate 250 mcg and salmeterol 50 mcg, one puff twice a day) by his primary care doctor.

Initial pulmonary assessment Even with this step up in his medication, Mr. T continued to be symptomatic and require rescue inhaler use. Therefore, he was referred to a pulmonologist, who performed the initial work-up shown here:

• Spirometry, pre-albuterol: FEV1 79%, post-albuterol: 12% improvement
• Methacholine challenge: PC 20 : 1.0 mg/mL
• Chest X-ray: Within normal limits

Continued pulmonary assessment His dose of inhaled corticosteroid (ICS) and LABA was increased to fluticasone 500 mcg/salmeterol 50 mcg, one puff twice daily. However, he continued to have symptoms and returned to the pulmonologist for further work-up, shown here:

• Chest computed tomography (CT): Normal lung parenchyma with no scarring or bronchiectasis
• Sinus CT: Mild mucosal thickening
• Complete blood count (CBC): Within normal limits, white blood cells (WBC) 10.0 K/mcL, 3% eosinophils
• Immunoglobulin E (IgE): 25 IU/mL
• Allergy-skin test: Positive for dust, trees
• Exhaled NO: Fractional exhaled nitric oxide (FeNO) 53 parts per billion (pbb)

Assessment for comorbidities contributing to asthma symptoms After this work-up, tiotropium was added to his medication regimen. However, he remained symptomatic and had two more flares over the next 3 months. He was assessed for comorbid conditions that might be affecting his symptoms, and results showed:

• Esophagram/barium swallow: Negative
• Esophageal manometry: Negative
• Esophageal impedance: Within normal limits
• ECG: Within normal limits
• Genetic testing: Negative for cystic fibrosis, alpha1 anti-trypsin deficiency

The ear, nose, and throat specialist to whom he was referred recommended only nasal inhaled steroids for his mild sinus disease and noted that he had a normal vocal cord evaluation.

Following this extensive work-up that transpired over the course of a year, Mr. T continued to have symptoms. He returned to the pulmonologist to discuss further treatment options for his refractory asthma.

Diagnosis Mr. T has refractory asthma. Work-up for this condition should include consideration of other causes for the symptoms, including allergies, gastroesophageal reflux disease, cardiac disease, sinus disease, vocal cord dysfunction, or genetic diseases, such as cystic fibrosis or alpha1 antitrypsin deficiency, as was performed for Mr. T by his pulmonary team.

Treatment options When a patient has refractory asthma, treatment options to consider include anticholinergics (tiotropium, aclidinium), leukotriene modifiers (montelukast, zafirlukast), theophylline, anti-immunoglobulin E (IgE) antibody therapy with omalizumab, antibiotics, bronchial thermoplasty, or enrollment in a clinical trial evaluating the use of agents that modulate the cell signaling and immunologic responses seen in asthma.

Treatment outcome Mr. T underwent bronchial thermoplasty for his asthma. One year after the procedure, he reports feeling great. He has not taken systemic steroids for the past year, and his asthma remains controlled on a moderate dose of ICS and a LABA. He has also been able to resume exercising on a regular basis.

Approximately 10% to 15% of asthma patients have severe asthma refractory to the commonly available medications. 2  One key aspect of care for this patient population is a careful workup to exclude other comorbidities that could be contributing to their symptoms. Following this, there are several treatment options to consider, as in recent years there have been several advances in the development of asthma therapeutics. 2

Treatment options for refractory asthma There are a number of currently approved therapies for severe, refractory asthma. In addition to therapy with ICS or combination therapies with ICS and LABAs, leukotriene antagonists have good efficacy in asthma, especially in patients with prominent allergic or exercise symptoms. 2  The anticholinergics, such as tiotropium, which was approved for asthma in 2015, enhance bronchodilation and are useful adjuncts to ICS. 3-5  Omalizumab is a monoclonal antibody against IgE recommended for use in severe treatment-refractory allergic asthma in patients with atopy. 2  A nonmedication therapeutic option to consider is bronchial thermoplasty, a bronchoscopic procedure that uses thermal energy to disrupt bronchial smooth muscle. 6,7

Personalizing treatment for each patient It is important to personalize treatment based on individual characteristics or phenotypes that predict the patient's likely response to treatment, as well as the patient's preferences and practical issues, such as adherence and cost. 8

In this case, tiotropium had already been added to Mr. T's medications and his symptoms continued. Although addition of a leukotriene modifier was an option for him, he did not wish to add another medication to his care regimen. Omalizumab was not added partly for this reason, and also because of his low IgE level. As his bronchoscopy was negative, it was determined that a course of antibiotics would not be an effective treatment option for this patient. While vitamin D insufficiency has been associated with adverse outcomes in asthma, T's vitamin D level was tested and found to be sufficient.

We discussed the possibility of Mr. T's enrollment in a clinical trial. However, because this did not guarantee placement within a treatment arm and thus there was the possibility of receiving placebo, he opted to undergo bronchial thermoplasty.

Bronchial thermoplasty  Bronchial thermoplasty is effective for many patients with severe persistent asthma, such as Mr. T. This procedure may provide additional benefits to, but does not replace, standard asthma medications. During the procedure, thermal energy is delivered to the airways via a bronchoscope to reduce excess airway smooth muscle and limit its ability to constrict the airways. It is an outpatient procedure performed over three sessions by a trained physician. 9

The effects of bronchial thermoplasty have been studied in several trials. The first large-scale multicenter randomized controlled study was  the Asthma Intervention Research (AIR) Trial , which enrolled patients with moderate to severe asthma. 10  In this trial, patients who underwent the procedure had a significant improvement in asthma symptoms as measured by symptom-free days and scores on asthma control and quality of life questionnaires, as well as reductions in mild exacerbations and increases in morning peak expiratory flow. 10  Shortly after the AIR trial, the  Research in Severe Asthma (RISA) trial  was conducted to evaluate bronchial thermoplasty in patients with more severe, symptomatic asthma. 11  In this population, bronchial thermoplasty resulted in a transient worsening of asthma symptoms, with a higher rate of hospitalizations during the treatment period. 11  Hospitalization rate equalized between the treatment and control groups in the posttreatment period, however, and the treatment group showed significant improvements in rescue medication use, prebronchodilator forced expiratory volume in the first second (FEV1) % predicted, and asthma control questionnaire scores. 11

The AIR-2  trial followed, which was a multicenter, randomized, double-blind, sham-controlled study of 288 patients with severe asthma. 6  Similar to the RISA trial, patients in the treatment arm of this trial experienced an increase in adverse respiratory effects during the treatment period, the most common being airway irritation (including wheezing, chest discomfort, cough, and chest pain) and upper respiratory tract infections. 6

The majority of adverse effects occurred within 1 day of the procedure and resolved within 7 days. 6  In this study, bronchial thermoplasty was found to significantly improve quality of life, as well as reduce the rate of severe exacerbations by 32%. 6  Patients who underwent the procedure also reported fewer adverse respiratory effects, fewer days lost from work, school, or other activities due to asthma, and an 84% risk reduction in emergency department visits. 6

Long-term (5-year) follow-up studies have been conducted for patients in both  the AIR  and  the AIR-2  trials. In patients who underwent bronchial thermoplasty in either study, the rate of adverse respiratory effects remained stable in years 2 to 5 following the procedure, with no increase in hospitalizations or emergency department visits. 7,12  Additionally, FEV1 remained stable throughout the 5-year follow-up period. 7,12  This finding was maintained in patients enrolled in the AIR-2 trial despite decreased use of daily ICS. 7

Bronchial thermoplasty is an important addition to the asthma treatment armamentarium. 7  This treatment is currently approved for individuals with severe persistent asthma who remain uncontrolled despite the use of an ICS and LABA. Several clinical trials with long-term follow-up have now demonstrated its safety and ability to improve quality of life in patients with severe asthma, such as Mr. T.

Severe asthma can be a challenge to manage. Patients with this condition require an extensive workup, but there are several treatments currently available to help manage these patients, and new treatments are continuing to emerge. Managing severe asthma thus requires knowledge of the options available as well as consideration of a patient's personal situation-both in terms of disease phenotype and individual preference. In this case, the patient expressed a strong desire to not add any additional medications to his asthma regimen, which explained the rationale for choosing to treat with bronchial thermoplasty. Personalized treatment necessitates exploring which of the available or emerging options is best for each individual patient.

Published: April 16, 2018

• 1. National Asthma Education and Prevention Program: Asthma Care Quick Reference.
• 2. Olin JT, Wechsler ME. Asthma: pathogenesis and novel drugs for treatment. BMJ . 2014;349:g5517.
• 3. Boehringer Ingelheim. Asthma: U.S. FDA approves new indication for SPIRIVA Respimat [press release]. September 16, 2015.
• 4. Peters SP, Kunselman SJ, Icitovic N, et al. Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N Engl J Med . 2010;363:1715-1726.
• 5. Kerstjens HA, Engel M, Dahl R. Tiotropium in asthma poorly controlled with standard combination therapy. N Engl J Med . 2012;367:1198-1207.
• 6. Castro M, Rubin AS, Laviolette M, et al. Effectiveness and safety of bronchial thermoplasty in the treatment of severe asthma: a multicenter, randomized, double-blind, sham-controlled clinical trial. Am J Respir Crit Care Med . 2010;181:116-124.
• 7. Wechsler ME, Laviolette M, Rubin AS, et al. Bronchial thermoplasty: long-term safety and effectiveness in patients with severe persistent asthma. J Allergy Clin Immunol . 2013;132:1295-1302.
• 8. Global Initiative for Asthma: Pocket Guide for Asthma Management and Prevention (for Adults and Children Older than 5 Years).
• 10. Cox G, Thomson NC, Rubin AS, et al. Asthma control during the year after bronchial thermoplasty. N Engl J Med . 2007;356:1327-1337.
• 11. Pavord ID, Cox G, Thomson NC, et al. Safety and efficacy of bronchial thermoplasty in symptomatic, severe asthma. Am J Respir Crit Care Med . 2007;176:1185-1191.
• 12. Thomson NC, Rubin AS, Niven RM, et al. Long-term (5 year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial. BMC Pulm Med . 2011;11:8.

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Case study: 60-year-old female presenting with shortness of breath.

Deepa Rawat ; Sandeep Sharma .

Affiliations

Last Update: February 20, 2023 .

• Case Presentation

The patient is a 60-year-old white female presenting to the emergency department with acute onset shortness of breath.  Symptoms began approximately 2 days before and had progressively worsened with no associated, aggravating, or relieving factors noted. She had similar symptoms approximately 1 year ago with an acute, chronic obstructive pulmonary disease (COPD) exacerbation requiring hospitalization. She uses BiPAP ventilatory support at night when sleeping and has requested to use this in the emergency department due to shortness of breath and wanting to sleep.

She denies fever, chills, cough, wheezing, sputum production, chest pain, palpitations, pressure, abdominal pain, abdominal distension, nausea, vomiting, and diarrhea.

She reports difficulty breathing at rest, forgetfulness, mild fatigue, feeling chilled, requiring blankets, increased urinary frequency, incontinence, and swelling in her bilateral lower extremities that are new-onset and worsening. Subsequently, she has not ambulated from bed for several days except to use the restroom due to feeling weak, fatigued, and short of breath.

There are no known ill contacts at home. Her family history includes significant heart disease and prostate malignancy in her father. Social history is positive for smoking tobacco use at 30 pack years. She quit smoking 2 years ago due to increasing shortness of breath. She denies all alcohol and illegal drug use. There are no known foods, drugs, or environmental allergies.

Past medical history is significant for coronary artery disease, myocardial infarction, COPD, hypertension, hyperlipidemia, hypothyroidism, diabetes mellitus, peripheral vascular disease, tobacco usage, and obesity.  Past surgical history is significant for an appendectomy, cardiac catheterization with stent placement, hysterectomy, and nephrectomy.

Her current medications include fluticasone-vilanterol 100-25 mcg inhaled daily, hydralazine 50 mg by mouth, 3 times per day, hydrochlorothiazide 25 mg by mouth daily, albuterol-ipratropium inhaled every 4 hours PRN, levothyroxine 175 mcg by mouth daily, metformin 500 mg by mouth twice per day, nebivolol 5 mg by mouth daily, aspirin 81 mg by mouth daily, vitamin D3 1000 units by mouth daily, clopidogrel 75 mg by mouth daily, isosorbide mononitrate 60 mg by mouth daily, and rosuvastatin 40 mg by mouth daily.

Physical Exam

Initial physical exam reveals temperature 97.3 F, heart rate 74 bpm, respiratory rate 24, BP 104/54, HT 160 cm, WT 100 kg, BMI 39.1, and O2 saturation 90% on room air.

Constitutional:  Extremely obese, acutely ill-appearing female. Well-developed and well-nourished with BiPAP in place. Lying on a hospital stretcher under 3 blankets.

HEENT: 

• Head: Normocephalic and atraumatic
• Mouth: Moist mucous membranes 
• Macroglossia
• Eyes: Conjunctiva and EOM are normal. Pupils are equal, round, and reactive to light. No scleral icterus. Bilateral periorbital edema present.
• Neck: Neck supple. No JVD present. No masses or surgical scarring. 
• Throat: Patent and moist

Cardiovascular:  Normal rate, regular rhythm, and normal heart sound with no murmur. 2+ pitting edema bilateral lower extremities and strong pulses in all four extremities.

Pulmonary/Chest:  No respiratory status distress at this time, tachypnea present, (+) wheezing noted, bilateral rhonchi, decreased air movement bilaterally. The patient was barely able to finish a full sentence due to shortness of breath.

Abdominal:  Soft. Obese. Bowel sounds are normal. No distension and no tenderness

Skin: Skin is very dry

Neurologic: Alert, awake, able to protect her airway. Moving all extremities. No sensation losses

• Initial Evaluation

Initial evaluation to elucidate the source of dyspnea was performed and included CBC to establish if an infectious or anemic source was present, CMP to review electrolyte balance and review renal function, and arterial blood gas to determine the PO2 for hypoxia and any major acid-base derangement, creatinine kinase and troponin I to evaluate the presence of myocardial infarct or rhabdomyolysis, brain natriuretic peptide, ECG, and chest x-ray. Considering that it is winter and influenza is endemic in the community, a rapid influenza assay was obtained as well.

Largely unremarkable and non-contributory to establish a diagnosis.

Showed creatinine elevation above baseline from 1.08 base to 1.81, indicating possible acute injury. EGFR at 28 is consistent with chronic renal disease. Calcium was elevated to 10.2. However, when corrected for albumin, this corrected to 9.8 mg/dL. Mild transaminitis is present as seen in alkaline phosphatase, AST, and ALT measurements which could be due to liver congestion from volume overload.

Initial arterial blood gas with pH 7.491, PCO2 27.6, PO2 53.6, HCO3 20.6, and oxygen saturation 90% on room air, indicating respiratory alkalosis with hypoxic respiratory features.

Creatinine kinase was elevated along with serial elevated troponin I studies. In the setting of her known chronic renal failure and acute injury indicated by the above creatinine value, a differential of rhabdomyolysis is determined.

Influenza A and B: Negative

Normal sinus rhythm with non-specific ST changes in inferior leads. Decreased voltage in leads I, III, aVR, aVL, aVF.

Chest X-ray

Findings: Bibasilar airspace disease that may represent alveolar edema. Cardiomegaly noted. Prominent interstitial markings were noted. Small bilateral pleural effusions

Radiologist Impression: Radiographic changes of congestive failure with bilateral pleural effusions greater on the left compared to the right

• Differential Diagnosis
• Acute on chronic COPD exacerbation
• Acute on chronic renal failure
• Bacterial pneumonia
• Congestive heart failure
• Pericardial effusion
• Hypothyroidism
• Influenza pneumonia
• Pulmonary edema
• Pulmonary embolism
• Confirmatory Evaluation

On the second day of the admission patient’s shortness of breath was not improved, and she was more confused with difficulty arousing on conversation and examination. To further elucidate the etiology of her shortness of breath and confusion, the patient's husband provided further history. He revealed that she is poorly compliant with taking her medications. He reports that she “doesn’t see the need to take so many pills.”

Testing was performed to include TSH, free T4, BNP, repeated arterial blood gas, CT scan of the chest, and echocardiogram. TSH and free T4 evaluate hypothyroidism. BNP evaluates fluid load status and possible congestive heart failure. CT scan of the chest will look for anatomical abnormalities. An echocardiogram is used to evaluate left ventricular ejection fraction, right ventricular function, pulmonary artery pressure, valvular function, pericardial effusion, and any hypokinetic area.

• TSH: 112.717 (H)
• Free T4: 0.56 (L)
• TSH and Free T4 values indicate severe primary hypothyroidism. 

BNP can be falsely low in obese patients due to the increased surface area. Additionally, adipose tissue has BNP receptors which augment the true BNP value. Also, African American patients with more excretion may have falsely low values secondary to greater excretion of BNP. This test is not that helpful in renal failure due to the chronic nature of fluid overload. This allows for desensitization of the cardiac tissues with a subsequent decrease in BNP release.

Repeat arterial blood gas on BiPAP ventilation shows pH 7.397, PCO2 35.3, PO2 72.4, HCO3 21.2, and oxygen saturation 90% on 2 L supplemental oxygen.

CT chest without contrast was primarily obtained to evaluate the left hemithorax, especially the retrocardiac area.

Radiologist Impression: Tiny bilateral pleural effusions. Pericardial effusion. Coronary artery calcification. Some left lung base atelectasis with minimal airspace disease.

Echocardiogram

The left ventricular systolic function is normal. The left ventricular cavity is borderline dilated.

The pericardial fluid is collected primarily posteriorly, laterally but not apically. There appeared to be a subtle, early hemodynamic effect of the pericardial fluid on the right-sided chambers by way of an early diastolic collapse of the RA/RV and delayed RV expansion until late diastole. A dedicated tamponade study was not performed. 

The estimated ejection fraction appears to be in the range of 66% to 70%. The left ventricular cavity is borderline dilated.

The aortic valve is abnormal in structure and exhibits sclerosis.

The mitral valve is abnormal in structure. Mild mitral annular calcification is present. There is bilateral thickening present. Trace mitral valve regurgitation is present.

• Myxedema coma or severe hypothyroidism
• Pericardial effusion secondary to myxedema coma
• COPD exacerbation
• Acute on chronic hypoxic respiratory failure
• Acute respiratory alkalosis
• Bilateral community-acquired pneumonia
• Small bilateral pleural effusions
• Acute mild rhabdomyolysis
• Acute chronic, stage IV, renal failure
• Elevated troponin I levels, likely secondary to Renal failure 
• Diabetes mellitus type 2, non-insulin-dependent
• Extreme obesity
• Hepatic dysfunction

The patient was extremely ill and rapidly decompensating with multisystem organ failure, including respiratory failure, altered mental status, acute on chronic renal failure, and cardiac dysfunction. The primary concerns for the stability of the patient revolved around respiratory failure coupled with altered mental status. In the intensive care unit (ICU), she rapidly began to fail BiPAP therapy. Subsequently, the patient was emergently intubated in the ICU.  A systemic review of therapies and hospital course is as follows:

Considering the primary diagnosis of myxedema coma, early supplementation with thyroid hormone is essential. Healthcare providers followed the American Thyroid Association recommendations, which recommend giving combined T3 and T4 supplementation; however, T4 alone may also be used. T3 therapy is given as a bolus of 5 to 20 micrograms intravenously and continued at 2.5 to 10 micrograms every 8 hours. An intravenous loading dose of 300 to 600 micrograms of T4 is followed by a daily intravenous dose of 50 to 100 micrograms. Repeated monitoring of TSH and T4 should be performed every 1 to 2 days to evaluate the effect and to titrate the dose of medication. The goal is to improve mental function. Until coexistent adrenal insufficiency is ruled out using a random serum cortisol measurement, 50 to 100 mg every 8 hours of hydrocortisone should be administered. In this case, clinicians used hydrocortisone 100 mg IV every 8 hours. Dexamethasone 2 to 4 mg every 12 hours is an alternative therapy.

The patient’s mental status rapidly worsened despite therapy. In the setting of her hypothyroidism history, this may be myxedema coma or due to the involvement of another organ system. The thyroid supplementation medications and hydrocortisone were continued. A CT head without contrast was normal.

Respiratory

For worsening metabolic acidosis and airway protection, the patient was emergently intubated. Her airway was deemed high risk due to having a large tongue, short neck, and extreme obesity. As the patient’s heart was preload dependent secondary to pericardial effusion, a 1-liter normal saline bolus was started. Norepinephrine was started at a low dose for vasopressor support, and ketamine with low dose Propofol was used for sedation. Ketamine is a sympathomimetic medication and usually does not cause hypotension as all other sedatives do. The patient was ventilated with AC mode of ventilation, tidal volume of 6 ml/kg ideal body weight, flow 70, initial fio2 100 %, rate 26 per minute (to compensate for metabolic acidosis), PEEP of 8.

Cardiovascular

She was determined to be hemodynamically stable with a pericardial effusion. This patient’s cardiac dysfunction was diastolic in nature, as suggested by an ejection fraction of 66% to 70%. The finding of posterior pericardial effusion further supported this conclusion. The posterior nature of this effusion was not amenable to pericardiocentesis. As such, this patient was preload dependent and showed signs of hypotension. The need for crystalloid fluid resuscitation was balanced against the impact increased intravascular volume would have on congestive heart failure and fluid overload status. Thyroid hormone replacement as above should improve hypotension. However, vasopressor agents may be used to maintain vital organ perfusion targeting a mean arterial pressure of greater than 65 mm Hg as needed. BP improved after fluid bolus, and eventually, the norepinephrine was stopped. Serial echocardiograms were obtained to ensure that the patient did not develop tamponade physiology. Total CK was elevated, which was likely due to Hypothyroidism compounded with chronic renal disease.

Infectious Disease

Blood cultures, urine analysis, and sputum cultures were obtained. The patient's white blood cell count was normal. This is likely secondary to her being immunocompromised due to hypothyroidism and diabetes. In part, the pulmonary findings of diffuse edema and bilateral pleural effusions can be explained by cardiac dysfunction. Thoracentesis of pleural fluid was attempted, and the fluid was analyzed for cytology and gram staining to rule out infectious or malignant causes as both a therapeutic and diagnostic measure. Until these results return, broad-spectrum antibiotics are indicated and may be discontinued once the infection is ruled out completely.

Gastrointestinal

Nasogastric tube feedings were started on the patient after intubation. She tolerated feedings well. AST and ALT were mildly elevated, which was thought to be due to hypothyroidism, and as the TSH and free T4 improved, her AST and ALT improved. Eventually, these values became normal once her TSH level was close to 50.

Her baseline creatinine was found to be close to 1.08 in prior medical records. She presented with a creatinine of 1.8 in the emergency department. Since hypothyroidism causes fluid retention in part because thyroid hormone encourages excretion of free water and partly due to decreased lymphatic function in returning fluid to vascular circulation.  Aggressive diuresis was attempted. As a result, her creatinine increased initially but improved on repeated evaluation, and the patient had a new baseline creatinine of 1.6. Overall she had a net change in the fluid status of 10 liters negative by her ten days of admission in the ICU.

Mildly anemic otherwise, WBC and platelet counts were normal. Electrolyte balance should be monitored closely, paying attention to sodium, potassium, chloride, and calcium specifically as these are worsened in both renal failure and myxedema. 

Daily sedation vacations were enacted, and the patient's mental status improved and was much better when TSH was around 20. The bilateral pleural effusions improved with aggressive diuresis. Breathing trials were initiated when the patient's fio2 requirements decreased to 60% and a PEEP of 8. She was eventually extubated onto BiPAP and then high-flow nasal cannula while off of BiPAP. Pericardial fluid remained stable, and no cardiac tamponade pathology developed. As a result, it was determined that a pericardial window was unnecessary. Furthermore, she was not a candidate for pericardiocentesis as the pericardial effusion was located posterior to the heart. Her renal failure improved with improved cardiac function, diuretics, and thyroid hormone replacement.

After extubation patient had speech and swallow evaluations and was able to resume an oral diet. The patient was eventually transferred out of the ICU to the general medical floor and eventually to a rehabilitation unit.

Despite the name myxedema coma, most patients will not present in a coma status. This illness is at its core a severe hypothyroidism crisis that leads to systemic multiorgan failure. Thyroid hormones T3, and to a lesser extent, T4 act directly on a cellular level to upregulate all metabolic processes in the body. Therefore, deficiency of this hormone is characterized by systemic decreased metabolism and decreased glucose utilization along with increased production and storage of osmotically active mucopolysaccharide protein complexes into peripheral tissues resulting in diffuse edema and swelling of tissue. [1]

Myxedema coma is an illness that occurs primarily in females at a rate of 4:1 compared to men. It typically impacts the elderly at the age of greater than 60 years old, and approximately 90% of cases occur during the winter months. Myxedema coma is the product of longstanding unidentified or undertreated hypothyroidism of any etiology. Thyroid hormone is necessary throughout the body and acts as a regulatory hormone that affects many organ systems. [2] In cardiac tissues, myxedema coma manifests as decreased contractility with subsequent reduction in stroke volume and overall cardiac output.  Bradycardia and hypotension are typically present also. Pericardial effusions occur due to the accumulation of mucopolysaccharides in the pericardial sac, which leads to worsened cardiac function and congestive heart failure from diastolic dysfunction. Capillary permeability is also increased throughout the body leading to worsened edema. Electrocardiogram findings may include bradycardia and low-voltage, non-specific ST waveform changes with possible inverted T waves.

Neurologic tissues are impacted in myxedema coma leading to the pathognomonic altered mental status resulting from hypoxia and decreased cerebral blood flow secondary to cardiac dysfunction as above. Additionally, hypothyroidism leads to decreased glucose uptake and utilization in neurological tissue, thus worsening cognitive function.

The pulmonary system typically manifests this disease process through hypoventilation secondary to the central nervous system (CNS) depression of the respiratory drive with blunting of the response to hypoxia and hypercapnia. Additionally, metabolic dysfunction in the muscles of respiration leads to respiratory fatigue and failure, macroglossia from mucopolysaccharide driven edema of the tongue leads to mechanical obstruction of the airway, and obesity hypoventilation syndrome with the decreased respiratory drive as most hypothyroid patients suffer from obesity.

Renal manifestations include decreased glomerular filtration rate from the reduced cardiac output and increased systemic vascular resistance coupled with acute rhabdomyolysis lead to acute kidney injury. In the case of our patient above who has a pre-existing renal disease status post-nephrectomy, this is further worsened.  The net effect is worsened fluid overload status compounding the cardiac dysfunction and edema. [3]

The gastrointestinal tract is marked by mucopolysaccharide-driven edema as well leading to malabsorption of nutrients, gastric ileus, and decreased peristalsis. Ascites is common because of increased capillary permeability in the intestines coupled with coexistent congestive heart failure and congestive hepatic failure. Coagulopathies are common to occur as a result of this hepatic dysfunction.

Evaluation: The diagnosis of myxedema coma, as with all other diseases, is heavily reliant on the history and physical exam. A past medical history including hypothyroidism is highly significant whenever decreased mental status or coma is identified. In the absence of identified hypothyroidism, myxedema coma is a diagnosis of exclusion when all other sources of coma have been ruled out. If myxedema coma is suspected, evaluation of thyroid-stimulating hormone (TSH), free thyroxine (T4), and serum cortisol is warranted. T4 will be extremely low. TSH is variable depending on the etiology of hypothyroidism, with a high TSH indicating primary hypothyroidism and a low or normal TSH indicating secondary etiologies. Cortisol may be low indicating adrenal insufficiency because of hypothyroidism.  [4]

Prognosis: Myxedema coma is a medical emergency. With proper and rapid diagnosis and initiation of therapy, the mortality rate is still as high as 25% to 50%. The most common cause of death is due to respiratory failure. The factors which suggest a poorer prognosis include increased age, persistent hypothermia, bradycardia, low score Glasgow Coma Scale, or multi-organ impairment indicated by high APACHE (Acute Physiology and Chronic Health Evaluation) II score. For these reasons, placement in an intensive care unit with a low threshold for intubation and mechanical ventilation can improve mortality outcomes. [3] [5]

• Pearls of Wisdom
• Not every case of shortness of breath is COPD or congestive heart failure (CHF). While less likely, a history of hypothyroidism should raise suspicion of myxedema coma in a patient with any cognitive changes.
• Myxedema is the great imitator illness that impacts all organ systems. It can easily be mistaken for congestive heart failure, COPD exacerbation, pneumonia, renal injury or failure, or neurological insult.
• Initial steps in therapy include aggressive airway management, thyroid hormone replacement, glucocorticoid therapy, and supportive measures.
• These patients should be monitored in an intensive care environment with continuous telemetry. [6]
• Enhancing Healthcare Team Outcomes

This case demonstrates how all interprofessional healthcare team members need to be involved in arriving at a correct diagnosis, particularly in more challenging cases such as this one. Clinicians, specialists, nurses, pharmacists, laboratory technicians all bear responsibility for carrying out the duties pertaining to their particular discipline and sharing any findings with all team members. An incorrect diagnosis will almost inevitably lead to incorrect treatment, so coordinated activity, open communication, and empowerment to voice concerns are all part of the dynamic that needs to drive such cases so patients will attain the best possible outcomes.

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Case Study of 60 year old female presenting with Shortness of Breath Contributed by Sandeep Sharma, MD

Disclosure: Deepa Rawat declares no relevant financial relationships with ineligible companies.

Disclosure: Sandeep Sharma declares no relevant financial relationships with ineligible companies.

This book is distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) ( http://creativecommons.org/licenses/by-nc-nd/4.0/ ), which permits others to distribute the work, provided that the article is not altered or used commercially. You are not required to obtain permission to distribute this article, provided that you credit the author and journal.

• Cite this Page Rawat D, Sharma S. Case Study: 60-Year-Old Female Presenting With Shortness of Breath. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan-.

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Long-term outcomes of combination biologic therapy in uncontrolled severe asthma: a case study

Affiliations.

• 1 Department of Health Sciences, Respiratory Unit, ASST Santi Paolo e Carlo, San Paolo Hospital, University of Milan, Milan, Italy.
• 2 Department of Internal Medicine, Asthma and Allergy, Norbert Barlicki Memorial Teaching Hospital No. 1; Medical University of Lodz, Lodz, Poland.
• PMID: 35913268
• DOI: 10.1080/02770903.2022.2109162

Introduction: Treatment with biologics has significantly reduced the social and economic burden of severe asthma. However, some patients may still feature a suboptimal control of their symptoms while on therapy. In this subset of asthmatic patients, a benefit from a dual biologic therapy has sporadically been reported in literature. Our aim is to add our experience to the limited body of evidence supporting combination biologic therapies.

Case study: Here we present the case of a 68-year-old nonsmoker female, with an allergic and eosinophilic corticosteroid-dependent severe asthma. She displayed well controlled comorbidities and good adherence to the inhaled therapy. Omalizumab was started in 2008 with an initial remarkable clinical improvement. After nine years of biologic therapy, she reported a gradual worsening of her symptoms and exacerbations. Mepolizumab was then added in 2019.

Results: The addition of Mepolizumab resulted in a meaningful amelioration of her quality of life, asthma control, number of exacerbations and 6-minute-walking-distance at 3-year follow-up. The average Prednisone dosage was tapered from 25 mg to 20 mg daily. No adverse events were observed since the introduction of the second biologic.

Conclusion: Our experience indicates that Mepolizumab may be beneficial and safe as an add-on biologic in a patient whose allergic and eosinophilic asthma remains uncontrolled despite treatment with an anti-IgE strategy. Further studies on a larger number of patients are required to demonstrate whether the positive outcomes published so far are replicable on a larger scale.

Keywords: Severe asthma; allergic asthma; biologic therapy; eosinophilic asthma; uncontrolled asthma.

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• Case Reports
• Anti-Asthmatic Agents*
• Asthma* / chemically induced
• Asthma* / drug therapy
• Biological Therapy
• Omalizumab / therapeutic use
• Quality of Life
• Anti-Asthmatic Agents

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Gas Stove Pollution Risk Is Greatest in Smaller Homes, Study Finds

Gas-burning ranges, a significant contributor to indoor pollution, can produce and spread particularly high levels of some pollutants in smaller spaces.

By Hiroko Tabuchi

For decades, scientists have worked to clean up air pollution from factories, cars and power plants. But researchers are increasingly turning their attention to the air that people breathe indoors. And one appliance has come to the fore as a source of pollutants harmful to human health: the humble gas stove.

A new study from researchers at Stanford University sheds light on how much Americans may be exposed, indoors, to nitrogen dioxide, which comes from burning coal and gas and has been linked to asthma and other respiratory conditions.

The researchers found that, across the country, short-term nitrogen dioxide exposure from typical gas stove use frequently exceeded benchmarks set by both the World Health Organization and the United States Environmental Protection Agency. In the longer term, using gas or propane stoves meant that the typical American could breathe in three-quarters of the nitrogen dioxide levels deemed safe by the W.H.O. within their own homes.

As with outdoor pollution , disadvantaged households may be more exposed, the researchers found. Because gas more easily spreads throughout smaller spaces, people in homes smaller than 800 square feet were exposed to four times more nitrogen dioxide in the long term than people in homes larger than 3,000 square feet, the study found. Black and Latino households were exposed to 20 percent more nitrogen dioxide compared with the national average.

“We’ve done a really good job in this country of reducing outdoor pollution,” said Rob Jackson, professor of earth system science at the Stanford Doerr School of Sustainability and a principal investigator on the study, which was published on Friday in Science Advances. “But we’ve ignored the risks that people face indoors. And that’s the air that we’re breathing most of the time.”

And though home cooks who use a gas stove are particularly exposed to nitrogen dioxide, he said, “we’re getting a better handle on the migration of pollution down the hall, to the living room and the bedroom.”

The focus on gas stoves isn’t without critics. When a Biden administration official spoke about the health hazards of gas stoves last year, Republican politicians and their allies accused the administration of overreach and of planning to ban gas stoves outright.

Next week, House Republicans are set to meet on a bill called the Hands Off Our Home Appliances Act, which would make it harder for the Department of Energy to set more stringent energy-efficiency standards on household appliances, including gas stoves.

Health experts say that the health risks posed by gas stoves are significant. “There really is no safe amount of exposure to these toxicants produced by gas or propane, or any fossil fuel, outside or inside,” said Kari Nadeau, chairwoman of the Department of Environmental Health at the Harvard T.H. Chan School of Public Health.

The Stanford study estimated that long-term exposure to nitrogen dioxide from stoves was likely causing up to 50,000 cases of asthma in children.

Some cities and counties have tried to move away from gas altogether, as part of a transition to cleaner forms of energy. Over the past few years, more than 140 cities and local governments have sought to restrict gas hookups in new buildings or have taken other measures to end the use of natural gas in new buildings, though those measures have been challenged in court .

“It isn’t ideal to tell people, they have to rip a perfectly good gas stove out of their home,” Dr. Jackson said. But requiring new homes to install electric stoves, which the study found had virtually no harmful emissions, made sense, he said. “Otherwise, we’re putting dirty polluting infrastructure into the next set of homes, and it will be there and 50 years. No one benefits from that.”

The Stanford team took direct measurements of nitrogen dioxide emissions and concentrations at about 100 homes in San Francisco, Los Angeles, New York City and other major U.S. cities, and used indoor air-quality monitoring and epidemiological risk calculations to estimate exposure and health consequences.

They found that home cooks were exposed to three times more nitrogen dioxide pollution compared to the average, said Yannai Kashtan, a Ph.D. candidate at Stanford and the study’s lead researcher. Mr. Kashtan was the subject of a recent article on the debate at Stanford about fossil fuel funding for climate research.

For this study, the researchers also found that the pollution traveled quickly out of the kitchen, down hallways, and into living rooms and bedrooms.

Good ventilation, for example turning on the range hood or opening a window, helped to reduce exposure. But more than that, the study found that “the kind of stove you cook on matters the most,” Mr. Kashtan said. “Ultimately, the best way is to reduce pollution at the source.”

Hiroko Tabuchi covers the intersection of business and climate for The Times. She has been a journalist for more than 20 years in Tokyo and New York. More about Hiroko Tabuchi

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