hesi case study peds asthma

Nursing Case Study for Pediatric Asthma

Watch More! Unlock the full videos with a FREE trial

Included In This Lesson

Study tools.

Access More! View the full outline and transcript with a FREE trial

Anthony is a 6-yr-old male patient brought to the pediatric ER with a history of asthma since he came home from the NICU as an infant. He lives with his parents, Bob and Josh, who adopted him after fostering him from age 4 months. They have tried the usual nebulizer treatments but Anthony is not responding as usual, so they brought him for evaluation.

Initial assessment in triage reveals both inspiratory and expiratory wheezes, dyspnea, tachypnea, diaphoresis, and retractions.

BP 70/40 mmHg SpO2 93% on room air HR 131 bpm RR 32bpm at rest Temp 38.3°C

What physiologic issue is Anthony suffering from based on the assessment findings?

• Respiratory distress is evidenced by both vital signs and physical assessment findings. His RR and HR are high. He is also sweating and having retractions which may indicate he is working hard to try to establish oxygen exchange.

What signs and symptoms might occur that would show worsening of his condition?

• Skin color changes (i.e. blue or bluish around the mouth or even inside the mouth, blue nail beds, gray or pale compared to usual)
• Grunting on exhalation (this indicates the body is trying to keep air in the lungs)
• Stridor (this is heard in the upper airway and can be an ominous sign)
• Changes in the level of consciousness (becoming lethargic or drowsy)

Anthony is pale but not gray. His lips do indicate a very faint bluish tinge. He can speak but it appears difficult.

What medications might the nurse expect the provider to order?

• Short-acting beta-agonists (SABAs)
• Racemic albuterol – A racemic mixture of albuterol (salbutamol) is the primary SABA used for quick relief of acute asthma symptoms and exacerbations.
• Levalbuterol – Levalbuterol (Levosalbutamol), the R-enantiomer, is the active isomer of racemic albuterol that confers the bronchodilator effects. Levalbuterol is approved in the United States for the treatment of bronchospasm in children ≥4 years of age via hydrofluoroalkane (HFA) metered-dose inhaler (MDI) and ≥6 years of age via solution for nebulizer

What side effects might occur from the medications ordered?

• “The most common side effects are tremor, increased heart rate, and palpitations” Anthony may report feeling jittery due to the activation of beta receptors.

After administration of racemic albuterol, Anthony now has a RR of 22 and O2 saturation of 95% on room air. However, the provider decides to admit him to the inpatient pediatric observation unit. His parents ask if there are ways to keep him from continually being admitted to the hospital.

What are some education topics to bring up to Anthony’s parents?

• Controlling asthma triggers — The factors that set off or worsen asthma symptoms are called “triggers.” Identifying and avoiding asthma triggers is essential to keeping symptoms under control. Common asthma triggers generally fall into several categories:
• Allergens (including dust mites, pollen, mold, cockroaches, mice, cats, and dogs)
• Respiratory infections, such as the common cold or the flu
• Irritants (such as tobacco smoke, chemicals, and strong odors or fumes)
• Exercise or other physical activity

What does the nurse understand about this medication?

• Systemic corticosteroids are an essential treatment option for many disease states, especially asthma. These medications reduce the length and severity of asthma exacerbations and reduce the need for hospitalization or ED visits. It is important for asthma patients to receive prednisolone as soon as possible after the onset of symptoms that are bronchodilator-unresponsive to attain these benefits.
• Although usually prescribed for a 5- to 7-day period, oral corticosteroids are not without adverse effects. The most common adverse effects are the same for the majority of oral corticosteroids and include increased appetite, weight gain, flushed face.
• Increased risk of infections, especially with common bacterial, viral and fungal microorganisms. Thinning bones (osteoporosis) and fractures happen over time, be mindful this may cause problems in an energetic child. Suppressed adrenal gland hormone production may result in a variety of signs and symptoms, including severe fatigue, loss of appetite, nausea and muscle weakness.

Anthony sleeps during the night shift and the next day, his pediatrician makes rounds and discusses a change in the severity rating of Anthony’s asthma.

What does the nurse know about asthma severity and how it is determined?

• Asthma severity is the intrinsic intensity of the disease. Assessment of asthma severity is made on the basis of components of current impairment and future risk. The severity is determined by the most severe category measured

Bob and Josh are interested in meeting with respiratory therapy for assistance with inhalers. They say that Anthony has trouble using inhaler devices.

Inviting respiratory therapy to provide parent teaching is an example of what? How can this department help the family?

• Interdisciplinary team collaboration.
• Teaching about medications, proper inhaler (or other equipment) use, thorough explanation of peak expiratory flow (PEF) measuring, ways to help control RR.

After lunch, Anthony is ready to be discharged. His parents verbalize gratitude to the staff and thank the team for helping with education.

What can the nurse help Bob and Josh start to establish to try to help them with Anthony’s condition?

• Setting goals and planning. Preparing for an action plan (“Asthma ‘action plan’ is a form or document that your child’s provider can help you put together; it includes instructions about how to monitor symptoms and what to do when they happen. Asthma action plans are available for children up to five years old, for children five years and older and adults and for school. An action plan can tell you when to add or increase medications, when to call your child’s provider, and when to get immediate emergency help. This can help you know what to do in the event of an asthma attack. Different people can have different action plans, and your child’s action plan will likely change over time.”) 

View the FULL Outline

When you start a FREE trial you gain access to the full outline as well as:

• SIMCLEX (NCLEX Simulator)
• 6,500+ Practice NCLEX Questions
• 2,000+ HD Videos
• 300+ Nursing Cheatsheets

“Would suggest to all nursing students . . . Guaranteed to ease the stress!”

References:

View the full transcript, nursing case studies.

This nursing case study course is designed to help nursing students build critical thinking.  Each case study was written by experienced nurses with first hand knowledge of the “real-world” disease process.  To help you increase your nursing clinical judgement (critical thinking), each unfolding nursing case study includes answers laid out by Blooms Taxonomy  to help you see that you are progressing to clinical analysis.We encourage you to read the case study and really through the “critical thinking checks” as this is where the real learning occurs.  If you get tripped up by a specific question, no worries, just dig into an associated lesson on the topic and reinforce your understanding.  In the end, that is what nursing case studies are all about – growing in your clinical judgement.

Nursing Case Studies Introduction

Cardiac nursing case studies.

• 6 Questions
• 7 Questions
• 5 Questions
• 4 Questions

GI/GU Nursing Case Studies

• 2 Questions
• 8 Questions

Obstetrics Nursing Case Studies

Respiratory nursing case studies.

• 10 Questions

Pediatrics Nursing Case Studies

• 3 Questions
• 12 Questions

Neuro Nursing Case Studies

Mental health nursing case studies.

• 9 Questions

Metabolic/Endocrine Nursing Case Studies

Other nursing case studies.

• 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

11k Accesses

14 Citations

12 Altmetric

Metrics details

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

Case presentation

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

Conclusions

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

Peer Review reports

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

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

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

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

Case presentations

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

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

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

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

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

Discussion and conclusions

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

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

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

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

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

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

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

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

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

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

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

Indications for omalizumab in children and adolescents with severe asthma

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

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

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

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

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

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

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

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

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

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

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

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

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

Abbreviations

Anti-immunoglobulin E

Body mass index

IgE receptor

Forced expiratory flow between 25% and 75%

Forced expiratory volume in the first second

Gastroesophageal reflux

Inhaled corticosteroids

Intensive care unit

Interleukin

Long-acting β 2 -agonist

Oral leukotriene receptor antagonist

Quality of life

Randomized controlled trials

Short-acting β 2 -agonists

Sleep-disordered breathing

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

Article   PubMed   Google Scholar  

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

Article   Google Scholar  

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

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

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

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

Article   CAS   PubMed   Google Scholar  

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

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

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

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

Article   CAS   PubMed   PubMed Central   Google Scholar  

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

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

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

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

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

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

Article   PubMed   PubMed Central   Google Scholar  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Article   PubMed Central   Google Scholar  

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

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

CAS   PubMed   Google Scholar  

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

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

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

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

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

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

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

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

Google Scholar  

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

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

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

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

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

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

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

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

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

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

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

Article   CAS   Google Scholar  

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Download references

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.

No funding was secured for this study.

Availability of data and materials

All relevant data and materials are published in the manuscript.

Author information

Authors and affiliations.

Department of Translational Medical Sciences, Federico II University, Via Sergio Pansini 5, 80131, Naples, Italy

Virginia Mirra, Silvia Montella & Francesca Santamaria

You can also search for this author in PubMed   Google Scholar

Contributions

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

Corresponding author

Correspondence to Francesca Santamaria .

Ethics declarations

Ethics approval and consent to participate.

This study was approved by the ethics committee “Carlo Romano”, Federico II University, Naples, Italy. Children’s parents/legal guardians gave informed written consent to participate. The description of our cases adheres to the CARE standards of reporting checklist.

Consent for publication

Children’s parents/legal guardians provided informed written consent for the case report to be published.

Competing interests

The authors declare that they have no competing interests to disclose. Authors have no financial relationships relevant to this article to disclose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/ ), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article, unless otherwise stated.

Reprints and permissions

About this article

Cite this article.

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

Download citation

Received : 24 May 2016

Accepted : 29 January 2018

Published : 21 February 2018

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

Share this article

Anyone you share the following link with will be able to read this content:

Sorry, a shareable link is not currently available for this article.

Provided by the Springer Nature SharedIt content-sharing initiative

• Severe asthma
• Adolescents
• Asthma exacerbations

BMC Pediatrics

ISSN: 1471-2431

• Submission enquiries: [email protected]
• General enquiries: [email protected]

• Skip to main content

Update your browser for the best possible experience

As of January 1st, 2020, Internet Explorer (versions 11 and below) is no longer supported by Evolve. To get the best possible experience using Evolve, we recommend that you use another web browser. For HESI iNet users click here .

• Search Menu
• Sign in through your institution
• Advance Articles
• Supplements
• Author Guidelines
• Reviewer guidelines
• Submission Site
• Open Access
• Self-Archiving Policy
• Why Publish?
• Advertising & Corporate Services
• Advertising
• Reprints and ePrints
• Sponsored Supplements
• Branded Books
• Journals Career Network
• About Paediatrics & Child Health
• About The Canadian Paediatric Society
• Editorial Board
• Journals on Oxford Academic
• Books on Oxford Academic

Article Contents

Case 1 diagnosis: allergy bullying, clinical pearls.

• < Previous

Case 1: A 12-year-old girl with food allergies and an acute asthma exacerbation

• Article contents
• Figures & tables
• Supplementary Data

Lopamudra Das, Michelle GK Ward, Case 1: A 12-year-old girl with food allergies and an acute asthma exacerbation, Paediatrics & Child Health , Volume 19, Issue 2, February 2014, Pages 69–70, https://doi.org/10.1093/pch/19.2.69

• Permissions Icon Permissions

A 12-year-old girl with a history of asthma presented to the emergency department with a three-day history of increased work of breathing, cough and wheezing. She reported no clear trigger for her respiratory symptoms, although she had noted some symptoms of a mild upper respiratory tract infection. With this episode, the patient had been using a short-acting bronchodilator more frequently than she had in the past, without the expected resolution of symptoms.

On the day of presentation, the patient awoke feeling ‘suffocated’ and her mother noted her lips to be blue. In the emergency department, her oxygen saturation was 85% and her respiratory rate was 40 breaths/min. She had significantly increased work of breathing and poor air entry bilaterally to both lung bases, with wheezing in the upper lung zones. She was treated with salbutamol/ipratropium and received intravenous steroids and magnesium sulfate. Her chest x-ray showed hyperinflation and no focal findings.

Her medical history revealed that she was followed by a respirologist for her asthma, had good medication adherence and had not experienced a significant exacerbation for six months. She also had a history of wheezing, dyspnea and pruritis with exposure to peanuts, chickpeas and lentils; she had been prescribed an injectible epinephrine device for this. However, her device had expired at the time of presentation. In the past, her wheezing episodes had been seasonal and related to exposure to grass and pollens; this presentation occurred during the winter. Further history revealed the probable cause of her presentation.

Although reluctant to disclose the information, our patient later revealed that she had been experiencing significant bullying at school, which was primarily related to her food allergies. Three days before her admission, classmates had smeared peanut butter on one of her schoolbooks. She developed pruritis immediately after opening the book and she started wheezing and coughing later that day. This event followed several months of being taunted with peanut products at school. The patient was experiencing low mood and reported new symptoms of anxiety related to school. The review of systems was otherwise negative, with no substance use.

The patient's asthma exacerbation resolved with conventional asthma treatment. Her pulmonary function tests were nonconcerning (forced expiratory volume in 1 s 94% and 99% of predicted) after her recovery. The trigger for her asthma exacerbation was likely multifactorial, related to exposure to the food allergen as well as the upper respiratory infection. A psychologist was consulted to assess the symptoms of anxiety and depression that had occurred as a result of the bullying. During the hospitalization, the medical team contacted the patient's school to provide education on allergy bullying, treatment of severe allergic reactions and its potential for life-threatening reactions with exposure to allergens. The medical team also recommended community resources for further education of students and staff about allergy bullying and its prevention.

Allergy bullying is a form of bullying with potentially severe medical outcomes. In recent years, it has gained increasing notoriety in schools and in the media. Population-based studies have shown that 20% to 35% of children with allergies experience bullying. In many cases (31% in one recent study [ 1 ]), this bullying is related directly to the food allergy. From a medical perspective, there are little published data regarding allergy bullying, and many health care providers may not be aware of the issue.

Allergy bullying can include teasing a child about their allergy, throwing food at a child, or even forcing them to touch or eat allergenic foods. Most episodes of allergy bullying occur at school, and can include episodes perpetrated by teachers and/or staff ( 2 ).

Allergy bullying can lead to allergic reactions, which may be mild or severe (eg, urticaria, wheezing, anaphylaxis), but may also lead to negative emotional consequences (sadness, depression) ( 2 ) and an overall decrease in quality of life measures ( 1 ). Adolescents commonly resist using medical devices, such as injectible epinephrine devices, and bullying may be a contributing factor for this ( 3 ). Attempting to conceal symptoms in a bullying situation may place children at risk for a worse outcome.

Physicians can play a key role in detecting allergy bullying and its health consequences. In many cases, children have not discussed this issue with their parents ( 1 ). Given the prevalence of bullying, its potential to lead to severe harm, including death, and the lack of awareness of this issue, clinicians should specifically ask about bullying in all children and teens with allergies. Physicians can also work with families and schools to support these children, educate their peers and school staff, and help prevent negative health outcomes from allergy bullying.

Online resources

www.anaphylaxis.ca − A national charity that aims to inform, support, educate and advocate for the needs of individuals and families living with anaphylaxis, and to support and participate in research. This website includes education modules for schools and links to local support groups throughout Canada.

www.whyriskit.ca/pages/en/live/bullying.php − A website for teenagers with food allergies; includes a segment that addresses food bullying.

www.foodallergy.org − Contains numerous resources for children and their families, including a significant discussion on bullying and ways to prevent it.

Allergy bullying is common but is often unrecognized as a factor in clinical presentations of allergic reactions.

Physicians should make a point of asking about bullying in patients with allergies and become familiar with resources for dealing with allergy bullying.

Physicians can play roles as advocates, educators and collaborators with the school system to help make the school environment safer for children with allergies who may be at risk for allergy bullying.

Google Scholar

Email alerts

Citing articles via, looking for your next opportunity.

• About Paediatrics & Child Health
• Recommend to Your Librarian
• Advertising and Corporate Services

Affiliations

• Online ISSN 1918-1485
• Print ISSN 1205-7088
• Copyright © 2024 Oxford University Press
• About Oxford Academic
• Publish journals with us
• University press partners
• What we publish
• New features  
• Open access
• Institutional account management
• Rights and permissions
• Get help with access
• Accessibility
• Media enquiries
• Oxford University Press
• Oxford Languages
• University of Oxford

Oxford University Press is a department of the University of Oxford. It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide

• Copyright © 2024 Oxford University Press
• Cookie settings
• Cookie policy
• Privacy policy
• Legal notice

This Feature Is Available To Subscribers Only

Sign In or Create an Account

This PDF is available to Subscribers Only

For full access to this pdf, sign in to an existing account, or purchase an annual subscription.

HESI Case Studies Asthma – Flashcards

Unlock all answers in this set

Haven't found what you were looking for, search for samples, answers to your questions and flashcards.

• Enter your topic/question
• Receive an explanation
• Ask one question at a time
• Enter a specific assignment topic
• Aim at least 500 characters
• a topic sentence that states the main or controlling idea
• supporting sentences to explain and develop the point you’re making
• evidence from your reading or an example from the subject area that supports your point
• analysis of the implication/significance/impact of the evidence finished off with a critical conclusion you have drawn from the evidence.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings
• My Bibliography
• Collections
• Citation manager

Save citation to file

Email citation, add to collections.

• Create a new collection
• Add to an existing collection

Add to My Bibliography

Your saved search, create a file for external citation management software, your rss feed.

• Search in PubMed
• Search in NLM Catalog
• Add to Search

Modifications to HEDIS and CSTE algorithms improve case recognition of pediatric asthma

Affiliation.

• 1 Department of Pediatrics, University of Connecticut Health Center, Hartford, Connecticut, USA. [email protected]
• PMID: 16871628
• DOI: 10.1002/ppul.20476

Our objective was to validate the Council of State and Territorial Epidemiologists (CSTE) definition of "probable" asthma and the Health Plan Employer Data and Information Set (HEDIS) definition of persistent asthma for diagnosis of pediatric asthma, and examine modifications that improve case recognition. CSTE and HEDIS criteria were applied to a cross-sectional study of 3,905 Medicaid children with physician-confirmed diagnosis of asthma/no asthma using a validated survey instrument based upon National Asthma Education and Prevention Program (NAEPP) Guidelines. Modified criteria were applied to another group of 1,458 non-Medicaid children from a managed care organization (MCO). Of 1,852 Medicaid children with physician-confirmed asthma, 906 had persistent asthma. CSTE identified 61% of children with "probable" asthma; HEDIS identified 44% of children with persistent asthma. Correct identification increased with greater disease severity. A modified CSTE increased sensitivity from 0.61 to 0.90, while maintaining high specificity. Three new HEDIS algorithms increased sensitivity from 0.44 to >0.84, with specificity >0.89. When applied prospectively to MCO children, these new algorithms demonstrated improved sensitivity. In conclusion, studies using current CSTE or HEDIS algorithms for case recognition underestimate asthma prevalence and overestimate asthma severity in children. Modified algorithms improve the identification of "probable" and persistent asthma.

(c) 2006 Wiley-Liss, Inc.

PubMed Disclaimer

Similar articles

• Diagnosis and management of asthma in preschool and school-age children: focus on the 2007 NAEPP Guidelines. Horner CC, Bacharier LB. Horner CC, et al. Curr Opin Pulm Med. 2009 Jan;15(1):52-6. doi: 10.1097/MCP.0b013e32831da8ea. Curr Opin Pulm Med. 2009. PMID: 19077706 Review.
• Use of the health plan employer data and information set for measuring and improving the quality of asthma care. Gelfand EW, Colice GL, Fromer L, Bunn WB 3rd, Davies TJ. Gelfand EW, et al. Ann Allergy Asthma Immunol. 2006 Sep;97(3):298-305. doi: 10.1016/S1081-1206(10)60793-4. Ann Allergy Asthma Immunol. 2006. PMID: 17042134 Review.
• Validity of the HEDIS criteria to identify children with persistent asthma and sustained high utilization. Fuhlbrigge AL, Carey VJ, Finkelstein JA, Lozano P, Inui TS, Weiss ST, Weiss KB. Fuhlbrigge AL, et al. Am J Manag Care. 2005 May;11(5):325-30. Am J Manag Care. 2005. PMID: 15898221
• Limits of the HEDIS criteria in determining asthma severity for children. Cabana MD, Slish KK, Nan B, Clark NM. Cabana MD, et al. Pediatrics. 2004 Oct;114(4):1049-55. doi: 10.1542/peds.2003-1162-L. Pediatrics. 2004. PMID: 15466104 Clinical Trial.
• Assessing the quality of asthma care provided to Medicaid patients enrolled in managed care organizations in Connecticut. Apter AJ, Van Hoof TJ, Sherwin TE, Casey BA, Petrillo MK, Meehan TP. Apter AJ, et al. Ann Allergy Asthma Immunol. 2001 Feb;86(2):211-8. doi: 10.1016/S1081-1206(10)62693-2. Ann Allergy Asthma Immunol. 2001. PMID: 11258692
• Association Between Aluminum Exposure From Vaccines Before Age 24 Months and Persistent Asthma at Age 24 to 59 Months. Daley MF, Reifler LM, Glanz JM, Hambidge SJ, Getahun D, Irving SA, Nordin JD, McClure DL, Klein NP, Jackson ML, Kamidani S, Duffy J, DeStefano F. Daley MF, et al. Acad Pediatr. 2023 Jan-Feb;23(1):37-46. doi: 10.1016/j.acap.2022.08.006. Epub 2022 Sep 28. Acad Pediatr. 2023. PMID: 36180331 Free PMC article.
• Predicting Continuity of Asthma Care Using a Machine Learning Model: Retrospective Cohort Study. Tong Y, Lin B, Chen G, Zhang Z. Tong Y, et al. Int J Environ Res Public Health. 2022 Jan 22;19(3):1237. doi: 10.3390/ijerph19031237. Int J Environ Res Public Health. 2022. PMID: 35162261 Free PMC article.
• Using a Constraint-Based Method to Identify Chronic Disease Patients Who Are Apt to Obtain Care Mostly Within a Given Health Care System: Retrospective Cohort Study. Tong Y, Liao ZC, Tarczy-Hornoch P, Luo G. Tong Y, et al. JMIR Form Res. 2021 Oct 7;5(10):e26314. doi: 10.2196/26314. JMIR Form Res. 2021. PMID: 34617906 Free PMC article.
• Ranking Rule-Based Automatic Explanations for Machine Learning Predictions on Asthma Hospital Encounters in Patients With Asthma: Retrospective Cohort Study. Zhang X, Luo G. Zhang X, et al. JMIR Med Inform. 2021 Aug 11;9(8):e28287. doi: 10.2196/28287. JMIR Med Inform. 2021. PMID: 34383673 Free PMC article.
• Using Computational Methods to Improve Integrated Disease Management for Asthma and Chronic Obstructive Pulmonary Disease: Protocol for a Secondary Analysis. Luo G, Stone BL, Sheng X, He S, Koebnick C, Nkoy FL. Luo G, et al. JMIR Res Protoc. 2021 May 18;10(5):e27065. doi: 10.2196/27065. JMIR Res Protoc. 2021. PMID: 34003134 Free PMC article.

Publication types

• Search in MeSH

Related information

Grants and funding.

• R01HL70785/HL/NHLBI NIH HHS/United States
• U18HS11147/HS/AHRQ HHS/United States

LinkOut - more resources

Full text sources.

• Ovid Technologies, Inc.
• Genetic Alliance
• MedlinePlus Consumer Health Information
• MedlinePlus Health Information

• Citation Manager

NCBI Literature Resources

MeSH PMC Bookshelf Disclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

An official website of the United States government

The .gov means it’s official. Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

The site is secure. The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

• Publications
• Account settings

Preview improvements coming to the PMC website in October 2024. Learn More or Try it out now .

• Advanced Search
• Journal List
• BMC Pediatr

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

Virginia mirra.

Department of Translational Medical Sciences, Federico II University, Via Sergio Pansini 5, 80131 Naples, Italy

Silvia Montella

Francesca santamaria, associated data.

All relevant data and materials are published in the manuscript.

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.

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 – 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 ].

Recommended options for initial controller treatment in children and adults according to GINA Guidelines [ 5 ]

Theophylline is not recommended for children 6–11 years, while tiotropium is not indicated in patients < 18 years

ICS inhaled corticosteroids, LTRA leukotriene receptor antagonist, LABA long-acting β 2 -agonist, anti-IgE anti-immunoglobulin E therapy, OCS oral corticosteroids

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 ].

Clinical characteristics of described patients with difficult asthma

GER Gastroesophageal reflux, ICU Intensive care unit

Clinical findings at baseline and after 12 months of follow-up in patients with difficult asthma

BD bronchodilator, Δ % predicted changes from the pre-bronchodilator values, FeNO fractional exhaled nitric oxide, Ppb part per billion, QoL Quality of Life defined according to references [ 14 ], c-ACT Children Asthma Control Test evaluated according to references [ 79 , 80 ], NA Not Available

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 – 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 – 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 – 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 – 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 – 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 – 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 – 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 – 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 – 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.

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.

No funding was secured for this study.

Availability of data and materials

Abbreviations.

Authors’ contributions

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

Ethics approval and consent to participate

This study was approved by the ethics committee “Carlo Romano”, Federico II University, Naples, Italy. Children’s parents/legal guardians gave informed written consent to participate. The description of our cases adheres to the CARE standards of reporting checklist.

Consent for publication

Children’s parents/legal guardians provided informed written consent for the case report to be published.

Competing interests

The authors declare that they have no competing interests to disclose. Authors have no financial relationships relevant to this article to disclose.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Contributor Information

Virginia Mirra, Email: [email protected] .

Silvia Montella, Email: ti.oiligriv@4002anima .

Francesca Santamaria, Phone: +39 0817463495, Email: ti.aninu@ramatnas .

• HESI ENTRANCE EXAM
• Exams Bundles
• NR & NUR Exams
• AQA PAPERS AND MARK SCHEME
• Study Material
• Exams and Certifications
• PORTAGE LEARNING
• Ihuman Case Study

Learn exams

[email protected], hesi pn pediatrics proctored exam version 11 (complete and verified study material) (2pages) learnexams, section 1 : hesi pn 100 min.

1. HESI PN PEDIATRICS PROCTORED EXAM VERSION 11 (Complete And Verified Study material) (2pages) LEARNEXAMS

• Description
• Associate quiz

The nurse is teaching the parents of an infant with tonsillitis caused by group A ß-hemolytic streptococci about the importance of compliance with antibiotic therapy. What teaching regarding this infection is important to share with the parents? - Teach parents to administer antibiotics for the full course of treatment even if the infant is feeling better. A child was sent home from school with head lice. The child's mother has called the help line nurse for guidance. What are three (3) measures the nurse will inform the mother about to address the infestation of pediculosis capitis? - 1% permethrin shampoo spinosa 0.9% topical suspension , remove nits with a nit comb, repeat in 7 days after shampoo treatment, wash clothing and bedding in hot water, for difficult cases use malathion 0.5%, bag and seal items that cannot be washed into a tightly sealed bag for 14 days, boil combs, brushes, and hair accessories for 10 minutes. What are the expected physical growth mile markers for a 6 months infant? - Rolls from back to front, holds bottle, begins to sit without support What are the common causes of iron deficiency anemia and which children are at risk? - Lack of iron intake and excessive milk intake. Children who are at risk are pre term or low birth weight infants and formula fed infants.

Average Rating

Join over 1.6 million students using Learnexams real exams, practice tests and expert solutions to improve their grades and reach their goals.

Other Pages

Modal title.

• Upload a document
• Create a quiz
• Bundle items
• Offer study services
• Respond to requests

How it works

• Support and Help
• Regulations

• Study Documents Lecture notes, book summaries and practice exams for your course.
• Study Services Tutors who offer tutoring, thesis help and translation for your course.
• Quizzes Use quiz questions to test whether you know the subject matter.
• Studybot Receive immediate answers to your study questions.

Sell your lecture notes and other study documents.

Create your own quizzes. Then sell them to others.

Package documents and quizzes together to earn more cash.

Work as a tutor and provide personalized learning in your area of expertise.

View students’ requests and send a proposal of your relevant services.

• View all your notifications
• Studies & Theses
• Assignments & Homework
• Lecture notes
• Examinations
• Book Reports
• Presentations

Choose a country

• Netherlands
• View all documents
• View all textbooks

Sell summaries and other study documents

What do you need help with.

• Proofreading & editing
• Translation
• Other study problems
• View all services
• Respond to request
• Place a request

Work as a tutor and provide personalized learning.

• Secondary Education
• View all quizzes

Create quiz

• Create quiz by AI Beta
• Create your own quiz

How can Studybot help?

• Explain topic
• Create quiz questions
• Receive inspiration
• Do research
• View all options
• Explain problem
• Spelling and grammar checker
• Create practice exam
• Create analysis
• Make a study plan
• My studybot answers
• View all answers

Receive immediate answers to your study questions

• Chamberlain

HESI OB PEDS EXIT EXAM NEWEST 2024 COMPLETE 110 QUESTIONS AND CORRECT DETAILED ANSWERS (VERIFIED ANSWERS) |ALREADY GRADED A+

HESI OB PEDS EXIT EXAM NEWEST 2024 COMPLETE 110 QUESTIONS AND CORRECT DETAILED ANSWERS (VERIFIED ANSWERS) |ALREADY GRADED A+ HESI OB PEDS EXIT EXAM NEWEST 2024 COMPLETE 110 QUESTIONS AND CORRECT DETAILED ANSWERS (VERIFIED ANSWERS) |ALREADY GRADED A+

Preview document (3 of 31 pages)

Download all 31 pages for $ 35 .06

Knoowy benefits

$ 35 .06.

Specifications

• Level: University
• School: Chamberlain
• Course: Nursing
• Subject: Hesi ob
• All documents for this course ›
• Date of exam: 2024
• Year of study: 2024
• Section: Examinations
• Made on: 07-01-2024
• Language: English
• Hesi ob pedriatics

250 documents uploaded

18 documents sold

I am passionate and reliable in my work as a tutor, for all your assignments and questions on Various subjects, please don't hesitate to reach out to me. this page contains updated exam solution . May you Prosper in your field of studies.

Earn from your summaries?

Do you make summaries or do you have any completed assignments? Upload your documents to Knoowy and earn money.

You may also find these Examinations helpful

CRCST EXAM QUESTIONS AND CORRECT ANSWERS 300 REAL EXAM QUESTIONS AND ANSWERS LATEST 2023-2025 | VE

CRCST EXAM QUESTIONS AND CORRECT ANSWERS 300 REAL EXAM QUESTIONS AND ANSWERS LATEST 2023-2025 | VERIFIED ANSWERS CRCST EXAM QUESTIONS AND CORRECT ANSWERS 300 REAL EXAM QUESTIONS AND ANSWERS LATEST 2023-2025 | VERIFIED ANSWERS CRCST EXAM QUESTIONS AND...

ATI RN NURSING CARE OF CHILDREN 16 LATEST VERSIONS 2022-2023/NURSING CARE OF CHILDREN ATI PROCTORED

ATI RN NURSING CARE OF CHILDREN 16 LATEST VERSIONS 2022-2023/NURSING CARE OF CHILDREN ATI PROCTORED REAL EXAM QUESTIONS AND CORRECT ANSWER|AGRADE ATI RN NURSING CARE OF CHILDREN 16 LATEST VERSIONS 2022-2023/NURSING CARE OF CHILDREN ATI PROCTORED REAL ...

COMMUNITY HEALTH EXAM 2 2023-2025 QUESTIONS AND ANSWERS// GRADED A+

COMMUNITY HEALTH EXAM 2 2023-2025 QUESTIONS AND ANSWERS// GRADED A+ COMMUNITY HEALTH EXAM 2 2023-2025 QUESTIONS AND ANSWERS// GRADED A+ COMMUNITY HEALTH EXAM 2 2023-2025 QUESTIONS AND ANSWERS// GRADED A+ COMMUNITY HEALTH EXAM 2 2023-2025 QUESTIONS AND A...

COM 316 / COM316 EXAM 1 LATEST 2023-2024 GENDER AND COMMUNICATION QUESTIONS AND CORRECT ANSWERS

COM 316 / COM316 EXAM 1 LATEST 2023-2024 GENDER AND COMMUNICATION QUESTIONS AND CORRECT ANSWERS COM 316 / COM316 EXAM 1 LATEST 2023-2024 GENDER AND COMMUNICATION QUESTIONS AND CORRECT ANSWERS COM 316 / COM316 EXAM 1 LATEST 2023-2024 GENDER AND CO...

Subjects of Nursing - Chamberlain

Related quiz questions.

Earn money and help students with your study services

Test yourself and earn money with selfmade quizzes

• Study Documents
• Study Services
• Upload documents
• Create quizzes
• Support & Help
• Platform guidelines
• Report abuse
• Terms of use
• Privacy policy

Buy and sell summaries and other study documents for: University - Secondary Education - All study documents

Get the help of tutors: Tutoring - Proofreading & editing - Research - Assignments & homework - Translation - Other study problems

Learning support: Learning quiz questions - Create quiz questions - Ask a studybot question - Studybot answers

Upon registration you agree to our privacy statement and terms and conditions .

• € Euro (EUR)
• $ US Dollar (USD)
• Discount: - $   
• Total: $   

Deal: get 10% off when you purchase 3 or more items!

[inviter] gives you € 2.50 to purchase summaries.

At Knoowy you buy and sell the best studies documents directly from students. <br> Upload at least one item, please help other students and get € 2.50 credit.

Knoowy uses functional, analytical, and marketing cookies 🍪. See our privacy policy for more details.