Early recognition and prevention of acute asthma exacerbation, SCD-related pain and ACS will decrease the effects of both asthma and SCD on the lungs, ultimately improving quality of life and survival. One of the barriers to effective management of children with respiratory symptoms is failure to appropriately recognize asthma in these children [52
]. In children with SCD, cough is likely to be interpreted as the presence of infection, while chest pain or tightness are likely to be interpreted as sickle cell pain requiring analgesics rather than as a sign of asthma. The misclassification of these symptoms may result in worsening asthma. In addition, significant heterogeneity exists in how physicians diagnose asthma in children with SCD. In a survey of clinicians on the important factors required in establishing an initial diagnosis of asthma, only 60% of physicians surveyed correctly identified wheeze, symptomatic improvement with bronchodilator, recurrent cough, exclusion of other diagnosis and peak flow measurements [53
]. A significant number of physicians are reluctant to use systemic corticosteroids in these children because of side effects (see next section). In the absence of specific guidelines for this cohort, it is important that physicians familiarize themselves with the NHLBI recommendations for both prevention of asthma and treatment of acute asthma exacerbation (Box 1
Box 1. National Heart, Lung and Blood Institute recommendations for treatment of acute asthma
- Early recognition of worsening asthma symptoms by patient and physicians are important in the management that takes place in the acute care setting such as the emergency department, physician’s office or urgent care.
- Oxygen to relieve hypoxemia in moderate or severe exacerbations.
- SABA to relieve airflow obstruction.
- Addition of inhaled ipratropium bromide in severe exacerbations.
- Systemic corticosteroids to decrease airway inflammation in moderate or severe exacerbations for patients who fail to respond promptly and completely to a SABA.
- Consideration of adjunct treatments, such as intravenous magnesium sulfate or heliox, in severe exacerbations that are unresponsive to the initial treatments listed above.
- Monitoring response to therapy with serial measurements of lung function.
- Preventing relapse of the exacerbation, or recurrence of another exacerbation by providing: referral to follow-up asthma care within 1–4 weeks; an ED asthma discharge plan with instructions for medications prescribed at discharge, increased medications or advice to seek medical care if asthma worsens; review of inhaler techniques whenever possible; and consideration of initiating inhaled corticosteroids.
ED: Emergency department; SABA: Short-acting β-agonsit.
Reproduced with permission from [20
Typical chest x-ray findings of asthma include hyperinflation of the lungs with flattening of the diaphragm, increased bronchial markings and atelectasis from mucus plugging [54
]. These findings can easily be mistaken for and managed as an infiltrate associated with ACS, instead of an acute asthma exacerbation.
Treatment to reduce asthma-related morbidity requires that asthma severity be classified based on frequency of symptoms and history of exacerbation. Additionally, attempts should be made to recognize exercise-induced symptoms because the majority of these children may not be very active in sports and might have difficulty with activities of daily living, such as coughing or wheezing while walking or climbing up stairs.
Bronchodilators are one of the most commonly prescribed medications for the management of asthma particularly in the setting of an acute exacerbation. These may be in the form of albuterol or other β adrenergic agonists. To date, no randomized controlled studies have been done examining the specific effects of inhaled bronchodilators in children with SCD [55
]. In the setting of ACS, however, bronchodilator use improves oxygenation, clinical outcome and is associated with a mean improvement in FEV1
of about 27% [56
]. As such, in children with ACS where symptoms overlap with asthma, bronchodilator use may improve both asthma and ACS.
Leukotrienes are metabolites of arachidonic acid which, are released during inflammation. These metabolites have effects on both the vasculature as well as airways leading to vaso- and broncho-constriction, and may be important mediators in both SCD and asthma. Individuals with SCD have higher levels of urinary cysteinyl leukotrienes E4 at baseline and significantly increased levels during periods of sickle cell pain and ACS [58
], making it particularly attractive as a future targeted treatment. No studies however have been done looking at the role of leukotriene modifiers in the treatment of asthma in this cohort.
Inhaled or systemic corticosteroids are the cornerstone of maintenance and acute management in children with asthma. However, guidelines for use of this class of medication for children with SCD are unclear. Inhaled corticosteroids were found to be superior to leukotriene modifiers in persistent asthma with the end points of decreased use of albuterol as rescue medication, lower asthma symptoms score, decreased night time cough and awakenings, as well as increased percentage of asthma symptom-free days [61
]. Systemic corticosteroids can be used in the treatment of children with SCD to hasten recovery. Beneficial effect of systemic dexamethasone was demonstrated in a randomized controlled trial of 43 children with SCD and ACS, with a median age of 6.7 years. Duration of hospitalization was lower in children who received dexamethasone, at time intervals of 47 versus 80 h (p = 0.005) [62
]. Other variables such as need for blood transfusions, mean duration of oxygen, analgesic therapy and duration of fever were also lower in the dexamethasone group. However, readmission rate within 72 h after discharge was increased in those who received dexamethasone, although not statistically significant between the two groups (27 vs 4.7%; p = 0.095). A significant weakness in the trial was the observation that participants were not evaluated for the presence of pre-existing asthma, as children with asthma have a higher rate of ACS [62
]. Perhaps the beneficial effect of the corticosteroid treatment group when compared with the nontreatment group was related to being treated for an unrecognized asthma exacerbation.
The high readmission rate associated with steroid administration in SCD was supported in a large multi-institutional retrospective study consisting of 3090 individuals with 5247 hospital admissions for ACS, of which 874 (17%) were associated with corticosteroid use [63
]. Using propensity score analysis to adjust for confounding factors, systemic corticosteroid use was associated with a comorbid asthma diagnosis (OR: 3.9; 95% CI: 3.2–4.8), increased length of stay (OR: 25; 95% CI: 14–38%) and readmission rates within 72 h of discharge (OR: 2.3; 95% CI: 1.6–3.4).
In addition to hospital readmission, systemic corticosteroid use in individuals with SCD is associated with cerebral hemorrhage and fat emboli. Strousse et al.
identified systemic corticosteroid administration as a possible cause of life threatening problems [64
]. In this retrospective case–control study looking for risk factors for hemorrhagic strokes in SCD, hemorrhagic stroke was associated with use of systemic corticosteroids within 14 days prior to event (OR: 20; 95% CI: 2.9–217; p < 0.0005) [64
]. While the exact mechanism for this association is not fully understood, the use of corticosteroid is associated with hypertension which is a well-established factor for stroke in patients without SCD [65
]. Johnson et al.
also reported a fatal case of methylprednisone used in the management of acute asthma exacerbation in a 25 year old male with history of SCD-Sβ+ thal [66
]. Although asthma responded to treatment with corticosteroid the patient deteriorated 18 h after discontinuation of the corticosteroid with severe pain similar to his known vaso-occlusive pain. Autopsy findings were consistent with fat embolism in the lungs, multiple scattered foci of necrosis in the bone marrow as well as a decrease in the amount of fat in the bone marrow for his age [66
Not all studies demonstrate adverse effects of corticosteroid in patients with SCD. In a retrospective chart review of 63 children aged 17 months to 20 years admitted for ACS who received prednisone as part of their treatment regimen, Kumar et al.
did not find an increased rate of hospital readmission [67
]. Although this difference is unclear, the most likely explanation is the exceeding small size of the study when compared with aforementioned hospital study, the lack of a prospective data collection with careful entry criteria, as was the case for the randomized trial and the possible difference between dexamethasone and prednisone, with the former having a longer half-life.
In summary, given the importance of corticosteroids in the management of an asthma exacerbation, corticosteroids should be used with caution, but not withheld when patients with SCD have asthma exacerbations. The optimal dosing schedule for systemic corticosteroids has not been established for individuals with SCD and asthma, but minimizing the exposure to corticosteroids in SCD while not eliminating its benefits is a solid strategy to undertake, until evidence-based guidelines are developed.