Abstract and Introduction
Abstract
Children with sickle cell disease (SCD) and a comorbid condition of asthma have increased numbers of vaso-occlusive pain and acute chest syndrome episodes, and all-cause mortality. When assessed systematically, asthma prevalence is probably similar among children with SCD when compared with the general African–American population. With increasing recognition of the importance of asthma in the management of SCD, hematologists must become familiar with asthma and develop a multidisciplinary approach, including early recognition, appropriate management and referral to asthma specialists.
Introduction
Sickle cell disease (SCD) is one of the common hemoglobinopathies worldwide and is inherited as an autosomal recessive disorder by mendalian genetics. Hemoglobin SS (SCD-SS) and sickle cell-β0thalassemia (SCD-S β0thal) are the most severe phenotypes, occurring in approximately 60% of individuals with SCD in North America. Other compound heterozygote phenotypes, including hemoglobin SC (SCD-SC) and sickle cell-β+ thalassemia (SCD-Sβ+ thal) occur in approximately 9–12% and 1%, respectively, based on data from newborn cohort studies. The underlying defect in SCD-SS is a single nucleotide substitution, which results in a hemoglobin molecule that has substitution of glutamic acid with valine at position 6 of the β-globin molecule. SCD-SC occurs from single nucleotide exchange resulting in the substitution of glutamic acid with lysine also at position 6 of the hemoglobin molecule. These amino acid switches change the net electrical charge of the hemoglobin molecule making it easily susceptible to polymerization under states of low oxygen tension and stress. SCD-Sβ+ thal and SCD-Sβ0thal phenotypes are due to impaired production of β-hemoglobin chains resulting from gene deletions or mutations in the presence of the sickle cell mutation in the other β-globin allele. SCD-Sβ+ thal is characterized by decreased production, and SCD-Sβ0thal by complete absence, of the β-chain. Atopic asthma, a chronic disorder of the airways, is characterized by recurrent episodes of airway narrowing from inflammation, mucus plugging and bronchoconstriction culminating in airway remodeling. Similar to SCD, asthma exhibits significant heterogeneity in clinical presentation in children. Diagnosis of asthma is primarily based on symptoms and clinical findings, and can be supported by pulmonary function tests, such as the presence of airway obstruction and bronchodilator response on spirometry, which may also be useful in monitoring effectiveness of treatment. Supporting laboratory tests include elevation of total serum IgE levels, peripheral blood eosinophilia and specific allergen sensitivity. Despite being supportive for the diagnosis of asthma, the use of laboratory or pulmonary function studies alone are not indicative of an asthma diagnosis. In our clinical experience, in the setting of acute asthma exacerbation, many patients with SCD will not have decreased oxygen saturation[10] and will not have any audible wheezing; however, when spirometry is performed there is evidence of airway reversibility that correlates with the current symptoms.
Epidemiology of Asthma & SCD
Newborn screening data between 1990 and 1999 reported an incidence of SCD of one in 2474 of live births.[11] All 50 states and the District of Colombia currently have active screening programmes for hemoglobinopathies.[12] In the USA, SCD population estimates ranged from 104,000 to 138,900 based on birth cohort disease prevalence, but from 72,000 to 98,000 when corrected for early mortality.[13]
The past 20 years have seen a doubling in the incidence of asthma, with about 34 million people affected.[14] Between 2006 and 2008, asthma prevalence was 9.3% amongst children under the age of 17 years, with prevalence in African–Americans at 14.6% and multiracial children, 13.6%, when compared with Caucasians, 8.2%.[15] Unlike children, the prevalence of asthma in African–Americans adults is 7.8%, similar to the general population prevalence of 7.3%.[15] These prevalence estimates for asthma were based on eliciting a positive response by an adult member of a family to the question 'have you ever been told by a doctor or other health care professional that you have asthma?' and 'do you still have asthma?'.[15] When the prevalence of asthma in SCD is compared with the general African–American population, there appears to be a similar or slightly higher prevalence of asthma, only one study was designed to address prevalence in the same geographic area (Table 1). Variation in asthma prevalence in SCD is as a result of different definitions used in the diagnosis of asthma. Less stringent definitions of asthma as well as a selection bias towards individuals with underlying lung disease results in a higher prevalence of asthma. However, in Saint Louis (MO, USA) where children with SCD have been assessed for asthma using standardized clinical and pulmonary function criteria, the prevalence of asthma in SCD is similar to that seen in the Saint Louis city elementary schools where the racial mixture is similar to that in the SCD clinic.
Rationale for Article
Asthma is a distinct, common comorbid condition in SCD; associated with an increase in SCD-related morbidity and premature mortality. Despite the well recognized clinical entity of asthma, particularly in children, nuances of asthma diagnosis in children with SCD are challenging with common symptoms of asthma such as cough, wheeze, chest pain and exercise intolerance attributed to infection or SCD instead of asthma. Further compounding the diagnosis is the fact that while positive test results for airway lability, such as methacholine challenge test and bronchodilator response, are strong predictors for asthma in the general population, their association with asthma in SCD is far less clear. In children with SCD, a physician diagnosis of asthma remains the primary basis of children at risk for pain and acute chest syndrome. Among all children with SCD, evaluation for asthma risk factors should be carried out routinely and repeatedly, but the results of these tests should not supersede the physician diagnosis of asthma. Understanding the nuances of diagnosis of asthma, particularly in children with SCD, is critical because a physician diagnosis of asthma is one of the few established risk factors associated with SCD-related morbidity.
Optimal management of asthma in children with SCD has not been established, but practical approaches to care can be gleaned from asthma management in the general population. Until more asthma specific studies on therapy in SCD are available, asthma in children and adults with SCD should be recognized early and managed according to National Heart, Lung and Blood Institute (NHLBI) guidelines for asthma therapy in the general population. This article will highlight challenges in diagnosis and management of asthma among individuals with SCD.
Asthma & Sickle Cell Pain
Vaso-occlusive pain is the leading cause of admissions to hospital, and even in a state of relative good health, a significant number of children have some amount of pain. In the multi-institutional study, Cooperative Study of Sickle Cell Disease (CSSCD), a prospective cohort of 291 infants was followed for a mean length of 11 years and 4062-patient-years. Of these children, 16.8% had a diagnosis of asthma. An increased incidence of painful episodes (1.39 vs 0.47 events per patient-year; p < 0.001) was noted in children with asthma compared with those without asthma. In a second cohort study of 1016 children from the Silent Cerebral Infarct Multi-Center Clinical (SIT) trial, a diagnosis of asthma occurred in 22% of the cohort and was associated with an increased rate of vaso-occlusive pain episodes that resulted in hospitalization and acute chest syndrome (ACS) episodes. After final adjustment for age, hemoglobin F and baseline hemoglobin levels, vaso-occlusive pain rates were 73 and 57 episodes per 100 patient-years among children with and without an asthma diagnosis respectively (p = 0.0176). However, a single institution retrospective cohort study from France did not find an impact of asthma on pain episodes. A total of 297 children with sickle cell anemia were enrolled, 25 with a history of asthma and 272 without a history of asthma, with follow-up at 7 and 6 years, respectively, for a total of 1805 patient-years. No association existed between asthma and the rate of vaso-occlusive pain episodes (72 and 60 pain episodes per 100 patient-years; p = 0.53). This lack of association between asthma and SCD-related pain might be attributed to: the sample size, as the absolute rate of pain for patients with and without asthma were similar to that obtained in the CSSCD; differences in management of pain within France;[21] or the inherent limitations of a single-center study when compared with a multicentered study that did find a significant relationship between vaso-occlusive pain and asthma.
Lower airway obstruction (LAO) is a common risk indicator of asthma. Using spirometry in a single institutional study with LAO defined as forced expiratory volume in 1 s (FEV1)/forced vital capacity ratio (FVC) < 95% CI and adjusted for age and gender,[22] children with LAO had more than twofold the admission rates for either pain or ACS compared with children with normal lung function when assessed prospectively from time of pulmonary function test (PFT).[23] In this review of PFT records of 102 children with SCD, children with LAO had twice the rate of morbidity when compared with children with normal lung function (2.5 vs 1.2 hospitalizations for pain or ACS per patient-year; p = 0.003; risk ratio: 2.0; 95% CI: 1.3–3.3). Children with restriction did not have different rates of future morbidity compared with children with normal lung function (1.4 vs 1.2 hospitalizations for pain or ACS per patient-year; p = 0.68; rate ratio: 1.1; 95% CI: 0.6–2.1). LAO was also associated with increased risk of morbidity, even in those children without a diagnosis of asthma. Several limitations exist in this study, including but not limited to referral bias of a hospital based cohort that had to receive spirometry evaluation for inclusion and a small sample size that is sensitive to outliers. As a single institution study with several limitations, the study results require repeating before significant confidence can be placed in the association between LAO- and SCD-related morbidity.
Asthma & Acute Chest Syndrome
Acute chest syndrome is the leading cause of death and admissions to the pediatric intensive care unit in children and adolescents, and the second most common cause of admission after vaso-occlusive pain episodes in children. Multiple ACS definitions have been proposed; although significant differences exist in terms of clinical symptoms needed, it is accepted that an infiltrate or new radiodensity on imaging is an important criterion that needs to be fulfilled. Other clinical features include hypoxemia, respiratory distress, fever, need for blood transfusion and rapid deterioration in clinical status. Differentiating between an acute asthma exacerbation and ACS is a challenge clinically as they can present with similar symptoms. Wheezing and cough, a common clinical presentation of asthma, are also common findings of ACS, and a new radiodensity on chest x-ray may represent either atelectasis or infiltrate. One usually needs to treat for both asthma and ACS in the setting of a previous doctor diagnosis of asthma. In the CSSCD infant cohort, asthma was associated with more frequent ACS episodes, 0.39 versus 0.20 events per patient-year (p < 0.001),[18] and a similar twofold rate of ACS per patient-year (0.31 vs 0.16 events/patient; p = 0.03) was found in the French study.[21] Recurrent ACS episodes are associated with abnormal lung function among children with SCD.[27] Also, the proportion of children with a physician diagnosis of asthma increases linearly as the number of ACS episodes increase.[28]
Given, the intrinsic limitations of the study design of most SCD studies, where careful delineation of asthma was not part of the original purpose of the study, we are unable to determine whether ACS predisposes to asthma or vice versa. However, children with ACS are diagnosed with asthma at a younger age compared with those without ACS,[29] suggesting that asthma is a predictor of the occurrence of ACS. In the SIT trial, involving 1016 children with SCD, An et al. also confirmed that a doctor diagnosis of asthma was associated with increased incidence rates of ACS.[19] In this large study, after final adjustment for age, hemoglobin F and baseline hemoglobin levels, ACS incidence rates were 22 and 12 episodes per 100 patient-years among children with and without an asthma diagnosis, respectively (p < 0.0001). Severe recurrent wheezing is associated with increased rates of hospitalization for ACS, risk ratio = 2 (95% CI: 1.2–3.4; p = 0.005). In a retrospective study, by Knight-Maddenet al. children with recurrent episodes of ACS were more likely to have atopic asthma and bronchial hyper-reactivity compared with those with only a single ACS event, 53 versus 8% (Odds ratio [OR]: 8.1; 95% CI: 2.3–28.6; p < 0.001). While the results of these studies do not demonstrate causality, they show a close association between ACS and asthma, suggesting that a diagnosis of asthma predisposes to future ACS episodes.
The diagnosis of asthma at different ages is a challenge particularly in younger children; our group follows the premise that asthma is a lifelong condition, as demonstrated by progressive decline in lung function over 15 years in persons who gave a self report of asthma and at 28 years in children with frequent wheezing. Probably the most compelling support that a diagnosis of asthma precedes ACS is based on the observation that in the CSSCD, children with a diagnosis of asthma presented with ACS at 2.4 years compared with 4.6 years in children without asthma (hazard ratio: 1.64; 95% CI: 1.13–2.39; p = 0.01). Additionally, results from two retrospective studies, suggest, but do not confirm, that a previous diagnosis of asthma is associated with future ACS episodes. In the first study a history of asthma and home use of inhaled β adrenergic agonists were associated with increased readmission within 14 days of discharge for an ACS episode, OR = 3.8 (95% CI: 0.9–15; p = 0.06) and OR = 6 (95% CI: 1.2–3; p < 0.05), respectively. In the second study, Boyd et al. reviewed medical records of children admitted for pain of children with asthma (cases), 35% developed ACS in hospital compared with 12% in children without asthma (controls). Children with a physician diagnosis of asthma were about four-times more likely to develop ACS and also had longer hospitalizations for ACS, 5.6 compared with 2.6 days (p = 0.01). The association between asthma and SCD is not limited to patients with hemoglobin SS. In a retrospective study, a greater proportion of children with SCD-SC had a prior history of asthma or wheezing than those with SCD-SS, 50.7 versus 33.8% (p = 0.04).
Asthma & Mortality
Life expectancy in SCD has improved over the past 20–30 years and is partially dependent on SCD phenotype. In a prospective study that followed 3764 individuals from birth to 66 years of age, the median age at death for males and females were 42 and 48 years of age for SCD-SS and SCD-Sβ0thal, but 60 and 68 years of age for SCD-SC, respectively (p < 0.001), much lower than the general population. Pulmonary findings on autopsy may include findings consistent with acute asthma exacerbation and or pulmonary hypertension.
A risk for premature death among those with SCD-SS and asthma was demonstrated in the CSSCD prospective cohort of 138 individuals with asthma and 1825 individuals without asthma. Individuals were identified at a mean age of 9.7 and 14.2 years (p < 0.001), respectively, and followed for a total of 18,495 patient-years. Hazard ratio for the comorbid condition of asthma was 2.36 (95% CI: 1.21–4.62; p = 0.01). Although result of this study does not establish a cause and effect relationship between asthma and premature mortality, it provides compelling support of at least a strong association.
A causal link between the presence of asthma and premature death is suggested by the report of Field et al. of two adolescents with histories of severe persistent asthma in addition to SCD Both individuals were prescribed appropriate treatment for their asthma and had recently received medical care from a pediatric asthma specialist; however, both adolescents died suddenly in the midst of increased respiratory symptoms consistent with asthma exacerbation, where post mortem findings were consistent with asthma. Taken together, these data underscore the importance of not only diagnosing asthma in children and adults with SCD, but also understanding the optimal management for this vulnerable population.
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