Jeffrey Glassberg

Painful episodes in children with sickle cell disease and asthma are temporally associated with respiratory symptoms.

Background Little is known about the temporal relationship between an asthma exacerbation and a painful episode in a child with sickle cell disease (SCD). We tested the hypothesis that respiratory symptoms either immediately precede or occur concomitantly with painful episodes more frequently in children with SCD and asthma when compared with children with SCD without asthma. Methods A cohort study was conducted. As part of standard care, the primary hematologist referred all children with SCD for evaluation by a pulmonologist. The definition of asthma was based on the National Heart Lung and Blood Institutes guidelines. All painful episodes during a 25-month sampling frame were reviewed. Events that were diagnosed as asthma exacerbations were excluded from analysis. Respiratory symptoms (cough, wheeze, tachypnea, retractions, or grunting) were included if they occurred up to 96 hours before a painful episode. Results A total of 74 children were evaluated for a painful episode. Of these patients, 36 were diagnosed with asthma (mean age 9.8 y; range 2.4 to 19.4) and 38 were determined not to have asthma (mean age, 9.8 y; range 2.4 to 19.5). Among the children with pain and asthma, the odds ratio of having antecedent or concurrent respiratory symptoms was 4.9 (95% confidence intervals, 2.2-10.7) when compared with children with pain and without asthma. Conclusions In children with both SCD and asthma, respiratory symptoms are a risk factor for painful episodes within 96 hours.

Emergency Provider Analgesic Practices and Attitudes Toward Patients With Sickle Cell Disease

STUDY OBJECTIVE We determine whether emergency provider attitudes and demographics are associated with adherence to national guidelines for the management of acute sickle cell disease pain. METHODS We conducted a cross-sectional survey of emergency providers at the 2011 annual American College of Emergency Physicians Scientific Assembly, using a validated instrument to assess provider attitudes and self-reported analgesic practices toward patients with sickle cell disease. Multivariable, relative risk regressions were used to identify factors associated with adherence to guidelines. RESULTS There were 722 eligible participants, with a 93% complete response rate. Most providers self-reported adherence to the cornerstones of sickle cell disease pain management, including parenteral opioids (90%) and redosing opioids within 30 minutes if analgesia is inadequate (85%). Self-reported adherence was lower for other recommendations, including use of patient-controlled analgesia, acetaminophen, non-steroidal anti-inflammatory drugs and hypotonic fluids for euvolemic patients. Emergency providers in the highest quartile of negative attitudes were 20% less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.8; 95% confidence interval [CI] 0.7 to 0.9). High-volume providers (those who treat more than 1 sickle cell disease patient per week), were less likely to redose opioids within 30 minutes for inadequate analgesia (risk ratio 0.9; 95% CI 0.8 to 0.9). Pediatric providers were 6.6 times more likely to use patient-controlled analgesia for analgesia (95% CI 2.6 to 16.6). CONCLUSION The majority of emergency providers report that they adhere to national guidelines about use of opioids for sickle cell disease-related acute pain episodes. Other recommendations have less penetration. Negative attitudes toward individuals with sickle cell disease are associated with lower adherence to guidelines.

Wheezing and asthma are independent risk factors for increased sickle cell disease morbidity

To assess the associations between a doctor diagnosis of asthma and wheezing (independent of a diagnosis of asthma) with sickle cell disease (SCD) morbidity, we conducted a retrospective review of Emergency Department (ED) visits to the Mount Sinai Medical Center for SCD between 1 January 2007 and 1 January 2011. Outcomes were ED visits for pain and acute chest syndrome. The cohort included 262 individuals, median age 23·8 years, (range: 6 months to 67·5 years). At least one episode of wheezing recorded on a physical examination was present in 18·7% (49 of 262). Asthma and wheezing did not overlap completely, 53·1% of patients with wheezing did not carry a diagnosis of asthma. Wheezing was associated with a 118% increase in ED visits for pain (95% confidence interval [CI]: 56–205%) and a 158% increase in ED visits for acute chest syndrome (95% CI: 11–498%). A diagnosis of asthma was associated with a 44% increase in ED utilization for pain (95% CI: 2–104%) and no increase in ED utilization for acute chest syndrome (rate ratio 1·00, 95%CI 0·41–2·47). In conclusion, asthma and wheezing are independent risk factors for increased painful episodes in individuals with SCD. Only wheezing was associated with more acute chest syndrome.

Longitudinal analysis of pulmonary function in adults with sickle cell disease

Among adults with sickle cell disease (SCD), pulmonary complications are a leading cause of death. Yet, the natural history of lung function in adults with SCD is not well established. We conducted a retrospective cohort study of adults with SCD who had repeated pulmonary function tests performed over 20 years of age. Ninety‐two adults were included in this cohort. Rate of decline in FEV1 for men and women with SCD was 49 cc/year (compared with 20–26 cc/year in the general population). Further studies are needed to identify factors which impact the rate of lung function decline in adults with SCD. Am. J. Hematol. 2008.

Risk factors for increased ED utilization in a multinational cohort of children with sickle cell disease.

OBJECTIVES The objective was to identify clinical, social, and environmental risk factors for increased emergency department (ED) use in children with sickle cell disease (SCD). METHODS This study was a secondary analysis of ED utilization data from the international multicenter Silent Cerebral Infarct Transfusion (SIT) trial. Between December 2004 and June 2010, baseline demographic, clinical, and laboratory data were collected from children with SCD participating in the trial. The primary outcome was the frequency of ED visits for pain. A secondary outcome was the frequency of ED visits for acute chest syndrome. RESULTS The sample included 985 children from the United States, Canada, England, and France, for a total of 2,955 patient-years of data. There were 0.74 ED visits for pain per patient-year. A past medical history of asthma was associated with an increased risk of ED utilization for both pain (rate ratio [RR] = 1.28, 95% confidence interval [CI] = 1.04 to 1.58) and acute chest syndrome (RR = 1.60, 95% CI = 1.03 to 2.49). Exposure to environmental tobacco smoke in the home was associated with 73% more ED visits for acute chest syndrome (RR = 1.73, 95% CI = 1.09 to 2.74). Each

Among emergency physicians, use of the term “Sickler” is associated with negative attitudes toward people with sickle cell disease

10,000 increase in household income was associated with 5% fewer ED visits for pain (RR = 0.95, 95% CI = 0.91 to 1.00, p = 0.05). The association between low income and ED utilization was not significantly different in the United States versus countries with universal health care (p = 0.51). CONCLUSIONS Asthma and exposure to environmental tobacco smoke are potentially modifiable risk factors for greater ED use in children with SCD. Low income is associated with greater ED use for SCD pain in countries with and without universal health care.

Inhaled steroids reduce pain and sVCAM levels in individuals with sickle cell disease: A triple‐blind, randomized trial

Maternity & Child Hospital, Dammam, Saudi Arabia Al-Omran Scientific Chair, College of Medicine, King Faisal University, Al-Ahsa, Saudi Arabia Conflict of interest: Nothing to report. R01 HL 068970; RC2 HL 101212; R01 87681. Contract grant sponsor: King Abdulaziz City for Science and Technology; Contract grand number: KACST ARP-30–367 *Correspondence to: Abdulrahman Alsultan, Sickle Cell Disease Research Center and Department of Pediatrics, College of Medicine, King Saud University, Riyadh, Saudi Arabia. E-mail: aalsultan@gmail.com Received for publication 26 February 2013; Accepted 4 March 2013 Published online 4 March 2013 in Wiley Online Library (wileyonlinelibrary.com) DOI 10.1002/ajh.23434

Cough and wheeze events are temporally associated with increased pain in individuals with sickle cell disease without asthma

Clinical and preclinical data demonstrate that altered pulmonary physiology (including increased inflammation, increased blood flow, airway resistance, and hyper‐reactivity) is an intrinsic component of Sickle Cell Disease (SCD) and may contribute to excess SCD morbidity and mortality. Inhaled corticosteroids (ICS), a safe and effective therapy for pulmonary inflammation in asthma, may ameliorate the altered pulmonary physiologic milieu in SCD. With this single‐center, longitudinal, randomized, triple‐blind, placebo controlled trial we studied the efficacy and feasibility of ICS in 54 nonasthmatic individuals with SCD. Participants received once daily mometasone furoate 220 mcg dry powder inhalation or placebo for 16 weeks. The primary outcome was feasibility (the number who complete the trial divided by the total number enrolled) with prespecified efficacy outcomes including daily pain score over time (patient reported) and change in soluble vascular cell adhesion molecule (sVCAM) levels between entry and 8‐weeks. For the primary outcome of feasibility, the result was 96% (52 of 54, 95% CI 87%‐99%) for the intent‐to‐treat analysis and 83% (45 of 54, 95% CI 71%‐91%) for the per‐protocol analysis. The adjusted treatment effect of mometasone was a reduction in daily pain score of 1.42 points (95%CI 0.61‐2.21, P = 0.001). Mometasone was associated with a reduction in sVCAM levels of 526.94 ng/mL more than placebo (95% CI 50.66‐1003.23, P = 0.03). These results support further study of ICS in SCD including multicenter trials and longer durations of treatment. www.clinicaltrials.gov (NCT02061202)

Wheezing in children with sickle cell disease.

Human clinical studies and murine models suggest that pulmonary inflammation is an intrinsic component of sickle cell disease (SCD) (Field et al, 2011, Morris et al, 2003, Nandedkar et al, 2008, Pawar et al, 2008, Pritchard et al, 2012, Pritchard et al, 2004) and a growing body of retrospective and cross-sectional studies demonstrates that symptoms, such as cough or wheeze, often occur without asthma and are associated with increased SCD complications (pain, acute chest syndrome and death) (Cohen et al, 2011, Field et al, 2011, Glassberg et al, 2012). To better understand the incidence of respiratory symptoms over time, and to identify the percentage of individuals without asthma who could potentially benefit from pulmonary-anti-inflammatory therapy, we conducted a prospective, longitudinal cohort study of individuals with SCD who do not have asthma.

A Randomized Controlled Trial Comparing Two Vaso-occlusive Episode (VOE) Protocols in Sickle Cell Disease (SCD)

Purpose of review The purpose of this article is to provide a comprehensive review of wheezing in sickle cell disease (SCD), including epidemiology, pathophysiology, associations between wheezing and SCD morbidity and finally the clinical approach to evaluation and management of individuals with SCD who wheeze. Recent findings Wheezing is common in SCD and in some individuals represents an intrinsic component of SCD-related lung disease rather than asthma. Emerging data suggest that, regardless of the cause, individuals with SCD and with recurrent wheezing are at increased risk for subsequent morbidity and premature mortality. We believe individuals who acutely wheeze and have respiratory symptoms should be managed with a beta agonist and short-term treatment of oral steroids, typically less than 3 days to attenuate rebound vaso-occlusive disease. For those who wheeze and have a history or examination associated with atopy, we consider asthma treatment and monitoring per National Heart, Lung and Blood Institute asthma guidelines. Summary Wheezing in SCD should be treated aggressively both in the acute setting and with controller medications. Prospective SCD-specific clinical trials will be necessary to address whether anti-inflammatory asthma therapies (leukotriene antagonists, inhaled corticosteroids) can safely mitigate the sequelae of wheezing in SCD.