High Frequency of Asthma, Sepsis and Acute Chest Syndrome in Children with Sickle Cell Disease and Pulmonary Hypertension.

Abstract

Pulmonary hypertension (PH) is an important co-morbidity in sickle cell disease (SCD). Despite increasing research in adults, the prevalence and implication of this condition in children is unknown. Charts of 362 SCD patients followed at Children's Hospital & Research Center Oakland were reviewed in order to determine clinical associations of PH in adults and children with SCD. Patients with underlying lung abnormalities or those on chronic transfusions were more likely to have echocardiograms in this cohort, however the diagnosis of PH was often unrecognized. Of the 110 pediatric patients, 61 were screened by an echocardiogram with 15 meeting echocardiogram criteria for PH (24.6%.) The ages of children with PH ranged from 7 to 17 years (mean 12.7±3 years). Of the 252 adults, 148 were screened and 81 were considered to have PH (53.7%). Only 52% of patients with PH based on abnormal echocardiography were identified by a clinician as having PH, and although 38 (46.9%) were receiving chronic transfusions, only 4% were specifically treated for PH. Of the 15 children with PH, only 9 carried that diagnosis of PH in their charts, and none were on therapy geared towards PH. A different clinical phenotype for PH in adults versus children was identified. Associations with PH for adults included age, renal and lung disease, Hepatitis C, chronic transfusions, and a history of acute chest syndrome (ACS), with ACS being protective (OR [95% CI]: 0.40 [0.16 – 1.00], p <0.05). For children, a history of sepsis (7.00 [1.29 – 39.7], p= 0.01), ACS (8.2 [1.04 – 367], p<0.05) or obstructive lung disease suggestive of asthma (4.70 [1.4 – 16.4], p=0.01) was associated with PH, possibly reflecting distinct aspects of endothelial dysfunction. Logistic regression of their 3 significant univariant variables found that only a history of sepsis (adjusted OR 2.16; 95% CI 1.2–28.3, p=0.031) remained significant, with the history of asthma or obstructive lung disease nearly so (adjusted OR 1.86; 95% CI 0.93 −14.9, p=0.062) with an area of the receiver operator curve of 0.80. It is well documented that asthma and ACS are associated with complications in SCD, and these data demonstrate an association of these conditions with PH in children with SCD as well. This is the first report to identify a relationship between bacteremia or sepsis and PH in children with SCD. Asthma, sepsis and ACS are all conditions associated with arginine dysregulation and low nitric oxide bioavailability, a shared mechanism with hemolysis-associated PH. PH is a common complication in SCD that affects children as well as adults. The diagnosis is often missed, even with echocardiographic evidence of PH, likely related to lower pulmonary pressures occurring in patients with SCD, compared to levels typically associated with PH. Children with PH have a different profile of complications than adults with PH, suggesting alternate mechanisms of disease pathogenesis in children that may require different screening methods and potentially even different treatment approaches. Since PH is associated with high mortality and morbidity, universal screening by Doppler echocardiagram should target children as well as adults. Increased awareness is essential to identify patients at risk, and new therapies are critically needed.