Pediatric Cardiology

, Volume 29, Issue 2, pp 309–312

Pulmonary Hypertension in Children and Adolescents with Sickle Cell Disease

Authors

    • Center for Sickle Cell DiseaseHoward University
  • A. Campbell
    • Center for Sickle Cell DiseaseUniversity of Michigan
  • M. Teshome
    • Center for Sickle Cell DiseaseUniversity of Michigan
  • S. Onyeagoro
    • Center for Sickle Cell DiseaseHoward University
  • C. Sylvan
    • Center for Sickle Cell DiseaseHoward University
  • A. Akintilo
    • Center for Sickle Cell DiseaseHoward University
  • S. Hutchinson
    • Center for Sickle Cell DiseaseUniversity of Michigan
  • G. Ensing
    • Center for Sickle Cell DiseaseUniversity of Michigan
  • P. Gaskin
    • Department of Pediatrics and Child HealthHoward University
    • Pediatric CardiologyUniversity of Maryland
  • G. Kato
    • Vascular Therapeutics Section, National Heart, Lung and Blood Institute, and the Critical Care Medicine DepartmentClinical Center, National Institutes of Health
  • S. Rana
    • Department of Pediatrics and Child HealthHoward University
  • J. Kwagyan
    • General Clinical Research CenterHoward University
  • V. Gordeuk
    • Center for Sickle Cell DiseaseHoward University
    • General Clinical Research CenterHoward University
  • J. Williams
    • Center for Sickle Cell DiseaseUniversity of Michigan
  • O. Castro
    • Center for Sickle Cell DiseaseHoward University
Article

DOI: 10.1007/s00246-007-9018-x

Cite this article as:
Onyekwere, O.C., Campbell, A., Teshome, M. et al. Pediatr Cardiol (2008) 29: 309. doi:10.1007/s00246-007-9018-x

Abstract

The prevalence of pulmonary hypertension (PHTN) in the pediatric sickle cell disease (SCD) population is not known despite its high prevalence in adult patients. Our hypothesis was that increased pulmonary artery pressures (PAPs) would be found in SCD children and adolescents, especially those with a history of pulmonary complications: acute chest syndrome, obstructive sleep apnea, asthma, and reactive airway disease. Fifty-two SCD children, 23 of whom had underlying pulmonary disease, were screened for PHTN, which was defined as a tricuspid regurgitant jet velocity (TRV) of at least 2.5 m/s. Twenty-four (46.15%) SCD patients had increased PAP (i.e., TRV ≥2.5 m/s), and 6 (11.5%) had significant PHTN (i.e., TRV ≥3.0 m/s). Pulmonary disease was marginally associated with PHTN (odds ratio 2.80 and confidence interval 0.88 to 8.86; p = 0.0795). As in adult SCD patients with PHTN, this complication was correlated with the degree of hemolysis as manifested by significantly higher lactate dehydrogenase and bilirubin, lower hemoglobin and hematocrit levels, and a strong association with Hb-SS phenotype. However, after statistical adjustment for age and sex, increased serum LDH was not associated with the development of PHTN. Further studies are needed to clarify the prevalence and mechanisms of PHTN in pediatric and adolescent patients with SCD.

Keywords

HemolysisPulmonary diseaseSickle cell diseaseTricuspid valve regurgitation

Pulmonary hypertension (PHTN) is a serious complication of sickle cell disease (SCD) in adults that is associated with high morbidity and mortality. PHTN is defined as a resting mean pulmonary artery pressure (PAP) >25 mm Hg [13, 19]. It can be primary (idiopathic) or secondary to a number of other clinical conditions. Chronic hypoxia is a classic cause of secondary PHTN. Hypoxia can be a consequence of congenital right-to-left shunts, congenital lung abnormalities, chronic obstructive or interstitial lung disease, or ventilation disorders. Other secondary causes of PHTN include chronic thromboembolic pulmonary disease, pulmonary artery stenosis, left ventricular failure with increased pulmonary wedge pressure, and chronic hemolytic disorders [6]. Hemoglobinopathies are now being recognized as common causes of PHTN by way of a mechanism that involves nitric oxide dysfunction associated with intravascular hemolysis.

Recently we reported a high prevalence (32%) of PHTN among adults with SCD [7]. At 40-month follow-up, 40% of these patients had died [8]; hence, the diagnosis carries an unacceptable high morbidity and mortality rate similar to that of other forms of PHTN.

The prevalence of PHTN in the pediatric SCD population is not yet known despite its high prevalence in adult SCD patients. In the Cooperative Study of SCD, echocardiography was performed on 191 individuals (71% children or young adults), and it was concluded that these patients did not have increased PAP because the mean right ventricular systolic time interval was normal [3]. However, the right ventricular wall thickness and tricuspid regurgitant jet velocities (TRVs) were not reported in this study, and it is possible that some of the patients had evidence for increased PAP by these measures. Serjeant’s group [5] performed echocardiograms in 40 Jamaican adolescents, age 11 to 18 years old, with SCD, and their PAPs ranged from 17 to 39 mm Hg [5]. Central venous pressure was assumed to be 14 mm Hg, so it can be inferred that the TRVs were all within the normal range.

The age of onset of PHTN and its predisposing factors in children and adolescents with SCD are not known. Two retrospective studies―one from Children’s Hospital, Oakland, CA, in 2004 [9] and another recently reported by Suell [15]―are available: The first reported a 25% prevalence of PHTN in SCD children and the second noted increased PAP in SCD adolescents [15].

Here we report the results of a prospective screening study to determine the prevalence of PHTN in pediatric SCD patients. Some of these patients had a history of pulmonary problems, including asthma, obstructive sleep apnea, and ≥1 episode of acute chest syndrome, and some were screened shortly after having a vaso-occlusive event.

Materials and Methods

We enrolled 52 pediatric patients with SCD ages 8 to 24 years between 2004 and 2005. All patients attended the Centers for Sickle Cell Disease at Howard University, Washington, DC, or at the University of Michigan, Detroit, MI. All patients and/or their parents gave written, Institutional Review Board–approved informed consent and assent as appropriate. Each participant underwent a complete history, physical examination, and review of medical records to determine their SCD phenotype (SS, SC, or S-β thalassemia and fetal Hb level). To be eligible for this study, all patients had to have a history of SCD and regular follow-up in one of the two institutions. Some of the patients had a history of pulmonary problems, such as acute chest syndrome (as defined by ≥1 episode), obstructive sleep apnea (as documented by a sleep study), or asthma or reactive airway disease (as documented by abnormal pulmonary function test). Echocardiographic evaluation was performed in all patients to obtain the TRV and allow for the calculation of PAP. Thirty-eight participants were at steady state, and 14 were tested shortly after recovery from a vaso-occlusive event. All echocardiograms were performed and reviewed by each institution’s pediatric cardiologist. Any echocardiogram that was found to be technically inadequate was repeated. Those patients identified as having PHTN were referred to the institution’s cardiology and hematology services for further evaluation and management.

Diagnosis of PHTN

For the purposes of this study, any participant found to have a TRV ≥2.5 m/s was classified as having PHTN. Further note was made as to whether the TRV was 2.5 to 2.9 m/s (increased PAP) or ≥3.0 m/s (significant PHTN).

Statistical Analysis

Data analyses included descriptive, univariate, and multivariate methods. Descriptive statistics were used to describe and summarize the characteristics of the study sample. Student t and chi-square tests were used to univariately examined the association of PHTN with various risk factors. The independence of these risk factors was further examined in separate multiple logistic regression analysis with adjustment for age and sex. All analyses were conducted using SAS software (version 9; SAS Institute, Cary, NC), and tests were performed two-sided at the 5% level of significance. Data are generally expressed as mean ± SD or number (%).

Results

Table 1 lists the clinical and demographic data of 52 pediatric and adolescent SCD patients who underwent Doppler echocardiographic evaluation. Twenty-four patients (46.2%) had increased PAP (i.e., TRV ≥2.5 m/s, and 6 of these patients (11.5%) had significant PHTN (i.e., TRV ≥3.0 m/s). Thirty-three had a history of pulmonary disease (≥1 episode of acute chest syndrome, obstructive sleep apnea, reactive airway disease, or asthma), and 14 were evaluated shortly after hospitalization for an acute event. Fifteen of 28 patients without PTHN had a history of pulmonary disease (asthma, reactive airway disease, obstructive sleep apnea, or ≥1 episode of acute chest syndrome), and 6 were evaluated shortly after hospitalization for an acute event. As described for adult SCD patients with PHTN, hemolysis was an important risk factor for this complication. Pediatric patients with increased TRV had significantly higher serum lactate dehydrogenase (LDH) and bilirubin levels and lower Hb concentrations, and PHTN was less common in hemoglobin SC disease. However, hematocrit was an independent risk factor. Four patients with moderate to severe PHTN were on a long-term transfusion program. After 9 months of follow-up of those patients with PHTN, only one died from a pulmonary complication. Pulmonary disease was not significantly associated with PHTN (odds ratio 2.80 and confidence interval [CI] 0.88 to 8.86; p = 0.0795).
Table 1

Clinical and demographic data of 52 SCD adolescents who underwent echocardiography at Howard University and the University of Michigan

Clinical and demographic data

PHTN ( =  24)

No PHTN (= 28)

p

Age in years (mean  ±  SD)

16.21 ± 3.26

16.00 ± 3.27

0.819

No. female (%)

9 (38)

16 (57)

0.159

No. with pulmonary disease (%)

18 (75)

15 (54)

0.479

No. with chronic blood transfusion therapy (%)

3(12.5)

5(18)

0.2839

No. with Hb-SS (%)

22 (92)

21 (75)

0.0203a

Hb concentration in g/dL (mean ± SD)

8.05 ± 1.63

9.38 ± 1.70

0.0059a

% Hematocrit (mean ± SD)

22.83 ± 5.19

27.51 ± 5.05

0.0018a

WBC Th/mm3 (mean ± SD)

11.68 ± 3.09

11.40 ± 3.26

0.741

Platelet Th/mm3 (mean ± SD)

443 ± 176

395 ± 164

0.327

% HbF (mean ± SD)

5.79 ± 5.16

6.00 ± 5.24

0.926

LDH IU/L (mean ± SD)

479 ± 156

364 ± 103

0.0065a

Total bilirubin mg/dL (mean ± SD)

4.2 ± 2.69

2.61 ± 1.39

0.0091a

Creatinine concentration in mg/dL (mean ± SD)

0.66 ± 0.33

0.57 ± 0.19

0.247

AST in mU/mL (mean ± SD)

57 ± 33

45.3 ± 21

0.143

ALT in mU/mL (mean ± SD)

35 ± 17

33 ± 18

0.754

ALT = alanine aminotransferase; AST = aspartate aminotransferase; Th = thousand; HbF = fetal Hb; Hb-SS = sickle cell anemia phenotype; WBC = white blood cell

aIndicates statistical significance at the 5% level

Results of multiple logistic regression analysis with statistical adjustment for age and sex are listed in Table 2. The results showed that a 1 g/dL increase in Hb concentration and a 1% increase in hematocrit decreased the risk of PHTN by 65% (odds ratio 0.35 and CI 0.17 to 0.28; p = 0.0050) and 27% (odds ratio 0.73 and CI 0.58 to 0.91; p = 0.0049), respectively. There was a 2-fold increase in risk for PHTN for each increase (1 mg/dL) in total bilirubin concentration (odds ratio 2.138 and CI 1.08 to 4.24; p = 0.0297). In addition, hemoglobin SS phenotype (Hb-SS) was associated with a 12-fold increase in risk for PHTN (odds ratio 11.9 and CI 1.28 to 110.46; p = 0.0293).
Table 2.

Logistic regression analysis of PHTN risk factors

Risk factor

Odds ratioa

95% CIa

p

Hb-SS

11.9

1.28 to 110.46

0.0293

Hb concentration in g/dL

0.35

0.17 to 0.28

0.0050

% Hematocrit

0.73

0.58 to 0.91

0.0049

LDH IU/L

1.01

1.00 to 1.01

0.0993

Total bilirubin mg/dL

2.14

1.08 to 4.24

0.0297

aOdds ratios and CIs were adjusted for age and sex

Discussion

PHTN is characterized by abnormally high PAPs and is associated with hyperproliferation of pulmonary vascular endothelium. It is an increasingly recognized complication of SCD [1, 2, 9, 13, 14, 16]. PHTN was defined by the 1987 by the National Heart, Blood, and Lung Institute/National Institutes of Health National Registry as a mean PAP >25 mm Hg at rest or >30 mm Hg with exercise [4, 12]. The pathogenesis of PHTN in SCD is multifactorial. Factors that increase the intracellular concentration of hemoglobin (Hb), red blood cell dehydration, increase time spent by Hb in the microcirculation, increased expression of adhesion molecules endothelial VCAM-1 and erythrocyte a4b1, or increase the deoxygenation of Hb, all contribute to increased Hb-S polymerization. Increased expression of adhesion molecules on erythrocytes (a4b1, CD36) and endothelial cells (VCAM-1, sVCAM-1, ICAM-1, CD36), interaction with leukocytes, increased levels of circulating inflammatory cytokines (C-reactive protein, interleukin-6, tumor-necrosis factor [TNF] α-308, TNFβ+252), abnormal nitric oxide metabolism, enhanced microvascular thrombosis (PAI-1, thrombomodulin), and endothelial damage are all believed to contribute to the obstruction of arterioles by polymer-containing sickle erythrocytes. These factors are integral to the pathogenesis of PHTN in SCD.

PHTN occurs frequently in SCD patients, and we are currently actively following-up a cohort of 216 adult and 52 pediatric SCD patients, 32% and 46% of them with PHTN, respectively. The higher prevalence in our pediatric cohort could have been caused by the low number of patients screened and to some extent the history of pulmonary disease. After 40 months of follow-up of the adult cohort, 40% of those with PHTN have died, whereas only one patient died in the pediatric and adolescent cohort after 9 months of follow-up. It is clear that in adults with SCD, this complication carries an unacceptably high morbidity and mortality rate, similar to those of patients with untreated primary PHTN and PHTN secondary to other diseases. The prognosis of adult SCD patients with PHTN is poor even though their mean PAPs are lower and their cardiac outputs higher than patients with primary PHTN. However, in SCD children and adolescents with PHTN, mortality is low; they seem to respond to a chronic transfusion program, but their disease is associated with high morbidity, especially in those with pulmonary disease.

Hemolysis, as noted in the adult patients, seems to be a contributing factor in SCD children. Also, chronic hypoxia caused by SCD and/or pulmonary disease, such as acute chest syndrome, asthma, obstructive sleep apnea, and reactive airway disease, seems to contribute to the development of PHTN in our children with SCD. How these abnormalities relate to the nitric oxide dysregulation seen in SCD patients is unknown.

In conclusion, early echocardiographic evaluation of pediatric SCD patients with or without pulmonary disease may provide information on the prevalence and risk factors associated with the development of PHTN. Careful follow-up and early institution of therapy will likely decrease the morbidity and mortality associated with PHTN in these patients. Further studies are needed to clarify the prevalence and mechanisms of PHTN in children and adolescent with SCD as well as the role of nitric oxide metabolism.

Acknowledgments

We thank the staff members, patients, and parents who took part in this study.

Copyright information

© Springer Science+Business Media, LLC 2007