The Journal of Pediatrics
Volume 149, Issue 1 , Pages 3-4, July 2006

The outcomes of sickle cell disease in adulthood are clear, but the origins and progression of sickle cell anemia-induced problems in the heart and lung in childhood are not

  • Jessica H. Boyd, MD

      Affiliations

    • Department of Pediatrics, Washington University, St. Louis, MO
    • ,
  • Robert C. Strunk, MD

      Affiliations

    • Department of Pediatrics, Washington University, St. Louis, MO
    • ,
  • Wayne J. Morgan, MD, CM

      Affiliations

    • Department of Pediatrics and Arizona Respiratory Center, University of Arizona, Tucson, AZ
    • Corresponding Author InformationReprint requests: Dr Wayne J. Morgan, Department of Pediatrics, University of Arizona, 1501 North Campbell Avenue, Tucson, Arizona 85724.

Article Outline

Abbreviations:  ACS, Acute chest syndrome , FEV1, Forced expiratory volume in 1 second , FVC, Forced vital capacity , RV, Right ventricular , SCA, Sickle cell anemia , SCD, Sickle cell disease , SCLD, Sickle cell lung disease

 

Individuals with sickle cell anemia (SCA) have a shortened life expectancy when compared with ethnic matched controls. Two well-documented etiologies of this reduced life span are chronic lung disease and pulmonary hypertension. The Cooperative Study of Sickle Cell Disease, a multicenter natural history study, identified acute chest syndrome (ACS) as a leading cause of premature death.1 Recurrent ACS is a significant, independent risk factor associated with sickle cell lung disease (SCLD).2 Powars et al2 suggest that SCLD, an important cause of death in adults with sickle cell disease (SCD), is progressive and results in pulmonary hypertension in the later stages of disease. Further, the importance of pulmonary hypertension as a risk factor for death was recently highlighted by Gladwin et al,3 who found that pulmonary hypertension as indicated by a tricuspid regurgitation jet velocity >2.5 m per second is a predictor of death among persons with SCD. The progression of SCLD to pulmonary fibrosis suggests that recurrent ACS may be associated with restrictive lung disease, and in adults, restrictive lung disease has been the predominant pattern of pulmonary function abnormality.2, 4 However, the relationship between ACS and lung function is unclear, as other studies have found both restrictive and obstructive changes.5, 6, 7 Some of this confusion may relate to the age at which subjects are studied, with adults presenting with a more restrictive picture,2, 3, 4 whereas children appear more obstructive.7

See related articles, p 23 and p 17

Few studies have focused on these two complications, pulmonary hypertension and chronic lung disease, and their associated pathophysiologies in children with SCA. This issue of The Journal has two articles that begin to address abnormalities of the heart and lung present in children with SCA. Quereshi et al8 address right ventricular (RV) abnormalities in SCA in a small cohort of 32 children 6 months to 21 years of age and age-matched healthy controls. The prevalence of pulmonary hypertension among children with SCA in this cohort was determined to be 16%, and the mean age at presentation was 13 years. The authors also reported that although volume overload remained unchanged during childhood, disproportionate RV hypertrophy, a possible precursor to pulmonary hypertension, occurred in 25% of the population. Gladwin’s findings in adults3 support the importance of understanding the development of pulmonary hypertension in children. The data from Quereshi et al8 suggest that early diagnosis might be possible, offering the potential for developing both preventative and therapeutic strategies.9

These data, however, are not without limitations. Children who had undergone an echocardiogram were included in this study, but the reasons for doing the echocardiograms were not presented. This could have led to a selection bias, consequently overestimating the prevalence of pulmonary hypertension and disproportionate RV hypertrophy among children with SCA. On the other hand, Quereshi et al8 did not distinguish between those children with a history of ACS and those without, and it is possible that recurrent ACS might be an important predictor of the development of pulmonary hypertension. Although it is difficult to infer changes over time from a cross-sectional study, the correlation between age and pulmonary hypertension suggests that more investigation is needed to determine at which age screening with echocardiography is warranted and to determine the interval at which screening should occur.

The article by Sylvester et al10 in this issue of The Journal addresses lung disease in children with SCA. The authors examined the pulmonary function of 20 children who have had an ACS episode and 20 age-matched children with SCA without an ACS episode. This study finds increases in mean airway resistance, total lung capacity, and residual volume in children with SCA who have experienced an ACS episode as compared with those who have not. Thus, these data do not demonstrate a relationship in childhood between ACS and restrictive changes in lung function, as might be suggested from the relationship between ACS and SCLD.2 However, the lung function data do show subtle obstructive changes that are not completely explained by the association between asthma and ACS.11, 12 Also, although airway resistance, some isovolume flows and forced expiratory volume in 1 second/forced vital capacity (FEV1/FVC) were different between groups, several lung function variables did not demonstrate obstruction and the changes in FEV1/FVC seemed to vary with the predicted equation used. Nonetheless, this study seems to support the findings of lower airway obstruction reported by Koumbourlis et al.7

Despite the subtlety of the findings, the Sylvester et al10 study raises important questions regarding the relationship between pulmonary function abnormalities and SCD-related morbidity in children. Previous studies have identified that both obstructive and restrictive patterns of lung function are common in SCD.6, 7 Airway hyperresponsiveness has also been described in this population,7, 13 and asthma has been associated with an increased risk of ACS in children with SCD.11, 12 In the study by Sylvester et al,10 the direction of association can not be determined because pulmonary function before the ACS episode that classified children as a case for this study is not known. Further, the relationship between respiratory illness and the subsequent development of SCLD is likely to be complex.

Asthma and acute wheezing illnesses are common in childhood and are associated with lower levels of lung function in later childhood in children without SCA.14 Because an acute wheeze-associated respiratory illness or asthma exacerbation could easily meet the definition of ACS or precipitate ACS in a child with SCD, it is not surprising that studies of lung function early in life in children with ACS tend to demonstrate a more obstructive pattern. However, with recurrent episodes and the development of SCLD, damage to the pulmonary vasculature and parenchyma may then progress leading to restrictive lung disease and pulmonary hypertension. Longitudinal multicenter studies are necessary to better define temporal relationships between ACS, wheezing, asthma, and pulmonary function abnormalities, and to determine the progression of abnormalities of lung function in children to SCLD in adults. It will be important to enroll a cohort of young children before the first episode of ACS and to perform serial lung function testing and echocardiography. More extensive phenotyping for asthma, including methacholine challenge and airway inflammatory markers, and the study of gene modifiers and genotype-environment interactions are necessary to elucidate the pathophysiology in the lung and its relation to SCD-related morbidity and mortality.

Significant progress has been made to study major sources of morbidity and mortality in SCD. Mortality in children with SCD has been greatly reduced with the recognition of the role of infection and the widespread use of penicillin prophylaxis. Further investigation of pulmonary hypertension, ACS, and SCLD in SCA is needed given the significant, persistent contribution to death in the face of improved survival to adulthood. Multicenter investigations to study sufficiently large populations of both adults and children are necessary to understand the natural history and interrelationship of these conditions and to develop therapy to target potentially modifiable stages of the disease.

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References 

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  2. Powars D , Weidman JA , Odom-Maryon T , Niland JC , Johnson C . Sickle cell chronic lung disease (prior morbidity and the risk of pulmonary failure) . Medicine . 1988;67:66–76
  3. Gladwin MT , Sachdev V , Jison ML , Shizukuda Y , Plehn JF , Minter K , et al.   Pulmonary hypertension as a risk factor for death in patients with sickle cell disease . New Engl J Med . 2004;350:886–895
  4. Miller GJ , Sergeant GR . An assessment of lung volumes and gas transfer in sickle-cell anaemia . Thorax . 1971;26:309–315
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  7. Koumbourlis AC , Zar HJ , Hurlet-Jensen A , Goldberg MR . Prevalence and reversibility of lower airway obstruction in children with sickle cell disease . J Pediatr . 2001;132:188–192
  8. Qureshi N , Joyce JJ , Ning Qi N , Chang RK . Right ventricular abnormalities in sickle cell anemia (evidence of a progressive increase in pulmonary vascular resistance) . J Pediatr . 2006;149:23–27
  9. Machado RF , Martyr S , Kato GJ , Barst RJ , Anthi A , Robinson MR , et al.   Sildenafil therapy in patients with sickle cell disease and pulmonary hypertension . Br J Hematol . 2005;130:445–453
  10. Sylvester KP , Patey RA , Milligan P , Rafferty GF , Broughton S , Rees D , et al.   Impact of acute chest syndrome on lung function of children with sickle cell disease . J Pediatr . 2006;149:17–22
  11. Boyd JH , Moinuddin A , Strunk RC , DeBaun MR . Asthma and acute chest in sickle cell disease . Pediatr Pulmonol . 2004;38:229–232
  12. Knight-Madden JM , Forrester TS , Lewis NA , Greenough A . Asthma in children with sickle cell disease and its association with acute chest syndrome . Thorax . 2005;60:206–210
  13. Leong MA , Dampier C , Varlotta L , Allen JL . Airway hyperreactivity in children with sickle cell disease . J Pediatr . 1997;131:278–283
  14. Morgan WJ , Stern DA , Sherrill DL , Guerra S , Holberg CJ , Guilbert TW , et al.   Outcome of asthma and wheezing in the first 6 years of life (follow-up through adolescence) . Am J Respir Crit Care Med . 2005;172:1253–1258

PII: S0022-3476(06)00390-8

doi:10.1016/j.jpeds.2006.04.056

Refers to article:

  • Right ventricular abnormalities in sickle cell anemia: Evidence of a progressive increase in pulmonary vascular resistance

    Naveen Qureshi, James J. Joyce, Ning Qi, Ruey-Kang Chang
    The Journal of Pediatrics July 2006 (Vol. 149, Issue 1, Pages 23-27)

  • Impact of acute chest syndrome on lung function of children with sickle cell disease

    Karl P. Sylvester, Richard A. Patey, Peter Milligan, Gerrard F. Rafferty, Simon Broughton, David Rees, Swee Lay Thein, Anne Greenough
    The Journal of Pediatrics July 2006 (Vol. 149, Issue 1, Pages 17-22)

The Journal of Pediatrics
Volume 149, Issue 1 , Pages 3-4, July 2006

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