© 2004 American Thoracic Society
Sickle Cell Disease—Pulmonary Complications and a Proinflammatory State?Guy's, King's and St. Thomas' School of Medicine King's College London, United Kingdom Pulmonary complications frequently lead to mortality and morbidity in patients with sickle cell disease. In a multicenter study, more than 20% of the adults suffered fatal pulmonary complications. (1). Lung function abnormalities are present in young children with sickle cell disease (2). Restrictive abnormalities become more prominent with increasing age (2) and even young adults with sickle chronic lung disease have restrictive lung disease with abnormal diffusing capacity and hypoxemia. The development of pulmonary hypertension increases the mortality up to seven fold (3). A major risk factor for sickle chronic lung disease is recurrent episodes of acute chest syndrome (4), which are the leading cause of death and the second most common cause of hospitalization in adults (1, 5).
An important goal is to effectively treat and preferably prevent acute chest syndrome; this will best be achieved by a thorough understanding of its pathophysiology. A proinflammatory state has been suggested to exist in sickle cell disease, which could predispose to acute chest syndrome in response to a trigger such as infection (6). Evidence for this includes a leucocytosis, which, in the absence of infection, is associated with an increased risk of adverse outcome (7). In addition, elevated cytokine levels have been reported. The findings, however, are not consistent; for example, interleukin levels (IL-6, IL-10, and IL-4) were raised only in 78%, 41%, and 13% respectively of steady-state patients (8). Tumor necrosis factor-
In this issue of the Journal (pp. 687–695), Holtzclaw and colleagues (12) provide data to further extend the debate regarding the importance of a possible proinflammatory state and the development of pulmonary complications. They examined transgenic sickle cell and control mice at baseline and after administration of endotoxin lipopolysaccharide. Cytokine and vascular cell adhesion molecule levels in blood and bronchoalveolar lavage fluid, white cell counts, mRNA expression, survival, lung histology and results of a measure of airways obstruction were assessed. At baseline, levels of circulating leucocytes and vascular cell adhesion molecules were elevated in the sickle cell mice. The lack of other significant findings may reflect the small numbers of animals studied, as IL-6 levels are reported raised in transgenic sickle mice (13). In response to the lipopolysaccharide challenge, the sickle cell compared with the control mice had significantly higher serum and bronchoalveolar levels of cytokines (TNF- The trigger used by Holtzclaw (12) was the endotoxin lipopolysaccharide, which is not a common trigger for acute chest syndrome. In a 30-center study (6), specific causes for acute chest syndrome were only identified in 38% of cases, including 27 different infectious pathogens. Common infectious triggers are community organisms; viral infections being important in the winter months. The animals were studied for only four hours post challenge, thus it cannot be determined whether progression to the expected chronic changes of sickle cell disease would occur. The sickle cell mice had a greater mortality, but their lung histology was normal and there were no significant differences in the lung histology of the sickle cell and control mice. The only finding suggesting that the enhanced inflammatory response was associated with pulmonary dysfunction was the higher "airway obstruction" in the sickle mice. Airway obstruction was assessed indirectly, using a single chamber whole body plethysmograph and measurement of enhanced pause, which incorporates ratios of exhalation to relaxation time and peak inspiratory to peak expiratory flow. Increased enhanced pause results following methacholine challenge have been associated with increased IgE production and eosinophil lung infiltration and inhibited by pretreatment with a ß-agonist (14). The methodology used by the authors, however, makes assumptions that the temperature gradient between the alveolar and chamber air, the breathing pattern, and the lung volume all remain constant (15). Monitoring of the temperature gradient and breathing pattern, however, were not documented and a constant lung volume cannot be guaranteed by a lack of histological change (12). Because they documented an increase in airway tone without any histological change although with increased cytokine expression, Holtzclaw and colleagues (12) hypothesize that the airways obstruction in sickle cell disease is not typical asthma pathophysiology. Yet, results of uncontrolled studies suggest bronchodilator administration is helpful in acute chest syndrome; in one series (6), a fifth of patients so treated had a positive response. In addition, bronchial hyperreactivity may be common in children with sickle cell disease; being present in 64% of those without a known history of reactive airway disease (16). In conclusion, the results of the study of Holtzclaw and colleagues (12) support the concept of an exaggerated response to an inflammatory challenge in sickle cell disease. The relationship to the pulmonary complications of sickle cell disease, however, needs to be interpreted with caution. The data should encourage longer-term animal studies and clinically based investigations examining the temporal relationship of changes in cytokine levels and lung function and their responses to treatment. Whether there is link between asthma/bronchial hyperreactivity and the pulmonary complications of sickle cell disease also merits further investigation. If such a link does exist, aggressive administration of antiasthma therapy might improve outcome. FOOTNOTES Conflict of Interest Statement: A.G. does not have a financial relationship with a commercial entity that has an interest in the subject of this editorial. REFERENCES
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levels have been reported to be raised at baseline, elevation is particularly marked if there is infection (