Pulmonary Complications of Sickle Cell Anemia
A Need for Increased Recognition, Treatment, and Research

KARIN R. MINTER and MARK T. GLADWIN

Critical Care Medicine Department, Clinical Center; and Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland

	INTRODUCTION

TOP INTRODUCTION ACUTE PULMONARY DISEASE CHRONIC PULMONARY DISEASE CONCLUSIONS REFERENCES

One of every 650 African Americans (0.15%) is born with sickle cell disease and about 8% are heterozygous for the sickle cell gene. According to the United States Census Bureau there were 35,509,000 African Americans counted in the year 2000, which would indicate that there are approximately 50,000 patients with sickle cell anemia in this country. Thirty five per cent of the African American population was between 30 and 54 yr of age in the year 2000. This demographic explains the increasing number of adult patients with sickle cell disease. However, the increased number of adults with sickle cell anemia is due only in part to population growth. Mortality rates for children with sickle cell anemia have declined because of penicillin prophylaxis, Haemophilus influenzae and Streptococcus pneumoniae vaccination, widespread implementation of newborn screening programs for early detection, and improvements in parental education (1). Despite significant improvements in the life expectancy of patients with sickle cell disease the median age at death is 42 yr for men and 48 yr for women (2). Pulmonary complications account for a large proportion of deaths among adults with sickle cell anemia (Table 1) (2, 6). According to the Cooperative Study of Sickle Cell Disease (CSSCD), a prospective multicenter study of 3,764 patients, more than 20% of adults likely had fatal pulmonary complications of sickle cell anemia (2). Acute and chronic pulmonary complications of sickle cell anemia are common but often underappreciated by healthcare providers. These conditions have clearly emerged as major threats to the well-being and longevity of patients with sickle cell disease.

	ACUTE PULMONARY DISEASE

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Patients with sickle cell anemia frequently develop acute pulmonary complications of their illness including asthma, thromboembolism, and acute chest syndrome. A number of studies suggest that asthma is a significant comorbidity in patients with sickle cell anemia. Santoli and coworkers measured pulmonary function in 49 patients with sickle cell anemia and found that 37% of the patients had obstructive lung disease, defined by a ratio of the forced expiratory volume in 1 s to the forced vital capacity (FEV₁/FVC) <80% of predicted with normal total lung capacity. Twenty per cent of these patients had mixed obstructive and restrictive pulmonary function, and 20% had restrictive defects alone (9). In a retrospective analysis of 63 children with sickle cell disease receiving routine pulmonary function testing, 35% had obstructive lung disease (10). In one of the few controlled studies, Leong and Stark evaluated 40 patients with sickle cell disease and 10 sibling control subjects. They found that approximately 60% of the patients with sickle cell disease had airway reactivity (to cold air challenge) whereas none of the control subjects had reactive airways (11). The effects of uncontrolled asthma and the impact of intensive therapy on other complications of sickle cell anemia, such as vaso-occlusive crisis and the acute chest syndrome, have not been explored.

People with sickle cell disease appear, on the basis of natural history and evidence from autopsy, to be at increased risk for thromboembolism (8, 12, 13). This observation has been attributed to a putative hypercoagulable state. Although controversial, several mechanisms have been proposed to explain this hypercoagulability including platelet reactivity, hydroxyl radical formation, fibronectin and thrombospondin elevation, deficient proteins S and C, and elevated levels of Factor VIII and tissue factor (14). There are no comprehensive epidemiological studies assessing the incidence and prevalence of thromboembolism in patients with sickle cell anemia.

Acute chest syndrome is the most common cause of death and the second most common cause of hospitalization of adults with sickle cell anemia (2, 8, 13). The acute chest syndrome is defined as a new pulmonary infiltrate on chest radiograph accompanied by fever, chest pain, and a variety of respiratory symptoms including coughing, wheezing, and tachypnea (19, 20). Both the CSSCD and the Multi-Center Acute Chest Syndrome Study (MACSS), a prospective study of 671 episodes of acute chest syndrome in 538 patients, found that acute chest syndrome often develops after vaso-occlusive crisis (2, 19). Multiple factors may contribute to the respiratory distress associated with the acute chest syndrome, including infection (21, 22), pulmonary fat embolism (23, 24), iatrogenic fluid overload, hypoxemia and atelectasis secondary to splinting from painful rib and sternal infarctions (25), and pulmonary vascular obstruction due to sickling and endothelial adherence of erythrocytes resulting in infarction of the pulmonary parenchyma (19). The pathogenesis of acute chest syndrome has been reviewed (20, 28, 29).

	CHRONIC PULMONARY DISEASE

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Most patients with sickle cell anemia develop abnormal pulmonary function characterized by airway obstruction, restrictive lung disease, abnormal diffusing capacity, and hypoxemia (7, 9, 10, 30). In a series of 16 young adults (20-40 yr of age, with sickle cell anemia and no history of pulmonary disease) who participated in physiologic studies at the National Institutes of Health, mean arterial Pa_o2 was 89 ± 8.7 mm Hg (33). Chronic occult pulmonary injury by similar mechanisms invoked for the acute chest syndrome may be the cause of these pulmonary function abnormalities.

Pulmonary hypertension is increasingly recognized as a complication of sickle cell anemia (34). Retrospective studies of echocardiograms performed at tertiary care sickle cell disease centers have reported that up to 40% of patients have moderate to severe pulmonary hypertension (40, 41). Sutton and colleagues (40) reviewed echocardiograms of 60 consecutive patients with sickle cell anemia. Twelve of these patients had tricuspid regurgitant jet velocities of greater than 2.5 m/s with calculated mean pulmonary systolic pressure of 53 mm Hg and evidence of right ventricular pressure overload (dilation of the right ventricle with paradoxical motion of the septum). Hemodynamic studies of 10 sickle cell patients with cardiopulmonary symptomatology demonstrated elevated pulmonary systolic and diastolic pressures (median, 50/25 mm Hg; range, 25/12-89/35 mm Hg), high cardiac outputs (median, 9.2 L/min; range, 3.1-14.5 L/min) and normal to high pulmonary capillary wedge pressures (median, 17 mm Hg; range, 12-24 mm Hg) (38). Similar measurements in sickle cell patients have been published by other investigators (34, 35, 42, 43). The hemodynamic profiles differ from patients with primary pulmonary hypertension in that the pulmonary pressures tend to be lower and the cardiac outputs are higher, resulting in more modest elevation in pulmonary vascular resistance. The mean values of pulmonary vascular resistance from three studies ranged from 250 to 329 dyn/s per cm⁵ (35, 38, 43).

To reduce the inherent bias in retrospective analyses of echocardiograms performed for other clinical indications at tertiary care referral centers, we have initiated a prospective screening study of individuals with sickle cell anemia in the greater Washington DC region. Volunteers are being recruited from sickle cell support groups, by multimedia advertisement, and from area sickle cell clinics. Preliminary data from 70 patients participating in this study confirm a prevalence of mild-to-severe pulmonary hypertension of approximately 30% (defined by a tricuspid jet velocity >2.5 m/s).

Sickle cell patients with pulmonary hypertension have a significantly increased mortality rate compared with sickle cell patients without pulmonary hypertension. Sutton and colleagues reported a 40% mortality rate in sickle cell patients with pulmonary hypertension at 22 mo (odds ratio [OR] 7.86, 95% confidence interval [CI] = 2.63 to 23.4), compared with sickle cell patients without pulmonary hypertension (40). Powars and colleagues (7) reported a mean survival of 2.5 yr for sickle cell patients with chronic lung disease and elevated pulmonary artery pressures. Aboubakr and colleagues performed a retrospective analysis of echocardiograms obtained for clinical indications in patients with sickle cell disease. This analysis revealed a 30% prevalence of pulmonary hypertension and a 30% 2-mo mortality rate (44). Investigators at Howard University are monitoring patients with both pulmonary hypertension and sickle cell disease and approximately 50% of these patients have died over a 24-mo period (O. Castro, personal communication). These data suggest that this complication of sickle cell disease, like primary pulmonary hypertension and pulmonary hypertension secondary to other causes, carries a high morbidity and mortality rate. Case series describing the pathologic changes observed in the pulmonary vasculature are summarized in Table 2 (35, 37, 42, 45, 46).

The etiology of the secondary pulmonary hypertension in individuals with sickle cell disease is likely multifactorial, caused by chronic hypoxemia, in situ thrombosis, and parenchymal and vascular injury due to sequestration of sickle erythrocytes, fat embolization, and infection. Notably, thalassemia is another chronic hemolytic disease that is associated with secondary pulmonary hypertension (prevalence ranging from 10 to 93% depending on the patient population studied) (47). There are a number of pathogenic mechanisms that are similar between thalassemia and sickle cell anemia. Both patient populations suffer from chronic hemolysis resulting in the liberation of free hemoglobin, heme, and iron. Plasma and membrane-associated hemoglobin, heme, and free iron can both scavenge nitric oxide and catalyze the formation of reactive oxygen and nitrogen species (52). Both patients with sickle cell disease and thalassemia commonly receive blood transfusions, further releasing cell-free hemoglobin into the circulation. Patients with sickle cell anemia are functionally asplenic because of autoinfarction of the spleen in early childhood whereas patients with thalassemia often have their spleens surgically removed. Thus both populations are exposed to a variety of circulating mediators that would otherwise be removed by a functional spleen. In particular, increased platelet levels and platelet-derived mediators such as thrombospondin may contribute to vasculopathy in asplenic patients (56). Activated platelets release thrombospondin, which binds to CD36 surface molecules on endothelial cells and erythrocytes and to sulfated glycans on reticulocytes, resulting in adhesion of red cells to endothelium (57). Retarding erythrocyte transit across the capillary bed promotes erythrocyte deoxygenation, intracellular sickle hemoglobin (HbS) polymerization, and vaso-occlusion. Chronic anemia and transfusion in both illnesses result in high cardiac output states and chronic iron deposition leading to injury of organs such as the heart, liver, and possibly the pulmonary vasculature. The higher prevalence of pulmonary vasculopathy observed with these disorders suggests that there may be a distinct syndrome of hemolysis-associated secondary pulmonary hypertension.

	CONCLUSIONS

TOP INTRODUCTION ACUTE PULMONARY DISEASE CHRONIC PULMONARY DISEASE CONCLUSIONS REFERENCES

The African American population is growing and more children with sickle cell anemia are surviving into adulthood and developing pulmonary complications of their disease. In addition to asthma, thromboembolism, acute chest syndrome, and chronic pulmonary fibrosis, pulmonary hypertension is a common complication of adult patients with sickle cell anemia. Appropriate therapies and strategies for prevention of pulmonary hypertension in sickle cell anemia are unknown. Further research exploring therapies such as oxygen, nitric oxide, prostacyclin, L-arginine supplementation, chronic transfusion, and hydroxyurea is indicated. Other needs for clinical research include the etiology of sudden death, right and left ventricular dysfunction, and the impact of intensive asthma therapy on child and adult clinical outcomes. Clinicians should screen patients with sickle cell anemia for pulmonary hypertension and attempt to identify reversible causes such as hypoxemia, thromboembolism, and asthma. Hydroxyurea, approved by the Food and Drug Administration as a therapy for sickle cell anemia, increases fetal hemoglobin levels, thereby altering the kinetics and equilibrium dynamics of hemoglobin S polymerization, and reduces the rates of vaso-occlusive crisis, acute chest syndrome (ACS), and transfusion (60, 61). Although hydroxyurea has not been studied in sickle cell patients with pulmonary hypertension, we believe that all such patients should be treated with this medication, with the goal of increasing the fetal hemoglobin levels to 20-30% of total hemoglobin (62). For years hematologists and pediatricians have pioneered the research and treatment of patients with sickle cell anemia. The frequency and severity of pulmonary complications in adults with sickle cell anemia now require the attention of pulmonary specialists.

	Footnotes

Correspondence and requests for reprints should be addressed to Mark T. Gladwin, M.D., Warren G. Magnuson Clinical Center, Critical Care Medicine Department, Building 10, Room 7D43, 10 Center Drive, MSC 1662, Bethesda, MD 20892-1662. E-mail: mgladwin{at}nih.gov

(Received in original form April 24, 2001 and accepted in revised form September 19, 2001).

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