Sickle cell disease and pulmonary hypertension ... - Wiley Online Library

Sickle cell disease and pulmonary hypertension in Africa: A global perspective and review of epidemiology, pathophysiology, and management Zakari Y. Aliyu,1,2,3* Gregory J. Kato,1,4 James Taylor IV,1 Aliyu Babadoko,3 Aisha I. Mamman,3 Victor R. Gordeuk,2 and Mark T. Gladwin1,4 Secondary pulmonary hypertension (PAH) has been shown to have a prevalence of 30% in patients with sickle cell disease (SCD) with mortality rates of 40% at 40 months after diagnosis in the United States. The burden of SCD is highest in sub-Saharan Africa, especially in Nigeria (West Africa), where approximately 6 million people are afflicted. The true global incidence, prevalence, and burden of SCD and its associated end organ complications however remain unknown. Chronic hemolysis represents a prominent mechanistic pathway in the pathogenesis of SCD-associated pulmonary hypertension via a nitric oxide (NO) scavenging and abrogation of NO salutatory effects on vascular function, including smooth muscle relaxation, downregulation of endothelial adhesion molecules and inhibition of platelet activation. Many known infectious risk factors for PAH are also hyperendemic in Africa, including Human Immunodeficiency Virus/Acquired Immune Deficiency Syndrome (HIV/AIDS), chronic hepatitis B and C, and possibly malaria. Interactions between these infectious complications and SCD-related hemolysis could yield an even higher prevalence of pulmonary hypertension and compound the existing global health systems challenges in managing SCD. Indeed, our preliminary analysis of African immigrants currently in the United States suggests that pulmonary hypertension represents a significant complication of SCD in the African subcontinent. There is clearly a need to include Africa and other parts of the world with high SCD prevalence in future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide. Am. J. Hematol. 83:63–70, 2008. Published 2007 Wiley-Liss, Inc.y

Introduction There are limited data on the exact number of individuals affected with homozygous sickle cell disease (SCD) worldwide. Based on the World Health Organization published global prevalence map of SCD and other data, we estimate that about 20–25 million individuals world wide have homozygous SCD; 12–15 million in sub-Saharan Africa, 5–10 million in India and about 3 million distributed in different parts of the world [1,2]. In comparison, about 70,000 patients with SCD live in the United States. As life expectancy improves among these patients in the United States and Western Europe, end organ complications associated with older age are now being observed in adults with increasing frequency, including pulmonary hypertension [3– 5]. Pulmonary hypertension is now recognized to be a common complication of SCD and other hemolytic disorders, and is associated with increased morbidity and mortality [4–7]. Considering the high prevalence in sub-Saharan Africa of both SCD and other causes of pulmonary arterial hypertension, such as HIV/AIDS, an exploration of the prevalence of pulmonary hypertension and a possible pathological interaction between disease triggers is indicated. In the present review, we examine existing data in an effort to understand the likely burden of undiagnosed pulmonary hypertension in Africa. This exercise can serve as a starting point for future comprehensive studies on the epidemiology and treatment of end organ complications of an aging SCD population world-wide. Pathophysiology The sickle mutation results in a single amino acid change in the b-globin subunit of hemoglobin (Glu ? Val), Published 2007 Wiley-Liss, Inc. y This article is a US Government work and, as such, is in the public domain in the United States of America. American Journal of Hematology

and it is inherited as an autosomal recessive trait. The protean clinical features of homozygous SCD result from chronic hemolysis, vascular occlusion, and tissue ischemia and end-organ damage. Vasoocclusion results from a dynamic combination of abnormalities in hemoglobin structure and function, red blood cell membrane integrity, erythrocyte density, endothelial activation and cellular adhesion, vascular smooth muscle, inflammatory mediators, and coagulation [8,9]. These pathophysiologic events translate into clinical manifestations that fall into four general categories: hemolytic anemia and its complications, vasoocclusive crisis and bone marrow fat embolization

1 Vascular Medicine Branch, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland; 2Center of Sickle Cell Disease and Department of Medicine, Howard University, Washington, DC; 3 Department of Hematology and Blood Transfusion, Ahmadu Bello University, Zaria, Nigeria; 4Clinical Center, National Institutes of Health, Bethesda, Maryland

Contract grant sponsor: National Institutes of Health (NIH); Contract grant sponsor: NHLBI; Contract grant number: 2 R25 HL003679-08; Contract grant sponsor: Howard University GCRC, NCRR, NIH; Contract grant number: 2MOI RR10284-10. *Correspondence to: Zakari Y. Aliyu, National Institutes of Health, Building 10-CRC, Room 5-5140, 10 Center Drive, Bethesda, MD 20892-1662. E-mail: [email protected] Received for publication 15 May 2007; Revised 13 July 2007; Accepted 18 July 2007 Am. J. Hematol. 83:63–70, 2008. Published online 1 October 2007 in Wiley InterScience (www.interscience. wiley.com). DOI: 10.1002/ajh.21057

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syndromes, proclivity to infections and organ dysfunction. Organ damage often results from a combination of progressive vasculopathy and acute infarction; clinical manifestations include stroke, retinopathy, avascular necrosis of bone, priapism, splenic infarction, sequestration and involution, nephropathy, hepatopathy, and secondary pulmonary hypertension [9,10]. Chronic hemolysis (extravascular and intravascular) leading to anemia is the sine qua non of homozygous SCD. Intravascular hemolysis results in the release of hemoglobin and erythrocyte enzymes, such as arginase I, into the plasma [11]. When the capacity of protective hemoglobinscavenging mechanisms has been saturated (haptoglobin, CD163, and hemopexin), the plasma levels of cell-free hemoglobin increase [12]. Free hemoglobin reacts with nitric oxide (NO), produced by endothelial NO synthase, at a near-diffusion limited rate to produce methemoglobin and nitrate. This is a scavenging or inactivation reaction, because the vasodilator NO is oxidized to the inert nitrate (NO32) [12,13]. Arginase I pathologically released into blood plasma converts plasma L-arginine, the substrate for NO synthesis by endothelial NO synthase, into ornithine. These combined effects, NO scavenging by hemoglobin and arginine catabolism by arginase, result in a state of NO resistance and insufficiency termed hemolysis-associated endothelial dysfunction [13]. NO plays a major role in maintaining vascular homeostasis: NO regulates basal and stress-mediated smooth muscle relaxation and vasomotor tone; transcriptionally downregulates endothelial adhesion molecule expression (endothelin-1, VCAM-1, ICAM-1, Pselectin, E-selectin); and inhibits platelet activation and aggregation. Thus, the scavenging of NO is expected to have broad deleterious effects on vascular function. We have hypothesized that chronic hemolysis represents a fundamental mechanistic pathway in the development of proliferative pulmonary vasculopathy that results in pulmonary hypertension [12,13]. Pulmonary hypertension is also an increasingly recognized complication of other chronic hemolytic conditions including thalassemia, paroxysmal nocturnal hemoglobinuria, hereditary spherocytosis and stomatocytosis, and microangiopathic hemolytic anemias [4–7,14]. We and others have suggested that hemolytic anemia drives a ‘‘clinical sub-phenotype’’ of SCD that is also observed in other chronic hemolytic diseases; the elements of this subphenotype include pulmonary hypertension, cutaneous leg ulceration, and priapism [15,16]. Consistent with this thesis, in the United States National Institutes of Health (NIH)–Howard University pulmonary hypertension screening cohort, pulmonary hypertension, priapism and cutaneous leg ulceration were all epidemiologically associated with indices of high hemolytic rate [4,15]. In patients enrolled in the Cooperative Study of Sickle Cell Disease (CSSCD) both priapism and cutaneous leg ulceration were associated with indices of high hemolytic rate [16,17]. In recently presented data at the 2007 American Society of Hematology Meetings, Nolan and Steinberg presented data from the CSSCD that in a Bayesian Network analysis, indices of hemolysis were associated with risk of death, suggesting a link with cardiovascular (i.e., pulmonary hypertension) disease [18]. In contrast, the risk of vasoocclusive-hyperviscosity complications of SCD, such as acute vasoocclusive crisis, osteonecrosis of bone and the acute chest syndrome is associated with high steady state hemoglobin (low hemolytic rate), low fetal hemoglobin, and high white blood cell counts [10,19]. Further supporting distinct mechanisms of disease, the risk of developing pulmonary hypertension in adults with SCD is neither related to the frequency of vasoocclusive pain crisis and the acute chest syndrome, nor is it related to leukocyte counts or fetal he-

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moglobin levels (in marked contrast to the risk of vasoocclusive crisis) [4,20]. Epidemiology of pulmonary hypertension in the United States The classic definition of pulmonary hypertension is a mean pulmonary artery pressure (MPAP) > 25 mmHg (or >30 mmHg during exercise) determined by right heart catheterization [21,22]. Retrospective studies performed at a tertiary care sickle cell center in the United States have reported that 20–40% of screened adult SCD patients have moderate to severe pulmonary hypertension with an approximate 20% mortality over a 12-month follow up period [23,24]. The systolic pulmonary artery pressures can be estimated by echocardiographic measurement of the tricuspid regurgitant jet velocity (V) and estimation of the central venous pressure (CVP). These values can be translated mathematically, based on the modified Bernoulli equation 4V 2 1 CVP, to a pulmonary artery systolic pressure (Figs. 1 and 2) [22]. Echocardiographic quantification of the tricuspid regurgitant jet velocity provides a noninvasive option to screen for pulmonary hypertension. We prospectively defined pulmonary hypertension as a tricuspid regurgitant jet velocity of greater than or equal to 2.5 m/s, which occurs in less than 5% of the normal population, and moderate-to-severe pulmonary hypertension as a value greater than or equal to 3.0 m/s [4]. Tricuspid regurgitant jet velocity in sickle cell patients correlates well with ‘‘gold standard measures of pulmonary artery systolic pressure’’ determined by right heart catheterization in experienced centers (R values between 0.77 and 0.9) [4]. Using this measurement, we found that approximately 30% of patients with SCD have a tricuspid regurgitant jet velocity of greater than or equal to 2.5 m/s and 9% have a value greater than or equal to 3.0 m/s [4]. These values have been reproduced in other screening cohorts: Ataga and colleagues from North Carolina recently reported a prevalence of pulmonary hypertension of 30% among 60 sickle cell patients (18 years of age; mean ± SD age, 37 ± 13 years) followed at a University Medical Center [25]. DeCastro and colleagues from Duke University, North Carolina, have also reported similar findings [26]. In our study, independent correlates of pulmonary hypertension included a self-reported history of cardiovascular or renal complications, systolic hypertension, high lactate dehydrogenase levels (index of hemolysis), high levels of alkaline phosphatase, and low transferrin concentrations (indicating iron overload). In men, a history of priapism was a significant association with elevated pulmonary pressures. No relationship was found between high pulmonary pressures and fetal hemoglobin level, white-cell count, platelet count, or use of hydroxyurea therapy. These findings suggest that pulmonary hypertension risk is associated with renal insufficiency, systemic vasculopathy (relative systolic hypertension), hemolytic rate (high LDH, low hemoglobin), cholestatic liver dysfunction (high alkaline phosphatase), and iron-overload [4]. Most of the existing data on pulmonary hypertension in SCD is in the adult population. However, there is emerging information on the prevalence of the disease in the pediatric population. Nelson et al. recently reported a prevalence of pulmonary hypertension of 31% among children with SCD based on a prospective screening study by Doppler echocardiography. We have also recently reported the prevalence of pulmonary hypertension in children based on the results of 11 small screening studies published or presented in abstract form. Based on our analysis of aggregated results from these studies involving over 600 children with SCD, about 30% of pediatric sickle cell populations

American Journal of Hematology DOI 10.1002/ajh

Figure 1. Severe pulmonary hypertension in a 28 year old Nigerian female with homozygous SCD; TRV 5 3.2 m/s. TRV measured by spectral Doppler (short arrow), color Doppler showing blue regurgitant jet from the right atrium (RA) from the right ventricle (RV).

Figure 2. 2D echocardiography: Apical four chamber view of the heart with color flow Doppler (enlarged view of figure 1) showing regurgitant (blue color) jet velocity across the tricuspid valve.

have a Tricuspid regurgitant velocity (TRV) 2.5 m/s. This would suggest that the prevalence of pulmonary hypertension in the pediatric population is nearly identical to that of adults with SCD [27,28]. A consistent theme in several of the pediatric reports is the correlations of high TRV to the same variables seen in adults: low hemoglobin levels, high reticulocyte counts, bilirubin, and LDH levels. As in adults, these markers implicate hemolysis associated mechanisms in pediatric pulmonary hypertension [27,28]. While Doppler echocardiography is an excellent screening tool for pulmonary hypertension and associated right heart (and or coexisting left heart) dysfunction, it has limited availability in several developing countries. Technical expertise and cost concerns remain barriers to many screening and diagnostic modalities in sub-Saharan Africa. Cardiac catheterization is the gold standard for the diagnosis of pulmonary hypertension and identifying coexisting pulmonary venous hypertension. This ‘‘gold standard’’ is also not available in most health care centers including tertiary hospitals in sub-Saharan Africa and many other parts of the developing world. Therefore alternative validated screening measures for pulmonary hypertension are needed. The N-terminal pro-BNP assay is emerging as a potential screening biomarker for pulmonary hypertension associated with SCD. B-type natriuretic peptide (BNP) is a cardiac neurohormone synthesized in the cardiac ventricles. It is released as a preproBNP peptide and is cleaved into proBNP. ProBNP is subsequently cleaved into BNP and the inactive N-terminal proBNP peptide (NTproBNP). The release of BNP into the circulation is directly proportional to the ventricular expansion and volume overload of the ventricles and therefore reflects the decompensated state of the ventricles. The effects of BNP—vasodilatation, natriuresis, and diuresis—lead to some improvement of the loading conditions of the failing heart [29]. Although BNP is the active neurohormone, both BNP and NTproBNP have been described as useful markers for the diagnosis and exclusion of congestive heart failure both systolic and diastolic dysfunctions and right heart failure and plasma concentrations correlate with the functional classification of patients according to the New York Heart Associa-

tion (NYHA) [29]. We evaluated this biomarker in the NIH– Howard cohort and in the Multicenter Study of Hydroxyurea cohort. In the NIH–Howard cohort, we found that an NTBNP value of 160 pg/mL had a positive predictive value for the diagnosis of pulmonary hypertension of close to 80%, represented the 75th percentile for the population, and was associated with an increased risk of prospective death. Using this value of NT-BNP in the Multicenter Study of Hydroxyurea cohort we found that this was associated with a threefold increase risk of death over 9 years of follow-up and was strongly associated with indices of hemolytic anemia [30]. Additional studies are needed to validate the role of the NT-BNP as a screening stool for sickle cell PAH. NT-BNP is also a relatively expensive test even in the United States. It is however a quick, easy, reproducible test and can be monitored serially along with other blood test in the course of managing sickle cell patients. Accumulating evidence indicates that patients with SCD and pulmonary hypertension have as high a mortality rate as patients with idiopathic pulmonary arterial hypertension despite having much lower tricuspid regurgitant jet velocity values determined by echocardiography and lower mean pulmonary artery pressures determined by right heart catheterization. Castro and colleagues first reported that pulmonary hypertension diagnosed by right heart catheterization was associated with a median survival of 25.6 months among sickle cell patients [31]. This data was based on an analysis of the hemodynamic data in 34 adult patients with SCD at right-sided cardiac catheterization and determination of the relationship of pulmonary hypertension to patient survival. The median post-catheterization follow-up was 23 months for patients with pulmonary hypertension and 45 months for those without pulmonary hypertension. Eleven patients (55%) with pulmonary hypertension died compared to 3 (21%) patients without pulmonary hypertension (v2 5 3.83; P 5.0503). In the NIH cohort, a tricuspid regurgitant jet velocity of greater than or equal to 2.5 m/s was associated with mortality rates of 16% at 20 months of follow-up (rate ratio, 10.1; 95% confidence interval [CI] 2.2–47.0; P < 0.001); updated cohort survival now reveals an associated mortality of 40% at 40 months [4]. This has been confirmed


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by Ataga and colleagues who recently reported pulmonary hypertension was associated with an increased risk of death regardless of severity (relative risk, 9.24; 95% CI 1.2–73.3; P 5 0.01) based on 93 adult sickle cell patients followed over a median follow-up period of 2.6 years (range 0.2–5.1 years) [25]. We propose that severe anemia, comorbid organ dysfunction, and episodes of sudden severe SCD related events such as vasoocclusive crisis and hyperhemolysis, and the acute chest syndrome, may produce acute on chronic pulmonary pressure elevation and result in right heart failure. Acute elevations in pulmonary pressures during vasoocclusive crisis or exercise have been documented [32]. Diastolic dysfunction is present in about 18% of adult SCD patients and the combination of diastolic dysfunction and pulmonary hypertension that occurs in about 11% of patients confers an extremely poor prognosis [33]. Global epidemiology and emerging risk factors for pulmonary hypertension There are an estimated 70,000 patients in the United States with SCD. Using an estimated prevalence of pulmonary hypertension among adult SCD patients in the United States of 30%, the estimated number of cases of pulmonary hypertension would be 23,000. Using a more conservative screening value of 9% (tricuspid regurgitant jet velocity 3.0 m/sec) one would expect 6,300 cases. Based on a 40% forty months mortality for adults with tricuspid regurgitant jet velocity 2.5 m/sec, mortality rates associated with pulmonary hypertension could approach 8,400 deaths over the next 4–5 years. While this is may be an alarming statistic for the United States, SCD is a global phenomenon, and SCD-related pulmonary hypertension likely also occurs globally. The sickle-cell gene is distributed widely throughout subSaharan Africa (as a result of heterozygote advantage against malaria), the Middle East and parts of the Indian subcontinent, where carrier frequencies range from 5% to 40% or more of the population [1,2]. Each year about 300,000–400,000 infants are born with major hemoglobin disorders—including more than 200,000 cases of sickle-cell disease in Africa, 150,000 in Nigeria alone [34,35]. The public health implications of sickle-cell anemia are significant. When health impact is measured by under-five mortality, sickle-cell anemia contributes the equivalent of 5% of under-five mortality rates on the African continent, more than 9% of such deaths in West Africa, and up to 16% of under-five deaths in individual West African countries [34]. The high burden of infectious diseases including HIV/AIDS, malaria, and diarrheal diseases contribute to the high childhood mortality rates in sub-Saharan Africa. Hemolysis associated pulmonary hypertension may worsen the already poor outcome of sickle cell patients especially children in Africa. The prevalence and outcomes of SCDrelated pulmonary hypertension in Africa have not been investigated both in the adult and pediatric populations. Extrapolating from our U.S SCD cohort, a large number of SCD patients in Nigerian and the rest of Africa may be at risk for PAH. No data currently exists on the prevalence of pulmonary hypertension among Africans. To begin to address this issue, we conducted a subgroup analysis of the prevalence of PAH among African immigrants versus all other patients in our NIH cohort of 266 patients with SCD (141 men and 125 women; mean ± SD age, 38 ± 16 years). Pulmonary hypertension was defined as a tricuspid jet velocity 2.5 m/sec. Pulmonary hypertension occurred in 36.4% of all 266 patients. Twenty nine (11%) patients were identified as Africans including 17 Nigerians, 4 Ghanaians, 2 from Niger, 2 Zambians, 2 Liber-

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ians, and 2 from Sierra Leone. Thirteen (44%) of the African patients had PAH (OR 5 1.49, 95% CI 0.68–3.24, P 50.3) and 9 (55%) of the Nigerians had pulmonary hypertension (OR 5 2.25, 95% CI 0.48–10.4, P 5 0.4). Homozygous SS was observed in 97% of the Africans versus 76% overall (P 5 0.008). Our study was unable to identify a statistically significant difference between African immigrants with SCD and other SCD populations, suggesting that this complication arises with equal frequency in Africa. The African immigrant patients in our cohort did not have associated pathogens such as HIV/AIDS, chronic hepatitis B or C, or recent history of malaria to explain the development of this complication [36]. We have recently initiated a largescale screening study of pulmonary hypertension in Northern Nigeria (Zaria) using echocardiography and BNP screening [37]. Several known infectious risk factors for pulmonary hypertension are also hyperendemic in developing countries; especially sub-Saharan Africa, including HIV/AIDS, malaria, chronic hepatitis B and C, schistosomiasis, and hookworm [38–42]. Interactions between these infectious diseases and SCD-related hemolytic vasculopathy might lead to an even higher prevalence of pulmonary hypertension in African patients with SCD. Sub-Saharan Africa has just over 10% of the world’s population and is home to almost 64% of all HIV-infected individuals, with an estimated 21.6 million to 27.4 million people living with HIVinfection. In 2005, an estimated 2.3 million to 3.1 million people in the region became newly infected, and up to 2.3 millions adults and children died of AIDS-related illnesses [38]. HIV/AIDS is now recognized as an independent risk factor for PAH [43,44]. The histopathology of HIV-associated pulmonary hypertension is similar to that of idiopathic pulmonary hypertension, with the development of a plexogenic pulmonary vasculopathy. The incidence of pulmonary hypertension is 1,000 times higher in HIV patients as compared to the general population with an incidence of pulmonary hypertension of about 1–5 per 1000 per year among HIV-positive patients, while in the general population it is 1–2 cases per million people [43,44]. While the prognosis of HIV infection has been improved with antiretroviral therapy, the prevalence of severe PAH remains unchanged [45]. There is one report of severe PAH in sickle cell patients with HIV/AIDS, suggesting a possible interaction between HIV/AIDS and sickle cell anemia may result in severe PAH [46]. SCD patients are more susceptible to malaria and have a poorer outcome with the disease [47,48]. Acute and chronic malarial infections are associated with intravascular hemolysis and a depletion of NO associated with intravascular hemolysis has been described in animal models, supporting a mechanism similar to that of hemolysis-associated vasculopathy as in SCD [49]. Whether patients with severe malarial infection develop pulmonary hypertension is unknown. The rare data available from animal studies on the association between malaria and pulmonary hypertension involved the infection of young turkeys with Plasmodium durae, which produced a significant increase in the mean relative right ventricular mass in the infected group [50,51]. The murine models of both SCD and alloimmune hemolytic anemia develop pulmonary hypertension associated with global impairment in NO bioavailability [52]. While these studies suggest that interactions may exist between SCD, malaria, and risk of pulmonary hypertension, clinical studies are required to test this thesis. Additional infectious causes of pulmonary hypertension and diseases that may coexist and potentially worsen hemolytic pulmonary hypertension in tropical regions include schistosomiasis, hookworm and chronic hepatitis B and C infections. Hepatitis C


and B are established causes of chronic liver disease and may be contributory causes of chronic lung disease and pulmonary hypertension (portopulmonary hypertension). The prevalence of pulmonary hypertension related to hepatitis B and C is estimated to be about 5% [53]. The prevalence of hepatitis B and C in a country with high sickle cell prevalence like Nigeria is estimated to be about 5–15% respectively with a HIV/AIDS coinfection rate as high as 70% [54,55]. The prevalence of HIV, HCV, and hepatitis B among sickle cell patients has been reported as between, 5% for HIV/AIDS, 5–35% for HCV and 5–20% for hepatitis B [56–58]. No data exist on the prevalence of pulmonary hypertension in sickle cell patients with chronic hepatitis B or C. The associations of HIV/AIDS, malaria and other endemic tropical infectious diseases and the impact of these conditions on the natural history, treatment, and outcome of pulmonary hypertension in SCD represent one of our major active research endeavors in Africa. Management Therapy for SCD-related pulmonary hypertension remains challenging as many of these patients may be asymptomatic, mildly symptomatic and may not meet conventional indications for hydroxyurea therapy. Complete history and physical examination, complete blood count and metabolic profile and NT-BNP measurements, 6-min walk testing for functional assessment, and echocardiography to determine TRV and estimate right ventricular systolic pressure can point to the diagnosis of pulmonary hypertension and provide a global picture of clinical severity. Our general approach includes a through evaluation to identify and manage other causes of pulmonary hypertension such as chronic thromboembolic disease, reactive airways disease, obstructive sleep apnea, and left ventricular diastolic dysfunction (Table 1). We recommend and provide maximal SCD treatment with hydroxyurea therapy at maximum tolerated dose and judicious use of blood transfusion support, red cell growth factor support (in the setting of coexisting renal disease) and iron chelating agents where indicated. Specific therapy for pulmonary hypertension includes pulmonary vasodilators and antiremodeling agents [59] (Table 2). The key to the management of SCD and its complications includes early identification through screening, adequate patient education and counseling, prophylaxis therapy (childhood penicillin, vaccinations and folate supplementation where indicated), and the appropriate use of hydroxyurea. Hydroxyurea is the most successful drug therapy for SCD and the only therapy specifically approved in the United States for SCD. It is however underutilized in this disease. Treatment with hydroxyurea is associated with significant decreases in the rate of painful crises and hospital admissions, the incidence of chest syndrome, priapism and hepatic sequestration, and blood transfusion requirements [60–62]. Hydroxyurea treatment also reduces mortality by 40% [60]. The efficacy of hydroxyurea in SCD is related to its ability to increase red cell content of hemoglobin F, doserelated reduction in white cell count, increased water content of red cells, increased deformability and successful microvascular navigation of sickled cells and altered adhesion of red blood cells to endothelium by decreasing the expression of endothelial adhesion molecules [3]. While hydroxyurea has antihemolytic properties and a potential NO donor effect, it has not been shown to impact mortality of SCD related pulmonary hypertension. This has however not been evaluated in a prospective, randomized clinical trial [4,63]. SCD patients in most of sub-Saharan Africa are hydroxyurea naı¨ve and thus could provide an opportunity to investigate the efficacy of this drug in SCD-related pulmonary hypertension. For example, at the initiation of a study of SCD by the


TABLE I. Pulmonary Hypertension in Sickle Cell; Differential Diagnoses With Special Considerations for Evaluating Sickle Cell Patients in Sub-Saharan Africa [77] Pulmonary arterial hypertension Idiopathic and familial Congenital systemic-to-pulmonary shunts/congenital birth defects Toxic-metabolic and drug related (Considerations for herbal and traditional medicines) Infectious: l l

HIV-associated pulmonary arterial hypertension Hepatitis B and C: Porto-pulmonary hypertension

Hemolytic: l l l l

Sickle cell hemolysis Other hemoglobinopathies related pulmonary hypertension Acute and chronic malaria (hypothetical) G6PD related deficiency (hypothetical)

Other causes of portal pulmonary hypertension with high prevalence in Africa Alcohol liver disease, Bantu iron siderosis Pulmonary venous hypertension (Rheumatic heart disease a major consideration in Africa) Left ventricular dysfunction Valvular heart diseases Pulmonary hypertension associated with lung diseases and/or hypoxemia Chronic obstructive pulmonary disease Alveolar hypoventilation disorders Sleep-disordered breathing Interstitial lung disease Sarcoidosis Pulmonary hypertension due to chronic thrombotic and/or embolic disease l l

Thromboembolic obstruction of proximal pulmonary arteries Nonthrombotic pulmonary embolism * Parasites: Schistosomiasis, hookworm, ascariasis * Tumor emboli * Foreign material

United States National Institutes of Health and Ahmadu Bello University Hospital in Zaria, Nigeria, none of the patients were being treated with hydroxyurea as of July 2006. Niprisan (Nix-0699, Nicosan, Hemoxin) is an antisickling, phytopharmaceutical approved for the prophylactic management of SCD in Nigeria. It was developed at the Nigerian National Institute for Pharmaceutical Research and Development (NIPRD). In one randomized, double-blind clinical trial conducted under NIPRD’s auspices, the drug was reported to substantially reduce severity scores in selfreported pain assessments by Nigerian patients with SCD [64,65]. There are limited data on the safety and efficacy of Niprisan in general and it has also not been studied in pulmonary hypertension. The phytopharmaceutical has not been well studied or approved in the United States or any other country outside Nigeria. Numerous questions also surround the adequacy and appropriateness of the reported clinical studies that led to its approval in Nigeria. The development of Niprisan, however, represents unique research opportunities for exploring the role of phytopharmaceuticals in SCD and it also represents a promising African indigenous effort in sickle cell drug development that may warrant international support for validation and standardization. Chronic simple or exchange transfusion may be effective in ameliorating dyspnea and improving functional capacity in severe pulmonary or cardiac disease in SCD. Anecdotes among adult health care providers suggest that chronic transfusion therapy can reduce hemolytic rate and pulmo-

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TABLE II. Approach to the Diagnosis and Management of Pulmonary Hypertension in Sickle Cell Disease 1. Screen for pulmonary hypertension. 2. Risk stratification. a. Mild-to-moderate pulmonary hypertension (TRV 5 2.5-2.9 m/s). b. Severe pulmonary hypertension (TRV 5 3.0 m/s and above). c. Determine functional status: l New York Heart Association classification. l Six minute walk test. d. Determine co-exiting left ventricular systolic/diastolic dysfunction (Echocardiographic determination of ejection fraction, E-A ratio, deceleration time and tissue Doppler assessments.) 3. Exclude other cause of pulmonary hypertension: (Table I). 4. Patient education and counseling. 5. Maximize management for coexisting left ventricular diseases (diastolic and systolic). 6. Institute disease specific management: a. Mild-moderate pulmonary hypertension. l Consider referral to sickle cell specialist centers and or enrollment into clinical trails. l Cardiac catherterization may be required for definitive diagnosis of PAH and identifying associated pulmonary venous hypertension. l Cardiology and or pulmonology referral indicated in symptomatic patients. l Prophylactic therapy: Pneumococcal vaccine, annual influenza vaccination and childhood vaccinations and booster vaccinations for adults), and folate supplementation. l In sub-Saharan Africa: Malarial prophylaxis, counseling for oral rehydration therapy and World Health Organization recommended vaccinations. l Evaluate for indications for hydroxyurea. Counsel on risks/ benefits, feasibility and compliance. Address pregnancy and contraception issues. l Determine need for judicious red cell transfusion support. Hemoglobin goal of 10g/dl for symptomatic PAH or symptomatic left heart failure. l Screen for alloimmunization by extended red cell phenotyping. l Evaluate for microalbuminuria/ proteinuria and coexisting renal dysfunction, arrange nephrology referral. Note: Renal adjustment of hydroxyurea dosing. l Use hematopoietic growth factor support (erythropoietin or darbepoetin) in conjunction with hydroxyurea in patients with relative renal insufficiency or renal failure. l Asses for iron overload and chelation therapy. b. Severe pulmonary hypertension: TRV: 3.0 m/s and above. 1. All earlier steps listed for mild to moderate cases (Table I). 2. Cardiology and or pulmonary consultation for cardiac catherterization as definitive diagnostic step for PAH. 3. Referral to specialize PAH centers and clinical trials. 4. Therapy with pulmonary vasodilators, nitric oxide donating agents and vascular remodeling agents’ best in clinical trail settings. a. Selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5(PDE5); Sildenafil. [NAION] b. Endothelin-1 (ET-1) antagonist: Bosentan. Patients need monitoring for worsening anemia and hepatic injury. c. Epoprostenol: PGI2, PGX, prostacyclin, Flolan. Use in sickle cell is strictly experimental and used in our experience in SCD patients with severe life threatening pulmonary hypertension. These patients often have right heart failure and are managed initially in intensive care units.

nary pressures in children with SCD. In our experience with adults we have not seen a change, suggesting that irreversible pulmonary vasculopathy has developed. Screening for

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iron overload and aggressive iron chelating treatment with deferoxamine or deferasirox is important in all SCD patients with iron overload, especially in setting of pulmonary hypertension, since iron-overload is associated with both pulmonary hypertension and left ventricular diastolic dysfunction, and the combination of both factors is associated with a worse prognosis [33]. While there is well-documented evidence for the beneficial effects of therapy with prostanoids, endothelin antagonists, and phosphodiesterase 5 inhibitors in patients with idiopathic PAH and related diseases, the use of these drugs for sickle cell related pulmonary hypertension is currently being investigated. There is increasing interest in the use of sildenafil in sickle cell related pulmonary hypertension [66]. Our group has reported the safety and efficacy of sildenafil in sickle cell patients with pulmonary hypertension in a small patient population. Sildenafil therapy (mean duration 6 ± 1 months) decreased the estimated pulmonary artery systolic pressure (50 ± 4 to 41 ± 3 mmHg; difference 9 mmHg, 95% CI 0.3–17, P 5 0.043) and increased the 6-min walk distance (384 ± 30 to 462 ± 28 m; difference 78 m, 95% CI 40–117, P 5 0.0012). We currently have a much larger number of sickle cell pulmonary hypertension patients on sildenafil. The drug has been well tolerated and safe in both males and females [67]. The major side effects we observe rarely include transient headaches and transient eye-lid edema. A very rare potential side effect reported with sildenafil is nonarteritic anterior ischemic optic neuropathy [68,69]. While no episodes of priapism were observed in these subjects, we only included patients on chronic transfusion therapy or males with impotence. Additional studies underway include a currently planned international multicenter study for the natural history and treatment of pulmonary hypertension with sildenafil in patients with SCD, sponsored by the National Institutes of Health. The study referred to as the ‘‘Pulmonary Hypertension and Sickle Sildenafil Therapy’’ (Walk-PHASST) involves the screening goal of approximately of 1000 patients with SCD age 12 and above with an enrollment goal of 130–140 patients. L-Arginine is the nitrogen donor for synthesis of NO, a potent vasodilator that is deficient during times of sickle cell crisis. This deficiency may play a role in pulmonary hypertension. The enzyme arginase hydrolyzes arginine to ornithine and urea, and thus, it may compete with NO synthase, leading to decreased NO production. Morris and colleagues have studied the effects of arginine therapy (and arginase activity) on pulmonary hypertension in patients with SCD. Oral arginine produced a 15.2% mean reduction in estimated pulmonary artery systolic pressure (63.9 ± 13 to 54.2 ± 12 mmHg, P 5 0.002) after 5 days of therapy in 10 patients. Arginase activity was elevated almost twofold (P 5 0.07) in patients with pulmonary hypertension and was though to limit arginine bioavailability [70]. From the Morris study, arginine may represent a promising new therapy that warrants further investigation in sickle cell pulmonary hypertension. NO therapy might be beneficial for patients with sickle cell acute chest syndrome because of its ability to ameliorate pulmonary hypertension and ventilation/perfusion mismatch. NO may confer some protection against polymerization of sickle hemoglobin and exert a reversible antiplatelet effect that may be beneficial in acute chest syndrome and pulmonary hypertension [71–74]. Conclusions Adult patients and possibly adolescent patients with SCD are at increased risk for the development of pulmonary hypertension. This complication of SCD is common, frequently silent (asymptomatic patients), under diagnosed


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