A. Clinical Aspects Page 2

9. Bone and joint disease in sickle cell disease. Aguilar C, Vichinsky E, Neumayr L. Hematol Oncol Clin North Am. 2005;19:929-41.

Bone and joint disorders are the most common cause of chronic pain in patients who have sickle cell disease. The femoral head is the most common area of bone destruction in sickle cell patients, although other disease-related problems include avascular necrosis of the humeral head, changes in the thoracic and lumbar spine, infection with encapsulated organisms (Salmonella and Staphylococcus aureus are the most common), bone marrow disturbances, and dental effects. Complications can occur at any location: epiphyseal, metaphyseal, or diaphyseal. This article highlights aspects of sickle cell disease that affect healthy bone and joint function and discusses treatment options.

The prevalence rate of avascular necrosis of the femoral head increases with age. A 3% prevalence rate has been reported in those less than 15 years, and this rises to 50% in those over 35 years. In patients younger than 30 years who do not have sickle cell disease, hemiresurfacing of the femoral head is a promising treatment option. However, for those who have sickle cell disease, the failure rate has been reported to be 100%. Total hip arthroplasty provides the best opportunity for clinical improvement but the early and late complication rates are high. Technical difficulties related to marrow hyperplasia and the presence of sclerotic intramedullary bone, vaso-occlusive crises, major transfusion reactions, blood loss, acute chest syndrome, congestive heart failure, intraoperative femoral fractures, femoral perforations, greater than usual infection rates, and late aseptic loosening are some of the added complications to performing total hip arthroplasty in patients with sickle cell disease.

This article also reviews humeral infarcts, vertebral infarcts, dactylitis, osteomyelitis, bone marrow disturbances (infarcts and hyperplasia) and other bony effects of sickle cell disease.

10. Bone involvement in sickle cell disease. Almeida A, Roberts I. Br J Haematol. 2005;129:482-90.

This article reviews frequent and important complications of sickle cell disease. The authors first discuss the acute problems related to bone involvement in sickle cell disease, with particular reference to differentiating infection from infarction, and then describe the long-term effects of sickle cell disease on bone mineral density, growth, and chronic bone and joint damage.

Acute bone problems in sickle cell disease:
Vaso-occlusive crises: Vaso-occlusive crises affect virtually all patients with sickle cell disease, often beginning in late infancy and recurring throughout life.
Dactylitis: In children under the age of 7 years, particularly those aged 1 2 years, vaso-occlusive crises frequently occur in the small bone of the hands and feet (dactylitis), which still contain hemopoietic bone marrow at this age in children with sickle cell disease.
Osteomyelitis: The increased susceptibility of sickle cell disease patients to infections, including osteomyelitis, has long been recognized with several mechanisms postulated including hyposplenism, impaired complement activity and the presence of infarcted or necrotic bone.
Septic arthritis: Septic arthritis is also seen in sickle cell disease and is generally caused by the same organisms as osteomyelitis. It rarely develops in isolation; instead, it tends to occur in association with a painful vaso-occlusive crisis.
Other acute bone problems in sickle cell disease: The authors list rib infarcts, stress fractures, vertebral collapse, orbital compression syndrome because of orbital bone infarction, dental cries, pulpal necrosis, and mandibular osteomyelitis secondary to dental infections.

Chronic bone problems in sickle cell disease:
Chronic skeletal problems are common in sickle cell disease. Many patients suffer from chronic pain because of avascular necrosis, vertebral collapse and/or chronic arthritis. In addition, hyperplasia of the bone marrow may cause osteopenia and growth disturbance.

The authors conclude that musculoskeletal complications of sickle cell disease are the major source of acute and chronic morbidity. Finally, the authors point out that it is clear that most, if not all patients with homozygous sickle cell disease have abnormal skeletal growth and maturation.

11. Bone marrow embolism in sickle cell disease: a review. Dang NC, Johnson C, Eslami-Farsani M, Haywood LJ. Am J Hematol. 2005;79:61-7.

The most recent review of the literature on the fat embolism syndrome in sickle cell patients appeared 6 years ago and new understandings of this medical entity have since emerged.

Only 24 cases of the fat embolism syndrome associated with sickle cell disease have been reported, possibly because of under-diagnosis. The syndrome has been recognized as a significant cause of death in the acute chest syndrome in sickle cell patients. One-third of cases presented with fever and 2/3 had an initial presentation with pain crises. All patients showed respiratory distress, 1/2 had petechiae, 3/4 were lethargic and 3/4 had CNS involvement, most of whom had mental confusion, were agitated, or had peripheral involvement such as spasticity or depressed deep tendon reflexes. Nearly 1/4 of patients were comatose on admission. Signs, symptoms, and laboratory observations may also indicate involvement of the kidneys, liver, and cardiopulmonary circulation suggestive of the multi-organ failure syndrome which has a similar dire potential prognosis. Thrombocytopenia and leukocytosis often occur.

The diagnosis of fat embolism syndrome is based mainly on clinical grounds and has centered on its pulmonary, cerebral, and cutaneous symptoms. The specificity of diagnostic tests, including fat globules in the urinary sediment, bronchoalveolar lavage, and measurement of serum secretory phospholipase A₂, has been low.

The only successful treatment approach reported has been intensive supportive care and prompt use of either exchange or multiple simple transfusions, with the authors recommending the former. A high index of suspicion and aggressive clinical management are the keys to a successful outcome.

12. Chronic sickle cell lung disease: new insights into the diagnosis, pathogenesis and treatment of pulmonary hypertension. Machado RF, Gladwin MT. Br J Haematol. 2005;129:449-64.

This article provides a detailed discussion of epidemiology, clinical manifestations, diagnostic evaluation, pathogenesis and treatment of pulmonary hypertension which is a common complication of sickle cell disease (SCD). In spite of the mild elevations in pulmonary artery pressures in these patients, the associated morbidity and mortality is high. In fact, in adult patients with SCD, pulmonary hypertension is emerging as the major independent risk factor for death. One report suggests a 40% mortality rate at 22 months with an odds ratio for death of 7.86 (2.63-23.4); others have reported a mean survival of 2.5 years in SCD patients with chronic lung disease with pulmonary hypertension; another report indicates that pulmonary hypertension confirmed by right heart catheterization was associated with a 50% 2-year mortality.

The etiology of pulmonary hypertension is probably multifactorial, including hemolysis, impaired nitric oxide bioavailability, chronic hypoxemia, thromboembolism, parenchymal and vascular injury because of sequestration of sickle erythrocytes, chronic liver disease and asplenia. Interestingly, pulmonary hypertension is emerging as a common, and probably, invariant sequella of lifelong hemolytic anemia in other hereditary and acquired hemolytic diseases, such as thalassemia, stomatocytosis and spherocytosis.

There are currently limited specific data on the effects of any treatment modality for pulmonary hypertension in patients with SCD. A large trial evaluating the effects of therapy for pulmonary hypertension in the SCD population is clearly indicated. The authors state that it is estimated that around 250,000 children worldwide are born with homozygous sickle cell anemia every year. Despite significant improvements in the life-expectancy of patients with SCD, the authors indicate that the median age at death is 42 years for men and 48 years for women.

13. Pulmonary hypertension as a risk factor for death in patients with sickle cell disease. Gladwin MT, Sachdev V, Jison ML, et al. N Engl J Med. 2004;350:886-95.   (Comment in: N Engl J Med. 2004;350:857-9. )

The authors performed Doppler echocardiographic assessments of pulmonary-artery systolic pressure in 195 consecutive adult patients with sickle cell disease. Pulmonary hypertension was diagnosed in 32% of the patients. A tricuspid regurgitant jet velocity of at least 2.5 m per second, as compared with a velocity of less than 2.5 m per second, was strongly associated with an increased risk of death (rate ratio, 10.1; 95 percent confidence interval, 2.2 to 47.0; p<0.001) and remained so after adjustment for other possible risk factors in a proportional-hazards regression model. They concluded that pulmonary hypertension is common in adults with sickle cell disease and appears to be a complication of chronic hemolysis. It is resistant to hydroxyurea therapy, and confers a high risk of death.

In the commentary by EP Vichinsky, he points out that autopsy studies reveal clinically unsuspected obliterative pulmonary vasculopathy with signs of pulmonary hypertension in a third of all patients with sickle cell disease. Retrospective studies have shown that as many as 60 percent of patients with sickle cell disease are affected by pulmonary hypertension.

14. Pulmonary hypertension in patients with sickle cell disease: a longitudinal study. Ataga KI, Moore CG, Jones S, Olajide O, Strayhorn D, Hinderliter A, Orringer EP Br J Haematol. 2006;134:109-15.

Although pulmonary hypertension (PHT) is a common complication in patients with sickle cell disease (SCD), the rate of development of PHT and the factors that affect disease progression are unknown. We observed 93 patients over a median follow-up period of 2.6 years (range 0.2-5.1 years). Data were censored at the time of death or loss to follow-up. Pulmonary hypertension was associated with an increased risk of death (relative risk, 9.24; 95% confidence interval: 1.2-73.3; P = 0.01). There was no difference in the risk of death when patients with different degrees of PHT were compared. Lactate dehydrogenase and blood urea nitrogen were significantly associated with PHT in a logistic regression model. Higher levels of fetal haemoglobin and treatment with hydroxycarbamide were observed more frequently in patients without PHT. Thirteen per cent of patients with no previous evidence of PHT developed PHT following 3 years of observation. In conclusion: (1) PHT, regardless of severity, is associated with an increased risk of death in SCD patients; (2) haemolysis is strongly associated with PHT in SCD; (3) high levels of fetal haemoglobin and hydroxycarbamide therapy may decrease the occurrence of PHT; (4) screening for PHT is indicated for SCD patients in their non-crisis, steady states.

15. Bloodstream infection in adults with sickle cell disease: association with venous catheters, Staphylococcus aureus, and bone-joint infections. Zarrouk V, Habibi A, Zahar JR, Roudot-Thoraval F, Bachir D, Brun-Buisson C, Legrand P, Godeau B, Galacteros F, Lesprit P. Medicine (Baltimore). 2006;85:43-8.

Although well documented in children with sickle cell disease (SCD), the incidence, cause, and outcome of bloodstream infection (BSI) are poorly defined in adults with SCD. Through a 5-year retrospective analysis of a cohort of 900 patients followed at their institution, the authors identified 56 episodes of BSI in 47 patients. The incidence rate of BSI was 1.2 episodes per 100 patient-years. As compared to the patients followed in the cohort, those with BSI were more likely to be younger (p = 0.001), to have Hb-S disease (p = 0.008), severe disease (p = 0.001), or additional immunosuppression (p = 0.05). BSI was hospital-acquired in 46% of cases and mainly associated with venous catheters (41%) and Staphylococcus aureus (34%). Pneumococci were rarely identified (10.7%). Despite an adequate duration of antibiotic therapy, the course of BSI was marked by a high frequency of associated bone-joint infection. Bone-joint infection was noted in 18 patients (32% of episodes) and occurred either during the initial BSI episode (13 patients) or 1-6 months after BSI resolution (5 patients). Factors associated with the occurrence of bone-joint infection were previous osteonecrosis (relative risk, 2.5; 95% confidence interval, 1.2-5.3) and S. aureus infection (relative risk, 3.8; 95% confidence interval, 1.8-8.4).

In conclusion, BSI is a rare event in adults with SCD compared to children. It mainly occurs in those with a severe underlying disease and a venous catheter. These patients have a high risk of associated bone-joint infection and therefore must be closely monitored.

16. Hemolysis-associated priapism in sickle cell disease. Nolan VG, Wyszynski DF, Farrer LA, Steinberg MH. Blood 2005;106:3264-3267.

Priapism is a sustained, painful, and unwanted erection of the penis that pathophysiologically is the result of either increased arterial inflow (ie, high flow) or, more commonly, the failure of venous outflow (ie, low flow), resulting in blood trapping within the erectile bodies. Although uncommon in the general population, priapism was recognized as a serious complication of SCD as early as 1934. Since then, many researchers have estimated its incidence and prevalence in various populations and the choices for its treatment.

In general, about 30% of males with SCD under the age of 20 years reported having had at least one episode of priapism; for adult men, frequencies of 30% to 45% are estimated. Among patients with priapism, about 75% had their first occurrence before the age of 20 with the mean age being around 12 to 15 years. Few published studies, however, have described the clinical characteristics of their participants with priapism.

Using data from the Cooperative Study of Sickle Cell Disease (CSSCD), the authors assembled a large cohort of patients with priapism to study their clinical, laboratory, demographic, and social characteristics.

Case subjects, compared with control subjects, had significantly lower levels of hemoglobin; higher levels of lactate dehydrogenase, bilirubin, and aspartate aminotransferase; and higher reticulocyte, white blood cell, and platelet counts. On the basis of these findings the authors suggest an association of priapism with increased hemolysis. Hemolysis decreases the availability of circulating nitric oxide, which plays an important role in erectile function.

17. Hospital readmission for adult acute sickle cell painful episodes: frequency, etiology, and prognostic significance. Ballas SK, Lusardi M. Am J Hematol. 2005;79:17-25.

The authors state that with the advent of newborn screening, penicillin prophylaxis, routine immunization, and improving health care, most children with sickle cell disease (SS) are now surviving into adulthood. However, with age, new complications of the disease emerge, chronic pain syndromes evolve, and progressive organ failure sets in. This constellation of events has a negative impact on the quality of life of patients with SS and is associated with increased morbidity and mortality.

The acute sickle cell painful episode is the most common cause of hospitalization of patients with sickle cell anemia SS. In order to determine the pattern of hospital admissions of patients with SS and the causes of frequent hospital readmissions and their prognostic significance, the authors conducted a prospective longitudinal and observation cohort study of all adult patients in their sickle cell center between January 1998 and December 2002. One hundred eighty-two adult patients with sickle cell disease were followed at the center and of these, 136 patients (75%) were admitted to the hospital during this period.

Results indicated that about 50% of patients hospitalized for acute painful episodes were readmitted within 1 month after discharge, and about 16% of all admissions were within 1 week after discharge. The mean score of pain intensity was >7 (on a scale of 1-10, 10 being the most severe pain) throughout the hospital stay. Causes of hospital readmission included premature discharge, withdrawal syndrome, and recurrence of new acute episodes. Readmission within 1 week after discharge was associated with higher mortality than otherwise. This finding is similar to previous data showing that patients with SS who are admitted frequently to the hospital with prolonged hospitalization are at risk for early mortality.

18.Psychological complications in sickle cell disease. Anie KA. Br J Haematol. 2005;129:723-9.

This review examines the evidence for some of the common psychological complications found across the life span of patients with sickle cell disease (SCD). The review is based only on published work. Electronic searches of medical and psychological databases were conducted with a focus on three main areas: psychological coping, quality of life and neuropsychology. Psychological complications were identified in both children and adults with SCD, and included inappropriate pain coping strategies; reduced quality of life owing to restrictions in daily functioning, anxiety and depression; and neurocognitive impairment.

There is considerable evidence for neuropsychological complications as a result of cerebrovascular accidents in children with SCD. These have been shown to result in significant neuropsychological deterioration. Subtle neuropsychological decline is associated with silent cerebral infarcts and, generally, children with SCD are at risk educationally because of possible cognitive and intellectual impairment as compared with siblings or non-affected peers.

The authors conclude that psychological complications in patients with SCD are common. Utilization of psychological interventions including patient education, cognitive behavioral therapy, and special educational support to help improve the quality of life of patients are recommended.

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