Charlotte F.J. van Tuijn

Sickle cell disease-related organ damage occurs irrespective of pain rate: implications for clinical practice

This study shows that clinically relevant forms of organ damage occur irrespective of the frequency of painful crises in adults with sickle cell disease. In daily clinical practice, the frequency of painful crises (pain rate) is an important parameter of sickle cell disease severity. We assessed the prevalence of sickle cell disease-related organ damage and complications and their relation to pain rate. Organ damage and history of vaso-occlusive complications were obtained via systematic screening of consecutive patients and by chart review. In 104 adult sickle cell patients pain rate was related to a history of acute chest syndromes, avascular osteonecrosis, iron overload, priapism and cholelithiasis. However, major disease-related complications, such as microalbuminuria and pulmonary hypertension, were detected in 23% and 24% respectively of patients without painful crises in the study period underlining the importance of systematic screening for developing organ damage in sickle cell patients irrespective of pain rate.

Large and Medium-Sized Pulmonary Artery Obstruction Does Not Play a Role of Primary Importance in the Etiology of Sickle-Cell Disease-Associated Pulmonary Hypertension

BACKGROUND Pulmonary hypertension (PHT) occurs in approximately 30% of adult patients with sickle-cell disease (SCD) and is a risk factor for early death. The potential role of pulmonary artery obstruction, whether due to emboli or in situ thrombosis, in the etiology of SCD-related PHT is unknown. METHODS Consecutive SCD patients were screened for PHT (defined as a tricuspid regurgitant jet flow velocity > or = 2.5 m/s) employing echocardiography and were evaluated for pulmonary artery obstruction with ventilation-perfusion (VQ) scintigraphy. RESULTS Fifty-three HbSS, 6 HbSbeta(0)-thalassemia, 20 HbSC, and 6 HbSbeta(+)-thalassemia patients were included. The overall prevalence of PHT was 41% in HbSS/HbSbeta(0)-thalassemia patients and 13% in HbSC/HbSbeta(+)-thalassemia patients. High-probability VQ defects (Prospective Investigation of Pulmonary Embolism Diagnosis criteria) were detected in two patients, one of whom had PHT. In HbSS/HbSbeta(0)-thalassemia patients with PHT, 19 patients (86%), 2 patients (9%), and 1 patient (5%) had low-, intermediate-, or high-probability scan results as compared to 30 patients (97%), 1 patient (3%), and 0 patients (0%) in HbSS/HbSbeta(0)-thalassemia patients without PHT (p = 0.31). In HbSC/HbSbeta(+)-thalassemia patients with PHT, 3 patients (100%), 0 patients (0%), and 0 patients (0%) had low-, intermediate-, and a high-probability scan as compared to 19 patients (90%), 1 patient (5%), and 1 patient (5%) in HbSC/HbSbeta(+)-thalassemia patients without PHT (p = 0.86). There were no statistical differences in irregular distribution of the radiopharmaceutical or nonspecific signs associated with PHT between patients with and without PHT. CONCLUSIONS Although small pulmonary artery obstruction cannot be excluded, large to medium-sized pulmonary artery obstruction is an unlikely primary causative factor in SCD-related PHT.

Pain rate and social circumstances rather than cumulative organ damage determine the quality of life in adults with sickle cell disease

Due to the significant morbidity associated with sickle cell disease (SCD), sickle cell patients have a reduced quality of life (QoL). Even though pain is considered an important determinant of QoL in sickle cell patients, factors such as organ damage and socioeconomic circumstances may also be important. Therefore, we determined the contribution of chronic organ damage and sickle cell-related complications to QoL and also analyzed the effect of vaso-occlusive crises and socioeconomic circumstances on QoL. Consecutive adult sickle cell patients were included. QoL was represented in a physical component scale (PCS) and a mental component scale (MCS) and assessed with SF-36 forms. Higher pain rates were related to lower QoL scores. Both occupation and the level of education were significantly related to PCS while no relation with MCS or pain rate was found. Thirty-five percent of the patients were unemployed when compared with 6% of the general population and 16% of immigrants without SCD. Neither genotype nor the presence of chronic organ damage were significantly related to QoL. In conclusion, a reduced QoL was mainly determined by pain rate, occupation, and educational level. Chronic organ damage, although a major factor determining life expectancy in SCD, was not a determinant of QoL.

Daily pain in adults with sickle cell disease-a different perspective.

Previous reports demonstrated that patients with sickle cell disease (SCD) experience pain on more than half of the observed days. Yet, these high incidences do not seem to match observations in our population. In this prospective cohort study, we aimed to assess the frequency and characteristics of daily, self‐reported pain among adult SCD patients in the Netherlands. Consecutive patients were enrolled during routine outpatient visits and followed up to 6 months. A total of 55 patients completed 5,982 diary observation days. Median age was 27 years (IQR 23‐43). Patients reported SCD related pain on 17% of the observed days; on 13% of these days this pain was not defined as a painful crisis, while 3% was reported as a painful crisis but managed at home, and on 1% of the observed days patients were admitted to the hospital. Analgesics were used on 52% of days with pain with a relatively infrequent use of oral opioids (9% of pain days). This first European study on pain in SCD indicates that pain appears to be significantly less frequent in our population as compared to previous study cohorts from the United States, and may be more representative for current SCD populations in other Western countries. Besides a more widespread use of hydroxycarbamide in modern disease management, differences in organization and accessibility of healthcare between countries may also explain this discrepancy.

Prospective evaluation of chronic organ damage in adult sickle cell patients: A seven-year follow-up study

Organ damage in sickle cell disease (SCD) is a crucial determinant for disease severity and prognosis. In a previous study, we analyzed the prevalence of SCD-related organ damage and complications in adult sickle cell patients. We now describe a seven-year follow-up of this cohort.All patients from the primary analysis in 2006 (n = 104), were included for follow-up. Patients were screened for SCD-related organ damage and complications (microalbuminuria, renal failure, elevated tricuspid regurgitation flow velocity (TRV) (≥2.5 m/seconds), retinopathy, iron overload, cholelithiasis, avascular osteonecrosis, leg ulcers, acute chest syndrome (ACS), stroke, priapism and admissions for vaso-occlusive crises (VOC) biannually. Upon 7 years of follow-up, progression in the prevalence of avascular osteonecrosis (from 12.5% to 20.4%), renal failure (from 6.7% to 23.4%), retinopathy (from 39.7% to 53.8%) was observed in the whole group. In HbSS/HbSβ0 -thal patients also progression in microalbuminuria (from 34% to 45%) and elevated TRV (from 40% to 48%) was observed while hardly any progression in the prevalence of cholelithiasis, priapism, stroke or chronic ulcers was seen. The proportion of patients with at least one episode of ACS increased in the group of HbSS/HbSβ0 -thal patients from 32% to 49.1%. In conclusion, 62% of the sickle cell patients in this prospective cohort study developed a new SCD-related complication in a comprehensive care setting within 7 years of follow-up. Although the hospital admission rate for VOC remained stable, multiple forms of organ damage increased substantially. These observations underline the need for continued screening for organ damage in all adult patients with SCD.

N-terminal pro-B-type natriuretic peptide, tricuspid jet flow velocity, and death in adults with sickle cell disease

To the Editor: Both elevated N-terminal prohormone brain natriuretic peptide (NT-proBNP) levels (>160 pg/mL) and elevated tricuspid regurgitant jet flow velocity (TRV 2.5 m/sec) have been related to the presence of (echocardiography defined) pulmonary hypertension and the risk of early death in patients with sickle cell disease (SCD) [1–3]. Recent guidelines advise to use NT-proBNP levels to identify patients at risk for mortality when transthoracic Doppler to measure TRV is not available [4]. We studied the relation between elevated NT-proBNP levels (>160 pg/mL), elevated TRV ( 2.5 m/sec), and the risk of mortality in a cohort of 85 adult outpatients with sickle cell anemia (HbSS) or compound heterozygous states such as HbSb-thalassemia (HbSb-thal), HbSb-thalassemia (HbSb-thal), and sickle-hemoglobin C (HbSC) [5]. Patients were excluded if they had a history of chronic obstructive pulmonary disease or poorly controlled asthma, congestive heart failure, painful crisis, or acute chest syndrome in the preceding 4 weeks and/or blood transfusion within 3 months prior to performing study related tests. The mean age at baseline analysis was 34 years (median 30; interquartile range (IQR): 23–47). We followed patients for a median of 82 months (IQR 75–85) during which three patients were lost to follow-up and 12 patients (11 HbSS and 1 HbSb-thal) died. Median age at death was 53 years (IQR 37–60). Baseline trans-thoracic echocardiographic results were available from 81 patients and echocardiography was repeated every 2 years in steady-state conditions. TRV 2.5–2.9 m/sec was considered elevated, a TRV>2.9 m/sec severely elevated, and TRV was considered normal in patients with trace or no tricuspid regurgitation (undetectable values were assigned a value of 1.3 m/sec) [1]. In 25 patients (31%) a TRV 2.5–2.9 m/sec was measured at baseline (22 (39%) HbSS/HbSb-thal and 3 (12%) HbSC/HbSb-thal patients) and a TRV >2.9 m/sec in two HbSS patients. Twenty of 56 patients with a TRV <2.5 m/sec at baseline developed an increased TRV ( 2.5 m/sec) during follow-up (5.3% per year). Having a TRV 2.5 m/sec measured at baseline did not result in a significant increased hazard rate (HR) for mortality for these patients as calculated by Cox regression analysis (HR 1.6 [confidence interval (CI) 0.5–5.2], P 5 0.4). Figure 1A. Introducing age in a multivariate Cox-regression analysis did not change the HR for mortality in patients with TRV 2.5 m/sec (HR 1.1 [CI 0.3–3.7], P 5 0.9). The HR for mortality in a subgroup of HbSS/ HbSb-thal patients with a TRV 2.5 m/sec was 1.1 [CI 0.4–3.4], P 5 0.9. Plasma NT-proBNP levels were available from 77 patients at baseline after quantitation in EDTA anticoagulated plasma employing an ELISA (Roche). In 14 patients a NTproBNP value 160 pg/mL was measured (all HbSS/HbSb-thal patients), of whom 50% also had a TRV level of 2.5 m/sec at baseline. Figure 1C. Using the previously defined cut-off value for NT-proBNP of 160 pg/mL as a risk factor for early death [6], patients with elevated NT-proBNP levels had a HR of death of 10.0 [CI 2.9–34.4], P< 0.001, compared to patients with normal NT-proBNP levels (<160 pg/mL). Figure 1B. In the HbSS/ HbSb-thal group alone this HR was 6.3 [CI 1.8–21.6], P 5 0.003. Given the low number of deaths during follow-up, a multivariate Cox-regression survival analysis was performed for only two variables at the time, always including NT-proBNP levels. None of analyzed variables that may affect NT-proBNP plasma levels (such as age, renal function, TRV, ferritin, or hemoglobin levels) could solely explain the increased HR for death for patients with NT-proBNP plasma levels of 160 pg/mL. Therefore, an elevated NT-proBNP level identifies especially HbSS/HbSb-thal patients at high risk of death independent of an elevated TRV. We hypothesize that NT-proBNP levels are likely to be determined by several prognostic factors in SCD such as diastolic dysfunction, hypoxia, age, rate of hemolysis, inflammation, renal function and iron overload. NT-proBNP might therefore be useful as a simple prognostic biomarker in the clinically asymptomatic state reflecting the severity of the generalized vasculopathy and organ dysfunction in SCD. Importantly, both the lack of an association of TRV to mortality and the relatively low mortality in our cohort, as well as in a recent European SCD cohort, are in contrast with earlier studies in the United States (US) [1–3]. As TRV was significantly related to mortality in SCD in a study of comparable size [2], our relatively small sample size is not likely to be an explanation for this conflicting observation. Also the relative low number Figure 1. Bone marrow biopsies show progression of neoplastic spindle-shaped mast cells and osteosclerosis between 2009 and 2013 with no therapy (A– B), stable disease before and after bosutinib (B–C), and response to cladribine regarding mast cells (C–D). (hematoxylin and eosin (H&E), 103 objective). [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.] CORRESPONDENCE

Inflammatory and endothelial markers during vaso-occlusive crisis and acute chest syndrome in sickle cell disease

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