Sickle cell disease (SCD) is associated with early mortality. We sought to determine the incidence, cause, and risk factors for death in an adult population of patients with SCD. All patients aged ≥18 years seen at the Adult Sickle Cell Center at Duke University Medical Center between January 2000 and April 2005 were enrolled. Forty-three patients (21 males and 22 females) died during the study period. Median age of survival was 39 years for females (95% CI 34–56), 40 years for males (95% CI 34–48), and 40 years overall (95% CI 35–48). Cardiac causes of death accounted for 25.6% (11/43 patients); pulmonary, 14.0% (6 patients); other SCD related, 32.6% (14 patients); unknown, 14.0% (6 patients); and others, 14.0% (6 patients). Pulseless electrical activity arrest, pulmonary emboli, multi-organ failure, and stroke were the most frequent causes of death. Among the deceased patients, the most common pre-morbid conditions were cardiopulmonary: ACS/pneumonia (58.1%), pHTN (41.9%), systemic hypertension (HTN) (25.6%), congestive heart failure (CHF) (25.6%), myocardial infarction (20.9%), and arrhythmias (14.0%). Tricuspid regurgitant jet velocity (TRv) was significantly higher (3.1 m/s vs. 2.6 m/s, p<0.001) and hemoglobin significantly lower (8.3 g/dL vs. 9.2 g/dL, p<0.05) in deceased patients as compared to patients who lived, respectively. With improved preventive and therapeutic advances, including hydroxyurea therapy, acute complications such as infection are no longer the leading cause of death; instead causes of death and pre-morbid conditions are shifting to chronic cardiopulmonary complications. Further, arrhythmia leading to premature death is under-recognized in SCD and warrants further investigation.
sickle cell disease; adult; mortality; risk factors; cardiopulmonary complications
While anemia is associated with poor functional and mortality outcomes in the elderly, the impact of hemoglobin decline is less studied.
We evaluated the determinants and consequences of hemoglobin decline in 3.758 non-anemic participants from the Cardiovascular Health Study, a prospective cohort of community-dwelling elderly ≥65 years old at baseline and followed for up to 16 years. Hemoglobin was measured at baseline and 3 years later and anemia defined by World Health Organization (WHO) criteria. We modeled hemoglobin decline in two ways: 1) per each 1g/dL decrease in hemoglobin and 2) development of anemia by the WHO criteria.
Among participants without baseline anemia, hemoglobin decreased by 0.4g/dL and 9% developed anemia over 3 years. Baseline increasing age, female sex, diabetes, and kidney disease predicted hemoglobin decline over 3 years. Baseline increasing age, being African-American, and kidney disease predicted anemia development over 3 years. Hemoglobin decline was associated with subsequent worse cognitive function in men and anemia development with subsequent worse cognitive function in women. Both anemia development (HR 1.39, 95% CI 1.15, 1.69) and hemoglobin decline (HR 1.11, 95% CI 1.04, 1.18 per 1g/dL decrease) predicted subsequent mortality in men and women.
Hemoglobin decreases identified a large group of elderly individuals at risk for subsequent adverse outcomes who would not be identified using the WHO anemia criteria. These data may allow clinicians to identify at-risk elderly individuals for early intervention to improve the quality and quantity of life.
Anemia; Hemoglobin; Elderly; Mortality; Function; Epidemiology
Patients with thalassemia (Thal) have low bone mass which can lead to fracture and decreased quality of life. There are no noninvasive anabolic therapies available to improve bone health in Thal. A longitudinal cross-over pilot trial was conducted to evaluate the effectiveness of low magnitude whole body vibration (WBV) therapy on bone in 18 patients with Thal (9 adults, 10 male, 22.1 ± 10.7 years). Subjects were asked to stand on a vibrating platform (30 Hz, 0.3 g) for 20 min/day for 6 months. Areal bone mineral density (aBMD) by DXA and volumetric BMD by peripheral quantitative computed tomography (pQCT) was assessed at baseline, 6 and 12 months. Adherence in the first 3 months was greater when compared with the second 3 months (14 ± 6 vs. 10 ± 7 min/day, P=0.007). Intention to treat analysis revealed a significant increase in whole body BMC (2.6%; P = 0.021), BMC/Ht (2.6%, P = 0.02) and aBMD (1.3%; P = 0.036), as well as a net increase in serum markers of bone formation (Osteocalcin/CTx, P = 0.027) in the adult subjects. These preliminary findings suggest that vibration therapy may be an effective nonpharmacologic intervention in Thal. Future research is needed to confirm these findings in a larger sample for longer duration.
Heritability is the proportion of observed variation in a trait among individuals in a population that is attributable to hereditary factors. The HEIRS Family Study estimated heritability of serum iron measures. Probands were HFE C282Y homozygotes or non-C282Y homozygotes with elevated transferrin saturation (TS > 50%, men; TS > 45%, women) and serum ferritin concentration (SF > 300 μg/L, men; SF > 200 μg/L, women). Heritability (h2) was estimated by variance component analysis of TS, natural logarithm (ln) of SF, and unsaturated iron-binding capacity (UIBC). Participants (N=942) were 77% Caucasians, 10% Asians, 8% Hispanics, and 5% other race/ethnicities. Average age (SD) was 49 (16) y; 57% were female. For HFE C282Y homozygote probands and their family members, excluding variation due to HFE C282Y and H63D genotype and measured demographic and environmental factors, the residual h2 (SE) was 0.21 (0.07) for TS, 0.37 (0.08) for ln SF, and 0.34 (0.08) for UIBC (all P < 0.0004 for comparisons with zero). For the non-C282Y homozygote proband group, residual h2 was significant with a value of 0.64 (0.26) for ln SF (p=0.0096). In conclusion, serum iron measures have significant heritability components, after excluding known genetic and non-genetic sources of variation.
HFE; familial aggregation; transferrin saturation; serum ferritin concentration
The myeloproliferative neoplasms (MPNs) are a particularly useful model for studying mutation accumulation in neoplastic and the mechanisms of the molecular cells, understanding underlying defects our current This review summarizes acquisition. present their in patients with an MPN, and the effects of mutations targeting Janus kinase 2 (JAK2)-mediated intracellular signaling on DNA damage, and on the elimination of mutation-bearing cells by programmed cell death. Moreover, we discuss findings that suggest that the acquisition of disease-initiating mutations in hematopoietic stem cells of some MPN patients may be the consequence of an inherent genomic instability that was not previously appreciated.
JAK2; mutation; genomic instability; clonal evolution
Hydroxyurea (HU) is underutilized in sickle cell disease (SCD). Patient adherence with taking HU and with required drug monitoring is a provider perceived barrier to HU utilization.(1-4) To determine process issues that may contribute to these barriers we sought to: 1) describe how providers monitor and adjust HU dosing in children with SCD in clinical practice and 2) identify providers' methods of assessing HU adherence. A pilot-tested survey was emailed to American Society of Pediatric Hematology/Oncology (ASPHO) members. Descriptive statistics were performed. Thirty-one percent (n=350) of 1128 surveys were returned; 63% (220 of 350) of respondents provided care for children with SCD. Most providers (64.7%) follow labs monthly and almost half (41.9%) see patients monthly. The majority (61.9%) adjusted HU dosing using maximum tolerated dose commonly determined using ANC (27.9%), platelets (26.5%), and WBC count (11.2%). Adherence was primarily assessed using patient interview (84.2%), MCV (75.3%), and HbF levels (70.7%). The majority of providers perform monthly monitoring and assess HU adherence using unreliable methods. Determining optimal frequency of monitoring HU and more reliable methods of assessing adherence are essential to balancing safety and the elimination of barriers to promote HU utilization.
Hydroxyurea; Monitoring; Adherence; Sickle Cell Disease; Children
We report here the 10-year follow-up of 86 patients who underwent allogeneic stem cell transplantation (ASCT) for myelodysplastic syndrome (MDS). All patients received the busulfan, cytosine arabinoside, and cyclophosphamide (BAC) preparative regimen which consisted of busulfan 16 mg/kg, cytosine arabinoside 8 g/m2 IV, and cyclophosphamide 120 mg/kg IV. Fifty-nine patients (69%) had de novo MDS; 26 (30%) had secondary MDS (treatment related), and one had a preceding aplastic anemia which progressed to MDS before transplant. Cytogenetics (80 patients) was classified as good (34%), intermediate (17%), or poor (42%). With a median follow-up for survivors of 124 months, the 10-year Kaplan-Meier estimates for overall survival (OS) was 43% (95% confidence interval [CI]: 31–53%). Cumulative nonrelapse mortality (NRM) and relapse was 43% (95% CI: 32–54%) and 19% (95% CI: 11–27%), respectively. No patient relapsed after 2 years. In patients with RAEB-T/AML, 10-year relapse-free survival (RFS), relapse, and NRM was 36%, 36%, and 27%, respectively. Younger age (P = 0.05), human leukocyte antigen (HLA) match (P = 0.002), good risk cytogenetics (P = 0.008), and having a related donor (P = 0.03) significantly improved overall and RFS in the multivariable analysis. The long-term follow-up of patients receiving the BAC regimen with ASCT in this study indicated durable relapse-free and OS with acceptable toxicity in this group of patients with high-risk features.
Venous thromboembolism (VTE) is an increasingly common complication encountered in tertiary care pediatric settings. The purpose of this review is to summarize the epidemiology, current and emerging pharmacotherapeutic options, and management of this disease. Over 70% of VTE occur in children with chronic diseases. Although they are seen in children of all ages, adolescents are at greatest risk. Pediatric VTE is associated with an increased risk of in-hospital mortality; recurrent VTE and post-thrombotic syndrome are commonly seen in survivors. In recent years, anticoagulation with low molecular weight heparin has emerged as the mainstay of therapy, but compliance is limited by its onerous subcutaneous administration route. New anticoagulants either already approved for use in adults or in the pipeline offer the possibility of improved dose stability and oral routes of administration. Current recommended anticoagulation course durations are derived from very limited case series and cohort data, or extrapolations from adult literature. However, the pathophysiologic underpinnings of pediatric VTE are dissimilar from those seen in adults and are often variable within groups of pediatric patients. Clinical studies and trials in pediatric VTE are underway which will hopefully improve the quality of evidence from which therapeutic guidelines are derived.
Previous studies report lower systemic blood pressures in patients with sickle cell disease (SCD) than in appropriate controls. The etiology of the lower systolic and diastolic blood pressures (SBP and DBP) remains uncertain. Blood pressure measurements from patients followed at our center (UNC cohort) were compared with values obtained from the Cooperative Study of Sickle Cell Disease (CSSCD) and healthy control subjects. Associations of SBP and DBP with clinical and laboratory covariates were performed in the UNC cohort. Patients in the UNC cohort were significantly older and had a higher BMI than those in the CSSCD (p <0.0001). There were no differences in the SBP and DBP between SCD patients in the UNC cohort and control subjects. In the SS/SD/Sβ0 thalassemia group, SBP was higher in the UNC cohort than in the CSSCD (p < 0.0001). On multivariate analysis, significant correlations were noted between SBP and age, BMI, history of hypertension and absolute neutrophil count. Compared with historic controls, SBP was significantly higher in our SCD patient cohort. There was no difference when blood pressure was compared between our patient cohort and control subjects. Age, BMI and neutrophil count may contribute to the modulation of SBP in SCD.
Sickle cell disease; Systemic Blood pressure; Hemolysis; Absolute neutrophil count; Body mass index
Clinical trials of sickle cell disease (SCD) pain treatment usually observe only small decrements in pain intensity during the course of hospitalization. Sub-optimal analgesic management and inadequate pain assessment methods are possible explanations for these findings. In a search for better methods for assessing inpatient SCD pain in adults, we examined several pain intensity and interference measures in both arms of a randomized controlled trial comparing two different opioid PCA therapies. Based upon longitudinal analysis of pain episodes, we found that scores from daily average Visual Analogue Scales (VAS) and several other measures, especially the Brief Pain Inventory (BPI), were sensitive to change in daily improvements in pain intensity associated with resolution of vaso-occlusive pain. In this preliminary trial, the low demand, high basal infusion (LDHI) strategy demonstrated faster, larger improvements in various measures of pain than the high demand, low basal infusion (HDLI) strategy for opioid PCA dosing, however, verification in larger studies is required. The measures and statistical approaches used in this analysis may facilitate design, reduce sample size, and improve analyses of treatment response in future SCD clinical trials of vaso-occlusive episodes.
sickle cell disease; pain; longitudinal models
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The current treatment protocol for ALL involves an intense chemotherapy regimen yielding cure rates of nearly 80%. However, new therapies need to be designed not only to increase the survival rate but also to combat the risk of severe therapy associated toxicities including secondary malignancies, growth problems, organ damage, and infertility. The c-Myb proto-oncogene is highly expressed in immature hematopoietic cells. In this study, we demonstrate that loss of c-Myb itself decreased the viability of these leukemic cells. Additionally, the inhibition of c-Myb caused a decrease in cell proliferation, significantly increased the number of cells in G0/G1 phase of the cell cycle, increased the sensitivity of pre-B-ALL cells to cytotoxic agents in vitro, and significantly delayed disease onset in a mouse model of leukemia. Furthermore, we demonstrate that Bcl-2 is a target of c-Myb in pre-B-ALL cells. Our results identify c-Myb as a potential therapeutic target in pre-B-ALL and suggest that suppression of c-Myb levels or activity, in combination with currently used therapies and/or dose reduction, may lead to a decrease in toxicity and an increase in patient survival rates. Because c-Myb is aberrantly expressed in several other malignancies, targeting c-Myb will have broad clinical applications.
The toll-like receptor (TLR) 7 agonist 852A, a small-molecule imidazoquinoline, stimulates plasmacytoid dendritic cells to produce multiple cytokines. We conducted a Phase II study of 852A in patients with recurrent hematologic malignancies. The primary objective was assessing the activity of 852A administered subcutaneously twice weekly for 12 weeks. Secondary objectives were assessing the safety of 852A and its ability to activate the immune system with prolonged dosing.
Patients with relapsed hematologic malignancies of any age with adequate organ function were eligible. Patients initiated dosing at 0.6 mg/m2 twice weekly and escalated by 0.2 mg/m2 after every 2 doses as tolerated to a target dose of 1.2 mg/m2. Patients with responses or stable disease were eligible for additional cycles.
Seventeen patients (15 males) entered the study: 6 with AML, 5 ALL, 4 NHL, 1 Hodgkin’s lymphoma, and 1 multiple myeloma. The mean age was 41 years (12–71 years). The median number of prior chemotherapy regimens was 5 (range=1–14). Thirteen patients completed all 24 injections. Grade 3–4 toxicities included nausea, dyspnea, fever, myalgia, malaise, and cough. Responses included 1 complete response (ALL), 1 partial response (AML), 2 stable disease (AML and NHL), and 9 progressive disease.
This is the first in-human hematologic malignancy trial of a subcutaneously (SC) delivered TLR7 agonist using a prolonged dosing schedule. 852A was safely administered up to 1.2 mg/m2 twice weekly with evidence of sustained tolerability and clinical activity in hematologic malignancies. Systemic TLR agonists for the treatment of hematologic malignancies warrant further study.
acute leukemia; immunotherapy; 852A; phase 2
Elevated body iron stores are associated with morbidity and mortality due to oxidative stress. Hereditary hemochromatosis, a common condition caused by HFE gene mutations, can lead to excess iron storage and disease but clinical penetrance of HFE gene mutations is low and many people with elevated iron stores lack HFE mutations. We analyzed data from the Hemochromatosis and Iron Overload Screening Study to assess the relationship among HFE genotype (individuals with either homozygous or compound heterozygous status for C282Y and/or H63D HFE mutations were defined as genotype positive, or G+), elevated iron phenotype (individuals exceeding gender-specific transferrin saturation and serum ferritin threshold levels were considered phenotype positive, or P+), and leukocyte telomere length, a marker of biological aging and cumulative oxidative stress. In unadjusted analyses in comparison to individuals who were G−P−, G+P− were not significantly different (OR 0.74; 95% CI 0.26–2.04), while the G+P+ (OR 2.03; 95% CI 1.15–3.56), and G−P+ (OR 2.24; 95% CI 1.5–3.29) had increased risk of short telomeres (<=25th percentile) rather than long telomeres (>=75th percentile). In analyses adjusting for age, gender, and race/ethnicity, the effect of individuals with elevated iron phenotypes having short telomeres persisted with G+P+ individuals (OR 1.94; 95% CI 1.02–3.72), and G−P+ individuals (OR 2.17; 95% CI 1.39–3.39) being significantly different from the G−P− group. In conclusion, elevated iron phenotype, but not HFE genotype, was associated with shortened telomeres. Further studies will be needed to determine whether telomere length provides a marker for morbidities specifically associated with iron overload.
Iron overload is associated with significant morbidity and mortality yet is easily treated. The objective of this study was to create a tool that could be easily adapted to clinical practice that indicates the likelihood of a patient having undetected iron overload. We used the National Health and Nutrition Examination Survey (NHANES) 1999–2002 for US adults aged 20 years and older to build a model (unweighted n=8,779). We chose potential variables for inclusion that could be gathered by self-report or measured without laboratory data and were suggested by past literature on hemochromatosis and iron overload. We computed logistic regressions to create the scores by initially evaluating the variables’ relationship with elevated ferritin and elevated transferrin saturation and then using odds ratios to correspond to scores. The resulting score on the IRon Overload ScreeNing Tool (IRON) was then validated with data on 13,844 adults in the NHANES III, 1988-94. Predictors in the final tool were age, gender, previous diagnoses of liver condition, osteoporosis or thyroid disease. The IRON score yielded an area under the curve (AUC) in the NHANES 1999-02 of 0.720 and an AUC of 0.685 in the NHANES III validation sample. The IRON score is a tool to assist in identification of patients with iron overload that has several qualities that make it attractive for use in clinical practice with an undifferentiated patient population including brevity, easily collected information and predictive ability comparable to other tools that help in directing screening.
There are few descriptions of young adults with self-reported hemochromatosis or iron overload (H/IO). We analyzed initial screening data in 7,343 HEmochromatosis and IRon Overload Screening (HEIRS) Study participants ages 25–29 years, including race/ethnicity and health information; transferrin saturation (TS) and ferritin (SF) measurements; and HFE C282Y and H63D genotypes. We used denaturing high-pressure liquid chromatography and sequencing to detect mutations in HJV, TFR2, HAMP, SLC40A1, and FTL. Fifty-one participants reported previous H/IO; 23 (45%) reported medical conditions associated with H/IO. Prevalences of reports of arthritis, diabetes, liver disease or liver cancer, heart failure, fertility problems or impotence, and blood relatives with H/IO were significantly greater in participants with previous H/IO reports than in those without. Only 7.8% of the 51 participants with previous H/IO reports had elevated TS; 13.7% had elevated SF. Only one participant had C282Y homozygosity. Three participants aged 25–29 years were heterozygous for potentially deleterious mutations in HFE2, TFR2, and HAMP promoter, respectively. Prevalences of self-reported conditions, screening iron phenotypes, and C282Y homozygosity were similar in 1,165 participants aged 30 years or greater who reported previous H/IO. We conclude that persons who report previous H/IO diagnoses in screening programs are unlikely to have H/IO phenotypes or genotypes. Previous H/IO reports in some participants could be explained by treatment that induced iron depletion before initial screening, misdiagnosis, or participant misunderstanding of their physician or the initial screening questionnaire.
Current response criteria for light-chain amyloidosis (AL) relegate FLC response to a subsidiary status relative to serum M-protein response. Given that light chains form the substrate for amyloid fibril formation, we hypothesized that changes in FLC might better predict outcome compared to changes in intact immunoglobulin levels. Two patient cohorts were studied, 347 patients who underwent an autologous stem-cell transplant (SCT) and 96 patients treated with melphalan/dexamethasone. We identified the lowest value following therapy for intact serum M-protein and the difference between involved and uninvolved FLC (FLC-diff). We first examined the relative contribution of M-protein and FLC-diff on the overall survival (OS), and found that FLC reduction, rather than M-protein reduction, significantly impacted OS. The median OS was not reached among those with a 50% decrease in FLC-diff compared to 20 months for the remainder. On regression analysis, a 90% reduction in FLC-diff following SCT best predicted being alive at 3 or 5 years. The median OS among those with a 90% decrease was not reached compared to 37.4 months for the rest P < 0.001. The current study supports the notion that FLC response is a more useful measure of hematological response than M-protein response. It also highlights the importance of achieving at least a 90% reduction in the FLC-diff to improve the outcome of patients with light-chain AL. Am. J. Hematol. 86:251–255, 2011.
How often elevated serum ferritin in primary-care patients reflects increased iron stores (normally 0.8 g in men, 0.4 g in women) is not known. The Hereditary Hemochromatosis and Iron Overload Screening (HEIRS) study screened 101,168 primary-care participants (44% Caucasians, 27% African-Americans, 14% Asians/Pacific Islanders, 13% Hispanics, 2% others). Follow-up clinical evaluation was performed in 302 of 333 HFE C282Y homozygotes regardless of iron measures and 1,375 of 1,920 nonhomozygotes with serum ferritin >300 μg/L (men), >200 μg/L (women) and transferrin saturation >50% (men), >45% (women). Quantitative phlebotomy was conducted in 122 of 175 C282Y homozygotes and 122 of 1,102 nonhomozygotes with non-transfusional serum ferritin elevation at evaluation. The estimated prevalence in the Caucasian population of C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 20 per 10,000 men and 4 per 10,000 women; this constellation was predictive of iron stores >4 g in men and >2 g in women. The estimated prevalence per 10,000 of non-C282Y homozygotes with serum ferritin >900 μg/L at evaluation was 7 among Caucasians, 13 among Hispanics, 20 among African Americans, and 38 among Asians and Pacific Islanders, and this constellation was predictive of iron stores >2 g but <4 g. In conclusion, serum ferritin >900 μg/L after initial elevations of both serum ferritin and transferrin saturation is predictive of mildly increased iron stores in multiple ethnic populations regardless of HFE genotype. Serum ferritin >900 μg/L in male C282Y homozygotes is predictive of moderately increased iron stores.
In 2010, the Food and Drug Administration (FDA) added a black box warning to anti-D immune globulin (Rho(D) immune globulin, anti-D) for immune thrombocytopenia (ITP) to warn of the complications related to severe hemolysis. The objective of this retrospective medical record review was to examine recent trends in anti-D use to treat ITP and rates of adverse events in a single large pediatric hematology program. Over a 7-year period, 176 (35%) of 502 ITP patients at our center received anti-D. Anti-D was the second most commonly prescribed drug for ITP from 2003 to 2010 overall and was given first most frequently (41%). Sixty-four percent of patients responded to anti-D, but 36% had adverse effects, including five patients requiring hospitalization. From 2003 to 2010, the use of anti-D as an initial therapy for ITP significantly decreased (P < 0.001). This trend preceded the 2010 FDA black box warning. In our experience, anti-D was associated with a significant number of adverse effects when used as a treatment for ITP, although none were life-threatening. Despite recent guidelines suggesting anti-D therapy for initial treatment for ITP, anti-D therapy for ITP has significantly decreased over the past 7 years.
While standard clinical prognostic factors predict outcome in diffuse large B-cell lymphoma (DLBCL), predicting the outcome of patients might be further refined using biological factors. We tested whether serum cytokines could provide prognostic information in DLBCL patients. Thirty cytokines were measured in pre-treatment samples from newly diagnosed DLBCL patients using a multiplex ELISA. Sixty-nine patients treated with R-CHOP plus epratuzumab were used in an initial cohort and 185 patients treated with standard R-CHOP served as a subsequent validation cohort. In the initial cohort, elevated serum IL-10 (interleukin-10; HR=6.6, p=0.022), GM-CSF (granulocyte macrophage colony-stimulating factor; HR=10.8, p=0.027) and IP-10 (interferon-inducible protein-10, CXCL10; HR=3.32, p=0.015) were associated with event-free survival (EFS). An identical analysis of the subsequent validation cohort confirmed that elevated serum levels of IP-10 were strongly associated with a poor EFS (HR=2.42, p= 0.0007); and also identified IL-8 (interleukin-8; HR=3.40, p= 0.00002) and IL-2R (interleukin-2 receptor, CD25; HR=2.59, p= 0.0012) as significantly associated with prognosis. The prognostic significance of elevated IP-10 remained significant after adjustment for the International Prognostic Index (IPI; EFS – HR 1.99, p=0.009, overall survival- HR 1.93, p=0.021). Elevated pretreatment serum IP-10 levels are therefore associated with an increased likelihood of disease relapse and an inferior survival in patients with DLBCL.
IP-10; CXCL10; cytokines; diffuse large B-cell lymphoma; prognosis
To establish a method to identify patients with primary immune thrombocytopenia (ITP) utilizing administrative data from diverse data sources that would be appropriate for epidemiologic studies of ITP, regardless of patients’ age and source of health care.
Study Design and Setting
Medical records of the Oklahoma University Medical Center, 1995–2004, were reviewed to document the accuracy of the administrative code ICD-9-CM 287.3 for identifying children and adults with ITP, using novel, explicit levels of evidence to identify patients with a definite diagnosis. The proportion of patients diagnosed by hematologists compared to non-hematologists and the proportion of patients diagnosed as outpatients compared to inpatients were determined.
For children, age <16 years, 323 outpatient medical records were reviewed; 225 adult outpatient medical records were reviewed. The positive predictive value for the administrative code for identifying patients with a definite diagnosis of ITP by a hematologist was 0.72 in children and 0.69 in adults. In 98% of children and 92% of adults seen as outpatients, the definite diagnosis of ITP was established by a hematologist. One hundred eighteen child and 141 adult inpatient medical records were reviewed. In 95% of children and 83% of adults, the definite diagnosis of ITP by a hematologist was established as an outpatient.
This study confirmed the previously reported positive predictive value for the administrative code for identifying patients with ITP. Additionally, it was determined that analysis of hematologists’ outpatient administrative codes identified most children and adults with ITP.
primary immune thrombocytopenia; ITP; administrative data; validity; ICD-9-CM 287.3
To determine the prevalence of ITP in Oklahoma regardless of age, clinical characteristics, insurance status, and source of health care.
Study Design and Setting
Patients with ITP were identified by the administrative code ICD-9-CM 287.3 in Oklahoma hematologists’ offices for a 2-year period, 2003–2004. Prevalence was estimated separately for children (<16 years old) and adults because of their distinct clinical characteristics. Oklahoma census data for 2000 was used as the denominator.
Eighty-seven (94%) of 93 eligible Oklahoma hematologists participated; 620 patients with ITP were identified. The average annual prevalences were: 8.1 (95% CI 6.7, 9.5) per 100,000 children, 12.1 (95% CI 11.1, 13.0) per 100,000 adults, and 11.2 (95% CI 10.4, 12.0) per 100,000 population. Among children and adults less than age 70 years, the prevalence was greater among women. Among adults aged 70 years and older, the prevalence was greater among men. The highest prevalence of ITP was among men age 80 years and older.
These data document for the first time the prevalence of ITP regardless of age, clinical characteristics, insurance status, and source of health care. The methodology developed for this prevalence analysis may be adaptable for epidemiologic studies of other uncommon disorders which lack specific diagnostic criteria and are treated primarily by medical specialists.
primary immune thrombocytopenia; ITP; prevalence; demographics; administrative data; ICD-9-CM 287.3
The complement pathway plays a central role in innate immunity, and also functions as a regulator of the overall immune response. We evaluated whether polymorphisms in complement genes are associated with event-free survival (EFS) in follicular (FL) and diffuse large B-cell (DLBCL) lymphoma. We genotyped 167 single nucleotide polymorphisms (SNPs) from 30 complement pathway genes in a prospective cohort study of newly diagnosed FL (N=107) and DLBCL (N=82) patients enrolled at the Mayo Clinic from 2002–2005. Cox regression was used to estimate Hazard Ratios (HRs) for individual SNPs with EFS, adjusting for FLIPI or IPI and treatment. For gene-level analyses, we used a principal components based gene-level test. In gene-level analyses for FL EFS, CFH (p=0.009), CD55 (p=0.006), CFHR5 (p=0.01), C9 (p=0.02), CFHR1 (p=0.03), and CD46 (p=0.03) were significant at p<0.05, and these genes remained noteworthy after accounting for multiple testing (q<0.15). SNPs in CFH, CFHR1, and CFHR5 showed stronger associations among patients receiving any rituximab, while SNPs from CD55 and CD46 showed stronger associations among patients who were observed. For DLBCL, only CLU (p=0.001) and C7 (p=0.03) were associated with EFS, but did not remain noteworthy after accounting for multiple testing (q>0.15). Genes from the Regulators of Complement Activation (CFH, CD55, CFHR1, CFHR5, CD46) at 1q32-q32.1, along with C9, were associated with FL EFS after adjusting for clinical variables, and if replicated, these findings add further support for the role of host innate immunity in FL prognosis.
non-Hodgkin lymphoma; complement pathway; SNPs; prognosis; prospective cohort
In hemophilia A, up to 25% of new anti-factor VIII (FVIII) inhibitory antibodies (inhibitors) occur in patients with mild or moderate disease . Once the inhibitor develops, options for management include observation, immune modulation, and immune tolerance induction (ITI). Currently, there is little data to guide a clinician’s management decisions. In a case series, 8/26 subjects with mild or moderate hemophilia complicated by an inhibitor underwent ITI; 2 successful, 2 unsuccessful and 4 partially successful . In a systematic review of the literature, 12/16 patients with mild or moderate hemophilia responded to rituximab for treatment to eradicate the inhibitor . To increase our understanding of treatment options for inhibitor eradication in patients with mild or moderate hemophilia A complicated by an inhibitor, a secondary analysis of clinical and treatment characteristics in a cohort of 36 patients with mild or moderate hemophilia A and inhibitor was undertaken. In multivariate analyses, rituximab alone (n=6) and other immune modulating treatments alone (n=2) were significantly associated with an increased likelihood of inhibitor clearance [hazard ratio (HR) of 4.4 (95% CI 1.06–20.03) and 10.21 (95% CI 1.17–78.28), respectively] whereas ITI alone (n=9) was not [HR 1.35 (95% CI 0.44–4.07)].
Hemophilia A; Immunotherapy
We estimated life expectancy at birth for Gaucher disease type 1 (GD1) patients by comparing survival data from GD1 patients enrolled in ICGG Gaucher Registry to the U.S. population using standard life table methods. 2,876 GD1 patients had 102 reported deaths in 13,509 person-years of follow-up. Estimated life expectancy at birth was 68 y, compared with 77 y in reference population; splenectomized patients, 64 y; nonsplenectomized, 72 y. Causes of death for 63/102 patients were malignancy (17/63), cardiovascular (11/63), and cerebrovascular (8/63). Estimated life expectancy at birth for GD1 patients was ~9 y less than reference population. Malignancies did not contribute to shortened life expectancy.