ABOUT THE NHLBI BIOLOGIC SPECIMEN REPOSITORY

The NHLBI has been vigilant in surveillance for new and emerging infectious agents that might contaminate the U.S. blood supply, and be transmitted by transfusions. Since the mid-1970s, the Institute's Blood Division has established and supported several large blood specimen repositories to perform prospective and retrospective studies of blood donors and recipients. These linked donor/recipient repositories proved vital for research that showed non-A, non-B hepatitis was in fact due to hepatitis C virus (HCV) infection, and showed the value of surrogate marker and anti-HCV screening. These specimens also were used to study the risks of transmission of HIV, HTLV I/II, and HHV-8 by transfusions. The NHLBI Biologic Specimen Repository is managed by the Blood Division through Contract N01-HB-87144. About 90% of the samples are from the blood safety program, and the rest from other NHLBI programs. Use of these samples has been extensive, and from 1991-2004, a total of 148,667 specimens from the NHLBI Biological Specimen Repository were sent to various investigators.

Listed below are the various specimen collections held at the NHLBI Biologic Specimen Repository:

Division of Blood Diseases and Resources (DBDR)

• Retrovirus Epidemiology Donor Study (REDS) - This multicenter study involved a wide variety of epidemiologic and laboratory investigations of risks from known infectious agents, and has developed several novel strategies to assess potential new infectious threats and proposed safety initiatives.

Specimen types: serum, plasma, whole blood

Number of specimens: 2,528,616

The REDS repository has been invaluable for numerous studies on donor screening and supplemental tests. Examples of studies include: (1) An investigation to establish the prevalence and significance of HHV-8 infection among blood donors and to evaluate the performance of HHV-8 antibody and DNA assays; (2) A project to assess the residual value of anti-HBc for the detection of occult HBV infection in donors; and (3) A seroepidemiologic investigation of the long-term consequences of HTLV I/II infection.

• Transfusion-Transmitted Viruses Study (TTVS) - Collections of blood donor samples and pre- and post-transfusion samples of recipients and controls, with subsequent follow-up samples of donor/recipient pairs associated with infectious hepatitis in the recipient.

Specimen type: plasma

Number of specimens: 249,068

The TTVS repository has been used in a variety of studies, such as the evaluation and validation of HCV immunoassays in screening blood donors. In addition, specimens have been requested to look at poorly characterized hepatotropic viruses, transmissibility of new viruses (hepatitis G, HHV-8) by transfusion, and the dynamics of HBV/HCV viral replication and seroconversion in recipients.

• Transfusion Safety Study (TSS) - Collections of representative blood donor samples, with selected recall of recipients if donor specimens test positive for new markers. Also includes specimens from hemophiliacs and patients with congenital anemias such as sickle cell disease patients.

Specimen types: plasma, buffy coat

Number of specimens: 225,960

This repository was essential to establish transmission rates of HIV and HTLV I/II by transfusion, and to identify virologic and host factors which influence infection and clinical outcome. Studies with TSS specimens continue on the role of the HIV co-receptor CCR5 in viral transmission and disease progression, investigation of possible transmission of HHV-8 by clotting factor concentrates, and evolution of HIV quasi-species.

• ACTG Protocol 185 - A multi-Institute (NHLBI, NIAID, NICHD) clinical trial to evaluate the efficacy of HIV hyperimmune globulin for the reduction of vertical transmission in HIV-infected women.

Specimen types: plasma, serum, buffy coat, peripheral blood mononuclear cells, DNA and HIV hyperrimmune globulin evaluated in the trial.

Number of specimens: 76,893

Virologic and serologic assays with specimens from women and infants in this trial have helped to determine risk factors for perinatal transmission of HIV in women treated with zidovudine. Studies were also conducted with this resource to investigate other factors associated with the risk of mother-to-baby transmission.

• Trial to Reduce Alloimmunization to Platelets (TRAP) - A clinical trial to determine the best, clinically useful procedure to prevent or minimize platelet alloimmunization as a cause for refractoriness to platelet transfusions.

Specimen types: plasma, serum

Number of specimens: 63,411

The specimens are useful to evaluate new techniques to detect new antibodies and refractoriness to platelet transfusion. Another potential benefit of these samples is that the patients are multiply transfused, and therefore, their specimens may be used to detect new infectious agents transmitted by transfusion.

• Viral Activation Transfusion Study (VATS) - The purpose of this study was to determine if viral activation occurs following blood transfusion and if leukocyte depletion or irradiation can prevent it. It also evaluated the role of donor leukocytes producing this activation by examining the effects of removing leukocytes by filtration or abolishing their ability to proliferate by gamma irradiation. Finally, the study examined the persistence of donor lymphocytes after transfusion.

Specimen Types: buffy coat, lymphocytes, plasma, platelets, red blood cells, serum, whole blood

Number of specimens: 92,733

• Cooperative Study of Sickle Cell Disease (CSSCD) and Multicenter Study of Hydroxyurea (MSH) - These two studies address the natural history and clinical course of sickle cell disease, and efficacy and safety of hydroxyurea in the treatment of the disease, respectively.

Specimen types: serum, DNA

Number of specimens: 9,550

Specimens from patients enrolled in the CSSCD will be used to identify candidate genes which might explain the variability and severity of sickle cell disease. Samples from the MSH are under investigation to ascertain any effects that hydroxyurea may have on chromosomes of recipients.

Other divisions of the NHLBI also utilize the services of the NHLBI Biologic Specimen Repository. Below is a list of the various collections maintained by the contractor:

Division of Lung Diseases (DLD)

• A Case Control Etiologic Study of Sarcoidosis (ACCESS) - The purpose of ACCESS is to identify the cause(s) of sarcoidosis.

Specimen types: plasma, DNA, bronchial/alveolar lavage fluid (BALF)

Number of specimens: 49,164

Samples are being used and will continue to be utilized in genetic and other ancillary studies of sarcoidosis.

• Acute Respiratory Distress Syndrome Clinical Network (ARDSNET) - This clinical study is evaluating novel therapies for the treatment of acute lung injury and acute respiratory distress syndrome.

Number of specimens: 47,324

Approximately 1,300 plasma specimens and 100 BALF samples have been used by the investigators. Future use is expected to be in studies of pathogenesis and genetic factors which influence susceptibility to disease.

• Prospective Study of the Pulmonary Complications of HIV Infection (PACS) - A multicenter, prospective study of pulmonary complications of HIV-infected patients and negative controls.

Specimen types: serum

Number of specimens: 54,835

A few samples have been used in studies of tuberculosis and Pneumocystis carinii pneumonia. Future use will focus on circulating IgG anti-P.D. antibodies to determine if this would detect TB in anergic subjects.

• Pediatric Pulmonary and Cardiovascular Complications of Vertically Transmitted HIV Infection (P2C2) - This study follows cohorts of HIV-infected and uninfected infants born to HIV-infected mothers to assess cardiovascular and pulmonary involvement of the disease.

Specimen types: serum

Number of specimens; 8,939

Serum samples have been used to determine the HIV status of several infants who either died or dropped out of the study before HIV cultures could be obtained. A study of the effects of anti-retroviral therapy on cardiovascular function is using serum samples from untreated P2C2 infants as controls. The P2C2 study was conducted before therapy was available.

• Lymphangioleiomyomatosis (LAM) Registry - The goal of this study is to examine the clinical features of persons referred for lung transplantation and assess the efficacy of this therapy.

Specimen types: serum, plasma, DNA, RNA, lung tissue, renal tissue

Number of specimens: 12,041

The specimens are being utilized to study the pathogenesis and genetic components of LAM.

• Registry of Patients With Deficiency of Alpha1-Antitrypsin - The objective of this study is to characterize the clinical and laboratory course of patients with severe alpha1-antitrypsin deficiency.

Specimen types: serum

Number of specimens: 4,500

The specimens are to be used to study the inflammatory response associated with alpha1-antitrypsin deficiency.

Division of Prevention and Population Sciences (DPPS)

• Honolulu Heart Program (HHP) - This was an observational cohort study of the effect of acculturation on the development of coronary heart disease (CHD) in 8,000 Japanese-American men living in Hawaii. Risk factors studied include diet, physical activity, socioeconomic status, cognitive function, and cardiovascular risk factors, such as blood pressure and impaired pulmonary function.

Specimen types: serum, plasma

Number of specimens: 80,269

Serum and plasma samples are expected to be used in studies primarily on lipids and lipoproteins in subjects with CHD.

• NHLBI Growth and Health Study (NGHS) - This is an observational cohort study of factors associated with the development of obesity in 2379 girls, ages 9-10 at baseline. Factors studied include diet, physical activity, socioeconomic status, health beliefs and attitudes, psychosocial influences, racial differences in obesity development, and association of obesity with cardiovascular disease risk factors.

Specimen types: serum

Number of specimens: 11,095

NGHS specimens are currently not available.

• Dietary Approaches to Stop Hypertension (DASH) and DASH-Sodium - (1)DASH - An outpatient controlled, randomized human dietary study conducted on 459 adults age 22 and older, 60% African American, who had higher than optimal blood pressure. The study found that compared to a typical American diet, the DASH diet (low-fat dairy products and reduced saturated fat, total fat, and cholesterol) substantially and quickly lowered blood pressure. (2) DASH-Sodium - A randomized, controlled, outpatient human diet trial, which compares three levels of sodium intake and two dietary patterns on blood pressure among adults with higher than optimal blood pressure, or Stage I hypertension. The study confirmed that the DASH diet lowers blood pressure and the lower the dietary sodium the better for blood pressure lowering.

Specimen types: plasma, serum, buffy coat, urine

Number of specimens: 15,287

DASH and DASH-2 specimens are currently not available.

• Premier: Lifestyle Interventions for Blood Pressure Control (PREMIER) - To compare the effectiveness of advice versus two multicomponent lifestyle interventions to control blood pressure in participants with Stage 1 hypertension or higher than optimal blood pressure.

Specimen types: serum, plasma buffy coat, urine

Number of specimens: 21,928

• Dietary Intervention Study in Children (DISC) - Specimens enrolled in this study have been used to research the effect of a low-fat dietary intervention on insulin related biomarkers among adolescent girls.

Specimen types: serum

Number of specimens: 8,750

DISC specimens are currently not available.

Division of Cardiovascular Diseases (DCVD)

• Thrombolysis in Myocardial Infarction (TIMI) - TIMI is comprised of 3 studies: (1) TIMI 1 - a randomized trial to assess the safety and efficacy of rt-PA versus heparin on patency and thrombus formation as detected by coronary angiogram in 300 patients with acute Q wave myocardial infarction or unstable angina. (2) TIMI 2 - a double-blind, randomized trial to assess the safety and efficacy of rt-PA versus heparin, with randomization to either cardiac catheterization or conservative strategy in 2948 patients with acute Q wave myocardial infarction. (3) TIMI 3A - a randomized trial to assess the safety and efficacy of rt-PA versus heparin on patency and thrombus formation as detected by coronary angiogram in 306 patients with acute non-Q wave myocardial infarction or unstable angina. (4) TIMI 3B - a double-blind, randomized trial assessing the safety and efficacy of rt-PA versus heparin, and randomization to either cardiac catheterization or conservative strategy in 1473 patients with acute non-Q wave myocardial infarction or unstable angina.

Specimen types: DNA, RNA

Number of specimens: 42,540

No plans have been finalized about the future use of the specimens.

The Institute has other studies besides those listed above, some ongoing and others completed, that store biologic specimens from human subjects. For example, the Women's Health Initiative (WHI) is amassing a large repository from samples from approximately 100,000 subjects. DECA has 16 studies in its Clinical Applications and Prevention Program with over 104,000 samples housed in different locations. Also in DECA, the Epidemiology and Biometry Program supports 8 projects that currently store more than 1,000,000 samples/aliquots collected from individuals enrolled in these studies.

In total, the NHLBI Biologic Specimen Repository also contains clinical, epidemiologic, virologic, and serologic information associated with the specimens, which is of great importance to research on blood, lung, and cardiovascular diseases. Many collections have been used extensively over 30 years after the original study (e.g., TTVS), and in September, 1997, the Repository Review Committee confirmed that the informed consents allowed all samples to be available for further research with specific approval. Therefore, the Institute has promoted the availability, access, and use of the Repository samples.

The National Heart, Lung, and Blood Institute's Biologic Specimen Repository is administered by the Transfusion Medicine Scientific Research Group and operated by a contractor. Questions about policy should be addressed to the Project Officer below, and requests for catalogs should be addressed to the NHLBI Biologic Specimen Repository, c/o the Contractor.

Transfusion Medicine and Cellular Therapeutics Branch:

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