Hepatitis C Virus Transmission from an Antibody-Negative Organ and Tissue Donor,

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CDC's MMWR follow up on Hepatitis C Virus Transmission from an

Antibody-Negative Organ and Tissue Donor, April 4, 2003, with

introductory commentary by Dr. Louis Aledort.Introductory Comment by

Louis Aledort, M.D. The Weinfeld Professor of Clinical Research in

Hemophilia, The Mount Sinai Medical Center, New York Chairman, Clearant

Scientific Advisory BoardThe following report appeared in the April 4,

2003 issue of Morbidity & Mortality Weekly Report, published by the

Centers for Disease Control and Prevention. The article summarizes the

preliminary investigation of a donor who was the probable source of

Hepatitis C Virus infection in at least eight tissue and organ transplant

recipients. This case, and the CDC’s continued, ongoing investigation,

proves once again that flaws exist in the current methods of processing

donated tissues and organs. As this article points out, donor screening

remains the primary method of preventing transmission of viral infections

from organs and tissues. However, as it is clear from the article, this

is not enough to prevent infection transmission. The CDC agrees that new

technologies to sterilize donated tissue should be explored. The CLEARANT

PROCESS™ offers great promise in preventing future cases of viral

transmission such as the one detailed here. A patented process based on

gamma irradiation, the CLEARANT PROCESS™ substantially inactivates all

types of known pathogens, including viruses, bacteria, fungi and prions,

in the final package without damaging the structural integrity of the

tissue. I applaud the CDC for following up on this case and encourage all

of us in the industry to work towards improved safety standards.Hepatitis

C Virus Transmission from an Antibody-Negative Organ and Tissue Donor ---

United States, 2000­2002. MMWR Weekly, April 4, 2003 / 52(13); 273-276 In

June 2002, a physician reported to the Oregon Department of Human

Services (DHS) a case of acute hepatitis C in a patient who had received

a patellar tendon with bone allograft from a donor approximately 6 weeks

before onset of illness. At the time of the donor's death in October

2000, his serum had no detectable antibody to hepatitis C virus

(anti-HCV). The ensuing investigation conducted by CDC and DHS confirmed

that the donor, although anti-HCV--negative, was HCV RNA--positive and

the probable source of HCV infection for at least eight organ and tissue

recipients. This report summarizes

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the preliminary results of the investigation. Although transmission from

anti-HCV--negative tissue donors probably is rare, determining the

frequency of transplantations from such donors and the risk for

transmitting HCV to recipients is important in evaluating whether

additional prevention measures are warranted. The donor was a man in his

40s with a history of hypertension and heavy alcohol use who died of an

intracranial hemorrhage. At the time of death, he had no signs or

symptoms of hepatitis, and his alanine aminotransferase and aspartate

aminotransferase levels were normal. Physical examination revealed no

skin markings indicative of injection-drug use or evidence of liver

disease. A questionnaire administered to the donor's next of kin revealed

no history of injection-drug use or blood transfusion. At the time of the

donor's death, his serum tested negative for anti-HCV by a

second-generation enzyme immunoassay (EIA) (Abbott HCV EIA 2.0, Abbott

Laboratories, Abbott Park, Illinois) and negative for human

immunodeficiency virus (HIV)-1, HIV-2, human T-lymphotropic virus (HTLV)

I, HTLV II, hepatitis B virus, and syphilis. In July 2002, stored, frozen

serum obtained premortem from the donor tested negative for anti-HCV with

a third-generation EIA (ORTHO® HCV Version 3.0 ELISA, Ortho-Clinical

Diagnostics, Raritan, New Jersey) but positive for HCV RNA (AMPLICOR®HCV

Test, version 2.0, Roche Molecular Systems, Branchburg, New Jersey). The

donor's HCV genotype was 1a, as determined from the 300-nucleotide

sequence of the nonstructural coding region NS5b (1,2). A case was

defined as laboratory-confirmed HCV infection, with a viral genotype

identical to that of the donor, in a recipient not known to have been

infected before transplantation. A definite case was defined as one that

occurred in a recipient who was both anti-HCV-- and HCV RNA--negative

before transplantation. A probable case was defined as one that occurred

in a recipient for whom no serum was available before transplantation.

The organ procurement and tissue distribution agencies provided an

inventory of grafts recovered from the donor and the contact information

for each health-care provider or facility that had received grafts.

Health-care providers were contacted to obtain clinical information and

to arrange for testing of recipients. Recipients' post-transplantation

and stored pretransplantation sera, when available, were tested for

anti-HCV by EIA 2.0 or 3.0 and for HCV RNA (by using either AMPLICOR®HCV

Test, version 2.0, or HCV RNA DetectR™ PLUS by TMA, Specialty

Laboratories, Santa , California). Specimens positive for anti-HCV

by EIA were tested with a supplemental recombinant immunoblot assay

(RIBA®, Chiron Corporation, Emeryville, California). HCV genotype was

determined for all HCV RNA--positive samples (1,2). Of 91 organs and

tissues recovered from the donor, 44 were transplanted into 40 recipients

during October 2000--July 2002. Of the remaining 47 grafts, 44 tissues

were removed from distribution in July 2002, and two tissues and one

organ had been discarded earlier. Of the 40 recipients, six received

organs, 32 received tissues, and two received corneas. Recipients were

located in 16 states and two foreign countries. All

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tissues had been treated with surface chemicals or antimicrobials. Bone

grafts also underwent gamma irradiation. Eight cases were identified

among the 40 recipients; all cases were HCV genotype 1a. Among the six

organ recipients, post-transplantation serum was available for three, and

definite cases occurred in all three. Of the 32 tissue recipients, three

were known to have been HCV-infected before transplantation, and test

results were not available for another two (one bone and one tendon with

bone recipient). Among the remaining 27 tissue recipients, five probable

cases occurred: in one of two recipients of saphenous vein, in one of

three recipients of tendon, and in all three recipients of tendon with

bone (including the index patient). One other recipient was found to be

HCV-infected after transplantation with genotype 3a. No cases occurred in

recipients of skin (n = two) or irradiated bone (n = 16). Of the two

cornea recipients, one was infected before transplantation. The other

recipient was anti-HCV--negative; however, as of March 27, HCV RNA

testing had not been performed. Reported by: PR Cieslak, MD, K Hedberg,

MD, AR , MD, MA Kohn, MD, Oregon Dept of Human Svcs. F Chai, PhD,

OV Nainan, PhD, IT , PhD, BP Bell, MD, Div of Viral Hepatitis,

National Center for Infectious Diseases; BD Tugwell, MD, PR Patel, MD,

EIS officers, CDC.Editorial Note: This report describes transmission of

HCV by tissues and organs from a donor whose serum tested

anti-HCV--negative at the time of death. However, stored serum tested

subsequently was HCV RNA--positive. The donor was the probable source of

HCV infection for at least eight recipients of organs or tissues. All

cases occurred in recipients of organs or soft tissues; no infections

were found among those who had received skin or irradiated bone. HCV

transmission from tissue donors has been reported infrequently; the only

tissue types reported previously to transmit HCV are nonirradiated bone

and tendon with bone (3--5). By contrast, transplanted organs from

infected donors are known to carry a high risk for transmitting HCV (6).

At the time of death, the donor probably was in the 8--10 week window

period between infection with HCV and development of a detectable

HCV-antibody response (7). Although available data are limited, HCV

transmission by organ and tissue donors during this period appears to be

uncommon; only one previous report describes HCV transmission from a

tissue donor in whom anti-HCV testing (using a less sensitive

first-generation assay) was negative (3). The frequency of

transplantation from antibody-negative, HCV RNA--positive organ and

tissue donors is not known. However, among voluntary blood donors, whose

characteristics probably differ from those of organ and tissue donors,

approximately four per 1,000,000 blood donations are from donors who are

anti-HCV--negative and HCV RNA--positive (8).

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Donor screening is the primary means of preventing transmission of viral

infections from organs and tissues. The Food and Drug Administration

(FDA) and the Health Resources and Services Administration (HRSA) provide

regulatory guidance or oversight for screening of tissue and organ

donors. In addition, organ procurement organizations are required by the

Centers for Medicare & Medicaid Services to ensure that appropriate

donor screening tests are performed by a laboratory certified in

accordance with the Clinical Laboratory Improvement Amendments of 1988.

The donor screening process includes medical chart review, interview of

the donor's next of kin, physical assessment, and testing of donor serum.

Guidelines require that organ and tissue donors be tested for anti-HCV.

Nucleic acid testing (NAT) to detect HCV RNA among organ and tissue

donors is not performed routinely and has several limitations. Organ

viability declines rapidly as a function of time after donor death.

Because NAT often is not immediately accessible and can require 1--2 days

to complete, it might be impractical in the setting of organ

transplantation. By contrast, tissues often can be stored for months to

years before use, allowing ample time for NAT. However, postmortem serum

frequently is the only sample available for testing from tissue donors.

NAT to detect HCV RNA has not been approved by FDA for use on serum

samples obtained postmortem, and the performance of available assays in

this setting has not been evaluated. Tissue processing methods (e.g.,

gamma irradiation) might affect the likelihood of transmission of HCV and

other viruses from infected donors (3,9). In this investigation, no cases

occurred in recipients of irradiated bone. Irradiation is not applied

routinely to all tissue types because it can impair tissue structural

integrity. This investigation was initiated by a clinician who suspected

allograft-associated HCV transmission and alerted the state health

department. When a new case of hepatitis C is diagnosed in a recent

tissue or organ recipient, health-care providers should notify local or

state health departments promptly so an investigation can be initiated

and, if necessary, tissues can be recalled to prevent further

transmission. Centers performing transplantation should maintain adequate

records of graft recipients to facilitate investigations of

allograft-associated infections. CDC, in collaboration with FDA and HRSA,

will determine whether changes in organ and tissue donor screening

guidelines are warranted. Assessing the performance of available NAT and

anti-HCV assays in postmortem specimens would provide essential

information about the period during which donor screening can be

performed reliably. Although transmission from anti-HCV--negative tissue

donors probably is rare, determining the frequency of transplantations

from such donors and the risk for transmitting HCV to recipients will be

useful for evaluating the benefits and limitations of additional

prevention measures.

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AcknowledgmentsThis report is based on information contributed by H

Homan, Multnomah County Health Dept; DN Gilbert, MD, Providence Portland

Medical Center and Oregon Health and Science Univ; C Corless, MD, Oregon

Health and Science Univ; S Kemeny, MD, Providence Portland Medical

Center, Portland, Oregon. M Kainer, MD, Tennessee Dept of Health. W

Kuhnert, PhD, Div of Viral Hepatitis; D Jernigan, MD, Div of Healthcare

Quality Promotion, National Center for Infectious Diseases; K Kiang, MD,

K Lofy, MD, EIS officers, CDC. References 1. Simmonds P, Holmes EC, Cha

TA, et al. Classification of hepatitis C virus into six major genotypes

and a series of subtypes by phylogenetic analysis of the NS-5 region. J

Gen Virol 1993;74:2391--9. 2. Cody SH, Nainan OV, Garfein RS, et al.

Hepatitis C virus transmission from an anesthesiologist to a patient.

Arch Intern Med 2002;162:345--50. 3. Conrad EU, Gretch DR, Obermeyer KR,

et al. Transmission of the hepatitis-C virus by tissue transplantation. J

Bone and Joint Surg Am 1995;77:214--24. 4. Pereira BJG, Milford EL,

Kirkman RL, et al. Low risk of liver disease after tissue transplantation

from donors with HCV. Lancet 1993;341:903--4. 5. Eggen BM, Nordbo SA.

Transmission of HCV by organ transplantation. N Engl J Med 1992; 326:411.

6. Pereira BJG, Milford EL, Kirkman RL, Levey AS. Transmission of

hepatitis C virus by organ transplantation. N Engl J Med

1991;325:454--60. 7. Busch MP, Kleinman SH, B, Stramer SL,

Hewlett I, Preston S. Nucleic acid amplification testing of blood donors

for transfusion-transmitted infectious diseases: report of the

Interorganizational Task Force on Nucleic Acid Amplification Testing of

Blood Donors. Transfusion 2000;40:143--59. 8. Stramer SL, Caglioti S,

Strong DM. NAT of the United States and Canadian blood supply.

Transfusion 2000;40:1165--8. 9. Simonds RJ, Holmberg SD, Hurwitz RL, et

al. Transmission of human immunodeficiency virus type 1 from a

seronegative organ and tissue donor. N Engl J Med

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