Pathogen Reduction Technologies: Where Are We Going and What Is Keeping Us from Getting There?
By Ashley Smith

With the public expressing its expectation that the blood supply be completely safe and free from infection, the transfusion medicine community has shown a continued interest in the development of pathogen-reduction technologies. However, the slow progress toward the adoption of this technology in the United States has left some wondering, where are we going and what’s going to happen? These questions were posed in the session “TTD II: Where Are We Going with Pathogen Reduction?” (9210-S) — during which time the speakers reviewed the impetus toward adoption of pathogen-reduction strategies aimed to protect blood safety while addressing the barriers to full implementation.  

Pathogen Reduction – A New Paradigm

Harvey Alter, MD, of the Department of Transfusion Medicine at the National Institutes of Health, explained to the audience how in the wake of the HIV crisis of the 1970s and 1980s, the blood community adopted the precautionary principle — an assertion that measures need to be taken to face all potential risks. “Pathogen reduction is the ultimate precautionary principle by eradicating almost all potential for infectious disease transmission even before risk has been conclusively established and, possibly, even before the agent has been recognized,” he said.

Historically, there has been a long interval between the recognition of a disease that poses a threat to the blood supply and the development and implementation of a test assay for the agent. Although the interval has decreased with recent assays, the community still operates reactively. “A reactive strategy is fundamentally and inevitably delayed,” Alter explained. “We need to move toward a pre-emptive strategy of pathogen reduction — the new paradigm in transfusion safety.”

The Newest Risks

Zootic and vector-borne agents currently pose one of the greatest levels of threat to blood safety and most, if not all, of these agents may be transfusion transmitted. According to Alter, any agent capable of causing disease in man that has an asymptomatic “viremic” phase is a transfusion-transmission threat. The likelihood of this happening is highly dependent on the duration of the viremia, while the level of concern for an agent is dependent upon the severity of the ensuing disease.

Dengue — a mosquito-borne flavivirus — is an example of an agent of concern for the community because the vector and the virus distribution continue to expand. “It has a five-day viremia and most cases are subclinical,” Alter said. “This is a perfect set-up for transfusion transmission.” Three cases were recently reported from Singapore, and there are two previously recognized transfusion-transmitted cases and two transplant cases. Other threats that may emerge include malaria, HHV-8, Babesia, lyme disease, chikengunya, HAV and vCJD. “Of these threats, only vCJD is not amenable to pathogen-reduction technologies,” Alter noted. 

Benefits and Limitations

There are many advantages to pathogen reduction, including effectively inactivating most clinically relevant viruses, bacteria, spirochetes, rickettsia and protozoa. Pathogen reduction also prevents transfusion-associated graft-versus-host disease and, as Alter explained, “It offers probable pre-emptive protection against pathogenic agents that will inevitably emerge in the future.”

But, as with any technology, there can be limitations. “There is a decreased yield, but the clinical effect is marginal,” Alter said. The technology also is insufficient to kill some high-titer agents such as hepatitis A virus and parvovirus B-19. Another disadvantage is that there is no single process for all products and no proven inactivation system for red blood cells. Cost remains an additional concern. However, Alter noted that “There are offsets to the cost that could be applied, such as eliminating some current assays that would be redundant, eliminating bacterial testing, eliminating radiation and reducing donor exclusions based on geography.”

To reach the goal of pathogen reduction, Alter noted that there needs to be a paradigm shift in the attitudes and approaches to the technology. “It is time for the blood community to move from a reactive strategy to a proactive and preemptive one, from a resistive mindset to a receptive and enabling frame of mind,” Alter concluded. “I believe that the precautionary principle and morals dictate that we implement what we have — which is pathogen reduction.”

Roadblocks to the New Paradigm

Along the path to any new technology, roadblocks emerge, and pathogen reduction is no exception. John Chapman, PhD, of ThermoGenesis Corp., outlined what barriers remain for pathogen reduction, including technological, regulatory approval and toxicity concerns.

Pathogen reduction proves to be a formidable technical challenge because the products must be capable of inactivating the microbial load of a blood product to the noninfectious level without damaging or losing the blood component. “Research and development is complex and expensive,” Chapman explained. “And, because the blood supply is safer than ever, product safety requirements are higher than ever.”

Regulatory hurdles in the U.S. also remain for these products. The Food and Drug Administration (FDA) has a duel mission of protecting the public health by assuring the safety and efficacy of human blood products and advancing public health by encouraging innovations that make products more effective, safer and more affordable. “The primary task for the FDA is to develop a risk-benefit analysis of products like pathogen-reduction technologies,” Chapman said. “And this means weighing the risks — damage to the transfusion product and toxicity to the recipient, personnel running the technology and the environment — against the benefits of reducing the presence of known and potential threats.” Because of these issues, pathogen-reduction technologies still lack FDA approval for implementation in the U.S.

Many toxicology risk assessments have been performed on pathogen-reduction technologies. “From the general findings of studies on the safety of pathogen-reduced blood components, the residual levels of active ingredients are below the detection limit of toxicity assays, including genotoxicity,” Chapman said. “There are no assays that you can perform that will distinguish between a treated and untreated product,” he said. Limitations do exist, however, because diverse reaction products of the active agents are present in the pathogen-reduced blood components. In addition, it is not possible to establish large safety margins for reaction products due to dosing volume constraints.

Chapman concluded with a recommendation that the community come together to develop a consensus on the need — or lack thereof — for pathogen reduction and resolve the regulatory/industry stalemate so that product development and implementation can continue to move forward.

Where North America Stands

Many in the European blood community have adopted and implemented pathogen-reduction technologies but the acceptance process has been slow within the U.S. even though the community has continued to express an interest in the technology. Harvey Klein, MD, also from the NIH, stated that this may be because of the current safety of the volunteer blood supply, the lack of a single method to treat all components, the success of surveillance and screening in dealing with emerging pathogens, and the cost.  

To address these concerns, international experts in the field gathered in Toronto in March 2007 for a consensus conference on pathogen inactivation. “After hearing multiple presentations, the panel recommended that pathogen inactivation be implemented,” Klein said.  The panel also included specific details regarding the implementation of this technology and stated that it “should be implemented when a feasible and safe method to inactive a broad spectrum of infectious agents is available.” The panel did recognize that no system currently inactivates all components, but Klein noted that its recommendation addressed this by stating, “The absence of an integrated system does not imply that pathogen inactivation of any one component should be delayed until a method is proven satisfactory for all components.”

As for developments in the U.S., Klein highlighted the January 2008 meeting of the U.S. Department of Health and Human Services’ Advisory Committee on Blood Safety and Availability that focused on known and unknown threats to the blood supply and current pathogen-reduction technologies. “At this meeting, the committee unanimously passed a resolution that said pathogen reduction would result in a pro-active, pre-emptive strategy that would broadly render most known agents noninfectious and prevent emerging agents from being transfusion risks,” he said. The resolution included the following recommendations:

·          Encouraging the secretary of HHS to set as a top priority the “urgent” development of pathogen-reduction technologies.

·          Requesting resources to overcome current barriers to development and validation of technologies.

·          Highlighting the need for safety monitoring of pathogen-reduced blood products through a national hemovigilance system.

·          Stating that all other efforts to improve blood safety and availability should not be compromised.

Pathogen-reduction technologies are available throughout Europe, and Klein noted that Health Canada and Hema-Quebec have decided to follow the lead of the European blood community in Europe and move forward with the technology. Even as these other countries move forward and studies are published addressing barriers such as toxicity, each speaker noted that it remains everyone’s best guess as to when, where and if pathogen-reduction technologies will play a role in protecting the safety of the U.S. blood supply.