The Next Revolution in Blood Technology: Pathogen Reduction
The blood industry has been shaken by a series of seismic shifts in recent years and the next shock is already cresting the horizon: Pathogen Reduction Technology (PRT) has the potential to transform how blood products reach patients. Other upsets have been sudden and jarring, such as 2016’s Zika epidemic and its nation-wide impact on blood availability. In the span of a single year, an emerging pathogen was identified as a threat to the blood supply, nucleic acid tests were developed, and a new guidance was adopted by the FDA.
Slower-developing changes, such as the continuing decrease in transfusions, have occurred over a longer time span, but are continuing to reshape the landscape.
A new paradigm
PRT is not simply another tool. It is a paradigm shift in how we think about the safety of the blood supply. The importance of PRT was highlighted by in two of the seven summary recommendations in the recent RAND Corporation report titled “Toward a Sustainable Blood Supply in the United States.” The RAND Report cited a recent perspective published in the New England Journal of Medicine[i] that was co-authored by Richard J. Benjamin, then the Chief Medical Officer of the American Red Cross. The NEJM article also advocated for the wide-spread adoption of PRT as a tool to address emerging pathogens, among other challenges.
The promise of PRT is that it shifts the safety of the blood supply from being primarily reactive to proactive. A recent paper identified over 80 emerging pathogens that could cause transfusion-related infections[ii]. Notably, Zika was not even on the horizon in 2009, when the paper was published. Other concerns, such as dengue and chikungunya have only grown in significance.
Although major outbreaks grab headlines, rare or obscure diseases, or pathogens found outside their endemic range, are a significant concern as well. While any individual pathogen may remain below the status of a major outbreak, their obscurity means that they fall below the threshold at which regulatory agencies require universal testing. A case of transfusion-acquired ehrlichiosis[iii], a disease caused by an intra-cellular bacterial pathogen normally transmitted by tick bite, is one such example.
According to a recent paper in Transfusion[iv], the risk of acquiring a transfusion-associated infection from red blood cells (RBC) obtained under standard screening and collection deferral protocols, ranges from 0.00031% (1 in 322,600) to 0.22% (1 in 454), depending on the recipient’s vulnerability to cytomegalovirus and the likelihood of receiving blood from regions where Babesia microtii is endemic. That is a wide range in estimated risk, but it is certainly non-zero. The study accounts for the chance receiving blood from a donor who was recently infected with a blood-borne pathogen, such as HIV, but who was not yet producing a detectable antibody signature.
Aside from the very real threat of undetected pathogens slipping through the cracks, a reactive approach also depresses overall collections. While tests for new pathogens are being developed, potential donors are deferred based on travel or lifestyle considerations. Donor recruitment is already a major challenge, and each deferment further reduces collections. Blood collection was entirely stopped for months during the height of the Zika outbreak in Puerto Rico (and in the previous outbreak in Tahiti in 2013[v])
The quick response of blood centers and regulatory agencies was effective. There are no known cases of transfusion-initiated Zika infections in the United States. Each such incident, however, adds to the stressors affecting blood collections organizations.
Inactivation vs detection
The promise of PRT lies in its mechanism of action. Rather than detecting antibodies or a nucleic acid signature, PRT inactivates pathogens in situ. There are two broad categories (chemical-only and chemical+light) and several distinct methods, each with characteristic strengths and limitations.
Fresh-frozen plasma (FFP) is normally filtered to remove protozoa, white blood cells and bacteria, and treated to eliminate prion contaminants. SD Plasma has been further treated with a solvent/detergent mixture that can physically disrupt the envelopes of membrane-bound viruses such as HIV, HBV, and HCV, that are freezing-resistant and small enough to escape filtration. An early SD Plasma product approved for use in the U.S. in 1996 (Plas+SD from Vitex) was discontinued in 2003 after significant adverse events were observed.
A different SD plasma product, Octaplas[vi] from Octapharma, however, was approved for use in the US in 2013. In contrast to Plas+SD, Octaplas has been shown to be safe and effective[vii] after decades of use in Europe. It is important to note, however, that protein-coated virus particles, such as hepatitis A and human parvovirus, are resistant to the detergent treatment. Due to the use of membrane-disrupting technology, SD protocols cannot be extended to membrane-bound blood products such as platelets or red blood cells.
The other major approach to PRT uses a combination of single-wavelength ultra-violet light and a chemical additive that catalyzes nucleic acid cross-links when activated by UV. The chemical additive varies with each system, and the blood fraction that is being targeted. The Intercept system from Cerus[viii] uses a class of chemicals called psoralens[ix] that are derived from plant-based compounds. The plasma and platelet treatments use a compound called amotosalen, while the RBC system uses amustaline S-303 in conjunction with glutathione. The Mirasol system from TerumboPCT[x] uses riboflavin (aka vitamin B2) as the photoactive compound, and the Macopharma[xi] system uses methylene blue. The additive chemicals catalyze reactions that damage nucleic acids, but do not bind to DNA or RNA.
As of early 2017, only the Intercept plasma[xii] and platelet[xiii] system has been approved for use in the United States, although both Mirasol and the Intercept RBC systems are undergoing clinical trials in pursuit of FDA approval.
Because the photo-activated systems target nucleic acids, they have a very broad spectrum of activity. Published data indicates a 4–6 log reduction in infectious agent titer in cell-free and cell-associated viral, bacterial and protozoal pathogens. In lab trials, this method is as effective as gamma irradiation in inactivating white blood cells (leukoreduction), although that use is not part of the FDA approved label claim. Finally, because the treatment is effective against cytomegalovirus, PRT-treated blood products are considered CMV-.
PRT used with platelets effectively adds an extra day of viability since the initial overnight culture test is not required. The treatment does not extend the usable date, but platelets can be released for use a day earlier than under current methods. Perhaps more significantly, an FDA guidance expected to be released in early 2017 will recommend that non-PRT treated platelets in day 4 or 5 of viability undergo a rapid bacterial contamination test within 24 hours prior to use. PRT-treated platelets, on the other hand, can be used through their labeled life span without additional testing. Version two of the draft guidance is available here.
The way forward
There are no magic bullets in medicine, and PRT is no exception. Bacterial endospores and some protein-coated viruses have been shown to resist the treatment. Viruses present at very high concentrations may be reduced by 6-log, but could still provide an infectious dose. Prions, lacking genetic material, are unaffected.
The other, and arguably more significant, barrier to adoption of PRT in the US is economics. PRT systems add significant cost to treated units. As the RAND Report makes clear, blood centers are already under severe strain from falling demand for blood products, increased competition among suppliers, and cost-cutting measures by hospitals.
With only one system currently available for platelets and plasma, and no RBC or whole blood-approved systems, the FDA is unlikely to require PRT treatment of blood products in the near future. With no regulatory mandate, adding significant cost to units is a difficult proposition.
Despite these limitations, PRT adoption in the US is moving ahead. In 2015, HHS and the Armed Services Blood Program announced a $46 million project to study Intercept and Mirasol PRT use with whole blood. Additionally, the already-approved platelet and plasma system from Intercept is being used to treat all platelets at the Walter Reed National Military Medical Center.[xiv] This initiative is in line with the RAND Report recommendation that HHS investigate subsidizing PRT-adoption, support increased R&D of blood product technology, and investigate updating regulatory framework to emphasize pro-active pathogen reduction in addition to an improved HV network to catch pathogens resistant to PRT.
An additional pathway forward could include marrying innovative distribution networks for blood products with access to novel technologies. Whereas a single blood center may not be able to subsidize PRT for all their clients, a single lab with PRT could conceivably process units from multiple centers under a cost-sharing arrangement. With access to nationwide system of blood distribution, such progressive blood centers could supply hospitals that have prioritized a proactive approach to blood safety.
PRT could be the next revolution in blood technology. Some big players are betting on it already. If multiple whole-blood technologies are approved for use in the US, costs could fall dramatically. How it’s implemented, who benefits, and who is hurt remains to be seen. One thing is certain: if one of those 80 emerging diseases does not cause the next crisis in blood collection, another one will.
Originally published at www.bloodbuy.com.