Breathing easy with pathogen inactivation

In this issue of Blood, Corash and colleagues report the results of a blinded expert analysis of patient experiences in the SPRINT trial of transfusion of pathogen-inactivated platelets and document the lack of any pulmonary toxicity of this approach to providing safer platelet transfusion.

Because of the recognition of the HIV threat almost 3 decades ago, the sought-after “holy grail” in blood transfusion has been pathogen inactivation (PI), a treatment that would render residual or undetected pathogens in the unit noninfectious. Success with PI in plasma-protein derivatives reopened the potential for use in hemophiliacs without the fear that a patient's next treatment might transmit a fatal disease. Multiple means of treating plasma for transfusion have been developed as well and have been widely adopted in Europe. (Although one of these remains licensed in the United States, none are currently marketed.)¹  Inactivating pathogens in cellular blood components has proven more difficult to achieve and even more difficult for US regulatory authorities to accept.

Red blood cells are the most frequently transfused component (16 million units annually in the United States) and the component furthest from practical application of PI techniques. The first 2 techniques, based on nucleic acid cross-linking without using photo-activated chemistry, resulted in immunologic responses in recipients that led to the abandonment of one of these and the modification of the other.¹  Two techniques are currently under active investigation, and appear to provide useful reductions in pathogen concentrations without neoantigen formation, albeit with a reduction in the allowable storage period for the cells of ∼ 1 week.

Despite the more complex physiology of platelets, this blood component has 2 viable means of PI that can be applied, and more are under development. The first to reach the market in Europe was Intercept (Cerus Corporation) which uses UVA activation of a psoralen derivative (amotosalen) to cross-link the nucleic acids of pathogens and prevent their replication. Riboflavin (vitamin B2) can also be similarly activated with UVA + UVB and is the basis of the Mirasol system of PI (CaridianBCT), also in use in Europe. Both approaches appear to place some metabolic stress on platelets and reduce their recovery and shorten their survival by 15%-20% in autologous radiolabeled reinfusion studies. However, clinical trials have demonstrated useful platelet count increments in thrombocytopenic patients.^2,3  The SPRINT trial of Intercept platelets was a US-based randomized, controlled trial which used the bleeding assessment of a blinded observer as its primary endpoint to document no difference in WHO grade 2 bleeding among patients receiving PI platelets.⁴  A more recent study using other criteria suggested an increased risk of bleeding with PI platelet use.⁵  However, more than 250 000 doses of Intercept platelets have been transfused across multiple European jurisdictions, and detailed hemovigilance reporting has failed to identify any associated increase in bleeding or other complications nor any increase in blood component usage.^6,7  However, US Food and Drug Administration (FDA) licensure of the technique has proven to be a daunting task.

The most oft-stated concern of FDA officials is that 5 of the 318 patients receiving PI platelets in the SPRINT trial were noted as having developed acute respiratory distress syndrome while none of the 327 control patients had this adverse event recorded.⁴  The low overall frequency of reported patients who developed acute lung injury (0.8%) was also unexpected and raised the question of accuracy of categorization of subject status. Corash and colleagues⁸  engaged an expert panel to review the records of all 148 subjects with any kind of pulmonary event recorded during the trial and apply the American-European Consensus Conference criteria for acute lung injury and acute respiratory distress syndrome. The reanalysis was conducted in a blinded fashion, and the panel reviewed the medical records for each patient, not just the reported categorization that had been made without use of standardized definitions. Their report, published in this issue, clarifies that PI with the Intercept system is not associated with any increase in clinically serious pulmonary complications and confirms the apparent safety of the approach documented through hemovigilance reports from Europe. In fact, patients who developed respiratory difficulties had a longer time to the onset of mechanical ventilation if they had received PI rather than control platelets. Overall, the analysis uncovered that hematology-oncology patients receiving platelet transfusions have about a 5% risk of developing acute lung injury.

Whether publication of this reanalysis will bring PI platelets closer to clinical availability in the United States is uncertain. FDA officials have been aware of these data for years but continue to maintain that another clinical trial to address the issue is needed. The likely size (> 3000 patients) and cost of the study may effectively preclude Intercept licensure in the United States and also complicate the trials of other PI techniques to come, delaying access to advances that other countries have found beneficial.

Do we need PI at all, though? Isn't the blood supply safe? Although improvements in donor screening and testing techniques have reduced the risks of transmission of HIV and hepatitis C virus to below 0.5-1 in 1 million units, other risks remain. Most worrisome is the continued risk of bacterial contamination in platelet units (stored at room temperature). Culturing of platelet units detects probably less than half of the bacterially contaminated ones,⁹  and the implementation of other detection techniques (using rapid immunologic methods) has been slow. As a result, there are still probably 30-100 cases of sepsis after platelet transfusion annually in the United States and perhaps several dozen deaths.¹⁰  Furthermore, the development of tests for other pathogens that we know represent continued risk to transfusion recipients—including babesia, malaria, and other insect-borne agents—is hampered by high costs and the potential for selective rather than universal implementation (because of geographical variation in risk), thus reducing manufacturers' remuneration. Recognition that the “Next New Virus” may disseminate widely through transfusion before it can be recognized, and before a test can be developed and implemented, provides additional sobriety. As a result, the safety of the blood supply is not what either transfusion medicine specialists nor recipients would like.¹¹  Application of PI techniques, likely soon to be available for all labile blood components, would address this problem. The report of Corash and colleagues⁶  relieves the concern that one of these techniques posed a new, additional threat to patients and, hopefully, brings implementation of PI techniques for platelets one step closer to reality in the United States.