Emerging Pathogen Threats in Transfusion Medicine: Improving Safety and Confidence with Pathogen Reduction Technologies

The paper addresses how globalization, climate change, and human behavioral shifts have increased the emergence and re-emergence of infectious diseases, many of which pose risks to transfusion medicine. Classic bloodborne pathogens (HIV, HBV, HCV) and an increasing list of arboviruses (e.g., West Nile, dengue, Zika, yellow fever, tick-borne encephalitis, Japanese encephalitis, Powassan) have been implicated in transfusion transmission. Historically, transfusion safety measures have been reactive, moving from immunological assays to NAT-based screening (HBV/HCV/HIV; in some regions WNV, Babesia, Zika). While effective once implemented, reactive strategies are inadequate for unpredictable, rapidly emerging threats. Pathogen reduction (PR) offers a proactive approach by disrupting pathogens or modifying nucleic acids to prevent replication. PR has long been used successfully for plasma-derived products and has more recently been implemented for labile blood components (platelets, plasma, whole blood) using various technologies (e.g., methylene blue + visible light; amotosalen + UVA; riboflavin + UV; UV-C). Clinical trials, including the AIMS trial in a malaria-endemic setting, demonstrated reduced transfusion-transmitted malaria with riboflavin + UV whole blood treatment. The article aims to outline recent viral outbreaks relevant to transfusion (mpox, SARS-CoV-2, Ebola, hepatitis E) and describe how riboflavin + UV PRT can mitigate emerging transfusion risks.

The review synthesizes evidence on pandemic preparedness and transfusion safety, emphasizing the role of PRT as a proactive mitigation tool—particularly when using convalescent plasma early in outbreaks before transmission dynamics are fully understood. Key preparedness components reviewed include surveillance, stockpiles, emergency planning, infection control, vaccination, communication, and R&D; gaps remain in surveillance, response speed, and resources. The paper reviews emerging viruses and their transfusion implications: 1) Mpox: DNA frequently detected in blood by PCR; case reports raise concerns about needlestick-mediated spread; infectivity thresholds have been examined by correlating DNA copies with PFU; blood-borne transmission cannot be ruled out. 2) SARS-CoV-2: Despite RNAemia reports in donors and patients, no confirmed transfusion transmissions; infectious virus has not been isolated from RNA-positive blood; model data suggest high IV doses are required for infection; donor RNAemia prevalence is low; pandemic response measures caused significant blood shortages globally. 3) Ebola: High viremia in severe cases, multiple routes of transmission, and low infectious dose warrant caution; while transfusion transmission has not been reported, persistence of virus/RNA in some bodily fluids post-illness is documented; blood demand during outbreaks is high. 4) Hepatitis E: Increasing reports of transfusion transmission globally (Europe, Asia), often from asymptomatic donors; non-enveloped nature complicates inactivation; some transmissions occurred despite psoralen+UVA PRT; underscores need for robust mitigation. The review compiles experimental and clinical evidence for riboflavin + UV PRT effectiveness across blood components against these pathogens and discusses how PRT may preserve convalescent plasma antibody functionality.

This is a narrative review summarizing publicly available data and published studies (per the Data Availability Statement). Experimental methods cited from included studies evaluating riboflavin + UV PRT efficacy typically involved: - Spiking blood components (plasma, platelets, whole blood) with cultured virus to clinically relevant titers. - Treating products per manufacturer instructions with riboflavin and specified UV doses. - Measuring infectious titers pre- and post-treatment via plaque assays or infectivity readouts. - In some studies, varying energy doses (e.g., 30%, 60%, 100% of target) to assess inactivation kinetics. - Assessing preservation of antibody function in convalescent plasma using neutralization assays (live-virus PRNT and pseudovirus RVPN) and ELISAs for spike RBD/S1/S2. Specific methodological details cited include: - Mpox: Plasma and whole blood (n=3 each) spiked with mpox (USA_2003) at 3.50 and 3.08 log10 pfu/mL; post-treatment titers below detection. - SARS-CoV-2: Plasma and whole blood spiked with 3–4 log10 pfu/mL (USA-WA1/2020); plasma reached detection limit at 60% target UV dose; whole blood showed mean 3.30 log10 reduction; additional studies showed no detectable plaques post-treatment in plasma and platelet products with pretreatment >4.3 log10 pfu/mL. - Preservation of SARS-CoV-2 convalescent plasma function: Neutralizing antibody activity and ELISA reactivities minimally affected after treatment. - Ebola: Riboflavin + UV reduced EBOV to non-detectable in nonhuman primate serum (≥2.8–≥3.2 log reduction) and in human whole blood (≥3.0 log reduction) without reducing protective antibody titers in plasma. - Hepatitis E: Platelets/plasma spiked with HEV genotype 3 (JRC-HE3) and genotype 4 (UA1) showed >3 log and >2 log inactivation, respectively.

- Pathogen Reduction Technology (PRT) with riboflavin + UV is pathogen-agnostic and demonstrated broad efficacy across blood products (plasma, platelets, whole blood) against emerging viral threats. - Mpox: In plasma and whole blood spiked to ~3.50 and 3.08 log10 pfu/mL, post-treatment infectious virus was below the limit of detection. - SARS-CoV-2: In plasma, infectious titers reached the limit of detection at 60% of the target UV dose; in whole blood, average reduction was 3.30 log10. Additional studies confirmed no detectable virus in treated plasma and platelet products with pre-treatment titers >4.3 log10 pfu/mL. - SARS-CoV-2 convalescent plasma: Neutralizing antibody function and spike ELISA signals were minimally affected after PRT, suggesting therapeutic properties are preserved while reducing infectious risk. - Ebola virus: Riboflavin + UV reduced EBOV to non-detectable levels in nonhuman primate serum (≥2.8–≥3.2 log reduction) and human whole blood (≥3.0 log reduction), without decreasing protective antibody titers in plasma. - Hepatitis E virus: Achieved >3 log inactivation for genotype 3 and >2 log for genotype 4 in platelet/plasma contexts. - Clinical impact beyond viruses: In the AIMS randomized trial in a malaria-endemic region, riboflavin + UV treatment of whole blood reduced transfusion-transmitted malaria by 87%. - Public health context: During COVID-19, precautionary donor deferrals and operational changes led to significant blood shortages (e.g., WHO-estimated 20–30% regional reductions; meta-analysis estimated average 38% decrease in donations), highlighting the value of proactive measures like PRT to maintain safety and availability amidst uncertainty.

The findings support PRT as a proactive layer of safety for transfusion medicine, capable of reducing infectious risks from both known and newly emerging pathogens, including when diagnostic testing may lag. The technology has demonstrated efficacy across multiple blood components and pathogens (mpox, SARS-CoV-2, Ebola, HEV) and can preserve the functional integrity of critical therapeutic components such as neutralizing antibodies in convalescent plasma. PRT complements existing donor screening and NAT, potentially narrowing window-period risks and alleviating the need for rapid, repeated introduction of agent-specific tests that may be costly and implemented after transmission has occurred. Experience in countries with national PRT adoption shows reduced bacterial transmission with platelets, and in malaria-endemic settings, whole blood PRT significantly decreased malaria transmission. Nevertheless, PRT is not universally effective against all pathogens to the same degree; performance varies with pathogen properties (e.g., non-enveloped viruses can be more difficult), and rare transmissions have been reported with some PRT technologies. Implementation decisions must weigh epidemiology, transfusion risk, costs, and clinical effectiveness, which vary across regions and over time. Continued technology development, including methods suitable for whole blood componentization and red cell products without toxic compounds, is crucial for broader, universal application.

The paper concludes that ongoing environmental and societal changes will continue to drive emergence of infectious diseases that threaten transfusion safety and availability. Proactive pathogen reduction methods for blood components—already in global use for plasma, platelets, red cells (under development), and whole blood—offer a practical strategy to reduce risks from emerging agents in real time, even before transfusion transmission risk is fully characterized. Evidence shows riboflavin + UV PRT can inactivate mpox, SARS-CoV-2, Ebola virus, and HEV in relevant blood components while preserving therapeutic antibody function in convalescent plasma. Given likely future emergence of pathogens, investment in scalable, cost-effective, and logistically practical PRT solutions for all blood components is prudent. The authors highlight initial clinical experiences suggesting universal component pathogen reduction is feasible and may enhance preparedness and resilience of blood systems.

- PRT methods cannot fully eliminate all infectious risks; efficacy varies by pathogen structural and genetic properties, and rare transmissions have been reported despite PRT with some technologies. - Non-enveloped viruses (e.g., HEV, parvovirus B19) can be more challenging to inactivate completely. - PRT treatment may impact component quality, sometimes necessitating increased transfusion frequency or volume to achieve therapeutic goals. - Cost-effectiveness depends on local epidemiology and system constraints; adding new tests reactively can be costly with low detection yields. - The review relies on published and publicly available data; direct comparative clinical effectiveness across pathogens and components may be limited by heterogeneity of study designs and endpoints.