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This report is being filed to provide additional information in h.6 and h.11.Investigation: an investigation was conducted for a journal article that references terumo bct product.Journal article, titled bacterial contamination rates in extracorporeal photopheresis by pamler et al june 2020 was reviewed with primary purpose of screening for allegations of terumo bct device causing or contributing to death/injury or device malfunctions.Background: extracorporeal photopheresis (ecp) is an immunosuppressive treatment that involves leukocyte apheresis, psoralen and uv light treatment, and subsequent reinfusion.Patients treated with ecp are usually immunosuppressed.Bacterial contamination therefore poses a much unwanted risk, but incidence data are lacking.Patients and methods: we screened all (b)(4) consecutive ecp procedures scheduled within a roughly 3-year period for eligibility.Those with missing data on ecp method (inline or offline) or type of venous access (peripheral or central) were excluded.Ecps with complete aerobic and anaerobic microbial testing of baseline patient blood samples (n = 1637) and of ecp cell concentrates (n = 1814) were included in the analysis.Results: a test for microbial contamination was positive for (b)(4) of the cell concentrates, with central venous access was the most significant risk factor for the contamination (odds ratio = 19).Patient blood samples were positive in (b)(4) of cases, but no patients became septic.Staphylococcus spp.Were most abundant, and products with bacterial contamination did not cause side effects after reinfusion.There were no significant differences in contamination rates between inline and offline ecp.Conclusion: these findings stress the importance of sterile procedures and the benefits of using peripheral over central venous access for reducing the risk of bacterial contamination in ecp.Summary of terumo bct product in relation to the journal article: ecp treatment protocol treatment was carried out as either closed inline or open offline ecp as described above.Closed inline photopheresis can be administered with a single needle and was therefore preferentially but not exclusively used for patients with limited venous access.Other patients received offline ecp.Photopheresis was carried out as described previously.Briefly, standardized open offline ecp and closed inline ecp procedures were used.Open offline ecp was performed with the cobe spectra (cobe, terumo bct), spectra optia (optia, terumo bct) or the amicus (fresenius kabi) device using acid citrate dextrose (acd-a) for anticoagulation.Heparin was additionally used if clotting was observed.Patients received calcium as required.Ecp was delivered via a central or peripheral venous access depending on the condition of the patient's veins.Required connections in open offline ecp were between patient and apheresis tubing set, for sampling and 8-mop application, to the uv irradiation bag, and back to the patient.Transfusion sets with 200 m filters were used for the latter.Closed inline ecp was performed with the uvar xts (therakos).There were no connection steps apart from venous punctuation and sampling with 8-mop addition.Sterility testing blood samples for sterility testing were taken from the peripheral or central venous line before the start of apheresis.Samples from the cell concentrates were taken before 8-mop addition and uv illumination at the bedside, as closed inline ecp does not allow removal of the bag.Treatments and sampling were performed in controlled environment equipped with h13 filtered ventilation.Aerobic and anaerobic culture bottles (bd bactec standard anaerobic/f and aerob/f, respectively) were incubated for 7 days at 30-32c with a sample volume of 3-5 ml and 7-10 ml, respectively.Positive cultures were isolated and differentiated by matrix-assisted laser desorption ionization-time of flight (maldi tof, bruker daltonik gmbh life sciences) mass spectrometry, and antibiotic resistance testing was performed using the bd phoenix system.Results bacterial contamination rate complete information on the ecp method (online or offline), type of vascular access (central or peripheral), and bacterial contamination rate (sterility testing) was available for (b)(4) ecp cell concentrates.We identified a positive microbial test results in a total of (b)(4) ecp cell concentrates (b)(4)).Central venous access, which was required in (b)(4) of the ecp procedures, was more frequently associated with bacterial contamination of ecp cell concentrates ((b)(4) positive) than peripheral access ((b)(4) positive, table 2, (b)(4)).Patient blood samples collected before the start of the procedure were available in (b)(4) cases.From these, (b)(4) tested positive, with significant differences between central and peripheral venous access (table 2, (b)(4)).Overall, we found 73 cases of (b)(4) treatments, in which sterility testing was positive either in cell concentrates and/or patient blood samples.The rate of overlap between procedures with positive ecp cell concentrates and positive patient blood sample was low ((b)(4)).In an additional 10 procedures, only the cell concentrate was positive ((b)(4)), and in another 47 instances, only the patient blood sample was positive ((b)(4)).Patient blood samples had a significantly higher contamination rate than samples from cell concentrates ((b)(4) respectively, (b)(4)).Contamination proportions in patients blood and in cell concentrates were not equally distributed.The frequency of positive samples for patients blood and for cell concentrate samples was unequally distributed (fig.2).Patients with fewer ecp treatments tended to have more frequent unsterile findings.Of note, we did not detect significant differences between inline and offline ecp with regard to bacterial detection rates in ecp cell concentrates or patient blood samples ((b)(4), respectively, table 2).In addition, none of the bacterially contaminated products caused adverse events upon reinfusion.Bacterial species distribution samples testing positive for microbiological contamination exhibited a large and heterogenous variety of germs.The majority of the identified bacteria or fungus belong to the human skin flora, mouth flora, and/or intestinal flora: staphylococcus epidermidis, propionibacterium acnes, acinetobacter iwoffi, actinomyces odontolyticus, staphylococcus capitis, micrococcus luteus, staphylococcus aureus, staphylococcus hominis, citrobacter freundii, candida guilliermondii, enterobacter cloacae, prevotella bivia, haemophilus parainfluenzae, staphylococcus haemolyticus, staphyloccous simulans, staphylococcus lugdunesis, enterococcus faecium, klebsiella pneumoniae, and capnocytophaga ochracea.In addition, some species are environmental bacteria that can be found in soil, air, and/or water: spores, micrococcus luteus, bacillus pumilus (resistant to uv light), candida guilliermondii, enterobacter cloacae, and pseudomonas aeruginos.Interestingly, bacillus altitudinis is a germ which was first isolated from cryogenic tubes used for collecting air samples from high altitudes.Five patient blood samples contained two different bacteria (acinetobacter iwoffii and staphylococcus aureus, staphylococcus aureus and staphylococcus epidermidis, staphylococcus simulans and staphylococcus epidermidis, staphylococcus lugdunensis and staphylococcus capitis, prevotella bivia and haemophilus parainfluenza).In one of these cases, the cell concentrate also tested positive, but only for one bacterial species (prevotella bivia).The distribution of detected bacterial species separated by ecp system type is shown in table 3.Discussion bacterial contamination rates in platelet concentrates from healthy donors reportedly range from (b)(4) the frequency of positive culture tests that failed in confirmation testing is usually higher, i.E., (b)(4).Negative confirmation testing can occur due to inappropriate diagnostic techniques and may reflect contamination with low numbers of bacteria in the inoculum or with bacteria that require special growth conditions.We did not distinguish between these factors and included all positive findings.Thus, the initial positive frequencies are technically closer to those observed in our patients.Bacterial contamination rates in hematopoietic stem cell apheresis range from (b)(4), averaging about (b)(4).Higher frequencies in patients may be caused by additional handling steps during the procedure.These include disinfection as well as the diversion of the first milliliters after venipuncture for predonation sampling which, however, has been shown to substantially decrease the contamination rate.The type of venous access used is another difference between healthy blood donors and patients undergoing apheresis.In our study, a central venous catheter (cvc) was required in (b)(4) of ecp procedures, and cvc use was associated with a 19-fold higher risk for cell concentrate contamination.Though none of the patients became obviously septic at the time of treatment, these findings illustrate the risk of bacteremia in patients with a central venous line.Microbial contamination risk was not evenly distributed among the patients.We found a subgroup of patients with a high frequency of contaminations up to a maximum of (b)(4) of the cell concentrates.Patients with high contamination rates had a comparable low treatment number, e.G., because of uncontrollable grade iv graft-versus-host disease.In addition, central venous catheter contamination contributed to positive findings.Bacterial contamination in these patients indicates therefore at least in part the severity of the underlying disease.We found (b)(4) different bacterial species with staphylococcus spp.Being most abundant.Most of the bacteria we detected were part of human skin flora.These may indicate a contamination by the handling steps.However, these may also indicate that patients for ecp with skin diseases cannot be disinfected successfully with standard procedures.Contamination with the same bacterial type in bag and patient supports this explanation.Per literature review, we found that bacterial contamination affects (b)(4) of the products during pbsc collection and processing.Most of the positive cultures were due to common skin flora or environmental micro-organisms including coagulase-negative staphylococci (48 isolates).At our laboratory, the rate of contamination of autologous pbsc was higher than previously mentioned.Possible reasons for this may be a more sensitive microbiological detection technique, more patients with indwelling catheters, a higher number of previously infected patients and poorer sterile working conditions.(luis larrea, quality control of bacterial contamination in autologous peripheral blood stem cells for transplantation.Haematologica, 2004;89:1234-1235).Per literature review, the incidence of culture-positive hpc(a) products reported in the literature has ranged from (b)(4), with most between (b)(4).The most commonly identified organisms are coagulase-negative staphylococci, followed by other common skin flora and environmental microorganisms (see table 2).(joseph schwartz et al.: mobilization and collection of peripheral blood hematopoietic progenitor cells apheresis: principles and practice, 3rd edition p.499).Per an internal tbct technical report, the phenomenon of bacterial contamination in blood products, especially platelets, is known to occur.With current technologies, given the nature of microorganisms on human skin and the mechanical act of piercing the skin coupled with the fact that platelets must be incubated at room temperature it is not possible to eliminate this phenomenon from occurring.The devices terumo bct manufactures in (b)(6), co, vietnam, costa rica and harmac to collect, separate and store blood products are terminally sterilized to an sal of 1.0 x 10-6.Additionally, a sterility assurance system has been designed and employed to ensure this sal will be achieved for every product manufactured.Therefore, it may be concluded bacterial contamination observed in collected blood products from terumo bct devices is most likely due to the inherit hazard of collecting blood as it relates to bacterial contamination.Since this was a journal publication to assess bacterial contamination rates in extracorporeal photopheresis from (b)(6) 2012 through (b)(6), 2015, the lot numbers were not requested; therefore, a dhr search could not be conducted for this specific incident.All lots must meet acceptance criteria for release.Since this was a journal publication to assess bacterial contamination rates in extracorporeal photopheresis from (b)(6) 2012 through (b)(6) 2015, the lot numbers were not requested; therefore, a disposable lot history search could not be conducted.Root cause: a root cause assessment was performed for the reported microbial contamination.The authors stated that bacterial contamination rates in hematopoietic stem cell apheresis range from (b)(4), averaging about (b)(4).Higher frequencies in patients may be caused by additional handling steps during the procedure.These include disinfection as well as the diversion of the first milliliters after venipuncture for predonation sampling which, however, has been shown to substantially decrease the contamination rate.The type of venous access used is another difference between healthy blood donors and patients undergoing apheresis.In our study, a central venous catheter (cvc) was required in (b)(4) of ecp procedures, and cvc use was associated with a 19-fold higher risk for cell concentrate contamination.Though none of the patients became obviously septic at the time of treatment, these findings illustrate the risk of bacteremia in patients with a central venous line.Patients with high contamination rates had a comparable low treatment number, e.G., because of uncontrollable grade iv graft-versus-host disease.In addition, central venous catheter contamination contributed to positive findings.Bacterial contamination in these patients indicates therefore at least in part the severity of the underlying disease.Most of the bacteria we detected were part of human skin flora.These may indicate a contamination by the handling steps.However, these may also indicate that patients for ecp with skin diseases cannot be disinfected successfully with standard procedures.Contamination with the same bacterial type in bag and patient supports this explanation.In addition, the authors stated that none of the bacterially contaminated products caused adverse events upon reinfusion.The journal did not specify any medical intervention.Citation: pamler, i., richter, e., hutchinson, j.A., h hnel, v., holler, e., gessner, a., burkhardt, r., & ahrens, n.(2020).Bacterial contamination rates in extracorporeal photopheresis.Transfusion, 60(6), 1260 1266.Https://doi.Org/10.1111/trf.15801.
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