key: cord-1023773-5spbwhkh authors: Bianchi, Maria; Orlando, Nicoletta; Valentini, Caterina Giovanna; Papacci, Patrizia; Vento, Giovanni; Teofili, Luciana title: Infectious Complications in Neonatal Transfusion: Narrative Review and Personal Contribution date: 2020-09-16 journal: Transfus Apher Sci DOI: 10.1016/j.transci.2020.102951 sha: 2826484ac91eaf30a6db46050abc526788b964a7 doc_id: 1023773 cord_uid: 5spbwhkh Neonates and prematures are among the most transfused categories of patients. Adverse reactions due to transfusions, such as transfusion-transmitted infections, can affect the rest of their lives. In this systematic review, we revised the literature concerning transfusion-transmitted infection in neonates. We reported case-reports and case-series previously published and we integrated these data with our experience at local neonatal intensive care unit. Moreover, we illustrated strategies for mitigating transfusion-transmitted infections, including donor selection and testing, pathogen inactivation technologies and combined approaches, as for Cytomegalovirus infection, integrating leukoreduction and identification of seronegative donors. Neonatal transfusion medicine is a modern discipline presenting many areas of debate. For many aspects, including the indications to transfuse definite blood components (i.e. red blood cell -RBC, platelet, or plasma units), the precise triggers for transfusion, or the strategies to prevent adverse consequences of blood products, there is a great variability across neonatal transfusion guidelines and recommendations from different countries. Noteworthy, neonates, particularly those born before their due date, Nevertheless, for distinct types of pathogens, such as cytomegalovirus (CMV), neonates represent by far the most frequently affected population. In the first part of this review, we summarize the literature reports on transfusiontransmitted infections in neonates (i.e. infant in their first 28 days of life). In the second part, we describe the data gathered on this issue at our neonatology. Finally, we discuss which specific approaches to prevent transfusion-transmitted infections are currently recommended in the neonatal setting, with particular regard to the CMV infection. We performed a systematic search on the databases PubMed using the following studies, case report, case series and reviews. Discrepancies were discussed and resolved together. In total, 275 references were identified on May 2020. In the end, 44 papers were included and discussed in the review (Figure 1) . In Tables 1 and Table 2 we summarized case-reports and case-series of TTI from 1976 to 2018. In Table 1 , we reported CMV infection in neonates undergoing blood transfusions in a wide range of years with different transfusion practices [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] . Transfusions and viral shedding in the milk of seropositive mothers are the two main routes implicated in transmitting post-natal CMV infection. Several papers showed that blood components from CMV-seropositive donors are potentially the major cause of CMV infections in neonates. Testing CMV status of the donor is the most effective strategy in preventing transfusionassociated CMV infection [3] [4] [5] [8] [9] [10] [11] . Moreover, exposing neonates to a low number of donors may be also preventive [2, 6, 8] . Only one paper reported different data but, in this study, infants rarely received more than two transfusions [7] . The role of passive maternal antibody transmission seems to be not protective in preventing CMV infection [1, 4] . Some authors proposed blood components treatments to prevent CMV transmission. In the 80', we reviewed experiences dealing with RBC freezing in a glycerol medium [13, 14] and washing to remove leukocyte [15, 16] . These methods may be considered obsolete. In fact, frozen RBCs need additional technologies, they are expensive and not based on a cost-effectiveness analysis. Washing to remove leukocyte may be easily overcome with last-generation leukoreduction filters. In Table 2 , we reported TTI due to different etiological agents [17] [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] . For hepatitis A, post-transfusion transmission was confirmed in all cases and index patients were also responsible to spread HAV through fecal-oral via causing nosocomial infection in other patients, their parents and personnel [17, [19] [20] 22] . For Hepatitis B and C, asymptomatic or untested donors (i.e. NAT testing not yet available) were responsible for transmission J o u r n a l P r e -p r o o f [21, 27, 28] . Only one TTI HIV infection was reported and it happened at the beginning of the 80's [18] . Some microbes are mainly transmitted by some blood components such as RBC (malaria parasites, Babesia) or platelet concentrates (bacteria) [23] [24] [25] [26] [29] [30] . Records relative to patients admitted at our neonatology department from January Transfusion of blood components is known to carry infectious risks to the recipients. Several actions can be put in place to prevent infections such as careful donor selection and deferral, leukoreduction, implementation of testing and pathogen inactivation. Yersinia species contamination), recent fever and/or respiratory symptoms (for influenza virus, Coronavirus, etc.) or antibiotic treatment [31] . In addition, at the time of collection, health professionals must carefully inspect donor skin to avoid venipuncture in scared skin and, most important, perform diversion of the initial blood (from 10 to 30 mL) after J o u r n a l P r e -p r o o f venipuncture, in a satellite pouch, to avoid bacterial contamination, especially Grampositive organisms [32] . Leukoreduction is the reduction of white blood cell (WBC) concentration in blood components, RBCs, platelet concentrates and plasma obtained from the fractionation of whole blood or apheresis. There are many methods of LR but, currently, this process may be performed using selective last-generation LR filters, which allow obtaining less than one million residual WBCs in an RBC or PC unit. Over the past thirty years, it has been demonstrated that LR can reduce some adverse reactions due to blood component transfusion such as febrile non-hemolytic transfusion reactions, immunization against HLA and HPA antigens, which may cause refractoriness to platelet transfusion, and transmission of CMV [33, 34] . Some early studies demonstrated that both policies, namely the use of CMV seronegative blood components and LR, may be able to determine a significant reduction of CMV infection in high-risk patients. However, controversies concerning "the gold standard" practice (only LR, only CMV-donor status, and LR plus CMV-donor status) are still ongoing [35] [36] [37] . Nowadays, infections still represent a great risk but the epidemiology of TTI is changed over the years. The introduction of NAT testing (Nucleic Acid Amplification) for HIV, HBV and HCV had significantly lowered the residual risk of 1:1 million to 1:10 million, while risk for bacterial contamination is still high (1:2,000 to 1:5,000) in platelet concentrates, with a high rate of fatal sepsis (10%) [38] . Underestimation of these phenomena may be also due to clusters of patients receiving platelet concentrates. Adult and pediatric patients with onco-hematological diseases as well as prematures who easily present sepsis, comorbidities and immune system deficits during the course of their disease often received several platelet transfusions from different donors [38] . In the last years, an important strategy to minimize the risk of TTI is pathogen reduction technologies. These are effective on several well-known viruses as well J o u r n a l P r e -p r o o f emerging viruses, bacteria and protozoa. Different technologies have been developed for acellular (plasma) and cellular blood components (platelet concentrates). Acellular blood components may be inactivated with solvent-detergent (SD) for plasma pool or with methylene blue (MB) for single plasma units. SD plasma is generally performed by pharmaceutical industries using tri(n-butyl) phosphate and octonynol for 1-1.5 hours at +30°C. The main limitation of this method is the lack of efficiency on envelope-free viruses such as Parvovirus B19, Hepatitis A and E. This limit is overcame with additional testing on donors. MB plasma is not indicated for pediatric patients since adverse events were reported, as well as interference with phototherapy treatment [39, 40] . SD or MB method cannot be used for cellular blood components because may be responsible for cellular damages with a consequent effect on transfusion efficacy and risks of adverse events. Gram-negative bacteria are rare and mainly due to asymptomatic bacteremia in blood donors, after red blood cell transfusions or use of blood cell-saver during surgeries [47] . Pathogen inactivation technologies are able to inactivate a wide range of Gram positive (from 3.6 to >6.9 log reduction) and negative bacteria (4.5 to >6.7 log reduction) without compromising platelet functions and reducing residual leukocytes in blood components (INTERCEPT™) as well as they are active on slow-growing bacteria (Mirasol ®) [42] . In terms of safety, some studies reported experiences in pediatric patients. Platelets concentrates treated with INTERCEPT™ system were successfully transfused in 46 neonates (less than 28 days) without any adverse events. Mirasol-platelet concentrates were transfused in 51 children showing no difference in the rate of adverse events when compared to patients no-receiving Mirasol-platelet concentrates. For THERAFLEX® the only concern is on the use of MB in neonates, which can determine, as already described, adverse effects [41] . Notwithstanding the efficacy of leukoreduction in removing residual white blood cells, viral transmission from blood components remains at risk for CMV and donations from CMV sero-positive donors may represent a risk for nonimmune patients. CMV is a worldwide endemic herpesvirus and the prevalence of CMV seronegative individuals varies according age, country and ethnicity [48] . For example, a French study J o u r n a l P r e -p r o o f on general people reported a prevalence of 42% for CMV-IgG antibodies among individuals aged 15-49, with a higher frequency in females than in males [49] . A German study carried out among blood donors showed a seroprevalence of 30% for those aged 18-30, and of 80% for those older than 65 years, with female donors having a 15% higher risk at all ages [50] . Regarding ethnicity, a British study carried out among pregnant females showed a CMV seroprevalence of 49% among White British women, of 89% among South Asian UK born women and of 98% among South Asian women born in South Asia [51] . During the primary infection, CMV replication occurs in several cells including myeloid cells, and is followed by an IgM response. Therefore, viral transmission can occur if the donor is in the window phase [52] . [53] . Indeed, seronegative blood products became the standard to prevent CMV transmission in patients at risk. Since CMV is mainly present in white blood cells, the modern filters for leukodepletion have significantly reduced this risk in cellular products, dropping from 10-59% of fresh blood to 3% or less in leukodepleted products [48] . In 1995, a study of Bowden et al. in HSCT patients, found that leukodepleted blood products reduced the day-21 risk for CMV infection/disease to a similar extent as using blood from CMV-seronegative donors [36] . At a secondary analysis carried out at posttransplant day 100, however, there were fewer CMV infection and disease in the J o u r n a l P r e -p r o o f seronegative arm [36] . At present, it is unknown if testing CMV DNA can further reduce the risk for CMV transmission of leukodepleted blood products. Noteworthy, among 2,400 blood donor samples serially collected at 10-year intervals, CMV DNA was found in 4.3% of samples from donors in their 60s and in 1.0% of samples from donors younger than 60 years, whereas none of the 562 seronegative samples was found DNA positive [54] . Maternal milk transmission seems to be the main responsible for post-natal CMV infection if CMV-seronegative and leukoreduced blood products are used. In a seminal study on 2,061 CMV-seronegative and leukoreduced transfusions to 310 neonates, none of postnatal CMV infection was linked to transfusion, whereas all 28 infants with CMV infection were fed with maternal breast milk from CMV-seropositive mothers [55] . Although theoretically estimated below the threshold of 1 in 1 million [56] , the residual CMVtransmission risk in leukodepleted products has never been evaluated in randomized or even large case-control neonate populations, but only in a pilot study including 20 neonates [57] . In 2005, a meta-analysis of controlled studies available at that time in HSCT patients, indicated that CMV-seronegative blood components are more efficacious than leukodepleted blood components in preventing transfusion-acquired CMV infection [57] . Similarly, our data gathered in neonates not receiving maternal milk suggest that leukoreduction alone might be not sufficient to defeat the risk for transfusion-transmitted CMV infection in fetuses or neonates. Notably, at variance with CMV infection transmitted by fresh maternal milk, which is mild and self-limiting in the majority of patients, 9 out of 10 patients in our series required antiviral therapy [59] . The numerous reports on transfusion-transmitted infections in newborn recipients in the past literature clearly show that blood donor testing has made over years blood neonatal transfusion progressively safer. The implementation of pathogen inactivation in J o u r n a l P r e -p r o o f plasma and platelet units further protects patients from non-screened infectious agents. Unfortunately, however, no similar methodologies are so far available for RBC concentrates. 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A review of the literature and meta-analysis Very low birth weight infants born to cytomegalovirus-seropositive mothers fed with their mother's milk: a prospective study Patogen Outcome Seeberg et al. 1981 Infant 1/ET with blood from four different donors HAV A female baby was the source of the outbreak in a pediatric surgical ward. TTI is associated with a period of viremia and viremia of 25 days before the onset of jaundice.One blood donor was responsible for HAV transmission and he was identified one month after donation. Four infants were transfused with the same packed RBC from a donor unknowingly infected with Babesia microti.Two of the infants developed high-grade of parasitemia.