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Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018)
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Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018) Impact sur la sécurité transfusionnelle des dernières épidémies d’arboviroses en Polynésie franc¸aise (2012–2018) F. Beau a,∗ , S. Lastère b , H.-P. Mallet a , S. Mauguin c , J. Broult a , S. Laperche d a Centre de transfusion sanguine de Polynésie franc¸aise, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, BP 4530, 98713 Papeete, Tahiti, French Polynesia b Laboratoire de biologie, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, Tahiti, French Polynesia c Unité d’hémovigilance, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, Tahiti, French Polynesia d Institut national de la transfusion sanguine, département des agents transmissibles par le sang, centre national de référence risques infectieux transfusionnels, Paris, France
a r t i c l e
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Article history: Available online xxx Keywords: Arboviruses French Polynesia Blood donors Nucleic acid testing Pathogen reduction
a b s t r a c t Background. – Several successive arbovirus outbreaks have affected French Polynesia (FP) in the recent past years due to different dengue serotypes (DENV) present for several decades, Zika (ZIKV) (2013–2014) and chikungunya (CHIKV) (2014–2015) viruses with a potential impact on blood safety and blood supply due to the geographical isolation of these islands. This study reports an assessment of the impact of these outbreaks on blood products supply and infectious safety in FP and discuss the effectiveness of implemented preventive measures. Methods. – To ensure the infectious safety of blood products during outbreaks, several measures have successively been introduced as the selection of donors suspected of infection, the nucleic acid testing (NAT) and the pathogen reduction of platelets and plasmas. Results. – The donor deferral rate increased by 6% between 2012 and 2014 without changes in the number of collected donations. NAT excluded five blood donations reactive for DENV RNA, 42 for ZIKV and 34 for CHIKV. As Zika screening could not been implemented before the third month of the outbreak, 36 blood products from ZIKV-infected donors were transfused to 26 recipients. However, no transfusiontransmitted arbovirus has been reported. Conclusion. – The last past arboviruses outbreaks did not have a significant impact on blood supply in FP. The measures introduced to prevent arbovirus transmission by transfusion were able to maintain infectious safety for all blood products without impairing self-sufficiency. ´ e´ franc¸aise de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights © 2019 Societ reserved.
r é s u m é Mots clés : Arbovirus Polynésie franc¸aise Donneurs de sang Dépistage génomique viral Atténuation des pathogènes
Objectifs. – Plusieurs épidémies successives d’arbovirus ont affecté la Polynésie Franc¸aise (PF) ces dernières années : les quatre sérotypes de dengue (DENV) présents depuis plusieurs décennies, les virus Zika (ZIKV) (2013–2014) et chikungunya (CHIKV) (2014–2015) avec un impact potentiel sur la sécurité transfusionnelle et l’approvisionnement en produits sanguins lié à l’isolement géographique de ces îles. Cette étude présente une évaluation de l’impact de ces épidémies sur l’approvisionnement et la sécurité infectieuse des produits sanguins en PF, et discute l’efficacité des mesures préventives adoptées.
∗ Corresponding author. E-mail address: [email protected] (F. Beau). https://doi.org/10.1016/j.tracli.2019.12.001 ´ e´ franc¸aise de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved. 1246-7820/© 2019 Societ
Please cite this article in press as: Beau F, et al. Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018). Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.12.001
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Méthodes. – Pour assurer la sécurité infectieuse des produits sanguins lors d’épidémies, plusieurs mesures ont été successivement introduites : la sélection des donneurs suspects d’infection, le dépistage génomique viral (DGV) et l’inactivation des pathogènes des plaquettes et du plasma. Résultats. – Le taux d’exclusion des donneurs a augmenté de 6 % entre 2012 et 2014, sans diminution du nombre de dons recueillis. Le DGV a permis d’exclure cinq dons de sang réactifs pour l’ARN du DENV, 42 pour ZIKV et 34 pour CHIKV. 36 produits sanguins issus de donneurs infectés par le ZIKV ont été transfusés à 26 receveurs du fait d’un dépistage instauré au troisième mois de l’épidémie. Cependant, aucune transmission d’arbovirus par voie transfusionnelle n’a été constatée. Conclusion. – Les dernières épidémies d’arbovirus n’ont pas eu d’impact significatif sur l’approvisionnement en sang de la PF. Les mesures mises en place pour prévenir la transmission des arbovirus par transfusion ont permis de maintenir la sécurité infectieuse pour tous les produits sanguins sans affecter l’autosuffisance. ´ e´ franc¸aise de transfusion sanguine (SFTS). Publie´ par Elsevier Masson SAS. Tous droits © 2019 Societ ´ ´ reserv es.
1. Introduction French Polynesia (FP) is an overseas territory located in the South Pacific with 118 geographically scattered islands and 275,918 inhabitants (census 2017). FP has a large autonomy, particularly in the field of health, and blood transfusion activities are under territory’s jurisdiction with however regulatory rules derived to those adopted in mainland France. The French Polynesia Blood Bank (FPBB) ensures the entire blood supply of FP for labile blood products (LBP). Blood donations are only collected in the two main islands: Tahiti and Moorea. In 2018, 6219 blood donations were collected leading to the production of 5615 red blood cells units (RBCs), 998 therapeutic plasmas prepared either from whole blood (67%) or apheresis (33%), and 590 platelets concentrates mainly prepared from whole blood (93%), apheresis (7%). In the context of arbovirus (arthropod-borne virus) infection epidemic waves that regularly affect the FP archipelagos, the FPBB must face the blood supply challenge in this tropical and isolated environment with a scattered population, In the last past years, several arbovirus outbreaks have affected FP due to the presence of at least two mosquito species competent for arboviruses: Aedes aegypti and Aedes polynesiensis [1–7]. Dengue virus (DENV) is present in FP since several decades [1–4] and more recently Zika virus (ZIKV) (2013–2014) [5] and chikungunya virus (CHIKV) (2014–2015) [6] infections emerged. Dengue virus has been present for a long time in FP and was the only arbovirus reported in French Polynesia until the recent emergence of CHIK and ZIKV [7,8]. DENV was responsible for successive outbreaks of variable intensities involving the four serotypes, a new serotype, mostly coming from southeast Asia, Pacific area country or tropical America, replacing the previous one [1–4,7]. In 2013, the outbreak involved DENV-3 associated with DENV-1 [4,5]. Serotype 1 appears rooted since 2001 with permanent circulation and epidemic peaks in 2006 and 2013 [1,2,4]. The seroprevalence surveys reported more than 80% of anti-dengue antibodies rate in the general population, mainly directed against DENV-1, with an estimated proportion of asymptomatic cases of 51% [8,9]. In October 2013, for the first time, a new arbovirus infection due to ZIKV, has been identified as circulating in FP. Although the origin of this viral emergence remains nowadays unknown, it has been shown that strains were phylogenetically close to those isolated in Yap Island in 2007 and in Cambodia in 2010 [5]. The epidemic lasted 6 months, from October 2013 to March 2014 with a peak at week 9. The estimated attack rate of symptomatic cases ranged from 34 to 46% and about 50% of infections were estimated to be asymptomatic [10]. Although the majority of patients showed mild clinical symptoms, severe forms have been described, such as Guillain-Barré syndrome [11].
The following outbreak due to CHIKV, was observed between October 2014 and March 2015. The virus belonged to the Asian lineage present in the Caribbean area since late 2013 [6]. The number of symptomatic cases was estimated at 68,000, but the attack rate was probably higher. The post-epidemic seroprevalence survey performed in 2015, showed that 76% of the population had anti-chikungunya antibodies [9]. Although the number of blood transfusion-transmitted arboviruses reported worldwide is low compared to those from mosquitoes-bite, arboviruses are at risk for transfusion transmission due to a viraemic phase before symptoms onset, the frequency of asymptomatic forms and the high infection rates observed during outbreaks [12]. The objective of this study was to describe in detail the preventive measures introduced to avoid the transmission of these arboviruses by blood transfusion and to assess the impact of epidemics on blood supply in FP. 2. Methods 2.1. Measures ensuring blood safety 2.1.1. Pre-donation interview and post-donation information Donor selection targeted on exposed subjects is not feasible in a region of active viral circulation. Thus, during the pre-donation interview, the donors with a recent history of arbovirus or “dengue like syndrome” were deferred for a 28-days period after resolution of symptoms. The donors were also encouraged to report any fever or clinical symptoms suggesting arbovirus infection within 15 days after blood donation allowing to destroy LBP prepared from a donor disclosing a suspicious infection. Furthermore, NAT positive donors were called by phone by the FPBB to collect information on the occurrence of post-donation clinical symptoms with the date of onset. 2.1.2. Nucleic acid testing Since 2013, nucleic acid testing (NAT) was introduced whenever an arboviral epidemic occurred. All blood donations were screened over the course of the epidemic in minipools of 10 by the FP hospital center laboratory, with subsequent individual testing when a pool resulted positive. RealStar® dengue RT-PCR assay 2.0 (Altona diagnostics, Hamburg, Germany) was introduced in April 2013 for DENV, and RealStar® chikungunya RT-PCR assay 1.0 then 2.0 (Altona diagnostics) was used from October 2014 to the end of April 2015 (namely one month after the end of the epidemic) for CHIKV. As no licensed assay was available, a ZIKV-NAT based on an inhouse assay developed at the Louis Malarde Institute (Papeete, FP)
Please cite this article in press as: Beau F, et al. Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018). Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.12.001
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was introduced in minipools of 3 samples, on January 13, 2014 (i.e. 12 weeks after the beginning of Zika epidemic) and stopped early May 2014 [13,14]. An additional retrospective NAT screening of blood donations collected between November 21, 2013 and January 2014 was carried out in order to ensure safety of RBCs in stock. 2.1.3. Pathogen reduction of blood products All plasmas and platelets concentrates produced by FPBB are treated with amotosalen (INTERCEPTTM Cerus Corporation, Concord, CA, USA) according to the manufacturer’s instructions. This pathogen reduction method has been reported effective to inactivate a very large number of pathogens, including arboviruses [15,16]. Started in 2010 for platelets, pathogen reduction was introduced for fresh frozen plasmas in April 2015. Before and during the ZIKV and CHIKV outbreaks, the FPBB imported all plasmas from mainland France (Établissement Franc¸ais du Sang of Aquitaine Region). 2.1.4. Lookback investigations According to the haemovigilance reporting system in place in FP, the adverse events occurring in transfused patients are subject to specific investigations including interview and clinical examination of recipients and, in case of transfusion with arbovirus contaminated LBP, the serological testing on pre- and post-transfusion blood samples when available [14,17]. This latter case only occurred during the ZIKV epidemic, and the detection of immunoglobulin G class (IgG) antibodies against ZIKV was performed by the Louis Malardé Institute, according to a protocol previously described [8]. The ZIKV molecular testing was not performed for the recipients because they were sampled more than 10 weeks after the contaminated transfusion, which exceeded the ZIKV estimated viraemia duration. 2.2. Impact on blood supply The impact of arboviruses outbreaks on blood supply was assessed on the basis of changes in the number of donations, the proportion and causes of deferral, and LBP distribution activity, over five consecutive years, from 2012 to 2016. The FPBB activity parameters were retrieved from the INLOG database CTS server software.6.6.6.1.2. 3. Results 3.1. Impact on blood safety 3.1.1. NAT results From April 15, 2013 to December 31, 2018 five (0.015%) of the 34,000 blood donations tested for DENV RNA were positive (1/6800 donations). From November 21, 2013 to May 2, 2014, among the 1505 donations tested for ZIKV RNA, 42 donors (2.80%) (1/36 donations) were positive, of which seven donors reported post-donation symptoms between three and 10 days after donation. From October 13, 2014 to April 30, 2015, during the CHIKV outbreak, 3433 blood donations were tested, of which 34 (0.99%) were positive (1/101 donations). Among the 34 positive cases, nine were asymptomatic (26%) and six called back spontaneously after donation for symptoms (17.6%). 3.1.2. Lookback investigations To date, there is no reported DENV or CHIKV transfusion-related infection in FP. For ZIKV, the retrospective screening showed that some LBP from infected patients had been transfused: 30 RBCs and six platelets concentrates were transfused to 26 patients: 23
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received a single RBCs (associated with two and four platelets concentrates respectively for two of them), 2 received two RBCs and 1 three RBCs. A post-transfusion investigation could be conducted in 12 patients. The time between transfusion and screening for ZIKV antibodies ranged from 10 to 35 weeks (median value 16 weeks post-transfusion). No clinical or serological ZIKV infection has been evidenced for these patients. 3.2. Impact on blood supply As shown in Fig. 1, the number of donations and distributed RBCs during the ZIKV and CHIKV outbreaks did not decrease compared to the previous year. However, the donor deferral rate increased by 6% between 2012 and 2014 (Fig. 1). During the CHIKV outbreak (October, 2014 to March, 2015), the main cause of deferral was an arbovirus infection history within the 28 days before donation (Fig. 2). The Table 1 summarizes feature and impact of epidemics in FP for the three viruses. 4. Discussion The intense circulation of several arboviruses during the last years in French Polynesia raised questions on the safety of blood transfusions but also on sustainability of the blood supply. Indeed, the loss of blood components cannot be easily compensated by external supplies due to the geographical isolation of Polynesian Islands. Unexpectedly, the number of donations and distributed LBP did not decrease during the last arboviruses outbreaks, contrarily of what has been previously reported in Europe [18]. In order to limit the blood shortage, the 6% increase in the donor deferral rate observed between 2012 and 2014 (Fig. 1) was offset by increased blood donation campaigns and efforts to recruit donors. The deferral rate was higher during CHIKV than during the ZIKV outbreak (Fig. 2), certainly due to a higher proportion of symptomatic cases. On the other hand, the CHIKV epidemic has also led to a high rate of staff absenteeism, with an average of 38 days of illness per month, compared to 25 days in non-epidemic periods. Despite this obstacle, the FPBB remained operational. Thanks to the general and specific measures that have been successively taken in our geographical area, the blood safety related to arbovirus infections has been ensured throughout the entire periods of outbreaks. Firstly, the territory health authorities introduced general vector control measures to reduce sources of mosquito breeding as soon as the epidemic was identified [2]. Then, specific blood safety measures have been introduced including a pre-donation interview and a clinical examination focused on arbovirus infections. Moreover, donors were systematically encouraged to provide post-donation information, although the effectiveness of such measures could be hampered by a high proportion of asymptomatic cases estimated in FP around 50% for DENV and ZIKV, and 15% for CHIKV infections [9,10]. In our experience only seven (16.7%) and six (17.6%) post-donation calls were recorded among donors with a NAT positive for ZIKV and CHIKV, respectively. The detection of viral RNA, described as an effective measure in the absence of clinical symptoms [19], was performed in minipools to reduce the cost of screening, even though it has been reported that NAT sensitivity decreases when samples are tested in pools [12,15]. Despite this limitation, DENV NAT has reduced the risk of DENV transmission by blood transfusion and the residual risk was
Please cite this article in press as: Beau F, et al. Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018). Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.12.001
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Fig. 1. Numbers of blood donations collected (black bars) and red blood cells (RBCs) distributed (grey bars) per quarter, percentages of quarterly (solid curve) and annual (dotted curve) deferred donations. French Polynesia Blood Bank (FPBB), 2012 to 2016.
Fig. 2. Percentages per month of deferred blood donations with a history of arboviral infection less than 28 days old (solid curve) and all causes combined (dotted curve). French Polynesia Blood Bank (FPBB), 2012 to 2016. Table 1 Characteristics and impact of arbovirus-related epidemics in French Polynesia since 2013. Arbovirus
Dengue virus
Zika virus
Chikungunya virus
Post-epidemic seroprevalence in overall population (2014–2015) [9,10] Proportion of asymptomatic cases [9,10] Period of NAT screening
83 ± 3%
49 ± 7%
76 ± 5%
50–80% 04.15.2013 to present
15% 10.13.2014 to 04.30.2015
Number of NAT tested donations Number of NAT positive donations Impact on blood supply
34,000 (at 12.31.18) 5 (0.015%) None
50–80% 11.21.2013 to 05.02.2014 retrospectively: 11.21.13 to 01.12.14 1505 42 (2.80%) None
Transfusion of contaminated blood products
None
Transfusion-transmitted infection in FP
None
Yes 36 blood products 26 recipients None
3433 34 (0.99%) Increase in the proportion of deferred donations None
None
NAT: nucleic acid testing; FP: French Polynesia.
estimated at 1/260,000 donations for the 2014–2016 period, i.e. one contaminated donation for approximately 40 years of FPBB activity [20]. The availability of a specific molecular assay that can be quickly applied in blood services in case of outbreak is the main obstacle
of NAT introduction. The delay in NAT implementation during the ZIKV outbreak due to the lack of licensed assay, led to the entry of contaminated donations into the transfusion chain [13,14,17]. In contrast, the early introduction of CHIKV NAT allowed to rule out 34 donations from infected donors.
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Compared to other French overseas territories that have recently experienced arboviruses outbreaks, the proportion of positive RNA donations detected by CHIKV and ZIKV-NAT was slightly higher in FP. Among the blood donations, 1.84% were positive for ZIKV during the epidemic in Martinique Island vs 2.80% in FP [21]. For CHIKV, respectively 0.36% and 0.42% donations were positive in Guadeloupe and Martinique vs 0.99% in FP [22]. These results should be interpreted with regard to the length of the screening period and the overall attack rate. This latter parameter was higher for the both viruses in FP than in the French West Indies, as confirmed by post-epidemic seroprevalence data: respectively for ZIKV 49% vs 42% in Martinique and for CHIKV 76% vs 60% in Martinique and Guadeloupe [9,10,23]. The introduction of pathogen reduction for platelets and plasma as an effective method to prevent transmitted-transfusion of DENV, CHIKV and ZIKV [15,16], completed the set of safety measures. Pathogen reduction is of great interest in FP, which is endemic area regularly affected by arboviruses outbreaks. However, this technology is not yet currently approved for use with RBCs, which are the main transfused LBP (80%). Due to the existence of an asymptomatic viraemic period and frequent asymptomatic forms, arboviruses meet the criteria for transmitted-transfusion agent as defined by the American Association of Blood Banks in 2009 [15,24]. However, reported transfusion transmission cases are limited and only described for DENV, West Nile virus, tick-borne encephalitis virus, Colorado tick fever virus and Ross river virus [12,25–27] and more recently for ZIKV during the epidemic in Brazil [28,29]. In our experience, no cases of DENV, CHIKV or ZIKV transmission by transfusion have been reported during the FP outbreaks. Nevertheless, only 12 of 26 patients that were transfused with LBP contaminated with ZIKV could be investigated after the transfusion [14,17]. Furthermore, the high rate of asymptomatic cases and the possible lack of sensitivity of the ZIKV antibodies detection test have been the main limitations to confirm transfusion-related ZIKV infection in our post-transfusion investigations [14,17]. Regarding the specificity of the ZIKV serological assay, in our experience the recombinant antigen used for the ZIKV ELISA serology did not present a DENV-ZIKV cross-reaction. A previous seroprevalence survey conducted in FP blood donor population with the same serological test during the 2011–2013 period (before the ZIKV epidemic) only reported 0.8% ZIKV IgG versus 80.3% DENV IgG [8]. Moreover, in our lookback investigations, only 3 out of 12 recipients were seropositive for ZIKV [14,17]. These proportions should have been higher in the case of DENV-ZIKV cross-reaction. For CHIKV, all contaminated LBP has been screened by NAT and removed from transfusion chain. The high immunization level against DENV observed in the adult population [8,9] and the well-demonstrated effectiveness of mitigation by pathogen reduction method used for platelets and plasma [15,16], probably explain the absence of transfusion-transmitted DENV in FP despite long and sustained circulation among the population and the frequency of outbreaks. However, the prevalence of antibodies varied with serotypes and ranged from 88% (DENV-1) to 51% (DENV-2). Regarding to this latter serotype, which is responsible for the current new epidemic, the transfusion transmission cannot be excluded in the non-immune population.
5. Conclusion The arboviral threat currently exists in French Polynesia. During the redaction of this article, a new DENV epidemic occurred related to DENV-2, which reemerged in March 2019 after more than 20 years of silence.
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The combined preventive measures led to limit the risk of transmission of arboviruses by transfusion without impairing the blood supply during epidemics thanks to efforts made to maintain a sufficient number of blood donations. However, the emergence of an unexpected virus such as ZIKV, highlighted the limit of preventive strategies. Indeed, the delayed implementation of NAT due to the initial unavailability of assay led to transfuse contaminated LBP. Moreover, in case of co-circulation of several arboviruses, as recently occurred in FP [4,5,7], the specific NAT assays have to be added, making the donation testing process cumbersome, until automated multiplex NAT techniques become available. Several studies have proposed a targeted implementation of arbovirus NAT according to the local epidemiological situation in order to optimize screening costs [12,15,19,30]. A reliable strategy could consist to define an incidence threshold in the general FP population at which arbovirus-specific NAT would be implemented [20]. For DENV systematically screened in FP blood donors, the trigger strategy could be used to switch from minipool to individual-donation testing during times of increased transfusion transmission risk (indicated by detection of minipool DENV positive donations and/or an increased incidence of DENV cases in the general population) as applied for West Nile virus in the USA or more recently recommended by the FDA for ZIKV [12,31]. Another affordable strategy would be to reserve arbovirus-free tested LBP for “at risk” considered patients. In the future, if pathogen reduction technologies able to inactivate infectious agents in RBCs components become available and approved, a new approach without arbovirus NAT screening (or at least the adoption of a pool strategy detecting high viral loads that could escape to the inactivation process) could be proposed [19,30]. Every scenario should be considered to maintain blood collections consistent with the LBP needs in FP, even if past outbreaks did not have a significant impact on the blood supply. To date, the measures introduced to prevent arboviruses transmission by transfusion have made it possible to maintain infectious safety for all blood products without impairing self-sufficiency of this territory.
Disclosure of interest The authors declare that they have no competing interest.
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Original article
Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018) Impact sur la sécurité transfusionnelle des dernières épidémies d’arboviroses en Polynésie franc¸aise (2012–2018) F. Beau a,∗ , S. Lastère b , H.-P. Mallet a , S. Mauguin c , J. Broult a , S. Laperche d a Centre de transfusion sanguine de Polynésie franc¸aise, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, BP 4530, 98713 Papeete, Tahiti, French Polynesia b Laboratoire de biologie, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, Tahiti, French Polynesia c Unité d’hémovigilance, hôpital du Taaone, centre hospitalier de Polynésie franc¸aise, Pirae, Tahiti, French Polynesia d Institut national de la transfusion sanguine, département des agents transmissibles par le sang, centre national de référence risques infectieux transfusionnels, Paris, France
a r t i c l e
i n f o
Article history: Available online xxx Keywords: Arboviruses French Polynesia Blood donors Nucleic acid testing Pathogen reduction
a b s t r a c t Background. – Several successive arbovirus outbreaks have affected French Polynesia (FP) in the recent past years due to different dengue serotypes (DENV) present for several decades, Zika (ZIKV) (2013–2014) and chikungunya (CHIKV) (2014–2015) viruses with a potential impact on blood safety and blood supply due to the geographical isolation of these islands. This study reports an assessment of the impact of these outbreaks on blood products supply and infectious safety in FP and discuss the effectiveness of implemented preventive measures. Methods. – To ensure the infectious safety of blood products during outbreaks, several measures have successively been introduced as the selection of donors suspected of infection, the nucleic acid testing (NAT) and the pathogen reduction of platelets and plasmas. Results. – The donor deferral rate increased by 6% between 2012 and 2014 without changes in the number of collected donations. NAT excluded five blood donations reactive for DENV RNA, 42 for ZIKV and 34 for CHIKV. As Zika screening could not been implemented before the third month of the outbreak, 36 blood products from ZIKV-infected donors were transfused to 26 recipients. However, no transfusiontransmitted arbovirus has been reported. Conclusion. – The last past arboviruses outbreaks did not have a significant impact on blood supply in FP. The measures introduced to prevent arbovirus transmission by transfusion were able to maintain infectious safety for all blood products without impairing self-sufficiency. ´ e´ franc¸aise de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights © 2019 Societ reserved.
r é s u m é Mots clés : Arbovirus Polynésie franc¸aise Donneurs de sang Dépistage génomique viral Atténuation des pathogènes
Objectifs. – Plusieurs épidémies successives d’arbovirus ont affecté la Polynésie Franc¸aise (PF) ces dernières années : les quatre sérotypes de dengue (DENV) présents depuis plusieurs décennies, les virus Zika (ZIKV) (2013–2014) et chikungunya (CHIKV) (2014–2015) avec un impact potentiel sur la sécurité transfusionnelle et l’approvisionnement en produits sanguins lié à l’isolement géographique de ces îles. Cette étude présente une évaluation de l’impact de ces épidémies sur l’approvisionnement et la sécurité infectieuse des produits sanguins en PF, et discute l’efficacité des mesures préventives adoptées.
∗ Corresponding author. E-mail address: [email protected] (F. Beau). https://doi.org/10.1016/j.tracli.2019.12.001 ´ e´ franc¸aise de transfusion sanguine (SFTS). Published by Elsevier Masson SAS. All rights reserved. 1246-7820/© 2019 Societ
Please cite this article in press as: Beau F, et al. Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018). Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.12.001
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Méthodes. – Pour assurer la sécurité infectieuse des produits sanguins lors d’épidémies, plusieurs mesures ont été successivement introduites : la sélection des donneurs suspects d’infection, le dépistage génomique viral (DGV) et l’inactivation des pathogènes des plaquettes et du plasma. Résultats. – Le taux d’exclusion des donneurs a augmenté de 6 % entre 2012 et 2014, sans diminution du nombre de dons recueillis. Le DGV a permis d’exclure cinq dons de sang réactifs pour l’ARN du DENV, 42 pour ZIKV et 34 pour CHIKV. 36 produits sanguins issus de donneurs infectés par le ZIKV ont été transfusés à 26 receveurs du fait d’un dépistage instauré au troisième mois de l’épidémie. Cependant, aucune transmission d’arbovirus par voie transfusionnelle n’a été constatée. Conclusion. – Les dernières épidémies d’arbovirus n’ont pas eu d’impact significatif sur l’approvisionnement en sang de la PF. Les mesures mises en place pour prévenir la transmission des arbovirus par transfusion ont permis de maintenir la sécurité infectieuse pour tous les produits sanguins sans affecter l’autosuffisance. ´ e´ franc¸aise de transfusion sanguine (SFTS). Publie´ par Elsevier Masson SAS. Tous droits © 2019 Societ ´ ´ reserv es.
1. Introduction French Polynesia (FP) is an overseas territory located in the South Pacific with 118 geographically scattered islands and 275,918 inhabitants (census 2017). FP has a large autonomy, particularly in the field of health, and blood transfusion activities are under territory’s jurisdiction with however regulatory rules derived to those adopted in mainland France. The French Polynesia Blood Bank (FPBB) ensures the entire blood supply of FP for labile blood products (LBP). Blood donations are only collected in the two main islands: Tahiti and Moorea. In 2018, 6219 blood donations were collected leading to the production of 5615 red blood cells units (RBCs), 998 therapeutic plasmas prepared either from whole blood (67%) or apheresis (33%), and 590 platelets concentrates mainly prepared from whole blood (93%), apheresis (7%). In the context of arbovirus (arthropod-borne virus) infection epidemic waves that regularly affect the FP archipelagos, the FPBB must face the blood supply challenge in this tropical and isolated environment with a scattered population, In the last past years, several arbovirus outbreaks have affected FP due to the presence of at least two mosquito species competent for arboviruses: Aedes aegypti and Aedes polynesiensis [1–7]. Dengue virus (DENV) is present in FP since several decades [1–4] and more recently Zika virus (ZIKV) (2013–2014) [5] and chikungunya virus (CHIKV) (2014–2015) [6] infections emerged. Dengue virus has been present for a long time in FP and was the only arbovirus reported in French Polynesia until the recent emergence of CHIK and ZIKV [7,8]. DENV was responsible for successive outbreaks of variable intensities involving the four serotypes, a new serotype, mostly coming from southeast Asia, Pacific area country or tropical America, replacing the previous one [1–4,7]. In 2013, the outbreak involved DENV-3 associated with DENV-1 [4,5]. Serotype 1 appears rooted since 2001 with permanent circulation and epidemic peaks in 2006 and 2013 [1,2,4]. The seroprevalence surveys reported more than 80% of anti-dengue antibodies rate in the general population, mainly directed against DENV-1, with an estimated proportion of asymptomatic cases of 51% [8,9]. In October 2013, for the first time, a new arbovirus infection due to ZIKV, has been identified as circulating in FP. Although the origin of this viral emergence remains nowadays unknown, it has been shown that strains were phylogenetically close to those isolated in Yap Island in 2007 and in Cambodia in 2010 [5]. The epidemic lasted 6 months, from October 2013 to March 2014 with a peak at week 9. The estimated attack rate of symptomatic cases ranged from 34 to 46% and about 50% of infections were estimated to be asymptomatic [10]. Although the majority of patients showed mild clinical symptoms, severe forms have been described, such as Guillain-Barré syndrome [11].
The following outbreak due to CHIKV, was observed between October 2014 and March 2015. The virus belonged to the Asian lineage present in the Caribbean area since late 2013 [6]. The number of symptomatic cases was estimated at 68,000, but the attack rate was probably higher. The post-epidemic seroprevalence survey performed in 2015, showed that 76% of the population had anti-chikungunya antibodies [9]. Although the number of blood transfusion-transmitted arboviruses reported worldwide is low compared to those from mosquitoes-bite, arboviruses are at risk for transfusion transmission due to a viraemic phase before symptoms onset, the frequency of asymptomatic forms and the high infection rates observed during outbreaks [12]. The objective of this study was to describe in detail the preventive measures introduced to avoid the transmission of these arboviruses by blood transfusion and to assess the impact of epidemics on blood supply in FP. 2. Methods 2.1. Measures ensuring blood safety 2.1.1. Pre-donation interview and post-donation information Donor selection targeted on exposed subjects is not feasible in a region of active viral circulation. Thus, during the pre-donation interview, the donors with a recent history of arbovirus or “dengue like syndrome” were deferred for a 28-days period after resolution of symptoms. The donors were also encouraged to report any fever or clinical symptoms suggesting arbovirus infection within 15 days after blood donation allowing to destroy LBP prepared from a donor disclosing a suspicious infection. Furthermore, NAT positive donors were called by phone by the FPBB to collect information on the occurrence of post-donation clinical symptoms with the date of onset. 2.1.2. Nucleic acid testing Since 2013, nucleic acid testing (NAT) was introduced whenever an arboviral epidemic occurred. All blood donations were screened over the course of the epidemic in minipools of 10 by the FP hospital center laboratory, with subsequent individual testing when a pool resulted positive. RealStar® dengue RT-PCR assay 2.0 (Altona diagnostics, Hamburg, Germany) was introduced in April 2013 for DENV, and RealStar® chikungunya RT-PCR assay 1.0 then 2.0 (Altona diagnostics) was used from October 2014 to the end of April 2015 (namely one month after the end of the epidemic) for CHIKV. As no licensed assay was available, a ZIKV-NAT based on an inhouse assay developed at the Louis Malarde Institute (Papeete, FP)
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was introduced in minipools of 3 samples, on January 13, 2014 (i.e. 12 weeks after the beginning of Zika epidemic) and stopped early May 2014 [13,14]. An additional retrospective NAT screening of blood donations collected between November 21, 2013 and January 2014 was carried out in order to ensure safety of RBCs in stock. 2.1.3. Pathogen reduction of blood products All plasmas and platelets concentrates produced by FPBB are treated with amotosalen (INTERCEPTTM Cerus Corporation, Concord, CA, USA) according to the manufacturer’s instructions. This pathogen reduction method has been reported effective to inactivate a very large number of pathogens, including arboviruses [15,16]. Started in 2010 for platelets, pathogen reduction was introduced for fresh frozen plasmas in April 2015. Before and during the ZIKV and CHIKV outbreaks, the FPBB imported all plasmas from mainland France (Établissement Franc¸ais du Sang of Aquitaine Region). 2.1.4. Lookback investigations According to the haemovigilance reporting system in place in FP, the adverse events occurring in transfused patients are subject to specific investigations including interview and clinical examination of recipients and, in case of transfusion with arbovirus contaminated LBP, the serological testing on pre- and post-transfusion blood samples when available [14,17]. This latter case only occurred during the ZIKV epidemic, and the detection of immunoglobulin G class (IgG) antibodies against ZIKV was performed by the Louis Malardé Institute, according to a protocol previously described [8]. The ZIKV molecular testing was not performed for the recipients because they were sampled more than 10 weeks after the contaminated transfusion, which exceeded the ZIKV estimated viraemia duration. 2.2. Impact on blood supply The impact of arboviruses outbreaks on blood supply was assessed on the basis of changes in the number of donations, the proportion and causes of deferral, and LBP distribution activity, over five consecutive years, from 2012 to 2016. The FPBB activity parameters were retrieved from the INLOG database CTS server software.6.6.6.1.2. 3. Results 3.1. Impact on blood safety 3.1.1. NAT results From April 15, 2013 to December 31, 2018 five (0.015%) of the 34,000 blood donations tested for DENV RNA were positive (1/6800 donations). From November 21, 2013 to May 2, 2014, among the 1505 donations tested for ZIKV RNA, 42 donors (2.80%) (1/36 donations) were positive, of which seven donors reported post-donation symptoms between three and 10 days after donation. From October 13, 2014 to April 30, 2015, during the CHIKV outbreak, 3433 blood donations were tested, of which 34 (0.99%) were positive (1/101 donations). Among the 34 positive cases, nine were asymptomatic (26%) and six called back spontaneously after donation for symptoms (17.6%). 3.1.2. Lookback investigations To date, there is no reported DENV or CHIKV transfusion-related infection in FP. For ZIKV, the retrospective screening showed that some LBP from infected patients had been transfused: 30 RBCs and six platelets concentrates were transfused to 26 patients: 23
3
received a single RBCs (associated with two and four platelets concentrates respectively for two of them), 2 received two RBCs and 1 three RBCs. A post-transfusion investigation could be conducted in 12 patients. The time between transfusion and screening for ZIKV antibodies ranged from 10 to 35 weeks (median value 16 weeks post-transfusion). No clinical or serological ZIKV infection has been evidenced for these patients. 3.2. Impact on blood supply As shown in Fig. 1, the number of donations and distributed RBCs during the ZIKV and CHIKV outbreaks did not decrease compared to the previous year. However, the donor deferral rate increased by 6% between 2012 and 2014 (Fig. 1). During the CHIKV outbreak (October, 2014 to March, 2015), the main cause of deferral was an arbovirus infection history within the 28 days before donation (Fig. 2). The Table 1 summarizes feature and impact of epidemics in FP for the three viruses. 4. Discussion The intense circulation of several arboviruses during the last years in French Polynesia raised questions on the safety of blood transfusions but also on sustainability of the blood supply. Indeed, the loss of blood components cannot be easily compensated by external supplies due to the geographical isolation of Polynesian Islands. Unexpectedly, the number of donations and distributed LBP did not decrease during the last arboviruses outbreaks, contrarily of what has been previously reported in Europe [18]. In order to limit the blood shortage, the 6% increase in the donor deferral rate observed between 2012 and 2014 (Fig. 1) was offset by increased blood donation campaigns and efforts to recruit donors. The deferral rate was higher during CHIKV than during the ZIKV outbreak (Fig. 2), certainly due to a higher proportion of symptomatic cases. On the other hand, the CHIKV epidemic has also led to a high rate of staff absenteeism, with an average of 38 days of illness per month, compared to 25 days in non-epidemic periods. Despite this obstacle, the FPBB remained operational. Thanks to the general and specific measures that have been successively taken in our geographical area, the blood safety related to arbovirus infections has been ensured throughout the entire periods of outbreaks. Firstly, the territory health authorities introduced general vector control measures to reduce sources of mosquito breeding as soon as the epidemic was identified [2]. Then, specific blood safety measures have been introduced including a pre-donation interview and a clinical examination focused on arbovirus infections. Moreover, donors were systematically encouraged to provide post-donation information, although the effectiveness of such measures could be hampered by a high proportion of asymptomatic cases estimated in FP around 50% for DENV and ZIKV, and 15% for CHIKV infections [9,10]. In our experience only seven (16.7%) and six (17.6%) post-donation calls were recorded among donors with a NAT positive for ZIKV and CHIKV, respectively. The detection of viral RNA, described as an effective measure in the absence of clinical symptoms [19], was performed in minipools to reduce the cost of screening, even though it has been reported that NAT sensitivity decreases when samples are tested in pools [12,15]. Despite this limitation, DENV NAT has reduced the risk of DENV transmission by blood transfusion and the residual risk was
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Fig. 1. Numbers of blood donations collected (black bars) and red blood cells (RBCs) distributed (grey bars) per quarter, percentages of quarterly (solid curve) and annual (dotted curve) deferred donations. French Polynesia Blood Bank (FPBB), 2012 to 2016.
Fig. 2. Percentages per month of deferred blood donations with a history of arboviral infection less than 28 days old (solid curve) and all causes combined (dotted curve). French Polynesia Blood Bank (FPBB), 2012 to 2016. Table 1 Characteristics and impact of arbovirus-related epidemics in French Polynesia since 2013. Arbovirus
Dengue virus
Zika virus
Chikungunya virus
Post-epidemic seroprevalence in overall population (2014–2015) [9,10] Proportion of asymptomatic cases [9,10] Period of NAT screening
83 ± 3%
49 ± 7%
76 ± 5%
50–80% 04.15.2013 to present
15% 10.13.2014 to 04.30.2015
Number of NAT tested donations Number of NAT positive donations Impact on blood supply
34,000 (at 12.31.18) 5 (0.015%) None
50–80% 11.21.2013 to 05.02.2014 retrospectively: 11.21.13 to 01.12.14 1505 42 (2.80%) None
Transfusion of contaminated blood products
None
Transfusion-transmitted infection in FP
None
Yes 36 blood products 26 recipients None
3433 34 (0.99%) Increase in the proportion of deferred donations None
None
NAT: nucleic acid testing; FP: French Polynesia.
estimated at 1/260,000 donations for the 2014–2016 period, i.e. one contaminated donation for approximately 40 years of FPBB activity [20]. The availability of a specific molecular assay that can be quickly applied in blood services in case of outbreak is the main obstacle
of NAT introduction. The delay in NAT implementation during the ZIKV outbreak due to the lack of licensed assay, led to the entry of contaminated donations into the transfusion chain [13,14,17]. In contrast, the early introduction of CHIKV NAT allowed to rule out 34 donations from infected donors.
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Compared to other French overseas territories that have recently experienced arboviruses outbreaks, the proportion of positive RNA donations detected by CHIKV and ZIKV-NAT was slightly higher in FP. Among the blood donations, 1.84% were positive for ZIKV during the epidemic in Martinique Island vs 2.80% in FP [21]. For CHIKV, respectively 0.36% and 0.42% donations were positive in Guadeloupe and Martinique vs 0.99% in FP [22]. These results should be interpreted with regard to the length of the screening period and the overall attack rate. This latter parameter was higher for the both viruses in FP than in the French West Indies, as confirmed by post-epidemic seroprevalence data: respectively for ZIKV 49% vs 42% in Martinique and for CHIKV 76% vs 60% in Martinique and Guadeloupe [9,10,23]. The introduction of pathogen reduction for platelets and plasma as an effective method to prevent transmitted-transfusion of DENV, CHIKV and ZIKV [15,16], completed the set of safety measures. Pathogen reduction is of great interest in FP, which is endemic area regularly affected by arboviruses outbreaks. However, this technology is not yet currently approved for use with RBCs, which are the main transfused LBP (80%). Due to the existence of an asymptomatic viraemic period and frequent asymptomatic forms, arboviruses meet the criteria for transmitted-transfusion agent as defined by the American Association of Blood Banks in 2009 [15,24]. However, reported transfusion transmission cases are limited and only described for DENV, West Nile virus, tick-borne encephalitis virus, Colorado tick fever virus and Ross river virus [12,25–27] and more recently for ZIKV during the epidemic in Brazil [28,29]. In our experience, no cases of DENV, CHIKV or ZIKV transmission by transfusion have been reported during the FP outbreaks. Nevertheless, only 12 of 26 patients that were transfused with LBP contaminated with ZIKV could be investigated after the transfusion [14,17]. Furthermore, the high rate of asymptomatic cases and the possible lack of sensitivity of the ZIKV antibodies detection test have been the main limitations to confirm transfusion-related ZIKV infection in our post-transfusion investigations [14,17]. Regarding the specificity of the ZIKV serological assay, in our experience the recombinant antigen used for the ZIKV ELISA serology did not present a DENV-ZIKV cross-reaction. A previous seroprevalence survey conducted in FP blood donor population with the same serological test during the 2011–2013 period (before the ZIKV epidemic) only reported 0.8% ZIKV IgG versus 80.3% DENV IgG [8]. Moreover, in our lookback investigations, only 3 out of 12 recipients were seropositive for ZIKV [14,17]. These proportions should have been higher in the case of DENV-ZIKV cross-reaction. For CHIKV, all contaminated LBP has been screened by NAT and removed from transfusion chain. The high immunization level against DENV observed in the adult population [8,9] and the well-demonstrated effectiveness of mitigation by pathogen reduction method used for platelets and plasma [15,16], probably explain the absence of transfusion-transmitted DENV in FP despite long and sustained circulation among the population and the frequency of outbreaks. However, the prevalence of antibodies varied with serotypes and ranged from 88% (DENV-1) to 51% (DENV-2). Regarding to this latter serotype, which is responsible for the current new epidemic, the transfusion transmission cannot be excluded in the non-immune population.
5. Conclusion The arboviral threat currently exists in French Polynesia. During the redaction of this article, a new DENV epidemic occurred related to DENV-2, which reemerged in March 2019 after more than 20 years of silence.
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The combined preventive measures led to limit the risk of transmission of arboviruses by transfusion without impairing the blood supply during epidemics thanks to efforts made to maintain a sufficient number of blood donations. However, the emergence of an unexpected virus such as ZIKV, highlighted the limit of preventive strategies. Indeed, the delayed implementation of NAT due to the initial unavailability of assay led to transfuse contaminated LBP. Moreover, in case of co-circulation of several arboviruses, as recently occurred in FP [4,5,7], the specific NAT assays have to be added, making the donation testing process cumbersome, until automated multiplex NAT techniques become available. Several studies have proposed a targeted implementation of arbovirus NAT according to the local epidemiological situation in order to optimize screening costs [12,15,19,30]. A reliable strategy could consist to define an incidence threshold in the general FP population at which arbovirus-specific NAT would be implemented [20]. For DENV systematically screened in FP blood donors, the trigger strategy could be used to switch from minipool to individual-donation testing during times of increased transfusion transmission risk (indicated by detection of minipool DENV positive donations and/or an increased incidence of DENV cases in the general population) as applied for West Nile virus in the USA or more recently recommended by the FDA for ZIKV [12,31]. Another affordable strategy would be to reserve arbovirus-free tested LBP for “at risk” considered patients. In the future, if pathogen reduction technologies able to inactivate infectious agents in RBCs components become available and approved, a new approach without arbovirus NAT screening (or at least the adoption of a pool strategy detecting high viral loads that could escape to the inactivation process) could be proposed [19,30]. Every scenario should be considered to maintain blood collections consistent with the LBP needs in FP, even if past outbreaks did not have a significant impact on the blood supply. To date, the measures introduced to prevent arboviruses transmission by transfusion have made it possible to maintain infectious safety for all blood products without impairing self-sufficiency of this territory.
Disclosure of interest The authors declare that they have no competing interest.
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Please cite this article in press as: Beau F, et al. Impact on blood safety of the last arboviruses outbreaks in French Polynesia (2012–2018). Transfusion Clinique et Biologique (2019), https://doi.org/10.1016/j.tracli.2019.12.001