Vector-borne Diseases and Transfusion Safety. Susan L. Stramer, Ph.D. VP, Scientific Affairs Nov

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1 Vector-borne Diseases and Transfusion Safety Susan L. Stramer, Ph.D. VP, Scientific Affairs Nov

2 Conflict of Interest Disclosure I hereby declare the following potential conflicts of interest concerning my presentation: Research Funding: Abbott Laboratories, Hologic/Grifols, Roche, Cerus Honoraria: Hologic/Grifols, Roche, Cerus Advisory: Chair, AABB Tranfusion-Transmitted Diseases Committee; Scientific Advisory Committee, HemaQuebec 2

3 Vector-Borne agents that are, or have the potential to be, transfusion transmitted Arboviruses Rickettsia Bacteria Protozoa -Yellow Fever - Dengue/Zika -Chikungunya/Ross River -St Louis Encephalitis -Colorado Tick Fever -Crimean Congo HF -Eastern Equine Encephalitis -Japanese Encephalitis -West Nile -LaCrosse -Tick-borne Encephalitis Complex (Powassan) -Anaplasma phagocytophilum -Ehrlichia ewingii -Erlichia chaffeensis -Orientia tsutsugamushi -Rickettsia prowasekii -Rickettsia rickettsii -Borrelia burgdorferi -Borrelia spp. -Yersinia pestis -Babesia spp -Leishmania spp. -Plasmodium spp. -Trypanosoma cruzi -Trypanosoma brucei BOLDED and UNDERLINED agents are transfusion transmissible - Western Equine Encephalitis - Severe fever with thrombocytopenia syndrome 3

4 General Patterns of Mosquito-Borne Arboviral Disease Transmission Enzootic Enzootic Urban Epidemic Culex spp Aedes spp Haemogogus spp Aedes aegypti +/- Aedes albopictus West Nile virus Dengue viruses Yellow fever virus Chikungunya virus Zika virus * No known enzootic reservoir for dengue 1-4 viruses 4

5 Enzootic versus Urban Epidemic Spread Enzootic transmission: WNV Humans don t infect mosquitoes Humans incidental hosts Lifelong immunity Human herd immunity not relevant Human travel irrelevant Mosquito surveillance important Urban epidemic: DENV, YFV, CHIKV, ZIKV Humans readily infect mosquitoes Humans amplifying hosts Lifelong immunity Human herd immunity very important Spread by human travel Mosquito surveillance less important 5

6 West Nile virus as a Model of Success Emerged and is endemic in the US 18,795 WNND cases ( ) Transmitted by a large number of mosquitoes 58 different mosquito species, mostly Culex spp. Amplified by bird hosts 288 avian species > 80% asymptomatic Transfusion/transplant transmitted 23 transfusion transmissions (2002) Intervention US/Canada = 2003 testing by MP/ID-NAT MP-NAT surveillance ; ID-NAT seasonal ; 13 transmissions 4,355 RNA confirmed-pos donors ( ) Outside of the US = 28-day travel deferrals 6

7 Incidence of WNV Neuroinvasive Disease Annual Incidence per 100,000 by county

8 Yearly statistics for WNV in the US: example of a rapidly emerging agent and a successful intervention, Year (No.) Reported WNND (18,725) WNV- RNA confirmed positive s (4,355) N/A * Transfusion cases^ (36) *** WNND = West Nile virus neuroinvasive disease. N/A = not available; prospective testing not introduced until * reported from CDC ArboNet; reported from the AABB WNV site. ^ All transfusion-transmission cases were identified from May-Oct. *** 1 WNV NAT-untested granulocyte. + = Data available through Dec ;

9 What happened in the US? Unexposed population, human and avian US strain virulent to corvids Mosquito feeding preference shifts to humans in summer due to the dispersal of breeding birds Irrigation patterns, standing water (abandoned swimming pools), tires, etc. Movement into Caribbean, Central and S Americas Human disease, however, is infrequent Why aren t there overlapping WNV and dengue chikungunya epidemics? (Zika?) Nov 2013 first confirmed cases of autochthonous CHIKV in the Americas March 2015 first confirmed cases of autochthonous 9 ZIKV in the Americas

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11 Percent WNV confirmed-positive donors requiring ID-NAT for detection, , ARC 100 ID-NAT only Identifiable 90 Percent of Confirmed Cases retrospective prospective

12 Frequency Viral loads at index for 1508 of 1576 confirmed-positive donors MP Identifiable ARC, Donors with PCR results at index Mean viral load (copies/ml) ID-NAT Only Identifiable Viral Load (copies/ml) < >500-1,000 >1,000-5,000 Median viral load (copies/ml) MP-NAT Identifiable , ID-NAT Only Identifiable >5,000 12

13 WNV confirmed-positive donors requiring ID-NAT for detection 20 Seronegative (44) Seroreactive (196) Seronegative Seroreactive Cases Year Start End Start End /10/2009 8/12/2009 7/19/2009 9/16/ /17/2010 9/27/2010 7/2/ /12/ /1/ /3/2011 8/1/ /11/ /13/ /5/2012 7/3/ /8/

14 Index viral load distributions for 635 confirmed-positive donations ARC, , days 6.9 days 0.9 day 10.8 days 61, , , Viral loads (VL) in copies/ml (31 samples with viral loads <100 and without a final quantitative value were excluded); those listed by each marker category (ID-NAT required for identification [IDNAT P] or MP-NAT identifiable (MPNAT P] and antibody [Ab] negative [N] or positive [P]) are the medians, interquartile ranges and maximum values. 14 Dodd et al., TMR 2015

15 Performance characteristics of WNV-NAT based on the number of reactive donations, ARC, # Tested # TMAreactive # Confirm positive # False positive % Specificity % PPV MP-NAT 23,910, ID-NAT 2,883, All NAT 26,793, PVDs 26,793, * *There were 107 confirmed-positive donations that were not classified as presumed viremic donations (PVDs); thus, the overall sensitivity of the PVD designation is 93.2%. PVDs had the highest positive predictive value (PPV). Dodd et al., TMR

16 WNV: What did we learn? Imported infections unpredictable and may be overwhelming Acute infections transmissible by transfusion NAT offers rapid route to testing Pooled testing may have inadequate sensitivity Epidemic continues to be unpredictable 16

17 Arbovirus Comparison Characteristic Dengue Chikungunya Zika Virus family Flaviviridae Togaviridae Flaviviridae Viral genus Flavivirus Alphavirus Flavivirus Serotypes Genotypes Vectors Symptoms / illness Symptomatic: Asymptomatic Illness outcome Multiple per serotype Aedes aegypti Aedes albopictus Acute febrile illness 3-4 (ECSA) 2 (Asian) Aedes aegypti Aedes albopictus Acute febrile illness Aedes aegypti Aedes albopictus Acute febrile illness 25:75 75:25 25:75 Severe dengue plasma leakage Rarely severe, arthralgias Rarely severe, microcephaly, Guillian-Barré 17

18 Clinical Features: ZIKV, DENV and CHIKV Features ZIKV DENV CHIKV Fever Rash Conjunctivitis Arthralgia Myalgia Headache Hemorrhage Shock

19 Dengue Incidence is Rapidly Increasing in the Americas Number Cases Year Source: Pan American Health Organization (PAHO) 19

20 Dengue viruses Mosquito-borne flavivirus ; 4 closely related types Most important arbovirus Rapidly expanding global footprint; >2.5 billion people (~1/3 world s population) live in areas of risk; endemic in >100 countries Asia/Latin America leading cause of hospitalization in children Humans are the amplifying host No vaccine or specific treatment; vector control is the only effective intervention Immunity to a given type is lifelong but cross reactivity between types is short lived and increases risk for severe dengue 50-80% asymptomatic Transfusion transmission reported Kidney, BM transplant, need-stick and lab infections No FDA-licensed test Testing under IND occurred in Puerto Rico; overall yield comparable to WNV 20

21 TT-DENV: seven cases/clusters by year Hong Kong, 2002: one case with PCR and serologic, no sequence confirmation Singapore, 2007: cluster of 3 cases from single donation, confirmed by envelope sequencing Puerto Rico, 2007: single case confirmed by envelope sequencing Brazil, 2012: viremic donors transmit to 6 recipients with minimal disease, retro study; no sequence confirmation Puerto Rico, : 2 (3?) transmissions from Ag negative/tma positive donors, retro study; no sequence confirmation Brazil, 2014: single case from regular platelet donor without sequence comparison Singapore, 2014: single case with sequence identity with donor 21

22 2007 Puerto Rico Donation Retrospective Study Stramer et al. Transfusion 2012;52: of 15,325 TMA (+) 1:529; 12 PCR (+) copies/ml, DENV-1, 2, 3 12 infected mosquito cultures, 6 IgM (+) Study Period TMA positive donations week of onset of symptoms TMA = Transcription Mediated Amplification 22

23 Maximum Likelihood Sequence Analysis of DENV-2 Env (1482 nucleotides) DENV-2 best studied All are highly conserved, but identical sequences (D/R) * * * NGC Mara4 Venezuela Thai 2001 PR3 PR PR 2009 PR 2008 PR 2008 PR 2007 Jamaica 2008 Dominican Rep Colombia 2007 Mexico 2002 Brazil 2006 Thai 2006 Thai 2003 Subclades: Asian American SE Asian Transfusion transmission 10 8 copies/ml DENV-2 prbc recipient developed DHF 3 days post transfusion * India 2006 Sri Lanka 1989 P7-863 Malaysia 1969 Australia 1993 Burkina Faso 1983 Indian Pacific PR159 IQT2133 Peru Ven2 Venezuela South American West Africa 1981 Guinea 1981 Sylvatic 0.1 * Bootstrap values 70 Stramer et al. Transfusion 2012;52:

24 Comparison to estimated prevalence of viremic donations - PR, ; Petersen et al. Transfusion 2012 (Aug) Dashed lines are simultaneous 95 th percentile-t confidence bands; light lines depict 100-sample realizations of the 500 used to compute the average prevalence of dengue viremia boxed% = RNA (TMA) donor prevalence from all years of testing % % % % 24

25 No. Donations Tested; N=270,049 No. Reactive; N=386 No. (%) Confirmed Positive; N=173 Rate of Confirmed Positives No. False Positive; N=213 Rate of False Positives NS1 Ag , (9) 1:18, :1,693 Retrospective TMA Dengue Blood Donation Screening under IND in Puerto Rico ( ) 53, (8) 1:6,681 90* 1:594 Prospective TMA 1: , (91) + (0.17%) * NS1 Ag positive control cross contamination + 20 (13%) NS1 Ag positive at index 16 1:5,551 Transfusion

26 NS1 Ag Screening 2010 Dengue Seroconverter (DENV-1) 054V58459 Donor #9 NS1 Ag S/CO Mean TMA S/CO IgM P/N IgG Titer Quant PCR 40 Duration (+): 5,0E <12 days RNA by PCR 4,5E+10 <19 days NS1 Ag 4,0E+10 Relative Number ~36 days RNA by TMA (mid-point) 3,5E+10 3,0E+10 2,5E+10 2,0E+10 1,5E+10 PCR Viral Load (copies/ml) 1,0E ,0E ,0E+00 Days Post Donation 26

27 Dengue Donor Follow-up Follow donors to development of symptoms, determine viral and immune dynamics 13 symptoms occurred at significantly higher rates in RNApos donors (cases) vs false pos (controls) Secondary (n=72) >> Primary (n=6); of those at p< 0.01 Fever, backache, headache, chills, sore throat, body pain, joint pain Rash, backache, chills, fever Viral median decline from first detection => 7.5 days IgM median appearance => 4 days => maximum at 21.5 days => decline by day 50 27

28 40 Observed period of RNA detection from time of first detection 51/80 followed donors provided follow-up within 60 days of index 34/80 followed donors provided follow-up within 21 days of index TMA S/CO N Median 95% CI IgM neg IgM pos p= Days 28

29 10 9 Appearance of IgM 8 IgM NR donors with complete profiles including 2 positive samples or 1 positive with an S/CO > 2 within 30 days of index IgM S/CO * days to peak IgM * - MAC ELISA and InBIOS ELISA Days Post Index

30 IgM Reactive Donors at Index Donors 40 Samples IgM S/CO * Days post Index * - MAC ELISA and InBIOS ELISA 30

31 Comparisons of DENV viral loads 1.3x10^10 Primary Copies/mL 7.0x10^8 DENV-1 p= x10^7 DENV-4 Copies/mL p= x10^7 2nd (N= 25) (N= 19) (N= 8/17) (N= 35/155) Copies/mL 5.3x10^8 IgM Neg p= x10^7 IgM Pos Copies/mL 1.0x10^9 Sympt p= x10^7 Asympt (N= 35/81) (N= 9/87) (N= 18/48) (N= 8/30) 31

32 Why are there only 7 clusters of TT dengue despite high levels of viremia in donors? Unknown why the number of TT-dengue cases is so low in the face of massive outbreaks Lack of effective hemovigilance Cannot distinguish mosquito from blood-borne transmission Lack of recognition of dengue nonspecific symptoms in severely ill patients Transfusion of Ab-pos units in endemic areas Recipients in an endemic area have antibody Heterologous type => severe dengue Different outcomes dependent on the route of transmission: mosquito vs transfusion Promotors in mosquito saliva 32

33 DENV-4 in Brazilian Donors 0.51% confirmed RNA positive in Rio 39,134 donors consented 42 DENV RNA + units into 35 recipients 0.80% confirmed RNA positive in Recife 1:200 1:125 Sabino EC et al. JID to 16 susceptible recipients 37.5% (6/16) infected vs. 0.93% of control recipients Record review finds no significant differences between cases and controls re: morbidity or mortality 33

34 Recipients of DENV TMA-reactive blood transfusions All recipients of DENV RNA-reactive blood transfusions; n=46 Died 24 hrs after transfusion; n=3 Lived 24 hrs after transfusion; n=42 Discharged 48 hrs after transfusion; n=1 Fever 2 weeks post transfusion; n=13 No Fever >2 weeks of transfusion; n=29 New fever; n=6 Continuous fever; n=7 New or other dengue-like symptoms; n=12 No new or other dengue-like symptoms; n=17 New or other dengue-like symptoms; n= RNA pos (qpcr) 7x10^7 c/ml No new or other dengue-like symptoms; n= (IgM pos) ** (TMA RR) prior units transfused Cases 1 and 2 were considered presumptive DENV-transfusion transmissions based on medical record review. 34 Matos et al., Transfusion 2015

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36 Days 1-3 Days 4-8 Days >8 NAT IgM IgG (PRNT)

37 Chikungunya Virus Response Reunion and islands of the Indian Ocean, >300,000 cases; >40% of population infected with 75% symptomatic Mutation viral env protein associated with increased viremia ECSA strain 2006 N Italy 337 cases (spread via Ae. albopictus, ECSA strain imported from India); risk of a viremic donation est 1.05/100,000 donations Interventions: Suspend/stop blood collection in areas with risk above a certain threshold (e.g., > that of HBV transfusion risk) Implemented platelet pathogen inactivation CHIKV NAT Donor deferral if lives in or traveled to an epidemic area Public concern undoubtedly demanded an intervention Petersen, Stramer, Powers. Transfusion Med Reviews 2010;24 37

38 Distribution of CHIKV symptomatic infections per week Reunion Island Overall risk = 132 per 100,000 dtns (1:758) Peak risk = 1500 per 100,000 dtns (1:67) Brouard et al., 2008 Transfusion 48 38

39 Puerto Rico 27,084 suspected cases Puerto Rico: 31,433 cases French West Indes 1 Dec Apr 2015 Guadeloupe: 81,350 cases Martinique: 72,520 cases 39

40 Oct 28, Puerto Rico, Passive Dengue Surveillance System

41 French Measures in the Caribbean Gallian P et al, Blood 2014;123:3679 Strategy INTERCEPT PC in place since 2010 Surveillance via French HV system 72h quarantine for blood products that are not pathogen inact d waiting for post-donation information (PDI) PCR of all samples in batches post transfusion (Marseilles) Results Real-Star QPCR by Altona; 63% LOD = 140 copies/ml 4 RNA pos/2149 screened Martinique (1:250) x10 8 copies/ml 10-2x10 5 pfu/ml 2 symptomatic (61-66 yo) 2 asymptomatic (41-43 yo) No CHIKV or any transfusion transmissions (TTI) reported 41

42 Prospective detection of CHIKV in blood donors, Caribbean 2014 Martinique Feb 24-Apr 9 4 RNA pos/2149 screened x10 8 copies/ml 2 symptomatic (61-66 years old) 2 asymptomatic (41-43 years old) Gallian et al., 42

43 Blood transfusion during arbovirus outbreaks French Polynesia: global strategy Blood product quarantine => rash and fever Pathogen Inactivation (Intercept) NAT Blood safety Courtesy of Didier Musso 43

44 Intercept and Arbovirus Inactivation (infectivity models) Platelet (log 10 reduction) Plasma (log 10 reduction) WNV > 6 > 6.8 CHIKV > 6.4 > 7.6 DENV > 5 > 5.7 ZIKV > > 6.6 Musso et al., Transfusion; 2014 Aubrey et al., Transfusion; 2016 Santa Maria et al., AABB;

45 Puerto Rico Executive Order Summary In response to the CHIKV epidemic declared in Puerto Rico, Governor issued an Executive Order in July 2014 requiring additional pre-donation screening questions and deferral Targeted symptoms => past 7 days Exposure to someone with DENV or CHIKV => past 7 days 28-day deferral if a yes response 3-day required platelet hold and call-back of donors for evidence of symptoms (RBCs 7-day passive hold) Products discarded if symptoms are reported or if contact was not established The Red Cross elected to suspend platelet collections in Puerto Rico in August 2014, following by the introduction of PI in March 2015 Platelets to meet patient need supplied from the US mainland 45

46 CHIKV in PR Donors 557 collections Apr 4-Aug Neg for ID markers including DENV RNA by TMA Screened by CHIKV TMA 95% detection 16 copies/ml Singlet => dilutions to 10^8 No donor reported PDI up to 12 days post donation 3 (0.54%, 1:186) TMA RR and confirmed by orthogonal methods (3 pos and 3 neg controls) 1/3 reported PDI from call back copies/ml: 2.9x Chiu et al., EID 2015:21(8). Genomic assays for Identification of CHIKV in Puerto Rico

47 3 CHIKV-pos donors were in the Caribbean clade - Molecular clock analysis showed this clade was an offshoot of the Asian strain predicted to have emerged in the Western Hemisphere in early PR isolates diverged from the other Caribbean strains 1.7 years prior to the study 47

48 First probable case of TT-Ross River Virus Hoad VC, Speers DJ, Keller AJ, Seed CR et al.: First reported case of transfusion-transmitted Ross River virus infection. Med J Aust. 2015;202: p RBC recipient - symptoms consistent with RRV IgM detected Haemagglutination inhibition (HI) positive Archive sample tests RRV PCR positive

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50 Estimated donor deferral rate (%) in the US from a 14- or 28-day deferral by geographic region comparing 2 surveys Area of travel in the past: Summer Survey Fixed sites only; paper survey; Americas only primarily Winter Survey All sites; electronic survey; Worldwide 14-day 28-day 14-day 28-day Mexico Caribbean Central and South America All above* All travel (global)* N/A *Individual areas and sums are not the same due to incomplete reporting of travel destination and travel to multiple places. Spencer et al., AABB 2015; Plenary 51

51 Comparison of US-reported cases of DENV, CHIKV and ZIKV to the CDC, DENV CHIKV ZIKV Year Local Import Local Import Local Import (FL) (FL) 2, (FL) (TX) (Nov 8) 2 (FL) (FL) 3,989 52

52 Mayaro Adapting to urban Aedes aegypti & albopictus? Chikungunya-like illness Recent cases in Haiti, far from former regions Rift Valley fever Expanding range out of Africa Increasing virulence (i.e., more hemorrhagic fever ) 19 potential mosquito vectors in North America Wild/domestic epizootics with increased human contact

53 Crimean-Congo hemorrhagic fever Tick transmission by old world Hyalomma sp. present in Germany & U.K. Importation of vectors to North America reported High fatality rate Spread from Africa to Asia, two cases in Spain in 2016 Usutu Mosquito-borne by Culex pipiens (Aedes albopictus?) Avian amplification & reservoirs with massive bird die offs in EU 6% seroprevalence around Modena, Italy Encephalitic syndrome in immunocompromised

54 Summary Mosquito-borne viruses are an increasingly recognized threat to transfusion safety Interventions are not widely available, have long development times and are costly Processes for determining when decisions to do more are needed 55