Mars Stone1, Sonia Bakkour2, Marion C Lanteri3, Donald Brambilla4, Graham Simmons2, Roberta Bruhn2, Zhanna Kaidarova5, Tzong-Hae Lee5, Jose Orlando Alsina6, Phillip C Williamson7, Susan A Galel8, Lisa L Pate8, Jeffrey M Linnen9, Steve Kleinman10, Michael P Busch2. 1. Vitalant Research Institute, San Francisco, CA, USA; Department of Laboratory Medicine, University of California, San Francisco, CA, USA. Electronic address: mstone@vitalant.org. 2. Vitalant Research Institute, San Francisco, CA, USA; Department of Laboratory Medicine, University of California, San Francisco, CA, USA. 3. Vitalant Research Institute, San Francisco, CA, USA; Department of Laboratory Medicine, University of California, San Francisco, CA, USA; Cerus Corporation, Concord, CA, USA. 4. RTI International, Rockville, MD, USA. 5. Vitalant Research Institute, San Francisco, CA, USA. 6. Banco de Sangre de Servicios Mutuos, Guaynabo, PR, USA. 7. Creative Testing Solutions, Tempe, AZ, USA. 8. Roche Molecular Systems, Pleasanton, CA, USA. 9. Grifols Diagnostic Solutions, San Diego, CA, USA. 10. Department of Pathology and Laboratory Medicine, University of British Columbia, Victoria, BC, Canada.
Abstract
BACKGROUND: Characterisation of the dynamics of Zika virus persistence following acute infection is needed to inform blood donor and diagnostic testing policies and understand the natural history of Zika virus infection. We aimed to characterise the natural history, persistence, and clinical outcomes of Zika virus infection through a prospective study in initially asymptomatic Zika virus RNA-positive blood donors. METHODS: Zika virus-infected blood donors identified through Zika virus nucleic acid amplification test (NAAT) screening at three blood collection organisations in the USA were enrolled into a 1-year follow-up study, with blood and body fluid samples and detailed symptom data collected at up to seven visits. All samples were tested for Zika virus RNA by real-time PCR (rtPCR); follow-up plasma, whole blood, and urine were also tested by replicate NAAT. Plasma was tested for flavivirus-specific IgM and IgG by ELISA. Zika virus RNA persistence for each assay or sample type and plasma antibody persistence from estimated date of plasma NAAT-detectable infection were calculated from follow-up data using survival statistical methods. FINDINGS: Between July 6, 2016 and March 7, 2017, we enrolled 53 participants. From the estimated date of plasma NAAT-detectable infection, Zika virus RNA was detectable in plasma for 9·9 days (95% CI 8·1-12·0), in red blood cells for 95·4 days (62·8-129·1), and in whole blood for 73·5 days (39·8-107·5). Replicate NAATs (one or more of eight replicates positive) extended detection of Zika virus RNA in plasma to 34·8 days (19·9-56·2) and in whole blood (at least one of two tests positive) to 104·8 days (76·7-129·9). Urine was rtPCR reactive up to 14·5 days (10·5-20·3) and saliva up to 26·4 days (19·7-38·7). Zika virus IgM persisted for 237·7 days (128·7-459·5) from estimated time since plasma NAAT-detectable infection. Zika virus RNA fell below detectable limits more rapidly in the saliva of participants with pre-existing dengue virus IgG than in those without. Of 25 donors identified pre-seroconversion with symptom data at the first or second study visit, 16 (64%) developed multiple Zika virus-related symptoms after asymptomatic index donations, compared with nine (36%) of 25 donors detected after seroconversion. INTERPRETATION: Determination of viral marker persistence is enhanced by follow-up of blood donors who are pre-symptomatic or asymptomatic, Zika virus RNA-positive, and antibody negative. Zika virus RNA persists in red blood cells for several months following clearance from plasma and body fluids, and replicate, highly sensitive NAATs extend RNA detection in all compartments. Whole blood testing can extend detection of acute infection for diagnostics and monitoring of pregnant women, sexual partners, and travellers. FUNDING: National Heart, Lung, and Blood Institute, Biomedical Advanced Research and Development Authority.
BACKGROUND: Characterisation of the dynamics of Zika virus persistence following acute infection is needed to inform blood donor and diagnostic testing policies and understand the natural history of Zika virus infection. We aimed to characterise the natural history, persistence, and clinical outcomes of Zika virus infection through a prospective study in initially asymptomatic Zika virus RNA-positive blood donors. METHODS: Zika virus-infected blood donors identified through Zika virus nucleic acid amplification test (NAAT) screening at three blood collection organisations in the USA were enrolled into a 1-year follow-up study, with blood and body fluid samples and detailed symptom data collected at up to seven visits. All samples were tested for Zika virus RNA by real-time PCR (rtPCR); follow-up plasma, whole blood, and urine were also tested by replicate NAAT. Plasma was tested for flavivirus-specific IgM and IgG by ELISA. Zika virus RNA persistence for each assay or sample type and plasma antibody persistence from estimated date of plasma NAAT-detectable infection were calculated from follow-up data using survival statistical methods. FINDINGS: Between July 6, 2016 and March 7, 2017, we enrolled 53 participants. From the estimated date of plasma NAAT-detectable infection, Zika virus RNA was detectable in plasma for 9·9 days (95% CI 8·1-12·0), in red blood cells for 95·4 days (62·8-129·1), and in whole blood for 73·5 days (39·8-107·5). Replicate NAATs (one or more of eight replicates positive) extended detection of Zika virus RNA in plasma to 34·8 days (19·9-56·2) and in whole blood (at least one of two tests positive) to 104·8 days (76·7-129·9). Urine was rtPCR reactive up to 14·5 days (10·5-20·3) and saliva up to 26·4 days (19·7-38·7). Zika virus IgM persisted for 237·7 days (128·7-459·5) from estimated time since plasma NAAT-detectable infection. Zika virus RNA fell below detectable limits more rapidly in the saliva of participants with pre-existing dengue virus IgG than in those without. Of 25 donors identified pre-seroconversion with symptom data at the first or second study visit, 16 (64%) developed multiple Zika virus-related symptoms after asymptomatic index donations, compared with nine (36%) of 25 donors detected after seroconversion. INTERPRETATION: Determination of viral marker persistence is enhanced by follow-up of blood donors who are pre-symptomatic or asymptomatic, Zika virus RNA-positive, and antibody negative. Zika virus RNA persists in red blood cells for several months following clearance from plasma and body fluids, and replicate, highly sensitive NAATs extend RNA detection in all compartments. Whole blood testing can extend detection of acute infection for diagnostics and monitoring of pregnant women, sexual partners, and travellers. FUNDING: National Heart, Lung, and Blood Institute, Biomedical Advanced Research and Development Authority.
Authors: Joseph R Biggs; Ava Kristy Sy; Oliver J Brady; Adam J Kucharski; Sebastian Funk; Yun-Hung Tu; Mary Anne Joy Reyes; Mary Ann Quinones; William Jones-Warner; James Ashall; Ferchito L Avelino; Nemia L Sucaldito; Amado O Tandoc; Eva Cutiongco-de la Paz; Maria Rosario Z Capeding; Carmencita D Padilla; Martin L Hibberd; Julius Clemence R Hafalla Journal: Viruses Date: 2021-07-23 Impact factor: 5.048
Authors: Amanda E Calvert; Kalanthe Horiuchi; Karen L Boroughs; Yee T Ong; Kimberly M Anderson; Brad J Biggerstaff; Mars Stone; Graham Simmons; Michael P Busch; Claire Y-H Huang Journal: J Clin Microbiol Date: 2021-07-19 Impact factor: 5.948
Authors: Mars Stone; Clara Di Germanio; David J Wright; Hasan Sulaeman; Honey Dave; Rebecca V Fink; Edward P Notari; Valerie Green; Donna Strauss; Debbie Kessler; Mark Destree; Paula Saa; Phillip C Williamson; Graham Simmons; Susan L Stramer; Jean Opsomer; Jefferson M Jones; Steven Kleinman; Michael P Busch Journal: Clin Infect Dis Date: 2022-03-09 Impact factor: 9.079