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Ready to upload
Record number:
1946
Adverse Occurrence type:
MPHO Type:
Estimated frequency:
Report of the DTAC about the risk of HCV transmission from the donor to the recipient via organs for the period of 2008 to 2016 taking into account the most recent changes in donor populations due to the opioid crisis and the use of donors with increased risk for eclipse period (NAT not reactive, serology not reactive) or window period infection (NAT reactive, serology not reactive) for HCV: in total 15 donation cases with proven or probable donor-derived HCV infection transmitted to 32 out of 36 recipients without HCV infection (and risk of acquiring HCV for other reasons).
In 7 cases eclipse period donor infection (NAT not reactive, serology not reactive) caused HCV Transmission (here estimated risk is 1:1000; 7 of 7 cases were increased risk donor according to PHS Guideline [and CoE defintion]).
In 4 cases window period infection (NAT reactive, serology not reactive) caused HCV Transmission ; 2 of 4 cases were increased risk donor according to PHS Guideline [and CoE defintion]).
In 3 cases human errors caused HCV transmission.
In 1 case initial false negative serology and NAT caused HCV transmission.
To this point the authors conclude that appropriate data about infection risks of the donor and guidance for recipient management is detrimental to decrease risks. From 2008 to 2016, organs from 5,294 donors with a history of intravenous drug use (IVDU), 5,156 donors with drug intoxication as a mechanism of death, and 11,143 donors characterized as increased risk were procured. These data were used for risk estimates about transmission (PHS increased risk depending on classification ranges from 0.08 to 0.12%). Regarding the issue of IV-drug-abuse the authors of this study came to lower transmission rates because they used the key questions of "any iv-drug abuse or cause of death due to iv-drug". Other studies using the defintion of "iv-drug abuse during a previous period recently, e.g. 2 months" provide higher transmission rates - as explained by the authors.
The key issue is that a significant increase in donors due to death related to iv-drug abuse exists in the US which requires a change in providing information to clinicians responsible for accepting organs and obtaining informed consent of recipients.
Of the organ recipients from donors with HCV-infection in eclipse or window period all liver recipients developed HCV infection whereas in other organs the rates were not always 100% - probably due to differing amounts of HCV reservoir.
Of note, in 80 further reports to DTAC related to HCV transmission, no donor derived transmission could be confirmed: 15 due to false positive NAT, 19 due to false positive serology, 25 due to indentification of other sources causing HCV infection of the recipient and in the other cases reports were made for other reasons or data were insufficient for further conclusions.
Time to detection:
Not reported for pragmatic reasons on the DTAC publication. If readers are interested in more details about this issue they may refer to the authors or other papers cited here. Zahid and colleagues (2019) published a study of HCV transmission via organs and provided this summary of their findings with respect to viral kinetics: in the 3 days between transplantation and anti-HCV therapy initiation, plasma HCV levels increased markedly in each participant, indicating productive de novo infection of HCV with ongoing virus replication in the recipient host prior to therapy. Peak viremia ranged from 2.9–6.6 log10 IU/mL at day 3 to 5 after transplantation. Upon initiation of anti-HCV therapy, plasma viral load (VL) dropped quickly, reaching a level undetectable by clinical assay in a median of 9 days (range 5–18 days).
Alerting signals, symptoms, evidence of occurrence:
Not reported for pragmatic reasons, if readers are interested in more details about this issue they may refer to the authors. Current literature indicates HCV is most often detected in organ recipients when they are asymptomatic due to post-transplant recipient testing for infectious diseases -- for example, US OPTN policy 15.3.C. requires that all transplant recipients be tested for HIV, HBV, and HCV pre-transplant, and testing for these infections by NAT (due to immunosuppression, antibody response may not occur or may be delayed) 28-54 days after transplant and liver recipients must be re-tested by HBV NAT 335-395 days post-transplant.
Demonstration of imputability or root cause:
For the Kaul et al paper from OPTN/DTAC, imputability is not mentioned separately, but literature on the summarized cases provide proper data (as well as single case analysis)--and the Organ Procurement and Transplant Network Disease Transmission Advisory Committee (OPTN DTAC) always reviews imputability with criteria similar to that used by NOTIFY. Therefore imputability exists for every case, but not all data are mentioned in this summary report ->given that DTAC minimum imputability requirements to be included in the report is probable, and certainly also includes definite, this record is labeled as probable. However, the totality of the literature indicates that HCV is definitely transmissible via transplanted organs, and despite NAT testing of donors, unintended transmission cases still occur (Suryaprasad 2015) due to viral eclipse period.
Imputability grade:
3 Definite/Certain/Proven
Groups audience:
Keywords:
References:
Suggest new keywords:
Hepatitis C
transmission risk
IV drug abuse
window period
eclipse period
HCV
Reference attachment:
Suggest references:
1) Daniel R. Kaul, Susan M. Tlusty, Marian G. Michaels, Ajit P. Limaye, Cameron R. Wolfe. Donor derived hepatitis c in the era of increasing intravenous drug use: a report of the disease transmission advisory committee. https://doi.org/10.1111/ctr.13370
2) Pereira et al. N Engl J Med 1991;Transmission of hepatitis C virus by organ transplantation. 325:454-460 DOI: 10.1056/NEJM199108153250702
3) Zahid MN, Wang S, Learn GH, Abt PL, Blumberg EA, Reese PP, Goldberg DS, Shaw GM, Bar KJ. High multiplicity infection following transplantation of hepatitis C virus-positive organs. J Clin Invest. 2019 May 21;129(8):3134-3139. doi: 10.1172/JCI127203. PMID: 31112523; PMCID: PMC6668813.
4) Durand CM, Chattergoon MA. Bypassing the bottleneck: intentional hepatitis C transmission with organ transplant. J Clin Invest. 2019 Jun 24;129(8):3038-3040. doi: 10.1172/JCI129982. PMID: 31232703; PMCID: PMC6668816.
5) Tugwell BD, Patel PR, Williams IT, Hedberg K, Chai F, Nainan OV, Thomas AR, Woll JE, Bell BP, Cieslak PR. Transmission of hepatitis C virus to several organ and tissue recipients from an antibody-negative donor. Ann Intern Med. 2005 Nov 1;143(9):648-54. doi: 10.7326/0003-4819-143-9-200511010-00008. PMID: 16263887.
6) Suryaprasad A, Basavaraju SV, Hocevar SN, Theodoropoulos N, Zuckerman RA, Hayden T, Forbi JC, Pegues D, Levine M, Martin SI, Kuehnert MJ, Blumberg EA; Organ Transplantation Hepatitis C Investigation Team. Transmission of Hepatitis C Virus From Organ Donors Despite Nucleic Acid Test Screening. Am J Transplant. 2015 Jul;15(7):1827-35. doi: 10.1111/ajt.13283. Epub 2015 May 5. PMID: 25943299. https://www.amjtransplant.org/article/S1600-6135(22)00290-8/fulltext
7) HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C https://www.hcvguidelines.org/unique-populations/organs-from-hcv-viremic-donors
Note:
cross link to 1846 (MG: not sure who made this note, that paper is not related to HCV and I didn't see that there are other HCV in organ references within the library)
MG: I can't open any of the PDFs that are listed in things I'm reviewing today (10/9/23). I did upload several more references.
MG: Asking a TID clinician to do another second review of this so that they can add any clinical information that might be useful, particularly HCV presentation post-transplant when there isn't NAT performed to detect the HCV in the presymptomatic stage (as is described in the papers here).
Expert comments for publication:
Report of the DTAC about the risk of HCV Transmission from the donor to the recipient via organs for the period of 2008 to 2016 taking into account the most recent changes in donor populations due to the opioid crisis with the use of donors with increased risk for eclipse period (NAT not reactive, serology not reactive) or window period infection (NAT reactive, serology not reactive) for HCV. Although this paper reports on unexpected HCV transmissions, and the imputability grade is mixed for this publication, HCV has been known to be transmissible via organs since at least 1991 (see Pereira et al NEJM 1991). There is expected/anticipated transmission of HCV via organs in the US (DTAC only evaluates transmission events that are unexpected) due to the availability of direct acting antivirals against HCV (see Zahid et al 2019 and Durand 2019) that are able to treat HCV(-) recipients of organs from HCV(+) donors. Health Resources and Services Administration noted, also in 2019, a rise in unexpected HCV transmission, probably due at least in part to the US opioid epidemic, as discussed at https://optn.transplant.hrsa.gov/news/unexpected-hcv-donor-derived-transmissions-on-the-rise/ .
There are HCV treatment guidelines now available for D(+)/R(-) in organ transplantation from AASLD/IDSA (available here: https://www.hcvguidelines.org/unique-populations/organs-from-hcv-viremic-donors)
The following observations by the authors require critical consideration when evaluating donors:
1) " the median time between admission to the hospital and obtaining the specimen for NAT was 41 hours with a range of 13 to 96 hours. Thus, non-reactive NAT testing outside of the reported window period was not found. Modeling data suggest that the risk of a negative NAT test in a recently infected donor decays considerably after 5 days from exposure to HCV (see: Annambhotla PD, et al. A model to estimate the probability of human immunodeficiency virus and hepatitis C infection despite negative nucleic acid testing among increased-risk organ donors.Transpl Infect Dis. 2017 Apr;19(2):10.1111/tid.12676). Thus, ideally NAT would be obtained as late in the process as possible, but practical considerations limit the feasibility of performing NAT testing later in the evaluation period as results are most useful if available at the time of organ offer."
2) "Changes in required testing combined with the opioid epidemic itself and local outbreaks of HCV among the IVDU population might alter the local risk of HCV transmission from a donor with a history of intravenous drug use and/or drug intoxication as a mechanism of death."