Follow-Up of Plasma Donors after Quarantine Storage: Results of a 5-Year Survey in Germany

Abstract

Background and Objectives

In 1993, a quarantine storage of 6 months was introduced for plasma for transfusion and was reduced to 4 months in 2003, owing to the improvements of screening assays used in German blood establishments. The presented survey analyses the value of quarantine storage under the current screening conditions.

Materials and Methods

From 2015 to 2019, we collected data on the total amount of released quarantine plasma as well as on the number of quarantine plasma not released due to a reactive screening test of a follow-up donation.

Results

Responding establishments covered 84% of plasma units released within the sampled period. In 3,583,913 (99.98%) of the total 3,584,664 test pairs, all screening assays revealed a negative result, leading to plasma release from quarantine storage. In 442 out of the residual 751 cases, confirmed positive results for human immunodeficiency virus (24), hepatitis C virus (22), or hepatitis B virus (396) were obtained in the follow-up donations. Of them, 372 revealed negative ID-NAT results in their retain samples confirmed by using highly sensitive individual donor nucleic acid amplification technology. In 70 cases, no testing of retain samples was performed as plasma was released for fractionation. The maximum theoretical risk for an undetected human immunodeficiency virus, hepatitis C or B virus infection was less than 0.0001%.

Conclusion

No positive donation were found under the current screening regime and the quarantine storage during the 5-year survey period. In view of the current type and sensitivity of screening tests in German blood establishments, the results allow a reassessment of the value of quarantine storage of plasma regarding duration and release modalities. Due to the more sensitive donor screening, shorter quarantine periods as well as dispensing quarantine storage can be discussed. A reduction in the safety standard of plasma transfusions need not be feared, and the availability of plasma for transfusions could be facilitated.

Introduction

In Germany, the quarantine storage of fresh frozen plasma was established in 1993 to increase the safety standard for transfusion-related infections according to the scientific knowledge of that time [1]. The main objective of this measure was the prevention of human immunodeficiency virus (HIV), hepatitis C virus (HCV), and hepatitis B virus (HBV) transmission by quarantine plasma (QP) harvested before antibodies against these viruses were detectable in donors, i.e., during the diagnostic window period. After improvement of HIV and HCV serum diagnosis and the introduction of mandatory nucleic acid amplification technology (NAT) tests for HCV and HIV, quarantining of QP was reduced in 2003 from 6 to 4 months [2].

To date, only three HCV and two HIV transmissions occurred by cellular blood components during more than 17 years of NAT testing in Germany, indicating a very limited residual risk. Therefore, further reduction of quarantining interval for retesting of the donor or even discontinuation of quarantining of QP was discussed [3]. In order to evaluate the benefit of quarantine storage under the current screening regime, the Paul-Ehrlich-Institut (PEI) initiated a survey. Blood establishments (BEs) were asked to collect the number of QP release processes with and without a confirmed virus infection following a previous screening negative blood or plasma donation over a period of 5 years (2015−2019).

Material and Methods

According to the German Drug Law (AMG) [4], the PEI is authorized to collect data from pharmaceutical manufacturers for surveillance reasons. We used this tool to obtain an update of the effectiveness of the 4-month quarantine storage of plasma.

Using an electronic Case Report Form, we collected for the years 2015−2019 the following items:

1. Number of plasma units released because of negative screening results in a post-quarantine follow-up donation.

2. Number of plasma units not released because of a confirmed positive/reactive screening result in a follow-up donation. Confirmation followed a defined testing algorithm [5].

3. Type of confirmed positive screening assay which prevented plasma release.

4. Sensitivity of NAT tests used as screening assays for HIV, HCV, and HBV (limit of detection calculated per single donation).

5. Donation date of the original blood or plasma donation and date of follow-up donation that decided on the plasma destiny.

6. Result of individual donor (ID)-NAT on retain samples of the original donation if applicable.

The number of other positive screening results in follow-up donations, e.g., hepatitis E virus (HEV), syphilis, and parvovirus B19, was reported by the participating BE without further details.

Statistical Analyses

In order to estimate the maximum theoretical risk of an undetected positive HIV, HCV, or HBV case in the absence of any observed case, we calculated the exact upper 95% Poisson confidence limit for 0 as described by Daly et al. [6]. The result was divided by the number of donations with retested donation pairs. The statistical analysis was conducted using SAS, version 9.4 (SAS Institute, Cary, NC, USA).

Results

Of the 103 contacted BE, 30 responded, which yielded us data on 83.8% of all QP units released in Germany within a period of 5 years (see report 2019 at www.pei.de/tfg-21). Altogether 3,584,665 test pairs for HIV, HBV, and HCV had been obtained. These pairs consisted of (i) screening negative donations and its test sensitivity prior to quarantine storage, (ii) the screening results of the corresponding follow-up donation, and (iii) in case of a positive screening result of the follow-up donation the result of HIV, HCV, or HBV ID-NAT testing of the donation retain sample prior to quarantine storage. It is to mention that not only screening results required for release of QP had been reported, i.e., with a donation interval of 120 days or more. Also, positive donations with shorter donation intervals were included within the responses. Few data pairs were obtained with a donation interval of more than 1 year. In one case of an HCV positive donation, the interval to the previous donation was more than 8 years and therefore excluded from further evaluation.

In 3,583,913 out of 3,584,664 test pairs (99.98%), all screening assays yielded negative results leading to plasma release from quarantine storage (Table 1). In 442 out of the residual 751 cases, confirmed positive results for HIV (24), HCV (22), and HBV (396) were obtained in the follow-up donations. Of them, 372 revealed negative ID-NAT results in their retain samples, tested by ID-NAT assays with a minimum limit of detection of 100 (HIV), 20 (HCV), or 5 IU/mL (HBV).

Table 1.

Summary of QP release data, 2015-2019

	Screening-negative donations prior to quarantine	Screening-negative follow-up donations	Screening-positive follow-up donations
			HIV, HCV, HBV				other pathogensa
			screening positive	thereof retain sample positive	thereof retain sample negative	thereof retain sample not tested
Donation pairs Release for transfusion	3,584,664 No	3,583,913 Yes	442 No	0 No	372 No	70 No	309 No

HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus.

^aThese follow-up donations tested negative for HIV, HCV, and HBV in donor screening.

In 70 cases, no testing of retain samples was performed as plasma was released for fractionation. Of them, 68 follow-up donations tested exclusively positive for antibody to hepatitis B core antigen and 2 exclusively positive for hepatitis B surface antigen. A vaccination effect was assumed for the latter 2 cases as both donors were hepatitis B surface antigen negative in a later control donation. The majority of screening-positive follow-up donations (252) was observed within 4 months and 1 year, 164 between 5 and 119 days after storage start, and only a minority (26) later than 1 year (Table 2).

Table 2.

442 follow-up donations with a confirmed positive screening result for HIV, HCV, and HBV

	Screening-reactive follow-up donation	Interval to previous donation			Result of retain sample
		<120 days	120-365 days	>365 days	positive	negative	not done
HIV-NAT only	0				0
HIV Ag/Ab only	0				0
HIV-NAT, Ag/Ab	24	10	12	2	0	24
Total HIV	24	10	12	2	0	24
HCV-NAT only	2		2		0	2
Anti-HCV only	8	4	4		0	8
HCV-NAT, anti-HCV	12	4	5	3	0	12
Total HCV	22	8	11	3	0	22
HBV-NAT only	1	1			0	1
HBsAg only	8	5	3		0	6	2a
Anti-HBc only	379	138	221	20	0	311	68a
HBV-NAT, HBsAg, anti-HBc	1			1	0	1
HBV-NAT, HBsAg	6	2	4		0	6
HBV-NAT, anti-HBc	1		1		0	1
Total HBV	396	146	229	21	0	326	70
Total	442	164	252	26	0	372	70

Anti-HBc, antibody to hepatitis B core antigen; anti-HCV, antibody to hepatitis C antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HIV, human immunodeficiency virus; NAT, nucleic amplification technique. ^a Dedicated as plasma for fractionation.

Not only HIV, HCV, or HBV positive follow-up donations prevented release of the respective QP from quarantine storage but also further 309 pathogen positive follow-up donations, among them were HEV, syphilis, and parvovirus B19 (Table 1). Within the survey period, the screening sensitivities (calculated per single donation) for minipool (MP)-NAT assays varied from 686−4,829 IU/mL (median 1,433) for HIV, 70−1,440 (median 672) for HCV, and 14−864 (median 125) for HBV; two BE used highly sensitive ID-NAT assays for all test parameters. Based on 0 observed events among 3,584,594 donations with complete test pairs, the maximum theoretical risk for an undetected positive HIV, HBV, or HCV case was 1 to 1,196,568, i.e., less than 0.0001%.

Discussion

This is the first analysis on the safety benefit of plasma quarantine storage after its introduction in 1993 [1]. Since then, the safety standard for donor screening has been improved. Additional tests were mandatory (HCV-NAT, antibody to hepatitis B core antigen, HIV 1/2 dual target NAT testing) or voluntarily (HBV-NAT testing) established. By improving the overall screening quality, it was also possible to increase the sensitivity of donor screening tests. Initially, e.g., a sensitivity of 10,000 IU per mL was required for HIV-NAT assays based on the individual donation [7], and detection of at least 5,000 IU per mL was required for HCV-NAT assays [8]. In the meantime, the sensitivity of NAT testing significantly improved nearly 10-fold.

Because the risk of transmission has been continuously reduced, cost and benefit of the quarantine storage of QP were repeatedly discussed in the recent years [3] and led to a reduction of the duration of quarantine storage in 2003 [2]. Our data covered more than 3.5 million plasma release procedures. In 442 cases, a positive screening test for HIV, HCV, or HBV was obtained in a follow-up donation. No hidden infections were found as proven by a negative ID-NAT test result of the retain samples. This as well as the fact that no QP transmission has been documented during the observed period of 5 years [9] underline the high plasma safety standard of the established donor screening in Germany.

The presented results may stipulate a new discussion on the value of plasma quarantine storage and its duration under the current screening conditions. Most likely a quarantine revision will require new definitions of test sensitivities for HIV, HBV, and HCV screening assays. There is evidence that shortening or even dispensing quarantine storage would not measurably affect the safety of plasma transfusion. A calculated residual risk of 0.0001% for a possible transmission of a hepatitis or HIV infection does not necessarily have to be reduced. Screening for HEV was not obligatory during the survey period and today plasma can be released despite an HEV positive result of a pre-quarantine donation [10]. Nevertheless, it would be of additional interest to collect and evaluate data on HEV screening for a more comprehensive view balancing safety and economics.

Statement of Ethics

All applicable data protection rules were respected. No patient samples were used.

Conflict of Interest Statement

The authors have no conflicts of interest to declare.

Funding Sources

None.

Author Contributions

Sarah Anna Fiedler, Doris Oberle, Olaf Henseler, Margarethe Heiden, and Markus Benedikt Funk developed the concept and collected and analyzed the data; all the authors wrote the manuscript and have approved the final version of the manuscript. All the authors have reviewed and approved the submitted version of the manuscript; the manuscript has neither been published nor is it under consideration for publication elsewhere.

Data Availability Statement

All data generated or analyzed during this study are included in this article. Further inquiries can be directed to the corresponding author.

Funding Statement

None.