Transfusion-transmitted hepatitis E: What we know so far?

Table 1 Extrahepatic manifestations associated with hepatitis E virus infection

System	Extrahepatic manifestations
Neurological	Guillain-Barré syndrome (GBS)
	Neuralgic amyotrophy
	Neuropathy
	Bell’s palsy
	Encephalitis
	Transverse myelitis
	Myositis
	Myasthenia gravis
	Pseudotumor cerebri
	Seizure
Renal	Decrease glomerular filtration rate
	Glomerulonephritis
	Nephrotic syndrome
	Mixed cryoglobulinemia
Hematological	Thrombocytopenia
	Hemolytic anemia
	Aplastic anemia
	Hemophagocytic syndrome
	Monoclonal gammopathy of uncertain significance (MGUS)
Others	Thyroiditis
	Pancreatitis
	Myocarditis
	Polyarthritis

Table 2 Hepatitis E virus ribonucleic acid prevalence in donor, only studies include more than 1000 study subjects are included

Ref.	Country	Initial screening method	Number of donations screened	Number positive donations	Prevalence (95%CI)	HEV genotype: n/N	Median (range) viral load, IU/mL	Outcome of recipient
Europe
Fischer et al[45], 2015	Austria	RT-PCR (plasma pool of 96 samples) with 95% LOD 11.6 IU/mL	58915	7	0.012%	3: 7/7	(2200 to 290000)	N/A
Vercouter et al[46], 2019	Belgium	RT-PCR (plasma pool of 6 samples) with 95% LOD 18.6 IU/mL	38137	7	0.018%	N/A	(153 to 8710)	N/A
Harritshøj et al[47], 2016	Denmark	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	25637	11	0.043% (0.02% - 0.07%)	3 (in 2 samples)	13 (unquantifiable to 920)	(1) Look-back testing was performed in 7 recipients; all were tested negative for HEV RNA and anti-HEV IgM; (2) No recipient developed transaminitis; and (3) One patient had strongly positive anti-HEV IgG assay which may indicate recent HEV infection or secondary immune response by HEV re-exposure.
Gallian et al[48], 2014	France	RT-PCR (plasma pool of 96 samples) with 95% LOD 23 IU/mL	53234	22	0.045% (0.043%-0.047%).	3c: 5/14; 3f: 8/14; 3 1/14	(468 to 5155800)	N/A
Westhölter et al[49], 2018	Germany	RT-PCR (plasma pool of 24 samples) with 95% LOD 18.6 IU/mL	18737	23	0.123%	3: 6/7	(120 to 11200000)	(1) Retrospective analysis of 4 viremic donors showed that they were HEV-positive in previous donations; (2) In 3 donors, testing of the previously donated blood in pools of 24 samples failed to identify viremic donations but were tpositive in unpooled samples; (3) Fourteen recipients had received HEV RNA positive blood products; (4) One immunosuppressed recipient tested positive for HEV RNA, developed acute on chronic liver failure, and died; and (5) One immunocompetent recipient developed acute self-limited episode of hepatitis E
Dreier et al[50], 2018	Germany	RT-PCR with 95% LOD 4.7 IU/ml for FFP, platelet concentrates, and RBC supernatant; 95% LOD 8.9 IU/mL for RBCs.	235524	182	0.077%	3: 4/4	(< 25 to 69.4)	(1) Nine viremic donations were transfused to 6 different recipients; (2) Two recipients were immunocompromised (heart transplantation and leukemia); (3) Two recipients died shortly after transfusion for reasons other than HEV infection; and (4) None of the other 4 recipients developed acute HEV infection or had detectable HEV RNA / anti-HEV IgG
Corman et al[51], 2013	Germany	RT-PCR (plasma pool of 96 samples mixed in metapools of 20)	93955	14	0.015%	3: 14/14	(3.1 to 4.8 Log10 IU/mL)	N/A
Vollmer et al[52], 2012	Germany	RT-PCR (plasma pool of 48 samples) with 95% LOD 4.7 IU/ml	16125	13	0.081%	3: 13/13	(13 to 68100)	N/A
Baylis et al[53], 2012	Germany	RT-PCR (plasma pool of 96 samples) with 95% LOD 250 IU/mL	18,100	4	0.022%	3	(3.26 to 5.35 log10 copies/mL)	Donations screened positive for HEV were excluded from pharmaceutical production
O'Riordan et al[54], 2016	Ireland	TMA assay with 95% LOD 5.5 IU/mL	24985	5	0.020% (0.0065%-0.0467%)	3: 3/3	(10 to 44550)	N/A
Spreafico et al[55], 2020	Italy	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	9726	1	0.010% (0.00%-0.06%)	N/A	N/A	N/A
Spada et al[56], 2018	Italy	RT-PCR, plasma pool and sensitivity varies according to anti-HEV IgG and IgM status	10011	0	N/A	N/A	N/A	N/A
Hogema et al[57], 2015	Netherlands	RT-PCR (plasma pool of 96 samples) with 95% LOD 38.4 IU/mL with the EasyMag extraction method and 10.3 IU/mL using Qiagen extracts	59474	41	0.069%	3c: 15/17; 3f: 2/17	N/A	N/A
Slot et al[58], 2013	Netherlands	RT-PCR (plasma pool of 48 or 480 samples) with 95% LOD 25 IU/mL	40176	13	0.032%	3: 16/17	(< 25 to 470000)	N/A
Grabarczyk et al[59], 2018	Poland	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	12664	10	0.079% (0.043%-0.145%)	3i: 2/3; 3c: 1/3	(16 to 6586 in 4 patients with positive results in qPCR)	N/A
Rivero-Juarez et al[60], 2019	Spain	RT-PCR (plasma pool of 8 samples) with sensitivity 670 IU/mL	11313	4	0.035% (0.01%-0.09%)	3: 4/4	(10788 to 2000000)	(1) Five patients received transfusions from HEV-infected donors; and (2) None of them showed an increase in alanine aminotransferase levels after transfusion
Sauleda et al[61], 2015	Spain	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	9998	3	0.030% (0.01%-0.09%)	3f (in 1 sample)	(250 to 2755)	N/A
Baylis et al[53], 2012	Sweden	RT-PCR (plasma pool of 96 samples) with 95% LOD 250 IU/mL	95835	12	0.013%	3	(3.20 to 5.68 log10 copies/mL)	Donations screened positive for HEV were excluded from pharmaceutical production
Harvala et al[62], 2019	United Kingdom	RT-PCR (plasma pool of 24 samples) with 95% LOD 18.6 IU/mL	1838747	480	0.026%	3c: 112/149; 3e: 21/1493f: 12/149; 3a: 1/149; 2 distantly related to 3h, and 1 clustered distantly with 3a	883 (1 to 3230000)	N/A
Thom et al[63], 2018	United Kingdom	RT-PCR (plasma pool of 24 samples)	94302	38	0.040%	3: 10/10	N/A	N/A
Hewitt et al[64], 2014	United Kingdom	RT-PCR (plasma pool of 24 samples)	225000	79	0.035%	3: 79/79	3900 (50 to 2.37 × 106)	(1) Forty-three patients who had received blood components from HEV-infected donors were followed up; (2) The overall transmission rate was 42% (18 of 43 exposed patients); (3) One recipient developed clinical hepatitis and 4 recipients developed asymptomatic transaminitis; and (4) Four heavily immunosuppressed patients had delayed (37-38 wk) seroconversion or no antibodies detected
Cleland et al[65], 2013	United Kingdom	Nested PCR (plasma pool of 24 samples) with 95% LOD 201 IU/mL	43560	3	0.0069%	3: 3/3	N/A	N/A
North America
Delage et al[66], 2019	United States	RT-PCR on individual samples with 95% LOD 18.6 IU/mL	50724	3	0.0059%	3: 2/3; genotyping was unsuccessful in 1 patient	(23 to 1420)	N/A
	Canada		50765	11	0.022%	3 (in 1 sample)	(< 10 to 3080)
Roth et al[67], 2017	United States	RT-PCR (plasma pool of 96 samples) with 95% LOD 18.6 IU/mL	128021	4	0.003%	3a: 3/3	(3.0 to 3.8 log IU/mL)	N/A
Stramer et al[68], 2016	United States	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	18829	2	0.011% (0.0018%-0.351%)	N/A	14 IU/mL in one sample	N/A
Xu et al[69], 2013	United States	RT-PCR (plasma pool of 7 to 8 samples) with 95% LOD 400 IU/mL and nested PCR with 95% LOD 200 IU/mL	1939	0	N/A	N/A	N/A	N/A
Baylis et al[53], 2012	United States	RT-PCR (plasma pool of 96 samples) with 95% LOD 250 IU/mL	51075	0	N/A	N/A	N/A	N/A
Asia
Wen et al[70], 2018	China	RT-PCR on individual plasma	5345	15	0.281%	One 4h, another one clustered between genotype 2 and 4i	N/A	N/A
Tsoi et al[71], 2019	Hong Kong	RT-PCR with 95% LOD 7.89 IU/mL	10000	2	0.02%	4 (in 1 sample)	N/A	N/A
Katiyar H et al[72], 2018	India	RT-PCR (plasma pool of 3 samples) with LOD 100 IU/mL	1799	0	N/A	N/A	N/A	N/A
Minagi T et al[73], 2016	Japan	RT-PCR (plasma pool of 50 or 500 samples) with 95% LOD 152 IU/mL	620140	36	0.0058%	3: 36/36	(< 1.69 to 7.22 log10 copies/mL)	N/A
Intharasongkroh et al[74], 2019	Thailand	RT-PCR (plasma pool of 6 samples) with 95% LOD 53.5 IU/mL	30115	26	0.086%	3: 6/6	N/A	N/A
Others
Hoad et al[75], 2017	Australia	TMA (plasma pool of 6 samples)	74131	1	0.0013%	N/A	180	N/A
Shrestha et al[76], 2016	Australia	TMA assay on individual plasma with 95% LOD 7.9 IU/mL	14799	1	0.0068% (0.0002%-0.0376%	3	15000	N/A
Hewitt et al[77], 2018	New Zealand	RT-PCR (plasma pool of 8 to 12 samples)	5000	0	N/A	N/A	N/A	N/A
Maponga et al[78], 2020	South Africa	TMA assay on individual plasma with 95% LOD 7.9IU/mL	10000	1	0.01%	3	79000	All donations from donors with active HEV infection were discarded

CI: Confidence interval; FFP: Fresh frozen plasma; HEV: Hepatitis E virus; Ig: Immunoglobulin; LOD: Limit of detection; RBC: Red blood cells; RNA: Ribonucleic acid; RT-PCR: Real time polymerase chain reaction; TMA: Transcription mediated amplification.

Table 3 Seroprevalence of hepatitis E in blood donors

Ref.	Country	Number of donations screened	Assay used	Number of samples positive for HEV IgG antibodies	Anti-HEV IgG prevalence (95%CI)	Number of samples positive for HEV IgM antibodies	Anti-HEV IgM prevalence (95%CI)	Number of samples positive for HEV RNA in anti-HEV IgM positive	Viral load, IU/mL	Genotype
Europe
Fischer et al[45], 2015	Austria	1203 (from HEV RNA negative donors)	Wantai	163	13.55% (11.6%-15.5%)	N/A	N/A	0	N/A	N/A
Vercouter et al[46], 2019	Belgium	356 (from HEV RNA negative donors)	Wantai	31	8.71% (6.20%-12.10%)	0	N/A	0	N/A	N/A
Miletić et al[87], 2019	Croatia	1036	3 commercial ELISA assays were used, only findings with highest prevalence are shown	209	20.17%	46	4.44%	0	N/A	N/A
Holm et al[88], 2015	Denmark	504	In-house NIH assay	54	10.7% (8.2%-13.7%)	N/A	N/A	N/A	N/A	N/A
			Wantai	100	19.8% (16.4%-23.6%)
Dimeglio et al[89], 2018	France	300	Wantai	23	7.7% (4.9%-11.3%)	2	0.6% (0.1%-2.4%)	0	N/A	N/A
Juhl et al[90], 2013	Germany	1019	RecomWell assay and Western blot	69	6.8% (5.3%-8.3%)	N/A	N/A	N/A	N/A	N/A
Dalekos et al[91], 1998	Greece	3016	Abbott assay and Western blot	8	0.27%	0	N/A	N/A	N/A	N/A
O'Riordan et al[54], 2016	Ireland	1076	Wantai	57	5.3% (4.0%-6.8%)	2	0.19%	0	N/A	N/A
Spreafico et al[55], 2020	Italy	767	DiaPro	52	6.8% (5.1%-8.8%)	0	N/A	0	N/A	N/A
Spada et al[56], 2018	Italy	10011	Wantai	869	8.7% (8.14%-9.25%)	46	0.4% (0.34% - 0.61%)	0	N/A	N/A
De Sabato et al[92], 2017	Italy	170	Bio-Chain Institute and Western blot	15	8.82%	3	1.76%	0	N/A	N/A
Lucarelli et al[93], 2016	Italy	313	Wantai	153	48.9% (43%-54%)	2	0.6% (0.08%-2.3%)	1	100	3
Puttini et al[94], 2015	Italy	132	EIAgen HEV IgG kit	12	9.1%	N/A	N/A	N/A	N/A	N/A
Hogema et al[95], 2014	Netherlands	513	Wantai	58	11.31%	N/A	N/A	N/A	N/A	N/A
Slot et al[58], 2013	Netherlands	5239	Wantai	1401	26.7% (25.6%-28.0%)	49	0.94%	4	Range: < 25 to 3700	3
Grabarczyk et al[59], 2018	Poland	3079	Wantai	1340	43.52% (41.78%-45.28%)	39	1.27% (0.93%-1.73%)	N/A	N/A	N/A
Sauleda et al[61], 2015	Spain	1082	Wantai	216	19.96% (17.60%-22.32%)	13	1.20%	0	N/A	N/A
			Mikrogen	116	10.72% (8.90%-12.60%)
Mateos et al[96], 1999	Spain	863	Abbott assay and Western blot	34	3.9%	0	N/A	N/A	N/A	N/A
Niederhauser et al[97], 2018	Switzerland	3609	Wantai	737	20.4% (19.1%-21.8%)	N/A	N/A	N/A	N/A	N/A
Kaufmann et al[98], 2011	Switzerland	550	MP Biomedicals	27	4.9%	N/A	N/A	N/A	N/A	N/A
Thom et al[63], 2018	United Kingdom	1714	Wantai	104	6.1% (5.0%-7.3%)	N/A	N/A	N/A	N/A	N/A
Cleland et al[65], 2013	United Kingdom	1559	Wantai	73	4.7% (3.6%-5.8%)	0	N/A	N/A	N/A	N/A
Beale et al[99], 2011	United Kingdom	262	Wantai	31	11.8%	4	1.5%	0	N/A	N/A
North America
Zafrullah et al[100], 2018	United States	5040 (from HEV RNA negative donor)	DSI	569	11.29%	146	2.90%	0	N/A	N/A
			MP Biomedicals	537	10.65%	93	1.85%
			Wantai	619	12.28%	34	0.67%
Stramer et al[68], 2016	United States	4499	MP Biomedicals	329	7.3% (6.6%-8.1%)	26	0.58% (0.39%-0.85%)	N/A	N/A	N/A
Xu et al[69], 2013	United States	1939	Wantai	364	18.8% (17.0%-20.5%)	8	0.4% (0.1%-0.7%)	0	N/A	N/A
South America
Di Lello et al[101], 2020	Argentina	391	DiaPro	44	11.3%	8	2.0%	0	N/A	N/A
Bangueses et al[102], 2020	Uruguay	400	DiaPro	40	10%	19	4.75%	3	N/A	3
Asia
Nouhin et al[103], 2016	Cambodia	301	Wantai	85	28.2% (23.4%-33.5%)	3	1.0% (0.01%-1.8%)	1	956	3
Chen et al[104], 2019	China	4044	Wantai	799	19.8% (18.6%-21.0%)	43	1.1% (0.8%-1.4%)	2	N/A	4
Wen et al[70], 2018	China	5345	Wantai	1227	22.96%	38	0.71%	15	N/A	N/A
Wang et al[105], 2017	China	9069	Wantai	2682	29.57%	131	1.44%	5	N/A	N/A
Ma et al[106], 2015	China	816	Wantai	172	21.1%	4	0.5%	0	N/A	N/A
Ren et al[107], 2014	China	10741	Wantai	2945	27.42%	109	1.01%	0	N/A	N/A
Zhuang et al[108], 2014	China	486	ELISA based on antigen protein pB166 and MPII	113	23.3%	N/A	N/A	N/A	N/A	N/A
Tsoi et al[71], 2019	Hong Kong	2000	Wantai	315	15.8% (14.2%-17.4%)	16	0.8%	0	N/A	N/A
Tripathy et al[109], 2019	India	2447	Wantai	433	17.70% (16.23%-19.26%)	5	0.20%	2	Ranged from 3.5 × 104 to 4.6 × 105 copies/mL	1
Katiyar et al[72], 2018	India	633	Wantai	383	60.5%	N/A	N/A	0	N/A	N/A
Gajjar et al[110], 2014	India	460	DiaPro	N/A	N/A	22	4.78%	N/A	N/A	N/A
Parsa et al[111], 2016	Iran	700	DiaPro	42	6.0%	5	0.71%	5 (only 50 seropositive blood donors were tested)	N/A	1
Hesamizadeh et al[112], 2016	Iran	559	DiaPro	45	8.05%	N/A	N/A	N/A	N/A	N/A
Naeimi et al[113], 2015	Iran	628	HEV IgG, Pasto, Iran	105	16.72%	N/A	N/A	N/A	N/A	N/A
Ehteram et al[114], 2013	Iran	530	DiaPro	76	14.3%	N/A	N/A	N/A	N/A	N/A
Taremi et al[115], 2007	Iran	399	DiaPro	31	7.8%	N/A	N/A	N/A	N/A	N/A
Takeda et al[116], 2010	Japan	12600	in-house ELISA	431	3.42%	N/A	N/A	N/A	N/A	N/A
Shrestha et al[117], 2016	Nepal	1845	Wantai	773	41.9% (39.7%-44.2%)	55	3.0% (2.2%-3.8%)	N/A	N/A	N/A
Nasrallah et al[118], 2017	Qatar	5854	Wantai	1198	20.46%	34	0.58%	4	N/A	N/A
Jupattanasin et al[119], 2019	Thailand	630	EUROIMMUN test kit	187	29.7% (26.2%-33.4%)	N/A	N/A	N/A	N/A	N/A
Africa
Traoré et al[120], 2016	Burkina Faso	1497	DiaPro and Wantai	584	39%	13	0.87%	N/A	N/A	N/A
Ibrahim et al[121], 2011	Egypt	760	N/A	N/A	N/A	3	0.39%	2	N/A	N/A
Meldal et al[122], 2013	Ghana	239	4 commercial assays were used, findings reactive in; at least two serological assays are shown	11	4.6%	14	5.9%	0	N/A	N/A
Lopes et al[123], 2017	South Africa	300	Fortress Diagnostics	76	25.3%	0	N/A	N/A	N/A	N/A
Ben-Ayed et al[124], 2015	Tunisia	426	Globe; Diagnostics Srl ELISA	19	4.46%	N/A	N/A	N/A	N/A	N/A
Others
Hewitt et al[77], 2018	New Zealand	1013	Wantai	98	9.7% (7.9%-11.7%)	N/A	N/A	N/A	N/A	N/A
			MP Biomedicals	82	8.1% (6.5%-10.0%)

ALT: Alanine aminotransferase; CI: Confidence interval; DSI: Diagnostic Systems Incorporated; ELISA: Enzyme-linked immunosorbent assay; HEV: Hepatitis E virus; NIH: National Institutes of Health.

Table 4 Reported cases of transfusion transmitted hepatitis E

Study	Number of patients	Comorbidity	Blood component received (n)	Viral load of transfused blood product IU/mL	Genotype	Treatment	Outcome
Okano et al[137], 2020	1	AML on chemotherapy	Plt	N/A	3b	Nil	Spontaneous resolution and developed HEV antibodies after cessation of chemotherapy for AML
Gallian et al[138], 2019	23	Solid organ transplant, n = 9; allogeneic hematopoietic stem cells transplant, n = 4; hematologic malignancies, n = 5; immunosuppressant, n = 2; immunocompetent, n = 3	RBC n = 7; apheresis Plt n = 3; whole blood-derived pooled Plt n = 6; FFP n = 7	Ranged from 1.14 × 103 to 31 × 62.106	3a, n = 1; 3c, n = 4; 3f, n = 16; 3, n = 1; 4d, n = 1	Ribavirin, n = 15	Acute HEV infection, n = 8; spontaneous resolution, n = 4; ribavirin treatment, n = 3; immunosuppressant reduction, n = 1; chronic HEV infection, n = 14, all immunosuppressed; resolution with ribavirin, n = 10; resolution with immunosuppressant reduction, n = 4; One solid organ transplant recipient did not clear HEV infection despite ribavirin and died of multiorgan failure
Ledesma et al[139], 2019	2	Allogeneic BMT, n = 1; liver transplant, n = 1	Plt	3 × 104	3e	Ribavirin, n = 1	The patient received BMT remained HEV-infected and IgM/IgG-negative until death; the patient with liver transplant was treated successfully with a course of ribavirin
Satake et al[140]a, 2017	19	Hematologic malignancies, n = 6; organ transplant, n = 2; systemic disease, n = 8; no major comorbidity, n = 3	RBC n = 10; Plt n = 6; FFP n = 3	Ranged from 1.5 × 102 to 5.3 × 106	4, n = 2	N/A	Two patients with malignant lymphoma and two who had received liver transplant developed chronic hepatitis E; the two liver transplant recipients were successfully cleared of HEV by ribavirin
Lhomme et al[141], 2017	3	Solid organ transplant	One patient received RBC; one patient received RBC and Plt; one patient received Plt and FFP	Ranged from 3.6 to 8.2 log IU	3, n = 1; 3f, n = 2	N/A	N/A
Yamazaki et al[142], 2017	2	Hematologic malignancies treated with chemotherapy	N/A	N/A	3b	N/A	Did not become chronic hepatitis E
Belliere et al[143], 2017	1	Heart transplant	RBC	1430 copies/mL	3	Ribavirin	Died from multi-organ failure despite treatment
Riveiro-Barciela et al[144], 2017	1	Immunocompetent, admitted for disseminated infection	RBC	75000	3	Nil	Spontaneous resolution
Hoad et al[145], 2017	1	Liver transplant	FFP	947	3	Ribavirin	Resolved with treatment
Matsui et al[146], 2015	1	AMI post CABG with hemorrhagic cardiac tamponade	Plt	106.8 copies	3	Nil	Spontaneous resolution
Huzly et al[147], 2013	1	Immunocompromised	Apheresis Plt	30888-37273	3f	N/A	N/A
Coilly et al[148], 2013	1	Liver transplant	RBC	3.5 log10	3c	Ribavirin	Resolved with treatment
Boxall et al[149], 2006	1	Lymphoma on chemotherapy	RBC	N/A	3	Nil	Spontaneous resolution
Mitsui et al[150], 2004	1	Hemodialysis	RBC	N/A	3	Nil	Subclinical infection without elevated ALT

^aTwo cases were not confirmed by sequence identity and should only be considered as probable TT-HEV.

ALT: Alanine aminotransferase; AMI: Acute myocardial infarction; AML: Acute myeloid leukemia; BMT: Bone marrow transplant; CABG: Coronary artery bypass graft; FFP: Fresh-frozen plasma; HEV: Hepatitis E virus; Ig: Immunoglobulin; Plt: Platelet concentrates; RBC: Red blood cell.