Human Herpesvirus 8 Causes a Wide Spectrum of Disease in Liver Transplant Recipients and May be Donor Derived: Case Series and Systematic Review of an Emerging Challenge

ABSTRACT

Background

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma (KS)‐associated herpesvirus, can cause severe disease in liver transplant (LT) recipients, be donor‐derived, and present variably. We describe HHV8 disease post‐LT.

Methods

HHV8 disease was identified post‐LT in New South Wales (NSW), 2017–2024, and from systematic review. Reports were compared by suspected donor‐derived infection (DDI) and disease manifestation, using chi‐square and t‐tests. Survival was investigated with Cox proportional hazards.

Results

Of 188 records, 79 publications (131 cases) were included, plus four NSW cases (n = 135). Median onset was 7 months posttransplant (IQR: 5–13), with 33% suspected DDI. After median 12 months of follow‐up, 68/125 had disease remission/regression; 59/135 died (49 HHV8‐related). In NSW, Case 1 was proven DDI: visceral KS, 6 months post‐LT; complete remission occurred with immunosuppression modification and chemotherapy. Case 2 was probable DDI: KS, multicentric Castleman's disease, and hemophagocytic lymphohistiocytosis, 3 months post‐LT; the patient died despite immunosuppression modification, hydrocortisone and rituximab. Case 3 was possible DDI: KS‐herpesvirus‐induced cytokine syndrome, 6 months post‐LT; died despite immunosuppression modification and ganciclovir. Case 4 was unlikely DDI: visceral KS, 5 months post‐LT; complete remission occurred with surgery and immunosuppression modification. Survival was worse with visceral KS and non‐KS disease (aHR 5.83 and 4.32, p = 0.002). Reduced immunosuppression, mTORi, and chemotherapy improved survival (aHRs 0.53, 0.36, 0.43; p = 0.006, 0.044, and 0.030). Treatment effects diverged by KS and non‐KS disease. Donor screening identified more KICS and DDI, with improved non‐KS disease survival.

Conclusion

Post‐LT HHV8 disease is heterogeneous, with high mortality. Targeted treatments and possibly donor screening improve survival.

Among 135 cases of post‐liver transplant HHV8 disease (4 from NSW), presentations varied, and mortality was high (44%). Donor screening was rare, and donor‐derived infection was suspected in 33%. Survival improved with mTORi, reduced immunosuppression, chemotherapy, and, for non‐KS disease, donor screening.

Abbreviations

aHR

adjusted hazard ratio

BM

bone marrow

BBV

blood‐borne viruses

CMV

cytomegalovirus

CRP

C reactive protein

CT

computed tomography

DDI

donor‐derived infection

HCC

hepatocellular carcinoma

HCV

hepatitis C virus

HHV8

human herpes virus 8

HIV

human immunodeficiency virus

HLH

hemophagocytic lymphohistiocytosis

IRB

increased risk behaviors

KICS

Kaposi sarcoma herpesvirus inflammatory cytokine syndrome

KS

Kaposi sarcoma

KSHV

Kaposi sarcoma‐associated herpesvirus

LT

liver transplantation

MCD

multicentric Castleman disease

MSM

men who have sex with men

mTORi

mammalian target of rapamycin inhibitor

NK

natural killer

PCR

polymerase chain reaction

PEL

primary effusion lymphoma

PET

positron emission tomography

PTLD

posttransplant lymphoproliferative disease

SOT

solid organ transplantation

1. Introduction

Human herpesvirus 8 (HHV8), also known as Kaposi sarcoma (KS)‐associated herpesvirus (KSHV), is an oncogenic, gamma‐herpesvirus infecting B cells, macrophages, and endothelial and epithelial cells. It has latent and lytic phases with differential gene expression [1]. HHV8 produces viral IL‐6, a homolog of human IL‐6, which promotes B‐cell growth and may contribute to disease manifestations, including KS, multicentric Castleman's disease (MCD), primary effusion lymphoma (PEL), KS‐herpesvirus inflammatory cytokine syndrome (KICS), and other posttransplant lymphoproliferative diseases (PTLDs) [2]. While immunocompetent hosts are rarely symptomatic, HHV8‐related diseases can be severe in immunocompromised individuals.

Global HHV8 seroprevalence ranges from 30%–50% in Africa, and 10%–30% in the Mediterranean, to < 5% in non‐endemic regions [3, 4, 5]. In Australia, estimates are 5.8% in blood donors [6] and 18% among men who have sex with men (MSM) [7], although estimates are limited by available testing [8, 9, 10]. HHV8 transmission is primarily via saliva, but also occurs through sexual, vertical, and parenteral routes, including injecting drug use, blood transfusion, and organ transplantation. Higher prevalence occurs among migrants from endemic regions and individuals with increased risk behaviors (IRB) for other blood‐borne viruses (BBV) [11], including people who inject or inhale drugs, and MSM, particularly those with HIV coinfection [12, 13]. While there is increasing acceptance of organs from IRB donors [14], a recent series describes six suspected HHV8 donor‐derived infection (DDI) cases from IRB donors, with four deaths [15].

Posttransplant HHV8 infections may be donor‐derived, result from recipient latent infection reactivation, or de novo acquisition. HHV8‐related disease in solid organ transplant recipients (SOTr) is uncommon; a recent systematic review (SR) identified just 337 cases (80 in liver transplant recipients [LTrs]) [16]. Underdiagnosis may occur due to varied and non‐specific disease presentations and limited testing availability. LTrs with DDI HHV8 may have worse outcomes compared to other SOTrs [17], possibly due to a higher burden of transmitted virus [18]. Transplant‐specific treatment data are scarce, and often inferred from HIV‐associated HHV8 disease [19]. Donor screening programs, previously limited to endemic regions, are now being trialed in non‐endemic settings such as the United Kingdom, though strategies vary and effectiveness remains uncertain [13, 20, 21, 22, 23].

This review describes HHV8 disease in LTrs through a single‐center case series and an SR of case reports.

2. Methods

2.1. Cases Identified in NSW

HHV8 disease cases among LTrs at the Australian National Liver Transplant Unit, Royal Prince Alfred Hospital (RPAH), were identified from a prospective registry, supplemented with medical record review. All diagnoses were made by multidisciplinary team consensus (including representatives from liver transplant [LT], infectious diseases, microbiology, histopathology, and hematology). Donor risk factors were retrieved from routine organ donation information, per national guidelines [11]. Prospective HHV8 screening is not performed in Australia, and serology is unavailable. Retrospective qualitative PCR testing of donors and recipients was undertaken when clinically indicated (quantitative PCR is not routinely available). Suspected DDIs were categorized using an international algorithm [24] and reported to the NSW Organ & Tissue Donation Service for review at the Vigilance Safety Adverse Event Reporting Committee [25]. Where DDI was considered, HHV8 testing of other recipients of the same donor was recommended. Waiver of consent was granted by the RPAH research ethics board.

2.2. Systematic Review

A SR of published cases was undertaken to assess HHV8 disease presentations, treatments, and DDI among LTrs. We searched Medline (Ovid) until October 14, 2025 (full search strategy in Table S1). Additional cases were identified from guidelines and reference lists. Included reports provided individual LTr case details with any HHV8‐related disease. No language restriction was applied. Titles and abstracts were screened by a single author (K.W.), and full texts by two authors (S.A. and K.W.). Data were extracted into a predefined spreadsheet, with 10% quality checked by a third author (T.M.). For non‐English texts, a native language speaker was preferred for extraction; otherwise, ChatGPT (GPT‐4) was used. Data extracted included publication information (country, year), transplant details (organs, year), and HHV8 disease details (type, timing, donor screening, suspected DDI, treatments given, outcomes [death, disease remission, or regression], and follow‐up time). Suspected DDI status was not independently verified, and misclassification may have occurred. Results were synthesized according to HHV8 disease entity and suspicion of DDI. Descriptive statistics summarized cases with frequencies and proportions, median and interquartile range; chi‐square or Student's t‐tests compared characteristics between groups. Cox proportional hazards models investigated survival from diagnosis. Significant factors (at alpha 0.4) on univariable analysis were incorporated into multivariable models, which were then selected by backward stepwise elimination. Models were stratified by presence or absence of KS to account for divergent treatment strategies.

3. Results

3.1. Cases Identified in NSW

3.1.1. Case 1: Visceral Kaposi Sarcoma

A 58‐year‐old Portuguese‐born man underwent LT for hepatocellular carcinoma (HCC) complicating alcohol‐related and treated hepatitis C virus (HCV) cirrhosis. The donor but not recipient had IRB for BBVs (Table 1). Six months post‐LT, he presented with fever and abdominal pain with elevated C reactive protein (CRP), acute kidney injury, and cholestatic liver function derangement. Imaging demonstrated a large pleural effusion, ascites, and widespread positron emission tomography (PET)‐avid lymphadenopathy. Ascitic and pleural cytology was negative. Histopathology from liver and inguinal lymph node (LN) biopsies demonstrated KS, with positive HHV8 immunohistochemistry (IHC) (Table 1); blood HHV8 PCR was positive. The diagnosis was visceral KS without cutaneous involvement. Management included switching from tacrolimus to everolimus (trough levels 6–8 ng/mL), prednisolone reduction, and five cycles of paclitaxel chemotherapy. He remains in remission at 5 years. Retrospective blood HHV8 PCR was positive in the donor but not recipient pre‐LT. Two of three other recipients of the same donor (lung and kidney) had HHV8 DNAemia posttransplant; neither developed HHV8‐related disease. This case was classified as a proven DDI.

TABLE 1.

Summary of four cases of HHV8 disease post‐LT from a single center.

	Case 1	Case 2	Case 3	Case 4
Donor‐derived infection investigation and outcome
Recipient place of birth	Portugal	Vietnam	Australia	New Zealand
Recipient testing for HHV8 PCR
Pretransplant	Serum: ND	NT	Serum: ND	NT
Posttransplant	Blood: D Liver Bx: D	Blood: D BM Bx: D LN Bx: D	Blood: D BM Bx: D	Blood: D Vocal cord nodule: D
Donor risk factors for HHV8 c	Increased risk behaviors, STI < 12 months	Born in Myanmar, HBV exposed	Increased risk behaviors, HCV exposed, syphilis exposed	Born in Singapore, increased risk behaviors
Donor HHV8 PCR (retrospective)	Plasma: D	Plasma: D	Plasma: ND	Plasma: ND
Donor IHC–liver biopsy	Negative	NT	Negative	NT
Other organs transplanted: posttransplant blood HHV8 PCR	3 recipients–no evidence of HHV8 disease: Lung: D Heart: ND Kidney: D	Liver only donor	2 recipients–no evidence of HHV8 disease: Kidney 1: ND Kidney 2: NT	Liver only donor
Donor‐derived transmission categorization [24]	Proven	Probable	Possible to unlikely a	Unlikely to possible a
Recipient clinical presentation, management, and outcome
Time from transplant to presentation	6 months	3 months	6 months	5 months
Immunosuppression at presentation	Prednisone 5 mg OD Tacrolimus 5 mg BD	Prednisone 15 mg OD Tacrolimus SR 2 mg OD	Prednisolone 5 mg OD Tacrolimus 2 mg BD Sirolimus 2 mg OD	Prednisolone 5 mg OD Tacrolimus 2.5 mg BD Mycophenolate mofetil 500 mg BD
Clinical features	Fever Abdominal pain Ascites Pleural effusions Elevated CRP Renal impairment PET avid LNs	Fevers Lethargy Abdominal pain Diarrhea Peripheral edema Elevated CRP Elevated ferritin Pancytopenia Lung infiltrates PET avid LNs	Fever Fatigue/lethargy Diarrhea Peripheral edema Ascites and pleural effusions Elevated CRP Renal failure Iron deficient anemia Thrombocytopenia Hyponatremia	Throat restriction on swallowing Deranged LFTs Hypopharyngeal nodules PET avid LNs Lung nodules Hepatic nodule
Time from presentation to diagnosis	3 weeks	8 weeks	6 weeks	3 weeks
HHV8‐related diagnosis	Kaposi sarcoma (pleural effusion, ascites, liver, LNs)	Kaposi sarcoma (LNs); multicentric Castleman disease; hemophagocytic lymphohistiocytosis	Kaposi sarcoma virus induced cytokine syndrome; possible primary effusion lymphoma	Kaposi sarcoma (hypopharyngeal nodules, liver, lung, LNs)
Use of antivirals	Valganciclovir prophylaxis for 3 months posttransplant	Valganciclovir prophylaxis on presentation (then held due to cytopenias)	Valganciclovir prophylaxis for 3 months posttransplant. Treatment on presentation with ganciclovir for CMV DNAemia (with possible partial clinical response)	Valganciclovir prophylaxis for 3.5 months posttransplant
Treatments	Change in immunosuppression (cease CNI, commence mTORi); paclitaxel	Hydrocortisone; rituximab	Change in immunosuppression (cease CNI, recommence mTORi)	Change in immunosuppression (cease MMF, reduce CNI, commence mTORi)
Time from presentation to death	N/A	2 months	2 months	N/A
Outcome	In remission at 5 years follow up	Death	Death	In remission at 19 months follow up
Clinical Images
Image Description	Transjugular core liver biopsy (A) H&E (B) IHC b , x200; demonstrates intrahepatic Kaposi sarcoma, a mass‐forming lesion, comprising abnormal spindle cells, that stain strongly with HHV‐8 immunohistochemistry.	Left axillary LN core biopsy (A) H&E (B) IHC, x200; shows intranodal Kaposi sarcoma, a solid mass, with abnormal spindled cells, staining with HHV‐8.	Ascitic fluid cell block (A) H&E (B) IHC, x400; high cellularity, dissociated, large cells with some plasmacytoid morphology, HHV‐8 positive.	Nasolaryngoscopic view of exophytic, smooth mass arising from the right aryepiglottic fold, prolapsing into the hypopharynx.

Abbreviations: Bx, biopsy; CRP, C reactive protein; CNI, calcineurin inhibitor; D, detected; H&E, hematoxylin and eosin staining; HHV8, human herpesvirus 8; IHC, immunohistochemistry; LN, lymph node; mTORi, mammalian target of rapamycin inhibitor; N/A, not applicable; ND, not detected; NT, not tested; PCR, polymerase chain reaction; PET, positron emission tomography; STI, sexually transmitted infection.

^a Cases 3 and 4 likelihood evaluations are limited by the available samples from the donor, that were retrospectively tested with PCR being plasma, and the limited follow‐up of other recipients in Case 3 (no other recipients existed in Case 4).

^b Immunohistochemistry (IHC) using HHV8 immunoperoxidase (BioSB, mouse monoclonal antibody, clone 13B10) which labels the latent nuclear antigen protein.

^c Donor risk behaviors are not described in more detail to avoid identification.

3.1.2. Case 2: Kaposi Sarcoma With Plasma‐Cell Variant of Multicentric Castleman Disease and Hemophagocytic Lymphohistiocytosis

A 58‐year‐old Vietnamese man underwent LT for recurrent cholangitis and HCC. Neither the recipient nor the donor had IRB for BBV. Three months posttransplant, he presented with lethargy, fevers, and abdominal pain, with hypotension requiring inotropic support. PET‐CT scan demonstrated avid subcentimeter LNs above and below the diaphragm, and a bowel lesion. Initial diagnoses (cholangitis, sigmoid adenocarcinoma) delayed further investigations, but were unrelated. Progressive pancytopenia ensued despite cessation of marrow suppressive agents, with increasing edema, daily fevers, and high ferritin (11 000 µg/L). Bone marrow (BM) biopsy demonstrated hemophagocytosis. Natural killer (NK) cell function was normal, but soluble CD25 was elevated. HLH was diagnosed. He received high‐dose dexamethasone and rituximab, with etoposide planned. Axillary LN biopsy demonstrated KS, with a plasmacytic component in surrounding nodal tissue suggesting plasma‐cell variant of Castleman disease (Table 1). HHV8 IHC on BM biopsy and blood PCR were positive. Given poor performance status, he was transitioned to comfort care and died. HHV8 was retrospectively detected by PCR from donor plasma. This case was classified as a probable DDI (no other recipients from the same donor; no retrospective pretransplant recipient HHV8 testing).

3.1.3. Case 3: Kaposi Sarcoma Herpesvirus Inflammatory Cytokine Syndrome

A 68‐year‐old Australian‐born male underwent LT for alcohol‐related cirrhosis with HCC. The donor, but not recipient, had IRB, and prior HCV (antibody positive, PCR negative) and syphilis (rapid plasma reagin 1:2, Treponema pallidum particle agglutination reactive) infections. Five months posttransplant, the recipient presented with fatigue, fevers, peripheral edema, diarrhea, and ascites. He had iron deficiency anemia, hyponatremia, and elevated CRP. Imaging revealed ascites, pleural effusions, and multiple subcentimeter intra‐abdominal LNs. He had CMV DNAemia (23 243 copies/mL) treated with ganciclovir. Ascitic fluid showed a heavy infiltrate of intermediate‐large CD138‐positive plasmacytoid cells with lambda light chain restriction. Pleural fluid aspirate was unremarkable. BM biopsy showed hypercellular aspirate with bilineage dysplasia. Gastroscopy, CT enteroscopy, capsule endoscopy, colonoscopy, and renal biopsy were non‐diagnostic. The spleen and BM, but not LNs were mildly PET‐avid. Temporary improvement following initiation of ganciclovir was followed by a fluctuating course with recurrent fevers, intermittent inotrope requirement, transfusion‐dependent anemia, progressive thrombocytopenia, and oliguric renal failure. Sirolimus and prednisolone were then ceased empirically. Six weeks into admission, a diagnosis of KICS was made with HHV8 detected by IHC on ascitic fluid plasma cells (Table 1) and BM biopsy, and blood PCR. PEL was considered, but not confirmed (insufficient cytological atypia). Tacrolimus was switched to sirolimus, and rituximab treatment was considered, but the patient died from fulminant multi‐organ failure prior to initiation. HHV8 was not detected on retrospective PCR testing of pretransplant recipient or donor plasma, nor of formalin‐fixed, post‐implantation (donor) liver biopsy. Among two other recipients from the same donor, HHV8 was not detected by PCR on blood for one recipient, and the other was not tested; neither developed HHV8 disease. This case was classified as a possible‐unlikely DDI.

3.1.4. Case 4: Visceral Kaposi Sarcoma

A 52‐year‐old New Zealand‐born man underwent LT for primary sclerosing cholangitis with suspected intrahepatic cholangiocarcinoma, treated with neo‐adjuvant chemoradiotherapy. The donor, but not recipient, had IRB for BBV. The recipient was treated with pulse methylprednisolone and mycophenolate mofetil (MMF) for biopsy‐proven mild acute T‐cell‐mediated rejection 11 days posttransplantation. Four months post‐LT, he reported oropharyngeal dysphagia. Nasolaryngoscopy demonstrated a mass at the right aryepiglottic fold (Table 1). Subtotal excision demonstrated KS with HHV8 IHC positivity. Cholestatic liver enzymes were slightly elevated. PET‐CT identified likely KS in the lungs, LNs, and liver. MMF was ceased, and tacrolimus was switched to sirolimus. PET scan 3 months post‐diagnosis showed complete remission, which has continued to 19 months. Retrospective pretransplant serum HHV8 PCR was negative for the donor, and not done for the recipient; there were no other recipients of organs from the same donor. This case was classified as an unlikely‐possible DDI.

3.2. Systematic Review of HHV8 Disease in LT Recipients

After screening 188 records, we included 79 publications reporting 131 cases of HHV8 disease post‐LT (Figure S1), with four NSW cases added (total 135 cases, Table 2, Table S2).

TABLE 2.

Case report characteristics by suspicion of donor‐derived infection.

	All	DDI suspected	DDI not suspected	p value
Cases (n, row %)	135 (100)	45 (33)	90 (67)
Disease manifestations a
Kaposi sarcoma	99 (73)	24 (53)	75 (83)	< 0.001
Visceral b	69 (70)	20 (83)	49 (65)	0.095
Cutaneous b	46 (46)	6 (25)	40 (53)	0.015
Multicentric Castleman disease	12 (9)	3 (7)	9 (10)	0.521
Hemophagocytic lymphohistiocytosis	11 (8)	5 (11)	6 (7)	0.374
Kaposi sarcoma virus induced cytokine syndrome	22 (16)	16 (36)	6 (7)	< 0.001
Primary effusion lymphoma	4 (3)	1 (2)	3 (3)	0.720
Other c	11 (8)	6 (13)	5 (6)	0.119
Multiple	19 (14)	8 (18)	11 (12)	0.382
Year of publication				0.001
1990–1999	16 (12)	1 (2)	15 (17)
2000–2009	33 (24)	6 (13)	27 (30)
2010–2019	39 (29)	13 (29)	26 (29)
2020+	47 (35)	25 (56)	22 (24)
Onset posttransplant (months, median, IQR) e	7 (5–13)	5 (4–8)	9 (6–17)	0.002
Region reporting				0.017
Europe	84 (62)	32 (71)	52 (58)
Americas	28 (21)	10 (22)	18 (20)
Asia	17 (13)	0 (0)	17 (19)
Oceania	6 (4)	3 (7)	3 (3)
Africa	0 (0)	0 (0)	0 (0)
Donor screening program	23 (17)	19 (42)	4 (4)	< 0.001
Treatment a
Reduction in immunosuppression	96 (71)	32 (71)	64 (71)	1
CNI	86 (64)	27 (60)	59 (66)	0.527
Other immunosuppression	41 (30)	11 (24)	30 (33)	0.290
mTORi	58 (43)	26 (58)	32 (36)	0.014
Steroids	17 (13)	6 (13)	11 (12)	0.854
Antivirals	39 (29)	25 (56)	14 (16)	< 0.001
Chemotherapy	30 (22)	10 (22)	20 (22)	1
Rituximab	21 (16)	12 (27)	9 (10)	0.012
Surgery	17 (13)	0 (0)	17 (19)	0.002
Other d	29 (21)	11 (24)	18 (20)	0.553
None	10 (7)	0 (0)	10 (11)	0.020
Follow‐up period (median, IQR) f	12 (2–40)	6 (2–60)	12 (2–40)	0.374
Death	59 (44)	21 (47)	38 (42)	0.624
Death attributed to HHV8 disease	49 (36)	20 (44)	29 (32)	0.164
HHV8 disease remission/regression g	68 (54)	21 (50)	47 (57)	0.482

Abbreviations: CNI, calcineurin inhibitor; DDI, donor‐derived infection; HHV8, human herpesvirus 8; IQR, interquartile range; mTORi, mammalian target of rapamycin inhibitor.

^a Indicates non‐exclusive categories.

^b Visceral and cutaneous KS are reported as percentage of KS cases.

^c Other manifestations were: inflammatory syndrome not meeting KICS criteria (5); lymphoproliferative neoplasm/lymphoma (3); immune thrombocytopenia (2); HHV8‐positive novel spindle cell hepatic neoplasm (1); encephalitis (1).

^d Other treatments (and case numbers used) were: IVIg (6), alpha‐interferon (5), tocilizumab (5), antibiotics (3), probenecid (3), calcineurin inhibitor (3), G‐CSF (2), cryotherapy (2), radiotherapy (2), bortezomib (1), embolization (1), vvHD with cytokine filter (1), diuretics (1), albumin (1), and intrapleural cidofovir (1).

^e Time to diagnosis from transplant was not recorded for 4 cases.

^f Follow‐up time was not recorded for 12 cases.

^g HHV8 disease status was not recorded for 10 cases.

3.2.1. HHV8 Distribution and Disease Manifestations

Most reports were from Europe (62%), followed by the Americas (21%). Median onset was 7 months post‐LT (IQR 5–13). Most cases involved KS (99/135, 73%: cutaneous only 22/91 [24%], visceral only 45/91 [49%], both 24/91 [26%], and site not reported 8/99). Additional diseases included KICS (22), MCD (12), HLH (11), PEL (4), and other manifestations (n = 11: inflammatory syndrome not meeting KICS criteria [5], non‐PEL PTLD [3], immune thrombocytopenic purpura [2], de novo HHV8‐positive spindle cell hepatic neoplasm [1], and HHV‐8 encephalitis [1]). Multiple HHV8‐related diagnoses were present in 14% of cases, more commonly with MCD, HLH, and non‐PEL PTLD (Table S3). Inflammatory syndromes (KICS, non‐KICS inflammation, and HLH) were only recognized from 2010 onwards, while earlier reports were almost exclusively KS.

3.2.2. Treatment of HHV8 Disease

The most common treatments for HHV8 disease were immunosuppression modification (71%), mammalian target of rapamycin inhibitors (mTORi, 43%), chemotherapy (22%: anthracyclines 15/30; vinca alkaloids 9/30; taxanes 4/30; bleomycin 3/30; etoposide 2/30; combinations 6/30), and antivirals (29%: ganciclovir/valganciclovir 16/39, cidofovir 12/39, foscarnet 8/39, and 8/39 cidofovir, or foscarnet not further specified, including multiple regimes 5/39). Other treatments (21% [29/135] patients) included intravenous immunoglobulin (6/29), alpha interferon (5/29), and tocilizumab (5/29).

Treatments differed by HHV8 disease (Table S3), particularly diverging between KS and inflammatory syndromes. Rituximab was used more in HLH (73% vs. 10%, p < 0.001), KICS (45% vs. 10%, p < 0.001), MCD (50% vs. 12%, p = 0.001), and non‐PEL PTLD (100% vs. 14%, p < 0.001), and used less in KS (9% vs. 33%, p = 0.001) than other HHV8 diseases. Antivirals were prescribed more for KICS (86% vs. 18%, p < 0.001) and non‐KICS inflammatory syndromes (80% vs. 27%, p = 0.010), and less commonly for KS (14% vs. 69%, p < 0.001) than for other diseases. Surgery was not used for KICS (0% vs. 15%, p = 0.052) and was more frequently used for KS (16% vs. 3%, p = 0.038). Steroids were prescribed more frequently in HLH (73% vs. 7%, p < 0.001), chemotherapy in KS (27% vs. 3%, p = 0.019), and mTORis in KICS (68% vs. 38%, p = 0.009), compared with other diseases.

3.2.3. Donor Screening Programs

Donor screening was reported in five publications (23 cases); most were in Europe, with one in the USA. Diagnoses of KICS and non‐KICS inflammatory syndromes were associated with donor screening (p < 0.001). Suspected DDI were also more common with donor screening (p < 0.001).

3.2.4. Donor‐Derived HHV8

DDI was suspected in 33% of cases; however, most reports did not identify a suspected infection source. DDI cases were increasingly recognized over time (p = 0.001), more commonly in Europe (71%, p = 0.017). Suspected DDI cases presented earlier (median presentation of 5 vs. 9 months post‐LT, p = 0.002) than other cases.

Suspected DDI presented less commonly with KS (53% vs. 83%, p < 0.001) and more commonly with KICS (36% vs. 7%, p < 0.001) than where DDI was not suspected. KS in suspected DDI was less often cutaneous (25% vs. 53%, p = 0.015), but had similar visceral involvement (83% vs. 65%, p = 0.095) compared to non‐DDI cases.

Suspected DDI cases received more mTORi (58% vs. 36%, p 0.014), rituximab (27% vs. 10%, p = 0.002), and antivirals (56% vs. 16%, p < 0.001). No suspected DDI cases were managed surgically (0% vs. 19%, p = 0.002), or given no treatment (0% vs. 11%, p = 0.020).

3.2.5. Survival

A total of 44% of LTrs with HHV8 disease died; most deaths (49/59, 83%) were attributed to HHV8 disease. Remission or regression of disease was reported in 54% of cases (disease status was not reported in 10 cases). Death was more common among PEL than non‐PEL cases (100% vs. 42%, p = 0.021), while remission or regression was more common among non‐KICS inflammatory cases than other diseases (100% vs. 53%, p = 0.037).

There were 276 person‐years (median 12 months) of follow‐up across 123 cases with information suitable for survival analysis. There was no significant collinearity in any models (VIF < 5). On multivariable analysis, survival was worse with visceral KS (adjusted hazard ratio, aHR 5.83; 95% CI 2.20–15.43) or non‐KS diseases (aHR 4.32; 95%CI 1.58–11.76; p = 0.002) compared to cutaneous KS (Figure 1, Table S4A). Treatment with mTORi was associated with improved survival (aHR 0.36; 95%CI 0.17–0.74; p = 0.006, Figure S2), as was reduction in immunosuppression (aHR 0.53; 95%CI 0.28–0.98; p = 0.044), and chemotherapy (aHR 0.43; 95%CI 0.20–0.92; p = 0.030).

FIGURE 1.

Univariable (A) and multivariable (B) Cox proportional hazards for death with 95% confidence intervals, among case reports of HHV8 disease post liver transplant. Twelve cases were excluded from the survival model as no follow‐up period was provided. DDI: donor‐derived infection, HHV8: human herpesvirus 8, KS: Kaposi sarcoma, mTORi: mammalian target of rapamycin inhibitor.

Stratified analysis showed diverging treatment effects by KS status (Table S4B). On univariable analysis, there was improved survival with rituximab for non‐KS cases (log‐rank = 0.033) that was not seen in KS cases (non‐significant effect in opposing direction, log‐rank = 0.700; Figure S3). A nonsignificant trend to improvement in survival with antivirals was also seen among non‐KS cases (p = 0.077). On multivariable analysis, reduction in immunosuppression was associated with improved survival for both non‐KS and KS cases. However, for non‐KS cases, donor screening was associated with improved survival (aHR 0.21; 95% CI 0.07–0.66; p = 0.008), while for KS cases, mTORi use (aHR 0.31; 95%CI 0.11–0.83; p = 0.021), surgery (aHR 0.18; 95%CI 0.06–0.50; p = 0.001), and chemotherapy (aHR 0.41; 95%CI 0.18–0.96; p = 0.039) were associated with improved survival.

4. Discussion

We report four cases of HHV8 disease post‐LT from a non‐endemic region with only two prior published cases and expand the global evidence base from 80 to 135 cases. The case series demonstrates the diverse clinical spectrum and diagnostic challenges in HHV8 disease, including 2/4 proven/probable DDI. The SR demonstrates a high mortality rate post‐LT (44%, including 36% from HHV8), higher than estimates across all organs (20% 90‐day overall survival [16]). Within the limits of observational data, it also shows the potential for improved survival with disease‐specific treatment, and for non‐KS cases with donor screening.

4.1. Recognizing the Spectrum of HHV8‐Related Diseases

This series demonstrates the spectrum of inflammatory and malignant HHV8 diseases. Multiple HHV8‐related conditions may co‐exist, and their clinical features and treatments can overlap. These characteristics make recognition of HHV8 as the driver of disease challenging (Figure 2) [18].

FIGURE 2.

Schema of HHV8‐related conditions, with summary of clinical features and proposed treatments (compatible but uncommon manifestations are in brackets). CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; CRP, C reactive protein; EPOCH, etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin; HLH, hemophagocytic lymphohistiocytosis; IL‐6, interleukin 6; KICS, Kaposi sarcoma herpesvirus virus inflammatory cytokine syndrome; KS, Kaposi sarcoma; LDH, lactate dehydrogenase; MCD, multicentric Castleman disease; mTORi, mammalian target of rapamycin inhibitor; NK, natural killer; PEL, primary effusion lymphoma; sCD25, soluble CD25; sIL2R, soluble interleukin‐2 receptor.

Cases 1 and 4 demonstrate KS with visceral involvement, including the transplanted liver. KS is a disease of mesenchymal and endothelial cells of blood vessels and lymphatics, leading to multicentric vascular hyperplasia and characteristic elongated tumor “spindle” cells [26]. KS is much more common among SOTrs than the general population (SIR > 50) [34, 35, 36], although the absolute risk remains low (e.g., < 0.1%, USA [37, 38]; 2%, Italy [39, 40]). In both Cases 1 and 4, KS was diagnosed promptly. Case 1 had longstanding remission following treatment, while Case 4 has early remission with immunosuppression reduction only. In the SR, visceral KS was associated with worse survival than cutaneous‐only KS post‐LT, which may relate to diagnostic delays or more aggressive disease course.

Case 2 demonstrates lymphoproliferative HHV8 disease, with MCD arising alongside LN KS, complicated by HLH. MCD is a lymphoproliferative disease involving enlarged LNs in multiple regions, with characteristic hyperplasia on biopsy, and systemic symptoms. Among HHV8‐positive, HIV‐negative MCD, SOTrs are infrequent [41, 42, 43]. Consistent with other studies, many (42%) patients in our series with MCD had concurrent KS, mostly visceral, and 25% had concurrent HLH, a hyper‐inflammatory condition which can be triggered by HHV8 [44]. We found that 91% of HHV8‐related HLH co‐occurred with other HHV8 diseases.

Case 3 demonstrates the non‐malignant inflammatory process, KICS [45]. Diagnosis requires clinical manifestations plus systemic inflammation, high‐level HHV8 DNAemia, and exclusion of MCD. Rarely described posttransplant [46], we compile 22 cases of KICS in LTrs, mostly the sole HHV8 disease manifestation. Most were suspected DDI (80%). Five additional non‐KICS inflammatory syndrome cases [22], falling short of the KICS definition, all had contrastingly good outcomes following early treatment. All 27 inflammatory cases were described after 2010, given the recent formal description of KICS. Recognition of these cases may still be limited by clinician awareness.

Case 3 fell short of a PEL diagnosis despite atypical HHV8‐positive plasma cells in ascitic fluid. PEL is a diffuse large B‐cell lymphoma of plasmablastic cells infected with HHV8, which accumulate in body cavities; it rarely occurs post‐SOT [1, 47]. We identified only four cases of PEL post‐LT, occurring without other HHV8 diseases. All died within short follow‐up period. Other forms of HHV8‐associated PTLD have been described, with varied features [19, 48]. Only 1/3 of non‐PEL HHV8‐related PTLD cases died.

4.2. Diagnostic Testing for HHV8 Diseases

Limitations to the timely diagnosis of HHV8 disease and attribution of DDI in our local cases include common diagnostic testing constraints. First, serology for HHV8 is not widely available. As DNAemia is uncommon in latent infection, PCR alone cannot reliably identify donor or recipient exposure pre‐LT. HHV8 serology tests are challenged by the differential antigen expression of the virus and subjectivity of immunofluorescence assays; there is limited availability of standardized commercial tests. Second, for recipient monitoring, qualitative HHV8 PCR is important (but was not available to us), as higher DNAemia is associated with severe posttransplant HHV8 disease, particularly KICS. Improved diagnostics are important for implementing donor screening, attributing DDI, and improving recipient diagnosis and monitoring.

4.3. Current Management of HHV8 Diseases

The treatment of HHV8 diseases post‐LT varies according to the condition. Immunosuppression modification is first‐line management [18], but can be insufficient. We found that mTORi use was associated with improved survival, which may reflect an indirect anti‐tumor effect [49], direct stimulation of T‐cell functionality [50], or reduction in viral replication [51]. Despite this, mTORis were only prescribed in 43% of HHV8 disease cases, suggesting room for improved management.

The role of antivirals in HHV8 disease remains uncertain, although we found a trend toward improved survival for non‐KS cases on univariable analysis. Valganciclovir reduced oral HHV8 shedding in a small randomized controlled trial [52]. The use of high‐dose zidovudine with valganciclovir to treat MCD in 14 people with HIV was promising: three had a complete response, one had a partial response, and nine demonstrated disease stability [53]. Post‐LT, a case report describes successful treatment of MCD with valganciclovir plus immunosuppression modification [54]. More recently, a large single‐center study reported on the inclusion of antivirals in a management bundle for SOTrs with KICS; however, the contribution of the antiviral to the outcome could not be assessed [22]. We suggest cautious use of antivirals in select non‐KS HHV8 disease cases, especially those with substantial HHV8 DNAemia, weighed against potential toxicities such as cytopenias and renal toxicity [55, 56].

Chemotherapy is the standard treatment for visceral KS or KS non‐responsive to immunosuppression modification, most commonly with doxorubicin and paclitaxel [18, 19, 57]. We found that chemotherapy was associated with improved survival, particularly in KS cases. For PEL, chemotherapy including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), sometimes with etoposide, is typically recommended [1, 58], based on studies in people with HIV (no data exist in SOT). Etoposide may be used for HLH, combined with steroids, and for MCD [19, 41]. Chemotherapy is not recommended for KICS [46].

Rituximab has greatly improved prognosis in HIV‐positive patients with MCD and is considered first‐line therapy [59, 60]. It can be used for HLH [44] or KICS, where a recent prospective study was suggestive of improvements in survival (without meeting power) [22, 46]. However, rituximab may increase risk of, or worsen, KS [59, 61]. We found a divergence in survival with rituximab stratified by KS and non‐KS cases on univariable analysis, but the improvement in survival for non‐KS cases lost power on multivariable analysis (only 35 contributing cases).

Tocilizumab has also been successfully used to treat MCD or KICS associated with HIV [62, 63]. We found five cases, mostly inflammatory, treated with tocilizumab, which was insufficient for survival analysis.

4.4. HHV8 as a DDI

HHV8 can be transmitted via allografts, but the true rate of DDI is unknown given differences in screening methods and potential for asymptomatic DNAemia. Three prospective European studies screened SOT donors for HHV8 [9, 17, 64]. The French cohort accepted any lytic or latent assay as seropositive (combined seroprevalence 12.0%) and had low rates of HHV8 DNAemia (3.4%) among at‐risk LTrs. Two smaller Italian cohorts used a combined latent and lytic approach, and reported lower donor seroprevalences (around 4%), with higher DNAemia rates (25%–50%) among at‐risk LTrs. Across the studies, among LTrs with HHV8 DDI, HHV8 disease occurred in 50%–100% of cases, often leading to death. Available data suggest that LTrs develop HHV8 DNAemia and disease at around twice the rate of other SOTrs [9, 17].

We found 33% of cases were suspected DDI, although interpretations of this categorization are tempered by likely misclassification error. Nonetheless, we found suspected DDI presented earlier, with severe manifestations (KICS, visceral KS). Increasing reports of HHV8 DDI over time may reflect increasing awareness. Survival did not differ by DDI status, possibly because centers identifying HHV8 DDI are more experienced, with earlier detection and intervention. Consistent with this, fewer DDI cases had no treatment than non‐DDI cases. This highlights the importance of awareness among transplant clinicians about HHV8‐related diseases.

Approaches to mitigating mortality from HHV8 DDI, including screening of donors and/or SOTrs for HHV8, vary globally [18, 21]. Screening is more common among centers with prior posttransplant HHV8 diagnoses [21], and in endemic regions (e.g., Italy [20, 46]), allowing for close monitoring and early intervention [22]. Recently, the UK, a non‐endemic region, has begun screening with HHV8 serology for all donors following a series of fatal suspected DDIs. SOTrs are monitored closely for development of HHV8 DNAemia and/or disease [23, 65]. Although few studies involved donor screening programs, we found these were associated with an increased detection of HHV8 DDI, increased detection of inflammatory HHV8 manifestations (KICS/non‐KICS inflammatory syndromes), and improved survival in non‐KS disease. This adds weight to emerging evidence on the utility of donor screening, likely from early detection and treatment. Potential concerns around universal donor screening include practical issues (e.g., the availability of standardized serology testing), cost‐effectiveness (particularly in low prevalence settings), and uncertainty about preemptive management of asymptomatic recipient DNAemia (not studied here). Increasing data point to higher rates of HHV8 DDI from donors with IRB for BBV, and targeted HHV8 screening of IRB donors could be considered in low prevalence settings. However, this has not been adopted as a strategy in any published studies or guidelines, and could risk re‐stigmatizing a donor group that has been historically under‐utilized. Where donor screening is not performed, clinicians must be aware of HHV8‐related presentations, have a high index of suspicion, and test promptly if HHV8 disease is suspected.

4.5. Strengths and Limitations

This review provides four demonstrative cases of HHV8 disease post‐LT in a region with limited prior reports. It provides an SR and analysis of reported cases, with novel insights on treatments and donor screening, particularly for non‐KS cases. However, publication bias is likely when summarizing case reports, which may overrepresent severe or successfully treated cases and will miss unrecognized cases. Categorization of reported diseases and suspected DDI is likely to be biased, although it is the best available data. We could not completely account for all confounding factors, for example, disease severity at treatment initiation. These limited data highlight the importance of further research and reporting in this area.

5. Conclusion

HHV8‐related disease post‐LT is uncommon but associated with diverse presentations and high mortality. Survival is improved with disease‐specific treatments, and possibly donor screening. Studies implementing screening in low‐prevalence settings and consensus management protocols are needed.

Author Contributions

Karen M. J. Waller: conceptualization, methodology, investigation, validation, formal analysis, writing – original draft. Sudarshan Arvind: investigation, data curation, writing – review and editing. Simone I. Strasser: resources, writing – review and editing. Ken Liu: resources, writing – review and editing. Geoff W. McCaughan: resources, writing – review and editing. David G. Bowen: resources, writing – review and editing. Madeleine Gill: resources, writing – review and editing. Rebecca Davis: resources, writing – review and editing. William Rawlinson: resources, writing – review and editing. Sacha Stelzer‐Braid: resources, writing – review and editing. Geoff Watson: resources, writing – review and editing. Vinay Vanguru: resources, writing – review and editing. Tina Marinelli: conceptualization, validation, writing – review and editing, supervision.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Information File 1: tid70293 sup 0001 SuppMat.docx

Supporting Information File 2: Visual Abstract

Data Availability Statement

All relevant data are provided as Supporting Information related to the systematic review.