HHV‐8 Infection in Solid‐Organ Transplant—Pathogenesis, Epidemiology, Clinical Manifestations and Management

ABSTRACT

Human herpesvirus‐8 (HHV‐8) is an oncogenic herpesvirus that poses unique challenges in solid‐organ transplantation. Although uncommon, HHV‐8–associated diseases including Kaposi sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and the KSHV inflammatory cytokine syndrome (KICS) can lead to significant morbidity, graft loss, and death. The clinical spectrum ranges from indolent cutaneous lesions to fulminant systemic inflammation, yet recognition is often delayed because of nonspecific presentations and the lack of standardized screening or monitoring strategies. Regional differences in HHV‐8 seroprevalence and immunosuppressive regimens further complicate prevention and management. This review summarises current understanding of HHV‐8 infection in solid‐organ transplant recipients, focussing on epidemiology, transmission pathways, pathogenesis, clinical manifestations, diagnostic approaches, and management principles for each major syndrome. It also highlights knowledge gaps, therapeutic challenges, and priorities for research and standardized surveillance to improve outcomes in this rare but important group of transplant‐related complications. We propose a risk‐stratified donor and recipient screening algorithm and a practical management framework for recipients with HHV‐8 PCR positivity but without symptoms, to guide clinical practice in the absence of standardized guidelines.

Abbreviations

AST

American Society of Transplantation

CHOP

Cyclophosphamide, Doxorubicin, Vincristine, Prednisone

EBV

Epstein–Barr Virus

HHV‐8

Human Herpesvirus 8

IL

Interleukin

KICS

KSHV Inflammatory Cytokine Syndrome

KS

Kaposi Sarcoma

LANA‐1

Latency‐Associated Nuclear Antigen 1

MCD

Multicentric Castleman Disease

mTOR

Mammalian Target of Rapamycin

NAT

Nucleic Acid Testing

PCR

Polymerase Chain Reaction

PDGF

Platelet‐Derived Growth Factor

PEL

Primary Effusion Lymphoma

SOT

Solid Organ Transplant

VEGF

Vascular Endothelial Growth Factor

1. Introduction

Human herpesvirus‐8 (HHV‐8), a gammaherpesvirus, underlies a spectrum of neoplastic and inflammatory disorders that can occur in solid organ transplant (SOT) recipients, including Kaposi sarcoma (KS), multicentric Castleman disease (MCD), primary effusion lymphoma (PEL), and the KSHV inflammatory cytokine syndrome (KICS) [1]. In SOT recipients, chronic immunosuppression impairs viral control and increases susceptibility to HHV‐8–associated disease, which can carry substantial morbidity and mortality [2]. Screening and monitoring remain not standardized; pre‐transplant serology may help identify risk in all SOT programmes, although its cost‐effectiveness may be limited in very low‐prevalence settings [3].

HHV‐8‐associated disease may result from transmission via donor organs or blood products, or from reactivation of latent infection in a seropositive recipient [4]. Management is challenging and requires individualized strategies that balance reduction or modification of immunosuppression with syndrome‐directed therapy. Given that guidance is based largely on case series, small cohorts, and experience extrapolated from HIV‐associated disease, this review summarises practical, clinician‐focused principles across epidemiology and transmission, clinical phenotypes, diagnosis, screening and monitoring, and treatment, and highlights pragmatic strategies for transplant programs. Despite recent reviews, three areas remain poorly addressed in the current literature: (1) how to screen donors and recipients when no FDA‐approved or CE‐marked HHV‐8 assay exists; (2) what to do clinically when a recipient tests positive by PCR but remains asymptomatic; and (3) how to integrate geographic seroprevalence and donor risk‐factor data into a practical, risk‐stratified surveillance algorithm. This review aims to address these specific gaps.

2. Epidemiology and Transmission

2.1. Global Patterns and Risk Strata

HHV‐8 is globally distributed but shows marked geographic variability, with highest community seroprevalence in parts of sub‐Saharan Africa (50%–70%), intermediate prevalence around the Mediterranean (10%–30%), and lower prevalence in many regions of North America and Asia (< 5%) [5, 6, 7]. Reported HHV‐8 seroprevalence among solid organ transplant donors and recipients varied substantially across geographic regions, reflecting the heterogeneous global epidemiology of HHV‐8. Across published studies, donor seroprevalence ranged from approximately 1.1%–25.2%, whereas recipient seroprevalence ranged from 2.4% to 40.6%, with higher seroprevalence observed among recipients in most comparative studies (Table 1) [8, 9, 10, 11, 12, 13, 14, 15]. The highest seroprevalence rates were reported in endemic regions such as sub‐Saharan Africa and the Mediterranean, whereas consistently low rates were observed in North America and most parts of Asia. Several factors may contribute to this difference. Recipients often have chronic conditions such as end‐stage renal disease requiring dialysis or repeated transfusions and may also come from older, socioeconomically disadvantaged, or other high‐risk groups, all of which increase their risk of prior HHV‐8 exposure [14, 15]. Local and regional epidemiologic patterns should be considered when stratifying HHV‐8 risk before and after transplantation. Donors at elevated risk of HHV‐8 seropositivity include those of sub‐Saharan African or Mediterranean origin, men who have sex with men (MSM), and persons living with HIV (PLWHIV). In the HOPE cohort of kidney transplants from donors with HIV to recipients with HIV in the United States, KSHV seroprevalence reached up to 40.6% among recipients and 25.2% among donors, with MSM as the strongest independent risk factor [13]. Identification of such donor risk factors should be incorporated into standard pre‐transplant evaluation, especially in programs serving diverse or high‐risk populations.

TABLE 1.

Seroprevalence of HHV‐8 among SOT donor and recipients and HHV‐8 related diseases in cohort studies, 2000–2025.

Study (First author, year)	Country	Donor/recipient population	Donor seroprevalence (%)	Recipient seroprevalence (%)	HHV‐8 related diseases in D+/R‐ (%)	HHV‐8 related diseases in R+ (%)	HHV‐8 related diseases in D‐/R‐ (%)	Total HHV‐8 disease cases
Marcelin et al. (2004) [8]	France	Liver donors & recipients	3.3% (4/122)	2.4% (3/122)	50.0% (2/4)	0 (0/3)	0 (0/115)	2
Francès et al. (2009) [9]	France	Kidney donors & recipients	1.1% (40/3693)	3.2% (161/4969)	4.7% (3/64)	13.0% (21/161)	0 (0/4744)	24
Pietrosi et al. (2011) [10]	Italy	Liver donors & recipients	4.4% (8/179)	10.2% (22/215)	37.5% (3/8)	0 (0/19)	0.7% (1/152)	4
Chiereghin et al. (2017) [11]	Italy	Solid organ donors & recipients	4.0% (10/249)	18.0% (93/517)	25.0% (3/12)	1.1% (1/93)	0 (0/346)	4
Durand et al. (2022) [12]	US	Liver donors & recipients with HIV	26.1% (6/23)	21.2% (7/33)	NA	NA	NA	3
Nambiar et al. (2025) [13]	US	Kidney donors & recipients with HIV	25.2% (33/131)	40.6% (143/352)	NA	NA	NA	5
Mularoni et al. (2025) [14]	Italy	Solid organ donors & recipients	3.3% (45/1349)	8.4% (155/1856)	26.5% (13/49)	1.9% (3/155)	0.3% (5/1652)	21
Roo‐Brand et al. (2025) [15]	Netherlands	Solid organ donors & recipients	2.8% (4/144)	10.3% (15/145)	NA	NA	NA	NA

2.2. Mode of HHV‐8 Transmission in SOT

There are three primary modes (Table 2).

TABLE 2.

Modes of HHV‐8 infection in transplant recipients.

Mode of infection	Source of HHV‐8	Timing of infection	Risk of HHV‐8 related disease	Clinical significance
Donor‐derived infection (DDI, D+/R−)	Organ from HHV‐8–seropositive donor	At the time of transplantation	+++	Highest‐risk scenario (45% transmission, 26% disease) [14]. May present early post‐transplant and associated with severe illness [16, 17, 18].
Reactivation (R+)	Latent virus within the recipient's own cells	Any time post transplantation	++	Most common mode of HHV‐8 disease. Risk is heightened by immunosuppression [14, 17].
De novo infection (community‐acquired, D‐/R‐)	Community exposure (via saliva, blood)	Any time post transplantation	+	The rarest pathway for HHV‐8 disease (< 1%). Sporadic case in endemic areas [10, 14].

2.2.1. Donor‐Derived Primary Infection (D+/R−)

The seronegative recipient receives a seropositive organ. This is the highest‐risk scenario, in the large cohort, HHV‐8 transmission occurred in 44.9% of D+/R– transplants, and 25.6% of recipients developed HHV‐8–related disease [14]. Lacking pre‐existing immunity, recipients may present early in post‐transplant period, and illness can be severe disease [16, 17].

2.2.2. Reactivation in Seropositive Recipients (R+)

Loss of immune control under maintenance immunosuppression or antirejection therapy leads to viral activation of latent HHV‐8. The French prospective study of kidney recipients showed a 13% cumulative KS incidence at 3 years among R+, with older age and Black race identified as risk factors [9]. Although reactivation is the most common mode of HHV‐8 disease, its clinical course is generally less aggressive than primary infection [14, 17].

2.2.3. De Novo (Community‐Acquired) Infection (D−/R−)

The least common and occurs when seronegative recipients acquire HHV‐8 post‐transplant from community exposures. Blood transfusion is a recognized transmission route in regions without universal leukoreduction (e.g., sub‐Saharan Africa), where high HHV‐8 seroprevalence and non‐leukoreduced whole blood make transfusion‐transmission clinically relevant; however, in high‐income countries with near‐universal leukoreduction, blood transfusion is not considered a significant HHV‐8 transmission risk [4, 5]. In two Italian cohorts of D–/R– transplants, HHV‐8–related disease occurred in 0.3%–0.7% of recipients with presentations including KICS or MCD [10, 14].

2.3. Pathogenesis of HHV‐8 Related Disease

HHV‐8 pathogenesis in SOT reflects the interaction between viral biology, host immunity, and immunosuppressive therapy. In immunocompetent hosts, CD8⁺ T‐cells and NK cells maintain viral latency, but chronic immunosuppression particularly with calcineurin inhibitors, corticosteroids, or T‐cell–depleting agents impairs this control, allowing viral reactivation or donor‐derived primary infection [19].

The virus infects endothelial, monocyte and B‐cell lineages, alternating between latency and lytic replication [20]. Latent proteins (LANA‐1, vCyclin, vFLIP) promote cell survival, whereas lytic proteins (vIL‐6, vGPCR) drive cytokine release and angiogenesis through IL‐6, IL‐10, VEGF, and PDGF [4, 21]. mTOR inhibitors exert antiproliferative and antiangiogenic effects that may counter these mechanisms [22].

Clinical phenotype depends on the infected cell type and the dominant viral programme. Endothelial proliferation produces KS, plasmablastic B‐cell expansion and cytokine dysregulation lead to MCD and KICS, and malignant transformation of B cells results in PEL [4, 20, 23, 24]. Table 3 summarises these pathogenetic mechanisms.

TABLE 3.

Summary of clinical features, diagnosis and management of HHV‐8 related disease in SOT recipients.

	Kaposi sarcoma (KS)	Primary effusion lymphoma (PEL)	Multicentric castleman disease (MCD)	KSHV inflammatory cytokine syndrome (KICS)
Pathogenesis	Infection of endothelial/spindle cell Latent‐dominant Viral proteins (LANA‐1, vCyclin, vFLIP) drive angiogenesis via VEGF, PDGF.	B‐cell origin (often EBV co‐infection) Latent‐dominant NF‐κB activation and viral miRNAs promoting proliferation.	Plasmablast proliferation in lymph nodes with lytic‐active HHV‐8 replication. vIL‐6 and host IL‐6/IL‐10 drive cytokine excess.	Systemic lytic replication within HHV‐8–infected B cells Cytokine release (vIL‐6, host IL‐6/IL‐10) and multiorgan inflammatory response.
Clinical features	Violaceous macules, papules, or nodules on skin (often lower limbs) Mucosal, nodal, or visceral disease in advanced cases	Malignant pleural, pericardial, or peritoneal effusions with B symptoms Uncommon extra‐cavitary (mass‐like lesion)	Fever, cachexia Generalised lymphadenopathy Splenomegaly Cytopenia	Fever, cachexia Splenomegaly Organ dysfunction Cytopenia
Key diagnostic findings	Biopsy showing spindle‐cell vascular proliferation; HHV‐8 LNA‐1–positive by immunostain. HHV‐8 viraemia (by PCR/NAT) usually low or absent.	Effusion cytology/cell‐block IHC: HHV‐8+ large plasmablastic cells; pan‐B antigens often negative	Lymph‐node biopsy showing plasmablastic or mixed variant; HHV‐8 LNA‐1 positive Plasma HHV‐8 viraemia (PCR/NAT) elevated and correlates with activity.	Markedly elevated HHV‐8 viraemia (by PCR/NAT) High IL‐6/IL‐10 Exclusion of MCD on lymph‐node biopsy.
Main management principles	Reduce or withdraw IS; convert to mTORi. Local therapy for limited lesions Systemic chemotherapy (liposomal doxorubicin or paclitaxel) for disseminated or refractory disease.	Anthracycline‐based chemotherapy (CHOP/EPOCH) Rituximab (if CD20+). IS management as adjunct. Prognosis generally poor (median survival < 1 yr).	Rituximab‐based regimen ± chemotherapy. Add antivirals (ganciclovir/valganciclovir/cidofovir) or IL‐6 blockade (tocilizumab/siltuximab) as adjuncts.	Rituximab Antiviral agent (ganciclovir/foscarnet/cidofovir) IL‐6 pathway blockade (tocilizumab/siltuximab) Intensive supportive care.

Abbreviations: CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; EBV, Epstein–Barr virus; IHC, immunohistochemistry; IL, interleukin; LANA‐1, latency‐associated nuclear antigen 1; mTOR, Mammalian Target of Rapamycin; PDGF, platelet‐derived growth factor; VEGF, vascular endothelial growth factor.

3. Clinical Manifestations

3.1. Post‐Transplant Kaposi Sarcoma (PT‐KS)

Kaposi sarcoma is the most frequent HHV‐8–associated disease following SOT. It typically arises during the first 2 years after transplantation, although both early and late presentations have been reported [25]. Atypical involvement has also been described, including allograft KS, pelvic lymphadenopathy, bladder, penile, and tonsillar KS, particularly in the donor‐derived setting [26, 27, 28, 29]. The timing of onset varies by organ transplanted and the mode of HHV‐8 infection. In liver transplant recipients, PT‐KS tends to occur earlier, with a median time of 6 months [30]. Cases attributed to primary HHV‐8 infection often develop shortly after transplantation, typically within the first 6 months, and follow an aggressive clinical course [17, 25]. Cutaneous disease is the most common manifestation, often beginning as violaceous macules, papules, or nodules on the lower extremities, but mucosal, lymph node, and visceral involvement are not uncommon. In a large kidney transplant cohort of 55 PT‐KS cases, skin involvement was universal, with the legs affected twice as often as the arms [27]. Oral, conjunctival, and palatal lesions were also described in North African series [28]. Pulmonary KS, though rare, has been increasingly recognized in lung transplant recipients, where it may present as raised, red‐purple, polypoid endobronchial lesions that bleed easily. These cases often arise after intensified immunosuppression for rejection and are associated with rapid clinical decline [31].

3.2. Post‐Transplant Primary Effusion Lymphoma (PT‐PEL)

Primary effusion lymphoma is a rare but highly aggressive HHV‐8–driven B‐cell malignancy that usually arises after prolonged immunosuppression, although early cases within the first year post‐transplantation have also been reported [32, 33]. It most often manifests as malignant effusions involving the pleural, peritoneal, or pericardial cavities, occasionally accompanied by extracavitary lesions in the lung parenchyma, gastrointestinal tract, myocardium, or lymph nodes [34, 35]. Patients usually present with dyspnea, ascites, or constitutional “B symptoms” such as fever, weight loss, and night sweats. Cytologic examination of the effusion fluid demonstrates large atypical lymphoid or plasmablastic cells that are positive for HHV‐8 and often co‐infected with EBV [33]. The disease generally follows a rapidly progressive course with limited responsiveness to chemotherapy or reduction of immunosuppression [34].

Collectively, published evidence indicates that PT‐PEL remains an exceptionally rare but highly aggressive complication of solid organ transplantation. Among the 13 reported cases, most patients were men (92%), with kidney transplantation accounting for the largest proportion of cases (38%), followed by heart and liver transplantation (23% each). Pleural involvement was the predominant clinical presentation (77%), whereas concurrent Kaposi sarcoma was reported in approximately one‐third of patients (31%), highlighting the shared HHV‐8 pathogenesis of these disorders. These observations suggest that unexplained serosal effusions in HHV‐8–infected transplant recipients should prompt early evaluation for PT‐PEL. Detailed clinical characteristics of all published cases are summarised in Supporting Information S1: Table S1.

3.3. Post‐Transplant Multicentric Castleman Disease (PT‐MCD)

Multicentric Castleman disease represents a lymphoproliferative disorder driven by lytic replication of HHV‐8 within B cells and associated cytokine excess [23]. Clinical presentation was typically systemic, with fever, night sweats, weight loss, and fatigue, accompanied by generalised lymphadenopathy, splenomegaly, and hepatomegaly [36, 37]. Histopathology usually demonstrates the plasma cell or mixed variant, with consistent HHV‐8 positivity and variable EBV co‐detection [38]. Concomitant KS was noted in several cases [39, 40]. Prognosis is heterogeneous, ranging from rapid progression with death within a few months to prolonged survival in some patients [36, 40]. Outcomes were particularly poor in cases with concurrent KS [40].

Collectively, the published literature on PT‐MCD remains limited to 15 reported cases, the majority of which occurred in men (93%) following kidney (53%) or liver (40%) transplantation. Most patients presented with constitutional symptoms accompanied by generalised lymphadenopathy and splenomegaly, while concurrent Kaposi sarcoma was identified in approximately one‐quarter of cases (27%). Despite the small number of reported cases, these findings demonstrate a remarkably consistent clinical phenotype across different transplant populations. Detailed clinical characteristics of all published cases are summarised in Supporting Information S1: Table S2.

3.4. Post‐Transplant KSHV Inflammatory Cytokine Syndrome (PT‐KICS)

PT‐KICS is an increasingly recognized inflammatory manifestation of HHV‐8 infection in transplant recipients. It shares clinical features with MCD and is driven by the lytic phase of HHV‐8 replication, leading to HHV‐8–associated polyclonal B‐cell lymphoproliferation and excessive production of IL‐6 and IL‐10, culminating in a cytokine storm [23]. It is characterised by fever, constitutional symptoms, splenomegaly, lymphadenopathy, serous effusions, and frequently accompanied by multiorgan dysfunction [41]. Laboratory abnormalities included cytopenias (especially anemia and thrombocytopenia), hypoalbuminemia, hyponatremia, and elevated CRP. HHV‐8 DNAemia was consistently high, frequently exceeding 10⁵–10⁶ copies/mL, and pro‐inflammatory cytokines (IL‐6, IL‐10) were markedly elevated [42]. The syndrome may overlap with MCD but lacks the histologic features of lymph‐node involvement [41]. KICS carries a poor prognosis when unrecognised; however, prompt initiation of rituximab combined with antiviral and immunomodulatory therapy can be lifesaving [14, 43].

To our knowledge, 22 cases of PT‐KICS have been reported (Supporting Information S1: Table S3). Most occurred in men (64%), with a median age of 57 years (range, 31–68 years). The underlying transplants were predominantly liver (59%) or combined liver–kidney (14%), followed by heart (9%), lung (9%), heart–kidney (5%), and liver–kidney (5%). PT‐KICS consistently presented as a fulminant hyperinflammatory syndrome characterised by persistent fever, serosal effusions, cytopenias, hypoalbuminemia, and markedly elevated inflammatory markers. HHV‐8 viraemia was uniformly high, with a median peak viral load of approximately 2.2 × 10⁵ copies/mL (range, 1.7 × 10⁴ to > 1 × 10⁷ copies/mL). Concurrent Kaposi sarcoma was present in 8 of 22 patients (36%), highlighting the close clinical overlap between PT‐KICS and other HHV‐8–associated disorders.

4. Screening and Monitoring

A crucial first step in mitigating the risk of post‐transplant HHV‐8‐related complications is the pre‐transplant screening of both organ donors and recipients. The primary goal of screening is to identify HHV‐8 seropositive donors who could transmit the virus to seronegative recipients (D+/R‐), a scenario associated with the highest risk of primary infection and subsequent disease. Similarly, identifying seropositive recipients (R+) allows for heightened post‐transplant surveillance for viral reactivation.

HHV‐8 screening in transplant donors and candidates is not routinely performed in pretransplant evaluations [44]. The American Society of Transplantation provides a weak recommendation for pre‐transplant serological screening of donors and recipients in endemic areas to risk stratify HHV‐8 associated disease. In low‐seroprevalence regions, targeted screening of at‐risk individuals or those from endemic areas may also be considered [3]. Despite these recommendations, practice remains inconsistent. An international survey of 51 transplant centres in 15 countries found that HHV‐8–associated diseases had been diagnosed within the past 5 years in 67% of centers, yet only 17 (33%) routinely performed pretransplant serologic screening and 21 (41%) posttransplant HHV‐8 NAT monitoring [45].

Emerging data suggest that combining serologic assays for donor and recipient screening with molecular surveillance in antibody‐mismatched pairs may allow earlier detection of HHV‐8–related complications, especially non‐neoplastic syndromes such as KICS [14]. Although there is no clear consensus on the optimal schedule for monitoring, recent protocols have implemented HHV‐8 PCR testing every 15 days during the first 3 months and monthly thereafter up to 1 year in recipients at risk for disease [14]. Ultimately, this gap between cautious guideline recommendations and clinical practice underscores the need for standardized, evidence‐based screening and monitoring strategies to improve early recognition of HHV‐8–associated disease in transplant recipients. Importantly, the lack of standardization across PCR platforms and the absence of an international reference standard substantially contribute to current monitoring gaps, limiting inter‐center comparability of HHV‐8 viral load data [45].

4.1. Practical Donor and Recipient Screening Framework

A critical and unresolved challenge in HHV‐8 management is how to screen donors and recipients when no FDA‐approved or CE‐marked diagnostic assay currently exists for donor screening. Available HHV‐8 assays include indirect immunofluorescence assays (IFA) targeting lytic antigens, ELISA‐based assays (K8.1 or ORF73/LANA‐1), and nucleic acid testing (NAT/PCR) on whole blood or peripheral blood mononuclear cells (PBMC). Each has important limitations: IFA offers high sensitivity but is operator‐dependent and has limited specificity; ELISA K8.1 has higher specificity but may miss early infection; NAT on PBMC is most sensitive for detecting latent infection but is not standardised across laboratories [11].

We propose a risk‐stratified screening approach based on regional seroprevalence and donor risk profile. In low‐prevalence settings (< 5%), routine HHV‐8 serology is not required for all donors, but targeted serological screening (ELISA K8.1 or IFA) should be considered for donors with identifiable risk factors (MSM, PLWHIV, origin from sub‐Saharan Africa or Mediterranean regions, personal history of KS) [13]. Supplemental NAT is warranted if the donor is seronegative but high‐risk. In endemic regions (seroprevalence ≥ 10%) or programmes serving high‐risk populations, universal pre‐transplant HHV‐8 serology for both donors and recipients is advisable [3]. Pre‐transplant serology in recipients serves to identify R+ individuals who warrant enhanced post‐transplant surveillance for viral reactivation.

For post‐transplant monitoring, D+/R− pairs represent the highest‐risk group and should undergo HHV‐8 NAT (whole blood or PBMC) every 2 weeks during the first 3 months, then monthly to 12 months post‐transplant, in line with the protocol reported by Mularoni et al. R+ recipients should be monitored by NAT at 1, 3, and 6 months post‐transplant, with intensification if T‐cell‐depleting agents are used [14]. D−/R− pairs require no routine monitoring in low‐prevalence settings. All centres should document and report NAT‐positive cases prospectively to build the evidence base for threshold‐based interventions.

4.2. Managing the HHV‐8 PCR‐Positive but Asymptomatic Recipient

A common and poorly addressed clinical scenario is the recipient who tests positive by HHV‐8 PCR during routine post‐transplant surveillance but remains clinically well. No randomised data exist to guide this situation. Based on available case series and mechanistic rationale [14, 43], we propose a pragmatic approach. Asymptomatic recipients with detectable but stable viraemia should be managed with enhanced clinical and virological surveillance, with no pharmacological intervention. Those with rising or persistently elevated viremia should prompt consideration of immunosuppression reduction where graft function and rejection risk permit; antiviral therapy may be considered but is not supported by controlled trial data. Recipients with any level of viraemia accompanied by new fever, cytopenias, hypoalbuminemia, or other systemic symptoms should be evaluated immediately for overt HHV‐8 syndrome and treated according to the dominant clinical phenotype.

Decisions regarding intervention in the asymptomatic viraemic recipient should involve multidisciplinary discussion including transplant infectious disease, transplant surgery or nephrology, and hematology. Prospective documentation of NAT‐positive recipients and their outcomes is essential to define clinically meaningful viral load thresholds and guide future evidence‐based recommendations.

5. Management Strategies

5.1. Post‐Transplant Kaposi Sarcoma

The cornerstone of therapy is reduction or modification of immunosuppression, particularly tapering or discontinuing calcineurin inhibitors, which promote KS progression [46]. Recent meta‐analysis showed that withdrawal or reduction in immunosuppression alone results in complete remission in 47.8% of patients with PT‐KS [47].Transition to mTOR inhibitors such as sirolimus or everolimus is recommended, given their dual immunosuppressive and antiangiogenic properties, and has been associated with regression of cutaneous and visceral lesions in multiple reports [22]. Chemotherapy is usually required in patients with visceral involvement or rapidly evolving KS, with liposomal doxorubicin or paclitaxel being the most commonly used agents [48, 49]. In the largest retrospective European cohort, 16% of patients received chemotherapy, most commonly liposomal doxorubicin, bleomycin‐based regimens, vinblastine, or paclitaxel. At 6 months, response rates among patients with visceral KS were broadly comparable between those treated with chemotherapy (28% complete, 44% partial) and those managed without chemotherapy (32% complete, 55% partial), reflecting its use in more aggressive disease. Chemotherapy may be considered in combination with mTOR inhibitors or as salvage therapy after relapse or progression, although its role remains adjunctive rather than first‐line in the management of PT‐KS [50]. Localized disease can be treated with surgical excision, cryotherapy, or radiotherapy [51, 52, 53]. Interferon‐α has been used historically in non‐transplant KS, but is rarely employed in transplant recipients, due to high risk of graft rejection [54]. Finally, antiviral agents are not effective in PT‐KS, as neoplastic spindle cells typically harbour latent rather than lytic HHV‐8 infection [4].

5.2. Post‐Transplant Primary Effusion Lymphoma

Management of PT‐PEL is particularly difficult, with no standardized regimen and guidance typically derived from individual case reports. Reduction of immunosuppression or conversion to a mTOR inhibitor is generally attempted, but this strategy alone is insufficient, often leading to graft rejection and high rates of mortality [35, 60]. Most cases require systemic chemotherapy. The choice of regimen is largely extrapolated from HIV‐associated PEL, where EPOCH (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisone) or CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combined with antiretroviral therapy has achieved response rates of 40%–50% and extended median survival from 2 to 3 months without therapy to 5–6 months [55]. In PT‐PEL, anthracycline‐based chemotherapy regimens such as CHOP or its variants (COP, CVP, BV‐CHP) are most frequently reported, with survival ranging from 4 to 14 months [32, 56, 57].

5.3. Post‐Transplant Multicentric Castleman Disease (PT‐MCD)

There is limited data to guide management of PT‐MCD. Reduction of immunosuppression or conversion to an mTOR inhibitor has only scarce supporting evidence, and modulation of immunosuppression alone has generally been associated with poor outcomes [39, 40, 58]. Based on the excellent remission rates and survival observed with rituximab in HIV‐associated MCD and the limited but encouraging data in SOT recipients, rituximab‐based therapy is recommended as the cornerstone of treatment [2, 59]. Nevertheless, evidence in the post‐transplant setting remains heterogeneous. Among 15 reported PT‐MCD cases, only 4 received rituximab, of whom 2 achieved remission and remained alive, underscoring both its potential benefit and the uncertainty of outcomes in this population [36, 60, 61, 62].

Antiviral agents such as ganciclovir, cidofovir, and foscarnet have a theoretical role in targeting lytic HHV‐8 replication, but expert opinion advises against their use as monotherapy [2]. Instead, antivirals are generally considered adjuncts to immunosuppression modulation and/or rituximab. In six reported PT‐MCD cases managed with adjunctive antivirals, three patients survived, reflecting the uncertain contribution of antiviral therapy to outcomes [10, 36, 60, 61, 62, 63]. Finally, CHOP‐based chemotherapy has only one reported case of successful use in PT‐MCD in combination with immunosuppression reduction [64].

5.4. Post‐Transplant Kaposi Sarcoma Inflammatory Cytokine Syndrome (PT‐KICS)

Management of PT‐KICS is extremely challenging due to its fulminant presentation, limited therapeutic experience, and reliance on treatment strategies largely extrapolated from HIV‐associated KICS. In transplant recipients, only a limited number of cases have been reported, but available experience highlights the need for urgent intervention with a bundled approach that includes immunosuppression modification, antiviral therapy to target viremia, and measures to control the cytokine storm [14, 43]. Immunosuppressive modification combined with antivirals or antivirals alone has generally proven inadequate, with most patients progressing to death, likely because hyperinflammatory response rather than viraemia is the major driver of clinical decline [14].

Rituximab, through depletion of HHV‐8–infected CD20⁺ B cells that serve as viral and cytokine reservoirs, has emerged as a key therapeutic agent [59]. In the largest series to date, Mularoni et al. reported markedly improved survival among SOT recipients treated with rituximab, with mortality rates of 25% in treated patients (2/8) compared with 100% in those who did not receive rituximab (3/3) [14]. IL‐6 pathway inhibitors such as tocilizumab have also been used as adjunctive therapy in selected cases. In the series reported by Bonazzetti et al., the mortality rate among treated patients was 25% (1/4) [43]. When KICS coexists with KS, standard KS therapy such as liposomal doxorubicin should be added to the KICS treatment bundle [42, 43]. Importantly, delayed recognition can be fatal even when rituximab and chemotherapy are administered, underscoring the critical role of early HHV‐8 PCR/NAT surveillance and rapid therapeutic escalation. Table 3 summarises the management strategies of each HHV‐8–associated syndrome in SOT recipients.

6. Future Directions

Future efforts should focus on standardising risk‐based surveillance and refining therapeutic strategies for HHV‐8–associated diseases in solid organ transplantation. Transplant programs should consider targeted pre‐transplant HHV‐8 serologic screening for donors and recipients from endemic regions or with relevant risk factors, and implement early post‐transplant HHV‐8 PCR/NAT monitoring for high‐risk pairs (D+/R–) or recipients receiving potent T‐cell–depleting therapies. Establishing predefined escalation algorithms—specifying who to contact, what diagnostics to order, and how to initiate therapy—may shorten time to recognition and treatment.

Further research is needed to clarify the optimal timing and intensity of immunosuppression modification, the role of mTOR‐inhibitor conversion, and the additive benefit or sequencing of antivirals with rituximab in HHV‐8–driven inflammatory syndromes such as MCD and KICS. Collaborative multicenter networks and prospective registries integrating clinical, virologic, and immunologic data will be essential to harmonise diagnostic criteria, refine treatment strategies, and identify predictors of severe disease.

In summary, HHV‐8–associated diseases demand early recognition, decisive immunosuppression modification, and syndrome‐specific therapy. Pragmatic, risk‐based surveillance and bundled care can improve outcomes even in the absence of randomized data. International collaboration will be key to reducing preventable morbidity, mortality, and graft loss in this vulnerable population.

Author Contributions

Sorawit Chittrakarn: conceptualization, literature review, formal analysis, and writing – original draft. Pornpan Koomanachai: writing – review and editing. Kamonlawat Sutthipool: writing – review and editing. Lauren Ogawa: literature review, writing – original draft, writing – review and editing. Joanna M. Schaenman: conceptualization, supervision, writing – review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

The authors have nothing to report.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Supporting Information S1

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.