Pingping Xiao
Qingqing Wang
Tingting Li
Zhigao Dong
Junnan Su
Yongquan Chen- 1Department of Hematology and Rheumatology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
- 2Department of Radiology, The Second Affiliated Hospital of Xiamen Medical College, Xiamen, China
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome. The cause of onset broadly distinguishes primary from acquired HLH. However, an increasing number of carrying HLH gene mutation cases have been reported in adults, and the relationship between genetic alterations and the onset of HLH in adults is still being explored. In this case, a 43-year-old woman with a one-month history of abnormal liver function and fever presented for evaluation. Laboratory data indicated pancytopenia, elevated ferritin levels, decreased fibrinogen levels, and the presence of phagocytes in the bone marrow. She was diagnosed with HLH and found to have a heterozygous mutation in the UNC13D gene. The onset of symptoms in this patient coincided with the exacerbation of human herpesvirus 6B infection. From our review of case reports published in the past seven years, patients with HLH carrying this heterozygous gene mutation were diagnosed in adults. The patient remains alive and healthy after comprehensive treatment. The genetic background must not be overlooked in the etiological diagnosis of adult hemophagocytic lymphohistiocytosis, even in the presence of infectious pathogenic factors. Future studies need to be undertaken involving a larger number of cases, along with virology and genomics correlation.
1 Introduction
Hemophagocytic lymphohistiocytosis (HLH) has broad clinical manifestations, including fever, hepatitis, hepatosplenomegaly, cytopenia, high ferritin levels, coagulopathy, and hypertriglyceridemia. HLH occurs as a result of a “state of excessive immune activation” or uncontrolled immune responses. Mortality estimates range from 20%–88% (1). Familial HLH (FHL) is caused by biallelic defects in PRF1, UNC13D, STX11, or STXBP2 that severely impair granule-mediated cytotoxicity, the process by which perforin/granzyme-containing granules fuse with the plasma membranes of natural killer (NK) cells or cytotoxic T lymphocytes to induce apoptosis in target cells (2). Acquired HLH, which occurs secondary to infection, malignancy, and rheumatic disease, has a poor prognosis and is fatal in 50%–75% of patients, with early death attributable to progressive multiorgan damage. Human herpesvirus 6B (HHV-6B) is a ubiquitous herpes virus that infects >95% of adults (3).Adult-onset infectious HLH associated with genetic mutations is relatively uncommon. Here, we report the case of a 43-year-old female patient with HLH and HHV-6B infection, in whom a heterozygous mutation in the UNC13D gene was identified. We also provide a review of recent reports on patients with HLH carrying heterozygous UNC13D mutations. Our case report aims to emphasize that the genetic background should not be overlooked in the etiological diagnosis of adult HLH, even when infectious pathogens are present. We also explored the potential association between UNC13D gene mutations, HHV-6B infection, and HLH in adults.
2 Case presentation
A 43-year-old woman presenting with a one-month history of abnormal liver function and fever was referred to our hospital. Upon physical examination, her vital signs were as follows: temperature, 39.2 °C; blood pressure, 136/94 mmHg; heart rate, 120 beats/min; and respiratory rate, 20 breaths/min. She did not present with sternal tenderness, superficial lymphadenopathy, hepatomegaly, or splenomegaly, and she had no relevant personal or family medical history.
Her laboratory blood test results at admission were as follows: hemoglobin level, 149.0 g/L (normal range [NR], 115–150 g/L); white blood cell count, 2.41 × 109/L (NR, 4–10 × 109/L); platelet count, 272 × 109/L (NR, 125–350 × 109/L); reticulocyte percentage, 1.95% (NR, 0.3–3.0%); serum glutamic oxaloacetic transaminase, 366.50 IU/L (NR, 13.0–35.0 IU/L); serum glutamic pyruvic transaminase, 265.60 IU/L (NR, 7.0–40.0 IU/L); serum γ-glutamyl transpeptidase, 175 IU/L (NR, 7.0–45.0 IU/L); and serum lactate dehydrogenase, 739.00 IU/L (NR, 100.0–240.0 IU/L). Serum alkaline phosphatase levels were elevated (177.80 IU/L; NR, 35–100 IU/L), and triglyceride levels were measured at 1.48 mmol/L (NR, 0.4–1.8 mmol/L). Coagulation function and erythrocyte sedimentation rate were also within the NR. She tested negative for Epstein–Barr virus (EBV), respiratory virus, and hepatitis virus. Results were negative for the antinuclear antibody, antiphospholipid antibody, anti-extractable nuclear antigen antibody, antineutrophil cytoplasmic antibody, rheumatoid factor, and anti-cyclic citrullinated peptide tests. Tumor indices, including carcinoembryonic antigen, alpha-fetoprotein, carbohydrate antigen 199, and carbohydrate antigen 125 levels, were within the NR. Metagenomic next-generation sequencing (NGS) was used to detect HHV-6B sequences in the peripheral blood and ascites, for which the viral load counts were 75944 and 7707 copies/mL, respectively (NR, <1000 copies/mL). Decreased numbers of CD3+ T cells (188/μL; NR, 470–3260/μL), CD4+ T cells (108/μL; NR, 200–1820/μL), and CD8+ T cells (73/μL; NR, 130–1350/μL) were measured via flow cytometry. IL-6 levels were elevated to 85.84 pg/mL (NR, 0–10.3 pg/mL), and those of IFN-γ rose to 15.14 pg/mL (NR, 0–7.42 pg/mL).
After admission, the patient received symptomatic treatment, including anti-infection, liver protection, antipyretic, and other supportive treatments, which still could not prevent subsequent disease progression. On admission and during hospitalization, the changes of her white blood cell, hemoglobin, platelet counts, ferritin level, body temperature and fibrinogen level were shown in Figures 1A–C. Her computed tomography scans of the chest and whole abdomen were performed at different time points (Figures 2A–C). Owing to the unexplained persistent high fever, progressive decline in complete blood count, elevated serum ferritin levels, and progressive hepatosplenomegaly, HLH was suspected. Bone marrow puncture revealed a large number of hemophagocytes that had phagocytosed red blood cells, granulocytes, lymphocytes, and platelets (Figures 3A, B). The patient met six of the eight HLH 2004 diagnostic criteria (4). Consequently, the diagnosis of HLH was established on the 10th day after admission. After a multidisciplinary evaluation and communication with the patient, HLH-94 treatments (dexamethasone 15 mg/day, etoposide [VP16] 0.1 g twice a week) combined with gamma-globulin (0.4 g/kg, days 1–5) were administered. The patient was unable to tolerate the side effects of VP16, which led to acute pulmonary edema and respiratory failure requiring treatment with veno-venous extracorporeal membrane oxygenation. Subsequently, VP16 was replaced with ruxolitinib 10 mg twice per day. The therapeutic scheme was shown in Figure 2D. The pleural effusion were obviously resolved (Figure 2A). The sizes of the enlarged liver, spleen and pancreas were significantly reduced (Figures 2B, C). Whole-exome sequencing revealed a heterozygous UNC13D c.2588G>A/p.G863A mutation on Chr17 (Figure 3C). This UNC13D mutation could not be identified in three immediate family members because of the loss of contact over many years.
Figure 1. Synopsis of the clinical course. (A–C) Dynamic changes in (A) blood cell count, (B) body temperature and ferritin levels, and (C) coagulation function. APTT, partial thromboplastin time; Fib, fibrinogen; Hb, hemoglobin; PLT, platelet; PT, prothrombin time; WBC, white blood cell. *The serum ferritin levels exceed the upper limit of the reference range (>1500ng/mL).
Figure 2. Time course of treatment and computed tomography findings. (A) The lung (new infectious lesions and massive pleural effusion, red circle); (B) the liver and spleen (enlargement, red circle); (C) the pancreas (acute pancreatitis, red circle); (D) the timeline of the patient’s treatment. Dex, dexamethasone; ECMO, extracorporeal membrane oxygenation.
Figure 3. Bone marrow morphology and gene mutation. (A) The hemophagocytes are round and have phagocytosed late erythroblasts and platelets (black arrow). (B) The hemophagocytes have phagocytosed late erythroblasts, neutrophilic granulocytes, and platelets (black arrow). (C) Screen capture from the integrative genomics viewer showing the genetic structure of the identified heterozygous variant, UNC13D c.2588G>A/p.G863A, on Chr17.
Her white blood cell, hemoglobin, and platelet counts gradually increased (Figure 1A), and her ferritin levels decreased and body temperature returned to normal (Figure 1B) after treatment for half a month. Fibrinogen level also gradually normalized during therapy(Figure 1C). The patient recovered rapidly and was discharged from the hospital after 40 days, after which she continued to receive an oral ruxolitinib tapering regimen. Follow-up for about half a year showed good recovery, and the patient was able to return to normal activity. The peripheral blood NGS test for HHV-6B virus was negative.
3 Discussion
Herein, we described an adult patient who presented with an unexplained fever and multiple organ failure. The patient was admitted to the intensive care unit for treatment due to symptom exacerbation and was ultimately diagnosed with HLH. HHV-6B infection detected via next-generation sequencing in her peripheral blood and ascites, together with analysis of the patient’s medical history, suggested that viral infection was the cause of secondary HLH in the patient; however, a heterozygous gene mutation characteristic of HLH was found upon genetic testing of the patient. Infection-related HLH is the most common form of acquired HLH in both children and adults, with EBV infection predominantly occurring in Asian populations (5). Therefore, testing and screening for herpes virus infection in adult patients during the diagnostic process for HLH is of great significance to assist in the search for the etiology or predisposing factors for HLH. Our patient tested negative for EBV and other viruses but was positive for high HHV-6B loads, as detected via next-generation sequencing.
HHV-6B infects most individuals within the first three years of life and often manifests as roseola (6). Reactivation of HHV-6B is rare and typically asymptomatic in immunocompetent individuals (7). In contrast, HHV-6B is a major cause of opportunistic infections, which lead to life-threatening complications in immunocompromised individuals. However, this is common and associated with a wide range of end-organ diseases in immunocompromised patients (8). Unlike other human herpes viruses, HHV-6B can integrate into chromosomes as a mechanism of latency, which may result in the inheritance of chromosomally integrated (CI) HHV-6B (9). Our patient’s peripheral blood test for the HHV6B virus was negative after recovery. Based on this result, we can exclude the possibility that the individual carries CI HHV-6B. People with CI HHV-6B always have high levels of plasma viremia, regardless of virus reactivation due to cell breakage. Therefore, the patient’s current condition is likely attributable to an acquired HHV-6B infection, rather than the reactivation of chromosomal integration of the HHV-6B virus.HHV-6B hampers the host immune responses by downregulating class I major histocompatibility complex molecules (MHC-I), which impedes the presentation of antigens to CD8+ T cells. The downregulation of MHC-I disengages inhibitory receptors on NK cells, leading to their activation and the subsequent killing of target cells when NK cell-activating receptors interact with stress ligands that have been upregulated on those cells. NK cells are known to respond to HHV-6B infection (10), and HHV-6B also participates in the mechanism controlling their activity. Weaver et al. (11) reported that the HHV-6B U20 glycoprotein binds to UL16-binding protein 1, masking it from recognition by NK group 2 member D and interfering with NK cell activation. Rizzo et al. (12) considered that HHV-6B infections have a remarkable effect on the expression of miRNAs and transcription factors, subsequently inducing the impairment of NK cell function and facilitating virus escape strategies. HHV-6B also sequesters the NF-κB p65 subunit to inhibit innate immune responses, including those of NK cells (13). In summary, infection with the HHV-6B virus results in reduced NK cell activity in vivo, aligning with the pathophysiological changes observed in HLH.
UNC13D is documented to have more than 200 distinct mutations and is a contributing factor to FHL3, in which compound heterozygous mutations occur at approximately 47.6%, homozygous mutations at 36.6%, and heterozygous mutations at 15.6% (14). UNC13D homozygous mutations associated with HLH often occur during childhood in primary HLH, which differ from UNC13D heterozygous mutations that often occur in adults with HLH, consistent with hypomorphic mutations (15). As shown in Table 1, after conducting a literature review spanning nearly seven years, we identified 18 adult patients diagnosed with hemophagocytic syndrome who exhibited mutations in the UNC13D gene. All patients were aged 18 years or older, with the youngest being 18 and the oldest 48. Specifically, these patients had single heterozygous mutations without complex heterozygous variants. Regrettably, the literature provided limited additional information, omitting details on viral infections—including those mentioned in the present study, such as EBV and HHV-6B—and treatment protocols. UNC13D plays a critical role in the biogenesis, tethering, and priming of cytotoxic vesicles and in the endoplasmic reticulum (16). The monoallelic UNC13D c.2588G>A variant could partially impair NK cell cytotoxicity; deficiencies in UNC13D genes compromise cytolytic granule exocytosis at the immunological synapse, which impairs the cytotoxic activity of T/NK cells (17).
Table 1. Cases of hemophagocytic lymphohistiocytosis carrying the UNC13D heterozygous mutation in adults published in last seven years.
HHV-6B infection may influence heterozygous UNC13D mutations in individual with HLH through a variety of mechanisms. For example, viral infection may alter the intracellular environment, triggering the production of cytokines and signaling molecules that interfere with the normal expression and regulation of UNC13D, thereby accelerating the emergence of disease-causing mutations. Our patient presented with decreased levels of CD4+ and CD8+ T cell subsets following admission; simultaneously, the levels of inflammatory markers (IL-6 and IFN-γ) increased. During HH6VB infection or reactivation, the virus may trigger the activation of the mutated UNC13D gene in patients, leading to decreased NK and T cell activity, release of inflammatory factors, and activation of phagocytes to induce phagocytosis. We hypothesize that if the onset of mutation occurs in UNC13D, this will further disrupt the balance of the immune system, increase the likelihood of related diseases, or aggravate the existing condition due to further disorders of the immune system after viral infection.
Allogeneic hematopoietic stem cell treatment should be considered for patients with homozygous UNC13D mutations. The adult patient with an UNC13D heterozygous mutation reported in the present study is currently healthy and alive after treatment with ruxolitinib and dexamethasone (Ru-D). Zhou et al. reported that the Ru-D regimen had a higher response rate and led to favorable survival outcomes in adult patients with HLH (18). The prognosis of patients with HLH and heterozygous UNC13D mutations should be correlated with the age of onset; many subsequent developments can lead to lymphoma. Allogeneic hematopoietic stem cell transplantation is also recommended if a donor is available.
4 Conclusion
In conclusion, HHV-6B infection may act as a trigger in patients with heterozygous UNC13D mutations, and it may also accelerate the pathogenicity of these mutations in adults with HLH. We suspect that the heterozygous UNC13D mutation variant could be conditionally pathogenic in HLH and might be triggered by viruses, such as HHV-6B, or by age-related immune function decline in adults. A limitation of this study is that the UNC13D mutation could not be identified in the patient’s three immediate family members due to loss of contact. Another limitation is that it is just a single case. Future studies need to be undertaken involving a larger number of cases, along with virology and genomics correlation.
Data availability statement
The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.
Ethics statement
Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article. Written informed consent was obtained from the participant/patient(s) for the publication of this case report.
Author contributions
PX: Writing – original draft, Writing – review & editing. QW: Investigation, Writing – review & editing. TL: Data curation, Writing – review & editing. ZD: Supervision, Writing – review & editing. JS: Formal Analysis, Writing – review & editing. YC: Project administration, Resources, Writing – review & editing.
Funding
The author(s) declare that no financial support was received for the research and/or publication of this article.
Acknowledgments
We would like to acknowledge the hard and dedicated work of all the hospital staff. We also appreciate the selfless dedication of our patient.
Conflict of interest
The authors declare that the research was conducted in the absence of commercial or financial relationships that could be construed as potential conflicts of interest.
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References
1. Hayden A, Park S, Giustini D, Lee AY, and Chen LY. Hemophagocytic syndromes (HPSs) including hemophagocytic lymphohistiocytosis (HLH) in adults: A systematic scoping review. Blood Rev. (2016) 30:411–20. doi: 10.1016/j.blre.2016.05.001
2. Henter JI, Sieni E, Eriksson J, Bergsten E, Hed Myrberg I, Canna SW, et al. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited. Blood. (2024) 144:2308–18. doi: 10.1182/blood.2024025077
3. Deschenes L, Joly JR, Couillard M, and Richer G. Seroprevalence of antibodies against human herpesvirus 6 in the Quebec City area. Can J Infect Dis. (1992) 3:179–84. doi: 10.1155/1992/837029
4. La Rosee P, Horne A, Hines M, von Bahr Greenwood T, Machowicz R, Berliner N, et al. Recommendations for the management of hemophagocytic lymphohistiocytosis in adults. Blood. (2019) 133:2465–77. doi: 10.1182/blood.2018894618
5. Meng GQ, Wang JS, Wang YN, Wei N, and Wang Z. Rituximab-containing immuno-chemotherapy regimens are effective for the elimination of EBV for EBV-HLH with only and mainly B lymphocytes of EBV infection. Int Immunopharmacol. (2021) 96:107606. doi: 10.1016/j.intimp.2021.107606
6. Combet M, Gautheret-Dejean A, Luyt CE, Weiss N, Mayaux J, Lecronier M, et al. Clinical features and outcomes of Human Herpesvirus-6 DNAemia in critically ill patients: a retrospective multicenter analysis. Clin Infect Dis. (2025). doi: 10.1093/cid/ciaf199
7. Geraudie B, Charrier M, Bonnafous P, Heurte D, Desmonet M, Bartoletti MA, et al. Quantitation of human herpesvirus-6A, -6B and -7 DNAs in whole blood, mononuclear and polymorphonuclear cell fractions from healthy blood donors. J Clin Virol. (2011) 53:151–5. doi: 10.1016/j.jcv.2011.10.017
8. Bucciol G, Willemyns N, Verhaaren B, Bossuyt X, Lagrou K, Corveleyn A, et al. Child neurology: familial hemophagocytic lymphohistiocytosis underlying isolated CNS inflammation. Neurology. (2022) 99:660–4. doi: 10.1212/WNL.0000000000201124
9. Zerr DM, Meier AS, Selke SS, Frenkel LM, Huang ML, Wald A, et al. A population-based study of primary human herpesvirus 6 infection. N Engl J Med. (2005) 352:768–76. doi: 10.1056/NEJMoa042207
10. Lusso P, Malnati MS, Garzino-Demo A, Crowley RW, Long EO, and Gallo RC. Infection of natural killer cells by human herpesvirus 6. Nature. (1993) 362:458–62. doi: 10.1038/362458a0
11. Weaver GC, Schneider CL, Becerra-Artiles A, Clayton KL, Hudson AW, and Stern LJ. The HHV-6B U20 glycoprotein binds ULBP1, masking it from recognition by NKG2D and interfering with natural killer cell activation. Front Immunol. (2024) 15:1363156. doi: 10.3389/fimmu.2024.1363156
12. Rizzo R, Soffritti I, D’Accolti M, Bortolotti D, Di Luca D, and Caselli E. HHV-6A/6B infection of NK cells modulates the expression of miRNAs and transcription factors potentially associated to impaired NK activity. Front Microbiol. (2017) 8:2143. doi: 10.3389/fmicb.2017.02143
13. Hirai M, Amaliin K, Huang JR, Aktar S, Mori Y, and Arii J. HHV-6B ribonucleotide reductase sequesters NF-kappaB subunit p65 to inhibit innate immune responses. iScience. (2025) 28:111710. doi: 10.1016/j.isci.2024.111710
14. Amirifar P, Ranjouri MR, Abolhassani H, Moeini Shad T, Almasi-Hashiani A, Azizi G, et al. Clinical, immunological and genetic findings in patients with UNC13D deficiency (FHL3): A systematic review. Pediatr Allergy Immunol. (2021) 32:186–97. doi: 10.1111/pai.13323
15. Miao Y, Zhu HY, Qiao C, Xia Y, Kong Y, Zou YX, et al. Pathogenic gene mutations or variants identified by targeted gene sequencing in adults with hemophagocytic lymphohistiocytosis. Front Immunol. (2019) 10:395. doi: 10.3389/fimmu.2019.00395
16. Duong VT, Lee D, Kim YH, and Oh SO. Functional role of UNC13D in immune diseases and its therapeutic applications. Front Immunol. (2024) 15:1460882. doi: 10.3389/fimmu.2024.1460882
17. Wei C, Zhang Y, Zhao D, Zhang W, and Zhou D. Germline defects of familial haemophagocytic lymphohistiocytosis-Related genes may represent a predisposing factor for mature T- and natural killer-cell lymphoma. Br J Haematol. (2025) 207:842–50. doi: 10.1111/bjh.20231
18. Zhou D, Huang X, Zhu L, Hu X, Yang X, Xie M, et al. Ruxolitinib combined with dexamethasone for adult patients with newly diagnosed hemophagocytic lymphohistiocytosis in China. Blood. (2025) 146:318–27. doi: 10.1182/blood.2024026139
19. Gu J, An N, Wang X, Xiao M, and Luo H. UNC13D c.2588G>A nucleotide variant impairs NK-cell cytotoxicity in adult-onset EBV-associated hemophagocytic lymphohistiocytosis: A pedigree study. Int J Mol Sci. (2025) 26. doi: 10.3390/ijms26178683
20. Bloch C, Jais JP, Gil M, Boubaya M, Lepelletier Y, Bader-Meunier B, et al. Severe adult hemophagocytic lymphohistiocytosis (HLHa) correlates with HLH-related gene variants. J Allergy Clin Immunol. (2024) 153:256–64. doi: 10.1016/j.jaci.2023.07.023
21. Xinh PT, Chuong HQ, Diem TPH, Nguyen TM, Van ND, Mai Anh NH, et al. Spectrum mutations of PRF1, UNC13D, STX11, and STXBP2 genes in Vietnamese patients with hemophagocytic lymphohistiocytosis. Int J Lab Hematol. (2021) 43:1524–30. doi: 10.1111/ijlh.13674
Keywords: hemophagocytic lymphohistiocytosis, familial HLH, human herpesvirus 6B, UNC13D, case report
Citation: Xiao P, Wang Q, Li T, Dong Z, Su J and Chen Y (2025) Human herpesvirus 6B infection in an adult with hemophagocytic lymphohistiocytosis carrying an UNC13D mutation: a case report and literature review. Front. Immunol. 16:1679372. doi: 10.3389/fimmu.2025.1679372
Received: 05 August 2025; Accepted: 18 November 2025; Revised: 18 November 2025;
Published: 28 November 2025.
Edited by:
Paolo Lusso, National Institutes of Health (NIH), United StatesReviewed by:
Pietro Tralongo, University of Messina, ItalyPayman Sadeghi, Tehran University of Medical Sciences, Iran
Copyright © 2025 Xiao, Wang, Li, Dong, Su and Chen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Pingping Xiao, eGlhb3BwMDAyNkAxNjMuY29t