AUCTORES
Globalize your Research
Case Report | DOI: https://doi.org/10.31579/2640-1053/115
1 Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.
2 Bone Marrow Transplantation Center, Department of Hematology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
*Corresponding Author: Cancan Lu, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, China.
Citation: Cancan Lu, Yishan Ye, Jimin Shi, Yamin Tan. (2022). Massive digestive tract bleeding caused by EBV-triggered Hemophagocytic Lymphohistiocytosis and digestive tract vascular malformation. Cancer Research and Cellular Therapeutics. 6(3); Doi:10.31579/2640-1053/115
Copyright: © 2022 Cancan Lu, this is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Received: 23 March 2022 | Accepted: 30 May 2022 | Published: 10 June 2022
Keywords: hemophagocytic lymphohistiocytosis（hlh; severe; eb virus infection; digestive tract vascular malformation; gastrointestinal bleeding
We introduced a patient with fetal EBV-triggered who finally developed multidrug-resistant septicemia, perianal abscess, massive alimentary tract bleeding due to gastrointestinal vascular malformation, and acute respiratory distress syndrome. His EB virus maintained chronically active under multiple drug treatments. Interestingly, continuous EB virus infection and a probable idiopathic gastrointestinal vascular malformation might be the cause of the severe digestive tract bleeding.
Hematopoietic lymphocytic tissue disease (HLH), also known as hematopoietic cell syndrome (HPS), is a series of clinical syndromes caused by genetic or acquired immunodeficiency [1]. The most common clinical features of HLH are fever, enlargement of the liver, spleen, lymph nodes, progressive pancytopenia, abnormal liver function, blood coagulation dysfunction, etc. It may also be accompanied by an abnormality in central nervous system. HLH could be either idiopathic or secondary, with idiopathic mainly happened in children or teenagers and secondary in adults. It is mainly caused by infections (bacteria, fungi, Epstein -Barr virus), autoimmune diseases or tumors [2]. Chronic active Epstein-Barr virus infection (CAEBV) is one of Epstein-Barr virus (EBV) -positive T or NK lymphoproliferative diseases. Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis s (EBV-HLH) is a blood cell lymphocytic histiocytosis caused by the activation of EB virus infection, which is more severe than other HLH types, and has a high death rate and a poor prognosis [3].
A 25-year-old, previously healthy young man from China showed fever and discomfort in the nasopharynx in July 2019. Nasopharyngoscopy showed bilateral nasal mucosal erosion. The Blood routine: WBC 3.0×10 ^ 9 / L, HGB 113 g / L, PLT 87×10 ^ 9 / L, CRP13.53mg / L,Bone marrow morphology showed a small population of abnormal lymphocytes with immature morphology and abnormal nuclear, monocytes and monocytes were occasionally seen. A second bone marrow morphology showed the proportion of myeloid primordial cells was not high and no obvious abnormalities were seen. Immunotyping showed no obvious abnormalities in the phenotype. Bone marrow biopsy showed no obvious abnormalities of lymphocytes. Meanwhile the blood EB virus DNA was 32657.0 copies / ml. The tonsillary biopsy showed reactive lymphocyte hyperplasia with EBV infection. A ferritin level > 500μg/L, hepatosplenomegaly, lymphadenopathy, hypofibrinogenemia, according to all these he was diagnosised of “EB virus infection, hematopoietic syndrome”.
We initiated anti-inflammatory treatment with methylprednisolone, anti-infection with meropenem, and symptomatic supportive treatment such as sodium phosphonate antiviral and infusion of plasma. The patient still had daily high fever, progressive enlargement of liver and spleen, reexamination of EB virus DNA showed 5.9×10 ^ 3 copies /ml, sCD25: 22050pg /ml. Because the disease is out of control, the fever persists, we added ruxolitinib in 2019-08-12, and the maximum dose was increased to 20mg twice daily. 2019-08-27 PET-CT showed a. The left lower inferior parietal mucosa is thickened, and FDG metabolism is significantly increased; b. hepatosplenomegaly, FDG metabolism is unevenly increased; c. the whole-body bone marrow FDG metabolism is increased (the 7th rib on the right was serious), the rest were not significantly abnormal. Because of the poor effect of early treatment, we decided to use first-line chemotherapy for hemophagocytic syndrome. From 2019-08-28, Treatment was initiated based on the HLH-2004 protocol with DXM 10mg/m2 qd for 2 weeks, VP-16 100mg/m2, biw×2 weeks, and gradually reduced, 225 mg of cyclosporine twice daily. Because this person is young, in order to figure out the cause of hemophagocytic and distinguish between primary and secondary, we did a genetic test and a heterozygous mutation (NM_001099856: exon5: c.G753C: p.Q251H) was detected in the IKBKG gene, as well as the same mutation in his mother. The level of EB DNA is still high and the fever persists after chemotherapy, we decided to use the second-line regimen.
Since 12th September in 2019, we give him chemotherapy as Hyper-CVAD part A (CTX 600mg q12h d1-3; VDS 4mg d4, d11; Ridox 60mg d4; DXM 40mg d1-d4, d11-14). The liver and spleen contracted slightly, but the EB virus level was still high. 3 days after finish of chemotherapy, blood culture showed positive for Pseudomonas aeruginosa (multidrug resistance), and perianal abscess.
12th October in 2019, the results of routine blood test showed that WBC 5.3×10 ^ 9 / L, RBC 1.65×10 ^ 12/L, HGB 48g/L, PLT 51×10 ^ 9/L. And since 12th October he Began to relieve a large amount of black stools, enhanced abdomen CT examination revealed nodular enhanced foci in the upper cavity of the jejunum, considering as vascular malformations (Figure 1), partial resection of the small intestine was operated on 13th October, and pathology suggested mild inflammation of the small intestinal mucosa. On 21th October, a new bone marrow morphology showed one type of abnormal lymphocytes and hemophagocytic, considering the possibility of lymphoma. Bone marrow biopsy showed a large number of EBER-positive T lymphocyte infiltration with hemophagocytic, considering as a T-lymphocyte proliferative disease related to severe EBV infection (Figure 2). Immunohistochemistry showed CD3 +, TIA +, EBER +, ≥100 / HPF, CD20-, CD30 individual +, CD56-, and hemophagocytic can be seen. Subsequently, the patient suffered from acute respiratory failure, septic shock, and acute renal insufficiency, and his Parents decided to give up treatment, he died shortly after leaving the hospital on 31th October.
We report a case of HLH that turn into a worse rapidly with bleeding from a gastrointestinal malformation of the digestive tract. Kumakura et al [4] proposed a disease called autoimmune-associated hemophagocytic syndrome (AAHS) in 1997. The pathogenesis of AAHS can be explained by autoantibody-mediated, immune complex-mediated, or cytokine-mediated mechanisms: First, autoantibodies may react with blood cells, and thus pass-through stimulated tissue cells through Fc receptors (mainly in the bone marrow). Second, blood cells sensitized by the immune complex may be engulfed by tissue cells through complement-receptor interactions. Finally, uncontrolled production of inflammatory cytokines may activate tissue cells [5-7]. HLH pathophysiology is based on the cytotoxic function of natural killer lymphocytes (NK cells) and cytotoxic T lymphocytes (CTL), hyperproliferation and subsequent absence of cytokine storms [8].
Organ infiltration with high cytokine levels is associated with signs and symptoms of HLH. Long-term fever is caused by high levels of interleukin 1 (IL1), interleukin 6 (IL6), and tumor necrosis factor alpha (TNFα). Hemocytosis is due to high concentrations of TNFαand phagocytic cells. Macrophages infiltrate the bone marrow infiltration of hematopoietic components (red blood cells, white blood cells, platelets, precursors and cell debris [9-14]. Fibrosis increased by increased plasminogen activators expressed by activated macrophages, and serum plasmin levels increased, which led to abnormal HLH coagulation function caused by macrophage tissue infiltration, accompanied by liver dysfunction. Activated macrophages emit high levels of ferritin, and activated lymphocytes produce high concentrations of the soluble form of the IL-2 receptor (sCD25). HLH diagnostic guidelines by Henter et al released in 1991: (1) temperature > 38.5 ℃, lasting> 7 days), (2) splenomegaly, (3) cytopenia involving two of three cell lineages in the peripheral blood, (4) hypertriglyceridemia and / or a decrease in fibrinogen (<1> 2400 U/mL (sCD25≥6400pg / ml) [16]. Diagnosis of secondary HLH necessitates the fulfillment of five of the above eight criteria. Since not all of diagnostic criteria occur simultaneously, so diagnosis is often very difficult.
During the disease process, CAEBV can lead to two deadly diseases: hemophilic lymphocytic tissue disease and chemotherapy-resistant lymphoma. Treatment should be taken before the onset of these two diseases. Currently, allo-HSCT is the only effective treatment strategy to eradicate EBV-infected T cells or NK cells. Even if when the exact cause of the patient remains unknown, since the duration from the onset of disease to transplantation can be a factor that affects HLH progression and death, it is necessary to start looking for donors when being diagnosis of HLH. Transplantation should be used as soon as possible after the patient’s medication has been released clinically. Finally, non-steroidal anti-inflammatory drugs (FANS) such as indomethacin, naproxen and ibuprofen may work, but we are still lack of the previous treatment experience for patients with HLH.
This patient's gene mutation detection analysis report shows that a heterozygous mutation (NM_001099856: exon5: c.G753C: p.Q251H) was detected in the IKBKG gene, and this mutation was Inherited from his mother. IKBKG is associated with immunodeficiency type 33 and simple immunodeficiency, the main symptom of this type of disease are decreased immune system function, repeated infections, and abnormal growth of ectodermal tissue. In regard to this patient, the immune deficiency caused by this gene may be related to the CAEBV, but unfortunately we do not have data on his immune function before the onset of the disease.
Chronic EBV infection is very rare with gastrointestinal bleeding. As far as we know, the number of previously reported cases is not large, but most of them have a poor prognosis, whether it is patients with normal immune function or immune deficiency. Xu L et al have reported a case of chronic active Epstein-Barr virus infection in the small intestine of a 5-year-old Chinese boy. The patient later showed gastrointestinal bleeding and be diagnosed of an internal carotid aneurysm on the right. Hemorrhage improved and the right internal carotid aneurysm disappeared at a later follow-up [17]. Wang Y et al reported a case of middle-aged woman who went to the hospital for fever, blood in the stool, and after a partial bowel resection, the pathology confirmed that the disease was caused by EB virus infection, and the patient died shortly [18]. Denicola RP et al reported a case of acute gastrointestinal bleeding caused by EB virus-infected viral colitis in middle-aged and elderly women, who recovered and was discharged after active treatment [19]. Xu N et al Reported 21 adult CAEBV patients, 2 cases of gastrointestinal bleeding, one of which had underwent colectomy and was pathologically confirmed as colitis caused by CAEBV [20]. The CAEBV of this patient is clear, but the intestinal pathology did not indicate intestinal EBV infiltration, so we consider that the gastrointestinal bleeding is caused by congenital vascular malformation and severe infection.
We hypothesized that if the patient could obtain earlier treatment with HLH-04 or DEP-based combination therapy, there would be more chances to operate an allogeneic hematopoietic stem cell transplantation. But Arai et al reported that, OS 100
Author contributions: Cancan Lu wrote the manuscript.
Yishan Ye revised the manuscript, approved the final version, and is the article guarantor. Jimin Shi and Yamin Tan analyzed and interpreted the data.
Financial disclosure: None to report.
Informed consent was obtained for this case report.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
