Massive digestive tract bleeding caused by EBV-triggered
Hemophagocytic Lymphohistiocytosis and digestive tract vascular
malformation
Cancan Lu1, Yishan Ye2, Jimin
Shi2, Yamin Tan2
Author information
- Department of Hematology, Jinhua Municipal Central Hospital, Jinhua,
Zhejiang, China.
- Bone Marrow Transplantation Center, Department of Hematology, The
First Affiliated Hospital, School of Medicine, Zhejiang University,
Hangzhou, China
Can Can Lu:280212092@qq.com.
Yishan Ye:yeyishan@hotmail.com.
Jimin Shi:shijimin@zju.edu.cn.
Yamin Tan: yamin0001@126.com.
Abstract
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.
Key words: Hemophagocytic lymphohistiocytosis(HLH); Severe; EB virus
infection; Digestive tract vascular malformation; Gastrointestinal
bleeding.
1. Introduction
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].
2. Case report
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 13thOctober, 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.
3 Discussion
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 (<1.5 g
/ l) ,(5) hemophagocytosis seen in the bone marrow or lymph nodes
[15]. In addition, Three other standards were added in 2004: (6) low
natural killer cell activity, (7) ferritin levels (≥500 μg / L) , (8) a
soluble interleukin-2 receptor level > 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
disease. 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% after HSCT of inactive and OS 0% after
HSCT of active disease [21]. Some patients with a diagnosis of
secondary HLH can treatmented through plasmapheresis without
chemotherapy [22]. Despite the development of treatment strategies
for EBV-HLH, the prognosis of patients with progressive and refractory
diseases is still poor. JAK 2 inhibitors can have preventive and
therapeutic effects on HLH [23]. In addition, bortezomib and
ganciclovir have been suggested to reduce the burden of disease
[24].
We report this case to remind doctors that the treatment should be given
promptly when diagnosed of severe HLH, especially with many
complications. In addition, attention needs to be taken to the
prevention of gastrointestinal bleeding during the treatment.
Disclosures
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.
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Figure legends
Figure 1: Enhanced abdomen CT examination revealed nodular enhanced foci
in the upper cavity of the jejunum, considering as vascular
malformations. And the arrow point.
Figure 2: 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.