Virus-associated Hemophagocytic Syndrome Research Articles

HLH Secondary to Influenza

Introduction Hemophagocytic lymphohistiocytosis (HLH) is a pathological condition characterized by excessive inflammation and tissue damage resulting from an aberrant immune system response. HLH can be classified into two distinct categories: primary HLH and secondary HLH. Secondary hemophagocytic lymphohistiocytosis (HLH) is an acquired condition that can be precipitated by various infections, malignancies, or rheumatological disorders. Herein, we present a rare case of HLH secondary to influenza B infection. Case Presentation A 37-year-old who routinely vapes and smokes cannabis presented to the emergency department with subjective fevers, body pains, fatigue, productive cough, shortness of breath, nausea, non-bloody, non-bilious vomiting, and watery diarrhea for one week. He was tachypneic, tachycardic, and febrile (101.1 F). He had loud bibasilar crackles on auscultation. Hb 14.8, total WBC 2.2, platelets 170, AKI with serum creatinine 1.9, and transaminitis with AST/ALT/ALP 130/56/122 U/L were the patient's initial lab results. Rapid influenza, strep, and COVID-19 antigen tests were negative. He exhibits hypoxemia with pH 7.46, pCO2 32.5, pO2 52.1, HCO3 22.9, and FIO2 40%. Urinalysis showed nonsignificant. CRP was 8.3 mg/dL. Negative procalcitonin. chest x-ray and ct showed bilateral diffuse patchy airspace infiltration, suggesting infectious process with mild pleaural effusion. In the critical care unit, he received Antibiotics and inhaled therapy for acute hypoxic respiratory failure with severe ARDS. After deteriorating, he was intubated. The respiratory pathogen panel detected Influenza B. Blood cultures and remaining pneumonia workup were negative. The lab results suggested HLH (table 1). Autoimmune tests were negative. Oseltamivir was given for 5 days. Repeat chest x-rays showed stable pulmonary infiltrates in the right middle and lower lobes, but the patient decompensated clinically with increasing ventilator requirements and dyssynchrony despite heavy sedation, paralytics, and proning and was transferred to a different hospital for ECMO evaluation on day 12. Discussion Primary and secondary HLH: Secondary HLH is caused by infections, malignancies, or rheumatological illnesses, while primary HLH is hereditary. The mortality outcome of HLH is extremely dependent on early detection and treatment 1. Due to the rarity of this disease entity, difficult diagnostic criteria, and concern for alternate diagnoses, internists may be less aware of it. Further complicating the diagnosis is the fact that the first bone marrow biopsy may not always show hemophagocytosis 2. This is why it is important to be cognizant of this diagnosis and it's diagnostic criteria. Our patient was suspected of HLH based on HScore for reactive hemophagocytic syndrome and the newest updated HLH diagnostic criteria (5 of 8 criteria should be met) 6. EBV is the most common viral infection which can cause HLH. CMV, Parvo, HSV, and H1N1 are other infections. HLH-Influenza B connection is poorly documented 7 Only one case of HLH induced by influenza B in a healthy patient was found in literature. To our knowledge, Our 38-year-old patient is the second known case of secondary HLH secondary to Influenza B in a healthy patient. Influenza B seldom causes HLH. This connection in adulthood is poorly researched. Patients with influenza virus infections have significant intestinal apoptosis and reactive hemophagocytic activity in bone marrow, lungs, and liver3. Influenza variants reduce CD8+ T cell cytotoxicity and perforin expression, likely causing HLH syndrome 4. A study suggests that virus-associated hemophagocytic syndrome (VAHS) is a common consequence of severe 2009 influenza A (H1N1) infection and contributes to multiorgan failure and mortality. 9 (36%) of 25 severely ill patients with confirmed 2009 influenza A (H1N1) infection developed VAHS, and 8 (89%) died 5. Conclusion: We present this case to raise awareness among physicians regarding the potential occurrence of hemophagocytic lymphohistiocytosis (HLH) as a complication in adult patients who present with influenza B virus infection accompanied by fever and pancytopenia. The aim is to emphasize the importance of considering HLH as a differential diagnosis in order to facilitate timely identification and initiation of appropriate treatment for this condition.

Establishment of Epstein-Barr Virus (EBV) Latent Gene-Expressing T-Cell Lines with an Expression Vector Harboring EBV Nuclear Antigen 1.

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic or recurrent infectious mononucleosis-like symptoms and is associated with EBV-associated T/natural killer (NK)-cell lymphoproliferative disorders, which frequently lead to the development of life-threatening complications, such as virus-associated hemophagocytic syndrome and EBV-positive apparent leukemia/lymphoma mainly in T- and NK-cell lineages. In order to clarify the EBV genes responsible for the diseases, we introduced the plasmid coding sequences of EBV-encoded small RNAs (EBERs) and/or latent membrane protein (LMP) 1 into human T-lymphocyte virus-I-negative human T-cell lines using a gene expression vector harboring EBV nuclear antigen 1, established the G418-resistant transformants of five T-cell lines, and quantitatively examined the expression of EBERs and LMP1 using real-time reverse transcriptase-polymerase chain reaction. The expression levels of EBERs in T-cell transformants with EBER DNA paralleled those in EBV-positive human T- and NK-cell lines, SNTK cells. The expression of LMP1 mRNA varied in SNTK cells and in human T-cell transformants, and the expression of LMP1 mRNA in T-cell lines expressing both EBERs and LMP1 was much lower than that in the same cell line expressing LMP1 mRNA alone. The currently employed gene expression system and currently obtained transformants may be useful for the analyses of the pathophysiology of CAEBV and EBV-positive T/NK-cell lymphoproliferative disorders.

Dengue associated hemophagocytic syndrome: a case report

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive and life-threatening syndrome of excessive immune activation. Several conditions are responsible for triggering HLH in clinically stable patients who respond to treatment of the underlying condition alone. These conditions include infection, rheumatological diseases and lymphoid malignancies. We are discussing a case of HLH who presented at age of 22 years that was triggered by dengue virus infection. Patient presented with an acute febrile illness and was diagnosed with dengue hemorrhagic fever. Despite appropriate supportive therapy, he had clinical deterioration. Evaluation revealed features of HLH. He was successfully treated with glucocorticoids and had an uneventful recovery. This case adds to the limited adult cases of virus-associated hemophagocytic syndrome in the literature and emphasizes the need for prompt recognition and treatment of this rare complication.
 BIRDEM Med J 2023; 13(1): 49-51

Role of Monocytes/Macrophages in Covid-19 Pathogenesis: Implications for Therapy.

cov-Emerging studies from SARS-CoV-2-infected patients indicate a preponderant role of monocytes/macrophages in the pathogenesis of this viral infection, in a similar way to that previously observed in other coronavirus outbreaks (SARS and MERS). The clinical presentation of severe patients resembles viral-associated hemophagocytic syndrome, a rare condition previously seen during lethal influenza pandemics and during previous SARS and MERS coronavirus outbreaks. SARS-CoV-2 infection triggers an over-exuberant inflammatory response due to the development of a cytokine storm and the depletion of the adaptative immune compartment, which may prelude sepsis in many cases. The present review summarizes past evidence on the role of monocytes/macrophages in previous coronavirus outbreaks and the emerging knowledge on their role in COVID-19 pathogenesis. Treatment strategies incorporating the blockade of migration and differentiation of monocyte-macrophage, such as granulocyte macrophage-colony stimulating factor inhibitors, might enhance the promising results seen so far with selective cytokine blockade.

Clinical Characteristics and Prognostic Analysis of 59 Adult Patients with Epstein-Barr Virus-Associated Hemophagocytic Syndrome

To analyze the clinical characteristics and the prognostic risk factors of adult patients with Epestein-Barr virus-associated hemophagocytic syndrome (EBV-HLH) so as to enhance the understanding of EBV-HLH and diagnosis and treatment level. The clinical manifestation and survival data of 59 adult patients with EBV-HLH admitted in our hospital from January 2013 to August 2018 were analyzed retrospectively. The most common clinical manifestations of 59 patients were high fever (100%), liver dysfunction (91.5%), however the skin rashes (1.7%), and neurologic abnormality (3.4%) were rare. 96.6% of the patients showed the elevation of serum ferritin and LDH level, and hypoproteinemia and sCD25≥2 400 U/ml were found in 93.2% and 92.3% of the patients, respectively. The median survival time of 59 patients was 2.5±0.7 months; overall survival rate of 1, 3, 6 and 12-month was 69.5%±6.0%, 44.7%±6.6%, 23.9%±5.8%, 19.7%±5.5%, respectively. Univariate survival analysis showed that the patients with EBV-DNA copies≥5×105/ml (P＜0.05), LDH level≥600 U/L (P＜0.05) and Plt count＜20×109/L (P＜0.05) had poor prognosis, and there was statistically difference in the overall survival rate (P＜0.01) between HLH-94/2004 group and the group treated without etoposide (not HLH-94/2004). Multivariate analysis revealed that LDH level≥600 U/L (P＜0.05), Plt count＜20×109/L (P＜0.05) and treatment protocol (not HLH-94/2004) (P＜0.01) were independent prognostic risk factors in 59 patients with EBV-HLH. EBV-HLH assocites with severe clinical features, high mortality rate and poor prognosis of patients. EBV-DNA copies≥5×105/ml (P＜0.05), LDH level≥600 U/L (P＜0.05) and Plt count＜20×109/L (P＜0.05) are the poor prognostic factors, and the treatment with HLH-94/2004 protocol can effectively improve the survival of EBV-HLH patients, should be applied as early as possible.

A case report of severe liver injury and hemophagocytic syndrome caused by chronic EB virus infection related to a mutation in the LYST gene.

Background: Hemophagocytic syndrome (HPS) is a syndrome of excessive immune activation characterized by various clinical symptoms of extreme inflammation. Epstein-Barr virus (EBV) is the most frequent infection associated with HPS, often referred to as virus-associated HPS. EBV-HPS is a serious disorder in which monoclonal growth of T cells infected with EBV and activated macrophages cause pancytopenia, high fever and severe liver injury due to primary infection or reactivation of EBV. Methods: A 22-year-old patient presenting with fever, pancytopenia and splenomegaly was diagnosed with hemophagocytic syndrome (HPS) associated with chronic Epstein-Barr virus (EBV) infection. The patient had been ill for more than one year and was more sensitive to glucocorticoid therapy. However, after tapering off the hormone therapy, the patient relapsed. Results: In view of the long-term glucocorticoid therapy of the patient, glucocorticoid-related side effects may have occurred. Therefore, intermittent VP-16 chemotherapy was given, and the glucocorticoid was reduced gradually to discontinuation. The patient, his brother and his parents had mutations in the HPS related genes. There was the same HPS gene mutation in the patient and his father (the variation c.4863-4 G>A (heterozygosity) in the introns around the LYST gene), and the same HPS gene mutation in the elder brother and mother (missense mutation c.603 G>T (p.Leu 201phe heterozygosity) in the Exon8 of STXBP2 gene). Therefore, there were no suitable sibling donors for the patient, who awaited an unrelated donor. It is presumed that the secondary HPS may have a genetic background. There have been HPS related gene mutations before symptom onset, and these can induce HPS due to infection and other factors. Conclusion: The detection of hemophagocytic related gene mutations for HPS high-risk populations with chronic EBV infection, tumors and autoimmune diseases can be beneficial in predicting the risk of HPS. STXBP2 gene mutations are common in patients with HPS, while LYST gene mutations are rarely reported. This case report provides some reference for the diagnosis of other patients.

Inherited Immunodeficiencies With High Predisposition to Epstein-Barr Virus-Driven Lymphoproliferative Diseases.

Epstein–Barr Virus (EBV) is a gamma-herpes virus that infects 90% of humans without any symptoms in most cases, but has an oncogenic potential, especially in immunocompromised individuals. In the past 30 years, several primary immunodeficiencies (PIDs) associated with a high risk to develop EBV-associated lymphoproliferative disorders (LPDs), essentially consisting of virus-associated hemophagocytic syndrome, non-malignant and malignant B-cell LPDs including non-Hodgkin and Hodgkin’s types of B lymphomas have been characterized. Among them are SH2D1A (SAP), XIAP, ITK, MAGT1, CD27, CD70, CTPS1, RASGRP1, and CORO1A deficiencies. Penetrance of EBV infection ranges from 50 to 100% in those PIDs. Description of large cohorts and case reports has refined the specific phenotypes associated with these PIDs helping to the diagnosis. Specific pathways required for protective immunity to EBV have emerged from studies of these PIDs. SLAM-associated protein-dependent SLAM receptors and MAGT1-dependent NKG2D pathways are important for T and NK-cell cytotoxicity toward EBV-infected B-cells, while CD27–CD70 interactions are critical to drive the expansion of EBV-specific T-cells. CTPS1 and RASGRP1 deficiencies further strengthen that T-lymphocyte expansion is a key step in the immune response to EBV. These pathways appear to be also important for the anti-tumoral immune surveillance of abnormal B cells. Monogenic PIDs should be thus considered in case of any EBV-associated LPDs.

Infusion of leukocytes from HLA haplo-identical familial donors as an adjuvant in the HLH-2004 protocol to treat the virus-associated adult hemophagocytic lymphohistiocytosis: a retrospective study of 26 patients.

Adult hemophagocytic lymphohistiocytosis (HLH) is a fatal disease with poor survival and a limited role of drug therapies. To help to recognize virus and enhance survival, we infused leukocytes derived from human leukocyte antigen (HLA) haplo-identical familial donors to patients. We retrospectively investigated 26 adult virus-associated hemophagocytic syndrome (VAHS) patients' medical records from 2006-2017. Eleven of the 26 patients accepted relatives' derived leukocytes infusions in addition to drug therapies recommended in the HLH-2004 protocol. The leukocyte doses ranged from 0.75 to 3.30×108 per kilogram of body weight. The other 15 patients accepted immunosuppressive and supportive therapies referred to in the HLH-2004 protocol. We compared the treatment outcomes of the two groups of patients. Patients in the cell infusion group had a lower viral load (P = 0.023) and better laboratory results and prolonged overall survival (60.44 vs. 20.18weeks, P = 0.047). A factor that might relate to overall survival is platelet count (P = 0.032), except for the leukocyte infusions (P = 0.012). For patients without acceptable donors, infusions of leukocytes from HLA haplo-identical familial donors could be a feasible treatment to prolong overall survival as an adjuvant to drug therapies.

Disruption of vascular endothelial homeostasis in systemic juvenile idiopathic arthritis-associated macrophage activation syndrome: The dynamic roles of angiopoietin-1 and -2

To assess the role of angiopoietin (Ang)-1 and Ang-2 and to investigate the clinical significance of serum levels of them in systemic juvenile idiopathic arthritis (s-JIA)-associated macrophage activation syndrome (MAS), we determined these levels in 51 patients with s-JIA, 11 patients with polyarticular JIA (poly-JIA), 12 patients with virus associated hemophagocytic syndrome (VAHS), 12 patients with Kawasaki disease (KD), and 15 age-matched healthy controls (HC). The results were compared with clinical features of MAS. During the MAS phase, serum Ang-1 levels were significantly decreased compared with those during the active and inactive phases. Serum Ang-2/1 ratio were significantly elevated during the MAS phase, compared with those during the active and inactive phases. There was a rapid increase in the Ang-2/1 ratio at the onset of MAS. Serum Ang-1 and the Ang-2/1 ratio significantly correlated with measures of disease activity, including AST and LDH. Ang-2/1 dysregulation was also observed in patients with VAHS, whereas not observed in most cases of KD. The homeostasis of vascular endothelial function by Ang-1 and Ang-2 is disrupted in MAS. Serum Ang-1 levels and the Ang-2/1 ratio might represent promising indicators of disease activity for MAS.

血球貪食症候群を呈し急激な転帰をたどった重症熱性血小板減少症候群の1例

78歳，女性．意識障害を主訴として搬送され，血球貪食症候群（hemophagocytic syndrome：HPS）を呈し，急激な経過で全身状態の悪化，死亡に至った．マダニによる刺し口は認められなかったが，SFTSV（severe fever with thrombocytopenia syndrome virus）が検出され，重症熱性血小板減少症候群（severe fever with thrombocytopenia syndrome：SFTS）と診断した．本疾患はSFTSVによるダニ媒介性感染症で，2011年，中国で新たに発見され，日本国内では2013年以降，西日本を中心に症例報告がある．ウイルス関連血球貪食症候群（virus-associated hemophagocytic syndrome：VAHS）の原因の1つとしてSFTSを鑑別する必要がある．

Acute Kidney Injury with Epstein Barr Virus-Associated Hemophagocytic Syndrome

A 59-year-old man, who was treated for schizophrenia and psoriasis vulgaris with risperidone and cyclosporine, presented with high fever and myalgia. Those did not respond to treatment for neuroleptic malignant syndrome for two weeks, and multiple organ dysfunction developed, so he was admitted to our hospital, but died two days later. Autopsy detected the hemophagocytosis, Epstein Barr Virus (EBV)-reactivated cells, and the absence of glomerulonephritis and interstitial tubulitis. We considered that hemophagocytic syndrome (HPS) and myalgia were caused by reactivated EBV and the viremia under immunosuppression, and renal failure was caused by sepsis-like state by cytokine storm of HPS.

単純ヘルペスウイルス感染から劇症肝炎・ウイルス関連血球貪食症候群を呈した一例

単純ヘルペスウイルス感染から劇症肝炎・ウイルス関連血球貪食症候群を呈した一例

Virus-associated hemophagocytic syndrome in renal transplant recipients: report of 2 cases from a single center.

Virus-associated hemophagocytic syndrome (HPS) is a potentially fatal complication of immunosuppression for transplantation. However, it presents with heterogeneous clinical symptoms (fever, disturbed consciousness, and hepatosplenomegaly) and laboratory findings (pancytopenia, elevated hepatic enzyme levels, abnormal coagulation, and hyperferritinemia), impeding diagnosis. Case 1: A 39-year-old female developed fever 4 years after ABO-incompatible living-related renal transplantation. Laboratory findings revealed thrombocytopenia, elevated hepatic enzymes, Epstein-Barr virus (EBV) DNA seropositivity, and hyperferritinemia. EBV-associated HPS was confirmed by bone marrow aspiration. Steroid pulse therapy and etoposide were ineffective. Disseminated intravascular coagulation resulted in multiple organ failure, and the patient died 32 days after disease onset. Case 2: A 67-year-old male was admitted with rotavirus enteritis a month after living-unrelated renal transplantation. He developed sudden-onset high fever, disturbance of consciousness, and tachypnea 8 days after admission. Laboratory findings revealed elevated hepatic enzyme levels, hyperkalemia, and hyperferritinemia. Emergency continuous hemodiafiltration ameliorated the fever, and steroid pulse therapy improved abnormal laboratory values. Varicella-zoster virus meningitis was confirmed by spinal tap. Acyclovir improved consciousness, and he was discharged 87 days after admission. Fatal virus-associated HPS may develop in organ transplant patients receiving immunosuppressive therapy. Pathognomonic hyperferritinemia is useful for differential diagnosis.

The use of therapeutic play in the intensive care of a preschool child with virus-associated hemophagocytic syndrome

Hospitalization is a stressful experience for children that increases their anxiety and fears, generates resistance and noncompliance, and, as a result, delays necessary treatments. Developing an age-appropriate intervention to reduce the hospitalization-related stress perceived by children is an important component of pediatric nursing. This case study used therapeutic play and drawing to care for a virus-associated hemophagocytic syndrome preschooler who stayed in our pediatric intensive care unit (PICU) between 11/13/2012 and 11/19/2012. Stressors faced by the patient included separation from primary caregiver, unfamiliarity with the medical environment and equipment, non-comprehension of the treatment and medication regimens, and loss of control. The patient displayed incorporative behaviors such as crying, screaming, refusing to be touched, and requesting parental accompaniment. Painting and picture books were used as developmentally appropriate interventions to understand the patient's feelings and to provide a means for him to project and release emotions. This strategy successfully assisted the child to overcome the perceived stress of hospitalization and to cooperate with healthcare providers on his treatment.

Hemophagocytic lymphohistiocytosis in adults.

Hemophagocytic lymphohistiocytosis in adults.

BK virus-associated hemophagocytic syndrome in a renal transplant recipient

Hemophagocytic syndrome (HPS) is a life-threatening hematological disorder in immunocompromised patients. Reactive HPS is observed in patients with systemic infection, neoplasia or auto-immune diseases. It is a rare hematological disorder after renal transplantation and must be suspected when fever and pancytopenia are seen in association with viral infections. HPS is usually associated with infection with the Cytomegalovirus and Epstein-Barr viruses. We report here a case of BK-virus-associated HPS.

Clinical analysis of Epstein-Barr virus-associated hemophagocytic syndrome in children

The primary infection of Epstein-Barr virus (EBV) may results in hemophagocytic syndrome, known as EBV-associated hemophagocytic syndrome (EBV-AHS), but the clinical risk factors complicating this fatal disease in children with infectious mononucleosis (IM) are unknown. The aim of this study was to identify clinical features of EBV-AHS and to evaluate the curative effect of HLH-2004 protocol. The clinical and laboratory data of 644 IM children including 27 children developed into EBV-AHS and 43 HPS children associated with other diseases were retrospectively analyzed and logistic regression was used to identify the clinical risk factors complicating EBV-AHS. The results showed as follows: (1) the prevalence of EBV-AHS in IM children was 4.2% (27/644), and the prevalence in group aged younger than 3 years was higher than in other age groups. The incidence age of EBV-AHS was significantly younger than that of other HPS patients; (2) Liver function damage of group aged older than 7 years was much more severe in HPS patients. (3) Compared with other HPS patients, male patients were more common and liver function damage was severe in EBV-AHS patients, especially in the patients aged at 2 years or younger. (4) The fatality rate in the EBV-AHS patients was 37.0% (10/27). (5)After treatment with HLH-2004 protocol, the fatality rate in patients with EBV-AHS decreased from 50.0% to 18.2%, the overall survival (OS) of 3 years significantly increased (P = 0.032). It is concluded that IM is a benign self-limited disease, of which only about 4.2% patients will develop into EBV-AHS. Clinical risk factors identified in this study may be helpful for early diagnosis of IM children with complicated EBV-ASH, the HLH-2004 protocol can obviously improve prognosis of EBV-HPS.

Extracorporeal membrane oxygenation: the MOTOR of cytokine production?

The usefulness of extracorporeal membrane oxygenation (ECMO) is being rediscovered in the wake of the pandemic of H1N1 influenza. However, it has been reported that patients who received ECMO often developed virus-associated hemophagocytic syndrome (VAHS), compared with those without ECMO support. Although there is ample evidence that extensive cytokine activation is a key factor in VAHS, ECMO itself could be a potential trigger to exacerbate the pathology by amplifying cytokine activation. In this study, we investigated whether mediators such as cytokines may be produced by ECMO.

Meningoencephalopathy as a clinical manifestation of Epstein-Barr virus-associated hemophagocytic syndrome

A 17-year-old Japanese woman with refractory Epstein–Barr virus-associated hemophagocytic syndrome (EB-VAHS) developed meningoencephalopathy with seizures. A magnetic resonance imaging (MRI) examination showed multiple lesions with gadolinium enhancement in the cortex of the hemisphere, hypothalamus and brainstem. In addition, contrast-enhanced fluid-attenuated inversion recovery (FLAIR) images showed the abnormal enhancement of the leptomeninges. A cerebrospinal fluid analysis detected Epstein–Barr virus polymerase chain reaction positivity, the absence of pleocytosis and an increased protein level. Prompt initiation of high-dose steroid therapy dramatically improved the symptoms and abnormal MRI findings. This case suggests that contrast-enhanced FLAIR images and Epstein–Barr virus polymerase chain reaction using a cerebrospinal fluid sample might be useful for the early detection of central nervous system involvement in VAHS.

Meningoencephalopathy as a clinical manifestation of Epstein-Barr virus-associated hemophagocytic syndrome

Meningoencephalopathy as a clinical manifestation of Epstein-Barr virus-associated hemophagocytic syndrome