流式细胞术在噬血细胞综合征诊断中的应用进展

噬血细胞性淋巴组织细胞增多症(Hemophagocytic lymphohistiocytosis,HLH)是一种以免疫系统过度激活,导致炎性细胞因子分泌过多为特征的综合征。患者通常表现为高热、细胞减少、高铁蛋白血症和肝脾肿大。其疾病过程从轻度到致命的多器官衰竭不等,该病进展迅速,且容易误诊,病死率高。对该疾病的早期认识和及时诊治有助于预防致命的后果。现行的HLH诊治中国专家共识中,对于最后2个标准[即sIL-2受体和自然杀伤(natural killer,NK)细胞活性]的测定,流式细胞术发挥着重要作用。近年来,利用流式细胞术检测潜在生物标志物为HLH的诊断开辟了新的途径。本综述将围绕流式细胞术在其中的应用展开对该疾病的一些思考。     

Wilson's disease

Wilson's disease, an autosomal recessive disorder of copper metabolism, most often becomes apparent in adolescence and may present with a multitude of signs and symptoms. Early diagnosis and treatment can prevent irreversible damage to the liver and the central nervous system. The diagnosis is confirmed by hepatic biopsy and quantitation of copper in the tissues. Treatment is chelation of excess copper. If untreated, Wilson's disease is fatal.     

A fatal case of primary cutaneous gamma–delta T‐cell lymphoma complicated by HLH and cardiac amyloidosis

Gamma–delta T‐cell lymphomas (GD‐TCL) are rare and rapidly fatal neoplasms that are often associated with Hemophagocytic Lymphohistiocytosis (HLH), a syndrome of fevers, cytopenias, and multiorgan failure that often leads to a rapid death. We report the first case demonstrating an association between GD‐TCL, HLH, and cardiac amyloidosis, presenting a novel mechanism for rapid deterioration in these patients.     

儿童噬血细胞性淋巴组织细胞增生症发病机制和诊治研究进展

噬血细胞性淋巴组织细胞增生症（HLH）,又称为噬血细胞综合征（HPS）,在儿童时期多见,临床起病急、进展迅猛,病死率高.HLH病因复杂多样,但细胞毒T淋巴细胞和NK细胞毒效应低下、细胞因子风暴和多器官高炎症反应及组织器官免疫损伤为显著病理生理特征和共同的发病环节.近年来国际上在HLH的遗传缺陷、诊断和治疗方面取得较大进展.本文结合我们的临床诊治经验,重点就儿童HLH的病因、分类、流行病学、发病机制、诊断标准和诊治研究进展做一综述.     

Current and future directions of pathologic analysis in hemophagocytic syndrome

Hemophagocytic syndrome is a rare disorder with dysfunction of cytotoxic T lymphocyte (CTL) or NK cell activity, leading to excessive production of inflammatory cytokines and various clinical symptoms. HLH can be classified as either primary or secondary form; primary HLH includes familial hemophagocytic lymphohistiocytosis (FHL) and several immune deficiencies. All affected genes are involved in the transport and membrane fusion, or exocytosis of perforin/granzyme in lytic granules. Making a rapid screening of FHL with flow cytometry followed by genetic analysis is mandatory for the appropriate treatment of this fatal disease. Whereas, pathogenesis of secondary HLH is still unknown; several genetic backgrounds to affect on the pathway of T-cell activity will be associated with secondary HLH. With perforin- or Munc-deficient mouse model that develop HLH-like symptoms after virus infection, CD8+ T cells and interferon-gamma have been proven to be necessary for the HLH development. These data will provide new targets for specific therapeutic intervention of HLH in the future.     

成人噬血细胞性淋巴组织细胞增多症一例并文献复习

目的探讨噬血细胞性淋巴组织细胞增多症(HLH)的临床特点、发病机制、治疗方案及预后。方法回顾分析1例成人HLH患者的临床资料并进行文献复习。结果患者经积极规范治疗,病情明显好转。结论 HLH病情凶险,进展迅速,早期积极治疗可以治愈。     

Haemophagocytic lymphohistiocytosis: Five years’ experience at tertiary hospitals in Free State Province,South Africa

Background Haemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome if not recognised and managed early. It involves an uncontrolled pathological activation of the immune system, and it is either genetic or acquired. It presents with clinical and laboratory features of severe inflammation. Early initiation of effective therapy may reduce mortality from 95% to 35%. ObjectivesTo raise awareness of HLH among healthcare professionals, particularly intensivists. MethodsWe report nine cases of secondary HLH seen at tertiary hospitals in Bloemfontein, South Africa. Results All patients presented with fever, hypertriglyceridaemia, hyperferritinaemia, transaminitis and cytopenia. Haemophagocytosis was noted on bone marrow biopsy in 66.7% (n=6/9) of the patients. More than one-third (44.4%; n=4/9) of the cases were triggered by a lymphoma, 44% (n=4/9) were associated with infection and 11% (n=1/9) were associated HIV. Finally, 11.1% (n=1) of the patients were triggered by an underlying autoimmune disease. More than half (55.6%; n=5/9) of the cases had a fatal outcome. Conclusion A high index of suspicion may promote the accurate diagnosis of HLH in patients presenting with fever, transaminitis and unexplained cytopenia. Contributions of the study HLH is a rare, life-threatening condition that may be missed in the intensive care setting. This report emphasises the importance of clinical suspicion, early diagnosis and appropriate intervention.     

Miliary tuberculosis-associated hemophagocytic lymphohistiocytosis with a high level of soluble interleukin-2 receptor successfully treated with concomitant recombinant thrombomodulin: A case report

Hemophagocytic lymphohistiocytosis (HLH) is a fatal disease characterized by a highly inflammatory state due to the abnormal activation of T lymphocytes and macrophages. Miliary tuberculosis (MTB) is a rare cause of HLH and its clinical appearances occasionally resembles that of intravascular lymphoma (IVL). A 76-year-old woman presented with persistent fever and fatigue. Abnormal laboratory findings showing thrombocytopenia (13,000/μL), hypofibrinogenemia (101 mg/dL), hyperferritinemia (2,312 ng/mL), and markedly elevated soluble interleukin-2 receptor (sIL-2R) level (32,200 U/mL), in addition, hemophagocytosis in the bone marrow (BM) smear, were suggestive of IVL-associated HLH. The pathology of the BM biopsy specimen showed granuloma with non-caseous necrosis, and culture tests using sputum, gastric fluid, urine, and peripheral and bone marrow blood revealed the presence of Mycobacterium tuberculosis, leading to the final diagnosis of MTB-associated HLH. Anti-TB medications and corticosteroids were administered, but thrombocytopenia, hypofibrinogenemia, and hyperferritinemia persisted. Concomitant use of recombinant thrombomodulin (rTM) enabled regression of clinical status. In this case, BM biopsy served as the diagnosis of MTB-associated HLH, although IVL-associated HLH is initially suspected by an extremely high level of sIL-2R. Furthermore, this case report informs that using rTM could improve the outcomes of MTB-associated HLH.     

Human parechovirus-3 infection in nine neonates and infants presenting symptoms of hemophagocytic lymphohistiocytosis

Human parechovirus-3 (HPeV-3) has been reported to cause a sepsis-like illness in neonates and young infants. We experienced the occurrence of HPeV-3 infection in nine neonates and young infants (eight boys, one girl; aged 14–52 days, median 31 days). They were admitted to our hospital with the chief complaints of fever persisting for 3–5 days (median 4 days) and lethargy. Five infants presented with abdominal distension and six had a rash (including acral reddening), as was previously reported with this viral infection. Abdominal distension with navel protrusion and acral reddening during the course were characteristic. Laboratory data were characterized by elevated values for serum AST, LDH, FDP, D-dimer, ferritin, soluble IL-2 receptor, triglyceride, choline esterase, and urinary β₂-microglobulin. Two of our nine patients presented with a hemophagocytic lymphohistiocytosis (HLH)-like illness and required specific therapy. These data suggest that HPeV-3 is an important virus that can cause hypercytokinemia, which sometimes leads to HLH, and systemic inflammatory response syndrome in neonates and young infants.     

The optimal treatment of venous thrombosis: current status and future perspectives

Acute deep venous thrombosis (DVT) of the lower extremities is a serious and potentially fatal disorder, which often complicates the course of hospitalized patients but may also affect ambulatory and otherwise healthy people. Venous thrombosis is uncommon in young individuals and becomes more frequent with advancing age. The clinically important problems associated with venous thrombosis are death from pulmonary embolism, morbidity resulting from the acute event, recurrent venous thromboembolic events, the post-thrombotic syndrome, and the inconvenience and side-effects of investigations and treatment. The main objectives of treatment of DVT are prevention of (both fatal and nonfatal) pulmonary embolism and thrombus extension in the acute phase of the disease, prevention of recurrences of venous thromboembolism in the months following the acute episode, and prevention of late sequelae (post-thrombotic syndrome). These objectives are satisfactorily achieved with anticoagulant drugs (heparin and vitamin K antagonists), which therefore are the mainstays of DVT treatment. Other therapeutic options have a more limited application.     

What’s in a name? The heterogeneous clinical spectrum and prognostic factors in a cohort of adults with hemophagocytic lymphohistiocytosis

Purpose

Hemophagocytic lymphohistiocytosis (HLH) in adults is rare but frequently fatal. Diagnosis is often delayed and treatment approaches vary significantly in contrast to the protocol-driven approach typically used in pediatric HLH. To improve care of these complex patients, this study retrospectively examined the prevalence, clinical characteristics, therapies and outcomes of adult HLH patients at two large tertiary care centers.

Richter综合征的诊断与治疗研究进展

Richter综合征(RS)是一种由低度恶性淋巴细胞增殖性疾病,向更高度恶性淋巴细胞增殖性疾病转化和(或)并发的一种疾病,多为B细胞疾病之间的转化.导致RS转化的影响因素复杂,发病率低,现行治疗方案对该病患者的预后差,诊断金标准为活组织检查.目前,RS主要治疗方案包括化疗、造血干细胞移植(HSCT)及新药试验等,部分年轻患者可从HSCT治疗中获益.若在RS转化早期及时诊断,选择合适治疗方案,则可能延长患者生存期.笔者拟就目前对RS的发病机制及其诊断与治疗的相关研究进展进行综述.     

Platelet refractoriness in acquired hemophagocytic syndrome

BACKGROUND: Acquired hemophagocytic syndrome (AHPS) is a severe inflammatory disorder often caused by Epstein‐Barr virus (EBV). Proliferation of activated macrophages produces uncontrolled cytokine production. Thrombocytopenia is common in AHPS, previously attributed to inadequate or ineffective marrow platelet (PLT) production. PLT transfusion response is not well reported. Two patients with fatal AHPS developed unexplained PLT transfusion refractoriness before definitive diagnosis. CASE REPORTS: PLT refractoriness was noted during the care of two patients. The refractoriness was determined to be nonimmune and both demonstrated various clinical signs and laboratory findings consistent with AHPS. The first patient's AHPS was attributable to EBV infection. In the other patient, no underlying cause could be found. Both patients had an aggressive clinical course and succumbed to this relatively rare syndrome. The PLT refractoriness was evident before the AHPS diagnosis was made. DISCUSSION: AHPS is not generally a consideration in the evaluation of nonimmune PLT refractoriness. However, these illustrative cases make an argument for its consideration in the differential diagnosis of PLT refractoriness in severely ill patients. Once present, it is unclear if the refractoriness can be reversed by AHPS‐targeted therapy.     

可溶性IL-2受体及NK细胞活性在噬血细胞性淋巴组织细胞增多症中的意义

本研究通过检测噬血细胞性淋巴组织细胞增多症(HLH)患者外周血中可溶性IL-2受体(sCD25)及NK细胞活性,探讨它们在HLH中的意义。应用酶联免疫吸附法检测20例HLH患者、15例正常对照者、20例急性髓系白血病(AML)患者及20例系统性红斑狼疮(SLE)患者外周血血清sCD25水平;用流式细胞术CD107a标记法及传统的LDH释放法检测HLH组及正常对照组外周血NK细胞活性。结果显示:HLH组血清sCD25水平较正常对照组、AML组及SLE组均明显升高(P<0.001);HLH组NK细胞活性明显低于正常对照组(P<0.05);将流式细胞术CD107a标记法与传统的LDH释放法检测NK细胞活性进行相关分析,该两种检测方法之间具有显著相关性(r=0.73,P<0.05)。结论:血清sCD25及外周血NK细胞活性检测是HLH重要的辅助诊断指标,流式细胞术CD107a标记法检测NK细胞活性简单、稳定、重复性高,有助于HLH的临床诊断。     

PD-1 blockader-associated atypical hemophagocytic lymphohistiocytosis: A cautionary case report

Hemophagocytic lymphohistiocytosis (HLH) is a fatal immune hyperactivity syndrome with high mortality. It seriously endangers human health. HLH associated with immune checkpoint inhibitors is rare, and no particular diagnostic guidelines or treatment regimens exist. A 36-year-old patient with metastatic right atrial angiosarcoma was treated with programmed cell death-1 (PD-1) blockader toripalimab and pazopanib, a vascular endothelial growth factor receptor blockader. However, the patient presented to our center with HLH, and he accepted combination therapy of therapeutic plasma exchange (TPE) and immunotherapy. The patient improved quickly, after only one TPE procedure. Finally, he was discharged after completing two TPE procedures. We summarize a case of PD-1 blocker associated atypical HLH that was successfully treated with TPE. Further evidence is needed to elucidate whether TPE has therapeutic potential for immunotherapy associated HLH.     

Small cell lung cancer starting with diabetes mellitus: Two case reports and literature review

BACKGROUND Small-cell lung cancer(SCLC)is a type of fatal tumor that is increasing in prevalence.While these are unpleasant facts to consider,it is vitally important to be informed,and it is important to catch the disease early.Typically,lung cancer does not show severe clinical symptoms in the early stage.Once lung cancer has progressed,patients might present with classical symptoms of respiratory system dysfunction.Thus,the prognosis of SCLC is closely related to the early diagnosis of the disease.Ectopic adrenocorticotropic hormone(ACTH)syndrome(EAS)is related to cancer occurrence,especially for SCLC with the presence of Cushing's syndrome,which is dependent on markedly elevated ACTH and cortisol levels.CASE SUMMARY In the current report,we describe two middle-age patients who were originally diagnosed with diabetes mellitus with no classical symptoms of lung cancer.The patients were eventually diagnosed with SCLC,which was confirmed by bronchoscopic biopsy and histopathology.SCLC-associated diabetes was related to EAS,which was an endogenous ACTH-dependent form of Cushing’s syndrome with elevated ACTH and cortisol levels.Multiple organ metastases were found in Patient 1,while Patient 2 retained good health at 2 years follow-up.EAS symptoms including thyroid dysfunction,hypercortisolism and glucose intolerance were all resolved after anticancer treatment.CONCLUSION In conclusion,SCLC might start with diabetes mellitus and increased cortisol and hypokalemia or other EAS symptoms.These complex clinical features were the most significant factors to deteriorate a patient’s condition.Early diagnosis and treatment from clinicians were essential for the anti-cancer treatment for patients with SCLC.     

Aggressive natural killer cell leukemia with skin manifestation associated with hemophagocytic lymphohistiocytosis: A case report

BACKGROUNDAggressive natural killer cell leukemia (ANKL) is a rare natural killer cell neoplasm characterized by systemic infiltration of Epstein–Barr virus and rapidly progressive clinical course. ANKL can be accompanied with hemophagocytic lymphohistiocytosis (HLH). Here, we report a case of ANKL with rare skin lesions as an earlier manifestation, accompanied with HLH, and review the literature in terms of etiology, clinical manifestation, diagnosis and treatment.CASE SUMMARYA 30-year-old woman from Northwest China presented with the clinical characteristics of jaundice, fever, erythema, splenomegaly, progressive hemocytopenia, liver failure, quantities of abnormal cells in bone marrow, and associated HLH. The immunophenotypes of abnormal cells were positive for CD2, cCD3, CD7, CD56, CD38 and negative for sCD3, CD8 and CD117. The diagnosis of ANKL complicated with HLH was confirmed. Following the initial diagnosis and supplementary treatment, the patient received chemotherapy with VDLP regimen (vincristine, daunorubicin, L-asparaginase and prednisone). However, the patient had severe adverse reactions and complication such as severe hematochezia, neutropenia, and multiple organ dysfunction syndrome, and died a few days later. CONCLUSIONThis is the first reported case of ANKL with rare skin lesions as an earlier manifestation and associated with HLH.     

Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice

Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are 2 similar diseases characterized by a cytokine storm, overwhelming inflammation, multiorgan dysfunction, and death. Animal models of HLH suggest that disease is driven by IFN-γ produced by CD8⁺ lymphocytes stimulated by persistent antigen exposure. In these models and patients with “primary” HLH, the antigen persists due to genetic defects, resulting in ineffective cytotoxic responses by CD8⁺ T cells and poor pathogen clearance. However, infectious triggers are often not identified in patients with MAS, and some patients with HLH or MAS lack defects in cytotoxic T cell killing. Herein, we show that repeated stimulation of TLR9 produced an HLH/MAS-like syndrome on a normal genetic background, without exogenous antigen. Like previous HLH models, TLR9-induced MAS was IFN-γ dependent; however, unlike other models, disease did not require lymphocytes. We further showed that IL-10 played a protective role in this model and that blocking IL-10 signaling led to the development of hemophagocytosis. IL-10 may therefore be an important target for the development of effective therapeutics for MAS. Our data provide insight into MAS-like syndromes in patients with inflammatory diseases in which there is chronic innate immune activation but no genetic defects in cytotoxic cell function.     

Eosinophilic gastroenteritis.

Four patients with eosinophilic gastroenteritis are presented to illustrate the protean manifestations of this disorder. While the cause is unknown, the complications many, and the differential diagnosis often challenging, the treatment is simple and consists of low-dose, alternate-day administration of corticosteroids. Diagnosis depends on gastrointestinal biopsy, which usually can be obtained without surgery.     

Understanding organ dysfunction in hemophagocytic lymphohistiocytosis

OBJECTIVE: This review aims to help critical care clinicians maintain a high level of suspicion regarding the diagnosis of Hemophagocytic Histiolymphocytosis (HLH). It describes the clinical and laboratory features of HLH, outlines its pathophysiology and reviews the most frequent etiologies related to HLH. Prognostic factors and therapeutic options are also reported. DATA SOURCES: Review of the literature. RESULTS: The diagnosis of HLH relies on the association of clinical abnormalities and hemophagocytosis in bone marrow, spleen, or lymph node specimens. Liver, pulmonary, renal, cardiac and skin involvement may occur at various degrees possibly leading to multiple organ failure. Three main etiologies can be found, namely infections, lymphoproliferative diseases, or connective tissue diseases. Immune deficiency is often retrieved. Mortality can be as high as 50%. Although clinically mimicking severe sepsis, HLH has a distinct pathophysiology on which specific therapy is based. Early diagnosis and treatment is mandatory to increase the chances of survival. CONCLUSION: The comprehensive management of severe HLH requires the involvement of a multidisciplinary team in order to determine the best therapeutic strategy and to identify the underlying cause.