Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by pancytopenia and multiple organ infiltrations of lymphocytes and histiocytes with proliferation and hemohpagocytic activity. HLH is classified as primary (or familial) and secondary. Familial HLH is common in infants and young children, and is related to genetic defects. This article aims to review research advances on PRF1, UNC13D, STX11 and STXBP2, as well as the other 5 genes associated with familial HLH based on molecular genetics, and to summarize diagnosis and treatment methods for this disease.
Humans ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; etiology ; genetics ; therapy ; Molecular Biology

Adult ; HIV Infections ; complications ; diagnosis ; Humans ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; etiology ; Male

Hemophagocytic lymphohistiocytosis (HLH) is named as hemophagocytic syndrome (HPS) and is a complicated disease with reactive hyperplasia of mononuclear/macrophagocytic system. This disease characterised by release of massive cytokines and severe functional destruction of visceral organs, which results from immune function disturbance causing by various pathogenic factors. The cardinal clinical symptoms of HLH are prolonged fever, hepatosplenomegaly, cytopenia, elevated ferritin and triglycerides, low fibrinogen, symptom in nerve system and so on. Nevertheless, impaired function of natural killer cells and cytotoxic T-cell is characteristic for HLH. HLH has of two different types that may be difficult to distinguish from one another: a primary and a secondary form. The combined immunochemotherapy of dexamethasone, etoposide and cyclosporin A and hematopoietic stem cell transplantation are considered as the effective therapies for HLH. In this article, the recent advance in research on the etiological factors, pathogenesis, clinical manifestations, laboratory examination, diagnosis as well as recommended therapy of HLH were reviewed.
Humans ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; etiology ; immunology ; pathology ; therapy ; Mononuclear Phagocyte System

Hemophagocytic lymphohistiocytosis (HLH) has been described in patients with advanced stages of human immunodeficiency virus (HIV) infection, but rarely occurs during the seroconversion stage of acute HIV infection. We report a case of acute HIV syndrome that presented with virus-associated HLH. The patient recovered spontaneously without any immunomodulating therapy. This case suggests that acute HIV infection should be included in the differential diagnosis of HLH and indicates that HLH associated with acute HIV infection can have a favorable outcome.
Acquired Immunodeficiency Syndrome/complications/*diagnosis ; Adult ; Diagnosis, Differential ; HIV Infections/complications/*diagnosis ; Humans ; Korea ; Lymphohistiocytosis, Hemophagocytic/etiology/*pathology ; Male

OBJECTIVEThe clinical features of four cases of visceral leishmaniasis (VL)-associated hemophagocytic lymphohistiocytosis (VL-HLH) were retrospectively analyzed for the purpose of helping the diagnosis of secondary HLH.

METHODClinical data of three childhood cases of VL-HLH documented in our hospital and one case diagnosed in the Capital Institute of Pediatrics was reviewed retrospectively, with particular emphasis on peculiar clinical manifestations and on clues to the diagnosis of this relatively rare disease entity.

RESULTThree children were from endemic areas of VL, and the other one had lived in endemic area for one year, which was revealed by detailed history-taking. Clinically, VL-HLH is characterized by persistent fever, hepatosplenomegaly and pancytopenia, which is similar to those of HLH, and is one of the important reasons of delayed diagnosis or misdiagnosis. Based on the HLH-2004 protocol, all the four cases met the diagnostic criteria of HLH. In addition, bone marrow aspirate and immunologic detection of VL-specific antibody via rk39 dipstick test during the early disease course of VL-HLH yielded negative results. Two cases who received HLH-targeted therapy responded reasonably well, with rapid temperature normalization and spleen retraction. Nevertheless, Hb remained lower than normal, which we believed to be related to persistent red cell destruction by the invading parasite Leishmania donovani.

CONCLUSIONVL, a parasitic disease caused by Leishmania donovani, which is currently endemic just in 6 provinces in China, shares similar clinical picture of HLH and is an easily ignored underlying cause of secondary HLH. We suggest that VL should be in the list of differential diagnosis for any patients with HLH who lives in or has a definite travel history to endemic areas. Repeated bone marrow studies are highly warranted to make a definite diagnosis of VL, because bone marrow aspirate or rk39 dipstick test during early disease course might yield negative results. Although VL-HLH responds quite well to HLH-tailored chemotherapy, specific therapy against VL must be given to prevent disease recurrence, and HLH-targeted chemotherapy might be discontinued to prevent chemotherapy-related toxicities.

Child ; Child, Preschool ; Female ; Humans ; Infant ; Leishmania donovani ; Leishmaniasis, Visceral ; complications ; diagnosis ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; etiology ; parasitology ; Male

Hemophagocytic lymphohistiocytosis (HLH) was a life-threatening syndrome due to the uncontrolled immune activation of cytotoxic T lymphocytes, natural killer (NK) cells, and macrophages. HLH is characterized by primary and secondary causes, the early diagnosis and treatment of patients are closely related to the prognosis and clinical outcome of patients. The clinical presentation is variable but mostly includes prolonged fever, splenomegaly, coagulopathy, hypertriglyceridemia, and hemophagocytosis, none of them is specific and particular for HLH. Tuberculosis (TB) infection is one of the causes of HLH. HLH caused by TB is very rare clinically, but it has a high mortality. For patients with fever of unknown origin, HLH-related clinical manifestations sometimes present before the final diagnosis of TB, and HLH is associated with the most significant mortality rate. This article is mainly about a 28-year-old patient with HLH who suffered from severe TB infection. The patient attended a hospital with a history of 2 months of prolonged fever, 10 days booger and subcutaneous hemorrhage in lower limbs. Before this, he was in good health and denied any history of tuberculosis exposure. Combined with relevant laboratory test results (such as splenomegaly, hemoglobin, platelet count, and hypertriglyceridemia) and clinical manifestations (e.g. fever), the patient was diagnosed with hemophagocytic lymphohistiocytosis, but the etiology of HLH remained to be determined. To confirm the etiology, the patient was asked about the relevant medical history (intermittent low back pain) and was performed chest CT scan, bone marrow biopsy, and fundus photography. Finally, he was diagnosed with hemophagocytic lymphohistiocytosis caused by hematogenous disseminated pulmonary tuberculosis. In response to this, intravenous methylprednisolone and anti-tuberculosis treatment (isoniazid, pyrazinamide, moxifloxacin, and amikacin) were administered to the patient. After more than a month of treatment, the patient recovered from HLH caused by severe TB infection. Therefore, this case suggests that we should be vigilant to the patient who admitted to the hospital with fever for unknown reasons, to diagnose HLH as early as possible and clarify its cause, then perform interventions and treatment, especially HLH secondary to tuberculosis. Also, cases of atypical TB and severe TB should be carefully monitored to achieve early diagnosis and early intervention.
Male ; Humans ; Adult ; Lymphohistiocytosis, Hemophagocytic/diagnosis* ; Splenomegaly ; Tuberculosis, Pulmonary/diagnosis* ; Bone Marrow/pathology* ; Fever/etiology* ; Hypertriglyceridemia/complications*

OBJECTIVETo investigate the clinical features of hemophagocytic syndrome (HPS) and to improve its recognition, early diagnosis and to reduce misdiagnosis.

METHODSA retrospective study was carried out to analyze the underlying diseases, clinical characteristics, laboratory findings and outcomes in 41 patients with HPS.

RESULTSHPS was clinically characterized by prolonged fever (100%), hepatomegaly (97.6%), splenomegaly (95.1%), and other features including lymph adenopathy (65.9%), respiratory symptoms (53.7%), hydrops of multiple serous cavity (26.8%), jaundice (26.8%), central nervous system involvement (14.6%), alimentary tract hemorrhage (12.2%) and skin rash (12.2%). Laboratory data indicated that liver dysfunction was the most prominent feature (100%) mainly manifested with elevated liver enzymes and hypoalbuminemia, and the others were hemophagocytosis in bone marrow (92.7%), pancytopenia 70.7%), coagulation abnormalities (52.4%), DIC, hypertriglyceridemia and refractory hyponatremia. The underlying disease of infection (IAHS) was most common (63.4%), in which EBV-AHS was predominant, making up to 69.2%. Fourteen patients died, 11 of them with IAHS (nine were EBV-AHS) and the other 3 non-IAHS (one of them was malignant lymphoma). The case-fatality rate was increased with the elevated levels of LDH and AST, the correlation coefficient was 0.486 and 0.516 (P < 0.05), respectively. Logistic regression analysis showed that age < 3 years old, levels of LDH > 2000 U/L and AST level > 200 U/L were independent prognostic factors (P value was 0.031, 0.002 and 0.001, respectively).

CONCLUSIONThere are various underlying diseases and clinical manifestations for HPS. EBV-AHS is the extremely dangerous situation with high mortality. Age, levels of LDH and AST are the death-associated risk factors. Repeat bone marrow examinations are helpful for diagnosis in time.

Adolescent ; Child ; Child, Preschool ; Female ; Herpesvirus 4, Human ; Humans ; Infant ; Lymphohistiocytosis, Hemophagocytic ; diagnosis ; etiology ; Male ; Prognosis ; Retrospective Studies

Central Nervous System Diseases ; etiology ; Child ; Female ; Humans ; Infant ; Lymphohistiocytosis, Hemophagocytic ; complications ; diagnosis ; genetics ; Magnetic Resonance Imaging ; Male ; Mutation ; Perforin ; genetics

Kaposi sarcoma herpes virus (KSHV), also known as human herpesvirus-8, plays an important role in the pathogenesis of Kaposi sarcoma (KS), multicentric Castleman disease (MCD) of the plasma cell type, and primary effusion lymphoma. KSHV is rarely associated with the hemophagocytic syndrome (HPS), but when it does occur, it most occurs in immunocompromised patients. We report herein an unusual case of KSHV-associated HPS in an immunocompetent patient. A previously healthy 62-yr-old male was referred for evaluation of leukocytopenia and multiple lymphadenopathies. After a lymph node biopsy, he was diagnosed with MCD of the plasma cell type. KSHV DNA was detected in the lymph node tissue by polymerase chain reaction. Following a short-term response of the leukocytopenia to prednisolone, mental change, left side weakness, fever, thrombocytopenia, hemolytic anemia, and renal failure developed. Despite intravenous immunoglobulin therapy and plasmapheresis, he expired. The lymph nodes were infiltrated by hemophagocytic histiocytes in the sinuses. Pulmonary nodules and gastric erosions were shown to be KS. KSHV DNA was detected in the stomach, lung, and liver. This is the first case of multiple KSHV associated diseases including MCD and KS with KSHV-associated hemophagocytic syndrome in an HIV-negative, non-transplant, immunocompetent patient.
Autopsy ; Giant Lymph Node Hyperplasia/complications/*diagnosis/pathology ; HIV Seronegativity ; Herpesviridae Infections/*diagnosis ; Herpesvirus 8, Human/*isolation & purification ; Humans ; Immunocompetence ; Lymphohistiocytosis, Hemophagocytic/*diagnosis/etiology ; Magnetic Resonance Imaging ; Male ; Middle Aged ; Polymerase Chain Reaction ; Sarcoma, Kaposi/complications/*diagnosis

Various manifestations of brain involvement for patients with virus-associated hemophagocytic syndrome have been reported. Here, we report on the sequential magnetic resonance (MR) findings of acute demyelination of the entire brain with subsequent brain atrophy in a follow-up study of a 25-month- old boy who was admitted with fever and then diagnosed with infectious mononucleosis and EBV-associated hemophagocytic syndrome. We also review other conditions that should be included in the differential diagnosis of this disease.
Male ; *Magnetic Resonance Imaging ; Lymphohistiocytosis, Hemophagocytic/etiology/*pathology/virology ; Humans ; Epstein-Barr Virus Infections/complications/*pathology ; Diagnosis, Differential ; Demyelinating Diseases/complications/*pathology/virology ; Child, Preschool ; Brain Diseases/complications/*pathology/virology