What Is Hemophagocytic Lymphohistiocytosis?

Hemophagocytic syndrome (HLH) is considered to be a type of histiocytosis of reactive proliferation of mononuclear macrophages. It is mainly due to cytotoxic killer cells (CTL) and NK cell functional defects that cause antigen clearance disorders. A group of clinical syndromes caused by continuous antigen stimulation and excessive activation and proliferation, producing a large number of inflammatory cytokines. Hemophagocytic syndrome is mainly manifested as fever, splenomegaly, reduced whole blood cells, high triglycerides, low fibrinogen, high serum ferritin, and can be found in bone marrow, spleen or lymph node biopsy.

Basic Information

nickname

Reactive histiocytosis

English name

hemophagocyic histiocytosis

Visiting department

Internal medicine

Common causes

Autosomal recessive or X-linked inheritance, infections, malignant tumors, autoimmune diseases, drugs, acquired immunodeficiency, etc.

Common symptoms

Bleeding, infection, multiple organ failure, fever, hepatosplenomegaly, whole blood cell reduction, etc.

Causes of hemophagocytic syndrome

Hemophagocytic syndrome is mainly divided into primary (hereditary) and secondary. The former is an autosomal recessive or X-linked inheritance with a definite genetic defect or family history. The latter can be caused by various factors such as infection (mainly EB virus infection), malignant tumors, autoimmune diseases, drugs, acquired immunodeficiency (such as transplantation), and so on.

Clinical manifestations of hemophagocytic syndrome

Familial hemophagocytic syndrome

The age of onset is generally early, most of which occur within 1 year of age, but there are also older patients. Clinical manifestations are diverse, with fever and hepatosplenomegaly in the early stages, rash, lymphadenopathy, and neurological symptoms. Most of the fever is persistent, and it can also retreat by itself. Hepatosplenomegaly was obvious. The rash is not characteristic and is mostly transient. Approximately half of the patients may have lymphadenopathy, and those who are significantly enlarged should be distinguished from lymphoma. Central nervous system involvement occurs mostly in the late stages, with increased excitability, full frontal ridges, changes in muscle tone and convulsions, and signs of local nervous system. Lungs can be infiltrated by lymphocytes or macrophages, which is difficult to distinguish from infection. Common causes of death are bleeding, infection, multiple organ failure, and DIC.

2. Secondary hemophagocytic syndrome

(1) Severe infections associated with infection-associated hemophagocytic syndrome can cause a strong immune response, mostly in immunodeficiency patients. It is often caused by a virus, but it can also be caused by bacterial, fungal, rickettsia, and protozoal infections. The clinical manifestations are evidence of infection in addition to the manifestations of hemophagocytic syndrome.

(2) Tumor-associated hemophagocytic syndrome Acute leukemia, lymphoma, seminoma, etc. may be complicated or secondary to hemophagocytic syndrome before, during, and after treatment. Because the primary disease may be hidden, especially in patients with lymphoma, it is very easy to misdiagnose it as infection-associated hemophagocytic syndrome.

(3) Macrophage activation syndrome is a serious complication of chronic rheumatic diseases in children. It is more common in patients with systemic juvenile rheumatoid arthritis. On the basis of chronic rheumatic diseases, patients have manifestations of hemophagocytic syndrome such as fever, hepatosplenomegaly, reduced whole blood cells, abnormal liver function, and central nervous system disease.

Hemophagocytic syndrome test

Blood routine

Most of them are pancytopenia, and thrombocytopenia is more obvious.

2. Biochemical detection

Elevated triglycerides can occur early, and transaminase and bilirubin can also be elevated. Common low-density lipoprotein cholesterol is reduced, low-density lipoprotein cholesterol and very low-density lipoprotein cholesterol are reduced, and the disease can be recovered when the disease is relieved. Lactate dehydrogenase is often elevated, and those with extreme elevations need to exclude blood / lymphatic tumors. Serum ferritin can be significantly increased, which can be used as a means to diagnose and monitor the disease.

3. Bone marrow examination

Blood phagocytosis can be seen in bone marrow smears, and early blood phagocytosis is not obvious. Multiple bone marrow smears can help find blood phagocytosis. In addition, bone marrow biopsy should be performed to perform bone marrow pathology to exclude blood / lymphatic tumors.

4. Coagulation function

Coagulation dysfunction often exists in disease activities, and effective coagulation function is restored in treatment. It can be found that prothrombin time and partial thromboplastin time can be prolonged, fibrinogen can be significantly reduced, and D-dimer can be increased.

5. Immunological examination

There may be a decrease in the number and function of NK cells, and an increase in cytokine soluble CD25, IFN-, and TNF.

6. Imaging examination

Pulmonary infiltrates can be seen on chest radiographs, and abnormalities such as abnormal brain white matter, demyelinating changes, hemorrhage, atrophy, or edema can be seen on skull CT and MRI.

7. Cerebrospinal fluid

The cells are moderately increased, usually 5-50 × 10 / L, mainly lymphocytes. Cerebrospinal fluid protein increased, sugar decreased. Some patients have neurological symptoms, but no abnormalities in cerebrospinal fluid.

Diagnosis of hemophagocytic syndrome

No specific diagnostic method is currently available. The 2004 diagnostic criteria developed by the International Organization of Cell Associations are now widely used, and HLH diagnosis can be established by meeting one of the following two:

1. Molecular diagnosis of HLH

Mutations in genes such as PRF1, UNC13D, Munc18-2, Rab27a, STX11, SH2D1A or BIRC4;

2. Meet 5 of the following 8 diagnostic criteria

Fever; Splenomegaly; Hematocrit (affects peripheral blood cells of line 2 or 3): hemoglobin <90g / L (newborn: hemoglobin <100g / L), platelets <100 × 10 / L, neutrophils <1.0 × 10 / L; hypertriglyceridemia and / or hypofibrinogenemia: fasting triglycerides 3.0mmol / L ( 2.65g / L), fibrinogen 1.5g / L; bone marrow Hemophagocytic phenomenon was found in the spleen or lymph nodes instead of evidence of malignancy; NK cell activity was reduced or lacking (according to local laboratory indicators); ferritin 500 g / L; soluble CD25 (sIL-2R) 2400U / mL.

Differential diagnosis of hemophagocytic syndrome

First of all, it is necessary to distinguish between congenital or secondary, especially to distinguish the former from virus-associated hemophagocytic syndrome. Secondly, tumor-associated hemophagocytic syndrome must be strictly excluded. Due to the staged nature of the disease, early patients may not show all the features, making early diagnosis difficult. Repeated examinations of the bone marrow or repeated relevant examinations may be helpful for early diagnosis.

Hemophagocytic Syndrome Treatment

Familial hemophagocytic syndrome has a poor prognosis and rapid disease progression, and bone marrow transplantation is recommended as early as possible. The treatment of secondary hemophagocytic syndrome is more complicated. On the one hand, it must be treated for primary diseases, such as chemotherapy for blood / lymphatic tumors, and anti-infective treatment for infection-associated hemophagocytic syndrome. Hemophagocytic syndrome treatment should be used to control the development of the disease while treating the primary disease. At present, HLH-2004 regimen is widely used in the world to treat secondary hemophagocytic syndrome. The 2004 protocol was based on dexamethasone, etoposide, and cyclosporine, and was divided into the initial 8-week treatment period and the maintenance treatment period, followed by intrathecal injection. The use of gamma globulin in the acute phase can help alleviate the condition.

If treatment is difficult, failed, or the disease recurs, bone marrow transplantation may be considered.