Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistocytosis, was first reported in 1979 by Risdall et al. It was first reported by Risdall et al. in 1979. The syndrome is characterized by fever, hepatosplenomegaly, and allogeneic cytopenia. The syndrome is divided into two major groups, one primary or familial and the other secondary, the latter of which can be caused by infections and tumors. Primary HPS, or familial HPS, is an autosomal recessive disorder whose onset and exacerbation are often associated with infection; secondary HPS is divided into infection-associatedhemophagocytic syndrome (IAHS), which is mostly associated with viral infections, and those caused by viruses are called viral-associated HPS (VAS). The virus-associated hemophagocyticsyndrome (VAHS); the tumor-associated HPS (malignancy-associated hemophagocytic syndrome, Qu Honglan, Department of Hematology Oncology, Second Affiliated Hospital of Inner Mongolia University for Nationalities).
hemophagnocytic syndrome,MAHS).
1. familialhemophagocytic syndrome (familialhemophagocytic syndrome)
1.1 Age of onset is generally early, 70% occurring within 1 year of age, and may even develop before birth, with clinical manifestations at birth. Most of them develop in infancy and early childhood, but there are also cases that develop as late as 8 years old. The onset of HPS in adults does not exclude familial HPS, and the age of onset is similar in the same family.
1.2 Symptoms and signs are varied, with early fever, hepatomegaly, splenomegaly, rash, lymph node enlargement and neurological symptoms. Fever persists and may subside on its own; hepatosplenomegaly is obvious and progressive; rash is not characteristic and often transient, often accompanied by high fever when the rash appears; about half of the patients have enlarged lymph nodes, and some have huge lymph nodes. Symptoms of the central nervous system usually appear late in the course of the disease, but can also occur in the early stages, manifesting as increased excitability, fullness of fontanelle, neck tonicity, increased or decreased muscle tone, and convulsions. There may also be VI or VII pairs of cranial nerve palsy, ataxic hemiparesis or total paralysis, blindness, impaired consciousness, and increased intracranial pressure. Pulmonary symptoms are mostly due to lymphocyte and macrophage infiltration in the lungs, but it is difficult to differentiate from infection.
1.3 Laboratory tests
Blood picture: mostly whole blood cytopenia, thrombocytopenia is obvious, the degree of leukopenia is mild; observation of platelet changes can be used as an indication of the activity of the disease. When the disease is in remission, the platelets can be seen to rise first; when the disease is deteriorating, the platelets can also be seen to fall first.
Bone marrow: The bone marrow in the early stage of the disease shows moderate proliferative bone marrow picture, and phagocytosis is not obvious, often showing reactive histiocyte proliferation without malignant cell infiltration. In the extreme stages of the disease, in addition to increased histiocytes, there are more or less phagocytic histiocytes, mainly phagocytosing red blood cells, but also platelets and nucleated cells. In the late stage, the bone marrow is less proliferative, which is difficult to distinguish from cytotoxic drug-induced myelosuppression. In some cases, large granular lymphocytes with elongated cytosol like horsetails or pineal granules are seen in the bone marrow, which may be a specific type of lymphocytes in HPS.
Hypercytokinemia: Increased levels of the following factors are common in familial HPS and in the active phase of secondary HPS: IL-l receptor antagonist, soluble IL-2 receptor (sIL-2), γ-interferon (IFN-γ), and tumor necrosis factor (TNF).
Lipids: Increased triglycerides are seen, which can appear early in the disease. Lipoprotein electrophoresis commonly shows elevated very low-density lipoprotein cholesterol and low-density lipoprotein cholesterol, and decreased high-density lipoprotein cholesterol. When the disease is in remission, lipoprotein cholesterol may return to normal.
Liver function: transaminases and bilirubin may be elevated, and the degree of change is consistent with the degree of liver involvement. In case of systemic infection, hyponatremia, hypoalbuminemia and increased serum ferritin may be present.
Coagulogram: In active disease, there are often coagulation abnormalities, especially in the active phase of the disease, with hypofibrinogenemia and prolonged partial thromboplastin time, which may be prolonged in the presence of liver damage.
Cerebrospinal fluid: moderate cytosis (5-50×106/L), mainly lymphocytes, possibly monocytes but rarely phagocytes, increased protein, but in some cases the cerebrospinal fluid may be normal even with clinical manifestations of encephalitis.
Immunological examination: familial HPS often has reduced natural killer cells and T-cell activity.
Imaging: Interstitial pulmonary infiltrates are seen on chest radiographs in some patients. In advanced patients, abnormalities can be found on cranial CT or MRI, with changes such as old or active infection, demyelination, hemorrhage, atrophy or (and) edema. Sometimes brain calcifications can also be detected by CT examination.
1.4 The main pathological finding is a benign lymphohistiocytic infiltrate in the monocyte-macrophage system, with phagocytosis of histiocytes, most often of red blood cells and sometimes of platelets and white blood cells. The organs involved are the spleen, lymph nodes, bone marrow, and brain. The spinal cord; in addition, it can also be seen in the thyroid, lung, heart. In addition, it can also be found in the thyroid, lung, heart, intestine, kidney and pancreas.
1.5 Diagnosis The diagnostic criteria are: ① fever for more than 1 week with fever peak ≥ 38.5℃; ② hepatosplenomegaly with whole blood cytopenia involving ≥ 2 cell lines, reduced or abnormal bone marrow proliferation and abnormal liver function, blood lactate dehydrogenase (LDH) ≥ 1000 U/L or ≥ normal mean + 3S, and coagulation dysfunction, blood fibrinogen ≤ 1.5 g/L with hematopoietic ferritin ≥ 1000ng/mL or ≥ normal + 3S; ④ phagocytosis accounting for ≥ 2% of bone marrow nucleated cells, or (and) involvement of bone marrow, liver, and spleen. Histological changes in the lymph nodes and central nervous system. Some atypical cases do not meet the above criteria, such as predominantly
The manifestations of hemocytopenia, hyperlipidemia and hypofibrinogenemia also depend on the severity of the visceral involvement, and in some patients these manifestations may appear late. At the onset of the disease, a number of patients may have no splenomegaly or even phagocytosis.
1.6 Differential diagnosis is most likely to confuse familial HPS with secondary HPS, especially with viral-associated HPS, because viral infections are not only associated with viral-associated HPS, but in patients with familial HPS, there is also often a viral infection, and familial HPS is often induced by viral infections. Familial HPS is an autosomal recessive disorder, and family history is often not asked for, adding to the difficulty of diagnosis. It is generally accepted that the onset of HPS before the age of 2 years suggests familial HPS, while those with onset after the age of 8 years are considered secondary HPS. those with onset between the ages of 2 and 8 years are judged on the basis of clinical manifestations, and if it is still difficult to be sure, they should be treated as familial HPS. Secondly, it should be distinguished from malignant histiocytosis (malignant group). It is difficult to distinguish between the two on bone marrow films, but HPS is much more common than malignant group. However, if there is a clinical outbreak, severe hepatic impairment, high degree of histiocyte malignancy in the bone marrow, and especially if abnormal histiocyte infiltration is found in the liver, spleen or other organs, it is appropriate to consider the malignant group first; otherwise, the diagnosis should be HPS.
1.7 Treatment
a. Chemotherapy: commonly used chemotherapeutic drugs are cytotoxic drugs, such as pergolide or vincristine in combination with adrenocorticotropic hormone, or repeated plasma exchange, or VP16 or VM26 in combination with adrenocorticotropic hormone. Some have achieved good results with VP16, adrenocorticotropic hormone, intrathecal aminomethylcollidine (MTX) and cranial irradiation. Some advocate the application of the above drugs in remission in small doses for maintenance treatment.
b. Immunotherapy: Some people have achieved satisfactory results with cyclophilin A for familial HPS, and similarly, remission can be induced with anti-thymocyte globulin (ATG).
c. Hematopoietic stem cell transplantation: Although the above chemotherapy can lead to remission, in some cases for up to 9 years, it still cannot cure familial HPS. Fisher et al. (1986) first reported that patients with familial HSP were cured by bone marrow transplantation, and at the International Pediatric Hematology Oncology Symposium held in Shanghai in 2000, the Japanese scholar Imashukn reported five cases of HPS caused by EBV. The application of hematopoietic stem cell transplantation, followed by cyclocilin A plus VP16, greatly improved the prognosis of this disease.
d. Treatment protocol: The International Society of Histocytes proposed a protocol for the treatment of familial HPS in 1994 (HLH94): dexamethasone 10 mg/m2 daily with VP16 150 mg/m2 weekly for 3 weeks, reduced from week 4, VP16 every 2 weeks from week 9, and cyclophilin A 5-6 mg/kg daily orally for 1 year. For those with neurological symptoms, MTX1 was administered intrathecally every 2 weeks for the first 8 weeks. In case of familial HPS, allogeneic hematopoietic stem cell transplantation is pursued. In the case of non-familial HPS, treatment is discontinued after 8 weeks of treatment depending on the condition.
1.8 The survival of patients with familial HPS without treatment is approximately 2 months, while the prognosis is greatly improved with the application of chemotherapy. Some patients survive more than 9 years after chemotherapy, but only allogeneic hematopoietic stem cell transplantation can cure familial HPS.
2 Secondary hemoPhagocytic syndrome (secondary hemoPhagocytic syndrome)
2.1 Infection-associated hemophagocytic syndrome (IAHS) is a strong immune response caused by severe infection, lymphohistiocytosis with phagocytosis, which often occurs in immunodeficient individuals and is called virus-associated HPS (VAH) when caused by viral infection, but other microbial infections such as bacterial, fungal, rickettsial, and protozoal infections can also cause HPS. In addition to the common manifestations of HPS (as described previously), there is evidence of infection. The bone marrow examination shows proliferation of lymphohistiocytes and phagocytosis of red blood cells, platelets and nucleated cells.
2. l. l Prognosis 198 pediatric cases of infection-associated HPS have been followed. Of these, 103 cases (52%) died from complete cytopenia, organ failure, or diffuse intravascular coagulation (DIC). 3 deaths occurred in 6 cases under 3 years of age, while only 29 deaths occurred in 76 cases over 3 years of age. l. The prognosis for those who developed the disease under 1 year of age was extremely poor, with only 9 of the 29 cases surviving. The prognosis is better for those caused by bacteria, but the worst for those caused by EBV, with 72 deaths in 99 cases caused by EBV, and the death rate is also around 50% for those caused by other viruses.
2.1.2 Treatment with immunosuppressants, mostly with adrenocorticotropic hormone and (or) VP16, has yielded better results. Especially for EBV, VP16 and cyclophilin A have the best effect because VP16 can inhibit the synthesis of viral nuclear antigens and cyclophilin A can reduce hypercytokinemia. As for the application of intravenous gammaglobulin, there are different opinions. Some advocate its application, while others are against it. The aim of treatment of this disease is to suppress its difficult-to-control lymphocyte and macrophage activity. If pathogenic microorganisms can be identified, effective antimicrobial therapy should be applied promptly. If HPS occurs while immunosuppressive agents are being applied, the immunosuppressive agents should be discontinued. Life-threatening manifestations of difficult-to-control hyperthermia, progressive allogeneic cytopenia, DIC and multi-organ failure are indications for the application of immunosuppressive agents. The treatment regimen is the same as that for familial HPS.
2.2 Malignancy-associated hemophagocytic syndrome (MAHS) This disease is divided into two major groups: acute lymphoblastic leukemia (acute gonorrhea) associated HPS, acute gonorrhea that may be co-infected with or without infection before or during treatment. in addition to acute gonorrhea The second category is lymphoma-associated hemophagocytic, syndrome (LAllS), which is often subclinical in nature and has no lymphoma manifestations, so it is often misdiagnosed as infection-associated HPS. It is often misdiagnosed as infection-associated HPS, and especially as EBV-associated lymphoma.
If HPS occurs in an immunodeficient patient before treatment, treatment is mainly anti-infective and anti-tumor; if HPS occurs after chemotherapy and the tumor is in remission, anti-tumor treatment should be stopped and anti-infective treatment should be added with adrenocorticotropic hormone and VP16; in rapidly progressive MAHS, treatment should target cytokine-induced damage, using the aforementioned HLH94 protocol.
I. Diagnostic criteria
1. fever of more than 1 week with a fever peak ≥ 38.5°C.
2. hepatosplenomegaly with complete cytopenia involving ≥ 2 cell lines, reduced or abnormal myelodysplasia and abnormal liver function, blood lactate dehydrogenase (LDH) ≥ 1000 U/L or ≥ normal mean + 3S, and coagulation dysfunction with blood fibrinogen ≤ 1.5 g/L with hematopoietic ferritin ≥ 1000 ng/mL or ≥ normal + 3S.
3. phagocytosis accounting for ≥ 2% of bone marrow nucleated cells, or (and) involvement of bone marrow, liver, spleen. Histological changes in the lymph nodes and central nervous system.
II. Differentiation from malignant group
1. Etiology.
Most patients with HPS can find the primary cause by bacterial culture, serum immunology, and histopathology; MH is often of unknown etiology.
2. response to treatment.
HPS is often treated for the primary disease is often effective, most patients recover with the improvement of the primary disease; MH patients with rapid disease progression, poor prognosis, antibiotics, antiviral, hormonal therapy is ineffective, the vast majority of patients die within a few months.
3. Bone marrow characteristics.
HPS patients with bone marrow histiocytes are mainly Hem, abnormal histiocytes are not seen or occasionally, and multinucleated giant histiocytes are not seen; more than half of MH patients have Hem and mononuclear-like or lymphoid histiocyte hyperplasia, but there are often naive polymorphic abnormal histiocytes, and multinucleated giant histiocytes have greater diagnostic value, but the detection rate is low. For patients with Hem hyperplasia suspected to be HPS, if the etiology is unknown, multiple bone marrow aspirations or biopsies of the lesions should be performed at different stages of the disease in order to increase the detection rate of abnormal tissue cells.
4. NAP score
Most patients with BHPS have an increased NAP score, while patients with MH often have a reduced or even zero NAP score.