Hemophagocytic syndrome (HPS), also known as hemophagocytic lymphohistiocytosis (HLH), is a severe or even fatal inflammatory state caused by the non-malignant proliferation of lymphocytes and histiocytes that secrete large amounts of inflammatory factors, and it is divided into two major categories: primary hemophagocytic syndrome and acquired hemophagocytic syndrome. Primary HPS onset is mostly <2 years old and is mostly associated with autosomal or sex chromosome recessive inheritance. Acquired hps can appear at any age, with a prevalence of >8 years, and no clearly existing immunodeficiency has been identified. I. Etiology of acquired hps The more common causes of acquired hps are infection, malignancy (malignant lymphoma is more common), autoimmune disease, drugs, etc. Post-transplant related hps has also been reported. Infection-associated HPS is mostly caused by viral infections, with EBV infection being the most common. Some non-viral pathogens such as bacteria, fungi, and protozoa can also cause HPS, and tuberculosis-induced HPS has also been reported. Most malignancy-associated HPS occurs in adults, with malignant lymphoma-associated HPS predominating HJ. Rheumatic diseases can also cause HPS secondary to macrophage activation syndrome (MAS), which has been referred to as MAS. II. Pathophysiological mechanisms of acquired HPs We have now recognized that abnormal immune regulation, accumulation of immunoreactive cells, and massive production of inflammatory cytokines play a central role in the pathogenesis of acquired phagocytic syndromes. Infection and other factors act on the organism, leading to excessive activation of T lymphocytes and the production of a large number of cytokines such as interleukin (IL)-l, IL-6, tumor necrosis factor (TNF-a) and interferon (IFN-γ), and IL I-1 and IL-6 can pass through the blood. The cerebrospinal fluid barrier acts directly on the hypothalamic thermoregulation point, causing fever, while TNF-a and IFN-γ play a negative regulatory role on bone marrow hematopoiesis, i.e., they inhibit bone marrow hematopoiesis, resulting in a decrease in various types of blood cells. It was found that elevated inflammatory factors such as TNF-a and IFN-γ are the most important causes of hematocrit, while macrophages and histiocytes play only a minor role in hematocrit caused by excessive activation and phagocytosis of blood cells. Also, elevated TNF Ia can inhibit lipoprotein lipase levels and lead to elevated triglyceride levels. Activated macrophages not only secrete ferritin, but also activate fibrinogen, leading to hypofibrinogenemia. Activated lymphocytes, on the other hand, can produce large amounts of soluble IL-2 receptors (sCD25). Therefore, high levels of serum ferritin and sCD25 expression can be detected in patients with HPS. large numbers of lymphocytes and macrophages infiltrate the organs and eventually progress to the severe state of HPS. Clinical manifestations, laboratory and ancillary tests of acquired HPS 1. Clinical manifestations: Acquired HIS has diverse clinical manifestations. Wang Niyi et al. analyzed 72 patients with confirmed HPS from a multicenter source and found that 100% of the patients had fever, and the rest were, in order, splenomegaly (83.3%), respiratory symptoms (63.9%), hepatomegaly (54.2%), superficial lymph node enlargement (48.6%), jaundice (38.9%), rash (34.8%), plasma cavity effusion (33.3%), and skin bruising or bruising. %), skin bruising or bleeding spots (33.3%), central nervous system symptoms (5.6%), and renal function impairment (4.2%). Similar cases have been reported from abroad, such as persistent fever, hematocrit, and splenomegaly as the main clinical manifestations. However, skin rash, lymphadenopathy and diarrhea are less common. Central nervous system symptoms can be found in more than half of the patients, which may be related to the fact that these literature mostly report cases in children. 2. Laboratory tests: These include tests for various diagnostic specificities of HPS, etc. Studies have confirmed that most patients with HPS have hepatic impairment, with the most significant elevation of portal aminotransferase (AST), which may be related to the impaired function of multiple organs in patients with severe liver damage involving mitochondria, as well as damage to cardiomyocytes. Lymphocytes and histiocytes in HPS can also infiltrate the central nervous system and cause cerebrospinal fluid changes, so a lumbar puncture can be performed to detect these indicators. This suggests that monitoring of triglyceride levels is also becoming increasingly important. 3. Ancillary tests: Chest X-ray may show pulmonary lesions, such as interstitial lung changes, pulmonary edema and pleural effusion. Abdominal ultrasound may suggest manifestations such as ascites, gallbladder wall thickening and kidney enlargement? CT and MRI suggest possible cerebral white matter atrophy and calcification. Diagnostic criteria for acquired HPS According to HLH-2004 diagnostic criteria, molecular biology diagnosis of HPS or 5 out of 8 of the following indicators can be diagnosed: (1) fever: persistent >7 d, temperature >38.5°C; (2) splenomegaly (subcostal I >3 cm); (3) hematocrit (at least two out of three lines in peripheral blood): hematocrit <90 g/L (infants <4 weeks: hematocrit <100 g/L), platelets <100×109/l, neutrophils <1.0×109 several and not due to reduced bone marrow hematopoiesis; (4) hypertriglyceridemia and/or hypofibrinogenemia: fasting triglycerides ≥3.0>500 pg/L; (8) significantly elevated levels of soluble IL-2 receptors (scms) . The diagnosis of HPS is highly suspected if the patient has persistent fever and antibiotic therapy is ineffective for 2 weeks, along with other systemic clinical manifestations that cannot be explained by the primary cause. In 2009, the American Society of Hematology (ASH) made appropriate modifications to the HLH-2004 diagnostic criteria: (1) molecular biological diagnosis consistent with HPS or x-linked lymphoid hyperplasia syndrome (XLP); (2) at least three of the following four indicators: (1) fever, (2) splenomegaly, (3) hematocrit reduction (at least two or more of the three lines in peripheral blood), ④ manifestations of hepatitis; (3) at least one of the following indicators out of four: ① phagocytosis found in bone marrow, spleen or lymph nodes, ② elevated ferritin, ③ elevated soluble IL-2 receptor (sCD25) levels (age-related), ④ reduced or absent NK cell activity; (4) other indicators that can support the diagnosis of HLH. (i) hypertriglyceridemia, (ii) hypofibrinogenemia, and (iii) hyponatremia. A foreign study has examined peripheral blood NK cell activity and serum sCD25 levels in patients with HPS and found that 100% of patients in the confirmed group had abnormal NK cell activity and serum sCD25 levels in the early stages of the disease. This indicates that reduced NK cell activity and increased sCD25 levels can be used as sensitive indicators for the early diagnosis of acquired HPS. Increased serum ferritin levels are also an important criterion for the diagnosis of HPS, but one study reported that out of 330 patients with ferritin >500 pg/L, only 10 patients were diagnosed with HPS, and only when ferritin was >10 000 pg/L did it have 90% sensitivity and 96% specificity for the diagnosis of HPS. Also, elevated serum ferritin is influenced by many factors and can occur in all diseases that can lead to abnormal iron metabolism, thus lacking specificity in the diagnosis of acquired HPS. The amino acid side chains in ferritin are modified by glycosylation and are called glycosylated ferritin. Wang Zhaoge et al. used the phytohemagglutinin adsorption method to study patients with confirmed HPS and normal controls and found that the percentage of glycosylated ferritin in patients with confirmed acquired HPS was significantly lower compared to normal controls, with a statistically significant difference (P<0.01). Moreover, the ratio of glycated ferritin was lower than 20% in patients diagnosed with acquired hps. This suggests that glycated ferritin may be a more reliable laboratory indicator for the early diagnosis of acquired hps, and that an increase in serum ferritin and a decrease in glycated ferritin ratio may be more sensitive and specific for the diagnosis of the disease. hps pathogenesis is the formation of hypercytokinemia, so the study of various important cytokines is essential. tnf produced by t lymphocytes can cause hps patients with hemocytopenia, and sustained release can also cause fever, shock, cachexia and tissue damage in the body. Serum tnf-a levels were measured in patients with confirmed hps and normal controls, and it was found that the level of this cytokine was significantly increased in patients with confirmed hps, and the difference between the two groups was statistically significant, with a sensitivity of 63.9% in the diagnosis of hps, suggesting that increased tnf-a levels may be a sensitive indicator for the diagnosis of hps. Patients suspected of hps should undergo bone marrow aspiration and lumbar puncture. A statistical analysis of patients with acquired hps showed that phagocytosis occurred in only a minority of patients in the early stages of the disease, with a sensitivity of 76.7% and a specificity of 77.8% in the diagnosis of hps. Thus, it can be seen that the phagocytic phenomenon is important in the diagnosis of acquired hps, but the absence of phagocytic phenomenon does not exclude the diagnosis of hps. V. Differential diagnosis of acquired HPs A variety of diseases can produce clinical manifestations of HPS, such as Chediak.Higashsi syndrome (CHS), Griscelli syndrome (GS), X-linked lymphoid hyperplasia syndrome (Xlinked lympholiferative syndrome (XLP), Langerhans cell histiocytosis, etc. There are many similarities between the clinical manifestations of primary HI S and acquired HI S, and the differentiation between them is a difficult task. Mutations in the perforin gene are an important cause of primary HIS, and other genes such as MUNCl3-4 and STXll also play an important role in its pathogenesis, so genetic testing can be used as one of the indicators for differential diagnosis.MAS is a group of disease manifestations that appear in rheumatic immune diseases, a special type of HPS that occurs mostly in systemic juvenile rheumatoid arthritis and adult Streptococcus suis. rheumatoid arthritis and adult Still's disease. Unlike classical HPS, MAS mainly causes cardiovascular system diseases and disorders of coagulation mechanisms. VI. Treatment of acquired HPS In recent years, the number of cases of HPS has been increasing year by year as people become more aware. The disease is dangerous and has a high mortality rate if not treated in a timely manner. The current treatment for HPS is based on the HLH.2004 treatment protocol, with induction therapy from week l to week 8 and a basic protocol of etoposide + dexamethasone + cyclosporine, with maintenance therapy after induction therapy. In children and young adults with EBV-associated HPS, immunochemotherapy including etoposide and corticosteroids provides a good prognosis. Corticosteroids combined with cyclosporine, a potent immunosuppressant with significant T-cell suppressive effects, can control hypercytokinemia and have significant efficacy in the treatment of MAS. The HLH-2004 regimen has been effective in the treatment of patients with primary HPS. However, this regimen has an induction treatment cycle of 8 weeks and a maintenance treatment cycle of 32 weeks, which may not be tolerated by patients with acquired HPS who have poor organ function, thus delaying the treatment of the primary disease. It is now recognized that the key to treating acquired HPS is to first control the life-threatening pathology of hypercytokinemia, eliminate its continued activation of T-lymphocytes and macrophages, and reduce the damage of the inflammatory storm on all organs of the body. Wang et al. improved on the principle of the HLH-2004 regimen by using high-dose methylprednisolone in combination with fludarabine, which achieved good results. Fludarabine is an antimetabolite antitumor agent that inhibits the activation of T cells and avoids the production of excessive cytokines that cause the activation of macrophages and CTL. Methylprednisolone can kill lymphocytes and inhibit the production of over-meal cytokines. In addition, gammaglobulin can be added adjuvantly, which mainly acts on the Fc receptors of macrophages to reduce their phagocytosis of leukocytes, while down-regulating the activity of helper T cells and enhancing the immunity of the body. Treatment of HPS with this regimen controls the hypercytokinemia and the associated inflammatory factor storm in the short term, thus greatly improving the overall survival of HPS patients at 15 weeks (63.O%), which is higher than the overall survival of HPS treated with each different regimen (46.8%). VII. Prognosis of acquired HPS HPS is aggressive and difficult to diagnose, and if left untreated, patients can die quickly from infection and multi-organ failure. The study found that platelet counts and fibrinogen levels were significantly lower in patients in the HPS death group than in those in the survivor group, suggesting that both may be poor prognostic factors for HPS. The study also noted that most deaths in HPS cases occurred in the first 8 weeks, and although there were some individual deaths after 15 weeks, the cause of death was worsening of the primary disease and was not related to HPS. This suggests that treatment should now be directed at HPS to control phagocytosis-related symptoms in a timely manner, providing the opportunity to treat the primary disease, and then treating the primary disease correctly, which can significantly improve the prognosis of HPS patients and guarantee their long-term survival.