Etoposide Therapy of Cytokine Storm Syndromes.

Etoposide has revolutionized the treatment of primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), and it is, together with corticosteroids, the most widely used therapy for HLH. In the early 1980s, long-term survival in primary HLH was <5% but with the etoposide-/dexamethasone-based protocols HLH-94 and HLH-2004, in combination with stem cell transplantation, 5-year survival increased dramatically to around 60% in primary HLH, and based on analyses from the HLH-2004 study, there is likely room for further improvement. Biologically, etoposide administration results in potent selective deletion of activated T cells as well as efficient suppression of inflammatory cytokine production. Moreover, etoposide has also been reported to promote programmed cell death (apoptosis) rather than proinflammatory lytic cell death (pyroptosis), conceivably ameliorating subsequent systemic inflammation, i.e., a treatment very suitable for cytokine storm syndromes (CSS). The combination of etoposide and corticosteroids may also be beneficial in cases of severe or refractory secondary HLH (sHLH) with imminent organ failure, such as infection-associated HLH caused by Epstein-Barr virus (EBV) or malignancy-triggered HLH. In CSS associated with rheumatic diseases (macrophage activation syndrome, MAS or MAS-HLH), etoposide is currently used as second- or third-line therapy. Recent studies suggest that etoposide perhaps should be part of an aggressive therapeutic intervention for patients with severe refractory or relapsing MAS, in particular if there is CNS involvement. Importantly, awareness of sHLH must be further increased since treatment of sHLH is often delayed, thereby missing the window of opportunity for a timely, effective, and potentially life-saving HLH-directed treatment.

IL-1 Family Blockade in Cytokine Storm Syndromes.

Interleukin-1 is a prototypic proinflammatory cytokine that is elevated in cytokine storm syndromes (CSSs), such as secondary hemophagocytic lymphohistiocytosis (sHLH) and macrophage activation syndrome (MAS). IL-1 has many pleotropic and redundant roles in both innate and adaptive immune responses. Blockade of IL-1 with recombinant human interleukin-1 receptor antagonist has shown efficacy in treating CSS. Recently, an IL-1 family member, IL-18, has been demonstrated to be contributory to CSS in autoinflammatory conditions, such as in inflammasomopathies (e.g., NLRC4 mutations). Anecdotally, recombinant IL-18 binding protein can be of benefit in treating IL-18-driven CSS. Lastly, another IL-1 family member, IL-33, has been postulated to contribute to CSS in an animal model of disease. Targeting of IL-1 and related cytokines holds promise in treating a variety of CSS.

Macrophage Activation Syndrome in Viral Sepsis.

Macrophage activation syndrome (MAS) is a life-threatening systemic hyperinflammatory syndrome triggered by various infections, particularly viral infections, autoimmune disorders, and malignancy. The condition is characterized by an increased production of proinflammatory cytokines resulting in a cytokine storm and has been associated with poor clinical outcomes. During the COVID-19 pandemic, patients with severe manifestations developed features similar to those of MAS, although these characteristics remained well defined within the lung. Additionally, other viral infections including EBV, the herpes family of viruses, hepatitis viruses, influenza, HIV, and hemorrhagic fevers can be complicated by MAS. The diagnosis and management of the condition remain challenging due to the lack of consensus on specific guidelines, especially among the adult population. Currently, therapeutic options primarily rely on medications that are typically used to treat primary hemophagocytic lymphohistiocytosis, such as corticosteroids and etoposide. In addition, cytokine-targeted therapies present promising treatment options. The objective of this review is to discuss the emergence of MAS in the context of viral infections including, but not limited to, its occurrence in COVID-19.

Unmasking the Culprits: A Case of Epstein-Barr Virus-Associated Hemophagocytic Lymphohistiocytosis Presenting With Mouth Ulcers and Nosebleeds.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive syndrome of excessive immune activation. It usually occurs in children, mainly during the first year of life. Primary hemophagocytic lymphohistiocytosis is more common and usually occurs in immunocompromised patients. Secondary hemophagocytic lymphohistiocytosis, on the other hand, is less common, especially in immunocompetent patients. Here, we intend to present a case of a 55-year-old male patient who had no known immune deficiency, presented with epistaxis, and was found to have Epstein-Barr virus (EBV)-induced hemophagocytic lymphohistiocytosis.

Comprehensive evaluation of immune dysregulation in secondary hemophagocytic lymphohistiocytosis.

Host immune dysfunction plays a crucial role in the onset, progression, and outcome of hemophagocytic lymphohistiocytosis (HLH). This study aimed to comprehensively evaluate the peripheral immune profiles in patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), and explore their predictive value for patient prognosis. A total of 77 patients with sHLH were enrolled in this study, with 31 of them experiencing mortality. Flow cytometry was used to assess the percentages, absolute numbers, and phenotypes of lymphocyte subsets. Simultaneously, cytokine levels and routine laboratory indicators were also collected. In sHLH patients, lymphocyte subset absolute numbers were significantly impaired, accompanied by T cell hyperactivation, B cell hyperactivation, and increased plasmablast proliferation. Prognostic analysis revealed that lower CD8+ T cell percentages, elevated APTT, IL-6, IL-10 levels, and increased CD4+CD28null T cell proportions were associated with poor patient outcomes. The study demonstrates dysregulation in the counts and phenotypes of lymphocyte subsets in sHLH patients. Several key factors, including IL-6, IL-10, APTT, and various T cell percentages, have potential as prognostic markers and therapeutic targets in sHLH.

Hemophagocytic Lymphohistiocytosis Associated With Human Herpesvirus-6 (HHV-6) Infection in an Immunocompetent Adult: A Case Report.

Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder characterized by extreme immune activation and excessive inflammation. It has been reported in patients with familial cases, immunodeficiencies, malignancies, stem cell transplants, and viral etiologies. This report describes acquired HLH associated with Human herpesvirus-6 (HHV-6) infection in a 76-year-old previously healthy male. The patient was admitted to the hospital due to fever, chills, and abdominal pain. The diagnostic workup revealed gallbladder wall thickening on imaging, concerning for cholecystitis. The patient was started on treatment for sepsis. Further clinical deterioration led to an extensive infectious workup. The patient was found to have elevated soluble IL-2Ra levels, and a bone marrow biopsy was performed, which revealed HLH. A positive HHV-6 polymerase chain reaction in the cerebrospinal fluid and serum confirmed the viral infection. Treatment involved the initiation of high-dose steroids, etoposide, and ganciclovir. Despite these interventions, the patient's clinical status worsened, leading to the implementation of comfort measures, and the patient eventually died. This case underscores the importance of considering HHV-6 as a potential cause of HLH in immunocompetent adults. From this case, we infer that a heightened level of vigilance is necessary to recognize and intervene in this challenging condition promptly.

Severe Lymphoma-Associated Hemophagocytic Syndrome in a Young Woman.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by profound immune system activation. In adults, most cases of HLH are due to an underlying pathology- such as infection, malignancy, or autoimmune disease. It is a disease that can progress to rapid clinical deterioration and be difficult to diagnose. Nevertheless, regardless of etiology, most patients with HLH benefit from treatment. This paper highlights the challenges involved in diagnosing and managing this condition in practice, with an emphasis on how young, previously healthy young adults can present in a critically ill state.

Comparison of different treatment regimens and analysis of prognostic factors in secondary hemophagocytic lymphohistiocytosis in adults: A single-center retrospective study.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease caused by immune hyperactivation. The overall survival (OS) of adults with secondary HLH remains suboptimal and new treatment strategies are needed. OBJECTIVES: This study aimed to compare the efficacy of different regimens in the treatment of secondary HLH in adults and analyze the prognostic factors affecting patient survival. MATERIAL AND METHODS: The clinical data of 245 adults with secondary HLH admitted to our hospital from January 2016 to October 2021 were analyzed retrospectively. The patients were divided into 3 groups according to different treatment regimens: corticosteroids therapy + chemotherapy + supportive treatment group (JHZ group), chemotherapy + supportive treatment group (HZ group) and corticosteroids therapy + supportive treatment group (JZ group). The clinical efficacy was compared among the 3 groups after treatment, and progression-free survival (PFS) and overall survival (OS) were calculated. Additionally, risk factors associated with prognosis were also analyzed with Cox regression analysis. RESULTS: The objective response rate (ORR) in the JHZ group was higher than that in the HZ group and JZ group, but there was no significant difference between the 3 groups. Also, the patients in the JHZ group had the longest OS and median PFS. Further Cox regression analysis suggested that hyperbilirubinemia was an independent risk factor for OS in secondary HLH patients. CONCLUSIONS: A combination of corticosteroids therapy, chemotherapy and supportive therapy is superior to the other 2 regimens in the clinical benefit in the treatment of secondary HLH in adults, and thus may be a preferred and feasible treatment regimen. Moreover, hyperbilirubinemia was a risk factor for prognosis that has crucial guiding significance for clinical treatment of patients with secondary HLH.

Association of a decreased platelet count with poor survival in patients with adult secondary hemophagocytic lymphohistiocytosis.

We aimed to examine the association between baseline platelet count (PLT) and the prognosis of adult secondary hemophagocytic lymphohistiocytosis (sHLH). Data from 292 patients with pretreatment platelet counts were retrospectively analysed from January 2016 to December 2020. We categorized platelet count into quartiles. Multivariable Cox proportional hazards models and restricted cubic splines (RCS) were used to evaluate the relationship between platelet count and mortality. During a median follow-up of 53 (interquartile ranges, 17-223) days, a total of 208 deaths occurred. After adjusting for multiple variables, a non-linear and inverse relationship was observed between platelet count and mortality in sHLH patient (P for nonlinearity=0.002). For non- lymphoma-associated haemophagocytic lymphohistiocytosis (non-LHLH), a similar curve was also observed (P for nonlinearity =0.028). Decreased PLT (PLT Q4) was associated with an increased risk of mortality (adjusted hazard ratio: 1.97; 95% confidence interval: 1.28-3.04; Ptrend =0.005). Similar results were observed in the LHLH subgroup (adjusted hazard ratio: 1.84; 95% confidence interval: 1.05-3.24; Ptrend =0.024) but not in the non-LHLH subgroup (Ptrend =0.266). Baseline platelet count demonstrated a nonlinear and inverse association with an increased risk of mortality among adult sHLH patients. This method is used to identify sHLH patients with inferior overall survival due to its low cost and universal availability.

[Analysis of High-Risk Clinical Factors of Early Death in Secondary Hemophagocytic Lymphohistiocytosis].

OBJECTIVE: To explore the high-risk clinical factors of early death in patients with secondary hemophagocytic lymphohistiocytosis (sHLH), and further identify the clinical factors related to the rapid progression of sHLH in the short term. METHODS: The clinical manifestations, laboratory examination and prognosis of sHLH patients were retrospectively analyzed. Continuous variables were grouped by median, univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were used to explore the risk factors affecting early death of sHLH. Then, a nomogram model was established with independent risk factors, Bootstrap resampling method was used for verification, and consistency index (C-index) and calibration curve were used to detect the prediction accuracy. RESULTS: A total of 126 sHLH patients were enrolled, with a median age of 48.5(16-88) years, including 74 males and 52 females. Fifty-five patients (43.6%) died within 30 days, including 39 males and 16 females. Univariate regression analysis showed that lymphocyte count <0.45×109/L, platelet count (PLT) <39.5×109/L, prothrombin time (PT)≥13.3 s, activated partial thromboplastin time (APTT)≥39.7 s, albumin (ALB) <25.9 g/L, lactate dehydrogenase (LDH)≥811 U/L, creatinine (Cr) ≥67 µmol/L and procalcitonin (PCT)≥0.61 ng/ml were risk factors for death within 30 days in sHLH patients. Multivariate regression analysis showed that lymphocyte count <0.45×109/L, APTT≥39.7 s and ALB <25.9 g/L were independent risk factors for death within 30 days in sHLH patients. A nomogram model was established based on the above three risk factors, its C-index was 0.683, and the calibration chart showed good agreement between the observed and predicted values of sHLH. CONCLUSIONS: Lymphopenia, prolonged APTT, and hypoalbuminemia are risk factors for early death of sHLH patients. Early identification and positive intervention are expected to reduce early mortality in sHLH patients. The nomogram model based on the above risk factors provides a method for clinicians to evaluate sHLH.

Hemophagocytic Lymphohistiocytosis: A Rare Complication of COVID-19 in a Patient With Sickle Cell Anemia.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition that can be fatal due to overwhelming macrophage activation and cytokine production. It can be primary (familial/genetic) or secondary. It is associated with infections, malignancies, and rheumatologic and immunodeficiency disorders. We report a middle-aged female patient with sickle cell anemia who presented with COVID-19 infection that triggered a vaso-occlusive crisis and resulted in HLH. She had preexisting high ferritin levels and cytopenias, making the diagnosis more challenging. A high index of suspicion and timely treatment is essential to prevent adverse outcomes.

Secondary Hemophagocytic Lymphohistiocytosis: A Series of Three Cases.

Hemophagocytic lymphohistiocytosis (HLH) is a disease of abnormal activation of the immune system, either due to a familial cause or a sporadic cause, in relation to various triggering agents. Secondary HLH is a complication of various diseases, such as infections, malignancies, and autoimmune disorders. In our case series, we present three cases of secondary HLH with varied etiologies. Case 1 involved an 18-year-old male with a history of pulmonary tuberculosis, presenting with fever, hepatosplenomegaly, and elevated inflammatory markers. HLH was treated with steroids alongside antitubercular therapy (ATT). In case 2, a 17-year-old male presented with dengue fever, fever, hepatosplenomegaly, and elevated inflammatory markers. HLH was managed with steroids and etoposide. In case 3, a 29-year-old female with systemic lupus erythematosus (SLE) presented with fever, hepatosplenomegaly, and a positive antinuclear antibody (ANA) test. Steroid therapy was initiated for HLH. The prognosis depends on various factors. The management of such cases necessitates expeditious treatment of the underlying disease in conjunction with amelioration of the cytokine storm with the immunosuppressive agents precipitated by the secondary conditions. Once the underlying cause of the cytokine storm is treated, the lethal progression of the disease may come to a halt.

Secondary Hemophagocytic Lymphohistiocytosis Due to Typhoid Fever.

Hemophagocytic lymphohistiocytosis (HLH) is a potentially fatal hyper-inflammatory state that is caused by a highly activated but ineffective immune system. It can be primary or secondary to triggers like infections, malignancies, and autoimmune conditions. The authors present the case of a young male with a fever and abdominal pain due to typhoid. He continued to have a high-spiking fever and developed dyspnea, requiring oxygen therapy despite being treated with appropriate antibiotics. Laboratory evaluation revealed cytopenias and deranged liver function tests, and abdominal imaging revealed hepatosplenomegaly. These clinical and laboratory findings raised suspicion of HLH secondary to typhoid fever. Further investigations were suggestive of hyperferritinemia and hypofibrinogenemia, and bone marrow aspirates showed hemophagocytes. The patient was treated with immunosuppression (dexamethasone) and antibiotics and showed remarkable recovery. Hemophagocytic lymphohistiocytosis should be suspected in patients with tropical infections like enteric fever, tuberculosis, malaria, dengue, etc. that worsen despite appropriate treatment, as late diagnosis is associated with greater mortality.

Ehrlichia-Induced Hemophagocytic Lymphohistiocytosis (HLH) With No Response to Doxycycline Treatment.

Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening condition characterized by the persistent activation of antigen-presenting cells and multisystemic inflammation. Ehrlichiosis is a tick-born infection that primarily infects the white blood cells and can present with a variety of symptoms, including fever, fatigue, and multisystemic complications. Here, we present a 58-year-old female hospitalized for a urinary tract infection. Her hospital course was complicated by HLH, which was later discovered to be precipitated by an Ehrlichia chaffeensis infection. The patient did not respond to the doxycycline treatment, developed multiorgan failure, and passed away after a few weeks of treatment trials.

Risk factors and prognosis of early death in secondary hemophagocytic lymphohistiocytosis.

The aim of our study was to summarize the clinical characteristics of early death patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), analyze the risk factors of early death, and analyze the survival of patients. The clinical characteristics of 324 newly diagnosed sHLH patients admitted to the First Affiliated Hospital of Zhejiang University Medical College and Zhejiang Provincial Cancer Hospital from January 2014 to February 2021 were analyzed retrospectively. Analyze the independent risk factors of early death, compare the secondary diseases and treatment methods of patients with early death group and non early death group, and analyze the survival of all patients with sHLH. Among the 324 newly diagnosed patients with sHLH, 134 died early, with an early mortality rate of 41.4%. Comparing the clinical characteristics of patients with early death group and patients with non early death group, logistic regression model was used to conduct multifactor analysis. Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L were independent risk factors for early death of newly diagnosed sHLH patients (P < 0.05). Comparing the secondary diseases and treatment methods between early death group and non early death group, the proportion of sHLH patients secondary to lymphoma was higher in early death group than that in non early death group (P < 0.05). The proportion of sHLH patients secondary to connective tissue disease and infection was lower in early death group than that in non early death group (P < 0.05), and the proportion of sHLH patients used hormone combined chemotherapy was lower in early death group than that in non early death group (P < 0.05). The median follow-up time of all patients was 12.0 (1-65) months. The 5-year OS rates of patients with age > 60 years and age ≤ 60 years were 25.8% and 49.6% respectively (P < 0.001); The 5-year OS rates of patients with Plt > 20.0 × 109/L and Plt ≤ 20.0 × 109/L were 52.5% and 25.5% respectively (P < 0.001); The 5-year OS rates of patients with APTT > 36.0 s and APTT ≤ 36.0 s were 34.5% and 57.4% respectively (P < 0.001); The 5-year OS rates of patients with LDH > 1000.0 U/L and LDH ≤ 1000.0 U/L were 23.3% and 56.3% respectively (P < 0.001). Age > 60 years, Plt ≤ 20.0 × 109/L, APTT > 36.0 s and LDH > 1000.0 U/L are independent risk factors for early death of sHLH patients. The early mortality of lymphoma associated HLH (LA-HLH) patients is high, and early use of hormone combined chemotherapy can reduce the early mortality.

Presentations and outcomes of familial hemophagocytic lymphohistiocytosis in the pediatric intensive care units (PICUs).

Objectives: We aimed to describe Familial Hemophagocytic Lymphohistiocytosis (F-HLH) patients' clinical features, intensive care courses, and outcomes. Methods: Multi-center retrospective cohort study of pediatric patients diagnosed with F-HLH from 2015 to 2020 in five tertiary centers in Saudi Arabia. Patients were classified as F-HLH based on their genetic confirmation of known mutation or on their clinical criteria, which include a constellation of abnormalities, early disease onset, recurrent HLH in the absence of other causes, or a family history of HLH. Results: Fifty-eight patients (28 male, 30 female), with a mean age of 21.0 ± 33.9 months, were included. The most common principal diagnosis was hematological or immune dysfunction (39.7%), followed by cardiovascular dysfunction in 13 (22.4%) patients. Fever was the most common clinical presentation in 27.6%, followed by convulsions (13.8%) and bleeding (13.8%). There were 20 patients (34.5%) who had splenomegaly, and more than 70% of patients had hyperferritinemia >500 mg/dl, hypertriglyceridemia >150 mg/dl and hemophagocytosis in bone marrow biopsy. Compared to deceased patients 18 (31%), survivors had significantly lower PT (p = 041), bilirubin level of <34.2 mmol/L (p = 0.042), higher serum triglyceride level (p = 0.036), and lesser bleeding within the initial 6 h of admission (p = 0.004). Risk factors for mortality included requirements of higher levels of hemodynamic (61.1% vs. 17.5%, p = 0.001) and respiratory (88.9% vs. 37.5%, p < 0.001) support, and positive fungal cultures (p = 0.046). Conclusions: Familial HLH still represents a challenge in the pediatric critical care setting. Earlier diagnosis and prompt initiation of appropriate treatment could improve F-HLH survival.

Primary Gastrointestinal Diffuse Large B-cell Lymphoma Presenting as Ileal Perforation.

Diffuse large B-cell lymphoma (DLBCL) is the most common form of non-Hodgkin's lymphoma and can rarely present as a primary gastrointestinal malignancy. Primary gastrointestinal lymphoma (PGIL) is associated with a significant risk of perforation and peritonitis, with high rates of mortality. Here we describe a case of a newly diagnosed PGIL in a previously healthy 22-year-old male presenting for new-onset abdominal pain with diarrhea. Early hospital course was characterized by peritonitis and severe septic shock. Despite multiple surgical interventions and resuscitative efforts, the patient's condition continued to deteriorate until cardiac arrest and death on hospital day five. A diagnosis of DLBCL of the terminal ileum and cecum was made by pathology post-mortem. The prognosis for these patients can be improved through early intervention with chemotherapy regimens and surgical resection of the malignant tissue. This report highlights DLBCL as a rare cause of gastrointestinal perforation that can culminate in precipitous multiorgan failure and death.

Hemophagocytic lymphohistiocytosis in gastric cancer: A rare syndrome for the oncologist. Case report and brief review.

Hemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by uncontrolled activation of the immune system. HLH is a reactive mononuclear phagocytic response that occurs in association with a constellation of conditions such as malignancies and infections. The clinical diagnosis of HLH remains challenging because HLH can present with symptoms that significantly overlap with other causes of cytopenia, such as sepsis, autoimmune diseases, hematological cancers, and multiorgan failure. A 50-year-old man went to the emergency room (ER) for hyperchromic urine, melena, gingivorrhagia, and spontaneous abdominal wall hematomas. The first blood tests showed severe thrombocytopenia, alteration of the INR, and consumption of fibrinogen, and therefore, a diagnosis of disseminated intravascular coagulation (DIC) was made. A bone marrow aspirate showed numerous images of hemophagocytosis. With the suspicion of immune-mediated cytopenia, oral etoposide, intravenous immunoglobulin, and intravenous methylprednisolone were administered. Then, a diagnosis of gastric carcinoma was performed with a lymph node biopsy and gastroscopy. On the 30th day, the patient was transferred to the oncology ward of another hospital. On admission, he had serious piastrinopenia, anemia, hypertriglyceridemia, and hyperferritinemia. He was supported with a platelet transfusion and underwent a bone biopsy that showed a picture compatible with myelophthisis from diffuse medullary localization of a carcinoma of gastric origin. A diagnosis of HLH secondary to solid neoplasm was formulated. The patient started chemotherapy with oxaliplatin, calcium levofolinate, 5-fluorouracil bolus, 5-fluorouracil for 48 h (mFOLFOX6), and methylprednisolone. Six days after the third cycle of mFOLFOX6, the patient was discharged with the stabilization of his piastrinopenia condition. The patient continued chemotherapy with an improvement in his clinical conditions and normalization of hematological values. After 12 cycles of mFOLFOX, it was decided to start maintenance chemotherapy with capecitabine but, unfortunately, after only one cycle, HLH reappeared. The oncologist has to keep in mind the existence of HLH when there is an unusual clinical presentation of cancer, such as cytopenia affecting ≥2 lineages and alterations of ferritin and triglycerides other than fibrinogen and coagulation. Increased attention and additional research as well as a close collaboration with hematologists are needed to benefit patients with solid tumors complicated by HLH.

Clinical features and risk factors for secondary hemophagocytic lymphohistiocytosis in elderly patients with severe SARS-CoV-2 infection: a multicenter retrospective cohort study / 中华危重病急救医学

Objective:To explore the incidence of secondary hemophagocytic lymphohistiocytosis (sHLH) in elderly patients with severe SARS-CoV-2 infection, and to analyze and summarize its clinical features and risk factors for early identification of high-risk groups.Methods:A retrospective cohort study was conducted. From January to May 2020, No. 960 Hospital of People's Liberation Army, the Second Hospital Affiliated to Cheeloo College of Medicine of Shandong Province, the First Rehabilitation Hospital of Shandong Province, the Public Health Clinical Center Affiliated to Shandong University, and Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine received 248 patients over 60 years old who were diagnosed with severe SARS-CoV-2 infection during their assistance to Hubei or support for diagnosis and treatment of SARS-CoV-2 infection in Shandong Province. The clinical data of patients were collected. According to the hemophagocytic lymphohistiocytosis diagnosis scoring (HScore) criteria, the patients were divided into sHLH group (HScore > 169) and non-sHLH group (HScore < 98). The demographic data, clinical features, laboratory results, the proportion of organ failure and 60-day mortality of patients were collected and compared between the two groups. The risk factors of sHLH and 60-day death were evaluated through binary multivariate Logistic regression analysis in elderly patients with severe SARS-CoV-2 infection. The receiver operator characteristic curve (ROC curve) was plotted to analyze the diagnostic value of indicators only or combined for sHLH.Results:Among 248 elderly patients with severe SARS-CoV-2 infection, 82 patients with incomplete data and untraceable clinical outcomes, and 35 patients with HScore of 98-169 were excluded. Finally, 131 patients were enrolled in the final follow-up and statistics, including 25 patients in the sHLH group and 106 patients in the non-sHLH group. Compared with the non-sHLH group, plasma albumin (ALB), hemoglobin (Hb), lymphocyte count (LYM), platelet count (PLT), fibrinogen (Fib) and prealbumin (PAB) in the sHLH group were significantly reduced, while alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), MB isoenzyme of creatine kinase (CK-MB), serum creatinine (SCr), C-reactive protein (CRP), D-dimer, ferritin (Fer), lactate dehydrogenase (LDH), procalcitonin (PCT), cardiac troponin I (cTnI), triglycerides (TG), interleukin-6 (IL-6), total bilirubin (TBil) were significantly higher. The fever and fatigue in the sHLH group were more severe than those in the non-sHLH group, and the patients in the sHLH group had higher rates of shock, acute kidney injury, liver dysfunction, and cardiac injury than the non-sHLH group. The 60-day mortality of patient in the sHLH group was significantly higher than that in the non-sHLH group [84.0% (21/25) vs. 40.6% (43/106), P < 0.01]. Binary multivariate Logistic regression analysis showed that high Fer [odds ratio ( OR) = 0.997, 95% confidence interval (95% CI) was 0.996-0.998], D-dimer ( OR = 0.960, 95% CI was 0.944-0.977), LDH ( OR = 0.998, 95% CI was 0.997-0.999) and TG ( OR = 0.706, 95% CI was 0.579-0.860) were independent risk factors for sHLH in elderly patients with severe SARS-CoV-2 infection (all P < 0.01), while elevated Fer ( OR = 1.001, 95% CI was 1.001-1.002), LDH ( OR = 1.004, 95% CI was 1.002-1.005) and D-dimer ( OR = 1.036, 95% CI was 1.018-1.055) were independent risk factors for 60-day death of patients (all P < 0.01). The death risk of the sHLH patients was 7.692 times higher than that of the non-sHLH patients ( OR = 7.692, 95% CI was 2.466-23.987, P = 0.000). ROC curve analysis showed that a three-composite-index composed of LDH, D-dimer and TG had good diagnostic value for sHLH in elderly patients with severe SARS-CoV-2 infection [area under the ROC curve (AUC) = 0.920, 95% CI was 0.866-0.973, P = 0.000]. Conclusions:Elderly patients with severe SARS-CoV-2 infection complicated by sHLH tend to be critically ill and have refractory status and worse prognosis. High Fer, LDH, D-dimer and TG are independent risk factors for sHLH, and are highly suggestive of poor outcome. The comprehensive index composed of LDH, D-dimer and TG has good diagnostic value, and can be used as an early screening tool for sHLH in elderly patients with severe SARS-CoV-2 infection.

Analysis of High-Risk Clinical Factors of Early Death in Secondary Hemophagocytic Lymphohistiocytosis / 中国实验血液学杂志

OBJECTIVE@#To explore the high-risk clinical factors of early death in patients with secondary hemophagocytic lymphohistiocytosis (sHLH), and further identify the clinical factors related to the rapid progression of sHLH in the short term.@*METHODS@#The clinical manifestations, laboratory examination and prognosis of sHLH patients were retrospectively analyzed. Continuous variables were grouped by median, univariate and multivariate Cox regression analysis and Kaplan-Meier survival curve were used to explore the risk factors affecting early death of sHLH. Then, a nomogram model was established with independent risk factors, Bootstrap resampling method was used for verification, and consistency index (C-index) and calibration curve were used to detect the prediction accuracy.@*RESULTS@#A total of 126 sHLH patients were enrolled, with a median age of 48.5(16-88) years, including 74 males and 52 females. Fifty-five patients (43.6%) died within 30 days, including 39 males and 16 females. Univariate regression analysis showed that lymphocyte count <0.45×109/L, platelet count (PLT) <39.5×109/L, prothrombin time (PT)≥13.3 s, activated partial thromboplastin time (APTT)≥39.7 s, albumin (ALB) <25.9 g/L, lactate dehydrogenase (LDH)≥811 U/L, creatinine (Cr) ≥67 μmol/L and procalcitonin (PCT)≥0.61 ng/ml were risk factors for death within 30 days in sHLH patients. Multivariate regression analysis showed that lymphocyte count <0.45×109/L, APTT≥39.7 s and ALB <25.9 g/L were independent risk factors for death within 30 days in sHLH patients. A nomogram model was established based on the above three risk factors, its C-index was 0.683, and the calibration chart showed good agreement between the observed and predicted values of sHLH.@*CONCLUSIONS@#Lymphopenia, prolonged APTT, and hypoalbuminemia are risk factors for early death of sHLH patients. Early identification and positive intervention are expected to reduce early mortality in sHLH patients. The nomogram model based on the above risk factors provides a method for clinicians to evaluate sHLH.