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BACKGROUND: Haemophagocytic lymphohistiocytosis (HLH) is a syndrome that occurs in patients with severe systemic hyperinflammation. GATA binding protein 2 (GATA2) is a transcription factor and key component in haematopoiesis and stem cell biology.
METHODS: Three patients with HLH, one with Mycobacterium avium infection, one with Epstein-Barr virus (EBV) infection, and one with Mycobacterium kansasii infection, were all subsequently found to have a defect in the GATA2 gene through genetic testing.
CONCLUSIONS: GATA2 deficiency syndrome should be considered in patients with myelodysplastic syndrome, nontuberculous mycobacterium infection and HLH. In addition, the GATA2 gene variant may be a genetic defect that could be the cause of the primary HLH. However, further studies are needed to confirm the role of GATA2 pathogenic variants in the pathogenesis of HLH.

UNASSIGNED: Autoimmune diseases are not contraindications for immune checkpoint inhibitors (ICI) therapy in patients with cancer. However, immune-related adverse events (irAEs) are frequently observed in patients receiving ICIs including dermatitis, thyroiditis, colitis, and pneumonitis. Thrombocytopenic purpura, aplasia, and haemophagocytic lymphohistiocytosis (HLH) are rarely observed during ICIs.
UNASSIGNED: We report the case of a male patient with pre-existing untreated HLA B27 and ankylosing spondylitis with gastric cancer and liver metastases. The 79-year-old man was treated with anti-HER2 trastuzumab and anti-PD-1 nivolumab. Seventeen days after the seventh cycle of treatment, he presented at the emergency department with acute fever, confusion, and hypotension. Laboratory results showed pancytopenia, and elevation of ferritin and triglyceride. No infections were detected. Although not seen in a bone marrow biopsy, clinical presentation, and absence of infection, together with an H-score of 263, indicated HLH. The patient was treated with dexamethasone for four days and discharged on a tapering dose of steroids. At the two-month follow-up, clinical presentation was normal and blood test almost normalised. At 8 months, no liver metastases were observed.
UNASSIGNED: In a patient with a pre-existing autoimmune condition, immunotherapy led to the development of HLH, which was controlled by glucocorticoid. Absence of the feature of haemophagocytosis in the bone marrow biopsy did not exclude the diagnosis, as HLH can occur in the spleen or in the liver. Glucocorticoid therapy did not prevent the anti-cancer effect of ICIs, and liver metastases disappeared 8 months post-HLH. This case warrants further research on the interplay between autoimmunity and ICI response, as well as ICI-induced irAEs.
CONCLUSIONS: Haemophagocytic lymphohistiocytosis (HLH) post seventh cycle of trastuzumab (anti-HER2) and nivolumab (anti-PD-1) was controlled with glucocorticoid.Breach of tolerance was due to immunotherapy-induced HLH in a patient with pre-existing autoimmune condition (HLA B27- positive ankylosing spondylitis).There was a complete disappearance of liver metastases 8 months post-HLH.

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Paediatric haemophagocytic lymphohistiocytosis (pHLH) is a potentially life-threatening condition with significant diagnostic and therapeutic difficulties. The purpose of this study was to describe the clinical presentation, the diagnostic challenges, and the outcomes of haemophagocytic lymphohistiocytosis (HLH) in children assessed at Mukalla Hospital, Yemen. Data from 20 medical records of HLH patients admitted between January 2010 and May 2022 were retrospectively analysed. The median age at presentation was 3.5 ± 5.1 years. Male: female ratio was 1:1. The median time for referral to the hospital was 30 ± 64 days. The most common clinical manifestations were fever and pallor in 95% of cases, and splenomegaly (85%). Hepatomegaly, chest, renal and neurological manifestations were detected in 80%, 45%, 15% and 20% of cases, respectively. Bone marrow haemophagocytosis was detected in 60% of cases. Sixteen patients fulfilled the HLH diagnostic criteria, and 11 patients (55%) received the HLH 2004 protocol. Out of the 20 patients, three (15%) patients are alive. Fourteen patients died, with overall mortality of 82.35%. All mortalities were due to HLH disease with multi-organ failure. Relapse was noticed in five patients either during treatment or after full recovery. pHLH is a challenging emergency with a high mortality rate. High clinical suspicion is essential for early detection and intervention to improve the prognosis.

BACKGROUND: Chimeric antigen receptor T-cell (CAR-T) therapy is increasingly used in patients with refractory haematological malignancies but can induce severe adverse events. We aimed to describe the clinical features and outcomes of patients admitted to the intensive care unit (ICU) after CAR-T therapy.
METHODS: This retrospective observational cohort study included consecutive adults admitted to either of two French ICUs in 2018-2022 within 3 months after CAR-T therapy.
RESULTS: Among 238 patients given CAR-T therapy, 84 (35.3%) required ICU admission and were included in the study, a median of 5 [0-7] days after CAR-T infusion. Median SOFA and SAPSII scores were 3 [2-6] and 39 [30-48], respectively. Criteria for cytokine release syndrome were met in 80/84 (95.2%) patients, including 18/80 (22.5%) with grade 3-4 toxicity. Immune effector cell-associated neurotoxicity syndrome (ICANS) occurred in 46/84 (54.8%) patients, including 29/46 (63%) with grade 3-4 toxicity. Haemophagocytic lymphohistiocytosis was diagnosed in 15/84 (17.9%) patients. Tocilizumab was used in 73/84 (86.9%) patients, with a median of 2 [1-4] doses. Steroids were given to 55/84 (65.5%) patients, including 21/55 (38.2%) given high-dose pulse therapy. Overall, 23/84 (27.4%) patients had bacterial infections, 3/84 (3.6%) had fungal infections (1 invasive pulmonary aspergillosis and 2 Mucorales), and 2 (2.4%) had cytomegalovirus infection. Vasopressors were required in 23/84 (27.4%), invasive mechanical ventilation in 12/84 (14.3%), and dialysis in 4/84 (4.8%) patients. Four patients died in the ICU (including 2 after ICU readmission, i.e., overall mortality was 4.8% of patients). One year after CAR-T therapy, 41/84 (48.9%) patients were alive and in complete remission, 14/84 (16.7%) were alive and in relapse, and 29/84 (34.5%) had died. These outcomes were similar to those of patients never admitted to the ICU.
CONCLUSIONS: ICU admission is common after CAR-T therapy and is usually performed to manage specific toxicities. Our experience is encouraging, with low ICU mortality despite a high rate of grade 3-4 toxicities, and half of patients being alive and in complete remission at one year.

We report a case of an adult female with disseminated tuberculosis, cytomegalovirus viraemia and haemophagocytic-lymphohistiocystosis syndrome associated with neutralizing anti- interferon gamma (IFNγ) autoantibodies demonstrated by absent IFNγ stimulated STAT1 phosphorylation in the presence of patient sera. A brief review of immunodeficiency caused by anti-IFNγ autoantibodies is also described.

UNASSIGNED: Melioidosis is caused by Burkholderia pseudomallei, a Gram-negative, saprophytic bacillus, commonly found in soil or contaminated water. As infection with this bacterium produces a wide variety of clinical manifestations the organism is aptly called the \'great mimicker\'. Even though it is non-fastidious and an easily cultivable organism, it can be misidentified in automated identification systems.
UNASSIGNED: A 24-year-old primigravida presented with complaints of fever and myalgia of 45 days\' duration. She was diagnosed to have haemophagocytic lymphohistiocytosis (HLH) based on clinical and laboratory parameters. Blood and bone marrow culture sent to the microbiology laboratory grew non-fermenting Gram-negative bacilli which were misidentified as Burkholderia cepacia by matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) technology. It was subsequently identified as B. pseudomallei by 16S rRNA gene sequencing. The patient was commenced on intensive phase therapy with intravenous ceftazidime for 2 weeks, followed by maintenance therapy with oral trimethoprim and sulfamethoxazole for 3 months. In view of HLH, she was treated with intravenous dexamethasone for 2 weeks which was later switched to oral dexamethasone for a period of 6 weeks. She responded well to the treatment, but had to undergo medical termination of her pregnancy as there was severe intrauterine growth restriction of the fetus.
UNASSIGNED: Prognosis of melioidosis is excellent if early diagnosis and appropriate antibiotic treatment is provided. In this era of automation, it is important to determine if the suspected pathogen is listed in the database of the automated identification system.

UNASSIGNED: Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by an excessive inflammatory response. Limited data exist on adult HLH.
UNASSIGNED: In this national, retrospective cohort study, we analysed data from the US National Inpatient Sample database collected between October 1, 2006 and December 31, 2019. Using the International Classification of Diseases (ICD) codes, we identified all adult patients who were admitted non-electively with the diagnosis of HLH. We described demographic characteristics, triggers, and associated conditions. Trends of diagnosis, treatment, and in-hospital mortality were analysed using joinpoint models. In-hospital mortality rates were compared using multivariable logistic regression models that adjusted for demographic characteristics and associated conditions. Finally, we described resource utilization outcomes including cost of hospitalization and length of stay.
UNASSIGNED: We identified 16,136 non-elective adult HLH admissions. The population pyramid showed a bimodal distribution, with peaks in young adults (16-30 years) and older adults (56-70 years). Joinpoint regression analysis revealed a significant increase in HLH incidence per 100,000 admissions over the study period (Average Annual Percent Change [APC] = 25.3%, p < 0.0001), and no significant change in rates of in-hospital mortality (slope = -0.01; p = 0.95) or administration of in-hospital HLH treatment (slope = 0.46, p = 0.20). The most common associated conditions were malignancy (4953 admissions [30.7%]), infections (3913 admissions [24.3%]), autoimmune conditions (3362 admissions [20.8%]), organ transplant status (639 admissions [4%]), and congenital immunodeficiency syndromes (399 admissions [2.5%]). In-hospital mortality was higher in older adults and males. Furthermore, Congenital immunodeficiency syndromes had the worst in-hospital mortality rate (mortality rate 31.1%, adjusted OR 2.36 [1.56-3.59]), followed by malignancies (mortality rate 28.4%, adjusted OR 1.80 [1.46-2.22]), infections (mortality rate 21.4%, adjusted OR 1.33 [1.10-1.62]), other/no trigger (mortality rate 13.6%, adjusted OR 0.73 [0.58-0.92]), autoimmune (mortality rate 13%, adjusted OR 0.72 [0.57-0.92]), and post-organ transplant status (mortality rate 14.1%, adjusted OR 0.64 [0.43-0.97]). The overall mean length of stay was 14.3 ± 13.9 days, and the mean cost of hospitalization was $54,900 ± 59,800.
UNASSIGNED: We provide insight into the burden of adult HLH in the USA. The incidence has been increasing and the outcomes remain dismal. This signifies the growing need for the development of updated diagnosis and treatment protocols that are specific to adult HLH.
UNASSIGNED: None.

UNASSIGNED: Epstein-Barr virus (EBV) is a common cause of secondary haemophagocytic lymphohistiocytosis (HLH). While B cells are reservoirs for EBV, infection within T cells and NK cells in this disease can be difficult to treat.
UNASSIGNED: A 19-year-old female presented with a 6-week history of coryzal symptoms on a background of Crohn\'s disease. On examination, she was febrile and tachycardic with mild tonsillar enlargement and splenomegaly. New trilineage cytopenias and elevation in liver enzymes were detected, with acute EBV subsequently confirmed on whole blood PCR. A diagnosis of EBV-associated HLH was supported further with elevated serum ferritin, triglycerides and soluble CD25, low fibrinogen and the presence of haemophagocytosis in the bone marrow.
UNASSIGNED: Corticosteroids, IVIG and rituximab were given, and anakinra was subsequently added due to ongoing fevers. EBV infection was then demonstrated within CD8+ T cells on EBER Flow-FISH assay. Ruxolitinib was commenced and her fevers abated on day 5, with improvement in other HLH parameters. She was discharged after a 39-day hospital admission. To date, she has remained in remission of HLH, despite developing COVID-19 infection during the convalescence phase of HLH.
UNASSIGNED: EBV viraemia requires adequate treatment to control EBV-associated HLH as rituximab may be insufficient, and corticosteroid resistance can result in continued EBV infection in CD8+ T cells. This entity is known as T-cell-EBV-HLH. Ruxolitinib is a novel treatment strategy in this specific context and has several advantages, including inhibition of corticosteroid resistance to promote apoptosis of EBV-infected T cells.