UNASSIGNED: Our aim was to better understand and raise awareness of the diagnosis journey and quantify any barriers for timely diagnosis of haemophagocytic lymphohistiocytosis (HLH), to support patients\' struggle with diagnosis and reduce time to diagnosis.
UNASSIGNED: Patients diagnosed with, or caregivers for those diagnosed with primary or secondary HLH and physicians involved in the treatment of HLH were recruited. Quantitative interviews were undertaken with patients/caregivers to quantify key elements of the diagnosis journey, followed by qualitative interviews with participants. Interviews took place between March-May 2021.
UNASSIGNED: Thirty-three patients/caregivers and nine physicians took part in this mixed methods study. Lack of physician awareness of HLH was a common frustration for patients/caregivers, causing delayed diagnosis. All physicians indicated bone-marrow testing is a key step in the diagnosis process, and some patients/caregivers had frustrations around testing. Emergency care doctors, although not usually involved in the diagnosis process, were among the most-seen specialists by patients/caregivers. Patients/caregivers suggested potential improvements in available information, such as providing information on treatment options and condition management.
UNASSIGNED: Patients/caregivers and physicians agreed on the need to raise overall awareness of HLH signs/symptoms among priority groups of physicians to recognise how signs/symptoms can progress and develop. Improvements in the testing process and communication would directly impact the speed of diagnosis and support patients/caregivers during the diagnostic journey, respectively.
UNASSIGNED: Raising awareness of key issues, such as signs/symptoms, tests and diagnostic procedures, and improved communication and support for patients/caregivers, are key to speeding up HLH diagnosis and improving outcomes.

Bacille Calmette-Guérin (BCG) is a live-attenuated vaccine routinely administered to newborns to prevent severe forms of tuberculosis (TB) in TB-endemic countries. Disseminated BCG vaccine disease is a classic feature of children with human immunodeficiency virus (HIV) or primary immunodeficiency disorders (PIDs) and is associated with high mortality. We report a case of a 6-month-old infant with disseminated BCG disease and hemophagocytic lymphohistiocytosis mimicking juvenile myelomonocytic leukemia with no demonstrable features of HIV or PID even after extensive laboratory work-up and succumbed to progressive disease. Disseminated BCG disease is a rare and potentially fatal complication of BCG vaccine, and prompt immunological evaluation complemented by initiation of 4-drug antitubercular therapy and definitive treatment with antiretroviral therapy or hematopoietic stem cell transplant is warranted.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome for which early recognition and treatment are essential for improving outcomes. HLH is characterized by uncontrolled immune activation leading to fever, cytopenias, hepatosplenomegaly, coagulation abnormalities, and elevated typical markers. This condition can be genetic or secondary, with the latter often triggered by infections. Here, we present a unique case of HLH secondary to acute otitis media (AOM), a common ear infection.
METHODS: We describe a 4-year-old boy who initially presented with a high fever and otalgia, later diagnosed with bilateral AOM. Despite antibiotic treatment, his condition deteriorated.
METHODS: The patient fulfilled diagnostic criteria for HLH.
METHODS: Aggressive treatment by using combination therapy with immunoglobulins, intravenous steroids (dexamethasone), cyclosporine, and etoposide was performed.
RESULTS: After 1 month of treatment, improvement in the otologic symptoms was observed, and hematological findings gradually improved and normalized.
CONCLUSIONS: The link between AOM and HLH may be associated with inflammatory responses and immunological mechanisms, highlighting the importance of considering HLH in severe infection cases. This case emphasizes the need for prompt diagnosis and management, especially in secondary HLH scenarios, to improve patient outcomes. It is imperative to be aware of the potential correlation between these 2 conditions, and healthcare professionals should consider the likelihood of HLH.

OBJECTIVE: To present a rare case of neonatal lupus erythematosus (NLE) associated with suspected hemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome (MAS).
METHODS: A female infant weighing 2,995 g was born to a mother without medical history of any disease. At birth, the patient had erythematous papules on her face and trunk. She was admitted at 1 day of age with elevated C-reactive protein levels. The patient was diagnosed with NLE based on the presence of anti-Ro/SSA and anti-La/SSB antibodies. Thereafter, it became clear that the antibody levels in her mother were also elevated. At 20 days of age, the infant showed elevated transaminases, ferritin, triglyceride, and soluble interleukin-2 receptor levels. Although HLH or MAS was suspected, she did not fulfill the diagnostic criteria. Thereafter, these abnormal values spontaneously improved, and the skin rash improved with the use of topical steroids. The patient was discharged at 39 days of age. At 1 year of age, the patient\'s growth and development were normal.
CONCLUSIONS: NLE should be considered in infants with an unexplained skin rash at birth. When a diagnosis is made, close observation of the infant\'s clinical features is needed to determine whether they will develop HLH or MAS.

Magnesium transporter 1 (MAGT1) gene loss-of-function variants lead to X-linked MAGT1 deficiency with increased susceptibility to EBV infection and N-glycosylation defect (XMEN), a condition with a variety of clinical and immunological effects. In addition, MAGT1 deficiency has been classified as a congenital disorder of glycosylation (CDG) due to its unique role in glycosylation of multiple substrates including NKG2D, necessary for viral protection. Due to the predisposition for EBV, this etiology has been linked with hemophagocytic lymphohistiocytosis (HLH), however only limited literature exists. Here we present a complex case with HLH and EBV-driven classic Hodgkin lymphoma (cHL) as the presenting manifestation of underlying immune defect. However, the patient\'s underlying immunodeficiency was not identified until his second recurrence of Hodgkin disease, recurrent episodes of Herpes Zoster, and after he had undergone autologous hematopoietic stem cell transplant (HSCT) for refractory Hodgkin lymphoma. This rare presentation of HLH and recurrent lymphomas without some of the classical immune deficiency manifestations of MAGT1 deficiency led us to review the literature for similar presentations and to report the evolving spectrum of disease in published literature. Our systematic review showcased that MAGT1 predisposes to multiple viruses (including EBV) and adds risk of viral-driven neoplasia. The roles of MAGT1 in the immune system and glycosylation were highlighted through the multiple organ dysfunction showcased by the previously validated Immune Deficiency and Dysregulation Activity (IDDA2.1) score and CDG-specific Nijmegen Pediatric CDG Rating Scale (NPCRS) score for the patient cohort in the systematic review.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by the uncontrolled activation of cytotoxic T lymphocytes, NK cells, and macrophages, resulting in an overproduction of pro-inflammatory cytokines. A primary and a secondary form are distinguished depending on whether or not it is associated with hematologic, infectious, or immune-mediated disease. Clinical manifestations include fever, splenomegaly, neurological changes, coagulopathy, hepatic dysfunction, cytopenia, hypertriglyceridemia, hyperferritinemia, and hemophagocytosis. In adults, therapy, although aggressive, is often unsuccessful. We report the case of a 41-year-old man with no apparent history of previous disease and an acute onset characterized by fever, fatigue, and weight loss. The man was from Burkina Faso and had made trips to his home country in the previous five months. On admission, leukopenia, thrombocytopenia, increased creatinine and transaminases, LDH, and CRP with a normal ESR were found. The patient also presented with hypertriglyceridemia and hyperferritinemia. An infectious or autoimmune etiology was ruled out. A total body CT scan showed bilateral pleural effusion and hilar mesenterial, abdominal, and paratracheal lymphadenopathy. Lymphoproliferative disease with HLH complication was therefore suspected. High doses of glucocorticoids were then administered. A cytologic analysis of the pleural effusion showed anaplastic lymphoma cells and bone marrow aspirate showed hemophagocytosis. An Epstein-Barr Virus (EBV) DNA load of more than 90000 copies/mL was found. Bone marrow biopsy showed a marrow localization of peripheral T lymphoma. The course was rapidly progressive until the patient died. HLH is a rare but usually fatal complication in adults of hematologic, autoimmune, and malignant diseases. Very early diagnosis and treatment are critical but not always sufficient to save patients.

UNASSIGNED: This study aims to discuss the clinical manifestations and treatment of Familial hemophagocytic lymphohistiocytosis (FHL) caused by a mutation in the UNC13D gene.
UNASSIGNED: A 6-year-old female child presented with unexplained febricity, splenomegaly, pancytopenia, hemophagocytic lymphohistiocytosis in bone marrow, decreased NK cell activity, soluble CD25 levels > 44000ng/ml. Genetic sequencing revealed a mutation in the UNC13D gene. Additionally, the patient experienced intermittent fever with seizures characterized by involuntary twitching of the left upper limb. Head magnetic resonance imaging (MRI) showed white matter lesions.
UNASSIGNED: According to the HLH-2004 diagnostic criteria revised by the International Society of Histiocytosis the patient was diagnosed with FHL. Despite receiving HLH-2004 treatment, the disease relapsed. However, after a salvage allogeneic Hematopoietic Stem Cell Transplant (HSCT), febricity, abnormal blood cells, and neurological symptoms significantly improved.
UNASSIGNED: Prompt performance of allogeneic HSCT is crucial upon diagnosis of FHL, especially when neurological involvement is present.

Hemophagocytic lymphohistiocytosis (HLH) is an aggressive hematological disorder caused by uncontrolled activation of cytotoxic T-cells (CTL), natural killer (NK) cells, and macrophages leading to hyperinflammation and cytokine storm. The clinical course is characterized by high-grade fever, cytopenia, and multiorgan dysfunction. HLH is classified as either primary/familial or secondary, the latter being most often triggered by infections, malignancies, and autoimmune disorders. Viral infections are commonly known to cause HLH with Epstein-Barr virus (EBV), cytomegalovirus (CMV), influenza virus, adenovirus, and parvovirus being most often implicated. Hepatitis E virus (HEV) has infrequently been reported to cause HLH with less than five cases being reported in the literature. We report a case of a young man who presented with hepatitis E-associated HLH.

Objective: To investigate the clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis (HLH) and their impact on prognosis. Methods: Sixty-three primary HLH patients with complete medical records admitted and diagnosed at Beijing Friendship Hospital of Capital Medical University from January 2013 to December 2022 were selected. The patients\' clinical and laboratory features, genetic and rapid immunological indicator characteristics, treatment outcomes and prognosis were retrospectively analyzed. Follow-up was up to June 30, 2023, with a median follow-up time [M (Q1, Q3)] of 47 (21, 76) months. Overall survival was analyzed using Kaplan-Meier survival curve, and prognostic factors were analyzed using Cox proportional hazards regression model. Results: Sixty-three primary HLH patients included 35 males and 28 females, with a median age [M (Q1, Q3)] of 17 (7, 27) years. Clinical manifestations at the initial diagnosis mainly included fever (93.7%, 59/63), splenomegaly (87.3%, 55/63), hemophagocytosis (65.1%, 41/63), hepatomegaly (52.4%, 33/63) and central nervous system (CNS) involvement (38.1%, 24/63). A total of 39 patients (61.9%) were diagnosed with EB virus (EBV) infection at initial diagnosis.PRF1 and UNC13D gene mutations were the most common mutations, and the highest frequency mutation site in the PRF1 gene was c.1349C>T, and that of UNC13D gene was c.2588G>A. A total of 76.2% (48/63) of patients had reduced activity of natural killer (NK) cells. Cytotoxic cell degranulation function was impaired or absent in 52.7% (29/55) of patients, of which 79.2% (19/24) of patients with primary HLH with defects in degranulation-related genes had impaired degranulation function. The 1-year and 3-year overall survival rates were 74.8% and 66.7%, respectively. Cox multivariate analysis suggested that peripheral blood EBV≥10 000 copies/ml (HR=3.523, 95%CI: 1.418-8.757, P=0.007) was the risk factor for prognosis. Conclusions: The main clinical manifestations of primary HLH patients at the initial diagnosis include fever, splenomegaly, hemophagocytosis, hepatomegaly, and CNS involvement. PRF1 and UNC13D are the most commonly mutated genes. High copy number EBV infection in peripheral blood is the risk factor for prognosis.
目的： 探讨原发性噬血细胞综合征（HLH）患者的临床和基因突变特征及对预后的影响。 方法： 回顾性选取2013年1月至2022年12月首都医科大学附属北京友谊医院收治并确诊的63例病历资料完整的原发性HLH患者为研究对象，分析患者的临床及实验室特征、基因突变特征、功能学特征、治疗转归及预后。随访截至2023年6月30日，中位随访时间［M（Q1，Q3）］为47（21，76）个月。采用Kaplan-Meier生存曲线分析总生存率，采用Cox比例风险回归模型分析预后影响因素。 结果： 63例原发性HLH患者包括男35例，女28例，中位发病年龄［M（Q1，Q3）］为 17（7，27）岁。初诊时临床表现主要为发热（93.7%，59/63）、脾大（87.3%，55/63）、噬血现象（65.1%，41/63）、肝大（52.4%，33/63）及中枢神经系统受累（38.1%，24/63），39例患者（61.9%）初诊时合并EB病毒感染。PRF1和UNC13D基因突变最常见（74.6%，47/63），PRF1基因最常见的变异位点是c.1349C>T，UNC13D基因最常见的变异位点是c.2588G>A。76.2%（48/63）患者自然杀伤细胞活性减低，52.7%（29/55）患者细胞毒细胞脱颗粒功能减低或缺如。脱颗粒相关基因缺陷的原发性HLH患者中，79.2%（19/24）存在脱颗粒功能受损。1年、3年总生存率分别为74.8%、66.7%。多因素Cox比例风险回归模型分析显示，外周血EB病毒拷贝数≥10 000拷贝/ml（HR=3.523，95%CI：1.418~8.757，P=0.007）是影响预后的危险因素。 结论： 原发性HLH患者初诊时临床表现主要为发热、脾大、噬血现象、肝大及中枢神经系统受累；PRF1和UNC13D基因是最常见的突变基因；外周血高拷贝数EB病毒感染是影响预后的危险因素。.

Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening hyperinflammatory syndrome characterised by persistent fevers, cytopenia, hepatosplenomegaly and systemic inflammation. Secondary HLH can be triggered by various aetiologies including infections, malignancies and autoimmune conditions. We highlight the complexity of HLH diagnosis and management by describing a case of an adolescent Salvadoran immigrant with HLH, newly diagnosed HIV, Streptococcal bacteraemia and disseminated histoplasmosis. The patient presented with neurological and ocular findings along with persistent fevers and cytopenia. He was diagnosed with HLH and treated with anakinra in addition to receiving treatment for HIV, Streptococcal bacteraemia and histoplasmosis. The patient\'s HLH resolved without corticosteroids or chemotherapy, which are considered the mainstays for HLH treatment. This case underscores the need for the evaluation and management of multiple infections and individualised management in patients presenting with HLH to achieve favourable outcomes.