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Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare complication of dengue fever with potentially life-threatening consequences and high mortality. Therefore, this study aims to investigate the prevalence, management and outcome of HLH in dengue fever., Methods: The major electronic databases, including PubMed, ScienceDirect and Ovid SP, were searched from inception until 31 January 2024 to identify relevant studies. Pooled prevalence and mortality were calculated using the random-effects generic inverse variance model with a 95% CI. All the statistical analysis was conducted using R programming., Results: A total of nine studies with 157 patients with HLH, 576 patients with severe dengue and 5081 patients with dengue fever were included in this meta-analysis. The prevalence of HLH in severe dengue (22.1%, 95% CI 8.07 to 48.0%) was significantly higher than the prevalence in dengue fever (3.12%, 95% CI 0.37 to 21.9%). The prevalence of HLH in severe dengue was higher in the paediatric population (22.8%, 95% CI 3.9 to 68.4%) compared with the adult population (19.0%, 95% CI 3.0 to 63.9%). The overall mortality rate was 20.2% (95% CI 9.7 to 37.2%)., Conclusion: The prevalence of dengue-associated HLH was low in patients with dengue fever but is significantly higher in patients with severe dengue and a high mortality rate., (© The Author(s) 2024. Published by Oxford University Press on behalf of Royal Society of Tropical Medicine and Hygiene.)

The non-Langerhans cell histiocytoses (N-LCH) represent a group of rare diseases with different clinical presentations and imaging features to classical LCH. While there is a long list of entities, only few present with musculoskeletal soft tissue and osseous manifestations alongside the more commonly reported systemic findings. Erdheim-Chester disease (ECD) is typically seen in adults as bilateral and symmetrical long bone osteosclerosis. Rosai-Dorfman disease (RDD) is more commonly seen in children and young adults with bone involvement usually being a manifestation of extra-nodal disease. Primary osseous RDD is very rare, with both displaying rather non-specific imaging features of an expansile lucent lesion with or without an extra-osseous component. Juvenile xanthogranuloma (JXG) is a benign disorder typically seen in very young children. The most common imaging manifestation is a dermal or sub-dermal soft tissue mass. This article reviews the musculoskeletal imaging appearances of the commoner N-LCH. [ABSTRACT FROM AUTHOR]

Familial haemophagocytic lymphohistiocytosis (FHL) is an inherited immune deficiency with defective cytotoxicity of natural killer cells and cytotoxic T lymphocytes. A highly stimulated, but ineffective immune response leads to severe hyperinflammation. Clinical and laboratory features are characteristic, but unspecific; thus awareness of FHL is important for early diagnosis. FHL is rapidly fatal without treatment. Standard‐of‐care therapy is etoposide and corticosteroids, followed by haematopoietic stem cell transplantation (HSCT). Conclusion: FHL has become a curable disease with present treatment. Additional cytokine‐directed therapy still has to prove its value. Earlier HSCT and less toxic conditioning regimens will lead to improved cure rates. [ABSTRACT FROM AUTHOR]

Summary: Chimeric antigen receptor T‐cell (CAR T‐cell) therapy is associated with significant toxicities secondary to immune activation, including a rare but increasingly recognised severe toxicity resembling haemophagocytic lymphohistiocytosis (carHLH). We report the development of carHLH in 14·8% of paediatric patients and young adults treated with CD19‐specific CAR T‐cell therapy with carHLH, occurring most commonly in those with high disease burden. The diagnosis and treatment of carHLH required a high index of suspicion and included multidrug immunomodulation with variable response to therapies. Compared to patients without carHLH, patients with carHLH had both reduced response to CAR T‐cell therapy (P‐value = 0·018) and overall survival (P‐value = < 0·0001). [ABSTRACT FROM AUTHOR]

Disseminated adenovirus infection is well recognised in transplant patients and carries a high mortality. Treatment options are limited and potentially hepatotoxic and nephrotoxic. Adenovirus is one of many known triggers for haemophagocytic lymphohistiocytosis (HLH), a life-threatening hyper-inflammatory response. We present a patient with disseminated adenovirus-driven HLH occurring 25 years after a heart-lung transplant, the longest documented in the literature.A 75-year-old man presented to the emergency department with a two week history of fever, cough and diarrhoea. Past medical history included heart-lung transplant. He was febrile and tachycardic but appeared well. Blood tests showed acute kidney injury, transaminitis and pancytopenia. Chest radiograph was unremarkable. Initial treatment was with co-amoxiclav and intravenous fluids. Computerised tomography of thorax and abdomen showed moderate splenomegaly.After 48 h, he remained febrile and hypotensive with worsening renal and hepatic function. Antibiotic therapy was broadened to meropenem and amikacin. Nasopharyngeal swabs returned positive for adenovirus PCR and subsequently, the preliminary diagnosis was adenovirus gastroenteritis with hypovolaemia. Blood cultures were negative with undetectable cytomegalovirus and Epstein-Barr Virus DNA in blood samples.On day 4 he developed fulminant multi-organ failure. HLH was suspected, given bone marrow and splenic involvement with laboratory investigations showing hyperferritinemia, hypertriglyceridemia and haemophagocytosis on bone marrow biopsy. Cidofovir/Brincidofovir were discussed as potential treatments but were difficult to obtain with concern regarding toxicity. Intravenous immunoglobulins were commenced for HLH on day 6. Adenovirus was later detected by PCR in urine, stool and blood samples. He continued to deteriorate and died on day 8.This case highlights the importance of considering a broad range of infectious aetiologies in all transplant recipients, even those on stable immune suppression. Immune senescence in an increasingly older transplant population may represent an additional risk factor to consider. Early diagnosis is crucial in such cases.

Introduction: Haemophagocytic Lymphohistiocytosis (HLH) is a rapidly progressive life threatening condition in which activated macrophages engulf haematopoietic cells. HLH is often overlooked because of its rarity and lack of awareness of this prevailing condition. Though previously attempts have been made to quantify hemophagocytes in marrow aspirates, to the best of present knowledge, none of the studies have correlated the number of hemophagocytes with the clinical outcomes of the patients. Aim: To study the role of laboratory parameters and number of hemophagocytes detected in bone marrow aspirates in determining the clinical outcome of the patients. Materials and Methods: This was a prospective observational study conducted in Apollo Hospitals, Chennai between November 2013 to November 2015 on 41 patients who had hemophagocytosis in bone marrow aspirates. The laboratory parameters and clinical findings of these patients were obtained and were correlated with the outcome of these patients. The role of quantification of hemophagocytes in determining the outcome of the patients was also studied. The continuous variables were expressed either as mean±SD or median, as appropriate. All the categorical variables were expressed either as percentage or proportions. P-value was derived using Chisquare test or Fischer’s exact test and value of

X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.

The difficulties and challenges of applying the HLH-2004 diagnostic criteria to early identification and diagnosis of haemophagocytic lymphohistiocytosis have been fully addressed in previous studies. However, the distribution of the diagnostic time lag of haemophagocytic lymphohistiocytosis and related patient characteristics remain unclear. This study investigated the time lags between symptom onset and diagnosis and between hospital admission and diagnosis among pediatric patients with haemophagocytic lymphohistiocytosis, and identified factors that associated with a shorter or longer diagnostic time lag. The cohort of patients with haemophagocytic lymphohistiocytosis was drawn from a tertiary children's hospital and consisted of 122 pediatric patients. The distributions of symptom-to-diagnosis and admission-to-diagnosis time lags were assessed. Clinical characteristics within 48 h of admission and the fulfillment of HLH-2004 diagnostic criteria were compared among admission-to-diagnosis time lag categories. Logistic regression analyses were conducted to identify factors associated with an admission-to-diagnosis time lag >3 days. The median interval from first symptom onset to HLH diagnosis was 12 days (range 4–71 days) and the median interval from hospital admission to HLH diagnosis was 2 days (range 0–23 days). The following factors were negatively associated with admission-to-diagnosis > 3 days: Epstein–Barr virus infection; admission through pediatric intensive care unit; diagnosis established without NK-cell activity and soluble CD25 tests; the performance of all readily available diagnostic tests for HLH (within 48 and 72 h); concurrent fever, splenomegaly, and cytopenias within 48 h; hemophagocytosis, hypertriglyceridemia and/or hypofibrinogenemia within 48 h; and elevated ferritin, total bilirubin, alanine aminotransferase, and prothrombin time within 48 h. Our findings suggest that performance of adequate diagnostic tests for HLH is essential for early diagnosis of HLH. Once suspected, immediate and adequate diagnostic tests for HLH should be arranged for PICU patients. Improvements in diagnostic procedures and monitoring plans are needed to promote early diagnosis of HLH.

Objectives To carry out a review of clinical characteristics, laboratory profiles, management and outcomes of patients with Kawasaki disease (KD) and macrophage activation syndrome (MAS). Methods Medical records of patients treated for KD and MAS between January 1994 and December 2019 were reviewed. Patient demographics, clinical signs, laboratory values, coronary artery abnormalities, treatments and outcomes of patients with KD and MAS were recorded. We also performed a review published studies on the subject. Results Of the 950 cases with KD, 12 (1.3%; 10 boys, 2 girls) were diagnosed with MAS. The median age at diagnosis was 4 years (range 9 months–7.5 years). The median interval between onset of fever and diagnosis of KD was 11 days (range 6–30). Thrombocytopenia was seen in 11 patients. The median pro-brain natriuretic peptide value was 2101 pg/ml (range 164–75 911). Coronary artery abnormalities were seen in 5 (41.7%) patients; 2 had dilatation of the left main coronary artery (LMCA), 1 had dilatation of both the LMCA and right coronary artery (RCA), 1 had dilatation of the RCA and 1 had bright coronary arteries. All patients received IVIG as first-line therapy for KD. MAS was treated with i.v. methylprednisolone pulses followed by tapering doses of oral prednisolone. Additional therapy included i.v. infliximab (n  = 4), second-dose IVIG (n  = 1) and oral ciclosporin (n  = 1). Conclusion MAS is an unusual and underrecognized complication of KD. In our cohort of 950 patients with KD, 1.3% had developed MAS. KD with MAS is associated with an increased propensity towards development of coronary artery abnormalities. [ABSTRACT FROM AUTHOR]

Discussion We report a patient with KS who had multiple, fatal complications of anti-PD-1 therapy that presented as lichenoid dermatitis progressing to severe SJS/TEN-like eruption, with concurrent HLH. Cutaneous reactions are the most common irAE, occurring in 17-40% of patients receiving PD-1/programmed death-ligand 1 (PD-L1) inhibitors;4 although rare, fatal cases of TEN from nivolumab have been reported.5,6 PD-1/PD-L interactions are important for maintenance of peripheral tolerance. Keywords: KSHV/HHV8; Kaposi sarcoma; immunotherapy; haemophagocytic lymphohistiocytosis; PD-1; late effects of therapy EN KSHV/HHV8 Kaposi sarcoma immunotherapy haemophagocytic lymphohistiocytosis PD-1 late effects of therapy e44 e47 4 06/18/21 20210615 NES 210615 Anti-programmed cell death 1 (PD-1) therapy is increasingly considered for therapy of refractory Kaposi sarcoma (KS), a human herpesvirus-8 (HHV-8)-associated neoplasm. [Extracted from the article]

Objective The objective of this study was to analyse the features, therapeutic approaches, and outcomes for adult patients with haemophagocytic lymphohistiocytosis (HLH) at a single centre. Methods This study was a retrospective chart review of all patients >18 years of age diagnosed with HLH according to HLH-2004 or H-score criteria at Ochsner Medical Center-New Orleans between 2013 and 2019. Results A total of 29 patients with HLH met inclusion criteria. A total of 7 patients had an underlying malignancy, 12 had an autoimmune disease, 2 were transplant patients, and 2 had a combination of malignancy, autoimmune disease, or immunodeficiency. A total of 6 patients developed HLH precipitated by infection alone. All 29 patients presented with fever. A total of 28 (97%) patients met H-score criteria, and only 20 (67%) met HLH-2004 criteria. Fifteen patients were treated with the HLH-2004 protocol. Of those treated with the HLH-2004 protocol, 73% (11/15) died, 8% (1/15) had recurrence of HLH, and 20% (3/15) had resolution of HLH. A total of 14 patients were treated with targeted therapy. Of those treated with targeted therapy, 93% (13/14) had resolution of HLH and 1 died. Targeted therapy included pulse steroids, tocilizumab, anakinra, IVIG, CSA, rituximab, and/or CYC in addition to antiviral or antibiotic therapy. Conclusion Our findings suggested that the rheumatologic patient population responded well to a targeted therapeutic approach and poorly to the HLH-2004 protocol. Whether the poor outcomes found with the use of the HLH-2004 protocol are secondary to the protocol itself or the aggressive nature of malignancy-associated HLH is unclear. Further studies are needed to develop tailored therapeutic regimens. [ABSTRACT FROM AUTHOR]

Summary: We performed a multicentre, non‐randomised trial (NCT03533790) to investigate the efficacy of ruxolitinib combined with the doxorubicin‐etoposide‐methylprednisolone (Ru‐DEP) regimen as a salvage therapy for refractory/relapsed haemophagocytic lymphohistiocytosis (HLH). All patients failing to achieve a complete or partial response 2 weeks after initial HLH‐94/HLH‐04 regimen or relapsed after remission were enrolled in the study between June 2018 and June 2019. The efficacy was evaluated 2 weeks after initiating Ru‐DEP salvage therapy. Fifty‐four eligible patients with refractory/relapsed (R/R) HLH were enrolled. One case could not be evaluated for efficacy. Excluding 12 patients who had previously received the DEP regimen, the overall response rate was 32 of 41 (78·0%) patients, with eight of 41 (19·5%) achieving complete response and 24 of 41 (58·5%) attaining a partial response. Of the R/R HLH patients who had previously received the DEP regimen, 7 of 12 (58·3%) achieved a partial response. Ferritin and soluble CD25 concentrations were significantly lower (P < 0·05), while the platelet count increased significantly (P = 0·034), and triglycerides decreased significantly (P = 0·002) compared with those before treatment. The Ru‐DEP regimen may be a safe and effective salvage therapy, remaining effective in refractory/relapsed HLH following DEP treatment, especially in macrophage activation syndrome. In addition, the regimen can be considered for patients with contraindications to glucocorticoid, especially those with gastrointestinal bleeding. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy is increasingly used in the management of early and advanced malignancy. There is limited data regarding the associations between immunotherapy, malignancy, pain and haemophagocytic lymphohistiocytosis. Case: A 40-year-old woman was diagnosed with advanced melanoma, with metastases to her brain, liver, lung, adrenal glands and bone. She had moderate opioid requirements prior to the initiation of therapy. Following doublet immunotherapy with nivolumab and ipilimumab, she experienced a severe pain crisis associated with pyrexia and haemophagocytic lymphohistiocytosis. Possible courses of action: Management dilemmas included whether or not to initiate non-steroidal and steroidal anti-inflammatory therapies, how to address the patient's nociceptive, neuropathic and inflammatory pain, and how to manage the haemophagocytic lymphohistiocytosis. Formulation of management plan: The patient required rapid up-titration of analgesia, including methadone, ketamine, hydromorphone, pregabalin and benzodiazepines. Ketorolac and high dose steroid therapy were administered for pain management and to mitigate treatment associated inflammation and haemophagocytic lymphohistiocytosis. Outcome: The patient's pain was inadequately managed despite multimodal analgesia, and stigmata of inflammation progressed. She died 14 days following treatment. Lessons: The case demonstrates that severe pain may be a consequence of immunotherapy given for advanced, high volume melanoma. Research avenues: There is laboratory evidence suggesting an association between immunotherapy, malignancy, pain and haemophagocytic lymphohistiocytosis. Further clinical evidence is required in order to understand these intersecting phenomena. [ABSTRACT FROM AUTHOR]

Corona Virus Disease of 2019 (COVID-19) is spreading throughout the world and the United States with confirmed cases in all 50 states. Cytokine Release Syndrome (CRS), or cytokine storm, is being increasingly reported with severe cases of COVID-19 patients and is a common cause of death in these patients. Hereby, authors report a case of critically ill COVID-19 patient who developed cytokine storm. She had a remarkable increase in inflammatory markers and went into multiorgan failure and death in less than 48 hours. Among inflammatory markers, ferritin has a high sensitivity for CRS. This case report sheds light on the importance of following the level of inflammatory markers (especially ferritin) closely in COVID-19 patients. The goal is to diagnose CRS before the patient goes into a full cytokine storm and multiorgan failure, as it may be too late to react then. Even when the patient is clinically stable, a high ferritin level could be the calm before the storm.

MAS, which is currently grouped under secondary or acquired haemophagocytic lymphohistiocytosis (sHLH), is a rare and fatal disorder that results from excess activation of T-cells and macrophages. Though the pathogenesis of MAS is poorly understood, various proinflammatory cytokines like interleukins (IL-1, IL-6), tumor necrosis factor α (TNF α), interferons are thought to play significant roles. MAS is associated with various clinical features such as non-remitting fever, bleeding, cytopenias, splenomegaly, hepatic dysfunctions, increased levels of triglyceride, ferritin and decreased levels of albumin and fibrinogen. Early diagnosis and interventions are crucial to reduce mortality risk but diagnosis is not often easy due to persistence of wide range of features that overlap with other rheumatic diseases, most commonly sJIA (systemic juvenile idiopathic arthritis). Corticosteroids and cyclosporins are commonly used for MAS treatment. Intravenous immunoglobulins, biologic agents like IL-1 blockers (anakinra, canakinumab), IL-6 blockers (tocilizumab) are also frequently used. Moreover there is still the need of genetic and immunohistological study in order to understand the exact mechanism of the syndrome development and establishment of novel therapies with lesser toxicities.

Abstract Background Haemophagocytic lymphohistiocytosis is a life-threatening disease resulting from primary or secondary hyper-inflammatory disorders. The typical symptoms include persistent fever, splenomegaly, cytopenia and significant elevation of serum ferritin. Case presentation We report a 30-year-old Chinese female patient who was diagnosed with chronic active Epstein-Barr virus infection more than 9 months prior and has since been presenting with cutaneous lymphoproliferative disorders mimicking hydroa vacciniforme and subsequent haemophagocytic lymphohistiocytosis. Exome sequencing suggested novel digenic heterozygous STXBP2 (c.592A > C, p.Thr198Pro) and LYST (c.830A > T, p.His277Leu) mutations. Conclusions This is the first case report in which adult HLH was associated with novel digenic mutations of STXBP2 and LYST combined with Epstein-Barr virus infection. It could also be the first polygenic model report, given that the pathogenicity of other mutated genes still remains unclear. We additionally conducted an in-depth, two-generation pedigree analysis to further illustrate the mode of inheritance in this case.

ABSTRACT Congenital cytomegalovirus infection causes lethal diseases with neurological, visual, auditory and systemic injuries, including the hemophagocytic syndrome. Hemophagocytic lymphohistiocytosis (HLH) can be caused by primary hereditary immunological defects, as well as several infectious triggering factors, such as viruses, bacteria and fungus, among them the cytomegalovirus (CMV). Here we present the case report of a male newborn male, delivered by cesarean at term (gestation age of 39 weeks), weighing 3,250 g, with suffusion skin lesions spread throughout the body, anemia, generalized edema, hepatosplenomegaly, thrombocytopenia associated with grunts and difficulty breathing, treated with ganciclovir after receiving the diagnosis of congenital CMV infection. After a few days of hospitalization, the patient presented with high fever, persistent hepatosplenomegaly and pancytopenia, in addition to elevated ferritin and triglycerides, receiving the diagnosis of HLH treated with immunosuppressive therapy, corticosteroids and intravenous human immunoglobulin. The present case report highlights the importance for health professionals to carry out the investigation of congenital diseases, especially in developing countries, as well as their complications, such as HLH.

Aims: Haemophagocytosis in the bone marrow of patients who have succumbed to coronavirus disease 19 (COVID‐19) has not been widely studied. The aims of the present study were to perform morphological analyses and morphometry of haemophagocytosis in the bone marrow of patients with severe COVID‐19, and to correlate the findings with the clinical course of the disease. Methods and results: In this single‐centre study performed at the University Hospital Jena, bone marrow specimens of 15 deceased patients who had experienced a severe course of COVID‐19 were sampled from the vertebral column during autopsy. Slides of the bone marrow were stained with routine stains or immunohistochemically, and further examined for haemophagocytosis by the use of light microscopy. To substantiate the morphological findings, additional slides were stained for CD163 and morphometry was performed. In all bone marrow samples, an increase in cellularity was found. Haemophagocytes with erythrophagocytosis were detected in 67% of the deceased patients. In tissues with low numbers of haemophagocytes or ill‐defined haemophagocytes, an increase in iron deposits was frequently seen. Morphological findings were then correlated with several important clinical data, and the HScore (probability of having a reactive hemophagocytic syndrome) was calculated to posthumously confirm the diagnosis of secondary haemophagocytic lymphohistiocytosis. The median duration of disease and the hospitalisation time were lower in patients with haemophagocytosis (n = 10) than in patients without haemophagocytosis (n = 5). In addition, patients with haemophagocytes showed increased inflammatory parameters 2–5 days prior to death, in contrast to patients without haemophagocytes. Conclusions: Haemophagocytosis is a common finding in the bone marrow of deceased individuals with severe COVID‐19, and may indicate fatal severe acute respiratory syndrome coronavirus 2 infections. [ABSTRACT FROM AUTHOR]

Introduction: Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder with high mortality. The aim of this review is to update clinical management of relapsed/refractory HLH in adults, with a focus on current and new therapies.Methods: We searched relevant articles in Embase and PUBMED with the MESH term "hemophagocytic lymphohistiocytosis; refractory; relapsing; adult."Results: One hundred eight papers were found; of these, 22 were retained for this review. The treatment of HLH in adult is based on the HLH-94 regimen. The response rate is lower than in pediatric patients, and 20-30% are refractory to this therapy. DEP regimen and allogenic hematopoietic stem cell transplantation (HSCT) are associated with complete response and partial response in 27% and 49.2%, respectively. However, many patients fail to achieve a stable condition before HSCT, and mortality is higher in them. New drugs have been developed, such as emapalumab, ruxolitinib, and alemtuzumab, and they may be used as bridges to the curative HSCT. They are relatively well tolerated and have few or mild side effects. With these agents, the rate of partial response ranges from 14.2% to 100%, while the rate of complete response is highly variable according to study and medication used. The number of patients who achieved HSCT ranged from 44.8% to 77%, with a survival rate of 55.9% to 100%. However, the populations in these studies are mainly composed of mixed-age patients (pediatric and adult patients), and studies including only adult patients are scarce.Conclusion: Relapsed or refractory HLH in adult patients is associated with poor outcome, and consolidation with HSCT may be required in some cases. Mortality related to HSCT is mainly due to active HLH disease before HSCT and post HSCT complications. New drugs, such as empalumab, ruxolitinib, and alemtuzumab are interesting since these agents may be used as bridges to HSCT with increases in the numbers of patients proceeding to HSCT and survival rate. [ABSTRACT FROM AUTHOR]

The authors present the case of a 58-year-old man with the unique combination of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and, later on, haemophagocytic lymphohistiocytosis admitted to the intensive care unit. During his ICU stay the patient developed a variety of complications including acute respiratory distress syndrome, pulmonary embolism, right heart failure and suspected HLH leading to multiorgan failure and death. Despite the proven diagnosis of haemophagocytic lymphohistiocytosis, the excessively high ferritin levels of the patient did not seem fully explained by this diagnosis. Therefore, the authors want to highlight different causes of hyperferritinaemia in critically ill patients and underline the importance of differential diagnoses when interpreting continuously rising ferritin levels.

Background: Haemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening syndrome characterised by hyperinflammation and macrophage activation. Viral infections such as Epstein-Barr virus (EBV) are a well-recognised trigger of HLH but the treatment of such cases is not well-defined. We present a case of primary EBV driven HLH that was successfully treated with the interleukin-1 inhibitor anakinra in addition to rituximab and high-dose steroids. Case: A 22-year-old female with no past medical history developed a mononucleosis-like illness lasting five days characterised by fevers, sore throat and neck swelling. Two weeks following this she presented with fevers, night sweats, fatigue and right upper quadrant pain. She was diagnosed with HLH based on high fevers with hyperferritaemia, hypertriglyceridaemia, pancytopaenia, abnormal liver function tests and hepatosplenomegaly. Extensive investigation revealed an EBV viral load of 23,000,000 copies/ml with nil other obvious triggers. A diagnosis of primary-driven EBV HLH was made. She was treated with the interleukin-1 inhibitor anakinra, methylprednisolone and IVIG and a single dose of rituximab.Following the commencement of treatment, the patient made a dramatic improvement. Her EBV viral load reduced to 660 within nine days and her blood counts and liver function returned to normal. She was discharged from hospital on day sixteen. She continued the anakinra for 5 weeks at a weaning dose and completed a 12-week weaning dose of steroids. She has returned to her studies and has no lasting complications from her illness. Discussion: This case highlights the potential of primary EBV infection to cause fulminant HLH. The prompt diagnosis and treatment of HLH using anakinra and rituximab in addition to conventional HLH treatment was safe, and associated with a dramatic clinical improvement. The use of anakinra has been documented in other cases of HLH but none, to our knowledge, of primary EBV-driven HLH with no underlying haematological or rheumatological condition.

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Congenital cytomegalovirus infection causes lethal diseases with neurological, visual, auditory and systemic injuries, including the hemophagocytic syndrome. Hemophagocytic lymphohistiocytosis (HLH) can be caused by primary hereditary immunological defects, as well as several infectious triggering factors, such as viruses, bacteria and fungus, among them the cytomegalovirus (CMV). Here we present the case report of a male newborn male, delivered by cesarean at term (gestation age of 39 weeks), weighing 3,250 g, with suffusion skin lesions spread throughout the body, anemia, generalized edema, hepatosplenomegaly, thrombocytopenia associated with grunts and difficulty breathing, treated with ganciclovir after receiving the diagnosis of congenital CMV infection. After a few days of hospitalization, the patient presented with high fever, persistent hepatosplenomegaly and pancytopenia, in addition to elevated ferritin and triglycerides, receiving the diagnosis of HLH treated with immunosuppressive therapy, corticosteroids and intravenous human immunoglobulin. The present case report highlights the importance for health professionals to carry out the investigation of congenital diseases, especially in developing countries, as well as their complications, such as HLH. [ABSTRACT FROM AUTHOR]

Background: 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., Case Description: 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., Conclusions: 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., Learning Points: 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., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Summary: Epstein–Barr virus‐associated haemophagocytic lymphohistiocytosis (EBV‐HLH) is one of the most common subtypes of secondary HLH. However, more than 30% of patients do not respond to traditional treatment. Here, we investigated the efficacy and safety of the L‐DEP regimen as a salvage therapy for paediatric refractory EBV‐HLH. We retrospectively analysed 26 paediatric patients with refractory EBV‐HLH who received the L‐DEP regimen at Beijing Children's Hospital from 1 January 2016 to 31 March 2019. Five of the patients achieved complete response (CR) and 11 achieved partial response (PR), indicating an overall response rate of 61·5% (CR + PR). Ten of the 16 patients who achieved CR or PR received allogenic haematopoietic stem cell transplantation (allo‐HSCT), and seven were still alive at the last follow‐up on 30 April 2020. Two of the 10 patients who did not respond were alive after allo‐HSCT. Major side effects included increased amylase, bone marrow suppression and coagulation disorders, though these could be controlled by supportive therapy in most cases. Thus, we conclude that the L‐DEP regimen is an effective and relatively safe salvage therapy for children with refractory EBV‐HLH. This regimen also provides a bridge to allo‐HSCT. [ABSTRACT FROM AUTHOR]

Background. Haemophagocytic lymphohistiocytosis (HLH) is a potentially life-threatening syndrome if not recognised and managed early. It involves an uncontrolled pathological activation of the immune system, and it is either genetic or acquired. It presents with clinical and laboratory features of severe inflammation. Early initiation of effective therapy may reduce mortality from 95% to 35%. Objective. To raise awareness of HLH among healthcare professionals, particularly intensivists. Methods. We report nine cases of secondary HLH seen at tertiary hospitals in Bloemfontein, South Africa. Results. All patients presented with fever, hypertriglyceridaemia, hyperferritinaemia, transaminitis and cytopenia. Haemophagocytosis was noted on bone marrow biopsy in 66.7% (n=6/9) of the patients. More than one-third (44.4%; n=4/9) of the cases were triggered by a lymphoma, 44% (n=4/9) were associated with infection and 11% (n=1/9) were associated HIV. Finally, 11.1% (n=1) of the patients were triggered by an underlying autoimmune disease. More than half (55.6%; n=5/9) of the cases had a fatal outcome. Conclusion. A high index of suspicion may promote the accurate diagnosis of HLH in patients presenting with fever, transaminitis and unexplained cytopenia. [ABSTRACT FROM AUTHOR]

Background: Dengue fever is an arthropod-borne flavivirus infection that is highly prevalent in the tropics. A proportion of clinical cases develop severe dengue, defined by life-threatening complications including haemorrhage, capillary leak and multi-organ failure. Recently there has been increasing recognition that some cases of severe dengue may be a consequence of HLH. To our knowledge, this is the first report of treatment with Anakinra for dengue-induced HLH. Case report: We report a case of Dengue fever triggering HLH in an eighteen-year-old female returning traveller from India, diagnosed with systemic lupus erythematosus (SLE) two months prior to presentation. The patient initially presented to a district general hospital emergency department (ED) with a three-day history of flu-like symptoms, fever, erythematous rash, widespread joint pain, nausea and chills. Acute Dengue virus infection was confirmed with serum polymerase chain reaction (PCR) testing. On day two, she was admitted to intensive care for multi-organ support necessitated by refractory hypotension, oligo-anuric severe acute kidney injury (AKI), acute liver failure with lactataemia and type one respiratory failure.The possibility of Dengue-induced HLH was considered early with multiple criteria for diagnosis met including hyperferritinaemia, pancytopenia, lipaemia and a marked transaminitis. HLH-directed therapy was commenced with intravenous immunoglobulins (IVIG), intravenous methylprednisolone (IVMP) and Anakinra. Subsequent bone marrow biopsy analysis demonstrated clear evidence of HLH, in the context of a persistent and marked Dengue viraemia. We observed resolution of HLH markers as well as reducing requirements for multi-organ support after initiation of Anakinra therapy.During her recovery, the patient unexpectedly developed focal neurology; intracranial imaging demonstrated widespread, discreet parenchymal lesions thought to be haemorrhagic in nature, which were deemed too severe an insult to recover from. On day 19, the difficult decision of withdrawing care after deep discussion with the family was reached, soon after which the patient passed away. A post-mortem examination was not arranged.

Background: Syndromes of iron overload have been shown to increase the risk of severe clinical disease in viral infections. Immune dysfunction is similarly described in hereditary haemochromatosis (HH). We present here the case of a 51-year-old man who developed severe coronavirus disease 2019 (COVID-19) complicated by suspected haemophagocytic lymphohistiocytosis (HLH). He was found to have HH post-mortem and we propose a link between his iron overload and the development of severe COVID-19. Case report: The initial clinical presentation consisted of cough, shortness of breath and fever. Pancytopenia, markedly elevated ferritin and d-dimer were present. Computed tomography (CT) showed bilateral ground glass changes consistent with COVID-19, widespread lymphadenopathy and splenomegaly. A subsequent combined nose and throat swab was positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). HLH was suspected based upon the H-score and Anakinra, an IL-1 receptor antagonist, was commenced. Liver function acutely worsened and magnetic resonance cholangiopancreatography (MRCP) revealed hepatic haemosiderosis. Intense splenic and cervical lymph node uptake were seen on a positron emission tomography (PET) scan and high doses of intravenous steroids were administered due to concerns over haematological malignancy. Results: Day fourteen of admission heralded the start of progressive clinical deterioration with rapid increase in oxygen demands. Continuous positive airway pressure (CPAP) was trialled without success and the patient unfortunately died seventeen days into admission. Results returned after his death showed homozygous C282Y mutation of the HFE gene consistent with a diagnosis of HH. Post-mortem examination revealed widespread haemosiderin deposition in the liver along with lung pathology in keeping with severe COVID-19 and widespread splenic infarctions. Conclusion: An association between HH and COVID-19 is not currently described in the literature. What does exist, however, is an evidence base for the detrimental impacts iron overload has on viral infections in general and the negative effects of HH on the immune system. We therefore postulate that the underlying metabolic and immune disturbances seen in HH should be considered a potential risk factor for the development of severe COVID-19. This case also adds to the evidence that hyperinflammation appears to be a unique and interesting characteristic of this novel viral disease.

Introduction: Haemophagocytic Lymphohistiocytosis (HLH), during HIV infection is a rare complication with a poor prognosis. There are few data on HLH within the Amazon region. The objective was to describe epidemiological, clinical and therapeutic features of HIV-related HLH in French Guiana.Methods: A retrospective analysis of adult HIV patients at Cayenne hospital with HLH between 2012 and 2015. A diagnosis of HLH was given if the patient presented at least 3 of 8 criteria of the HLH-2004 classification.Results: Fourteen cases of HLH were tallied during the study period. The mean age was 46 years with a sex ratio of 1.8. The most frequent etiology of HLH was an associated infection (12/14). Confirmed disseminated histoplasmosis, was found in 10 of 14 cases, and it was suspected in 2 other cases. The CD4 count was below 200/mm3 in 13/14 cases. An HIV viral load >100,000 copies/ml was observed in 13/14 cases. An early treatment with liposomal amphotericin B was initiated in 12/14 cases. The outcome was favorable in 12/14 of all cases and in 10/12 cases involving histoplasmosis. Case fatality was 2/14 among all cases (14.3%) et 1/10 among confirmed disseminated histoplasmosis with HLH (10%). During the study period 1 in 5 cases of known HIV-associated disseminated histoplasmosis in French Guiana was HLH.Conclusion: Histoplasmosis was the most frequent etiology associated with HLH in HIV-infected patients in French Guiana. The prognosis of HLH remains severe. However, a probabilistic empirical first line treatment with liposomal amphotericin B seemed to have a favorable impact on patient survival.

A 44-year-old woman with no significant medical history presented with a 3-week history of high-grade fevers, fatigue and shortness of breath. Laboratory investigation was significant for lymphopenia and thrombocytopenia which progressively worsened during her hospital stay, along with new-onset anaemia, and elevated ferritin, transaminase and triglycerides. A computerized tomography (CT) scan of the abdomen revealed retroperitoneal lymphadenopathy. A bone marrow biopsy confirmed the diagnosis of haemophagocytic lymphohistiocytosis (HLH). Extensive infectious work-up revealed high IgG titres for Bartonella henselae and Coxiella burnetii. Interestingly, the left supraclavicular node was negative for both microbes by polymerase chain reaction (PCR), but the biopsy revealed anaplastic large T-cell lymphoma.

The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the “hyperferritinemic syndrome” category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies.

Abstract Background Haemophagocytic lymphohistiocytosis (HLH) is considered to be a large challenge for clinicians due to the variable overlaps of symptoms with other severe diseases and a high rate of mortality. Prompt diagnosis and treatment are crucial to avoid a fatal outcome. However, very limited reports have focused on HLH during chemotherapy (Ch-HLH) due to a low incidence and insufficient knowledge. Case presentation A 22-year-old male was diagnosed with acute monocytic leukemia with FLT3-ITD and DNMT3A mutations and pulmonary infection. He received IA regimen (Idarubicin, 8 mg/m2/d for 3 days and cytarabine, 100 mg/m2/d for 7 days) chemotherapy, anti-infection drugs and blood components transfusions. During the stage of bone marrow suppression, he presented with a fever, cytopenia (WBC, 0.43 × 109/L; Hb, 73 g/L and PLT, 1 × 109/L), refractory coagulation dysfunction (APTT, 104.0 s; PT, 30.5 s and Fbg, 0.87 g/L), splenomegaly (3 cm below the costal margin), hyperferritinemia (SF > 3000 μg/L), increased soluble interleukin-II receptors (sIL-2R > 7500 u/mL) and haemophagocytosis in the bone marrow and was diagnosed with HLH. After he was treated with methylprednisolone at 500 mg/d for 3 days, 120 mg/d for 3 days and 80 mg/d for 3 days, followed by a gradually reduced dose combined with powerful anti-infection drugs, his symptoms subsided and his abnormal parameters recovered to normal levels. Conclusion Patients with HLH in acute leukemia have a high rate of mortality. This case report provides helpful clinical experiences relative to the recognition and treatment of Ch-HLH for clinicians.

Introduction: Haemophagocytic Lymphohistiocytosis (HLH), during HIV infection is a rare complication with a poor prognosis. There are few data on HLH within the Amazon region. The objective was to describe epidemiological, clinical and therapeutic features of HIV-related HLH in French Guiana. Methods: A retrospective analysis of adult HIV patients at Cayenne hospital with HLH between 2012 and 2015. A diagnosis of HLH was given if the patient presented at least 3 of 8 criteria of the HLH-2004 classification. Results: Fourteen cases of HLH were tallied during the study period. The mean age was 46 years with a sex ratio of 1.8. The most frequent etiology of HLH was an associated infection (12/14). Confirmed disseminated histoplasmosis, was found in 10 of 14 cases, and it was suspected in 2 other cases. The CD4 count was below 200/mm3 in 13/14 cases. An HIV viral load >100,000 copies/ml was observed in 13/14 cases. An early treatment with liposomal amphotericin B was initiated in 12/14 cases. The outcome was favorable in 12/14 of all cases and in 10/12 cases involving histoplasmosis. Case fatality was 2/14 among all cases (14.3%) et 1/10 among confirmed disseminated histoplasmosis with HLH (10%). During the study period 1 in 5 cases of known HIV-associated disseminated histoplasmosis in French Guiana was HLH. Conclusion: Histoplasmosis was the most frequent etiology associated with HLH in HIV-infected patients in French Guiana. The prognosis of HLH remains severe. However, a probabilistic empirical first line treatment with liposomal amphotericin B seemed to have a favorable impact on patient survival. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE)-associated haemophagocytic lymphohistiocytosis (HLH) is called acute lupus haemophagocytic syndrome (ALHS), which is relatively rare but life-threatening. We present the case of a 43-year-old woman diagnosed with SLE with panniculitis, pleuritis, and autoimmune hepatitis. She was treated with high-dose glucocorticoids. Although disease activity temporarily improved, she developed fever, elevation of liver enzymes, hyperferritinemia, severe inflammatory response, and thrombocytopenia a month after starting glucocorticoids. Bone marrow biopsy was performed and haemophagocytosis was observed. She was diagnosed with ALHS on day 49. Since she developed ALHS during administration of glucocorticoids, her ALHS was determined to be refractory to glucocorticoid monotherapy; therefore, additional immunosuppressive agents were needed. She was treated with methylprednisolone pulse, plasma exchange and cyclosporine A (CyA). However, CyA was discontinued on day 54 because CyA-induced hypertensive encephalopathy was suspected. Subsequently, rituximab (RTX) was introduced to treat refractory ALHS on day 56; the disease activity subsequently reduced. After four courses of RTX, her ferritin levels and platelet counts were within the normal range and the glucocorticoid dose could be tapered to betamethasone 2.0 mg/day on day 132. No subsequent recurrence of SLE and ALHS was observed until day 132. RTX might therefore be an effective therapeutic option for refractory ALHS. [ABSTRACT FROM AUTHOR]

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening medical condition characterized by hyperphagocytosis secondary to an inappropriate over-activation of macrophages and lymphocytes that driven by excessive cytokines production which resulted in cellular destructions. Dengue induced hemophagocytic lymphohistiocytosis (HLH) is a serious condition and may prove fatal if not detected early and treated appropriately. Diagnosis of HLH is challenging and usually missed as clinical and laboratory findings are nonspecific. It should be suspected with prolonged fever beyond seven days associated with splenomegaly, hyperferritinemia, worsening cytopenias and development of multiorgan dysfunction. A proportion of patients recovered with supportive therapy, however most required interventions with corticosteroids, intravenous immunoglobulin or chemotherapy. We report 3 cases of dengue associated HLH. Among them 2 patients were treated with steroid with good outcome, and one died from MODS. [ABSTRACT FROM AUTHOR]

Objectives Anakinra is a selective IL-1 inhibitor, which has been used in the context of secondary haemophagocytic lymphohistiocytosis. Although usually given in the s.c. form, previous anecdotal reports have emphasized its utility when given i.v. Our aim is to report our experience on the beneficial effects of anakinra i.v. in patients with SARS-CoV-2 and evidence of hyperinflammation. Methods We report four patients with severe COVID-19 infection requiring intensive care admission and ventilatory support. Results All four patients showed evidence of deterioration, with hyperferritinaemia and increasing oxygen requirements and with superadded bacterial infections. Upon commencement of anakinra i.v. there was subsequent improvement in the patients clinically, with reduction in ventilatory support and inotropic support, and biochemically, with rapid improvement in inflammatory markers. Conclusion Anakinra is safe to use i.v. in patients with COVID-19 and evidence of superadded bacterial infection. Although its utility has not been confirmed in a randomized trial, current research in the COVID-19 pandemic aims to establish the utility of immunosuppression, including IL-1 blockade, on the outcomes of patients with moderate to severe disease. Our case series supports its use in patients with severe, life-threatening COVID-19 and evidence of hyperinflammation. [ABSTRACT FROM AUTHOR]

Background Haemophagocytic lymphohistiocytosis (HLH) is an uncommon but serious systemic inflammatory response with high mortality rates. It can be triggered by malignancy or infectious agents, often in the context of immunosuppression. Literature covering HLH in heart transplantation (HTx) is scarce. Case summary A 25-year-old male with a history of celiac disease underwent HTx at Sahlgrenska Hospital in 2011 due to giant cell myocarditis and was treated with tacrolimus, mycophenolate mofetil (MMF), and prednisolone. He developed several episodes of acute cellular rejections (ACR) during the first 3 post-HTx years, which subsided after addition of everolimus. In May 2017, the patient was admitted to the hospital due to fever without focal symptoms. He had an extensive inflammatory reaction, but screening for infectious agents was negative. Haemophagocytic lymphohistiocytosis was discussed early, but first dismissed since two bone marrow biopsies revealed no signs of haemophagocytosis. Increasing levels of soluble IL-2 were considered confirmative of the diagnosis. Even with intense immunosuppressant treatment, the patient deteriorated and died in progressive multiorgan failure within 2 weeks of the symptom onset. Discussion A 25-year-old HTx recipient with an extensive inflammatory response, fulfilled criteria for HLH, but the diagnosis was delayed due to normal bone marrow biopsies. A background with autoimmune reactivity and immunosuppressive therapy may have contributed to HLH, but the actual trigger was not identified. Haemophagocytic lymphohistiocytosis can occur in HTx recipients in the absence of malignancy, identifiable infectious triggers and signs of haemophagocytosis. Early diagnosis and intervention are likely to be of importance for a favourable outcome. [ABSTRACT FROM AUTHOR]

Keywords: tumour immunotherapy; haemophagocytic lymphohistiocytosis; haematotoxicity EN tumour immunotherapy haemophagocytic lymphohistiocytosis haematotoxicity 985 992 8 06/08/20 20200601 NES 200601 Immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies, have proven effectiveness in treating many cancers; thus, their field of action is rapidly expanding.[1] These immunotherapies enhance T cell activity, which can lead to immune-related adverse events (irAEs) in 70-90% of patients, according to the ICI used.[2] Haemophagocytic lymphohistiocytosis (HLH) is a rare and severe condition characterised by T cell hyperactivation that can be measured by soluble IL-2r (CD25).[3] It may be of primary or secondary origin, due mainly to infections, cancers or autoimmune disorders. We confirm that HLH is a rare complication of ICI, as only one case was identified among the 745 patients included in one of the three pharmacovigilance databases, the French Reisamic prospective registry enrolling patients treated with anti-PD-1 or anti-PD-L1 at a single center between 2014 and 2019. Treatment with immune checkpoint inhibitors is an emerging cause of HLH, but it should be borne in mind that cancer patients may have other associated causes of HLH, such as an infectious disease or progression of cancer itself. [Extracted from the article]

The coronavirus disease 2019 (COVID-19), an acute respiratory disease caused by severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), has been declared as a worldwide public health emergency. Interestingly, severe COVID-19 is characterized by fever, hyperferritinemia, and a hyper-inflammatory process with a massive release of pro-inflammatory cytokines, which may be responsible for the high rate of mortality. These findings may advocate for a similarity between severe COVID-19 and some challenging rheumatic diseases, such as adult onset Still's disease, secondary hemophagocytic lymphohistiocytosis, and catastrophic anti-phospholipid syndrome, which have been included in the "hyperferritinemic syndrome" category. Furthermore, as performed in these hyper-inflammatory states, severe COVID-19 may benefit from immunomodulatory therapies. [ABSTRACT FROM AUTHOR]

Summary: Lymphoma‐associated haemophagocytic lymphohistiocytosis (L‐HLH) is characterized by excessively activated macrophages and cytotoxic T lymphocytes, but few reliable markers for activated macrophages are available clinically. This study, designed to discover novel biomarkers for the diagnosis of lymphoma patients with L‐HLH, was initiated between 2016 and 2018. Fifty‐seven adult lymphoma patients were enrolled — 39 without HLH and 18 with HLH. The differential serum protein expression profile was first screened between lymphoma patients with and without L‐HLH by a quantitative mass spectrometric approach. Soluble V‐set and immunoglobulin domain‐containing 4 (sVSIG4), specifically expressed by macrophages, was significantly upregulated in the L‐HLH group. Subsequently, sVSIG4 concentration was confirmed by enzyme‐linked immunosorbent assay to be significantly increased in lymphoma patients with L‐HLH. When it was exploited for the diagnosis of lymphoma patients with L‐HLH, the area under a receiver operating characteristic curve was 0·98 with an optimal cut‐off point of 2195 pg/ml and the corresponding sensitivity and specificity were 94·44% and 94·87% respectively. In addition, the one‐year overall survival was significantly worse in patients with a sVSIG4 concentration above 2195 pg/ml compared with those below 2195 pg/ml (5·3% vs. 72·2%, P < 0·0001). sVSIG4 may be a surrogate marker of activated macrophages for the diagnosis of lymphoma patients with L‐HLH. [ABSTRACT FROM AUTHOR]

Objective: In the context of systemic autoimmunity, that is systemic lupus erythematosus (SLE) or adult-onset Still's disease (AOSD), secondary haemophagocytic lymphohistiocytosis (HLH; also referred to as macrophage activation syndrome (MAS) or more recently MAS-HLH) is a rare and potentially life-threatening complication. Pathophysiological hallmarks are aberrant macrophage and T cell hyperactivation and a systemic cytokine flare, which generate a sepsis-like, tissue-damaging, cytopenic phenotype. Unfortunately, for adult MAS-HLH we lack standardized treatment protocols that go beyond high-dose corticosteroids. Consequently, outcome data are scarce on steroid refractory cases. Aside from protocols based on treatment with calcineurin inhibitors, etoposide, cyclophosphamide and anti-IL-1, favourable outcomes have been reported with the use of intravenous immunoglobulin (IvIG) and plasma exchange (PE). Methods: Here we report a retrospective series of steroid refractory MAS-HLH, the associated therapeutic regimes and outcomes. Results: In this single-centre experience, 6/8 steroid refractory patients survived (median follow-up: 54.4 (interquartile range: 23.3–113.3) weeks). All were initially treated with PE, which induced partial response in 5/8 patients. Yet, all patients required escalation of immunosuppressive therapies. One case of MAS-HLH in new-onset AOSD had to be escalated to etoposide, whereas most SLE-associated MAS-HLH patients responded well to cyclophosphamide. Relapses occurred in 2/8 cases. Conclusion: Together, early use of PE is at most a supportive measure, not a promising monotherapy of adult MAS-HLH. In refractory cases, conventional cytoreductive therapies (i.e. cyclophosphamide and etoposide) constitute potent and reliable rescue approaches, whereas IvIG, anti-thymoglobulin, and biologic agents appear to be less effective. [ABSTRACT FROM AUTHOR]

La histoplasmosis diseminada (HD) es una infección fúngica oportunista en pacientes con infección por VIH gravemente inmunocomprometidos. El síndrome hemofagocítico (SHF), que puede presentarse en estos pacientes coinfectados cuando la respuesta inmunitaria está significativamente alterada, suele estar asociado a una elevada mortalidad. Describir las características epidemiológicas, clínicas, analíticas y microbiológicas, así como evaluar la presencia de SHF, en pacientes con HD-VIH. Estudio retrospectivo de serie de casos, consistente en la revisión de registros clínicos de pacientes con diagnóstico de HD e infección VIH, durante los años 2014 y 2015. El 1,3% (8/597) de los pacientes VIH presentaron HD. El 100% se hallaban en estadio C3 y el 75% (6/8) no se encontraban en terapia antirretroviral combinada (TARVc). Los dos pacientes restantes habían comenzado recientemente el tratamiento con TARVc (posible síndrome de reconstitución inmunológica). El 62,5% (5/8) cumplieron con criterios diagnósticos de SHF. Las manifestaciones clínicas más frecuentes fueron el síndrome linfoproliferativo y consuntivo, el compromiso respiratorio y la citopenia. En el 75% (6/8) de los pacientes se aisló Histoplasma en ganglios, en el 25% (2/8) en muestras hemáticas y en uno adicionalmente en tejido intestinal. La terapia antifúngica fue anfotericina B desoxicolato; no se emplearon adyuvantes. La mortalidad global fue del 50%. En nuestra serie la coinfección HD-VIH progresó en la mayoría de los casos a SHF con elevada mortalidad. El cuadro clínico puede asemejarse al de otras enfermedades sistémicas, como la tuberculosis, o presentarse simultáneamente a ellas. Con el fin de obtener un diagnóstico precoz y poder prescribir la terapia específica oportuna es importante poseer un adecuado índice de sospecha en pacientes con síndrome linfoproliferativo y consuntivo asociado a citopenia grave. Disseminated histoplasmosis (DH) is an opportunistic fungal infection in severely immunocompromised patients with HIV infection. Haemophagocytic syndrome (HFS), which can occur in these co-infected patients when the immune response is significantly altered, is often associated with high mortality. To describe the epidemiological, clinical, analytical and microbiological characteristics, along with studying the presence of HFS, in patients with DH-HIV. A retrospective study was conducted on a case series using data from the clinical records of patients diagnosed with DH and HIV infection during the years 2014 and 2015. DH was diagnosed in 8 (1.3%) of 597 HIV patients. All patients were in stage C3, and 75% (6/8) were not receiving combined antiretroviral therapy (CART). The remaining two patients had recently begun CART (possible immune reconstitution syndrome). Five (62.5%) of the 8 patients met criteria for HFS. The most frequent clinical symptoms were lymphoproliferative and consumptive syndrome, respiratory compromise, and cytopenia. Histoplasma was isolated in lymph nodes of 75% (6/8) of the patients, in blood samples in 25% (2/8), and also in intestinal tissue in one patient. The antifungal therapy was amphotericin B deoxycholate, without adjuvants. The overall mortality was 50%. In this case series, DH-HIV co-infection frequently progressed to HFS with high mortality. The clinical picture may resemble that of other systemic opportunistic infections, such as tuberculosis, or can take place simultaneously with other infections. Clinical suspicion is important in patients with severe cytopenia and lymphoproliferative and consumptive syndrome in order to establish an early diagnosis and prescribing a timely specific therapy. [ABSTRACT FROM AUTHOR]

Background: Immune checkpoint inhibitor (ICI) use in clinical practice has unravelled a spectrum of immunerelated adverse events (irAEs) due to immune system hyper-activation. ICI-related haemophagocytic lymphohistiocytosis (HLH) has been recently outlined in single case reports, raising a concern about the need of increasing our knowledge on this rare yet life threatening ICI haematological toxicity. Methods: To determine ICI-related HLH clinical, haematological, and coagulation features, its timing and outcome, concurrent irAEs and concomitant infections, we performed a retrospective observational cross-sectional study and queried VigiBase, the WHO global database of suspected adverse drug reactions (ADRs), on September 30th, 2018. We retrieved the individual case safety reports reporting HLH in association with ipilimumab, nivolumab, pembrolizumab, atezolizumab, avelumab or durvalumab, gathered in the database starting from the ICIs' approval dates by the US Food and Drug Administration. The main outcome measures were co-suspected drugs, concurrent irAEs, HLH clinical, haematological and coagulation features, concomitant infections, HLH median time to onset and outcome. Results: Among 49'883 ICI-related ADRs collated in VigiBase as of September 30th, 2018, HLH was reported in 38 cases of which 34 (90%) mentioned ICIs as the solely suspected drugs. ICI-related HLH showed clinical, haematological and coagulation features similar to those of HLH with different etiology. Concurrent irAEs occurred in 5 (13%) patients and 6 (16%) reported concomitant viral infections. 31 (82%) cases defined ICI-related HLH outcome, which resolved in 19 (61%) cases. HLH developed a median of 6.7 weeks after initiation of ICI treatment (IQR 2.9-15.4, n = 18, 47%). Conclusions: By evaluating the largest cohort of ICI-related HLH cases, we observed that ICI-related HLH arises with a delayed timing with respect to initiation of ICI treatment, and usually presents without other irAEs and concomitant infections. Keeping in mind these findings, clinicians should consider ICIs' involvement in the onset of HLH whenever they diagnose a disease of this group of syndromes in cancer patients treated with ICIs. [ABSTRACT FROM AUTHOR]

Severe primary paediatric immunodeficiency syndromes are rare and potentially fatal unless suspected, diagnosed and treated early. We provide clinical guidance and support for on-call consultant paediatricians working in secondary level hospitals on how to recognise and manage children with these conditions. Our paper addresses four conditions that risk the most severe outcomes if they are not adequately cared for during on-call periods, such as weekends: severe combined immunodeficiency, haemophagocytic lymphohistiocytosis, severe congenital neutropaenia and chronic granulomatous disease. CONCLUSION: On-call paediatricians are provided with advice on handling the most severe primary immunodeficiencies. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohisticytosis (HLH) is a syndrome of uncontrolled, severe systemic inflammation (hyperinflammation) arising either from a genetic immune system defect [primary (pHLH)] or triggered as a complication of malignancy, infection, or rheumatologic disease [secondary (sHLH)]. Patients with HLH often have non-specific symptoms and become progressively and critically unwell, with fever, cytopenia and multi-organ failure. Untreated, HLH is almost universally fatal, but even when treated, mortality is high, particularly when HLH complicates malignancy. HLH is managed with immunosuppression, and this can seem difficult to justify in such unwell patients. This review aims to examine the diagnostic and treatment challenges posed by sHLH and to improve recognition among rheumatologists who, being expert in the management of multisystem diseases and in the use of immunosuppression, are ideally placed to deliver care and build an evidence base for better disease characterization and treatment. [ABSTRACT FROM AUTHOR]