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The term ‘cytokine storm’ (CS) applies to a pathological autoimmune reaction when the interactions that lead to cytokine production are destabilised and may even lead to death. CS may be induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In this study, we present our analysis of certain pathological processes that induce a CS in pregnant and postpartum women. We draw our attention to the similarities between the severe course of Coronavirus Disease 2019 (COVID-19) and haemophagocytic lymphohistiocytosis (HLH). It is noteworthy that many of the criteria used to diagnose HLH are described as COVID-19 mortality predictors. Cytokine storms are considered to be an important cause of death in patients with the severe course of SARS-CoV-2 infection. Due to the fact that pregnant women are in an immunosuppressive state, viral pulmonary infections are more perilous for them—possible risks include miscarriage, intrauterine growth restriction or birth before the term; sometimes ventilation support is needed. HLH should be considered in pregnant and puerperal women suffering from moderately severe to severe COVID-19 and presenting with: fever unresponsive to antibiotic therapy, cytopenia, hepatitis and hyperferritinaemia. The HLH disorder is rare and difficult to diagnose; however, its early detection could reduce patient mortality.

Despite distinct diagnostic criteria, several gastrointestinal pathologies can masquerade haemophagocytic lymphohistiocytosis (HLH) during the peripartum period. Acute fatty liver of pregnancy, HELLP (haemolysis, elevated liver enzymes and low platelets) syndrome, miliary tuberculosis, visceral leishmaniasis, abdominal surgical emergencies, haemolytic anaemias and haematological malignancies may have clinical and laboratory presentation similar to that of HLH. In this report, we present the case of a 26-year-old woman with 38-weeks' gestation and abdominal pain, vomiting, intermittent fever and non-productive cough for 1--2 months. A thorough investigation suggested HLH and the patient was successfully treated with corticosteroids. This patient demonstrates the importance of a focused investigation strategy and timely management to prevent mortality and morbidity to both the mother and fetus in this rare and fatal disease. [ABSTRACT FROM AUTHOR]

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare disorder of immune dysregulation. FHL inherited in an autosomal recessive pattern is classified into five subtypes based on underlying genetic defects. Mutations in four genes including PRF1, UNC13D, STX11 and STXBP2 are responsible for FHL2 to FHL5 respectively. The cause of FHL1 is associated with mutations in an unknown gene located at 9q21.3-22. This study aims to report the clinical features and genetic results of nine Iranian patients suffering from -haemophagocytic lymphohistiocytosis. Nine patients (five males and four females) suspected to FHL whose genetic evaluation of PRF1 and STX11 revealed no mutations, were entered the study to investigate UNC13D mutations. Primers were designed to amplify all coding regions and exon-intron boundaries of the gene. PCR products were then sequenced and analyzed by sequence analysis tools including BLAST. The most frequent clinical manifestations observed in the patients were fever and hepatosplenomegaly. In this study, five mutations were detected in UNC13D including four novel mutations (c.1434_1446delACCCATGGTGCAGinsTGGTGCT, c.1933C>T, c.1389+1G>C and c.2091+1G>A) besides to a previously reported deletion (c.627delT). The pathogenicity of the missense mutation was assessed using online prediction tools including SIFT and PolyPhen2. The study results may provide valuable information for genetic counseling especially for those who have a history of immunodeficiency diseases in their family and can be used for prenatal diagnosis.

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acinetobacter baumannii is one of the most important nosocomial pathogens, and thus it is required to investigate how it disseminate in hospitals and infect patients. We performed whole genome sequencing for 24 A. baumannii strains isolated successively from the blood of a single patient to evaluate whether repeated infections were due to re-infection or relapse infection and to investigate within-host evolution. The whole genome of the first strain, BL1, was sequenced de novo using the PacBio RSII system. BL2–BL24, were sequenced with an Illumina Hiseq4000 and mapped to the genome sequences of BL1. We identified 42 single-nucleotide variations among the strains. The SNVs differentiated the strains into three groups, BL1, BL2–BL16, and BL17–BL24, indicating that the patient suffered from re-infections or co-infections by similar, but different strains. The results also showed that A. baumannii strains in each group were rather stable at the genomic level. Our study emphasizes the importance of intensive infection control.

Adult-onset Still’s disease (AoSD) is a rare systemic autoinflammatory disease characterized by arthritis, spiking fever, skin rash and elevated ferritin levels. The reason behind the nomenclature of this condition is that AoSD shares certain symptoms with Still’s disease in children, currently named systemic-onset juvenile idiopathic arthritis. Immune dysregulation plays a central role in AoSD and is characterized by pathogenic involvement of both arms of the immune system. Furthermore, the past two decades have seen a large body of immunological research on cytokines, which has attributed to both a better understanding of AoSD and revolutionary advances in treatment. Additionally, recent studies have introduced a new approach by grouping patients with AoSD into only two phenotypes: one with predominantly systemic features and one with a chronic articular disease course. Diagnosis presupposes an extensive diagnostic workup to rule out infections and malignancies. The severe end of the spectrum of this disease is secondary haemophagocytic lymphohistiocytosis, better known as macrophage activation syndrome. In this review, we discuss current research conducted on the pathogenesis, diagnosis, classification, biomarkers and complications of AoSD, as well as the treatment strategy at each stage of the disease course. We also highlight the similarities and differences between AoSD and systemic-onset juvenile idiopathic arthritis. There is a considerable need for large multicentric prospective trials.

Key message: Hemophagocytic lymphohistiocytosis (HLH) has been reported as a rare complication of immune checkpoint inhibitors (ICI); however, ICI‐related HLH is a life‐threatening and comparatively late adverse event. Early diagnosis is critical, and it should be included in the differential diagnosis especially in patients with cytopenia with fever and hyperferritinaemia. [ABSTRACT FROM AUTHOR]

Two CD19 chimeric antigen receptor (CAR) T cell therapies are now approved by the US Food and Drug Administration for the treatment of relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) and histological variants: axicabtagene ciloleucel (axi-cel) and tisagenlecleucel (tisa-cel) (Neelapu I et al i , [6]; Schuster I et al i , [9]). Clinically, it remains unclear as to when the HLH features of CRS are significant enough to consider treatment with therapies used for non-CAR T-associated HLH, such as etoposide or methotrexate (Neelapu I et al i , [8]). Our case series suggests that the timing of onset of CAR T-associated HLH may differ between patients, with concern when delayed or recurrent HLH symptoms occur with a rising ferritin level, which is when HLH-directed therapies should be considered. [Extracted from the article]

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare disorder of immune dysregulation. FHL inherited in an autosomal recessive pattern is classified into five subtypes based on underlying genetic defects. Mutations in four genes including PRF1, UNC13D, STX11 and STXBP2 are responsible for FHL2 to FHL5 respectively. The cause of FHL1 is associated with mutations in an unknown gene located at 9q21.3-22. This study aims to report the clinical features and genetic results of nine Iranian patients suffering from - haemophagocytic lymphohistiocytosis. Nine patients (five males and four females) suspected to FHL whose genetic evaluation of PRF1 and STX11 revealed no mutations, were entered the study to investigate UNC13D mutations. Primers were designed to amplify all coding regions and exon-intron boundaries of the gene. PCR products were then sequenced and analyzed by sequence analysis tools including BLAST. The most frequent clinical manifestations observed in the patients were fever and hepatosplenomegaly. In this study, five mutations were detected in UNC13D including four novel mutations (c.1434_1446delACCCATGGTGCAGinsTGGTGCT, c.1933C>T, c.1389+1G>C and c.2091+1G>A) besides to a previously reported deletion (c.627delT). The pathogenicity of the missense mutation was assessed using online prediction tools including SIFT and PolyPhen2. The study results may provide valuable information for genetic counseling especially for those who have a history of immunodeficiency diseases in their family and can be used for prenatal diagnosis. [ABSTRACT FROM AUTHOR]

Summary: Haemophagocytic lymphohistiocytosis (HLH) is a severe, even fatal, inflammatory condition. Epstein–Barr virus (EBV) infection‐associated HLH (EBV‐HLH) is one of the most common types of secondary HLH. Etoposide is a key drug in HLH‐94/04 regimen. We sought to identify the importance of etoposide in the initial treatment of EBV‐HLH. Ninety‐three patients with EBV‐HLH of all ages admitted to our centre in 2017 were divided into two groups according to whether the initial treatment contained etoposide or not. The survival of the group whose initial therapy included etoposide (Group 1, 52 patients; 6‐month survival rate 0·769) was significantly better than that of the group whose initial therapy did not include etoposide (Group 2, 41 patients; 6‐month survival rate 0·269) (P < 0·001). In patients aged <18 years old, the survival of Group 1 patients was not significantly better than that of Group 2 patients (P = 0·447), in contrast to patients aged ≥18 years, where the survival of Group1 patients was significantly better than that of Group 2 patients (P < 0·001). We concluded that including etoposide in the initial treatment of EBV‐HLH patients can improve their prognosis, especially adult patients. This may be because that adult patients are recognized as "higher risk" patients. [ABSTRACT FROM AUTHOR]

Background and aim: Epstein-Barr virus (EBV) is a proposed trigger in the etiopathogenesis of inflammatory bowel disease (IBD) and is associated with lymphoproliferative diseases. Nevertheless, testing for EBV DNA in the intestinal mucosa and screening for EBV infection before initiation of a drug therapy are not routinely performed. The aim of this article is to increase awareness of the relevance of EBV infection in specific clinical situations. Methods: In this short communication, we describe the disease course of three IBD patients with EBV infection, varying from EBV reactivation during disease flare up to a trigger of EBV-related mucocutaneous ulcer (EBV-MCU) and haemophagocytic lymphohistiocytosis (HLH). Results: Our first patient was diagnosed with EBV reactivation-associated severe colitis and showed a rapid clinical improvement after induction therapy with infliximab and azathioprine. Without antiviral treatment, the patient remained in complete remission and no complications of EBV were seen. After diagnosing EBV-MCU in the second patient, immunosuppressive medication was discontinued and four infusions of rituximab resulted in a rapid clinical recovery and eventually complete response. After discontinuation of the immunosuppression in our last patient with haemophagocytic lymphohistiocytosis, treatment with a combination of corticosteroid and antiviral therapy resulted in a complete recovery over a time span of several weeks. Conclusion: EBV infection has a wide variety of potentially life-threatening clinical manifestations in IBD patients. Testing for EBV in case of a flare up and screening for EBV before the start of immunosuppressive therapy will create awareness for EBV-related symptoms or complications during follow-up. [ABSTRACT FROM AUTHOR]

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 FROM AUTHOR]

The high-dose hook effect, or prozone effect, can lead to negative or falsely lowered plasma ferritin results. Here, cases of a 16-year-old boy and a 70-year-old woman with haemophagocytic lymphohystiocytosis with extremely high concentrations of plasma ferritin (387,000  μg/L and 138,000  μg/L, respectively) are presented. In both cases, falsely lowered ferritin results were reported without any analyser flag. This article emphasizes the importance of recognition of the high-dose hook effect, since a watertight solution is lacking. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome, which if not promptly treated, can lead rapidly to critical illness and death. HLH is termed macrophage activation syndrome (MAS) when associated with rheumatic disease (where it is best characterized in systemic JIA) and secondary HLH (sHLH) when associated with other triggers including malignancy and infection. MAS/sHLH is rare and coupled with its mimicry of other conditions, is underrecognized. These inherent challenges can lead to diagnostic and management challenges in multiple medical specialties including haematology, infectious diseases, critical care and rheumatology. In this review we highlight the pathogenesis of MAS/sHLH including its underlying triggers, key clinical features and diagnostic challenges, prognostic factors and current treatments in adults. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a rare and severe clinical syndrome that can be classified as either primary or secondary. Secondary HLH can be triggered by a variety of diseases. Pregnancy-related HLH has already been observed clinically. However, most of these cases occur during pregnancy. Considering that the periods before and after delivery have different clinical features, we presented the first case series of HLH that presented during the postpartum stage of pregnancy. From these cases, we concluded that postpartum HLH is a common form of pregnancy-related HLH. Patients with postpartum HLH may suffer more complicated pathogenesis. Cytopenia was not as common as in other types of HLH, but liver dysfunction was present in almost all cases. The standard therapy of HLH-94/04 was very effective, and the outcomes of postpartum HLH were better. [ABSTRACT FROM AUTHOR]

Acinetobacter baumannii is one of the most important nosocomial pathogens, and thus it is required to investigate how it disseminate in hospitals and infect patients. We performed whole genome sequencing for 24 A. baumannii strains isolated successively from the blood of a single patient to evaluate whether repeated infections were due to re-infection or relapse infection and to investigate within-host evolution. The whole genome of the first strain, BL1, was sequenced de novo using the PacBio RSII system. BL2–BL24, were sequenced with an Illumina Hiseq4000 and mapped to the genome sequences of BL1. We identified 42 single-nucleotide variations among the strains. The SNVs differentiated the strains into three groups, BL1, BL2–BL16, and BL17–BL24, indicating that the patient suffered from re-infections or co-infections by similar, but different strains. The results also showed that A. baumannii strains in each group were rather stable at the genomic level. Our study emphasizes the importance of intensive infection control. [ABSTRACT FROM AUTHOR]

BACKGROUND Haemophagocytic lymphohistiocytosis (HLH) is a rare clinical syndrome characterised by activation of the mononuclear phagocytic system, and often leads to progressive multiple organ failure. The diagnosis of HLH is made late by most physicians. METHODS To confirm the diagnosis of acquired HLH made in a single-institution series of adult patients with HLH-04 criteria, we applied the HScore and evaluated prognostic factors associated with clinical outcome. RESULTS A total of 174 patients with a median age of 51 years (range 17–90) were included. Male/female ratio was 111/63. In 92/174 (52.9%) patients, there were potential haematological diseases (4 acute leukaemia, 1 thrombotic thrombocytopenic purpura, 3 Hodgkin’s lymphoma [HL], 17 B-cell non-Hodgkin’s lymphoma [NHL], 67 T-cell NHL including 22 natural killer / T-cell NHL [NK/t-cell NHL). Six (3.4%) patients had autoimmune disease and 76 (43.7%) undiagnosed underlying disease. There were 44 (25.3%) patients with Epstein-Barr virus infection, 11 (6.3%) with cytomegalovirus, 1 (0.5%) syphilis, 9 (5.2%) hepatitis B virus and 3 (1.7%) human immunodeficiency virus. More than 95% of patients had hyperferritinaemia, high lactate dehydrogenase, fever and low albumin, whereas 89.1% of patients had bone marrow phagocytosis. By the HScore, 4/174 patients had a >50% and 16/174 patients had a >90% probability of not having HLH. All 174 patients fulfilled more than five of the HLH-04 diagnostic criteria, but 16 of them had a low probability of HLH by the HScore. In a multivariate analysis, lymphopenia and hypofibrinogenaemia were independent prognostic factors for death. CONCLUSION In our study, viral infection was not an independent prognostic factor. NK/T-cell -NHL was associated with worse prognosis compared with B-cell NHL and T-cell NHL (p = 0.036) and similar to other aetiologies.

Resumen: El síndrome hemofagocítico (SHF) o linfohistiocitosis hemofagocítica es una entidad con elevada mortalidad, típicamente reconocida en la edad pediátrica. Sin un correcto tratamiento, el SHF puede ser fatal: el riesgo de una rápida progresión a fallo multiorgánico y de afectación del sistema nervioso central con secuelas a largo plazo, son las consecuencias más graves de un retraso diagnóstico. Por lo tanto, el SHF es una urgencia médica que los pediatras deben saber identificar en un paciente con fiebre y afectación progresiva del estado general. La aplicación de los criterios diagnósticos de SHF, que consideran datos clínicos y analíticos (incluyendo un aspirado de médula ósea), y la búsqueda del factor desencadenante (infeccioso, oncológico, reumatológico, metabólico), son claves para poder instaurar un tratamiento dirigido, que neutralice el desencadenante y frene la hiperinflamación. En la presente revisión se exponen los datos más relevantes sobre la fisiopatología, diagnóstico y tratamiento de esta grave enfermedad para pediatras generales. Abstract: Haemophagocytic syndrome, or haemophagocytic lymphohistiocytosis (HLH), is a disorder with high mortality, typically recognised at paediatric age. Without proper treatment, HLH can be fatal. The risk of a rapid progression to multi-organ failure and central nervous system involvement leading to long-term sequelae, are the most feared consequences of a diagnostic delay. Therefore, HLH is a medical emergency that paediatricians should be able to identify in a patient with fever and progressive worsening of general condition. The application of the HLH diagnostic criteria, which include clinical and analytical data (as well as a bone marrow aspirate), and the search for a trigger (infectious, oncological, rheumatological, or metabolic). These are decisive for the establishment of a targeted treatment, which aims at neutralising the trigger and reducing the hyper-inflammation. The most relevant data for general paediatricians are presented in this review, including the physiopathology, diagnosis, and treatment of this serious disease.

Introduction: Dengue fever is a widely prevalent viral infection in the tropical countries. Many patients with dengue fever are known to have severe cytopenias and the mechanism for the same is not known. Macrophage Activation Syndrome (MAS) is a life threatening complication that is known to be triggered by viral infections. This study attempts to examine the possibility of MAS as an underlying cause of cytopenias in dengue fever. Hyperferritinemia which is an important diagnostic criteria for MAS is known to occur in dengue fever also. Aim: The primary objective of the study was to assess the correlation between ferritin levels and mean platelet drop among patients admitted with dengue fever. Secondary objective was to do a subgroup analysis and compare the patients treated according to WHO standard protocols in dengue fever with those who were also given steroids and compare outcomes. Materials and Methods: This was a retrospective study done over a period of 18 months. Patients with dengue fever who satisfied the criteria for MAS were selected and the mean change in platelet count between the time of admission and 48 hours later was calculated. This was compared with the ferritin levels. Subgroup analysis was also done and the groups were correlated on two important clinical outcomes-the mean platelet drop and length of stay in hospital. Results: Total of 26 patients were enrolled in the study (n=26), of whom 18 (69.2%) were male. Pearson’s correlation coefficient (-0.231) was calculated to compare Ferritin levels with mean platelet drop and it showed that there was no correlation. There was no difference between the two groups with respect to mean platelet drop (p=0.08) and length of stay (p=0.443) in hospital. Conclusion: Hence, it can be concluded that hyperferritinemia does not correlate with the severity of platelet drop. There was no significant change in outcomes in patients with dengue fever associated MAS who were treated with steroids or with only standard treatment protocol.

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. [ABSTRACT FROM AUTHOR]

At the time of submission of this manuscript the patient has been alive and well for 21 months after PD-1 blockade treatment. Kwong et al. reported seven patients with refractory and relapsed NKTCL treated with PD-1 blockade, including five of seven patients with HLH. In short, PD-1 blockade might restore the imbalanced immunological function and control EBV infection and EBV-associated HLH. The efficacy and safety of PD1 blockade in EBV infection and EBV-associated HLH should be further explored. [Extracted from the article]

Background: Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening syndrome characterized by an excessive inflammatory response. Limited data exist on adult HLH., Methods: 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., Findings: 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., Interpretation: 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., Funding: None., Competing Interests: All authors declare no competing interests., (© 2023 The Author(s).)

Haemophagocytic lymphohistiocytosis (HLH) is a possibly life-threatening syndrome of immune dysregulation and can be divided into primary (hereditary) and secondary forms (including malignancy-associated HLH (M-HLH)). We retrospectively analysed epidemiological, clinical, virological and laboratory data from patients with M-HLH treated at our department between 1995 and 2014. Out of 1.706 haemato-/oncologic patients treated at our department between 1995 and 2014, we identified 22 (1.29%) patients with secondary HLH (1.3-18.0, median 10.1 years; malignancy induced n = 2; chemotherapy induced n = 20). Patients with acute myeloblastic leukaemia (AML) developed HLH significantly more often than patients with acute lymphoblastic leukaemia (ALL) (10/55, 18.2% vs. 6/148, 4.1%, p = 0.0021). As possible viral triggers, we detected BKV (53.8% of the tested patients), HHV-6 (33.3%), EBV (27.8%), CMV (23.5%), ADV (16.7%) and PVB19 (16.7%) significantly more frequently than in haemato-/oncologic patients without HLH. Despite lacking evidence of concurrent bacterial infection, C-reactive protein (CRP) and procalcitotnin (PCT) were elevated in 94.7 and 77.7% of the patients, respectively. Ferritin and sIL2R were markedly elevated in all patients. HLH-associated mortality significantly (p = 0.0276) decreased from 66.6% (1995-2004) to 6.25% (2005-2014), suggesting improved diagnostic and therapeutic management. Awareness of HLH is important, and fever refractory to antibiotics should prompt to consider this diagnosis. Elevated ferritin and sIL2R seem to be good markers, while inflammatory markers like CRP and PCT are not useful to discriminate viral triggered HLH from severe bacterial infection. Re-/activation of several viruses may play a role as possible trigger. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Summary: Haemophagocytic lymphohistiocytosis (HLH) constitutes a spectrum of immunological disorders characterized by uncontrolled immune activation and key symptoms such as fever, splenomegaly, pancytopenia, haemophagocytosis, hyperferritinaemia and hepatitis. In genetic or primary HLH, hyperactivated CD8+ T cells are the main drivers of pathology. However, in acquired secondary HLH, the role of lymphocytes remains vague. In the present study the involvement of lymphocytes in the pathogenesis of a cytomegalovirus‐induced model of secondary HLH was explored. We have previously reported CD8+ T cells to be redundant in this model, and therefore focused on CD4+ helper and regulatory T cells. CD4+ T cells were activated markedly and skewed towards a proinflammatory T helper type 1 transcription profile in mice displaying a severe and complete HLH phenotype. Counter to expectations, regulatory T cells were not reduced in numbers and were, in fact, more activated. Therapeutic strategies targeting CD25high hyperactivated T cells were ineffective to alleviate disease, indicating that T cell hyperactivation is not a pathogenic factor in cytomegalovirus‐induced murine HLH. Moreover, even though T cells were essential in controlling viral proliferation, CD4+ T cells, in addition to CD8+ T cells, were dispensable in the development of the HLH‐like syndrome. In fact, no T or B cells were required for induction and propagation of HLH disease, as evidenced by the occurrence of cytomegalovirus‐associated HLH in severe combined immunodeficient (SCID) mice. These data suggest that lymphocyte‐independent mechanisms can underlie virus‐associated secondary HLH, accentuating a clear distinction with primary HLH. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is rare. Although Kawasaki disease (KD) has been reported as a precursor to HLH, coronary arteritis occurring at the onset of secondary HLH, not in association with KD, has not been reported. An 8-year-old girl presented with virus-induced secondary HLH associated with a giant aneurysm and ectasia of the coronary arteries which was detected incidentally at onset of the disease. She did not fulfill the criteria for diagnosis of KD. The coronary lesions improved after 6 months of treatment with dexamethasone and etoposide. Echocardiography early in the course of HLH is a useful tool to detect the unusual finding of coronary arteritis which may carry significant clinical sequelae. [ABSTRACT FROM AUTHOR]

Haemophagocytic lymphohistiocytosis (HLH) is a rare condition not commonly observed in neonatal units. It poses a challenge to neonatal staff to source expertise and information when diagnosing and treating patients with this condition. This article uses a case study of a neonate with HLH to analyse interdisciplinary team dynamics in hospital and explore how teams can effectively share knowledge and learn from each other when treating patients with rare and complex conditions. [ABSTRACT FROM AUTHOR]

We describe a 15-month-old child who presented with a history of fever for the preeding two days and multiple episodes of seizures of one day duration. Physical examination revealed generalized lymphadenopathy and hepatosplenomegaly. The child developed erythematous maculopapular rash, hypotension and required tracheal intubation and mechanical ventilation. Bone marrow aspiration confirmed the diagnosis of hemophagocytic lymphohistiocytosis (HLH). He was treated with dexamethasone, etoposide and cyclosporine, recovered and is doing well on follow-up. HLH is a rare haematological disorder involving the mononuclear phagocyte system. Since it mimics other disorders, its timely diagnosis remains a challenge. It is an aggressive and potential fatal disease of infancy and childhood, if left untreated. HLH may mimic a number of systemic infections thereby causing difficulty in early diagnosis.

Haemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory condition with impairment of cytotoxic T-cells and natural killer cells. Causes in infants are mostly hereditary immune defects as well as various infectious triggering factors, amongst these cytomegalovirus (CMV). Vertical CMV transmission may occur in utero, during birth, and by breast feeding. Usually, a CMV infection transmitted via breast milk is symptomatic only in very immature preterm infants. We report on a late preterm infant born after 35 + 5 weeks of gestation with a birth weight of 1840 g, being admitted to our intensive care unit at the age of 9 weeks with acute enteritis and severe dehydration. After a prolonged recovery, the infant developed a sepsis-like condition with hyperpyrexia, hepatosplenomegaly, and pancytopenia. Combination with high ferritin levels (2809 μg/l), hypertriglyceridaemia (481 mg/dl), elevated soluble IL-2 receptor (sCD25, 9120 U/ml), and reduced perforin expression allowed diagnosis of HLH, caused by an acute CMV infection. Since connatal CMV infection had been ruled out earlier, we report the rare case of secondary HLH triggered by a postnatally acquired symptomatic CMV infection in an immunocompetent infant, most likely transmitted via breast milk. The infant was successfully treated with ganciclovir without need for immunosuppressive therapy. [ABSTRACT FROM AUTHOR]

The genetic basis of haemophagocytic lymphohistiocytosis ( HLH) has not been elucidated in 10% of affected patients. In this study, we report four HLH episodes in three patients with HAX1 gene mutations. We screened the mutations associated with congenital neutropenia ( CN) because the neutropenia persisted following HLH treatment. There were homozygous HAX1 mutations detected in all patients. This is the first case series of patients with CN caused by HAX1 mutation who presented with HLH. We hypothesize that severe neutropenia persists after an HLH episode in children without HLH mutations (especially infants) because these patients have CN caused by HAX1 mutations. [ABSTRACT FROM AUTHOR]

Background: Macrophage activation syndrome (MAS) is a severe complication of rheumatic disease in childhood, particularly in systemic Juvenile Idiopathic Arthritis (sJIA). It is characterize by an uncontrolled activation and proliferation of T lymphocytes and macrophages. Main content: MAS is currently classified among the secondary or acquired forms of haemophagocytic lymphohistiocytosis (sHLH). The reason is that MAS shares clinical and laboratory features with primary genetic HLH (pHLH). In this context is conceivable that some of the pathogenic mechanisms of pHLH may be involved in other forms of HLH. Heterozygosity for mutations of genes involved in pHLH may lead to a cytotoxic defect and to a development of clinical overt disease. But other different contributors might be involved to the development of MAS such as infections or underlying inflammation. In MAS, the inflammatory status of the patient is a major contributor of the disease. Indeed, the majority of the MAS episodes occurs during active disease phases or at disease onset. In addition, recent evidence in animals and humans suggest that genetics may also play a major role in contributing to hyperinflammation and particularly to macrophages hyper-responses. Conclusions: We hypothesize that HLH may be one unique clinical syndrome, to whose generation different mechanisms may contribute, and maintained by one final effector mechanism. [ABSTRACT FROM AUTHOR]

Introduction: Macrophage activation syndrome (MAS) is a rare complication of autoimmune diseases. The background of the diseases is immune system dysfunction. The disease is characterized by varying symptomatology and the different dynamics of accumulation of symptoms. Case report: A female patient diagnosed with adult-onset Still's disease was admitted to the hospital because of fever, weakness, skin rash and dyspepsia which had lasted for several days. Diagnostic tests revealed the presence of anti-nuclear antibodies, pancytopenia, hypertriglyceridemia, hyperferritinemia, hypofibrinogenemia, elevated activity of liver enzymes, and increased antibiotic therapy and intravenous pulses of methylprednisolone was unsuccessful and provided no improvement. On the basis of bone marrow cytological examination, the diagnosis of MAS was established. The patient was treated with dexamethasone and cyclosporine A with improvement. The patient was followed up in the rheumatology out-patient department for 20 months without the relapse of MAS. Conclusion: Macrophage activation syndrome is a rare, dangerous complication of autoimmune diseases, requiring rapid diagnosis and aggressive treatment. [ABSTRACT FROM AUTHOR]

Invasive mould infections are life-threatening and mainly occur in immunocompromised patients. Whereas aspergillosis is described during haemophagocytic lymphohistiocytosis (HLH), only a few cases of concomitant mucormycosis with HLH have been reported. Here, we present an uncommon coinfection of mucormycosis and aspergillosis associated with HLH probably due to a varicella zoster virus (VZV) viraemia which was unresponsive to triple antifungal therapy (liposomal amphotericin B combined with isavuconazole and caspofungin). A review of the cases of mucormycosis with HLH showed that this uncommon association was always lethal and underscored the relevance of screening for mould infections in patients with HLH. [ABSTRACT FROM AUTHOR]

Background: Macrophage activation syndrome is described as a "clinical syndrome of hyperinflammation resulting in an uncontrolled and ineffective immune response" in the context of an autoinflammatory or rheumatic disease. Current associations of macrophage activation syndrome with autoimmune disease most notably include a host of rheumatological conditions and inflammatory bowel disease. Epidemiological studies have shown that macrophage activation syndrome is precipitated by autoimmune disease more commonly than previously thought. Diagnosing the precipitating factor is essential for effective treatment and prognosis. Case presentation: We report a case of a six year old girl with coeliac disease diagnosed after two episodes of secondary haemophagocytic lymphohistiocytosis. Her condition only responded to treatment once the patient was placed on a gluten free diet. Further immunological testing confirmed anti-transglutaminase and anti-endomysial antibodies, however histological biopsy was deemed inappropriate due to the severity of her condition. She has remained stable with no further episodes of macrophage activation syndrome since commencing a gluten free diet. Conclusion: This case report is the first literature that links macrophage activation syndrome to coeliac disease and highlights the challenge of diagnosing coeliac disease with unusual features such as associated prolonged fever. Clinicians should have a low threshold for screening children with other autoimmune diseases for coeliac disease. [ABSTRACT FROM AUTHOR]

Macrophage Activation Syndrome (MAS) is a rare form of Haemophagocytic Lymphohistiocytosis (HLH) associated with rheumatologic conditions. It is characterised by haemophagocytosis and cytokine overproduction, resulting from the activation and uncontrolled proliferation of T lymphocytes and macrophages. The patient being reported is an elderly female with Rheumatoid Arthritis (RA), who presented with fever and was found to have MAS. She later developed Acute Respiratory Distress Syndrome (ARDS) and died. Such a scenario has rarely been reported.

Introduction. Haemophagocytic lymphohistiocytosis (HLH) is a disorder characterised by long-standing fever, splenomegaly and bicytopoenia or pancytopoenia. Lymphadenopathy, jaundice and neurological symptoms may also occur. HLH may ensue in various forms of innate or acquired immunodeficiency with impaired cytotoxic lymphocyte function resulting in excessive macrophage activation. Objective. To describe and analyse clinical characteristics of patients treated for HLH at the University Children’s Hospital of Belgrade from August 2000 to August 2010. Methods. Retrospective analysis of medical records. Results. Diagnosis of HLH was established in 13 children (five boys and eight girls) aged from one month to 14 years. In six children HLH was secondary (to visceral leishmaniasis in two, Ebstein-Barr virus infection in one, Langerhans’ cell histiocytosis in one and systemic juvenile rheumatoid arthritis in two). Of the remaining seven patients, genes for perforin and syntaxin 11 were examined in two and no mutations were found. Of the remaining seven patients, genes encoding perforin and syntaxin 11 were analyzed in two, but no mutations were found. All children had fever, splenomegaly, cytopoenias, hyperferritinaemia and hypertriglyceridaemia, but haemophagocytosis was seen in only six (46.1%). Six children were cured (four with secondary HLH and two with primary HLH). Two children are undergoing treatment, while five succumbed (three before treatment could be administered and two due to complications). In four of the six cured children, HLH arose in the first year of life. Cure rate in those who underwent haematopoietic stem cell trans- plantation was 2/3. Conclusion. Results underscore the importance of timely diagnosis and treatment of HLH, warranting that in all children with fever, splenomegaly and/or cytopoenias, with or without haemophagocytosis, HLH be actively sought.

The granule-dependent cytotoxic activity of T and natural killer lymphocytes has progressively emerged as an important effector pathway not only for host defence but also for immune regulation. The analysis of an early-onset, severe, primary immune dysregulatory syndrome known as hemophagocytic lymphohistiocytosis (HLH) has been decisive in highlighting this latter role and identifying key effectors on the basis of gene mutation analyses and mediators in the maturation and secretion of cytotoxic granules. Studies of cytotoxicity-deficient murine counterparts have helped to define primary HLH as a syndrome in which uncontrolled T-cell activation in response to lymphocytic choriomeningitis virus infection results in excessive macrophage activation and inflammation-associated cytopenia. Recent recognition of late-onset HLH, which occurs in a variety of settings, in association with hypomorphic, monoallelic mutations in genes encoding components of the granule-dependent cytotoxic pathway or even in the absence of such mutations has broadened our view about the mechanisms that underlie the perturbation of immune homeostasis. These findings have led to the development of a model in which disease occurs when a threshold is reached through the accumulation of genetic and environmental risk factors. Nevertheless, validation of this model will require further investigations.

Hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory hyperferritinemic syndrome, is triggered by various etiologies and diseases and can lead to multiorgan dysfunction and death. There are two types of HLH: primary and secondary. Primary HLH (pHLH) is caused by a genetic mutation resulting in dysfunction in cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, hyperactivated immune cells, and hypercytokinemia. In secondary HLH (sHLH), an underlying etiology is the cause of the disease. Infections, malignancy, and autoimmune diseases are well-known triggers for sHLH. Infectious triggers for sHLH are most frequently viruses, where different mechanisms, including dysregulated CTLs and NK cell activity and persistent immune system stimulation, have been reported. Similarly, in severe coronavirus disease 2019 (COVID-19) patients, a hyperinflammatory mechanism leading to hypercytokinemia and hyperferritinemia has been demonstrated. A similar dysfunction in CTLs and NK cells, persistent immune system stimulation with increased cytokines production, and severe end-organ damage have been reported. Therefore, a significant overlap is present between the clinical and laboratory features seen in COVID-19 and sHLH. However, SARS-CoV-2, similar to other viruses, can trigger sHLH. Hence, a diagnostic approach is needed in severe COVID-19 patients presenting with multiorgan failure, in whom sHLH should be considered., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Fadlallah et al.)

Haemophagocytic lymphohistiocytosis is a rare inflammatory condition. It can present in adult general medical patients and is a challenging diagnostic conundrum. This article provides an overview of the pathophysiology and clinical presentation of the syndrome for the general physician who will be rarely confronted with this problem but will have to act promptly when the situation arises. Treatment is also briefly discussed, although this usually occurs in a specialist setting after the diagnosis has been established. [ABSTRACT FROM AUTHOR]

Background: Both haemophagocytic lymphohistiocytosis and acute necrotizing encephalopathy are life-threatening condition. It presents major diagnostic difficulties, since it may have a diversity in clinical picture and with many conditions leading to the same clinical presentation. So it is key important to understand the disorders. Case presentation: We report a pediatric case of haemophagocytic lymphohistiocytosis with specific presentation which predominantly featured as acute necrotizing encephalopathy of childhood. We discuss the diagnosis and differential diagnosis, and speculate the etiology of haemophagocytic lymphohistiocytosis is due to hypersensitivity. Conclusion: Haemophagocytic lymphohistiocytosis and brain damage in this case may be induced by hypersensitivity, which have good clinical outcome if diagnosed and treated early. [ABSTRACT FROM AUTHOR]