Acute kidney injury in critical care: complications of hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is an immune dysfunction characterized by an exaggerated and pathological inflammatory response, potentially leading to systemic inflammatory reactions and multiple-organ failure, including renal involvement. HLH can be classified as primary or secondary, with primary HLH associated with genetic mutations affecting cell degranulation capacity, and secondary HLH often linked to infections, tumors, and autoimmune diseases. The pathogenesis of HLH is not fully understood, but primary HLH is typically driven by genetic defects, whereas secondary HLH involves the activation of CD8+ T cells and macrophages, leading to the release of inflammatory cytokines and systemic inflammatory response syndrome (SIRS). The clinical presentation of HLH includes non-specific manifestations, making it challenging to differentiate from severe sepsis, particularly secondary HLH due to infections. Shared features include prolonged fever, hepatosplenomegaly, hematopenia, hepatic dysfunction, hypertriglyceridemia, and hypofibrinogenemia, along with histiocytosis and hemophagocytosis. However, distinctive markers like dual hemocytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevated sCD25 levels may aid in differentiating HLH from sepsis. Indeed, no singular biomarker effectively distinguishes between hemophagocytic lymphohistiocytosis and infection. However, research on combined biomarkers provides insights into the differential diagnosis. Renal impairment is frequently encountered in both HLH and sepsis. It can result from a systemic inflammatory response triggered by an influx of inflammatory mediators, from direct damage caused by these factors, or as a consequence of the primary disease process. For instance, macrophage infiltration of the kidney can lead to structural damage affecting various renal components, precipitating disease. Presently, tubular necrosis remains the predominant form of renal involvement in HLH-associated acute kidney injury (HLH-AKI). However, histopathological changes may also encompass interstitial inflammation, glomerular abnormalities, microscopic lesions, and thrombotic microangiopathy. Treatment approaches for HLH and sepsis diverge significantly. HLH is primarily managed with repeated chemotherapy to eliminate immune-activating stimuli and suppress hypercellularity. The treatment approach for sepsis primarily focuses on anti-infective therapy and intensive symptomatic supportive care. Renal function significantly influences clinical decision-making, particularly regarding the selection of chemotherapy and antibiotic dosages, which can profoundly impact patient prognosis. Conversely, renal function recovery is a complex process influenced by factors such as disease severity, timely diagnosis, and the intensity of treatment. A crucial aspect in managing HLH-AKI is the timely diagnosis, which plays a pivotal role in reversing renal impairment and creating a therapeutic window for intervention, may have opportunity to improve patient prognosis. Understanding the clinical characteristics, underlying causes, biomarkers, immunopathogenesis, and treatment options for hemophagocytic lymphohistiocytosis associated with acute kidney injury (HLH-AKI) is crucial for improving patient prognosis.

HLH and Recurrent EBV Lymphoma as the presenting manifestation of MAGT1 Deficiency: A Systematic Review of the Expanding Disease Spectrum.

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

Infantile Disseminated Bacille Calmette-Guérin Disease with Hemophagocytosis and Mimicking Juvenile Myelomonocytic Leukemia: A Case Report with Concise Literature Review.

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

Spontaneously Resolved Suspected Hemophagocytic Lymphohistiocytosis or Macrophage Activating Syndrome Associated with Neonatal Lupus Erythematosus: A Case Report.

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

Successful management of haemophagocytic lymphohistiocytosis in an adolescent with newly diagnosed HIV/AIDS and histoplasmosis.

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

Hemophagocytic lymphohistiocytosis associated with acute otitis media: A case report.

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

Hemophagocytic Lymphohistiocytosis: A Rare Complication of Acute Hepatitis E Infection.

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

Pathogenesis of Hemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome: A Case Report and Review of the Literature.

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

[Clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis and their impact on prognosis].

Objective: To investigate the clinical and genetic mutation characteristics of patients with primary hemophagocytic lymphohistiocytosis (HLH) and their impact on prognosis. Methods: Sixty-three primary HLH patients with complete medical records admitted and diagnosed at Beijing Friendship Hospital of Capital Medical University from January 2013 to December 2022 were selected. The patients' clinical and laboratory features, genetic and rapid immunological indicator characteristics, treatment outcomes and prognosis were retrospectively analyzed. Follow-up was up to June 30, 2023, with a median follow-up time [M (Q1, Q3)] of 47 (21, 76) months. Overall survival was analyzed using Kaplan-Meier survival curve, and prognostic factors were analyzed using Cox proportional hazards regression model. Results: Sixty-three primary HLH patients included 35 males and 28 females, with a median age [M (Q1, Q3)] of 17 (7, 27) years. Clinical manifestations at the initial diagnosis mainly included fever (93.7%, 59/63), splenomegaly (87.3%, 55/63), hemophagocytosis (65.1%, 41/63), hepatomegaly (52.4%, 33/63) and central nervous system (CNS) involvement (38.1%, 24/63). A total of 39 patients (61.9%) were diagnosed with EB virus (EBV) infection at initial diagnosis.PRF1 and UNC13D gene mutations were the most common mutations, and the highest frequency mutation site in the PRF1 gene was c.1349C>T, and that of UNC13D gene was c.2588G>A. A total of 76.2% (48/63) of patients had reduced activity of natural killer (NK) cells. Cytotoxic cell degranulation function was impaired or absent in 52.7% (29/55) of patients, of which 79.2% (19/24) of patients with primary HLH with defects in degranulation-related genes had impaired degranulation function. The 1-year and 3-year overall survival rates were 74.8% and 66.7%, respectively. Cox multivariate analysis suggested that peripheral blood EBV≥10 000 copies/ml (HR=3.523, 95%CI: 1.418-8.757, P=0.007) was the risk factor for prognosis. Conclusions: The main clinical manifestations of primary HLH patients at the initial diagnosis include fever, splenomegaly, hemophagocytosis, hepatomegaly, and CNS involvement. PRF1 and UNC13D are the most commonly mutated genes. High copy number EBV infection in peripheral blood is the risk factor for prognosis.

Allogeneic hematopoietic stem cell transplant for familial hemophagocytic lymphohistiocytosis: a case report and literature review.

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

A need for greater awareness: a mixed methods study of patient and healthcare professional perspectives on the diagnosis journey for haemophagocytic lymphohistiocytosis (HLH).

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

Subcutaneous Panniculitis-Like T-Cell Lymphoma With Hemophagocytic Lymphohistiocytosis.

Subcutaneous panniculitis-like T-cell lymphoma (SPTLP), a unique variant of primary cutaneous T-cell lymphomas, clinically mimics subcutaneous panniculitis. It is typified by the development of multiple plaques or subcutaneous erythematous nodules, predominantly on the extremities and trunk. Epidemiological findings reveal a greater incidence in females than males, affecting a wide demographic, including pediatric and adult cohorts, with a median onset age of around 30 years. Diagnosis of SPTLP is complex, hinging on skin biopsy analyses and the identification of T-cell lineage-specific immunohistochemical markers. Treatment modalities for SPTLP are varied; while corticosteroids may be beneficial initially for many patients, a substantial number require chemotherapy, especially in cases of poor response or relapse. Generally, SPTLP progresses slowly, yet approximately 20% of cases advance to hemophagocytic lymphohistiocytosis (HLH), often correlating with a negative prognosis. We report a case of a young male patient presenting with prolonged fever, multiple skin lesions accompanied by HLH, a poor clinical course, and eventual death, diagnosed postmortem with SPTLP. In addition, we also present a literature review of the current evidence of some updates related to SPTLP.

Survival Against the Odds-Hemophagocytic Lymphohistiocytosis Amidst the Shadows of Disseminated Histoplasmosis: A Case Report and Literature Review.

Hemophagocytic lymphohistiocytosis (HLH) secondary to Histoplasma capsulatum is rare, impacting <1% globally, with a mortality rate of up to 31%. Herein, we present a rare case of HLH secondary to H capsulatum, affecting a 57-year-old female with rheumatoid arthritis. Extensive investigations were unrevealing and despite broad-spectrum antibiotics, her condition worsened, leading to respiratory failure requiring extracorporeal membrane oxygenation (ECMO) support, shock requiring multiple vasopressors, and acute kidney injury (AKI) requiring hemodialysis. Diagnosis confirmed disseminated histoplasmosis (DHP), prompting Amphotericin B and methylprednisolone treatment, resulting in significant improvement and discharge with posaconazole therapy. Secondary HLH, primarily arising from severe infections like DHP, is discussed. Limited research exists on this condition in human immunodeficiency virus (HIV)-seronegative individuals. Diagnosis involves HLH-2004 and HScore criteria. Managing histoplasmosis-associated HLH remains challenging due to multiorgan failure risks and treatment complexities and needs further research.

[Clinical analysis of cytomegalovirus infection-associated hemophagocytic lymphohistiocytosis in five patients without underlying diseases].

The clinical data of five patients [one male and four female; median age: 31 (21-65) years] with cytomegalovirus (CMV)-induced hemophagocytic lymphohistiocytosis (HLH) diagnosed and treated in the First Affiliated Hospital of Nanjing Medical University were retrospectively analyzed from January 2011 to December 2020. None of the patients had any underlying disease, and all were immunocompetent. The main clinical presentations were fever in all five patients, splenomegaly in four, enlarged lymph nodes in two, liver enlargement in one, and rash in three. Pulmonary infection was found in three patients, two of whom developed respiratory failure. Two patients had jaundice. Central nervous system symptoms and gastrointestinal bleeding were observed in one case. All patients received glucocorticoids and antiviral therapy. One patient was treated with the COP (cyclophosphamide+vincristine+prednisone) chemotherapy regimen after antiviral therapy failed and he developed central nervous system symptoms. After treatment, four patients achieved remission, but the fifth pregnant patient eventually died of disease progression after delivery. CMV-associated HLH in an immunocompetent individual without underlying diseases is extremely rare, and most patients have favorable prognosis. Antiviral therapy is the cornerstone of CMV-HLH treatment.

Haemophagocytic lymphohistiocytosis secondary to Epstein-Barr and cytomegalovirus coinfection.

Haemophagocytic lymphohistiocytosis (HLH) is a rare and life-threatening disorder caused by uncontrolled activation of the immune system, leading to phagocytosis of blood cells and cytokine storm. HLH can manifest in childhood due to a genetic mutation, but in adults HLH arises secondary to viral infections, autoimmune diseases or neoplastic processes. The most common viral infections associated with HLH are Epstein-Barr virus (EBV) and cytomegalovirus (CMV). EBV and CMV coinfection associated with HLH, however, is exceedingly rare. We present a case of HLH secondary to EBV and CMV coinfection in a young adult who presented with recurrent intermittent high-grade fevers and epistaxis. This case illustrates the importance of considering HLH in patients with idiopathic fevers and to consider all the potential aetiologies for HLH to ensure proper treatment.

Characteristics of Virology and Immune Inflammation of Epstein-Barr Virus Infection Related Non-Neoplastic Diseases in Children.

BACKGROUND: The goal was to study the difference of virological, immunologic, and inflammatory indicators between Epstein-Barr associated infectious mononucleosis (EBV-IM) and EBV associated hemophagocytic lymphohistiocytosis (EBV-HLH) and to explore the evaluation indicators for monitoring the therapeutic efficacy of EBV-HLH. METHODS: Twenty children with EBV-IM (IM group) and 10 children with EBV-HLH (HLH group) were selected. Virology indicators were detected; the absolute count of lymphocyte, and lymphocyte subsets were detected; the levels of immunoglobulin and ferritin were assayed. RESULTS: Compared to the IM group, the HLH group showed a decrease in EBV-specific VCA-IgM antibody levels (U = 29.0, p = 0.006) and an increase in EBV-specific NA-IgG antibody levels (U = 17.0, p = 0.001), while there was no significant difference in EB-DNA loads (t = 0.417, p = 0.680). The counts of lymphocytes, and various lymphocyte subsets in the HLH group were lower than those in the IM group. Inflammatory markers in the HLH group were significantly higher than those in IM group. Dynamic monitoring of virological, immunological, and inflammatory indicators in HLH patients during treatment showed that EBV DNA gradually decreased in patients with good prognosis. Inflammatory indicators significantly decreased and returned to normal, lymphocyte count significantly increased and returned to normal during treatment. However, patients with poor prognosis showed rebound increase in EBV DNA and inflammatory indicators in the later stage of treatment, while lymphocyte count further decreased with the recurrence of the disease. CONCLUSIONS: Exhausted and damaged immune function in host by persistent stimulation of EB viral antigen is one of the main pathogeneses of EB-HLH. Lymphocyte count and serum ferritin level are effective indicators to monitor the therapeutic efficacy during the treatment to HLH.

Familial Hemophagocytic Lymphohistiocytosis in a Premature Low Birth Weight Infant: a Rare Case Report.

BACKGROUND: Familial hemophagocytic lymphohistiocytosis (FHL) onset in the fetal and neonatal periods is sporadic, and infants are susceptible to intrauterine death. Early and accurate diagnosis and treatment are the keys to preventing complications and death in FHL patients due to the complex and diverse clinical manifestations of the disease. METHODS: We report a rare case of a preterm infant with a low birth weight of 2,010 g and a gestational age of 32 + 4 weeks who presented with a leaky syndrome similar to sepsis after birth. Anti-infective, other support, and symptomatic treatments were not effective. Bone marrow examination results on day 13 suggested hemophago-cytosis. RESULTS: Various compound heterozygous UNC13D genes were found by exome sequencing, which confirmed the diagnosis of FHL type 3. Genetic variants of this locus have never been reported in the literature. CONCLUSIONS: Neonatal onset FHL is challenging to diagnose, especially in premature infants. It is necessary to complete exome sequencing if the patient has no apparent pathogen infection or effective treatment.

Heterogeneity of macrophage activation syndrome and treatment progression.

Macrophage activation syndrome (MAS) is a rare complication of autoimmune inflammatory rheumatic diseases (AIIRD) characterized by a progressive and life-threatening condition with features including cytokine storm and hemophagocytosis. Predisposing factors are typically associated with microbial infections, genetic factors (distinct from typical genetically related hemophagocytic lymphohistiocytosis (HLH)), and inappropriate immune system overactivation. Clinical features include unremitting fever, generalized rash, hepatosplenomegaly, lymphadenopathy, anemia, worsening liver function, and neurological involvement. MAS can occur in various AIIRDs, including but not limited to systemic juvenile idiopathic arthritis (sJIA), adult-onset Still's disease (AOSD), systemic lupus erythematosus (SLE), Kawasaki disease (KD), juvenile dermatomyositis (JDM), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), etc. Although progress has been made in understanding the pathogenesis and treatment of MAS, it is important to recognize the differences between different diseases and the various treatment options available. This article summarizes the cell types and cytokines involved in MAS-related diseases, the heterogeneity, and treatment options, while also comparing it to genetically related HLH.

mNGS helped diagnose scrub typhus-associated HLH in children: a report of two cases.

Background: Scrub typhus, caused by the Orientia tsutsugamushi (Ot), is a widespread vector-borne disease transmitted by chigger mites. Hemophagocytic lymphohistiocytosis (HLH) is considered to be one of the potentially severe complications. The diagnosis of scrub typhus-associated HLH may be overlooked due to the non-specific clinical characteristics and the absence of pathognomonic eschar. Case presentation: We obtained clinical data from two patients in the South of Sichuan, China. The first case involved a 6-year-old girl who exhibited an unexplained fever and was initially diagnosed with sepsis, HLH, and pulmonary infection. The other patient presented a more severe condition characterized by multiple organ dysfunction and was initially diagnosed with septic shock, sepsis, HLH, acute kidney injury (AKI), and pulmonary infection. At first, a specific examination for scrub typhus was not performed due to the absence of a characteristic eschar. Conventional peripheral blood cultures yielded negative results in both patients, and neither of them responded to routine antibiotics. Fortunately, the causative pathogen Orientia tsutsugamushi (Ot) was detected in the plasma samples of both patients using metagenomics next-generation sequencing (mNGS) and further confirmed by polymerase chain reaction. Subsequently, they both were treated with doxycycline and recovered quickly. Conclusion: The unbiased mNGS provided a clinically actionable diagnosis for an uncommon pathogen-associated infectious disease that had previously evaded conventional diagnostic approaches.