Hemophagocytic lymphohistiocytosis and myopericarditis induced by campylobacter: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe disorder characterized by excessive activation of the immune system, leading to hypercytokinemia and damage to multiple organs. We report a rare case of HLH with myopericarditis caused by Campylobacter infection. CASE PRESENTATION: A 28-year-old male patient with a history of hypertension without medicine control presented at the hospital after a four-day fever, decreasing urine amount, rashes on his trunk and limbs, and other symptoms. He was admitted with a provisional diagnosis of atypical infection and allergic skin rash related to diclofenac. However, his condition deteriorated, and he developed shock, tachycardia, chest distress, and bilateral pleural effusion after admission. Further investigations revealed cardiogenic shock related to myopericarditis, and he was transferred to the ICU. In addition, a stool PCR panel subsequently revealed a positive result for Campylobacter. On day 6, he was diagnosed with HLH. Under Clarithromycin and dexamethasone infusion, leukocytosis, anemia and thrombocytopenia with cardiogenic shock status improved. Then, he was later discharged in stable condition. CONCLUSIONS: HLH and myopericarditis caused by Campylobacter are very rare. Early detection of Campylobacter-induced HLH and multiple organ failure, as well as prompt use of antibiotics and immunosuppressants, can be helpful for prognosis.

Subcutaneous panniculitis-like T-cell lymphoma: fever and facial swelling with hemophagocytic syndrome.

We report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL) in a young man presenting with fever and facial swelling. He had pancytopenia and hemophagocytic syndrome (HPS) on evaluation. The histopathological examination of skin punch biopsy from the face and chest wall showed SPTCL. Given the associated HPS, he was started on steroid and multidrug chemotherapy following which he had symptomatic improvement.

Current and emerging pharmacotherapies for cytokine release syndrome, neurotoxicity, and hemophagocytic lymphohistiocytosis-like syndrome due to CAR T cell therapy.

INTRODUCTION: Chimeric antigen receptor (CAR) T cells have revolutionized the treatment of multiple hematologic malignancies. Engineered cellular therapies now offer similar hope to transform the management of solid tumors and autoimmune diseases. However, toxicities can be serious and often require hospitalization. AREAS COVERED: We review the two chief toxicities of CAR T therapy, cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and the rarer immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome. We discuss treatment paradigms and promising future pharmacologic strategies. Literature and therapies reviewed were identified by PubMed search, cited references therein, and review of registered trials. EXPERT OPINION: Management of CRS and ICANS has improved, aided by consensus definitions and guidelines that facilitate recognition and timely intervention. Further data will define optimal timing of tocilizumab and corticosteroids, current foundations of management. Pathophysiologic understanding has inspired off-label use of IL-1 receptor antagonism, IFNγ and IL-6 neutralizing antibodies, and janus kinase inhibitors, with data emerging from ongoing clinical trials. Further strategies to reduce toxicities include novel pharmacologic targets and safety features engineered into CAR T cells themselves. As these potentially curative therapies are used earlier in oncologic therapy and even in non-oncologic indications, effective accessible strategies to manage toxicities are critical.

Does your unwell patient have haemophagocytic lymphohistiocytosis?

Haemophagocytic lymphohistiocytosis is a severe systemic hyperinflammatory syndrome characterised by dysregulation of immune cells and excessive production of cytokines, also known as a cytokine storm. It has distinctive clinical features with fever, hyperferritinaemia and falling blood counts. In adults, this usually occurs secondary to an underlying driver or trigger including infection, malignancy or rheumatic diseases. Prompt treatment with immunomodulatory therapy, including corticosteroids and the recombinant IL-1 receptor antagonist anakinra, is recommended to switch off the cytokine storm. Etoposide-based regimens are sometimes needed, and newer therapies such as emapalumab and JAK inhibitors are increasingly being used. The incidence of haemophagocytic lymphohistiocytosis has increased significantly over the last 20 years which may partly reflect increased awareness of the condition. Although relatively rare, haemophagocytic lymphohistiocytosis can be encountered by a broad range of hospital physicians, so knowing how to diagnose and treat this condition is essential. This article reviews the pathogenesis, clinical features, causes, diagnosis and treatment of haemophagocytic lymphohistiocytosis to improve physician recognition and management of this condition to improve future patient outcomes.

Secondary hemophagocytic lymphohistiocytosis in pediatric patients with visceral leishmaniasis and Epstein-Barr virus infection.

Visceral leishmaniasis-associated hemophagocytic lymphohistiocytosis (VL-HLH) is indistinguishable from those of HLH of other etiologies due to the overlap symptoms, posing a serious threat to life. In this study, we aimed to provide insights for early diagnosis and improve outcomes in pediatric patients with VL-HLH. We retrospectively analyzed the clinical and laboratory data of 10 pediatric patients with VL-HLH and 58 pediatric patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH). The median time from symptom onset to cytopenia in patients with VL-HLH and EBV-HLH was 11 days (interquartile range, 7-15 days) and five days (interquartile range, 3.75-9.25 days) (P = 0.005). Both groups showed liver injury and increased lactate dehydrogenase levels; however the levels of aspartate aminotransferase, alanine aminotransferase, direct bilirubin, and lactate dehydrogenase in patients with VL-HLH were significantly lower than those in patients with EBV-HLH (P < 0.05). The fibrinogen and triglyceride levels were almost normal in VL-HLH patients but were significantly altered in EBV-HLH cases ( P < 0.05). The positive rate of first bone marrow microscopy examination, anti-rK39 IgG detection, and blood metagenomic next-generation sequencing was 50%, 100%, and 100%, respectively. After VL diagnosis, eight patients were treated with sodium stibogluconate and two were treated with liposomal amphotericin B. All the patients with VL-HLH recovered. Our study demonstrates that regular triglyceride and fibrinogen levels in pediatric patients with VL-HLH may help in differential diagnosis from EBV-HLH. VL-HLH is milder than EBV-HLH, with less severe liver injury and inflammatory responses, and timely treatment with antileishmanial agents is essential to improve the outcomes of pediatric patients with VL-HLH.

Histiocytic necrotizing lymphadenitis with hemophagocytic lymphohistiocytosis in adults: A single-center analysis of 5 cases.

BACKGROUND: Histiocytic necrotizing lymphadenitis (HNL) is a self-limited inflammatory disease of unknown pathogenesis. A very small fraction of patients with HNL could develop hemophagocytic lymphohistiocytosis (HLH), a hyperinflammatory disorder. These patients are diagnosed as HNL with HLH (HNL-HLH). HNL-HLH in the pediatric population has been systemically studied, however, the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH remain to be explored. We aimed to explore the clinical, laboratory, and radiological features and outcomes of adult patients with HNL-HLH. METHODS: We collected the clinical data of patients with HNL-HLH admitted to the First Affiliated Hospital of Nanjing Medical University from October 2010 to June 2015. All the patients underwent lymph node biopsy and have a pathological diagnosis of HNL. The age, gender, clinical presentation, lymph node signs, laboratory findings and imaging data, and pathological findings of the patients were collected. RESULTS: In this study, we reported five adult patients with HNL-HLH. All five patients showed enlarged lymph nodes and prolonged fever. Laboratory findings were consistent with the diagnosis of HLH. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed enlarged lymph nodes with increased FDG uptake and splenic hypermetabolism could be present. All the patients responded well to corticosteroids and had a good prognosis. Two of the five patients were diagnosed with systemic lupus erythematosus during the follow-up. CONCLUSIONS: Our study demonstrated that adult patients with HNL-HLH showed distinct clinical, laboratory, and radiological features. And the prognosis is good and patients could be managed with steroids and supportive care.

Lamotrigine-Induced Hemophagocytic Lymphohistiocytosis with DRESS.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory reaction syndrome caused by genetic or acquired immune dysregulation. The majority of adult HLH cases are caused by tumors, rheumatic immune disorders, and infections. However, drug-induced HLH is rarely reported. METHODS: We report a case of HLH in an adult caused by the administration of lamotrigine, to our knowledge, only nine other cases of lamotrigine-associated HLH have been reported in adult patients. RESULTS: After discontinuing lamotrigine and using steroid hormones for the HLH, the patient's condition has been brought under control. CONCLUSIONS: This case confirms that dexamethasone is also effective for drug-induced HLH. Usually, after discontinuing the relevant medications, there is no need for further maintenance treatment.

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

Background: Hemophagocytic Lymphohistiocytosis (HLH) is a rare and life-threatening condition characterized by a severe impairment of the immune homeostasis. While Familial-HLH (FHL) is a known cause, the involvement of other Inborn Errors of Immunity (IEI) in pediatric-HLH remains understudied. Objective: This systematic review aimed to assess the clinical features, triggers, laboratory data, treatment, and outcomes of pediatric HLH patients with IEI other than FHL (IEInotFHL), emphasizing the importance of accurate identification and management. Methods: A systematic search for studies meeting inclusion criteria was conducted in PubMed, EMBASE, MEDLINE, and Cochrane Central. Quality assessment was performed through JBI criteria. Results: A comprehensive search yielded 108 records meeting inclusion criteria, involving 178 patients. We identified 46 different IEI according to IUIS 2022 Classification. Combined immunodeficiencies, immune dysregulation disorders, and phagocyte defects were the IEI most frequently associated with HLH. In 75% of cases, HLH preceded the IEI diagnosis, often with an unrecognized history of severe infections. Triggers reflected the specific infection susceptibilities within IEI groups. Liver and central nervous system involvement were less common than in FHL cases. Treatment approaches and outcomes varied, with limited long-term follow-up data, limiting the assessment of therapeutic efficacy across IEI groups. Conclusion: A comprehensive evaluation encompassing immunological, infectious, and genetic aspects is essential in pediatric-HLH. Relying solely on FHL or EBV susceptibility disorders tests is insufficient, as diverse other IEI can contribute to HLH. Early recognition of HLH as a potential warning sign can guide timely diagnostic investigations and facilitate tailored therapeutic interventions for improved outcomes. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=371425, PROSPERO, CRD42022371425.

Human herpesvirus-6 infection in a critically ill and immunocompetent patient: a case report.

BACKGROUND: Human herpesvirus-6 is a rare infection in an immunocompetent adult. In existing literature, there is a dearth of knowledge that mainly exists as case reports and case series. CASE PRESENTATION: In this case report, we described a 29-year-old female of Myanmarese descent patient from Myanmar who presented with altered mental status and non-specific respiratory and gastrointestinal symptoms. She was initially treated for pneumonia and discharged well. However, she re-presented to the hospital and was subsequently treated for severe central nervous system infection. Cerebrospinal fluid studies detected human herpesvirus-6 polymerase chain reaction with associated high serum human herpesvirus-6 concentration. This infection also triggered hemophagocytic lymphohistiocytosis. Treatment was initiated against both human herpesvirus-6 infection and hemophagocytic lymphohistiocytosis, and she responded to antiviral treatment and steroids, respectively. CONCLUSION: This case study highlights the need for prompt diagnosis and treatment of this severe disease and the dangerous complications. Additionally, the authors share insights on the diagnostic challenges faced in the treatment of this patient.

Hemophagocytic lymphohistiocytosis induced by nivolumab/ipilimumab combination therapy: A case of lung adenocarcinoma that responded to early steroid pulse therapy.

BACKGROUND: Immune checkpoint inhibitors have been reported to have excellent therapeutic effects on various malignant tumors. However, immune-related adverse events can occur, targeting various organs. CASE PRESENTATION: A 49-year-old male with lung carcinoma was started on carboplatin + pemetrexed + nivolumab (every 3 weeks) + ipilimumab (every 6 weeks), and nivolumab/ipilimumab was administered in the 3rd course. Subsequently, fever and fatigue developed, and grade 3 liver damage was also noted, so he was admitted to Kindai University Hospital. A bone marrow aspirate examination was performed on the third day of illness, and a definitive diagnosis of hemophagocytic lymphohistiocytosis (HLH) was made. It was determined that immediate therapeutic intervention was necessary, and pulse therapy with methylprednisolone was started on the third day of illness. After 3 days of pulse treatment, a rapid recovery of platelet values, a decrease in ferritin levels, and a decrease in lactate dehydrogenase were observed. Subjective symptoms such as fever and fatigue also quickly improved. CONCLUSION: Early diagnosis and treatment for HLH resulted in a positive response. The number of HLH cases may increase in the future due to the expansion of immune checkpoint inhibitor indications.

Recent advances and evolving concepts in Still's disease.

Still's disease is a rare inflammatory syndrome that encompasses systemic juvenile idiopathic arthritis and adult-onset Still's disease, both of which can exhibit life-threatening complications, including macrophage activation syndrome (MAS), a secondary form of haemophagocytic lymphohistiocytosis. Genetic insights into Still's disease involve both HLA and non-HLA susceptibility genes, suggesting the involvement of adaptive immune cell-mediated immunity. At the same time, phenotypic evidence indicates the involvement of autoinflammatory processes. Evidence also implicates the type I interferon signature, mechanistic target of rapamycin complex 1 signalling and ferritin in the pathogenesis of Still's disease and MAS. Pathological entities associated with Still's disease include lung disease that could be associated with biologic DMARDs and with the occurrence of MAS. Historically, monophasic, recurrent and persistent Still's disease courses were recognized. Newer proposals of alternative Still's disease clusters could enable better dissection of clinical heterogeneity on the basis of immune cell profiles that could represent diverse endotypes or phases of disease activity. Therapeutically, data on IL-1 and IL-6 antagonism and Janus kinase inhibition suggest the importance of early administration in Still's disease. Furthermore, there is evidence that patients who develop MAS can be treated with IFNγ antagonism. Despite these developments, unmet needs remain that can form the basis for the design of future studies leading to improvement of disease management.

Exposure-safety relationship for patients with primary hemophagocytic lymphohistiocytosis treated with emapalumab.

Primary hemophagocytic lymphohistiocytosis (pHLH) is an immune-mediated, hyperinflammatory disorder. Interferon-γ (IFNγ) plays a key role in the pathophysiology of pHLH. Emapalumab, a fully human, anti-IFNγ monoclonal antibody neutralizes both free and receptor-bound IFNγ. However, inhibiting IFNγ-mediated signaling could result in immune dysfunction and immunosuppression. This exploratory exposure-safety analysis investigated the relationship between emapalumab and the incidence of adverse events in patients with pHLH. Increased exposure to emapalumab was not associated with an increased predicted risk of severe adverse events, infection, or infusion-related reactions. Emapalumab was associated with a favorable and manageable safety profile across all assessed doses and treatment durations.

Filgrastim-induced hemophagocytic lymphohistiocytosis in a patient with mantle cell lymphoma: A case report.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disease potentially induced by various causes. Very few reports have described HLH induced by granulocyte colony-stimulating factor (G-CSF) and those few previous reports have uniformly indicated that continuing G-CSF is unfeasible once HLH has been induced. A 52-year-old Japanese man who had been diagnosed with mantle cell lymphoma with systemic and central nervous system involvements received rituximab, hyper-fractionated cyclophosphamide, vincristine, Adriamycin and dexamethasone (R-HCVAD)/methotrexate and cytarabine. During the second cycle of R-HCVAD, the patient developed severe back pain, thrombocytopenia, elevated serum lactate dehydrogenase and ferritin levels, and hemophagocytosis in the bone marrow. Complete remission (CR) of mantle cell lymphoma was confirmed on whole-body computed tomography, brain magnetic resonance imaging, and bone marrow biopsy. The patient was diagnosed with HLH induced by filgrastim. HLH recovered with intravenous methylprednisolone at 1 g/day for 3 days, followed by oral prednisolone tapered off over 5 days. The patient continued chemotherapy with a change in the G-CSF formulation from filgrastim to lenograstim and prophylactic administration of corticosteroids. He safely completed scheduled chemotherapy without recurrence of HLH and successfully maintained CR of lymphoma. Although rare, G-CSF potentially induces HLH. Changing the G-CSF formulation and steroid prophylaxis may allow safe continuation of G-CSF.

Ruxolitinib-based regimen in children with primary hemophagocytic lymphohistiocytosis.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a rare immune disorder and hematopoietic stem cell transplan- tation (HSCT) is the only potentially curative treatment. Given the high pre-HSCT mortality of pHLH patients reported in the HLH-2004 study (17%), more regimens to effectively control the disease and form a bridge with HSCT are needed. We conducted a retrospective study of pHLH children treated by ruxolitinib (RUX)-based regimen. Generally, patients received RUX until HSCT or unacceptable toxic side-effect. Methylprednisolone and etoposide were added sequentially when the disease was suboptimally controlled. The primary end point was 1-year overall survival. Twenty-one pHLH patients (12 previously treated and 9 previously untreated) were included with a median follow-up of 1.4 years. At last follow-up, 17 (81.0%) patients were alive with a 1-year overall survival of 90.5% (95% confidence interval: 84.1-96.9). Within the first 8 weeks, all patients had an objective response, of which 19 (90.5%) achieved complete response (CR) and two (9.5%) achieved partial response (PR) as a best response. Seventeen (81.0%) patients received HSCT, of which 13 (76.5%) had CR, three (17.6%) had PR and one (5.9%) had disease reactivation at the time of HSCT. Fifteen (88.2) patients were alive post- HSCT. Notably, eight (38.1%) patients received zero doses of etoposide, suggesting the potential of RUX-based regimen to reduce chemotherapy intensity. Patients tolerated RUX-based regimen well and the most frequently observed adverse events were hematologic adverse events. Overall, RUX-based regimen was effective and safe and could be used as a bridge to HSCT for pHLH children.