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1.
BMJ Case Rep ; 17(6)2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38844353

ABSTRACT

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.


Subject(s)
Histoplasmosis , Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Histoplasmosis/diagnosis , Histoplasmosis/drug therapy , Histoplasmosis/complications , Male , Adolescent , HIV Infections/complications , HIV Infections/drug therapy , Interleukin 1 Receptor Antagonist Protein/therapeutic use , Interleukin 1 Receptor Antagonist Protein/administration & dosage , Acquired Immunodeficiency Syndrome/complications , Treatment Outcome
2.
Zhonghua Nei Ke Za Zhi ; 63(5): 486-489, 2024 May 01.
Article in Chinese | MEDLINE | ID: mdl-38715486

ABSTRACT

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.


Subject(s)
Antiviral Agents , Cytomegalovirus Infections , Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/virology , Lymphohistiocytosis, Hemophagocytic/etiology , Male , Cytomegalovirus Infections/complications , Cytomegalovirus Infections/drug therapy , Cytomegalovirus Infections/diagnosis , Female , Adult , Retrospective Studies , Middle Aged , Antiviral Agents/therapeutic use , Young Adult , Aged , Cytomegalovirus , Prognosis
3.
Intensive Care Med ; 50(6): 849-860, 2024 Jun.
Article in English | MEDLINE | ID: mdl-38748265

ABSTRACT

Hematological malignancies may require rapid-onset treatment because of their short doubling time, notably observed in acute leukemias and specific high-grade lymphomas. Furthermore, in targeted onco-hematological scenarios, chemotherapy is deemed necessary as an emergency measure when facing short-term, life-threatening complications associated with highly chemosensitive hematological malignancies. The risks inherent in the disease itself, or in the initiation of treatment, may then require admission to the intensive care unit (ICU) to optimize monitoring and initial management protocols. Hyperleukocytosis and leukostasis in acute leukemias, tumor lysis syndrome, and disseminated intravascular coagulation are the most frequent onco-hematological complications requiring the implementation of emergency chemotherapy in the ICU. Chemotherapy must also be started urgently in secondary hemophagocytic lymphohistiocytosis. Tumor-induced microangiopathic hemolytic anemia and plasma hyperviscosity due to malignant monoclonal gammopathy represent infrequent yet substantial indications for emergency chemotherapy. In all cases, the administration of emergency chemotherapy in the ICU requires close collaboration between intensivists and hematology specialists. In this review, we provide valuable insights that aid in the identification and treatment of patients requiring emergency chemotherapy in the ICU, offering diagnostic tools and guidance for their overall initial management.


Subject(s)
Hematologic Neoplasms , Intensive Care Units , Humans , Intensive Care Units/organization & administration , Hematologic Neoplasms/drug therapy , Hematologic Neoplasms/complications , Tumor Lysis Syndrome/etiology , Tumor Lysis Syndrome/drug therapy , Antineoplastic Agents/therapeutic use , Antineoplastic Agents/adverse effects , Disseminated Intravascular Coagulation/drug therapy , Disseminated Intravascular Coagulation/etiology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/complications
4.
Expert Opin Pharmacother ; 25(3): 263-279, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38588525

ABSTRACT

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.


Subject(s)
Cytokine Release Syndrome , Immunotherapy, Adoptive , Lymphohistiocytosis, Hemophagocytic , Neurotoxicity Syndromes , Receptors, Chimeric Antigen , Humans , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/drug therapy , Cytokine Release Syndrome/immunology , Cytokine Release Syndrome/therapy , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/therapy , Lymphohistiocytosis, Hemophagocytic/drug therapy , Neurotoxicity Syndromes/etiology , Neurotoxicity Syndromes/immunology , Immunotherapy, Adoptive/adverse effects , Immunotherapy, Adoptive/methods , Receptors, Chimeric Antigen/immunology , Animals
5.
Zhonghua Er Ke Za Zhi ; 62(5): 467-472, 2024 May 02.
Article in Chinese | MEDLINE | ID: mdl-38623016

ABSTRACT

Objective: To analyze the efficacy and safety of the L-DEP regimen (asparaginase, liposome doxorubicin, etoposide and methylprednisolone) as a salvage therapy for the refractory primary hemophagocytic lymphohistocytosis triggered by Epstein-Barr virus infection (EBV-pHLH) in children. Methods: In this retrospective case study, clinical and laboratory data before and after L-DEP regimen of 4 children diagnosed with EBV-pHLH in Beijing Children's hospital between January 2016 and June 2022 were collected, and the efficacy and safety of L-DEP regimen for the treatment of EBV-pHLH were analyzed. Results: Among 4 patients, there were 3 females and 1 male with the age ranged from 0.8 to 7.0 years. Two of them showed compound heterozygous mutations of PRF1, one with a heterozygous mutation of UNC13D, one homozygous mutation of ITK. Before the L-DEP therapy, all of them had anemia and a soaring level of soluble CD25, 3 patients had neutropenia and thrombopenia, 3 patients had a high level of ferritin, 3 patients had hypofibrinogenemia and 1 patient had hypertriglyceridemia. After receiving 1 or 2 cycles of L-DEP treatment, three achieved remission, including complete remission (1 case) and partial remission (2 cases), and the other one had no remission. The levels of blood cell counts, soluble CD25, triglyceride, fibrinogen and albumin were recovered gradually in 3 patients who got remission. All four patients underwent hematopoietic stem cell transplantation (HSCT) after L-DEP regimen, and three survived. All patients had no severe chemotherapy related complications. The main side effects were bone marrow suppression, infection and pancreatitis, which recovered after appropriate treatments, apart from one who died from severe infection after urgent HSCT. Conclusion: L-DEP regimen could be served as an effective and safe salvage treatment for refractory pediatric EBV-pHLH, and also provide an opportunity for patients to receive HSCT.


Subject(s)
Asparaginase , Epstein-Barr Virus Infections , Etoposide , Lymphohistiocytosis, Hemophagocytic , Salvage Therapy , Humans , Lymphohistiocytosis, Hemophagocytic/therapy , Lymphohistiocytosis, Hemophagocytic/drug therapy , Male , Female , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/complications , Retrospective Studies , Salvage Therapy/methods , Child , Infant , Child, Preschool , Etoposide/administration & dosage , Asparaginase/administration & dosage , Doxorubicin/administration & dosage , Methylprednisolone/administration & dosage , Mutation , Membrane Proteins/genetics , Treatment Outcome , Perforin/genetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Liposomes , Herpesvirus 4, Human/genetics
6.
BMJ Case Rep ; 17(4)2024 Apr 02.
Article in English | MEDLINE | ID: mdl-38569732

ABSTRACT

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.


Subject(s)
Angioedema , Lymphohistiocytosis, Hemophagocytic , Lymphoma, T-Cell , Panniculitis , Male , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Panniculitis/diagnosis , Panniculitis/drug therapy , Panniculitis/etiology , Lymphoma, T-Cell/complications , Lymphoma, T-Cell/diagnosis , Lymphoma, T-Cell/drug therapy , Skin/pathology , Angioedema/pathology , Fever/etiology
7.
Int J Pharm ; 657: 124127, 2024 May 25.
Article in English | MEDLINE | ID: mdl-38621611

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening clinical syndrome characterized by a positive feedback loop between cytokine storm and macrophages and lymphocytes overactivation, which could serve as a valid therapeutic target for HLH treatment. In this study, the clinically extensively used JAK1/2 inhibitor ruxolitinib was encapsulated into macrophage membrane-coated nanoparticles (M@NP-R) with high drug-loading efficiency for targeted HLH treatment. In vitro and in vivo studies demonstrated that M@NP-R not only efficiently adsorbed extracellular proinflammation cytokines, like IFN-γ and IL-6 to alleviate the cytokine storm, but also effectively dampened macrophage activation and proliferation by intracellular JAK/STAT signaling pathway inhibition. M@NP-R treatment significantly ameliorated the clinical and laboratory manifestations of HLH in mouse models, including trilineage cytopenia, hypercytokinemia, organomegaly, hepatorenal dysfunction, and tissue inflammation. Importantly, M@NP-R significantly enhanced the survival of the lethal HLH mice. Altogether, M@NP-R successfully blocked the positive feedback loop between the cytokine storm and macrophage overactivation by depleting extracellular inflammatory cytokines and inhibiting the intracellular JAK/STAT signaling pathway, both of which worked synergistically in HLH treatment. As ruxolitinib has already been extensively used in clinics with favorable safety, and M@NP is biodegradable and highly biocompatible, M@NP-R has good prospects for clinical translation.


Subject(s)
Cytokine Release Syndrome , Cytokines , Lymphohistiocytosis, Hemophagocytic , Macrophages , Nanoparticles , Nitriles , Pyrazoles , Pyrimidines , Animals , Lymphohistiocytosis, Hemophagocytic/drug therapy , Pyrazoles/administration & dosage , Pyrazoles/pharmacology , Pyrimidines/administration & dosage , Pyrimidines/pharmacology , Mice , Cytokines/metabolism , Cytokine Release Syndrome/drug therapy , Macrophages/drug effects , Macrophage Activation/drug effects , Mice, Inbred C57BL , Signal Transduction/drug effects , RAW 264.7 Cells , Disease Models, Animal , Male , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/administration & dosage , Humans
8.
Am J Trop Med Hyg ; 110(6): 1217-1222, 2024 Jun 05.
Article in English | MEDLINE | ID: mdl-38579699

ABSTRACT

Enteric fever is a major contributor to rising health care costs in developing countries. Associated disease-related complications and drug resistance further compound this problem. Hemophagocytic lymphohistiocytosis (HLH) is an uncommon complication of enteric fever with high morbidity and mortality. This systematic review aimed to evaluate the clinical characteristics and treatment outcomes in enteric fever-associated HLH syndrome. We searched major electronic databases (PubMed, Google Scholar, and Scopus) to identify the cases of enteric fever associated with HLH from inception until June 2023. Prespecified data regarding clinical presentation, outcomes, and HLH therapy were collected. A total of 53 cases of enteric fever with HLH were included in the final analysis. The mean age of patients was 20 years, and the proportions of female and pediatric patients were 52.8% and 45.3%, respectively. The mean duration of illness was 10.4 days. A total of 39.6% of patients had enteric fever-associated complications; coagulopathy and encephalopathy were the most common (23.1% and 13.5%). The overall mortality rate was 9.4% in HLH. A total of 51% of patients received HLH-specific therapy (corticosteroids in 41.5% and intravenous immunoglobulin in 20.8% of patients). On multivariate analysis, high ferritin levels (≥5,000 ng/mL) were significantly associated with mortality (hazard ratio, 3.01; 95% CI = 0.62-14.12, P = 0.041). Enteric fever with secondary HLH is associated with high mortality. This review reveals the potential role of ferritin in disease prognosis. In cases with significantly elevated ferritin levels, the role of immunosuppressants or combination antibiotics should be explored.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Typhoid Fever , Lymphohistiocytosis, Hemophagocytic/mortality , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/drug therapy , Humans , Typhoid Fever/complications , Typhoid Fever/drug therapy , Typhoid Fever/mortality , Female , Male , Young Adult , Adult , Adolescent , Treatment Outcome , Immunoglobulins, Intravenous/therapeutic use , Child
10.
Front Immunol ; 15: 1371490, 2024.
Article in English | MEDLINE | ID: mdl-38686382

ABSTRACT

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) is characterized by a widespread maculopapular rash, lymphadenopathy, fever, and multisystem involvement. Conversely, hemophagocytic lymphohistiocytosis (HLH) is an infrequent yet critical condition presenting with fever, hepatosplenomegaly, cytopenias, coagulation abnormalities, and elevated inflammatory markers. The overlapping clinical and laboratory features between DRESS and HLH poses a significant diagnostic challenge. Secondary HLH (sHLH) typically occurs in adults triggered by viral infections, malignancies, rheumatologic diseases, or immune deficiencies. Recently, COVID-19 has also been identified as one of the triggers for sHLH. Herein, we present a case of Sulfasalazine-induced DRESS coinfected with COVID-19 that subsequently progressed into HLH. Our patient exhibited common hepatorenal and splenic involvement along with rare cholecystitis and appendicitis. However, a significant improvement was observed upon the addition of etoposide and azathioprine. We hypothesize that excessive activation of the immune system and cytokine storm due to DRESS combined with COVID-19 infection led to more extensive systemic damage resulting in HLH development. This highlights the potential for severe consequences when DRESS coincides with HLH during a COVID-19 infection.


Subject(s)
COVID-19 , Coinfection , Drug Hypersensitivity Syndrome , Lymphohistiocytosis, Hemophagocytic , SARS-CoV-2 , Sulfasalazine , Humans , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , COVID-19/complications , COVID-19/immunology , Drug Hypersensitivity Syndrome/etiology , Drug Hypersensitivity Syndrome/diagnosis , Sulfasalazine/adverse effects , Coinfection/drug therapy , Male , Middle Aged , Female
11.
BMC Infect Dis ; 24(1): 382, 2024 Apr 08.
Article in English | MEDLINE | ID: mdl-38589812

ABSTRACT

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.


Subject(s)
Anemia , Campylobacter , Lymphohistiocytosis, Hemophagocytic , Myocarditis , Thrombocytopenia , Male , Humans , Adult , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Shock, Cardiogenic/etiology , Shock, Cardiogenic/complications , Anemia/complications , Thrombocytopenia/complications , Myocarditis/diagnosis , Myocarditis/complications
12.
Br J Hosp Med (Lond) ; 85(3): 1-12, 2024 Mar 02.
Article in English | MEDLINE | ID: mdl-38557089

ABSTRACT

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.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Neoplasms , Adult , Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Cytokine Release Syndrome , Neoplasms/complications , Adrenal Cortex Hormones , Diagnosis, Differential
13.
Blood Adv ; 8(9): 2248-2258, 2024 May 14.
Article in English | MEDLINE | ID: mdl-38429096

ABSTRACT

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening, hyperinflammatory syndrome. Emapalumab, a fully human monoclonal antibody that neutralizes the proinflammatory cytokine interferon gamma, is approved in the United States to treat primary HLH (pHLH) in patients with refractory, recurrent, or progressive disease, or intolerance with conventional HLH treatments. REAL-HLH, a retrospective study, conducted across 33 US hospitals, evaluated real-world treatment patterns and outcomes in patients treated with ≥1 dose of emapalumab between 20 November 2018 and 31 October 2021. In total, 46 patients met the pHLH classification criteria. Median age at diagnosis was 1.0 year (range, 0.3-21.0). Emapalumab was initiated for treating refractory (19/46), recurrent (14/46), or progressive (7/46) pHLH. At initiation, 15 of 46 patients were in the intensive care unit, and 35 of 46 had received prior HLH-related therapies. Emapalumab treatment resulted in normalization of key laboratory parameters, including chemokine ligand 9 (24/33, 72.7%), ferritin (20/45, 44.4%), fibrinogen (37/38, 97.4%), platelets (39/46, 84.8%), and absolute neutrophil count (40/45, 88.9%). Forty-two (91.3%) patients were considered eligible for transplant. Pretransplant survival was 38 of 42 (90.5%). Thirty-one (73.8%) transplant-eligible patients proceeded to transplant, and 23 of 31 (74.2%) of those who received transplant were alive at the end of the follow-up period. Twelve-month survival probability from emapalumab initiation for the entire cohort (N = 46) was 73.1%. There were no discontinuations because of adverse events. In conclusion, results from the REAL-HLH study, which describes treatment patterns, effectiveness, and outcomes in patients with pHLH treated with emapalumab in real-world settings, are consistent with the emapalumab pivotal phase 2/3 pHLH trial.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Humans , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/mortality , Lymphohistiocytosis, Hemophagocytic/etiology , Female , Male , Treatment Outcome , Adolescent , Child , Retrospective Studies , Child, Preschool , Infant , Young Adult , Antibodies, Monoclonal/therapeutic use , Adult
14.
Blood ; 143(23): 2386-2400, 2024 Jun 06.
Article in English | MEDLINE | ID: mdl-38446698

ABSTRACT

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) comprises a severe hyperinflammatory phenotype driven by the overproduction of cytokines, many of which signal via the JAK/STAT pathway. Indeed, the JAK1/2 inhibitor ruxolitinib has demonstrated efficacy in preclinical studies and early-phase clinical trials in HLH. Nevertheless, concerns remain for ruxolitinib-induced cytopenias, which are postulated to result from the blockade of JAK2-dependent hematopoietic growth factors. To explore the therapeutic effects of selective JAK inhibition in mouse models of HLH, we carried out studies incorporating the JAK1 inhibitor itacitinib, JAK2 inhibitor fedratinib, and JAK1/2 inhibitor ruxolitinib. All 3 drugs were well-tolerated and at the doses tested, they suppressed interferon-gamma (IFN-γ)-induced STAT1 phosphorylation in vitro and in vivo. Itacitinib, but not fedratinib, significantly improved survival and clinical scores in CpG-induced secondary HLH. Conversely, in primary HLH, in which perforin-deficient (Prf1-/-) mice are infected with lymphocytic choriomeningitis virus (LCMV), itacitinib, and fedratinib performed suboptimally. Ruxolitinib demonstrated excellent clinical efficacy in both HLH models. RNA-sequencing of splenocytes from LCMV-infected Prf1-/- mice revealed that itacitinib targeted inflammatory and metabolic pathway genes in CD8 T cells, whereas fedratinib targeted genes regulating cell proliferation and metabolism. In monocytes, neither drug conferred major transcriptional impacts. Consistent with its superior clinical effects, ruxolitinib exerted the greatest transcriptional changes in CD8 T cells and monocytes, targeting more genes across several biologic pathways, most notably JAK-dependent proinflammatory signaling. We conclude that JAK1 inhibition is sufficient to curtail CpG-induced disease, but combined inhibition of JAK1 and JAK2 is needed to best control LCMV-induced immunopathology.


Subject(s)
Disease Models, Animal , Lymphohistiocytosis, Hemophagocytic , Nitriles , Pyrazoles , Pyrimidines , Animals , Pyrimidines/pharmacology , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/chemically induced , Lymphohistiocytosis, Hemophagocytic/pathology , Pyrazoles/pharmacology , Pyrazoles/therapeutic use , Mice , Janus Kinase 1/antagonists & inhibitors , Janus Kinase 1/metabolism , Janus Kinase 1/genetics , Pyrroles/pharmacology , Pyrroles/therapeutic use , Janus Kinase 2/antagonists & inhibitors , Janus Kinase 2/genetics , Janus Kinase 2/metabolism , Mice, Inbred C57BL , Sulfonamides/pharmacology , Sulfonamides/therapeutic use , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/genetics , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Piperidines/pharmacology , Humans , Benzenesulfonamides , Bridged-Ring Compounds , Pyrrolidines
15.
Ann Hematol ; 103(5): 1541-1547, 2024 May.
Article in English | MEDLINE | ID: mdl-38467825

ABSTRACT

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.


Subject(s)
Epstein-Barr Virus Infections , Leishmaniasis, Visceral , Lymphohistiocytosis, Hemophagocytic , Child , Humans , Epstein-Barr Virus Infections/complications , Epstein-Barr Virus Infections/drug therapy , Epstein-Barr Virus Infections/diagnosis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Lymphohistiocytosis, Hemophagocytic/etiology , Herpesvirus 4, Human , Leishmaniasis, Visceral/complications , Leishmaniasis, Visceral/diagnosis , Leishmaniasis, Visceral/drug therapy , Retrospective Studies , Fibrinogen , Triglycerides/therapeutic use , Lactate Dehydrogenases
18.
Front Immunol ; 15: 1282804, 2024.
Article in English | MEDLINE | ID: mdl-38415256

ABSTRACT

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.


Subject(s)
Immune System Diseases , Lymphohistiocytosis, Hemophagocytic , Child , Humans , Disease Susceptibility , Homeostasis , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/drug therapy , Immune System Diseases/diagnosis
19.
Clin Lab ; 70(2)2024 Feb 01.
Article in English | MEDLINE | ID: mdl-38345991

ABSTRACT

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.


Subject(s)
Lymphohistiocytosis, Hemophagocytic , Rheumatic Diseases , Adult , Humans , Lamotrigine/adverse effects , Lymphohistiocytosis, Hemophagocytic/chemically induced , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Anticonvulsants/adverse effects , Syndrome
20.
Immun Inflamm Dis ; 12(2): e1202, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38411294

ABSTRACT

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.


Subject(s)
Histiocytic Necrotizing Lymphadenitis , Lymphohistiocytosis, Hemophagocytic , Adult , Humans , Child , Histiocytic Necrotizing Lymphadenitis/complications , Histiocytic Necrotizing Lymphadenitis/diagnosis , Histiocytic Necrotizing Lymphadenitis/drug therapy , Lymphohistiocytosis, Hemophagocytic/complications , Lymphohistiocytosis, Hemophagocytic/diagnosis , Lymphohistiocytosis, Hemophagocytic/drug therapy , Positron Emission Tomography Computed Tomography/adverse effects , Lymph Nodes , Biopsy/adverse effects
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