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.

Enteric Fever-Associated Hemophagocytic Lymphohistiocytosis: A Systematic Review of Clinical Characteristics and Outcomes.

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.

Clinical Features of Non-Hodgkin Lymphoma-Associated Hemophagocytic Syndrome: a Retrospective Study.

BACKGROUND: This study aims to improve the understanding of lymphoma-associated hemophagocytic syndrome, and find effective methods to identify and manage this fatal disease. METHODS: Patients diagnosed with non-Hodgkin lymphoma-associated hemophagocytic syndrome from January 2008 to December 2022 in our center were included. Univariate and multivariate analyses were also conducted using the Cox proportional hazards model. RESULTS: Among 26 patients, 22 patients were diagnosed with T/NK cell lymphoma, while 4 patients were diagnosed with diffuse large B cell lymphoma. A total of 16 patients died with a median follow-up of 71 (26, 236) days. Compared with B cell lymphoma-associated hemophagocytic syndrome patients, T/NK cell lymphoma patients are younger, have lower platelet count, fibrinogen concentration, and serum albumin, have higher blood ß2-mi-croglobulin levels and ferritin, are more likely to be infected with Epstein-Barr virus, are more inclined have a simultaneously occurrence of lymphoma and hemophagocytic syndrome. In multivariate analysis, fibrinogen, albumin, cholinesterase, uric acid, triglyceride, and ferritin are significantly associated with overall mortality. CONCLUSIONS: LAHS is a rare disease with poor prognosis. Early anti-inflammatory treatment combined with anti-lymphoma therapy can improve the overall survival time of patients. Prospective multi-center studies with larger sample sizes and longer follow-up periods are needed to further investigate optimal treatment and prognosis.

Comprehensive evaluation of immune dysregulation in secondary hemophagocytic lymphohistiocytosis.

Host immune dysfunction plays a crucial role in the onset, progression, and outcome of hemophagocytic lymphohistiocytosis (HLH). This study aimed to comprehensively evaluate the peripheral immune profiles in patients with newly diagnosed secondary hemophagocytic lymphohistiocytosis (sHLH), and explore their predictive value for patient prognosis. A total of 77 patients with sHLH were enrolled in this study, with 31 of them experiencing mortality. Flow cytometry was used to assess the percentages, absolute numbers, and phenotypes of lymphocyte subsets. Simultaneously, cytokine levels and routine laboratory indicators were also collected. In sHLH patients, lymphocyte subset absolute numbers were significantly impaired, accompanied by T cell hyperactivation, B cell hyperactivation, and increased plasmablast proliferation. Prognostic analysis revealed that lower CD8+ T cell percentages, elevated APTT, IL-6, IL-10 levels, and increased CD4+CD28null T cell proportions were associated with poor patient outcomes. The study demonstrates dysregulation in the counts and phenotypes of lymphocyte subsets in sHLH patients. Several key factors, including IL-6, IL-10, APTT, and various T cell percentages, have potential as prognostic markers and therapeutic targets in sHLH.

A case of Crimean-Congo haemorrhagic fever complicated with portal vein thrombosis and hemophagocytosis.

OBJECTIVES: Crimean-Congo haemorrhagic fever (CCHF) is a zoonotic viral infection which is an important public health problem in Turkey. CCHF causes fever and bleeding and can lead to severe health outcomes. The study aims to report a case of a male patient with severe CCHF, hemophagocytic lymphohistiocytosis (HLH) treated with steroids and portal vein thrombosis. CASE REPORT: A 37-year-old man was admitted to the emergency department with complaints of high fever, headache, myalgia and diarrhoea. The patient travelled to the endemic region of Turkey. In laboratory findings, thrombocytopenia, abnormal liver function tests and elevated coagulation parameters were observed. Real-time polymerase chain reaction assay was used for diagnosis of CCHF. Hypofibrinogenemia, hypertriglyceridemia, elevated ferritin and d-dimer levels were observed in the clinical follow-up. Prednisolone treatment was performed due to considered the diagnosis of HLH. Portal vein thrombosis was detected on abdominal computed tomography scan. He was successfully treated with ribavirin, corticosteroids, anticoagulant and supportive therapy. CONCLUSION: The clinical presentation of CCHF can range from self-limiting flu-like to severe symptoms possibly fatal. Acute portal vein embolism is a rare complication that has not been reported before to our knowledge. Corticosteroids may be a life-saving treatment for CCHF patients presenting with HLH.

Hemophagocytic lymphohistiocytosis and macrophage activation syndrome: two rare sides of the same devastating coin.

Hemophagocytic lymphohistiocytosis (HLH) is a rare genetic hyperinflammatory syndrome that occurs early in life. Macrophage activation syndrome (MAS) usually refers to a secondary form of HLH associated with autoimmunity, although there are other causes of secondary HLH, such as infections and malignancy. In this article, we reviewed the concepts, epidemiology, clinical and laboratory features, diagnosis, differential diagnosis, prognosis, and treatment of HLH and MAS. We also reviewed the presence of MAS in the most common autoimmune diseases that affect children. Both are severe diseases that require prompt diagnosis and treatment to avoid morbidity and mortality.

Immunopathology of and potential therapeutics for secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome: a translational perspective.

Secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) is a life-threatening immune disorder triggered by rheumatic disease, infections, malignancies, or medications. Characterized by the presence of hemophagocytic macrophages and a fulminant cytokine storm, sHLH/MAS leads to hyperferritinemia and multiorgan failure and rapidly progresses to death. The high mortality rate and the lack of specific treatments necessitate the development of a new drug. However, the complex and largely unknown immunopathologic mechanisms of sHLH/MAS, which involve dysfunction of various immune cells, diverse etiologies, and different clinical contexts make this effort challenging. This review introduces the terminology, diagnosis, and clinical features of sHLH/MAS. From a translational perspective, this review focuses on the immunopathological mechanisms linked to various etiologies, emphasizing potential drug targets, including key molecules and signaling pathways. We also discuss immunomodulatory biologics, existing drugs under clinical evaluation, and novel therapies in clinical trials. This systematic review aims to provide insights and highlight opportunities for the development of novel sHLH/MAS therapeutics.

Febrile Ulceronecrotic Mucha-Habermann Disease Associated With Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature.

ABSTRACT: Mucha-Habermann disease (MHD) is an inflammatory skin disease characterized by polymorphous eruptions of erythematous, necrotic macules that have been reported for similarities to cutaneous T-cell lymphoma. Febrile ulceronecrotic MHD (FUMHD) represents a severe variant of MHD, marked by ulcers, hemorrhagic bullae, and systemic symptoms. Herein, we report a case of a severely atypical lymphomatoid expression of FUMHD associated with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 21-year-old woman was admitted to the hospital with a rapidly progressive necrotic papular rash. Physical examination revealed right orbital swelling, bilateral hemorrhagic auricular bullae, and multiple ulcerative purpuric papulonodules on the trunk, face, and extremities. Biopsy indicated a dermal and subcutaneous infiltrate of atypical CD8 + lymphocytes with loss of CD5 and reduction in CD7 expression, along with features of lymphomatoid vasculitis. A diagnosis of a severely atypical lymphomatoid expression of FUMHD was made. The patient also met 7 of 9 HLH-2004 criteria, leading to a diagnosis of HLH. Positron emission tomography/computed tomography, flow cytometry, and rheumatologic workup were unremarkable. Treatment with an eight-week course of etoposide and dexamethasone for HLH led to rapid clinical improvement. Over time, her skin lesions regressed and eventually scabbed over to leave hyperpigmented scars, confirming the diagnosis of MHD. She has remained stable, off therapy for 4 years. Although potentially fatal, FUMHD often exhibits favorable outcomes and may resolve without recurrence, as in our patient. FUMHD should be considered in the differential diagnosis for patients presenting with cutaneous CD8 + necrotizing angiocentric lymphoproliferative disease complicated by 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.

Hemophagocytic lymphohistiocytosis following enteric fever: A rare autopsy case report.

ABSTRACT: Hemophagocytic lymphohistiocytosis (HLH) is a severe and frequently underdiagnosed disorder of systemic immune dysregulation resulting in hypercytokinemia and histologically evident hemophagocytosis, We report a case of a 34-year-old man who presented with breathlessness, generalized weakness, and fever of unknown origin with pancytopenia. Clinically the patient was admitted for febrile illness, and treated symptomatically but his general condition worsened leading to death within 21 hours of admission. A complete autopsy was performed. The deceased had a significant past history of repeated episodes of fever, weight loss, and axillary lymphadenopathy over a period of 8 months with multiple hospital admissions. He was also diagnosed with enteric fever (Widal test and Typhi IgM positive) at the start of these episodes. Hemogram during this period revealed persistent pancytopenia. Serum ferritin, serum triglycerides, and liver function tests were consistently deranged. Investigations for the etiology of fever and blood cultures were negative while the bone marrow aspirate revealed a normocellular marrow. CT abdomen-pelvis showed mild hepatomegaly with enlarged retroperitoneal lymph nodes. Infective endocarditis, lymphoma, and bronchopneumonia were being considered the clinical diagnoses. The significant autopsy findings were hepatosplenomegaly with retroperitoneal lymphadenopathy and multiple gastric ulcers. On microscopy, the liver, spleen, bone marrow, and lymph nodes showed characteristic hemophagocytosis. Post-mortem histopathological examination clinched the diagnosis of HLH and fulfilled six out of eight diagnostic criteria of the HLH-2004 protocol. We discuss the clinical course and diagnosis of this unique case and strive to create awareness about secondary HLH induced by common diseases, such as enteric fever.

Initial diagnosis of extranodal NK/T-cell lymphoma in pericardial fluid with concomitant hemophagocytic lymphohistiocytosis (HLH).

Extranasal natural killer/T-cell lymphoma arising in the heart is rare and typically presents with non-specific clinical symptoms, necessitating a biopsy for a definitive diagnosis. We report an unusual case of a 48-year-old male who initially presented with chest pain and shortness of breath. Subsequent diagnosis via pericardial fluid analysis, including flow cytometry and immunohistochemical stains, revealed extranasal NK/T-cell lymphoma without sinonasal involvement. The analysis identified neoplastic lymphoid cells expressing CD2, cytoplasmic CD3, Epstein-Barr virus, and CD56 and exhibiting increased Ki-67 staining. Additionally, the patient developed hemophagocytosis lymphocytosis secondary to NK/T cell lymphoma. Treatment included an interleukin-1 receptor antagonist (anakinra), dexamethasone, rituximab, and etoposide. Unfortunately, the patient's condition rapidly deteriorated, leading to multiorgan failure and eventual demise. Given the rarity of this lymphoma, early diagnosis based on a high suspicion level provides the best chance for improved overall survival.

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.

Performances of the H-score and the HLH-2004 score in the positive diagnosis of secondary hemophagocytic lymphohistiocytosis.

Hemophagocytic lymphocytosis (HLH) is a rare clinical and biological entity that can be life-threatening. Early diagnosis can improve the overall prognosis of HLH. OBJECTIVES: The aims of this study are to evaluate the performances of HLH-2004-score and H-score in identifying patients with secondary HLH and to determine an optimal H-score cut-off for our population. METHODS: A retrospective study that involved all patients, with images of hemophagocytosis in myelograms analyzed at the laboratory of hematology, followed at these departments: clinical-hematology, internal-medicine, infectious-diseases and gastroenterology, University-Hospital "Hédi-Chaker", Sfax-Tunisia, (June2017-May2021). We identified two groups of patients: "HLH" and "Not-HLH". Then, for each patient, we calculated the HLH-2004-score and the H-score. RESULTS: Forty-two patients were included in this study. Twenty-five (60 %) belonging to group "HLH" and seventeen (40 %) to group "Not-HLH" with a mean age (38.72 vs. 39.82 years, p = 0.846) respectively. The study of the performances demonstrated that H-score had better performances. The best cut-off value of H-score for our population was 158.5, allowing a gain in sensitivity (from 92 % to 96 %) compared to the original study cut-off of 169. CONCLUSION: Both H-score and HLH-2004-score showed excellent discriminative powers with better performances for H-score. The new H-score cut-off at 158.5 can be applied to our population.