Plasma signaling factors in patients with langerhans cell histiocytosis (LCH) correlate with relative frequencies of LCH cells and t cells within lesions

Langerhans cell histiocytosis (LCH) lesions contain an inflammatory infiltrate of immune cells including myeloid-derived LCH cells. Cell-signaling proteins within the lesion environment suggest that LCH cells and T cells contribute majorly to the inflammation. Foxp3+ regulatory T cells (Tregs) are enriched in lesions and blood from patients with LCH and are likely involved in LCH pathogenesis. In contrast, mucosal associated invariant T (MAIT) cells are reduced in blood from these patients and the consequence of this is unknown. Serum/plasma levels of cytokines have been associated with LCH disease extent and may play a role in the recruitment of cells to lesions. We investigated whether plasma signaling factors differed between patients with active and non-active LCH. Cell-signaling factors (38 analytes total) were measured in patient plasma and cell populations from matched lesions and/or peripheral blood were enumerated. This study aimed at understanding whether plasma factors corresponded with LCH cells and/or LCH-associated T cell subsets in patients with LCH. We identified several associations between plasma factors and lesional/circulating immune cell populations, thus highlighting new factors as potentially important in LCH pathogenesis. This study highlights plasma cell-signaling factors that are associated with LCH cells, MAIT cells or Tregs in patients, thus they are potentially important in LCH pathogenesis. Further study into these associations is needed to determine whether these factors may become suitable prognostic indicators or therapeutic targets to benefit patients. Copyright © 2022 Mitchell, Kvedaraite, von Bahr Greenwood, Lourda, Henter, Berzins and Kannourakis

Screening for neurodegeneration in Langerhans cell histiocytosis with neurofilament light in plasma

Patients with Langerhans cell histiocytosis (LCH) may develop progressive neurodegeneration in the central nervous system (ND-CNS-LCH). Neurofilament light protein (NFL) in cerebrospinal fluid (CSF) is a promising biomarker to detect and monitor ND-CNS-LCH. We compared paired samples of NFL in plasma (p-NFL) and CSF in 10 patients (19 samples). Nine samples had abnormal CSF-NFL (defined as ≥380 ng/l) with corresponding p-NFL ≥ 2 ng/l. Ten samples had CSF-NFL < 380 ng/l; eight (80%) with p-NFL < 2 ng/l (p < 0.001; Fisher's exact test). Thus, our results suggest that p-NFL may be used to screen for ND-CNS-LCH. Further studies are encouraged, including the role of p-NFL for monitoring of ND-CNS-LCH

Altered populations of unconventional T Cell lineages in patients with Langerhans Cell Histiocytosis

Langerhans cell histiocytosis (LCH) lesions are defined by the presence of CD1a+/CD207+ myeloid cells, but many other immune cells are present including unconventional T cells, which have powerful immunoregulatory functions. Unconventional T cell lineages include mucosal-associated invariant T (MAIT) cells, type I natural killer T (NKT) cells and gamma-delta (γδ) T cells, which are associated with many inflammatory conditions, although their importance has not been studied in LCH. We characterized their phenotype and function in blood and lesions from patients with LCH, and identified a deficiency in MAIT cell frequency and abnormalities in the subset distributions of γδ T cells and NKT cells. Such abnormalities are associated with immune dysregulation in other disease settings and are therefore potentially important in LCH. Our study is the first to recognize alterations to MAIT cell proportions in patients with LCH. This finding along with other abnormalities identified amongst unconventional T cells could potentially influence the onset and progression of LCH, thereby highlighting potential targets for new immune based therapies

Clinical presentation of hemophagocytic lymphohistiocytosis in adults is less typical than in children

OBJECTIVE: Hemophagocytic lymphohistiocytosis in adults is largely underdiagnosed. To improve the rate and accuracy of diagnosis in adults, the clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis were analyzed in and compared between adults and children in a Chinese cohort. METHOD: Data from 50 hemophagocytic lymphohistiocytosis patients, including 34 adults and 16 children who fulfilled the 2004 hemophagocytic lymphohistiocytosis diagnostic criteria, were collected and analyzed. RESULTS: 1. Etiological factors: The proportion of Epstein-Barr virus infection was lower in adults compared with children, whereas fungal infection and natural killer/T cell lymphoma were more frequent in adults (

Hyperinflammation in critically ill

Background: A wide spectrum of inflammatory responses, with overlapping characteristics, is encountered in critically ill patients in intensive care. At one extreme, critically ill patients may develop the potentially fatal condition secondary hemophagocytic lymphohistiocytosis (sHLH), characterized by excessive inflammation (hyperinflammation), driven by a ‘cytokine storm’, and multiple organ failure. Infections, malignancies and autoimmune diseases are the most common conditions associated with the development of sHLH. Prompt diagnosis and early appropriate intervention is crucial to improve survival in sHLH. Corticosteroids are a cornerstone of HLH therapy. The addition of the cytotoxic drug etoposide has been instrumental in the successful treatment of primary HLH, and may reduce morbidity and mortality also in selected cases of sHLH. While it is established that defective lymphocyte cytotoxicity causes primary HLH , the cause of sHLH remains incompletely understood. Aims: The overall aim of the thesis was to broaden our knowledge of hyperinflammation and HLH in critically ill, with a focus on intensive care, to better identify the critically ill patients with hyperinflammation that could benefit from anti-inflammatory therapy, in order to reduce morbidity and improve survival. We also aimed to investigate the role of cytotoxic lymphocytes, and possible genetic correlations, in the pathogenesis of hyperinflammation and sHLH in critically ill. Methods: The studies included several critically ill patient cohorts in intensive care, some with extracorporeal membrane oxygenation (ECMO) support, with various underlying condition s. Results: Secondary HLH was encountered in critically ill patients in intensive care with a high proportion of malignancies and immunosuppression, in influenza AH1N1 infected patients, in severe dengue, and in systemic autoimmune conditions. The mortality in sHLH in critically ill is high. HLH patients were generally younger, with fewer comorbidities and predominantly male. Hyperferritinemia, which correlated with elevated soluble IL-2R and CRP, and thrombocytopenia were identified in critically ill in ICU, and were more prominent in inflammatory responses such as sepsis. However, the highest median levels of ferritin, and soluble IL-2R, were observed in HLH patients, who also demonstrated other common manifestations of sHLH such as cytopenias, elevated liver function tests and triglycerides, hemophagocytosis in the bone marrow and splenomegaly. In global diseases, such as severe dengue and pandemic influenza AH1N1, we found that a proportion of patients do develop hyperinflammation, albeit not always recognized which therefore limits appropriate treatment. A subset of critically ill patients not meeting HLH criteria (i.e. with <5 of 8 diagnostic HLH-2004 criteria and a median HScore of 138), but with high SOFA score (median 16.5) and fatal outcome, had similar levels of ferritin to HLH patients and highly elevated liver tests, but HLH patients had a significantly higher ferritin/ALT ratio, a possible novel diagnostic aid for the diagnosis of HLH. A faster rate of increase of ferritin was associated with a higher risk of death. In critically ill in ICU and severe dengue, elevated AST and SOFA score were independent risk factors of mortality. Reduced absolute numbers of NK cells and CTLs, and reduced lymphocyte cytotoxicity, were observed in critically ill, more prominent in sHLH patients with hyperferritinemia, probably contributing to the development of sHLH. Rare variants in HLH-causing genes were identified in a few patients. With regard to specific treatment, a number of children with severe MAS-HLH despite conventional therapy responded promptly to the addition of moderately dosed etoposide. Conclusions: Secondary HLH can be identified in various conditions in critically ill patients, who should be monitored for signs of hyperinflammation and progressive organ failure for prompt HLH evaluation using currently available diagnostic tools, including ferritin and soluble IL-2R, and additional helpful parameters. Early diagnosis and appropriate HLH-directed therapy, including etoposide in selected cases, is likely beneficial to reduce morbidity and improve survival in sHL

Foxp3+ tregs from langerhans cell histiocytosis lesions co-express CD56 and have a definitively regulatory capacity

Langerhans cell histiocytosis (LCH) lesions contain myeloid lineage ‘LCH’ cells. Regulatory T cells (Tregs) are also enriched within lesions, although their role in LCH pathogenesis is unknown. LCH cells are thought to produce the transforming growth factor beta (TGF-β) within lesions, however whether Tregs contribute is unestablished. Using flow cytometry, we analyzed relative frequencies of live Tregs from LCH patients and identified CD56 expression and TGF-β production by lesion Tregs. While CD56+ Tregs were enriched in lesions, overall CD56+ T cells were reduced in the blood from active LCH patients compared to non-active disease patients, and there was a negative correlation between CD8+CD56+ T cells and Tregs. We propose that inducing a Treg phenotype in T cells such as CD56+ T cells may be a mechanism by which LCH cells divert inflammatory T cell responses. Thus, Tregs within LCH lesions are likely an important component in LCH pathogenesis. © 202

Clinical and laboratory signs of haemophagocytic lymphohistiocytosis associated with pandemic influenza A (H1N1) infection in patients needing extracorporeal membrane oxygenation A retrospective observational study

BACKGROUND: Severe pandemic influenza has been associated with the hyperinflammatory condition secondary haemophagocytic lymphohistiocytosis (HLH). OBJECTIVES: To determine the frequency, degree, character and possible cause of influenza-associated HLH in critically ill patients with severe acute respiratory distress syndrome due to influenza A (H1N1) infection requiring extracorporeal membrane oxygenation (ECMO) support at our hospital. DESIGN: A retrospective observational study. PATIENTS AND SETTING: Medical data were retrieved retrospectively from 11 consenting patients of thirteen adults infected with pandemic influenza A (H1N1) 2009 requiring ECMO between July 2009 and January 2010 at the ECMO Centre of Karolinska University Hospital, Stockholm, Sweden. All patients were evaluated for HLH using HLH-2004 criteria and HScore. RESULTS: Eleven patients (median age 31 years) were included in the study and all survived. All patients showed signs of multiple organ dysfunction and pronounced inflammation, more severe in the four patients with HLH who had significantly higher peak serum concentrations of ferritin (P = 0.024), alkaline phosphatase (P = 0.012) and gamma-glutamyl transferase (P = 0.024), lower concentration of albumin (P = 0.0086) and more frequently hepatomegaly (P = 0.048). Abnormal lymphocyte cytotoxicity (lytic units &lt;10) and a low proportion of natural killer (NK) cells were observed in three of four patients with HLH. Notably, we found a significant inverse correlation between serum ferritin concentration and NK cell and cytotoxic T lymphocyte percentages (r(s) = -0.74, P = 0.0013 and r(s) = -0.79, P = 0.0025, respectively). One HLH patient received HLH-directed cytotoxic therapy, another intravenous immunoglobulin and the other two no specific HLH-directed therapy. CONCLUSION: Critically ill patients, including healthy young adults, with pandemic influenza may develop HLH and should be monitored for signs of hyperinflammation and increasing organ dysfunction, and evaluated promptly for HLH because HLH-directed therapy may then be beneficial. The association of low NK percentages with hyperferritinaemia may suggest a role for reduced NK cell numbers, possibly also cytotoxic T lymphocytes, and subsequently reduced lymphocyte cytotoxicity, in the pathogenesis of hyperinflammation and secondary HLH

Clinical presentation of hemophagocytic lymphohistiocytosis in adults is less typical than in children

OBJECTIVE: Hemophagocytic lymphohistiocytosis in adults is largely underdiagnosed. To improve the rate and accuracy of diagnosis in adults, the clinical and laboratory characteristics of hemophagocytic lymphohistiocytosis were analyzed in and compared between adults and children in a Chinese cohort. METHOD: Data from 50 hemophagocytic lymphohistiocytosis patients, including 34 adults and 16 children who fulfilled the 2004 hemophagocytic lymphohistiocytosis diagnostic criteria, were collected and analyzed. RESULTS: 1. Etiological factors: The proportion of Epstein-Barr virus infection was lower in adults compared with children, whereas fungal infection and natural killer/T cell lymphoma were more frequent in adults (P19 mmol/L and lactate dehydrogenase >500 U/L compared with adults (P<0.05). 3. The time interval from the onset of symptoms to clinical diagnosis was significantly shorter in pediatric patients than in adults (P<0.05). CONCLUSIONS: Certain clinical features were different between the two groups. The less characteristic clinical presentation of hemophagocytic lymphohistiocytosis in adults may make the disease more difficult to diagnose. Our findings suggest that hemophagocytic lymphohistiocytosis should be considered when an adult patient presents with the above-mentioned symptoms