Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory syndrome induced by aberrantly activated macrophages and cytotoxic T cells. The primary (genetic) form, caused by mutations ...affecting lymphocyte cytotoxicity and immune regulation, is most common in children, whereas the secondary (acquired) form is most frequent in adults. Secondary HLH is commonly triggered by infections or malignancies but may also be induced by autoinflammatory/autoimmune disorders, in which case it is called macrophage activation syndrome (MAS; or MAS-HLH). Most information on the diagnosis and treatment of HLH comes from the pediatric literature. Although helpful in some adult cases, this raises several challenges. For example, the HLH-2004 diagnostic criteria developed for children are commonly applied but are not validated for adults. Another challenge in HLH diagnosis is that patients may present with a phenotype indistinguishable from sepsis or multiple organ dysfunction syndrome. Treatment algorithms targeting hyperinflammation are frequently based on pediatric protocols, such as HLH-94 and HLH-2004, which may result in overtreatment and unnecessary toxicity in adults. Therefore, dose reductions, individualized tailoring of treatment duration, and an age-dependent modified diagnostic approach are to be considered. Here, we present expert opinions derived from an interdisciplinary working group on adult HLH, sponsored by the Histiocyte Society, to facilitate knowledge transfer between physicians caring for pediatric and adult patients with HLH, with the aim to improve the outcome for adult patients affected by HLH.
Summary
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.
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome that often requires critical care support and remains difficult to diagnose. These guidelines are meant to aid in the early ...recognition, diagnosis, supportive care, and treatment of patients with hemophagocytic lymphohistiocytosis in ICUs.
The literature searches were performed with PubMed (MEDLINE).
Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome."
The Histiocyte Society developed these consensus recommendations on the basis of published reports and expert opinions with level of evidence provided for each recommendation. They were endorsed by the Society of Critical Care Medicine.
Testing for hemophagocytic lymphohistiocytosis should be initiated promptly in all patients admitted to ICUs with an unexplained or disproportionate inflammatory response, especially those with rapid clinical deterioration. Meeting five or more of eight hemophagocytic lymphohistiocytosis 2004 diagnostic criteria serves as a valuable diagnostic tool for hemophagocytic lymphohistiocytosis. Early aggressive critical care interventions are often required to manage the multisystem organ failure associated with hemophagocytic lymphohistiocytosis. Thorough investigation of the underlying triggers of hemophagocytic lymphohistiocytosis, including infections, malignancies, and autoimmune/autoinflammatory diseases, is essential. Early steroid treatment is indicated for patients with familial hemophagocytic lymphohistiocytosis and is often valuable in patients with acquired hemophagocytic lymphohistiocytosis (i.e., secondary hemophagocytic lymphohistiocytosis) without previous therapy, including macrophage activation syndrome (hemophagocytic lymphohistiocytosis secondary to autoimmune/autoinflammatory disease) without persistent or relapsing disease. Steroid treatment should not be delayed, particularly if organ dysfunction is present. In patients with macrophage activation syndrome, whose disease does not sufficiently respond, interleukin-1 inhibition and/or cyclosporine A is recommended. In familial hemophagocytic lymphohistiocytosis and severe, persistent, or relapsing secondary macrophage activation syndrome, the addition of prompt individualized, age-adjusted etoposide treatment is recommended.
Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.
Langerhans cell histiocytosis (LCH) is a potentially life-threatening inflammatory myeloid neoplasia linked to paediatric neurodegeneration, whereby transformed LCH cells form agglomerated lesions in ...various organs. Although MAP-kinase pathway mutations have been identified in LCH cells, the functional consequences of these mutations and the mechanisms that cause the pathogenic behaviour of LCH cells are not well understood. In our study, we used an in vitro differentiation system and RNA-sequencing to compare monocyte-derived dendritic cells from LCH patients to those derived from healthy controls or patients with Crohn's disease, a non-histiocytic inflammatory disease. We observed that Interferon-γ treatment exacerbated intrinsic differences between LCH patient and control cells, including strikingly increased endoand exocytosis gene activity in LCH patients. We validated these transcriptional patterns in lesions and functionally confirmed that LCH cells exhibited increased endo- and exocytosis. Furthermore, RNA-sequencing of extracellular vesicles (EV) revealed the enrichment of pathological transcripts involved in cell adhesion, MAP-kinase pathway, vesicle trafficking and T-cell activation in LCH patients. Thus, we tested the effect of the LCH secretome on lymphocyte activity and found significant activation of NK cells. These findings implicate EVs in the pathology of LCH for the first time, in line with their established roles in the formation of various other tumour niches. Thus, we describe novel traits of LCH patient cells and suggest a pathogenic mechanism of potential therapeutic and diagnostic importance.
Aim
To present the first case series of patients with Langerhans cell histiocytosis (LCH) also affected by Crohn's disease (CD), both of which are granulomatous diseases, and in LCH investigate the ...role of interleukin (IL)‐23, which is a well‐described disease mediator in CD.
Methods
A case series of three patients with LCH and CD were described; a cohort of LCH patients (n = 55) as well as controls (n = 55) were analysed for circulating IL‐23 levels; and the relation between the percentage of LCH cells in lesions and circulating IL‐23 levels was analysed in seven LCH patients.
Results
Differential diagnostic challenges for these two granulomatous diseases were highlighted in the case series, and it took up to 3 years to diagnose CD. Elevated IL‐23 levels were found in LCH patients. The amount of lesional LCH cells correlated with the levels of circulating IL‐23.
Conclusion
Both CD and LCH should be considered in patients with inflammatory gastrointestinal involvement. The IL‐23 pathway is a common immunological trait between these two granulomatous diseases.
Abstract
Background
Globally, ~500 000 people with severe dengue (SD) require hospitalization yearly; ~12 500 (2.5%) die. Secondary hemophagocytic lymphohistiocytosis (sHLH) is a potentially fatal ...hyperinflammatory condition for which HLH-directed therapy (as etoposide and dexamethasone) can be life-saving. Prompted by the high mortality in SD and the increasing awareness that patients with SD may develop sHLH, our objectives were to (1) determine the frequency of dengue-HLH in SD, (2) describe clinical features of dengue-HLH, (3) assess mortality rate in SD and dengue-HLH, and (4) identify mortality-associated risk factors in SD.
Methods
A 5-year retrospective single-center study in all adult patients with SD admitted to a tertiary intensive care unit in Malaysia.
Results
Thirty-nine of 180 (22%) patients with SD died. Twenty-one of 180 (12%) had HLH defined as an HLH probability ≥70% according to histo score (HScore); 9 (43%) died. Similarly, 12 of 31 (39%) fulfilling ≥4 and 7 of 9 (78%) fulfilling ≥5 HLH-2004 diagnostic criteria died. Peak values of aspartate aminotransferase (AST), alanine aminotransferase, lactate dehydrogenase, and creatinine correlated to fatality (odds ratios ORs, 2.9, 3.4, 5.8, and 31.9; all P < .0001), as did peak ferritin (OR, 2.5; P = .0028), nadir platelets (OR, 1.9; P = .00068), hepatomegaly (OR, 2.9; P = .012), and increasing age (OR, 1.2; P = .0043). Multivariable logistic regression revealed peak AST (OR, 2.8; P = .0019), peak creatinine (OR, 7.3; P = .0065), and SOFA (Sequential Organ Failure Assessment) score (OR, 1.4; P = .0051) as independent risk factors of death.
Conclusions
Be observant of dengue-HLH due to its high mortality. A prospective study is suggested on prompt HLH-directed therapy in SD patients with hyperinflammation and evolving multiorgan failure at risk of developing dengue-HLH.
Patient with severe dengue (SD) may develop secondary hemophagocytic lymphohistiocytosis (HLH), which is potentially fatal but treatable. We report an SD mortality of 22% and dengue-HLH mortality ~40%. Consider prompt HLH-directed therapy in patients with, or at risk of, dengue-HLH.
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.
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.
•Foxp3+ Tregs from Langerhans cell histiocytosis lesions co-express CD56•Foxp3+ Tregs from Langerhans cell histiocytosis lesions produce TGF-β•Treg enrichment in LCH patients is associated with reduced CD8+CD56+ T cells
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