Efficacy of T cell assays for the diagnosis of primary defects in cytotoxic lymphocyte exocytosis.

Primary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening disorder associated with autosomal recessive variants in genes required for perforin-mediated lymphocyte cytotoxicity. A rapid diagnosis is crucial for successful treatment. Although defective cytotoxic T lymphocyte (CTL) function causes pathogenesis, quantification of natural killer (NK) cell exocytosis triggered by K562 target cells currently represents a standard diagnostic procedure for primary HLH. We have prospectively evaluated different lymphocyte exocytosis assays in 213 patients referred for evaluation for suspected HLH and related hyperinflammatory syndromes. A total of 138 patients received a molecular diagnosis consistent with primary HLH. Compared to routine K562 cell-based assays, assessment of Fc receptor-triggered NK-cell and T cell receptor-triggered CTL exocytosis displayed higher sensitivity and improved specificity for the diagnosis of primary HLH, with these assays combined providing a sensitivity of 100% and specificity of 98.3%. By comparison, NK-cell exocytosis following K562 target cell stimulation displayed a higher inter-individual variability, in part explained by differences in NK-cell differentiation or large functional reductions following shipment. We thus recommend combined analysis of T cell receptor-triggered CTL and Fc receptor-triggered NK-cell exocytosis for the diagnosis of patients with suspected familial HLH or atypical manifestations of congenital defects in lymphocyte exocytosis.

The 2022 EULAR/ACR points to consider at the early stages of diagnosis and management of suspected haemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS).

OBJECTIVE: Haemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening systemic hyperinflammatory syndromes that can develop in most inflammatory contexts. They can progress rapidly, and early identification and management are critical for preventing organ failure and mortality. This effort aimed to develop evidence-based and consensus-based points to consider to assist clinicians in optimising decision-making in the early stages of diagnosis, treatment and monitoring of HLH/MAS. METHODS: A multinational, multidisciplinary task force of physician experts, including adult and paediatric rheumatologists, haematologist/oncologists, immunologists, infectious disease specialists, intensivists, allied healthcare professionals and patients/parents, formulated relevant research questions and conducted a systematic literature review (SLR). Delphi methodology, informed by SLR results and questionnaires of experts, was used to generate statements aimed at assisting early decision-making and optimising the initial care of patients with HLH/MAS. RESULTS: The task force developed 6 overarching statements and 24 specific points to consider relevant to early recognition of HLH/MAS, diagnostic approaches, initial management and monitoring of HLH/MAS. Major themes included the simultaneous need for prompt syndrome recognition, systematic evaluation of underlying contributors, early intervention targeting both hyperinflammation and likely contributors, careful monitoring for progression/complications and expert multidisciplinary assistance. CONCLUSION: These 2022 EULAR/American College of Rheumatology points to consider provide up-to-date guidance, based on the best available published data and expert opinion. They are meant to help guide the initial evaluation, management and monitoring of patients with HLH/MAS in order to halt disease progression and prevent life-threatening immunopathology.

Comparison of EULAR/PRINTO/PReS Ankara 2008 and 2022 ACR/EULAR Classification Criteria for Granulomatosis with Polyangiitis in Children.

OBJECTIVE: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmic antibody-associated vasculitis. The 2022 American College of Rheumatology/European Alliance of Associations for Rheumatology (ACR/EULAR)-endorsed classification criteria for GPA was derived using data only from adult patients. We aimed to assess the performance of the ACR/EULAR classification criteria for GPA in pediatric patients and compare it with the EULAR/Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology European Society (PReS)-endorsed Ankara 2008 criteria for GPA. METHODS: Retrospective data of pediatric patients with GPA in 20 centers from 9 countries were evaluated. The diagnosis of GPA was made according to the expert opinion. The sensitivity, specificity, positive predictive value, and negative predictive value of the criteria sets were evaluated. RESULTS: The study included 77 patients with GPA and 108 controls (immunoglobulin A vasculitis (n = 44), Takayasu's arteritis (n = 20), microscopic polyangiitis (n = 16), polyarteritis nodosa (n = 14), Behçet's disease (n = 12), eosinophilic granulomatosis with polyangiitis (n = 1), and Cogan's syndrome (n = 1)) with a median age of 17.8 and 15.2 years, respectively. Of patients with GPA, constitutional symptoms (85.7%) and ear-nose-throat involvement (79.2%) were the most common presentations. In the GPA group, 73 patients fulfilled the Ankara 2008 criteria and 69 the ACR/EULAR classification criteria. Sensitivities of the Ankara 2008 criteria and the ACR/EULAR classification criteria were 94.8% and 89.6%, while specificities were 95.3% and 96.3%, respectively. No significant difference was found between sensitivities and specificities of both classification criteria (p= 0.229 and p= 0.733, respectively). CONCLUSION: In children, both the ACR/EULAR and EULAR/PRINTO/PReS Ankara 2008 classification criteria for GPA perform well and similarly.

Consensus-Based Guidelines for the Recognition, Diagnosis, and Management of Hemophagocytic Lymphohistiocytosis in Critically Ill Children and Adults.

OBJECTIVE: 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. DATA SOURCES: The literature searches were performed with PubMed (MEDLINE). STUDY SELECTION: Keywords and medical subject headings terms for literature search included "macrophage activation syndrome," hemophagocytic lymphohistiocytosis," and "hemophagocytic syndrome." DATA EXTRACTION: 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. DATA SYNTHESIS: 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. CONCLUSIONS: Further studies are needed to determine optimal treatment for patients with hemophagocytic lymphohistiocytosis in ICUs, including the use of novel and adjunct therapies.

Juvenile idiopathic arthritis, marriage and parenthood: a nationwide matched cohort study.

OBJECTIVES: To compare trajectories of marriage and parenthood in individuals with JIA vs the general population. METHODS: Patients with JIA (n = 4399) were identified in the Swedish National Patient Register (2001-2016) and individually matched to up to five general population comparators on birthyear, sex and residence county (n = 21 981). Marriage and parenthood data were retrieved from the Total Population Register from age 18 y, and parenthood from the Multigeneration Register from age 15 y, respectively. Hazard ratios (HRs) were estimated using Cox regression adjusted for parental education, parental marital status and number of siblings. RESULTS: During a median of 6.3 years of follow-up, 362 patients with JIA and 1744 comparators got married (12.9 vs. 12.5 per 1000 person-years; HR 1.03, 95%CI 0.93-1.15). During a median of 8.8 years of follow-up, 680 patients with JIA and 3477 matched comparators became parents (17.1 vs 17.8 per 1000 person-years; HR 0.94, 95%CI 0.87-1.01). In the subgroup of patients with systemic onset JIA (SJIA), the adjusted hazard ratios for marriage and parenthood were 0.79 (95%CI 0.53-1.17) and 0.73 (95%CI 0.55-0.97), respectively. CONCLUSION: The times to first marriage and first parenthood are similar for patients with JIA and the general population, suggesting that adolescents with JIA transition into family life along a trajectory resembling their community peers. One exception is the subgroup of patients with systemic onset JIA, who become parents for the first time at a lower rate than general population comparators.

Population-based study of multisystem inflammatory syndrome associated with COVID-19 found that 36% of children had persistent symptoms.

AIM: Our aim was to describe the outcomes of multisystem inflammatory syndrome in children (MIS-C) associated with COVID-19. METHODS: This national, population-based, longitudinal, multicentre study used Swedish data that were prospectively collected between 1 December 2020 and 31 May 2021. All patients met the World Health Organization criteria for MIS-C. The outcomes 2 and 8 weeks after diagnosis are presented, and follow-up protocols are suggested. RESULTS: We identified 152 cases, and 133 (87%) participated. When followed up 2 weeks after MIS-C was diagnosed, 43% of the 119 patients had abnormal results, including complete blood cell counts, platelet counts, albumin levels, electrocardiograms and echocardiograms. After 8 weeks, 36% of 89 had an abnormal patient history, but clinical findings were uncommon. Echocardiogram results were abnormal in 5% of 67, and the most common complaint was fatigue. Older children and those who received intensive care were more likely to report symptoms and have abnormal cardiac results. CONCLUSION: More than a third (36%) of the patients had persistent symptoms 8 weeks after MIS-C, and 5% had abnormal echocardiograms. Older age and higher levels of initial care appeared to be risk factors. Structured follow-up visits are important after MIS-C.

A Two-to-Five Year Follow-Up of a Pediatric Acute-Onset Neuropsychiatric Syndrome Cohort.

Little is known about the long-term prognosis of children with pediatric acute-onset neuropsychiatric syndrome (PANS). Out of the 46 eligible patients from the Karolinska PANS cohort, 34 consented to participate in a follow-up (median 3.3 years). Participants underwent a thorough clinical evaluation and were classified according to their clinical course. Resulting groups were compared on clinical characteristics and laboratory test results. We observed significant reductions in clinician-rated PANS symptom severity and improved general function. Two patients were classified as remitted, 20 as relapsing-remitting, and 12 as having a chronic-static/progressive course. The latter group had an earlier onset, greater impairment and received more pharmacological and psychological treatments. Although remission was rare, the majority of children with PANS were significantly improved over the follow-up period but a non-negligible minority of patients displayed a chronic-static/progressive course and required additional treatments. The proposed definitions of flare and clinical course may be useful in future clinical trials.

Therapeutic administration of etoposide coincides with reduced systemic HMGB1 levels in macrophage activation syndrome.

BACKGROUND: Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. HMGB1 is a nuclear protein released extracellularly during proinflammatory lytic cell death or secreted by activated macrophages, NK cells, and additional cell types during infection or sterile injury. Extracellular HMGB1 orchestrates central events in inflammation as a prototype alarmin. TLR4 and the receptor for advanced glycation end products operate as key HMGB1 receptors to mediate inflammation. METHODS: Standard ELISA and cytometric bead array-based methods were used to examine the kinetic pattern for systemic release of HMGB1, ferritin, IL-18, IFN-γ, and MCP-1 before and during treatment of four children with critical MAS. Three of the patients with severe underlying systemic rheumatic diseases were treated with biologics including tocilizumab or anakinra when MAS developed. All patients required intensive care therapy due to life-threatening illness. Add-on etoposide therapy was administered due to insufficient clinical response with standard treatment. Etoposide promotes apoptotic rather than proinflammatory lytic cell death, conceivably ameliorating subsequent systemic inflammation. RESULTS: This therapeutic intervention brought disease control coinciding with a decline of the increased systemic HMGB1, IFN-γ, IL-18, and ferritin levels whereas MCP-1 levels evolved independently. CONCLUSION: Systemic HMGB1 levels in MAS have not been reported before. Our results suggest that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of HMGB1 antagonists. They also advocate therapeutic etoposide administration in severe MAS and provide a possible biological explanation for its mode of action.

Recommendations for the management of hemophagocytic lymphohistiocytosis in adults.

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.

Diagnostic challenges for a novel SH2D1A mutation associated with X-linked lymphoproliferative disease.

Mutations in SH2D1A, encoding the intracellular adaptor signaling lymphocyte activation molecule associated protein (SAP), are associated with X-linked lymphoproliferative disease type 1 (XLP1). We identified a novel hemizygous SH2D1A c.49G > A (p.E17K) variant in a 21-year-old patient with fatal Epstein-Barr virus infection-associated hemophagocytic lymphohistiocytosis. Cellular and biochemical assays revealed normal expression of the SAP variant protein, yet binding to phosphorylated CD244 receptor was reduced by >95%. Three healthy brothers carried the SH2D1A c.49G > A variant. Thus, data suggest that this variant represents a pathogenic mutation, but with variable expressivity. Importantly, our results highlight challenges in the clinical interpretation of SH2D1A variants and caution in using functional flow cytometry assays for the diagnosis of XLP1.

Development and initial validation of the MS score for diagnosis of macrophage activation syndrome in systemic juvenile idiopathic arthritis.

OBJECTIVE: To develop and validate a diagnostic score that aids in identifying macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (sJIA). METHODS: The clinical and laboratory features of 362 patients with sJIA-associated MAS and 404 patients with active sJIA without evidence of MAS were collected in a multinational collaborative project. Eighty percent of the study population was used to develop the score and the remaining 20% constituted the validation sample. A Bayesian Model Averaging approach was used to assess the role of each clinical and laboratory variables in the diagnosis of MAS and to obtain the coefficients of selected variables. The final score, named MAS/sJIA (MS) score, resulted from the linear combination of these coefficients multiplied by the values of each variable. The cut-off that best discriminated MAS from active sJIA was calculated by means of receiver operating characteristic (ROC) curve analysis. Score performance was evaluated in both developmental and validation samples. RESULTS: The MS score ranges from -8.4 to 41.8 and comprises seven variables: central nervous system dysfunction, haemorrhagic manifestations, active arthritis, platelet count, fibrinogen, lactate dehydrogenase and ferritin. A cut-off value ≥-2.1 revealed the best performance in discriminating MAS from active sJIA, with a sensitivity of 0.85, a specificity of 0.95 and a kappa value of 0.80. The good performance of the MS score was confirmed in the validation sample. CONCLUSION: The MS score is a powerful and feasible tool that may assist practitioners in making a timely diagnosis of MAS in patients with sJIA.

Confirmed efficacy of etoposide and dexamethasone in HLH treatment: long-term results of the cooperative HLH-2004 study.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome comprising familial/genetic HLH (FHL) and secondary HLH. In the HLH-94 study, with an estimated 5-year probability of survival (pSu) of 54% (95% confidence interval, 48%-60%), systemic therapy included etoposide, dexamethasone, and, from week 9, cyclosporine A (CSA). Hematopoietic stem cell transplantation (HSCT) was indicated in patients with familial/genetic, relapsing, or severe/persistent disease. In HLH-2004, CSA was instead administered upfront, aiming to reduce pre-HSCT mortality and morbidity. From 2004 to 2011, 369 children aged <18 years fulfilled HLH-2004 inclusion criteria (5 of 8 diagnostic criteria, affected siblings, and/or molecular diagnosis in FHL-causative genes). At median follow-up of 5.2 years, 230 of 369 patients (62%) were alive (5-year pSu, 61%; 56%-67%). Five-year pSu in children with (n = 168) and without (n = 201) family history/genetically verified FHL was 59% (52%-67%) and 64% (57%-71%), respectively (familial occurrence [n = 47], 58% [45%-75%]). Comparing with historical data (HLH-94), using HLH-94 inclusion criteria, pre-HSCT mortality was nonsignificantly reduced from 27% to 19% (P = .064 adjusted for age and sex). Time from start of therapy to HSCT was shorter compared with HLH-94 (P =020 adjusted for age and sex) and reported neurological alterations at HSCT were 22% in HLH-94 and 17% in HLH-2004 (using HLH-94 inclusion criteria). Five-year pSu post-HSCT overall was 66% (verified FHL, 70% [63%-78%]). Additional analyses provided specific suggestions on potential pre-HSCT treatment improvements. HLH-2004 confirms that a majority of patients may be rescued by the etoposide/dexamethasone combination but intensification with CSA upfront, adding corticosteroids to intrathecal therapy, and reduced time to HSCT did not improve outcome significantly.

Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages.

The histiocytoses are rare disorders characterized by the accumulation of macrophage, dendritic cell, or monocyte-derived cells in various tissues and organs of children and adults. More than 100 different subtypes have been described, with a wide range of clinical manifestations, presentations, and histologies. Since the first classification in 1987, a number of new findings regarding the cellular origins, molecular pathology, and clinical features of histiocytic disorders have been identified. We propose herein a revision of the classification of histiocytoses based on histology, phenotype, molecular alterations, and clinical and imaging characteristics. This revised classification system consists of 5 groups of diseases: (1) Langerhans-related, (2) cutaneous and mucocutaneous, and (3) malignant histiocytoses as well as (4) Rosai-Dorfman disease and (5) hemophagocytic lymphohistiocytosis and macrophage activation syndrome. Herein, we provide guidelines and recommendations for diagnoses of these disorders.

Development and Initial Validation of the Macrophage Activation Syndrome/Primary Hemophagocytic Lymphohistiocytosis Score, a Diagnostic Tool that Differentiates Primary Hemophagocytic Lymphohistiocytosis from Macrophage Activation Syndrome.

OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.

2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

To develop criteria for the classification of macrophage activation syndrome (MAS) in patients with systemic juvenile idiopathic arthritis (JIA). A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of 28 experts was first asked to classify 428 patient profiles as having or not having MAS, based on clinical and laboratory features at the time of disease onset. The 428 profiles comprised 161 patients with systemic JIA-associated MAS and 267 patients with a condition that could potentially be confused with MAS (active systemic JIA without evidence of MAS, or systemic infection). Next, the ability of candidate criteria to classify individual patients as having MAS or not having MAS was assessed by evaluating the agreement between the classification yielded using the criteria and the consensus classification of the experts. The final criteria were selected in a consensus conference. Experts achieved consensus on the classification of 391 of the 428 patient profiles (91.4%). A total of 982 candidate criteria were tested statistically. The 37 best-performing criteria and 8 criteria obtained from the literature were evaluated at the consensus conference. During the conference, 82% consensus among experts was reached on the final MAS classification criteria. In validation analyses, these criteria had a sensitivity of 0.73 and a specificity of 0.99. Agreement between the classification (MAS or not MAS) obtained using the criteria and the original diagnosis made by the treating physician was high (κ=0.76). We have developed a set of classification criteria for MAS complicating systemic JIA and provided preliminary evidence of its validity. Use of these criteria will potentially improve understanding of MAS in systemic JIA and enhance efforts to discover effective therapies, by ensuring appropriate patient enrollment in studies.

High systemic levels of the cytokine-inducing HMGB1 isoform secreted in severe macrophage activation syndrome.

Macrophage activation syndrome (MAS) is a potentially fatal complication of systemic inflammation. High mobility group box 1 (HMGB1) is a nuclear protein extensively leaked extracellularly during necrotic cell death or actively secreted by natural killer (NK) cells, macrophages and additional cells during infection or sterile injury. Extracellular HMGB1 orchestrates key events in inflammation as a prototypic alarmin. The redox states of its three cysteines render the molecule mutually exclusive functions: fully reduced "all-thiol HMGB1" exerts chemotactic activity; "disulfide HMGB1" has cytokine-inducing, toll-like receptor 4 (TLR4)-mediated effects­while terminally oxidized "sulfonyl HMGB1" lacks inflammatory activity. This study examines the kinetic pattern of systemic HMGB1 isoform expression during therapy in four children with severe MAS. Three of the four patients with underlying systemic rheumatic diseases were treated with biologics and two suffered from triggering herpes virus infections at the onset of MAS. All patients required intensive care unit therapy due to life-threatening illness. Tandem mass-spectrometric analysis revealed dramatically increased systemic levels of the cytokine-inducing HMGB1 isoform during early MAS. Disease control coincided with supplementary etoposide therapy initiated to boost apoptotic cell death, when systemic HMGB1 levels drastically declined and the molecule emerged mainly in its oxidized, noninflammatory isoform. Systemic interferon (IFN)-γ and ferritin peaked concomitantly with HMGB1, whereas interleukin (IL)-18 and monocyte chemotactic protein (MCP)-1 levels developed differently. In conclusion, this work provides new insights in HMGB1 biology, suggesting that the molecule is not merely a biomarker of inflammation, but most likely also contributes to the pathogenesis of MAS. These observations encourage further studies of disulfide HMGB1 antagonists to improve outcome of MAS.

Incidence and clinical presentation of primary hemophagocytic lymphohistiocytosis in Sweden.

BACKGROUND: Primary hemophagocytic lymphohistiocytosis (HLH) represents a group of inherited hyperinflammatory immunodeficiencies, including familial HLH (FHL), Griscelli syndrome type 2 (GS2), and X-linked lymphoproliferative syndrome (XLP). We previously reported an annual incidence of suspected primary HLH in Sweden 1971-1986 of 0.12 per 100,000 children. Here, we determined if the incidence had increased with concomitant awareness. PROCEDURE: Children <15 years old presenting with HLH 1987-2006 in Sweden were identified through the national mortality registry as well as by nation-wide inquiries to all pediatric centers. HLH was diagnosed according to the HLH-2004 diagnostic guidelines (in case of missing data of at least three of the eight diagnostic criteria, fulfillment of four was sufficient for inclusion). We defined primary HLH as patients presenting with HLH requiring transplantation or dying of disease. RESULTS: Remarkably, the minimal annual incidence rate of primary HLH remained 0.12 per 100,000 children, equating to 1.8 per 100,000 live births. Notably, an increased overall survival was observed in 1997-2006, relative to the period 1987-1996. During the subsequent 5-year period, 2007-2011, the incidence of genetically and/or functionally verified primary HLH was 0.15 per 100,000 children per year, suggesting that new assays may aid the identification of patients with primary HLH. CONCLUSION: The annual incidence of primary HLH in Sweden is 0.12-0.15 per 100,000 children per year. Pediatr Blood Cancer 2015;62:346-352. © 2014 Wiley Periodicals, Inc.

Chemoimmunotherapy for hemophagocytic lymphohistiocytosis: long-term results of the HLH-94 treatment protocol.

Hemophagocytic lymphohistiocytosis (HLH) used to have a dismal prognosis. We report the final results of HLH-94, the largest prospective diagnostic/therapeutic HLH study so far. The treatment includes immunosuppressive and cytotoxic therapy aiming at clinical remission, followed by HSCT in patients with familial, persistent, or recurrent disease. Altogether, 249 patients fulfilled inclusion criteria and started HLH-94 therapy (July 1994-December 2003); 227 (91%) were followed-up for ≥ 5 years. At 6.2 years median follow-up, estimated 5-year probability of survival was 54% ± 6%. Seventy-two patients (29%) died before HSCT, 64 within 1 year, 97% of whom had active disease. In 124 patients who underwent HSCT, 5-year survival was 66 ± 8%; tendency to increased survival (P = .064) in patients with nonactive disease at HSCT. Patients with familial disease had a 5-year survival of 50% ± 13%; none survived without HSCT. Patients deceased during the first 2 months more often had jaundice, edema, and elevated creatinine. Forty-nine patients (20%) were alive without signs of HLH activity and off-therapy > 1-year without HSCT; they presented at older age (P < .001), were more often female (P = .011), and less often had CNS disease (P < .001) or hepatomegaly (P = .007). To conclude, HLH-94 chemoimmunotherapy has considerably improved outcome in HLH. Collaborative efforts are needed to further reduce early mortality, HSCT-related mortality, and neurologic late effects.