CD38high/HLA-DR+CD8+ T lymphocytes display pathogen-specific expansion regardless of hemophagocytic lymphohistiocytosis.

The characteristic expansion of T CD38high/HLA-DR+CD8+ lymphocytes observed in hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) proved able to distinguish HLH/MAS from sepsis and systemic juvenile idiopathic arthritis. However, the performance of this marker in differentiating HLH/MAS from other pediatric febrile conditions with similar clinical onset and yet entirely different treatments remains unexplored. CD38high/HLA-DR+CD8+ frequencies measured in the peripheral fresh blood of pediatric patients attended for suspicion of HLH/MAS were retrospectively recorded and clinical characteristics were retrieved. CD38high/HLA-DR+CD8+ frequencies in HLH/MAS patients (15 patients; median: 22.0%, IQR: 11.0-49.0%) were compared with those who presented febrile conditions other-than-HLH (28 patients; median: 13.0%, IQR: 3.9-28.7%; p = 0.24). HLH and non-HLH patients were subsequently regrouped based on the presence of an identified infection (22 patients; median: 27.0%, IQR: 15.2-72.1%) and compared with those without infections (21 patients; median: 7.6%, IQR: 3.7-24.3%; p = 0.0035). CD38high/HLA-DR+CD8+ percentages were significantly higher only in the infection group compared with the noninfection one, with a patent pathogen-specific expansion in Epstein-Barr virus primoinfection and visceral leishmaniasis regardless of the presence of HLH. CD38high/HLA-DR+CD8+ frequencies do not appear as an HLH-specific marker as they naturally expand in other clinical situations that are common in childhood and may mimic HLH initial presentation.

A multidisciplinary non-invasive approach to monitor response to intravenous immunoglobulin treatment in neurodegenerative Langerhans cell histiocytosis: a real-world study.

Aims: Early detection and treatment of neurodegenerative Langerhans cell histiocytosis (ND-LCH) have been suggested to prevent neurodegenerative progression. The aim of the study is to validate a standardized multidisciplinary diagnostic work-up to monitor the intravenous immunoglobulins (IVIG) treatment response and the natural course of the disease in untreated patients. Methods: Patients with abnormal somatosensory evoked potentials (SEPs) received monthly 0.5 g/kg IVIG. The diagnostic protocol included structural 3T MRI, neurological examination, brainstem auditory evoked potentials (BAEPs) and SEPs. Results: Twenty-two patients were followed for 5.2 years (median) from the first MRI evidence of ND-LCH. Eleven patients received IVIG for 1.7 years (median). At treatment start neurological examination was abnormal in 10 patients, of whom two had severe clinical impairment and four had abnormal BAEPs. At last follow-up, 1/11 remained stable and 7/11 improved, while worsening of neurological or neurophysiological findings, or both, occurred in 3/11. Risk factors for worsening were a severe clinical or MRI ND-LCH at treatment initiation and prolonged exposure to LCH. Of the 11 untreated patients, none improved and three worsened. Conclusions: Using a standardized diagnostic protocol, we demonstrated that IVIG treatment can lead to clinical stabilization or improvement in all pauci-symptomatic patients with an MRI grading of less than 4.

Diagnostic Guidelines for Familial Hemophagocytic Lymphohistiocytosis Revisited.

Current HLH-2004-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here we performed a case-control study to test and possibly improve these clinical criteria. We also developed two complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (n=366) were children <16 years with verified familial and/or genetic FHL (n=341) or Griscelli syndrome type 2 (GS2) (n=25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329+361 children in two cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on the number of diagnostic criteria fulfilled from 17 variables studied, reveled almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%). Notably, assessment of the original HLH-2004 criteria revealed accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Since cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without NK-cell function was also studied which showed accuracy 99.0% (sensitivity 96.2%; specificity 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis.

Long-term outcome and prognosis of mixed histiocytosis (Erdheim-Chester disease and Langerhans Cell Histiocytosis).

Background: Erdheim-Chester disease (ECD) is a rare histiocytosis that may overlap with Langerhans Cell Histiocytosis (LCH). This "mixed" entity is poorly characterized. We here investigated the clinical phenotype, outcome, and prognostic factors of a large cohort of patients with mixed ECD-LCH. Methods: This retrospective study was performed at two referral centers in France and Italy (Pitié-Salpêtrière Hospital, Paris; Meyer Children's Hospital, Florence). We included children and adults with ECD diagnosed in 2000-2022 who had biopsy-proven LCH, available data on clinical presentation, treatment and outcome, and a minimum follow-up of one year. Outcomes included differences in clinical presentation and survival between mixed ECD-LCH and isolated ECD; we also investigated response to treatments and predictors of survival in the mixed cohort. Survival was analyzed using the Kaplan-Maier method and differences in survival with the long-rank test. Cox regression models were used to evaluate the potential impact of age and gender on survival and to identify predictors of non-response and survival. Findings: Out of a cohort of 502 ECD patients, 69 (14%) had mixed ECD-LCH. Compared to isolated ECD, mixed ECD-LCH occurred more frequently in females (51 vs. 26%, p < 0.001) and in patients with multisystem disease (≥4 sites). Mixed ECD-LCH more frequently involved long bones (91 vs. 79%, p = 0.014), central nervous system (51 vs. 34%, p = 0.007), facial/orbit (52 vs. 38%, p = 0.031), lungs (43 vs. 28%, p = 0.009), hypothalamic/pituitary axis (51 vs. 26%, p < 0.001), skin (61 vs. 29%, p < 0.001), and lymph nodes (15 vs. 7%, p = 0.028); the BRAFV600E mutation was also more frequent in mixed ECD-LCH (81 vs. 59%, p < 0.001). Targeted treatments (BRAF and/or MEK inhibitors) induced response more frequently than conventional therapies (interferon-α, chemotherapy), either as first-line (77 vs. 29%, p < 0.001) or as any line (75 vs. 24%, p < 0.001). After a median follow-up of 71 months, 24 patients (35%) died. Survival probability was comparable between ECD alone and mixed ECD-LCH (log-rank p = 0.948). At multivariable analysis, age at diagnosis (HR 1.052, 95% CI 1.008-1.096), associated hematologic conditions (HR 3.030, 95% CI 1.040-8.827), and treatment failure (HR 9.736, 95% CI 2.919-32.481) were associated with an increased risk of death, while lytic bone lesions with a lower risk (HR 0.116, 95% CI 0.031-0.432). Interpretation: Mixed ECD-LCH is a multisystem disease driven by the BRAFV600E mutation and targeted treatments are effective. Age at diagnosis, bone lesion patterns, associated hematologic conditions, and treatment failure are the main predictors of death in mixed ECD-LCH. Funding: None.

Corrigendum: HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

[This corrects the article DOI: 10.3389/fimmu.2024.1282804.].

HLH as an additional warning sign of inborn errors of immunity beyond familial-HLH in children: a systematic review.

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.

Outcome of primary hemophagocytic lymphohistiocytosis: a report on 143 patients from the Italian Registry.

Primary hemophagocytic lymphohistiocytosis (pHLH) is a severe, life-threatening hyperinflammatory syndrome caused by defects in genes of the granule-dependent cytotoxic pathway. Here we investigated the clinical presentation and outcome in a large cohort of 143 patients with pHLH diagnosed in the last 15 years and enrolled in the Italian registry. The median age at diagnosis was 12 months (interquartile range, 2-81), and 92 patients (64%) fulfilled the HLH-2004 criteria. Of 111 patients who received first-line combined therapy (HLH-94, HLH-2004, Euro-HIT protocols), 65 (59%) achieved complete response and 21 (19%) partial response. Thereafter, 33 patients (30%) reactivated, and 92 (64%) received hematopoietic stem cell transplantation, 78 of whom (85%) survived and were alive at a median follow-up from diagnosis of 67 months. Thirty-six patients (25%) died before hematopoietic stem cell transplantation and 14 (10%) after. Overall, 93 patients (65%) were alive after a median follow-up of 30 months. Unadjusted predictors of non-response were age <6 months and high ferritin and bilirubin levels, while predictors of pre-transplant and overall mortality were high ferritin and bilirubin levels. At multivariable analysis, high levels of ferritin predicted non-response, while high levels of bilirubin predicted pre-transplant and overall mortality. Despite recent advances in therapeutic management, pHLH remains a life-threatening condition with significant early mortality. Liver dysfunction is the main predictor of poor prognosis.

Rare Onset of Erdheim-Chester Disease in Children and Young Adults: A Case Series and Review of the Literature.

INTRODUCTION: Erdheim-Chester disease (ECD) is a rare histiocytic neoplasm that affects patients, predominantly males aged 40-70 years, with very heterogeneous clinical presentation and prognosis. In 2020, Goyal et al. proposed consensus recommendations for the management of patients with ECD, remarking on the exceptional presentation of the disease in the pediatric population. CASE PRESENTATION: The first patient, a 20-year-old male, underwent cervical laminectomy and partial removal of a cervical spine lesion, initially apparently consistent with cervical schwannomas. The second patient, a 9-year-old female, received surgery for an extra-axial lesion of the greater sphenoid wing, radiologically consistent with a meningioma. CONCLUSION: At present, 15 pediatric cases have been reported in the literature with involvement of the central nervous system, with no consensus on the diagnostic and therapeutic management, as Pegoraro et al. evidenced in their pediatric multicenter case series. The present article adds two new cases of ECD with onset in childhood and young adulthood, who received the diagnosis after neurosurgical procedures.

Approaching hemophagocytic lymphohistiocytosis.

Hemophagocytic Lymphohistiocytosis (HLH) is a rare clinical condition characterized by sustained but ineffective immune system activation, leading to severe and systemic hyperinflammation. It may occur as a genetic or sporadic condition, often triggered by an infection. The multifaceted pathogenesis results in a wide range of non-specific signs and symptoms, hampering early recognition. Despite a great improvement in terms of survival in the last decades, a considerable proportion of patients with HLH still die from progressive disease. Thus, prompt diagnosis and treatment are crucial for survival. Faced with the complexity and the heterogeneity of syndrome, expert consultation is recommended to correctly interpret clinical, functional and genetic findings and address therapeutic decisions. Cytofluorimetric and genetic analysis should be performed in reference laboratories. Genetic analysis is mandatory to confirm familial hemophagocytic lymphohistiocytosis (FHL) and Next Generation Sequencing is increasingly adopted to extend the spectrum of genetic predisposition to HLH, though its results should be critically discussed with specialists. In this review, we critically revise the reported laboratory tools for the diagnosis of HLH, in order to outline a comprehensive and widely available workup that allows to reduce the time between the clinical suspicion of HLH and its final diagnosis.

Hemophagocytic inflammatory syndrome in ADA-SCID: report of two cases and literature review.

Hemophagocytic inflammatory syndrome (HIS) is a rare form of secondary hemophagocytic lymphohistiocytosis caused by an impaired equilibrium between natural killer and cytotoxic T-cell activity, evolving in hypercytokinemia and multiorgan failure. In the context of inborn errors of immunity, HIS occurrence has been reported in severe combined immunodeficiency (SCID) patients, including two cases of adenosine deaminase deficient-SCID (ADA-SCID). Here we describe two additional pediatric cases of ADA-SCID patients who developed HIS. In the first case, HIS was triggered by infectious complications while the patient was on enzyme replacement therapy; the patient was treated with high-dose corticosteroids and intravenous immunoglobulins with HIS remission. However, the patient required HLA-identical sibling donor hematopoietic stem cell transplantation (HSCT) for a definitive cure of ADA-SCID, without HIS relapse up to 13 years after HSCT. The second patient presented HIS 2 years after hematopoietic stem cell gene therapy (GT), secondarily to Varicella-Zoster vaccination and despite CD4+ and CD8+ lymphocytes' reconstitution in line with other ADA SCID patients treated with GT. The child responded to trilinear immunosuppressive therapy (corticosteroids, Cyclosporine A, Anakinra). We observed the persistence of gene-corrected cells up to 5 years post-GT, without HIS relapse. These new cases of children with HIS, together with those reported in the literature, support the hypothesis that a major dysregulation in the immune system can occur in ADA-SCID patients. Our cases show that early identification of the disease is imperative and that a variable degree of immunosuppression could be an effective treatment while allogeneic HSCT is required only in cases of refractoriness. A deeper knowledge of immunologic patterns contributing to HIS pathogenesis in ADA-SCID patients is desirable, to identify new targeted treatments and ensure patients' long-term recovery.

Clinicogenomic associations in childhood Langerhans cell histiocytosis: an international cohort study.

Langerhans cell histiocytosis (LCH) is a rare neoplastic disorder caused by somatic genetic alterations in hematopoietic precursor cells differentiating into CD1a+/CD207+ histiocytes. LCH clinical manifestation is highly heterogeneous. BRAF and MAP2K1 mutations account for ∼80% of genetic driver alterations in neoplastic LCH cells. However, their clinical associations remain incompletely understood. Here, we present an international clinicogenomic study of childhood LCH, investigating 377 patients genotyped for at least BRAFV600E. MAPK pathway gene alterations were detected in 300 (79.6%) patients, including 191 (50.7%) with BRAFV600E, 54 with MAP2K1 mutations, 39 with BRAF exon 12 mutations, 13 with rare BRAF alterations, and 3 with ARAF or KRAS mutations. Our results confirm that BRAFV600E associates with lower age at diagnosis and higher prevalence of multisystem LCH, high-risk disease, and skin involvement. Furthermore, BRAFV600E appeared to correlate with a higher prevalence of central nervous system (CNS)-risk bone lesions. In contrast, MAP2K1 mutations associated with a higher prevalence of single-system (SS)-bone LCH, and BRAF exon 12 deletions seemed to correlate with more lung involvement. Although BRAFV600E correlated with reduced event-free survival in the overall cohort, neither BRAF nor MAP2K1 mutations associated with event-free survival when patients were stratified by disease extent. Thus, the correlation of BRAFV600E with inferior clinical outcome is (primarily) driven by its association with disease extents known for high rates of progression or relapse, including multisystem LCH. These findings advance our understanding of factors underlying the remarkable clinical heterogeneity of LCH but also question the independent prognostic value of lesional BRAFV600E status.

Whole-body magnetic resonance imaging for staging Langerhans cell histiocytosis in children and young adults.

INTRODUCTION: Radiographic skeletal survey (R-SS) is the standard imaging technique for the initial staging of Langerhans cell histiocytosis (LCH). Whole-body magnetic resonance imaging (WB-MRI) has been proposed as an effective, radiation-free alternative. METHODS: We prospectively assessed patients with LCH followed at three tertiary centers in Italy and Austria. Two national study protocols were independently designed, and data were then pooled to increase the power of their findings. R-SS and WB-MRI were performed at diagnosis and repeated at the follow-up to confirm the nature of the identified lesions and to study their evolution. RESULTS: Data from 67 patients were analyzed (52 from Italy and 15 from Austria). Compared to R-SS, WB-MRI identified 29 additional skeletal lesions in 14 patients (including two false-positive lesions). Two skeletal lesions were detected at R-SS and missed at WB-MRI (false negative). Per-lesion sensitivity rates were 78.6% (95% CI: 71.0-85.9) for R-SS and 98.4% (95% CI: 94.4-99.8) for WB-MRI, respectively. Based on WB-MRI findings, six patients would have been upstaged to a higher risk class than staging with R-SS. CONCLUSIONS: WB-MRI had a significantly higher detection rate for skeletal lesions compared to R-SS. Clinical and radiology expertise is required to avoid upstaging and overtreatment.

Additive Prognostic Impact of Gastrointestinal Involvement in Severe Multisystem Langerhans Cell Histiocytosis.

OBJECTIVE: To evaluate the prognostic impact of gastrointestinal involvement on the survival of children with Langerhans cell histiocytosis (GI-LCH) registered with the international clinical trials of the Histiocyte Society. STUDY DESIGN: This was a retrospective analysis of 2414 pediatric patients registered onto the consecutive trials DAL-HX 83, DAL-HX 90, LCH-I, LCH-II, and LCH-III. RESULTS: Among the 1289 patients with single-system LCH, there was no single case confined to the GI tract; 114 of 1125 (10%) patients with multisystem LCH (MS-LCH) had GI-LCH at initial presentation. GI-LCH was significantly more common in children aged <2 years at diagnosis (13% vs 6% in those aged >2 years; P < .001) and in those with risk organ involvement (15% vs 6% in those without risk organ involvement; P < .001). The 5-year overall survival (OS) in patients without risk organ involvement was excellent irrespective of GI disease (98% vs 97% in patients with GI-LCH; P = .789). In patients with risk organ involvement, the 5-year OS was 51% in 70 patients with GI-LCH vs 72% in 394 patients without GI-LCH (P < .001). CONCLUSIONS: GI-LCH has an additive unfavorable prognostic impact in children with MS-LCH and risk organ involvement. The emerding need for more intensive or alternative treatments mandates prospective evaluation.