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A vast body of evidence provides support to a central role of exaggerated production of interferon-γ (IFN-γ) in causing hypercytokinemia and signs and symptoms of hemophagocytic lymphohistiocytosis (HLH). In this chapter, we will describe briefly the roles of IFN-γ in innate and adaptive immunity and in host defense, summarize results from animal models of primary HLH and secondary HLH with particular emphasis on targeted therapeutic approaches, review data on biomarkers associated with activation of the IFN-γ pathway, and discuss initial efficacy and safety results of IFN-γ neutralization in humans.

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Hemophagocytic lymphohistiocytosis (HLH) is a rare but in most cases life-threatening immune-mediated disease of the hematopoietic system frequently associated with hematologic neoplasms. Here, we report on a case in which we detected a novel constellation of two missense variants affecting the PRF1 gene, leading to de novo primary HLH. Diagnostics included a comprehensive clinical work-up and standard methods of hematopathology as well as extended molecular genomics based on polymerase chain reaction (PCR) reactions and the calculation of three-dimensional molecule reconstructions of PRF1. Subsequently, a comprehensive review of the literature was performed, which showed that this compound heterozygosity has not been previously described. The patient was a 20-year-old female. Molecular diagnostics revealed two heterozygous missense variants in the PRF1 gene (A91V and R104C) on exon 2. Apart from the finding of two inconclusive genetic variants, all clinical criteria defined by the HLH study group of Histiocyte Society were met at initial presentation. The final diagnosis was made in cooperation with the Consortium of German HLH-reference centers. Here, chemotherapy did not lead to sufficient sustained disease control. Therefore, the decision for allogenic hematopoietic stem cell transplantation (alloHSCT) was made. Hitherto, the duration of response was 6 months. Due to severe and unmanageable hepatic graft-versus-host disease (GvHD), the patient died. We report on a novel constellation of a compound heterozygosity containing two missense variants on exon 2 of the PRF1 gene. To the authors' best knowledge, this is the first presentation of a primary HLH case harboring this genomic constellation with late-onset clinical manifestation.

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Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening hyperinflammatory syndrome characterized by profound immune system activation. In adults, most cases of HLH are due to an underlying pathology- such as infection, malignancy, or autoimmune disease. It is a disease that can progress to rapid clinical deterioration and be difficult to diagnose. Nevertheless, regardless of etiology, most patients with HLH benefit from treatment. This paper highlights the challenges involved in diagnosing and managing this condition in practice, with an emphasis on how young, previously healthy young adults can present in a critically ill state.

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HLH is a progressive syndrome of unchecked immune activation and tissue damage. If left untreated, patients with HLH survive for only a few months, due to progressive multi-organ failure. Prompt initiation of treatment for HLH is essential for the survival of affected patients. Several conditions are responsible for triggering HLH in clinically stable patients who respond to treatment of the underlying condition alone. These conditions include infection, rheumatological diseases and lymphoid malignancies. We report a rare case of primary HLH in a 32-year-old female who presented with fever, abdominal pain, pancytopenia and splenomegaly with the triggering factor being Dengue infection.

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PURPOSE: A need exists for reduced toxicity conditioning regimens that offer less toxicity while maintaining myeloablation, especially for primary immune deficiencies where myeloablation or high donor myeloid chimerism is required to achieve cure. We adapted a busulfan and fludarabine regimen by Gungor et al. for children and young adults undergoing allogeneic HCT for non-CGD primary immune deficiencies requiring myeloablation or high donor myeloid chimerism, and herein report our experience. METHODS: We retrospectively reviewed records of 41 consecutive patients who underwent allogeneic HCT for Wiskott-Aldrich syndrome (n = 12), primary HLH/XLP (n = 10), CD40L deficiency (n = 7), or other (n = 12) primary immune deficiencies with a conditioning regimen containing pharmacokinetic-guided busulfan dosing which achieved a cumulative AUC between 57 and 74 mg/L × h (65-80% of conventional myeloablative exposure), along with fludarabine and alemtuzumab or anti-thymocyte globulin at 3 transplant centers between 2014 and 2019. RESULTS: Forty-one patients underwent a first (n = 33) or second (n = 8) allogeneic HCT. Median age was 2.3 years (range, 0.3 years-19.8 years). All but one patient (97.5%) achieved neutrophil recovery at a median of 14 days (range, 11-34 days). One patient developed sinusoidal obstruction syndrome and two patients developed diffuse alveolar hemorrhage. Four patients developed grades II-IV acute GVHD. Three patients developed chronic GVHD. One-year overall survival was 90% (95% confidence interval [CI] 81-99%) and event-free survival was 83% (95% CI 71-94%). CONCLUSIONS: Our experience suggests that a reduced toxicity busulfan-fludarabine regimen offers low toxicity, low incidence of grades 2-4 GVHD, durable myeloid engraftment, and excellent survival, and may be considered for a variety of primary immune deficiencies where myeloablative HCT is desired.

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In this report, we evaluate the hypothesis that hemophagocytic lymphohistiocytosis in patients with defects of lymphocyte cytotoxicity is usually triggered by infections. We show that in the majority of patients, extensive virus PCR panels performed in addition to routine microbiological investigations remain negative and summarize 25 patients with onset of hemophagocytic lymphohistiocytosis in utero or within the first 10 days of life, in none of which an associated bacterial or viral infection was reported. These observations, even though preliminary, invite to consider a key role of lymphocyte cytotoxicity in controlling T-cell homeostasis also in the absence of apparent infectious stimuli.

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The diagnosis of hemophagocytic lymphohistiocytosis (HLH) can be a difficult one, and the distinction between primary versus secondary HLH can be particularly challenging during the early stages of diagnosis. This distinction is important to make as primary HLH requires allogeneic hematopoietic cell transplantation for a definitive cure. Flow cytometric screening tests for many of the genetic forms of HLH are available. However, not all patients with primary HLH are captured by these screening tests, due to the fact that no screening test is 100% sensitive, and additionally, some patients with "primary" forms of HLH may have mutations in genes which are yet to be discovered. In this issue of the European Journal of Immunology, Ammann et al. [Eur. J. Immunol. 2017. 47: 364-373] compare T-cell phenotype patterns among patients with primary and secondary HLH, and find that assessment of T-cell activation and differentiation may assist with the diagnosis of HLH. Furthermore, this phenotypic analysis has the potential to help make the important distinction between primary and secondary HLH.

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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome characterized by hyperactivation of lymphocytes and histiocytes. T cells play a key role in HLH pathogenesis, but their differentiation pattern is not well characterized in patients with active HLH. We compared T-cell activation patterns between patients with familial HLH (1°HLH), 2°HLH without apparent infectious trigger (2°HLH) and 2°HLH induced by a viral infection (2°V-HLH). Polyclonal CD8+ T cells are highly activated in 1°HLH and 2°V-HLH, but less in 2°HLH as assessed by HLA-DR expression and marker combination with CD45RA, CCR7, CD127, PD-1 and CD57. Absence of increased HLA-DR expression on T cells excluded active 1° HLH with high sensitivity and specificity. A high proportion of polyclonal CD127- CD4+ T cells expressing HLA-DR, CD57, and perforin is a signature of infants with 1°HLH, much less prominent in virus-associated 2°HLH. The similar pattern and extent of CD8+ T-cell activation compared to 2° V-HLH is compatible with a viral trigger of 1°HLH. However, in most 1°HLH patients no triggering infection was documented and the unique activation of cytotoxic CD4+ T cells indicates that the overall T-cell response in 1°HLH is different. This may reflect different pathways of pathogenesis of these two HLH variants.

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