key: cord-0018099-foc2oh9x authors: Zhou, Zijun; Zondag, Timo; Hermans, Maud; van Hagen, P. Martin; van Laar, Jan A. M. title: Hemophagocytic Lymphohistiocytosis in Activated PI3K Delta Syndrome: an Illustrative Case Report date: 2021-06-11 journal: J Clin Immunol DOI: 10.1007/s10875-021-01080-w sha: 45e41dd3d24129592e9487a3aab1e056383e95d2 doc_id: 18099 cord_uid: foc2oh9x nan To the Editor, Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition characterized by a dysregulated immune system. HLH is driven by impaired antigen clearance that leads to uncontrolled immune activation [1] . In primary HLH, a genetic mutation impairs the cytotoxic function of natural killer (NK) cells and cytotoxic T-cells, resulting in persistent antigen presentation and dysregulation of histiocyte activation. In secondary HLH (sHLH), unknown or non-genetic triggers result in a state of hyperinflammation. The most common triggers associated with HLH include infections, such as Epstein-Barr virus (EBV), hematological malignancies, and autoimmune diseases. Activated PI3K delta syndrome (APDS) is a primary immunodeficiency (PID) caused by a gain-of-function mutation in PIK3CD. As a result of the of the PI3K/AKT/mTOR pathway over-activation, T and B cell senescence is induced [2] [3] [4] . APDS is characterized by recurrent sinopulmonary infections, non-malignant lymphoproliferation, (persistent) viral infections, autoimmunity, and increased risk of lymphomas [5] . In APDS patients, HLH might be expected. However, it is only scarcely reported. Here, we describe a young adult with APDS who developed persistent EBV-related HLH. We subsequently discuss the association between HLH and APDS. A 19-year-old man of Indian descent was referred for the evaluation of chronic active EBV disease. The patient's medical history revealed congenital stenosis of the left bronchus, recurrent sinopulmonary infections, and autism spectrum disorder with an IQ of 80-86. EBV seroconversion was identified at 7 years of age when the patient presented idiopathic abdominal lymphadenopathy. Furthermore, a previous laboratory examination revealed IgA deficiency and low IgG2 and IgG4 levels without an overarching diagnosis. Four months before presentation, the patient developed fatigue, fever, night sweats, hepatosplenomegaly, anemia, hepatitis, weight loss of 10 kg, and lymphadenopathy ( Fig. 1) . Serum EBV copy numbers were repeatedly > 1500/mL. Histology of the three lymph nodes did not reveal any evidence of malignant lymphoma, but rather a markedly positive EBVencoded RNA (EBER). Chronically active EBV was diagnosed, and rituximab therapy of 500 mg weekly during 4 weeks was initiated. In the workup of PID, whole exome sequencing (confirmed by Sanger sequencing) revealed a heterozygous c.3074A > C, p.Glu1025Gly mutation in the PIK3CD gene (NM_005026.3), which is associated with APDS ( Fig. 2 ) [6] . Neither parent carried this mutation, suggesting a de novo origin. A stable condition without any additional immunosuppressive drugs was achieved for 3 months after which he developed high spiking fever, pneumonia, progressive lymphadenopathy, severe unexplained cardiomyopathy with progressive anemia, thrombocytopenia, and hyperferritinemia (Table 1) . Malignant lymphoma was excluded and hemophagocytosis was detected in the bone marrow ( Fig. 3A, B) . The patient therefore fulfilled six out of eight diagnostic HLH-04 criteria ( Table 2) [7] . His clinical status quickly deteriorated, and he developed acute respiratory distress syndrome and multiple organ failure. Salvage therapy was initiated with high-dose steroids, sirolimus, and intravenous immunoglobulin. PI3K delta inhibitors were withheld Zijun Zhou and Timo Zondag contributed equally to the manuscript. due to heart and respiratory failure. Etoposide was withheld due to leucopenia and severe sepsis with systemic infection (hospital acquired pneumonia with H. influenza, not responding to treatment). Within 1 month, the patient died from cardiac failure with refractory pulmonary edema. APDS is caused by a heterozygous gain-of-function mutation in PIK3CD. This mutation is known to activate leucocyte development, pushing immune cells towards differentiation and exhaustion by raising CD8 + CD57 + and CD8 + effector memory cells [2, 3] . This is indicative of a defective immune response that is incapable of effective elimination of pathogens. Persisting antigen presentation can then evoke HLH. Especially in the case of persistent EBV, a virus that is already able to trigger HLH, APDS patients are theoretically more prone to develop hyperinflammation and thus HLH [8] . Although chronically active EBV and EBV-associated lymphomas are common in APDS, HLH has only been reported in two APDS patients, who are summarized in Table 3 [9, 10] . Both patients were children at the time of APDS diagnosis, which suggests that genetic diagnosis is more often considered in pediatric HLH. Because a high index of suspicion is necessary to identify both HLH and APDS, underdiagnosis is likely. Present Cytopenias (affecting ≥ 2 of 3 lineages in the peripheral blood) Present Hemoglobin < 90 g/L 58 g/L Platelets < 100 × 10 9 /L 24 × 10 9 /L Neutrophils < 1.0 × 10 9 /L 3.84 × 10 9 /L Hypertriglyceridemia and/or hypofibrinogenaemia Not present Fasting triglycerides ≥ 3.0 mmol/L 6.58 mmol/L Fibrinogen ≤ 1.5 g/L Not done Hemophagocytosis in bone marrow or spleen or lymph nodes Present Low or absent NK-cell activity Not done Ferritin ≥ 500 µg/L Present (10,364 µg/L) Soluble IL-2 receptor ≥ 2400 U/mL Present (> 110,000 pg/mL) This case emphasizes the importance of genetic testing for PID (including HLH genes) in patients with the first episode of HLH, regardless of age. An increasing number of genetic mutations in older patients with HLH have been reported [11] . In particular, a medical history of recurrent infections, autoimmunity, developmental delay, and EBV-related HLH in young adults should indicate PID. Correct genetic diagnosis enables personalized treatment and thereby improving survival. Appropriate treatment of APDS patients developing HLH is a great therapeutic challenge. In our opinion, the mainstay of treatment should be appropriate management of APDS, such as hematopoietic stem cell transplantation or mTOR inhibitors, especially the new promising PI3K inhibitor leniolisib. By doing so, the patient is less susceptible to developing HLH. If HLH arises, an additional trigger (e.g., infectious or malignant) should be sought thoroughly and treated rigorously. In severe cases, HLH-directed therapy could be considered to halt the hyperinflammation. This therapy should consist of corticosteroids, with the addition of etoposide in life threatening cases [12] . This case illustrates that earlier diagnosis of APDS could have resulted in more adequate monitoring and targeted treatment before the occurrence of multi-organ failure. Data Availability Data transparency. Code Availability Not applicable. Ethics Approval To our opinion, this research does not necessitate ethic approval. It concerns a retrospective study in which no data could be traced back to the presented patient. The patient is not subjected to any intervention and no behavior is imposed. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency Exhaustion of the CD8(+) T cell compartment in patients with mutations in phosphoinositide 3-kinase delta PI3K in lymphocyte development, differentiation and activation Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis Adult haemophagocytic syndrome Activated phosphoinositide 3-kinase delta syndrome 1: clinical and immunological data from an Italian cohort of patients A rare case of activated phosphoinositide 3-kinase delta syndrome (APDS) presenting with hemophagocytosis complicated with Hodgkin lymphoma Pathogenic gene mutations or variants identified by targeted gene sequencing in adults with hemophagocytic lymphohistiocytosis Recommendations for the management of hemophagocytic lymphohistiocytosis in adults The authors declare no competing interests.