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      Using a Minimal Parameter Set for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Non-European Children


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          Case series

          Patients: Male, 4-day-old • Male, 29-day-old

          Final Diagnosis: Hemophagocytic lymphohistiocytosis (HLH)

          Symptoms: Fever

          Medication: —

          Clinical Procedure: —

          Specialty: Hematology • Immunology


          Challenging differential diagnosis


          Children with hemophagocytic lymphohistiocytosis require rapid diagnosis for timely treatment. However, diagnostic delays may arise in settings with limited clinical resources. To address this issue, a simplified rule for diagnosing hemophagocytic lymphohistiocytosis has recently been proposed. We retrospectively applied this diagnostic rule in 2 infants to evaluate its generalizability to non-European children.

          Case Reports:

          We present 2 cases of hemophagocytic lymphohistiocytosis, involving an Asian neonate with secondary hemophagocytic lymphohistiocytosis subsequent to echovirus infection and an African infant with familial hemophagocytic lymphohistiocytosis caused by PRF1 mutation. Limitations on time and clinical resources prevented tissue biopsy and measurement of natural killer cell activity in either case at our center. The Asian case did not meet HLH-2004 criteria, but both cases met a rapid diagnostic rule on admission to our center. Both cases were transported to a tertiary center and diagnosed with hemophagocytic lymphohistiocytosis based on HLH-2004 criteria. Although treatment suppressed disease activity, the Asian neonate died of multiple-organ failure at age 6 months. The African infant remains in remission after allogenic cord blood stem cell transplantation.


          A simplified diagnostic rule for hemophagocytic lymphohistiocytosis may be useful for early diagnosis of hemophagocytic lymphohistiocytosis in Asian and African children, especially in resource-limited clinical settings. Further investigation is required to elucidate whether early diagnosis with a simplified diagnostic rule improves treatment outcomes for children with hemophagocytic lymphohistiocytosis.

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          Most cited references5

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          HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis.

          In HLH-94, the first prospective international treatment study for hemophagocytic lymphohistiocytosis (HLH), diagnosis was based on five criteria (fever, splenomegaly, bicytopenia, hypertriglyceridemia and/or hypofibrinogenemia, and hemophagocytosis). In HLH-2004 three additional criteria are introduced; low/absent NK-cell-activity, hyperferritinemia, and high-soluble interleukin-2-receptor levels. Altogether five of these eight criteria must be fulfilled, unless family history or molecular diagnosis is consistent with HLH. HLH-2004 chemo-immunotherapy includes etoposide, dexamethasone, cyclosporine A upfront and, in selected patients, intrathecal therapy with methotrexate and corticosteroids. Subsequent hematopoietic stem cell transplantation (HSCT) is recommended for patients with familial disease or molecular diagnosis, and patients with severe and persistent, or reactivated, disease. In order to hopefully further improve diagnosis, therapy and biological understanding, participation in HLH studies is encouraged.
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            How I treat hemophagocytic lymphohistiocytosis.

            Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, occurring as either a familial disorder or a sporadic condition, in association with a variety of triggers. This immune dysregulatory disorder is prominently associated with cytopenias and a unique combination of clinical signs and symptoms of extreme inflammation. Prompt initiation of immunochemotherapy is essential for survival, but timely diagnosis may be challenging because of the rarity of HLH, its variable presentation, and the time required to perform diagnostic testing. Therapy is complicated by dynamic clinical course, high risk of treatment-related morbidity, and disease recurrence. Here, we review the clinical manifestations and patterns of HLH and describe our approach to the diagnosis and therapy for this elusive and potentially lethal condition.
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              Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis

              Publisher's Note: There is a [Related article:] Blood Commentary on this article in this issue. Whole-exome sequencing may identify specific therapeutic opportunities for patients with HLH. HLH should be conceptualized as a critical illness phenotype driven by toxic activation of immune cells from different underlying mechanisms. The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age ( P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy ( P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients.

                Author and article information

                Am J Case Rep
                Am J Case Rep
                The American Journal of Case Reports
                International Scientific Literature, Inc.
                26 January 2022
                : 23
                : e934037-1-e934037-3
                Department of Pediatrics, National Hospital Organization Beppu Medical Center, Beppu, Ōita, Japan
                Author notes
                Corresponding Author: Hiroshi Koga,e-mail: koga.hiroshi.ab@ 123456mail.hosp.go.jp

                Authors’ Contribution:


                Study Design


                Data Collection


                Statistical Analysis


                Data Interpretation


                Manuscript Preparation


                Literature Search


                Funds Collection

                Financial support: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

                Conflict of interest: The authors declare that they have no conflicts of interest

                © Am J Case Rep, 2022

                This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International ( CC BY-NC-ND 4.0)

                : 16 July 2021
                : 25 September 2021
                : 09 December 2021

                clinical decision rules,infant,lymphohistiocytosis, hemophagocytic,treatment outcome


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