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The hook effect is a well-described but clinically underappreciated immunoassay interference, where a falsely lowered result is caused by analyte excess. We describe a situation in which ferritin immunoassay results from a 27-year-old female with immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome were more than 1000 times lower at a reference laboratory than those determined in-house after dilution. This case underscores the importance for clinical care providers to be aware of the impact of the hook effect on ferritin measurements, and to promptly communicate with the laboratory when there are discrepancies between clinical symptoms and test results., (Published 2024. This article is a U.S. Government work and is in the public domain in the USA.)

Background: Neonatal hemophagocytic lymphohistiocytosis (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. There have been few large descriptive studies of nHLH., Objectives: The objective of this study was to perform a meta-analysis of published cases of nHLH., Methods: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30 days. Up to 70 variables were extracted from each case., Results: A total of 544 studies were assessed for eligibility, and 205 cases of nHLH from 142 articles were included. The median age of symptom onset was day of life 3 (interquartile range [IQR]: 0-11, n = 141). Median age at diagnosis was day of life 15 (IQR: 6-27, n = 87). Causes of HLH included familial HLH (48%, n = 99/205), infection (26%, n = 53/205), unknown (17%, n = 35/205), macrophage activation syndrome/rheumatologic (2.9%, n = 4/205), primary immune deficiency (2.0%, n = 5/205), inborn errors of metabolism (2.4%, n = 5/205), and malignancy (2.0%, n = 4/205). Fever was absent in 19% (n = 28/147) of all neonates and 39% (n = 15/38) of preterm neonates. Bicytopenia was absent in 26% (n = 47/183) of patients. Central nervous system (CNS) manifestations were reported in 63% of cases (n = 64/102). Liver injury (68%, n = 91/134) and/or liver failure (24%, n = 32/134) were common. Flow cytometry was performed in 22% (n = 45/205) of cases. Many patients (63%, n = 121/193) died within the period of reporting. Discernable values for HLH diagnostic criteria were reported between 30% and 83% of the time., Conclusions: Evaluation of nHLH requires rapid testing for a wide range of differential diagnoses. HLH diagnostic criteria such as fever and bicytopenia may not occur as frequently in the neonatal population as in older pediatric populations. Neurologic and hepatic manifestations frequently occur in the neonatal population. Current reports of nHLH suggest a high mortality rate. Future publications containing data on nHLH should improve reporting quality by reporting all clinically relevant data., (© 2024 Wiley Periodicals LLC.)

Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation, often associated with genetic defects of lymphocyte cytotoxicity. Though a distinctive constellation of features has been described for HLH, diagnosis remains challenging as patients have diverse presentations associated with a variety of triggers. We propose two concepts to clarify how HLH is diagnosed and treated: within the broader syndrome of HLH, "HLH disease" should be distinguished from "HLH disease mimics" and HLH subtypes should be categorized by specific etiologic associations, not the ambiguous dichotomy of "primary" and "secondary." We provide expert-based advice regarding the diagnosis and initiation of treatment for patients with HLH, rooted in improved understanding of its pathophysiology., (© 2019 Wiley Periodicals, Inc.)

Objective: To investigate CD163 as an effective biomarker for identifying and predicting the outcomes of sepsis-associated hemophagocytic lymphohistiocytosis (SAHS) in children., Methods: We prospectively enrolled presumed sepsis patients who had developed prolonged fever (>7 days), hepatosplenomegaly, cytopenias, and hyperferritinemia (>500 ng/mL) despite antibiotic therapy. Blood samples were collected within 24 hours after enrolment. A nested case-control study was performed. The number of patients who fulfilled the HLH-2004 criteria, 28-day mortality outcomes, and 90-day mortality outcomes were recorded., Results: Sixty-nine patients were enrolled in the study. Significant increases in the levels of ferritin and soluble CD163 (sCD163) and the percentage of CD163-positive peripheral blood mononuclear cells (mCD163) and decreases in fibrinogen levels and the percentage of natural killer cells (NK %) were observed in patients with SAHS (n = 23) compared with those of patients with sepsis (n = 46). The area under the ROC curve (AUC) for ferritin combined with sCD163 was superior to the AUC for either ferritin or sCD163 for distinguishing SAHS from sepsis. Moreover, sCD163 was a prognostic factor for 28-day mortality (0.857 [0.659-1.000])., Conclusions: sCD163 is a valuable biomarker for the differential diagnosis of SAHS from sepsis and effectively predicts 28-day mortality in children with SAHS., (© 2019 Wiley Periodicals, Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is characterized by dysregulated immune activation.  Primary HLH involves hereditary deficits in cytotoxic lymphocytes while secondary HLH is triggered by extrinsic factors. The HLH-2004 criteria are widely used for clinical diagnosis, yet their specificity for HLH or their ability to differentiate primary from secondary disease is unclear, potentially leading to inappropriate treatment. We describe several cases where fulfillment of HLH-2004 criteria obscured the diagnoses of underlying malignancies and delayed curative management. These issues are remedied without waiting for genetic testing results through an alternative diagnostic approach using flow cytometry-based immunologic assays and a thorough investigation for malignancy., (© 2018 Wiley Periodicals, Inc.)

Central nervous system (CNS) involvement in the context of hemophagocytic lymphohistiocytosis (HLH) is not uncommon. Given the immunosuppressive nature of HLH therapy, infectious complications are also seen. We describe a 9-year-old male who developed acute neurological decline secondary to aspergillosis while undergoing HLH therapy. The significant overlap observed in CNS neuroimaging of HLH and aspergillosis and the subtleties that may help differentiate the two are discussed. The importance of obtaining tissue for definitive diagnosis is underscored., (© 2016 Wiley Periodicals, Inc.)

Hyperferritinemia is a hallmark of hemophagocytic lymphohistiocytosis (HLH). In the HLH-2004 criteria, a ferritin value >500 µg/L is considered positive. However, this level was not determined based on evidence. We compared 123 patients with HLH and 320 patients with other hyperferritinemic conditions, calculated a receiver-operating characteristic, and determined sensitivity and specificity for different values. At 2,000 µg/L a trade-off is reached with sensitivity at 70% and specificity at 68%. If familial HLH and virus-associated acquired HLH are analyzed separately, sensitivity and specificity are similar for this level. The results may guide a potential modification of the current HLH criteria., (© 2014 Wiley Periodicals, Inc.)

Background: Despite several advances in the treatment of Epstein-Barr virus (EBV) in recent years, patients with Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis (EBV-HLH) do not always show satisfactory outcomes. We here conducted a nationwide survey in Japan to identify prognostic factors of EBV-HLH in children with this disease in an effort to improve the management and the outcomes of these patients., Procedure: Between January 2003 and June 2008, we enrolled 98 children younger than 18 years of age who were diagnosed with EBV-HLH. We then studied the clinical characteristics and laboratory findings at the time of diagnosis with the aim to identify prognostic factors for EBV-HLH., Results: The mean age of onset of EBV-HLH was 3.9 ± 2.8 years. Most of our patients presented with fever, hepatosplenomegaly, lymphadenopathy, and hemophagocytosis of bone marrow. Sixty-two percent of patients showed T cell clonality, and 97% had EBV infection in either T or natural killer cells. Most patients (60%) were treated with a multi-agent chemotherapeutic regimen, including corticosteroid, etoposide, and cyclosporine. After initial treatment, 90.3% of patients were in remission, and 7 patients (8.2%) experienced recurrence of EBV infection. Among several prognostic factors, patients with both hyperbilirubinemia (>1.8 mg/dl) and hyperferritinemia (>20,300 ng/ml) at the time of diagnosis had significantly poorer outcomes than those with low serum bilirubin and ferritin levels., Conclusions: These findings suggest that the therapeutic strategy for children with EBV-HLH could be tailored according to the laboratory findings at diagnosis., (© 2014 Wiley Periodicals, Inc.)

Background: Chédiak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by immunodeficiency, neurological dysfunction, and oculocutaneous albinism. Recently, several clinical CHS phenotypes have been reported. Here, we report results of a nationwide survey performed to clarify clinical characteristics and outcomes of CHS patients in Japan., Methods: Questionnaires were sent to 287 institutions to collect data regarding CHS patients diagnosed between 2000 and 2010, including results of lysosomal trafficking regulator (LYST) gene analysis. Cytotoxicity and degranulation activity of cytotoxic T lymphocytes were analyzed in available patient samples., Results: A total of 15 patients diagnosed with CHS were eligible for enrollment in this study. Of these, 10 (67%) had recurrent bacterial infections, five (33%) developed life-threatening hemophagocytic lymphohistiocytosis (HLH), and one patient had complicated malignant lymphoma. Hematopoietic stem cell transplantation (HSCT) was performed for six patients including three with HLH, and 10 of the enrolled patients have survived at the time of this writing. LYST analysis was performed for 10 patients; seven different mutations were detected in seven patients, whereas no mutation was identified in three patients. Cytotoxicity and degranulation activity were impaired in patients with and without LYST mutation., Discussion: Results of this survey indicate that one or two patients with CHS were newly diagnosed each year in Japan. The incidence of HLH was not as high as expected. Mutations of genes other than LYST were suspected in some cases. We conclude that determining indication for HSCT for CHS patients should be based on genetic and cytotoxic analysis., (Copyright © 2013 Wiley Periodicals, Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is a systemic disease resulting from the excessive release of inflammatory cytokines by macrophages under prolonged antigenic stimulation. If untreated, it leads to multiorgan failure and death. Necrotizing enterocolitis (NEC) has not previously been associated with HLH. Here we report four preterm infants who were diagnosed with HLH associated with NEC. Two patients received chemotherapy and one survived. The other two infants succumbed to multiorgan failure. These results suggest that NEC may be a common clinical manifestation of HLH in premature neonates., (Copyright © 2012 Wiley Periodicals, Inc.)

Hemophagocytic syndromes such as hemophagocytic lymphohistiocytosis (HLH) are life-threatening hyperinflammatory conditions caused by inherited or acquired immune disorders. Awareness of the clinical symptoms and diagnostic criteria for hemophagocytic syndromes is crucial to start timely life-saving therapy. We present a case of a 4-month-old boy presenting with HLH. However, the patient was subsequently diagnosed with biotinidase deficiency and was successfully treated with biotin-replacement therapy, upon which the hemophagocytic syndrome ceased. Subsequent laboratory evaluations revealed normal lymphocyte cytotoxicity and no mutations in genes associated with familial HLH were found. Biotinidase deficiency should be considered as a differential diagnosis of patients fulfilling HLH criteria., (Copyright © 2011 Wiley Periodicals, Inc.)

Two children presented with a history of fever and rash. Lab values revealed pancytopenia, elevated ferritin, coagulopathy, and elevated triglycerides. Both children quickly developed respiratory distress and hypotension requiring admission to the ICU. Bone marrow biopsies revealed hemophagocytosis. Studies for Ehrlichia returned positive. The patients were started on doxycycline and treated for hemophagocytic lymphohistiocytosis (HLH). Each made a full recovery. In both patients, testing for MUNC and perforin genes were found to have no mutation. These two cases demonstrate the importance of considering Ehrlichiosis as a possible trigger of HLH., (Copyright © 2010 Wiley-Liss, Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever, cytopenias, splenomegaly, and hemophagocytosis by macrophages activated by high cytokine levels. Chronic granulomatous disease (CGD) is characterized by recurrent infections, hyperinflammation, and excessive cytokine release. This may predispose patients with CGD to developing HLH during an infection. We conducted a retrospective review of patients with CGD, treated at our institution between 1999 and 2008. Three out of 17 patients developed HLH. Patients with CGD may be at increased risk for developing HLH. Remission of HLH was achieved after treatment with antimicrobials, steroids, and intravenous immunoglobulin This approach to treatment appears to be effective., (Copyright © 2010 Wiley-Liss, Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is difficult to diagnose and treat. Highly elevated ferritin is strongly associated with HLH and levels may provide a prognostic marker. A comprehensive review of ferritin data from our patients during treatment was analyzed with respect to mortality. A patient was 17 times more likely to die when percent ferritin decrease was less than 50% as compared to a 96% or greater decrease as indicated with multivariate logistic modeling. Higher maximum ferritin levels in the first 3 weeks also contributed to the odds of death (OR = 5.6; 90% CI = 1.2-24.9). Regular ferritin measurements may be useful predicting outcomes in HLH patients.

Secondary hemophagocytic lymphohistiocytosis (sHLH) is a reactive, proliferative disorder of the immune system resulting in lymphohistiocytic proliferation, hemophagocytosis, and cytokine dysregulation. The most common infectious trigger in sHLH is Epstein-Barr virus (EBV-HLH). Current treatment protocols for EBV-HLH have a cure rate of approximately 75%; however, there are significant toxicities associated with these therapies. We present two patients with EBV-HLH who experienced spontaneous resolution of their disease prior to the initiation of therapy, suggesting there may be a subgroup of patients with EBV-HLH who do well with conservative management and can avoid potentially toxic therapies., (Copyright 2010 Wiley-Liss, Inc.)

Background: Mutations in STX11 are responsible for Familial Hemophagocytic Lymphohistiocytosis (FHLH) type 4, a rare primary immunodeficiency which has previously been observed only in patients of Kurdish, Turkish, and Lebanese ethnic background., Methods: We reviewed our experience with STX11 mutations among North American patients and studied the impact of patient mutations upon syntaxin 11 expression and NK cell function., Results: Between 2007 and 2008, 243 patients with HLH (lacking disease-causing mutations in PRF1 and UNC13D) were referred for STX11 mutational analysis. We observed 1 novel homozygous nonsense mutation, 73 G > T (E25X), occurring in Hispanic siblings, and 2 novel biallelic heterozygous missense mutations, 106G > C (E36Q) and 616G > A (E206K), occurring in 1 Caucasian patient. The N-terminal nonsense mutation resulted in absence of detectable syntaxin 11 and abrogation of in vitro NK cell degranulation and function, while the biallelic heterozygous missense mutations resulted in detectable mutated syntaxin 11 and preservation of in vitro NK cell degranulation and cytotoxicity. The two sibling patients with the nonsense mutations presented with HLH during infancy, whereas the patient with biallelic heterozygous missense mutations presented at 5 years of age., Conclusion: We conclude that mutations in STX11 are responsible for HLH in approximately 1% of North American patients and can cause variable defects in syntaxin 11 expression and function with resultant impact on clinical phenotype.

Background: We investigated the characteristics, frequency, and prognosis of central nervous system (CNS) involvement in patients with hemophagocytic lymphohistiocytosis (HLH)., Procedure: Neurological manifestations were prospectively assessed in 92 children with HLH treated from January 2004 to August 2008 at our center; 82 (89%) had associated viral infections (69 Epstein-Barr virus), one empyema, while no associated disease was identified in the remaining nine. Prior to treatment, all underwent cerebrospinal fluid (CSF) evaluation, brain computer tomography (CT) and/or magnetic resonance imaging (MRI)., Results: At diagnosis, 43 (47%) children had CNS involvement. Twelve patients (13%) had neurological symptoms, including seizures, ataxia, coma, cranial nerve palsy, and hemiplegia. All patients improved after 8 weeks of therapy, but one later developed progressive neurological symptoms and six discontinued therapy due to progressive systemic symptoms and/or other reasons. Fifteen patients had CSF abnormalities that all normalized completely after 6 weeks of treatment. Thirty-six patients (39%) had neuroradiological abnormalities; with 5 still under treatment, 15 lost to follow-up, and 16 followed after completion of therapy. Of these 16, 12 improved, 3 were unchanged, and 1 progressed. Among all 21 children with CNS involvement followed after completion of therapy, 10 recovered completely, 10 improved (3 had remaining neuroradiological abnormalities), and 1 progressed clinically and neuroradiologically., Conclusion: Most patients reported here suffered from secondary HLH and since CNS involvement is frequent in HLH, brain MRI at diagnosis is recommended in all HLH patients. Clinical and CSF abnormalities often improved within 8 weeks of therapy, but CT/MRI abnormalities normalized more slowly and less frequently., (Copyright 2009 Wiley-Liss, Inc.)

Both hemophagocytic lymphohistiocytosis (HLH) and Kawasaki disease (KD) are diagnosed in patients with prolonged resistant fever by using a scoring system. Concurrent manifestation of both conditions has been reported previously. We describe an infant of 7 weeks whose condition fulfilled the criteria of HLH, but who, after clinical response to treatment, suddenly died from a myocardial infarction at 11 weeks. Post-mortem examination revealed a previously unknown coronary arteritis typical for KD. Since it is difficult to distinguish between KD and HLH, both diseases should be considered in young children with overlapping symptoms. Repeated echocardiograms may be helpful in these cases., ((c) 2009 Wiley-Liss, Inc.)

Hemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disorder of infancy and childhood that is invariably fatal if not treated. We report on the first patient to receive post-natal HSCT for HLH after receiving in utero chemotherapy for disease stabilization.

We report three cases of hemophagocytic lymphohistiocytosis (HLH) in infants within the first 6 weeks of life. Diagnosis of HLH was made early after symptoms started. All three cases were successfully treated with dexamethasone and none relapsed, indicating that not all cases of HLH in very young infants are familial.

Background: The identification of hemophagocytosis (HPC) in tissue or bone marrow (BM) represents only one of 5/8 criteria needed for the diagnosis of hemophagocytic lymphohistiocytosis (HLH). Yet, confirmation of HPC in bone marrow aspirates (BMA) is often relied upon to make therapeutic decisions. There is no standardized reporting criteria for the definition of "positive" BMA, and likely differs between institutions. The purpose of this study was to quantify the number of HPC in the initial BMA in patients diagnosed with HLH at our institution., Procedure: Patient charts were retrospectively reviewed. Numbers of HPC were counted per 500 nucleated cells in initial BMA., Results: Fifty-eight percent of patients had at least one HPC per 500 nucleated cells. Median number of HPC per 500 cells was 1 (0-12). Median time from initial BMA to HLH diagnosis was 0 days (-3 to 11), suggesting that HLH diagnosis was made regardless of the results of this initial BMA., Conclusion: The number of HPC at initial BMA is often low and variable, confirming that a BMA lacking HPC does not rule out the diagnosis of HLH, and a negative initial BMA should not delay therapy. We recommend that the BMA report should document negative as well as any positive findings of HPC., ((c) 2008 Wiley-Liss, Inc.)

We report a unique case of primary hemophagocytic lymphohistiocytosis (HLH) detected in an infant who had bone marrow biopsies demonstrating myelofibrosis, a finding not previously reported in primary HLH., ((c) 2007 Wiley-Liss, Inc.)

Background: Hemophagocytic lymphohistiocytosis (HLH) is a potentially lethal condition characterized by a pathologic inflammation. The diagnostic criteria for HLH include fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, abnormal natural killer cell (NK cell) functional assay, elevated soluble IL-2Ralpha level, and elevated ferritin level (>500 microg/L). Institution of timely therapy in these critically ill patients may be delayed by difficulties establishing the diagnosis. NK cell functional assay and soluble IL-2Ralpha level may require send-out to a specialized lab. However, ferritin level is available on a same-day basis at most institutions. In this study, we examined the utility of quantitative ferritin levels in diagnosing HLH., Procedure: All patients with ferritin values >500 microg/L obtained at Texas Children's Hospital between January 10, 2003 and January 10, 2005 were identified. Patient charts were reviewed for ferritin levels and hospital course., Results: During the study interval, 330 patients had ferritin levels >500 microg/L. Ten of the 330 patients were diagnosed with HLH. A ferritin level over 10,000 microg/L was 90% sensitive and 96% specific for HLH. Another diagnostic category with significantly elevated ferritin level was illness of unknown cause (n = 10), and only two of these patients were fully evaluated for HLH., Conclusions: Ferritin levels above 10,000 microg/L appear to be specific and sensitive for HLH. In patients without a significant medical history and a new onset of febrile illness with highly elevated ferritin levels, the diagnosis of HLH should be evaluated., ((c) 2007 Wiley-Liss, Inc.)

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.

Background: Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible. We studied the phenotypic differences among these subtypes in Japan., Methods: Forty patients clinically diagnosed with FHL were analyzed. Perforin abnormality was screened by flow cytometric analysis and/or DNA sequencing in these patients, and those without perforin abnormalities were further examined for the presence of mutations in the Munc13-4 gene by DNA sequencing. The correlation between clinical features and genetic subtypes was investigated., Results: Of the 40 HLH patients, 11 showed perforin gene mutations (classified as FHL2) and ten had Munc13-4 gene mutations (FHL3), but neither mutation was noted in 19 patients (non-FHL2/3). Although the majority of the patients developed the disease before the age of 1 year, the onset in three FHL2 patients with missense mutations was late (7, 11, and 12 years). Incidence of deficient natural killer cell activity was higher in FHL2 patients (9/9 FHL2, 4/9 FHL3, and 6/17 non-FHL2/3; P = 0.005). The serum levels of ferritin and soluble interleukin-2 receptor were significantly higher in FHL2 patients with nonsense perforin mutations compared to other subgroups (P < or = 0.05). Epstein-Barr virus infection was involved in 8 of the 40 HLH patients: one FHL2, one FHL3, and six non-FHL2/3., Conclusions: Although clinical features of FHL3 appear to be homogeneous, the heterogeneous clinical features of FHL2 depend upon the nature of perforin gene mutations. Characterization of the non-FHL2/3 group with regard to FHL1 or other novel gene mutations remains to be conducted.