Neonatal Hemophagocytic Lymphohistiocytosis Research Articles

An insight into neonatal hemophagocytic lymphohistiocytosis from a clinician's perspective.

An insight into neonatal hemophagocytic lymphohistiocytosis from a clinician's perspective.

Managing adult-onset Still's disease in pregnancy: A case report

BACKGROUND Adult-onset Still’s disease (AOSD) is a rare systemic inflammatory disorder characterized by fever, arthritis, skin rash, and systemic symptoms. The etiology of AOSD is unknown; however, it is thought to be related to immune dysregulation. Although a rare disease, AOSD can significantly impact reproductive health, particularly during pregnancy. This case study assesses the implications of pregnancy in a patient with AOSD, as well as the potential for heredity of the disease. Neonatal hemophagocytic lympho-histiocytosis (HLH) is a rare and life-threatening disorder characterized by hyperinflammation and uncontrolled activation of immune cells, leading to multiple organ dysfunction. This case report aimed to introduce neonatal HLH from a mother with AOSD. CASE SUMMARY This case study presents a 29-year-old female with AOSD who became pregnant and gave birth to a premature infant who was diagnosed with neonatal HLH. AOSD can significantly impact pregnancy and childbirth, as it may become more severe during pregnancy, with an increased risk of fetal loss and preterm birth. The management of AOSD during pregnancy involves the use of nonsteroidal anti-inflammatory drugs and glucocorticoids, as well as immunosuppressive agents in severe cases. However, the use of immunosuppressive agents during pregnancy may be associated with potential risks to the fetus. The hereditary implications of AOSD are unclear; however, available evidence suggests that genetic factors may play a role in the disease development. CONCLUSION AOSD can have significant implications for pregnancy and childbirth, including an increased risk of fetal loss and preterm birth. Neonatal HLH, a complication of AOSD in pregnancy, requires prompt diagnosis and management. Women with AOSD who are considering pregnancy should discuss their options with their healthcare provider and develop a management plan that addresses the potential risks to both mother and fetus.

Neonatal hemophagocytic lymphohistiocytosis: A meta-analysis of 205 cases.

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. The objective of this study was to perform a meta-analysis of published cases of nHLH. A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age ≤30days. Up to 70 variables were extracted from each case. 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. 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.

Neonatal Hemophagocytic Lymphohistiocytosis: Scoping Review and Analysis of 205 Cases

Background: Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of pathologic immune activation and uncontrolled inflammation. Neonatal HLH (nHLH), defined as HLH that presents in the first month of life, is clinically devastating. nHLH is estimated to comprise 10% of familial HLH (fHLH) diagnoses. There have been few, large descriptive studies of nHLH. Objectives: The primary objective of this study was to perform a scoping review and descriptive analysis of published cases of nHLH. The secondary objective of this study was to assess the reporting quality of published nHLH cases. Methods: A comprehensive literature database search was performed. Cases of HLH were eligible for inclusion if clinical analysis was performed at age < 30 days. As many as 70 variables were extracted from each case. Frequencies and percentages of variables reported per case in the articles included were provided. Qualitative variables were summarized by frequency and percentage. Quantitative variables which were not approximately normally distributed were summarized with median and interquartile range (IQR). Results: 544 studies were assessed for eligibility. Studies were excluded if they did not discuss nHLH (n=280), aggregated nHLH patient data with all ages (n=83), provided insufficient detail and/or data describing nHLH (n=28), and for other reasons (n=8).205 cases of nHLH from 142 articles were included. Cases were published from 31 countries from 1985-2023. Primary presenting features included fever (38.1%, n=67/176), organomegaly (11.9%, n=21/176) respiratory distress (11.4%, n=20/176), jaundice (4.5%, n=8/176), and signs of bleeding (3.4%, n-6/176). Symptoms began in utero in 20 patients (n=20/161). The median age of symptom onset was day of life (DOL) 3 (IQR: 0-14) (n=141). Median age at diagnosis was DOL 15 (IQR: 6-27) (n=87). The median time from initial evaluation to initiation of HLH therapy was 8 days (IQR: 3-14) (n=53). The frequency of HLH criteria and criteria median values are summarized in Table 1. The median number of diagnostic criteria met by patients were 5/8 (IQR: 4, 6). CNS manifestations were reported in 62.7% of cases (n=64/102). Skin manifestations were reported in 75.4% of cases (n=52/69). Liver injury (67.9%, n=91/134) and/or liver failure (23.9%, n=32/134) were common. Infections were reported in 46.7% of patients (n=70/150). Causes of nHLH included familial/inherited disease (46.8%, n=96/205), infection (26%, n=53), macrophage activation syndrome (2.9%, n=6), primary immunodeficiency (2.9%, n=6), inborn error of metabolism (2.4%, n=5), and malignancy (2%, n=4). Diagnosis was made using clinical and laboratory features (82.4%, n=169/205), gene panel (16.1%, n=33/205), sanger sequencing (1.0%, n=2/205), and ultra-rapid whole genome sequencing (0.5%, n=1/205). Genetic causes of fHLH included mutations in PRF1, STX11, STXBP2, UNC13D, NOCAR-H, and XIAP. The majority of patients (62.7%, n=121/193) died within the period of reporting. The estimated median survival time from nHLH onset of symptoms was 83 days. Only 4.4% (n=9/205) of studies reported complete data to calculate an H-score. Studies reported discernable values for HLH diagnostic variables at the following frequencies: temperature (71.7%), organomegaly (82.9%), hemoglobin (69.3%), thrombocytopenia (82.4%), neutrophils (55.1%), fibrinogen (64.4%), triglycerides (5.5%), hemophagocytosis (73.2%), ferritin (71.2%), low/absent NK cell activity (33.2%), and sIL2R (29.3%). Other clinically relevant variables such as the presence or absence of skin manifestations (33.7%), and CNS manifestations (49.8%) frequently went unreported. There were many cases that made a categorical description of a lab value (e.g., thrombocytopenia) without providing an absolute value (e.g., platelets level). Conclusions: This is the largest aggregated study of nHLH presentations, diagnostic criteria, clinical trajectory, and etiologic diagnoses. Neurologic, dermatologic, and hepatic manifestations occur in the neonatal population. Current reports of nHLH suggest a grim prognosis. Future publications containing data on nHLH should report all clinically relevant variables. Studies looking at multiple patients in aggregate should provide supplemental information with detailed nHLH cases.

A262 NEONATAL ACUTE LIVER FAILURE DUE TO PRESUMED GESTATIONAL ALLOIMMUNE LIVER DISEASE - A CASE REPORT

Abstract Background Neonatal acute liver failure (NALF) is a rare disease that is distinct from acute liver failure seen in older children and adults. Gestational alloimmune liver disease (GALD) is the most frequent cause, is initiated in utero by sensitization of the maternal immune system to a fetal hepatocyte antigen and subsequent production of maternal immunoglobulin G antibodies that cross the placenta. Maternal IgG binds to a fetal hepatocyte antigen and initiates an innate immune response involving the terminal complement cascade and membrane attach complex. The understanding of the alloimmune origin has led to the use of intravenous immunoglobulin (IVIG) treatment and exchange transfusion, significantly increasing survival. However, approximately 25% of patients may not respond and require salvage liver transplantation. In spite of an increased rate of comorbidities, concern for technical difficulties and limited graft availability, young infants eligible for transplant have been shown to have similar overall patient and graft survival rates compared to older children with other indications for liver transplant. Purpose The primary aim of our study is to report a case of NALF with successful liver transplant. Method We present the case of a preterm girl with NALF due to GALD refractory to medical management, requiring liver transplantation. Result(s) This is a 35-week preterm girl, with scant pre-natal care, birth weight of 1.825 kg and Apgar 9/9. She is the seventh child of non-consanguineous parents, with healthy siblings. On day-of-life (DOL) 1 she presented with acute kidney injury, progressive worsening metabolic acidosis and hyperammonemia and was found to be profoundly coagulopathic (INR 6), with normal liver enzymes and liver failure was diagnosed. Initial investigation ruled out congenital infections, sepsis, neonatal hemophagocytic lymphohistiocytosis and metabolic diseases. Magnetic resonance imaging of the body demonstrated findings in keeping with iron deposition in the thyroid, liver and pancreas, suggestive of GALD. Completed double volume exchange transfusion and IVIG on DOL 9 and repeat IVIG on DOL 13 and 15, with partial improvement in INR. Due to persistent ascites, conjugated hyperbilirubinemia and hyperammonemia she was transferred for urgent liver transplant assessment. Persistent liver dysfunction in the form of hyperammonemia, hypoglycemia and progressive coagulopathy led to transplant listing on DOL 30. ABO incompatible deceased donor liver transplant was completed on DOL 62 (4.075 kg, estimated dry weight 3.5 kg). The procedure was uncomplicated, liver enzymes normalized, coagulopathy and hypoglycemia resolved. She was transferred to the ward on post-operative day (POD) 6. and weaned off sedatives and transitioned to oral feeds within 2 weeks of transplant, with complex abdominal wound closure on POD 29. Conclusion(s) Successful liver transplantation is possible in neonates with acute liver failure due to GALD refractory to medical management and weighing 4kg or less. Please acknowledge all funding agencies by checking the applicable boxes below None Disclosure of Interest None Declared MICROBIOME & MICROBIAL THERAPY

Epidemiology and Outcomes of Neonatal Hemophagocytic Lymphohistiocytosis.

ObjectivesNeonatal hemophagocytic lymphohistiocytosis (HLH) is a rare entity. The objective of the study was to describe the prevalence, clinical characteristics, interventions and outcomes of neonates diagnosed with HLH in the United States.MethodsA retrospective analysis of 2009, 2012, and 2016 Kids' Inpatient Database was performed. Neonates discharged/died with a diagnosis of HLH were identified and analyzed.ResultsAmong 11,130,055 discharges, 76 neonates had a diagnosis of HLH. Fifty-two percent (95% CI: 38.6–63.6) were males and 54% (95% CI: 39.7–68.5) were white. Herpes simplex infection was present in 16% (95% CI: 9.2–28.1). 24.4% (95% CI: 14.5–37.9) received chemotherapy, 11.5% (95% CI: 5.2–23.6) IVIG and 3.6% (95% CI: 0.8–14.4) allogenic hemopoietic stem cell transplantation. Organ dysfunction was commonly seen and severe sepsis was documented in 26.6% (95% CI: 16.4–39.9). Median LOS was 16 (IQR 7–54) days. The mortality was 42% (95% CI: 30.8–55).ConclusionsHLH is a rare diagnosis and carries a high mortality in neonates. Herpes simplex virus is the most common infection associated with neonatal HLH. HLH should be considered in the differential diagnosis in neonates presenting with multi-organ dysfunction or sepsis.

Neonatal Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is extremely rare in the neonatal period. The incidence of neonatal HLH is not confirmed and may range from 1 in 50,000 to 150,000. The incidence varies based on ethnicity, particularly in populations in which consanguinity is common. HLH is associated with a high fatality rate and poor prognosis, making it important to recognize and diagnose it early. This review will concentrate primarily on the diagnosis and management of neonatal HLH.

Mitochondrial Disease as a Cause of Neonatal Hemophagocytic Lymphohistiocytosis.

Diagnosis of mitochondrial respiratory chain disorder (MRCD) is often difficult. Its pathogenesis is still unclear. We diagnosed MRCD by measuring the activity of the mitochondrial respiratory chain enzyme, and the patient also had hemophagocytic lymphohistiocytosis (HLH). A preterm female infant was born at 34 weeks of gestation. On day 6, HLH was revealed by bone marrow aspiration. She died on day 10 due to uncontrollable HLH. An autopsy was performed, and we measured the activity of the mitochondrial respiratory chain enzyme in the liver, muscle, and heart. The activity of complex I was decreased in all tissues. As we could not prove another origin of the HLH, she was diagnosed as having HLH caused by MRCD. It is useful to measure the activity of the mitochondrial respiratory chain enzyme for diagnosing MRCD. MRCD, which has a severe clinical course, may be related to HLH.

Neonatal hemophagocytic lymphohistiocytosis associated with a vertical transmission of coxsackievirus B1

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by fever, cytopenias, hepatosplenomegaly, and coagulopathy with the background of hypercytokinemia. Early diagnosis and etoposide therapy are not established for affected newborns. An afebrile infant suffered from apnea 4 days after birth, showing leukocytosis, thrombocytopenia, coagulopathy, and cerebrospinal fluid pleocytosis. Serum levels of ferritin and sIL-2R were high. Bone marrow studies revealed activated/hemophagocytosing macrophages. Coxsackievirus B1 (CB1) was isolated from the throat and stool. Serum anti-CB1 antibody titers were elevated in the patient (4→16; 6→43days after birth) and mother (128; 10days after delivery). Normal expressions of perforin and CD107a precluded inherited HLH. The vertically transmitted CB1-HLH was successfully treated without administration of corticosteroid, cyclosporine, or etoposide. Serum cytokine levels showed dominant expression of monokines (IL-1β/6/8, and TNF-α) but not IFN-γ, which is the central player of inherited HLH. The cytokine profile might represent a unique pathophysiology of enterovirus-driven neonatal HLH.

Juvenile Myelomonocytic Leukemia Presenting With Features of Neonatal Hemophagocytic Lymphohistiocytosis and Cutaneous Juvenile Xanthogranulomata and Successfully Treated With Allogeneic Hemopoietic Stem Cell Transplant

Juvenile xanthogranuloma (JXG) is rarely associated with either hemophagocytic lymphohistiocytosis (HLH) or juvenile myelomonocytic leukemia (JMML) and when in association with the latter there is usually neurofibromatosis type 1. We report a child who presented with JXG and HLH during the neonatal period and who subsequently developed JMML during early infancy in whom there is no evidence of neurofibromatosis type 1. The patient was refractory to standard HLH therapy but he is well and is now 42 months after mismatched unrelated donor hemopoietic stem cell transplant without evidence of HLH or JMML. His JXG lesions show involution, in keeping with the expected natural history of this disorder.

Neonatal Primary Hemophagocytic Lymphohistiocytosis in Turkish Children

Although the data on hemophagocytic lymphohistiocytosis (HLH) has gradually increased, the neonatal-onset HLH patients have usually been reported as case reports or together with other age groups of patients. The aim of this study was to draw attention to the clinical and laboratory characteristics of neonatal HLH cases. Herein, the data of 8 primary, neonatal-onset HLH patients are reported. Mutational analyses were performed in 7 of the patients and mutations in UNC13D gene were detected in 3 of the patients, whereas 2 patients were found to have perforin gene mutation. Four of the patients were symptomatic within the initial 10 days of life. One patient with perforin mutation (1122 G>A) had a very severe clinical course and died on the seventh day of life before receiving any specific treatment. Another patient with UNC13D 2783 G>C, who became symptomatic on the sixth day of life, underwent early hematopoietic stem cell transplantation and is currently alive at 8 years of age. Two of these 4 patients had extensively high serum ferritin levels mimicking neonatal hemochromatosis. Of the 4 patients who became symptomatic after 20th day of newborn period, 1 was found to have perforin gene mutation (445 G>A) and 2 siblings were detected to have a missense mutation in UNC13D (640 C>T) gene. The latter patients with UNC13D mutations could survive 3 and 4 months, although their parents ceased therapy. The patient with perforin mutation survived 11 months.

Successful Treatment of Neonatal Herpes Simplex-Type 1 Infection Complicated by Hemophagocytic Lymphohistiocytosis and Acute Liver Failure

Neonatal disseminated herpes simplex virus (HSV) infection with acute liver failure (ALF) and neonatal hemophagocytic lymphohistiocytosis (HLH) are severe diseases. We recently experienced a male infant with HLH and ALF induced by HSV type 1 (HSV-1). The infant, born at 39 weeks of gestation by normal delivery, developed a fever on day 4. On day 9, laboratory investigations showed progressive liver dysfunction and coagulopathy, and the serum ferritin was excessively elevated. Furthermore, the blood levels of interleukin (IL)-6, IL-10, and interferon-gamma were also elevated. HSV-1 DNA was detected in the serum and cerebrospinal fluid by the real-time PCR method. A diagnosis of HLH was established based upon the following criteria: fever, splenomegaly, cytopenia (two cell lines), serum ferritin (> 500 mug/l) and hypofibrinogenemia (< 150 mg/dl). High-dose acyclovir therapy, steroid pulse therapy using methylprednisolone, high-dose gamma globulin therapy and a blood transfusion were given. The patient recovered without neurological deficit. Neonatal disseminated HSV infections may be complicated by the development of HLH and hypercyokinemia. If HLH is suspected, not only high-dose acyclovir therapy but also anti-cytokine therapy should be considered.