Kobrinsky, Nathan L.

Abstract 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.

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.

The present study provides observational evidence that octreotide may be efficacious for the management of refractory abnormal uterine bleeding in women with bleeding diatheses.

PURPOSE: To determine the toxicity and response rate in children treated with dexamethasone, etoposide, cisplatin, high-dose cytarabine, and l-asparaginase (DECAL) for recurrent non-Hodgkin’s lymphoma (NHL) and Hodgkin’s disease (HD). PATIENTS AND METHODS: Ninety-seven children with recurrent NHL (n = 68) or HD (n = 29) were enrolled. Treatment consisted of two cycles of DECAL, then bone marrow transplantation or up to four cycles of ifosfamide, mesna, and etoposide alternating with DECAL maintenance therapy. RESULTS: After two cycles of DECAL induction therapy, complete response (CR) or partial response (PR) was reported in 19 (65.5%; 10 CRs and nine PRs) of 29 patients with HD and 29 (41.6%; 23 CRs and six PRs) of 68 patients with NHL. When only 24 patients with HD and 58 patients with NHL who were assessable for response were considered, the response rates were 79.2% (19 of 24 patients) and 50.0% (29 of 58 patients), respectively. Five-year event-free survival was 26% ± 9% and 23% ± 5% in patients with HD and NHL, respectively. Five-year survival was 31% ± 14% and 30% ± 6%, respectively. Although median time to treatment failure was significantly longer in patients with HD (EFS, P = .002; survival, P = .011), this difference did not translate into a higher long-term survival. Grade 3 or 4 toxic effects were observed during induction in 70 (72%) of 97 patients and during maintenance in 45 (70%) of 64 courses of DECAL therapy. Pancytopenia and systemic infections in particular were frequently observed. Other toxic effects were uncommon. Although not a formal part of the therapy or the study design, 42 patients who responded to therapy who underwent bone marrow transplant did not show any benefit from this approach. CONCLUSION: DECAL is an effective and tolerable salvage regimen for treating patients with recurrent NHL and HD.