scholarly journals 1011. Sepsis and Secondary Hemophagocytic Lymphohistiocytosis

2018 ◽  
Vol 5 (suppl_1) ◽  
pp. S301-S301 ◽  
Author(s):  
Farhan Fazal ◽  
Naveet Wig ◽  
Manish Soneja ◽  
Dipendra K Mitra ◽  
Sk Panda ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Immunosuppressive Treatment ◽  
Cell Activity ◽  
Unknown Etiology ◽  
Laboratory Features ◽  
Life Threatening ◽  
Non Hodgkins Lymphoma ◽  
Staphylococcal Aureus

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory condition diagnosed by HLH 2004 criteria. This criterion has common clinical and laboratory features with sepsis and tropical fevers, but there is marked difference in management and outcome of these two entities. The study is conducted to know whether there is any difference in the clinico-laboratory features, management, and outcome of sepsis with or without secondary HLH. Methods This is a prospective observational study where patients presenting with sepsis and bicytopenia are included. The patients underwent relevant investigations according to 2004 HLH diagnostic criteria. The patients are divided into sepsis with or without HLH. The underlying etiology, treatment, and outcome of the two groups are analysed. Results Fifty sepsis patients are included in the study, out of which 28 fulfilled the HLH diagnostic criteria which comprised of 18 men and 10 women. The etiology were bacterial (three enteric fever, three tuberculosis, two scrub typhus, one Staphylococcal aureus), viral (one dengue fever, two HIV, two encephalitis), fungal (one aspergillosis, one mucormycosis, two others), parasites (three malaria, one leishmania) malignancy (two hodgkin lymphoma, one non-Hodgkins lymphoma), and unknown etiology in six patients, with >1 etiology in three patients (Figure 2). The percentage of each criterion fulfilled in both groups is given in Figure 1, showing an increased occurrence of splenomegaly, low NK cell activity, hypertriglyceridemia in HLH patients. Steroids along with supportive treatment was given to 53% and etoposide was added in 7%. Treatment for underlying etiology alone without immunosuppressive treatment was given in 39%. The mortality in those with HLH vs. without HLH was 42% and 31%, respectively. The median duration of hospital stay was 18 and 36 days in HLH and without HLH group, respectively. Conclusion HLH should be suspected in sepsis patients with bicytopenia specially in tropical fevers. There is increased mortality if the sepsis patients fulfil HLH criteria. Early diagnosis and management is of paramount importance. Disclosures All authors: No reported disclosures.

Early Diagnosis and Treatment of the Patients with Acquired Hemophagocytic Lymphohistiocytosis

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3552-3552
Author(s):  
Zhao Wang ◽  
Yini Wang ◽  
Cuicui Feng ◽  
Liping Tian
Keyword(s):  
Early Diagnosis ◽  
Diagnostic Criteria ◽  
Peripheral Blood ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Clinical Symptoms ◽  
Interleukin 2 ◽  
Cell Activity ◽  
Final Diagnosis ◽  
Nk Cell Activity

Abstract Acquired hemophagocytic lymphohistiocytosis (HLH) is a life threatening condition characterized by uncontroling hyperinflammation on the basis of various infection, tumor and inherited immune deficiency. Awareness of the clinical symptoms and of the diagnostic criteria of HLH is crucial in order not to overlook HLH and to start life-saving therapy in time. In this study, we reviewed 57 suspected HLH patients from March 2006 to June 2008. 25 healthy subjects were enrolled in the study as control. NK cell activity in peripheral blood was tested by a released LDH assay. Meanwhile, solution interleukin-2 receptor (sCD25) was examined with ELISA double antibody sandwich assay. The level of glycosylated ferritin was also detected and the ratio of glycosylated ferritin to ferritin was determined. 41 out of 57 patients were definitely diagnosed according to HLH-2004 diagnostic criteria in this study and 16 patients were excluded. We found that the level of NK cell activity and the ratio of glycosylated ferritin in the all 41 final diagnozed HLH patients were significantly lower than those in the 16 excluded patients and 25 healthy control subjects (p<0.01). Meanwhile, the level of sCD25 in peripheral blood was much higher in all the 41 HLH patients than that in the excluded and healthy people (p<0.05). We compared the coincidence of each diagnostic index in the 41 HLH patients before and after final diagnosis. It was found that 100% patients had abnormal expression on NK cell activity, sCD25 and glycosylated ferritin in the early disease. The three diagnostic indexes were more sensitive and specific than other indexes, such as fever, hepatosplenomegaly, cytopenia, hyper-triglyceridemia, hypo-fibrinogenemia. 41 diagnosed patients received the regimen containing methylprednisolone and immunoglobulin, with or without fludarabine, 26 out of 41 were markedly improved after treatment, 10 out of 41 were exacerbated, and other 5 patients gave up treatment. It is concluded that detection of NK cell activity, sCD25 and glycosylated ferritin may play a very important role in the early diagnosis of HLH. Our data also suggest that fludarabine combined with methylprednisolone and immunoglobulin (FDIg) may provide a new viewpoint for HLH therapy.

Serum soluble CD25 and ferritin in distinguishing patients with uncomplicated hematologic malignancies from patients with hematologic malignancies complicated by hemophagocytic lymphohistiocytosis.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20072-e20072
Author(s):  
Adi Zoref Lorenz ◽  
Liron Hofstetter ◽  
Jun Murakami ◽  
Oren Pasvolsky ◽  
Elad Guber ◽  
...  
Keyword(s):  
Diagnostic Criteria ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Serum Levels ◽  
Hematologic Malignancies ◽  
Screening Criteria ◽  
Underlying Malignancy ◽  
Life Threatening ◽  
Sensitivity Specificity ◽  
Inflammatory Syndrome

e20072 Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyper-inflammatory syndrome with distinct clinical and laboratory features. In adults, HLH is often associated with underlying malignancy, most commonly hematologic malignancies (HM). HLH occurs in 1% of adults with HM and overall survival can be low as 10-20%. Abnormal serum levels of the inflammatory markers sCD25 and ferritin are diagnostic criteria for familial HLH. However, because these reactants are often elevated in malignancy, appropriate levels for diagnosis in HM-HLH are unknown. In this study, we establish optimal sCD25 and ferritin levels for the diagnosis of HM-HLH in adults. Methods: Patients from three centers in Israel and Japan with HM-HLH and HM in whom sCD25 testing was performed were studied. The diagnosis of HLH was according to the HLH 2004 diagnostic criteria. Initial (at HLH presentation) and the maximum ferritin levels were analyzed. Sensitivity, specificity, and optimal cutoffs were calculated by receiver operating characteristic (ROC). Results: 62 patients with HM's without HLH and 40 patients with HM-HLH were included. The distribution of ages and HM subtypes was similar between groups (mostly B cell, T/NK cell, and Hodgkin's lymphoma). The median sCD25 concentration in HM was 1776 U/ml versus 8077 U/ml in HM-HLH. The median initial/ maximum ferritin levels were 190/202 ng/ml for the HM group and 2267/4515 ng/ml for the HM-HLH group. Both sCD25 and ferritin were very sensitive but nonspecific. sCD25 > 2400 U/ml had a sensitivity/specificity of 95%/65%, while initial ferritin > 500 ng/ml had a sensitivity/specificity of 95%/75%. ROC analysis demonstrated optimal confirmatory cutoff values (maximizing specificity) of > 10,056 ng/ml for sCD25 (sensitivity/specificity 47%/95%). While initial ferritin demonstrated a cutoff of > 5231 ng/ml (sensitivity/specificity 22.5%/95%, AUC = 0.88) the maximum ferritin performed better with the cutoff of > 5748 ng/ml (sensitivity/specificity 45%/95%, AUC = 0.92). Conclusions: Our data suggest that the current HLH 2004 criteria of ferritin > 500 ng/ml and sCD25 > 2400 U/ml are effective screening criteria for the complication of HLH in HM patients. sCD25 > 10,000 U/ml and initial ferritin > 5,200 ng/ml are highly specific. Patients with suspected HM- HLH should have serial ferritin testing which increases specificity of this test. Future prospective studies are needed to confirm these findings.

scholarly journals 741. Ehrlichia chaffeensis Induced Hemophgocytic lymphohistiocytosis: A Descriptive Case Series

2021 ◽  
Vol 8 (Supplement_1) ◽  
pp. S468-S469
Author(s):  
jeffrey lin ◽  
Hanine El Haddad ◽  
Ayman Qasrawi ◽  
Gerhard Hildebrandt
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Spotted Fever ◽  
Immunosuppressive Treatment ◽  
Laboratory Data ◽  
Cell Activity ◽  
Clinical Signs ◽  
Case Series ◽  
Signs And Symptoms ◽  
Clinical Signs And Symptoms

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) secondary to tick borne illnesses is rarely reported. Clinical signs and symptoms of tick borne illnesses and HLH might overlap with fever, cytopenias and increased liver enzymes being common. We describe findings from case series of ehrlichiosis induced HLH. Methods We reviewed patients with ICD-10 codes corresponding to a diagnosis of HLH or macrophage activation syndrome (MAS) at University of University of Kentucky Medical Center between January 2008 and April 2020. Inpatients who were &gt;18 years of age without known immune compromise were included. 4 cases with confirmed underlying ehrlichiosis were identified at our institution. We searched PubMed for English-language articles containing the terms “ Hemophagocytic lymphohistiocytosis “ and “infection” or “tick borne” or “Ehrlichia”. Data on patient demographics, clinical signs and symptoms, laboratory data such as ferritin, platelet count, Il-2, NK cell activity, and outcomes were collected. Results We identified 16 cases of ehrlichiosis (1 had a coinfection with Rocky Mountain Spotted fever). Eleven out of 6 (68%) were male, median age was 58. All patients were febrile and thrombocytopenic on presentation and 8/14 (57%) were neutropenic. All had elevated ferritin (mean 36187 ng/mL, range 860 – more than 100000). CNS involvement was reported in 4 patients with a positive CSF Ehrlichia chaffensis PCR. All patients met at least 5 2004-HLH defining criteria and 10/14 (71%) patients had evidence of hemophagocytosis on bone marrow biopsy (table 1). Fourteen out of 15 (93%) patients received doxycycline and 9/15 (60%) received steroids +/- etoposide. Mortality for Ehrlichia induced HLH was 12.5%, significantly lower than that reported for all secondary HLH mortality (45%). Conclusion This review highlights the importance of considering Ehrilichiosis as a cause of HLH in endemic areas particularly as clinical signs and symptoms of the 2 entities overlap. While overall mortality rate due to HLH is elevated, Ehrlichia induced HLH seems to have a much favorable prognosis with prompt institution antimicrobial treatment. Additional prognostic factors that correlate with a more severe course dictate need for immunosuppressive treatment need to be further elucidated. Disclosures Gerhard Hildebrandt, MD, Bayer, Scotts-Miracle, Charlottes Webb CWBHF, Almmune Therapeutics Inc AIMT, Medical PPTYS TR Inc. MPW, Caretrust Reit Inc CTRE, ANGI Homeservices Inc (Shareholder)Bristil-Myers Squibb/Medarex, Crispr therapeutics, IDEXX Laboratories, Johnson & Johnson, Pfizer, Procter & Gamble, Vertex (Shareholder)Falk Foundation, Incyte, Takeda (Other Financial or Material Support, Travel, Accommodations, Expenses)Jazz Pharmaceuticals, Incyte, Morphosys, Alexion Pharmaceuticals, Karyopharm Therapeutics, Seattle Genetics (Consultant)Jazz Pharmaceuticals, Pharmacyclics, Incyte, AstraZeneca (Grant/Research Support)Novartis, Insys Therapeutics, Abbvie, GW Pharmaceuticals, Cardinal Health, Clovis Oncology, Cellectis, CVS Health, Celgene, Bluebird Bio (Shareholder)

scholarly journals Severe Fever with Thrombocytopenia Syndrome Virus Infection Associated with Hemophagocytic Lymphohistiocytosis as Poor Prognostic Factor

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S319-S319
Author(s):  
Sunmin Park ◽  
Juwon Kim ◽  
Hyo Youl Kim ◽  
Young Uh ◽  
Young Keun Kim
Keyword(s):  
Diagnostic Criteria ◽  
Clinical Features ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Inflammatory Diseases ◽  
Clinical Feature ◽  
Poor Prognostic Factor ◽  
Immune Mediated ◽  
Life Threatening ◽  
Christian Hospital ◽  
Severe Fever

Abstract Background Severe fever with thrombocytopenia (SFTS) is an emerging infectious disease caused by a novel bunyavirus designated SFTS virus (SFTSV) with a high fatality rate. Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated life-threatening disease triggered by infections, neoplasms and noninfectious inflammatory diseases. A few HLH associated with SFTSV were reported. According to the diagnostic criteria of HLH, 11 patients with SFTS were reviewed. Methods During last 2 years (2015–2016), 11 SFTS patients were diagnosed at the Wonju Severance Christian Hospital, Yonsei University Wonju College of Medicine, Wonju, South Korea. Clinical features were analyzed using diagnostic criteria of 2004-HLH trial. We described if the prognosis of SFTSV-infected patients was associated with clinical features of HLH. Results Of 11 patients, four patients were fulfillled the diagnostic criteria of 2004-HLH trial (five of eight criteria). Two patients were fulfilled the four criteria. Five patients were fulfilled three or less criteria. Three of six patients who fulfilled four or more criteria were died. There was no mortality in five patients who fulfilled three or less criteria. Hemophagocytosis in bone marrow (BM) was observed in all six patients who were taken BM study. Conclusion In SFTS, HLH was severe clinical feature and it might be associated with poor prognosis. Disclosures All authors: No reported disclosures.

scholarly journals Clinical Relevance of Diagnostic Criteria for Hemophagocytic Lymphohistiocytosis (HLH) and Survival Outcome of Adult HLH Patients: A Single-Center Prospective Cohort Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3718-3718
Author(s):  
Joon Young Hur ◽  
Kang Kook Lee ◽  
Jun Ho Jang ◽  
Kihyun Kim ◽  
Chul Won Jung ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Diagnostic Criteria ◽  
Prospective Cohort ◽  
Nk Cell ◽  
Cell Activity ◽  
Diagnostic Value ◽  
Adult Patients ◽  
Nk Cell Activity ◽  
Soluble Cd25 ◽  
Underlying Causes

Abstract Introduction Hemophagocytic lymphohistiocytosis (HLH) is an immune-mediated life-threatening condition in which activated macrophages phagocytize hematopoietic cells in various clinical situations from physiologic reactions to pathologic conditions such as malignancy. The diagnosis of HLH is currently done according to the HLH-2004 criteria which were mainly based on pediatric experiences even though underlying causes and clinical features of adult patients with HLH are different from pediatric patients. However, there is little information about the value of each item and its clinical relevance in the diagnosis of adult patients. Thus, we analyzed the diagnostic value of HLH-2004 criteria in adult patients who had symptoms or signs suspicious of hemophagocytosis. Methods We have conducted a prospective cohort study for adult HLH since January of 2017 (Prospective cohort for adult hemophagocytosis: NCT03117010). Adult patients older than 18 years having at least one of the following problems could be enrolled onto this prospective cohort: 1) Pathologically confirmed hemophagocytosis in bone marrow or lymph nodes; 2) Presence of at least 3 conditions among 8 items of HLH-2004 diagnostic criteria. After obtaining written informed consent, we performed laboratory tests for the diagnosis of HLH including natural killer (NK)-cell activity and soluble CD25 in blood. The primary objective of this study was to explore the feasibility and clinical usefulness of HLH-2004 criteria in adult patients, and secondary objective was to analyze underlying causes and outcomes of adult HLH. Results At the time of analysis, 44 patients were enrolled in the cohort, and their median age was 51.5 years (range, 19-85 years). Male (n=27) was more common than female (n=17). All patients had fever (body temperature ≥ 38.5°C) and splenomegaly was found in 29 patients (66%, Figure 1). Although cytopenia such as neutropenia and thrombocytopenia was commonly found, only 20 patients had bi-lineage cytopenia (45%). Hypofibrinogenemia and/or hypertriglyceridemia were also less common findings (n=18, 41%). Hemophagocytosis in bone marrow or lymph nodes was pathologically confirmed in 27 patients (61%). Elevated serum level of ferritin (≥ 500 mg/L) and soluble CD25 (≥ 2400 U/mL) were 42 (95%) and 35 patients (80%), respectively. Among 33 patients whose NK-cell activity was evaluated, 22 patients had low or absent NK-cell activity (67%). According to diagnostic criteria, 28 patients having at least five conditions were diagnosed with HLH, and the remaining patients including 7 patients with bone marrow hemophagocytosis could not be diagnosed. Among 28 patients with HLH, T/NK-cell (n=8) and B-cell lymphomas (n=7) were the most common underlying disorders (n=15, 54%). Infection including EBV (n=6) and rheumatologic disorders (n=3) accounted for non-malignancy associated HLH whereas the remaining four patients' cause was not identified. At the time of analysis, 14 patients died due to uncontrolled HLH or underlying disorders or infectious complications during treatment. The median overall survival of all patients was 13.9 months (95% CI: 10.9 - 16.9), and patients with HLH was not significantly different from patients without HLH (p=0.655). The survival outcome of patients with lymphoma was significantly worse than patients without it regardless of HLH diagnosis (p<0.001). Conclusions Fever and elevated level of serum ferritin were the most frequent condition in patients having suspicious symptoms of HLH. Low or absent NK-cell activity and increased level of soluble CD25 could have additional diagnostic value for timely diagnosis of adult HLH. Considering lymphoma is frequently associated with adult HLH, immediate evaluation for lymphoma should be done in adult patients suspicious of HLH. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Hemophagocytic Lymphohistiocytosis for the Internist and Other Primary Care Providers

2021 ◽  
Vol 12 ◽  
pp. 215013272110537
Author(s):  
Tanmayi Srinivas Pai ◽  
Fernando F. Stancampiano ◽  
Candido Rivera
Keyword(s):  
Primary Care ◽  
Immune System ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Immunosuppressive Treatment ◽  
Primary Care Providers ◽  
Outpatient Setting ◽  
Adult Patients ◽  
Diagnosis And Treatment ◽  
Care Providers ◽  
Life Threatening

Hemophagocytic lymphohistiocytosis (HLH) syndrome is a hyperinflammatory state that leads to life-threatening, disproportionate activation of the immune system and may be confused for and concomitantly exist with sepsis. However, its treatment differs from sepsis, requiring early initiation of immunosuppressive treatment. While HLH syndrome is more commonly diagnosed in children, internists and other primary care providers must be familiar with the diagnosis and treatment of adult patients with HLH in the hospital and outpatient setting. In this article, we review the essentials that an internist and other primary care providers managing adult HLH patients should know.

scholarly journals Hemophagocytic Lymphohistiocytosis: Retrospective Analysis for Prognostic Factors

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4615-4615 ◽  
Author(s):  
Bhagirathbhai Dholaria ◽  
William A Hammond ◽  
Amanda Shreders ◽  
Sarah Robinson ◽  
Taimur Sher
Keyword(s):  
Retrospective Analysis ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Clinical Laboratory ◽  
Conflicts Of Interest ◽  
Cell Activity ◽  
Significant Risk ◽  
P Value ◽  
Significant Heterogeneity ◽  
Treatment Pathways

Abstract Background Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic inflammatory condition. Due to rarity of the cases, it presents difficulties in diagnosis and management. Survival remains poor despite aggressive chemotherapy. Objective Patient outcomes varied markedly despite standardize therapy. Reliable prognostic disease markers may help to tailor intensity of therapy and predict long term outcomes. We attempt to look for variables associated with difference in mortality within 30 days of diagnosis. Methods We performed a retrospective search on mayo clinic patient database for the patients with the diagnosis of HLH from 2005 to 2015. HLH-04 criteria were used to select the study population. Patients were divided in two groups based on survival after the diagnosis. We analyzed different clinical and laboratory parameters to detect difference between the patients expired within 30 days of diagnosis and who survived longer than 30 days. Baseline Characteristics: Demographics: 40 patients were included in the analysis who met HLH- 04 criteria. Mean age was 49 years, 40% (16/40) were female and 60% (24/40) were male. Underlying HLH etiology was malignancy 37% (15/40), infection 20% (8/40), rheumatological 17% (7/40), idiopathic 20% (8/40). Two patients were peripartum and one with Kikuchi syndrome. EBV DNA PCR were positive in 32% (13/40) of patients. Table 1 show clinical and laboratory characteristics according to HLH-04 criteria. Treatment: Steroids were used in 92% (37/40), etoposide was used in 55% (22/40), and HLH 04 protocol (Etoposide/dexamethasone/cyclosporine) was used in 40% (16/40) of the patients. IVIG was used in 13% with underlying rheumatological process. Mean follow up was 57 weeks (0.1 to 336 weeks) for the whole group. Total 40% (16/40) died within 30 days of diagnosis. Results Risk of 30-days mortality was significantly higher in the patients with ferritin >5000 mcg/L at the time of diagnosis and age > 55 years. Out of total 40 patients, 54% (12/22) died in ferritin >5000mcg/L group and 22% (4/18) died in ferritin < 5000 mcg/L group within 30 days. (p-0.03) Death rate within 30 days was 65% (11/17) with age > 55 years and 22% (5/23) with age < 55 years at the time of diagnosis of HLH. (p-0.05) No difference between the groups in terms of gender, EBV positivity, underlying etiology and etoposide use was found in 30 days mortality. Table 2 summarizes the findings. Discussion HLH is a complex disorder with significant heterogeneity in terms of underlying etiology and response to treatments. Diagnosis is based on a set of clinical and investigational parameters. Most commonly used criteria are HLH-04. Treatment involves rapid immunosuppression with steroids, chemotherapy and calcineurin inhibitors. Previous retrospective studies have pointed out different risk factors associated with poor survival, which are malignancy, hypoalbuminemia, elevated creatinine and bilirubin. Ours is a relatively small retrospective analysis, but it shows significant prognostic value to elevated ferritin (>5000 mcg/L) at the time of diagnosis and age > 55 years. Survival remains poor in high risk patients despite aggressive therapy. Biological agents (IL1 and IL6 blockage) may provide new realm of therapy with tolerable toxicity profile. Conclusion Elevated ferritin at the time of diagnosis and older age are associated with significant risk of 30 day mortality in HLH. These factors can be incorporated in future clinical trials to choose different treatment pathways. Table. Clinical and laboratory characteristics according to HLH- 04 criteria Clinical/laboratory manifestation Presence of HLH 04 criteria (%) Fever > 38.5C 36/40 90 Splenomegaly 30/40 75 Hemoglobin < 9g/dl 22/40 55 ANC < 1000/microL 14/40 35 Platelets < 100, 000/microL 31/40 77 Triglyceride > 265 mg/dl 22/40 55 Ferritin > 500 mcg/L 36/40 90 Fibrinogen <150 mg/dl 12/38 31 sIL2- R > 1000u/ml 13/14 92 Low NK - cell activity 13/15 86 Presence of hemophagocytosis 33/39 84 Table 2. Difference in clinical variables based on survival after the diagnosis of HLH Survival < 30 days Survival > 30 days P value Age (years) 62 40 0.0004 Median time to start treatment (weeks) 40.7 8.6 0.23 Baseline ferritin (mcg/L) 32866 10667 0.01 Peak ferritin (mcg/L) 45870 29894 0.26 Albumin (g/dL) 2.3 2.6 0.41 LDH (U/L) 1271 720 0.51 Bilirubin (mg/dL) 8.9 4.5 0.14 Triglyceride (mg/dl) 260 276 0.70 Disclosures No relevant conflicts of interest to declare.

Secondary hemophagocytic lymphohistiocytosis (HLH): Five years’ experience at the UTHealth McGovern Medical School at Houston, Texas.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19578-e19578
Author(s):  
Frances Natalia Cervoni-Curet ◽  
Adan Rios ◽  
Binoy Yohannan ◽  
Hongyu Miao
Keyword(s):  
Bone Marrow ◽  
African American ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Pediatric Population ◽  
Cell Activity ◽  
Gene Mutations ◽  
Therapeutic Approaches ◽  
Nk Cell Activity ◽  
Secondary Hemophagocytic Lymphohistiocytosis

e19578 Background: Secondary HLH in adults is associated to infections, malignancies, and autoimmune disorders. HLH in children has been the basis for the management and treatment of HLH in adults. Despite their clinical similarities there are fundamental differences. Children’s HLH is caused by gene mutations in granule-mediated cytotoxicity while secondary HLH does not have known apparent genetic causes. This may affect the clinical outcomes based in how we approach the diagnosis and management of secondary HLH in adults. Methods: We reviewed 49 cases of secondary HLH at our institution over a five-year period. Patients median age was 47 years, with 31 males, 18 females. Fifteen were Caucasian, 10 Asians, 8 African American and 15 Hispanics. One was not specified. Results: Fever, hyperferritenemia and cytopenia correlated with 100% elevation of sCD25R, the most important biomarker of HLH. Patients with these three criteria were urgently treated with dexamethasone-etoposide (HLH-94 protocol) or dexamethasone alone (autoimmune related) while completing identification of other criteria described in the pediatric population together with treatment of the secondary cause. Conclusions: Secondary HLH is not rare. Etoposide and dexamethasone (preferred dose:40 mg total/day initially) are the most important current therapeutic approaches. Secondary HLH must be treated urgently and independently of the secondary cause. Treatment should not be delayed awaiting results of sCD25R, NK-cell activity and presence of hemophagocytosis in the bone marrow (often absent). Further work needs to be done to elucidate the physiopathology of secondary HLH.[Table: see text]

Efficacy of moderately dosed etoposide in macrophage activation syndrome - hemophagocytic lymphohistiocytosis (MAS-HLH)

2021 ◽  
pp. jrheum.200941
Author(s):  
AnnaCarin Horne ◽  
Tatiana von Bahr Greenwood ◽  
Samuel C.C. Chiang ◽  
Marie Meeths ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Lupus Erythematosus ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Macrophage Activation Syndrome ◽  
Macrophage Activation ◽  
Nk Cell ◽  
Cell Activity ◽  
Neutropenic Sepsis ◽  
Lymphocyte Cytotoxicity ◽  
Activation Syndrome

Objective Macrophage activation syndrome (MAS) constitutes one subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated to 5-10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH, administered with the objective to effectively reduce severe hyperinflammatory activity with limited side effects. Methods In addition to conventional anti-inflammatory treatment, moderately dosed etoposide was administered to seven children affected by rapidly progressing MAS-HLH with central nervous system (n=5) and/or pulmonary (n=5) involvement. Three had underlying systemic onset juvenile idiopathic arthritis (sJIA), two atypical sJIA (no arthritis at diagnosis), and two systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all seven and genetic analyses in six. Results All children promptly responded to moderately dosed etoposide (50-100 mg/m2 once weekly), added to conventional MAS-HLH treatment which was considered insufficient. The mean accumulated etoposide dose was 671 mg/m2 (range 300-1,050 mg/m2), as compared to 1,500 mg/m2 recommended the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3x109/L at therapy onset). Five/seven children had low percentages (<5%) circulating NK-cells prior to or in association with diagnosis; NK-cell activity was pathologically low in two/five children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2-9 years after onset); neurological symptoms had normalized in four/five affected children. Conclusion Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.

Novel Munc13-4 Mutations in Patients with Hemophagocytic Lymphohistiocytosis.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2807-2807
Author(s):  
Alessandra Santoro ◽  
Sonia Cannella ◽  
Antonino Trizzino ◽  
Cesare Danesino ◽  
Daniela Pende ◽  
...  
Keyword(s):  
Hemophagocytic Lymphohistiocytosis ◽  
Nk Cell ◽  
Donor Site ◽  
Genetic Defect ◽  
Cell Activity ◽  
Rapid Screening ◽  
Splice Donor Site ◽  
Cytotoxic Lymphocyte ◽  
Cycle Sequencing ◽  
Exon 20

Abstract Familial hemophagocytic Lymphohistiocytosis (FLH) is a rare disorder characterized by fever, hepatosplenomegaly, cytopenia, hypertriglyceridemia, hypofibrinogenemia and reduced natural killer (NK) cell activity. Several genetic defects have been recognized as associated with FHL. After identification of perforin gene (PRF1) mutation as the cause of about one third of cases of FHL (Stepp,1999), in 2003 the same group reported that another gene involved in cellular cytotoxicity, Munc13-4, encoding for a protein involved in granule release in cytotoxic lymphocyte, is associated with a subset of patients with FHL. We have analyzed for Munc13-4 mutations 16 families of patients diagnosed with FHL according to current criteria, in whom PRF1 mutations had been excluded; 14 were Italian, 1 from USA, one from UK. The 32 exons and their proximal flanking regions of Munc13-4 gene were amplified from genomic DNA and amplification products were directly sequenced by cycle sequencing approach (BigDye Terminator Applied Biosystems). Sequences of primers utilized for the amplification reactions were designed with dedicated software (Primer Express) according to the gene sequence retrived from Genebank. A total of 13 mutations were identified in 12 families; 3 had homozygous mutations, 5 had combined heterozygous mutations, and 4 had only one detectable mutated allele. Mutation 753+IG in exon 9 (splice donor site) had been already reported (Feldman 2003, zurStadt 2005); The following novel mutations were found: G175A in exon 3 (A59T), delC532 in exon 6 (178 fs), A610G in exon 7 (M204V), G1241T in exon 14 (R414L), A1847G in exon 20 (E616G), del GGAG 2346 (782 fs) in exon 24, A2599G (K867E) in exon 27, C2650T in exon 28 (Q884stop), C2782T in exon 29 (R928C), C2896T in exon 30 (R966W), 3082delC in exon 31 (1028fs), insG3226 in exon 32 (1076fs). Mutation A2599 was observed in 6 families; mutation A1847G in 3 families; C2782T and G1241T in 2 families. We have also identified the polymorphisms C279T, and A3198G. Mutations were scattered over different exons and almost entirely different from those reported so far. A2599G mutation was frequently observed and its role deserves further investigation. Screening of Munc13-4 mutations is a powerful tool to confirm the diagnosis, to refine the therapeutic choice including indication to HSCT, selection of familiar donor, and identification of carriers and prenatal diagnosis in most of the families with FHL not associated with PRF1 mutations. Due to lack of immunologic or flow-cytometric tools for rapid screening of Munc13-4 defective patients, the high number of coding exons and lack of mutation clustering, screening of Munc13-4 mutations, although expensive and time consuming, remains necessary and allowed us to identify the genetic defect in the majority of our patients with FHL not associated with PRF1 mutations.

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