Early Diagnosis Of Hemophagocytic Lymphohistiocytosis Research Articles

Early Diagnosis of Hemophagocytic Lymphohistiocytosis in an Adult Presenting With Sickle Cell Disease: A Case Report

Early Diagnosis of Hemophagocytic Lymphohistiocytosis in an Adult Presenting With Sickle Cell Disease: A Case Report

Imaging Spectrum of Neurological Manifestations of Hemophagocytic Lymphohistiocytosis in Pediatrics: A Case Series.

Hemophagocytic lymphohistiocytosis (HLH) is an uncommon condition, which can result either from a primary genetic abnormality affecting children or secondary to various conditions like malignancy or infection predominantly in adults. HLH is associated with immune dysregulation, resulting in an uncontrolled overproduction and infiltration of lymphocytes and histiocytes. The infiltration predominantly involves liver, spleen, lymph nodes, and central nervous system. Neuroimaging features on magnetic resonance imaging are highly nonspecific and variable. The most typical findings include periventricular white matter hyperintensities and diffuse atrophy. Ring or nodular enhancing or nonenhancing focal parenchymal lesions may be seen. Here, we present three pediatric cases of primary HLH with a wide spectrum of imaging findings involving cerebral and cerebellar cortex, white matter, deep gray matter, and brain stem. The findings in these patients range from small nonenhancing hemorrhagic lesions and enhancing small lesions to ill-defined mass with mass effect and midline shift. Lesions in deep gray matter including thalamus, basal ganglia, and also brain stem in HLH are rarely described in literature. Early diagnosis of HLH and timely management can improve the course of the disease.

S2272 A Rare Presentation of GI Bleeding Associated With Hemophagocytic Lymphohistiocytosis

Introduction: Hemophagocytic lymphohistiocytosis (HLH) is a rare disease caused by impaired function of cytotoxic T cells and NK cells that leads to hemophagocytosis. It is common in children and rarely seen in adults. Gastrointestinal bleeding (GIB) associated with HLH is extremely rare. We present a patient who has acute massive gastrointestinal bleeding associated with HLH. Case Description/Methods: A 70-year-old male with history of gout, started on allopurinol recently presented with jaundice (total, conjugated bilirubin, 23.8,13.7). After negative laboratory work up, liver biopsy showed occasional hemophagocytosis within foamy macrophages, perivenular hepatocanalicular cholestasis with feathery degeneration of hepatocytes, diffuse lobular edema with fibrosis, mixed portal inflammation with lobular macrophages and increased iron deposition within hepatocytes. He was thought to have drug induced cholestatic liver injury and allopurinol was stopped. The patient continued to have jaundice with high grade fevers, anemia, neutropenia and altered mental status. Further investigations revealed ferritin of >10,000 and CMV viremia prompting initiation with Ganciclovir. Bone marrow biopsy revealed hypercellularity with profound granulocytic hypoplasia, erythroid hyperplasia, adequate megakaryocytes, abundant macrophages and occasional with erythrophagocytosis and leukophagocytosis, and negative viral immunostaining and malignancy. He was started on a dexamethasone taper. The plan was to start dose adjusted etoposide when bilirubin improved; however, the patient developed a massive GIB with hemorrhagic shock with no extravasation on CT angiogram. Endoscopy was not done due to limited benefit in HLH. Family decided to pursue comfort care due to poor prognosis. Discussion: GIB associated with HLH is due to transmural lymphohistiocytic infiltration of macrophages resulting in localized ulcers or diffuse mucosal irritation in the gastrointestinal tract. Management of GIB is challenging, owing to difficulty in localizing mucosal bleeding and increased recurrent bleeding upon intervention, and thus has extremely high mortality. Guo et al conducted a study that estimated a 12.2% rate of having a GIB as a complication of HLH, with an associated mortality of 66%. Early diagnosis of HLH and treatment is the key. Emergent surgery or angioembolization for GIB has been partially successful in a few patients. We present a patient with secondary HLH complicated with GIB and multiorgan failure, despite early treatment.

Biomarkers for Early Diagnosis of Hemophagocytic Lymphohistiocytosis in Critically Ill Patients.

Many biomarkers have been proposed for the diagnosis of secondary hemophagocytic lymphohistiocytosis (HLH) in adults, but comparative studies are lacking. We analyzed ferritin, glycosylated ferritin, soluble CD25, CD163and CD14, IL-6, IFN-γ, IL-18, IL-10, IL-1ß, IL-12p70, IL-17α, IP-10, and CXCL9 levels to differentiate HLH from sepsis in critically ill patients. Of 120 patients, HLH was confirmed for 14 patients. Among the biomarkers tested, ferritin, IL-18, and glycosylated ferritin were the most efficient parameters for early diagnosis of HLH. With a sensitivity set at 85%, ferritin, IL-18, and glycosylated ferritin were the biomarkers with the highest specificity: 84, 79, and 71% respectively. Combining IL-18 with the HScore provided a new score with an increased specificity compared to the HScore alone, 86% compared to 70% with a sensitivity set at 100%. A distinct cytokine pattern was highlighted in patients with malignancy-triggered HLH, with highly increased levels of INF-ɣ and CXCL9, compared to HLH secondary to infection. This is the largest study available to date, comparing diagnostic biomarkers for HLH on a cohort of critically ill adult patients. Serum ferritin was the most discriminating parameter for early diagnosis of secondary HLH. IL18*HScore was identified as a highly potential score.

High serum ferritin alone as a predictor of mortality and hemophagocytic lymphohistiocytosis.

We report here utility of high serum ferritin alone as a predictor of mortality and diagnosis of hemophagocytic lymphohistiocytosis (HLH). We compared mortality in patients with high serum ferritin >5000 ng/mL versus <5000 ng/mL and looked for presence of HLH. Mortality was significantly higher (P‐value .0048) in patients with serum ferritin levels >5000 ug/dL. Of 21 patients with high serum ferritin, a median of three criteria were fulfilled to diagnose HLH. All patients had features of immune‐activation, and 76.2% patients had features of immune‐pathology favoring diagnosis of HLH. Serum ferritin can aid in prediction of mortality and help in the early diagnosis of HLH.

Atypical neuroimaging characteristics of hemophagocytic lymphohistiocytosis in infants: a case series of hemorrhagic brain lesions in the deep grey matter

Hemophagocytic lymphohistiocytosis (HLH) is a rare multisystem condition associated with uncontrolled overproduction and infiltration of lymphocytes and histiocytes predominantly in liver, lymph nodes, spleen, and central nervous system. Neuroimaging findings on MRI are fairly nonspecific and classically include periventricular white matter signal abnormalities and diffuse atrophy. Focal parenchymal lesions may demonstrate post contrast ring or nodular enhancement and calcification. However, the MR imaging characteristics can be highly variable. Here, we present two cases of HLH in infants with multiple hemorrhagic lesions mostly depicted in both thalami and basal ganglia regions. Thalamic, basal ganglia, and brain stem involvement with hemorrhagic changes in HLH are rarely described in literature. Early diagnosis of HLH may be lifesaving. Awareness of the disease is necessary to investigate its characteristic findings and avoiding a delay in diagnosis.

Synchronous hemophagocytic lymphohistiocytosis with Hodgkin's lymphoma in tubercular patient

We report an uncommon case of simultaneous presence of hemophagocytic lymphohistiocytosis (HLH) with Hodgkin's lymphoma and tuberculosis in an immunocompetent male. In the absence of treatment HLH is frequently associated with fatal outcome, although spontaneous partial regression is also noted. The early diagnosis of HLH is critical to prevent end organ failure. There are defined criteria for diagnosis of HLH but visualization of hemophagocytosis in bone marrow smear or biopsy along with fever, splenomegaly, elevated ferritin & triglycerides and peripheral blood cytopenias are highly suggestive of HLH. The pathologist and clinician should be aware of this uncommon entity so that early diagnosis and institution of therapy can be done to prevent poor prognostic outcome.

A Rare Cause of Hemophagocytic Lymphohistiocytosis: Fusobacterium Infection-A Case Report and Review of the Literature.

Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by excessive activation of the immune system. Bacterial infections are very rare precipitants of this disease. A 19-year-old gentleman presented with headache, fatigue, and malaise. He was found to be hypotensive, tachycardic, and febrile. Broad spectrum antibiotics were initiated, and a lumbar puncture ruled out meningitis. Patient progressively developed shock that required use of vasopressors, as well as renal and respiratory failure. Blood cultures grew Fusobacterium necrophorum. Given continued fevers despite appropriate antimicrobials, a bone marrow biopsy was performed revealing increased histiocytes with hemophagocytosis. Dexamethasone was added with dramatic clinical improvement. Our case highlights Fusobacterium as a rare precipitant of HLH and proves that a high index of clinical suspicion is crucial for early diagnosis of HLH, allowing for prompt initiation of HLH-specific immunosuppressive therapy that can be life-saving.

Hemophagocytic lymphohistiocytosis with neurological presentation: MRI findings and a nearly miss diagnosis

Hemophagocytic lymphohistiocytosis (HLH) is a rare disease with rarer neurological presentation. When this occurs, diagnosis may be delayed. This report aims to call attention to clinical, laboratory, and radiological features that should prompt the correct diagnosis. A 13-year-old girl presented with progressive increase in intracranial pressure and ataxia. MRI showed a diffuse tumor-like swelling of the cerebellum with tonsillar herniation and patchy white matter post-contrast enhancement. Regression of swelling with steroids ruled out glioma and medulloblastoma, and brain lymphoma was considered. Diagnosis of HLH was reached 2 months after onset when uncontrolled fever and severe elevation of liver enzymes occurred. Two bone marrow biopsies were needed to demonstrate hemophagocytosis. Familial HLH was confirmed by perforin gene mutations. Bone marrow transplantation was performed. The early diagnosis of HLH may be life saving. Awareness of the disease is necessary to investigate its characteristic findings, thus avoiding a delay in diagnosis.

Early Diagnosis and Treatment of the Patients with Acquired Hemophagocytic Lymphohistiocytosis

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.