Showing papers on "Hemophagocytic lymphohistiocytosis published in 1999"

Perforin Gene Defects in Familial Hemophagocytic Lymphohistiocytosis

Abstract: Familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly fatal, autosomal recessive immune disorder characterized by uncontrolled activation of T cells and macrophages and overproduction of inflammatory cytokines. Linkage analyses indicate that FHL is genetically heterogeneous and linked to 9q21.3-22, 10q21-22, or another as yet undefined locus. Sequencing of the coding regions of the perforin gene of eight unrelated 10q21-22–linked FHL patients revealed homozygous nonsense mutations in four patients and missense mutations in the other four patients. Cultured lymphocytes from patients had defective cytotoxic activity, and immunostaining revealed little or no perforin in the granules. Thus, defects in perforin are responsible for 10q21-22–linked FHL. Perforin-based effector systems are, therefore, involved not only in the lysis of abnormal cells but also in the down-regulation of cellular immune activation.

Localization of a Gene for Familial Hemophagocytic Lymphohistiocytosis at Chromosome 9q21.3-22 by Homozygosity Mapping

Abstract: Summary Familial hemophagocytic lymphohistiocytosis (FHL), also known as familial erythrophagocytic lymphohistiocytosis and familial histiocytic reticulosis, is a rare autosomal recessive disorder of early childhood characterized by excessive immune activation. Linkage of the disease gene to an ∼7.8-cM region between markers D9S1867 and D9S1790 at 9q21.3-22 was identified by homozygosity mapping in four inbred FHL families of Pakistani descent with a combined maximum multipoint LOD score of 6.05. This is the first genetic locus to be described in FHL. However, homozygosity by descent across this interval could not be demonstrated in an additional affected kindred of Arab origin, whose maximum multipoint LOD score was −0.12. The combined sample revealed significant evidence for linkage to 9q markers (LOD score with heterogeneity, 5.00). Identification of the gene(s) involved in the pathogenesis of FHL will contribute to an understanding of the control of T-lymphocyte and macrophage activation, which is central to homeostasis in the immune system.

Linkage of Familial Hemophagocytic Lymphohistiocytosis to 10q21-22 and Evidence for Heterogeneity

Abstract: Summary Familial hemophagocytic lymphohistiocytosis (FHL) is an autosomal recessive disorder characterized by the early onset of overwhelming activation of T lymphocytes and macrophages, invariably leading to death, in the absence of allogeneic bone marrow transplantation. Using genomewide genetic linkage analysis, we analyzed a group of 17 families with FHL and mapped a locus for FHL to the proximal region of the long arm of chromosome 10. Ten families showed no recombination with three tightly linked markers, D10S1650 (LOD score [ Z ]=6.99), D10S556 ( Z =5.40), and D10S206 ( Z =3.24), with a maximum multipoint LOD score of 11.22 at the D10S1650 locus. Haplotype analysis of these 10 families allowed us to establish D10S206 and D10S1665 as the telomeric and the centromeric flanking markers, respectively. Heterogeneity analysis and haplotype inspection of the remaining families confirmed that in seven families FHL was not linked to the 10q21-22 region, thus providing evidence for genetic heterogeneity of this condition.

Oversecretion of IL-18 in haemophagocytic lymphohistiocytosis: a novel marker of disease activity

Abstract: We investigated the significance of interleukin (IL)-18 levels in the pathophysiology of haemophagocytic lymphohistiocytosis (HLH). IL-18 levels were significantly elevated in all nine patients with active HLH compared with those of healthy controls. Serial determination of IL-18 levels in three cases, showed a gradual decrease compared with those of IL-12, interferon (IFN)-gamma or soluble Fas ligand (sFasL) in the course of clinical improvement, and seemed to be elevated until complete disappearance of disease activity. IL-18 and IFN-gamma (CC 0.711, P = 0.018), and IFN-gamma and sFasL (CC 0.849, P = 0.0049) levels were significantly correlated. On the other hand, correlation between IL-12 and IFN-gamma, IL-18 and sFasL, or IL-18 and IL-12 was not observed. IL-18, IFN-gamma and sFasL levels significantly correlated with disease activity such as fever and alanine transaminase (ALT) levels. IL-18 mRNA expression was enhanced in spleen, but not in peripheral blood mononuclear cells (MNC), bone marrow MNC, liver from patients of active HLH, or the tumour from a patient with lymphoma-associated haemophagocytic syndrome (LAHS). These results suggest that IL-18 may play important roles in the pathogenesis of HLH, particularly through induction of Th1 cells. IL-18 measurement may be useful for the diagnosis and for the detection of smouldering disease activity.

Hemophagocytic syndrome presenting as acute hepatic failure in two infants: clinical overlap with neonatal hemochromatosis.

Abstract: Two patients with hemophagocytic lymphohistiocytosis who presented with acute liver failure are reported. Both presented with fever, hepatosplenomegaly, markedly elevated liver function tests, abnormal coagulation profiles, and an increase in serum ferritin. Both infants were diagnosed with neonatal hemochromatosis based on a clinical picture of hepatic insufficiency with hyperferritinemia and were referred for liver transplantation. The first patient died of liver failure and septicemia before transplantation. Review of autopsy material revealed a hepatitis-like pattern and extensive infiltration of liver and other organs including bone marrow by histiocytes, some of which were hemophagocytic. The second patient underwent liver transplantation but died 44 days thereafter from progressive hemophagocytic lymphohistiocytosis. Examination of the resected liver demonstrated a hepatitis-like pattern, proliferation of histiocytes, and hemophagocytosis, and the bone marrow revealed hemophagocytic histiocytosis. Hemophagocytosis recurred in the allograft. Hepatic manifestations are common in hemophagocytic lymphohistiocytosis and overt hepatic failure may occur, but initial presentation as fulminant hepatic failure is not well recognized. Elevated serum ferritin can make the distinction from neonatal hemochromatosis and other forms of neonatal liver failure difficult. Hemophagocytic lymphohistiocytosis should be considered in the differential diagnosis of neonatal liver disease, especially when it is accompanied by cytopenias.

Improved outcome in haemophagocytic lymphohistiocytosis after bone marrow transplantation from related and unrelated donors: a single‐centre experience of 12 patients

Abstract: Haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a fivefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in five, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24.5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan.

Abstract: Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan

Induction of apoptosis and caspase activation in cells obtained from familial haemophagocytic lymphohistiocytosis patients.

Abstract: Familial haemophagocytic lymphohistiocytosis (FHL) is a rare and uniformly fatal disorder of early childhood characterized by fever, hepatosplenomegaly, cytopenia and widespread infiltration of vital organs by activated lymphocytes and macrophages. In order to test whether the massive accumulation of immune cells in these patients is associated with a perturbation of apoptosis, lymphocytes were isolated from eight patients and subjected to the chemotherapeutic agent etoposide or agonistic anti-Fas monoclonal antibodies in vitro. These stimuli elicited a normal apoptotic response in FHL patient cells when compared to healthy controls, as determined by phosphatidylserine exposure, DNA fragmentation, in vitro cleavage of the caspase-3-like substrate aspartate-glutamate-valine-aspartate-7-amino-4-methyl-coumarin (DEVD-AMC) and proteolysis of the anti-apoptotic protein Bcl-2. In addition, the degree of constitutive and Fas-triggered apoptosis in freshly isolated neutrophils was monitored in three children, with similar results. These studies indicate that immune cells derived from FHL patients are not inherently resistant to apoptosis induction. Specifically, etoposide-induced and Fas-triggered activation of intracellular caspases appears to remain intact in these individuals. However, the degree of spontaneous activation of caspase-3-like enzymes in activated lymphocytes was attenuated in three of the four patients tested prior to initiation of therapy, suggesting a possible biological deficiency in these individuals.

Genetic basis of hemophagocytic lymphohistiocytosis syndrome (Review).

Abstract: The group of immune disorders which leads to the occurrence of hemophagocytic lymphohistiocytosis (HLH) syndrome presents a strange paradox in that patients with these conditions associate a dramatic immune response to infection with the failure to establish an effective immune response. During the last few years, significant progress was made in the characterization and the understanding of the molecular basis involved in these inherited immune disorders. The hemophagocytic lymphohistiocytosis syndrome which characterized the evolution of the Chediak-Higashi syndrome and the Griscelli disease results from defects affecting intracellular trafficking. A defective SH2 protein interacting with T lymphocyte intracellular signaling pathways is the cause of the X-linked lymphoproliferative disease, whereas at least three distinct genetic defects can lead to the familial hemophagocytic lymphohistiocytosis. The molecular characterization of these latter defects is in progress. This review summarizes the recent advances as well as their implications in the diagnosis and the understanding of the physiopathology of these disorders.

Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection.

Abstract: A 2-year-old Japanese boy with a haemophagocytic lymphohistiocytosis (HLH) associated encephalopathy which developed after rotavirus infection is described. The neurological symptoms consisted of coma, seizures and spastic quadriplegia. On therapy with steroids, etoposide and cyclosporin A, the patient recovered without any neurological deficits. The interferon-gamma levels in serum and CSF were elevated at onset of the disease but had returned to normal at the time of clinical remission. Brain MRI revealed diffuse white matter abnormalities and parenchymal volume loss. Proton magnetic resonance spectroscopy revealed elevated lactate in the abnormal lesions observed on MRI, indicating that macrophages not exhibiting aerobic metabolism had infiltrated the CNS. At the time of clinical remission, the white matter abnormalities and brain lactate had disappeared. These findings suggested that the neurological symptoms resulted from the overproduction of cytokines by activated T-cells and macrophages. The pathophysiology of a HLH associated encephalopathy was considered to be a local immune response within the CNS, because interferon-gamma can induce the expression of major histocompatibility complex class I and II antigens on glial cells in the CNS.

Hemophagocytic lymphohistiocytosis in a patient with deletion of 22q11.2.

Abstract: We report on a new patient with deletion of 22q11 associated with hemophagocytic lymphohistiocytosis and a fatal outcome. She had minor facial anomalies and cardiac malformation corresponding to those described in del (22q11) syndrome, normal T and B cell function and NK activity; bone marrow aspiration showed active erythrophagocytosis. Our case in addition to two other children reported previously suggest that such a rare association between lymphocyte-macrophage activation and deletion of 22q11 may be more frequent than previously recognized.

Aplastic anemia after Mycoplasma pneumoniae infection: a report of two cases.

Abstract: Two very unusual cases of aplastic anemia complicating mycoplasma infection are described. Each patient had preexisting hematologic abnormalities at the time of the infection : reactive hemophagocytic syndrome in one, and autoimmune hemolytic anemia associated with cold autoantibodies in the other. This adds another entity to the protean manifestations of Mycoplasma pneumoniae infection.

Clonal change of infiltrating T-cells in children with familial hemophagocytic lymphohistiocytosis: possible association with Epstein-Barr virus infection

Abstract: BACKGROUND Although familial hemophagocytic lymphohistiocytosis (FHL) has been considered a T-cell disorder, to the authors' knowledge there are no previous reports on the clonal basis of FHL. In the current study the authors analyzed the clonality of T-cells in two FHL patients at the time of disease onset and at disease progression. METHODS Patient 1 had FHL and died of recurrent disease 4 months after bone marrow transplantation (BMT). His liver and spleen showed massive infiltrations of CD3+, CD4-, and CD8+ T-cells. The Epstein-Barr virus (EBV) genome was detected by in situ hybridization. Patient 2 also had FHL and died of progressive disease 9 weeks after the onset of disease despite chemotherapy. A polymerase chain reaction (PCR) analysis showed positive EBV genome in the peripheral blood, liver, and spleen of Patient 2. In the two patients, T-cell receptor-β and α-chain variable region (TCR Vβ and Vα) repertoires in peripheral mononuclear cells were analyzed at the time of disease onset and at disease progression by the inverse PCR method. When a high usage (> 15%) of a specific Vβ family member was observed, a clonal analysis was performed by PCR using β-chain joining region (Jβ) primers. The clonality of specific Vβ-Jβ fragments was confirmed by a single strand confirmation polymorphism (SSCP) analysis. RESULTS Although there was no preferential usage of Vβ in Patient 1, the exclusive expression of Jβ1.2 for Vβ13 was observed. A high frequency of Vβ13 also was observed at the time of disease progression, but the Jβ fragment for Vβ13 was polyclonal. In Patient 2, the restricted usage of Jβ1.6 for Vβ5a was observed at the time of disease onset, whereas Jβ1.1 and 1.2 for Vβ4 were observed exclusively at the time of disease progression. The clonality of Vβ13-Jβ1.2 in Patient 1 and Vβ5a-Jβ1.6 and Vβ4-Jβ1.1/Jβ1.2 in Patient 2 was confirmed by SSCP analysis. CONCLUSIONS These findings suggest that the polyclonal T-cell lymphoproliferative disease associated with EBV was induced after BMT in Patient 1, and that the clonal change of expanded T-cells also was induced by EBV in Patient 2. The clonal analysis of T-cells is a useful tool to clarify the pathogenesis of FHL. Cancer 1999;85:1636–43. © 1999 American Cancer Society.

Haemophagocytic lymphohistiocytosis in children.

Abstract: Objective: To evaluate the clinical and diagnostic features of children presenting with haemophagocytic lymphohistiocytosis (HLH), evolution of the disease and outcomes in response to treatment.

Original article Abdominal ultrasound findings in children with hemophagocytic lymphohistiocytosis

Abstract: . Hemophagocytic lymphohistiocytosis, avariant of histiocytosis, is characterized by an uncon-trolled activation of the cellular immune system, in-cluding hepatic mononuclear phagocytic cells. Ab-dominal ultrasound findings in children are evaluatedin this disease. We present six pediatric cases, twowith familial and four with sporadic hemophagocyticlymphohistiocytosis, examined by abdominal sonog-raphy. Three signs were frequently observed: thicken-ing of the gallbladder wall (all cases), increased peri-portal echogenicity (four cases), and enlarged lymphnodes in the porta hepatis (four cases). Hepatomega-ly, splenomegaly, and ascitic fluid may also be found.These imaging findings are not specific and may beseen in viral hepatitis. However, once hepatitis is ex-cluded, they may suggest the diagnosis of hemophag-ocytic lymphohistiocytosis in a critically ill child. Abone smear must be done to establish the diagnosis.Key words: Child, gastrointestinal tract – Gallblad-der, wall thickening – Liver, US – Histiocytosis –Hepatitis – Hemophagocytic lymphohistiocytosis –Hemophagocytic syndrome

Abdominal ultrasound findings in children with hemophagocytic lymphohistiocytosis.

Abstract: Hemophagocytic lymphohistiocytosis, a variant of histiocytosis, is characterized by an uncontrolled activation of the cellular immune system, including hepatic mononuclear phagocytic cells. Abdominal ultrasound findings in children are evaluated in this disease. We present six pediatric cases, two with familial and four with sporadic hemophagocytic lymphohistiocytosis, examined by abdominal sonography. Three signs were frequently observed: thickening of the gallbladder wall (all cases), increased periportal echogenicity (four cases), and enlarged lymph nodes in the porta hepatis (four cases). Hepatomegaly, splenomegaly, and ascitic fluid may also be found. These imaging findings are not specific and may be seen in viral hepatitis. However, once hepatitis is excluded, they may suggest the diagnosis of hemophagocytic lymphohistiocytosis in a critically ill child. A bone smear must be done to establish the diagnosis.

Prolonged gastrointestinal dysmotility in a patient with hemophagocytic lymphohistiocytosis treated with vincristine.

Abstract: Vincristine , an effective and widely used anticance r drug, carrie s far less risk of immunosuppression than other antine oplastic agents. Instead, use of the drug often is limited by neurotoxicity (1± 3). In addition to the most frequent manifestation of periphe ral somatic neuropathy, decreased tendon re ̄ exes, autonomic neuropathy may occur, often causing a gastrointe stinal motility proble m most frequently manifest as constipation and anorexia. In severe cases, paralytic ileus may deve lop. Sandle r et al reported symptoms relating to gastrointe stinal motility occurring in 46% of a group of leukemic childre n treated with vincristine (1). The risk of motility proble ms is dose dependent but not ordinarily cumulative with repeated use (2). Although the frequency of gastrointe stinal dysmotility is relative ly high, its outcome is not serious. Most gastrointe stinal symptoms disappear within several days and leave no lasting morbidity (2± 5). Kaufman et al (5) have reported ® ve childre n with severe ileus after extreme overdosage of vincristine (3.5± 35 mg). Even in such cases, surviving patients became free of gastrointe stinal symptoms within two weeks. Here we report a child who deve loped an extremely longlasting gastrointe stinal motility proble m following treatment of hemophagocytic lymphohis tiocytosis (HLH) with vincristine . CASE REPORT

A case of hemophagocytic lymphohistiocytosis with prolonged remission after syngeneic bone marrow transplantation.

Abstract: We report a 7-year-old girl with hemophagocytic lymphohistiocytosis who received a syngeneic bone marrow transplant from her twin sister. She presented with high fever and cough. Laboratory findings revealed pancytopenia, elevation of liver enzymes, and hyperferritinemia. Bone marrow examination revealed histiocytic hemophagocytes and lymphoblastoid cells. Southern blot analysis of the bone marrow cells revealed a monoclonal proliferation of EBV-infected lymphocytes. Although she underwent combined chemotherapy according to the HLH-94 protocol, she developed severe pancytopenia. Following myeloablative conditioning with busulfan (16 mg/kg), cyclophosphamide (120 mg/kg), and etoposide (1.5 g/m 2 ), she was transplanted with 6.6 × 10 8 /kg mononuclear cells from the twin sister. She remains in complete remission 23 months after transplantation.

The breakpoints of a constitutional inversion of chromosome 9 associated with haemophagocytic lymphohistiocytosis are not linked to the disease gene

Abstract: Haemophagocytic lymphohistiocytosis (HLH) is a severe disorder of early infancy consistent with an autosomal recessive inheritance. Neither the genetic locus nor the biochemical defect is known for the disease. A constitutional pericentric inversion of chromosome 9, with breakpoints in bands 9p23 and 9q31, has been reported in a case of HLH, suggesting a possible relationship between this chromosome abnormality and the disease. We investigated such an association, performing a genetic linkage analysis in a set of five consanguineous HLH families. 27 polymorphic markers on chromosome 9 were studied, excluding most of chromosome 9 as a putative site for the HLH gene.

Hemophagocytic lymphohistiocytosis

Abstract: Hemophagocytic lymphohistiocytosis (HLH) is a rare condition in children associated with immunodeficiency, life threatening infections and malignancy. Infection associated hemophagocytosis responds well to appropriate antimicrobioal therapy and rarely to steroids when the infective agent is suspected to be of viral origin.