Successful treatment of non-familial haemophagocytic lymphohistiocytosis with interferon and gammaglobulin

Two cases of non-familial haemophagocytic lymphohistiocytosis (HLH) are presented in which treatment with interferon alfa and gammaglobulin was associated with complete clinical remission. In one case, serological evidence of recent Epstein-Barr virus infection was found. Natural killer cell activity was within normal limits in both children, compatible with a secondary form of HLH. The combination of interferon alfa and intravenous gammaglobulin requires further evaluation in the treatment of non-familial HLH.     

Neonatal liver failure and haemophagocytic lymphohistiocytosis caused by a new perforin mutation

Acute liver failure is a rare heterogeneous syndrome in neonates. We report of a newborn with haemophagocytic lymphohistiocytosis presenting as acute liver failure. Pancytopenia and multi‐organ failure occurred later in the course. He carried two mutations of the perforin gene (PRF‐1), one of which not previously described, causing a complete loss of perforin expression and natural killer cell function. Conclusion: Perforin expression and function should be promptly assessed in neonatal/infantile acute liver failure, as haemophagocytic lymphohistiocytosis requires specific treatment and represents a contra‐indication to liver transplant.     

Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome

OBJECTIVES: To assess natural killer (NK) and cytotoxic functions in patients with systemic-onset juvenile rheumatoid arthrithis (soJRA) complicated by macrophage activation syndrome (MAS). METHODS: NK cells (CD56+/TCRalphabeta-), NK T cells (CD56+/TCRalphabeta+) and CD8+ cells were assessed for perforin expression by flow cytometry. NK cytotoxic activity was measured after coincubation of mononuclear cells with an NK-sensitive K562 cell line. RESULTS: Two major patterns of immunologic abnormalities were detected. Four of 7 patients had decreased NK activity, low NK cell numbers, and mildly increased levels of perforin expression in CD8+ and CD56+ cytotoxic cells. Three remaining patients with MAS, however, had decreased NK activity associated with low levels of perforin expression in all cytotoxic cell populations, a pattern indistinguishable from that in carriers of perforin-deficient familial hemophagocytic lymphohistiocytosis. Remarkably, two of these patients had previous episodes of MAS. CONCLUSIONS: NK dysfunction is an immunologic abnormality common to both familial hemophagocytic lymphohistiocytosis and MAS of soJRA. The extent of NK cell abnormalities in soJRA needs to be further investigated.     

Successful treatment with liposteroid followed by reduced intensity stem cell transplantation in an infant with perforin deficiency presenting with hemophagocytic lymphohistiocytosis

Perforin deficiency characterized by markedly reduced cytotoxic T and natural killer cell activities is one type of familial hemophagocytic lymphohistiocytosis (FHL). FHL is a fatal inherited disease, and treatment with stem cell transplantation has resulted in a normal activity of killer cells. We herein report a case of FHL with perforin deficiency that was primarily treated by the administration of liposteroid to reduce hypercytokinemia. Thereafter, allogenic bone marrow transplantation with nonmyeloablative conditioning was successfully performed without any adverse effects on the patient's physical or developmental status. These observations suggest that this treatment strategy might thus be recommended in infants with FHL to reduce treatment-related complications, especially in patients with relatively mild clinical courses.     

Cytotoxicity against Varicella zoster virus infected targets in children with acute leukemia

To eliminate the role of natural killer (NK), antibody-dependent cell-mediated cytotoxicity (ADCC), and polymorphonuclear leukocyte (PMN)-mediated cytotoxicity in Varicella zoster virus (VZV) infections, peripheral blood mononuclear cell (PBMC)-mediated NK and ADCC, and phorbol myristate acetate-stimulated PMN-mediated cytotoxicity against VZV-infected targets were studied in children with leukemia. Natural killer and PMN-mediated cytotoxic activity was depressed for 6 months after complete remission and ADCC activity was depressed for 1 year after complete remission. The magnitude of three cytotoxic mechanisms in leukemic children gradually increased while they continued in complete remission. These results suggested that decreased cytotoxic activities of PBMC and PMN might contribute to serious VZV infections and susceptibility to herpes zoster in leukemic children.     

Haemophagocytic lymphohistiocytosis following measles vaccination

A 19-month-old girl developed haemophagocytic lymphohistiocytosis following a measles vaccination. She developed persistent high fever 1 week after vaccination, and then showed pancytopenia, liver dysfunction and hepatosplenomegaly with marked haemophagocytosis. Based on the clinical and laboratory findings, she was diagnosed as having haemophagocytic lymphohistiocytosis probably due to measles vaccination. She did not respond fully to first-line immunosuppressive therapy and required immunochemotherapy with cytotoxic drugs. CONCLUSION: To the best of our knowledge, this is the first detailed report of haemophagocytic lymphohistiocyosis associated with measles vaccination documented in the English literature. Haemophagocytic lymphohistiocyosis should be kept in mind as one of the rare adverse effects of vaccination.     

Impaired natural killer activity in lymphohistiocytosis syndrome

In six patients with well-documented lymphohistiocytosis syndrome, natural killer activity was found to be profoundly impaired and could not be increased by incubation in vitro with interferon. This abnormality was not found in parents of the affected children. A clear correlation with the activity of the disease was observed, although a delay of a few weeks (possibly reflecting the life span of NK cells in blood) was seen in the disappearance of NK activity after the onset of the disease and its reappearance after remission. No absolute correlation was observed between NK activity and percentage of leukocytes detected by the Leu-7 monoclonal antibody. Our findings indicate that testing NK activity is useful for the diagnosis of lymphohistiocytosis syndrome and can be used as an index of activity of the disease, among other major clinical and biologic signs of this syndrome. Reversal of the NK activity defect (rather than detection of Leu-7 positive cells) appears to be a good criterion of complete remission.     

Clinical features of measles in immunocompromised children

Measles is often fatal for immunocompromised hosts. Protective immunity against measles has been studied but is still not completely understood. Recently, five cases of measles were encountered in immunocompromised children. Two of these were allogeneic bone marrow transplanted cases (one common variable immunodeficiency and one severe aplastic anemia) in remission, one Wilms' tumor case in remission, one hepatoblastoma case after cytotoxic therapy at disease onset and one exaggerating hemophagocytic syndrome case with suppressed natural killer cell activity. Clinical symptoms, laboratory findings and the immunologic backgrounds of these five patients were investigated. One of the patients, an 8 year old boy with hemophagocytic syndrome, died of giant cell pneumonia which was confirmed in the section of necropsy lung specimen. Two other patients who received allogeneic bone marrow transplants were not immune to measles, despite their own and their donors' immunizations. Their clinical symptoms were rather severe but both patients recovered and have remained seropositive for as long as 13 months. This fatality from measles is the first reported in a patient with hemophagocytic syndrome. Suppressed natural killer cell activity may be a poor prognostic factor. Also, secondary immunization failure for measles can occur in bone marrow transplanted patients with rather severe clinical symptoms.     

Treatment of EBV-induced lymphoproliferative disorder with epipodophyllotoxin VP16–213

A case of haemophagocytic lymphohistiocytosis consistent with X-linked lymphoproliferative disorder is described. Remission was observed after administration of VP-213, a cytotoxic drug generally used to treat histiocytosis. The child is currently in good clinical health.     

Fatal sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) with MUNC13-4 mutations: case reports

The authors report here sibling cases of familial hemophagocytic lymphohistiocytosis (FHL) type 3 that took fatal courses despite intensive treatment. The older brother achieved remission by immunochemotherapy, but a central nervous system lesion occurred before the introduction of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patient died on day +1 of allo-HSCT due to progression of the disease. The younger brother developed symptoms of hemophagocytic lymphohistiocytosis mimicking neonatal hemochromatosis at birth. He died without a chance to receive allo-HSCT. Both siblings showed low natural killer cell (NK) activity and the compound heterozygous Munc13-4 gene mutations 1596+1 and 1723insA were identified postmortem in the younger brother. With recent progress in the molecular diagnosis of FHL, prompt and most appropriate therapeutic measures should be introduced to improve the prognosis of FHL patients.     

Findings in familial haemophagocytic lymphohistiocytosis prior to symptomatic presentation

Familial haemophagocytic lymphohistiocytosis (FHL) is a rare, autosomal recessive disease of infancy and early childhood clinically characterized by fever, hepatosplenomegaly, lymphadenopathy, rash, neurological symptoms and icterus. Common laboratory findings include cytopenia, elevated liver enzymes, hyperbiliriubinaemia, hypofibrinogenaemia and hypertriglyceridaemia. The natural killer cell function is frequently decreased or absent. A diffuse lymphohistiocytic infiltration is seen in the reticuloendothelial system, often with haemophagocytosis. Molecular diagnosis is available in a minority of FHL families. Without adequate treatment and bone-marrow transplantation, the disease is fatal. A 6-wk-old child with FHL is presented. Shortly before the clinical onset of the disease, blood testing and bone-marrow examination had been carried out. All results were considered normal at that time. Conclusion: Blood tests and bone-marrow examination may be normal shortly before the clinical presentation and therefore do not exclude the diagnosis of FHL. There is a need for extended molecular diagnostic possibilities.     

NATURAL KILLER CELL NUMBERS AND CYTOTOXIC ACTIVITY IN PEDIATRIC HODGKIN DISEASE

In this study peripheral blood natural killer (NK) cell activity was evaluated in 17 pediatric cases with Hodgkin disease (HD) (9 untreated, 8 in remission) and 20 age-matched healthy children. Peripheral blood CD16 and CD56 molecule expressions were also examined. No difference related to NK cell numbers and cytotoxic activity was detected at either stage of the disease. In cases in which long-term remission has been achieved ( 5 years) NK cell activity was slightly but not significantly increased in parallel with remission duration. Finally, no relation between NK cell activity and the etiology, prognosis, and severity of the disease has been established in children with HD.     

Natural killer cell numbers and cytotoxic activity in pediatric Hodgkin disease

In this study peripheral blood natural killer (NK) cell activity was evaluated in 17 pediatric cases with Hodgkin disease (HD) (9 untreated, 8 in remission) and 20 age-matched healthy children. Peripheral blood CD16 and CD56 molecule expressions were also examined. No difference related to NK cell numbers and cytotoxic activity was detected at either stage of the disease. In cases in which long-term remission has been achieved ( 5 years) NK cell activity was slightly but not significantly increased in parallel with remission duration. Finally, no relation between NK cell activity and the etiology, prognosis, and severity of the disease has been established in children with HD.     

Natural killer cell immunodeficiency in siblings: defective killing in the absence of natural killer cytotoxic factor activity in natural killer and lymphokine-activated killer cytotoxicities

A immunodeficiency of natural killer cells as effectors for natural killer and lymphokine-activated killer cytotoxicities was first demonstrated in siblings. Two of three male siblings persistently lacked natural killer activity against K562 target cells as assayed by a 51Cr-release assay: percent lysis values were less than 1.0% as compared to the normal lymphocyte values of 43.5% +/- 6.2% (mean +/- SD). Their lymphocytes did not develop natural killer cell activity by changing effector to target ratios, prolonging the incubation time, or stimulating them with interferon-alpha or interleukin 2. Numbers of lymphocytes bearing Leu-7, CD16, or NKH-1 were normal but those of Leu-7-, CD16+ cells were decreased as estimated by flow cytometry. Single cell-in-agarose assays showed normal numbers of natural killer cells capable of binding to a target cell but incapable of killing it. They had depressed levels of lymphokine-activated killer activity, which was totally eliminated by the treatment with OKT3 and complement. This result indicates that the patients' natural killer cells are also defective in the capacity to work as effectors for lymphokine-activated killer activity. The patients' natural killer cells did not produce natural killer cytotoxic factor activity. Antibody-dependent cellular cytotoxicity and cytotoxic T lymphocyte cytotoxicity were normal. These results demonstrate a selective natural killer cell deficiency as effectors for natural killer and lymphokine-activated killer cytotoxicities with a familial tendency, in which there is defective killing with the absence of natural killer cytotoxic factor activity.     

Natural killer cell activity of peripheral blood and bone marrow mononuclear cells from patients with childhood acute lymphoblastic leukemia

Patients with untreated acute lymphoblastic leukemia had highly significantly reduced natural killer cell activity in peripheral blood (p less than 0.01) and bone marrow (p less than 0.001) mononuclear cells compared with that in peripheral blood mononuclear cells in normal healthy controls. Patients in remission had normal killer cell activity (p greater than 0.5) both in peripheral blood and bone marrow mononuclear cells. Thus, the natural killer cell activity correlated well with the disease activity in the patients.     

Natural Killer Cell Activity of Peripheral Blood and Bone Marrow Mononuclear Cells from Patients with Childhood Acute Lymphoblastic Leukemia

ABSTRACT. Patients with untreated acute lymphoblastic leukemia had highly significantly reduced natural killer cell activity in peripheral blood ( p <0.01) and bone marrow ( p <0.001) mononuclear cells compared with that in peripheral blood mononuclear cells in normal healthy controls. Patients in remission had normal killer cell activity ( p >0.5) both in peripheral blood and bone marrow mononuclear cells. Thus, the natural killer cell activity correlated well with the disease activity in the patients.     

Haemophagocytic lymphohistiocytosis in children

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. METHODOLOGY: The medical records of 12 children, aged 5 weeks to 13 years at diagnosis, with HLH managed at a single institution were reviewed. RESULTS: Presenting features were fever, hepatosplenomegaly, pancytopenia and hypertriglyceridemia or hypofibrinogenemia. Nine patients (75%) developed central nervous system (CNS) disease. Only one child with CNS disease survived. Five children had complete responses to therapy (42%), but all relapsed at a median of 1.5 months after starting treatment (range 2 weeks to 5 months). Two of the children treated are long-term survivors (17%), both after allogeneic bone marrow transplantation. All deaths occurred in the context of active disease. CONCLUSIONS: Haemophagocytic lymphohistiocytosis is a disease with a poor prognosis. Central nervous system complications are common and response to treatment usually is transient. This study provides support for the use of immunomodulatory therapy for remission introduction followed by consideration of allogeneic bone marrow transplantation.     

Natural Killer Cell Activity in Children With Acute Lymphoblastic Leukemia

Thirty-four children with acute lymphoblastic leukemia (ALL) and 45 normal children as controls were tested for natural killer (NK) cell activity in vitro using the K-562 cell line as target cell. In the group of patients off all chemotherapy, the levels of NK cell activity were found to be comparable to normal controls. The levels of activity in the intermittent chemotherapy group were higher than or the same as those of normal controls. Low levels of NK cell activity were observed, shortly after intermittent chemotherapy. Patients who had more than two remissions had levels of NK cell activity comparable to normal controls. In contrast, low levels of NK cell activity were found in patients shortly before relapse, but returned to normal levels after achieving complete remission. Significant differences in the clinical stages between relapse and remission were found by paired t-test analysis (0.02 < p < 0.05).     

Encephalopathy associated with haemophagocytic lymphohistiocytosis following rotavirus infection

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. Conclusion Haemophagocytic lymphohistiocytosis associated encephalopathy should be considered early in the differential diagnosis of cases with acute onset neuropathy. Received: 17 March 1998 / Accepted in revised form: 16 July 1998     

急性白血病患儿外周血T淋巴细胞亚群和NK细胞水平测定及临床意义

为探讨急性白血病患儿外周血T淋巴细胞亚群和NK细胞水平及意义 ,采用流式细胞技术测定 90例急性白血病患儿外周血T淋巴细胞亚群和NK细胞水平。结果 ,急性白血病患儿外周血T淋巴细胞亚群中CD3+ 、CD4+ 、CD4+ CD8+ 均明显低于对照组水平 (P <0 0 1) ,CD8+ 高于对照组水平 (P <0 0 1) ,NK细胞 (CD1 6+ 56+ )明显低于对照组水平 (P <0 0 1) ,经治疗缓解者T淋巴细胞亚群和NK细胞达正常水平。结果表明 ,T淋巴细胞亚群和NK细胞可作为急性白血病辅助诊断指标 ,为临床治疗提供实验依据