Chronic cold agglutinin disease of the "idiopathic" type is a premalignant or low-grade malignant lymphoproliferative disease.

We investigated the clinical, pathological, and immunological features of "idiopathic" cold agglutinin disease (CAD) in a population-based study. Fourteen patients were studied, giving a prevalence of about 14 per million with a mean age of 75 years. Haemolysis was present in all cases, but only eight patients had clinical symptoms of peripheral haemagglutination. Serum electrophoresis, immunofixation, morphological bone marrow evaluation, and flow cytometric immunophenotyping were used to detect any monoclonal lymphoproliferative disorder. Flow cytometry seemed to be a sensitive way to demonstrate a clonal B-cell proliferation. Some evidence of clonality was found in 13 patients, and a clonal lymphoproliferative disease was documented by flow cytometry or biopsy in 10 out of 11 patients. We conclude that CAD is a symptom-producing monoclonal lymphoproliferative disorder in nearly all patients.

[Chronic cold agglutinin disease]. / Kronisk kuldeagglutininsykdom.

Chronic cold agglutinin disease is an uncommon form of haemolytic anaemia. Traditionally the "idiopatic" form and the "secondary" form (seen in some cases of malignant lymphoma) have been regarded as two clearly different entities. We describe three patients with chronic cold agglutinin disease in a population of 100,000. They had been previously diagnosed as having idiopatic autoimmune haemolytic anaemia, but further investigations revealed lymphoproliferative bone marrow disease in all three cases. We discuss some pathogenetic features of cold agglutinin disease on the basis of our observations and the available literature. In conclusion, this disease represents a spectrum of clonal lymphoproliferative disorders rather than separate primary and secondary forms. The therapeutic principles are discussed. Corticosteroids should usually not be used to treat this disease.

[Homocysteine and methylmalonic acid. New tests--for what benefit?]. / Homocystein og metylmalonsyre. Nye prøver--til hvilken nytte?

A serum cobalamin level lower than 250 pmol/l combined with high values of plasma homocysteine and serum methylmalonic acid confirms the diagnosis of vitamin B12 deficiency. A low serum and erythrocyte folate level and high plasma homocysteine confirm folate deficiency. If the cobalamin level is higher than 250 pmol/l no further tests are needed. In patients with neurologic or psychiatric disorders combined with elevated levels of homocysteine and methylmalonic acid, cobalamin deficiency is likely if these levels decrease during vitamin B12 therapy. The causes of elevated homocysteine levels are often obscure, and homocysteine should therefore not be used as a screening test.

[Acquired von Willebrand's disease]. / Akvirert von Willebrands sykdom.

We describe a patient with acquired von Willebrand's disease and Waldenström's macroglobulinemia. He suffered from an acquired tendency to bleed. The laboratory findings were identical to those of congenital von Willebrand's disease. The acquired form of this bleeding disorder is seen in association with immunologically active B cell lymphomas, certain other malignant tumours, and autoimmune diseases. The incidence and prevalence are unknown, but this disorder is probably uncommon. We discuss possible pathogenetic mechanisms. Acquired von Willebrand's disease should be considered in patients with an acquired tendency to bleed, especially if the patient also has a lymphoproliferative, neoplastic, or autoimmune disease.

[Retinopathy as a complication of acute pancreatitis]. / Retinopati som komplikasjon til akutt pankreatitt.

We describe a case of acute, severe retinopathy in a patient with acute pancreatitis. The relative times of the organ manifestations, and comparisons with other published cases, strongly suggest that the pancreatitis was the cause of the retinal changes. This complication is unknown to most physicians, but ten to 12 cases have been published earlier. The pathogenesis is not known. We briefly discuss the significance of this complication and several possible pathogenetic mechanisms.

[Anemia with low serum cobalamin concentration. Problems of differential diagnosis]. / Anemi og lavt serum-kobalaminnivå. Differensialdiagnostiske problemer.

We reviewed the records of seven patients with low serum cobalamin levels that were difficult to interpret in relation to haemoglobin concentrations and clinical symptoms. Myelodysplastic syndrome was diagnosed in four out of five anaemic patients. Three of them had a true vitamin B12 deficiency at the same time. The fifth patient had a non-Hodgkin lymphoma with Coombs-negative autoimmune haemolytic anaemia. Two patients had low cobalamin levels without anaemia. Measurements of plasma homocysteine and serum methylmalonic acid may be useful for diagnosing true vitamin B12 deficiency.

[Visceral leishmaniasis (kala-azar)]. / Visceral leishmaniasis (kala azar).

Visceral leishmaniasis is a serious zoonosis which has very rarely been diagnosed in Norway. We report a case of visceral leishmaniasis in a Norwegian patient, and present an up-to-date review of the disease. We conclude that this disease should be considered even in Scandinavian patients if the appropriate symptoms and signs are present and there has been possibility of exposure. Simple blood tests and serum electrophoresis are of considerable value. If possible, the protozoa should be demonstrated by microscopy of bone marrow aspirate. We also discuss the identification of the parasites in bone marrow biopsy, which should be performed in pancytopenic patients. The diagnosis should be confirmed by culture or a serological test.

[Large granular lymphocytic leukemia]. / Storcellet granulaer lymfocyttleukemi.

Large granular lymphocyte leukaemia (LGL leukaemia) is a rare, chronic lymphoproliferative bone marrow disease which can be considered a subtype of chronic T-cell lymphocytic leukaemia (T-CLL). We describe three patients with large granular lymphocyte leukaemia. They all suffered from chronic disease with neutropenia and relative lymphocytosis. An expansion of mature lymphocytes with the CD3+, CD8+, CD57+ immunophenotype was demonstrated in all three patients. Two patients had a history of recurring infections. Serological findings compatible with rheumatic disease were present in all three patients, and two suffered from rheumatoid arthritis. We have made a brief survey of this disease, which is characterized by relative or absolute lymphocytosis, neutropenia, and an increased risk of infection. Rheumatoid arthritis and other associated autoimmune manifestations occur frequently. Large granular lymphocyte leukaemia should be considered a possible diagnosis in patients with chronic neutropenia and relative lymphocytosis, in particular if rheumatic manifestations are also present. Flow cytometric immunophenotyping is a sensitive method in diagnosing this disease.

[Hearing loss in autoimmune diseases]. / Hørselstap ved autoimmune sykdommer.

Several autoimmune disorders are associated with inner ear involvement. The resulting sensorineural loss of hearing may be improved by treatment with immunosuppressive agents. We describe a patient with oral ulcerations, systemic vasculitis, iridocyclitis and bilateral sudden deafness. After a course of systemic steroid treatment the hearing improved. Atypical Cogan's syndrome is the most likely diagnosis.

[Experiences from a stroke unit in a county hospital]. / Erfaringer med slagenhet ved et fylkessykehus.

We review our experience from a stroke unit run as a project in a county hospital serving a population of 95-100,000. The average length of stay in hospital was 33.5 days. The mortality rate was low (10%). 73% of the patients were discharged to their homes, either directly or after a short stay of less than three months in nursing homes. A questionnaire sent to the patients after the end of the project period confirmed that about 70% were living at home 1-15 months after discharge. These findings are in accordance with the results from other stroke units, and support the conclusions of other investigators that treatment in stroke units improves the outcome for patients with acute stroke. We also briefly discuss complications, follow-up after discharge, and the implications for the patients' families.

[Pulmonary changes as primary manifestations in Waldenström macroglobulinemia]. / Lungeforandringer som primaer manifestasjon av Waldenströms makroglobulinemi.

We describe a patient with a 19-year history of lymphocytic lung infiltrations. A diagnosis of lymphocytic interstitial pneumonitis was made in 1982 after an open lung biopsy, but in 1995 a comprehensive re-evaluation led to the diagnosis of Waldenström's macroglobulinaemia with primary bronchopulmonary involvement. It could also be demonstrated by polymerase chain reaction and immunological techniques that this disease had been present since before 1982. In 1995 it was still difficult to demonstrate bone marrow involvement, even with new and sensitive methods. We discuss some diagnostic problems of organ manifestations of uncommon systemic diseases. Pulmonary manifestations of Waldenström's macroglobulinaemia or other diseases of the immune system should be considered in patients with atypical lung disorders.

Acute phase haemolysis in chronic cold agglutinin disease.

We previously described a paradoxical form of chronic cold agglutinin disease (CAD) in which haemolysis occurred during episodes of fever but only marginally during exposure to colds. In order to investigate the molecular basis for this response we performed a 12-month prospective study of a patient with CAD and paradoxical haemolysis. Blood samples were collected monthly during health, and daily following hospitalization owing to hip fracture. During health we observed decreased levels of C3, undetectable C4, a non-functional classical pathway and a normal alternative pathway. Increased concentrations of C1-INH/C1rs complexes indicated continuous formation of C1-antibody-antigen complexes. There was a low-grade temperature-dependent fluctuating haemolysis as evidenced from measurements of lactate dehydrogenase. Following the hip fracture, the haemolysis increased. Levels of interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma and tumour necrosis factor (TNF)-alpha increased as did C1-INH, C3, C4, CRP, and lactate dehydrogenase. The results support our hypothesis stating that paradoxical haemolysis in CAD is controlled by the availability of early classical pathway complement molecules and that haemolysis following acute phase responses occurs as a consequence of increased complement synthesis.

Clinical immunology of chronic cold agglutinin disease.

We studied clinical and immunological characteristics of 15 patients with chronic cold agglutinin disease (CAD). Mean age at disease debut was 68 years for female and 67 years for male patients. The patients had no signs of other autoimmune diseases. All patients had V(H)4-34 encoded IgM kappa cold agglutinins (CA) in high titre. In five patients IgM increased significantly with advancing disease. Seven patients had reduced concentrations of lymphocytes, largely of CD4 and CD8 T cells. Percentages of NK cells (CD56) and B cells (CD19) were increased in seven and three patients, respectively. In six out of nine patients a clonal expansion of kappa positive B cells was found. Serum C3 was decreased in nine patients and C4 was decreased in 11 patients, six of whom had reduced CH50. Such data indicate that patients with CAD experience a continuous low-grade complement consumption. Five patients had experienced increased haemolysis during infections. After addition of active complement to patient sera in vitro, six sera showed increased haemolytic activity. Our results indicate that some patients with CAD have a relative deficit of complement in their serum and that an increase of complement production occurs during an acute phase reaction which enhances haemolysis. Our data also indicate that both CA titre and thermal amplitude are important characteristics when predicting complement activation and clinical course in CAD.

Human T lymphocyte activation in the presence of acute myelogenous leukaemia blasts: studies of allostimulated interferon-gamma secretion.

Normal peripheral blood mononuclear cells (PBMC responders) were cultured together with non-irradiated allogeneic PBMC (more than 95% leukaemia blasts) derived from patients with acute leukaemia (referred to as leukaemic PBMC stimulators). Cytokine secretion was determined as cytokine concentrations in supernatants. Both normal PBMC and enriched CD4+ and CD8+ T cells responded to allostimulation with interferon (IFN gamma) secretion. Interleukin-I (IL-1) receptor antagonist and IL-2-neutralizing antibodies decreased IFN gamma secretion. Exogenous IL-1 beta, IL-2 and IL-7 increased allostimulated IFN gamma secretion, whereas decreased levels were seen in the presence of IL-6, IL-10 and granulocyte-colony-stimulating factor (G-CSF). During allorecognition IFN gamma-neutralizing antibodies decreased acute myelogenous leukaemia (AML) blast secretion of G-CSF. We conclude that (i) both CD4+ and CD8+ T cells show allostimulated cytokine secretion in response to allogeneic stimulator cells containing a dominating population of native, cytokine-secreting leukaemia blasts, and (ii) IFN gamma released during this response can modulate the function of allogeneic AML blasts.

Interleukin 4 responses in acute leukaemia patients with severe chemotherapy-induced leucopenia.

T lymphocyte functions in acute leukaemia patients with severe chemotherapy-induced leucopenia were investigated using 3 different approaches: (i) analysis of serum concentrations of the T cell cytokine interleukin 4 (IL4) demonstrated that serum IL4 levels increased during complicating bacterial infections. However, this response was modulated by a concomitant increase in serum levels of the potential IL4 antagonist soluble IL4 receptor alpha chain (sIL4R alpha). (ii) Even during leucopenia a subset of T lymphocytes derived from leucopenic patients expressed the activation markers CD25 (IL2 receptor), CD71 (transferrin receptor) and HLA-DR. (iii) Subsets of circulating CD4+ and CD8+ T lymphocytes could undergo clonogenic proliferation in vitro, and a majority of these clones secreted IL4. CD4+ clones showed higher IL4 levels than CD8+ clones. Our results indicate that T lymphocytes can be activated and contribute to cytokine responses in acute leukaemia patients with severe chemotherapy-induced cytopenia.

T-lymphocyte functions in acute leukaemia patients with severe chemotherapy-induced cytopenia: characterization of clonogenic T-cell proliferation.

Intensive chemotherapy for acute leukaemia is followed by a period of severe chemotherapy-induced leukopenia. We used a limiting dilution assay to investigate whether remaining CD4+ and CD8+ T lymphocytes derived from such leukopenic patients could be activated and undergo clonogenic proliferation. The activation signal in our model was accessory cells (irradiated normal peripheral blood mononuclear cells) + phytohaemagglutinin (PHA) + interleukin-2 (IL-2). During severe leukopenia a majority of circulating lymphocytes were CD4+ T cells. Clonogenic proliferating T lymphocytes were detected for all patients. Higher frequencies of clonogenic cells were detected in the CD8+ subset as compared to the CD4+ subset. However, for both subsets frequencies of proliferating cells were decreased compared with healthy individuals. The CD4+ and CD8+ lymphocytes were also capable of proliferation in response to alloactivation, and accessory cells mainly containing acute myelogenous leukaemia blast were efficient as accessory cells for activation. For the CD4+ cells, increased proliferation was detected in the presence of acute myelogenous leukaemia (AML) blasts compared with normal accessory cells. Based on our results we conclude that: (1) although acute leukaemia patients with therapy-induced leukopenia have both a quantitative and a qualitative T-cell defect, (2) the remaining T-cell population includes a subset capable of clonogenic proliferation. However, (3) proliferation of the clonogenic CD4+ cells can be modulated by AML blasts.

[Future requirements for hematologists]. / Fremtidig behov for spesialister i blodsykdommer.

Today there are not enough specialists in haematology in Norway. During the period 1990-1995 2.5 specialists in haematology qualified per year. In order to meet future requirements for haematologists at Norwegian municipal and university hospitals, it has been estimated by the Norwegian Society for Haematology that the number of specialists qualifying per year should be increased to ten for the next ten years.

[Empirical antibiotic treatment of patients with acute myelogenous leukemia]. / Empirisk antibiotikabehandling hos pasienter med akutt myelogen leukemi.

All febrile episodes (a total of 276) which occurred in 85 patients with acute myelogenous leukaemia treated in four Norwegian centres during the period 1990-1994 were studied retrospectively in order to assess the efficacy of antibiotic treatment. 72% of these episodes were initially treated with benzyl penicillin and aminoglycoside (standard treatment), while alternative empirical treatment was given in the remaining cases. The treatment was successful in 94% of the febrile episodes initially treated with standard treatment and in 96% of the episodes which received alternative antibiotics. For both types of treatment, a change to second line antibiotic regimen was made for various reasons in a majority of cases. The combination benzyl penicillin and aminoglycoside seems to be a safe empirical treatment for febrile neutropenia in patients with acute myelogenous leukaemia in our treatment centres, provided that the treatment is modified in patients with unsatisfactory clinical response.