Fever of unknown origin (FUO) in an immunocompetent adult due to cytomegalovirus (CMV) with polyclonal gammopathy.

Fever of unknown origin (FUO) may be due to infection, malignancy, collagen vascular/inflammatory disorders, or other causes. Cytomegalovirus (CMV) infection is a rare cause of FUO in immunocompetent adults. We present a case of FUO due to CMV in an immunocompetent adult with polyclonal gammopathy on serum protein electrophoresis (SPEP).

[Aetiological spectrum of hyperferritinemia]. / Spectre étiologique des hyperferritinémies.

UNLABELLED: Serum ferritin levels may be increased in many conditions: renal diseases, liver diseases, human immunodeficiency virus infection. The purpose of this study was to assess the aetiological spectrum of high serum ferritin levels in a 1200-bed university hospital, to compare our results with the data already published and to assess a potential association between aetiology and ferritin levels. PATIENTS AND METHODS: Patients with a serum ferritin level higher than 600 microg/l were retrospectively included between 15 November 2003 and 15 January 2004, and their medical records were reviewed. RESULTS: Ninety-eight patients (38 women and 60 men; median age: 59,5 years [19-92]) were recruited in departments of hepatology and gastroenterology (22%), haematology (14%) and internal medicine (18%). Diagnosis performed were: non-HIV systemic infections (23,8%), haematological diseases (16,1%), alcoholism (11,2%) and malignancies (9,8%). Dialysed chronic renal failure, liver diseases, haemochromatosis and systemic inflammatory diseases counted for 4.2 to 5.2% of cases. Serum ferritin level lied between 600 and 1000 microg/l for 50 patients, between 1000 and 1500 microg/l for 24, and over 1500 microg/l for 24. There was no significant difference between the three groups as regards the etiological distribution. DISCUSSION: In our study, chronic renal failure was not a major cause of high ferritin level: this is probably due to the current use of erythropoietin, which has decreased the use of blood transfusions. The two major aetiology of hyperferritinemia were non-HIV infections and malignancies.

Angioimmunoblastic lymphadenopathy with dysproteinemia--lack of a prognostic value of clear cell morphology.

It has been suggested that angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is closely related to peripheral T cell lymphoma (PTCL). However, the clinical course of AILD-like PTCL is notoriously unpredictable. A minor portion of patients enjoyed prolonged remission with steroid-only treatments (indolent AILD) while most others died rapidly despite the use of intensive chemotherapy (aggressive AILD). Recently, it has been suggested that histological features such as the presence or absence of clear cells and convoluted cells are of high prognostic value. The validity of this observation was addressed in this study. Eighteen patients who presented between 1977 and 1994 at the National Taiwan University Hospital were retrospectively studied. There were 11 men and 7 women, with a median age of 47 years. Twelve patients had received various regimens of systemic chemotherapy, and the other 3 patients had been treated with steroids alone. Eight patients had indolent AILD and 6 aggressive AILD. The follow-up period in 4 patients was too short to be analyzed. The histopathology of these cases was divided, according to the criteria of Aozasa et al., into group I (neither cells), 4 patients; group II (only convoluted cells), 1 patient, and group III (clear cells with or without convoluted cells), 13 patients. Contrary to others, our data revealed that group III patients were doing better than group I patients. Univariate analysis of other pertinent clinical features, including sex, age, lymphadenopathy, B symptoms, hepatosplenomegaly, hypergammaglobulinemia, elevated serum lactate dehydrogenase, and treatment regimens, revealed none of them to be prognostically relevant. However, patients who had achieved complete remission by steroids or other systemic chemotherapy had a significantly better prognosis than those who had not. Together, these preliminary data suggested that (1) the presence or absence of clear cells and convoluted cells failed to predict the clinical behavior, and (2) induction of complete remission by steroids or other chemotherapeutic agents is an important prognostic index.

Clonal identification of trisomies 3, 5 and X in angioimmunoblastic lymphadenopathy with dysproteinemia by fluorescence in situ hybridization.

Trisomies 3, 5 and X in six Japanese patients with AILD were detected by fluorescence in situ hybridization (FISH). Trisomies 3 and X were detected using centromeric probes. Cosmid probes locating on 5q31.1, the commonly deleted region, was used to detect trisomy 5. FISH detected three patients with trisomy 3 alone, one with trisomy 5 alone and one with all the three trisomies analysed. The sample that showed all three aberrations was further analysed by dual color FISH. The three trisomies were present on different cells. The AILD cells with trisomy 5 tended to replicate slowly, whereas those with trisomy 3 seem to have a proliferative advantage. An increase in the histopathological stage was reflected in the increase in the percentage of trisomy 3 cells in one patient.

Treatment of angioimmunoblastic lymphadenopathy with dysproteinemia using 2-chlorodeoxyadenosine.

Angioimmunoblastic lymphadenopathy with dysproteinemia (AILD) is an atypical lympho-proliferative disorder with borderline features that often constitute a diagnostic challenge for the hematopathologist and a therapeutic dilemma for the treating clinician. Morphologically, the involved lymph nodes in this disorder are characterized by abnormal infilitration by immunoblasts and plasma cells, often in clusters or sheets. Regressed follicles may be seen; these are referred to as "burned out." Neovascularization is prominent, and a background of inflammatory cells is usually present. AILD was originally thought to represent an exaggerated autoimmune response. Because of the short median survival of the patients and the demonstration of T-cell clonality, AILD now is considered an aggressive lymphoma and is recognized as a subset of peripheral T-cell lymphoma by the REAL classification. In this article we present a patient with AILD who achieved durable partial remission after treatment with one cycle of 2-chlorodeoxyadenosine.

Increased levels of interleukin-6 (IL-6) in serum and spontaneous in vitro production of IL-6 by lymph node mononuclear cells of patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD), and clinical effectiveness of cyclosporin A.

Serum levels of cytokines and in vitro cytokine production by lymph node mononuclear cells (LNMC) were studied in four patients with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD) or AILD-type T cell lymphoma. An increased level of serum interleukin-6 (IL-6) was detected on initial diagnosis in both of two patients examined. Spontaneous production of IL-6 by LNMC was detected in all four patients studied. Immunosuppressive therapy with cyclosporin A (CsA) was attempted in a 68-year-old man, who was refractory to intensive combination chemotherapy. The increased level of IL-6 in this patient decreased to normal within 3 weeks of CsA administration and the patient became symptom-free. One and a half months later, the IL-6 level gradually increased along with clinical exacerbation. We also measured serum levels of IL-1 alpha, IL-2, IL-4, IFN-alpha, gamma and TNF-alpha in parallel with IL-6, but these factors were only sporadically detected. IL-6 production by LNMC was stimulated by IL-2 but inhibited by CsA. These observations suggest that IL-6 is one of the important cytokines to be involved in the pathophysiology of AILD and CsA is a useful reagent for relieving symptoms.

Lipids and cardiovascular disease: do the findings and therapy apply equally to men and women?

Dyslipoproteinemia is prevalent in women as well as in men. In both, its consequences--premature atherosclerosis and CAD morbidity and mortality--are more common. Although clinical evidence of the benefits of cholesterol lowering is less abundant in women, it is not entirely absent. As in men, cholesterol lowering in women is associated with a decline in CAD risk and with regression of coronary atherosclerosis. Lipoprotein risk factors have some special characteristics in women. Low-density lipoprotein cholesterol may be a less important risk factor in women, perhaps because estrogen protects the arterial wall against LDL deposition. High-density lipoprotein cholesterol is a better predictor of risk in women than in men. Triglycerides are an independent predictor of CAD risk in postmenopausal women. The effects of endogenous gonadal hormones in life-cycle changes in women is evident. As girls pass through puberty, HDL-C levels do not fall as they do in boys of the same age. In pregnancy, LDL-C, HDL-C, and triglyceride levels all rise. However, LDL-C stays elevated until well after delivery, whereas triglycerides fall to baseline at about the time of delivery, and HDL-C levels begin to fall at about 24 weeks. Interestingly, this fall in HDL-C is not accompanied by a fall in apoA-I levels, implying a change in HDL composition during the latter portion of pregnancy. After menopause, LDL-C levels rise sharply, whereas HDL-C levels decline modestly. Again, this decline in HDL-C is accompanied by a rise in apoA-I levels, implying a change in HDL composition. Diet, weight loss, and exercise are less effective in altering lipoprotein levels in women than in men. The reasons for this are not clear, although it is reasonable to speculate that endogenous gonadal hormones play a role. Genetic dyslipoproteinemia occurs in women, although the effect on CAD rates may be mitigated by the generally higher levels of HDL-C enjoyed by women. Exogenous hormones in the form of OCs and postmenopausal HRT affect circulating lipoprotein levels according to their composition. Generally, estrogens have favorable effects, raising HDL-C and lowering LDL-C levels. Progestins are either neutral or oppose estrogen effects, depending on their dose and androgenicity. Use of modern OCs probably does not adversely affect CAD risk except in combination with cigarette smoking. However, HRT has a strong favorable effect on CAD risk when unopposed estrogen is used, probably due to increases in HDL-C levels.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: Heart disease is the number 1 cause of death among women in the US, yet health providers, the public, women's health organizations, and women overlook this fact. Risk factors and the progression of cardiovascular disease (CVD) are different in women than in men. For example, women are more likely to develop and succumb to heart disease at more advanced ages than men. This may be due to the protective effect of estrogen that occurs to at least middle age when menopause occurs. The clinical studies examining means to prevent CVD in the 1960s and 1970s basically included only middle aged or older men. Yet scientists have since learned that reproductive hormones do not allow them to extrapolate the results of these studies to women. For example, some interventions identified in those trials do not as effectively affect lipoprotein levels in women as they do in men. These interventions include diet, weight loss, and exercise. Instead, cholesterol screening and management, hormone replacement therapy for cardiovascular indications, and public health messages promoting a low fat diet can be effective in women. As is the case with men, women often have a genetic predisposition for dyslipoproteinemia. High density lipoprotein cholesterol is a more significant CVD risk factor in women than in men while low density lipoprotein is more significant in men than in women. Even though estrogen therapy may prevent heart attacks, its price may be too high since it increases the risk of breast cancer. Many obstetrician-gynecologists feel confident of their ability to screen for cholesterol, yet they are not as confident in their ability to provide dietary counseling or managing drug therapy.

Congenital atransferrinemia. A case report and review of the literature.

A four-year-old Polynesian girl with a two-year history of severe microcytic, hypochromic anemia (which was refractory to iron therapy) had a decreased beta-globulin fraction on serum protein electrophoresis, resulting from the absence of the transferrin (TRF) band. Subsequent assays for TRF showed a level below the detectable range. Liver biopsy revealed significant deposition of hemosiderin within hepatocytes and Kupffer cells, in addition to early fibrosis. Two bone marrow aspirates were hypercellular, with decreased myeloid-erythroid ratios. This case represents the eighth reported example of congenital atransferrinemia, a rare, apparently autosomal recessive disease.

[Evaluating thyroid gland function in patients with protein anomalies]. / Beurteilung der Schilddrüsenfunktion bei Patienten mit Proteinanomalien.

The euthyroid hyperthyroxinemia (EHT) is characterized on the one hand by a normal basal THS or TRH-TSH response but also by high plasma values of total thyroxine (TT4) on the other. However if only TT4 is assessed, "hyperthyroidism" may be diagnosed erroneously. EHT may be caused by an increase of specific thyroxine binding proteins which may be hereditary (permanent) or acquired (transient). The most frequent disturbance is due to an estrogen induced increase of thyroxine binding globulin (TBG) in the course of pregnancy, anticonceptive drugs or estrogen treatment. The albumin associated HT (FDH syndrome), first reported in 1979, has autosomal dominant traits. 144 patients with FDH syndrome were observed during the period between 1984 and 1990, i.e. 7% (1986) of all hyperthyroid patients explored. Family screening is required to prevent unjustified treatment. Additionally existing disturbances of thyroid function as well as other protein binding anomalies may both cause problems in differential diagnosis. Prealbumin associated hyperthyroxinemia (PAAH), first published in 1982, may be due to an inherited increase in affinity, but may also be the consequence of a true elevation of prealbumin plasma concentration in the course of an islet cell cancer; both conditions are extremely rare. Nearly as rare are patients with plasma autoantibodies directed against T4 and/or T3 (5 cases); yet, a reverse T3 autoantibody could be observed in merely 1 case. By means of our modified radio-thyroxine-agarosegel-iceelectrophoresis all such protein anomalies may be diagnosed and differentiated in 1 procedure. Moreover, all other types of EHT must be taken into consideration by differential diagnosis.

Platelet IgG, IgA, IgM, and albumin: correlation of platelet and plasma concentrations in normal subjects and in patients with ITP or dysproteinemia.

IgG, IgA, IgM, and albumin are primarily known as plasma proteins. Their presence in platelets is poorly understood. The total platelet content of IgG, IgA, and albumin, measured in solubilized platelets by an enzyme-linked immunosorbent-assay (ELISA) technique, was greater than 90% secreted after stimulation by thrombin, consistent with an alpha-granule location. The platelet concentrations of these proteins correlated with their plasma concentrations in normal subjects and over a wide range of abnormalities in patients with IgG or IgA myeloma or liver cirrhosis. IgM was not detectable in normal platelets but was measurable and related to the plasma IgM concentration in patients with macroglobulinemia. In patients with idiopathic thrombocytopenic purpura (ITP), the platelet concentrations of IgG, IgA, and albumin were all twofold to threefold higher than normal despite normal plasma concentrations. Platelet surface IgG, measured by 125I-monoclonal antibody binding, constituted less than 1% of the total platelet IgG, and it appeared to be a pool distinct from the alpha-granule IgG since its concentration in normal subjects and patients did not correlate with either plasma or total platelet IgG concentrations. These observations are consistent with hypotheses that megakaryocytes incorporate plasma proteins into developing alpha-granules by pinocytosis and that the increased ratio of platelet to plasma of IgG, IgA, and albumin in ITP may reflect a younger average age of these platelets.

[Evaluation of an automated system of measuring erythrocyte aggregation in dysglobulinemia treated by plasma exchange]. / Evaluation d'un système automatique de mesure de l'agrégation érythrocytaire dans les dysglobulinémies traitées par échange plasmatique.

Characteristics of a new erythrocyte aggregameter were evaluated in 7 patients with monoclonal dysglobulinemia (5 multiple myeloma, 1 Waldenström disease, 1 CLL with monoclonal immunoglobulin) treated by plasma exchange. This apparatus measures modifications of light retro-diffused by erythrocytes suspension after shear arrest. All parameters measured: Ta, Tf, S10, gamma D, gamma S were modified after plasma exchange: either immediately after the first or after the second or third plasma exchange. These findings demonstrate the value of this new technique for evaluating red cell aggregation. These data should be completed by rheological assessment of dysglobulinemia treated by plasma exchange.

Alterations of blood group antigens in angio-immunoblastic lymphadenopathy with dysproteinemia.

Antigen analysis of the red cell membrane in a patient with angio-immunoblastic lymphadenopathy with dysproteinemia (AILD) with red cell autoantibody revealed that four blood group antigens had been acquired. These four antigens consisted of S of MNSs blood group, Lua of Lutheran blood group, and K and Kpa of Kell-Cellano blood group. These antigens disappeared and the Coombs' test became negative after complete remission induced by combination chemotherapy. Free amino acid analysis after Dispase treatment of red cell membrane suggested that the antigenic modifications were associated with abnormal composition of amino acids.

[Factors interfering with and influencing the measurement of direct and indirect parameters of free thyroxine]. / Stör- und Einflussgrössen bei der Bestimmung direkter und indirekterParameter für das freie Thyroxin.

PIP: Factors influencing and interfering with free thyroxin (FT4) parameters and their measurement methods are presented. Mot serum thyroxin is bound to specific transport proteins by thyroxin-binding protein (TBG), thyroxin-binding prealbumin (TBPA) and albumin. The total serum thyroxin (TT4) depends not only on the amount of thyroid gland secretion, but also on the concentration of these transport proteins. Measurement of direct and indirect parameters of a small amount of FT4 can indicate thyroid function when binding protein anomalies exist. Radioimmunoassay (RIA) is one FT4 determination method. Factors influencing FT4 parameters include age, pregnancy, disease, medications (lower hormonal metabolism under phenytoin). Interfering factors are serum proteins (albumin deficiency), atypical serum components (abnormal T4 binding albumin, T4 binding inhibitors), serum metabolites (free fatty acids in fasting) and medications (fatty acid liberation by heparin). Estrogen-induced TBG increase in pregnancy does not affect FT4 determination, although it interferes with TT4 assessment. Nonthyroidal illness (NTI) and anorexia nervosa influence FT4 measurement, as do drugs (salicylate). Indirect FT4 parameters are the FT4 Index (FT4-I) and the TT4/TBG Quotient used for the measurement of FT4 concentration by means of the T3 Uptake Test (3U). Dialysis procedure allows for direct measurement of FT4 serum concentration. T4 Analog Tracers resolve the methodical problems issuing from FT4-RIA. Various other FT4 assay methods include immune extraction, 2 Step FT4-RIA GammaCoat, FT4-RIA LisoPhasde, and Liquisol Ft4-RIA. Finally, highly sensitive immunoassays may make it possible in the near future to measure basal thyroid-stimulating hormone as a rational alternative to the determination of FT4 parameters.^ieng

Thrombin binding and response in platelets from patients with dyslipoproteinemias: increased stimulus-response coupling in type II hyperlipoproteinemia.

Platelets were obtained from patients with various hyperlipidemias [type II, type V, lecithin-cholesterol acyltransferase (LCAT) deficiency] and hypolipidemias (abetalipoproteinemia, Tangier disease) to ascertain relationships among plasma lipids, platelet lipids, thrombin binding and thrombin-induced platelet aggregation, and to compare these data with those previously obtained on stimulus-response coupling in platelets following in vitro modification of membrane microviscosity. Washed platelets were studied for their ability to bind 125I-thrombin in the range of 10(-10) to 10(-6) mol/L (10 mU/mL to 100 U/mL) and to aggregate with thrombin at concentrations less than 10(-9) mol/L (100 mU/mL). The values for binding and aggregation in eight patients from six kindred with familial hypercholesterolemia, taken as a group, fell in the low normal range. If divided into two groups, patients with overt cardiovascular disease bound normal amounts of thrombin but were more responsive to it, whereas patients without overt cardiovascular disease bound lower amounts of thrombin but gave an aggregation response in the normal range. These results suggest that platelet hyperresponsiveness in familial hypercholesterolemia arises from an alteration in the coupling mechanism between thrombin binding and response such that platelets from patients with familial hypercholesterolemia are able to respond with lower receptor occupancy than is the case with normal platelets. Thrombin binding and aggregation were within normal ranges for platelets from abetalipoproteinemia patients (N = 4) and type V hyperlipoproteinemia (N = 2), although in the latter case the response appeared to be less at very low thrombin concentrations (less than 30 mU/mL). Thrombin binding was elevated in Tangier disease (N = 3) but with lower responsiveness at lower thrombin concentrations. Thrombin binding was also elevated in LCAT deficiency (N = 2), and one patient showed increased and another showed decreased aggregation responses. In general, increased plasma cholesterol levels resulted in increased stimulus-response coupling (type II), whereas increased triglyceride levels resulted in decreased coupling (type V, Tangier), and there was no apparent alteration in the coupling mechanism with overall reduction in plasma lipid levels as in abetalipoproteinemia.

Antithrombin III Padua: a "new" congenital antithrombin III abnormality with normal or near normal activity, normal antigen, abnormal migration and no thrombotic disease.

A "new" antithrombin III abnormality is described in four members of a family. The proposita is a 38 years old female who showed no thrombotic disease and the following laboratory pattern: normal routine clotting tests, normal or near normal AT III activity (chromogenic substrates S-2238 and Chromozym Th) both in plasma and in serum and in the presence or absence of heparin, slightly decreased antifactor Xa activity (chromogenic substrate S-2222), normal progressive antithrombin, normal AT III antigen but abnormal migration in the agarose-heparin bidimensional system. In the latter test, one major abnormal peak, less anodal than the normal counterpart, and a smaller, apparently normal peak, were seen. In agarose without heparin the pattern was similar to normal both in plasma and in serum. Heparin tolerance to heparin in vivo and in vitro was slightly increased but still within normal limits. The two sons and a paternal aunt showed the same pattern. The hereditary pattern seems therefore autosomal dominant. The abnormality described appears different from AT III Budapest. The toponym of antithrombin III Padua is proposed to define this peculiar abnormality.

Factor XIII deficiency associated with Klippel-Weber disease, platelet dysfunction and cryofibrinogenemia.

A 23-year-old woman with factor XIII deficiency was presented. The patient had no consanguinity, but familial traits were present. A bleeding tendency and poor wound healing had been noted in the patient since birth. She had hemangiomas in the leg and vulva (Klippel-Weber disease). Hematologic studies revealed platelet dysfunction, cryofibrinogenemia and mild chronic disseminated intravascular coagulation with prolonged PT and PTT, hypofibrinogenemia, a high turnover rate of 125I-fibrinogen and mild elevation of fibrinogen-fibrin degradation products, beta-thromboglobulin and platelet factor 4. A decrease in clot retraction and a marked reduction in maximal amplitude of thrombelastogram were also found. The assay of the factor XIII level was 10% by the antiserum inhibition method, and the assay of subunits A and S were 16 and 29%, respectively, by the electroimmunoassay method. Transamidase activity of factor XIII was 26%. The level of factor XIII of her sister was low, similar to that of the patient. The concentration of cold-insoluble globulin in EDTA-plasma was 36.5 mg/dl.