Immune activation markers to predict AIDS and survival in HIV-1 seropositives.

Neopterin concentrations in body fluids of HIV-1 seropositives provide predictive information. In 1986, we examined serum and urine neopterin concentrations in 29 HIV-1 seropositives. Serum levels of soluble IL-2 receptor (sIL2R), soluble CD8 (sCD8), tumour necrosis factor alpha (TNF-alpha) and circulating immune complexes (CIC) were retrospectively analysed in 1989. All individuals had increased serum and urine neopterin, sIL2R and CIC concentrations, 27/29 had increased sCD8 concentrations, whereas all had normal TNF-alpha levels. During a 3-year follow-up, high urine and serum neopterin concentrations were significantly associated with progression to AIDS and with the occurrence of AIDS-associated death. Both neopterin variables were of similar predictive value (p less than 0.001, generalized Wilcoxon test). sIL2R concentrations were of borderline significance in predicting the onset of AIDS (p = 0.05). All other parameters lacked predictive information in our study. We conclude, that chronic immune activation is detectable in almost all HIV-1 seropositives. Chronic immune activation may be associated with HIV-1 replication and may contribute to the immunopathology of HIV-1 infection.

Comparison of serum and urine neopterin concentrations in patients with HIV-1 infection.

Urine and serum neopterin concentrations are now widely used to monitor patients with HIV-1 infection. However, there are no published studies comparing the levels in urine and serum, and relating both to the patients' immune status. Urine and serum neopterin concentrations correlated closely in our study population of 37 HIV-1 seropositive patients (34 homosexuals, 3 drug addicts) and 10 HIV-1 seronegative homosexuals. Our data further show that urine and serum neopterin concentrations correlate almost identically with the clinical and immunological presentation of HIV-1 infected individuals, as expressed by the Walter Reed Staging classification. In addition, there was no difference between the correlation of neopterin concentrations in either serum or urine with the Quetelet indices. It will depend on the clinical situation whether blood or urine sampling is preferred. Collection and handling of urine samples from HIV infected patients is less risky to health care personnel in HIV settings.

Serum trace element levels in HIV-infected subjects.

The absolute number of T4 cells and the serum concentrations of Ca, Cu, Fe, K, Mg, P, Se, and Zn were determined in 59 Walter-Reed staged, HIV-infected men, compared to healthy controls, serum levels of Ca, Cu, and Fe were significantly higher, those of P and Se significantly lower in the HIV-infected subjects. In the HIV-infected cases, but not in the controls, the concentrations of Se and Zn, of Ca with Cu and Fe, and of Fe with P, were directly correlated. In the controls, the correlation between the levels of K and Mg was direct, and inverse between those of Zn and P. Trace element levels did not significantly correlate with WR-stage. However, the absolute number of T4 cells was directly correlated with the serum Mg concentration.

[Comparison of bio-availability, antianaemic efficacy, tolerance and drug costs in oral iron(II) and iron(III) preparations (author's transl)]. / Vergleich von Bioverfügbarkeit, antianämischer Wirksamkeit, Verträglichkeit und Arzneikosten bei oralen Eisen(II)- und Eisen(III)-Präparaten.

In addition to a clinical study which investigated the bio-availability of three oral iron preparations S, L and X by using postabsorption serum iron concentration curves, the same drugs were compared in order to study their antianaemic efficacy, tolerance and drug costs arising during and iron therapy. Moreover, these iron drugs were related to other current clinical reports. Within all three iron preparations a very good correlation was found between bio-availability and haematopoietic efficacy: The very good absorbability of the bivalent quick release stick capsule preparation S (= 100%) corresponded with a very good capacity of haemoglobin regeneration (2,6 +/- 0,4 g Hb/1/day) whereas due to a very low absorbability (10% to 16%) the antianaemic efficacy of both iron(III) preparations L and X had to be rated as moderate to predominantly poor. In normal therapeutic dosis all three iron preparations showed no differences in tolerance. The ratio of side effects was similar to that after ingestion of placebo. In comparing the drug costs during a therapy leading to a real absorption of 1 g of iron the most effective iron(II)sulfate preparation S is 3.6 to 12.6 times cheaper than the compared trivalent preparations L and X. Therefore, there is no justification for the further production or introduction on the market of trivalent iron preparations.

[Investigations of the bioavailability of iron from bi- and trivalent iron salts (author's transl)]. / Untersuchungen zur Bioverfügbarkeit des Eisens aus Eisen(II)- und Eisen(III)-Salzen

In a clinical pilot study, performed as an intraindividual comparison, 3 oral iron preparations, one bivalent iron sulfate (quick release stick capsule preparation) and two trivalent iron citrate complex preparations with different additives, were investigated on 9 healthy young male test persons by the iron absorption test (postabsorption serum iron concentration curves) in order to study the bioavailability of these drugs and their compatibility. Whereas both iron drugs proved equally compatible when administered in therapeutical doses, it was again confirmed that the enteral bioavailability of the ferrous iron sulfate is superior to that of the ferric iron complex preparation. According to these results the medication of ferric iron preparations seems once again to be proved unsuitable, trivalent iron having first to be reduced to bivalent absorbable iron, there however being usually not enough "reducing capacity" in the gastrointestinal tract to do this.

[Clinical course of hairy cell leukemias]. / Beobachtungen zum Verlauf von Hairy-cell-Leukosen.

When analyzing 20 cases of hairy-cell leukosis we can compare a group with a medium survival time (16 months since clinical beginning of the illness) to a group with a long survival time (80 months). Patients (historically older) with short survival times are characterized by a combination of short anamnestic dormancy, younger age, severe symptoms and the applying of a steroid and cytostatic therapy instead of splenectomy. Prevalent causes of death were infections which seemed to increase by cytostasis. Patients with a longer survival time were characterized by a longer survival time were characterized by a longer anamnestic dormancy (up to 15 years), and clinically bland indications that permitted splenectomy. In this group we find interesting cases in which after splenectomy the infiltration of the bone marrow was greatly reduced, being in one case merely 10% after 10 years. These findings ought to be discussed with respect to the aspect of the extremely slow and spleen dependent kinetics of the pathognomy of the cell fractions. As to the origin of the hairy cells and to mark the difference to other lymphomas of the spleen it is necessary to stress the fact that the rate of immunoglobuline did not change in any of the 20 cases observed.

Agranulocytosis induced by antithyroid therapy: effects of treatment with granulocyte colony stimulating factor.

A 26-year-old woman was admitted to hospital with high fever, severe tonsillitis, and gastroenteritis. Because of Graves' disease she had been treated with methimazole for 18 months. Leukopenia and agranulocytosis in combination with a typical bone marrow, exhibiting a complete arrest of myelopoiesis at the stage of promyelocytes led to the diagnosis of an antithyroid therapy induced agranulocytosis. After 1 week of antibiotic treatment without changes in neutrophil counts, granulocyte colony stimulating factor treatment at a dose of 300 micrograms/day subcutaneously was started. Twenty-four hours after the first administration the neutrophil counts began to rise, to 4389/microliters, with a maximum after the third administration and stabilizing at normal levels within 10 days. Since agranulocytosis is considered to be a severe and fatal complication of methimazole therapy, treatment with granulocyte colony stimulating factor seems to be useful for this life-threatening condition.

[Acute retinal necrosis and herpes encephalitis. The key role of the ophthalmologist in diagnosing opportunistic infections in AIDS, successful therapy with acyclovir (Zovirax)]. / Akute Retinanekrose und Herpes-Enzephalitis. Schlüsselrolle des Augenarztes bei der Diagnose opportunistischer Infektionen bei AIDS, erfolgreiche Therapie mit Acyclovir (Zovirax).

A 43-year-old homosexual man was hospitalized in April 1988 because of acute epigastric pain. It was known that he had had a HIV infection for a year, and in April 1988 it was defined as stage Walter Reed I. Acute, exudative, nonspecific pancreatitis was diagnosed. Three weeks later cerebral symptoms (disturbances of consciousness), hypoacusis, and impaired vision developed. The ocular fundus displayed areas of edema and whitish clouding in the retina, first in the left eye and later also in the right. These were initially assumed to be anemic infarctions until the differential diagnosis of acute retinal necrosis with possible herpesvirus infection was made. On the basis of ophthalmoscopic findings cytomegalovirus retinitis appeared improbable. Serologic examinations showed increased levels of IgG antibody titers of cytomegalovirus and herpes simplex virus (both 1:20,000). Therapy with intravenous infusions of Acyclovir was instituted (1500 mg/d). After a few days the patient regained consciousness as well as his hearing and vision. There was complete resolution of the retinal exudates. This excellent therapeutic result of Acyclovir therapy confirmed the diagnosis of acute retinal necrosis syndrome, identified the cerebral symptoms as herpes encephalitis, and explained the entire disease process as the first opportunistic infection in HIV infection, i.e., by that time the patient had developed stage Walter Reed 6 (AIDS). Problems of differential diagnosis and the therapeutic schedule with Acyclovir are discussed.

[Kinetics and differentiation of monocytes in man (author's transl)]. / Zur Kinetik und Differenzierung der Monozyten beim Menschen.

This paper gives a short review of the monocytopoiesis in the bone marrow, the kinetics of monocytes in the blood, the differentiation of monocytes in the tissue and presents new data on monocyte transit time through the peripheral blood. Monocyte kinetics were studied in three hematologically normal persons, four patients with Hodgkin's disease and four patients with chroniclymphocytic leukemia using 3H-TdR-pulse-injection or 3H-TdR continuous infusion. The average value of the mean blood monocyte transit time was 25.1 hours. The mean blood transit times of haematologically normal persons and patients with lymphatic disorders did not differ significantly.

Advantages of isovolemic large-volume erythrocytapheresis as a rapidly effective and long-lasting treatment modality for red blood cell depletion in patients with polycythemia vera.

Long-term survival of patients with polycythemia vera (PV) is essentially determined by the ability to reduce the risk of thromboembolic complications resulting from the altered rheological conditions by the high red blood cell (RBC) mass of these patients. RBC depletion to normal hematocrit (Hct) values is the first line therapy and should be preferred to chemotherapy (or P32) because of the long-term risk of acute leukemia or other secondary malignancies. RBC depletion is accomplished much more effectively and rapidly by erythrocytapheresis (EA) than by repeated phlebotomies and has been shown to be well tolerated and accepted by the patients (8). The main indications for EA for a PV patient (often newly diagnosed) are high risk Hct values of >55-60% that can be reduced to the normal range within 1-2 h. The long-lasting effect (median interval between 2 EA treatments: ca. 6 months) is partially the result of the massive loss of iron, a growth factor for erythropoesis. This has been shown by in vitro studies in erythroid progenitor cells of PV patients before and after EA (11). The advantages and possible disadvantages of EA treatment are discussed.

[Trace element concentrations in HIV infected patients]. / Spurenelementkonzentrationen bei HIV-Infizierten.

The serum concentrations of Ca, Cu, Fe, K, Mg, P, Se and Zn and the absolute number of T4 cells were determined in 59 HIV-infected men. Serum levels of Ca, Cu and Fe were significantly higher, those of P and Se significantly lower in the infected, compared to healthy controls. In the HIV-infected cases the concentrations of Se and Zn, of Ca with Cu and Fe, and of Fe with P, were directly correlated. In the controls, the correlation between the levels of K and Mg was direct, and inverse between those of Zn and P. WR-stage and trace element levels did not correlate. The absolute number of T4-lymphocytes was directly correlated with the serum Mg concentration.

[The prognostic significance of lymphocyte subpopulations and macrophages in peripheral blood and in bronchoalveolar lavage in AIDS patients with suspected Pneumocystis carinii pneumonia]. / Die prognostische Bedeutung von Lymphozytensubpopulationen und Makrophagen im peripheren Blut und in der bronchoalveolären Lavage bei AIDS-Patienten mit Verdacht auf Pneumocystis-carinii-Pneumonie.

In 36 HIV seropositive patients with the clinical manifestation of AIDS and a suspected Pneumocystis carinii infection, lymphocyte subpopulations were analyzed in the peripheral blood (PBL) and compared with the results of the bronchoalveolar lavage (BAL). Of those 36 patients, 29 showed a highly abnormal CD4/CD8 ratio in both the PBL and the BAL. The clinical course of these 29 patients was unpredictable. In seven patients, however, the CD4/CD8 ratio in the BAL was normal or only slightly altered, despite a highly abnormal CD4/CD8 ratio in the PBL. Five of these seven patients improved greatly during the clinical course. The positive outcome of the clinical course was even more strongly correlated with the number of macrophages in the BAL. Twelve of the 36 patients showed normal or only slightly changed numbers of macrophages in the BAL. Eleven of these twelve patients (92%) improved rapidly during antibiotic therapy, while the clinical course was unpredictable in patients with markedly reduced macrophage counts in the BAL.

[Hematomorphological differential diagnosis of small cell lymphoma. What is the atypical chronic lymphadenosis?]. / Hämato-morphologische Differentialdiagnose kleinzelliger Lymphome. Was ist die atypische chronische Lymphadenose?

More importance is being attached to haematologic cell morphology, particularly in the field of small-cell non-Hodgkin lymphomas. This shifting of diagnostical validity from the structural substrate to the cellular one can clearly be illustrated by the transition of classification according to Rappoport to that according to Lennert (Kiel-classification). Here minute cytomorphological criteria acquire a new validity by their significance in the microscopic cut preparation and in the electron-microscope as well as by their correlation to cell-immunological parameters. Thus, it is possible to make a differential diagnostics of the extending small-cell lymphomas from the blood picture. It enables an ensured morphological differentiation to be made for typical B-lymphadenosis, prolymphocytic leukaemia, T-cell lymphadenosis, lymphoplasmocytoid immunocytoma, centrocytoma, and hairy cell leukaemia. The relevance of this differentiation can be further identified by a consequent immunologic cell characterization.

[Agranulocytosis caused by infectious-toxic bone marrow damage after Borrelia infection]. / Agranulozytose durch infektiös-toxische Knochenmarkschädigung nach Borrelien-Infektion.

A 19-year-old girl developed a fever of up to 40 degrees C and, during an episode of high fever, generalized seizures. Physical examination on admission was unremarkable, except for several small lymph nodes. Differential blood count showed a leukopenia (1700/microliters) with 14% stab and 7% segmented neutrophils. After initial clinical improvement she again became feverish and the differential count now showed agranulocytosis with a total white cell count of 1400/microliters. Because of the time of year and the geographic location borreliosis was now considered in the differential diagnosis. The antibody titre against Borrelia was raised to 1:64 (IgM) and 1:256 (IgG). Her condition and the differential blood count rapidly improved on intravenous antibiotic treatment with cefotiam (2 g two times daily) and gentamicin (120 mg two times daily), as well as filgrastim (granulocyte-colony stimulating factor) subcutaneously. Antibiotic treatment was continued after 6 days with oral ampicillin (1 g three times daily) for 3 weeks. Follow-up examination six weeks later found the patient to be symptom-free.

Regulated plasma levels of colony-stimulating factors, interleukin-6 and interleukin-10 in patients with acute leukaemia and non-hodgkin's lymphoma undergoing cytoreductive chemotherapy.

Endogenous plasma levels of granulocyte colony stimulating factor (G- CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF),IL-6 and IL-10 were measured in a total of 70 patients undergoing cytoreductive chemotherapy for treatment of acute leukaemia or non-Hodgkin's lymphomas. the diagnoses were acute myeloid leukaemia (AML; n = 30), acute lymphoblastic leukaemia (ALL;n=6), non-Hodgkin's lymphomas (NHL; n=11) and other malignant haematological disorders including myelodysplastic syndromes (n=23). After chemotherapy, plasma G-CSF was elevated (mean 5.6 ng/ml; range 1.2-10 ng/ml), and was inversely correlated with white blood cell counts (WBC) (r=-0.7, p<0.001). Occurrence of fever (T>38.0 degrees C) during severe myelosuppression (WBC<1x10(9)/1) was associated with an additional increase of G-CSF levels (P<0. (P<0.001). Plasma IL-6 correlated significantly with fever (range <1 to 1100 pg/ml, mean 130 pg/ml; r=0.5, P<0.001) but revealed only a weak association with WBC or platelet counts. In patients treated with recombinant G-CSF (n = 9), an association between IL-6 and fever was still observed after chemotherapy. During the nonfebrile status (total n = 242; AML n = 124), IL-6 levels remained <9 pg/ml in 90% of cases, whereas G-CSF increased with leucopenia (r = -0.72;P<0.001). In contrast, endogenous GM-CSF remained normal and IL-10 showed only a slight increase (21% of samples; maximum 22 pg/ml) in severe leucopenia. In particular, IL-10 levels did not correlate with G-CSF or IL-6 levels. We conclude that systemic release of G-CSF and IL-6 is obviously nit abrogated by cytoreductive chemotherapy in acute leukaemia and NHL may add to the therapeutic efficacy of recombinant cytokines. Also, plasma levels of G-, GM-CSF or IL-6 appear to be regulated by separate mechanisms.

Treatment of polycythemia vera by isovolemic large-volume erythrocytapheresis.

Excess red blood cells (RBC) in patients with polycythemia vera (PV) are usually removed by repeated phlebotomy. In order to improve the efficacy of this treatment, we used isovolemic large-volume erythrocytapheresis (EA) by a cell separator. A retrospective analysis of our experience with 69 PV patients (206 EA procedures) is reported. EA induced a rapid, well-tolerated, and long-lasting reduction of Hct, Hb, and RBC counts, as well as an immediate disappearance or reduction of clinical symptoms of PV, while tissue oxygen tension - as measured in 8 patients - increased. Hct was reduced by EA from 56.8% +/- 5.6% to 41.9% +/- 6.6%, Hb from 17.5 +/- 2.3 to 12.7 +/- 2.4 g%, RBC counts from 7.4 +/- 0.9 to 5.4 +/- 0.9 x 10(6)/mm3. The mean volume of the apherisate was 1410 +/- 418 ml, (mean Hct 79.7% +/- 9.3%), and the actual RBC volume removed 1113 +/- 367 ml. The isovolemic procedure was well tolerated and the acceptance by patients seemed to be better than with repeated phlebotomy. In 21 patients whose Hct values (Hct before and after EA 58% +/- 5.7% and 41.5% +/- 4.9%) were regularly followed after EA the mean period with Hct less than 50% after a single EA procedure was 6.1 +/- 4.1 months (median, 6); in 14 out of these 21 patients a Hct of less than 43% after EA was reached and their mean period with Hct less than 50% after EA was 7.6 +/- 4.0 months (median, 7.5). For three patients this period was 11, 13, and 15 months, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

[HIV-associated lymphomas]. / HIV-assoziierte Lymphome.

Forty-one HIV-positive homosexual men (mean age 39.8 [23-72] years) with malignant lymphomas were examined with the object of exploring the clinical and pathological spectrum of HIV-associated lymphomas in Central Europe, and their therapeutic aspects. There were 33 patients with non-Hodgkin lymphoma of high malignancy and four with non-Hodgkin lymphoma of low malignancy; four further patients suffered from Hodgkin's disease. 27 patients died during the period of observation. The mean survival period after diagnosis was 5.5 months. It depended on the stage reached by the lymphoma at the time of diagnosis: 11.8 months in stage I, 10.6 months in stage II, 7 months in stage III, 3.3 months in stage IV and 1.3 months in patients with primary involvement of the central nervous system by the lymphoma. Eight out of nine patients with highly malignant non-Hodgkin lymphoma in stage I or II attained complete and lasting remissions after chemotherapy or irradiation. However, only minimal prolongation of life was achieved in the 16 patients with lymphomas in stages III or IV. The response rate among all patients treated (complete and partial remissions) was 75%; 45% achieved complete remission. Hodgkin's disease responded well to standard therapy, but the disease rapidly recurred in every case.

Mitoxantrone and VP-16 in refractory acute myelogenous leukemia.

Phase I/II-studies suggested that mitoxantrone is effective in the treatment of acute leukemia. In this study we have investigated its efficacy in combination with VP-16 in patients with refractory acute myelogenous leukemia. The regimen consists of: mitoxantrone 10 mg/m2/day i.v. from days 1 to 5, VP-16 100 mg/m2/day as short infusion from days 1 to 3. A dosis escalation of VP-16 was attempted. As of August 1985, 27 patients have been enrolled in the study and 21 patients are now evaluable. Of these 21 patients, 6 (28.6%) have achieved complete remission including 3 with primary refractory disease, 2 with early relapse (less than 6 months after CR), and 1 with relapse under maintenance therapy. Two other patients have attained a partial remission. Toxicity was mild and, except one case of early death, no life threatening complications were observed. This combination seems to be an active regimen in refractory acute myelogenous leukemia and its incorporation in front line therapy seems warranted.

DNA-synthesizing T and non-T cells in bacterial infections.

The results of autoradiographic determination of DNA-synthesizing lymphocytes (3H-thymidine) in 10 patients with bacterial infections were compared with results in 10 normal patients and contrasted with 23 CLL patients in different stages [12]. In patients with infectious diseases the absolute number of T cells was lower and the mean values of S-phase T cells and S-phase non-T cells was higher than in normal persons. In contrast to the patients with infections, CLL patients in stage o--III have lower S-phase T cell values and higher S-phase non-T cell values. In stage IV, on the other hand, all DNA-synthesizing lymphocytes are increased.