Rare fatal simultaneous mould infection of the lung caused by Aspergillus flavus and the basidiomycete Coprinus sp. in a leukemic patient.

The basidiomycete Coprinus sp. was isolated repeatedly from bronchial secretions and bronchoalveolar lavage of a 40-year-old woman suffering from a relapse of acute lymphoblastic leukemia 5 years after she underwent autologous bone marrow transplantation. Post-mortem microbiological investigation of lung tissue revealed simultaneously growing Coprinus sp. and Aspergillus flavus. Histopathological examination of the lung demonstrated septate hyphae characteristic of both Aspergillus and Coprinus. The basidiomycete Coprinus sp. should be considered as a potential opportunistic pathogen because of its excellent growth at 37 degrees C.

[Invasive mold infections in the university clinics of Leipzig in the period from 1992-1994]. / Invasive Schimmelpilzinfektionen am Universitätsklinikum Leipzig im Zeitraum 1992-1994.

Invasive mould infection, e. g. aspergillosis in the first place, is a common infection in immunocompromised patients. The diagnosis of invasive mould infection is difficult in the absence of confirmation by tissue biopsy and histological studies. Therefore, prevalence of invasive mould infections at the School of Medicine of the Leipzig University between 1992 and 1994 was investigated. The diagnosis of invasive mould infection was suspected on clinical, mycological, and radiological findings. The definitive diagnosis was obtained by identification of characteristic mould hyphae on stained smears, and/or positive culture, and/or the detection of Aspergillus antigen (Pastorex) in serum, bronchial secretion, or bronchoalveolar fluid, and confirmed by histopathology. In altogether 21 patients the definitive diagnosis invasive mould infection was recorded, among them 20 invasive aspergilloses. Underlying diseases were leukaemia (n = 11), aplastic anaemia (n = 2), non-Hodgkin-lymphoma (n = 1), systemic lupus erythematosus (n = 1), kidney transplantation (n = 1), peritonitis after Billroth II anastomosis (n = 1), Polymyalgia rheumatica (n = 1), AIDS plus Burkitt lymphoma (n = 1), glioblastoma (n = 1), and subarachnoid haemorrhage (n = 1). As causative fungi were isolated: Aspergillus fumigatus (n = 13), Aspergillus terreus (n = 1), Aspergillus flavus as rare simultaneous injection with the basidiomycete Coprinus spec. in a leukaemic patient (n = 1), and the dematiaceous fungus Scedosporium prolificans in an AIDS patient with Burkitt lymphoma (n = 1). In four patients the invasive mould infection was confirmed histopathologically without isolation and differentiation of the causative agent. Nineteen of the 21 patients with invasive mould infections died corresponding to a mortality rate of 90%.

[Detection of mixed lymphoid chimerism after allogeneic bone marrow transplantation: demonstration by interphase cytogenetics in paraffin-embedded tissue]. / Gemischter lymphoider Chimärismus nach allogener Knochenmark-transplantation: Nachweis durch Interphase-Zytogenetik an paraffineingebettetem Gewebe.

In bone marrow transplantation (BMT) the detection of residual host lymphoid or haematopoietic cells surviving conditioning therapy is because of its association to graft-versus-host disease, graft-versus-leukemia reaction, and relapse of leukemia a matter of great interest. We studied the occurrence of this mixed lymphoid chimerism (MC) in the formol-fixed lymphatic tissue of lymph nodes and spleen from 21 autopsies after allogeneic sex-mismatched BMT (5 females, 16 males, survival 5 to 1140 days after BMT). In situ hybridisation with biotinylated centromer-specific anti-X- and anti-Y-chromosome probes was performed on pepsin-digested paraffin sections. The number of double X-, single X-, and Y-chromosome bearing cells was analysed microscopically. Because of artefacts only 14 cases remained for valid investigation. MC was detected in 6 cases (5 out of 11 males 5 days to 840 days and 1 out of 3 females 76 days after BMT). MC occurred after whole body irradiation with 10 Gy (n = 5) and 7 Gy (n = 1). In 1 autopsy relapse of leukemia caused host cell infiltration. Cases with MC did not express histological signs of acute or chronic graft-versus-host disease, but 5 out of 8 with complete lymphoid chimerism did. The sensitivity of interphase cytogenetics on paraffin embedded tissue is low.

[Fungal infections in granulocytopenic and immunocompromised patients]. / Pilzinfektionen bei granulozytopenischen und immunsupprimierten Patienten.

Opportunistic fungus infections in neutropenic immunocompromised patients have strikingly increased, especially with the improvement of antibiotic treatment. Their outcome is often fatal because of the difficulties in diagnosis and treatment. Therefore a rationale of surveillance diagnostics and empiric treatment in risk patients is necessary. In these patients a continuous weekly mycotic diagnosis of mouth, throat, faeces, urine, vagina, as well as of the blood is necessary. During an aggressive neutropenia-producing chemotherapy an antimycotic prophylaxis with the aim of reducing fungal colonization in the gastrointestinal tract (sometimes in the respiratory pathways, too) should be performed. Fever of unknown origin lasting longer than 4-5 days in spite of broad spectrum antibiotic treatment and/or positive diagnostic findings must lead to treating risk patients empirically using amphotericin B 1 mg/kg/d or a combination of amphotericin B 0.3-0.5 mg/kg/d together with flucytosin (Ancotil) 150 mg/kg/d. In case of a beginning candidiasis, patients can first be treated with fluconazol (Diflucan). The dose is 400 mg/d, later on 200 mg/d. It is pointed out that, much more often than usual, in risk patients with fever, atypical pneumonia, meningoencephalitis or other organ symptoms fungal infections should be taken into consideration. The most common opportunistic fungal diseases are presented and details concerning the different antimycotic drugs are given.

[Pulmonary roentgen findings in interstitial pneumonia after bone marrow transplantation]. / Pulmonale Röntgenbefunde bei interstitiellen Pneumonien nach Knochenmarktransplantation.

In 10-40% of the patients interstitial pneumonias develop after bone marrow transplantation. The identification of causative agents is often problematic, so that particularly clinical but also blood gas-analytic findings allow the making of a diagnosis. The typical X-ray-morphological changes of the lung (particularly symmetrical, fine-reticular, interstitial multiplications of markings and fine-patchy, striated, partly confluent shadows), which are represented with the help of three instances of cases, confirm the diagnosis, are, however, often found only relatively late. Further diagnostic methods such as the computer tomography or the bronchoscopy, connected with lung biopsy and bronchoalveolar lavage, at present do not play an essential role at least in the early phase after the transplantation of the bone marrow.

[Experiences in the diagnosis and treatment of polyneuropathies in patients with malignant monoclonal gammopathy]. / Erfahrungen in Diagnostik und Therapie von Polyneuropathien bei Patienten mit maligner monoklonaler Gammopathie.

4 patients are reported having monoclonal gammopathies, who clinically exhibited a sensomotoric polyneuropathy being progressive during some years. The EMG showed axional failure and secondary demyelisation. In two of the patients an IgG-type multiple myeloma has been revealed, while in the other two ohnes an increase of abnormal IgM-mIg could be demonstrated. In all patients the liquor protein was found increased and the appropriate mIg has been found in the liquor. Immunohistochemically the appropriate immunoglobulins could be demonstrated on the peripheral nerve by means of immunofluorescence method. Electron microscopical studies of nerval biopsies supported the diagnosis of mIg-associated polyneuropathy. References to diagnostics and treatment of mIg-associated polyneuropathy are done.

Allogeneic bone marrow transplantation for leukaemia and aplastic anaemia. Results of the Leipzig BMT Group.

In acute leukaemias there was a stable plateau in the survival curve at 45% after two years if grafted in first complete remission (n = 20) but only 13% of the patients are disease-free alive if grafted in a more advanced stage of the disease (n = 8). In 16 patients transplanted for chronic myeloid leukaemia the overall survival is 40%, in cases with graft-versus-host disease (GVHD) prevention by cyclosporine survival rate could be improved. Only 8 patients with severe aplastic anaemia, partially in low performance status were able to be transplanted; three died of infections, another by acute GVHD. The fatal complications in our study characterize the international well-known major problems in BMT: GVHD, interstitial pneumonitis, infections, graft failure in aplastic anaemia and recurrence of leukaemia, especially in more advanced leukaemia stage.

Autologous bone marrow transplantation (ABMT) using unpurged marrow as intensification for first complete remission in acute leukaemia (AL).

In order to assess the clinical advantage of autologous bone marrow transplantation (ABMT) without ex vivo purging, the results in 26 patients (10 AML, 16 ALL) in 1. CR were analyzed retrospectively. All patients received 3 consolidation cycles "in-vivo purging" before marrow harvesting. Beside relapses infections and cardiac failure were the most frequent complications. After 1 to 12.5 months 11 cases relapsed with a higher probability in patients who had a longer period of induction and between CR and ABMT. 12 patients became relapse-free survivors 6 to 53 months after ABMT with a stable plateau after 12.5 months for 8 patients. In conclusion, ABMT following "in-vivo purging" as the strongest one-step postremission therapy in patients with acute leukaemias may be a way for better long-term results in these patients.

Immune recovery following bone marrow transplantation.

83 patients undergoing allogeneic or autologous BMT because of haematologic malignancies have been studied before and after transplantation at different intervals. The determinations consisted of lymphocyte counts, E-rosetting, lymphoblastic response, evaluation of serum immunoglobulin levels, skin testing, and in a smaller part of the patients surface marker studies using monoclonal antibodies of the BL-series. At first after BMT the lymphocyte and T cell counts went to normal between 4-18 weeks post transplant, about 4 weeks earlier in autologous than in allogeneic BMT. T suppressor cells showed an early increase compared to T helper cells which normalized much slower about 6 months after BMT. Lymphoblastic responses, however, tended to normal not before the second half of the first year both in autologous and allogeneic transplantation. Skin test reactivity became normal during the 2nd and 3rd year posttransplant, which was more complete in autologous than in allogeneic BMT. The IgG and IgM levels were depressed for half a year and IgA levels for 2 years. The most striking aspect was the multiphase course of lymphoblastic response in every individual patient. We suggest this to be the expression of sequential differentiation of donor lymphocytes.

Lethal complications in 30 patients after allogeneic BMT (BMT) and autografted (ABMT) patients (1980-1986) examined by autopsy.

Lethal and accompanying complications from 29 allogeneic, 8 autologous, and 1 syngeneic transplanted pts., died between 1980 and 1986 at the BMT-Center Leipzig were revisited. An important problem was that of systemic and local infections. We observed a predominance of bacterial and fungal infections within the first 3 weeks p.t., and later on a period of predominantly virus-associated infections. The most common early death (up to 3 months p.t.) was related to ICP, as a rule caused by CMV. GvHD was a common finding at autopsy, and GvHD of the bowel seems to facilitate infectious inflammations of the bowel. There was a positive correlation between severe GvHD and the occurrence of ICP. Neither of the died BMT pts. showed signs of relapse. After ABMT ICP did not occur. The lethal complications were septicaemia, local infections, relapse and haemorrhagic diathesis. A toxic effect of DMSO in 3 pts. must be taken into account. In conclusion, a rather small number of lethal factors indicates the steps in improving results of transplantation in the future.

[Results of therapy of 100 patients with acute leukemia--a retrospective unicenter 5-year analysis]. / Therapieergebnisse bei 100 Patienten mit akuter Leukämie--eine retrospektive unizentrische 5-Jahres-Analyse.

The results of therapy in 100 patients who newly fell ill (68 AML, 32 ALL) with acute leukaemia were evaluated (1981 to 1985). The 5-year-survival chance of all patients is 15% for AML, 18% for ALL, first of all it is depending on the degree of remission obtained. The CR rate is nearly 43% (AML) and 66% (ALL), respectively, shows a dependence upon age and is impaired above all by a high early death rate (supportive therapy). With increasing aggressiveness the results of the remission induction therapy improve, as it becomes clear in a comparison with an evaluation of patients 1965-1980 (CR: 15-32%). Also in the postremission therapy the results of intensive forms of therapy are more favourable: 4 years recurrence-free survival after CR in autologous bone marrow transplantation 50%, in allogenic bone marrow transplantation 40%, in cyclic chemotherapy 17%, in oral permanent therapy 0%. Starting from these findings the present conception of the therapy of acute leukaemias is discussed in connection with the literature.

[Cellular immunity in dialysis patients using the lymphocyte transformation test (LTT) in comparison to conservatively treated patients with chronic terminal renal failure]. / Untersuchungen zur zellulären Immunität bei Dialysepatienten mittels Lymphozytentransformationstest (LTT) im Vergleich zu konservativ behandelten Patienten mit chronisch-terminaler Niereninsuffizienz.

By means of the lymphocyte transformation test (LTT), using the mitogens phytohemagglutinin (PHA), concanavalin A (ConA), lipopolysaccharide (LPS) E. coli and the antigens tuberculin (PPD) and O-streptolysin, a contribution should be made for the judgment of the functional capacity of the immune system--in particular of the cellular immunity--in uraemia patients with and without dialysis therapy. In 33 patients with different duration of the dialysis (0.5 to 130 months) and 15 retention patients who were not yet treated by means of dialysis the LTT was controlled with stimulant agents mentioned above. In these cases was shown that dialysis patients managed metabolically regularly did not show a significant restriction of the cellular immunity in the LTT (PHA-stimulation over 0.55 transformed cells, con-A-stimulation over 0.37 transformed cells). The not dialysed patients with chronic uraemia showed a distinct diminution of the unspecific T-cell transformation by PHA and ConA, whereas the antigen-induced stimulation (PPD, O-streptolysin) was not disturbed in this case as well. In the two cases the B-cell transformation (on LPS) was not significantly disturbed. There was a good concordance with the clinical findings: scarcely general infects, no shunt infections, relatively many organ losses by rejection after transplantation in the dialysis patients. The not yet dialysed retention patients revealed clinically a higher inclination to an infect. There were no own experiences about the course after transplantation without preceding dialysis. It is discussed in how far also immunological investigations may play a role in the establishment of the optimum management of the dialysis, the moment of the beginning with the dialysis and for the "more individual preparation of the transplantation".

Transplantation of stem cells of embryonic liver in a patient with severe combined immunodeficiency.

A patient had severe combined immunodeficiency syndrome and X-chromosomal recessive heredity. Since the parents and siblings were not suitable as HLA-compatible bone marrow donors, stem cells from embryonic liver were transplanted intravenously in 3 stages (6 X 10(6); 3.5 X 10(6), and 9 X 10(7]. Transplantation was tolerated well; there were no signs of a graft-versus-host reaction. Examination of the immunological condition after transplantation showed evidence of T-cell reconstitution, immunohistochemistry revealed beginning immune globulin production. The child died at the age of 5 months due to respiratory failure.