Impact of diabetes on COVID-19-related in-hospital mortality: a retrospective study from Northern Italy.

PURPOSE: The purpose of this study was to evaluate the impact of pre-existing diabetes on in-hospital mortality in patients admitted for Coronavirus Disease 2019 (COVID-19). METHODS: This is a single center, retrospective study conducted at Policlinico di Monza hospital, located in the Lombardy region, Northern Italy. We reviewed medical records of 373 consecutive adult patients who were hospitalized with COVID-19 between February 22 and May 15, 2020. Data were collected on diabetes status, comorbid conditions and laboratory findings. Multivariable logistic regression was performed to evaluate the effect of diabetes on in-hospital mortality after adjustment for potential confounding variables. RESULTS: Mean age of the patients was 72 ± 14 years (range 17-98), 244 (65.4%) were male and 69 (18.5%) had diabetes. The most common comorbid conditions were hypertension (237 [64.8%]), cardiovascular disease (140 [37.7%]) and malignant neoplasms (50 [13.6%]). In-hospital death occurred in 142 (38.0%) patients. In the multivariable model older age (Relative Risk [RR] 1.06 [1.04-1. 09] per year), diabetes (RR 1.56 [1.05-2.02]), chronic obstructive pulmonary disease (RR 1.82 [1.13-2.35]), higher values of lactic dehydrogenase and C-reactive protein were independently associated with in-hospital mortality. CONCLUSION: In this retrospective single-center study, diabetes was independently associated with a higher in-hospital mortality. More intensive surveillance of patients with this condition is to be warranted.

Incidence of neoplastic disease following lung transplantation: a 17-year single-center experience.

OBJECTIVE: Chronic immunosuppressive therapy following solid organ transplantation has been correlated with an increased risk of posttransplantation neoplastic disease (PTND). In this study we evaluated PTND incidence and outcome at our institution over a 17-year period among patients receiving lung transplantation. MATERIALS AND METHODS: Between February 1992 and December 2008, we performed 290 lung transplantations in 280 patients, including 139 single (48% with 5 retransplantations), and 151 double lung transplantations (52% with 5 retransplantations). Among the 280 patients, 2 had undergone previous double lung transplantation in other hospitals. Follow-up of transplant recipients was performed up to December 2009. RESULTS: Forty-two patients died in the hospital, producing a cumulative early (30-day) mortality rate of 15%. Among the 238 patients discharged from the hospital who entered our follow-up program, 36 (15%) experienced PTND. The mean time between transplantation and diagnosis was 47 ± 42 months, and patients' mean age at time of diagnosis was 55 ± 14 years. Overall freedom from PTND was 97%, 84%, and 73% at 1, 5, and 10 years, respectively. PTND was considered to be the direct cause of death in 11 patients (30%). Overall survival of patients with PTND at five years (45%) did not differ from the remainder of the transplanted population (46%). However, PTND became a relevant cause of death in the long-term (>5 years) follow-up. CONCLUSION: Our experience confirms that PTND was frequently diagnosed following lung transplantation. Even if PTND did not seem to significantly affect the survival of patients undergoing lung transplantation, it may become a significant cause of death among those surviving beyond 5 years.

Neoplastic disease after heart transplantation: single center experience.

OBJECTIVES: Mandatory use of prolonged immunosuppression in organ transplantation is complicated by an increased incidence of cancer. The current study represents a retrospective analysis of the incidence of neoplasms in our heart transplantation program. METHODS: Four-hundred and seventy-four patients (403 male and 71 female; mean age, 48.6+/-12.1 years), with at least 30 days of follow-up, were enrolled in this study. Patients received triple immunosuppression with cyclosporin A, azathioprine and steroids. Moreover, as a prophylactic anti-lymphocyte therapy, 388 patients (82%) were administered RATG, 67 patients (14%) received ALG and 19 patients (4%) OKT3. The mean follow-up time was 71.1+/-43.0 months. RESULTS: Fifty-five patients (11.6%) developed malignant neoplasms. The cancer frequencies were: solid tumors, 55%; non-Hodgkin lymphomas (NHL), 20%; Kaposi's sarcomas, 11%; skin cancers, 9%; undifferentiated sarcomas and myelomas, 5%. Solid tumors mainly affected the lung (39%), bowel (16%), stomach (6.5%), liver (6.5%), pancreas (6.5%) and oral cavity (6.5%). The times to the onset of cancer from transplantation were: Kaposi's sarcoma, 12.7+/-16.8 months; skin cancers, 34.5+/-23.8 months; solid tumors, 54.3+/-38.7 months; NHL, 60.1+/-36.4 months; undifferentiated sarcomas and myelomas, 90.0+/-15.6 months. As determined by univariate and multivariate analyses, sex, number of treated rejections, previous history of tumor, average dose of cyclosporine and prednisone and cyclosporine blood levels did not increase the incidence of malignancies. Univariate analysis suggests a significant correlation between the type of prophylactic immunoglobulins and the average dose of azathioprine with the incidence of neoplasms. Both univariate and multivariate analyses demonstrated a significant correlation between patient's age at the time of transplantation and risk of cancer occurrence (risk increased by 1.074/year; P=0.0056 with multivariate Cox regression). CONCLUSIONS: Cancer is a strong limitation for long-term survival after heart transplantation. The only risk factor recognized is the patient's age at the time of transplant. Furthermore, the type of prophylactic globulins used for induction therapy and some specific immunosuppressant agent (azathioprine) may play a significant role in the development of malignancies after transplantation.

Bone marrow changes in heart transplant recipients with peripheral cytopenia.

BACKGROUND: We analyzed bone marrow changes in heart transplant recipients who develop peripheral cytopenia and underwent bone marrow biopsy (BMB). We correlated the changes in bone marrow with survival, acute and chronic rejection, infections, and malignancy. METHODS: The test group was constituted of 64 heart transplant recipients with peripheral cytopenia, in whom 82 BMBs were performed to assess marrow quantitative (cellularity, erythropoiesis, myelopoiesis, megakaryopoiesis, fibrosis, and blast cells) and qualitative (dyserythropoiesis, dysmyelopoiesis, and dysmegakaryopoiesis) changes. The control series was constituted of 217 matchable transplant recipients without cytopenia. Statistical analysis was aimed at assessing whether: (1) cytopenia is an independent risk factor for survival; (2) acute rejection, chronic rejection, infections, and malignancy predict cytopenia; (3) the degree in BMB change allows further stratification of the risk of death; and (4) characteristics and distribution of BMB lesions vary in patients with and without acute and chronic rejection, infections, and malignancy. RESULTS: In the test group, BMB specimens showed reduced cellularity in 68% of patients and dysplastic changes of a mild degree affecting all three marrow lines (erythropoietic in 88%, myelopoietic in 43%, and megakaryopoietic in 79%). At statistical analysis, peripheral cytopenia was an independent risk factor for survival, and malignancy proved to be a risk factor for cytopenia. Of BMB specimen changes, only dysmegakaryopoiesis showed a trend as a negative risk factor for survival. Acute rejection was associated with a high score of erythropoiesis, infections with a low score of dysmegakaryopoiesis, and malignancy with a high score of cellularity. CONCLUSIONS: Peripheral cytopenia is an independent risk factor for survival in heart transplant recipients. Different marrow changes correlate with transplantation-related complications, i.e., acute rejection, infection, and malignancy.

Cyclosporin-A in severe refractory anemia of myelofibrosis with myeloid metaplasia: a preliminary report.

BACKGROUND AND OBJECTIVE: Severe anemia is the outstanding problem in approximately 50 percent of patients with myelofibrosis with myeloid metaplasia (MMM). The present trial was based on the considerations that abnormal immune responses are frequently associated with MMM and that cyclosporin A (Cy-A) has proven to be effective in improving anemia in autoimmune disorders. The aim of this study was to evaluate the effect of Cy-A on anemia of MMM. DESIGN AND METHODS: We studied 10 patients with MMM and severe anemia who were not responsive to corticosteroids. Eight of them showed evidence of immune defects (direct or indirect Coombs' test, antinuclear or antimitochondrial antibodies, circulating immune complexes). Cy-A was delivered orally in two refracted doses of 5 mg per kilogram bw every day and the serum level of the drug was maintained between 100 and 200 ng/mL for at least 6 months. Clinical effects were measured by calculating a normalized transfusional need (NTN), and response was defined as about a 30% reduction in the initial transfusion requirement. Hematologic parameters, s-Epo, s-TfR, s-IL2R and lymphocyte flow cytometric analysis were also evaluated. The results were analyzed with the Student's t-test. RESULTS: Only 6 patients completed the entire 6 months of planned therapy. Three of these responded, with one no longer needing transfusions. A high CD4/CD8 ratio was predictive of response (mean value 4.7 +/- 3.5 in responders versus 0.9 +/- 0.4 in non-responders, p = 0.06). INTERPRETATION AND CONCLUSIONS: An immunomediated mechanism negatively affects erythropoiesis in MMM. Cy-A may be effective for patients with severe refractory anemia in this disease.

Membrane CD22 defines circulating myeloma-related cells as mature or later B cells.

Circulating clonally related earlier cells are present in multiple myeloma (MM) and may be involved in the dissemination of this disease, its recurrence, and chemoresistance. The nature, stage of differentiation, and size of this cell population remain uncertain. Unlike other B-cell markers, CD22 membrane expression is limited to the late differentiation stages comprised between mature B cells (CD22+) and plasma cells (PC; CD22-) and may thus be useful in delimiting the maturational state of circulating early myeloma cells. Peripheral blood clone-related cells were detected by anti-idiotypic (Id) monoclonal antibodies and found to express CD22 (92% to 95%), monotypic light and heavy chain (100%), and CD38 (45%), whereas bone marrow PC were CD22-negative. CD22 expression was also documented on functional myeloma PC precursors, defined as peripheral blood cells capable of in vitro cytokine-driven monotypic PC differentiation, because up to approximately 70% inhibition of this process was obtained in 10 myeloma patients through the use of biospecific antibodies (BsAb) that deliver the plant toxin saporin to CD22+ cells. As further evidence of CD22 on circulating abnormal cells, it was found that in the only patient analyzed for DNA content, a portion of the peripheral blood CD22+ cells killed were hyperdiploid. Collectively, these findings indicate that most peripheral blood myeloma PC precursors are mature or later B cells presenting membrane CD22. The pattern of CD22 expression suggests the existence in MM of a differentiation process analogous to the normal antigenic response, in which CD22+ B cells migrate to the bone marrow and lose CD22 with PC differentiation. In addition, the sensitivity of myeloma PC precursors to the cytotoxic effects of the anti-CD22 BsAb and the possibility of interfering with their differentiation have potential therapeutic relevance.

Factors increasing the risk of allograft vascular disease in heart transplant recipients.

Allograft vascular disease is the major cause of late cardiac graft failure. A multifactorial etiopathogenesis is supposed. Our study investigated factors associated with allograft vascular disease occurrence. After stratifying our series on the basis of potential risk factors, we calculated allograft vascular disease incidence rate in 267 grafts from 258 patients who underwent transplant between November 1985 and August 1996. Chi-square test was used for the identification of univariate risk factors to be included in a multivariate model. Multivariate analysis was based on a Poisson model. Seventy of the 267 grafts (26.2%) were diagnosed with allograft vascular disease. Heart disease other than idiopathic dilated cardiomyopathy, donor's age, number of mismatches for HLA-B = 2, presence of systo-diastolic hypertension, number of acute rejection positive endomyocardial biopsies > or = 7 and the association of human Cytomegalovirus and hepatitis C virus infections proved to be univariate risk factors, and were included in the Poisson multivariate model. The association of Cytomegalovirus and hepatitis C infections multiplied allograft vascular disease incidence rate by 3.9, systo-diastolic hypertension by 2.2, occurrence of 2 HLA-B mismatches by 2, a high number (> or = 7) of acute rejection positive-endomyocardial biopsies by 1.8, and heart disease other than idiopathic dilated cardiomyopathy by 1.8. The association of human Cytomegalovirus and hepatitis C virus infections, of HLA-B mismatches, of acute rejection-positive endomyocardial biopsies, as well as post-transplantation hypertension and native heart disease other than idiopathic dilated cardiomyopathy, proved to be positively associated with an increased risk of allograft vascular disease. Given the concordance of our data with those of numerous prior series, we are going to adopt a special surveillance angiographic protocol for patients with these factors.

Response to cyclosporin A and rhG-CSF in a case of aplastic anemia.

A 23-year-old male patient developed aplastic anemia and was treated with cyclosporin A and rhG-CSF. Bone marrow biopsy showed an improvement in cellularity with a recovery of all hematopoietic precursors after nine weeks of therapy. WBC increased after two weeks of treatment, mostly due to an increase in the absolute granulocyte cell count. Hb, RBC, Plts and reticulocytes showed an increase six weeks after the beginning of therapy. Of the serum cytokines, EPO levels progressively decreased, while sTfR increased in peripheral blood. A reverse correlation between blood neutrophil count and serum levels of G-CSF was observed, indicating an increased clearance of G-CSF. Finally, sIL-2R showed a rapid increase in the first week of treatment and prior to the increase in PMN cells. Thus, the use of cyclosporin A and rhG-CSF in our patient induced a complete recovery of hemopoiesis, and this may be explained by a synergic effect induced by the capacity of cyclosporin A to remove inhibitory factors and the stimulatory activity of rhG-CSF.

AL amyloidosis. Characterization of amyloidogenic cells by anti-idiotypic monoclonal antibodies.

BACKGROUND: AL amyloidosis is characterized by systemic tissue deposition of monoclonal Ig light chains synthesized by a bone marrow plasma cell (PC) clone whose biologic characteristics remain undetermined. EXPERIMENTAL DESIGN: Anti-idiotypic (anti-Id) monoclonal antibodies (MoAbs) were used as specific probes to identify and study amyloidogenic cells in two patients by means of immunofluorescence methods. These MoAbs recognized populations of bone marrow pre-PC, PC, and peripheral blood lymphocytes. To test whether the circulating Id+ lymphocytes were capable of PC differentiation, peripheral blood lymphocytes were incubated with the differentiation-inducing agents, interleukin-3 and interleukin-6 in liquid culture. Preincubation with the anti-Id MoAb and complement was used to inhibit formation of Id+PC in vitro. RESULTS: The anti-Id MoAb identified three types of cells in the bone marrow with cytoplasmic Ig having the same isotype as the monoclonal component: a) lymphoid cells, that were slightly larger than common peripheral blood lymphocytes (47% CD45RA+, 28% CD45R0+, 97% CD38-, 100% CD10-, 100% mu-chain-); b) lymphoplasmacytoid cells with more abundant cytoplasm and Id+ Ig (CD45RA-, CD45RO-, CD10-, 53% CD38+); 3) mature PC that were very similar to normal PC in morphology and antigenic profile (CD38+, PCA1+, CD56-). A different picture was seen when anti-Id MoAb were used to detect peripheral blood Id+ elements: analysis revealed a population of mature resting surface Ig+ B lymphocytes. Circulating Id+ lymphocytes differentiated in vitro to PC and lymphoplasmacytoid cells that were very similar to those present in the bone marrow. A significant reduction in the number of Id+ PC was obtained after incubation with the anti-Id MoAb and complement. CONCLUSIONS: This study shows that the amyloidogenic cell clone is constituted by at least the following cell populations: a fraction of bone marrow cells (lymphoid, lymphoplasmacytoid cells and PC) and a subset of peripheral blood post-switched B lymphocytes. The results suggest a relationship among these cells, indicating that circulating Id+ lymphocytes may be the possible precursors of the more differentiated bone marrow population.

Acute promyelocytic leukemia: morphological and clinical features.

BACKGROUND AND METHODS: Acute promyelocytic leukemia (APL) is not a morphologically homogeneous entity: to verify whether there is any relationship between this heterogeneity and other biological and clinical aspects, we studied 43 cases of APL with morphological, cytochemical, cytogenetic and immunological methods. RESULTS: Three morphological categories were present: a classic hypergranular type (30 cases), a microgranular type (6 cases) and a form with basophilic granules (M3b) that stained metachromatically with toluidine blue (7 cases). In all these groups there were cases with cytochemical features of both myeloid and monocytic type (alpha-naphthyl-acetate esterase positive). No immunological and cytogenetic differences were observed; the morphological variant with basophilic granules was more frequent in females; age distribution was not related to the morphological subtype; organomegaly was extremely rare in M3b. A low white blood cell count was constant in M3b, whereas no differences were observed in hemoglobin and platelet values. Severity of bleeding was worst in the group with toluidine blue metachromasia; this and the microgranular type had poor prognosis. CONCLUSIONS: Our study confirms the importance of identifying different cytologic categories in APL. In particular we focused our attention on a new variant with basophilic granules.

Pneumocystis carinii pneumonia in heart transplant recipients.

Seven cases of Pneumocystis carinii pneumonia (PCP) (two in 1988, three in 1989, one in 1990 and one in 1991) have been observed in a group of 241 heart transplant recipients transplanted in Pavia, Italy, from November 1985 through December 1991. Median time to onset of symptoms was 100 days after transplantation (range 59-333 days). Diagnosis was achieved in all patients by cytological examination of bronchoalveolar lavage (BAL) fluid and/or transbronchial biopsy. Clinical and roentgenographic features were remarkably similar in all PCP-affected heart transplant recipients. A dry, persistent hacking cough associated with dyspnoea was consistently observed. Fever ranged from 37.6 to 39.4 degrees C, median leukocyte count and median arterial oxygen saturation (SaO2) values were 7,300/mm3 (range 3,000-16,000/mm3) and 61% (range 49.3-93%), respectively. Median CD4+ count at the onset of symptoms was 211/mm3 (range 28-739/mm3). The only patient experiencing a recurrence of PCP had a CD4+ cell count of 28/mm3 at the end of treatment with trimethoprim-sulfamethoxazole (TMP-SMX). In all patients human cytomegalovirus was isolated from BAL fluids; however, treatment with TMP-SMX alone (20 mg/kg/day of TMP) was consistently followed by a complete recovery.

Immunocytochemical detection of factor XIII A--subunit in acute leukemia.

Factor XIII (FXIII) is a plasma pro-transglutaminase consisting of A and B subunits in a tetrameric structure. A cellular form of FXIII consisting exclusively of A subunits exists in platelets and monocytes: monocyte FXIII may be involved in connective tissue organization. To evaluate the expression and diagnostic significance of FXIII A subunit (FXIIIA) in acute leukemia, we performed an immunocytochemical study (PAP technique) with rabbit antiserum against FXIIIA on leukemic blasts of 48 cases. FXIIIA was detected only in myelomonocytic (M4), monocytic (M5) and megakaryocytic (M7) cases: in M4 and M5 samples the amount of blast cytoplasmic FXIIIA was closely correlated with the expression of monocyte-specific antigenic and cytochemical markers. Our data show immunocytochemical detection of FXIIIA to be useful for acute leukemia characterization.

[Endomyocardial biopsy in the heart transplant patient: the state of the art]. / La biopsia endomiocardica nel paziente cardiotrapiantato: stato dell'arte.

Data regarding 2176 endomyocardial biopsies (EMB) (Nov. '85-Dec. '89) performed in 164 transplanted hearts (4 etherotopic) from 158 patients (6 retransplants) are herein reported. This study was aimed to evaluate: 1) Incidence and characteristics of early ischemic myocardial damage. 2) The influence of different immunosurveillance protocols on incidence, degree and aggressiveness of acute rejection and the inflammatory infiltrate composition. 3) The immunophenotype of infiltrating cells in moderate acute rejection episodes. 4) HLA-DR antigen expression on myocyte sarcolemma. 5) Characterization of cells expressing immune response mediators. 6) Myocardial localization of opportunistic infections. 7) Useful information on chronic rejection. Our results demonstrate that: a) Mild rejection seldom progresses to moderate degree. b) Different immunosuppressive protocols can influence the incidence of acute rejection: in fact, in OKT3 protocol, the incidence of rejection episodes is higher than in other protocols as well as aggressiveness toward myocytes. c) Infiltrating cells maintain T lymphocyte prevalence with minor amounts of B lymphocytes and macrophages in the 3 different protocols. T cell subset characterization showed a slight prevalence of CD8 bearing cells over CD4 positive cells whereas CD57 cells were few and scattered. d) Class II Major Histocompatibility Complex (HLA-DR) expression never occurs on myocyte sarcolemma. e) TNF alpha is expressed in acute cardiac rejection by immunologically activated T lymphocytes and macrophages and the number of immunoreactive cells increases with progression of the rejection. f) Human cytomegalovirus infections can be primary or recurrent. Myocardial involvement has been observed in primary forms. Virus can affect endothelial cells (with no inflammatory reaction) or myocytes (myocarditis) and its diagnosis requires a combination of immunohistochemical and molecular biology techniques. Diagnosis of Toxoplasma gondii infection can be usually accomplished by routine histopathological study. g) Chronic rejection diagnosis is rarely based on biopsy derived information.

Functional effects of a monoclonal antibody directed against a distinct epitope on 4F2 molecular complex in human peripheral blood mononuclear cell activation.

The 4F2 antigenic complex is expressed on most human cell lines in culture, on monocytes and activated lymphocytes, but not on resting T and B lymphocytes. Monoclonal antibody (mAb) CB43 recognizes an epitope of the 4F2 heterodimer either located on the light chain or dependent on the conformation of the molecule. The binding of CB43 mAb to peripheral blood mononuclear cells (PBMC) induced a dose-dependent comitogenic effect in the presence of submitogenic concentrations of anti-CD3 mAb. Significant amounts of interleukin (IL)-1 beta but not IL-2 or interferon-gamma were released in the supernatant. Pretreatment of monocytes with CB43 mAb increased the phytohemagglutinin-induced T lymphocyte proliferation. However, CB43 mAb did not exert agonistic effects on activated T lymphocytes. Depletion of CB43+ cells from PBMC decreased the proliferation and generation of cytotoxic effector cells induced by a mannoprotein (MP) derived from Candida albicans cell wall but not by recombinant IL-2. Furthermore, depletion of CB43+ cells from PBMC preactivated with MP or rIL-2 led to a significant decrease in their cytotoxic activity. CB43 mAb did not inhibit the growth of cell lines nor the proliferation of T cells. Thus CB43 mAb identifies a distinct functional epitope on the 4F2 molecular complex and might be useful in further studying the role of this molecule in cellular activation.