Predictors of mortality in patients undergoing percutaneous aortic valve implantation.

AIM: Transcatheter aortic valve implantation (TAVI) became an attractive alternative to surgery for patients with severe aortic stenosis and high operative risk. The first multicenter randomized trial, conducted in such high risk cohort, showed 20% reduction in mortality in the group treated with TAVI compared to those treated with medical therapy (30.7% vs. 50.7% P=0.001) and a non-inferiority of TAVI compared to traditional valve surgical replacement for all-cause mortality at 1 year with, similar improvement of symptoms and physical performance. However, mortality rate of TAVI remains high (20-30% at one year). The purpose of this prospective single center study was to identify predictors of mortality and adverse events in patients undergoing TAVI in order to be able to select the ones who benefit most from the procedure. METHODS: Between June 2009 and June of 2011, 118 patients with severe aortic stenosis treated with TAVI at IRCCS Humanitas Clinical Institute were included in a prospective registry. Pre procedural clinical and ecocardiographic evaluations, surgical risk estimation, and procedural complications, defined by VASC criteria, were recorded. Clinical and echocardiographic evaluations were performed at 1, 6 and 12 months after the implants. To investigate the predictors of mortality, clinical and anatomical characteristics of alive patients were compared with those of death ones at one month and one year follow-up. RESULTS: The procedural success occurred in 92.4% of procedures; vascular complications (33%), bleeding complications (22%), postimplant paravalvolar grade ≥2 AR (20.4%) a new permanent pacemaker implant (19.7%), were the most common complications. Survival for the whole cohort at 30 days was 6.8%, survival at one year was 82.2%. In the logistic regression test, one month mortality was significantly adversely affected by the renal functional status (odd ratio 0.9356), by a previous history of coronary artery bypass grafting (odd ratio 39) and by the mean aortic annular diameter (odd ratio 0.512) (P=0.0005). One year mortality was influenced by high EuroSCORE (odd ratio 1.0399) and the presence of hemodynamically significant prosthetic regurgitation (odd ratio 3.8438). CONCLUSION: TAVI procedure, in high risk patients with critical aortic stenosis, can be accomplished with low procedural mortality. The worst outcome affects particularly patients with renal insufficiency and previous coronary bypass. However, the long-term mortality remains high due to the poor baseline conditions, mainly related to co-morbidity and to the presence of residual post-procedural aortic insufficiency.

Extracorporeal photopheresis for the prevention of acute GVHD in patients undergoing standard myeloablative conditioning and allogeneic hematopoietic stem cell transplantation.

GVHD is partly mediated by host APCs that activate donor T cells. Extracorporeal photopheresis (ECP) can modulate APC function and benefit some patients with GVHD. We report the results of a study using ECP administered before a standard myeloablative preparative regimen intended to prevent GVHD. Grades II-IV acute GVHD developed in 9 (30%) of 30 recipients of HLA-matched related transplants and 13 (41%) of 32 recipients of HLA-matched unrelated or HLA-mismatched related donor transplants. Actuarial estimates of overall survival (OS) at day 100 and 1-year post transplant were 89% (95% CI, 78-94%) and 77% (95% CI, 64-86%), respectively. There were no unexpected adverse effects of ECP. Historical controls receiving similar conditioning and GVHD prophylaxis regimens but no ECP were identified from the database of the Center for International Blood and Marrow Transplant Research and multivariate analysis indicated a lower risk of grades II-IV acute GVHD in patients receiving ECP (P=0.04). Adjusted OS at 1 year was 83% in the ECP study group and 67% in the historical control group (relative risk 0.44; 95% CI, 0.24-0.80) (P=0.007). These preliminary data may indicate a potential survival advantage with ECP for transplant recipients undergoing standard myeloablative hematopoietic cell transplantation.

Prophylaxis with weekly versus daily fluconazole for fungal infections in patients with AIDS.

We compared the efficacy of a 400-mg once-weekly dosage versus a 200-mg daily dosage of fluconazole for the prevention of deep fungal infections in a multicenter, randomized, double-blind trial of 636 human immunodeficiency virus-infected patients to determine if a less intensive fluconazole regimen could prevent these serious but relatively infrequent complications of AIDS. In the intent-to-treat analysis, a deep fungal infection developed in 17 subjects (5.5%) randomly assigned to daily fluconazole treatment and in 24 (7.7%) given weekly fluconazole during 74 weeks of follow-up (risk difference, 2.2%; 95% confidence interval [CI], -1.7% to 6.1%). Thrush occurred twice as frequently in the weekly versus daily fluconazole recipients (hazard ratio, 0.59; 95% CI, 0.40-0.89), and in a subset of patients evaluated, fluconazole resistance was infrequent. Fluconazole administered once weekly is effective in reducing deep fungal infections in patients with AIDS, but this dosage is less effective than the 200-mg-daily dosage in preventing thrush.

Filgrastim prevents severe neutropenia and reduces infective morbidity in patients with advanced HIV infection: results of a randomized, multicenter, controlled trial. G-CSF 930101 Study Group.

OBJECTIVE: To assess the effect of filgrastim treatment on the incidence of severe neutropenia in patients with advanced HIV infection, and the effect of initial filgrastim treatment on prevention of infectious morbidity. DESIGN: Randomized, controlled, open-label, multicenter study. SETTING: Outpatient centers and physician offices. PATIENTS: Men and women aged > 13 years, who were HIV antibody-positive, and had a CD4 cell count < 200 x 10(6)/l, absolute neutrophil count (ANC) 0.75-1.0 x 10(9)/l, and platelet count > or = 50 x 10(9)/l within 7 days of randomization were eligible. Two hundred and fifty-eight patients entered and 201 completed the study. INTERVENTION: Daily filgrastim (starting at 1 microg/kg daily, adjusted up to 10 microg/kg daily) or intermittent filgrastim (starting at 300 microg daily one to three times per week to a maximum of 600 microg daily 7 days weekly) was administered to maintain an ANC between 2 and 10 x 10(9)/l. Patients in the control group received filgrastim if severe neutropenia developed. MAIN OUTCOME MEASURES: Incidence of severe neutropenia (ANC < 0.5 x 10(9)/l) or death, incidence of bacterial and fungal infections, duration of hospitalization and intravenous antibacterial use, and safety. RESULTS: The primary endpoint of severe neutropenia or death was less frequent in patients who received daily (12.8%) or intermittent (8.2%) filgrastim compared with control patients (34.1%; P<0.002 and P<0.0001 for comparison with daily and intermittent groups, respectively). Filgrastim-treated patients developed 31% fewer bacterial infections and 54% fewer severe bacterial infections than control patients, required 26% less hospital days including 45% fewer hospital days for bacterial infections, and needed 28% fewer days of intravenous antibacterials. Filgrastim was not associated with an increase in HIV-1 plasma RNA level in a subset of patients in whom this was measured or any new or unexpected adverse events. CONCLUSION: Filgrastim was safe and effective in preventing severe neutropenia in patients with advanced HIV infection, and may reduce the incidence and duration of bacterial infections, incidence of severe bacterial infections, duration of hospital days for infections, and days of intravenous antibacterial agents.

Wasting syndrome in AIDS: pathophysiologic mechanisms and therapeutic approaches.

Wasting syndrome is a common complication of HIV infection and is marked by progressive weight loss and weakness, often associated with fever and diarrhea. The pathophysiologic mechanisms responsible for this syndrome are not well defined, but it is clear that this is a multifactorial process in which the relative contribution of individual etiologic factors vary among patients. Considerations include inadequate diet, malabsorptive phenomena, metabolic derangements, and cytokine activity. The onset of opportunistic infections is often accompanied by a hypermetabolic state characterized by progressive weight loss. Potential cytokines that may promote weight loss in AIDS patients include tumor necrosis factor, interleukin-1, interleukin-6, and alpha-interferon. At present there is no effective treatment. Multiple therapeutic methods, including enteral and parenteral alimentation, appetite stimulants, recombinant growth hormone, and cytokine modulators, are currently being explored.

Cerebral schistosomiasis caused by Schistosoma haematobium: case report.

The CNS is an unusual site of ectopic infection in schistosomiasis. Cerebral lesions are caused primarily by Schistosoma japonicum, and spinal cord lesions are due primarily to Schistosoma mansoni and Schistosoma haematobium. S. haematobium is an unusual cause of cerebral mass lesions although schistosomal eggs can be frequently found in the brains of individuals in countries where S. haematobium is endemic. We describe a patient with a space-occupying cerebral lesion and schistosomal granulomas on pathological examination. S. haematobium was identified in urine and serologically. The cerebral lesion responded to therapy with praziquantel and corticosteroids. It has been postulated that granulomatous lesions develop following egg laying by errant worms migrating in the vicinity of the cerebral circulation or in response to eggs deposited from more distant sites by embolization. A species-specific serological diagnosis can be made by FAST (Falcon assay screening test)-ELISA with western blot confirmation.

Benign metastasizing leiomyoma. A case report and review of the literature.

This is a case report of an asymptomatic, 65-year-old white female who was evaluated for multiple pulmonary nodules. This patient's presentation, clinical course and pathologic specimens are consistent with benign metastasizing leiomyoma. A review of this rare disorder is included in this report with emphasis on past cases, clinical overview and treatment.

Mycobacterium avium infection and AIDS: a therapeutic dilemma in rapid evolution.

Note from Dr. Merle A. Sande--The role of Mycobacterium avium as a pathogen in the human immunodeficiency virus-infected population has been confusing and controversial to clinicians who care for AIDS patients. The organism is commonly isolated from respiratory secretions of patients with other infections and often seems part of the resident flora; even when isolated from the bone marrow or bloodstream, its impact on the course of AIDS and contribution to systemic diseases are unknown. However, an increasing subset of patients without other documented opportunistic infections or malignancies has symptoms that respond to therapy directed against M. avium. Studies are in progress to evaluate chemotherapeutic agents. Accordingly, the subject is here reviewed and guidelines offered to infectious disease clinicians by one with a long-standing interest in mycobacterial disease who has made numerous contributions to the field.

Clinical, virologic, and immunologic effects of combination therapy with ribavirin and isoprinosine in HIV-infected homosexual men.

We evaluated the clinical, immunologic, and virologic effects of oral treatment with ribavirin and isoprinosine for up to 3 months in asymptomatic, HIV-culture-positive homosexual men. Fifteen consecutive men received isoprinosine 4 g/day (1 g q.i.d.), and 800 (9 men) or 1,200 mg/day (6 men) of ribavirin. Five men in each ribavirin dosage group completed at least 2 months of treatment. No unexpected toxicities were observed. Eight minor HIV-related events occurred in six men while on study. All men remained HIV-positive, and time to positive culture decreased by at least 4 days in three men from each treatment group. Serum p24 levels did not change in two men who were p24 antigenemic and received 800 mg/day of ribavirin. Treatment was associated with a generalized lymphopenia affecting all lymphocyte subsets including CD4, which was partially reversible 1 month after stopping treatment. Most of the men remained anergic on DTHS skin testing. No improvements were noted in in vitro lymphoproliferative responses to antigens or in NK cell activity (which decreased significantly in the 1,200 mg/day ribavirin group). Although well tolerated at the doses employed, the combination of ribavirin and isoprinosine produced an unexpected generalized lymphopenia and did not exhibit HIV-suppressive or immunorestorative effects.

Characterization of a thiol proteinase in Giardia lamblia.

Sonicated preparations of Giardia lamblia hydrolyze a variety of protein substrates including human immunoglobulin. Activity is increased by thiol-activating agents and inhibited by thiol proteinase inhibitors. About 55% of activity remains in the soluble fraction after high-speed centrifugation, and pretreatment with a nonionic detergent results in increased soluble activity. This suggests that the enzyme is membrane bound or associated with subcellular particles. Activity elutes as a major peak at 38,000 molecular weight by calibrated sieve chromatography. The favored sites of enzymatic cleavage of IgA1 are between the CH2 and CH3 domain and near the hinge region of the heavy chain. Similar cleavage patterns were identified using sonicated preparations of Entamoeba histolytica and Trichomonas vaginalis.

Effect of lithium carbonate in HIV-infected patients with immune dysfunction.

Ten homosexual men received oral lithium carbonate at doses that maintained their serum lithium concentrations between 0.5 and 1.5 mEq/L. Prior to treatment all patients had HIV isolated from PHA-activated peripheral blood lymphocytes (PBLs) using a quantitative antigen-capture enzyme-linked immunosorbent assay (ELISA) assay for detection, and had an absolute number of CD4 (helper) lymphocytes of less than 300/mm3. Eight of 10 patients developed symptoms of drug toxicity requiring discontinuation of the drug in 7 patients. Two patients completed only 4-5 weeks of lithium therapy, and 5 patients received 7-8 weeks. All patients remained culture positive for HIV during the trial, and viral titers as measured by the antigen capture assay were unchanged or increased. There were no significant changes in the absolute number of CD4 lymphocytes, CD4/CD8 ratio, or phytohemagglutinin (PHA) or tetanus toxoid induced proliferative responses. There was a significant decrease in mixed lymphocyte reaction (MLR). Lithium carbonate demonstrated no immunorestorative or antiviral activity when given in therapeutic doses. Drug toxicity limited therapy in the majority of patients.

Aeromonas hydrophila-associated colitis in a male homosexual.

A 37-year-old homosexual man was evaluated for a one-week history of hematochezia. Results of a physical examination were remarkable only for grossly bloody stool. Sigmoidoscopy to 30 cm showed a friable mucosa compatible with an acute colitis, and a rectal biopsy specimen demonstrated an increased plasma cell infiltrate. Stool cultures subsequently yielded Aeromonas hydrophila; serum human T-cell lymphotropic virus type III antibody titer was positive. The patient responded to a course of treatment with sulfamethoxazole and trimethoprim with resolution of his symptoms and restoration of the bowel to a normal sigmoidoscopic appearance. Aeromonas hydrophila infection should be considered in the differential diagnosis of acute proctocolitis, particularly in patients with underlying immunodeficiency states.

In vitro effects of thymosin and lithium on lymphoproliferative responses of normal donors and HIV seropositive male homosexuals with AIDS-related complex.

The in vitro effects of thymosin fraction 5 (TF5) and lithium chloride (LiCl) on the ability of peripheral blood mononuclear cells (PBMC) obtained from 37 normal male donors and 33 male patients with AIDS-related complex (ARC) to respond to alloantigenic stimulation (mixed leukocyte reaction, MLR) and to produce interleukin 2 (IL-2) in response to mitogens were studied. TF5 significantly increased MLR responses in normal donors (P less than 0.01) and in a group of 33 ARC patients with depressed cellular immunity (P less than 0.05). Similar effects were observed when LiCl was added to the MLR assays in both the normal and the ARC patient groups. Furthermore, TF5 and LiCl exhibited additive immunoenhancing properties. In 10 normal donors TF5 enhanced phytohemaggutinin (PHA)-induced IL-2 production as well as IL-2 production in response to pokeweed mitogen (PWM) (P less than 0.02). TF5-mediated enhancement of IL-2 production by PBMC obtained from ARC patients was observed in response to both mitogens, i.e., PHA and PWM. Additionally, LiCl increased PHA-induced IL-2 production in both normal subjects and ARC patients. LiCl and TF5 together had an additive effect in the enhancement of IL-2 production in both groups of subjects. Our data extend previous observations regarding the immunoregulatory activities of TF5 and LiCl and provide evidence that PBMC obtained from ARC patients have the potential to respond in vitro to these agents. The significance of these findings is discussed.

Clinical, immunological, and virological effects of ampligen, a mismatched double-stranded RNA, in patients with AIDS or AIDS-related complex.

10 patients with the acquired immunodeficiency syndrome (AIDS), AIDS-related complex (ARC), or lymphadenopathy syndrome (LAS) were given 200-250 mg ampligen, a mismatched double-stranded (ds) RNA with in-vitro antiviral activity against human immunodeficiency virus (HIV), twice a week for up to 18 weeks, without side-effects or toxicity. In all 9 patients who were positive for HIV RNA in peripheral blood mononuclear cells before therapy, levels became undetectable between days 10 and 40 of the start of therapy. 6 of the 7 patients with ARC or LAS also showed a progressive reduction in HIV load as measured by co-culture assays. All 10 patients had augmentation of delayed-type hypersensitivity skin reactions. Other changes noted during ampligen therapy included an increase in or maintenance of numbers of helper-inducer T lymphocytes, improvements in HIV-related symptoms, rises in titre of neutralising antibodies against HIV, and restoration of proper functioning of the natural lymphocyte antiviral dsRNA-dependent (2'-5'-oligoadenylate/RNA-ase L) pathway. Thus, in the short term, ampligen seems to have the dual ability to restore immunological function and to control HIV replication.

Phase I/II trial of thymosin fraction 5 and thymosin alpha one in HTLV-III seropositive subjects.

Forty-two male homosexuals and/or hemophiliacs with depressed helper/suppressor T-cell ratios were treated with one of three different doses of thymosin fraction 5 (TF5, 30, 60, and 120 mg), or a single dose of thymosin Alpha One (TA1, 600 micrograms), by daily subcutaneous (SQ) administration for 10 weeks, followed twice weekly for 4 weeks. No major toxicity was noted for any of the preparations tested, although three subjects treated with TF5 had to discontinue therapy because of severe local skin reactions. Of the doses and preparations tested, only 60 mg TF5 was capable of significantly improving (p less than 0.02) mean T-cell lymphoproliferative responses to alloantigens (MLR) for six HTLV-III seropositive subjects who were abnormal prior to therapy. Peripheral blood lymphocytes from subjects treated with 60 mg TF5 also exhibited a transient restoration of mean mitogen-induced interleukin-2 (IL-2) production to normal. No effects were observed with any of the four treatment regimens on absolute helper T-cell numbers, NK activity, antibody titers to HTLV-III, or in the expression of a variety of surrogate markers for acquired immunodeficiency syndrome (AIDS). Four of the six seropositive subjects treated with 60 mg TF5 exhibited a return to depressed baseline MLR, after switching to twice weekly injections. With a median follow-up time of 20 months, six cases of AIDS developed. However, none of the five subjects whose MLR improved following treatment progressed to AIDS. We recommend daily subcutaneous (SQ) administration of 60 mg (40 mg/m2) TF5 for use in combined modality trials, along with drugs capable of suppressing replication of HTLV-III.

Treatment of HTLV-III/LAV-infected patients with D-penicillamine.

13 asymptomatic, HTLV-III/LAV-infected male homosexuals with generalized lymphadenopathy were treated with oral D-penicillamine. All patients had depressed T4/T8 ratios and 12 had impaired T-cell function. An escalating dose schedule was employed over 2-6 weeks with doses from 0.5 to 2 g/day. Generalized skin rashes developed in 4 patients which required discontinuation of therapy in one patient. Two patients developed mild transient elevations of hepatocellular enzymes. Reversible decreases in lymph node size, absolute lymphocyte counts, and T-cell lymphoproliferative responses were observed in the majority of patients without change in baseline T4/T8 ratios. All 10 patients treated for at least 2 weeks exhibited evidence for suppression of HTLV-III/LAV replication; complete inhibition of virus expression was seen in 60% of patients treated for 6 weeks. Three of the patients treated for 6 weeks remained culture negative for at least 6 weeks after stopping the drug. D-Penicillamine appears to be an effective drug for suppressing HTLV-III/LAV expression in vivo. Its potential role in the treatment of patients with the acquired immune deficiency syndrome (AIDS) and AIDS-related complex (ARC) will require further evaluation.