Discontinuation of empirical antibiotic therapy in neutropenic acute myeloid leukaemia patients with fever of unknown origin: is it ethical?

Based on recommendations of the ECIL-4, we prospectively evaluated discontinuation of empirical antibiotic therapy in high-risk neutropenic acute myeloid leukaemia patients with fever of unknown origin. Seven patients (median neutropenia duration 30 days) were included. Four of them remained afebrile but quickly recovered from neutropenia. The other three had rapid recurrent fever. Two of these three patients had bacteraemia with susceptible strains and one of them was transferred to the ICU for septic shock. Median duration of sparing of antibiotics for the seven patients was 3 days (2–4). Because of these limited results the study was stopped.     

Why,when and how should immunosuppressive therapy considered in patients with immunoglobulin A nephropathy?

IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. Lifelong mesangial deposition of IgA1 complexes subsist inflammation and nephron loss, but the complex pathogenesis in detail remains unclear. In regard to the heterogeneous course, classical immunosuppressive and specific therapeutic regimens adapted to the loss of renal function will here be discussed in addition to the essential common renal supportive therapy. Renal supportive therapy alleviates secondary, surrogate effects or sequelae on renal function and proteinuria of high intraglomerular pressure and subsequent nephrosclerosis by inhibition of the renin angiotensin system (RAASB). In patients with physiological (ΔGFR < 1·5 ml/min/year) or mild (ΔGFR 1·5–5 ml/min/year) decrease of renal function and proteinuric forms (> 1 g/day after RAASB), corticosteroids have shown a reduction of proteinuria and might protect further loss of renal function. In patients with progressive loss of renal function (ΔGFR > 3 ml/min within 3 months) or a rapidly progressive course with or without crescents in renal biopsy, cyclophosphamide with high‐dose corticosteroids as induction therapy and azathioprine maintenance has proved effective in one randomized controlled study of a homogeneous cohort in loss of renal function (ΔGFR). Mycophenolic acid provided further maintenance in non‐randomized trials. Differentiated, precise, larger, randomized, placebo‐controlled studies focused on the loss of renal function in the heterogeneous forms of IgAN are still lacking. Prospectively, fewer toxic agents will be necessary in the treatment of IgAN.     

Interferon-α therapy in patients with Kaposi's Sarcoma and the acquired immunodeficiency syndrome

High dose IFN-α is an effective treatment for a subset of patients with Kaposi's Sarcoma, that is, those who lack systemic symptoms (e.g. fever, weight loss), and co-existing HIV-associated conditions (e.g. opportunistic infections), and whose cell-mediated immunity system is only mildly or moderately impaired. There is little evidence that the addition of chemotherapeutic agents to IFN-α improves treatment outcome. Response rates in excess of 40% have been reported with the addition of AZT to IFN-α, and may prove active in patients with more severely impaired T-cell immunity. There is evidence that in responding patients, IFN-α also suppresses HIV replication, and in vitro studies indicate synergistic suppression of HIV by the IFN-α-AZT combination; evidence for in vitro synergy is being sought.     

Are there reliable changes in memory and executive functions after cognitive behavioural therapy in patients with obsessive-compulsive disorder?

Introduction. Patients with obsessive-compulsive disorder (OCD) have impaired memory and executive functions, but it is unclear whether these functions improve after cognitive behavioural therapy (CBT) of OCD symptoms. The primary aim of this study was to investigate whether memory and executive functions change after CBT in patients with OCD.

Methods. We assessed 39 patients with OCD before and after CBT with neuropsychological tests of memory and executive functions. To correct for practice effects, 39 healthy controls (HCs) were assessed at two parallel time intervals with the neuropsychological tests.

Results. There were no changes in memory and executive functions after CBT in patients with OCD when results were corrected for practice effects. Patients performed worse on a test of visuospatial memory and organisational skills (Rey complex figure test [RCFT]) compared to HCs both before and after CBT (ps = .002–.036).

Conclusions. The finding of persistent poor RCFT performances indicates that patients with OCD have impaired visuospatial memory and organisational skills that may be trait-related rather than state-dependent. These impairments may need to be considered in treatment. Our findings underline the importance of correcting for practice effects when investigating changes in cognitive functions.     

Immune regulation and B-cell depletion therapy in patients with primary Sjögren's syndrome

Primary Sj?gren's syndrome (pSS) is an autoimmune exocrinopathy characterized by chronic inflammation and destruction of the salivary and lacrimal glands. B- and T- lymphocyte infiltrations in the salivary glands with development of germinal center-like structures are characteristic for pSS. Overexpression of soluble factors, such as interferon α (IFNα) and B-cell activating factor (BAFF), are supposed to be important factors in the initiation and continuation of this disorder. The efficacy and success of B-cell depleting therapy in reducing disease activity in pSS patients for about six to nine months supports the notion that B-cells are major key players in disease manifestation of pSS. In addition to B-cells, also Th-cells (mainly Th17) seem to be involved in the pathogenetic process. In this review, we will discuss recent research findings regarding the cytokines IFNα and BAFF as wells as the role of B- and T-cells in pSS. Emphasis will be put on the impact of B-cell depletion therapy as well as on the presumed impact of therapies aimed for targeting BAFF, either as a sole modality or as a combined treatment with B-cell depletion.     

Anti-viral triple therapy with telaprevir in haemodialysed HCV patients: Is it feasible?

IntroductionChronic hepatitis C virus (HCV) infection is the most common chronic liver disease in patients with end stage renal disease (ESRD) and is well known as a frequent cause of mortality and graft loss among haemodialysed and kidney transplant patients. Up to now, there are no data on antiviral efficacy and tolerability of available protease inhibitors (telaprevir and boceprevir) in HCV infected haemodialysed patients.MethodsWe report 4 cases of HCV infected haemodialysed patients, who have not responded to a prior course of pegylated interferon (Peg-IFN) and ribavirin (RBV) and who were listed for kidney transplantation (KTx). These 4 patients received a second-line antiviral treatment with Peg-IFN, RBV and telaprevir.ResultsAfter 12 weeks of triple therapy, tolerability was acceptable and HCV-RNA became undetectable in 3/4 patients. Mild side-effects included anaemia leading to increasing the doses of erythropoietin (EPO). Dose of RBV ranged from 200 mg three times a week to 200 mg/day.ConclusionTriple therapy with a first generation protease inhibitor could be the new standard for the treatment of HCV patients with ESRD. This needs to be confirmed by larger series.     

Estrogen therapy for hepatectomy patients with poor liver function?

Estrogen is well known to promote liver regeneration after partial hepatectomy. Administration of estradiol prior to partial hepatectomy also induces increased activity of DNA synthesis. Endogenous aromatase plays a key role in the conversion of testosterone to estradiol. The aromatase activity was induced by IL-6, which is a key factor for liver regeneration. It has been reported that IL-6 interacts with gp80/130 receptor and regulates the STAT1/3 pathway to induce DNA synthesis in hepatocyte. The IL-6 induced aromatase activity results in increased serum estradiol level. This corresponded well with observation that estradiol was elevated after partial hepatectomy. Therefore, it is very likely that estradiol and IL-6 synergize in stimulation of hepatocyte proliferation during liver regeneration. We propose that a short-term estradiol treatment may be beneficial for patients with poor liver function after hepatectomy.     

Cancer vaccines: should we be targeting patients with less aggressive disease?

There is enthusiasm for using vaccines to stimulate the immune system to treat cancer. In this article, the authors review the evolution of vaccines evaluated in clinical trials, starting with Phase III trials in metastatic disease and progressing to trials in the adjuvant setting. Data from these trials suggest that cancer vaccines may be more effective in patients with lower volume disease, and data from the E75 peptide vaccine trials suggest that vaccines may be most effective in less aggressive disease.     

Bone mass preservation with high-dose cholecalciferol and dietary calcium in HIV patients following antiretroviral therapy. Is it possible?

Objective: To evaluate whether treatment with 100,000?IU/month (equivalent to 3200?IU/day) of cholecalciferol and 1?g/day of dietary calcium supplementation in HIV patients following different cART regimens yields normal levels of vitamin D3 and PTH as well as whether changes in bone mineral density are clinically significant.

Methods: Consecutive HIV patients following different cART regimens received 100,000?IU/month (equivalent to 3200?IU/day) of cholecalciferol and 1?g/day of dietary calcium supplementation. The participants underwent BMD assessment via dual energy X-ray absorptiometry of the spine and hip at baseline (T0) and after 24 months (T1). Levels of 25(OH) vitamin D3 and parathyroid hormone (PTH) were assessed at T0 and T1. Quantitative variables were assessed with a paired t-test, independent t-test or analysis of variance, as appropriate. A chi-squared analysis was used to assess the association between qualitative variables. A p-value <0.05 was considered significant. Patients were divided into three groups depending on the cART regimen.

Results: A total of 79 patients were included (40 males, 51% and 39 females, 49%), with a mean age of 46.6 (SD ±11.2) years, a baseline CD4 count of 649 cells/µl and a mean 25 hydroxycholecalciferol (25(OH) D3) value of 25?+?10?ng/ml. After 24 months, the 25(OH) D3 increased to 40?+?11?ng/ml. The initial BMDs at T0 were estimated as 0.919 (±0.27) and 0.867 (±0.14) g/cm² at the spine and hip, respectively. After 24 months, the BMD was 0.933 (±0.15) g/cm² at the spine and 0.857 (±0.14) g/cm² at the hip. Based on a BMD change exceeding 3%, a worsening was observed in 23% of patients at the spine and 27% at the hip, whereas stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip.

Subgrouping patients based on antiretroviral therapy indicated that, at T1, there was a statistically significant increase in vitamin D3 concentration in all patients, while PTH concentration was not significantly reduced in patients taking tenofovir or efavirenz. BMD stability or improvement was demonstrated in 77% of patients at the spine and 73% at the hip after 24 months.

The multivariate analysis confirms a decrease in vitamin D3 and an increase in PTH levels in smokers, as well higher vitamin D3 concentrations in males and lower spine BMDs in menopausal females.

Conclusion: The proposed protocol of cholecalciferol and dietary calcium supplementation is safe and valid for correcting vitamin D abnormalities in almost all patients as well as reducing PTH levels in a high percentage of patients; however, it is not sufficient for normalization, particularly in patients exposed to tenofovir or efavirenz. At the spine, no significant BMD change was found in any of the therapy groups. At the hip, our data confirm a modest negative effect on bone mass caused by tenofovir and efavirenz.     

COVID-19 convalescent plasma as long-term therapy in immunodeficient patients?

ObjectivesThe patients with hematological malignancies are a vulnerable group to COVID-19, due to the immunodeficiency resulting from the underlying disease and oncological treatment that significantly impair cellular and humoral immunity. Here we report on a beneficial impact of a passive immunotherapy with convalescent plasma to treat a prolonged, active COVID-19 infection in a patient with a history of nasopharyngeal diffuse large B-cell lymphoma treated with the therapy inducing substantial impairment of particularly humoral arm of immune system. The specific aim was to quantify SARS-CoV2 neutralizing antibodies in a patient plasma during the course of therapy.Materials and methodsBesides the standard of care treatment and monitoring, neutralizing antibody titers in patient's serum samples, calibrated according to the First WHO International Standard for anti-SARS-CoV-2 immunoglobulin (human), were quantified in a time-dependent manner. During the immunotherapy period peripheral blood flow cytometry immunophenotyping was conducted to characterize lymphocyte subpopulations.ResultsThe waves of clinical improvements and worsening coincided with transfused neutralizing antibodies rises and drops in the patient's systemic circulation, proving their contribution in controlling the disease progress. Besides the patient's lack of own humoral immune system, immunophenotyping analysis revealed also the reduced level of helper T-lymphocytes and immune exhaustion of monocytes.ConclusionTherapeutic approach based on convalescent plasma transfusion transformed a prolonged, active COVID-19 infection into a manageable chronic disease.