Frequency Of Severe Infections Research Articles

Saliva as Alternative Specimen for Measuring Inflammatory Markers Interleukins (IL10, IL-4, and IL-1β) in Association with Disease Severity among COVID-19 Patients

Background: Saliva is a specimen that is easily collected by non-invasive means and does not require well-trained staff; it could be helpful in measuring inflammatory markers to determine COVID-19 severity. The aim of this study was to investigate saliva as an alternative specimen for measuring inflammatory markers IL-10, IL-4, and IL-1β among COVID-19 patients in relation to disease severity. Methods and Results: This cross-sectional study was conducted among COVID-19 patients in a fever clinic, isolated hotels, and hospitals providing care for positive COVID-19 patients and in public health centers for negative control patients in Jeddah, Saudi Arabia. A total of 151 subjects participated in this study, including 101 patients with COVID-19 and 50 healthy controls. Patients with COVID-19 were categorized according to the severity of their symptoms into mild (n=50) and severe cases (n=51). The salivary concentrations of IL-4, IL-10, and IL-1β were measured using sandwich MyBioSource ELISA Test Kits. The age of the study population ranged from 19 to 70 years old, with a mean age of 43.3±13.0 years. The distribution of the study population showed that more of the patients were men (65[64.4%]) than women (36[35.6%]) (P=0.004). The frequency of severe infection in men was higher than in women (35[68.6%] and 16[31.4%], respectively, P=0.008). The group of severe cases was significantly older than the group of mild cases (47.9±11.03 years and 38.64±13.82 years, respectively, P=0.0007). The volume of saliva was the smallest in severe COVID-19, compared to mild cases and controls (P=0.0000 in all cases). The salivary levels of IL-4, IL-10, and IL-1β were greater in the severe cases than in mild cases and controls (46.14±11.61 pg/mL, 12.86±1.99 pg/mL, and 27.45±11.47 pg/mL versus 19.31±5.72 pg/mL, 7.96±2.12 pg/mL, and 6.59±1.90 pg/mL, respectively; P=0.0000 in all cases). The salivary levels of IL-4 and IL-10 in mild cases were greater than in controls (19.31±5.72 pg/mL and 7.96±2.12 pg/mL versus 15.30±4.36 pg/mL and 6.02±0.89 pg/mL, respectively; P=0.0329 and P=0.000, respectively), but salivary IL-1β levels in mild cases did not differ from controls (6.59±1.90 pg/mL vs. 6.03±2.28 pg/mL, P=0.9129). Conclusion: Saliva could be used as an alternative sample in measuring IL-10, IL-4, and IL-1β with the suggestion of using IL-10 and IL-4 as markers for predicting disease severity.

Outcomes of SARS-CoV-2 infection in 126 children and adolescents with central nervous system tumors.

The Global Registry of COVID-19 in Childhood Cancer (GRCCC) seeks to describe the natural history of SARS-CoV-2 in children with cancer across the world. Here, we report the disease course and management of coronavirus disease 2019 (COVID-19) infection in the subset of children and adolescents with central nervous system (CNS) tumors who were included in the GRCCC until February 2021, the first data freeze. The GRCCC is a deidentified web-based registry of patients less than 19years of age with cancer or recipients of a hematopoietic stem cell transplant and laboratory-confirmed SARS-CoV-2 infection. Demographic data, cancer diagnosis, cancer-directed therapy, and clinical characteristics of SARS-CoV-2 infection were collected. Outcomes were collected at 30 and 60days post infection. The GRCCC included 1500 cases from 45 countries, including 126 children with CNS tumors (8.4%). Sixty percent of the cases were from middle-income countries, while no cases were reported from low-income countries. Low-grade gliomas, high-grade gliomas, and CNS embryonal tumors were the most common CNS cancer diagnoses (67%, 84/126). Follow-up at 30days was available for 107 (85%) patients. Based on the composite measure of severity, 53.3% (57/107) of reported SARS-CoV-2 infections were asymptomatic, 39.3% (42/107) were mild/moderate, and 6.5% (7/107) were severe or critical. One patient died from SARS-CoV-2 infection. There was a significant association between infection severity and absolute neutrophil count less than 500 (p=.04). Of 107 patients with follow-up available, 40 patients (37.4%) were not receiving cancer-directed therapy. Thirty-four patients (50.7%) had a modification to their treatment due to withholding of chemotherapy or delays in radiotherapy or surgery. In this cohort of patients with CNS tumors and COVID-19, the frequency of severe infection appears to be low, although severe disease and death do occur. We found that greater severity was seen in patients with severe neutropenia, although treatment modifications were not associated with infection severity or cytopenias. Additional analyses are needed to further describe this unique group of patients.

Outcomes of COVID-19 in Adult Males With Hemophilia A: A Propensity Score-Matched Analysis.

Background Hypercoagulability is a major pathologic event in COVID-19. Factor VIII plays an important role in hemostasis, and highlevels of factor VIII have been shown to be associated with an increased risk of thrombosis and severe disease. Little is known about the impact of COVID-19 on clinical outcomes in patients with hemophilia A. Methodology Retrospective data of adult male patients with COVID-19 with and without hemophilia A were retrieved from the TriNetX database (Cambridge, USA). The 1:1 propensity score-matching was performed to balance baseline characteristics. Patients were matched for age, race, body mass index, and medical comorbidities. Thirty-day outcomes were assessed. Results We identified 1,758 patients with pre-existing hemophilia A diagnosis prior to COVID-19 diagnosis and 5,191,908 comparators. After 1:1 propensity score matching, groups were balanced on demographics and comorbidities. All-cause mortality rates were similar between the two groups (HR 0.805; 95% CI 0.467-1.389). The frequency of severe infection, ICU admission, and composite thrombotic events did not differ between the groups. Patients with hemophilia A were hospitalized more frequently than those without a history of hemophilia A (19.2% vs. 14.4%; p<0.05). Additionally, gastrointestinal (GI) bleeding and composite bleeding events occurred more frequently in patients with hemophilia A (3.2% vs. 2.2%; p<0.05 and 4.0% vs. 2.8%; p<0.05, respectively). Conclusions The mortality of individuals with hemophilia A due to COVID-19 is comparable to the general population but with higher risks of hospitalization and bleeding.

Interim results of a multicenter retrospective-prospective observational post-marketing study of Extimia® BIOCAD (INN: empegfilgrastim) to evaluate safety and efficacy in patients with lymphoproliferative diseases receiving cytotoxic therapy

Aim. To assess the efficacy and safety of using the drug Extimia BIOCAD (international nonproprietary name INN: empegfilgrastim) in order to reduce the frequency and duration of neutropenia, the frequency of febrile neutropenia (FN) and infections manifested by FN in patients with lymphoproliferative diseases receiving myelosuppressive therapy.&#x0D; Materials and methods. This publication presents the interim results of a multicenter retrospective prospective observational post-marketing study of the safety and efficacy of the drug Extimia BIOCAD (INN: empegfilgrastim) in patients with lymphoproliferative diseases receiving cytotoxic therapy (LEGERITY). The interim data analysis included 40 patients with lymphoproliferative diseases (Hodgkins lymphoma, diffuse large B-cell lymphoma, multiple myeloma, primary mediastinal large B-cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia, splenic marginal zone lymphoma), who were treated in ten research centers of the Russian Federation (Moscow, St. Petersburg, regional clinics). The median age of patients was 48 (2172) years, 13/40 (32.5%) patients belonged to the older age group (60 years). Patients had functional status on the ECOG scale of 02 and received at least 2 chemotherapy injections against the background of prophylaxis with empegfilgrastim. Empegfilgrastim was administered at a dose of 7.5 mg subcutaneously once 24 hours after the end of the administration of cytotoxic chemotherapeutic agents. Primary endpoint: frequency of neutropenia 35 degrees of severity; secondary endpoints: frequency of FN; frequency of severe infections (34 stages); frequency of antibiotic prescription; relative dose intensity of therapy of the conducted chemotherapy courses; the incidence of all adverse reactions in patients who received at least one dose of the study drug empegfilgrastim; the incidence of all serious adverse reactions in patients who received at least one dose of the study drug empegfilgrastim; the incidence of CTCAE 5.0 grade 34 HP in patients who received at least one dose of the study drug empegfilgrastim; discontinuation rate of study drug empegfilgrastim due to adverse reactions.&#x0D; Results. The results of this study demonstrate that the incidence of neutropenia of 3 degree of severity after the 1st cycle of chemotherapy developed in 2/40 patients (5%) and as a result of high-dose therapy (R-DHAP). Neutropenia of any severity was reported in 5/40 patients (12.5%). Cases of FN development have not been registered. Severe infections (mucositis, enteropathy, pneumonia, etc.), as well as the use of antibacterial and antifungal drugs during 1 cycle of chemotherapy and in the inter-course period after 1 cycle of therapy were not recorded in any patient. The next course of myelosuppressive therapy was not delayed due to the development of neutropenia in any of the patients during the study. Adverse events, according to the researcher, associated with the use of empegfilgrastim, were registered in 2/40 patients (5%): moderate generalized pain syndrome (diffuse pain) of 1 severity and in one case ossalgia of 2 severity. No serious adverse reactions were reported.&#x0D; Conclusion. The results of the interim analysis of the study demonstrate the high efficacy of the first Russian original pegylated granulocyte colony-stimulating factor empegfilgrastim after a single administration of a fixed dose in the treatment of patients with aggressive and indolent lymphomas. The drug has a favorable tolerance profile in any age group of patients, especially in elderly patients. Administration of empegfilgrastim as a prophylaxis of neutropenia in patients with lymphoproliferative diseases receiving myelosuppressive therapy of varying intensity can reduce the burden on medical personnel, improve patient adherence to treatment, and contribute to the implementation of the therapeutic plan.

Risk factors for acute rejection in living-donor kidney transplant recipients in China: a subgroup analysis of a multi-center, registry study

Objective: To evaluate pre-and early post-transplantation risk factors for acute rejection(AR) in kidney recipients. Methods: This subgroup analysis of a multi-center registry study was conducted on living-donor kidney transplant recipients in China with 10 years of follow-up. This study analyzed 1 255 recipients including 921 males(73.4%) and with a mean age of (33±10)years. Data from patients were first analyzed with univariate analysis and then multivariate analysis was used for finding out the potential risk factors of AR. Results: A total of 106(8.4%) patients were suspected with AR after kidney transplantation, while 1 149 patients were considered as non-AR. Multivariable analysis demonstrated a significant influence of recipient age and cold ischemia time(CIT) on the occurrence of AR(OR: 0.956, 95% CI: 0.923-0.990; OR: 1.006, 95% CI: 1.002-1.011, respectively). The frequency of severe infection was significantly higher in the AR group than non-AR group(38.7% vs 10.8%; P<0.000 1). The occurrence of new-onset diabetes mellitus and tumors was similar in the two groups. Conclusions: Recipient age and CIT are risk factors for AR after living-donor kidney transplantation. Reducing CIT and intensive management of younger recipient could benefit kidney transplant patients.

Host contact and shedding patterns clarify variation in pathogen exposure and transmission in threatened tortoise Gopherus agassizii: implications for disease modelling and management

Most directly transmitted infections require some form of close contact between infectious and susceptible hosts to spread. Often disease models assume contacts are equal and use mean field estimates of transmission probability for all interactions with infectious hosts. Such methods may inaccurately describe transmission when interactions differ substantially in their ability to cause infection. Understanding this variation in transmission risk may be critical to properly model and manage some infectious diseases. In this study, we investigate how varying exposure and transmission may be key to understanding disease dynamics in the threatened desert tortoise Gopherus agassizii. We created heterogeneity in Mycoplasma agassizii exposure (the putative bacterial agent of a respiratory disease) by varying the duration of interactions between naturally infected and uninfected captive desert tortoises. Using qPCR, we identified new infections and compared models of transmission probability as a function of contact duration and pathogen load. We then examined the contact patterns of a wild tortoise population using proximity loggers to identify heterogeneity in contact duration. The top-ranked model predicting M.agassizii transmission included a dose term defined as the product of the number of days in proximity to an infected host and the infection level of that host. Models predicted low transmission probability for short interactions, unless the infectious host had a high load of M.agassizii: such hosts were predicted to transmit infection at higher rates with any amount of contact. We observed predominantly short-lived interactions in a free-ranging tortoise population and thus, expect transmission patterns in this population to vary considerably with the frequency and duration of high infection levels. Mean field models may misrepresent natural transmission patterns in this and other populations depending on the distribution of high-risk contact and shedding events. Rapid outbreaks in generally solitary species may result from changes to their naturally low-risk contact patterns or due to increases in the frequency of severe infections or super-shedding events - population characteristics that should be further investigated to develop effective management strategies.

PTH-096 Monocyte oxidative burst defect in alcoholic hepatitis is resistant to interferon gamma

Introduction An important cause of mortality in patients with severe alcoholic hepatitis (SAH) is infection. We and others have found that the oxidative burst response of phagocytic cells to E. coli is impaired in SAH which may contribute to susceptibility to infection. This is analogous to Chronic Granulomatous Disease, an inherited condition caused by a mutation in the enzyme NADPH oxidase which leads to predisposition to recurrent life-threatening infections. Treatment with interferon gamma (IFN-γ) reduces the frequency of severe infections in these patients. We sought to investigate the molecular mechanism underlying the monocyte oxidative burst (mOB) defect in SAH and determine whether IFN-γ can restore this defect in vitro . Method Peripheral blood mononuclear cells (PBMCs) were isolated from 6 patients with SAH and 4 healthy controls (HCs). Monocytes were isolated from PBMCs using magnetic MACS beads and negative selection. Monocytes were incubated with 50 ng/ml IFN-γ supplemented by 10% healthy serum for 24 h and the mOB to E. coli was quantified by oxidation of fluorogenic rhodamine and flow cytometry as previously described. Western blotting was used to quantify protein using monoclonal antibodies to components of the IFN-γ signalling pathway (pSTAT-1 and negative regulator SOCS-1) and glucose-6-phosphate dehydrogenase (G6PD, which generates NADPH substrate required for NAPDH oxidase function), in the monocytes of HCs and AH patients. G6PD enzyme activity was measured using a colorimetric kit. Quantitative PCR was used to determine expression of STAT-1 in monocytes stimulated for 24 h in 50 ng/ml IFN-γ. Results Surprisingly, SAH mOB defect was resistant to 24 h’ stimulation by 50 ng/mlIFN-γ. The level of unstimulated phosphorylated STAT-1 protein, a transcription factor activated by IFN-γ signalling was significantly reduced in monocytes of SAH patients compared to healthy controls (pSTAT-1: housekeeping gene 0.90 HC vs 0.14 SAH, p .05). q-PCR confirmed STAT-1 expression following stimulation with IFN-γ was significantly reduced in SAH compared to HCs (ΔCT 0.97 HC vs SAH 0.54, p .05). The level of SOCS-1 protein was significantly increased in monocytes of SAH patients compared to HCs (SOCS-1: housekeeping gene 0.98 HC vs 2.24 AH, p .05). There was no difference in G6PD enzyme activity or protein expression between groups. Conclusion Our study suggests that elevated levels of the inhibitory factor SOCS-1 may reduce phosphorylation and activation of STAT-1. Reduced pSTAT-1 may explain the resistance to IFN-γ observed and hence the burst defect in SAH. This work provides a novel insight into the impaired mOB in SAH and furthers our knowledge of the predisposition to infection observed in this patient group. Disclosure of interest None Declared.

Вакцинація груп ризику

Упродовж останніх десятиліть імунізація дозволила суттєво знизити захворюваність і смертність від вакцинокерованих інфекцій. Однак діти груп ризику не завжди адекватно вакцинуються, незважаючи на більшу частоту тяжких форм інфекцій, розвиток ускладнень. Це може бути зумовлено відсутністю рекомендацій з проведення вакцинації груп ризику або прихильності до їх виконання. Загальна мета — підвищити настороженість щодо імунізації дітей груп ризику. Конкретні цілі: вміти диференціювати специфічні групи ризику у дітей, знати особливості проведення вакцинації дітей груп ризику.

Mo1066 Mercaptopurine Therapy in IBD Patients Modulates GTPase RAC1

Background: In any immunosuppressive therapy, the question always arises whether this therapy increases the risk of infectious complications. The most serious problem in modern medicine have severe infectious complications of anticytokine therapy in patients with inflammatory bowel disease (IBD), having acquired immune deficiency. Accumulated to date show that in spite of the pronounced effect on immunnosupressivny alloreaktivnye and mitogen-provoked reactions, mesenchymal stromal cells (MSC) did not inhibit the activity of immune cells directed against infectious agents. Objective: To compare the risk of infectious complications in patients treated with anticytokine therapy with infliximab (IFX) and cell therapy using culture MSC. Methods: 60 patients with ulcerative colitis (UC) and Crohn’s disease (CD) at the age of 19 to 58 years (Me-29), who received a comprehensive anti-inflammatory therapy with culture MSCs, which were introduced under the scheme 0 1-26. 59 patients with UC and CD in age from 20 to 62 years (Me-38) received induction IFX therapy 0 2-6 and maintenance therapy after 8 weeks for 12 months. The observation time for both groups of patients was 64 weeks. Results: Frequency of severe infection (SI) among patients treated with MSCs was 1.6% (1 case of pneumonia). Frequency of severe SI among patients receiving IFX was 15.6% (6 cases). For individual forms that look as follows: pneumonia 3 cases (5.7%), throat abscess 1 case (1.9%), lung abscess 1 case (1.9%), pleural effusion a case of (1.9%). The frequency of exacerbations of chronic inflammatory disease and mild SI was 10.0% and 33.9% respectively (p < 0.05). The risk of developing tuberculosis, and activation of latent tuberculosis infection was higher in patients who received IFX, than in patients receiving cell therapy 0.03 (95%CI 0.17 0.72), (p = 0.0007, x2 13.4). The relative risk of developing opportunistic infections and infectious complications in patients with IBD receiving biological therapy MSCs compared with anticytokine therapy was 0.3 (95%CI 0.13 0.68), OR-0, 22 (95%CI 0.07 0.64), (p = 0.003, x2 8.6). Conclusions: The frequency of infectious complications, acute exacerbations of chronic inflammatory diseases, the risks of opportunistic infection and activation of latent tuberculosis infection was higher in patients who received IFX, than in patients receiving therapy of MSC.

Mesenchymal Stromal Cells Did Not Increase The Risk of Infectious Complications in Patients With Inflammatory Bowel Disease

In any immunosuppressive therapy, the question always arises - whether this therapy increases the risk of infectious complications? The most serious problem in modern medicine have severe infectious complications of anticytokine therapy in patients with inflammatory bowel disease (IBD), having acquired immune deficiency. Accumulated to date show that in spite of the pronounced effect on immunosuppression, alloreactivity and mitogen-provoked reactions, mesenchymal stromal cells (MSC) did not inhibit the activity of immune cells directed against infectious agents. Objective: To compare the risk of infectious complications in patients treated with anticytokine therapy with infliximab (IFX) and cell therapy using culture MSC. Materials and Methods. 60 patients with ulcerative colitis (UC) and Crohn’s disease (CD) at the age of 19 to 58 years (M-29), who received a comprehensive anti-inflammatory therapy with culture MSCs, which were introduced under the scheme 0-1-26. 59 patients with UC and CD in age from 20 to 62 years (M-38) received induction IFX therapy 0-2-6 and maintenance therapy after 8 weeks for 12 months. The observation time for both groups of patients was 64 weeks. Frequency of severe infection (SI) among patients treated with MSCs was 1.6% (1 case of pneumonia). Frequency of severe SI among patients receiving IFX was 15.6% (6 cases). For individual forms that look as follows: pneumonia - 3 cases (5.7%), throat abscess - 1 case (1.9%), lung abscess - 1 case (1.9%), pleural effusion - a case of (1.9%). The frequency of exacerbations of chronic inflammatory disease and mild SI was 10.0% and 33.9% respectively (P < 0.05). The risk of developing tuberculosis, and activation of latent tuberculosis infection was higher in patients who received IFX, than in patients receiving cell therapy 0.03 (95% CI 0.17-0.72), (P = 0.0007, x2-13.4). The relative risk of developing opportunistic infections and infectious complications in patients with IBD receiving biological therapy MSCs compared with anticytokine therapy was 0.3 (95% CI 0.13-0.68), OR-0.22 (95% CI 0.07-0.64), (P = 0.003, x2-8.6). The frequency of infectious complications, acute exacerbations of chronic inflammatory diseases, the risks of opportunistic infection and activation of latent tuberculosis infection was higher in patients who received IFX, than in patients receiving biological therapy MSC.

Lack of negative impact of Philadelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols

Lack of negative impact of <scp>P</scp>hiladelphia chromosome in older patients with acute lymphoblastic leukaemia in the thyrosine kinase inhibitor era: comparison of two prospective parallel protocols

Gemtuzumab Ozogamicin In Refractory Childhood Acute Myeloid Leukemia.

AbstractAbstract 1075 Introduction:Gemtuzumab ozogamicin, a CD33 linked calicheamicin, has been used in children with refractory AML since some years. In a phase I/II study, the treatment feasibility and moderate toxicity of the compound have been demonstrated (Zwaan et al. British Journal of Haematology, 2010).Here we report the treatment results of 62 children and adolescents with refractory AML after at least two intensive regimens (n=62; male n=40; female n=22) and/or allogeneic stem cell transplant (n=9). Twenty-eight children received GO-monotherapy (7.5mg/m2 day 1 and day 15; group A)*, in 34 children GO 3mg/m2 was combined with cytarabine (500mg/m2/d 96h continuous infusion; group B).The median age at initial diagnosis was 10 years (range 0.2 to 21 years). Nine children had secondary AML following a previous malignant disease and in 4 cases an acute leukemia of ambigious lineage (ALAL) had been diagnosed.The morphological subtypes were AML FAB M0 n=4; M1/M2 n=17 M3 n =1; M4/M5 n=25; M4Eo n=1; M6/M7 n=9, undifferentiated (AUL)/acute leukemia of ambiguous lineage (ALAL) n=5.In cytogenetics, most patients had a normal karyotype (n=16; including 7 with FLT3-ITD) followed by MLL-rearrangements (n=14), numerical aberrations (n=7; including FLT3-ITD n=2), others aberrations (n=10; FLT3-ITD n=1), complex karyotype (n=3) and BCR/ABL positive AML (n=1). Favorable translocations [t(8;21), inv 16, t(15;17)] were diagnosed in 4 patients. In 7 patients no cytogenetic results were available. Results:Five children suffered acute anaphylactic reaction during or short after infusion (CTC grade III n=3, grade IV n=2). Severe, long lasting myelosuppression has been observed in almost all patients. While the frequency of severe infection during myelosuppression was moderate, side effects such as mucositis have rarely been reported. A vena occlusive-disease (VOD)-like syndrome was observed in 5 children after alloSCT, in two cases with fatal outcome.An overall response (CR, CRp, PR) has been documented in 32 children (group A n=10/28, 36%; group B n=22/34, 65%). A higher response rate has been observed in children with AML FAB M1/2 with auer rods (n=18 response n=12, 67%) and AML with favorable aberrations (n=3/4). Six out of 10 children with FLT3-ITD positive AML responded to GO whereas patients with AUL/ALAL (n=9; response n=1, 11%) and AML FAB M6/7 (n=10; response n=3, 30%) showed a poorer response.Thirty-five patients received allogeneic SCT following GO treatment, 30 of the responders and 5 patients without GO response. In total 13 children are alive. Out of the responders 11 children or adolescents are still in complete remission (follow-up 2.7 years, 0.5 to 8.2 yrs.). Again children with AML FAB M1/2 and/or favorable cytogenetics had the best prognosis (7 /19 children alive, 37%). By contrast, none of the children with AML FAB M6/7, AUL or ALAL survived.Out of the 30 patients who did not respond to GO, following alloSCT 2 children are alive, however, the follow-up of 0.5 years (0.3 to 0.9 yrs) is very short. In conclusion,in this particular poor group of heavily pretreated children and adolescents with multiple relapsed, refractory AML, GO seems to improve the prognosis in some children and enables further treatment e.g. alloSCT. Based on the specific needs of children it is of importance that clinical trials continue in childhood AML to identify the appropriate patient group and schedule of GO combined with chemotherapy.* Seven patients out of this group were eligible for the International AML 2001/02 study “Salvage of refractory childhood AML with Mylotarg, Zwaan et al. BJH, 2010. Disclosures:No relevant conflicts of interest to declare.

Stellenwert von gegen TNF-α und CD20 gerichteten Biologika in der Therapie der Vaskulitis und des systemischen Lupus erythematodes

While the inhibition of TNF-alpha has been shown to improve vasculitis in vitro and in animal models, the clinical evidence for the efficacy of TNF-alpha blockade in most forms of vasculitis is mainly based on case reports and case series. Randomised controlled studies have so far not shown superiority of anti-TNF-alpha agents for Wegener's granulomatosis and giant cell arteritis. Moreover, in the context of Wegener's granulomatosis, a higher frequency and severity of infections are to be expected. In refractory cases of Behçet's disease therapy of uveitis and other organ manifestations is promising. Rituximab has achieved good effects in case reports of vasculitis. Results from controlled trials are not available. Observational studies indicate that in refractory systemic lupus erythematosus, and possibly also in several instances of small vessel vasculitis, rituximab can achieve good responses. The increased frequency of severe infections under TNF-alpha blockade requires a stringent benefit and risk assessment in addition to a multidisciplinary analysis of follow-up parameters. A detailed information of the patient regarding symptoms and signs of a possible infection are a prerequisite. Due to the complexity of the field and the danger of morbidity and mortality as a consequence of vasculitis or systemic lupus erythematosus on the one hand, and of the therapy on the other, biologics should only be used to treat these disorders in institutions fully equipped and staffed for this purpose.

Predictive Factors to Hypogammaglobulinemia and Non-Neutropenic Infection Complications after Rituximab/Chemotherapy Treatment

Rituximab is a chimerical human/mouse monoclonal anti-CD20 antibody successfully applied in B-cell lymphoproliferative disorders. The suppression of B-lymphocytes may induce hypogammaglobulinemia and increased risk for infection. These complications are rarely observed as a result of monotherapy with rituximab but have been often noted following combination with aggressive chemotherapy or in the setting of autologous stem cell transplantation (ASCT). In an attempt to study the role of rituximab in induction of hypogamma, we analyzed the frequency of this phenomenon, its possible causes, infectious complications and infection-related mortality in lymphoma patients treated with different chemotherapy regimens with or without rituximab. We analyzed 136 patients who received rituximab concurrently with chemotherapy (R-Chemo) and 46 patients who were treated with chemotherapy only, with follow-up period of up to five years. Following R-Chemo, 17 cases (12.5%) of severe hypogamma (defined as <60% of normal IgG range) were diagnosed, 21 patients (15.5%) had mild and moderate hypogammaglobulinemia, and 16 (12%) were found with decreased IgM alone. Multivariate analysis showed a significant increase of severe hypogamma when >6 doses of rituximab were given. Moreover, rituximab in >8 doses leaded to severe hypogamma in 50% of patients compared to 11.8% in patients treated with <8 doses (p .006) associated with 3 times more infections. The type of chemotherapy regimen didn't influence development of the hypogamma. Even myeloablative chemotherapy used in combination with rituximab before ASCT slightly increased the rate of severe hypogamma (p .06). Only the combination of fludarabine and rituximab (FR) compared to other Chemo-R, induced non-significant increase of severe hypogammaglobulinemia (21% vs 11%; p .02), severe non-neutropenic infection 19.4% vs 5.0% (p .005) and infection-related mortality 24% vs. 6% (p. 004). Multivariate analysis showed that patients post FR treatment were 6.4 times more prone to have severe infections than post other Chemo-R regimens (95% CI 1.49–27.0). Age and gender of patients, type of lymphoma, bone marrow involvement didn't affect the immunoglobulin level. We found a strong correlation between the IgG level and frequency of severe infections and mortality from infection (p <.01). Finally, the pre-treatment hypogamma was not found as a risk factor for infection. However, the duration of this phenomenon was found important: patients with severe hypogamma lasted >6 months were 4.5 times more likely to have severe infection (95%CI 1.19–18.5). In conclusion, we emphasized the importance of follow-up on immunoglobulin level in patients receiving rituximab. Hypogammoglobulinemia is not rare and is a clinical important phenomenon, leading to increase in infection and mortality rate in patients receiving R-Chemo. Longer treatment with more than six doses of rituximab significantly increases the incidence of hypogammoglobulinemia. The type chemotherapy regimen, except for fludarabine didn't affect the incidence of hypogammaglobulinemia and infection rate in our patients.

Genetically determined mannan-binding lectin deficiency is of minor importance in determining susceptibility to severe infections and vascular organ damage in systemic lupus erythematosus

Deficiency of mannan-binding lectin (MBL) has been reported to impact susceptibility to severe infections and atherosclerosis in systemic lupus erythematosus (SLE). In this study, MBL gene polymorphisms were analysed in 143 SLE patients and the frequency of severe infections and organ damage according to SLICC/ACR Damage Index regarding cerebrovascular accidents, angina pectoris, coronary by-pass surgery, myocardial infarction and peripheral arterial disease leading to significant tissue loss, were recorded during a mean follow-up time of 15 years from diagnosis. In a multiple logistic regression model, smoking (P = 0.001), hypertension (P = 0.030), alcohol intake (P = 0.027) and higher triglyceride concentration (P = 0.026) were associated with cerebrovascular, cardiovascular and peripheral arterial organ damage (CPAD), while the association with MBL deficiency did not reach significance (P = 0.098). Alcohol intake (>15 g/month) was inversely correlated with CPAD (OR = 0.29, 95%CI 0.096-0.87). MBL deficiency was not significantly more common in SLE patients with severe infections in a multivariate analysis (P > 0.3). In conclusion, classical risk factors such as smoking, hypertension, low alcohol intake and elevated triglyceride concentration were relatively more important for development of CPAD than MBL deficiency in SLE. Furthermore, MBL deficiency did not contribute to development of major infections in SLE.

Use of Hematopoietic Growth Factors in Elderly Patients Receiving Cytotoxic Chemotherapy

Myelosuppression is a common side effect in elderly patients undergoing chemotherapy. Neutropenia and anemia cause considerable morbidity, may increase mortality, and can result in a worse outcome of treatment in elderly patients compared to younger patients with comparable type and stage of disease. The availability and proven efficacy of hematopoietic growth factors such as granulocyte colonystimulating factor (G-CSF) or granulocyte-macrophage colony-stimulating factor (GM-CSF) and erythropoietin (EPO) have had a considerable impact on supportive care in cancer patients: Several randomized trials have demonstrated a reduction of neutropenia and the frequency of severe infections in elderly patients treated with G-CSF following myelotoxic chemotherapy compared with patients without growth factor support. Both for G-CSF and for recombinant human erythropoietin (rHu-EPO) several studies have demonstrated the safety and effectiveness of these molecules in elderly patients with regard to increasing hemoglobin concentrations, improving quality of life (rHu-EPO), and neutrophil recovery. Although a positive effect of the use of growth factors on overall survival in elderly cancer patients is not yet proven, a reduction of chemotherapy-induced side effects could clearly be shown. The National Comprehensive Cancer Network (NCCN) of cancer centers has recommended that all patients aged 70 years and older treated with CHOP or cytotoxic chemotherapy of comparable intensity should receive prophylactic G-CSF administration, and that the hemoglobin concentration be maintained at ≧12 g/dl in elderly patients undergoing chemotherapy.

Genetic heterogeneity of M type 3 group A streptococci causing severe infections in Tayside, Scotland.

To explain the worldwide increase in the frequency of severe infections by group A streptococci, molecular techniques are increasingly being employed to evaluate the genetic relationships of strains. We used restriction endonuclease analysis, pulsed-field gel electrophoresis (PFGE), the PCR, ribotyping, and DNA sequence analysis in a study of 13 group A streptococci isolated from a cluster of cases of serious infections over a 3-month period in Tayside, Scotland. Eight of the strains were M type 3; molecular characterization identified two subclones. The first, displaying PFGE profile 4, has been observed in Northern Scotland and has been circulating in New Zealand for over a decade. The second subclone has been documented only in the United Kingdom; it was first seen in 1993 in Scotland. Sequence analysis of emm-3 genes further differentiated the PFGE 4 subclone. DNA sequence analysis of virulence factors supports the suggestion that they may have recently been acquired by horizontal gene transfer.