Number Of Infectious Events Research Articles

Infection-Related Mortality in Children Undergoing Hematopoietic Stem Cell Transplants at a Referral Center in Mexico

Abstract Background Infections constitute a major cause of morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). In the pediatric population, infection-associated mortality rate ranging from 7% to 17% has been reported, depending on the type of HSCT, being lower in autologous transplants and higher in cases involving unrelated donors. Other factors related to HSCT that influence the clinical outcomes of these patients include the intensity of the conditioning regimen, the development of graft-versus-host disease (GVHD), cytotoxic and immunosuppressive effects of the medications used, the presence of disease activity prior to HSCT, length of hospital stay, and the use of intravascular devices, among many others. Methods All pediatric patients (under 16 years old) undergoing HSCT at the ‘Dr. José Eleuterio González’ University Hospital over a 55-month period (March 2019 – October 2023) were included. Clinical and epidemiological characteristics of the patients, mortality rate, and risk factors related to transplantation and infectious events (IEs) in these patients were recorded. Results A total of 75 patients who received HSCT were included, among them, 52 patients (69%) presented IEs. The mortality associated with IEs among these patients was 6% at day 30 and 12% at day 100, compared to 0% and 1.3% respectively in the non-IEs related deaths. The epidemiological characteristics, baseline diagnosis, donors and graft source are described in table 1. The average number of IEs in the associated mortality cases was 2.8 compared to 1.6 in the survival group. Among the mortality group (8 cases), 67% presented multiple infections and 33% single infections, with a 75% of them caused by viral infections. Regarding HSCT characteristics, in the group with IE-associated mortality, a higher proportion of haploidentical transplants, myeloablative conditioning regimens, lower use of total body irradiation, and a higher proportion of patients with detectable disease by flow cytometry prior to HSCT were observed compared to the survival group. Among non-infectious complications related to HSCT a lower frequency of acute GVHD grade I-II, a higher frequency of acute GVHD grade III-IV in the IE-associated mortality group was identified. Among the risk factors associated with hospital care, the IE-associated mortality group showed a higher use of central venous catheters, mucositis, systemic steroids, and pediatric intensive care unit stay compared to the survival group. Conclusion Pediatric patients undergoing HSCT present multiple risk factors that increase the incidence of infectious events and contribute to higher mortality rates. It is crucial to identify those factors related to adverse events and death to implement strategies that reduce exposure to these factors and improve the clinical outcomes.

Belumosudil Combination Therapy in Refractory Chronic Graft-Versus-Host Disease

Background: There are now 3 FDA approved oral drugs for chronic graft-versus-host disease (cGVHD) after 1-2 or more prior lines of therapy- ibrutinib, ruxolitinib and belumosudil. Encouraging overall response rates have been reported for all 3 agents; however, complete responses are rare and there are still a large number of patients who do not respond or lose the response over time. One of the approaches to overcome potential resistance to single agent use is to combine the new agents with each other or with other therapies (such as extracorporeal photopheresis (ECP), sirolimus, MMF) as there can be synergy across agents with different mechanisms of action. The 3 new drugs are all kinase inhibitors that block lymphocyte activation pathways and the production of proinflammatory cytokines. Preclinical studies showed their potential effects in cGVHD. Since the FDA approvals, it has been possible to use these drugs in various combinations for cGVHD treatment in daily clinical practice. In this retrospective review, we summarize our institution's real-world practice of using the ROCK2-inhibitor belumosudil in combination therapies since its FDA approval in July 2021. Methods: We conducted a retrospective chart review of patients treated with belumosudil in combination with other therapeutic agents at the Stanford Cancer Institute from July 2021 to July 2022. We collected descriptive statistics of standard outcomes of response as defined by the 2014 NIH Consensus Project on Criteria for Clinical Trials in cGVHD. Refractory cGVHD was defined as steroid-refractory or steroid-dependent cGVHD. Results: A cohort of 26 patients were evaluated (Table 1). The most common organ affected was skin (n = 20), followed by mouth (n = 19), eyes (n = 15) and joints/fascia (n=15). Patients were treated with a median number of 3 lines of prior therapies before initiating belumosudil. Combination therapies with belumosudil included several 3-4 drug combinations with concurrent use of ruxolitinib, ECP, prednisone, sirolimus or CNI. In instances in which belumosudil was combined with ruxolitinib, belumosudil was the add-on drug. The median follow-up period following initiation of belumosudil was 213.5 days. The overall response rate (ORR) following the addition of belumosudil was 77% (20/26). Responses to belumosudil used in combination were based on organ symptom scoring and global rating by clinician assessment according to the 2014 NIH Consensus Criteria and were seen in 85% (17/20) patients with skin involvement; 53% (8/15) patients with joint/fascial involvement, 33% (5/15) patients with eye involvement, 30% (3/10) patients with lung involvement, 11% (2/19) patients with mouth involvement, and 13% (1/8) patients with liver involvement (Table 2). No responses were seen in patients with GI (lower tract) involvement. No clinically evident adverse drug reactions occurred in the belumosudil combinations although variable dosing of the combined agents was used with the approved belumosudil dose of 200 mg po daily. Infectious adverse events occurred in 42% (11/26) of patients, consistent with the immunosuppressive effects of cGVHD therapies. Of these, 36% (5/14) was due to SARS-CoV2 infection, 29% (4/14) cytomegalovirus reactivation, 21% (3/14) bacterial infection, 7% (1/14) rhinovirus infection, and 7% (1/14) respiratory syncytial virus. The number of infection events with the new agent combination of belumosudil plus ruxolitinib was reviewed separately and was not increased over the other belumosudil combinations. No deaths have occurred in this cohort of 26 patients to date. Conclusion: In our institutional practice, administration of belumosudil in combination therapy appears safe, tolerable, and effective in patients with established, refractory cGVHD. The results of our retrospective study highlight the feasibility of the next phase of belumosudil research for combination therapy in this difficult-to-treat population. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Epidemiology and Risk Factors for the Development of Infectious Complications in Newly Diagnosed Multiple Myeloma: A Multicenter Prospective Cohort Study in Latin America.

Infections are a significant cause of morbidity and mortality in patients with multiple myeloma (MM). In Latin America, data on infectious complications in this patient population are lacking. We conducted a prospective cohort study of patients with newly diagnosed MM (NDMM) in seven Latin American countries between June 2019 and May 2020. Patients with active disease, on active therapy, and with a follow-up of 6 months from the time of diagnosis were included. Our primary end point was the number of infectious events that required hospitalization for ≥ 24 hours. Of 248 patients with NDMM, 89 (35.9%) had infectious complications (113 infectious events), the majority (67.3%) within the first 3 months from diagnosis. The most common sites of infection were respiratory (38%) and urinary tract (31%). The microbial agent was identified in 57.5% of patients with gram-negative bacteria (73.5%) as the most common pathogen. Viral infections were infrequent, and no patients with fungal infection were reported. In the multivariable analysis, diabetes mellitus (odds ratio [OR], 2.71; 95% CI, 1.23 to 6.00; P = .014), creatinine ≥ 2 mg/dL (OR, 4.87; 95% CI, 2.29 to 10.35; P < .001), no use of trimethoprim-sulfamethoxazole prophylaxis (OR, 6.66; 95% CI, 3.43 to 12.92; P < .001), and treatment with immunomodulatory drugs (OR, 3.02; 95% CI, 1.24 to 6.29; P = .003) were independent factors associated with bacterial infections. At 6 months, 21 patients (8.5%) had died, 47.6% related to infectious complications. Bacterial infections are a substantial cause of hospital admissions and early death in patients with NDMM. Antibiotic prophylaxis should be considered to reduce infectious complications in patients with MM.

The ISAQ Score Does Not Predict Adrenal Crisis in Patients with Primary Adrenal Insufficiency.

This study aimed to investigate the ability of the immune system assessment questionnaire (ISAQ) to predict adrenal crisis (AC) and infectious events in patients with primary adrenal insufficiency (PAI). This was a prospective single-centre study over three years. Patients answered the ISAQ at baseline and were seen every 4-6 months in the endocrine outpatient clinic. At each visit previous infectious periods which required an increase in daily glucocorticoid dosage and AC were reported and documented. Seventy-five patients with PAI (53 women; 43 patients with autoimmune PAI, 20 patients with salt-wasting congenital adrenal hyperplasia and 12 patients who underwent bilateral adrenalectomy) were analysed. Due to the COVID-19 pandemic and consecutive lockdown measures, the data were analysed separately for March 2018 to March 2020 (period 1), and March 2020 to March 2021 (period 2). During period 1 the ISAQ score significantly correlated with the number of reported infectious events (r=0.351; p<0.01), but not during period 2 (r=0.059, p=0.613), in which the number of infectious events per patient-year significantly decreased (1.1±0.1 vs 0.4±0.1; p<0.001). The frequency of AC decreased from 8.8 to 2.4 per 100 patient-years between the two study periods. The ISAQ score was not different between patients with or without AC. The ISAQ score does not identify patients prone to ACs. The COVID-19 pandemic and consecutive lockdown measures significantly diminished the frequency of infectious events and ACs.

Impact of treatment with immunomodulators and tumour necrosis factor antagonists on the incidence of infectious events in patients with inflammatory bowel disease.

BackgroundCorticosteroids, immunomodulators (IM) and tumour necrosis factor antagonists (anti-TNF) are commonly used in the treatment of inflammatory bowel disease (IBD) but they also supress the defence against infectious disease. The aim of this study was to analyse the incidence of infectious events in patients with IBD and the association to concomitant medical therapy.MethodsWe performed a retrospective medical chart review of patients with IBD aged 18–65 years included in the Swedish Registry of Inflammatory Bowel Disease in the catchment area of Umeå University Hospital, Sweden. Data were collected from the period 01 January 2006, to 31 January 2019. An infectious event was defined as an outpatient prescription of antimicrobials or a positive diagnostic test for infection.ResultsDuring a period of 5,120 observation-years, we observed 1,394 events in 593 patients. The mean number of infectious events per 100 person-years was 27.2 (standard deviation [SD]: 0.46). There were no differences in mean incidence rates between patients treated with no immunosuppression (23.0 events per 100 person-years, SD: 50.4), patients treated with IM monotherapy (27.6 events per 100 person-years, SD: 49.9), patients treated with anti-TNF monotherapy (34.3 events per 100 person-years, SD: 50.1) and patients on combination therapy (22.5 events per 100-person-years, SD: 44.2). In a multivariate logistic regression, female gender (adjusted odds ratio [AOR]: 2.24; 95% confidence interval [CI]: 1.49–3.37) and combination therapy (AOR: 3.46; 95% CI: 1.52–7.85) were associated with higher risks of infection (>32 events per 100 person years). Also, patients treated with any immunosuppression treatment for 25–75% (AOR: 2.29; 95% CI: 1.21–4.34) and for >75% (AOR: 1.93; 95% CI: 1.19–3.12) of the observation period were at higher risks compared to patients treated with immunosuppression <25% of the observation period.ConclusionWe observed no significant difference in risk for infections between patients on monotherapy with IM or anti-TNF and patients with low use of immunosuppression, but there was a significant risk for combination therapy.

RISK FACTORS FOR INFECTIOUS COMPLICATIONS IN ONCOLOGICAL PATIENTS WITH OSTEONECROSIS OF THE JAW FROM BISPHOSPHONATES

Objective: To evaluate the association between clinical factors with the number of infection events due to medication-related necrosis of the jaw (MRONJ) secondary to the use of injectable bisphosphonates in patients with cancer. Study design: Retrospective, observational study that included 21 cases of MRONJ and the following variables: age, underlying disease, necrosis classification, bone involved, triggering factor, frequency of bisphosphonate use, total number of doses of the drug, smoking history, underlying disease activity at the time of MRONJ diagnosis, chronic use of corticosteroids, and previous or current use of chemotherapy, immunosuppressants, and antiangiogenic drugs. The endpoint of interest was the number of exacerbations (new active infections). Results: Only 33% of the patients did not present with any infectious episode after the initial event; 28.6% had 1 episode, 19% had 3 episodes, 9.5% had 2 episodes, 1 patient presented 6 episodes, and 1 patient presented 7 episodes of exacerbation. Among the variables studied, classification of osteonecrosis (Class 2 + 3 vs Class 1, P = .05) and frequency of drug use (Monthly vs Quarterly; P = .002) showed significant association with the number of infectious events. Conclusions: The recurrence of MRONJ-associated infection was frequent in oncological patients and was associated with the monthly use of bisphosphonates and MRONJ classification.

Severe infections in patients with anti-neutrophil cytoplasmic antibody-associated vasculitis: a retrospective cohort study with a clinical phenotype approach.

Severe infections are common in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). We aimed to describe the characteristics of patients with AAV and severe infections according to clinical phenotype. Retrospective cohort study including patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Baseline characteristics were compared between patients with and without at least one severe infection. Demographics, comorbidities, clinical characteristics, laboratory and treatment were retrieved at diagnosis and at every infectious event. One hundred and eight patients were included (57 with and 51 without infections). Patients with an infection had received more frequently methylprednisolone boluses at AAV diagnosis than patients without infections (OR 2.6, 95% CI 1.1-5.9, p = 0.01). There were a total of 108 severe infections in 57 patients (median follow-up 18months). Thirty-two patients (56%) had an infectious complication within the first year of AAV diagnosis, 43 (75%) had pulmonary involvement during the first infection. The most frequent type of infection was pneumonia. Phenotypes were: Non-severe AAV (n = 11), severe PR3-AAV (n = 30), severe MPO-AAV (n = 9); the number of infectious events in each group was 11, 69, 18, respectively. Patients with severe MPO phenotype were older and required more frequently ICU stay compared to other phenotypes. Positive correlation was found between total of infections and pulmonary infiltrates due to vasculitis (ρ = 0.40, p = 0.003), endobronchial involvement (ρ = 0.40, p = 0.003), and alveolar hemorrhage (ρ = 0.34, p = 0.015). Severe infections, most commonly pneumonia, were frequent in this cohort, especially during the first year after diagnosis, in patients with pulmonary involvement and severe PR3 phenotype who received methylprednisolone boluses.

Autoimmune Neutropenia of Infancy- Unexpected Prevalence of Pseudomonas Skin Infections

Background: Autoimmune neutropenia of infancy (AIN), the most frequent type of severe neutropenia in young children, occurs due to recognition of membrane antigens by anti-neutrophil antibodies, resulting in peripheral neutrophil destruction. Despite the often severe and prolonged neutropenia, serious infectious complications are less frequent in AIN compared with other etiologies of severe neutropenia.Objectives and methods: The purpose of this historical prospective study was to describe the demographics and clinical course of AIN with a focus on the incidence of infectious events, the pathogens involved and assessment of contributing factors. Data was extracted from the medical records of AIN patients treated at the pediatric hematology clinic in Schneider Children's Medical Center of Israel between 2001-2016.Results: One hundred and one patients diagnosed with AIN were included in the study, representing a total of 175 patient-years of follow-up, with a mean of 1.9 years per patient. Mean age at presentation was 0.8 years and at resolution 2.8 years; 90% were healthy by the age 3.8 years. The reason for performing a blood count was febrile infection in 56.3% while nearly 20% were diagnosed by the routine blood count performed between ages 9-12 months in the well-baby clinic. Prophylactic antibiotic use did not correlate with the number of infectious events or days of fever. At least one microbiologically proven bacterial infection was identified in 26% of the patients including acute otitis, urinary tract infections, skin lesions and bacteremia. Bacterial isolates were mostly gram negative, predominantly Pseudomonas species (13/32, 40.6% of isolates) (Figure 1). Prevalence of significant skin infections, especially in the genital region, was very high (20% of infections). There were only 3 episodes of bacteremia out of 559 total febrile illnesses (0.5%).Discussion and conclusions: A standard treatment protocol for AIN is lacking, possibly due to a paucity of data in the literature. Severe bacterial infections in AIN are less common than in severe congenital neutropenia or chemotherapy induced neutropenia. The prevalence of bacteremia in AIN is not well defined in the post-pneumococcal vaccine era. In our cohort bacteremia was uncommon, while bacterial skin infections were much more prevalent, especially involving the genital area, with a high isolation rate of gram negative bacteria, especially Pseudomonas sp. This finding was surprising as ecthymal lesions are more commonly associated with hypoproductive neutropenias. The common practice of treating febrile illnesses in AIN with broad spectrum antibiotics may be unnecessary for a proportion of patients, while a subset of patients seems to be susceptible to gram negative skin infections and should be covered with anti-pseudomonal antibiotics. We recommend that patients with AIN and a febrile illness undergo a careful daily physical examination in addition to laboratory studies including blood counts and cultures of blood, urine and any other suspected sites of infection. Antibiotic therapy should be prescribed according to the clinical picture and the laboratory results. DisclosuresNo relevant conflicts of interest to declare.

Number of infection events per cell during HIV-1 cell-free infection

HIV-1 accumulates changes in its genome through both recombination and mutation during the course of infection. For recombination to occur, a single cell must be infected by two HIV strains. These coinfection events were experimentally demonstrated to occur more frequently than would be expected for independent infection events and do not follow a random distribution. Previous mathematical modeling approaches demonstrated that differences in target cell susceptibility can explain the non-randomness, both in the context of direct cell-to-cell transmission, and in the context of free virus transmission (Q. Dang et al., Proc. Natl. Acad. Sci. USA 101:632-7, 2004: K. M. Law et al., Cell reports 15:2711-83, 2016). Here, we build on these notions and provide a more detailed and extensive quantitative framework. We developed a novel mathematical model explicitly considering the heterogeneity of target cells and analysed datasets of cell-free HIV-1 single and double infection experiments in cell culture. Particularly, in contrast to the previous studies, we took into account the different susceptibility of the target cells as a continuous distribution. Interestingly, we showed that the number of infection events per cell during cell-free HIV-1 infection follows a negative-binomial distribution, and our model reproduces these datasets.

Transcriptomic Insight in the Control of Legume Root Secondary Infection by the Sinorhizobium meliloti Transcriptional Regulator Clr.

The cAMP-dependent transcriptional regulator Clr of Sinorhizobium meliloti regulates the overall number of infection events on Medicago roots by a so-far unknown mechanism requiring smc02178, a Clr-target gene of unknown function. In order to shed light on the mode of action of Clr on infection and potentially reveal additional biological functions for Clr, we inventoried genomic Clr target genes by transcriptome profiling. We have found that Clr positively controls the synthesis of cAMP-dependent succinoglycan as well as the expression of genes involved in the synthesis of a so-far unknown polysaccharide compound. In addition, Clr activated expression of 24 genes of unknown function in addition to smc02178. Genes negatively controlled by Clr were mainly involved in swimming motility and chemotaxis. Functional characterization of two novel Clr-activated genes of unknown function, smb20495 and smc02177, showed that their expression was activated by the same plant signal as smc02178 ex planta. In planta, however, symbiotic expression of smc02177 proved independent of clr. Both smc02177 and smb20495 genes were strictly required for the control of secondary infection on M. sativa. None of the three smc02177, smc02178 and smb20495 genes were needed for plant signal perception. Altogether this work provides a refined view of the cAMP-dependent Clr regulon of S. meliloti. We specifically discuss the possible roles of smc02177, smc02178, smb20495 genes and other Clr-controlled genes in the control of secondary infection of Medicago roots.

Antibiotic exposure and the risk for depression, anxiety, or psychosis: a nested case-control study.

Changes in the microbiota (dysbiosis) were suggested to increase the risk of several psychiatric conditions through neurologic, metabolic, and immunologic pathways. Our aim was to assess whether exposure to specific antibiotic groups increases the risk for depression, anxiety, or psychosis. We conducted 3 nested case-control studies during the years 1995-2013 using a large population-based medical record database from the United Kingdom. The study included 202,974 patients with depression, 14,570 with anxiety, and 2,690 with psychosis and 803,961, 57,862, and 10,644 matched controls, respectively. Cases were defined as individuals aged 15-65 years with any medical Read code for depression, anxiety, or psychosis. Subjects with diagnosis-specific psychotropic prescriptions > 90 days before index date were excluded. For every case, 4 controls were selected using incidence density sampling, matching on age, sex, practice site, calendar time, and duration of follow-up before index date. The primary exposure of interest was therapy with 1 of 7 antibiotic classes > 1 year before index date. Odds ratios (ORs) and 95% CIs were calculated for the association between each psychiatric disorder and exposure to individual classes of antibiotics using conditional logistic regression analysis. The risk was adjusted for obesity, smoking history, alcohol consumption, socioeconomic status, and number of infectious events before diagnosis. Treatment with a single antibiotic course was associated with higher risk for depression with all antibiotic groups, with an adjusted OR (AOR) of 1.23 for penicillins (95% CI, 1.18-1.29) and 1.25 (95% CI, 1.15-1.35) for quinolones. The risk increased with recurrent antibiotic exposures to 1.40 (95% CI, 1.35-1.46) and 1.56 (95% CI, 1.46-1.65) for 2-5 and > 5 courses of penicillin, respectively. Similar association was observed for anxiety and was most prominent with exposures to penicillins and sulfonamides, with an AOR of 1.17 (95% CI, 1.01-1.36) for a single course of penicillin and 1.44 (95% CI, 1.18-1.75) for > 5 courses. There was no change in risk for psychosis with any antibiotic group. There was a mild increase in the risk of depression and anxiety with a single course of antifungals; however, there was no increase in risk with repeated exposures. Recurrent antibiotic exposure is associated with increased risk for depression and anxiety but not for psychosis.

Prognostic Factors of Infections and Effect of Primary Anti-Infectious Prophylaxis in MDS Patients Treated with Azacitidine (AZA): A Prospective Study

Background: Hypomethylating agents, especially AZA, have become the reference first line treatment of high-risk MDS. Myelosupression, although less important than with chemotherapy, is however observed, leading to potentially life threatening infections. A retrospective study found unfavorable (unfav) cytogenetics and low platelet counts to be predictive factors of infections in high risk MDS and AML patients (pts) receiving AZA (Merkel and al, Am j Hemat 2012). However, prognostic factors of infections, and whether infection prophylaxis would be useful in this situation, has not been prospectively evaluated.Methods: Between June 2011 and March 2013, 120 high-risk MDS pts were included in a randomized phase II trial seeking the most promising drug association with AZA by comparison with AZA alone in higher risk MDS (including AML with 20 to 30% marrow blasts and CMML with > 10% marrow blasts) (NCT01342692). Pts received AZA (75mg/m²/dx7d every 4 weeks) alone (N=40), with Valproic acid (N=40) or with Lenalidomide (N=40) (10mg/dx14d every 4 weeks). G-CSF was not used. Infectious events (IE) (diagnosed as such by the treating physician), hospitalizations for sepsis and pts receiving antimicrobial prophylaxis were reported at each cycle. Predictive factors of the occurrence of IE were analyzed.Results: 75 (62.5%) pts developed 259 IE, including 61 requiring hospitalization in 46 pts (61.3% of infected patients). The number of IE and of infected patients were similar in the 3 study arms. 39 pts died during the study, 12 of them because of infection, none of whom had responded to AZA (4 progressions, 4 failures and 4 deaths before evaluation). IE were more common during the first two cycles of therapy, with 86 (31.3%), 52 (23.5%) 45 (18.9%), 26 (15%), 15(19.2%) and 24 (19.7%) IE during cycles 1, 2, 3, 4, 5, and 6, respectively. Fever of unknown origin (FUO) (39.6%) and pneumonia (28.8%) were the most common type of infections followed by ENT (9.9%), urinary tract (8.1%), skin (5.4%), dental (4.5%) and intra-abdominal (3.6%). 6,3% were bacteriemia. Among the 26 microbiologically documented IE, 13 were CG+ (4 staph aureus, 4 enteroccus species, 4 coag neg staph and 1 other), 9 were BG- (6 E Coli, 1 pseudomonas and 2 others) and 3 were viral (HSV1, influenza B, Hepatitis E) and only one patient had documented invasive fungal infection (asp fumigatus).Overall, 23 (19%), 22 (18%), 10(8%) pts received bacterial (Levofloxacine), fungal (posaconazole) and viral (Valaciclovir) prophylaxis resp. Predictive factors of IE were unfav karyotype (79.5% infections vs. 50.8% in pts with fav or int karyotype; p=0.005) and platelets (PLT) < 20 G/L (92.3% infections vs. 58.9% for platelets > 20 G/L; p=0.03). In multivariate analysis, only unfav karyotype was predictive of IE (p=0.01). Other baseline parameters (including ANC, IPSS, age, sex, Hb level, and BM blast %) and bacterial, fungal or viral prophylaxis had no significant predictive value on the occurrence of IE. In multivariate analysis, predictive factors of pulmonary infection were anemia at baseline (p=0.04) and unfav karyotype (p<0.001), while prophylaxis had no significant impact. Infected pts had significantly more hospitalizations and deaths than non-infected pts (p<0.0001 and p=0.028 resp.). In multivariate analysis, unfav karyotype (p<0.001) and PLT <20 G/L (p=0.05) were significantly predictive of hospitalization for infection, while baseline Hb <10g/dL (p=0.02), and unfav karyotype (p=0.03) were predictors of fatal infection.Conclusion: 62.5% of the 120 pts developed infections during AZA treatment, mainly during the first 2 cycles, and 10% of the pts died from infection. Only one invasive fungal infection was documented. Unfav karyotype was strongly predictive of IE, hospitalization for infection and fatal infections. Other significant predictive factors were baseline anemia for pulmonary infection and fatal infection, and thrombocytopenia for hospitalization for infection, while ANC was not a significant factor. Moreover, prophylaxis was not associated with a decrease of IE in our study, but the small number of pts who received it precludes any conclusion. DisclosuresAdes:celgene: Research Funding; Novartis: Research Funding. Fenaux:Novartis: Research Funding; celgene: Research Funding; Janssen: Research Funding.

Intracerebral Administration of Adeno-Associated Viral Vector Serotype rh.10 Carrying Human SGSH and SUMF1 cDNAs in Children with Mucopolysaccharidosis Type IIIA Disease: Results of a Phase I/II Trial

Mucopolysaccharidosis type IIIA is a severe degenerative disease caused by an autosomal recessive defect of a gene encoding a lysosomal heparan-N-sulfamidase, the N-sulfoglycosamine sulfohydrolase (SGSH), the catalytic site of which is activated by a sulfatase-modifying factor (SUMF1). Four children (Patients 1-3, aged between 5.5 and 6 years; Patient 4 aged 2 years 8 months) received intracerebral injections of an adeno-associated viral vector serotype rh.10-SGSH-IRES-SUMF1 vector in a phase I/II clinical trial. All children were able to walk, but their cognitive abilities were abnormal and had declined (Patients 1-3). Patients 1-3 presented with brain atrophy. The therapeutic vector was delivered in a frameless stereotaxic device, at a dose of 7.2×10(11) viral genomes/patient simultaneously via 12 needles as deposits of 60 μl over a period of 2 hr. The vector was delivered bilaterally to the white matter anterior, medial, and posterior to the basal ganglia. Immunosuppressive treatment (mycophenolate mofetil and tacrolimus) was initiated 15 days before surgery and maintained for 8 weeks (mycophenolate mofetil) or throughout follow-up (tacrolimus, with progressive dose reduction) to prevent elimination of transduced cells. Safety data collected from inclusion, during the neurosurgery period and over the year of follow-up, showed good tolerance, absence of adverse events related to the injected product, no increase in the number of infectious events, and no biological sign of toxicity related to immunosuppressive drugs. Efficacy analysis was necessarily preliminary in this phase I/II trial on four children, in the absence of validated surrogate markers. Brain atrophy evaluated by magnetic resonance imaging seemed to be stable in Patients 1 and 3 but tended to increase in Patients 2 and 4. Neuropsychological evaluations suggested a possible although moderate improvement in behavior, attention, and sleep in Patients 1-3. The youngest patient was the most likely to display neurocognitive benefit.

Fungal infections of rice, wheat, and grape in Europe in 2030–2050

Although models to predict climate impact on crop production have been used since the 1980s, spatial and temporal diffusion of plant diseases are poorly known. This lack of knowledge is due to few models of plant epidemics, high biophysical complexity, and difficulty to couple disease models to crop simulators. The first step is the evaluation of disease potential growth in response to climate drivers only. Here, we estimated the evolution of potential infection events of fungal pathogens of wheat, rice, and grape in Europe. A generic process-based infection model driven by air temperature and leaf wetness data was parameterized with the thermal and moisture requirements of the pathogens. The model was run on current climate as baseline, and on two time frames centered on 2030 and 2050. Our results show an overall increase in the number of infection events, with differences among the pathogens, and showing complex geographical patterns. For wheat, Puccinia recondita, or brown rust, is forecasted to increase +20–100 % its pressure on the crop. Puccinia striiformis, or yellow rust, will increase 5–20 % in the cold areas. Rice pathogens Pyricularia oryzae, or blast disease, and Bipolaris oryzae, or brown spot, will be favored all European rice districts, with the most critical situation in Northern Italy (+100 %). For grape, Plasmopara viticola, or downy mildew, will increase +5–20 % throughout Europe. Whereas Botrytis cinerea, or bunch rot, will have heterogeneous impacts ranging from −20 to +100 % infection events. Our findings represents the first attempt to provide extensive estimates on disease pressure on crops under climate change, providing information on possible future challenges European farmers will face with in the coming years.

Leptin and the Immune Response

Leptin is involved in the control of energy storage by the body. Low serum leptin levels, as seen in starvation, are associated with impaired inflammatory T cell responses that can be reversed by exogenous leptin. Common variable immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Several defects in T cell function have also been described, and allergy, autoimmune disease, and lymphomas or other malignancies can be present. Previous studies in Brazilian CVID patients have shown that, in contrast with mononuclear cells from healthy controls, CVID cells cultured with phytohemagglutinin and added leptin increased the proliferative response and decreased activation-induced apoptosis. Interleukin (IL)-2 and especially IL-4 production also increased significantly, although the effects of exposure to leptin were not observed uniformly in CVID patients. The majority, however, responded in some degree, and some exhibited completely restored values of the four parameters.These remarkable results indicate leptin could be used to improve immune function in these patients. On the other hand, we found no specific correlation between serum leptin levels and the number of infectious events over a 24-month period, presence of autoimmunity, allergies, or cancer in these patients. The results suggest that the absolute value of serum leptin does not determine the clinical behavior of patients or responses to leptin in vitro. Of note is the divergence between serum leptin, response to leptin in vitro, and the presence of autoimmunity, indicating the need to identify the cellular and molecular players involved in the regulation of the immune response by leptin in CVID.

Glutathione and Homoglutathione Play a Critical Role in the Nodulation Process of Medicago truncatula

Legumes form a symbiotic interaction with bacteria of the Rhizobiaceae family to produce nitrogen-fixing root nodules under nitrogen-limiting conditions. This process involves the recognition of the bacterial Nod factors by the plant which mediates the entry of the bacteria into the root and nodule organogenesis. We have examined the importance of the low molecular weight thiols, glutathione (GSH) and homoglutathione (hGSH), during the nodulation process in the model legume Medicago truncatula. Using both buthionine sulfoximine, a specific inhibitor of GSH and hGSH synthesis, and transgenic roots expressing GSH synthetase and hGSH synthetase in an antisense orientation, we showed that deficiency in GSH and hGSH synthesis inhibited the formation of the root nodules. This inhibition was not correlated to a modification in the number of infection events or to a change in the expression of the Rhizobium sp.-induced peroxidase rip1, indicating that the low level of GSH or hGSH did not alter the first steps of the infection process. In contrast, a strong diminution in the number of nascent nodules and in the expression of the early nodulin genes, Mtenod12 and Mtenod40, were observed in GSH and hGSH-depleted plants. In conclusion, GSH and hGSH appear to be essential for proper development of the root nodules during the symbiotic interaction.

Risks for frequent antimicrobial-treated infections in postmenopausal women.

Infections are a major cause of morbidity and mortality in older adults. Little is known about factors that alter the susceptibility to infection in the older population. This study in postmenopausal women examines health-related conditions and behavioral factors that may increase the risk of frequent infections, defined as having, on average, one or more infections per year. A prospective cohort study with 5 years of follow-up was conducted in 1320 women aged 55 to 80 years. The subjects were Group Health Cooperative of Puget Sound (GHC) enrollees screened for a large fracture prevention trial who also participated in a survey of dietary and supplemental vitamin use. The main outcome, total number of infection events per subject, was derived from a new method of identifying outpatient infections based on the antimicrobial prescription fills recorded in GHC automated pharmacy records. Prevalent lung disease (OR = 6.1, 95% CI 2.8-13.4), receiving a prescription for vitamin C (OR = 2.1, 95% CI 1.4-3.4), and the second and third tertiles of the Chronic Disease Score (OR = 1.7, 95% CI 1.1-2.7 and OR = 2.4, 95% CI 1.5-3.9, respectively) were associated with 5 or more antimicrobial-treated infections during follow-up. A body mass index (BMI) of less than 22 kg/m2 (OR = 0.6, 95% CI 0.3-1.0) was suggestive of an association. The study provides new information on risk factors for outpatient infections and raises new questions regarding the susceptibility to frequent infections in older women. In addition, the automated pharmacy record method used in this study offers a low-cost alternative for use in future epidemiologic research.

Prediction of sorghum downy mildew risk in Australia using daily weather data

The temporal and regional distributions of the potential number of infection events of the exotic disease sorghum downy mildew in Australia were predicted for the years 1957–1998. A set of rules based on overseas research on the influence of environmental factors on infection and sporulation was used to interrogate daily climatic data from 1957 to 1998 for 53 selected localities. Between November and February, sorghum was at arelatively low risk of infection from downy mildew, with the risk gradually increasing during the summer, reaching the greatest risk in May for most localities. During March to May there were geographical south-north, as well as west-east, increasing gradients of predicted downy mildew events in Queensland and New South Wales. In winter and early spring, the analysis indicated that disease would occur only in the coastal regions of Queensland, with serious implications for breeders’ nurseries in these areas. The temporal and regional distributions of events were closely related to those of relative humidity, night temperature and night length. Sorghum downy mildew was predicated to be a minor problem in most part of New South Wales.