Incidence Of Severe Bacterial Infections Research Articles

Explorations of Post-DLI Low-Dose Cyclophosphamide for Preventing Severe aGVHD

Background Relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious life-threatening complication. The granulocyte colony-stimulated factor mobilized donor lymphocyte infusions (gDLI) combined with chemotherapy is currently a commonly used treatment method. Nevertheless, gDLI may cause so severe acute graft-versus-host disease (aGVHD) as to impact prognosis. Posttransplant cyclophosphamide (PTCy) has been the backbone for GVHD prophylaxis by inducing tolerance to minor histocompatibility antigens in recipients, while the application of post-gDLI low-dose cyclophosphamide (PDCy) for GVHD prophylaxis has not yet been attempted. Methods To explore this possibility, a retrospective study was conducted. 20 patients relapsing after HSCT were administered 20 mg/kg/d cyclophosphamide（Cy）on day 3 (for matched related transplantation) or on days 3 and 4 (for haplo-identical or unrelated transplantation) after gDLI to prevent aGVHD (the PDCy group). Furthermore, through propensity score matching, 58 matched controls received other (for HID and URD) or no (for MSD) immunosuppressive therapy for GVHD prophylaxis (the Non-Cy group). Patients from the PDCy and the Non-Cy group were matched by transplantation type, CD3+ T cell counts, and age and gender of recipients and donors. An MRD complete response was undetectable MRD lower than 0.01% with qPCR, and a reduction of at least one-log fold in MRD load post gDLI was defined as an MRD response. Results The PDCy group comprised 9 and 11 men and women, respectively, with a median age of 38 (34-52, IQR) years. The Non-Cy group comprised 34 and 24 men and women, respectively, with a median age of 40 (29-47, IQR) years. The infused CD3+T cell dose in the PDCy and Non-Cy group was 3.0 *10^7/kg and 2.9 *10^7/kg, respectively (p=1.0). The interval between HSCT and gDLI was longer in the PDCy group when compared to the Non-Cy group (30.8 vs 6.5 months, p<0.01). And first recurrence accounted for a higher percentage in the Non-Cy group (93% vs 45%, p<0.01). Other transplant- and DLI-specific data did not exhibit any significant difference between the groups. With a median follow-up of 4.8 (0-37.1) months, the PDCy group had lower cumulative incidence of severe aGVHD (III-IV, 5% vs 31%, p=0.02; II-IV, 25% vs 52%, p=0.04, figure 1A, B), but no significant differences existed in 4-month OS (64% vs 59%, p=0.51, figure 1E) and NRM (20% vs 19%, p=0.5, figure 1D). Among 49 patients undergoing salvage treatment (PDCy group, n=16; Non-Cy group, n=33), there was no statistical difference in 4-month CIR (20% vs 47%, p=0.11, figure 1C) and rates of objective response (PR+CR, 68.8% vs 54.5%, p=0.6). Among 29 patients undergoing preemptive treatment (PDCy group, n=4; Non-Cy group, n=25), there was no statistical difference in the rates of MRD complete response (25% vs 42%, p=1) and MRD response (25% vs 50%, p=0.6) between the PDCy group and the Non-Cy group. The PDCy regimen didn't increase the incidence of severe bacterial infection (45% vs 33%, p=0.3), bacteremia (25% vs 16%, p=0.11), fungus infection (20% vs 29.3%, p=0.4), virus infection (5% vs 19%, p=0.1), hemorrhagic cystitis (n=1 vs n=1), and cardiac events (n=0 vs n=0). Conclusions In conclusion, on the premise of safety, the PDCy regimen could effectively protest against severe aGVHD after gDLI while preserving therapeutic response rates. However, the research results still require verification through longer follow-up and large prospective randomized studies.

Incidence and risk factors of neonatal bacterial infections: a community-based cohort from Madagascar (2018–2021)

BackgroundFew studies on neonatal severe bacterial infection are available in LMICs. Data are needed in these countries to prioritize interventions and decrease neonatal infections which are a primary cause of neonatal mortality. The BIRDY project (Bacterial Infections and Antimicrobial Drug Resistant among Young Children) was initially conducted in Madagascar, Senegal and Cambodia (BIRDY 1, 2012–2018), and continued in Madagascar only (BIRDY 2, 2018–2021). We present here the BIRDY 2 project whose objectives were (1) to estimate the incidence of neonatal severe bacterial infections and compare these findings with those obtained in BIRDY 1, (2) to identify determinants associated with severe bacterial infection and (3) to specify the antibiotic resistance pattern of bacteria in newborns.MethodsThe BIRDY 2 study was a prospective community-based mother and child cohort, both in urban and semi-rural areas. All pregnant women in the study areas were identified and enrolled. Their newborns were actively and passively followed-up from birth to 3 months. Data on clinical symptoms developed by the children and laboratory results of all clinical samples investigated were collected. A Cox proportional hazards model was performed to identify risk factors associated with possible severe bacterial infection.FindingsA total of 53 possible severe bacterial infection and 6 confirmed severe bacterial infection episodes were identified among the 511 neonates followed-up, with more than half occurring in the first 3 days. For the first month period, the incidence of confirmed severe bacterial infection was 11.7 per 1,000 live births indicating a 1.3 -fold decrease compared to BIRDY 1 in Madagascar (p = 0.50) and the incidence of possible severe bacterial infection was 76.3, indicating a 2.6-fold decrease compared to BIRDY 1 in Madagascar (p < 0.001). The 6 severe bacterial infection confirmed by blood culture included 5 Enterobacterales and one Enterococcus faecium. The 5 Enterobacterales were extended-spectrum β-lactamases (ESBL) producers and were resistant to quinolones and gentamicin. Enterococcus faecium was sensitive to vancomycin but resistant to amoxicillin and to gentamicin. These pathogns were classified as multidrug-resistant bacteria and were resistant to antibiotics recommended in WHO guidelines for neonatal sepsis. However, they remained susceptible to carbapenem. Fetid amniotic fluid, need for resuscitation at birth and low birth weight were associated with early onset possible severe bacterial infection.ConclusionOur results suggest that the incidence of severe bacterial infection is still high in the community of Madagascar, even if it seems lower when compared to BIRDY 1 estimates, and that existing neonatal sepsis treatment guidelines may no longer be appropriate in Madagascar. These results motivate to further strengthen actions for the prevention, early diagnosis and case management during the first 3 days of life.

The Incidence of Serious/Invasive Bacterial Diseases in Infants 90 Days Old or Younger at an Emergency Hospital in Japan.

Background The incidence of severe bacterial infections (SBIs) in infants aged ≤90 days is thought to have decreased because of widespread vaccination programs. However, relevant epidemiological data in Japan are scarce. Materials and methods This observational, single-center study investigated the epidemiology of fever in infants aged ≤90 days. SBI was defined as the presence of meningitis, urinary tract infections (UTIs), or bacteremia. Invasive bacterial infection(IBI) was defined as the presence of meningitis, bacteremic UTI, or bacteremia.We determined the incidenceof UTIs, bacteremia, meningitis, SBIs, and IBIs in the following three age groups: 0-28, 29-60, and 61-90 days. We subsequently calculated the relative incidence for the groups aged 29-60 and 61-90 days, using the group aged 0-28 days as the reference group. Results Herein, 58, 124, and 166 infants were included in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively.Of the total number of patients, 15.5%, 8.9%, and 16.9% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with SBI. The relative incidences were 1 for the 0-28 days group (reference group), 0.67 for the 29-60 days group (95% confidence interval [CI], 0.39-1.15), and 1.08 for the 61-90 days group (95% CI, 0.58-2.00). Of the total number of patients, 10.3%, 3.2%, and 0.6% in the 0-28 days, 29-60 days, and 61-90 days age groups, respectively, were diagnosed with IBI. Relative incidences were 1 (reference group), 0.50 (95% CI, 0.29-0.88), and 0.28 (95% CI, 0.19-0.41)for the 0-28 days, 29-60 days, and 61-90 days age groups, respectively. All cases of IBI were caused by Group B streptococcus (GBS), except for two cases of bacteremia, which were caused by Haemophilusinfluenzae. Conclusion The incidence of SBI was similar in the 0-28 days and 61-90 days age groups. However, the incidence of IBI decreased with increasing age. The incidence of UTIs was highest in the 61-90 days age group, and that of meningitis and bacteremia decreased with increasing age.

Low incidence of severe bacterial infections in hospitalised patients with COVID-19: A population-based registry study

Background Bacterial infections complicating COVID-19 are rare but present a challenging clinical entity. The aim of this study was to evaluate the incidence, aetiology and outcome of severe laboratory-verified bacterial infections in hospitalised patients with COVID-19. Methods All laboratory-confirmed patients with COVID-19 admitted to specialised healthcare hospitals in the Capital Province of Finland during the first wave of COVID-19 between 27 February and 21 June 2020 were retrospectively studied. We gathered the blood and respiratory tract culture reports of these patients and analysed their association with 90-day case-fatality using multivariable regression analysis. Results A severe bacterial infection was diagnosed in 40/585 (6.8%) patients with COVID-19. The range of bacteria was diverse, and the most common bacterial findings in respiratory samples were gram-negative, and in blood cultures gram-positive bacteria. Patients with severe bacterial infection had longer hospital stay (mean 31; SD 20 days) compared to patients without (mean 9; SD 9 days; p < 0.001). Case-fatality was higher with bacterial infection (15% vs 11%), but the difference was not statistically significant (OR 1.38 CI95% 0.56–3.41). Conclusions Severe bacterial infection complicating COVID-19 was a rare occurrence in our cohort. Our results are in line with the current understanding that antibiotic treatment for hospitalised COVID-19 patients should only be reserved for situations where a bacterial infection is strongly suspected. The ever-evolving landscape of the pandemic and recent advances in immunomodulatory treatment of COVID-19 patients underline the need for continuous vigilance concerning the possibility and frequency of nosocomial bacterial infections.

PB2188: APPLICATION PROSPECT OF LOW DOSE PORCINE ANTITHYMOCYTE GLOBULIN IN HLA MATCHED SIBLING DONOR TRANSPLANTATION

Background: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Aims: To investigate the preventive effect of low-dose porcine antithymocyte globulin (P-ATG) on graft versus host disease (GVHD) in HLA matched sibling donor transplantation. Methods: The clinical data of 60 patients with hematological malignancies who received MSD-HSCT from July 2020 to October 2021 were analyzed retrospectively. These patients / donors were older than 40 years old or the donors were female. Of these, 30 patients received Low-dose porcine ATG as a part of conditioning regimen (P-ATG group), while the other 30 patients didn’t receive ATG (No-ATG group). In addition to the fact that the ages of the patients and donor were older in P-ATG group, all patients’ other baseline characteristics and donor condition of the two groups were similar. Results: All patients engrafted in two groups. There were significant differences in the incidence of aGVHD ([23.3 (10.1-39.7)%] vs [50.0 (30.8-66.5)%], P = 0.0276), grade III-IV aGVHD ([16.7 (5.94-32.1)%] vs [40.0 (22.4-57.0)%], P = 0.0491) and cGVHD ([22.4 (6.03-45.1)%] vs [69.0 (43.4-84.8)%], P = 0.0009) between the P-ATG and No-ATG groups. But there was no significant difference in terms of 1-year OS ([79.9 (60.5-90.4)%] vs [84.0 (61.2-94.0)%], P = 0.4411) or RR ([13.6 (2.73-33.2)%] vs [15.2 (4.40-32.1)%], P = 0.7416). And there was also no significant difference with regard to the incidence of severe bacterial infection (P = 0.612), invasive fungal disease (P = 1.000) or CMV infection (P = 0.2976). 80% (4 / 5) of patients in P-ATG group died of secondary infection after grade III-IV aGVHD, and 16.7% (2 / 12) in No-ATG group. Summary/Conclusion: The application of low-dose P-ATG in the conditioning regimen of MSD-HSCT can significantly reduce the incidence of aGVHD, grade III-IV aGVHD and cGVHD, doesn’t increase the risk of recurrence after transplantation in patients / donors older than 40 years old or female donors. However, the patients in P-ATG group were older and had high mortality caused by secondary infection after grade III-IV aGVHD. Therefore, there was no significant difference in OS between the two groups.

Clinical Significance of Serum Immunoglobulin Level after Peri- pheral Blood Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Hematologic Malignancies

To investigate the clinical significance of post-transplantation serum immunoglobulin level in the outcome of patients with hemalologic malignancies treated by haploidentical peripheral hematopoietic stem cell transplanta-tion(Haplo-HSCT). The clinical data of 157 patients treated by haplo-HSCT were analyzed retrospectively. The overall survival rate (OS), graft versus host disease (GVHD) incidence, infection incidence, serum immunoglobulin level, the relationship of immunoglobulin levels with OS and transplant complications were analyzed. The 2-year OS rate was 59.2%(95%CI:51.6%-66.9%), 2-year relapse mortality was 11.5%(95%CI: 6.4%-16.6%), and non-relapse mortality was 29.3%(95%CI:21.7%-36.9%). The cumulative incidence of III-IV aGVHD was 16.6%(95%CI:10.8%-22.9%); the cumulative incidence of extensive cGVHD was 21.7%(95%CI:15.3%-28.6%); the cumulative incidence of severe bacterial infection within 1 year was 59.2%(95%CI:51.6%-66.2%); the cumulative incidence of invasive fungal infection was 47.1%(95%CI:38.9%-54.8%). The occurrence of extensive cGVHD after haplo-HSCT related with the gender match of donor-recipient and bacterial infection. The levels of IgG in patients with 0-II aGVHD and patients with III-IV aGVHD for 1 month after haplo-HSCT were (6.96±2.47) and (4.27±2.42) g/L （P=0.003）, IgG levels at 3 months afte haplo-HSCT were (8.71±4.47) and (6.65±2.95) g/L (P=0.038); IgG levels at 1 month after haplo-HSCT showed predictive value for III-IV aGVHD susceptibility(P=0.003); for patients with IgG<4 g/L at any time after haplo-HSCT, the incidence of extensive cGVHD was significantly increased (35.5% vs 18.3%) (P=0.037), the incidence of fungal infection within 1 year after haplo-HSCT was significantly increased(71.0% vs 41.3%) (P=0.003), and the 2-year survival rate was reduced significantly (P=0.035). Haplo-HSCT is effective for the treatment of hematologic malignancies. Patients with lower IgG at 1 month after haplo-HSCT are more likely to develop III-IV aGVHD, and IgG levels at 1 month after haplo-HSCT can predict its susceptibility to a certain extent. Patients with severe hypoimmunoglobulinemia (IgG<4 g/L) after haplo-HSCT are more likely to develop extensive cGVHD, fungal infection and show worse survival prognosis.

102 Patients with Primary Autoimmune Neutropenia : An Analysis of the European Severe Chronic Neutropenia International Registry (SCNIR)

Background: Primary Autoimmune Neutropenia (AIN) is the most frequent type of neutropenia in children with a prevalence of 1/100,000 between infancy and 10 years of age. Primary AIN is caused by anti-neutrophil antibodies binding to neutrophil-specific antigens, resulting in a decrease of circulating neutrophils in the blood, but normal numbers of mature neutrophils in the bone marrow. Typically, primary AIN is present from infancy on until spontaneous remission in early childhood, when anti-neutrophil antibodies disappear. Patients with primary AIN show severe to moderate neutropenia but only rarely suffer from serious infections. Patients remain in the registry for follow up after normalization of blood counts to evaluate late secondary events. Aims: Here we describe the cohort of AIN pts with positive anti-neutrophil antibody testing documented by the European Branch of the SCNIR. We analyzed the course of neutropenia, the frequency of G-CSF treatment for AIN, the incidence of severe bacterial infections and administration of AB prophylaxis. Methods: We identified 102 primary AIN patients within the neutropenia cohort documented by the European Branch of the SCNIR since 1994. We classified primary AIN by positive anti-neutrophil antibody testing (95 pts) or severe neutropenia in peripheral blood with normal bone marrow morphology in patients with age under 5 years (7 pts). Results: Primary AIN has been identified in 102 (61 female; 41 male) pts. The median age of the cohort is 5.18 years (range 1.37-22.71 years), with 630.28 pt years under observation. Median age at diagnosis was 12.07 months (range 0.9-70 months). All pts are currently alive, 40 patients already resolved from primary AIN at a median age of 3.02 years (range 0.83-9.08 years). Median follow-up time after neutropenia had resolved was 2.25 years (range 0-9.27 years). Sixteen of 102 pts (15.7%) received intermittent G-CSF treatment with a median dose of 4.5 µg/kg/day compared to 4.77 µg/kg/day for the congenital neutropenia cohort of the SCNIR Europe. Analysis of infections (tab.1) showed less minor and severe infections comparing to congenital neutropenia (CN) pts. Life-threatening infections like liver abscesses were not seen in primary AIN patients but in 1.8% of CN pts. Twelve AIN pts (11.7%) have received antibiotic prophylaxis for prevention of infection, 6 pts intermittent and 6 pts continuously. However, antibiotic prophylaxis was usually stopped before termination of AIN. Due to the milder course of infections most AIN pts were able to go to Kindergarten and to live a normal life. In 3 pts additional auto-immune related diseases were identified (autoimmune thrombocytopenia, allergic colitis and Kawasaki syndrome) during AIN. Sixteen of 102 AIN patients received genetic analysis, with no mutation being detected. In addition to the 102 AIN pts we identified another 31 CN pts who have initially been classified as AIN due to positive anti-neutrophil antibodies, but who were later genetically confirmed as CN (15 ELANE+, 8 HAX1+, 2 SBDS+, 2 CXCR4+, 2 CSF3R+, 1 G6PC3+). This proportion of pts showed more and more severe infections compared to primary AIN. Genetic testing has been performed in these pts due to ongoing infections and prolonged neutropenia until school age. Conclusions: Pts suffering from primary AIN present with severe to moderate neutropenia. A minority of pts might require G-CSF treatment on demand/interventionally due to antibiotic resistant infections, but long-term G-CSF treatment is regularly not indicated. Primary AIN is a self-limiting condition and in most pts neutropenia resolves until early childhood. Accumulation of secondary diagnoses like autoimmune related diseases, though postulated, has not been confirmed for AIN pts by our data. In AIN pts with severe infections, or prolonged neutropenia CN should be ruled out by genetic analysis and/or bone marrow morphology. Registries are needed to document long-term data on primary AIN pts to analyse potential additional features of primary AIN, possibly other accompanying autoimmune diseases. Disclosures No relevant conflicts of interest to declare.

Modified conditioning regimen improves outcomes of unrelated donor peripheral blood stem cell transplantation for β-thalassaemia major patients.

The objective of this study was to evaluate the feasibility of a modified conditioning regimen for the treatment of patients with β-thalassaemia major (TM), using unrelated donor peripheral blood stem cell transplantation (UD-PBSCT). A modified conditioning regimen based on intravenous busulfan, cyclophosphamide, fludarabine, and antithymocyte globulin was performed in 50 consecutive childhood patients with β-TM and a median age of 4.6 years (range, 2-12 years). According to Pesaro's classification, three classes of risk are identified using the criteria of degree of hepatomegaly, portal fibrosis, and quality of the chelation treatment. Patients with three adverse criteria constituted class III, none of the adverse criteria constituted class I, and one or two of the adverse criteria formed class II. Ten patients were class I, 36 class II, and four class III. All patients were transplanted with UDs containing 37 of 10/10 human leukocyte antigen (HLA)-matched pairs, 11 of 9/10 matched pairs, and two of 8/10 matched pairs. The median follow-up was 36 months (range, 9-96 months). All patients successfully achieved engraftment, two of whom developed persistentthrombocytopaenia. The incidence of acute graft-versus-host disease (aGVHD) grade III-IV and chronic graft-versus-host disease (cGVHD) were 12% and 8%, respectively. However, 8.3% of HLA-matched and 15.4% of HLA-mismatched patients developed aGVHD. The incidence of severe bacterial infections and fungal pneumonia was 12% and 20%, respectively. The 3-year overall survival, disease-free survival, graft rejection, and transplant-related mortality were 94%, 92%, 2%, and 6%, respectively. This modified conditioning protocol effectively improved outcomes of UD-PBSCT for patients with β-TM.

Outcomes of Immunocompetent Children Presenting with Fever and Neutropenia

BackgroundNeutropenia may alarm clinicians and prompt extensive evaluation in children with fever, even in immunocompetent patients. ObjectiveOur aim was to determine outcomes in previously healthy febrile children presenting to the emergency department with severe neutropenia. MethodsWe reviewed data from infants and children aged 3–36 months with fever and severe neutropenia, defined as a peripheral neutrophil count <500 × 103/μL, at our institution between January 1, 2012 and December 31, 2015. We compared our results to those from a similar study of children with a peripheral neutrophil count of 500–1000 × 103/μL. ResultsSevere neutropenia was recorded in 52 patients; severe bacterial infection (SBI) was found in 1 (1.9%), but none had a positive blood culture. Incidence of SBI was not different from that found in a study of similar patients with moderate neutropenia. ConclusionsImmunocompetent patients with fever and severe neutropenia do not carry a higher risk for SBI compared to patients with fever and moderate neutropenia. Such patients could potentially be followed closely with serial blood counts to ensure bone marrow recovery, without the use of antibiotics.

Effect of Antithymocyte Globulin Source on Outcomes of HLA-Matched Sibling Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Severe Aplastic Anemia

We wanted to evaluate efficacy of porcine antithymocyte globulin (ATG) in HLA-matched sibling donor allogeneic hematopoietic stem cell transplantation (MSD-HSCT) for patients with severe aplastic anemia (SAA). The clinical data of 113 SAA patients who received MSD-HSCT from January 2005 to November 2016 were analyzed retrospectively. Of these, 58 patients received rabbit ATG as a part of conditioning regimen (R-ATG group), whereas the other 55 patients received porcine ATG (P-ATG group). Patient baseline characteristics and donor conditions of the 2 groups were similar, except patients were older and more received peripheral blood stem cell transplantation in the P-ATG group. All patients engrafted in 2 groups. There were significant differences in the incidence of acute (20.7% ± 5.3% versus 43.4% ± 7.0%, P = .015) and chronic graft-versus- host disease (GVHD; 20.1% ± 5.8% versus 46.0% ± 7.9%, P = .003) between the R-ATG and P-ATG groups. However, there were no significant differences in terms of 3-year overall survival (93.1% ± 3.3% versus 84.4% ± 5.7%, P = .235), grades III to IV acute GVHD (3.4% ± 2.4% versus 12.3% ± 4.7%, P = .098), moderate to severe chronic GVHD (12.6% ± 4.9% versus 11.5% ± 4.9%, P = .905), or graft rejection (7.4% ± 3.6% versus 5.5% ± 3.1%, P = .852). There was also no significant difference with regard to the incidence of severe bacterial infection (P = .075), invasive fungal disease (P = .701), or cytomeglovirus viremia (P = .770). P-ATG showed satisfactory efficacy and safety compared with R-ATG in the setting of MSD-HSCT for SAA patients. P-ATG could be a potential alternative preparation for R-ATG, further offering the advantage of lower costs.

Genetic variation in TNFA predicts protection from severe bacterial infections in patients with end-stage liver disease awaiting liver transplantation

Augmented susceptibility to infections increases mortality in patients with end-stage liver disease (ESLD). We sought to determine the contribution of selected genetic variants involved in inflammatory signalling downstream of the Toll-like receptor 4 (TLR4) to severe bacterial infections (SBIs) in patients with ESLD. We retrospectively assessed incidence of SBIs in 336 adult ESLD patients enlisted for orthotopic liver transplantation (OLT) and genotyped them for TLR4 c.+1196C/T, CD14 c.-159C/T, TNFA c.-238G/A, TNFA c.-863C/A, IL1B c.-31C/T and IL1RN variable number of tandem repeats allelic variants. Principal findings were validated in an independent cohort of 332 ESLD patients. Thirty-four percent of patients from the identification cohort and 40% of patients from the validation cohort presented with SBI while enlisted for OLT. The presence of the variant allele TNFA c.-238A (rs361525) was associated with lower serum levels of TNF-α, and with significantly decreased risk of SBI in both cohorts. Multivariate analysis showed that the relative protection from SBI associated with this allele almost completely negated the increased susceptibility to SBI owed to advanced ESLD. Although not predictive of overall mortality, the presence of the TNFA c.-238A allele was associated with a complete prevention of SBI-related pre-transplant deaths. Our results suggest that genetic variability in inflammatory signalling is associated with the development of SBI in patients with ESLD. Specifically, we identified the importance of the TNFA c.-238A allele as a strong predictor of protection from SBI, and as a genetic marker associated with significantly improved pre-transplant survival in patients with SBI.

Severe Infections after Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation in Adults: Comparison of Cord Blood Transplantation with Peripheral Blood and Bone Marrow Transplantation

We evaluated the occurrence of severe infections in 192 consecutive adult recipients of volunteer unrelated donor allogeneic hematopoietic stem cell transplants, with a detailed analysis of severe infections after receipt of cord blood transplants (CBTs; n = 48) or bone marrow transplants (BMTs)/peripheral blood stem cell transplants (PBSCTs; n = 144). At a 3-year median follow-up, CBT recipients had a higher risk of developing any severe infection (85% versus 69% in BMT/PBSCT recipients, P < .01). CBT recipients had a higher incidence of severe bacterial infections before day +100, but at 3 years the risks of these and other infections were similar in the CBT and BMT/PBSCT groups. In addition, the 100-day and 3-year incidences of infection-related mortality (IRM) did not differ between groups ( P = .2 and .5, respectively). In multivariate analysis, the most significant risk factor for IRM in all 192 patients was monocytopenia (.2 × 10 9/L). In CBT recipients, only neutropenia (.2 × 10 9/L) on day +30 and low nucleated cell dose infusion (<2 × 10 7/kg) showed a trend for increased IRM ( P = .05 in both cases). Stem cell source had no effect on day +100 or 3-year nonrelapse mortality (NRM), cytomegalovirus infection, cytomegalovirus disease (7% versus 6%), or overall survival (36% versus 39%, respectively). The number of mismatches in HLA (A, B, and DRB1) had no effect on any outcome in CBT recipients. In contrast, in the BMT/PBSCT group, the presence of any mismatch by low or high-resolution HLA typing (A, B, C, and DRB1) increased NRM and decreased overall survival ( P < .01). IRM was the primary or secondary cause of death in 61% and 59% of CBT and BMT/PBSCT recipients who died, respectively. Our results confirm the relevance of severe infectious complications as source of severe morbidity and NRM after volunteer unrelated donor hematopoietic stem cell transplantation in adults, but suggest that CBT recipients have a similar risk of dying from an infection if an accurate selection of a cord blood unit is done.

Association of HLA-E Polymorphism with the Incidence of Severe Bacterial Infections in Sickle Cell Anemia.

While it is commonly admitted that the susceptibility to severe infections (septicemia, meningitis, or osteomyelitis) in Sickle Cell Anemia (SCA) patients is a major cause of mortality and morbidity, these complications remains poorly explained. However, several lines of evidence highlight the involvement of an immunogenetic modulation, including both innate and adaptive immune responses. HLA-E belongs to the HLA-class I non-classical family and is ubiquitously expressed. HLA-E molecules bind either to self-peptides from the leader sequences of various HLA-class I molecules and thus modulate NK (Natural killer) cell activation/inhibition, or to the microbial derived-peptides from human viruses or bacteria to induce T cell responses. Only two functional alleles, HLA-E*0101 and HLA-E*0103, differing by a single amino acid substitution in the α2 heavy chain domain and by their cell surface expression level, have been reported so far. In order to evaluate whether the HLA-E polymorphism could influence the incidence of severe bacterial infections in SCA, we analyzed a cohort of 99 SCA patients living in Paris, but for the majority, originating from black Africa. All patients were older than 5 years of age at inclusion. Among the cohort, 51 presented at least one severe bacterial infection and 48 did not disclose any major infectious episode in their clinical history. Statistical analysis showed that the incidence of severe bacterial infections are high when the patient's genotype was HLA-E*0101/E*0101 (47% in the first group versus 21% in the second group; χ2 = 7.54 p = 0.006, pc = 0.01, OR: 3.28, [95%CI = 1.28–9.07]), supporting a negative effect of this genotype. The genetic association herein found between HLA-E polymorphism and severe bacterial infections is of relevance, given the emerging evidence for the involvement of HLA-E molecules in pathogen-derived peptide presentation to human CD8+ T cells and hence in host response to pathogens. Furthermore, these data are in agreement with our previous findings in bone marrow transplantation settings, were the homozygous state for HLA-E*0101 allele is also a risk factor for early severe bacterial infections. Both situations by constitutively lowering the overall threshold of resistance to infection, might unmask anti infectious genetic factors normally silent.

COMPARISON OF INDUCTION THERAPY BASED ON CONTINUOUS VS. DISCONTINUOUS ADMINISTRATION OF ANTI-THYMOCYTE GLOBULINS IN RENAL-TRANSPLANT PATIENTS: EFFICACY AND LONG-TERM SAFETY

P767 Aims: The aim of our retrospective study was to compare two modes of administration of anti-thymocyte globulins (ATG) after renal transplantation. Methods: Before 1993, patients (group I, n=93) received fixed daily doses of ATG, i.e.,1 mg/kg for 8 consecutive days. Thereafter, ATG was either continued at the same dose for 15 days, in the case of delayed graft function, or was infused every other day at the same dose until serum creatinine level became <150 μmol/L. After 1993, patients (group II, n=66) received ATG at full dose (1 mg/kg/day) during the first 3 days and, thereafter, doses (1 mg/kg) were adapted according to CD2 lymphocyte count (in order to target CD2 T cells <50/mm3). Both groups received steroids, azathioprin, and cyclosporine A. The mean follow-up after transplantation was 116 ± 29 months in group I and 91 ± 17 months in group II. Results: ATG cumulative dose was significantly higher in group I than in group II (9.7 ± 4.5 vs. 7.4 ± 3.2 mg/kg, p=0.0002) and, consequently, ATG cost was higher in group I ($4155 ± 1829) than in group II ($3299 ± 1387, p = 0.01). Long-term patient survival and graft survival were similar in both groups at, respectively, 92.5% and 85% in group I and 93.9% and 94% in group II (p=ns). In contrast, the number of acute graft-rejection episodes was significantly higher in group I than in group II (40.9 vs. 15%, p=0.0005). The number of CMV reactivations was more important in group II (51 vs. 24%, p=0.031), which resulted in a higher proportion of CMV seropositive recipients in this group (29 vs. 3%, p=0.004). At 7 years after transplantation, serum creatinine level and creatinine clearance were similar in the two groups. Finally, the cumulative incidence of severe bacterial infections (48% in group I vs 50% in group II, p=ns) and cancers (36 % in group I vs 39 % in group II, p=ns) in the long term were also similar in both groups. Of all cancers, skin’s ones represented 30% in group I and 26 % in group II (p=ns). The time between the transplantation and the occurrence of a cancer was lower in group I as compared to group II (111 vs 85 months, p=0.03). In contrast, the time between the transplantation and the occurrence of a skin cancer was similar in both groups (115.34 vs 93.6 months, p=ns). Conclusion: In conclusion, adapting ATG doses according to CD2 lymphocyte count is safe and is less expensive than using full doses

Long-term follow-up and outcome of 39 patients with chronic granulomatous disease

Objectives: To evaluate the clinical long-term course in patients with chronic granulomatous disease (CGD) with respect to different CGD subtypes and currently used antimicrobial prophylactic measures. Study design: The records of 39 patients with CGD who were monitored during a period of 22 years were reviewed. All infections, infectious complications, and clinical outcomes were documented for a total observation period of 610 patient-years and were stratified with respect to different CGD subtypes. Results: Lymphadenitis, skin abscesses, and pneumonia occurred in 87%, 72%, and 59% of the patients, respectively. In 151 microbiologic isolates Staphylococcus aureus , Aspergillus species, Candida species, Pseudomonas species, and Salmonella species were the most frequently detected microorganisms. There were 167 severe infections requiring hospitalization and intravenous antimicrobial treatment, resulting in an incidence of 3.7 severe infections per 100 patient months (SI/100 PM). Long-term antibiotic prophylaxis significantly reduced the incidence of severe bacterial infections from 4.8 SI/100 PM to 1.6 SI/100 PM (P =.0035). In contrast, fungal infections increased under antibiotic prophylaxis from a mean incidence of 0.2 SI/100 PM to 1.9 SI/100 PM (P =.04). We found a 50% survival rate through the fourth decade of life, with a plateau after the third decade of life. Patients with a complete absence of cytochrome b558 showed an earlier manifestation of their disease and a higher incidence of infections and had significant lower survival than patients with only diminished cytochrome b558 or autosomal recessive CGD. Conclusions: Infections with Aspergillus species have become the major cause of infectious complications and death in patients with CGD. Prophylactic and therapeutic measures are needed to further increase life expectancy and quality for patients with CGD. (J Pediatr 2000;137:687-93)

Clinical experience with Filgrastim in AIDS.

Data have shown that neutropenia is a risk factor for severe bacterial infections. Two trials were done in HIV-infected patients to study the effect of Filgrastim on neutropenia and the incidence of severe bacterial infections. The incidence of Mycobacterium avium complex (MAC) infection in this setting was also evaluated. This paper reviews the results of these two studies, which suggest that Filgrastim is safe and effective in preventing severe neutropenia in patients with advanced HIV infection.

INCIDENCE OF MAJOR INFECTIONS IN CHILDREN WITH DISEASE CAUSED BY THE HUMAN IMMUNODEFICIENCY VIRUS (HIV)

42 children with HIV disease documented by positive serology have been followed at our institution over the last three years. 27 children presented with and continue to have clinical picture of AIDS-related complex. 15 developed major infections. These were Pneumocystis carinii (8), disseminated M. avium (3), disseminated CMV (1), pneumococcal meningitis (2) and pneumococcal endocarditis (1). Intravenous gammaglobulin is not routinely used in children with HIV disease at our institution. It will be informative to know if our incidence of severe bacterial infections is different from institutions where this treatment is routine. Prospective randomized trial to determine the efficacy of this treatment is in order.

Splenic Hypofunction in the Nephrotic Syndrome of Childhood

The reticuloendothelial system, including the spleen, subserves important immunologic functions. Loss of splenic function results in an increased incidence of severe bacterial infections and is accompanied by thrombocytosis. Several nephrotic children were noted to have remarkably high platelet counts and predisposition to bacterial infection with encapsulated organisms. We, therefore, investigated the splenic function of nine children with primary nephrotic syndrome and measured the phagocytic function of the spleen by sequestration of Technetium-99-labelled heat-treated autologous RBC, administered intravenously. Four children had decreased splenic function. Repeat studies performed in two of these children after remission of the nephrotic syndrome gave normal results. There were six episodes of bacterial infection (3 peritonitis, 1 septic arthritis, 1 cellulitis, and 1 Escherichia coli urinary tract infection) among the four patients with decreased splenic function. There were no episodes of bacterial infection among the five nephrotic children with normal splenic function. Nephrotic patients with decreased splenic function had significantly increased platelet counts (921,000 +/- 196,000; mean +/- SEM) compared to those with normal function (435,000 +/- 46,000; P less than 0.001). Our findings suggest the possibility that some nephrotic children may have decreased splenic function in association with increased susceptibility to bacterial infections.