Early Severe Infections Research Articles

The Role of RSV Infection in Asthma Initiation and Progression: Findings in a Mouse Model

Respiratory syncytial virus (RSV) is a common cause of severe lower respiratory tract diseases (bronchiolitis and pneumonia) during infancy and early childhood. There is increasing evidence which indicates that severe pulmonary disease caused by RSV infection in infancy is associated with recurrent wheezing and development of asthma later in childhood. However, the underlying mechanisms linking RSV infection to persistent airway hyperresponsiveness and dysfunction are not fully defined. To study these processes in ways which are not available in humans, animal models have been established and have provided valuable insight into the pathophysiology of RSV-induced disease. In this paper, we discuss experimental models of RSV infection in mice and highlight a new investigative approach in which mice are initially infected as neonates and then reinfected later in life. The findings shed light on the mechanisms underlying the association between early severe RSV infection and development of asthma later in childhood.

Analysis of early-stage infection risk factors after living donor liver transplantation in 25 children

Living donor liver transplantation (LDLT), which was first demonstrated in 1989, has now been widely used to cure many late-stage hepatic diseases and has achieved huge success, especially in the pediatric field. However, accumulated studies indicate that early-stage infection after LDLT is the main cause leading to its failure and the death of the patient. Here, we retrospectively analyzed 25 cases (from 2006 to 2009) of infections of children in our hospital, underwent LDLT and their correlated factors. To identify the factors most closely related to early stage infection, we categorized early stage infection levels as either mild, moderate or severe and we compared their related risk factors, including total length of stay in hospital (TLSH), length of stay in the intensive care unit (LSI), duration of catheterization (DC), length of pre-/post-operative antimicrobial agent application, length of immuno-suppressant agent application (LISA) and underlying diseases postoperatively. The results revealed the following. (i) Of 25 patients, 24 recipients were infected to various extents: 6 cases of mild infection, 14 cases of moderate infection and 4 cases of severe infection (one patient died). (ii) TLSH, LSI and durations of preoperative (DPAA) and postoperative (DPOAA) antimicrobial agent application were statistically different between the severe and moderate infection groups (P = 0.03 (TLSH), 0.004 (LSI), 0.003 (LAPP), 0.005 (DPOAA). (iii) Between the severe and mild infection groups, the TLSH (P = 0.016), LSI (P = 0.015), DAPP (P = 0.007) and DPOAA (P = 0.001) were also significantly different. (iv) In the case of LISA, only methylprednisolone (P = 0.01) and the calcineurin inhibitor ciclosporin A (P = 0.009) showed statistically significant differences between the moderate and mild infection groups. (v) Biliary atresia is the predominant underlying liver disease. (vi) In contrast to previous findings, there was no significant difference in DC among the three infection groups. (vii) Of all the 25 patients, 24 survive till now and the only one died was diagnosed as portal vein thrombosis (PVT) combined with high white blood count (>30 x 109/l) in venous blood. DPAA, DPOAA and biliary atresia are the risk factors most closely related to infection during liver transplantation in children, an observation worthy of future investigation. To avoid long term DPAA and long term DPOAA induced early severe infection, nosocomial infection control and drug resistant bacteria monitoring are worthy to be concerned after LDLT in children. Key words: Living donor liver transplantation, risk factor, children.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Haematological Lymphoid Malignancies: Long Term Follow-up in a Single Centre Series.

Abstract 4326 BackgroundPatients (pts) with recurrent and refractory haematological lymphoid malignancy (HLM) have a very limited survival expectance. RIC allo-SCT has been proposed as a strategy for retaining the graft versus malignancy effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 32 pts treated by RIC allo-SCT. Patients and methodsBetween April 2001 and November 2007, 32 pts with HLM underwent RIC allo-SCT with an HLA-identical sibling donor. Fifteen pts with multiple myeloma, 7 pts with Non-Hodgkin lymphoma, 6 pts with Chronic lymphoid leukaemia, 3 pts with Hodgkin lymphoma and 1 pt with Waldenstrom disease. At time of allo-SCT, 10 pts were in complete remission (3 received prior autologous transplant) and 22 in refractory/progressive disease (6 received prior autologous transplant). Median age was 38 years (range, 28-60) and the sex-ratio (M/F) 2,2. Median time from diagnosis to RIC allo-SCT was 18 (range,6-76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 6,2.106/kg (range, 1.9-13,6). ResultsNeutropenia occurred in all pts (100%) and the median duration of aplasia was 9 (range, 5-16) days. Only 10 pts (31 %) required red blood cells transfusions and 23 pts (71 %) needed platelets transfusions. Acute GVHD was observed in 15 cases (47 %) including 10 cases of grade II-IV. Fifteen pts (75 %) had chronic GVHD, of whom 9 with an extensive form. Four pts (12 %) had CMV reactivation at a median time 60 (range, 52-80) days after transplantation. Six pts (18 %) had late onset relapse at a median time of 13 (range, 4-45) months. TRM was 43 % at one year after RIC allo-SCT. With a median follow-up of 60 (range 18-97) months, 12 pts (37,5 %) are still alive in complete remission with full donor chimerism. Twenty pts (62,5 %) have died (5 early severe infections, 10 GVHD, 3 after relapse, one myocardial infarction, and one accident). Overall and progression-free survivals at 8 years are 31 % and 30 % respectively. ConclusionThis study, after a large follow-up, suggests that RIC allo-SCT is a potential therapy for refractory or progressive HLM. However, TRM is still high likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Disclosures:No relevant conflicts of interest to declare.

High rate of infection and immune disorders in patients with hepatitis C virus after liver transplantation

The aim of this prospective study was to analyze the incidence of serious infections and changes in immunological markers after liver transplantation (LT) in a cohort of patients with hepatitis C virus (HCV). This study included 34 patients who had LT, 20 patients with HCV etiology (HCV group), and 14 patients with alcoholic etiology (non-HCV group). Patients with HCV were more likely to have severe infections (80%) in comparison with patients in the non-HCV group (42%) (P=0.05). The HCV group had a 3-fold greater likelihood of early severe bacterial infections than the non-HCV group. At 1 week post LT, the HCV group showed higher values of CD19+ B cells/microL than the non-HCV group (P<0.05). At weeks 4 and 12 post LT, the HCV group had lower values of CD19+ B cells/microL (P<0.05). Our data suggest that HCV recurrence after LT was associated with a high incidence of early severe infections and immunological alterations, which may be related to this increased risk.

Reduced Intensity Conditioning (RIC) Allogeneic Stem Cell Transplantation (allo-SCT) in Patients with Multiple Myeloma (MM): Long Term Follow-up in a Single Centre Series

Background: RIC allo-SCT has been proposed as a strategy for retaining the graft versus myeloma effect of allo-SCT while decreasing transplant related mortality (TRM). Here, we retrospectively studied a series of 15 patients (pts) with MM treated by RIC allo-SCT.Patients and methods: Between April 2001 and December 2007, 15 pts with MM underwent RIC allo-SCT with an HLA-identical sibling donor. Initially, 8 pts had MM with Ig G, one IgA, 2 light chains, 3 non-secretory and one undetermined. Three pts were stage II and 12 stages III. At time of allo-SCT, 6 pts were in complete remission and 9 in refractory/progressive disease (2 received prior autologous transplants). Median age was 48 years (range, 38–60) and the sex-ratio (M/F) 1,5. Median time from diagnosis to RIC allo-SCT was 18 (range, 6–76) months. The conditioning regimen included Fludarabine 150mg/m2 and Melphalan 140mg/m2. GVHD prophylaxis consisted of association cyclosporine (cSA) and mycophenolate (MMF). All pts received G-CSF mobilised peripheral blood stem cells, with a median CD34+ cell count: 4,5.106/kg (range, 1.92–13).Results: Neutropenia occurred in all pts and the median duration of aplasia was 8 (range, 5–14) days. Only 3 pts (20 %) required red blood cells transfusions and 12 pts (80 %) needed platelets transfusions. Acute GVHD was observed in 6 cases (40 %) including 4 cases of grade II–IV. Eight pts (72 %) had chronic GVHD, of whom 5 with an extensive form. Three pts (20 %) had CMV reactivation at a median time 91 (range, 53–158) days after transplantation. Four pts (26 %) had late onset relapse at a median time of 826 (range, 248–1370) days. TRM was 33 % at one year after RIC allo-SCT. With a median follow-up of 50 (range 14–86) months, 5 pts (33 %) are still alive in complete remission with full donor chimerism. Ten pts (66 %) died (2 early severe infections, 3 acute GVHD, 3 after relapse, one myocardial infarction, and one public highway accident). Overall and progression-free survivals at 7 years are 37,5 % and 31,2 % respectively.Conclusion: This study suggests that RIC allo-SCT is a potential therapy for relapsed MM. However, TRM and relapse remain a matter of concern, likely due to the inclusion of refractory and heavily pretreated pts with many comorbid conditions. Future protocols, should aim for better patient selection, focussing on those pts in first chemosensitive relapse.

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.

9. Incidence and risk factors for early severe infections after UCB

9. Incidence and risk factors for early severe infections after UCB

Association of HLA-E Polymorphism with Severe Bacterial Infection and Early Transplant-Related Mortality in Matched Unrelated Bone Marrow Transplantation

Despite prophylactic measures, susceptibility to severe infections in patients who had undergone bone marrow transplantation (BMT) is quite variable. To evaluate the potential role of human leukocyte antigen (HLA)-E polymorphism on the incidence of early infections, we analyzed 77 unrelated-donor (UD) BMT pairs identically matched for classical HLA class I and class II alleles. Multivariate analysis taking into account the patient-, donor- and transplant-related factors showed that bacterial infections and transplant-related mortality (TRM) at day 180 were high when the donor genotype was HLA-E*0101/E*0101 (hazard ratio [HR]=2.20; P=0.03 and HR=2.12, P=0.048, respectively), suggesting that homozygous state for HLA-E*0101 allele is a risk factor for early severe bacterial infections and TRM in UD-BMT.

Incidence and Risk Factors of Early Severe Infections after Unrelated Cord Blood Transplantation. an Eurocord-Netcord Analysis.

Delayed neutrophil recovery and higher incidence of infections episodes have been observed after unrelated cord blood transplant (UCBT). However, no data is available on the incidence, type and risk factors for severe infections after UCBT. We have analyzed retrospectively 510 UCBT performed from 1994 to 2002 in 55 Eurocord centers. The median age was 6.9 years, the median follow-up for survivors was 36.6 months (3–100); 396 (77%) patients had hematological malignancies, 65 (13%) inborn errors and 49 (10%) bone marrow failure. Conditioning was TBI based in 50% and associated to ATG/ALG in 86%. CsA and corticoides for GVHD prophylaxis was frequently used (77%) and 269 patients (53%) received hematopoietic growth factor. The donor was more frequently 5/6 (n=216, 43%) or 4/6 (n=204, 41%) HLA disparate. The median number of nucleated cells and CD34+ cells infused was 3.8x10e7/kg and 1.6 x10e5/kg, respectively. 95% of the patients were transplanted in a LAF room. Prophylaxis of infections varied among centers. Incidence of first infections were analysed using competing risk analysis; risk factors were studied using cumulative hazard analysis of all infectious episodes occuring during 100 days after UCBT.Results: Cumulative Incidence (CI) of neutrophil recovery, acute GVHD (II–IV), and 100 days mortality were 75%, 38% and 32% respectively. CI at day 100 of first overall, bacterial, viral and fungal infections were respectively 69%, 49%, 32% and 10%. During the first 100 days, 686 severe infections episodes were diagnosed in 352 patients. A total of 404 episodes were from bacteria origin: 276 gram +; 124 gram- and 4 others, 189 severe viral infections or diseases episodes (142 CMV, 21 adenovirus, 12 EBV and 12 Herpes simplex or HHV6 and 2 para-myxo-virus, 54 episodes of severe fungal infections (26 candidemia, 20 aspegillus and 8 other), 5 episodes were of toxoplasmosis and 34 episodes were not classified. In a multivariate analysis the following factors decreased the cumulative hazard of 1) bacterial infections: shorter time to engraftment (HR: 0.22, p<0.0001); 2) viral infections: negative CMV serology (HR: 0.28, p<0.001); less than 3 out of 6 HLA disparate (HR: 0.21, p=0.03) and shorter time to engraftment (HR: 0.40, p=0.002); and finaly for 3) fungal infections: recipient's age <16 years (HR: 0.10, p=0.004), malignant disease (HR:0.13, p=0.03), shorter time to engraftment (HR:0.17, p=0.02); and absence of acute GVHD III-IV (HR 0.24, p=0.03). Considering all types of infections, among the factors cited above, period of UCBT performed (after 1998) was also associated with a decreased hazard of severe infections at day 100.In conclusion, in this retrospective analysis, bacterial infections appeared early, followed by viral and fungal infections during the first 100 days after UCBT. Delayed engraftment was frequently associated with increased risk of all types of infections. Aproaches that will improve time to engraftment after UCBT might decrease the incidence and severity of early infections after UCBT.

Lnterleukin-8 and procalcitonin in early diagnosis of early severe bacterial infection in critically ill neonates.

We studied the value of serum interleukin-8 (IL-8) and procalcitonin (PCT) in the early diagnosis of early severe bacterial infection in 58 critically ill ventilated neonates. ELISA was used for determining IL-8 and immunoluminometric assay for PCT. IL-8 and PCT were compared with routinely used serum C-reactive protein (CRP). Neonates were divided into four groups: Ia - proven severe bacterial infection (n = 9), Ib - clinical sepsis (n = 16), II - respiratory distress without bacterial infection (n = 12), and III - various types of neonatal distress (n = 21). Sera were collected on admission, at 24 h and 48 h after admission. There was no significant difference between groups Ia and Ib for either parameter at any time interval. Significant difference was found between group Ia+b (septic neonates) and group II for PCT and CRP at 24 and 48 h, but not for IL-8. There was no difference between group Ia+b and group III except for CRP at 24 h. Diagnostic accuracy was best for PCT on admission and for CRP at 24 h. Serum PCT and IL-8 are not specific markers for early severe bacterial infection in critically ill neonates and are not better than CRP.

Lnterleukin-6 (IL-6) and soluble receptors for interleukin-2 (slL-2R) in the diagnosis of early severe infection in the critically ill newborns.

The aim of our study was to evaluate the diagnostic accuracy of serial determination of interleukin-6 (IL-6) and soluble receptors of interleukin-2 (sIL-2R) in the diagnosis of early infection in the critically ill newborns and compare it with the routinely used C-reactive protein (CRP). Fourty-six critically ill newborns (median age 8 h, range 1-96 h), treated at the multidisciplinary intensive care unit, Division for Paediatric Surgery and Intensive Care, University Medical Centre Ljubljana, were included in the study. Newborns were divided into three groups: group I microbiologically confirmed severe infection (n = 14), group II suspected but not confirmed infection (n = 12) and group III respiratory distress syndrome without laboratory signs of infection. Serum concentrations of IL-6, sIL-2R and CRP were determined on admission and at 12 and 24 h after admission. On admission the concentrations of IL-6 and sIL-2R were significantly higher in group I than in group III, but there was no difference between groups I and II. On admission area under receiver operating characteristic (ROC) curve for IL-6 was 0.756, for IL-2R 0.821 and for CRP 0.799. Repeated determination at 12 h improved diagnostic accuracy for sIL-R and CRP but not for IL-6.

Les infections à entérovirus du nourrisson de moins de trois mois

Enterovirus infections in childhood (echoviruses, coxsackie viruses A and B, unclassified enteroviruses) are varied, nonspecific and benign (except for poliovirus infections). However, in infants, they may lead to severe neurological or cardiac lesions. In neonates, enterovirus infections are difficult to distinguish from late-onset bacterial infection. Maternal-fetal or postnatal transmission can induce early spontaneous abortions or severe neonatal infections. Diagnosis is usually based on viral cultures and, in recent years, on PCR techniques. At the present time, no potential effective drug is available: intravenous immunoglobulins, immunization or anti-proteases may be of interest.

Socioeconomic status, number of siblings, and respiratory infections in early life as determinants of atopy in children.

Asthma and allergic disorders have been on the increase in recent decades, especially among children living in affluent countries; some aspects of the "Western" way of life may explain this trend. We evaluated the relation of aeroallergen skin test reactivity with socioeconomic status, number of siblings, and respiratory infections in early life. We examined a total of 2,226 schoolchildren, ages 7-11 years, in three areas of Lazio, Italy. Skin prick tests were performed to assess atopic status, and self-administered questionnaires were completed by the parents. The prevalence of prick test positivity was greater among children whose fathers were in the highest educational level than among those in the lowest [prevalence ratio (PR) = 1.58; 95% confidence interval (CI) = 1.21-2.06]. There was also a lower prevalence of atopy among larger sibships (PR = 0.38 for subjects with four or more siblings vs those without siblings; 95% CI = 0.14-0.99). A history of bronchitis or bronchiolitis before age 2 years was weakly associated with an increased risk of atopy, whereas a history of pertussis or pneumonia was not. Both the effect of father's education and the influence of larger sibship size remained when we adjusted for several potential confounding factors, including respiratory infections in early life. We infer that higher socioeconomic status and lower sibling number are determinants of atopy in this Italian population. Protection arising from early severe respiratory infections does not explain this association, although we cannot exclude a role for other viral infections.

Le sida de l'enfant Africain

It is estimated in the absence of reliable data that 200,000 children, 90% of them in Africa and the Caribbean, became infected with HIV through 2989. 1.5 million fertile-aged women were also infected. A 25% increase in mortality among children under 5 in Africa is 1 probable result. A doubling or tripling of mortality among adults will cause a fertility decline and an increase in infant mortality due to malnutrition. 200,000 children are expected to be orphaned by AIDS by 1992. 60-70% of seropositive African children are believed to have been infected by their mothers. Over half of infants born to mothers seropositive for HIV1 develop the disease. Reasons why vertical HIV1 transmission is apparently more likely than in Europe are not yet known. Vertical transmission of HIV2 is apparently much less likely. Contamination by blood transfusions is still very frequent. Although data are scarce, contamination through broken skin is known to occur, through use of infected syringes, during traditional scarification or circumcisions, during delivery in certain maternity centers when scarce tools are reused to cut the umbilical cord. There is some risk of contamination through mother's milk, but it is greatly exceeded by the benefits to infants of breastfeeding, especially in impoverished families. 10-30% of AIDS cases in children develop before 6 months and are manifested by polyadenopathic syndrome, hepatosplenomegalies, persistent and invasive esophageal and perhaps cutaneous candidiasis, prolonged or recurring fever, and failure to grow. Pulmonary complications are frequent. After 6 months, initial manifestations of the disease are more varied. Very often there is a severe and rapid decline in the general state of health, ending in marasmus with opportunistic infections. Tuberculosis is frequent. Anemia, bleeding problems, and cutaneous signs are common. Laboratory diagnoses are not available in most African health services. A clinical finding of 3 or 4 signs of AIDS in the absence of known cause of immunodeficiency is most often the basis for diagnosis of AIDS. A positive ELISA result in a child with strong clinical signs of AIDS may be considered sufficient evidence, but there are numerous potential causes of error. AIDS typically progresses very rapidly in African children, with early initial signs, frequent and severe infections, delays in diagnosis and treatment, and interactions with malnutrition. Children of seropositive mothers should be monitored carefully. Even if not infected at birth, they face grave risks when their mothers become ill. Seropositive children should receive all schedule vaccinations as long as they remain asymptomatic. Health care personnel should minimize blood transfusions, sterilize all materials, and inform the public about HIV infection and its prevention. Educational campaigns are still the only true means of combatting AIDS.