Long-term Infection Risk Research Articles

Cumulative incidence and risk of infection in patients with rheumatoid arthritis treated with janus kinase inhibitors: A systematic review and meta-analysis.

Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19-1.52) and opportunistic (RR 2.69; 95% CI: 1.22-5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05-1.39), peficitinib (RR 1.40; 95% CI: 1.05-1.86) and upadacitinib (RR 1.30; 95% CI: 1.09-1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents.

Diminished measles immunity after paediatric liver transplantation-A retrospective, single-centre, cross-sectional analysis.

Liver transplantation in childhood has an excellent long-term outcome, but is associated with a long-term risk of infection. Measles is a vaccine-preventable infection, with case series describing severe courses with graft rejection, mechanical ventilation and even death in liver transplant recipients. Since about 30% of liver transplanted children receive liver transplants in their first year of life, not all have reached the recommended age for live vaccinations. On the contrary, live vaccines are contraindicated after transplantation. In addition, vaccination response is poorer in individuals with liver disease compared to healthy children. This retrospective, single-centre, cross-sectional study examines measles immunity in paediatric liver transplant recipients before and after transplantation. Vaccination records of 239 patients, followed up at Hannover Medical School between January 2021 and December 2022 were analysed. Twenty eight children were excluded due to stem cell transplantation, regular immunoglobulin substitution or measles vaccination after transplantation. More than 55% of all 211 children analysed and 75% of all those vaccinated at least once are measles seropositive after transplantation-48% after one and 84% after two vaccinations-which is less than in healthy individuals. Interestingly, 26% of unvaccinated children also showed measles antibodies and about 5-15% of vaccinated patients who were seronegative at the time of transplantation were seropositive afterwards, both possibly through infection. In multivariable Cox proportional hazards regression, the number of vaccinations (HR 4.30 [95% CI 2.09-8.83], p<0.001), seropositivity before transplantation (HR 2.38 [95% CI 1.07-5.30], p = 0.034) and higher age at time of first vaccination (HR 11.5 [95% CI 6.92-19.1], p<0.001) are independently associated with measles immunity after transplantation. In contrast, older age at testing is inversely associated (HR 0.09 [95% CI 0.06-0.15], p<0.001), indicating a loss of immunity. Vaccination in the first year of life does not pose a risk of non-immunity. The underlying liver disease influences the level of measles titres of twice-vaccinated patients; those with acute liver failure being the lowest compared to children with metabolic disease. In summary, vaccine response is poorer in children with liver disease. Liver transplant candidates should be vaccinated before transplantation even if this is earlier in the first year of life. Checking measles IgG and re-vaccinating seronegative patients may help to achieve immunity after transplantation.

Prevalence of infectious diseases in preterm infants: a 2-year follow-up from the Japan Environment and Children’s Study

Evidence regarding the long-term risk of infections in preterm infants is lacking. In this study, we examined whether preterm infants developed various common childhood infections more frequently than full-term infants by the age of 2 years by analyzing data from a questionnaire completed by 67,282 mother–toddler pairs in a nationwide birth cohort study. Of the target population, 2885 (4.3%) were born prematurely. After covariate adjustment for maternal and children factors, lower respiratory tract infections appeared more frequent in preterm than in full-term infants at both 1 and 2 years (adjusted odds ratio [aOR] 1.21, 95% confidence interval [CI] 1.05–1.41, and aOR 1.27, 95% CI 1.11–1.46, respectively). However, there was no significant difference in the frequencies of lower respiratory tract infection between preterm and full-term infants after Palivizumab administration. The risk of other common infections, such as in the upper respiratory tract infection, otitis media, urinary tract infection, gastroenteritis, herpangina, hand-foot-and-mouth disease, chickenpox, influenza virus, and adenovirus infections, was not higher in preterm than in full-term infants after covariates adjustment for maternal and children factors. These findings suggest Palivizumab prophylaxis could reduce the frequencies of lower respiratory tract infection in preterm to the same level as in full-term infants.

Infectious consequences of the AKI-to-CKD transition.

Acute kidney injury (AKI) is associated with short- and long-term complications but the consequences of the AKI-to-CKD transition are still poorly understood. We aimed to evaluate the association between the AKI-to-CKD transition and the long-term risk of infection. This retrospective study included patients admitted in a tertiary hospital with community-acquired AKI in 2013 and 2014 who had their estimated glomerular filtration rate (eGFR) assessed at 3months (±2weeks) after serum creatinine peaked in the AKI episode. Key exclusion criteria were baseline CKD or confounding factors (active neoplasia, primary immunodeficiency, human immunodeficiency virus, immunosuppressive drugs). The association between the AKI-to-CKD transition (defined as an eGFR <60ml/min/1.73m2 at 3months) and long-term infections (defined using clinical features, blood/urine analysis, cultures and imaging) was assessed during a follow-up of 9months (range 2-56). Among the 1731 patients admitted with AKI, 367 (21%) were included in the present analysis (64% male, 71±15years). Three months after AKI, 159 (43%) developed AKI-to-CKD transition. Baseline and post-AKI eGFR were independent predictors of AKI-to-CKD transition [hazard ratio (HR) 0.97, P=.044 and HR 0.96, P<.001, respectively].During follow-up, 153 (42%) patients developed an infection. Factors associated with infection were older age, cognitive impairment, lower post-AKI eGFR, eGFR loss from baseline to 3months and AKI-to-CKD transition. Adjusted Cox regression showed that baseline eGFR, 3-month eGFR, eGFR loss and AKI-to-CKD transition were independent predictors of the long-term risk of infection. The AKI-to-CKD transition independently predicts the long-term risk of infection following an episode of AKI.

Association between continuous-flow left ventricular assist device infections requiring long-term antibiotic use and post-heart transplant morbidity and mortality.

There exists controversy regarding the impact of infection in patients with a left ventricular assist device (LVAD) on post-heart transplant outcomes. This study evaluated the association between infections during LVAD support and the risk of early and late post-heart transplant infection, rejection, and mortality in transplant recipients bridged with an LVAD. This is a single-center retrospective observational cohort study of consecutive adults supported with a continuous flow LVAD undergoing heart transplant between 2006 and 2019 at the Toronto General Hospital. The grade of LVAD infection was classified as per International Society of Heart and Lung Transplantation guidelines. Patients were divided into three groups: (1) patients with LVAD-specific infection confirmed with positive cultures requiring long-term antibiotic use until the time of transplant; (2) patients with any type of infection in whom antibiotics were stopped at least 1 month before transplant; (3) patients without any infections between LVAD implant and transplant. Logistic regression and Cox proportional hazard models were used to evaluate early- and late-post transplant outcomes, respectively. We included 75 LVAD recipients: 16 (21%) patients had a chronic LVAD-related infection on suppressive antibiotics, 30 (40%) had a resolved infection, and 29 (39%) had no infections. During a median post-transplant follow-up time of 4 (2 to 7) years, 65 (87%) patients developed infections, 43 (64%) rejections, and 17 (23%) deaths. Both short- and long-term risks of infection, rejection, and mortality did not differ significantly among the groups. LVAD patients with infections did not have a significantly higher risk of infection, rejection, or mortality at any time point after transplant.

Alveolar Macrophages: Adaptation to Their Anatomic Niche during and after Inflammation.

At the early stages of life development, alveoli are colonized by embryonic macrophages, which become resident alveolar macrophages (ResAM) and self-sustain by local division. Genetic and epigenetic signatures and, to some extent, the functions of ResAM are dictated by the lung microenvironment, which uses cytokines, ligand-receptor interactions, and stroma cells to orchestrate lung homeostasis. In resting conditions, the lung microenvironment induces in ResAM a tolerogenic programming that prevents unnecessary and potentially harmful inflammation responses to the foreign bodies, which continuously challenge the airways. Throughout life, any episode of acute inflammation, pneumonia being likely the most frequent cause, depletes the pool of ResAM, leaving space for the recruitment of inflammatory monocytes that locally develop in monocyte-derived alveolar macrophages (InfAM). During lung infection, the local microenvironment induces a temporary inflammatory signature to the recruited InfAM to handle the tissue injury and eliminate the pathogens. After a few days, the recruited InfAM, which locally self-sustain and develop as new ResAM, gain profibrotic functions required for tissue healing. After the complete resolution of the infectious episode, the functional programming of both embryonic and monocyte-derived ResAM remains altered for months and possibly for the entire life. Adult lungs thus contain a wide diversity of ResAM since every infection brings new waves of InfAM which fill the room left open by the inflammatory process. The memory of these innate cells called trained immunity constitutes an immunologic scar left by inflammation, notably pneumonia. This memory of ResAM has advantages and drawbacks. In some cases, lung-trained immunity offers better defense capacities against autoimmune disorders and the long-term risk of infection. At the opposite, it can perpetuate a harmful process and lead to a pathological state, as is the case among critically ill patients who have immune paralysis and are highly susceptible to hospital-acquired pneumonia and acute respiratory distress syndrome. The progress in understanding the kinetics of response of alveolar macrophages (AM) to lung inflammation is paving the way to new treatments of pneumonia and lung inflammatory process.

Coincidental splenic irradiation and risk of functional hyposplenism in oesophageal cancer treatment

Definitive chemoradiotherapy (dCRT) and radical radiotherapy are central to the management of distal oesophageal carcinoma. This study sought to establish whether the spleen receives a significant incidental radiation dose when treating distal oesophageal carcinoma with the standardised dCRT or radical radiotherapy doses. In this single-centre retrospective study, all patients (n = 34) with distal oesophageal cancer, treated with either dCRT or radical radiotherapy over an 18-month period using a volumetric modulated arc therapy (VMAT) planning technique, were included. The median age was 74 years old: 56% were male; 50% (n = 17) had adenocarcinoma and 41% (n = 14) had squamous carcinoma. The majority (79%) received dCRT with a prescribed dose of 50 Gy in 25 fractions while the other 21% of patients were treated with radical radiotherapy alone (55 Gy in 20 fractions). The spleen was retrospectively contoured by one physician, and the V10 Gy and mean splenic dose (MSD) were calculated using Eclipse planning software. The median MSD was 14.4 Gy with a range of 0.75-28.3 Gy. The median V10 Gy was 62.7%. Of the cohort, 67.6% received an MSD of more than 10 Gy. Two-thirds of the patients received a dose of more than the 10 Gy. A review of the literature suggests that higher splenic radiation doses may increase the long-term risk of infection and impact on other outcomes. This study provides important evidence that the spleen receives a significant dose of radiation when treating distal oesophageal cancer and should be considered as an organ at risk.

Skin conditions in liver transplant recipients in a Singapore academic medical center: A retrospective cohort study

BackgroundLiver transplant recipients are at lifelong risk of immunosuppression-related cutaneous complications, such as malignancy and infection.ObjectiveOur study aims to assess the epidemiology of dermatologic conditions among liver transplant recipients in an academic medical center in Singapore.MethodsMedical records of liver transplant recipients on follow-up with gastroenterology and dermatology departments at the Singapore General Hospital between 2006 and 2021 were retrospectively reviewed. A literature review was subsequently performed on the keywords “liver transplant” and “dermatology.”ResultsA total of 99 liver transplant recipients were identified in this study. Sixty-nine patients (70%) had at least 1 dermatologic condition. Inflammatory skin conditions were the most common (53%), followed by cutaneous infection (36%) and benign cutaneous tumors (30%). Malignant and premalignant lesions were the least common skin conditions reported (10%). Our study results concurred with many other studies reported worldwide, demonstrating a low cutaneous malignancy burden after liver transplantation.LimitationsThe study included a small population size in a single center and did not have a pre-existing protocol for pretransplant dermatologic surveillance.ConclusionAlthough the incidence of skin cancer after liver transplant in Singapore is low, the patients will benefit from long-term dermatology surveillance, given the long-term risks of infection and malignant skin conditions.

Association between Continuous Flow Left Ventricular Assist Device Infections Requiring Long-Term Antibiotic Use and Post Heart Transplant Morbidity and Mortality

PurposeInfections in patients with a left ventricular assist device (LVAD) for bridge to heart transplant (HTx) do not appear to impact post-HTx survival. We evaluated the association between LVAD-related infections requiring long-term suppressive antibiotics and non-recent infections of any kind on the risk of early and late infection, rejection and mortality post-HTx in comparison to LVAD recipients without infection.MethodsThis is a single-center retrospective observational cohort study of consecutive adults with a durable continuous flow LVAD undergoing HTx between 2006-2019. Patients were grouped into: 1) LVAD-related infection requiring long-term antibiotic use until time of HTx; 2) any type of infection after LVAD implant in whom antibiotics were stopped at least 1 month prior to HTx; and 3) no infections between LVAD implant and HTx. LVAD-related infections included bacteremia, driveline or pocket. We evaluated the association between LVAD infection and post-HTx in-hospital infection, rejection and mortality using logistic regression, and long-term infection, rejection and mortality using Cox PH models.ResultsWe included 75 LVAD recipients; 16 (21%) patients had an LVAD-related infection on suppressive antibiotics, 30 (40%) had a non-recent infection, and 29 (39%) had no infections. During a median post-HTx follow-up time of 4 (2-7) years, we observed 65/75 (87%) infections, 43/67 (64%) rejections, and 17/75 (23%) deaths. Both short- and long-term risk of infection, rejection, and mortality did not differ significantly among the groups (Table 1).ConclusionLVAD patients with history of infections did not have higher risk of infection, rejection or mortality at any time point after HTx. Different post-HTx management strategies may have buffered the risk of adverse events in LVAD patients with infections. Infections in patients with a left ventricular assist device (LVAD) for bridge to heart transplant (HTx) do not appear to impact post-HTx survival. We evaluated the association between LVAD-related infections requiring long-term suppressive antibiotics and non-recent infections of any kind on the risk of early and late infection, rejection and mortality post-HTx in comparison to LVAD recipients without infection. This is a single-center retrospective observational cohort study of consecutive adults with a durable continuous flow LVAD undergoing HTx between 2006-2019. Patients were grouped into: 1) LVAD-related infection requiring long-term antibiotic use until time of HTx; 2) any type of infection after LVAD implant in whom antibiotics were stopped at least 1 month prior to HTx; and 3) no infections between LVAD implant and HTx. LVAD-related infections included bacteremia, driveline or pocket. We evaluated the association between LVAD infection and post-HTx in-hospital infection, rejection and mortality using logistic regression, and long-term infection, rejection and mortality using Cox PH models. We included 75 LVAD recipients; 16 (21%) patients had an LVAD-related infection on suppressive antibiotics, 30 (40%) had a non-recent infection, and 29 (39%) had no infections. During a median post-HTx follow-up time of 4 (2-7) years, we observed 65/75 (87%) infections, 43/67 (64%) rejections, and 17/75 (23%) deaths. Both short- and long-term risk of infection, rejection, and mortality did not differ significantly among the groups (Table 1). LVAD patients with history of infections did not have higher risk of infection, rejection or mortality at any time point after HTx. Different post-HTx management strategies may have buffered the risk of adverse events in LVAD patients with infections.

Increased risk of neonatal complications and infections in children of kidney-transplanted women: A nationwide controlled cohort study.

Information related to short- and long-term risks of children born to kidney-transplanted women remains limited. With the aim of investigating the risk of neonatal complications, and the short- and long-term risk of infections in offspring of kidney-transplanted women, all children born to kidney-transplanted women in Denmark from 1964 to 2016 were identified in a nationwide retrospective matched cohort study. A total of 124 children of kidney-transplanted women were identified and matched on gender, birth year, and number of siblings at birth 1:10 with children born to nontransplanted women identified in the Danish general population. Prevalence of low birth weight (37.9%, risk ratio [RR]=12.61; 95% confidence interval [CI], 8.5-18.5), premature birth (46.0%, RR=11.32; 95% CI, 8.1-15.7) and malformations (11.3%, RR=1.98; 95% CI, 1.2-3.4) was increased in children of kidney-transplanted women compared with controls. Similarly, prevalence of hospitalization due to infection was increased during the first year of life (21.0%, RR=1.94; 95% CI, 1.3-2.8), from age 1 to 5 (34.2%, RR=1.89; 95% CI, 1.4-2.5), and overall (41.9%, RR=1.67; 95% CI, 1.3-2.1). The risk of infection was also higher in children of kidney-transplanted mothers born preterm or with low birth weight compared with similar controls. In conclusion, risk of neonatal complications, malformations, and both early and late infection were increased in children born to kidney-transplanted women.

Efficacy and Tolerability of Isavuconazole versus Posaconazole for Fungal Prophylaxis after Lung Transplantation

Azole antifungals are commonly prescribed for fungal prophylaxis (ppx) following lung transplant, but have many side effects and drug interactions. Isavuconazole, a new broad-spectrum azole antifungal, may obviate these issues. We retrospectively reviewed all lung transplant recipients (LTR) from February 2018 through September 2019 who received either ISA or POS for fungal ppx for 3 months post-transplant. Prior to February 2019 all patients received POS for ppx. Starting February 2019, POS was replaced by ISA at standard dosing. All patients received basiliximab induction and standard triple immunosuppression post-transplant. Surveillance bronchoscopies were performed at 1, 3, 6, and 12 months post-transplant. In total, we reviewed 24 LTR who received ISA and 29 who received POS. Baseline characteristics were similar between groups. Median duration of follow-up was significantly shorter for the ISA group (137 vs. 340 days, p<0.01). Breakthrough fungal infections occurred in 3 (13%) and 2 (7%) patients in the ISA and POS groups, respectively (p=0.65). All ISA patients developed oropharyngeal candidiasis; in the POS group there was one each of candida empyema and mold colonization. Post-ppx fungal infections occurred in 1 (4%) and 5 (17%) patients in the ISA and POS groups, respectively (p=0.20). All of these were mold colonization except for one case of oropharyngeal candidiasis. There was no difference between fungal-infection free survival based on Kaplan-Meier analysis (p=0.69). POS was held in two cases and discontinued in 1 patient due to a drug interaction causing hepatotoxicity compared to zero patients receiving ISA (p=0.24). Breakthrough fungal infections were similar between LTR receiving ISA or POS for fungal ppx. Longer follow-up of ISA patients is needed for definitive comparison of long-term infection risk. POS was discontinued in more patients due to drug interactions. ISA is a reasonable choice for primary fungal ppx in LTR.

Long-Term Risk of Infections After Treatment of Childhood Leukemia: A Population-Based Cohort Study Using Administrative Health Data.

Infections are a frequent complication during childhood leukemia treatment. Little is known about the infectious risk in survivors. We compared the relative rate (RR) of infections after treatment completion between pediatric leukemia survivors and the general population. We performed a retrospective, population-based cohort study of children diagnosed with leukemia between 1992 and 2015 in Ontario, Canada, who were alive and relapse free 30 days after treatment completion (index date). Leukemia survivors were matched 5:1 with the general population by year of birth, sex, and rural status and stratified by initial treatment, including and excluding hematopoietic stem-cell transplantation (HSCT). The primary outcome was time to infections, as identified using validated diagnostic codes from administrative databases. Individuals were censored at the earliest of death, first relapse, loss to follow-up, or end of study. A total of 2,204 leukemia survivors were included and matched with 11,020 controls. The rate of infections was elevated after treatment completion compared with controls (RR, 1.51; 95% CI, 1.45 to 1.57) and at less than 1 year (RR, 1.77; 95% CI, 1.69 to 1.86); 1 to 4.99 years (RR, 1.66; 95% CI, 1.62 to 1.71), and 5 or more years (RR, 1.29; 95% CI, 1.22 to 1.36) from the index date. Among those whose initial treatment excluded HSCT, the rate remained elevated more than 5 years from the index date (RR, 1.29; 95% CI, 1.23 to 1.35). Infection-related death was significantly increased in leukemia survivors both among the entire cohort (hazard ratio, 149.3; 95% CI, 20.4 to 1,091.9) and among those without HSCT (hazard ratio, 92.7; 95% CI, 12.4 to 690.7). A significant association was found between a history of leukemia therapy and an increased risk of infections. Additional study is needed to establish which exposures in patients with leukemia lead to late infections.

Febrile Neutropenia and Long-term Risk of Infection Among Patients Treated With Chemotherapy for Malignant Diseases.

BackgroundFebrile neutropenia (FN) is a common complication to chemotherapy, associated with increased short-term morbidity and mortality. However, the long-term outcomes after FN are poorly elucidated. We examined the long-term risk of infection and mortality rates in cancer patients with and without FN.MethodsPatients aged >16 years treated with firstline chemotherapy were followed from 180 days after initiating chemotherapy until first infection, a new treatment with chemotherapy, death, or end of follow-up. Risk factors for infections were analyzed by competing risks regression, with death or another treatment with chemotherapy as competing events. Adjusted incidence rate ratios (aIRRs) of infection and death were analyzed using Poisson regression. In analyses of mortality, infection was included as a time-updated variable.ResultsWe included 7190 patients with a median follow-up (interquartile range) of 0.58 (0.20–1.71) year. A total of 1370 patients had an infection during follow-up. The aIRRs of infection were 1.86 (95% confidence interval [CI], 1.56–2.22) and 2.19 (95% CI, 1.54–3.11) for patients with 1 or >1 episode of FN compared with those without FN. Mortality rate ratios were 7.52 (95% CI, 6.67–8.48) <1 month after, 4.24 (95% CI, 3.80–4.75) 1–3 months after, 2.33 (95% CI, 1.63–3.35) 3–6 months after, and 1.09 (95% CI, 0.93–1.29) >6 months after an infection, compared with the time before infection.ConclusionsFN during chemotherapy is associated with a long-term increased risk of infection. Mortality rates are substantially increased for 6 months following an infection.

Glycemic Control and Risk of Infections Among People With Type 1 or Type 2 Diabetes in a Large Primary Care Cohort Study.

Diabetes mellitus (DM) increases the risk of infections, but the effect of better control has not been thoroughly investigated. With the use of English primary care data, average glycated hemoglobin (HbA1c) during 2008-2009 was estimated for 85,312 patients with DM ages 40-89 years. Infection rates during 2010-2015 compiled from primary care, linked hospital, and mortality records were estimated across 18 infection categories and further summarized as any requiring a prescription or hospitalization or as cause of death. Poisson regression was used to estimate adjusted incidence rate ratios (IRRs) by HbA1c categories across all DM, and type 1 and type 2 DM separately. IRRs also were compared with 153,341 age-sex-practice-matched controls without DM. Attributable fractions (AF%) among patients with DM were estimated for an optimal control scenario (HbA1c 6-7% [42-53 mmol/mol]). Long-term infection risk rose with increasing HbA1c for most outcomes. Compared with patients without DM, those with DM and optimal control (HbA1c 6-7% [42-53 mmol/mol], IRR 1.41 [95% CI 1.36-1.47]) and poor control (≥11% [97 mmol/mol], 4.70 [4.24-5.21]) had elevated hospitalization risks for infection. In patients with type 1 DM and poor control, this risk was even greater (IRR 8.47 [5.86-12.24]). Comparisons within patients with DM confirmed the risk of hospitalization with poor control (2.70 [2.43-3.00]) after adjustment for duration and other confounders. AF% of poor control were high for serious infections, particularly bone and joint (46%), endocarditis (26%), tuberculosis (24%), sepsis (21%), infection-related hospitalization (17%), and mortality (16%). Poor glycemic control is powerfully associated with serious infections and should be a high priority.

Long-term risk of infection in patients with Crohn's disease on anti-TNF treatment: A prospective single-center cohort study in China.

The aim of this study was to explore the long-term risk of infection in patients with Crohn's disease (CD) on infliximab (IFX) therapy. All CD patients treated with IFX were recruited from January 2008 to December 2015. Their characteristics and infectious events during IFX therapy were prospectively collected, and the risk of infection was evaluated using Cox regression. Seventy CD patients receiving IFX were consecutively recruited. During a median of 15 months, 15 patients experienced 17 infectious events which occurred within a median of 21 weeks after the initiation of IFX therapy. Of 17 infectious events, eight were viral infections, six were bacterial infections, and the others were fungal infections. IFX was discontinued in 6 (40.0%) out of 15 cases due to infections. Compared with those without infections, patients with infectious events were more likely of Montreal B1 (inflammatory) behavior, with concomitant use of systemic corticosteroids when infliximab was started but less mucosal healing when infections occurred (P < 0.05). By Cox hazard ratio (HR) analysis, patients with B1 behavior had a higher risk of developing infections than those with B3 (fistulizing) behavior (HR 4.897, P = 0.010). Successful corticosteroid withdrawal (HR 0.275, P = 0.035) or mucosal healing (HR 0.155, P = 0.002) were associated with a lower risk of infections. Long-term use of IFX in CD patients has a high risk of infections. Failure in mucosal healing and increased concomitant use of systemic corticosteroids are independent risk factors of infections during IFX therapy.

Association of gestational age and growth measures at birth with infection-related admissions to hospital throughout childhood: a population-based, data-linkage study from Western Australia

Reduced gestational age and low birthweight are associated with an increased risk of neonatal infections. However, the long-term risk of infection, especially in late preterm infants or those at near-normal birthweight, is unknown. We estimated whether rates of infection-related admissions to hospital for children in Western Australia were associated with age, gestational age, birthweight, and birth length. We did a population-based, data-linkage study using total-linked, registry data from the Western Australia Birth Register of all liveborn, non-Indigenous Australian singleton births recorded from Jan 1, 1980, to Dec 31, 2010. We followed up individuals from birth-related hospital discharge to age 18 years, death, or end of 2010, and linked to data about subsequent admissions to hospital or death registrations. Gestational age was assessed from both the last menstrual period and from estimates based on ultrasonography. We categorised birthweight by 500 g bands and birth length by 5 cm bands, and approximated the reference ranges for both to the 50th percentile. Because size at birth and gestational age are strongly associated, we calculated Z scores for gestational-specific and sex-specific birthweight, birth length, and ponderal index. Our primary outcomes were the number and type of infection-related admissions to hospital. We used multilevel negative binomial regression to generate rate ratios (RR) for such admissions, identified by codes from the International Classification of Diseases, versions 9 and 10-AM. We adjusted the RRs for maternal age at delivery, birth year, birth season, parity, sex, 5-min Apgar score, delivery method, socioeconomic status, and bronchopulmonary dysplasia. Of 719 311 liveborn singletons included in the analysis and followed up for 8 824 093 person-years, 365 867 infection-related admissions to hospital occurred for 213 683 (30%) children. Of the 719 311 children included in the analysis, 137 124 (19%) had one infection-related admission to hospital, 43 796 (6%) had two, 16 679 (2%) had three, and 16 084 (2%) had four or more. The 365 867 admissions to hospital included a diagnosis of infection of the upper respiratory tract for 174 653 (48%), the lower respiratory tract for 74 297 (20%), the gastrointestinal tract for 44 755 (12%), and a viral infection for 37 213 (10%). Infection-related rates of admissions to hospital increased by 12% for each week reduction in gestational age less than 39-40 weeks (RR 1·12, 95% CI 1·12-1·13), by 19% for each 500 g reduction in birthweight less than 3000-3500 g (1·19, 1·18-1·21), and by 41% for each 5 cm reduction in birth length less than 45-50 cm (1·41, 1·38-1·45). Gestational age-specific and sex-specific birthweight Z scores lower than the 25th to 50th percentile and birth length Z scores lower than the 10th to 25th percentile were associated with increased rates of infection-related admissions to hospital (eg, 1st-5th percentile RR 1·15, 95% CI 1·12-1·19, and 1·11, 1·07-1·14, respectively). Ponderal index Z scores lower than the 25th to 50th percentile were also associated with increased rates of infection-related admissions (eg, 1st-5th percentile RR 1·08, 95% CI 1·04-1·12). A gestational age of 41 weeks or later, a birthweight or birth length Z score above the 50th percentile, or a ponderal index Z score between the 75th and 95th percentile, were associated with modestly reduced rates of infection-related admissions to hospital. Children who were born with reduced gestational age, birthweight, and birth length have persistently increased rates of infection-related admissions to hospital until age 18 years. Pregnancy outcomes should be optimised to prevent infection occurring in this population, especially in resource-limited settings where suboptimum intrauterine growth and moderate prematurity are common. Australian National Health and Medical Research Council.

Clinically Significant Pocket Hematoma Increases Long-Term Risk of Device Infection: BRUISE CONTROL INFECTION Study

BackgroundThe BRUISE CONTROL trial (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial) demonstrated that a strategy of continued warfarin during cardiac implantable electronic device surgery was safe and reduced the incidence of clinically significant pocket hematoma (CSH). CSH was defined as a post-procedure hematoma requiring further surgery and/or resulting in prolongation of hospitalization of at least 24 h, and/or requiring interruption of anticoagulation. Previous studies have inconsistently associated hematoma with the subsequent development of device infection; reasons include the retrospective nature of many studies, lack of endpoint adjudication, and differing subjective definitions of hematoma. ObjectivesThe BRUISE CONTROL INFECTION (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial Extended Follow-Up for Infection) prospectively examined the association between CSH and subsequent device infection. MethodsThe study included 659 patients with a primary outcome of device-related infection requiring hospitalization, defined as 1 or more of the following: pocket infection; endocarditis; and bloodstream infection. Outcomes were verified by a blinded adjudication committee. Multivariable analysis was performed to identify predictors of infection. ResultsThe overall 1-year device-related infection rate was 2.4% (16 of 659). Infection occurred in 11% of patients (7 of 66) with previous CSH and in 1.5% (9 of 593) without CSH. CSH was the only independent predictor and was associated with a >7-fold increased risk of infection (hazard ratio: 7.7; 95% confidence interval: 2.9 to 20.5; p < 0.0001). Empiric antibiotics upon development of hematoma did not reduce long-term infection risk. ConclusionsCSH is associated with a significantly increased risk of infection requiring hospitalization within 1 year following cardiac implantable electronic device surgery. Strategies aimed at reducing hematomas may decrease the long-term risk of infection. (Bridge or Continue Coumadin for Device Surgery Randomized Controlled Trial [BRUISE CONTROL]; NCT00800137)

Clinical Impact of Telomere Shortening in Normal and Leukemia Cells in Chronic Lymphocytic Leukemia

Introduction: In chronic lymphocytic leukemia (CLL), short telomere length in the leukemia cells predicts poor prognosis. However, it is not known whether telomere length in normal tissues also predicts patient outcome and can improve the prognostic value of CLL telomere length. Prognosis in CLL is heterogeneous with the primary cause of death being cancer and infections, thought related to immunosuppression. The elderly, males and those with comorbidities have a particularly poor relative survival. Whether this reflects differences in the biology of CLL in these patient groups, or to extrinsic factors such as increased immunosuppression or fragility, is unknown. In normal individuals, the telomeres in somatic cells (ie, buccal cells (BC)) shorten with aging and prior comorbidities; short telomeres being predictive of early mortality related to infections, cancer and cardiovascular disease. In the present study, we have evaluated BC telomere length in patients with CLL, to determine if this is predictive of survival, and can enhance the predictive value of leukemia cell telomere length.Methods: The Manitoba CLL tumor bank contains 235 samples from newly diagnosed CLL patients between 2007-2011; with a median follow-up of 2 years. One-quarter of these patients required chemotherapy and one-tenth have died. Genomic DNA was extracted from purified CLL cells and buccal cells (BC) collected at diagnosis. Telomere length was established by multiplex quantitative real-time PCR. Telomere/standard (t/s) ratio was calculated using the beta-globulin gene as the standard. Statistical analysis was performed using Statistical Analysis Software (SAS) and Prism software.Results: The median adjusted telomere length was much shorter in CLL cells than in BCs being 0.53 and 2.01, respectively. In BCs, telomere length significantly shortened with increasing age (OR 1.04, CI 95% (1.00-1.078)) and at this short follow-up time, correlation with second malignancies was approaching significance (p=0.06). However, BC telomere length was not reflective of the number of comorbidities or survival. In contrast, telomere length in CLL cells was independent of age (p=0.44) and sex (p=0.75) confirming that these factors did not influence the cellular biology of the disease. Telomere length also correlated with other biological markers with short telomeres correlating with unmutated IgHV status (p<0.0001), Zap-70 positivity (p=0.05), and CD38 positivity (p=0.003). These patients with short telomeres also had clinical markers of poor prognosis including short lymphocyte doubling time (p=0.004), higher Rai stage (p=0.02) and an earlier time to treatment (p<0.0001). The prognostic value of CLL telomere length was not enhanced by the addition of BC telomere length.Conclusions: These results demonstrate that BC telomere length in CLL patients shorten with age, and short telomeres may predict subsequent second malignancies. Telomere length in CLL cells correlates with biological and clinical markers of aggressive disease, but it does not explain the poor prognosis seen in the elderly and male patients. While BC telomere length does not seem to influence the initial clinical course of CLL, ongoing studies are evaluating whether it is predictive of the long-term risk of infections and second malignancies. In addition, whether BC telomere length in CLL is shorter than in the normal population and whether shortening correlates with specific comorbidities is presently being determined. DisclosuresNo relevant conflicts of interest to declare.

Retained central venous lines (CVLs) after attempted removal: An 11-year series and literature review

BackgroundCentral venous lines (CVLs) are frequently used in the management of many neonatal and pediatric conditions. Failure to remove the luminal part of the line (retained CVL) is rare. Consequently, there is lack of experience and consensus in its optimal management. AimTo document the incidence and management of retained CVLs in a tertiary pediatric surgical centre with access to interventional cardiology services. To review the literature and report efficacy/morbidity of attempted extraction of retained CVLs. MethodsChildren with retained CVLs were identified from departmental morbidity and mortality records over an 11-year period. A literature search was performed in PubMed and Scopus to identify studies reporting retained CVLs (earliest date to 1 January 2012). This was supplemented by scanning bibliographies of retrieved articles. ResultsThe 11-year incidence of retained CVL was 0.3% (n=10; median duration in-situ 66.5 {range 47–146} months). The underlying pathology in 8 was cystic fibrosis. Antegrade transfemoral snare retrieval was successful in 6 of 7 attempts. In the remaining 3, a conservative approach was adopted following consultation with the family. None of the 4 with retained CVL developed complications (median follow-up 7.5 {range 1–53} months).The literature describes 38 pediatric index cases (including 10 from the current series). Seventeen (49%) were managed conservatively either intentionally or by default after failed endovascular removal attempt (n=4). No complications directly attributed to retained CVLs have been reported (median follow-up 40 {range 1–120} months). Reported morbidity associated with endovascular retrieval includes: procedural failure 30%, line embolization 8%, and intra-operative thrombo-embolism 8%. ConclusionLiterature regarding management of retained CVLs is anecdotal. Although uncommon, the complication should feature in consent for removal of CVLs. Conservative management carries long-term risks of infection, thrombosis, and even migration, albeit unquantified over a child's lifetime. Endovascular retrieval is feasible with appropriate expertise.

T-cell activation and transplantation tolerance

Transplantation of allogeneic or "nonself" tissues stimulates a robust immune response leading to graft rejection, and therefore, most recipients of allogeneic organ transplants require the lifelong use of immune suppressive agents. Excellent outcomes notwithstanding, contemporary immunosuppressive medications are toxic, are often not taken by patients, and pose long-term risks of infection and malignancy. The ultimate goal in transplantation is to develop new treatments that will supplant the need for general immunosuppression. Here, we will describe the development and application of costimulation blockade to induce transplantation tolerance and discuss how the diverse array of signals that act on T cells will determine the balance between graft survival and rejection.