Dynamics of virus-specific T cell immunity in pediatric liver transplant recipients.

Immunosuppression following solid organ transplantation (SOT) has a deleterious effect on cellular immunity leading to frequent and prolonged viral infections. To better understand the relationship between posttransplant immunosuppression and circulating virus-specific T cells, we prospectively monitored the frequency and function of T cells directed to a range of latent (CMV, EBV, HHV6, BK) and lytic (AdV) viruses in 16 children undergoing liver transplantation for up to 1 year posttransplant. Following transplant, there was an immediate decline in circulating virus-specific T cells, which recovered posttransplant, coincident with the introduction and subsequent routine tapering of immunosuppression. Furthermore, 12 of 14 infections/reactivations that occurred posttransplant were successfully controlled with immunosuppression reduction (and/or antiviral use) and in all cases we detected a temporal increase in the circulating frequency of virus-specific T cells directed against the infecting virus, which was absent in 2 cases where infections remained uncontrolled by the end of follow-up. Our study illustrates the dynamic changes in virus-specific T cells that occur in children following liver transplantation, driven both by active viral replication and modulation of immunosuppression.

Noroviruses as a Cause of Diarrhea in Immunocompromised Pediatric Hematopoietic Stem Cell and Solid Organ Transplant Recipients.

Case reports describe significant norovirus gastroenteritis morbidity in immunocompromised patients. We evaluated norovirus pathogenesis in prospectively enrolled solid organ (SOT) and hematopoietic stem cell transplant (HSCT) patients with diarrhea who presented to Texas Children's Hospital and submitted stool for enteric testing. Noroviruses were detected by real-time reverse transcription polymerase chain reaction. Clinical outcomes of norovirus diarrhea and non-norovirus diarrhea patients, matched by transplanted organ type, were compared. Norovirus infection was identified in 25 (22%) of 116 patients, more frequently than other enteropathogens. Fifty percent of norovirus patients experienced diarrhea lasting ≥14 days, with median duration of 12.5 days (range 1-324 days); 29% developed diarrhea recurrence. Fifty-five percent of norovirus patients were hospitalized for diarrhea, with 27% requiring intensive care unit (ICU) admission. One HSCT recipient developed pneumatosis intestinalis. Three HSCT patients expired ≤6 months of norovirus diarrhea onset. Compared to non-norovirus diarrhea patients, norovirus patients experienced significantly more frequent ICU admission (27% vs. 0%, p = 0.02), greater serum creatinine rise (median 0.3 vs. 0.2 mg/dL, p = 0.01), and more weight loss (median 1.6 vs. 0.6 kg, p < 0.01). Noroviruses are an important cause of diarrhea in pediatric transplant patients and are associated with significant clinical complications.

Clinical predictors of disease severity during the 2009-2010 A(HIN1) influenza virus pandemic in a paediatric population.

A novel influenza virus emerged in the United States in spring 2009, rapidly becoming a global pandemic. Children were disproportionally affected by the novel influenza A(H1N1) pandemic virus [A(H1N1)pdm]. This retrospective electronic medical record review study aimed to identify clinical predictors of disease severity of influenza A(HIN1)pdm infection in paediatric patients. Disease severity was defined on an increasing three-level scale from non-hospitalized, hospitalized, and admitted to the intensive care unit (ICU). From April 2009 to June 2010, 696 children presented to Texas Children's Hospital's emergency department, 38% were hospitalized, and 17% were admitted to the ICU. Presenting symptoms associated with severe influenza were dyspnoea [odds ratio (OR) 5·82], tachycardia (OR 2·61) and fatigue (OR 1·96). Pre-existing health conditions associated with disease severity included seizure disorder (OR 4·71), obesity (OR 3·28), lung disease (OR 2·84), premature birth (OR 2·53), haematological disease (OR 2·22), and developmental delay (OR 2·20). According to model fitness tests, presenting symptoms were more likely to predict severe influenza than underlying medical conditions. However, both are important risk factors. Recognition of clinical characteristics associated with severe disease can be used for triaging case management of children during future influenza outbreaks.

Staphylococcus aureus infections among children receiving a solid organ transplant: clinical features, epidemiology, and antimicrobial susceptibility.

BACKGROUND: Staphylococcus aureus is among the most common causes of healthcare-associated infection (HAI) in the United States. Patients who have received a solid organ transplant (SOT) represent a unique population for the acquisition of HAIs, given their preoperative organ failure, immunosuppression, and need for invasive procedures. However, limited literature is published on S. aureus infections among children with SOT. We describe the epidemiology, antimicrobial susceptibility, and clinical features of S. aureus infections among pediatric SOT recipients. DESIGN: An ongoing prospective S. aureus surveillance database from 2001 to 2012 was searched for infections in patients with a history of SOT at Texas Children's Hospital. Medical records and antibiotic susceptibility profiles were reviewed; specific attention was applied to the time since transplantation to infection. RESULTS: Out of the total of 696 transplants performed during the study period, 38 pediatric SOT recipients developed 41 S. aureus infections; the highest incidence of infection was among heart recipients. Overall, the most common infectious diagnoses were skin-and-soft-tissue infections (66.1%), followed by bacteremia (15.3%). Among isolates in SOT patients, 47.5%, 16.9%, and 6.7% were resistant to methicillin, clindamycin, or mupirocin, respectively. Three infections (7.3%) occurred in the early post-transplant period (<1 month), all of which were bacteremia (P = 0.007) and all caused by methicillin-susceptible S. aureus (MSSA). The majority of infections (90.2%) occurred in the late post-transplant period (>6 months). In 10 cases (16.9%), S. aureus infection was associated with graft rejection during the same admission. CONCLUSIONS: S. aureus represents an important cause of morbidity in pediatric SOT recipients. While the majority of infections occurred late after transplant (>6 months), those acquired in the early post-transplant period were more often invasive and caused by MSSA in our hospital. Physicians caring for SOT recipients should be aware of the risks posed by this pathogen and the potential concomitant morbidity including graft rejection.

Intra-Arterial Therapies for Liver Metastatic Breast Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: Performing a systematic review and meta-analysis to assess the evidence of intra-arterial therapies in liver metastatic breast cancer (LMBC) patients. METHODS: A systemic literature search was performed in PubMed, EMBASE, SCOPUS for studies regarding intra-arterial therapies in LMBC patients. Full text studies of LMBC patients (n ≥ 10) published between January 2010 and December 2020 were included when at least one outcome among response rate, adverse events or survival was available. Response rates were pooled using generalized linear mixed models. A weighted estimate of the population median overall survival (OS) was obtained under the assumption of exponentially distributed survival times. RESULTS: A total of 26 studies (1266 patients) were included. Eleven articles reported on transarterial radioembolization (TARE), ten on transarterial chemoembolization (TACE) and four on chemo-infusion. One retrospective study compared TARE and TACE. Pooled response rates were 49% for TARE (95%CI 32-67%), 34% for TACE (95%CI 22-50%) and 19% for chemo-infusion (95%CI 14-25%). Pooled median survival was 9.2 months (range 6.1-35.4 months) for TARE, 17.8 months (range 4.6-47.0) for TACE and 7.9 months (range 7.0-14.2) for chemo-infusion. No comparison for OS was possible due to missing survival rates at specific time points (1 and 2 year OS) and the large heterogeneity. CONCLUSION: Although results have to be interpreted with caution due to the large heterogeneity, the superior response rate of TARE and TACE compared to chemo-infusion suggests first choice of TARE or TACE in chemorefractory LMBC patients. Chemo-infusion could be considered in LMBC patients not suitable for TARE or TACE. LEVEL OF EVIDENCE: 3a.

Antenatal care service delivery and factors affecting effective tetanus vaccine coverage in low- and middle-income countries: Results of the Maternal Immunisation and Antenatal Care Situational analysis (MIACSA) project.

OBJECTIVES: To map the integration of existing maternal tetanus immunization programmes within antenatal care (ANC) services for pregnant women in low- and middle-income countries (LMICs) and to identify and understand the challenges, barriers and facilitators associated with high performance maternal vaccine service delivery. DESIGN: A mixed methods, cross sectional study with four data collection phases including a desk review, online survey, telephone and face-to-face interviews and in country visits was undertaken between 2016 and 2018. Associations of different service delivery process components with protection at birth (PAB) and with country groups were established. PAB was defined as the proportion of neonates protected at birth against neonatal tetanus. Regression analysis and structural equation modelling was used to assess associations of different variables with maternal tetanus immunization coverage. Latent class analysis (LCA), was used to group country performance for maternal immunization, and to address the problem of multicollinearity. SETTING: LMICs. RESULTS: The majority of LMICs had a policy on recommended number of ANC visits, however most were yet to implement the WHO guidelines recommending eight ANC contacts. Countries that recommended > 4 ANC contacts were more likely to have high PAB > 90%. Passive disease surveillance was the most common form of disease surveillance performed but the maternal and neonatal morbidity and mortality indicators recorded differed between countries. The presence of user fees for antenatal care and maternal immunization was significantly associated with lower PAB (<90%). CONCLUSIONS: Recommendations include implementing the current WHO ANC guideline to facilitate increased opportunities for vaccination during each pregnancy. Improved utilisation of ANC services by increasing the demand side by increasing the quality of services, reducing any associated costs and supporting user fee exemptions, or the supply side can also enhance utilisation of ANC services which are positioned as an ideal platform for delivery of maternal vaccines.

Vaccine implementation factors affecting maternal tetanus immunization in low- and middle-income countries: Results of the Maternal Immunization and Antenatal Care Situational Analysis (MIACSA) project.

OBJECTIVES: To examine the characteristics of existing maternal tetanus immunization programmes for pregnant women in low- and middle-income countries (LMICs) and to identify and understand the challenges, barriers and facilitators associated with maternal vaccine service delivery that may impact the introduction and implementation of new maternal vaccines in the future. DESIGN: A mixed methods, cross sectional study with four data collection phases including a desk review, online survey, telephone and face-to-face interviews and in country visits. SETTING: LMICs. RESULTS: The majority of countries (84/95; 88%) had a maternal tetanus immunization policy. Countries with high protection at birth (PAB) were more likely to report tetanus toxoid-containing vaccine (TTCV) coverage targets > 90%. Less than half the countries included in this study had a TTCV coverage target of > 90%. Procurement and distribution of TTCV was nearly always the responsibility of the Expanded Programme on Immunization (EPI), however planning and management of maternal immunization was often shared between EPI and Maternal, Newborn and Child Health (MNCH) programmes. Receipt of TTCV at the same time as the antenatal care visit correlated with high PAB. Most countries (81/95; 85%) had an immunization safety surveillance system in place although only 11% could differentiate an adverse event following immunization (AEFI) in pregnant and non-pregnant women. CONCLUSIONS: Recommendations arising from the MIACSA project to strengthen existing services currently delivering maternal tetanus immunization in LMICs include establishing and maintaining vaccination targets, clearly defining responsibilities and fostering collaborations between EPI and MNCH, investing in strengthening the health workforce, improving the design and use of existing record keeping for immunization, adjusting current AEFI reporting to differentiate pregnant women and endeavoring to integrate the provision of TTCV within ANC services where appropriate.

Host defense against systemic infection with Streptococcus pneumoniae is impaired in E-, P-, and E-/P-selectin-deficient mice.

Endothelial selectins mediate rolling of leukocytes on endothelium, a crucial step for leukocyte firm adhesion and emigration into sites of tissue injury and infection. To characterize the role of the endothelial selectins during bacterial sepsis in vivo, Streptococcus pneumoniae (1-10 x 10(6) colony-forming units) was inoculated intraperitoneally into wild-type mice and mice with E-, P-, or E-/P-selectin deficiencies. Mice were followed 10 d for morbidity, survival, clearance of bacteremia, and leukocyte migration to the peritoneal cavity and organs 48 h after infection. All selectin-deficient mice showed a more pronounced morbidity, a significantly higher mortality associated with persistent bacteremia, and a higher bacterial load when compared with wild-type mice. These differences were most remarkable in the E-selectin-deficient mice, which showed the highest rate of mortality and bacteremia (P

Paediatrician and Caregiver Awareness of Cryptosporidiosis and Giardiasis in Children: US Survey Responses.

There appears to be no published information concerning the awareness and knowledge about diarrhoea caused by Cryptosporidium spp. or Giardia lamblia among US paediatricians and caregivers of young children. Two concurrent, separate surveys were conducted among paediatricians and caregivers (~1000 respondents in each survey) of children ages 1-12 years concerning their knowledge, perceptions and attitudes in the diagnosis and treatment of parasitic diarrhoea. Awareness of parasite-induced diarrhoea was low for specific aspects among both paediatricians and caregivers. Educational efforts to improve awareness on the appropriate clinical presentation, management and treatment of cryptosporidiosis and giardiasis in children with persistent diarrhoea should be undertaken.

Diminution of the anti-polyribosylribitol phosphate response to a combined diphtheria-tetanus-acellular pertussis/Haemophilus influenzae type b vaccine by concurrent inactivated poliovirus vaccination.

BACKGROUND: Prelicensure studies of Haemophilus influenzae type b vaccines (Hib) and diphtheria-tetanus-acellular pertussis vaccines (DTaP) were evaluated with concurrent oral poliovirus vaccine (OPV). However, inactivated poliovirus vaccine (IPV) is now recommended. A trial was conducted in which infants received a DTaP and Hib vaccine, separately (+) or combined (/), with either all OPV, all IPV or sequential IPV-OPV for the primary series of vaccinations. METHODS: In this protocol 567 infants were equally randomized to receive one of the following: Reference Arm A, DTaP + Hib + OPV; Treatment Arm B, DTaP/Hib + OPV; Treatment Arm C, DTaP/Hib + IPV at 2 and 4 months and OPV at 6 months; or Treatment Arm D, DTaP/Hib + IPV. antibodies against all administered antigens were measured at 7 months of age. Children with an antibody response to Hib (anti-polyribosylribitol phosphate (anti-PRP) <0.15 microg/ml had an antibody titer repeated after the toddler booster immunization. RESULTS: A significant diminution in the anti-PRP response was observed at 7 months of age in children given two or three doses of IPV concurrently with DTaP/Hib, compared with the groups given OPV. The geometric mean concentration of anti-PRP, percentage of children with > or = 0.15 microg/ml and percentage of children with > or = 1.0 microg/ ml, respectively, were: A, 4.4, 98%, 81%; B, 3.2, 94%, 78%; C, 1.3, 86%, 58% and D, 1.2, 84%, 53%. CONCLUSION: In this trial concurrent IPV appeared to interfere with the anti-PRP response to DTaP/Hib vaccine, suggesting that introduction of new vaccines may require evaluation of immune responses to all concurrently administered vaccines.

Influenza A virus outbreak in a neonatal intensive care unit.

BACKGROUND: Nosocomial infections with influenza virus are rarely recognized in neonatal intensive care units (NICU). An outbreak of influenza A virus infection in the NICU of an urban county hospital during the 1997 to 1998 influenza season is reported. METHODS: Clinical and virologic data were recorded in all symptomatic NICU patients after influenza A infection was diagnosed in one infant in October, 1997. RESULTS: Influenza A/H3N2 was isolated from two of four symptomatic infants. The application of rapid diagnostic techniques for the characterization of influenza virus infection allowed the timely institution of basic infection control measures, limiting this outbreak. Resistance to amantadine was documented for the first time in this patient population by reverse transcription-PCR within 48 h of treatment in one case. CONCLUSIONS: Prevention by immunization is a priority in those caring for high risk NICU patients.

Vaccines in pregnancy.

The concept of maternal immunization to prevent infectious diseases during a period of increased vulnerability in the infant is supported by historical experience and carefully conducted studies of various viral and bacterial vaccines. Candidate vaccines should be minimally reactogenic, immunogenic, and safe. Health education and access to immunization should be a priority if maternal immunization is to succeed as a disease prevention strategy. The potential effect on the incidence of disease in the newborn and young infant can only increase as more candidate vaccines that could be administered during pregnancy become available. In the future, common infections and other, more dreaded diseases, such as herpes simplex virus infection, cytomegalovirus, and human immunodeficiency virus infection, could be prevented with this intervention. Further research on the safety and efficacy of maternal immunization must continue if the occurrence of serious infectious diseases in neonates and young infants is to be reduced.

A step ahead. Infant protection through maternal immunization.

The concept of maternal immunization to prevent infectious diseases during a period of increased vulnerability in infants is not new and is supported by historical experience and carefully conducted studies of various viral and bacterial vaccines. Candidate vaccines should be minimally reactogenic, immunogenic, and safe for maternal immunization to be considered as a disease prevention strategy. The possibilities increase as more potential candidate vaccines for use during pregnancy become available, including conjugate meningococcal vaccines, parainfluenza virus type 3 purified subunit vaccines, herpes simplex virus, cytomegalovirus, and HIV vaccines. Additional research on the safety and efficacy of maternal immunization must continue to effect the development of infectious diseases in neonates and infants.

A new generation of bio-derived ceramic materials for medical applications.

A new generation of bio-derived ceramics can be developed as a base material for medical implants. Specific plant species are used as templates on which innovative transformation processes can modify the chemical composition maintaining the original biostructure. Building on the outstanding mechanical properties of the starting lignocellulosic templates, it is possible to develop lightweight and high-strength scaffolds for bone substitution. In vitro and in vivo experiments demonstrate the excellent biocompatibility of this new silicon carbide material (bioSiC) and how it gets colonized by the hosting bone tissue because of its unique interconnected hierarchic porosity, which opens the door to new biomedical applications.

Disseminated adenovirus disease in immunocompromised and immunocompetent children.

A retrospective review of adenovirus infections at Texas Children's Hospital during 1990-1996 was performed to evaluate the epidemiology, clinical course, management, and outcome of disseminated adenovirus disease (DAD) in children. DAD with multiorgan involvement occurred in 11 (2.5%) of 440 adenovirus-infected patients. Six (54%) of the 11 were immunocompromised and 5 (45%) were immunocompetent. Mortality was 83% among the immunodeficient, 60% in the immunocompetent, and 73% overall. Two (28%) of the 7 patients receiving immunoglobulins with or without antivirals and 3 (75%) of the 4 not treated died of DAD. DAD was caused by particular serotypes (3, 5, and 7) and occurred at a younger age in immunocompetent children. Viremia and prolonged viral excretion were more common in the immunocompromised. Clinical features and outcome were similar in both groups. Prospective studies addressing the use of new antiviral agents, combination antiviral therapy, and preventive strategies are necessary to determine the optimal therapeutic approach for patients with DAD.

Ischaemia induces changes in the association of the binding protein 4E-BP1 and eukaryotic initiation factor (eIF) 4G to eIF4E in differentiated PC12 cells.

Ischaemia was obtained in vitro by subjecting nerve-growth-factor-differentiated PC12 cells to glucose deprivation plus anoxia. During ischaemia the rate of protein synthesis was significantly inhibited, and eIF4E-binding protein (4E-BP1) and eukaryotic initiation factor 4E (eIF4E) were significantly dephosphorylated in parallel. In addition, ischaemia induced an enhancement of the association of 4E-BP1 to eIF4E, which in turn decreased eIF4F formation, whereas no degradation of initiation factor 4G was observed. The treatment of PC12 cells with the specific p38 mitogen-activated protein kinase inhibitor SB203580 induced eIF4E dephosphorylation but did not cause any effect on protein synthesis rate. Rapamycin, the inhibitor of mammalian target of rapamycin ('mTOR'), but not PD98059, the inhibitor of extracellular signal-regulated protein kinases ('ERK1/2'), induced similar effects on 4E-BP1 phosphorylation to ischaemia; nevertheless, 4E-BP1-eIF4E complex levels were higher in ischaemia than in rapamycin-treated cells. In addition, both protein synthesis rate and eIF4F formation were lower in ischaemic cells than in rapamycin-treated cells.

Allergic reactions associated with airborne fish particles in IgE-mediated fish hypersensitive patients.

We evaluated the clinical characteristics found in 21 children who showed allergic reactions upon incidental inhalation of fish odors or fumes, from 197 diagnosed with IgE-mediated fish hypersensitivity. Allergic reactions to fish via ingestion began in most patients (86%) within the first 24 months of life. The vast majority (19/21) of patients showed cutaneous symptoms, either alone or, less frequently, associated with other clinical manifestations. Hake and flounder were the species of fish most frequently implicated in eliciting clinical manifestations upon ingestion. After diagnosis, all these patients were placed on a strict fish-avoidance diet. During this period of avoidance, patients reported allergic reactions (mean age 7 years) after incidental exposure to airborne fish odors or fumes. Clinical manifestations through inhalation were respiratory (mainly wheezing) in 12 patients and cutaneous (mainly urticaria) in nine patients. Nineteen of 21 patients reported three or more episodes upon exposure to fish aerosols; in most cases, these episodes occurred at home when other people were eating fish. In conclusion, incidental inhalation of fish odors or fumes could play an important role in accidental and unknown encounters with fish in children on fish-avoidance diets for fish IgE-mediated hypersensitivity. Such exposures could elicit clinical symptoms and could have some effect in delaying the development of tolerance.

Trichoderma longibrachiatum infection in a pediatric patient with aplastic anemia.

Trichoderma longibrachiatum infection of the skin in an 11-year-old child with severe aplastic anemia and prolonged neutropenia is reported. The patient received systemic antifungal therapy and underwent bone marrow transplantation. To our knowledge, this is the first description of T. longibrachiatum infection in a pediatric patient. It also is the first case successfully treated with medical therapy. A review of the literature suggests that Trichoderma spp. are recognized as human pathogens with increasing frequency, particularly for immunocompromised patients, and should be considered in the differential diagnosis of fungal infections in the pediatric population.