Association between medically diagnosed postnatal infection and childhood cancers: A matched case-control study in Denmark, 1978 to 2016.

Although the association between infection and childhood cancer has been long investigated, there is limited information on rarer cancers. This article aimed to explore the association between postnatal infection and childhood cancers in the Danish population. A matched case-control study was conducted using Danish nationwide registries from 1978 to 2016. Each childhood cancer case was matched 1:25 with controls by birth date within a week and sex. Postnatal infections were identified from the Danish National Patient Registry, which lists diagnoses seen in hospital, specialist or emergency care services. Multivariable conditional logistic regression was used to estimate adjusted odds ratios (adj.OR) and 95% confidence intervals (CI). Specific types of infections and the number of infection episodes were also considered. The study included 4125 childhood cancer cases and 103 526 matched controls with ages ranging from 0 to 19 years. Medically diagnosed postnatal infections were positively associated with many types of childhood cancer including acute lymphoblastic leukemia (adj.OR = 1.42; 95% CI: 1.23-1.63), acute myeloid leukemia (adj.OR = 1.80; 95% CI: 1.28-2.52), non-Hodgkin lymphoma (adj.OR = 1.53; 95% CI: 1.19-1.97) and central nervous system tumors (adj.OR = 1.57; 95% CI: 1.39-1.77). A higher number of infection episodes were also associated with an increased risk of these cancers. Specific infections such as viral, enteric and urinary tract infections were also strongly associated with specific types of cancer. In conclusion, children who later develop cancer appear to have adverse reactions to infections necessitating referral to specialized health care services, perhaps indicating dysregulated immune function.

Correlates of postnatal human cytomegalovirus transmission in term babies in the first year.

Postnatal human cytomegalovirus (HCMV) infection in newborns is well characterized for preterm infants but less so for term infants. We sought to analyze the rates and routes of HCMV transmission in full-term infants during the first year of life. A cohort of 120 HCMV seropositive mothers and their 122 newborns were tested after delivery for HCMV-DNA shedding in different bodily fluids. Postnatal HCMV infection was defined as the detection of >2.5 × 102 HCMV-DNA copies/mL in infants' saliva swabs. Maternal neutralizing antibody serum titer, HCMV-specific T-cell response, and HCMV glycoprotein B immunoglobulin G on breastmilk were analyzed. HCMV shedding was detected in 67 of 120 mothers (55.8%), and 20 of 122 infants (16.4%) developed HCMV infection within the first 3 months of life. Six additional infants were infected during the first year, for a postnatal infection rate of 21.3%. Viral shedding was more frequent in breastmilk than saliva, urine, and vaginal secretions, and the mothers of infected infants showed higher levels of HCMV-DNA in milk. No association was found between the antibody levels in serum or milk and maternal viral shedding, whereas a slightly lower frequency of HCMV-specific CD4+ T-cells with long-term memory phenotype was observed in women with HCM-DNA-positive milk. About one out of five infants develop HCMV infection within the first year of life. Breastmilk appears the major route of transmission of the infection, maternal saliva has a minor role whereas the role of vaginal secretions is negligible.

Incidence of congenital and postnatal cytomegalovirus infection during the first year of life in Mexican preterm infants.

Cytomegalovirus infection occurs commonly during infancy. Postnatal infection in term infants is usually asymptomatic; however, infection in preterm infants can be associated with clinical manifestations during the neonatal period. Nevertheless, few studies to assess the frequency of cytomegalovirus infection in preterm infants have been performed outside of high-income countries. We analyzed the incidence of congenital and postnatal cytomegalovirus infection in a cohort of preterm infants. Cytomegalovirus infection was detected during the neonatal period in four of 178 infants; in three of them, the virus was detected during the first 3 weeks of life and, therefore, congenital infection was confirmed (1.7% incidence). Postnatal infection was detected in 44 (36.4%) of 121 infants who were assessed after discharge from the neonatal intensive care unit. Cytomegalovirus infection was significantly associated with the duration of breastfeeding. In addition, we characterized cytomegalovirus strains detected in infants together with sequences available at GenBank, based on sequences of the UL18 gene. Cytomegalovirus UL18-sequences clustered in five distinct clades (A-E), and sequences obtained from infants in our study were distributed in four of the five clades; 44.4% of these sequences were included in clade E. Breastfeeding duration was shorter on average (5.6 months) in infants with sequences in clade E compared to infants with sequences in the other three clades (8.2 months; p = .07). In conclusion, we provide information regarding the high incidence of cytomegalovirus infection in preterm infants. Further studies are warranted to assess if cytomegalovirus strain characteristics are associated with the risk of infection acquisition during infancy.

Systemic and mucosal levels of lactoferrin in very low birth weight infants supplemented with bovine lactoferrin.

Lactoferrin supplementation may help prevent infections in preterm infants, but the efficacy has varied with different doses and products. We assessed the absorption and excretion of bovine lactoferrin (bLF) in 31 infants receiving 100, 200, or 300 mg·kg-1·day-1 of enteral bLF for 30 days. bLF and human lactoferrin (hLF) in infant saliva, blood, urine, and stool, as well as expressed (EBM) or donor breast milk (DBM) that were collected (i) before the treatment was initiated, (ii) at study day 22, and (iii) one week after treatment cessation, were measured using ELISA. During treatment, bLF was absorbed from the gastrointestinal tract and detected in plasma, saliva, and urine, as well as excreted in stool. Levels of bLF in the saliva and stool began to decline within 12 h after dosing, and bLF was undetectable in all samples one week after treatment. The concentrations of hLF exceeded those of bLF across sample types and time-points. Infants receiving EBM demonstrated higher levels of hLF in the saliva and stool than those receiving DBM. Neither bLF nor hLF levels varied by patient characteristics, bLF dosage, or infection status. This is the first study demonstrating bLF absorption into the bloodstream and distribution to saliva and urine in preterm infants. Future studies should further explore LF pharmacokinetics because higher and more frequent dosing may improve the clinical benefit of LF supplementation.

Epidemiology of cytomegalovirus Infection among mothers and infants in Colombia.

We assessed maternal and infant cytomegalovirus (CMV) infection in Colombia. Maternal serum was tested for CMV immunoglobulin G antibodies at a median of 10 (interquartile range: 8-12) weeks gestation (n = 1501). CMV DNA polymerase chain reaction was performed on infant urine to diagnose congenital (≤21 days of life) and postnatal (>21 days) infection. Maternal CMV seroprevalence was 98.1% (95% confidence interval [CI]: 97.5%-98.8%). Congenital CMV prevalence was 8.4 (95% CI: 3.9%-18.3%; 6/711) per 1000 live births. Among 472 infants without confirmed congenital CMV infection subsequently tested at age 6 months, 258 (54.7%, 95% CI: 50.2%-59.1%) had postnatal infection.

Women's perspectives on caesarean section recovery, infection and the PREPS trial: a qualitative pilot study.

BACKGROUND: In England, 27.8% of all pregnant women undergo caesarean sections (CS) to deliver their babies. Women undergoing CS are at risk of developing sepsis and post-natal infections, which not only contribute significantly to maternal mortality and morbidity, but also negatively impact upon post-natal recovery and wellbeing. This study explores patients' priorities in relation to CS recovery, focusing on their knowledge and experiences of infection prevention. The study formed part of the PREPS (Vaginal Preparation at caesarean section to Reduce Endometritis and Prevent Sepsis - a feasibility study of chlorhexidine) Trial; patients' views on the PREPS Trial were also sought. METHODS: Using qualitative methodology, two focus groups and six telephone interviews were carried out between September and October 2017 with a total of 21 women who had undergone a CS within the preceding six months. Focus groups and individual telephone interviews were audio-recorded and transcribed verbatim; a thematic analysis was conducted using NVivo 11. RESULTS: Women's priorities around CS recovery centred on pain (or the lack thereof), mobility and the ability to resume everyday activities, including caregiving. Those undergoing a CS for the first time reported not feeling confident in their ability to identify signs of infection and sought visiting health professionals' expertise and reassurance. Women were unable to recall whether they had received information regarding infection prevention and felt that they had not received sufficient advice. Some reported receiving general information regarding CS recovery, which ranged in quality. Prevention of womb infection is a major goal of the PREPS trial, however, the majority of women were not aware that womb (as opposed to wound) infection was a post CS risk. CONCLUSIONS: Women undergoing a CS want more information on what constitutes a 'normal' post-operative recovery and specifically would welcome written information and infection prevention advice. This should be a key element of improving post-CS maternal experiences and potentially reducing sepsis and infection rates. CS stigma negatively impacts women's recovery experiences and possibly information provision. The PREPS team incorporated findings regarding consent pathways for recruiting women into intrapartum research and developed two patient reported outcomes to collect in the main trial. TRIAL REGISTRATION: The PREPS trial has been registered with ISRCTN on the 10th July 2017 ( ISRCTN33435996 ).

Incidence, Risk Factors, and Morbidity of Acquired Postnatal Cytomegalovirus Infection Among Preterm Infants Fed Maternal Milk in a Highly Seropositive Population.

BACKGROUND: In preterm infants cytomegalovirus (CMV) infection acquired through maternal milk has been related to morbidity. However, infants who may receive higher titers of protective antibodies from highly seropositive mothers have not been studied in detail. METHODS: A cohort of 188 ≤30-week-old infants was monitored from admission to discharge. CMV-DNA, hematology, liver enzymes, neutralizing antibodies, and CMV-DNA-lactia were tested periodically. RESULTS: Mothers of 157 infants (83.5%) were CMV-seropositive. A total of 24/157 (15.3%) infants became infected (95% confidence interval [CI], 9.8-22.6), particularly those of lower gestational age (GA; relative risk [RR], 2.32; 95% CI, 1.01-5.34 for 23-26 weeks). Low (<1:64) neutralizing antibody titers were similarly detected in CMV-infected and uninfected infants. Mean DNA-lactia in mothers was higher in CMV-infected than in uninfected infants (5.34 log vs 4.60 log). Clinical findings suggestive of CMV disease were similar in CMV-infected (50.0%) and CMV-uninfected (51.1%) infants. Although transitory, >2 laboratory test abnormalities occurred more frequently among CMV-infected (39.1%) than CMV-uninfected (2.1%) infants. More severe stages of retinopathy of prematurity (ROP) were found among CMV-infected infants (adjusted RR, 2.51; 95% CI, 1.07-5.91). Although deaths were more frequent among infected infants, none of the deaths could be directly attributed to CMV. CONCLUSIONS: Postnatal CMV infection acquired by exposure to raw maternal milk is very frequent among extremely premature newborns, being facilitated by high DNA-lactia and lower GA, regardless of maternally acquired neutralizing antibody levels. The association with advanced stages of ROP is a concern and needs to be further explored in larger studies.

Human cytomegalovirus UL55, UL144, and US28 genotype distribution in infants infected congenitally or postnatally.

Cytomegalovirus (CMV) is the most common cause of congenital infection. This pathogen exhibits extensive genetic variability in the genes that encode structural envelope glycoproteins, regulatory proteins, and proteins that contribute to immune evasion. However, the role of specific viral strains in the outcome of congenital CMV infection is unclear. Variation in the UL55 gene encoding glycoprotein B (gB), the UL144 gene encoding TNF α-like receptor, and the US28 gene encoding ß-chemokine receptor was determined in 60 newborn infants with congenital CMV infection and 90 infants with postnatal or undefined CMV infection. CMV polymorphisms were studied in relation to disease outcome and viral load. Genotyping was performed by a sequencing analysis of PCR-amplified fragments, and the viral load was measured by quantitative real-time PCR. The results demonstrated that (1) the UL55 and US28 genotype distributions were similar among the group of congenital and postnatal CMV infection; (2) the UL144 B1 genotype was more prevalent in congenital than in postnatal infection and was detected in 70% of newborns with asymptomatic congenital infection; and (3) none of the examined genotype was significantly linked with symptomatic CMV infection. No relationship was observed between genotype and viral load. The results revealed that UL55, UL144, and US28 polymorphisms are not associated with the outcome of CMV infection in infants, but the presence of UL144 B1 genotype might be virological marker of asymptomatic infection at birth.

Zika virus vertical transmission in interferon receptor1-antagonized Rag1-/- mice results in postnatal brain abnormalities and clinical disease.

The mechanisms by which vertically transmitted Zika virus (ZIKV) causes postnatal brain development abnormalities and congenital disease remain poorly understood. Here, we optimized the established anti-IFNAR1 treated, Rag1-/- (AIR) mouse model of ZIKV infection to examine the consequence of vertical transmission on neonate survival and postnatal brain development. We found that modulating the infectious dose and the frequency of anti-IFNAR1 treatment of pregnant mice (termed AIRlow mice) prolonged neonatal survival allowing for pathogenesis studies of brain tissues at critical postnatal time points. Postnatal AIRlow mice all had chronic ZIKV infection in the brain that was associated with decreased cortical thickness and cerebellar volume, increased gliosis, and higher levels of cell death in many brain areas including cortex, hippocampus and cerebellum when compared to controls. Interestingly, despite active infection and brain abnormalities, the neurodevelopmental program remained active in AIRlow mice as indicated by elevated mRNA expression of critical neurodevelopmental genes in the brain and enlargement of neural-progenitor rich regions of the cerebellum at a developmental time point analogous to birth in humans. Nevertheless, around the developmental time point when the brain is fully populated by neurons, AIRlow mice developed neurologic disease associated with persistent ZIKV infection in the brain, gliosis, and increased cell death. Together, these data show that vertically transmitted ZIKV infection in the brain of postnatal AIRlow mice strongly influences brain development resulting in structural abnormalities and cell death in multiple regions of the brain.

Postnatal ocular toxoplasmosis in immunocompetent patients.

INTRODUCTION: Ocular toxoplasmosis is the most common cause of infectious posterior uveitis worldwide. It can be prenatal or postnatal in origin. Despite estimations that postnatal ocular toxoplasmosis is more prevalent, only several cases of proven postnatal ocular toxoplasmosis have been reported in non-epidemic settings. Here, the clinical evolution of ocular toxoplasmosis of conclusively proven postnatal origin in immunocompetent patients is reported. METHODOLOGY: Postnatal ocular toxoplasmosis was diagnosed based on clinical diagnosis supported by the longitudinal detection of Toxoplasma gondii-specific IgG, IgM and IgA antibodies in the serum as well as by direct detection of the parasite (bioassay) and/or its DNA (real-time PCR) in aqueous humor. RESULTS: Three cases involved adults in whom ocular toxoplasmosis developed during primary T. gondii infection, as part of the clinical presentation in two and as the sole manifestation in one patient. The fourth patient was a case of inactive ocular toxoplasmosis in a 14-year-old boy, where postnatal infection was confirmed by exclusion of maternal infection. The causative parasite strain was genotyped in only one case and it belonged to genotype II, the dominant type in Europe. One patient acquired the infection in Africa, suggesting an atypical strain. CONCLUSIONS: The distinction between prenatal and postnatal ocular toxoplasmosis is only possible in particular clinical situations, and requires extensive laboratory investigation. Genotyping of the parasite strain involved may be important, particularly if atypical strains are suspected, requiring tailored treatment approaches.

Cytomegalovirus alpha-chemokine genotypes are associated with clinical manifestations in children with congenital or postnatal infections.

Human cytomegalovirus (HCMV) is the leading cause of congenital infections. The aim of our study was to determine the prevalence of genotypes based on the highly polymorphic UL146 and UL147 HCMV genes and the relationship between the genotype and symptoms or viral load. We analyzed samples from 121 infants with symptomatic HCMV infection, including 32 congenitally infected newborns. The G7 and G5 genotypes were predominant in postnatal infection, whereas the G1 genotype was prevalent in congenital infection. Central nervous system (CNS) damage and hepatomegaly were detected more frequently among children infected with the G1 genotype than in those infected by other genotypes. An association between the viral genotype and viruria level was found. There was a strong correlation between HCMV genotypes determined through the UL146 and UL147 sequences (ĸ=0.794). In conclusion, we found that certain vCXCL genotypes are associated with clinical sequelae following HCMV infection.

Urine is superior to saliva when screening for postnatal CMV infections in preterm infants.

BACKGROUND: Cytomegalovirus (CMV) is the most frequently contracted virus in preterm infants. Postnatal infection is mostly asymptomatic but is sometimes associated with severe disease. To diagnose an infection, urine or saliva samples can be tested for CMV-DNA by real-time polymerase chain reaction (rtPCR). Although the diagnostic accuracy of testing saliva samples has not been determined in preterm infants, saliva is widely used because it is easier to obtain than urine. OBJECTIVES: To determine whether screening of saliva is equivalent to urine to detect a postnatal CMV infection in preterm infants. STUDY DESIGN: Between 2010 and 2013 saliva and urine samples were collected from infants admitted to the Neonatal Intensive Care Unit of the University Medical Center Utrecht and born with a gestational age (GA) below 32 weeks. Urine samples were obtained within three weeks after birth and urine and saliva samples at term equivalent age (40 weeks GA) and tested for CMV-DNA by rtPCR. Infants with a congenital CMV infection were excluded. RESULTS: Of 261 preterm infants included in the study, CMV-DNA was detected in urine of 47 and in saliva of 43 children. Of 47 infants with postnatal CMV infection, CMV was detected in 42 saliva samples (sensitivity 89.4%; CI 76.9-96.5). Of 214 children without postnatal CMV infection, one saliva sample tested positive for CMV (specificity 99.5%; CI 97.4-99.9). CONCLUSIONS: Screening saliva for CMV-DNA by rtPCR is inferior to urine to diagnose postnatal CMV infections in preterm infants.

[Usefulness of a real-time quantitative polymerase-chain reaction (PCR) assay for the diagnosis of congenital and postnatal cytomegalovirus infection]. / Utilidad de una técnica de Reacción en Cadena de la Polimerasa (PCR) cuantitativa en tiempo real en el diagnóstico de infección congénita y posnatal por citomegalovirus.

INTRODUCTION: Cytomegalovirus (CMV) is the main virus causing congenital and postnatal infections in the pediatric population. The aim of this study is to evaluate the usefulness of a quantitative real-time PCR in the diagnosis of these infections using urine as a single sample. PATIENTS AND METHODS: We studied all the urine samples of newborns (< 7 days) with suspected congenital infection, and urine of patients with suspected postnatal infection (urine negative at birth). Urines were simultaneously studied by cell culture, qualitative PCR (PCRc), and quantitative real-time PCR (PCRq). RESULTS: We analyzed 332 urine samples (270 to rule out congenital infection and 62 postnatal infections). Of the first, 22 were positive in the PCRq, 19 in the PCRc, and 17 in the culture. PCRq had a sensitivity of 100%, on comparing the culture with the rest of the techniques. Using the PCRq as a reference method, culture had a sensitivity of 77.2%, and PCRc 86.3%. In cases of postnatal infection, PCRq detected 16 positive urines, the PCRq 12, and the cell culture 10. The urines showed viral loads ranging from 2,178 to 116,641 copies/ml. CONCLUSIONS: The genomic amplification technique PCRq in real time was more sensitive than the other techniques evaluated. This technique should be considered as a reference (gold standard), leaving the cell culture as a second diagnostic level. The low cost and the automation of PCRq would enable the screening for CMV infection in large neonatal and postnatal populations.

Gestation and breastfeeding in schistosomotic mothers differently modulate the immune response of adult offspring to postnatal Schistosoma mansoni infection

Schistosoma mansoni antigens in the early life alter homologous and heterologous immunity during postnatal infections. We evaluate the immunity to parasite antigens and ovalbumin (OA) in adult mice born/suckled by schistosomotic mothers. Newborns were divided into: born (BIM), suckled (SIM) or born/suckled (BSIM) in schistosomotic mothers, and animals from noninfected mothers (control). When adults, the mice were infected and compared the hepatic granuloma size and cellularity. Some animals were OA + adjuvant immunised. We evaluated hypersensitivity reactions (HR), antibodies levels (IgG1/IgG2a) anti-soluble egg antigen and anti-soluble worm antigen preparation, and anti-OA, cytokine production, and CD4+FoxP3+T-cells by splenocytes. Compared to control group, BIM mice showed a greater quantity of granulomas and collagen deposition, whereas SIM and BSIM presented smaller granulomas. BSIM group exhibited the lowest levels of anti-parasite antibodies. For anti-OA immunity, immediate HR was suppressed in all groups, with greater intensity in SIM mice accompanied of the remarkable level of basal CD4+FoxP3+T-cells. BIM and SIM groups produced less interleukin (IL)-4 and interferon (IFN)-g. In BSIM, there was higher production of IL-10 and IFN-g, but lower levels of IL-4 and CD4+FoxP3+T-cells. Thus, pregnancy in schistosomotic mothers intensified hepatic fibrosis, whereas breastfeeding diminished granulomas in descendants. Separately, pregnancy and breastfeeding could suppress heterologous immunity; however, when combined, the responses could be partially restored in infected descendants.