To describe demographic and treatment characteristics of the Dutch vertically HIV-infected paediatric population from 1996 to 2012, and to investigate the long-term virological and immunological ...response to combination antiretroviral therapy (cART), with emphasis on the influence of age at cART initiation and initial CD4 cell counts.
Descriptive cohort study.
From 1996 to 2012, all paediatric HIV clinics in the Netherlands provided data on their HIV-infected population. Descriptive statistics, parametric and non-parametric comparative tests, and random-effects linear regression models were performed to investigate the different aspects of this cohort.
A total of 229 vertically HIV-infected children were included. The majority of all mothers (64%) and almost half of the children (43%) originated from sub-Saharan Africa. Ritonavir-boosted lopinavir and efavirenz have replaced indinavir, nelfinavir and nevirapine as preferred first-line cART regimens. Long-term CD4 T-cell reconstitution (with CD4 cell counts corrected for age) was independent of age and CD4 cell count at cART initiation. The decline in HIV viral load after cART introduction occurred faster over the studied time period. The percentage of children with an undetectable viral load rose substantially from 1996 to 2012. Mortality was 0.3 per 100 person-years.
A sustained immunological response in the Dutch paediatric HIV-infected population was independent of age as well as CD4 cell count at cART initiation, despite a higher initial HIV viral load in the youngest children. The percentage of children with an undetectable HIV viral load rose substantially over the years and there was a low mortality rate in comparison with reports from other industrialized countries.
Up to 7% of term and late-preterm neonates in high-income countries receive antibiotics during the first 3 days of life because of suspected early-onset sepsis. The prevalence of culture-proven ...early-onset sepsis is 0·1% or less in high-income countries, suggesting substantial overtreatment. We assess whether procalcitonin-guided decision making for suspected early-onset sepsis can safely reduce the duration of antibiotic treatment.
We did this randomised controlled intervention trial in Dutch (n=11), Swiss (n=4), Canadian (n=2), and Czech (n=1) hospitals. Neonates of gestational age 34 weeks or older, with suspected early-onset sepsis requiring antibiotic treatment were stratified into four risk categories by their treating physicians and randomly assigned 1:1 using a computer-generated list stratified per centre to procalcitonin-guided decision making or standard care-based antibiotic treatment. Neonates who underwent surgery within the first week of life or had major congenital malformations that would have required hospital admission were excluded. Only principal investigators were masked for group assignment. Co-primary outcomes were non-inferiority for re-infection or death in the first month of life (margin 2·0%) and superiority for duration of antibiotic therapy. Intention-to-treat and per-protocol analyses were done. This trial was registered with ClinicalTrials.gov, number NCT00854932.
Between May 21, 2009, and Feb 14, 2015, we screened 2440 neonates with suspected early-onset sepsis. 622 infants were excluded due to lack of parental consent, 93 were ineligible for reasons unknown (68), congenital malformation (22), or surgery in the first week of life (3). 14 neonates were excluded as 100% data monitoring or retrieval was not feasible, and one neonate was excluded because their procalcitonin measurements could not be taken. 1710 neonates were enrolled and randomly assigned to either procalcitonin-guided therapy (n=866) or standard therapy (n=844). 1408 neonates underwent per-protocol analysis (745 in the procalcitonin group and 663 standard group). For the procalcitonin group, the duration of antibiotic therapy was reduced (intention to treat: 55·1 vs 65·0 h, p<0·0001; per protocol: 51·8 vs 64·0 h; p<0·0001). No sepsis-related deaths occurred, and 9 (<1%) of 1710 neonates had possible re-infection. The risk difference for non-inferiority was 0·1% (95% CI −4·6 to 4·8) in the intention-to-treat analysis (5 0·6% of 866 neonates in the procalcitonin group vs 4 0·5% of 844 neonates in the standard group) and 0·1% (−5·2 to 5·3) in the per-protocol analysis (5 0·7% of 745 neonates in the procalcitonin group vs 4 0·6% of 663 neonates in the standard group).
Procalcitonin-guided decision making was superior to standard care in reducing antibiotic therapy in neonates with suspected early-onset sepsis. Non-inferiority for re-infection or death could not be shown due to the low occurrence of re-infections and absence of study-related death.
The Thrasher Foundation, the NutsOhra Foundation, the Sophia Foundation for Scientific research.
is an important cause of pneumonia and extra-pulmonary manifestations. We observed a rise in admissions due to
infections starting October 2023 in a regional hospital in the Netherlands and an ...increased incidence in national surveillance data. The incidence in the Netherlands has not been that high since 2011. The patients had a lower median age compared with 2019 and 2020 (28 vs 40 years).
should be considered in patients with respiratory symptoms, especially children.
Bacterial respiratory tract infections (RTIs) are a major global health burden, and the role of antigen-presenting cells (APCs) in mounting an immune response to contain and clear invading pathogens ...is well-described. However, most encounters between a host and a bacterial pathogen do not result in symptomatic infection, but in asymptomatic carriage instead. The fact that a pathogen will cause infection in one individual, but not in another does not appear to be directly related to bacterial density, but rather depend on qualitative differences in the host response. Understanding the interactions between respiratory pathogens and airway APCs that result in asymptomatic carriage, will provide better insight into the factors that can skew this interaction towards infection. This review will discuss the currently available knowledge on airway APCs in the context of asymptomatic bacterial carriage along the entire respiratory tract. Furthermore, in order to interpret past and futures studies into this topic, we propose a standardized nomenclature of the different stages of carriage and infection, based on the pathogen’s position with regard to the epithelium and the amount of inflammation present.
Current strategies for risk stratification and prediction of neonatal early-onset sepsis (EOS) are inefficient and lack diagnostic performance. The aim of this study was to use machine learning to ...analyze the diagnostic accuracy of risk factors (RFs), clinical signs and biomarkers and to develop a prediction model for culture-proven EOS. We hypothesized that the contribution to diagnostic accuracy of biomarkers is higher than of RFs or clinical signs.
Secondary analysis of the prospective international multicenter NeoPInS study. Neonates born after completed 34 weeks of gestation with antibiotic therapy due to suspected EOS within the first 72 hours of life participated. Primary outcome was defined as predictive performance for culture-proven EOS with variables known at the start of antibiotic therapy. Machine learning was used in form of a random forest classifier.
One thousand six hundred eighty-five neonates treated for suspected infection were analyzed. Biomarkers were superior to clinical signs and RFs for prediction of culture-proven EOS. C-reactive protein and white blood cells were most important for the prediction of the culture result. Our full model achieved an area-under-the-receiver-operating-characteristic-curve of 83.41% (±8.8%) and an area-under-the-precision-recall-curve of 28.42% (±11.5%). The predictive performance of the model with RFs alone was comparable with random.
Biomarkers have to be considered in algorithms for the management of neonates suspected of EOS. A 2-step approach with a screening tool for all neonates in combination with our model in the preselected population with an increased risk for EOS may have the potential to reduce the start of unnecessary antibiotics.
Mycoplasma pneumoniae (Mp) triggers Guillain-Barré syndrome (GBS) and elicits anti-galactocerebroside (GalC) antibodies. Specifically anti-GalC IgG is associated with Mp-GBS, possibly because of its ...better ability to cross the blood-nerve barrier (BNB). We here investigated CSF for the presence of anti-GalC in GBS. Intrathecal anti-GalC was found in 46% of Mp-GBS patients (n=6/13), in contrast to 16% of GBS controls (n=4/25) and 0% of non-GBS controls (n=0/7). The antibodies most likely originated from increased BNB permeability and/or intrathecal synthesis. Intrathecal anti-GalC IgG was specifically associated with Mp-GBS, further supporting that anti-GalC IgG contributes to the pathogenesis of GBS.
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•Although GBS is a peripheral neuropathy anti-GalC antibodies are found in CSF.•Intrathecal anti-GalC IgG is specifically associated with M. pneumoniae-GBS.•Anti-GalC IgG in CSF may be derived from blood and related to increased blood-nerve barrier permeability.•In one patient with additional CNS involvement, anti-GalC IgG most likely derived from intrathecal synthesis.
Mycoplasma pneumoniae (Mp) is carried in the upper respiratory tract (URT) of mice after symptomatic infection. B cells and Mp-specific antibodies are crucial for Mp clearance in the lungs of mice ...but are limited in clearing Mp from the URT.
Abstract
Background
Carriage of Mycoplasma pneumoniae (Mp) in the nasopharynx is considered a prerequisite for pulmonary infection. It is interesting to note that Mp carriage is also detected after infection. Although B cells are known to be involved in pulmonary Mp clearance, their role in Mp carriage is unknown.
Methods
In this study, we show in a mouse model that Mp persists in the nose after pulmonary infection, similar to humans.
Results
Infection of mice enhanced Mp-specific immunoglobulin (Ig) M and IgG levels in serum and bronchoalveolar lavage fluid. However, nasal washes only contained elevated Mp-specific IgA. These differences in Ig compartmentalization correlated with differences in Mp-specific B cell responses between nose- and lung-draining lymphoid tissues. Moreover, transferred Mp-specific serum Igs had no effect on nasal carriage in B cell-deficient μMT mice, whereas this enabled μMT mice to clear pulmonary Mp infection.
Conclusions
We report the first evidence that humoral immunity is limited in clearing Mp from the upper respiratory tract.
Antibody responses to
correlate with pulmonary
clearance. However,
-specific IgG antibodies can cross-react with the myelin glycolipid galactocerebroside (GalC) and cause neurological disorders. We ...assessed whether antiglycolipid antibody formation is part of the physiological immune response to
We show that antibodies against
proteins and glycolipids arise in serum of
-infected children and mice. Although antibodies to
glycolipids were mainly IgG, anti-GalC antibodies were only IgM. B-1a cells, shown to aid in protection against pathogen-derived glycolipids, are lacking in Bruton tyrosine kinase (Btk)-deficient mice.
-infected Btk-deficient mice developed
-specific IgG responses to
proteins but not to
glycolipids, including GalC. The equal recovery from
infection in Btk-deficient and wild-type mice suggests that pulmonary
clearance is predominantly mediated by IgG reactive with
proteins and that
glycolipid-specific IgG or IgM is not essential. These data will guide the development of
-targeting vaccines that avoid the induction of neurotoxic antibodies.
Recombination between repeated DNA elements in the genomes of Mycoplasma species appears to lie at the basis of antigenic variation of several essential surface proteins. It is therefore imperative ...that the DNA recombinatorial pathways in mycoplasmas be unravelled. Here, we describe the proteins encoded by the Mycoplasma genitalium MG352 and Mycoplasma pneumoniae MPN528a genes (RecUMge and RecUMpn respectively), which share sequence similarity with RecU Holliday junction (HJ) resolvases. RecUMge was found to: (i) bind HJ substrates and large double-stranded DNA molecules and (ii) cleave HJ substrates at the sequence 5′-G/TCdownward arrowC/TTA/GG-3′ in the presence of Mn²⁺. Interestingly, RecUMpn(from M. pneumoniae subtype 2 strains) did not possess obvious DNA binding or cleavage activities, which was found to be caused by the presence of a glutamic acid residue at position 67 of the protein, which is not conserved in RecUMge. Additionally, RecUMpn appears not to be expressed by subtype 1 M. pneumoniae strains, as these possess a TAA translation termination codon at position 181-183 of MPN528a. We conclude that RecUMge is a HJ resolvase that may play a central role in recombination in M. genitalium.
Homologous recombination between repeated DNA elements in the genomes of Mycoplasma species has been hypothesized to be a crucial causal factor in sequence variation of antigenic proteins at the ...bacterial surface. To investigate this notion, studies were initiated to identify and characterize the proteins that form part of the homologous DNA recombination machinery in Mycoplasma pneumoniae as well as Mycoplasma genitalium. Among the most likely participants of this machinery are homologs of the Holliday junction migration motor protein RuvB. In both M. pneumoniae and M. genitalium, genes have been identified that have the capacity to encode RuvB homologs (MPN536 and MG359, respectively). Here, the characteristics of the MPN536- and MG359-encoded proteins (the RuvB proteins from M. pneumoniae strain FH RuvBFH and M. genitalium RuvBMge, respectively) are described. Both RuvBFH and RuvBMge were found to have ATPase activity and to bind DNA. In addition, both proteins displayed divalent cation- and ATP-dependent DNA helicase activity on partially double-stranded DNA substrates. The helicase activity of RuvBMge, however, was significantly lower than that of RuvBFH. Interestingly, we found RuvBFH to be expressed exclusively by subtype 2 strains of M. pneumoniae. In strains belonging to the other major subtype (subtype 1), a version of the protein is expressed (the RuvB protein from M. pneumoniae strain M129 RuvBM129) that differs from RuvBFH in a single amino acid residue (at position 140). In contrast to RuvBFH, RuvBM129 displayed only marginal levels of DNA-unwinding activity. These results demonstrate that M. pneumoniae strains (as well as closely related Mycoplasma spp.) can differ significantly in the function of components of their DNA recombination and repair machinery.
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